174 Chapter 5 CHAPTER-5: New Synthetic Procedure to Prepare Olanzapine along with its Related Compounds. 5.1: Introduction Olanzapine 83 (26) is one of the known atypical antipsychotic drug and popularly used as a medication for the treatment of psychotic diseases in many countries. It has a profile of activity in invitro binding assays similar to that of the atypical antipsychotic agent Clozapine. Olanzapine was approved by the FDA in the year 1996 in United States of America. Olanzapine exhibits high levels of activity at surprisingly low dosage levels, making the drug highly desirable therapeutic candidate for the treatment of psychotic patients. The mechanism of action of Olanzapine 84 as with other drugs having efficacy in schizophrenia is unknown. However, it has been proposed that this drug’s efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. The mechanism of action of Olanzapine in the treatment of acute manic or mixed episodes associated with bipolar I disorder is unknown. It displays a broad pharmacological profile and is a selective monoaminergic antagonist with high binding affinity to serotonin 5HT2A/2C, dopamine D14, muscrinic M1-5 and adrenergic α1 receptors.
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174
Chapter 5
CHAPTER-5: New Synthetic Procedure to Prepare Olanzapine along
with its Related Compounds.
5.1: Introduction
Olanzapine83 (26) is one of the known atypical antipsychotic drug
and popularly used as a medication for the treatment of psychotic
diseases in many countries. It has a profile of activity in invitro binding
assays similar to that of the atypical antipsychotic agent Clozapine.
Olanzapine was approved by the FDA in the year 1996 in United States
of America. Olanzapine exhibits high levels of activity at surprisingly low
dosage levels, making the drug highly desirable therapeutic candidate
for the treatment of psychotic patients.
The mechanism of action of Olanzapine84 as with other drugs
having efficacy in schizophrenia is unknown. However, it has been
proposed that this drug’s efficacy in schizophrenia is mediated through a
combination of dopamine and serotonin type 2 (5HT2) antagonism. The
mechanism of action of Olanzapine in the treatment of acute manic or
mixed episodes associated with bipolar I disorder is unknown. It displays
a broad pharmacological profile and is a selective monoaminergic
antagonist with high binding affinity to serotonin 5HT2A/2C, dopamine
D14, muscrinic M1-5 and adrenergic α1 receptors.
175
Chapter 5
Table-5.1 Product details
Name of the drug Olanzapine
Active ingredient Olanzapine
Innovator Eli Lilly
Marketed by Eli Lilly
Brand Name Zyprexa
Structure
Chemical name 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-
thieno[2,3-b][1,5]benzodiazepine
Molecular formula C17H20N4S
Molecular Weight 312.44
Melting point 188-194ºC
CAS No. 132539-06-1
Approved Indication Zyprexa is indicated for
(i) the treatment of schizophrenia.
(ii) the treatment of acute mixed or manic
episodes associated with Bipolar I disorder.
Solubility Soluble in acetonitrile and practically insoluble
in water
176
Chapter 5
5.2: Reported Synthetic Schemes of Olanzapine
The first reported synthesis85 of Olanzapine (26) by Chakrabarti et
al., involves the reaction of (scheme 5.1) 2-fluoronitrobenzene (121) with
2-amino-5-methylthiophene-3-carbonitrile (122) in the presence of
sodium hydride and THF to give 2-(2-nitroanilino)-5-methyl thiophene-3-
carbonitrile (123). The nitrile group of thiophene derivative 123 was
catalytically hydrogenated and followed by treatment with ethanol to get
an amino ester 124, which was then reacted with N-methyl piperazine
(125) to give the amino amide 126 followed by cyclization in the
presence of titanium tetrachloride to give the desired compound 26.
Scheme 5.1
David O. Calligaro et al., disclosed two methods86 (schemes 5.2 &
5.3) for the synthesis of Olanzapine. Scheme 5.2 involves the reaction of
2-Chloronitrobenzene (127) with 2-amino-5-methylthiophene-3-
177
Chapter 5
carbonitrile (122) in the presence of lithium hydroxide to give the 2-(2-
nitroanilino)-5-methyl thiophene-3-carbonitrile (123) which was reduced
in the presence of stannous chloride and cyclized with HCl to afford
benzodiazepine derivative 128 in the form of HCl salt. The
benzodiazepine derivative was then reacted with N-methyl piperazine
(125) to give 26.
Scheme 5.2
The scheme 5.3 discloses an alternate process for preparing
compound 26 involving the reaction of benzodiazepine derivative 128
with piperazine (129) to result N-desmethyl Olanzapine (130) which
upon methylation using dimethyl sulphate afforded 26.
178
Chapter 5
Scheme 5.3
Zbigniew Majka et al., describes a process87 (scheme 5.4) for the
preparation of Olanzapine involving the use of N-desmethyl Olanzapine
(130) as the starting material wherein it was reacted with ethyl formate
to produce the corresponding N-formyl Olanzapine (131) which upon
reduction with a group I or II metal borohydride gave Olanzapine (26).
Scheme 5.4
Roman Lenarsic describes a process88 for the preparation (Scheme
5.5) of Olanzapine starting from the reaction of benzodiazepine-2,4-
diamine (132) with N-methyl piperazine to give bis (methyl piperazinyl)
benzodiazepine (133). The compound 133 upon reaction with
propionaldehyde in the presence of lithium diisopropylamide resulted
benzodiazepine-1-propanol (134), which on further reaction with
trifluoroacetic anhydride yielded the corresponding propylidene
179
Chapter 5
derivative 135. The propylidene derivative upon reaction with sulfur in
the presence of triethylamine gave the targeted compound 26.
Scheme 5.5
Zhengyong Wang89 describes a multi step process for the
preparation of Olanzapine (scheme 5.6) by protecting the amino group of
2-(2-nitroanilino)-5-methyl thiophene-3-carbonitrile (123) with benzyl
bromide to produce the protected intermediate 136. Cyclizing the
protected intermediate 136 via reduced intermediate compound 137
with tin chloride to produce benzodiazepine derivative 138, which was
then reacted with N-methyl piperazine to give N-protected Olanzapine
(139), finally which upon deprotection provided Olanzapine.
180
Chapter 5
Scheme 5.6
Rolf Keltjens et al., describes90 an improved process for the
preparation of Olanzapine (scheme 5.7). The process comprises reaction
of compound 128 or its salt with N-formyl piperazine 140 to form N-
formyl Olanzapine (131). The N-formyl Olanzapine or its salt was
reduced with Red-Al to form Olanzapine (26) or its salt.
181
Chapter 5
Scheme 5.7
5.2.1: Summary of reported synthetic schemes
As evident from the earlier reported synthetic schemes,
Olanzapine was synthetically prepared mainly by two types (i) cyclizing
the open chain derivative to form diazepine ring at the final stage of the
synthesis; (ii) cyclizing the open chain derivative to form an intermediate
compound containing diazepine moiety, which is then transformed to
desmethyl Olanzapine on reaction with piperazine, followed by its
conversion to Olanzapine. In another alternative disclosed methodology,
Olanzapine was also prepared by N-methylation of its corresponding
desmethyl derivative. In most of the above known synthetic procedures
for the preparation of Olanzapine, the reduction of nitro group is a
common step before the cyclization of the open chain derivative to afford
diazepine moiety. Use of many different reagents for the functional group
transformation may result in degradation of the product, which inturn
requires tedious purification procedures and results in low yield of the
final desired compound.
182
Chapter 5
5.3: Present Work
The earlier processes for the preparation of Olanzapine mainly
involved the reaction comprising the conversion of nitro functional group
to afford amino derivative, followed by cyclization under acidic
conditions to result diazepine derivative. The present research work
specifically avoids the use of nitro derivative as starting materials and
the use of reducing agents at any stage of the process. The present work
involves a simple two step process involving Suzuki coupling
mechanism91, 92 with the aid of organo metallic reagents resulting new
intermediate compounds for the preparation of Olanzapine. The
resulted product was in comparison with authentic sample. We have
further systematically identified, synthesized and characterized four
process related compounds of Olanzapine.
183
Chapter 5
5.3.1: Results and Discussion - Retro synthetic Pathway for
Olanzapine
Scheme 5.8
Accordingly scheme 5.8 has been systematically designed to get
Olanzapine with desired purity and appreciable yield. Scheme 5.8
described palladium catalyzed coupling of 2-amino-5-methylthiophene-
3-carbonitrile (122) with 1-bromo-2-iodobenzene (143) in the presence
of palladium mediated catalyst, xantphos ligand and cesium carbonate
base to give a novel intermediate compound 2-(2-bromophenylamino)-5-
methylthiophene-3-carbonitrile (142). The compound 142 was further
reacted with N-methyl piperazine in presence of trimethyl aluminum to
afford another novel imine derivative 141, which upon subsequent
cyclization to result Olanzapine (26).
184
Chapter 5
5.3.2: Synthesis of 2-(2-bromophenylamino)-5-methylthiophene-3-
carbonitrile (142)
Palladium-catalyzed cross-coupling reactions are among the most
useful synthetic methods for the reaction of halo derivatives with an
amine derivates, and the application of this property has been
specifically utilized for the synthesis of novel compound 142. A suitable
moles of compound 143 is coupled (scheme 5.8a) with 122 in the
presence of tris (dibenzylidineacetone) dipalladium catalyst, 4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene as ligand and cesium
carbonate as base in a mixture of 1,4-dioxane and xylene media to afford
novel compound 142 with 78.0% yield and having the purity of 98.7%
by HPLC analysis.
Scheme 5.8a
IR Spectrum (Fig.5.1) of 142 exhibited a sharp signal at about
3322 cm-1 corresponding to NH absorption and CN function absorption
at 2222 cm-1. In 1H-NMR spectrum (Fig.5.2), the down field region was
characterized by the presence of five aromatic proton signals at δ 7.59