Studies on the synthesis of anti-diabetic drug, …shodhganga.inflibnet.ac.in/bitstream/10603/101297/12/12...MD. UMAR KHAN Thesis Studies on the synthesis of anti-diabetic drug, Sitagliptin

Chapter III

F

F

F

N

ONH2

NN

N

FF

F

Studies on the synthesis of

anti-diabetic drug,

Sitagliptin

INTRODUCTION:

Diabetes is a multifactorial disease that is classified as chronic hyperglycemia due to defects in

insulin secretion, action or both, which results in abnormalities in carbohydrate, fat and protein

metabolism. The World Health Organization (WHO) reported in 2000 a worldwide prevalence

of 154.4 million subjects with diabetes and predicts that by the year 2025 there will be nearly

300 million diabetics. The American diabetes association estimates that there are a total of 18.2

million Americans suffering from diabetes, of whom two-thirds are diagnosed and one-third are

not. Over 90% of the diabetic patient population in the western world has been diagnosed with

type 2 diabetes (non-insulin-dependent diabetes, or adult-onset diabetes). Type 2 diabetes

occurs when the body is unable to efficiently use the insulin it produces and glucose levels in

the blood becomes abnormally elevated. This hyperglycemia contributes to numerous acute or

chronic complications, such as atherosclerosis, heart disease, stroke, hypertension, end-stage

renal disease and blindness, among others. Type 2 diabetes is strongly favored by genetic

MD. UMAR KHAN Thesis

Studies on the synthesis of anti-diabetic drug, Sitagliptin 169

Chapter - III

disposition. However, environmental factors also contribute significantly to its development.

The risk factors for type 2 diabetes include age, obesity, physical inactivity, family history of

diabetes, prior history of gestational diabetes, impaired glucose tolerance and race/ethnicity.[1-3]

There are several therapeutic options for the treatment of type 2 diabetes, which can include

lifestyle modification with diet and exercise, as well as drug therapy (Table-3.1).

Table-3.1

Insulin

Sensitizers

Biguanides (Metformin, Buformin, Phenformin)

TZDs/"Glitazones" (PPAR) (Pioglitazone, Rivoglitazone, Rosiglitazone,

Troglitazone)

Dual PPAR agonist (Aleglitazar, Muraglitazar, Tesaglitazar)

Insulin

Secretagogues

K+ ATP, Sulfonylureas (1st generation: Acetohexamide, Carbutamide,

Chlorpropamide, Metahexamide, Tolbutamide, Tolazamide)

K+ ATP, Sulfonylureas (2nd generation: Glibenclamide(Glyburide),

Glibornuride, Glipizide, Gliquidone, Glisoxepide, Glyclopyramide,

Glimepiride, Gliclazide)

K+ ATP, Meglitinides/"glinides" (Nateglinide, Repaglinide, Mitiglinide)

GLP-1 agonists (Exenatide, Liraglutide, Taspoglutide, Albiglutide,

Lixisenatide)

DPP-4 inhibitors (Alogliptin, Gemigliptin, Linagliptin, Saxagliptin,

Sitagliptin, Vildagliptin)

Analogs/Other

Insulins

Fast-acting (Insulin Lispro, Insulin aspart, Insulin Glulisine)

Short-acting (Regular Insulin)

Long-acting (Insulin Glargine, Insulin Detemir, NPH Insulin)

Ultra-long-acting (Insulin Degludec)

Inhalable (Exubera)

Alpha-

Glucosidase

Inhibitors

Acarbose, Miglitol, Voglibose

Amylin Analog Pramlintide

SGLT2

Inhibitors

Canagliflozin, Dapagliflozin, Empagliflozin, Remogliflozin, Sergliflozin,

Tofogliflozin

Other Benfluorex, Tolrestat



Chapter - III

The incretin hormone glucagon-like peptide-1 (GLP-1) has been the subject of research efforts

to develop agents for the treatment of type 2 diabetes. Hormonal regulation of insulin secretion

in response to glucose involves pancreatic and gastrointestinal hormones. Gut-derived insulin-

releasing incretins such as gastric-inhibitory polypeptide (GIP) and GLP-1 play a crucial role in

the regulation of insulin by acting on the pancreas to potentiate glucose-induced insulin

secretion.[4-5]

After ingestion of meals, GLP-1 and GIP are released (from L-cells and K-cells,

respectively) and then functions through their respective receptors. Because GLP-1 regulates

insulin in a strictly glucose-dependent manner,[6-8]

there is very little risk of hypoglycemia.[9]

GLP-1 has been shown to slow gastric emptying[10-11]

and reduce appetite,[12]

each beneficial in

controlling blood glucose. In addition, GLP-1 attenuates apoptosis in isolated human islets and

cultured β-cells. Due to those beneficial actions, GLP-1 was proposed to be a potential agent for

the treatment of diabetes. However, GLP-1 is not suitable for therapeutic use due to its

extremely short half-life. GLP-1 is only active if administrated as a continuous i.v. infusion

because it is rapidly hydrolyzed by the circulating enzyme dipeptidyl-peptidase IV (DPP-IV), a

serine protease which cleaves the molecule (a dipeptide) at the N-terminal, giving rise to the

inactive truncated fragment GLP-1 amide.[13-14]

Moreover, GLP-1 has been shown to act as a

GLP-1 receptor antagonist, blocking the effects of intact hormone. On the other hand,

administration of a DPP-IV inhibitor could enhance the half-life of GLP-1 and therefore

produce the same pleiotropic effects as exogenously administrated GLP-1 or GLP-1

analogues.[15-22]

There is significant interest in the identification of inhibitors of dipeptidyl-

peptidase IV (DPP-IV) for the treatment of type 2 diabetes.[23]

A major role of DPP-IV is the

degradation of the peptidic hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent

insulino-tropic polypeptide (GIP).[24]

A variety of DPP-IV inhibitors have been patented and

published in recent years (Table-3.2).[25]



Chapter - III

Table-3.2

Sr.

no.

Generic name

Systematic (IUPAC) name Structure

1

Sitagliptin (1)

(R)-4-oxo-4-[3-(trifluoromethyl)-5,6-

dihydro[1,2,4]triazolo[4,3-a]pyrazin-

7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-

2-amine

F

F

F

N

ONH2

NN

N

FF

F

2

Saxagliptin (2)

(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-

1-adamantyl)acetyl]-2-

azabicyclo[3.1.0]hexane-3-carbonitrile

HO

H2N N

OCN

3

Vildagliptin (3)

(S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]-

pyrrolidine-2-carbonitrile

HO

HN

N

O

NC

4

Linagliptin (4)

8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-

yn-1-yl)-3- methyl-1-[(4-

methylquinazolin-2-yl)methyl]-3,7-

dihydro-1H-purine-2,6-dione N

NN

N N

N

N

NH2

O

O

5

Gemigliptin (5)

(3S)-3-amino-4-(5,5-difluoro-2-

oxopiperidino)-1-[2,4-di(trifluoromethyl)-

5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-

7-yl]butan-1-one

N

O

F

F

NH2 O

N

N

NF

F

F

F

F F

6

Alogliptin (6)

2-({6-[(3R)-3-aminopiperidin-1-yl]-3-

methyl-2,4-dioxo-3,4-dihydropyrimidin-

1(2H)-yl}methyl)benzonitrile

NH2N

N

N

O

O

NC



Chapter - III

Sitagliptin (1), is a first-in-class treatment for type 2 diabetes,[26-28]

a disease which is staggering

in its effect on society. Sitagliptin (1),[29-30]

is a selective, potent DPP-IV inhibitor, is the active

ingredient in JANUVIA and JANUMET (a fixed dose combination with the diabetic agent

Metformin), which both recently received approval for the treatment of type 2 diabetes by the

FDA.[31]

It’s molecular formula is C16H15F6N5O and molecular weight is 407.314 g/mol.

Sitagliptin Phosphate, also known as Januvia, was recently touted as a future billion dollar boon

for the pharmaceutical industry. On June 26, 2012 Evaluate Pharma revealed it's World Preview

2018 projections, giving a nod to Merck's Januvia. With an estimated 10 billion dollars in

annual sales, Januvia (Sitagliptin Phosphate) is forecasted to be a top player in the global

pharmaceutical market.

REVIEW OF LITERATURE:

Number of methods has been developed for racemic and asymmetric synthesis of Sitagliptin.

Process, in which racemic Sitagliptin is intermediate,[32-38]

used to resolve finally with chiral

resolving agent[32-34]

, e.g. (R)-(-)-mandelic acid. The existing asymmetric synthesis of Sitagliptin

involves use of Schollkopf reagent to install key stereo centre and homologation of resulting α-

amino acid,[29, 39]

asymmetric hydrogenation of β-keto ester using Noyori's catalyst,[40-41]

substrate-controlled diastereoselctive hydrogenation using chiral auxillary,[42-48]

unprotected β-

enamine amide enantioselective hydrogenation,[49-56]

enzymatic reduction of β-enamine

amide,[57-58]

Evan's methodology of chiral induction,[59]

Michael addition of amines to

acrylates,[60-62]

use of chiral precursors,[63-67]

use of chiral β-amino acids and analogs,[68-74]

and

Curtius rearrangement of isocyanate to amine.[37,38]

http://en.wikipedia.org/wiki/Carbon

http://en.wikipedia.org/wiki/Hydrogen

http://en.wikipedia.org/wiki/Fluorine

http://en.wikipedia.org/wiki/Nitrogen

http://en.wikipedia.org/wiki/Oxygen

http://en.wikipedia.org/wiki/Gram

http://en.wikipedia.org/wiki/Mole_(unit)



Chapter - III

N

N

O

O

N

N

O

O

F

F

F

F

F

F O

O

HN

O

O

F

F

F O

OH

HN

O

O

F

F

F

HN

O

O

F

F

F

HN

O

O

O OH

F

F

F

HN

O

O

O N

NN

N

CF3

F

F

F

NH2 O

N

NN

N

CF3

O

N2

n-BuLi, THF

2,4,5-trifluorobenzyl

bromide (8)

HCl, CH3CN, MeOH

(Boc)2O, Et3N, MDC

LiOH, THF/Water

Et2O, Et3N,

isobutyl chloroformate

Diazomethane

silverbenzoate

Dioxane/water

HN

NN

N

CF3

.HCl

HOBt, EDC, DIPEA,DMF

MeOH, HCl

7 9 10

11 12

13 15

1

14

…..Scheme-3.1

Sitagliptin 1 was first synthesized by Edmondson et al in 2004.[39]

The β-amino acid derived

DPP-IV inhibitor in this report were synthesized by standard peptide coupling of β-amino acids

13 with fused heterocycles 14 (Scheme-3.1). Synthetic efforts focused on the synthesis of β-

amino acid, which are readily available via the Arndt-Eistert homologation of the corresponding

α-amino acid 11 and can be prepared using Schollkopf's bis-lactum methodology.[75]

For the

introduction of the desired (R)-stereochemistry in the α-amino acid 11, the Schollkopf's reagent

7 was employed. Alkylation of 7 with 2, 4, 5-trifluorobenzyl bromide 8 gave 9, which was

treated with hydrochloric acid followed by di-tert-butyl dicarbonate to give ester 10. Hydrolysis

afforded the α-amino acid 11, which was treated with isopropyl chloroformate followed by

diazomethane to give diazoketone 12. Subsequent rearrangement of 12, followed by hydrolysis

gave the desired β-amino acid 13. Coupling of 13 with 14 followed by deprotection of the amine

provided the desired compound 1 with 17% overall yield.



Chapter - III

F

F

F

O

OH

F

F

F

OH

O

O

O

O

F

F

F

O

OCH3

O

F

F

F

OH

OCH3

O

F

F

F

OH

OH

O

F

F

F

OH

NH

O

O

F

F

F

N OO F

F

F

OH

ONHO

F

F

F

N

ONHO

NN

N

CF3

F

F

F

N

ONH2

NN

N

CF3

MDC, DMF,

oxalyl chloride

meldrum's acid,

2,4,6-collidine

MeOH, MTBE

HCl

(S)-Binap-RuCl2

H2, 150 psi

THF, LiOH

H2O, MTBE

H2NO

EDC.HCl, H2O, Heptane

.HCl

TPP, DIAD

Toluene, MeOH

THF, LiOH

HN

NN

N

CF3

.HCl

NMM, EDC

10% Pd-C/ H2

40 psi

16 17 18

19 20

22 23 24

14

25 1

21

…..Scheme-3.2

First large-scale synthesis of Sitagliptin 1 started with the preparation of benzyloxy β-amino

acid 24 (Scheme-3.2).[40]

Preparation of 24 started with acid 16, which was converted to β-keto

ester 18 through meldrum's adduct 17. The asymmetric hydrogenation of 18 was carried out

using (S)-BinapRuCl2-triethylamine complex and a catalytic amount of acid, to yield β-hydroxy

ester 19. Following the reduction, the ester was hydrolyzed and β-hydroxy acid 20 was isolated

in 83% yield and 94% ee. The key building block was then elaborated to lactum 23 in a two-

step sequence. First, hydroxamate 22 was formed by coupling the carboxylic acid 20 with O-

benzyl hydroxylamine hydrochloride 21 using EDC. The cyclization to form 23 was carried out

using di-isopropyl azodicarboxylate (DIAD) and TPP. Lactum 23 was isolated in 81% yield and

optical purity of >99% ee. 23 was hydrolyzed to amino acid 24 with LiOH at room temperature.

Using EDC and N-methylmorpholine (NMM) as base, triazole 14 was coupled to 24 in >99%

assay yield. Obtained 25 was then subjected to hydrogenation with 10% Pd on carbon to isolate

1 in >99.5% purity. This first large-scale synthesis of Sitagliptin afforded the desired compound

in 45% yield over 9 steps.



Chapter - III

Despite the strength (45% overall yield, no chiral auxilary to control stereoselectivity, and

removal of Arndt-Eistert homologation step) of this route, several negative aspects (two peptide

couplings and Mitsunobu coupling wastage) cause for concern. Dreher et al[42]

simultaneously

searching for a direct preparation of β-keto amide intermediate 26 from trifluorophenylacetic

acid 16. In this approach acid 16 was activated with N,N'-carbonyl di-imidazole (CDI) and

treated with meldrum's acid to afford adduct 17 (Scheme-3.3).

F

F

F

O

OH

F

F

F

OH

O

O

O

O

F

F

F

O OTHF, CDI

meldrum's acid,

isopropyl acetate

16 17 26

HN

NN

N

CF3

.HCl

isopropyl acetate

DIPEA

14

N

NN

N

CF3

(S)-phenylglycine amide

IPA, AcOH

F

F

F

NH O

N

NN

N

CF3

CONH2F

F

F

NH O

N

NN

N

CF3

CONH2

F

F

F

N

ONH2

NN

N

CF3

PtO2, THF, MeOH

H2, 90 psi

20% Pd(OH)2-C

Formic acid

THF, MeOH,

27 28

1

…..Scheme-3.3

Isolated 17 was easily converted to 26 in 92% yield by treatment with triazole salt 14 and

Hunig's base. PGA-enamine 27 was prepared by heating 26 with (S)-phenylglycine amide in the

presence of acetic acid in 91% yield. Hyrdogenation was performed in a THF-MeOH mixture

using activated PtO2, to afford PGA-amine 28 with high selectivity (96.4% de) and 90% assay

yield. The hydrogenolysis of PGA-amine 28 was accomplished in THF/MeOH using Pd(OH)2/C

catalyst and formic acid as hydrogen source, to afford Sitagliptin 1 in 94.5% yield and 97% ee.

With this (S)-PGA enamine-amide route, 1 was prepared in 65% overall yield, in 4 chemical

steps. Since this is a chiral auxilary approach, a stoichiometric amount of (S)-PGA is required in

the process and the subsequent generation of 2-phenylacetamide as a by-product adds to the

waste burden. Xiao et al,[49]

converted 26 to enamine amide 29 by treating with ammonium



Chapter - III

acetate in methanol (Scheme-3.4). Direct asymmetric hydrogenation of 29 with Rhodium

complex in methanol yields 1 in 93% yield 94% ee. This approach is highly efficient with near

perfect optical and chemical purity in only three steps and 63% overall yield.

F

F

F

O

OH

F

F

F

OH

O

O

O

O

F

F

F

O ODMAc, DIPEA

DMAP,

meldrum's acid,

Pivaloyl chloride

16 17 26

HN

NN

N

CF3

.HCl

DMAc, NaHCO3

14

N

NN

N

CF3

MeOH,

NH4OAc, NH4OH

F

F

F

NH2 O

N

NN

N

CF3

F

F

F

N

ONH2

NN

N

CF3

[Rh(cod)Cl]2,

R,S-t-Bu-Josiphos

MeOH, H2, 200 psi

29

1

…..Scheme-3.4

Saville et al[58]

disclosure relates to polypeptides having transaminase activity, polynucleotides

encoding the polypeptides, and methods of using the polypeptides. β-keto amide 26 was directly

converted to Sitagliptin 1 using these transaminase polypeptides in 88-90% yield (Scheme-3.5).

F

F

F

O O

26

N

NN

N

CF3

F

F

F

N

ONH2

NN

N

CF3

Transaminase

Polypeptide

1

…..Scheme-3.5

Rasparini et al[59]

came with the novel process for the preparation of Sitagliptin 1, using Evan's

chiral auxilary methodology (Scheme-3.6). The key step in this process involves an alkylation

of the enolate 32 with an ester of a haloacetic acid 33, followed by a Curtius reaction. This multi

step asymmetric process gives Sitagliptin 1 in 9% overall yield with 99.5% enantiomeric purity

by HPLC.



Chapter - III

F

F

F O

OHHN

OO

Bn

+

F

F

F O

N

OO

Bn

Br

F

F

F

OOO

N

OO

Bn

O

O

F

F

F

OOO

OH

F

F

F

OOO

NCO

F

F

FNH

OO

O

OBn

F

F

FNH

OHO

O

OBn

F

F

F

N

ONH

NN

N

CF3

O OBn F

F

F

N

ONH2

NN

N

CF31

HN

NN

N

CF3

.HCl

14

30 3132

33

34

35 36 37

38

39

Pivaloyl chloride

TEA

NaHMDS

LiOH, H2O2 Curtius Reaction BnOH

HCOOH

EDC, HOBt

10% Pd-C

…..Scheme-3.6

F

F

F

Br

F

F

F

Cl

OH

F

F

F

O

F

F

F

OH

F

F

F

N3

F

F

F

N3

OH

O

F

F

F

N3 O

HN

NN

N

CF3

.HCl

14

N

NN

N

CF3

F

F

F

N

ONH2

NN

N

CF31

i-PrMgCl, THF,

CuI

O

Cl

NaOH (aq.)

MeOH

MgCl

CuI

MsCl, DMAP,

Et3N

NaN3

KMnO4

Acetone/water

TPP, THF

NH4OH

40 41 4243

44 45 46

…..Scheme-3.7

Chang et al[66]

prepared Sitagliptin in 44% overall yield with the use of chiral precursor (S)-

epichlorohydrin in 7 chemical steps (Scheme-3.7).

Liu et al[60]

prepared acrylate ester 49 to prepare Sitagliptin, through Michael addition of chiral

amine (Scheme-3.8).



Chapter - III

F

F

F

O

OCH3

O

18

NaBH4

MeOH

F

F

F

OH

OCH3

O

F

F

F

OAc

OCH3

OAc2O, Py tBuOK, EtOH

F

F

F

OCH3

O

NH

CH3

n-BuLi, THF

F

F

F

OCH3

ON CH3

Pd(OH)2

H2/MeOH

F

F

F

OCH3

OH2N

DIBOC, TEA

F

F

F

OH

OHNO

O

NaOH, EtOH

HN

NN

N

CF3

.HCl

14

F

F

F

N

ONH

NN

N

CF3

O O

MeOH,

Con. HCl

F

F

F

N

ONH2

NN

N

CF31

47 48 49

50

51 52 13

15

…..Scheme-3.8

Bartra Sanmarti et al[68]

discloses a process which comprises for the preparation of Sitagliptin,

or its pharmaceutically acceptable salts, or its solvates, including hydrates, (Scheme-3.9)

comprising: a) coupling an halo-2,4,5-trifluorobenzene 56 with a compound of formula 55 to

give N-protected Sitagliptin (57); the coupling being carried out via the formation of an

organocupric compound of the halo-2,4,5-trifluorobenzene 56 or, alternatively, via the

formation of a organozinc compound of a compound of formula 55; where R1 is hydrogen or an

amino protective group; R2 is an amino protective group; or alternatively R1 and R2 taken

together form a phtalimido group; X is Br or I; and Y is Br, I or R3SO3- wherein R3 is (C1-

C4)- alkyl, phenyl, or phenyl mono- or disubstituted by a (C1-C4)-alkyl radical; b) submitting

the N-protected Sitagliptin to a deprotection reaction; and c) optionally its conversion into a

pharmaceutically acceptable salt. It also comprises new intermediate compounds useful in such

preparation process.



Chapter - III

O

O

N

R1R2

HN

NN

N

CF3

+N

NN

N

CF3

O

HO

NR2R1

N

NN

N

CF3

O

I

NR2R1

F

F

F

X

M / Cu cat.

Zn / Pd cat

F

F

F

N

ON

NN

N

CF3

R2R1

F

F

F

N

ONH2

NN

N

CF31

53 14 54 55

56

57

…..Scheme-3.9

Allegrini et al[37]

disclosed a process for racemic Sitagliptin (Scheme-3.10). This process again

deals with Curtius rearrangement of acid 64 to isocyanate 65, which subsequently transformed

to Sitagliptin (±)1. Racemic acid 64 can be resolved with (L)-Cinchonidine to give through

synthetic sequence 1.

F

F

F

CHO

O

O

OEt

OEt

+

F

F

F

O

O

OEt

OEt

F

F

F

O

O

OEt

OEt

N

NN

N

CF3

O

Cl

NaH, THF

F

F

F

N

O

NN

N

CF3

O OEt

O OEt

F

F

F

N

O

NN

N

CF3

O OH

F

F

F

N

O

NN

N

CF3

N

C

O

F

F

F

N

O

NN

N

CF3

NH

O OR F

F

F

N

ONH2

NN

N

CF3(±)1

58 59 60 61

62

63 64 65

66

…..Scheme-3.10

PRESENT WORK:

The object of the present work was to uncover and overcome the many disadvantages of the

prior art. Present work details the journey towards development of a simple, safe, productive,



Chapter - III

eco-friendly and easy to handle commercial process for preparing Sitagliptin. yet another

objective of the present invention is to provide a stereo selective process for preparing

Sitagliptin using novel intermediates, which is simple, industrially applicable, eco-friendly and

economically viable. yet another objective of the present invention is to provide a safe,

productive and easy to handle novel pharmaceutically acceptable salts of Sitagliptin or solvates

or hydrates thereof, having improved physical and chemical properties.

Hence, we have developed and optimized the process, impurities formed in the process were

identified, prepared and characterized. Additionally, force degradation study of Sitagliptin was

also investigated. A mechanistic rationale for the formation of the various process impurities

and degradation products has been provided.

RESULTS AND DISCUSSION:

Three synthetic approaches are described herein, among which approach A deals with 13-

synthetic steps preparation of Sitagliptin, having steric controls via schollkopf's reagent derived

from L-valine-NCA 66 for lab scale synthesis of Sitagliptin 1. Approach B discloses a new

manufacturing process using 2, 4, 5-trifluorophenyl acetic acid, as key raw material consisting

three steps was developed and scaled up. However, due to costlier catalyst complex, efforts

were diverted to Approach C. β-lactum route being safe and scalable, even though nine

synthetic steps was optimized. Process development and identification of impurities also

included in this approach. Additionally, force degradation study of Sitagliptin was also carried

out. A mechanistic rationale for the formation of the various impurities and degradation

products has also been provided. Furthermore, nine different isomers of Sitagliptin have been

prepared. Approach D depicted nine different novel pharmaceutically acceptable salts of

Sitagliptin and its preparation.

APPROACH A:

Sitagliptin 1 was first synthesized by Edmondson et al in 2004.[39]

The β-amino acid derived

DPP-IV inhibitor in this report were synthesized by standard peptide coupling of β-amino acids



Chapter - III

13 with fused heterocycles 14 (Scheme-3.1). The above process uses diazomethane, which is

very dangerous and explosive reagent, and cannot be used at industrial scale. Further, in

homologation reaction Silver acetate was used which is costly reagent and commercially not

feasible. Parallel to this scheme, we have developed a process avoiding these reagents, and

prepared new intermediates for the preparation of the Sitagliptin 1, described schematically in

Scheme-3.11.

NH2

OHO

HN

OHOO

O

O

HN

O

O

OH

H2N

O O

H2N

O

.HCl

L-Valine (67) N-Ethoxycarbonyl valine (68) L-Valine-NCA (69)

Glycine (70) Ethyl ester of glycine. HCl (71)

O

HN

O

O

O

H2N

O

.HCl

+

NH2

NH

OO

ONH

HN

O

O

N

N

O

O

N

N

O

O

F

F

F

NH2

OO+

H2N

O O

F

F

F

F

F

F O

O

HN

O

O

F

F

F O

OH

HN

O

O

F

F

F

OH

HN

O

O

F

F

F

O

HN

O

O

S

O

O

F

F

F

CN

HN

O

O

F

F

F

HN

O

O

O OH

L-Valine-NCA (69) Ethyl ester of glycine. HCl (71) L-Val-Gly-OEt (72) Cyclic diamide (73)

Bislactim ether (74) Bislactim adduct (75) Amino ester (76)

N-BOC Amino ester (77) N-BOC Amino acid (11) N-BOC Amino alcohol (78)

Tosyl intermediate (79)

Cyano intermediate (80) N-BOC beta-Amino acid (13)

…..Scheme-3.11



Chapter - III

Coupling of 13 with 14 followed by deprotection of the amine provided the desired compound 1

(Scheme-3.12).

F

F

F

HN

O

O

O N

NN

N

FF

F

F

F

F

NH2 O

N

NN

N

FF

F

F

F

F

NH2 O

N

NN

N

FF

F

.H3PO4.H2O

N-BOC Sitagliptin (15)Sitagliptin base (1)

Sitagliptin phosphate monohydrate

F

F

F

HN

O

O

O OH

N-BOC beta-Amino acid (13)

HN

NN

N

CF3

.HCl

14

…..Scheme-3.12

Description of the process: The present invention relates to a stereo selective process for

preparing Sitagliptin of Formula 1,

F

F

F

N

ONH2

NN

N

CF31

which comprises:

a) reducing (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluorophenyl)-propanoic acid

of Formula 11,

F

F

F O

OH

HN

O

O

N-BOC Amino acid (11)

to give tert-butyl [(2R)-1-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]-carbamate of

Formula 78



Chapter - III

F

F

F

OH

HN

O

O

N-BOC Amino alcohol (78)

b) activating the tert-butyl[(2R)-1-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-

yl]carbamate of Formula 78 to give compound of Formula 79A

F

F

F

X

HN

O

O

(79)A

Wherein X represents leaving group.

c) cyanating the compound of Formula 79A to give tert-butyl(2R)-1-cyano-3-(2,4,5-

trifluorophenyl)propan-2-yl carbamate of Formula 80

F

F

F

CN

HN

O

O

Cyano intermediate (80)

d) hydrolyzing the compound of Formula 80 to (3R)-3-[(tert-butoxycarbonyl) amino]-4-

(2,4,5-trifluorophenyl)-butanoic acid of Formula 13

F

F

F

HN

O

O

O OH

N-BOC beta-Amino acid (13)

e) condensing (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl) butanoic

acid of Formula 13 with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-

a]pyrazine of Formula 14

HN

NN

N

CF3

.HCl

14



Chapter - III

to give tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]-triazolo-[4,3-

a]pyrazine-7(8H)-yl)-1-(2,4,5-trifluorophenyl)-4-oxobutan-2-yl-carbamate of Formula

15

F

F

F

HN

O

O

O N

NN

N

FF

F

N-BOC Sitagliptin (15)

deprotecting the tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]-triazolo[4,3-

a]pyrazine-7(8H)-yl)-1-(2,4,5-trifluorophenyl)-4-oxobutan-2-ylcarbamate of Formula

15 to give Sitagliptin of Formula 1;

f) isolating the obtained Sitagliptin of Formula 1

The Sitagliptin is converted to its pharmaceutically acceptable salts, solvates or hydrate thereof

using an acid selected from organic or inorganic acid.


The present invention relates to a stereo selective process to prepare Sitagliptin of Formula 1,

which comprises, reducing the activated (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluoro-

phenyl)-propanoic acid of Formula 11 in presence of suitable reducing agents in a solvent to

give tert-butyl-[(2R)-1-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate of Formula 78.

The acid group of (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluorophenyl)-propanoic acid

of Formula 11 is activated by making its mixed anhydride in organic solvent selected from

hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers or mixture thereof. The

mixed anhydride is prepared by treating (2R)-2-[tert-butoxycarbonyl) amino]-3-(2,4,5-trifluoro-

phenyl)-propanoic acid of Formula 11 with aliphatic or aromatic (substituted / unsubstituted)

haloformates with or without base. Bases are selected from organic bases, preferably

triethylamine, diisopropylethyl amine, N-methyl morpholine and likes or mixture thereof, more



Chapter - III

preferably, N-methyl morpholine at -70°C to 30°C, preferably -30°C to 0°C and more

preferably at -20°C to -10°C. This activated acid (mixed anhydride) is treated with reducing

agent selected from complex hydrides that can be used include, but are not limited to, lithium

aluminium hydride, sodium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium

hydride (Vitride), alanes(AlH3), boranes(BH3), sodium borohydride in a solvent, selected from

hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers, e.g. tetrahydrofuran

(dry or moist).

Yet another disclosure of the present invention is reduction of (2R)-2-[tert-

butoxycarbonyl)amino]-3-(2,4,5-trifluoro-phenyl)-propanoic acid of Formula 11 can also be

achieved using above said reducing agents without activation of acid group to give tert-butyl-

[(2R)-1-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]-carbamate of Formula 78.

tert-Butyl-[(2R)-1-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate of Formula 78 is

activated, using an activating agent (leaving group) to give compound of Formula 79A. Wherein

X represents leaving group.

Activation of alcohol is carried out by halogenation, esterification (carbonate, sulfonate,

phosphate, nitrate, etc.) or phenoxide formation. Activation of Formula 78 can be carried out,

but are not limited to, by making iodide, bromide, chloride, tosylates, mesylates, triflates,

nonaflates, fluorosulfonates, nitrates, phosphates, carbonates, substituted or unsubstituted

phenoxides. Activation of alcohol can be done in an organic solvent selected from

hydrocarbons, aromatic hydrocarbons, ethers, halogenated solvents, ketones or mixture thereof

with or without base selected from base. Bases are selected from organic bases, preferably

triethylamine, diisopropylethyl amine, N-methyl morpholine and likes or mixture thereof, more

preferably, triethylamine at a temperature -70°C to 70°C, preferably at -50°C to 30°C and more

preferably at -20°C to 10°C.

The activated compound of Formula 79A is cyanated using cyanating agent selected from

sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide and likes or mixture thereof

in an organic solvent selected from dimethyl sulfoxide, dimethyl formamide, alcohols or



Chapter - III

mixture thereof at 25°C to 190°C, preferably at 50°C to 150°C and more preferably at 80°C to

95°C to give tert-butyl(2R)-1-cyano-3-(2,4,5-trifluorophenyl)propan-2-yl carbamate of Formula

80.

The cyano compound of Formula 80 is hydrolyzed to give (3R)-3-[(tert-butoxycarbonyl)

amino]-4-(2,4,5-trifluorophenyl)-butanoic acid of Formula 13, using a base selected from alkali

or alkaline earth metal hydroxides in aqueous organic solvents, preferably sodium or potassium

hydroxide in aqueous alcohols selected from methanol, ethanol and likes or mixture thereof at a

temperature 50°C to reflux, more preferably 70°C to 80°C.

(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)-butanoic acid of Formula 13 is

condensed with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-a]pyrazine of Formula

14 to give tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]-triazolo[4,3-a]pyrazine-

7(8H)-yl)-1-(2,4,5-trifluorophenyl)-4-oxobutan-2-ylcarbamate of Formula 15.

F

F

F

HN

O

O

O N

NN

N

FF

F

N-BOC Sitagliptin (15)

which is deprotected to give Sitagliptin of Formula 1 using an acid selected from organic or

inorganic acids. Organic acid is more preferably trifluoroacetic acid in a solvent selected from

halogenated hydrocarbon e.g. dichloromethane. Inorganic acids are more preferably

hydrochloric acid or hydrobromic acid in alcohols.

Another aspect of the present invention relates to novel intermediate tert-butyl [(2R)-1-hydroxy-

3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate of Formula 78

F

F

F

OH

HN

O

O

N-BOC Amino alcohol (78)



Chapter - III

which has 'H-NMR (300 MHz) in CDCl3: (ppm) 1.39 (S, 9H, 3CH3); 2.18 (brs, 1H, OH); 2.75-

2.91 (m, 2H, CH2); 3.56-3.71 (m, 2H, CH2); 3.84 (S, 1H, CH); 4.86 (brs, 1H, NH); 6.86-6.95

(m, 1H, Ar-H); 7.03-7.12 (m, 1H, Ar-H).

Another aspect of the present invention also relates to novel intermediate of Formula 79A

F

F

F

X

HN

O

O

(79)A

wherein X represents leaving group.

In yet another aspect of the present invention relates to novel intermediate of Formula 79

F

F

F

O

HN

O

O

S

O

O

Tosyl intermediate (79)

which has 'H-NMR (300 MHz) in CDCl3: (ppm) 1.36 (S, 9H, 3CH3); 2.46 (S, 3H, CH3);2.76-

2.80 (m, 2H, CH2); 3.93-4.06 (m, 2H, CH2); 4.09-4.13 (m, 1H, CH); 4.74-4.76 (d, 1H, NH);

6.82-6.95 (m, 2H, 2Ar-H);7.35-7.38 (d, 2H, 2Ar-H); 7.77-7.80 (d, 2H, 2Ar-H).

Another aspect of the present invention also relates to novel intermediate tert-butyl-(2R)-1-

cyano-3-(2,4,5-trifluorophenyl)propan-2-yl carbamate of Formula 80

F

F

F

CN

HN

O

O

Cyano intermediate (80)

which has 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.46 (S, 9H, 3CH3); 2.52-2.59 (dd, 1H,

CH2); 2.72-2.79 (dd, 1H, CH2); 2.86-2.92 (m, 2H, CH2); 4.06-4.13 (m, 1H, CH); 4.75-4.78 (d,

1H, NH); 6.89-6.96 (m, 1H, Ar-H); 7.00-7.12 (m, 1H, Ar-H).



Chapter - III

The present invention also relates to an improved process to prepare (2R)-2-[tert-

butoxycarbonyl) amino]-3-(2,4,5-trifluoro-phenyl)-propanoic acid of Formula 11

F

F

F O

OH

HN

O

O

N-BOC Amino acid (11)

which comprises,

a) reacting (S)-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine of Formula 74

N

N

O

O

Bislactim ether (74)

with 2,4,5-trifluorobenzylbromide in the presence of base e.g. n-butyl lithium in dry

tetrahydrofuran to give (2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-

isopropylpyrazine of Formula 75

N

N

O

O

F

F

F

Bislactim adduct (75)

b) hydrolyzing (2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-

isopropylpyrazine of Formula 75 using an acid selected from organic or inorganic acid,

preferably inorganic acid selected from hydrochloric acid, hydrobromic acid at room

temperature (25-35°C) to give (R)-ethyl-2-amino-3-(2,4,5-trifluorophenyl)-propanoate

of Formula 76.

H2N

O O

F

F

FAmino ester (76)



Chapter - III

c) protecting (R)-ethyl-2-amino-3-(2,4,5-trifluorophenyl)propanoate of Formula 76 using

di-tert-butyl dicarbonate with or without base selected from organic or inorganic bases

at 20°C to 40°C more preferably at 25°C to 35°C to give tert-butyl-(R)-1-

(ethoxycarbonyl)-2-(2,4,5-trifluorophenyl) ethylcarbamate of Formula 77

F

F

F O

O

HN

O

O

N-BOC Amino ester (77)

d) hydrolyzing the tert-butyl-(R)-1-(ethoxycarbonyl)-2-(2,4,5-trifluoro-phenyl)ethyl-

carbamate of Formula 77 using a base selected from alkali or alkaline earth metal

hydroxides in aqueous solvents, preferably sodium or potassium hydroxide in water at a

temperature 10°C to reflux, more preferably 20°C to 40°C to give (2R)-2-[tert-

butoxycarbonyl)amino]-3-(2,4,5-trifluoro-phenyl) propanoic acid of Formula 11.

The (S)-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine of Formula 74 is prepared using the

prior-art processes reported in literature and given in Scheme-3.11.

Hence, we have developed a safe and alternate process for the preparation of Sitagliptin,

through novel intermediates which is not disclosed earlier. The invention is illustrated with the

following examples (in experimental section), which are provided by way of illustration only

and should not be construed to limit the scope of the invention.

APPROACH B:

Ikemoto et al[76]

discloses a process to prepare beta-ketoamides 26, which is as shown in

Scheme-3.13.

F

F

F

O

OH

F

F

F

OH

O

O

O

O

F

F

F

O ODMAc, DIPEA

DMAP,

meldrum's acid,

Pivaloyl chloride

16 17 26

HN

NN

N

CF3

.HCl

DMAc, NaHCO3

14

N

NN

N

CF3

…..Scheme-3.13



Chapter - III

In this patent Meldrum’s adduct 17 is prepared using an acid activating agent, which is selected

from pivaloyl chloride. This process suffers from less yield and low quality of ketoamide of

Formula 26.

MeOH,

NH4OAc, NH4OH

F

F

F

NH2 O

N

NN

N

CF3

[Rh(cod)Cl]2,

(R,S) t-Butyl-Josiphos

MeOH, H2, 200 psi

29

F

F

F

N

ONH2

NN

N

CF31

F

F

F

O O

26

N

NN

N

CF3

…..Scheme-3.14

Xiao et al[77]

discloses a process for the preparation of Sitagliptin, wherein the reduction of the

Enamine amide 29 is carried out by using rhodium metal and a chiral ferrocenyl diphosphine as

disclosed in Scheme-3.14.

In this patent diketo compound is isolated, aminated using ammonium acetate and thereafter

hydrogenated, by which the yield is less. The present inventors have found a process, which is

suitable for industrial preparation.

The present involves less number of steps, cost effective, consistent and industrially viable

processes for the production of Sitagliptin and its pharmaceutically acceptable salts.

Description of the process: The present invention relates to an improved process for preparing

Sitagliptin of Formula 1,

F

F

F

N

ONH2

NN

N

CF31



Chapter - III

which comprises:

a) reacting 2,4,5-trifluorophenylacetic acid of Formula 16, with Meldrum’s acid,

F

F

F

O

OH

16

in presence of carbodiimides in a solvent to give 2-(2-(2,4,5-trifluorophenyl)-1-

hydroxyethyledene)-5,5-dimethylcyclohexane-1,3-dione [Meldrum’s adduct] of Formula

17.

F

F

F

OH

O

O

O

O17

b) condensing compound of Formula 17, with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-

triazole[4,3-a]pyrazine of Formula 14,

HN

NN

N

CF3

.HCl

14

in the presence of base and a solvent to give 4-oxo-4[3-(trifluoromethyl)-5,6-

dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one of

Formula 26,

F

F

F

O O

26

N

NN

N

CF3

which in situ aminated using aminating reagent to give (2Z)-4-oxo-4-[3-(trifluoro-methyl)-

5,6-dihydro[1,2,4]triazolo-[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluoro-phenyl)but-2-en-2-

amine of Formula 29,



Chapter - III

F

F

F

NH2 O

N

NN

N

CF329

c) hydrogenating the compound of Formula 29 in a solvent to give Sitagliptin of Formula 1

and

d) isolating the compound of Formula 1 and converting to its acid addition salts.


The present invention relates to an improved process to prepare Sitagliptin, which comprises,

condensing Meldrum’s adduct of Formula 17 with 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]-

triazole[4,3-a]pyrazine of Formula 14 in the presence of base selected from but are not limited

to pyridine, 4-(dimethylamino)pyridine, diisopropyl-ethylamine, triethylamine, imidazole or

mixture thereof and a solvent selected from but are not limited to aromatic hydrocarbons such

as toluene, xylene, or mixture thereof; alky halides such as dichloromethane, chloroform, 1,2-

dichloroethane or mixture thereof; esters such as ethyl acetate, isopropyl acetate, n-propyl

acetate, n-butyl acetate or mixture thereof; ketones such as methyl ethyl ketone, methyl isobutyl

ketone, n-butanone or mixture thereof; at a temperature 25 to 110°C, preferably 55 to 85°C to

give 4-oxo-4[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-

trifluoro-phenyl)butan-2-one of Formula 26, which in situ aminated using ammonium chloride,

ammonium bromide, ammonium iodide, ammonium carbonate, ammonium formate, ammonium

acetate in combination of ethanolic ammonia or methanolic ammonia or in combination

ammonium acetate-aqueous ammonia, formic acid- aqueous ammonia, ammonium formate-

formic acid, or a mixture thereof in a solvent selected from alcohols, nitriles, ketones, alkyl

halides, esters, aromatic hydrocarbons such as toluene, xylene; amides, ethers, water or mixture

thereof to give (2Z)-4-oxo-4[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-

7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine of Formula 29.



Chapter - III

Hydrogenating (2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo-[4,3-a]-pyrazine-

7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine of Formula 29 in a solvent selected from

alcohols such as methanol, ethanol, isopropyl alcohol, n-butanol or a mixture thereof to give

(2R)-4-oxo-4{3-(trifluoromethyl)-5,6-dihydro{1,2,4}-triazolo[4,3-a]pyrazine-7(8H)-yl)-1-

(2,4,5-trifluoro-phenyl)-butane-2-amine (Sitagliptin) of Formula 1. The hydrogenation reaction

can be carried out in presence of catalyst such as rhodium phosphine complex. The reaction can

be carried out at a temperature in the range of 25-100°C, preferably at 50-75°C.

In yet another embodiment the present invention also relates to the preparation of Meldrum’s

adduct of Formula 17, which comprises:

F

F

F

OH

O

O

O

O17

reacting 2,4,5-trifluorophenylacetic acid of Formula 16, with Meldrum’s acid, in presence of

carbodiimides in a solvent to give 2-(2-(2,4,5-trifluorophenyl)-1-hydroxyethyledene)-5,5-

dimethyl-cyclohexane-1,3-dione [Meldrum’s adduct] of Formula 17.

In above coupling reaction carbodiimides are selected from but are not limited to N,N'-

dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide(DIC), 1-ethyl-3-(3-

dimethylamino-propyl)carbodiimide (EDC) and likes or mixture thereof. The solvent in the

above process is selected from but are not limited to aromatic hydrocarbons such as toluene,

xylene, n-hexane, n-heptane, cyclohexane or mixture thereof; alkyl halide such as

dichloromethane, chloroform, 1,2-dichloroethane or mixture thereof; ester such as ethyl acetate,

isopropyl acetate, n-butyl acetate or mixture thereof; Ketones such as acetone, methyl ethyl

ketone, methyl isobutyl ketone, n-butanone or mixture thereof; N,N-dimethylformamide,

dimethylacetamide; base selected from but are not limited to pyridine, 4-

(dimethylamino)pyridine, N,N-diisopropylethylamine, triethylamine, imidazole or mixture

http://en.wikipedia.org/wiki/Dicyclohexylcarbodiimide

http://en.wikipedia.org/wiki/N,N%27-Diisopropylcarbodiimide



Chapter - III

thereof; reaction is carried out at a temperature selected from -10 to 30°C, preferably at 0 to

10°C. The following examples (in experimental section), illustrate the nature of the invention

and are provided for illustrative purposes only and should not be construed to limit the scope of

the invention.

APPROACH C:

One of the preferred process of Sitagliptin 1 manufacturing comprises reaction of 2,4,5-

Triflurophenylacetic acid 16 with Meldrum's acid in the presence of N,N'-

dicyclohexylcarbodiimide, triethylamine and 4-(dimethylamino)pyridine to produce meldrum's

adduct 17. It was treated with methanol to obtain methyl 4-(2,4,5-trifluorophenyl)-3-

oxobutanoate 18. The above reaction mass containing keto ester is subjected for

enantioselective hydrogenation in presence of (S)-BINAP.RuCl2.Triethylamine

complex/hydrochloric acid to yield (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutanoate 19.

Hydrolysis of hydroxy ester 19 with aqueous sodium hydroxide produced (3S)-4-(2,4,5-

trifluorophenyl)-3-hydroxybutanoic acid 20 (Scheme-3.15).

Hydroxy acid 20 is reacted with O-benzyl hydroxylamine hydrochloride 21 in the presence of

N,N'-dicyclohexylcarbodiimide and N,N-diisopropylethyl amine to produce butanamide 22. In

next step, Diisopropyl azodicarboxylate is reacted with triphenyl phosphine to form adduct,

which on further reaction with 22 produce benzyl lactum 23. In final stage, 23 was treated with

aqueous sodium hydroxide to prepare benzyloxy butanoic acid 24, which is treated in-situ with

triazolopyrazine hydrochloride 14 in presence of N,N'-dicyclohexylcarbodiimide and N,N-

diisopropylethyl amine to produce O-benzyl Sitagliptin 25. Hydrogenation of 25 in presence of

20% palladium hydroxide on carbon to deprotect the benzyloxy group to give Sitagliptin base 1.

Although, the relation between synthetic route and impurity identity is often assumed and

investigated during development, the results are seldom made public. The purpose of this report

is to investigate the existed route and identification, synthesis (or isolation) and characterization

of impurities and degradents during the process development of important drug, Sitagliptin.



Chapter - III

F

F

F

O

OH

F

F

F

OH

O

O

O

O

F

F

F

O

OCH3

O

F

F

F

OH

OCH3

O

F

F

F

OH

OH

O

F

F

F

OH

NH

O

O

F

F

F

N OO F

F

F

OH

ONHO

F

F

F

N

ONHO

NN

N

FF

F

F

F

F

N

ONH2

NN

N

FF

F

MDC, DCC,

meldrum's acid,

DMAP/TEA

HCl

(S)-Binap-RuCl2

H2, 150 psi

NaOH, water

MDC, Toluene

HCl

H2NO

DCC, HOBt, DIPEA

Toluene

.HCl

TPP, DIAD

Toluene, MeOH

THF, NaOH

water

HN

NN

N

CF3

.HCl10% Pd-C/ H2

40 psi, MeOH

16 17 18

19 20

22 23 24

14

25 1

21

Toluene, HCl

DCC, HOBt, DIPEA

Toluene

MDC, water

HCl, NaOH

Toluene, IPA

MeOH

…..Scheme-3.15

PROCESS DEVELOPMENT AND IMPURITY PROFILE:

Key steps in this process for the preparation of Sitagliptin are, formation of meldrum's adduct

17, benzyl lactum 23 and Sitagliptin 1. During the formation of meldrum's adduct 17, two

impurities was observed. In the next step, for the formation of Butanoic acid 20, six impurities

was observed. Further, four, two and nine impurities are observed in the preparation of 22, 23

and 1. The presence of impurities in an active pharmaceutical ingredient (API) can have a

significant impact on the quality and safety of the drug products. Consequently, it is a regulatory

requirement to isolate and characterize these substances. Furthermore, ICH guidelines require

that drug substances and drug products be stressed to aid in the development of stability-

indicating analytical methods.

Preparation of meldrum's adduct, 17: For the process development of Sitagliptin 1, 2,4,5-

Triflurophenylacetic acid 16 is selected as a key raw material because of its commercial



Chapter - III

availability. It is also well documented in the chemical literature that, 16 can be converted easily

into Meldrum’s adduct 17 by using an acid activating agent, which is selected from pivaloyl

chloride. Hence, activation of acid 16 is tried in different solvent and used different bases, to

achieve more conversion to product. The results of optimization summarized in Table-3.3.

Table-3.3

Sr.

No.

Meldrum's

acid (m.eq.)

Base

(m.eq.)

Catalyst

(m.eq.)

Reagent

(m.eq.)

Solvent

(volume)

Time/

Temp.

(°C)

Unreacted

16

(%)

%

Conversion

to 17

1 1.1 DIPEA

(2.15)

DMAP

(0.08) 1.25

DMAc

(4.2)

3h/45-

50°C 2.94 76.49

2 1.1 DIPEA

(2.05)

DMAP

(0.08) 1.1

DMAc

(3.5)

3h/45-

50°C 16.14 61.94

3 1.1 TEA

(2.5) - 1.1

Toluene

(15)

4h/45-

50°C 11.28 57.1

4 1.1 DIPEA

(2.2)

DMAP

(0.08) 1.1

ACN

(3)

3h/45-

50°C 8.6 73.58

5 1.2 DIPEA

(2.5)

DMAP

(0.08) 1.2

DCM

(25)

3h/38-

40°C 23.64 57.03

6 1.2 DMAP

(4) - 1.3

DCM

(24)

16h/38-

40°C 11.4 44.98

7 1.1 DIPEA

(3.2)

DMAP

(0.08) 1.1

Toluene

(20)

1h/45-

50°C 5.28 33.83

8 1.1 TEA

(2.5) - 1.2

ACN

(5)

1h/45-

50°C 33.41 42.26

9 1.1 TEA

(2.5)

DMAP

(0.08) 1.1

DCM

(30)

2h/38-

40°C 1.6 53.26

This process using pivaloyl chloride as activating agent suffers from less yield and no

consistency in the quality and yield of the product. Hence, we tested this conversion with

different reagents to achieve good conversion of 16 to 17, as summarized in Table-3.4.



Chapter - III

Table-3.4

Sr.

No

.

Meldrum's

acid (m.eq.)

Base

(m.eq.)

Reagent

(m.eq.)

Solvent

(volume)

Time/

Temp.

(°C)

Unreacted

16

(%)

%

Conversion

1 1.1 DIPEA

(2.15) ECF (1.25)

Toluene

(10)

3h/30-

35°C ND 89.13

2 1.05 TEA

(2.2) ECF (1.1)

Toluene

(16)

2h/30-

35°C 2.89 76.89

3 1.1 TEA

(4) ECF (1.4)

EtOAc

(15) 1h/40°C 0.02 87

4 1.2 TEA

(2.52) ECF (1.2)

DCM

(24)

3h/20-

25°C 19.34 64.15

5 1.1 DIPEA

(2.10) SOCl2 (1.1)

Toluene

(10)

3h/45-

50°C 23.62 30.85

6 1.1 TEA

(3) SOCl2 (1.2)

DCM

(12)

4h/25-

30°C 46.71 23.65

7 1.1 DMAP

(2.5)

Oxalyl

chloride

(1.15)

DCM

(13) 1h/0-

5°C 0.5 46.95

8 1.1 TEA

(5)

Oxalyl

chloride

(1.15)

DCM

(22) 1h/0-

5°C 22.36 17.06

9 1.1 TEA

(1.3) MsCl (1.2) DCM (4)

1h/0-

5°C 42 26.2

10 1.6 TEA

(5) MsCl (1.5)

DCM

(12) 3h/30-

35°C 16 32

11 1.2 - CDI (1.6) THF

(5.2)

3h/50-

55°C 2.9 56.9

12 1.1 - CDI (1.2) DCM

(10)

24h/30-

35°C 1 85

13 1.1 - TPP/DIAD

(1.05/1.2) THF (10) 5h/65°C 40.29 ND

14 1.1 - TPP/DIAD

(1.05/1.2)

DCM

(10) 1h/35-

40°C 26.99 ND

15 1.1 DMAP

(1.2) DCC (1.1) DCM (8)

19h/0-

5°C 1.08 94



Chapter - III

Table-3.5

Sr.

No.

Base

(m.eq.)

Reagent

(m.eq.)

Solvent

(volume)

Time/

Temp.

(°C)

Unreacted

16

(%)

%

Conversio

n

1 DMAP (0.08) DCC (1.1) DCM (8) 20h/25°C 41.87 6.5

2 DMAP (1.2) DCC (1.1) DCM (8) 19h/0-5°C 1.08 94

3 DMAP (1.5) DCC (1.1) DCM (8) 1h/25°C ND 42.75

4 DMAP (0.2) DCC (1.2) DCM (8) 17h/0-5°C ND 55.41

5 DMAP (0.5) DCC (1.2) DCM (8) 16h/0-5°C ND 68.72

6 DMAP (1) DCC (1.2) DCM (8) 15h/0-5°C ND 94.78

7 TEA (1.2) DCC (1.2) DCM (8) 20h/0-5°C 1.49 76.45

8 IMIDAZOLE

(1.2) DCC (1.2) DCM (8)

16h/0-5°C,

40h/40°C ND 53.46

9 PYRIDINE

(1.2) DCC (1.2) DCM (8) 25h/0-5°C ND 64.53

10 DMAP (1) DCC (1.2) Acetonitrile

(8) 26h/0-5°C 0.06 94.36

11 DMAP (1) DCC (1.2) Acetone (8) 24h/0-5°C 7.69 65.5

12 DMAP (1) DCC (1.2) Ethyl

acetate (8) 1h/0-5°C 2.25 79.13

13 DMAP (1) DCC (1.2) Toluene (8) 16h/0-5°C ND 87.67

14 DMAP/TEA

(0.3:0.8) DCC (1.2) DCM (8) 14h/0-5°C 1.76 87.05

15 DMAP/TEA

(0.2:0.8) DCC (1.2) DCM (8) 4h/0-5°C 0.13 92.44

16 DMAP/TEA

(0.1:0.9) DCC (1.2) DCM (8) 2h/0-5°C ND 88.91

17 DMAP/TEA

(0.5:0.5) DCC (1.2) DCM (8) 3h/0-5°C ND 92.2

18 DMAP/TEA

(0.5:0.5) DCC (1.2) DCM (8) 1h/0-5°C ND 93.06



Chapter - III

From above table (3.4) it is clear that, only carbodiimides gives good conversion from 16 to

product 17. Further, we focused our efforts to optimize the process using DCC as coupling

reagent, in different solvents, different base ratios, temperatures and DCC equivalents which is

summarized in Table-3.5.

Hence, we optimized the process, and find out that even though, reaction is going well in ACN,

Toluene and ethyl acetate, there is a problem with the isolation of the product and the best

condition we got is sr. no. 17 and 18 from Table-3.5. By following this process we got

consistent result, good conversion of 16 to 17 and better yield. During the formation of

meldrum's adduct 17, two impurities was observed. One of the impurity formed due to cleavage

/ hydrolysis of meldrum's adduct to give keto acid, 81. The other is the contaminated by

product, DCU 82, given in Table-3.6.

Table-3.6

Impurities identified through LCMS analysis / obtained during synthesis:

O

F

F

F

OH

O

4-(2,4,5-TRIFLUOROPHENYL)-3-OXO-

BUTANOIC ACID

[KETO ACID], 81 [MF: C10H7F3O3; MW: 232]

HN

HN

O

1,3-DICYCLOHEXYLUREA

[DCU], 82

[MF: C13H24N2O; MW: 224]

The mechanism for the formation of impurity 81 is given in Scheme-3.16.

F

F

F

OH

O

O

O

O

HOH

F

F

F

O

O

O

OH

O

O H

HF

F

F

O

OH

OH

O

O

- acetone

F

F

F

OH

OH

O

F

F

F

O

OH

O

- CO2

17

81

…..Scheme-3.16



Chapter - III

Preparation of hydroxy acid, 20: For the preparation of 20, meldrum's adduct 17 is treated with

methanol to obtain keto ester 18. The process optimization of this stage is given in Table-3.7.

Table-3.7

Sr.

No. Conditions

Unreacted

17 % Conversion

Yield

(%w/w)

1

2h reflux in methanol, then cooled to room

temperature, concentrated and crystallized

with IPE/Hexanes

Not

detected 94.77 0.69

2 2h reflux in methanol, then cooled to room

temperature 0.12% 93.93 insitu

3 2 days in methanol, at room temperature 89.58% 8.63 Insitu

4 2h reflux in 20% w/w aq. methanol, then

cooled to room temperature 0.47% 72.64% -

Hence, meldrum's adduct refluxed in anhydrous methanol (5 volume) at 60-65°C for 2h to

obtain 18 in good quality.

The above reaction mass containing Keto ester 18, is subjected for enantioselective

hydrogenation at 50-55°C at a pressure of 113-170 psi., in presence of (S)-

BINAP.RuCl2.triethylamine complex/hydrochloric acid to yield hydroxy ester 19. This reaction

mass was concentrated to remove methanol and subjected to hydrolysis reaction with aqueous

sodium hydroxide to produce hydroxy acid 20.

During the formation of 20, six impurities was observed. One of the impurity formed due to

cleavage / hydrolysis of meldrum's adduct to give keto acid 81. Keto acid 81 is a carryover

impurity. Keto ester 18 and hydroxy ester 19 are the intermediates which left unreacted during

the preparation of 20. Decarboxylation of 81 can result in benzyl acetone impurity 83 given in

Table-3.8.



Chapter - III

Table-3.8


O

F

F

F

OH

O

4-(2,4,5-TRIFLUOROPHENYL)-

3-OXOBUTANOIC ACID

[KETO ACID], 81 [MF: C10H7F3O3; MW: 232]

O

F

F

F

OCH3

O

METHYL 4-(2,4,5-

TRIFLUOROPHENYL)-3-

OXOBUTANOATE

[KETO ESTER], 18

[MF: C11H9F3O3; MW: 246]

F

F

F

OCH3

OOH

(S)-METHYL 4-(2,4,5-

TRIFLUOROPHENYL)-3-

HYDROXYBUTANOATE

[HYDROXY ESTER], 19

[MF: C11H11F3O3; MW: 248] F

F

F

OH

O

(E)-4-(2,4,5-TRIFLUORO-

PHENYL)BUT-2-ENOIC ACID

[ENE ACID], 82 [MF: C10H7F3O2; MW: 216]

F

F

F

OH

OOH

(R)-4-(2,4,5-TRIFLUORO-

PHENYL)-3-HYDROXY-

BUTANOIC ACID

[R-HYRDOXY ACID], R-20

[MF: C10H9F3O3; MW: 234]

CH3

O

F

F

F 1-(2,4,5-

TRIFLUOROPHENYL)-

PROPAN-2-ONE

[BENZYL ACETONE], 83

[MF: C9H7F3O; MW: 188]

The origin for the formation of these impurities are given in Scheme-3.17.

F

F

F

OH

O

O

O

O17

methanol

F

F

F

O

OCH3

O

F

F

F

OH

OCH3

O

F

F

F

OH

OCH3

O

F

F

F

OH

OH

O

F

F

F

OH

OH

O

HCl

(S)-Binap-RuCl2

H2, 150 psi+

18 19 R-19

20 R-20

F

F

F

O

OH

O

- CO2

F

F

F

O

81 83

…..Scheme-3.17

Preparation of butanamide, 22: For the preparation of 22, hyrdoxy acid 20 is treated with O-

benzylhydroxylamine hydrochloride 21 with peptide coupling reagent. The process optimization

of this stage is given in Table-3.9.



Chapter - III

Table-3.9

Sr.

No. Conditions

Unrea-

cted

20

%

Conversion

/ purity

Yield

(%w/w)

1

20 + 21 in MDC (7vol), HOBt (0.2m.eq.), cooled to

0-5°C, DCC and DIPEA (1.2m.eq.) addition. After

compition of reaction (1h) water addn., DCU

separation., pH 2 product extraction in MDC,

concentration., crystallization with water:MeOH.

1.08% 62.08/59 1.3

2 Meldrum's adduct 17+ amine 21 in Toluene

(10vol), added TEA and heat to 80-85°C for 2hr. ND ND/ND -

3

acid 20 + amine 21 in MDC (18vol), HOBt

(0.2m.eq.), cooled to 0-5°C, Added DIPEA

(1.2m.eq.) in one lot, DCC addition. After

completion of reaction (1h) DCU separation., water

wash, pH 1.8 adjusted, product extraction in MDC,

conc., crystallization with MeOH:water.

2.3% 66.95/87.16 1.55

4

acid 20 + amine 21 in Toluene (18vol), HOBt

(0.2m.eq.), Added DIPEA (1.2m.eq.) in one lot,

DCC addition (20-25°C). After completion of

reaction (2h) DCU separation., wash with Toluene,

filtrate water added (5vol), product crystallization.,

filtration.

ND 88.49/99.17 1.31

5

acid 20 + amine 21 in Toluene (18vol), HOBt

(0.1m.eq.), Added DIPEA (1.05m.eq.) in one lot,

DCC addition (20-25°C). After completion of

reaction (2h) DCU separation., wash with Toluene,

filtrate water added (5vol), pH 1.5 adjusted, product

crystallization., filtration.

0.17% 85.15/98.27 1.25

During the formation of 22, four impurities was observed. 82 is the byproduct of DCC, which

formed during coupling reaction. Reaction of 82 with 21 results in the formation of 84.

Butanamide dimer 85 is the cross coupling impurity. Structures of these impurities are given in

Table-3.10.



Chapter - III

Table-3.10


HN

HN

O 1,3-DICYCLOHEXYLUREA

[DCU], 82

[MF: C13H24N2O; MW: 224]

HN

HN

NO

84

2-(BENZYLOXY)-1,3-

DICYCLOHEXYLGUANIDINE

[MF: C20H31N3O; MW: 329.5]

NH

OOH

O

F

F

F (R)-N-(BENZYLOXY)-4-(2,4,5-

TRIFLUOROPHENYL)-3-HYDROXY

BUTANAMIDE [R-BUTANAMID], R-22

[MF: C17H16F3NO3; MW: 339]

NH

OO

OH

O

F

F

F

F

F

F

O

[BUTANAMIDE DIMER], 85

[MF: C27H23F6NO5; MW: 555]

Preparation of benzyl lactum, 23: DIAD is reacted with triphenylphosphine to form adduct,

which on further reaction with butanamide, 22 produce benzyl lactum 23. This reaction runs for

1h. After that, byproduct TPPO 86 was filtered off and washed with toluene. The filtrate and

washings are combined and concentrated to remove toluene. Finally product was crystallized

from methanol at -25 to -30°C and maintained for completion of product crystallization.

In this reaction all carryover impurities were eliminated and contaminated only with the

byproduct TPPO 86 and S-benzyl lactum intermediate S-23. Structures of these impurities are

given in Table-3.11. The proposed mechanism of this conversion (Mitsunobu Reaction) is

given in Scheme-3.18.



Chapter - III

NN

O

O

OO +

NN

O

O

OOPPh3

Ph3P

F

F

F

OH

NH

O

O

22

NNH

O

O

OO

Ph3PF

F

F

OH

N

O

O

F

F

F

O

N

O

O

PPh3

N

HN

O

O

OO

H

F

F

F

O

N

O

O

PPh3

HN

NH

O

O

OO

F

F

F

N OO

23

…..Scheme-3.18

Table-3.11


F

F

F

N OO

(S)-4-(2,4,5-TRIFLUOROBENZYL)-1-

(BENZYLOXY)AZETIDIN-2-ONE

[(S)- O-BENZYL LACTAM

INTERMEDIATE], S-23 [MF: C17H14F3NO2; MW: 321]

P

O

TRIPHENYLPHOSPHINE OXIDE

[TPPO], 86

[MF: C18H15OP; MW: 278]

Preparation of Sitagliptin, 1: For the preparation of Sitagliptin from benzyl lactum 23, we have

divided this transformation in to three parts,

Part A: Benzyl lactum 23 is treated with aqueous sodium hydroxide at 45-50°C for 1h, and after

completion of reaction cooled to room temperature. pH of the reaction mass is adjusted to 1.5-2



Chapter - III

using hydrochloric acid and product extracted in toluene and concentrated to remove water

content in organic extracts. This concentrated layer having benzyloxybutanoic acid 24 is taken

as such for the preparation of O-benzyl Sitagliptin 25.

Part B: Benzyloxybutanoic acid 24 is reacted in-situ with triazolopyrazine hydrochloride 14 in

the presence of DCC and base in toluene for 1h at 25-35°C. Reaction was quenched by adding

water to reaction mass. Obtained by product DCU, 82 was removed by filtration and washed

with toluene. Filtrate was washed with brine and concentrated to have O-benzyl Sitagliptin 25,

taken as such for the preparation of Sitagliptin 1.

Part C: O-benzyl Sitagliptin 25, is dissolved in methanol and subjected for hydrogenation in the

presence of 20% palladium hydroxide on carbon at 55-60°C at a pressure of 43-70 psi for ~4h to

deprotect the benzyloxy group. Reaction mass was cooled to room temperature and catalyst was

removed by filtration. After methanol removal, product was extracted in DCM at pH 9 and

concentrated to obtain gummy mass which on crystallization with toluene give Sitagliptin 1.

In this step nine impurities appeared again analyzed by HPLC. Hydrolysis of Sitagliptin during

its preparation, results in the formation of Sitagliptin acid 87 and triazolopyrazine 14 impurities.

Also, 14 is the raw material used in the preparation of Sitagliptin, which can carry through the

synthesis to contaminate 1. Structures of these impurities are given in Table-3.12.

Table-3.12

Impurities identified through LCMS analysis / obtained during synthesis :

HN

NN

N

CF3 3-(TRIFLOROMETHYL)-5,6,7,8-

TETRAHYDRO[1,2,4]-TRIAZOLO-

[4,3-a]-PYRAZINE

[TRIFLUORO PYRAZINE], 14 [MF: C6H7F3N4; MW:192]

ONH2

OH

F

F

F (R)-3-AMINO-4-(2,4,5-

TRIFLUOROPHENYL)BUTANOIC ACID

[SITALGLIPTIN ACID], 87 [MF: C10H10F3NO2; MW: 233]



Chapter - III

N

OHN

NN

N

CF3

F

F

F

(R)-1-3-(TRIFLUOROMETHYL)-5,6-

DIHYDRO-[1,2,4]TRIAZOL[4,3-a]-

PYRAZIN-7(8H)-YL)-4-(2,4,5-

TRIFLUOROPHENYL)-3-(METHYL-

AMINO)BUTAN-1-ONE

[N-METHYL SITAGLIPTIN], 88

[MF: C17H17F6N5O; MW: 421 ]

N

ONH

NN

N

CF3

NH2

O

F

F

F

F

F

F

3-AMINO-N-(4-(3-(TRIFLUOROMETHYL)-

5,6DIHYDRO-[1,2,4]TRIAZOL[4,3-a]PYRAZIN-7(8H)-

YL)-1-(2,4,5-TRIFLUOROPHENYL)-4-OXOBUTAN-2-

YL)-4-(2,4,5-TRIFLUORO-PHENYL)BUTANAMIDE

[SITAGLIPTIN DIMER], 89

[MF: C26H23F9N6O2; MW: 622]

ONH

O

OH

F

F

F (R)-3-(BENZYLOXYAMINO)-4-(2,4,5-

TRIFLUOROPHENYL)BUTANOIC

ACID

[O-BENZYL BUTANOIC ACID], 24

[MF: C17H16F3NO3; MW: 339]

N

ONH

NN

N

CF3

OF

F

F

(R)-7-[(3R)-3-[(BENZYLOXY)AMINO]-4-(2,4,5-

TRIFLUOROPHENYL) BUTANOYL]-3-

(TRIFLUOROMETHYL)-5,6,7,8-TETRAHYDRO-[1,2,4]-

TRIAZOLO[4,3-a]-PYRAZINE

[O-BENZYLSITAGLIPTIN], 25

[MF: C23H21F6N5O2; MW: 513]

N

OOH

NN

N

CF3

F

F

F

(S)-1-(3-(TRIFLUOROMETHYL)-5,6-

DIHYDRO-[1,2,4]TRIAZOLO[4,3-

a]PYRAZIN-7-(8H)-YL)-4-(2,4,5-

TRIFLUOROPHENYL)-3-HYDROXY-

BUTAN-1-ONE

[HYDROXY SITAGLIPTIN], 90

[MF: C16H14F6N4O2; MW: 408]

N

O

NN

N

CF3

F

F

F

(E)-1-(3-(TRIFLUOROMETHYL)-5,6-DIHYDRO-

[1,2,4]TRIAZOLO[4,3-a]PYRAZIN-7-(8H)-YL)-4-(2,4,5-

TRIFLUOROPHENYL)BUT-2-EN-1-ONE and

(E)-1-(3-(TRIFLUOROMETHYL)-5,6-DIHYDRO-

[1,2,4]TRIAZOLO[4,3-a]PYRAZIN-7-(8H)-YL)-4-(2,4,5-

TRIFLUOROPHENYL)BUT-3-EN-1-ONE

[ENE SITAGLIPTIN], 91

[MF: C16H12F6N4O; MW: 390]

N

ONH2

NN

N

CF3

F

F

F

(S)-3-AMINO-1-[5,6-DIHYDRO-3-(TRIFLUORO-

METHYL)-1,2,4-TRIAZOLO[4,3-a]-PYRAZIN-7(8H)-YL]-

4-(2,4,5-TRIFLUORO-PHENYL)-1-BUTANONE

[(S)-SITAGLIPTIN BASE]

(or)

[SITAGLIPTIN ENANTIOMER], S-1

[MF: C16H15F6N5O; MW: 407 ]

Generation of methyl chloride in the reaction of methanol and hydrochloric acid during work-

up, on reaction with Sitagliptin 1 may yield N-Methyl Sitagliptin, 88. Hydrolysis of Sitagliptin

during its preparation, results in the formation of Sitagliptin acid 87, which on condensation

with 1 may yield Sitagliptin dimer 89. Impurities 24 and 25 are an intermediates in the



Chapter - III

manufacturing process of 1 and may carry to finished product due to incomplete reaction of

debenzylation of O-benzyl Sitagliptin 25 and incomplete condensation reaction of 14 with 24,

respectively.

Ene Sitagliptin 91 originates due to deamination of Sitagliptin may be during debenzylation

reaction. Hydroxy Sitagliptin 90 may surface due to reaction of 91 with any hydroxy group as a

Michael adduct. The preparation of these impurities are detailed in experimental section.

Positional isomers:

Possible isomers of Sitagliptin have been prepared starting with 2-(3,4,5-trifluorophenyl)acetic

acid (16A), 2-(2,3,6-trifluorophenyl)acetic acid (16B), 2-(2,3,5-trifluorophenyl)acetic acid

(16C), 2-(2,3,4-trifluorophenyl)acetic acid (16D) and 2-(2,4,6-trifluorophenyl)acetic acid (16E)

instead of 2-(2,4,5-trifluorophenyl)acetic acid (16) used for the preparation of Sitagliptin. This

is summarized schematically in Table-3.13.

Table-3.13

1. F

FO

OH

F

FOH

O

O

O

O

F

FOH

OH

O

F

FOH

NH

O

O

F

FN O

O

F

F

N

ONH2

NN

N

FF

F

F F F

F

F

F

16A 17A 20A

22A 23A 1A



Chapter - III

2. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

F F F

F

F

F

16B 17B 20B

22B 23B 1B

F

F

F

F

F

F

F

F

F

F

F

F

3. F

O

OH

F

OH

O

O

O

O

F

OH

OH

O

F

OH

NH

O

O

F

N OO

F

N

ONH2

NN

N

FF

F

F F F

F

F

F

16C 17C 20C

22C 23C 1C

F F F

F

F

F

4. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

F F F

F

F

F

16D 17D 20D

22D 23D 1D

F F F

F

F

F

F F F

F

F

F

5. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

16E 17E 20E

22E 23E 1E

F F F

F

F

F

F F F

F

F

F

F F F

F

F

F

Similarly, desfluoro- didesfluoro- and tridesfluoro- Sitagliptin and there intermediates were also

prepared, starting with corresponding isomers of phenyl acetic acid. This is summarized

schematically in Table-3.14.



Chapter - III

Table-3.14

1. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

16F 17F 20F

22F 23F 1F

F F F

F

F

F

F F F

F

F

F

2. F

O

OH

F

OH

O

O

O

O

F

OH

OH

O

F

OH

NH

O

O

F

N OO

F

N

ONH2

NN

N

FF

F

16G 17G 20G

22G 23G 1G

F F F

F

F

F

3. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

F F F

F

F

F

16H 17H 20H

22H 23H 1H

F F F

F

F

F

4. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

16I 17I 20I

22I 23I 1I

F F F

F

F

F



Chapter - III

5. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

F F F

F

F

F

16J 17J 20J

22J 23J 1J

6. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

16K 17K 20K

22K 23K 1K

F F F

F

F

F

7. O

OH

OH

O

O

O

O

OH

OH

O

OH

NH

O

O N OO

N

ONH2

NN

N

FF

F

16L 17L 20L

22L 23L 1L

Meldrum's acid was reacted with deferent phenyl acetic acid 16A-L in the presence of N,N'-

dicyclohexylcarbodiimide, triethylamine and 4-(dimethylamino)pyridine to produce meldrum's

adduct 17A-L. It was treated with methanol to obtain methyl 4-(2,4,5-trifluorophenyl)-3-

oxobutanoate 18A-L. The above reaction mass containing keto ester is subjected for

enantioselective hydrogenation in presence of (S)-BINAP.RuCl2.Triethylamine

complex/hydrochloric acid to yield (3S)-4-(2,4,5-trifluorophenyl)-3-hydroxybutanoate 19A-L.



Chapter - III

Hydrolysis of hydroxy ester 19A-L with aqueous sodium hydroxide produced (3S)-4-(2,4,5-

trifluorophenyl)-3-hydroxybutanoic acid 20A-L (Table-3.13 and Table-3.14).

Hydroxy acid 20A-L is reacted with O-benzyl hydroxylamine hydrochloride 21 in the presence

of N,N'-dicyclohexylcarbodiimide and N,N-diisopropylethyl amine to produce butanamide

22A-L. In next step, Diisopropyl azodicarboxylate is reacted with triphenyl phosphine to form

adduct, which on further reaction with 22A-L produce benzyl lactum 23A-L. In final stage,

23A-L was treated with aqueous sodium hydroxide to prepare benzyloxy butanoic acid 24A-L,

which is treated in-situ with triazolopyrazine hydrochloride 14 in presence of N,N'-

dicyclohexylcarbodiimide and N,N-diisopropylethyl amine to produce O-benzyl Sitagliptin

25A-L. Hydrogenation of 25A-L in presence of 20% palladium hydroxide on carbon to

deprotect the benzyloxy group to give Sitagliptin isomers 1A-L. The characterization data and

detailed experimental procedure given in details in experimental section.

APPROACH D:

Sitagliptin, chemically known as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-

5,6,7,8-tetrahydro-3-(trifluoromethyl)-[1,2,4]-triazolo[4,3-a]pyrazine is marketed in the form of

a phosphate monohydrate in United States under the trade name JANUVIA® and is indicated to

improve glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin phosphate is a glucagon-like peptide 1 (GLP-1) metabolism modulator,

hypoglycemic agent, and dipeptidyl peptidase IV inhibitor.

Edmondson et al[39]

discloses class of -amino tetrahydrotriazolo[4,3-a]pyrazines that are potent

inhibitors of DPP-IV and therefore useful for the treatment of Type 2 diabetes and specifically

discloses Sitagliptin and its pharmaceutically acceptable salts.

Cypes et al[51]

discloses crystalline Sitagliptin dihydrogenphosphate monohydrate; Ferlita et

al[78]

discloses amorphous Sitagliptin dihydrogenphosphate; Wenslow et al[79]

and Chen et al[80]

discloses the crystalline anhydrous forms of Sitagliptin dihydrogenphosphate.



Chapter - III

Ellison et al[81]

discloses crystalline anhydrous Sitagliptin dodecyl sulfate.

Ferlita et al[82]

discloses crystalline Sitagliptin hydrochloric acid, benzenesufonic acid, p-

toluenesulfonic acid, 10-camphorsulfonic acid, tartaric acid salts and hydrates thereof.

Padi et al[43]

discloses Sitagliptin salts such as, anhydrous crystalline dihydrogen phosphate

Form A, sulfuric acid, hydrobromic acid, methane sulfonic acid, acetic acid, benzoic acid,

oxalic acid, succinic acid, mandelic acid, fumaric acid and lactic acid.

Gidwani et al[83]

discloses Sitagliptin malate, glycolate, citrate, maleate salts.

Winter et al[84]

discloses crystalline Sitagliptin galactarate Form I, hemi-L-malate Form I, D-

gluconate Form I, thiocyanate Form I, L-aspartate Form I, ethanedisulfonate Form I,

pyrroglutamate Form I, glutarate Form I, acetate Form I, citrate amorphous form, hemicitrate

amorphous form, glycolate amorphous form, malice amorphous form.

Selic et al[85]

discloses Sitagliptin salts, such as D- & L-glucuronic acid, D- & L-lactic acid, D-

& L-mandelic acid, ethanesulfonic acid, capric acid, benzoic acid, hippuric acid, trans-cinnamic

acid, malonic acid, 1-hydroxy-2-naphtolic acid, crotonic acid, ascorbic acid.

Pilarski et al[86]

discloses Sitagliptin salts, such as sulfate, isopropanol solvate, quinate, (+)-

dibenzoyltartrate and orotate.

IP.COM[87]

discloses novel Sitagliptin salts, such as cinnamic, (phenylthio)acetic, caffeic,

crotonic, nitric, hydroiodic, malonic, hippuric and 4-hydroxybenzoic acid.

Salts often improve physical and biological characteristics of mother compounds without

modifying primary pharmacological activity, based on mechanism of action. Different salt

forms of the same pharmaceutically active moiety differ in their physical properties such as

melting point, solubility etc. These properties may appreciably influence pharmaceutical

properties such as dissolution rate, bioavailability. Discovering of new polymorphic forms and

solvates of a pharmaceutical product can provide materials having desirable processing



Chapter - III

properties, such as ease of handling, ease of processing, storage stability, and ease of

purification or as desirable intermediate crystal forms that facilitate conversion to other

polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful

compound or salts thereof can also provide an opportunity to improve the performance

characteristics of a pharmaceutical product and new salts of Sitagliptin that may have

advantageous physico-chemical and biokinetic properties such as suitable solubility in neutral,

acidic or alkaline water medium, solubility in technologically important organic solvents,

water/lipid partition coefficient, electrochargeability, thermal stability, water and oxygen

inertness, hygroscopicity, crystal shape, particle size and surface, dissolution profile,

compatibility with excipients and combined active ingredients or special properties for final

dosage form design.

In view of the foregoing, we have now found novel salts of Sitagliptin and new crystalline/

amorphous forms of Sitagliptin salts, which are stable and can be used in medical therapy.

OBJECTIVE:

The objective of the present invention is to provide a safe, productive and easy to handle novel

pharmaceutically acceptable salts of Sitagliptin or solvates or hydrates thereof, having improved

physical and chemical properties.

Yet another objective of the present invention is to provide novel salts of Sitagliptin or solvates

or hydrates thereof, which are crystalline or amorphous in nature.

Yet another objective of the present invention is to provide the process for the preparation of

salts of Sitagliptin or solvates or hydrates thereof.

DESCRIPTION OF THE PROCESS:

The present invention relates to novel salts of Sitagliptin of Formula I or solvates or hydrates

thereof, which are crystalline or amorphous,



Chapter - III

N

N

N

N

CF3

O

F

F

F

H NH2

. salt

1

wherein salt represents formate, picolinate, nicotinate, stearate, palmitate and laurate.

In another embodiment of the present invention, also relates to crystalline Sitagliptin

cinnamate hemihydrate, amorphous Sitagliptin cinnamate, amorphous Sitagliptin

nitrate, crystalline Sitagliptin nitrate hydrate, crystalline Sitagliptin formate, amorphous

Sitagliptin formate, crystalline Sitagliptin picolinate, amorphous Sitagliptin picolinate,

amorphous Sitagliptin nicotinate.


The present invention relates to novel salts of Sitagliptin of formula I or solvates or hydrates

thereof, wherein salt represents formate, picolinate, nicotinate, stearate, palmitate and laurate.

In another aspect of the present invention also relates to the crystalline Sitagliptin formate or

solvates or hydrates thereof. Crystalline Sitagliptin formate having powder X-ray diffraction

°2 values at 6.27, 7.80, 9.84, 12.53, 14.57, 14.95, 15.88, 16.62, 18.33, 19.32, 19.71, 20.32,

22.47, 23.47, 24.13, 24.87, 26.24, 26.99, 29.18, 30.37, 31.00, 34.31, 34.99, 36.98±0.2.

Another aspect of the present invention relates to the amorphous form of Sitagliptin formate.

In another aspect of the present invention relates to the crystalline Sitagliptin cinnamate or

solvates or hydrates thereof. Crystalline Sitagliptin cinnamate hemihydrate having powder X-

ray diffraction °2 values at 5.96, 6.49, 10.01, 11.82, 13.04, 14.93, 15.73, 16.41, 17.63, 18.51,

19.63, 20.70, 21.44, 22.62, 23.71, 25.14, 25.76, 26.30, 27.30, 28.83, 31.71, 33.19, 34.73, 36.07,

38.12±0.2.



Chapter - III

Another aspect of the present invention relates to the amorphous form of Sitagliptin cinnamate.

Another aspect of the present invention relates to the amorphous form of Sitagliptin nitrate.

In another aspect of the present invention relates to the crystalline Sitagliptin picolinate or

solvates or hydrates thereof. Crystalline Sitagliptin picolinate having powder X-ray diffraction

°2 values at 10.36, 13.63, 14.27, 14.76, 15.83, 16.72, 17.81, 18.99, 19.41, 20.57, 20.85, 22.17,

22.93, 24.43, 26.51, 26.85, 27.24, 28.76, 29.99, 30.55, 31.06, 31.85, 33.72, 34.63, 35.40, 36.59,

37.62, 38.47±0.2.

Another aspect of the present invention relates to the amorphous form of Sitagliptin picolinate.

In another aspect of the present invention relates to the crystalline Sitagliptin nicotinate or

solvates or hydrates thereof. Crystalline Sitagliptin nicotinate having powder X-ray diffraction

°2 values at 3.88, 5.49, 5.89, 10.40, 14.82, 15.31, 16.26, 16.73, 17.38, 18.04, 18.96, 19.46,

19.90, 21.11, 21.87, 22.57, 23.01, 23.40, 23.71, 24.26, 24.63, 25.00, 25.93, 26.94, 27.64, 29.93,

30.66, 31.27, 33.92±0.2.

Another aspect of the present invention relates to the amorphous form of Sitagliptin nicotinate.

In another aspect of the present invention relates to the crystalline Sitagliptin stearate or solvates

or hydrates thereof. Crystalline Sitagliptin stearate having powder X-ray diffraction °2 values

at 10.36, 13.63, 14.27, 14.76, 15.83, 16.72, 17.81, 18.99, 19.41, 20.57, 20.85, 22.17°, 22.93,

24.43, 26.51, 26.85, 27.24, 28.76, 29.99, 30.55, 31.06, 31.85, 33.72, 34.63, 35.40, 36.59, 37.62,

38.47±0.2.

Another aspect of the present invention relates to the amorphous form of Sitagliptin stearate.

In another aspect of the present invention relates to the crystalline Sitagliptin palmitate or

solvates or hydrates thereof. Crystalline Sitagliptin palmitate having powder X-ray diffraction

°2 values at 3.88, 5.49, 5.89, 10.40, 14.82, 15.31, 16.26, 16.73, 17.38, 18.04, 18.96, 19.46,



Chapter - III

19.90, 21.11, 21.87, 22.57, 23.01, 23.40, 23.71, 24.26, 24.63, 25.00, 25.93, 26.94, 27.64, 29.93,

30.66, 31.27, 33.92±0.2.

Another aspect of the present invention relates to the amorphous form of Sitagliptin palmitate.

In another aspect of the present invention relates to the crystalline Sitagliptin laurate or solvates

or hydrates thereof. Crystalline Sitagliptin laurate having powder X-ray diffraction °2 values at

7.08, 7.29, 12.24, 12.47, 14.15, 14.38, 14.63, 15.80, 16.24 18.90, 19.24, 20.13, 21.62, 22.01,

23.90, 24.59, 25.57, 25.83, 26.22, 26.57, 28.49, 29.19, 29.93, 30.99, 31.81, 32.72, 33.01, 34.17,

35.70, 36.48, 38.40±0.2.

Another aspect of the present invention relates to the amorphous form of Sitagliptin laurate.

Another aspect of the present invention relates to a process for the preparation of novel salts of

Sitagliptin, which comprises: a) providing a mixture comprising Sitagliptin (base) and

pharmaceutically acceptable acid selected from the group consisting of formic acid, picolinic

acid, nicotinic acid, stearic acid, palmitic acid and lauric acid; and b) isolating the obtained

Sitagliptin salt. Wherein said the mixture is prepared by dissolving Sitagliptin base in a solvent

selected from water alcohols, esters, ethers, hydrocarbons, or mixture thereof at temperature in

the range of 25 to 100°C and more preferably at 25 to 80

°C

Another aspect of the present invention relates to a process for the preparation of novel

amorphous salts of Sitagliptin, which comprises: a) dissolution of Sitagliptin salts in water,

alcohols or mixture thereof. b) filtration & lyophilization of the obtained filtrate.

Another aspect of the present invention relates to a process for the preparation of Sitagliptin

cinnamate hemihydrate, which comprises: a) addition of cinnamic acid to preheated solution of

Sitagliptin base in solvent; b) heating the solution; c) cooling to precipitate product; and d)

isolating the product. Wherein solvent is selected from isopropyl alcohol, toluene, ethyl acetate

etc.



Chapter - III

Another aspect of the present invention relates to a process for the preparation of amorphous

Sitagliptin nitrate, which comprises: a) dissolving crystalline Sitagliptin nitrate salt in DM

water; and b) lyophilized.

POWDER X-RAY DIFFRACTION (PXRD):

The X-ray powder diffractogram is obtained using Seifert, XRD, 3003 TT systems. The X-ray

generator was operated at 40 kv and 30 mA, using the K1 radiation source. It is scanned in the

diffraction range of 40 to 40

0 2 at a scan rate of 0.02

0 2 per second

The invention is illustrated with the following examples, which are provided by way of

illustration only and should not be construed to limit the scope of the invention.

CONCLUSION:

Hence, in the present work we have uncovered many disadvantages of the prior art. We have

developed simple, safe, productive, eco-friendly and easy to handle commercial process for the

preparation of Sitagliptin. Here we have provided a stereo selective process for preparing

Sitagliptin using novel intermediates, which is simple, industrially applicable, eco-friendly and

economically viable. Also, the present investigation provided a safe, productive and easy to

handle novel pharmaceutically acceptable salts of Sitagliptin or solvates or hydrates thereof,

having improved physical and chemical properties.

Hence, we have developed and optimized the process, impurities formed in the process were

identified, prepared and characterized. A mechanistic rationale for the formation of the various

process impurities and degradation products has been provided.



Chapter - III

EXPERIMENTAL:

(2S)-2-[(ethoxycarbonyl)amino]-3-methyl-butanoic acid (N-Ethoxycarbonyl valine, 68)

(S)-2-Amino-3-methylbutanoic acid, [L-Valine] (500g, 4.27 mole) was added to aqueous

solution of sodium hydroxide [410.26 g,10.26 mole in DM water,3000ml]at 0-5°C and stirred to

obtain a clear solution. Thereafter, ethylchloroformate (556.41 g, 5.13 mole) was added to

resulting solution at below 10°C and further stirred for 1 h. Reaction mass was washed with

diisopropylether (250 ml). Further, obtained aqueous layer was diluted with diisopropylether

(1500 ml) and pH of the biphasic solution adjusted to 1, with concentrated hydrochloric acid

(~500 ml). Organic layer was separated and aqueous layer was re-extracted with

diisopropylether (500 ml). Thereafter, combined organic extracts was washed with DM water

(500 ml) and concentrated to yield (2S)-2-[(ethoxycarbonyl)amino]-3-methylbutanoic acid, as

an oily mass.) Yield: 788.3 g (97.6%); Molecular Formula: C8H15NO4; Molecular Weight:

189.21; Mass (ESI, in –ve ion mode): 188.1 [(M-H)-]; 'H-NMR (300 MHz) in CDCl3: δ(ppm)

0.93-1.02 (2d, 6H, 2CH3); 1.22-1.28 (t, 3H, CH3); 2.21-2.27 (m, 1H, CH); 4.11-4.18 (q, 2H,

CH2);4.32-4.35 (m, 1H, CH); 5.16-5.19 (d, 1H, CONH); 8.20 (brs, 1H, COOH).

(2S)-2-[(tert-butoxycarbonyl)amino]-3-methyl-butanoic acid

(S)-2-Amino-3-methylbutanoic acid, [L-Valine] (50 g, 0.427 mole) was added to aqueous

solution of potassium carbonate (147.5 g, 1.068 mole in DM water,200 ml) at 25-30°C.

Toluene (200 ml) and di-tert-butyl bicarbonate (DIBOC, 112 g, 0.5128 mole) were added

sequentially to resulting biphasic solution at 25-30°C and further stirred for ~16 h. Reaction

mass was diluted with DM water (500 ml). Toluene layer was separated and aqueous layer was

washed with toluene (100 ml). To obtained aqueous layer, toluene (300 ml) was added and pH

of the biphasic solution adjusted to 1 to 1.5, with concentrated hydrochloric acid at 25-30°C.

Organic layer was separated and aqueous layer was re-extracted with toluene (100 ml).

Combined organic extracts are washed with 20% brine solution, and concentrated to yield (2S)-

2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid, as viscous oil. Yield: 92.52 g (99.77%);

Molecular Formula: C10H19NO4; Molecular Weight: 217.2; Mass (ESI, in –ve ion mode): 216.1



Chapter - III

[(M-H)-]; 'H-NMR (300 MHz) in CDCl3: δ(ppm) 0.93-1.03 (2d, 6H, 2CH3); 1.45 (S, 9H, 3CH3);

2.20-2.22 (m, 1H, CH); 4.22-4.26 (m, 1H, CH); 4.89-4.92 (d, 1H, CONH); 8.52 (brs, 1H,

COOH).

(S)-4-isopropyloxazolidine-2,5-dione (L-Valine-NCA, 69)

(2S)-2-[(Ethoxycarbonyl)amino]-3-methylbutanoic acid (500 g, 2.646 mole) was added to

thionyl chloride (1000 ml) at 20-25°C The contents were heated to 60°C and maintained for 20

minutes at the same temperature. Thereafter, reaction mass was cooled to 30-35°C and diluted

with cyclohexane (3500 ml) to crystallize the product. Obtained crystalline product was cooled

to 10-15°C and stirred for 30 min. Product was filtered under nitrogen atmosphere, washed

with cyclohexane ( 2 x 500 ml) and dried at 40-45°C under reduced pressure to give (S)-4-

isopropyloxazolidine-2,5-dione as off-white to light yellow crystals. Yield: 343.27g (91%);

Molecular Formula: C6H9NO3; Molecular Weight: 143.14; Mass (ESI, in –ve ion mode): 142.1

[(M-H)-]; 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.03-1.11 (2d, 6H, 2CH3); 2.20-2.30 (m, 1H,

CH); 4.17-4.20 (d, 1H, CH); 6.66 (brs, 1H, NH).

Ethyl 2-aminoacetate hydrochloride (Ethyl ester of glycine. HCl, 71)

2-Aminoacetic acid (500 g, 6.67 mole) and N,N-Dimethylformamide (10 ml) were added

sequentially to ethanol (2500 ml) at 25-30°C. Thereafter, the contents were cooled to 0-5°C and

thionyl chloride (952 g, 7.99 mole) was added slowly in a period of 1 h at 0-15°C. Reaction

mass was heated to reflux (70-75°C) and stirred for 2-3 h. Thereafter, reaction mass was cooled

to 50-60°C and was diluted with diisopropyl ether (1300 ml) to precipitate the product.

Obtained slurry was cooled to 0-5°C and stirred for 2 h to complete the precipitation of product.

Product was filtered, washed with diisopropyl ether ( 2 x 500 ml) and dried at 60-65°C under

reduced pressure to give ethyl 2-aminoacetate hydrochloride as white crystalline fluffy solid.

Yield: 916.28 g (98.5%); Molecular Formula: C4H10ClNO2; Molecular Weight: 139.58; Mass

(ESI, in +ve ion mode): 104.1 [(MH)+- HCl]; 'H-NMR (300 MHz) in DMSO-d6: δ (ppm) 1.21-

1.26 (t, 3H, CH3); 3.77 (S, 2H, CH2); 4.17-4.24 (q, 2H, CH2); 8.43 (brs, 3H, NH3+).



Chapter - III

Ethyl{[(2S)-2-amino-3-methylbutanoyl]amino}-acetate (L-Val-Gly-OEt, 72) and (S)-3-

isopropyl-piperazine-2,5-dione (Cyclic diamide, 73)

Ethyl, 2-aminoacetate Hydrochloride (40 g, 0.287 mole) was added to methylene chloride (400

ml) and cooled to 0-5°C. Added triethylamine (72.40 g, 0.717 mole and the contents were

further cooled to -60 to -70°C under nitrogen atmosphere. (S)-4-Isopropyl-oxazolidine-2,5-

dione (41 g, 0.287 mole), dissolved in dry tetrahydrofuran (320 ml) was added during 1 h

maintaining temperature -60 to -70°C and reaction mass was stirred for 3 h at -60 to -70°C

Thereafter, reaction mass temperature was raised to 20-25°C and stirred for30 min Insoluble

matter was filtered and washed with dry tetrahydrofuran (2 x 40 ml). Obtained filtrate was

concentrated at 30-35°C under reduced pressure to yield Ethyl {[(2S)—2-amino-3-

methylbutanoyl] amino}-acetate as an oil which was taken for cyclization immediately. Mass

(ESI, in +ve ion mode): 203 [(M-H)+]; 'H-NMR (300 MHz) in DMSO-d6: δ (ppm) 0.83-0.85 (d,

3H, CH3); 0.98-1.01 (d, 3H, CH3); 1.28-1.32 (t, 3H, CH3); 1.41 (brs, 2H, NH2); 2.21-2.25 (m,

1H, CH); 3.21-3.24 (m, 1H, CH); 3.93-3.97 (m, 2H, CH2); 4.15-4.22 (m, 2H, CH2); 7.60 (brs,

1H, NH).

Toluene (1000 ml) was added to above concentrated mass and heated to reflux for 12-16 h.

Thereafter, reaction mass was cooled to 0°C and filtered. Obtained product was washed with

diisopropyl ether (2 x 80 ml) and dried at 100±5°C under reduced pressure for 8 h to obtain (S)-

3-isopropylpiperazine-2,5-dione as white solid. Yield: 36 g (82.5%); Molecular Formula:

C7H12N2O2; Molecular Weight: 156.18; Mass (ESI, in +ve ion mode): 157.2 [MH]+; 'H-NMR

(300 MHz) in CDCl3: δ (ppm) 0.84-0.86 (d, 3H, CH3); 0.91-0.94 (d, 3H, CH3); 2.08-2.14 (m,

1H, CH); 3.51-3.53 (t, 1H, CH); 3.58-3.65 (dd, 1H, CH2); 3.78-3.85 (d, 1H, CH2); 8.00 (brs, 1H,

NH); 8.18 (brs, 1H, NH).

(S)-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine (Bislactim ether, 74)

(S)-3-Isopropylpiperazine-2,5-dione (115 g, 0.737 mole) was suspended in methylene chloride

(2300 ml), under nitrogen atmosphere, at 25-30°C. Triethyloxonium tetrafluoroborate (350.2 g,

1.843 mole) was added to above suspension and stirred at 25-30°C for ~20 h. Again,



Chapter - III

triethyloxonium tetrafluoroborate (140 g, 0.737 mole) was added to the reaction mass and

stirring was continued for more 48 h. Thereafter, aqueous solution of sodium dihydrogen

phosphate dihydrate (340 g) and disodium hydrogen phosphate dihydrate (1200 g) in DM water

(5000 ml) was added at 25-30°C and contents were stirred for 1 h. Organic layer was separated

and aqueous layer was re-extracted with methylene chloride (2 x 800 ml) at 25-30°C.

Combined organic layer was washed with 20% sodium chloride solution and concentrated.

Finally, product was purified by distilling concentrated mass at (105-120°C / ~5-10 mm Hg) to

obtain clear colorless oily (S)-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine, product. Yield:

135.2 g (86.5%); Molecular Formula: C11H20N2O2; Molecular Weight: 212.29; Mass (ESI, in

+ve ion mode): 213.2 [MH]+; 'H-NMR (300 MHz) in CDCl3: δ (ppm) 0.73-0.75 (d, 3H, CH3);

1.01-1.03 (d, 3H, CH3); 1.25-1.30 (2t, 6H, 2CH3); 2.19-2.25 (m, 1H, CH); 3.90-3.91 (d, 1H,

CH); 3.92-3.93 (d, 2H, CH2); 4.03-4.19 (2m, 4H, 2CH2).

(2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-isopropylpyrazine (Bislactim

adduct, 75)

Solution of (S)-3,6-Diethoxy-2,5-dihydro-2-isopropylpyrazine (124 g, 0.585 mole) in dry

tetrahydrofuran (1860 ml) was cooled to -70 to -75°C under dry nitrogen atmosphere and n-

Butyl lithium (275 g, 0.643 mole, ~15% in Hexanes) was added in a period of 1 h maintaining -

70 to -75°C. Thus, obtained slurry was stirred for 30 min. Thereafter, 2,4,5-

trifluorobenzylbromide (144.2 g, 0.643 mole) in dry tetrahydrofuran (1100 ml) was added

slowly to above reaction mass slowly at -70°C to -75°C in a period of 2 h. After addition,

reaction mass was stirred at -70°C to -75°C for 3-5 h. Reaction was quenched with DM water

(700 ml) at -40 to -45°C. Thereafter, temperature of the reaction mass was raised to 25°C and

concentrated at this temperature to remove tetrahydrofuran / hexanes. Concentrated mass was

diluted with ethyl acetate (1000 ml) and washed with 1N Hydrochloric acid (1 x 1000 ml).

Aqueous layer was re-extracted with ethyl acetate (2 x 250 ml). Finally, combined organic

layers were washed with 20% sodium chloride solution (500 ml) and concentrated under

reduced pressure to yield (2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-



Chapter - III

isopropylpyrazine, as an oil. Yield: 202.2 g (97%); Molecular Formula: C18H23F3N2O2;

Molecular Weight: 356.38; Mass (ESI, in +ve ion mode): 357.1 [MH]+; 'H-NMR (300 MHz) in

CDCl3: δ (ppm) 0.63-0.65 (d, 3H, CH3); 0.97-0.99 (d, 3H, CH3); 1.23-1.33 (2t, 6H, 2CH3); 2.20-

2.21 (m, 1H, CH); 2.93-2.96 (m, 1H, CH2); 3.11-3.14 (m, 1H, CH2); 3.54-3.56 (t, 1H, CH); 4.03-

4.05 (m, 1H, CH);4.08-4.20 (2m, 4H, 2CH2); 6.79 – 6.87 (m, 1H, Ar-H); 6.95-7.04 (m, 1H, Ar-

H).

(R)-ethyl 2-amino-3-(2,4,5-trifluorophenyl)-propanoate (Amino ester, 76)

(2R, 5S)-2-(2,4,5-Trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-isopropylpyrazine (170 g, 0.477

mole) and 1 N Hydrochloric acid (1020 ml) were added sequentially in acetonitrile (850 ml) at

25-30°C and reaction mass was stirred at this temperature for ~16 h. Thereafter, reaction mass

was concentrated under reduced pressure to remove acetonitrile. Obtained concentrated

aqueous layer was washed with diisopropyl ether (2 x 100 ml) at 25-30°C. Further, obtained

aqueous layer was diluted with diisoporopyl ether (500 ml) and pH was adjusted to 9.5 using

20% aqueous ammonia solution. Organic layer was separated and again aqueous layer was

extracted with diisopropyl ether (2 x 100 ml). Combined organic extracts are washed with 20%

sodium chloride solution and concentrated under reduced pressure. Obtained concentrated mass

was distilled and product distilling at 100-150°C / ~10 mm Hg was collected as colorless oil.

Yield: 104.39 g (88.5%); Molecular Formula: C11H12F3NO2; Molecular Weight: 247.21; Mass

(ESI, in +ve ion mode): 248 [MH]+; 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.24-1.28 (t, 3H,

CH3); 1.54 (brs, 2H, NH2); 2.80-2.87 (m, 1H, CH2); 2.97-3.03 (m, 1H, CH2); 3.63-3.67 (t, 1H,

CH); 4.12-4.20 (m, 2H, CH2); 6.86-6.94 (m, 1H, Ar-H); 7.03-7.25 (m, 1H, Ar-H).

tert-Butyl(R)-1-(ethoxycarbonyl)-2-(2,4,5-tri-fluorophenyl)ethylcarbamate (N-BOC Amino

ester, 77)

To a solution of (R)-Ethyl-2-amino-3-(2,4,5-trifluorophenyl)propanoate (73 g, 0.296 mole) in

methylene chloride (475 ml), triethylamine (107.5 g, 1.064 mole) and di-tert-butyl dicarbonate

(77.31 g, 0.355 mole) were added sequentially at 25-30°C. Thereafter, reaction mass was

stirred at 25-30°C for ~10 h, diluted with methylene chloride (150 ml) and washed with 1N



Chapter - III

Hydrochloric acid solution (500 ml). Organic layer was separated, washed with 20% sodium

chloride solution (200 ml) at 25-30°C, and concentrated at 45-50°C under reduced pressure to

obtain product as oil. Yield: 102.5 g (100%); Molecular Formula: C16H20F3NO4; Molecular

Weight: 347.33; Mass (ESI, in -ve ion mode): 346.2 [(M-H)-]; 'H-NMR (300 MHz) in CDCl3: δ

(ppm) 1.25-1.30 (t, 3H, CH3); 1.42 (S, 9H, 3CH3); 2.98-3.03 (m, 1H, CH2); 3.13-3.18 (m, 1H,

CH2); 4.15-4.23 (m, 2H, CH2); 4.46-4.52 (m, 1H, CH); 5.04-5.06 (d, 1H, NH); 6.85-6.90 (m,

1H, Ar-H); 6.93-7.00 (m, 1H, Ar-H).

(2R)-2[(tert-butoxycarbonyl)amino]-3-(2,4,5-tri-fluorophenyl)propanoic acid (N-BOC Amino

acid, 11)

tert-Butyl(R)-1-(ethoxycarbonyl)-2-(2,4,5-trifluorophenyl)ethylcarbamate (105g, 0.303 mole)

was added to aqueous solution of sodium hydroxide [36.31 g, 0.908 mole in DM water, 1250

ml] and stirred at 25-30°C for 20 h. Thereafter, 37% concentrated Hydrochloric acid was added

to reaction mass to adjust its pH 1 at 25-30°C. Reaction mass was extracted with ethyl acetate

(1 x 500 ml, 1 x 100 ml). Combined organic layer was washed with 20% sodium chloride

solution (1 x 100 ml) and concentrated to obtain a pale yellow oil. Hexanes (200 ml) was added

to the concentrated mass and further heated to reflux temperature. The contents were cooled to

room temperature and filtered. An off-white crystalline product was obtained after drying at 45-

50°C under reduced pressure. Yield: 93.5 g (97%); Molecular Formula: C14H16F3NO4;

Molecular Weight: 319.28; Mass (ESI, in -ve ion mode): 318 [(M-H)-]; 'H-NMR (300 MHz) in

CDCl3: δ (ppm) 1.35-1.41 (2S, 9H, 3CH3); 2.86-3.04 (m, 1H,CH2); 3.23-3.28 (m, 1H, CH2);

4.40-4.58 (dd, 1H, CH); 5.04-5.07 (d, 1H, NH); 6.87-6.95 (m, 1H, Ar-H); 6.99-7.07 (m, 1H, Ar-

H); 8.99 (brs, 1H, COOH); Melting Range:108-110°C; SOR: [α]20

D +0.2° (C=1, in methanol).

tert-butyl[(2R)-1-hydroxy-3-(2,4,5-trifluoro-phenyl)propan-2-yl]carbamate (N-BOC Amino

alcohol, 78)

Under nitrogen atmosphere, (2R)-2-[tert-Butoxycarbonyl)amino]-3-(2,4,5-trifluoro-phenyl)-

propanoic acid (85 g, 0.266 mole) was added to dry tetrahydrofuran (1020 ml) and cooled to -

15°C. N-methyl morpholine (40.5 g, 0.3996 moles) and ethylchloroformate (34.7 g, 0.3197



Chapter - III

moles) were added sequentially and the suspension was stirred at -15°C for 15 min. Thereafter,

reaction mass was filtered directly into a chilled reaction vessel under nitrogen pressure at -

15°C. Aqueous sodium borohydride solution [(20.25 g, 0.5329 mole) in DM water (170 ml)

containing sodium hydroxide (0.8 g)] was added to the obtained pre-cooled filtrate at -15°C.

Thereafter, reaction mixture was stirred at -15°C for 15 min and allowed to warm to room

temperature. After 3 h, water (170 ml) was carefully added to reaction mass and the resulting

solution was concentrated under reduced pressure to remove tetrahydrofuran. To the

concentrated mass, diisopropyl ether (250 ml) was added and pH was adjusted to 1 with 37%

hydrochloric acid. Organic layer was separated and washed with water (1 x 100 ml), 1 N

hydrochloric acid solution (1 x 100 ml) and again with water (2 x 100 ml). Organic layer was

concentrated under reduced pressure. Hexanes (400 ml) was added to concentrated mass and

heated to reflux. Obtained, crystalline product was cooled slowly to 0-5°C and stirred for 1 h.

Product was filtered, washed with hexanes (2 x 80 ml) and dried at 45-50°C as white crystals.

Yield: 77 g (94.75%); Molecular Formula: C14H18F3NO3; Molecular Weight: 305.29; Mass

(ESI, in +ve ion mode): 206.1[(MH)+-BOC]; 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.39 (S,

9H, 3CH3); 2.18 (brs, 1H, OH); 2.75-2.91 (m, 2H, CH2); 3.56-3.71 (m, 2H, CH2); 3.84 (S, 1H,

CH); 4.86 (brs, 1H, NH); 6.86-6.95 (m, 1H, Ar-H); 7.03-7.12 (m, 1H, Ar-H); Melting

Range:109-122°C; SOR: [α]20


(2R)-2-[(tert-butoxycarbonyl)amino]-3-(2,4,5-tri-fluorophenyl)propyl p-toluenesulfonate (Tosyl

intermediate, 79)

Dimethylaminopyridine (88.20 g, 072 mole) was added to a pre-cooled solution of tert-

butyl[(2R)-1-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate (100 g, 0.33 mole) in

methylene chloride (1500 ml) at 0°C under nitrogen atmosphere and thereafter, stirred to obtain

a clear solution. p-Toluenesulfonyl chloride (75 g, 0.3934 mole) was added in portions in a

period of 30 min at 0°C and reaction mass was stirred for further 3 h at same temperature.

Thereafter, reaction mass was washed with water (1000 ml), 2N Hydrochloric acid solution

(500 ml) and again with water (2 x 500 ml). Obtained, organic layer was concentrated under



Chapter - III

reduced pressure to yield (2R)-2-[(tert-butoxycarbonoyl) amino]-3-(2, 4, 5-trifluorophenyl)

propyl-p-toluenesulfonate, which can be used without further purification. Yield: 127.3 g

(84.6%); Molecular Formula: C21H24F3NO5S; Molecular Weight: 459.5; Mass (ESI, in +ve ion

mode): 360.0 [(MH)+-BOC]; 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.36 (S, 9H, 3CH3); 2.46

(S, 3H, CH3); 2.76-2.80 (m, 2H, CH2); 3.93-4.06 (m, 2H, CH2); 4.09-4.13 (m, 1H, CH); 4.74-

4.76 (d, 1H, NH); 6.82-6.95 (m, 2H, 2Ar-H); 7.35-7.38 (d, 2H, 2Ar-H); 7.77-7.80 (d, 2H, 2Ar-

H); SOR: [α]20


tert-butyl(2R)-1-cyano-3-(2,4,5-trifluorophenyl)-propan-2-yl carbamate (Cyano intermediate,

80)

Sodium cyanide (40.67 g, 0.8301 mole) was added to dried dimethyl sulfoxide (1780 ml) and

heated to 90-95°C to obtain a clear solution. Solution of (2R)-2-[(tert-Butoxy-carbonyl)amino]-

3-(2,4,5-trifluorophenyl)propyl p-toluenesulfonate (127 g, 0.277 mole) in dimethyl sulfoxide

(520 ml) was added slowly to cyanide solution at 90-95°C in a period of 1 h. After 2 h of

stirring, reaction mass was cooled to 25°C and diluted with DM water (3450 ml). Product was

extracted with diisoporopoylether (1000 ml). Aqueous layer was re-extracted with diisopropyl

ether (2 x 500 ml). Combined organic layer was washed with DM water (1 x 250 ml) and

concentrated under reduced pressure to obtain crude product which on stirring with hexanes

converted to crystalline product. Yield: 72 g (83%); Molecular Formula: C15H17F3N2O2;

Molecular Weight: 314.3; Mass (ESI, in -ve ion mode): 313.0 [(M-H)-]; 'H-NMR (300 MHz) in

CDCl3: δ (ppm) 1.46 (S, 9H, 3CH3); 2.52-2.59 (dd, 1H, CH2); 2.72-2.79 (dd, 1H, CH2); 2.86-

2.92 (m, 2H, CH2); 4.06-4.13 (m, 1H, CH); 4.75-4.78 (d, 1H, NH); 6.89-6.96 (m, 1H, Ar-H);

7.00-7.12 (m, 1H, Ar-H). Melting Range:126-133°C; SOR: [α]20


(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-tri-fluorophenyl)butanoic acid (N-Boc-β-amino

acid, 13)

Potassium hydroxide (27.64 g, 0.494 moles) was added to aqueous methanol [mixture of 30 ml

DM water with 280 ml methanol] at 25-30°C. Thereafter, tert-butyl (2R)-1-cyano-3-(2,4,5-

trifluorophenyl)propan-2-yl carbamate (62 g, 0.198 mole) was added and heated the reaction



Chapter - III

mass to reflux stirred for 12 h at this temperature. After completion of reaction, reaction mass

was concentrated, diluted with water (200 ml) and washed with methylene chloride (2 x 100

ml). Washed aqueous layer was diluted with methylene chloride (500 ml), cooled to 5°C and

pH was adjusted to 1, with 37% aqueous hydrochloric acid. Methylene chloride layer was

separated, aqueous layer more extracted with methylene chloride (2 x 250 ml). Obtained organic

layer was washed with 20% sodium chloride solution (100 ml) and concentrated under reduced

pressure to obtain crude product. This concentrated mass was refluxed with Hexanes, cooled to

room temperature and filtered. Yield: 56.3 g (85.7%); Molecular Formula: C15H18F3NO4;

Molecular Weight: 333.3; Mass (ESI, in -ve ion mode): 332.2 [(M-H)-]; 'H-NMR (300 MHz) in

CDCl3: δ (ppm) 1.37 (S, 9H, 3CH3); 2.53-2.66 (t, 2H, CH2); 2.86-2.89 (d, 2H, CH2); 4.15 (S,

1H, CH); 5.10-5.11 (d, 1H, NH); 6.87-6.95 (m, 1H, Ar-H); 7.02-7.11 (m, 1H, Ar-H); 7.52 (brs,

1H, COOH); Melting Range:102-109°C; SOR: [α]20


tert-butyl(R)-4-(3-(trifluoromethyl)-5,6-di-hydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-1-

(2,4,5-trifluoro-phenyl)-4-oxobutan-2-ylcarbamate (N-Boc Sitagliptin, 15)

(3R)-3-[(tert-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (23 g, 0.069 mole)

was suspended in a solution of DCC (14.94 g, 0.073 mole) in methylene chloride (690 ml).

Thereafter, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazole[4,3-a]pyrazine (17.36 g, 0.0759

mole) and 1-hydroxybenzotriazole (1.86 g, 0.0138 mole) were added sequentially to the above

suspension at 25-30°C. N,N-diisopropylethylamine (10.69 g, 0.0828 mole) was added in a

period of 15-20 min, and reaction mass was left at room temperature for 16 h. Thereafter,

reaction mass was cooled to 0°C, stirred for 1 h and filtered. Obtained filtrate was washed with

DM water, 1 N hydrochloric acid, water, 10% aqueous ammonia and then twice with water.

Washed methylene chloride layer was concentrated under reduced pressure, to obtain tert-

butyl(R)-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl)-1-(2,4,5-

trifluorophenyl)-4-oxobutan-2-ylcarbamate. Yield: 35 g (100%); Molecular Formula:

C21H23F6N5O3; Molecular Weight: 507.43; Mass (ESI, in -ve ion mode): 506.2 [(M-H)-]; 'H-

NMR (300 MHz) in CDCl3: δ (ppm) 1.35 (S, 9H, 3CH3); 2.62-2.93 (m, 4H, 2CH2); 3.92-4.30



Chapter - III

(m, 5H, 2CH2, CH); 4.93-5.02 (d, 2H, CH2): 5.33 (brs, 1H, NH); 6.81-6.89 (m, 1H, Ar-H);

7.03-7.12 (m, 1H, Ar-H); SOR: [α]20


(R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl)-4-

(2,4,5-trifluorophenyl)-butan-1-one (Sitagliptin, 1)

N-BOC-Sitagliptin (34 g, 0.067 mole) was added to a saturated methanolic hydrochloric acid

solution (170 ml) at 20-25°C, and stirred for 2 h at the same temperature. Thereafter reaction

mass was concentrated under reduced pressure to gave Sitagliptin as hydrochloric acid salt. To

obtained solid, methylene chloride (250 ml) and DM water (250 ml) was added at 25-30°C.

Aqueous layer was separated and organic layer re-extracted with water (2 x 50 ml). Combined

aqueous layer was again diluted with methylene chloride (250 ml) and pH was adjusted to 11.5

with 50% w/w aqueous sodium hydroxide solution. Organic layer was separated and aqueous

layer re-extracted with methylene chloride (2 x 100 ml). Thereafter, combined organic extracts

was washed with DM water and concentrated to an viscous oil having chiral purity 91.13%.

Yield: 23.2 g (85%).

To enhance the chiral purity of Sitagliptin Base, toluene was added to the concentrated mass (as

obtained above), and heated the contents to reflux temperature to obtain homogeneous solution.

Thereafter obtained solution was cooled slowly to 0-5°C to crystallize the product. Crystallize

product was filtered, washed with toluene and dried at 45-50°C / ~20 mm Hg. Obtained Chiral

purity 97.6%, which we can enhance by repeated crystallization with toluene. Molecular

Formula: C16H15F6N5O; Molecular Weight: 407.31; Mass (ESI, in +ve ion mode): 408.0

[(MH)+]; 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.79 (brs, 2H, NH); 2.47-2.51 (m, 2H, CH2);

2.64-2.71 (m, 1H, CH2); 2.76-2.83 (m, 1H, CH2); 3.52-3.58 (m, 1H, CH); 3.96-4.28 (m, 4H,

2CH2); 4.92-5.02 (d, 2H, CH2); 6.86-6.95 (m, 1H, Ar-H); 7.05-7.15 (m, 1H, Ar-H).

SITAGLIPTIN PHOSPHATE:

85% w/w Aqueous phosphoric acid solution (5.67g, 0.049 mole) was added to a solution of

Sitagliptin Base (20 g,0.049 mole) dissolved in 30 % v/v aqueous isopropyl alcohol (60 ml) at



Chapter - III

20-25°C. Thereafter, contents were heated to reflux temperature to obtain a clear solution and

cooled vary slowly to 20-25°C, diluted with isopropyl alcohol (150 ml), filtered and dried at

30-35°C/~ 20mmHg. IR (KBr, cm-1): 3407, 3060, 2919, 2737, 1671, 1636, 1516, 1504, 1452,

1438, 1427, 1371, 1341, 1277, 1244, 1232, 1209, 1149, 1087, 1065, 1024, 982 and 937. 'H-

NMR (300 MHz) in CDCl3: δ (ppm) 2.73 & 2.90 (2m, 2H, CH2); 2.92 (m, 2H, CH2); 3.58 (m,

1H, CH); 3.82-4.96 (m, 6H, 3CH2); 7.45 & 7.54 (2m, 2H, Ar-H).

5-[2-(2,4,5-trifluorophenyl)-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione

[Meldrum’s Adduct, 17]

2,4,5-Trifluorophenylacetic acid (250g, 1.316 mole) was added to methylene chloride (1250 ml)

at 0-5°C, Meldrum’s acid (208.4g,1.447 mole) and 4-(dimethylamino) pyridine (160.8g,

1.316mole) were added sequentially to above suspension maintaining 0-5°C. Thereafter, N,N-

dicyclohexylcarbodiimide (325.26 g, 1.579 mole) was also added slowly to reaction mass

maintaining 0-5°C and stirring was continued at this temperature to complete the reaction. After

completion of the reaction the reaction mass was filtered and filtrate was diluted with DM water

(1250 ml) and acidified. Thereafter, separated organic layer was added to pre-cooled DM water

(5000 ml) and pH of the biphasic solution was adjusted to 11 to 12 with aqueous sodium

hydroxide at 25-30°C. Organic layer was separated and aqueous extract was acidified and

cooled to 0-5°C. Precipitated product was filtered, washed and dried at 45-50°C under reduced

pressure to give Meldrum’s adduct. Yield: 400g (96%); Chromatographic Purity (by HPLC):

97.51%. Molecular Formula: C14H11F3O5; Molecular Weight: 316.23; Mass (ESI, in -ve ion

mode): 315.0 [(M-H)-]; IR (KBr, cm-1): 1735, 1655, 1579, 1525, 1430, 1384, 1338, 1309, 1264,

1214, 1154 and 924. 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.77 (S, 6H, 2CH3); 4.45 (s, 2H,

CH2); 6.98 (m, 1H, Ar-H); 7.16 (m, 1H, Ar-H); 15.51 (brs, 1H, OH). Following same

procedure, 17(A-L) was prepared, see (Table-3.15) for characterization data.

(2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-

(2,4,5-trifluorophenyl)butane-2-en-2-amine (Enamine amide, 29)



Chapter - III

Triethylamine (15.2g, 0.150 mole) was added to a mixture of Meldrum’s adduct 17 (50g, 0.158

mole) and triazolopyrazine hydrochloride 14 (36.15 g, 0.158 mole) in ethyl acetate (400 ml) at

25-30°C. Thereafter, the contents were heated to reflux at ~75°C for 5 hrs to complete the

reaction. After completion of the reaction the reaction mass was cooled to 25-30°C and diluted

with DM water (100 ml). The organic layer was separated and washed with saturated aqueous

sodium chloride solution and then concentrated under reduced pressure to yield an oily mass.

Methanol (500 ml) and ammonium acetate (60.9g, 0.79mole) was added to the concentrated

mass and heated the content to reflux at 60-65°C for 3 hrs. After completion of the reaction

aqueous ammonia solution (25 ml) was added and cooled to 0-5°C and stirred for ~90 min. The

obtained product was filtered, washed with pre-cooled methanol and dried at 45-50°C under

reduced pressure (~20mmHg) to give Enamine amide. Yield: 57.5g; Chromatographic purity

(by HPLC): 97.52%; Molecular Formula: C16H13F6N5O; Molecular Weight: 405.10; Mass (ESI,

in +ve ion mode): 406.0 [(MH)+]; IR (KBr, cm-1): 3408, 3305, 3045, 1627, 1619, 1537, 1519,

1508, 1431, 1423, 1384, 1372, 1328, 1280, 1262, 1222, 1208, 1176, 1148, 1028, 1013. 'H-NMR

(300 MHz) in CDCl3: δ (ppm) 3.44 (s, 2H, CH2); 3.89 (t, 2H, CH2); 4.14 (t, 2H, CH2); 4.85 (s,

2H, CH2); 4.89 (s, 1H, CH); 6.78 & 8.51 (2brs, 2H, NH2); 7.52 (m, 2H, Ar-H.

(R)-3-amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl)-4-

(2,4,5-trifluorophenyl)-butan-1-one (Sitagliptin, 1)

Enamine amide (350 g, 0.864 moles) was suspended in degassed methanol (2450 ml) and

rhodium phosphine complex was added under nitrogen atmosphere (Rhodium phosphine

complex was prepared by suspending bis(1,5-cyclooctadiene)rhodium (I) (1.75g) and (R,S)-t-

butyl Josiphos (4.2 g) in degassed methanol (1050 ml) under nitrogen atmosphere and stirred for

1 hr at 25-30°C). Thereafter, after degassing, reaction mass was hydrogenated under 200-280

psig at 48-50°C for ~30 hrs. After completion of hydrogenation, reaction mass was concentrated

at 45-50°C under reduced pressure (200-10 mm Hg) and diluted with DM water (2800 ml) and

methylene chloride (1750 ml). pH of biphasic solution was adjusted to 3.5 with hydrochloric

acid and organic layer was separated. Methylene chloride (1750 ml) was added to the separated



Chapter - III

aqueous layer and readjusted pH of biphasic solution to 9 with 10 %w/w aqueous sodium

hydroxide. Organic layer was separated and thereafter concentrated under reduced pressure

(400-100 mm Hg). Toluene (2800 ml) was added to concentrated mass and contents were stirred

for ~1 h at 45-50°C. Thereafter the contents were cooled slowly to 25-30°C and stirred at this

temperature for 1 h to complete the crystallization. Finally, filtered the product, washed with

toluene (2x350ml) and dried at 45-50°C under reduced pressure (~20 mm Hg). Yield: 262.5g;

Chromatographic purity (by HPLC): 99.55%; Chiral Purity (by HPLC): 99.86%; Molecular



2.64-2.71 (m, 1H, CH2); 2.76-2.83 (m, 1H, CH2); 3.52-3.58 (m, 1H, CH); 3.96-4.28 (m, 4H,

2CH2); 4.92-5.02 (d, 2H, CH2); 6.86-6.95 (m, 1H, Ar-H); 7.05-7.15 (m, 1H, Ar-H).

(R)-3-Amino-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl)-4-

(2,4,5-trifluorophenyl)-butan-1-one dihydrogenphosphate monohydrate (Sitagliptin phosphate

monohydrate)

Sitagliptin base (50g, 0.1229 moles) was suspended in a mixture of isopropyl alcohol (100 ml)

and DM water (50 ml) at 25-30°C and stirred to obtain a clear solution. Obtained solution was

filtered through hyflow and residue was washed with isopropyl alcohol (25 ml). Thereafter,

obtained filtrate was heated to 54-56°C and diluted phosphoric acid [87% w/w phosphoric acid

(14g) in dissolved in DM water (25 ml)] was added to it at 55-60°C. Reaction mass was seeded

with Sitagliptin phosphate monohydrate (0.25g) and stirring was continued for 2 hrs at this

temperature. Isopropyl alcohol (525 ml) was added slowly at 45-50°C to the reaction mass,

further cooled the contents slowly to 20-23°C and stirred at this temperature for 1 hr. Product

was filtered , washed with 10 %v/v aqueous isopropyl alcohol and dried at 40-45°C under

reduced pressure (~20 mmHg). Yield: 60g; Chromatographic purity (by HPLC): 100.0%;

Chiral Purity (by HPLC): 100.0%; Molecular Formula: C16H15F6N5O.H3PO4.H2O; Molecular

Weight: 523.3; Mass (ESI, in +ve ion mode): 408.0 [(MH)+]; IR (KBr, cm-1): 3407, 3060, 2919,

2737, 1671, 1636, 1516, 1504, 1452, 1438, 1427, 1371, 1341, 1277, 1244, 1232, 1209, 1149,



Chapter - III

1087, 1065, 1024, 982 and 937. 'H-NMR (300 MHz) in CDCl3: δ (ppm) 2.73 & 2.90 (2m, 2H,

CH2); 2.92 (m, 2H, CH2); 3.58 (m, 1H, CH); 3.82-4.96 (m, 6H, 3CH2); 7.45 & 7.54 (2m, 2H, Ar-

H).

(3S)-4-(2,4,5-Trifluorophenyl)-3-Hydroxybutanoic Acid [Hyrdoxy Acid, 20]

Meldrum's adduct 17 (485g, 1.53 mol) was suspended in methanol (2425 ml) and obtained

slurry was heated to reflux at 62-65°C. After 2 hr of reflux reaction mass became a clear

solution with evolution of carbon dioxide. After completion of reaction, (~ 4 hr) contents were

cooled to 25-30°C and degassed it by purging nitrogen gas for 30 min. Added (S)-

BINAP.RuCl2.triethylamine complex (0.73 g, 0.15% w/w) / hydrochloric acid (16 g, 0.08 mol)

under nitrogen atmosphere and hydrogenated the mass at 10-12 kgcm-1

at 50-55°C. After

completion of reaction, (~ 7 hr) reaction mass was concentrated at 45-55°C under reduced

pressure. A solution of sodium hydroxide (73.67 g, 1.84 mol) in DM water (970 ml) was

prepared at 25-30°C and added to above concentrated mass. After completion of hydrolysis,

reaction mass was filtered to remove any insoluble mass and washed with water. Thereafter, pH

of the filtrate was adjusted to 1-1.5 using concentrated hydrochloric acid (152 g) at 30-40°C.

Contents were cooled to 5-10°C, product was filtered, washed with precooled DM water (245

ml) and dried at 45-50°C under reduced pressure to get 20. Yield: 325 g (90%);


Formula: C10H9F3O3; Molecular Weight: 234.17; Mass (ESI, in -ve ion mode): 233.0 [(M-H)-];

IR (KBr, cm-1): 3254, 1713, 1633, 1521, 1435, 1420, 1330, 1291, 1190, 1157 and 860. 'H-

NMR (300 MHz) in CDCl3: δ (ppm) 2.53-2.59 (m, 2H, CH2); 2.80-2.82 (m, 2H, CH2); 4.27 (m,

1H, CH); 6.9 (m, 1H, Ar-H): 7.10 (m, 1H, Ar-H). Following same procedure, 20(A-L) was

prepared, see (Table-3.16) for characterization data.

(3S)-N-(Benzyloxy)-4-(2,4,5-Trifluorophenyl)-3-Hydroxy Butanamide [Butanamide, 22]

Hydroxy acid 20 (140 g, 0.59 mol) was suspended in toluene (1960 ml) and added O-benzyl-

hydroxylamine hydrochloride 21 (100.2 g, 0.63 mol) with HOBt (8.07 g, 0.06 mol) at 25-30°C.

DIPEA (84.9 g, 0.66 mol) was added and stirred at 25-30°C for 15 min to get a clear solution.



Chapter - III

Prepared a solution of DCC (135.57 g, 0.66 mol) in toluene (280 ml) and added at 25-30°C

during 1 hr to above reaction mass. After completion of reaction (~ 3 hr), insoluble DCU was

filtered and washed with toluene (2x140 ml). Filtrate was collected, diluted with DM water (560

ml) and adjusted pH 3.5 using concentrated hydrochloric acid (8 ml) at 25-30°C. Obtained bi-

phasic slurry was heated to 55-60°C to get clear solution. Toluene layer was separated and

concentrated at 50-55°C under reduced pressure to (~1260 ml) volume. Obtained slurry was

cooled to 25-30°C, stirred for 1 hr, filtered and washed. Product was dried at 45-50°C under

reduced pressure to obtain 22. Yield: 174 g (86%); Chromatographic purity (by HPLC):

99.85%; Chiral Purity (by HPLC): 94.51%; Molecular Formula: C17H16F3NO3; Molecular

Weight: 339.31; Mass (ESI, in -ve ion mode): 338.0 [(M-H)-]; IR (KBr, cm

-1): 3233, 3148, 2981,

2850, 1627, 1575, 1532, 1448, 1437, 1346, 1311, 1244, 1232, 1186, 1088, 1047, 1012, 892.

1HNMR (CDCl3, 300 MHz, δ ppm): 2.72 (d, 2H, CH2), 3.64 (m, 2H, CH2), 4.17 (m, 1H, CH),

4.88 (m, 2H, CH2), 6.84 (m, 1H, Ar-H), 7.07 (m, 1H, Ar-H), 7.36 (m, 5H, Ar-H), 8.12 & 8.89

(brs, 1H, CONH). Following same procedure, 22(A-L) was prepared, see (Table-3.17) for

characterization data.

(3R)-4-(2,4,5-trifluorobenzyl)-1-(benzyloxy)azetidin-2-one [Benzyl Lactam, 23]

TPP (119 g, 0.45 mol) was added to toluene (1100 ml) and heated the content to reflux to

remove water traces azeotropically. Reaction mass was cooled to 20-25°C and added DIAD (92

g, 0.45 mol) in 45 min at 20-25°C. Butanamide 22 (140 g, 0.41 mol) was added in lots at 20-

25°C. After completion of reaction, byproduct TPPO was filtered and washed with toluene

(2x140 ml). Filtrate was concentrated at 45-50°C under reduced pressure to obtain concentrated

mass. Methanol (700 ml) was added to concentrated mass and obtained solution was cooled to -

22±2°C, stirred for 1 hr. Obtained product was filtered and washed with precooled methanol

(2x70 ml, -20°C). Dried the product at 45-50°C under reduced pressure to get 23. Yield: 111.6 g

(85%); Chromatographic purity (by HPLC): 99.94%; Chiral Purity (by HPLC): 100.0%;

Molecular Formula: C17H14F3NO2; Molecular Weight: 321.29; Mass (ESI, in +ve ion mode):

322.1 [(MH)+]; IR (KBr, cm

-1): 1777, 1752, 1714, 1632, 1525, 1470, 1456, 1424, 1375, 1336,



Chapter - III

1237, 1216, 1202, 1180, 1153, 1048, 916, 890. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.31-2.37

(dd, 1H, CH2), 2.65-2.70 (dd, 1H, CH2), 2.70-2.74 (dd, 1H, CH2), 2.88-2.90 (dd, 1H, CH2), 3.62

(m, 1H, CH), 4.93 (s, 2H, CH2), 6.91 (m, 2H, Ar-H), 7.38 (m, 5H, Ar-H). Following same

procedure, 23(A-L) was prepared, see (Table-3.18) for characterization data.

(3R)- 3-amino-1-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]-pyrazin-7(8H)-yl]-4-

(2,4,5-trifluorophenyl)-1-butanone [Sitagliptin Base, 1]

Benzyl lactum 23 (90 g, 0.28 mol) was suspended to the mixture of DM water (270 ml) and

THF (90 ml) and added sodium hydroxide (13.46 g, 0.33 mol) at 25-30°C. After completion of

reaction (~ 4 h), pH of the reaction mass was adjusted to 1.5, using concentrated hydrochloric

acid (~45 ml) at 25-30°C. Obtained product 24 was extracted in toluene (2x720 ml), washed

with 10% w/w aqueous sodium chloride solution (180 ml) and concentrated to distill ~180 ml of

toluene to remove water traces. (HPLC purity of 24: 99.01%). The solution was cooled to 20-

25°C and added triazolopyrazine hydrochloride 14 (67.27 g, 0.29 mol), HOBt (3.78 g, 0.03 mol)

and DIPEA (39.78 g, 0.31 mol) at 20-25°C and stirred for 15 min. DCC (63.53 g, 0.31 mol) in

toluene (180 ml) was added at 20-25°C in ~1hr. After completion of reaction, which is

instantaneous, reaction mass was stirred for 2 hr, filtered DCU and washed with toluene (2x90

ml). Toluene filtrate was washed with water (450 ml) and then 10% w/w aqueous sodium

chloride solution (450 ml) and concentrated under reduced pressure to remove toluene.

Obtained concentrated mass (25, HPLC purity: 91.33%) was dissolved in methanol (1350 ml),

transferred to hydrogenation cell, added 20% w/w Pd(OH)2 on carbon (9 g, 10% w/w) degassed

and applied 3-5 kg of hydrogen pressure at 25-30°C. Reaction mass was heated to 60±2°C to

complete the debenzylation (~ 12-15 hr). After this time, reaction mass was cooled to 20-25°C,

catalyst was removed by filtration and washed with methanol (2x45 ml) at 25-30°C. Filtrate was

concentrated at 45-55°C under reduced pressure to remove solvents. Diluted with methylene

chloride (90 ml) and DM water (270 ml) and pH of the biphasic solution was adjusted to 0.8-1.0

using concentrated hydrochloric acid. Separated the aqueous layer and added methylene

chloride (450 ml). pH of the biphasic layer was adjusted to 11.5-12.0 using 50% w/w aqueous



Chapter - III

sodium hydroxide solution. Separated the aqueous layer and extracted with methylene chloride

(90 ml) at 20-25°C. Combined methylene chloride layers were washed with water (90 ml) and

concentrated under reduced pressure at 45-60°C. Added isopropyl alcohol (54 ml) and toluene

(846 ml) at 25-30°C and reaction mass was heated to 70-75°C. Cooled the content to 2-5°C

during 5 hr and maintained stirring for 2 hr. Filtered the product, washed with toluene (90 ml)

and dried at 55-60°C under reduced pressure to obtain crystalline 1. Yield: 69.56 g (61%);




2.64-2.71 (m, 1H, CH2); 2.76-2.83 (m, 1H, CH2); 3.52-3.58 (m, 1H, CH); 3.96-4.28 (m, 4H,

2CH2); 4.92-5.02 (d, 2H, CH2); 6.86-6.95 (m, 1H, Ar-H); 7.05-7.15 (m, 1H, Ar-H). Following

same procedure, 1 (A-L) was prepared, see (Table-3.19) for characterization data.

4-(2,4,5-trifluorophenyl)-3-oxobutanoic acid [Keto Acid, 81]

Aqueous sodium hydroxide solution was prepared by dissolving sodium hydroxide (7.42 g, 0.18

mol) in DM water (100 ml) at 30-40°C. Keto ester 18 (38 g, 0.15 mol) was added to above

solution and allowed to stir for 4 hr at 40±2°C. After 2hr of stirring HPLC observed two peaks,

76.57% and 19.42%. After 4 hr, HPLC monitoring observed two peaks, one 53.49% and

42.15%. Adjusted pH of the reaction mass to 1 using hydrochloric acid, and extracted in

methylene chloride. Concentrated mass shown presence of 81. Yield: 13.78 g;

Chromatographic purity (by HPLC): 90.13%; Molecular Formula: C10H7F3O3; Molecular

Weight: 232.16; Mass (ESI, in -ve ion mode): 231.1 [(M-H)-]; IR (KBr, cm-1): 1733, 1706,

1635, 1522, 1433, 1333, 1197, 1064 and 846. 'H-NMR (300 MHz) in CDCl3: δ (ppm) 3.61 (S,

2H, CH2); 3.86 (s, 2H, CH2); 6.92-7.09 (m, 2H, Ar-H); 8.62 (brs, 1H, OH).

Methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate [Keto Ester, 18]

Meldrum's adduct 17 (370 g, 1.17 mol) was suspended in methanol (1850 ml) and obtained

slurry was heated to reflux at 62-65°C. After 2 hr of reflux reaction mass became a clear

solution with evolution of carbon dioxide. After completion of reaction, contents were cooled to



Chapter - III

35-40°C and concentrated under reduced pressure, to obtain 18 as a crude product. Obtained

product was dissolved in diisopropyl ether (370 ml), filtered to remove any insoluble mass and

again concentrated under reduced pressure. Hexanes (740 ml) was added to concentrated mass

and stirred at 20-25°C. Crystallized product was filtered, washed and dried at 35-40°C under

reduced pressure to give Keto ester 18. Yield: 269.35 g; Chromatographic purity (by HPLC):

99.89%; Molecular Formula: C11H9F3O3; Molecular Weight: 246.18; Mass (ESI, in +ve ion

mode): 247.1 [(M-H)-]; IR (KBr, cm-1): 1738, 1723, 1636, 1523, 1437, 1342, 1236, 1215, 1157,

1091 and 848. 'H-NMR (300 MHz) in CDCl3: δ (ppm) 3.55 (s, 2H, CH2); 3.76 (s, 3H, CH3);

3.85 (s, 2H, CH2); 6.95 (m, 1H, Ar-H); 7.04 (m, 1H, Ar-H).

(S)-methyl 4-(2,4,5-trifluorophenyl)-3-hydroxybutanoate [Hydroxy Ester, 19]

Keto ester 18 (200 g, 0.81 mol) was suspended in methanol (1000 ml) and purged nitrogen gas

to obtained solution for 30 min at 25-30°C. Added (S)-BINAP.RuCl2.triethylamine complex

(0.3 g, 0.15%w/w) / hydrochloric acid (8.84 g, 0.08 mol) and stirred under hydrogen pressure

10-12 kgcm-1

at 50-55°C for 7 hr to yield hydroxy ester 19. Yield: 155 g; Chromatographic

purity (by HPLC): 96.13%; Molecular Formula: C11H11F3O3; Molecular Weight: 248.20; Mass

(ESI, in +ve ion mode): 248.9 [(MH)+]; IR (KBr, cm-1): 3476, 3062, 2957, 1729, 1633, 1520,

1440, 1425, 1334, 1274, 1212, 1153, 1100, 1057 and 841. 'H-NMR (300 MHz) in CDCl3: δ

(ppm) 2.53 (s, 2H, CH2); 2.80 (s, 2H, CH2); 3.72 (s, 3H, CH3); 4.28 (s, 1H, CH): 6.91 (m, 1H,

Ar-H); 7.13 (m, 1H, Ar-H).

(E)-4-(2,4,5-trifluorophenyl)but-2-enoic acid [Ene Acid, 82]

Hydroxy ester 19 (20 g, 0.08 mol) was dissolved in methylene chloride (200 ml) and cooled to

0-5°C. TEA (10.6 g, 0.10 mol) was added followed by MsCl (10.2 g, 0.09 mol) in methylene

chloride (20 ml) at 0-5°C during 1 hr. After completion of O-mesylation, TEA (10.6 g, 0.10

mol) was added and continued stirring of the reaction mass at 25-30°C for completion of

reaction (~7 hr). Reaction mass was washed with DM water (2x100 ml) and concentrated at 35-

40°C under reduced pressure. Sodium hydroxide (3.9 g, 0.09 mol) was dissolved in water (60

ml) and added to above concentrated mass at 25-30°C. After completion of the reaction, washed



Chapter - III

with methylene chloride (2x50 ml), acidified, extracted in methylene chloride (2x100 ml) and

concentrated to obtain solid, 82. Yield: 10 g (58%). Chromatographic purity (by HPLC):

91.95%; Molecular Formula: C10H7F3O2; Molecular Weight: 216.16; Mass (ESI, in -ve ion

mode): 214.7 [(M-H)-]; IR (KBr, cm-1): 3092, 2951, 1694, 1625, 1520, 1505, 1431, 1337, 1308,

1280, 1239, 1223, 1201, 1180, 1157, 970, 880 and 866. 'H-NMR (300 MHz) in CDCl3: δ (ppm)

3.33 (d, 2H, CH2); 6.30 (m, 1H, CH); 6.58 (d, 1H, CH); 6.91 (m, 1H, Ar-H): 7.27 (m, 1H, Ar-

H); 9.56 (brs, 1H, OH).

1-(2,4,5-trifluorophenyl)propan-2-one [Benzyl Acetone, 83]

After isolation of keto acid 81 at pH 1, adjusted pH of the reaction mass to 12 using aqueous

sodium hydroxide solution, and extracted in methylene chloride. Concentrated mass shown

presence of 83. Yield: 15.5 g; Chromatographic purity (by HPLC): 97.07%; Molecular

Formula: C9H7F3O; Molecular Weight: 188.15; Mass (GCMS): 188; IR (KBr, cm-1): 3063,

1724, 1635, 1523, 1434, 1411, 1361, 1344, 1317, 1234, 1214, 1155, 1105, 883 and 856. 'H-

NMR (300 MHz) in CDCl3: δ (ppm) 2.24 (s, 3H, CH3); 3.70 (s, 2H, CH2); 6.92-7.03 (m, 2H, Ar-

H).

2-(benzyloxy)-1,3-dicyclohexylguanidine [84]

O-benzyl-hydroxylamine hydrochloride 21 (10 g, 0.06 mol) was suspended in toluene (140 ml)

and added DIPEA (8.5 g, 0.06 mol) at 25-30°C. DCC (14.2 g, 0.07 mol) in toluene (20 ml) was

added to above reaction mass at 20-25°C in ~30 min. After completion of reaction (~ 20 hr),

filtered the product, washed with toluene (10 ml) and dried at 50°C under reduced pressure to

get 84. Yield: 13 g (63%); Chromatographic purity (by HPLC): 99.77%; Molecular Formula:

C20H31N3O; Molecular Weight: 329.48; Mass (ESI, in +ve ion mode): 330.0 [(MH)+]; IR (KBr,

cm-1): 3182, 2990, 2930, 2856, 2801, 2686, 2665, 2618, 1647, 1573, 1446, 1427, 1393 and

1377. 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.33 (m, 2H, CH2); 1.4 (m, 8H, 4CH2); 1.54 (m,

4H, 2CH2); 1.64 (m, 2H, CH2); 1.81 (m, 4H, CH2); 3.21 (m, 1H, CH); 3.68 (m, 1H, CH); 3.84

(m, 2H, NH); 4.97 (s, 2H, CH2); 7.39 (m, 5H, Ar-H).



Chapter - III

(R)-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid [Sitalgliptin Acid, 87]

Benzyl lactum 23 (50 g, 0.15 mol) was added in DM water (150 ml) and THF (50 ml) mixture

at 25-30°C. Sodium hydroxide (7.5 g, 0.18 mol) was added to obtained suspension and heated to

45-50°C to complete the reaction. Reaction mass was filtered to remove any insoluble and

transferred to hydrogenation cell, added 20% w/w Pd(OH)2 on carbon (5 g, 10% w/w) degassed

and applied 3-5 kg of hydrogen pressure at 25-30°C. Reaction mass was heated to 60±2°C to

complete the debenzylation (~ 12-15 hr). After this time, reaction mass was cooled to 20-25°C,

catalyst was removed by filtration and washed with DM water (50 ml) at 25-30°C. Filtrate was

concentrated at 45-55°C under reduced pressure to remove THF. Reaction mass pH was

adjusted to 4.0 using concentrated hydrochloric acid at 40-45°C. Cooled the content to 12-15°C

and maintained stirring for 2 hr. Filtered the product, washed with DM water (50 ml, 5-10°C)

and dried at 45-50°C under reduced pressure to obtain crystalline 87. Yield: 25 g (70%);

Chromatographic purity (by HPLC): 98.51%; Molecular Formula: C10H10F3NO2; Molecular

Weight: 233.19; Mass (ESI, in +ve ion mode): 234.0 [(M-H)-]; 'H-NMR (300 MHz) in CDCl3: δ

(ppm) 2.60 (dd, 2H, CH2); 2.93 (m, 2H, CH2); 3.70 (m, 1H, CH); 7.53 (m, 2H, Ar-H); 8.14 (brs,

2H, NH2).

(R)-1-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-

trifluorophenyl)-3-(methyl-amino)butan-1-one [N-Methyl Sitagliptin, 88]

Followed same process as described for the preparation of Enamine amide 29, instead of

ammonium acetate, monomethyl amine was used to get N-methyl enamine sitagliptin. This was

hydrogenated and processed as described for the preparation of Sitagliptin from enamine amide

29. Yield: 52.5g; Chromatographic purity (by HPLC): 97.18%; Molecular Formula:

C17H17F6N5O; Molecular Weight: 421.34; Mass (ESI, in +ve ion mode): 422.0 [(MH)+]; 'H-

NMR (300 MHz) in CDCl3: δ (ppm) 2.26 (s, 3H, CH3); 2.41 & 2.57 (2m, 2H, CH2); 2.60-2.78

(m, 2H, CH2); 3.07 (m, 1H, CH); 3.96-4.22 (m, 4H, CH2); 4.84-4.96 (m, 2H, CH2); 7.43 (m, 2H,

Ar-H).



Chapter - III

3-Amino-N-(4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazol[4,3-a]pyrazin-7(8h)-yl)-1-(2,4,5-

trifluorophenyl)-4-oxobutan-2-yl)-4-(2,4,5-trifluoro-phenyl)butanamide [Sitagliptin Dimer, 89]

O-Benzyl butanoic acid 24 (35 g, 0.10 mol) and Sitagliptin base 1 (42 g, 0.10 mol) was taken in

toluene (560 ml) and added HOBt (1.4 g, 0.01 mol) at 25-30°C. DCC (23.4 g, 0.11 mol) was

added during 30 min at 25-30°C and stirred for 1 hr. DCU was filtered and washed with toluene

(2x35 ml). Filtrate was washed with water (70 ml) then 10 % w/w sodium chloride solution (70

ml) and concentrated under reduced pressure to get N-benzyloxy Sitagliptin dimer (~84 g).

Obtained concentrated mass was dissolved in methanol (420 ml), transferred to hydrogenation

cell, added 20% w/w Pd(OH)2 on carbon (4 g, 10% w/w) degassed and applied 3-5 kg of

hydrogen pressure at 25-30°C. Reaction mass was heated to 60±2°C to complete the

debenzylation (~ 30 hr). After this time, reaction mass was cooled to 20-25°C, catalyst was

removed by filtration and washed with methanol (2x45 ml) at 25-30°C. Filtrate was

concentrated at 45-55°C under reduced pressure to remove solvents. Diluted with methylene

chloride (90 ml) and DM water (270 ml) and pH of the biphasic solution was adjusted to 0.8-1.0

using concentrated hydrochloric acid. Separated the aqueous layer and added methylene

chloride (450 ml). pH of the biphasic layer was adjusted to 11.5-12.0 using 50% w/w aqueous

sodium hydroxide solution. Separated the aqueous layer and extracted with methylene chloride

(90 ml) at 20-25°C. Combined methylene chloride layers were washed with water (90 ml) and

concentrated under reduced pressure at 45-60°C. Yield: 58.2 g (91%); Chromatographic purity

(by HPLC): 98.39%; Molecular Formula: C26H23F9N6O2; Molecular Weight: 622.2; Mass (ESI,

in +ve ion mode): 623.23 [(MH)+]; IR (KBr, cm

-1): 3437, 3059, 2933, 1655, 1521, 1443, 1425,

1334, 1277, 1211, 1152, 1099, 1019, 941 and 845. 'H-NMR (300 MHz) in CDCl3: δ (ppm) 1.94

(m, 2H, CH2); 2.44 (m, 2H, CH2); 2.70 (m, 2H, CH2); 2.70 & 2.89 (2d, 2H, CH2); 3.08 (m, 1H,

CH); 3.86-4.38 (m, 5H, 2CH2 & CH); 4.82 & 4.97 (2d, 2H, CH2); 7.29-7.47 (m, 4H, Ar-H); 7.96

(m, 1H, NH).

(R)-3-(benzyloxyamino)-4-(2,4,5-trifluorophenyl)butanoic acid [O-Benzyl Butanoic Acid, 24]



Chapter - III

Benzyl lactum 23 (55 g, 0.17 mol) was suspended to the mixture of DM water (165 ml) and

THF (55 ml) and added sodium hydroxide (8.22 g, 0.20 mol) at 25-30°C. After completion of

reaction (~ 4 h), pH of the reaction mass was adjusted to 1.5, using concentrated hydrochloric

acid at 25-30°C. Obtained product was extracted in toluene (2x440 ml), washed with 10% w/w

aqueous sodium chloride solution (220 ml) and concentrated to obtain 24. Yield: 50.64 g (88%).


Formula: C17H16F3NO3; Molecular Weight: 339.31; Mass (ESI, in +ve ion mode): 340.0

[(MH)+]; IR (KBr, cm

-1): 3064, 3033, 2928, 1712, 1633, 1521, 1516, 1513, 1454, 1424, 1333,

1290, 1209, 1153, 1100, 1019, 881, 840. 'H-NMR (300 MHz) in CDCl3: δ (ppm) 2.49 (dd, 1H,

CH2); 2.63 (dd, 1H, CH2); 2.75 (dd, 1H, CH2); 2.89 (dd, 1H, CH2); 3.49 (m, 1H, CH); 4.71 (s,

2H, CH2); 6.89 (m, 1H, Ar-H); 7.03 (m, 1H, Ar-H); 7.33 (m, 5H, Ar-H).

(R)-7-[(3R)-3-[(benzyloxy)amino]-4-(2,4,5-trifluoro-phenyl) butanoyl]-3-(trifluoromethyl)-

5,6,7,8-tetrahydro-[1,2,4]-triazolo[4,3-a]-pyrazine [O-Benzylsitagliptin, 25]

Followed same process as described for the preparation of Sitagliptin 1, starting from Benzyl

lactum 23 and isolated 25. Yield:32 g (98%). Chromatographic purity (by HPLC): 91.15%;

Molecular Formula: C23H21F6N5O2; Molecular Weight: 513.44; Mass (ESI, in +ve ion mode):

514.0 [(MH)+]; 'H-NMR (300 MHz) in CDCl3: δ (ppm) 2.36 (dd, 1H, CH2); 2.68 (m, 2H, CH2);

2.83 (dd, 1H, CH2); 3.55 (m, 1H, CH); 3.79 (m, 1H, CH2); 4.07 (dd, 3H, CH2); 4.63 (s, 2H,

CH2); 4.85-5.06 (m, 2H, CH2); 6.87 (m, 1H, Ar-H); 7.06 (m, 1H, Ar-H); 7.29 (m, 5H, Ar-H).

(S)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8h)-yl)-4-(2,4,5-

trifluorophenyl)-3-hydroxy-butan-1-one [Hydroxy Sitagliptin, 90]

Triethylamine (22.2g, 0.22 mole) was added to a mixture of Meldrum’s adduct 17 (70g, 0.22

mole) and triazolopyrazine hydrochloride 14 (50.27 g, 0.22 mole) in ethyl acetate (560 ml) at

25-30°C. Thereafter, the contents were heated to reflux at ~75°C for 5 hrs to complete the

reaction. After completion of the reaction the reaction mass was cooled to 25-30°C and diluted

with DM water (150 ml). The organic layer was separated and washed with saturated aqueous

sodium chloride solution and then concentrated under reduced pressure to yield an oily mass.



Chapter - III

Methanol (730 ml) was added and degassed it by purging nitrogen gas for 30 min. Added (S)-

BINAP.RuCl2.triethylamine complex (0.37 g, 0.4% w/w) / hydrochloric acid (2.35 g, 0.02 mol)

under nitrogen atmosphere and hydrogenated the mass at 10-12 kgcm-1

at 50-55°C. After

completion of reaction, (~30 hr) reaction mass was concentrated at 45-55°C under reduced

pressure. Dissolved in methylene chloride (200 ml) and washed with DM water (2x100 ml).

This was again concentrated under reduced pressure and dissolved in ethyl acetate (50 ml) at

25-30°C. Isopropyl ether (300 ml) was added to obtain pure product, which was filtered, washed

and dried at 45-50°C. Yield: 61.67 g (67%); Chromatographic purity (by HPLC): 99.00%;

Molecular Formula: C16H14F6N4O2; Molecular Weight: 408.3; Mass (ESI, in +ve ion mode):

409.1 [(MH)+]; IR (KBr, cm

-1): 1626, 1521, 1443, 1423, 1371, 1332, 1285, 1228, 1210, 1183,

1161, 1146, 1102, 1042, 1015, 984, 868, 842. 'H-NMR (300 MHz) in CDCl3: δ (ppm) 2.56 (m,

2H, CH2); 2.84 (d, 2H, CH2); 3.70 (m, 1H, CH); 3.92-4.24 (m, 4H, CH2); 4.34 (brs, 1H, OH);

4.92-5.13 (m, 2H, CH2); 6.91 (m, 1H, Ar-H); 7.15 (m, 1H, Ar-H).

(E)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8h)-yl)-4-(2,4,5-

trifluorophenyl)but-2-en-1-one [2-Ene Sitagliptin, 91A] and (E)-1-(3-(trifluoromethyl)-5,6-

dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8h)-yl)-4-(2,4,5-trifluorophenyl)but-3-en-1-one [3-

Ene Sitagliptin, 91B]

Hydroxy Sitagliptin 90 (50 g, 0.12 mol) was dissolved in methylene chloride (500 ml) and

cooled to 0-5°C. TEA (18.57 g, 0.18 mol) was added followed by MsCl (21.05 g, 0.18 mol) in

methylene chloride (40 ml) at 0-5°C during 1 hr. After completion of O-mesylation, TEA (18.57

g, 0.18 mol) was added and continued stirring of the reaction mass at 2-5°C for completion of

reaction (~24 hr). Reaction mass was washed with DM water (2x100 ml) and concentrated at

35-40°C under reduced pressure to get 91. Yield: 47.9 g (94%). Chromatographic purity (by

HPLC): 14.79% and 79.13% (mixture of 2-ene and 3-ene); Molecular Formula: C16H12F6N4O;

Molecular Weight: 390.1; Mass (ESI, in +ve ion mode): 391.14 [(MH)+]. This was separated by

preparative HPLC.



Chapter - III

2-Ene Sitagliptin, 91A: IR (KBr, cm-1

): 3050, 2924, 2853, 1744, 1663, 1629, 1519, 1425, 1370,

1335, 1275, 1211, 1188, 1150, 1092, 1064, 1042, 1015, 983 and 880. 'H-NMR (300 MHz) in

CDCl3: δ (ppm) 3.54 (d, 2H, CH2); 4.10-4.20 (m, 4H, 2CH2); 5.01 (s, 2H, CH2); 6.27 (d, 1H,

CH); 6.90-7.09 (m, 3H, CH & Ar-H).

3-Ene Sitagliptin, 91B: IR (KBr, cm-1

): 3446, 3075, 3055, 1648, 1510, 1451, 1439, 1429, 1401,

1338, 1322, 1313, 1276, 1262, 1241, 1213, 1182, 1167, 1143, 1107, 1021 and 973. 'H-NMR

(300 MHz) in CDCl3: δ (ppm) 3.53 (d, 2H, CH2); 3.98-4.28 (m, 4H, 2CH2); 4.91 & 5.04 (2s, 2H,

CH2); 6.52 (m, 2H, 2CH); 7.52 (m, 1H, Ar-H); 7.77 (m, 1H, Ar-H).

Salts:

7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)-butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-

[1,2,4]-triazolo-[4,3-a]pyrazine formate

Formic acid (1.13g, 0.0245 moles) was added to preheated solution of Sitagliptin base (10g,

0.0245mole) in 150 ml of isopropyl alcohol at 65-70°C. Thereafter, the contents was heated to

75-80°C and stirred at this temperature for 1 hr. Obtained solution was cooled to 25-30°C and

thereafter, precipitated product was stirred further for ~20h at this temperature. Product was

filtered, washed with isopropyl alcohol (2x10ml, 25-30°C) and dried at 55-65°C under reduced

pressure (10-50 mm Hg). Yield: 10.70g. Water content: 0.20%w/w (by KF).



Formic acid (0.60g, 0.0130 moles) was added to preheated solution of Sitagliptin base (5g,

0.0123mole) in 75 ml of toluene at 75-80°C. Obtained solution was cooled to 25-30°C and


filtered, washed with toluene (2x10ml, 25-30°C) and dried at 55-65°C under reduced pressure

(10-50 mm Hg). Yield: 5.38g. Water content: 0.35%w/w (by KF).





Chapter - III

Formic acid (0.60g, 0.0130 moles) was added to solution of Sitagliptin base (5g, 0.0123mole) in

150 ml of ethyl acetate at 25-30°C. Obtained solution was stirred at 25-30°C and thereafter,

precipitated product was stirred further for ~15h at this temperature. Product was filtered,

washed with ethyl acetate (2x10ml, 25-30°C) and dried at 55-65°C under reduced pressure (10-

50 mm Hg). Yield: 5.18g. Water content: 0.32%w/w (by KF).

7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluoro-phenyl)-butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-

[1,2,4]-triazolo-[4,3-a]pyrazine formate in acetone / isopropyl ether

Sitagliptin formate (10g) was suspended to acetone (50ml) and stirred at 25-30°C to obtain a

solution. To this solution, isopropyl ether (200ml) was added slowly during 30min. Obtained

slurry was stirred at 25-30°C for ~16hr. Product was filtered, washed with isopropyl ether

(2x10ml, 25-30°C) and dried at 55-65°C under reduced pressure (10-50 mm Hg). Yield: 8.95g.

Water content: 0.16%w/w (by KF).


[1,2,4]-triazolo-[4,3-a]pyrazine formate in acetone / isopropyl ether

Sitagliptin formate (10g) was suspended to ethanol (absolute alcohol, 50ml) at 25-30°C.

Obtained solution was heated to 45-50°C to obtain a solution. To this solution, cyclohexane

(100ml) was added slowly during 30min. Obtained slurry was stirred at 25-30°C for ~16hr.

Product was filtered, washed with cyclohexane (2x10ml, 25-30°C) and dried at 55-65°C under

reduced pressure (10-50 mm Hg). Yield: 9.05g. Water content: 0.14%w/w (by KF).


[1,2,4]-triazolo-[4,3-a]pyrazine cinnamate hemihydrate

Cinnamic acid (3.63g, 0.0245 moles) was added to preheated solution of Sitagliptin base (10g,

0.0245mole) in 150 ml of isopropyl alcohol at 65-70°C. Thereafter, the contents were heated to

70-75°C and stirred at this temperature for 1h. Obtained solution was cooled to 25-30°C and

thereafter, stirred further for ~20h at this temperature to obtain a product. It was filtered, washed



Chapter - III

with isopropyl alcohol (2x10ml, 25-30°C) and dried at 55-60°C under reduced pressure (10-50

mm Hg). Yield: 8.33g. Water content: 1.86%w/w (by KF).




0.1474mole) in 840 ml of 2%v/v aqueous isopropyl alcohol at 65-70°C. Thereafter, the contents

were heated to 70-75°C and stirred at this temperature for 1h. Obtained solution was cooled to

25-30°C and thereafter, stirred further for ~20h at this temperature to obtain a product. It was


pressure (10-50 mm Hg). Yield: 65.68g. Water content: 1.96%w/w (by KF).




0.0245mole) in 150 ml of toluene at 70-75°C. Thereafter, the contents were maintained at 70-

75°C and stirred at this temperature for 1h. Obtained solution was cooled to 25-30°C and

thereafter, stirred further for ~15hr at this temperature to obtain a product. It was filtered,

washed with toluene (2x10ml, 25-30°C) and dried at 55-60°C under reduced pressure (10-50

mm Hg). Yield: 13.58g. Water content: 1.72%w/w (by KF).



Cinnamic acid (3.63g, 0.0245 moles) was added to a solution of Sitagliptin base (10g,

0.0245mole) in 150 ml of ethyl acetate at 25-30°C. Thereafter, the contents were maintained at

25-30°C for ~15hr to obtain a product. It was filtered, washed with ethyl acetate (2x10ml, 25-

30°C) and dried at 55-60°C under reduced pressure (10-50 mm Hg). Yield: 11.52g. Water

content: 1.89%w/w (by KF).



Chapter - III


[1,2,4]-triazolo-[4,3-a]pyrazine cinnamate hemihydrate in ethyl acetate

Sitagliptin cinnamate (10g) was suspended to ethyl acetate (100ml) at 25-30°C. Obtained slurry

was heated to 75-77°C to obtained a clear solution). Obtained solution was cooled to 25-30°C

and thereafter, stirred further for ~15hr at this temperature to obtain a product. It was filtered,

washed with ethyl acetate (2x10ml, 25-30°C) and dried at 55-60°C under reduced pressure (10-

50 mm Hg). Yield: 6.32g. Water content: 1.75%w/w (by KF).

amorphous 7-[(3R)-3-amino-1-oxo-4-(2,4,5-tri-fluorophenyl)-butyl]-5,6,7,8-tetrahydro-3-

(trifluoro-methyl)-[1,2,4]-triazolo-[4,3-a]pyrazine cinnamate

Crystalline Sitagliptin cinnamate hemihydrate (5g) was dissolved in 650 ml of DM water at 25-

30°C. Thereafter, the contents were filtered and obtained filtrate was lyophilized to obtain

amorphous Sitagliptin cinnamate, which is hygroscopic in nature. Yield: 4.61 g.

amorphous 7-[(3R)-3-amino-1-oxo-4-(2,4,5-tri-fluorophenyl)-butyl]-5,6,7,8-tetrahydro-3-

(trifluoro-methyl)-[1,2,4]-triazolo-[4,3-a]pyrazine formate

Crystalline Sitagliptin formate (5g) was dissolved in 15 ml of DM water at 25-30°C. Thereafter,

the contents were filtered and obtained filtrate was lyophilized to obtain amorphous Sitagliptin

formate, which is hygroscopic in nature. Yield: 4.72 g.


[1,2,4]-triazolo-[4,3-a]pyrazine nicotinate

Nicotinic acid (1.51g, 0.0122 moles) was added to preheated solution of Sitagliptin base (5g,


70-75°C and stirred at this temperature for 1h. Obtained solution was concentrated at 40-45°C

under reduced pressure to distill ~60 of isopropyl alcohol and cyclohexane (100ml) was added.

Thereafter, precipitated product was stirred further for 5h at 25-30°C. Product was filtered,

washed with cyclohexane (2x10ml, 25-30°C) and dried at 50-60°C under reduced pressure (10-

50 mm Hg). Yield: 7.11 g. Water content: 1.72 %w/w (by KF).



Chapter - III


[1,2,4]-triazolo-[4,3-a]pyrazine picolinate

Picolinic acid (1.51g, 0. 0.0122 moles) was added to preheated solution of Sitagliptin base (5g,


70-75°C and stirred at this temperature for 1h. Obtained solution was cooled to 25-30°C and



pressure (10-50 mm Hg). Yield: 6.28 g. Water content: 0.12%w/w (by KF).


[1,2,4]-triazolo-[4,3-a]pyrazine nitrate

Nitric acid (60%w/w, 2.84g,, 0.0270 moles) was added to preheated solution of Sitagliptin base

(10g, 0.0245mole) in 100 ml of isopropyl alcohol at 50-60°C and contents were stirred at this

temperature for 1 hr. Obtained solution was cooled to 25-30°C and thereafter, precipitated

product was stirred further for ~2h at this temperature. Product was filtered, washed with

isopropyl alcohol (2x10ml, 25-30°C) and dried at 45-50°C under reduced pressure (~20 mm

Hg). Yield: 9.90 g. Water content: 0.28%w/w (by KF).


[1,2,4]-triazolo-[4,3-a]pyrazine nitrate hydrate

Nitric acid (60%w/w, 2.58g, 0.024 moles) was added to a suspension of Sitagliptin base (10g,

0.0245mole) in 50 ml of DM water at 25-35°C. Isopropyl alcohol (10ml) was added and

contents were stirred at this temperature for 1 hr. Obtained slurry was further cooled to 5-10°C

and stirred further for ~1h at this temperature. Product was filtered, washed with precooled

DM water (2x10ml, 5-10°C) and dried at 45-50°C under reduced pressure (~20 mm Hg). Yield:

9.50 g. Water content: 5.49%w/w (by KF).


[1,2,4]-triazolo-[4,3-a]pyrazine nitrate



Chapter - III

After dissolving Sitagliptin nitric acid (12g) in 120 ml of isopropyl alcohol at 45-50°C, contents

were cooled to 25-30°C stirred at this temperature for ~15hr at this temperature. Product was

filtered, washed with isopropyl acetate (2x12ml) and dried at 45-50°C under reduced pressure

(~20 mm Hg). Yield: 9.20 g. Water content: 0.25%w/w (by KF)

Amorphous 7-[(3R)-3-amino-1-oxo-4-(2,4,5-tri-fluorophenyl)-butyl]-5,6,7,8-tetrahydro-3-

(trifluoro-methyl)-[1,2,4]-triazolo-[4,3-a]pyrazine nitrate

Crystalline Sitagliptin nitrate (5g) was dissolved in 50 ml of DM water at 25-30°C. Thereafter,

the contents were filtered and obtained filtrate was lyophilized to obtain amorphous Sitagliptin

nitrate, which is hygroscopic in nature. Yield: 4.8g.

Table-3.15

Sr.

no. Compound Data

1 17A

HPLC purity: 98.74%; IR (KBr, cm-1

): 1739, 1651, 1622, 1594, 1532,

1448, 1425, 1396, 1385, 1360, 1311, 1241, 1204, 1038, 955, 911, 795. 1HNMR (CDCl3, 300 MHz, δ ppm): 1.74 (s, 6H, 2CH3), 4.33 (s, 2H,

CH2), 7.06 (m, 2H, Ar-H), 15.38 (brs, 1H, OH). MF: C14H11F3O5;

Exact Mass (m/z, 316.23); Observed: (in –ve ion mode) m/z; 315.0

[(M+-H)

-].

2 17B


): 1739, 1664, 1637, 1579, 1499,

1416, 1395, 1384, 1317, 1303, 1293, 1243, 1211, 1151, 1041, 998,

923. 1HNMR (CDCl3, 300 MHz, δ ppm): 1.78 (s, 6H, 2CH3), 4.60 (s,

2H, CH2), 6.87 (m, 1H, Ar-H), 7.12 (m, 1H, Ar-H), 15.62 (brs, 1H,

OH). MF: C14H11F3O5; Exact Mass (m/z, 316.23); Observed: (in –ve

ion mode) m/z; 315.0 [(M+-H)

-].

3 17C


): 1728, 1656, 1583, 1505, 1452,

1426, 1394, 1382, 1353, 1303, 1236, 1207, 1197, 1153, 1125, 1015. 1HNMR (CDCl3, 300 MHz, δ ppm): 1.77 (s, 6H, 2CH3), 4.52 (s, 2H,

CH2), 6.81 (m, 1H, Ar-H), 6.90 (m, 1H, Ar-H), 15.51 (brs, 1H, OH).

MF: C14H11F3O5; Exact Mass (m/z, 316.23); Observed: (in –ve ion

mode) m/z; 315.0 [(M+-H)

-].

4 17D


): 1745, 1732, 1657, 1586, 1516,

1486, 1424, 1397, 1382, 1329, 1297, 1264, 1204, 1049, 1026, 977,


2H, CH2), 6.97 (m, 2H, Ar-H), 15.51 (brs, 1H, OH). MF: C14H11F3O5;


[(M+-H)

-].



Chapter - III

5 17E


): 1731, 1650, 1626, 1608, 1565,

1503, 1445, 1425, 1398, 1383, 1320, 1306, 1203, 1156, 995. 1HNMR

(CDCl3, 300 MHz, δ ppm): 1.78 (s, 6H, 2CH3), 4.53 (s, 2H, CH2), 6.71

(m, 2H, Ar-H), 15.61 (brs, 1H, OH). MF: C14H11F3O5; Exact Mass

(m/z, 316.23); Observed: (in –ve ion mode) m/z; 315.0 [(M+-H)

-].

6 17F


): 1742, 1650, 1587, 1515, 1425,

1396, 1384, 1319, 1306, 1268, 1220, 1159, 1018, 999, 920, 783. 1HNMR (CDCl3, 300 MHz, δ ppm): 1.76 (s, 3H, CH3), 1.82 (s, 3H,

CH3), 4.33 (s, 2H, CH2), 6.86 (m, 2H, Ar-H), 7.15 (m, 1H, Ar-H). MF:

C14H12F2O5; Exact Mass (m/z, 298.07); Observed: (in –ve ion mode)

m/z; 297.1 [(M+-H)

-].

7 17G


): 1742, 1650, 1587, 1515, 1425,


CH2), 7.01 (m, 3H, Ar-H), 15.47 (brs, 1H, OH). MF: C14H12F2O5;


[(M+-H)

-].

8 17H


): 1739, 1649, 1594, 1521, 1437,

1425, 1396, 1385, 1327, 1272, 1204, 1156, 1120, 952, 911. 1HNMR


(m, 2H, Ar-H), 7.23 (m, 1H, Ar-H), 15.36 (brs, 1H, OH). MF:


m/z; 297.1 [(M+-H)

-].

9 17I


): 1732, 1650, 1583, 1496, 1458,

1425, 1398, 1380, 1320, 1303, 1283, 1270, 1232, 1203, 1152. 1HNMR


(m, 2H, Ar-H), 7.28 (m, 2H, Ar-H),15.46 (brs, 1H, OH). MF:

C14H13FO5; Exact Mass (m/z, 280.07); Observed: (in –ve ion mode)

m/z; 279.1 [(M+-H)

-].

10 17J


): 1743, 1651, 1592, 1526, 1489,

1448, 1423, 1394, 1382, 1321, 1304, 1285, 1266, 1208, 1144, 997,


2H, CH2), 6.98 (m, 1H, Ar-H), 7.14 (m, 1H, Ar-H), 7.28 (m, 2H, Ar-

H),15.35 (brs, 1H, OH). MF: C14H13FO5; Exact Mass (m/z, 280.07);

Observed: (in –ve ion mode) m/z; 279.1 [(M+-H)

-].

11 17K


): 1742, 1650, 1587, 1515, 1425,

1384, 1319, 1305, 1268, 1220, 1159, 1018, 999, 795. 1HNMR (CDCl3,

300 MHz, δ ppm): 1.72 (s, 6H, 2CH3), 4.38 (s, 2H, CH2), 7.02 (m, 2H,

Ar-H), 7.36 (m, 2H, Ar-H),15.34 (brs, 1H, OH). MF: C14H13FO5; Exact

Mass (m/z, 280.07); Observed: (in –ve ion mode) m/z; 279.1 [(M+-H)

-].

12 17L


): 1745, 1704, 1651, 1591, 1499,


CH2), 7.34 (m, 5H, Ar-H), 15.33 (brs, 1H, OH). MF: C14H14O5; Exact


-].



Chapter - III

Table-3.16

Sr.

no. Compound Data

1 20A


): 3422, 3246, 2934, 2687, 1733,

1708, 1622, 1593, 1533, 1450, 1388, 1352, 1304, 1233, 1201, 1054,

1015, 844. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.46 (m, 2H, CH2),

2.70 (m, 2H, CH2), 4.19 (m, 1H, CH), 6.48 (brs, 2H, OH), 6.84 (m, 2H,

Ar-H). MF: C10H9F3O3; Exact Mass (m/z, 234.14); Observed: (in –ve

ion mode) m/z; 233.0 [(M+-H)

-].

2 20B

HPLC purity: 100%; IR (KBr, cm-1

): 3333, 3250, 3088, 2972, 2943,

1717, 1640, 1612, 1531, 1495, 1462, 1448, 1403, 1353, 1305, 1243,

1217, 1086, 1054, 802. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.35 (m,

2H, CH2), 2.81 (m, 2H, CH2), 4.19 (m, 1H, CH), 6.77 (brs, 2H, OH),

6.97 (m, 2H, Ar-H). MF: C10H9F3O3; Exact Mass (m/z, 234.14);


-].

3 20C


): 3436, 2930, 1636, 1576, 1531,

1496, 1404, 1354, 1304, 1243, 1164, 1118, 1054, 1020, 854. 1HNMR

(CDCl3, 300 MHz, δ ppm): 2.58 (m, 2H, CH2), 2.87 (m, 2H, CH2), 4.30

(m, 1H, CH), 6.58 (brs, 2H, OH), 6.82 (m, 2H, Ar-H). MF: C10H9F3O3;


[(M+-H)

-].

4 20D


): 3381, 3083, 2936, 1712, 1638,

1617, 1513, 1486, 1410, 1308, 1261, 1200, 1156, 1058, 1010, 967,

811. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.55 (m, 2H, CH2), 2.86 (m,

2H, CH2), 4.27 (m, 1H, CH), 5.58 (brs, 2H, OH), 6.93 (m, 2H, Ar-H).

MF: C10H9F3O3; Exact Mass (m/z, 234.14); Observed: (in –ve ion

mode) m/z; 233.1 [(M+-H)

-].

5 20E


): 3413, 3196, 3111, 3010, 2930,

1717, 1644, 1610, 1502, 1440, 1399, 1346, 1315, 1291, 1256, 1160,

1119, 1083, 1063, 999, 983, 836. 1HNMR (CDCl3, 300 MHz, δ ppm):

2.35 (m, 2H, CH2), 2.75 (m, 2H, CH2), 4.16 (m, 1H, CH), 6.48 (brs,

2H, OH), 6.62 (m, 2H, Ar-H). MF: C10H9F3O3; Exact Mass (m/z,

234.14); Observed: (in –ve ion mode) m/z; 232.9 [(M+-H)

-].

6 20F


): 3377, 3083, 2937, 1717, 1620,

1604, 1506, 1427, 1276, 1186, 1157, 1138, 1097, 1052, 965, 851. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.52 (m, 2H, CH2), 2.81 (m, 2H,

CH2), 4.26 (m, 1H, CH), 6.48 (brs, 2H, OH), 6.82 (m, 2H, Ar-H), 7.21

(m, 1H, Ar-H). MF: C10H10F2O3; Exact Mass (m/z, 216.06); Observed:

(in –ve ion mode) m/z; 215.0 [(M+-H)

-].

7 20G


): 3219, 2930, 2672, 1709, 1496,

1434, 1387, 1293, 1212, 1191, 1098, 1055, 1019, 959, 856. 1HNMR


(m, 1H, CH), 6.28 (brs, 2H, OH), 6.96 (m, 3H, Ar-H). MF:


m/z; 215.1 [(M+-H)

-].



Chapter - III

8 20H


): 3427, 3308, 3058, 2968, 2945,

2674, 1709, 1516, 1434, 1413, 1336, 1288, 1276, 1205, 1173, 1158,

1113, 1087, 1078, 1022, 950, 882. 1HNMR (CDCl3, 300 MHz, δ ppm):

2.54 (m, 2H, CH2), 2.78 (m, 2H, CH2), 4.24 (m, 1H, CH), 4.95 (brs,

1H, OH), 6.94 (m, 1H, Ar-H), 7.07 (m, 2H, Ar-H). MF: C10H10F2O3;


[(M+-H)

-].

9 20I


): 3214, 3045, 2974, 2929, 2868,

2658, 2549, 1692, 1585, 1492, 1458, 1429, 1411, 1354, 1313, 1299,

1282, 1233, 1161, 1075, 1060, 863. 1HNMR (CDCl3, 300 MHz, δ

ppm): 2.55 (m, 2H, CH2), 2.87 (m, 2H, CH2), 4.31 (m, 1H, CH), 6.26

(brs, 1H, OH), 7.06 (m, 2H, Ar-H), 7.21 (m, 2H, Ar-H). MF:


m/z; 197.0 [(M+-H)

-].

10 20J


): 3233, 3082, 2931, 2869, 2660,

2554, 1691, 1615, 1588, 1488, 1451, 1428, 1409, 1304, 1288, 1274,

1247, 1141, 1076, 1059, 1015, 889. 1HNMR (CDCl3, 300 MHz, δ

ppm): 2.52 (m, 2H, CH2), 2.81 (m, 2H, CH2), 4.26 (m, 1H, CH), 6.82

(brs, 1H, OH), 6.95 (m, 3H, Ar-H), 7.26 (m, 1H, Ar-H). MF:


m/z; 197.0 [(M+-H)

-].

11 20K


): 3246, 3040, 2985, 2947, 2868,

2658, 2559, 1694, 1600, 1512, 1451, 1429, 1416, 1313, 1301, 1293,

1275, 1225, 1200, 1158, 1098, 1078, 1058, 831. 1HNMR (CDCl3, 300

MHz, δ ppm): 2.51 (m, 2H, CH2), 2.79 (m, 2H, CH2), 4.23 (m, 1H,

CH), 6.81 (brs, 1H, OH), 6.99 (m, 2H, Ar-H), 7.17 (m, 2H, Ar-H).

MF: C10H11FO3; Exact Mass (m/z, 198.07); Observed: (in –ve ion

mode) m/z; 197.2 [(M+-H)

-].

12 20L


): 3219, 3083, 3026, 3003, 2973,

2942, 2866, 2655, 2541, 1688, 1604, 1493, 1457, 1427, 1407, 1305,

1294, 1278, 1202, 1153, 1055, 1011, 889. 1HNMR (CDCl3, 300 MHz,

δ ppm): 2.51 (m, 2H, CH2), 2.79 (m, 2H, CH2), 4.26 (m, 1H, CH), 7.15

(brs, 1H, OH), 7.25 (m, 5H, Ar-H). MF: C10H12O3; Exact Mass (m/z,

180.08); Observed: (in –ve ion mode) m/z; 178.9 [(M+-H)

-].



Chapter - III

Table-3.17

Sr.

no. Compound Data

1 22A


): 3328, 3160, 2928, 2850, 1627,

1575, 1532, 1448, 1437, 1346, 1311, 1244, 1232, 1186, 1088, 1047,


3.46 (m, 2H, CH2), 4.16 (m, 1H, CH), 4.94 (m, 2H, CH2), 6.83 (m, 2H,

Ar-H), 7.39 (m, 5H, Ar-H), 8.12 & 8.89 (brs, 1H, CONH). MF:

C17H16F3NO3; Exact Mass (m/z, 339.11); Observed: (in –ve ion mode)

m/z; 338.0 [(M+-H)

-].

2 22B


): 3328, 3183, 2928, 2850, 1657,

1627, 1575, 1534, 1490, 1436, 1311, 1243, 1087, 1069, 932. 1HNMR


(m, 1H, CH), 4.92 (m, 2H, CH2), 6.81 (t, 1H, Ar-H), 7.03 (m, 1H, Ar-

H), 7.38 (m, 5H, Ar-H), 8.00 & 8.51 (brs, 1H, CONH). MF:


m/z; 338.1 [(M+-H)

-].

3 22C


): 3327, 2929, 2851, 1627, 1574,

1535, 1499, 1449, 1437, 1312, 1271, 1244, 1230, 1088, 892. 1HNMR

(CDCl3, 300 MHz, δ ppm): 2.83 (d, 2H, CH2), 3.61 (m, 2H, CH2), 4.18

(m, 1H, CH), 4.92 (m, 2H, CH2), 6.80 (m, 2H, Ar-H), 7.39 (m, 5H, Ar-

H), 8.18 & 8.74 (brs, 1H, CONH). MF: C17H16F3NO3; Exact Mass


-].

4 22D


): 3327, 3256, 2931, 2852, 1660,

1628, 1573, 1512, 1483, 1437, 1347, 1308, 1244, 1154, 1088, 1057,

1029, 961, 892. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.80 (d, 2H, CH2),

3.61 (m, 2H, CH2), 4.19 (m, 1H, CH), 4.99 (m, 2H, CH2), 6.92 (m, 2H,



m/z; 338.0 [(M+-H)

-].

5 22E


): 3328, 3182, 2928, 2851, 1655,

1627, 1574, 1536, 1499, 1448, 1437, 1311, 1244, 1230, 1160, 1088,


3.61 (m, 2H, CH2), 4.19 (m, 1H, CH), 4.92 (m, 2H, CH2), 6.66 (t, 2H,



m/z; 338.1 [(M+-H)

-].

6 22F


): 3326, 3237, 2927, 2851, 1655,

1627, 1604, 1574, 1524, 1506, 1454, 1369, 1273, 1139, 1098, 1082,

1047, 965, 855. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.78 (d, 2H, CH2),

3.46 (m, 2H, CH2), 4.19 (m, 1H, CH), 4.92 (m, 2H, CH2), 6.79 (m, 2H,

Ar-H), 7.17 (m, 1H, Ar-H), 7.37 (m, 5H, Ar-H), 8.20 & 8.82 (brs, 1H,

CONH). MF: C17H17F2NO3; Exact Mass (m/z, 321.12); Observed: (in

–ve ion mode) m/z; 320.0 [(M+-H)

-].

7 22G HPLC purity: 95.73%; IR (KBr, cm-1

): 3325, 3257, 3140, 2932, 2851,

1650, 1628, 1576, 1535, 1494, 1456, 1426, 1312, 1209, 1190, 1069,



Chapter - III

1056, 1011, 822. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.78 (d, 2H,

CH2), 3.59 (m, 2H, CH2), 4.23 (m, 1H, CH), 4.90 (m, 2H, CH2), 6.91

(m, 3H, Ar-H), 7.37 (m, 5H, Ar-H), 8.29 & 8.82 (brs, 1H, CONH).

MF: C17H17F2NO3; Exact Mass (m/z, 321.12); Observed: (in –ve ion

mode) m/z; 320.3 [(M+-H)

-].

8 22H


): 3325, 3258, 3140, 3068, 3031,

2932, 2851, 1650, 1628, 1576, 1535, 1494, 1456, 1439, 1426, 1312,

1270, 1209, 1190, 1140, 1098, 1069, 1012, 878. 1HNMR (CDCl3, 300

MHz, δ ppm): 2.71 (d, 2H, CH2), 3.42 (m, 2H, CH2), 4.16 (m, 1H, CH),

4.91 (m, 2H, CH2), 6.89 (m, 1H, Ar-H), 7.05 (m, 2H, Ar-H), 7.38 (m,

5H, Ar-H), 8.13 & 8.63 (brs, 1H, CONH). MF: C17H17F2NO3; Exact


-].

9 22I


): 3327, 3250, 2929, 2851, 1650,

1627, 1575, 1535, 1490, 1438, 1312, 1245, 1228, 1108, 1088, 1069,

1055, 893. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.83 (d, 2H, CH2), 3.46

(m, 2H, CH2), 4.23 (m, 1H, CH), 4.91 (m, 2H, CH2), 7.06 (m, 2H, Ar-

H), 7.21 (m, 2H, Ar-H), 7.38 (m, 5H, Ar-H), 8.09 & 8.61 (brs, 1H,

CONH). MF: C17H18FNO3; Exact Mass (m/z, 303.13); Observed: (in –

ve ion mode) m/z; 302.1 [(M+-H)

-].

10 22J


): 3327, 3135, 2929, 2850, 1656,

1627, 1576, 1536, 1487, 1448, 1436, 1311, 1245, 1231, 1087, 1069,

1013, 977, 892. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.76 (m, 2H,

CH2), 3.45 (m, 2H, CH2), 4.19 (m, 1H, CH), 4.91 (m, 2H, CH2), 6.93

(m, 3H, Ar-H), 7.22 (m, 1H, Ar-H), 7.38 (m, 5H, Ar-H), 8.10 & 8.74

(brs, 1H, CONH). MF: C17H18FNO3; Exact Mass (m/z, 303.13);


-].

11 22K


): 3327, 3245, 2927, 2851, 1663,

1627, 1575, 1509, 1436, 1381, 1312, 1244, 1218, 1161, 1101, 1086,


CH2), 3.25 (m, 1H, CH2), 3.44 (m, 1H, CH2), 4.18 (m, 1H, CH), 4.91

(m, 2H, CH2), 6.98 (t, 2H, Ar-H), 7.12 (t, 2H, Ar-H), 7.37 (m, 5H, Ar-

H), 8.09 & 8.75 (brs, 1H, CONH). MF: C17H18FNO3; Exact Mass


-].

12 22L


): 3327, 3245, 2927, 2851, 1663,

1627, 1575, 1509, 1436, 1381, 1312, 1244, 1218, 1161, 1101, 1086,


CH2), 3.18 (m, 1H, CH2), 3.46 (m, 1H, CH2), 4.22 (m, 1H, CH), 4.73-

4.95 (m, 2H, CH2), 7.26 (m, 5H, Ar-H), 7.37 (m, 5H, Ar-H), 8.09 &

8.77 (brs, 1H, CONH). MF: C17H19NO3; Exact Mass (m/z, 285.14);


-].



Chapter - III

Table-3.18

Sr.

no. Compound Data

1 23A


): 3317, 2984, 2957, 2937, 2879,

1732, 1621, 1530, 1479, 1468, 1461, 1454, 1387, 1382, 1376, 1362,

1352, 1332, 1322, 1312, 1265, 1181, 1146, 1107, 1044. 1HNMR

(CDCl3, 300 MHz, δ ppm): 2.39-2.44 (dd, 1H, CH2), 2.65-2.70 (dd,

1H, CH2), 2.70-2.74 (dd, 1H, CH2), 2.88-2.90 (dd, 1H, CH2), 3.62 (m,

1H, CH), 5.06 (m, 2H, CH2), 6.68 (m, 2H, Ar-H), 7.33 (m, 5H, Ar-H).

MF: C17H14F3NO2; Exact Mass (m/z, 321.1); Observed: (in +ve ion

mode) m/z; 322.1 [(MH)+].

2 23B

HPLC purity: 33.14%; 1HNMR (CDCl3, 300 MHz, δ ppm): 2.39-2.44

(dd, 1H, CH2), 2.65-2.70 (dd, 1H, CH2), 2.70-2.74 (dd, 1H, CH2), 2.88-

2.90 (dd, 1H, CH2), 3.62 (m, 1H, CH), 5.06 (m, 2H, CH2), 6.82 (m, 1H,

Ar-H), 7.12 (m, 1H, Ar-H), 7.33 (m, 5H, Ar-H). MF: C17H14F3NO2;

Exact Mass (m/z, 321.1); Observed: (in +ve ion mode) m/z; 322.1

[(MH)+].

3 23C


): 3313, 3067, 3034, 2984, 2956,

2938, 2879, 1773, 1637, 1606, 1500, 1476, 1468, 1463, 1455, 1421,

1376, 1362, 1348, 1314, 1265, 1190, 1181, 1146, 1125, 1118, 1097,

1044, 998, 984. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.33-2.39 (dd, 1H,

CH2), 2.67-2.70 (dd, 1H, CH2), 2.70-2.75 (dd, 1H, CH2), 2.88-2.90 (dd,

1H, CH2), 3.62 (m, 1H, CH), 5.06 (m, 2H, CH2), 6.60 (m, 1H, Ar-H),

6.81 (m, 1H, Ar-H), 7.36 (m, 5H, Ar-H). MF: C17H14F3NO2; Exact

Mass (m/z, 321.1); Observed: (in +ve ion mode) m/z; 322.1 [(MH)+].

4 23D


): 3292, 3071, 3033, 3018, 2983,

2967, 2936, 2889, 1764, 1653, 1637, 1624, 1618, 1512, 1499, 1488,

1472, 1469, 1461, 1456, 1376, 1307, 1291, 1261, 1183, 1109, 1045,

1022, 966. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.31-2.36 (dd, 1H,

CH2), 2.65-2.69 (dd, 1H, CH2), 2.69-2.73 (dd, 1H, CH2), 2.88-2.93 (dd,

1H, CH2), 3.64 (m, 1H, CH), 4.98 (m, 2H, CH2), 6.87 (m, 2H, Ar-H),

7.37 (m, 5H, Ar-H). MF: C17H14F3NO2; Exact Mass (m/z, 321.1);

Observed: (in +ve ion mode) m/z; 322.1 [(MH)+].

5 23E


): 3322, 3033, 3021, 2984, 2960,

2936, 2856, 1766, 1643, 1638, 1625, 1617, 1609, 1513, 1509, 1498,

1479, 1468, 1461, 1454, 1417, 1387, 1382, 1376, 1361, 1351, 1331,

1265, 1181, 1146, 1097, 1067, 1041, 999, 913. 1HNMR (CDCl3, 300

MHz, δ ppm): 2.39-2.44 (dd, 1H, CH2), 2.65-2.70 (dd, 1H, CH2), 2.70-

2.74 (dd, 1H, CH2), 2.88-2.90 (dd, 1H, CH2), 3.62 (m, 1H, CH), 5.06

(m, 2H, CH2), 6.64 (m, 2H, Ar-H), 7.33 (m, 5H, Ar-H). MF:

C17H14F3NO2; Exact Mass (m/z, 321.1); Observed: (in +ve ion mode)

m/z; 322.1 [(MH)+].

6 23F


): 1773, 1760, 1751, 1616, 1610,

1603, 1505, 1425, 1374, 1275, 1266, 1262, 1187, 1139, 1124, 1047,

1033, 968. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.32-2.37 (dd, 1H,

CH2), 2.63-2.67 (dd, 1H, CH2), 2.67-2.70 (dd, 1H, CH2), 2.89-2.95 (dd,

1H, CH2), 3.67 (m, 1H, CH), 4.92 (s, 2H, CH2), 6.79 (m, 2H, Ar-H),



Chapter - III

7.07 (m, 1H, Ar-H), 7.36 (m, 5H, Ar-H). MF: C17H15F2NO2; Exact

Mass (m/z, 303.11); Observed: (in +ve ion mode) m/z; 304.1 [(MH)+].

7 23G


): 1770, 1719, 1716, 1625, 1596,

1496, 1474, 1464, 1456, 1442, 1425, 1374, 1282, 1225, 1217, 1206,

1193, 1183, 1179, 1139, 1116, 1088, 1046, 1036. 1HNMR (CDCl3, 300

MHz, δ ppm): 2.35-2.40 (dd, 1H, CH2), 2.61-2.68 (dd, 1H, CH2), 2.66-

2.73 (dd, 1H, CH2), 2.88-2.95 (dd, 1H, CH2), 3.67 (m, 1H, CH), 4.93

(s, 2H, CH2), 6.79 (m, 1H, Ar-H), 6.94 (m, 2H, Ar-H), 7.36 (m, 5H, Ar-

H). MF: C17H15F2NO2; Exact Mass (m/z, 303.11); Observed: (in +ve

ion mode) m/z; 304.1 [(MH)+].

8 23H


): 1770, 1663, 1626, 1617, 1609,

1593, 1576, 1550, 1519, 1475, 1467, 1463, 1455, 1453, 1435, 1374,

1284, 1245, 1213, 1140, 1125, 1111. 1HNMR (CDCl3, 300 MHz, δ

ppm): 2.28-2.33 (dd, 1H, CH2), 2.61-2.66 (dd, 1H, CH2), 2.64-2.70

(dd, 1H, CH2), 2.78-2.85 (dd, 1H, CH2), 3.61 (m, 1H, CH), 4.91 (s, 2H,

CH2), 6.79 (m, 1H, Ar-H), 6.87 (m, 1H, Ar-H), 7.06 (m, 1H, Ar-H),

7.38 (m, 5H, Ar-H). MF: C17H15F2NO2; Exact Mass (m/z, 303.11);


9 23I


): 1772, 1759, 1753, 1584, 1493,

1469, 1455, 1441, 1375, 1278, 1233, 1184, 1108, 1090, 1047, 915. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.36-2.42 (dd, 1H, CH2), 2.64-

2.69 (dd, 1H, CH2), 2.65-2.73 (dd, 1H, CH2), 2.95-2.99 (dd, 1H, CH2),

3.72 (m, 1H, CH), 4.92 (s, 2H, CH2), 7.07 (m, 3H, Ar-H), 7.22 (m, 1H,

Ar-H), 7.37 (m, 5H, Ar-H). MF: C17H16FNO2; Exact Mass (m/z,

285.12); Observed: (in +ve ion mode) m/z; 286.1 [(MH)+].

10 23J


): 1772, 1759, 1753, 1584, 1493,

1469, 1455, 1441, 1375, 1278, 1233, 1184, 1108, 1090, 1047, 915. 1HNMR (CDCl3, 300 MHz, δ ppm): 2.36-2.42 (dd, 1H, CH2), 2.64-

2.69 (dd, 1H, CH2), 2.65-2.73 (dd, 1H, CH2), 2.95-2.99 (dd, 1H, CH2),

3.67(m, 1H, CH), 4.92 (s, 2H, CH2), 7.07 (m, 3H, Ar-H), 7.22 (m, 1H,

Ar-H), 7.37 (m, 5H, Ar-H). MF: C17H16FNO2; Exact Mass (m/z,


11 23K


): 1774, 1759, 1752, 1626, 1600,

1576, 1508, 1436, 1375, 1367, 1279, 1233, 1184, 1108, 1090, 1047,

915 . 1HNMR (CDCl3, 300 MHz, δ ppm): 2.30-2.35 (dd, 1H, CH2),

2.62-2.65 (dd, 1H, CH2), 2.64-2.70 (dd, 1H, CH2), 2.83-2.87 (dd, 1H,

CH2), 3.65(m, 1H, CH), 4.91 (s, 2H, CH2), 6.94-7.07 (m, 4H, Ar-H),

7.38 (m, 5H, Ar-H). MF: C17H16FNO2; Exact Mass (m/z, 285.12);


12 23L


): 1774, 1759, 1752, 1626, 1600,

1576, 1508, 1436, 1375, 1367, 1279, 1233, 1184, 1108, 1090, 1047,

915 . 1HNMR (CDCl3, 300 MHz, δ ppm): 2.30-2.35 (dd, 1H, CH2),

2.62-2.65 (dd, 1H, CH2), 2.64-2.70 (dd, 1H, CH2), 2.83-2.87 (dd, 1H,

CH2), 3.68(m, 1H, CH), 4.70 (s, 2H, CH2), 7.23-7.37 (m, 10H, Ar-H).

MF: C17H17NO2; Exact Mass (m/z, 267.13); Observed: (in +ve ion

mode) m/z; 268.1 [(MH)+].



Chapter - III

Table-3.19

Sr.

no. Compound Data

1 1A

HPLC purity: 96.92%; 1HNMR (CDCl3, 300 MHz, δ ppm): 2.47 (m,

2H, CH2), 2.60 (dd, 1H, CH2), 2.77 (dd, 1H, CH2), 3.58 (m, 1H, CH),

3.96-4.22 (m, 4H, 2CH2), 4.94-5.15 (m, 2H, CH2), 6.86 (t, 2H, Ar-H).

MF: C16H15F6N5O; Exact Mass (m/z, 407.12); Observed: (in +ve ion

mode) m/z; 408.1 [(MH)+].

2 1B


): 3380, 3310, 1637, 1603, 1492,

1463, 1440, 1370, 1355, 1341, 1324, 1299, 1286, 1261, 1241, 1213,

1184, 1162, 1142, 1132, 1089, 1015, 943. 1HNMR (CDCl3, 300 MHz,

δ ppm): 2.53 (m, 2H, CH2), 2.87 (m, 2H, CH2), 3.64 (m, 1H, CH2),

3.96-4.23 (m, 4H, 2CH2), 4.93-5.08 (m, 2H, CH2), 6.85 (m, 1H, Ar-H),

7.04 (m, 1H, Ar-H). MF: C16H15F6N5O; Exact Mass (m/z, 407.12);


3 1C


(m, 2H, CH2), 2.73-2.91 (2dd, 2H, CH2), 3.63 (m, 1H, CH), 3.96-4.22

(m, 4H, 2CH2), 4.94-5.14 (m, 2H, CH2), 6.79 (m, 1H, Ar-H), 6.85 (m,

1H, Ar-H). MF: C16H15F6N5O; Exact Mass (m/z, 407.12); Observed:

(in +ve ion mode) m/z; 408.1 [(MH)+].

4 1D


(m, 2H, CH2), 2.65-2.85 (m, 2H, CH2), 3.60 (m, 1H, CH), 3.92-4.32 (m,

4H, 2CH2), 4.94-5.11 (m, 2H, CH2), 6.95 (m, 2H, Ar-H). MF:

C16H15F6N5O; Exact Mass (m/z, 407.12); Observed: (in +ve ion mode)

m/z; 408.1 [(MH)+].

5 1E

HPLC purity: 80.57%; 1HNMR (CDCl3, 300 MHz, δ ppm): 2.51 (m,

2H, CH2), 2.79 (m, 2H, CH2), 3.59 (m, 1H, CH), 4.11-4.27 (m, 4H,

2CH2), 4.93 (m, 2H, CH2), 6.67 (t, 2H, Ar-H). MF: C16H15F6N5O;

Exact Mass (m/z, 407.12); Observed: (in +ve ion mode) m/z; 408.1

[(MH)+].

6 1F


(m, 2H, CH2), 2.69-2.86 (m, 2H, CH2), 3.61 (m, 1H, CH), 3.94-4.16 (m,

4H, 2CH2), 4.92-5.08 (m, 2H, CH2), 6.82 (m, 2H, Ar-H), 7.18 (m, 1H,

Ar-H). MF: C16H16F5N5O; Exact Mass (m/z, 389.13); Observed: (in

+ve ion mode) m/z; 390.1 [(MH)+].

7 1G


): 1646, 1494, 1433, 1342, 1289,

1249, 1237, 1214, 1189, 1161, 1147, 1088, 1015, 943, 862. 1HNMR

(CDCl3, 300 MHz, δ ppm): 2.40-2.57 (m, 2H, CH2), 2.69-2.86 (m, 2H,

CH2), 3.61 (m, 1H, CH), 3.94-4.16 (m, 4H, 2CH2), 4.92-5.08 (m, 2H,

CH2), 6.96 (m, 3H, Ar-H). MF: C16H16F5N5O; Exact Mass (m/z,


8 1H


(m, 2H, CH2), 2.59-2.79 (m, 2H, CH2), 3.59 (m, 1H, CH), 3.94-4.19 (m,

4H, 2CH2), 4.93-5.10 (m, 2H, CH2), 6.94 (m, 1H, Ar-H), 7.06 (m, 2H,




Chapter - III

+ve ion mode) m/z; 390.1 [(MH)+].

9 1I


(m, 2H, CH2), 2.62-2.79 (m, 2H, CH2), 3.58 (m, 1H, CH), 3.92-4.18 (m,

4H, 2CH2), 4.92-5.09 (m, 2H, CH2), 7.07 (m, 2H, Ar-H), 7.22 (m, 2H,


+ve ion mode) m/z; 372.2 [(MH)+].

10 1J


(m, 2H, CH2), 2.62-2.79 (m, 2H, CH2), 3.58 (m, 1H, CH), 3.92-4.18 (m,

4H, 2CH2), 4.92-5.09 (m, 2H, CH2), 6.92 (m, 2H, Ar-H), 6.98 (m, 1H,

Ar-H), 7.27 (m, 1H, Ar-H). MF: C16H17F4N5O; Exact Mass (m/z,


11 1K


(m, 2H, CH2), 2.62-2.79 (m, 2H, CH2), 3.58 (m, 1H, CH), 3.92-4.18 (m,

4H, 2CH2), 4.92-5.09 (m, 2H, CH2), 7.00 (t, 2H, Ar-H), 7.17 (t, 2H,


+ve ion mode) m/z; 372.2 [(MH)+].

12 1L


(m, 2H, CH2), 2.62-2.79 (m, 2H, CH2), 3.58 (m, 1H, CH), 3.92-4.18 (m,

4H, 2CH2), 4.92-5.09 (m, 2H, CH2), 7.19-7.34 (m, 5H, Ar-H). MF:

C16H18F3N5O; Exact Mass (m/z, 353.15); Observed: (in +ve ion mode)

m/z; 354.1 [(MH)+].



Chapter - III

SPECTRA:

…..1H NMR AND MASS SPECTRUM OF COMPOUND 66

…..1H NMR SPECTRUM OF COMPOUND 70



Chapter - III

…..MASS SPECTRUM OF COMPOUND 70




Chapter - III





Chapter - III





Chapter - III





Chapter - III





Chapter - III

….. MASS SPECTRUM OF COMPOUND 13




Chapter - III


….. 1H NMR SPECTRUM OF COMPOUND 18



Chapter - III

…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 19



Chapter - III




Chapter - III




Chapter - III


….. 1H NMR SPECTRUM OF COMPOUND 22



Chapter - III

….. MASS SPECTRUM OF COMPOUND 22

…..IR AND 1H NMR SPECTRUM OF COMPOUND 23



Chapter - III


…..IR AND 1H NMR SPECTRUM OF COMPOUND 24



Chapter - III





Chapter - III


…..IR SPECTRUM OF COMPOUND 90



Chapter - III





Chapter - III





Chapter - III




Chapter - III

…..IR, 1H NMR AND MASS SPECTRUM OF COMPOUND 1B



Chapter - III

…..1H NMR SPECTRUM OF COMPOUND 1A, 1E AND 1C



Chapter - III

…..1H NMR SPECTRUM OF COMPOUND 1D

…..IR AND 1H NMR SPECTRUM OF COMPOUND 1G



Chapter - III

….. 1H NMR SPECTRUM OF COMPOUND 1H

…..1H NMR AND MASS SPECTRUM OF COMPOUND 1F



Chapter - III

…..1H NMR AND MASS SPECTRUM OF COMPOUND 1K

…..1H NMR SPECTRUM OF COMPOUND 1J



Chapter - III

…..1H NMR SPECTRUM OF COMPOUND 1I

…..1H NMR AND MASS SPECTRUM OF COMPOUND 1L



Chapter - III

REFERENCES:

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Studies on the synthesis of anti-diabetic drug, …shodhganga.inflibnet.ac.in/bitstream/10603/101297/12/12...MD. UMAR KHAN Thesis Studies on the synthesis of anti-diabetic drug, Sitagliptin

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