1 Green Chemistry Innovation in the Synthesis of Medicines 198 th OMICS Group Conference International Summit on Past and Present Research Systems of Green Chemistry August 25-27, 2014 Hilton Philadelphia Airport, USA Life Research Hope Rakeshwar Bandichhor Ph.D. Director, API-R&D, Innovation Plaza IPDO, Dr. Reddy’s Laboratories, Hyderabad India http://www.drreddys.com/products/green-chemistry.html (Green Chemistry Website) Nature Medicine 2013, 19, 1200-1203 (Finding Right Chemistry)
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1
Green Chemistry Innovation in the Synthesis
of Medicines
198th OMICS Group Conference International Summit on Past and Present Research Systems
of Green Chemistry August 25-27, 2014
Hilton Philadelphia Airport, USA
Life Research Hope
Rakeshwar Bandichhor Ph.D.
Director, API-R&D, Innovation Plaza IPDO, Dr. Reddy’s Laboratories, Hyderabad
•Whatever you hear, see, smell, taste, and touch involves chemistry and chemicals (matter). •And all these processes involve intricate series of chemical reactions and interactions in the biological system. • With such an enormous range of biological actions which are governed by chemistry therefore it is essential to know about this subject at some level in order to understand the world around us.
>200 >1000 >7000 Chemicals
Green Tea Coffee Cigarette
Value added
products from nature
Understanding of life processes and
chemical matter at molecular level
Resource stressed planet
NN
NO
O
O H
H
HN
NN
N
N
N
HH
H
H
HH
N
NN
O
O
O
H
H
H
NN
NN
N
N
HH
HH
H
HN
N
NO
O
O
H
H
H
NN
NN
N
N
H
H
HH
HH
Utility Science Core and Integrative Science Sustainability Science
Evolving Path of Chemistry
3
Significance of Chemistry
Life Research Hope
Chemistry Signifies Love and Hate Relationship -can’t live without it but can’t accept everything that it has
-To quote Linus Pauling, Nobel Laureate in chemistry, from a 1983 UC Berkeley lecture: Chemistry is wonderful! I feel sorry for people who don't know anything about chemistry. They are missing an important source of happiness -- that of satisfying one's intellectual curiosity. The world is wonderful. Chemistry is an important part of it.
4
Green Chemistry
Life Research Hope
•Evolving discipline it does mean that the definition of green may change tomorrow e.g. Grignard reaction was considered to be one of the best reactions but today it is being replaced with greener metal catalyzed transformations.
•It is a subject that deals with prevention of waste in any activity around us by design.
Understanding the Pivotal Role of Organic Chemistry in Addressing the Challenges
10
Approaches
Life Research Hope
1. Consideration of GC (TP and GM) in design phase 2. Minimize the number of steps while maintaining the desired cost
component intact 3. Minimize or replace (Switch) non-green solvents 4. Work through multi-disciplinary scientific interface (Collaboration) 5. Renewable material based synthesis 6. Net output based energy efficient waste (unavoidable) management 7. Non-toxic and hazard free practices 8. Continuous mode of Chemistry/Engineering (flow technology) 9. In-expensive catalyst based transformations 10. Opt for asymmetric transformations 11. Use of immobilized recombinant enzymes for transformations with
very low dilutions 12. Educate and prepare young generation considering intuitive
knowledge potential to take a lead in this field
11
Approaches: Flow Technology
Life Research Hope
• Conventional method • Several Disadvantages
- Time and labor intensive - A number of unit processes - Needs extensive optimization
• Emerging Technology • Advantages over batch process - High surface area, precisely
controlled conditions - Rapid screening of reaction
conditions - “Scale-out” instead of “Scale-up” - Safety
Medium Size: Enantioselective Grignard Addition to Nitroolefin
Life Research Hope
CuI/TC
R2MgX
R1
NCuR2
L
L
O
OMgBr
SCO2
R1
N OO
R1
R2
NO
OMg
Br
H2O
R1
R2
NO2
I /
L
LR2Cu
L
L
Fe
PCy2Ph2P
=
CuPCy2Ph2P
NOMg
Br
H
R2
O
TS,
R1
R (major)
I
(S)(Rp)
Catalytic Cycle and Mechanistic Consideration
32
Medium Size: Enantioselective Grignard Addition to Nitroolefin
Life Research Hope
33
Medium Size: Regioselective Methylation
Life Research Hope
Sudhakar, Tetrahedron Lett., 2013, 54, 1661-1663
NH
NN
NR R
R1R1
CF3SO3H
O CCl3
NH
34
Medium Size: Regioselective Methylation
Life Research Hope
NH
NN
N
1 2
O2N O2N
N-2 product
NN
O2N
N-1 product3
2H-indazole 1H-indazole
"Mesource" +
Different Methods
Basic condition: No selectivity Acidic condition: N-1 (thermodynamic); N-2 (kinetic)
Trimethyloxonium tetrafluoroborate (Meerwein’s reagent) is considered to be the best reagent for regioselective methylation
35
Medium Size: Regioselective Methylation
Life Research Hope
Generality of the Methods
N
HN
NN
R R
N-2 productR= NO2, CO2Me, Cl, I, H, OMeR1= H,Me
NN
O2N NN
NO2
NN
O2N
NN
O2NN
N
NO2N
NMeO2C
NN
Cl NN
IN
N
NN
MeO
NN
MeO
87% 96% 97%
95% 94% 87%
85% 83% 79%
90% 78%
5a 5b 5c
5d 5e 5f
5g 5h 5i
5j 5k
1.0 eq. CF3SO3H
5 (a-k)
2.5 eq.CCl3CNHOMe
7 (a-k)
R1 R1
NN
O2N
N
N
NH
N NN
SNH2
O OHCl
4 5a
NH
NO2N
6
This reagent is suitable to both EWG and EDG containing substrates
36
Process Innovation: Grignard Reaction
Life Research Hope
ONC
F
N
HBr
1
NC
F
OH
OHN
HBr
2
OBr
O F
MgBrBr
F
OHO
Cl NCH3
CH3
Br
F
OHOH
Br
F
ONC
F
O
LiAlH4 or NaBH4
H3PO4 or TsOH orH2SO4
DMF,140°CNaH, DMSO
+
3 4 5 6
78
9
1
100 °C
10°C to 25°C
Ether, THF
Cu2(CN)2
First reported synthesis of Citalopram 1
37
Process Innovation: Grignard Reaction
Life Research Hope
Strategies for Process Improvements
1. Can we freshly prepare GR and use it in situ? 2. Can we avoid the use of LAH or Sodium borohydride reagent? 3. Can we avoid Copper cyanide? 4. Can we avoid NaH during alkylation? 5. Can we do most of the transformations at room temperature or
at least can we avoid higher temperature (>100 0C) ? 6. Is it possible to telescope this process to all possible extent? 7. ……………….etc
38
Process Innovation: Grignard Reaction
Life Research Hope
Outline Towards Realizing the Strategies : One Pot Synthesis of Diol HBr
NCO
O F
MgBrNC
F
OMgBr
O
F Br
+
ClMg N Cl N. HCl
NC
F
OH
OHN
NC
F
N HBr
Crude Citalopram HBr
HBr
Diol HBr2
10 4
11
12
13 9
Step 1.1
Step 1.2
Step 1.4Step 1.3
Step 2
O
Step 31
39
Process Innovation: Grignard Reaction
Life Research Hope
Role of Solvents and Inherent KF
40
Process Innovation: Grignard Reaction
Life Research Hope
Temperature Profile
41
Process Innovation: Grignard Reaction
Life Research Hope
DoE: Full Factorial
1.Pre DoE experiments 2.Based on domain knowledge, deciding on the
variable and response factors 3.Use of software e.g. Design Expert 4.Augmentation of initial results with the help of
Response Surface Model to arrive on the optimal conditions
5.Analysis of results by considering ANOVA variance method to derive significant model
42
Process Innovation: Grignard Reaction
Life Research Hope
process variables low high process variables low high BFB
(mol equiv.) 1.2 1.5
CPA (mol equiv.)
1.8 3.0
Mg (mol equiv.)
1.2 1.5 Mg
(mol equiv.) 2.0 4.0
Iodine (% w/w)
1 10 Iodine
(% w/w) 1 10
Operable ranges for DoE based on pre-DoE experiments
Response Factors >75% yield and >98% purity
43
Process Innovation: Grignard Reaction
Life Research Hope
Design space obtained for BFB and CPA Grignard reactions
44
Process Innovation: Grignard Reaction
Life Research Hope
Optimized Conditions
Diol HBr2
Step 1.4
Step 2
Step 3
1
Water, 98% H2SO495 °C, 6h, toluene
10% NaOH, silicagelIPA, 47% aq. HBr
aq. IPA
10 12
13 9
Step 1.2
Step 1.3
1.3 mol Mg0.04 mol iodine THF, 65 °C, 2h
1.0 mol
4, DCM-5 °C, 40 min
2.2 mol
3.0 mol Mg0.06 mol iodinetoluene, THF
90 °C, 3h
13, 0 °C, 1htoluene
CrudeCitalopram HBr
Over all yields
Over all E-factor
44%
53
411
Step 1.11.3 mol
68% (Step 1)
70%
93%
5% NH4Cl47% aq. HBr
45
Process Innovation: Grignard Reaction
Life Research Hope
Work up Simplification
46
Process Innovation: Grignard Reaction
Life Research Hope
Safety Consideration
1. Understanding the heat of reaction and adiabatic temperature rise
2. Comparison of the batch temperature profile inside the reactor (Tr) with the reactor jacket temperature profile (Tj) in isothermal mode reveals whether the reaction is instantaneous or not. (Exo or Endothermic)
3. Enthalpy can be calculated which indicates temperature rise in a given batch size
4. This helps to avoid accidents at a scale by keeping control system in place without compromising on process variables and responses
47
Process Innovation: Grignard Reaction
Life Research Hope
Safety Consideration
For 100g input of 10; Temperature rise for BFB Grignard is from 0 °C to 3 °C, E=170.2 KJ and Tad=146.69 °C; Temperature rise for CPA Grignard is from 0 °C to 1.5 °C, E=148.15 KJ and Tad=91.2 °C. Recommendation: Rate of heat exchange must be controlled by keeping efficient cooling in Jacket
48
Process Innovation: Grignard Reaction
Life Research Hope
Michael E Kopach <[email protected]> 05/10/2013 04:45 AM To "[email protected]" <[email protected]> Cc Subject Citalopram Paper Dear Rakesh, From on Grignard practioner to another – this is an outstanding paper: http://pubs.acs.org/doi/abs/10.1021/op3002596 Best Regards, Mike
Recently Developed Asymmetric Reduction Involving Biocatalysis is More Prefered
61
Major Innovation: Diastereoselective Reduction
Life Research Hope
Innovative Approaches
Strategy I Strategy II
FF
F
HN
NON
NN
CF3
NaBH4, MsOHNaBH4, MsOH
FF
F
HN
NON
NN
CF3
Yield ??; dr ??
FF
F
HN
NON
NN
CF3
NN
OOH
10 mol%
HSiCl3
FF
F
HN
NON
NN
CF3
Yield ??; dr ??
F
FF
N N
O
N
NN
CF3
Si
Cl
ClClN N
OHO H
HN
BO OMsMsO
H
OMsNN
NNF3CFF
F
H NBO OMs
MsO
H
OMsNN
NNF3CFF
F
Hor
62
Major Innovation: Diastereoselective Reduction
Life Research Hope
Evolution of Concept
dr : 83:17 undesired isomer
FF
F
HN
NON
NN
CF3
FF
F
HN
NON
NN
CF3
FF
F
NH2
NON
NN
CF3
NaBH4, MsOHDME:IPA
RT, overnight
Pd(OH)2/CHCO2H, H2O
MeOH, THF (1:1)
FF
F
HN
NON
NN
CF3
NaBH4, MsOHDME:IPA
RT, overnight
FF
F
HN
NON
NN
CF3
FF
F
NH2
NON
NN
CF3
Pd(OH)2/CHCO2H, H2O
MeOH, THF (1:1)
dr: 85:15 desired isomer
63
Major Innovation: Diastereoselective Reduction
Life Research Hope
FF
F
HN
NON
NN
CF3
NaBH4, MsOH
DME:IPA(20:7)
-40 0C, 12h
FF
F
HN
NON
NN
CF3
yield 85%; dr = 85:15
Required diastereomer crystallized with dr>99%
Pd(OH)2/C/HCO2H, H2O MeOH, THF
or Pd/C/H2
FF
F
NH2
NON
NN
CF3
H3PO4, IPA60-650C
FF
F
NH2
NON
NN
CF3
H3PO4 H2ONBO OMs
MsO
H
OMsNN
NNF3CFF
F
H
Bandichhor, R.; et al. WO 2011025932 A2 20110303
-90 0C: dr=93:07, Yield= >90%
7000 vs 700 USD
64
Major Innovation: Amino Acid
Life Research Hope
H2ON2
NH3
COCH4
H H
O
NH
CO2HCH3CO2H
HCO2H
NH
NH2
O
H2N NH2
O
Aminoacids
CO2 HCO2H Amino acids
HCN Amino acidsNH3
CO2 Amino acids
O
O
HO
Citric and
Glyoxylate cycles
1
starting point
prebiotic high energyinduced
NH3
Miller-Urey
Calvin
Karat
Our work
Different conceived approaches towards the synthesis of amino acids
Discovery of Redox System Enabling C-N-C Bonds Formation: Indicator of Prebiotic Synthesis of Amino Acid
65
Major Innovation: Amino Acid
Life Research Hope
EtO
ONH2
EtO
OOH
O
reduced
oxidized
HO
O
O
O
OH
OH
O
OH
1
2
3
4
5
6
NH3
Redox chemistry on ethyl glyoxylate and Cannizzaro reaction
66
Major Innovation: Amino Acid
Life Research Hope
EtOHN
OEt
O
O
O
EtO
O
O
NH4OAc
THFEtO
O
NH1 7
9
OHHO
NH2
O
2
EtON
OEt
O
OH
O
8
EtO
O
O
HO
OOH
O3
+
no metal-H2 source [(e.g. Ru or Ir or Pd or Cu or Fe etc.)-H2]
no hydride source
Synthesis of glycine 2
67
Major Innovation: Amino Acid
Life Research Hope
EtON
OEt
O
OH
OH
EtOHN
OEt
O
O
O
7 8H H
H
EtON
OEt
O
O
O
H2
H1
7
H
EtON
OEt
O
O
O
H2H
H1
EtON
OEt
O
O
O
H
H2H1
EtON
OEt
O
O
O
H2
H1
H
EtON
OEt
O
O
O
H2H
EtON
OEt
O
O
O
H
H1H2
8
H1
path a path b
step
1st
ep 2
Two different reaction pathways (a and b)
68
Major Innovation: Amino Acid
Life Research Hope
IS -50
257 267
136
-142
228
FS
0
Ener
gy, k
J/m
ol
Reaction coordinate
TS1 TS2
TS3 InS1
InS2
69
Major Innovation: Amino Acid
Life Research Hope
IS
FS
-39
220
-142
42
Ener
gy, k
J/m
ol
0
Reaction coordinate
InS
TS1
TS2
Bandichhor et al. Chem. Com. 2014 under revision
70
Major Innovation: Synthesis of Eribulin
Life Research Hope
O
Me
O
OO
O
OO
H
H
O
HO
OMe
H2N
OH
Eribulin19 stereocenters
Target 64 to 20 Steps
Late Stage Breast Cancer (Two Chemotherapies and Treated With Anthramycin and Taxane Class of Medicine)
HALAVEN is a clear, colorless, sterile
solution for intravenous administration. Each vial contains 1 mg of
eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95).
71
Major Innovation: Synthesis of Eribulin
Life Research Hope
OO O
O
O
MeOHO
H2N
O
O
H
H
H
OO
BA
C
Sulfone addition
Nozaki-Hiyama-Kishi (NHK) reaction
Ketal formation
NHK reaction /Cross metathesisOlefination
72
Inspiration
Life Research Hope
“A chain is as strong as its weakest link”
Reading Materials: 1. Scalable Green Chemistry: Case Studies from the Pharmaceutical Industry 2. Green Chemistry in the Pharmaceutical Industry Apart from Leading Journals 1. OPRD 2. Journal of Chemical Education
73
Recognition
Life Research Hope
Green Innovation Award-2013 in the Large MNC Category
Life Research Hope
Amit Biswas Vilas Dhahanukar Apurba Bhattacharya Dhileep K. Krishnamurthy P. Pratap Reddy Arnab Amar Namrata Dinesh Gade Srinivas David (Clinton Foundation) Nagaraju Udai Sudhakar Kiran Prasanth Pallavi ERR Gangula Chirotech team Srinivas (DRILS) All the Chemistry, PE and Formulation scientists at IPDO
The management of the Dr. Reddy’s Laboratories Ltd. is highly acknowledged for supporting the innovative research
IPDOChemistry Engineering
Formulation API R
&D&A
R&D
P ack eg i ngC
oll ab o rati o ns
Inte
llect
ual P
ro per t y
Reg ulatory
Oliver (Regensburg) Marisa (Upenn) Burgess (College Station) Greg Fu (MIT) Mike Kirsche (UT Austin) G. Mehta (DRILS) J. Iqbal (DRILS) V.K.Tandon (LU) Hajela (CDRI) S.N.Rastogi (CDRI)