WO2019239202A1 - Novel & improved synthesis of antipsychotic drug - Google Patents

Novel & improved synthesis of antipsychotic drug Download PDF

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Publication number
WO2019239202A1
WO2019239202A1 PCT/IB2018/056546 IB2018056546W WO2019239202A1 WO 2019239202 A1 WO2019239202 A1 WO 2019239202A1 IB 2018056546 W IB2018056546 W IB 2018056546W WO 2019239202 A1 WO2019239202 A1 WO 2019239202A1
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Prior art keywords
formula
compound
clozapine
solvent
base
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PCT/IB2018/056546
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French (fr)
Inventor
Dr. Rajeev Kumar DUBEY
Venkat Rao SIRUGU BATTULA
Ramesh Babu Potluri
Vamsi Krishna Potluri
Shiva Krishna Garikipati
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Sms Pharmaceuticals Ltd
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Publication of WO2019239202A1 publication Critical patent/WO2019239202A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid

Definitions

  • the present invention relates to novel synthesis of Clozapine which is an‘atypical’ antipsychotic drug.
  • the present invention further relates an improved process for the preparation of Clozapine.
  • the present invention particularly relates to an improved process for the preparation of Clozapine which is highly cost effective, commercially feasible & industrially advantageous.
  • Clozapine is a tricyclic dibenzodiazepine derivative which is an atypical antipsychotic drug.
  • the chemical name of Clozapine is 8-chloro- 11 -(4-methyl- l-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine.
  • the structural formula is:
  • the empirical formula is Ci 8 Hi9ClN 4 and the molecular weight is 326.83.
  • the main drawback of the above invention is the cost of starting material and also the narcotic effect of Anthranilic acid.
  • the use of Anthranilic acid in the preparation of Clozapine may not be suggested due to its narcotic properties.
  • Anthranilic acid and its derivatives are widely recognized to show narcotic effects.
  • the main object of the invention is to provide novel process for the preparation of Clozapine using simple and cost effective novel intermediates.
  • the another main object of the invention is to provide a simple, cost effective, improved and robust process for the preparation of Clozapine of Formula-I yielding at a high yield with high purity without formation of undesired impurities.
  • the present invention provides novel process for the preparation of Clozapine of Formula-I
  • the present invention provides compounds of Formulae 2, 4 and
  • the present invention provides an improved process for the preparation of Clozapine using 2-chlorobenzoic acid as a raw material characterized in that it comprises reacting compound of Formula- VI
  • reaction may be performed in the presence of a catalyst and a base, wherein the solvent is selected from Toluene, Xylenes, DMF, DMSO, DMAc or mixtures.
  • the present invention provides an improved process for the preparation of Clozapine of Formula-I
  • the present invention provides an improved process for the preparation of Clozapine of Formula-I
  • the present invention provides novel as well as improved process for the preparation of Clozapine or its salts
  • the inventors of the present invention have developed a novel approach a well as the improved process for the preparation of Clozapine which involves the use of simple and cost effective raw materials, wherein the starting material used in the present invention are non narcotic which are available commercially.
  • the improved process according to the present invention involves the less number of steps when compared to the prior art process, and also the Clozapine prepared according to the improved process does not contain any impurities more than prescribed levels. Further, the process involves less number of solvent extractions which gives good yield and quality of the product.
  • the inventors of the present invention have successfully developed the compound of Formula-I with good yield and high purity, the cost of the starting materials as used in the present invention such 2-chloro benzoic acid and halo benzene are very low and commercially viable comparatively with Anthranilic acid which is narcotic.
  • Base as used in the present invention is selected from organic base or inorganic base.
  • Inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides.
  • the example of inorganic base includes but not limited to NaHCO 3 , LiOH, NaOH, KOH, KHCO 3 , LiHCO 3 , Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , CaCO 3 , MgCO 3 , sodium hydride, Potassium tert butoxide, Sodium tert butoxide, magnesium hydroxide, MgH 2 , Mg(OMe) 2 , Mg(OH) 2 , Mg(OEt) 2 , MgHOMe, MgHOEt, CaH 2 , Ca(OMe) 2 and Ca(OEt) 2 and the like or mixtures thereof.
  • Organic base is selected from pyridine and its derivative, piperidine, nitrogen containing base.
  • the example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
  • Solvent as used in the present invention is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert-butylether, diethylether, diisopropyl ether, 1,4- dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl
  • Reducing agent as used in the present invention may be selected from Pd/C, Raney Nickel, Iron/acid, Iron/Lewis acids, Zinc, SnCl 2 , Na 2 S, LiAlH 4 and Na 2 S 2 0 4 .
  • Catalyst as used in the present invention may be selected from cuprous oxide, cupric oxide, cuprous iodide, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride. Cyclization of compound of Formula IV is carried out using alkyl chloroformates.
  • Acetylating agent as used in the present invention is selected from acetic acid, acetic anhydride and acyl halides.
  • the present invention provides novel process for the preparation of Clozapine of Formula-I
  • the present invention provides compounds of Formulae 2, 4 and
  • the present invention provides an improved process for the preparation of Clozapine using 2-chlorobenzoic acid as a raw material characterized in that it comprises reacting compound of Formula- VI
  • the present invention provides an improved process for the preparation of Clozapine of Formula-I
  • Triethylamine was taken in 50 mL of methylene chloride containing round bottom flask at room temperature. The reaction mass was stirred for 20 minutes at room temperature and then slowly added 6.0 gm of ethyl chloroformate over a period of 20 minutes and maintained for 2 hours at room temperature. After completion of the reaction methylene chloride was distilled off and the residue obtained was diluted with 20mL of Water and stirred for 30 minutes, dried the material after filtration of the desired product yielded 4.0gm.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to novel as well as improved process for the preparation of Clozapine of Formula I which involves anti-narcotic and highly cost effective raw materials.

Description

NOVEL & IMPROVED SYNTHESIS OF ANTIPSYCHOTIC DRUG
FIELD OF THE INVENTION
The present invention relates to novel synthesis of Clozapine which is an‘atypical’ antipsychotic drug.
The present invention further relates an improved process for the preparation of Clozapine. The present invention particularly relates to an improved process for the preparation of Clozapine which is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Clozapine is a tricyclic dibenzodiazepine derivative which is an atypical antipsychotic drug. The chemical name of Clozapine is 8-chloro- 11 -(4-methyl- l-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine. The structural formula is:
Figure imgf000002_0001
The empirical formula is Ci8Hi9ClN4 and the molecular weight is 326.83.
Analytical Profiles of Drug Substances and Excipients 1993 discloses a process for the preparation of Clozapine which involves the reaction of anthranilic acid with nitro intermediate followed by reduction and cyclization to give Clozapine. The process is given in the scheme below: Scheme-1:
Figure imgf000003_0001
The main drawback of the above invention is the cost of starting material and also the narcotic effect of Anthranilic acid. The use of Anthranilic acid in the preparation of Clozapine may not be suggested due to its narcotic properties. Anthranilic acid and its derivatives are widely recognized to show narcotic effects. Hence, it needs to develop the process for the preparation of Clozapine using other than Anthranilic acid as a raw material or starting material.
The present inventors have developed novel and improved process for the preparation of Clozapine which results in greater efficiency than the prior art processes with higher product purity. OBJECT OF THE INVENTION
The main object of the invention is to provide novel process for the preparation of Clozapine using simple and cost effective novel intermediates.
The another main object of the invention is to provide a simple, cost effective, improved and robust process for the preparation of Clozapine of Formula-I yielding at a high yield with high purity without formation of undesired impurities.
Figure imgf000003_0002
Formula-I
SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel process for the preparation of Clozapine of Formula-I
Figure imgf000004_0001
Formula-I
or its salts, which comprises,
a) Reacting compound of Formula-7
Figure imgf000004_0002
Formula-7
with halo benzene in the presence of a base to give compound of Formula-6,
Figure imgf000004_0003
Formula-6
b) Reacting compound of Formula-6 with acetylating agent to give compound of Formula-5
Figure imgf000004_0004
Formula-5
c) Reducing compound of Formula-5 in the presence of a suitable reducing agent in a solvent to give compound of Formula-4
Figure imgf000004_0005
Formula-4
d) Reacting compound of Formula-4 with compound of Formula-3
Figure imgf000005_0001
Formula-3
to give compound of Formula-2
Figure imgf000005_0002
Formula-2
e) Converting compound of Formula-2 to Clozapine or its salt.
In a preferred aspect, the present invention provides compounds of Formulae 2, 4 and
Figure imgf000005_0003
Formula-2 Formula-4 Formula-5
In another preferred aspect, the present invention provides an improved process for the preparation of Clozapine using 2-chlorobenzoic acid as a raw material characterized in that it comprises reacting compound of Formula- VI
Figure imgf000005_0004
Formula- VI
with 2-chlorobenzoic acid in a solvent and optionally the reaction may be performed in the presence of a catalyst and a base, wherein the solvent is selected from Toluene, Xylenes, DMF, DMSO, DMAc or mixtures.
In yet another preferred aspect, the present invention provides an improved process for the preparation of Clozapine of Formula-I
Figure imgf000006_0001
Formula-I
or its salts, which comprises,
a) Reacting compound of Formula- VI
Figure imgf000006_0002
Formula- VI
with 2-chlorobenzoic acid in the presence of base, solvent selected from Toluene, Xylenes, DMF, DMSO, DMAc, or mixtures and optionally in the presence of a catalyst to give compound of Formula-V
Figure imgf000006_0003
Formula-V
b) Reducing compound of Formula-V in the presence of a suitable reducing agent in a solvent to give compound of Formula-IV
Figure imgf000006_0004
Formula-IV
c) Cyclizing compound of Formula-IV to give compound of Formula- III
Figure imgf000007_0001
Formula-Ill
d) Reacting compound of Formula-Ill with compound of Formula- II
Figure imgf000007_0002
Formula-II
to give Clozapine or its salts.
In yet another preferred aspect, the present invention provides an improved process for the preparation of Clozapine of Formula-I
Figure imgf000007_0003
Formula-I
or its salts, which comprises,
a) Reacting compound of Formula- VI
Figure imgf000007_0004
Formula- VI
with 2-chlorobenzoic acid in DMF, Xylenes or mixture of DMF & Xylenes, in the presence of potassium carbonate and copper iodide as a catalyst to give compound of Formula-V
Figure imgf000007_0005
Formula-V b) Reducing compound of Formula-V in the presence of a suitable reducing agent in a solvent to give compound of Formula- IV
Figure imgf000008_0001
Formula-IV
c) Cyclizing compound of Formula-IV to give compound of Formula- III
Figure imgf000008_0002
Formula-Ill
d) Reacting compound of Formula-Ill with compound of Formula- II
Figure imgf000008_0003
Formula-II
to give Clozapine or its salts.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides novel as well as improved process for the preparation of Clozapine or its salts
Figure imgf000008_0004
Formula-I
The inventors of the present invention have developed a novel approach a well as the improved process for the preparation of Clozapine which involves the use of simple and cost effective raw materials, wherein the starting material used in the present invention are non narcotic which are available commercially. The improved process according to the present invention involves the less number of steps when compared to the prior art process, and also the Clozapine prepared according to the improved process does not contain any impurities more than prescribed levels. Further, the process involves less number of solvent extractions which gives good yield and quality of the product.
By adopting the both novel and improved routes, the inventors of the present invention have successfully developed the compound of Formula-I with good yield and high purity, the cost of the starting materials as used in the present invention such 2-chloro benzoic acid and halo benzene are very low and commercially viable comparatively with Anthranilic acid which is narcotic.
Base as used in the present invention is selected from organic base or inorganic base. Inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. The example of inorganic base includes but not limited to NaHCO3, LiOH, NaOH, KOH, KHCO3, LiHCO3, Na2CO3, K2CO3, Li2CO3, CaCO3, MgCO3, sodium hydride, Potassium tert butoxide, Sodium tert butoxide, magnesium hydroxide, MgH2, Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt, CaH2, Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof. Organic base is selected from pyridine and its derivative, piperidine, nitrogen containing base. The example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
Solvent as used in the present invention is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert-butylether, diethylether, diisopropyl ether, 1,4- dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof.
Reducing agent as used in the present invention may be selected from Pd/C, Raney Nickel, Iron/acid, Iron/Lewis acids, Zinc, SnCl2, Na2S, LiAlH4 and Na2S204.
Catalyst as used in the present invention may be selected from cuprous oxide, cupric oxide, cuprous iodide, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride. Cyclization of compound of Formula IV is carried out using alkyl chloroformates.
Acetylating agent as used in the present invention is selected from acetic acid, acetic anhydride and acyl halides.
The present invention provides novel process for the preparation of Clozapine of Formula-I
Figure imgf000010_0001
Formula-I
or its salts, which comprises,
a) Reacting compound of Formula-7
Figure imgf000010_0002
Formula-7
with halo benzene in the presence of K2C03 to give compound of Formula-6,
Figure imgf000010_0003
Formula-6
b) Reacting compound of Formula-6 with acetyl chloride to give compound of Formula-5
Figure imgf000011_0001
Formula-5
c) Reducing compound of Formula-5 in the presence of a suitable reducing agent in a solvent to give compound of Formula-4
Figure imgf000011_0002
Formula-4
d) Reacting compound of Formula-4 with compound of Formula-3
Figure imgf000011_0003
Formula-3
to give compound of Formula-2
Figure imgf000011_0004
Formula-2
e) Converting compound of Formula-2 to Clozapine or its salt.
In a preferred aspect, the present invention provides compounds of Formulae 2, 4 and
5
Figure imgf000012_0001
Formula-2 Formula-4 Formula-5
The present invention provides an improved process for the preparation of Clozapine using 2-chlorobenzoic acid as a raw material characterized in that it comprises reacting compound of Formula- VI
Figure imgf000012_0002
Formula- VI
with 2-chloro benzoic acid
Figure imgf000012_0003
in DMF, Xylenes or mixture of DMF & Xylenes in the presence of potassium carbonate and copper iodide as catalyst.
In a preferred embodiment, the present invention provides an improved process for the preparation of Clozapine of Formula-I
Figure imgf000012_0004
Formula-I
or its salts, which comprises,
a) Reacting compound of Formula- VI
Figure imgf000012_0005
Formula- VI
with 2-chlorobenzoic acid in DMF, Xylenes or mixture of DMF & Xylenes in the presence of potassium carbonate and copper iodide as catalyst to give compound of Formula-V
Figure imgf000013_0001
Formula-V
b) Reducing compound of Formula-V with sodium dithionate in a solvent to give compound of Formula-IV
Figure imgf000013_0002
Formula-IV
c) Cyclizing compound of Formula-IV using ethyl chloroformate to give compound of Formula-Ill
Figure imgf000013_0003
Formula-Ill
d) Reacting compound of Formula-Ill with compound of Formula- II
Figure imgf000013_0004
Formula-II
to give Clozapine or its salts.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention. Examples
Example-1: Preparation of compound of Formula-6
Figure imgf000014_0001
Formula-6
In a clean & dry round bottom flask fitted with reflux condenser, 5gm of 4-chloro-2- nitro aniline (Formula-7), 25mL bromo benzene was taken and stirred for 10-15 minutes and then added 8gm of anhydrous potassium carbonate (K2C03) followed by 0.5 gm of copper iodide base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux and maintained for 12 hours. After completion of the reaction mass was quenched in water, extracted with methylene chloride (3X15mL), the combined organics, washed with water (20mL), removed the solvent under reduced pressure to afford 4.5gm desired product. Example-2: Preparation of compound of Formula-5
Figure imgf000014_0002
Formula-5
In a clean & dry round bottom flask fitted with reflux condenser, 5gm of N-(4-chloro- 2-nitrophenyl)benzenamine (Formula-6), 0.5 gm Iodine was taken, added l2.0gm acetyl chloride drop wise under gentle stirring for 10-15 minutes and then slowly heated the reaction mass temperature to 50-55°C and maintained the reaction mass for 3 hours. After completion of the reaction mass was quenched in water (50mL), extracted with methylene chloride (3 X l5mL), the combined organics, washed with water (20mL), removed the solvent under reduced pressure. The resulting material 4.5 gm desired product was as such taken for next step.
Example-3: Preparation of compound of Formula-4
Figure imgf000015_0001
Formula-4
In clean and dried round bottom flask 5.0 gm of N-(4-chloro-2-nitrophenyl)-N- phenylacetamide (Formula-5), 50mL of methanol taken into at room temperature. Then added l5.0gm of sodium dithionate in lot wise (five lots) to the reaction mass at 50-55°C and maintain the reaction mass temperature for 120 minutes for completion of the reaction. The reaction mass was cooled to room temperature and filtered the reaction mass after TLC complies and removed the methanol of under reduced pressure; the obtained organic residue was diluted with water (50mL) and extracted with (3X25mL), the combined organics was washed with brine and distilled the solvent. The crystalized dark brown colored solid was dried to yielded 4.0 gm.
Example-4: Preparation of compound of Formula-2
Figure imgf000015_0002
Formula-2
In a clean & dry Round bottom flask 25gm of N-(4-chloro-2-aminophenyl)-N- phenylacetamide (Formula-4) and 9.3 gm of N-methyl piperizine was taken in toluene and the reaction mixture was cooled to 0-5°C and added l4.2gm of triphosgene lot wise. The whole reaction mass slowly rose to reflux and maintained for 4-5 hours. Cool to room temperature and reaction mass washed with 10% sodium carbonate and removed the solvent under reduced pressure to give l6gm of Formula-2.
Example-5: Process for the preparation of N-acetyl Clozapine
Figure imgf000016_0001
To a cooled solution of lOOml POCl3, added 20gm of N-(2-(N-phenylacetamido)-5- chlorophenyl)-4-methylpiperazine-l -carboxamide (Formula-2) and slowly rose the temperature for reflux for 3 hours, cooled reaction mixture after completion of the reaction and quenched the reaction mass in to water and pH adjusted to 7.5-8 with sodium carbonate and isolated the material by filtration to give to give lOgm of N-acetyl Clozapine.
Example-6: Process for the preparation of Clozapine
Figure imgf000016_0002
In a clean and dry round bottom flask lOgm of N-acetyl clozapine was taken in 50 ml of ethanol followed by addition 3.7gm of anhydrous potassium carbonate at room temperature and then heated for reflux, maintained the reaction mass for another 3 hours. After completion of the reaction, reaction mass was cooled to room temperature and filtered the excess of potassium carbonate and removed the solvent under reduced pressure and the obtained crude material was isolated in water to give 5gm of Clozapine.
Example-7: Preparation of compound of Formula- V
Figure imgf000016_0003
Formula-V
In a clean & dry round bottom flask fitted with Dean’s stork condenser, 25gm of 4- chloro-2-nitro aniline, 15gm of 2-chlorobenzoic acid was taken in 200mL of O-Xylene stirred for 10-15 minutes and then added 20gm of anhydrous potassium carbonate (K2C03) followed by lOgm of diisopropyl ethylamine base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux and collected the water. After completion of the reaction mass was quenched in water and pH adjusted to 2-3.5 with Cone. Hydrochloric acid. The precipitated solid material was isolated by filtration to afford 20gm desired product.
Example-8: Preparation of compound of Formula-V
Figure imgf000017_0001
Formula-V
In a clean & dry round bottom flask fitted with dean’s stork condenser, 25gm of 4- chloro-2-nitroaniline, l5gm of 2-chlorobenzoic acid was taken in 200mL of N,N- dimethylformamide stirred for 10-15 minutes and then added 20gm of anhydrous potassium carbonate (K2C03) followed by lOgm of diisopropyl ethylamine base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux and collected the water. After completion of the reaction mass was quenched in Water and pH adjusted to 2-3.5 with Cone hydrochloric acid. The precipitated solid material was isolated by filtration to afford 20gm desired product.
Example-9: Preparation of compound of Formula-V
Figure imgf000017_0002
Formula-V
In a clean & dry round bottom flask fitted with Dean’s stork condenser, 25gm of 4- chloro-2-nitro aniline, l5gm of 2-chlorobenzoic acid was taken in 200mL of N,N- dimethylacetamide stirred for 10-15 minutes and then added 20gm of Anhydrous potassium carbonate (K2C03) followed by lOgm of diisopropyl ethylamine base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux and collected the Water. After completion of the reaction mass was quenched in Water and pH adjusted to 2- 3.5 with cone hydrochloric acid. The precipitated solid material was isolated by filtration to afford 20gm desired product. Example-10: Preparation of compound of Formula-V
Figure imgf000018_0001
Formula-V
In a clean & dry round bottom flask fitted with Dean’s stork condenser, 25gm of 4- chloro-2-nitro aniline, l5gm of 2-chlorobenzoic acid was taken in lOOmL of N,N- dimethylformamide and lOOmL of O-Xylene stirred for 10-15 minutes and then added 20gm of Anhydrous potassium carbonate (K2C03) followed by lOgm of diisopropyl ethylamine base at room temperature with gentle stirring. Slowly heated the reaction mass temperature to reflux and collected the water. After completion of the reaction mass was quenched in Water and pH adjusted to 2-3.5 with cone. Hydrochloric acid. The precipitated solid material was isolated by filtration to afford 20gm desired product.
Example-11: Preparation of compound of Formula-IV
Figure imgf000018_0002
Formula-IV
In clean and dried round bottom flask 5.0 gm of 2-(4-chloro-2-nitrophenylamino) benzoic acid, 50mL of acetone taken into an aqueous solution of sodium bicarbonate (7.5gm in 20mL of water) at room temperature. Then added lO.Ogm of sodium dithionate in lot wise (five lots) to the reaction mass at 40°C and maintain the reaction mass temperature for 60-70 minutes for completion of the reaction. The reaction mass was cooled to room temperature after TLC complies and removed the excess of acetone under reduced pressure; the resulting aqueous mass pH was adjusted to 2-3 with cone. hydrochloric acid. The precipitated light brown colored solid was filtered and dried to yielded 4.0 gm.
Example-12: Preparation of compound of Formula-IV
Figure imgf000018_0003
Formula-IV
10 gm of 2-(4-chloro-2-nitrophenylamino) benzoic acid,, 200 mL of water was taken in a 500mL round bottom flask with gentle stirring at room temperature and then added l6.0gm of Iron powder as single lot or lot wise followed by 12.0 gm CaCl2 to the above reaction mass under stirring. The whole reaction mixture was heated to 90-l00°C and maintained for 1-3 Hrs. Once TLC complies then the reaction mass was cooled to room temperature and filter through hyflo bed. The filtered mother liquor pH was adjusted to 2-3 with cone hydrochloric acid. The precipitated light brown colored solid was filtered and dried to yield 8.0 gm of the title compound.
Example-13: Preparation of compound of Formula-Ill
Figure imgf000019_0001
Formula-Ill
5.0 gm of 2-(2-amino-4-chlorophenylamino) benzoic acid and l2.5gm of
Triethylamine was taken in 50 mL of methylene chloride containing round bottom flask at room temperature. The reaction mass was stirred for 20 minutes at room temperature and then slowly added 6.0 gm of ethyl chloroformate over a period of 20 minutes and maintained for 2 hours at room temperature. After completion of the reaction methylene chloride was distilled off and the residue obtained was diluted with 20mL of Water and stirred for 30 minutes, dried the material after filtration of the desired product yielded 4.0gm.
Example-14: Process for the preparation of Clozapine
Figure imgf000019_0002
In a lOOOmL round bottom flask 200 mL O-xylene and lOgm of 8-chloro-l l-oxo-10, l l-dihydro-5H-dibenzo-l,4-diazepine was taken at room temperature and stirred for 30 minutes. The reaction mass cooled to l0-l5°C and added 9.7 mL (l6.4gm) Titanium (IV) chloride in 20 mL of O-xylene was added drop wise over a period of 30 minutes with constant stirring. The reaction mixture was heated to reflux and maintain for 3 hours. The reaction mass was then cooled to lO°C. 20gm of l-Methylpiperizine was added to the reaction mass during a period of 30 minutes, and further it was maintained for 30-45 minutes at l0°C. The reaction mixture then heated to reflux for 4 hours. Check TLC 10% Methanol in chloroform (1:9). After completion of the reaction mass was distilled off to get the residue, it was partitioned between 2M Aq. Hydrochloric acid (300mL) and Ethyl acetate (300mL). Emulsion filter through hyflo bed and separate the layers and aq. Layer washed with Ethyl acetate (2Xl50mL) and the separated Aqueous layer was adjusted pH with Sodium hydroxide (pH~l4) and extracted with ethyl acetate (3Xl50mL), the combined organics were washed with Water (2 x 100ML), and followed by brine. The organic layer was distilled under reduced pressure, the optioned solid clozapine was crystalized in acetone and IPE and yielded 4gm of Clozapine.

Claims

We Claim:
1. Novel process for the preparation of Clozapine of Formula-I
Figure imgf000021_0001
Formula-I
or its salts, which comprises,
a) Reacting compound of Formula-7
Figure imgf000021_0002
Formula-7
with halo benzene in the presence of a base to give compound of Formula-6,
Figure imgf000021_0003
Formula-6
b) Reacting compound of Formula-6 with acetylating agent to give compound of Formula-5
Figure imgf000021_0004
Formula-5
c) Reducing compound of Formula-5 in the presence of a suitable reducing agent in a solvent to give compound of Formula-4
Figure imgf000021_0005
Formula-4
d) Reacting compound of Formula-4 with compound of Formula-3
Figure imgf000022_0001
Formula-3
to give compound of Formula-2
Figure imgf000022_0002
Formula-2
e) Converting compound of Formula-2 to Clozapine or its salt.
2. Novel process according to claim 1, wherein
in step a) halo benzene selected from iodobenzene, bromobenzene, chlorobenzene or fluorobenzene,
in step b) acetylating agent is selected from acetic acid, acetic anhydride and acyl chlorides, preferably acetyl chloride,
in step c) reduction is carried out in the presence of reducing agent selected from Pd/C, Raney Nickel, Iron/acid, Iron/Lewis acids, Zinc, SnCl2, Na2S, LiAlH4 and Na2S204, in step d) reaction of compound of Formula-4 with compound of Formula-3 is carried out in the presence of triphosgene in toluene,
in step e) the conversion of compound of Formula-2 to Clozapine is converted via the formation of N-acetyl Clozapine which may be isolated or carried out in-situ to obtain Clozapine, wherein Formula-2 is treated with POCl3 to obtain N-acetyl Clozapine.
3. Compounds of Formulae 2, 4 and 5 or their salts
Figure imgf000023_0001
Formula-2 Formula-4 Formula-5
4. An improved process for the preparation of Clozapine using 2-chlorobenzoic acid as a raw material characterized in that it comprises reacting compound of Formula- VI
Figure imgf000023_0002
with 2-chlorobenzoic acid in a solvent and optionally the reaction may be performed in the presence of a catalyst and a base, wherein the solvent is selected from Toluene, Xylenes, DMF, DMSO, DMAc or mixtures.
5. An improved process according to claim 4, wherein the reaction of compound of Formula- VI with 2-chlorobenzoic acid is carried out in the presence of base and copper iodide as catalyst.
6. An improved process for the preparation of Clozapine of Formula-I
Figure imgf000023_0003
Formula-I
or its salts, which comprises,
a) Reacting compound of Formula- VI
Figure imgf000024_0001
Formula- VI
with 2-chlorobenzoic acid in the presence of base, in a solvent selected from Toluene, Xylenes, DMF, DMSO, DMAc, or mixtures and optionally in the presence of a catalyst to give compound of Formula-V
Figure imgf000024_0002
Formula-V
b) Reducing compound of Formula-V in the presence of a suitable reducing agent in a solvent to give compound of Formula- IV
Figure imgf000024_0003
Formula-IV
c) Cyclizing compound of Formula-IV to give compound of Formula- III
Figure imgf000024_0004
Formula-Ill
d) Reacting compound of Formula- III with compound of Formula- II
Figure imgf000024_0005
Formula-II
to give Clozapine or its salts.
7. An improved process according to claim 6, wherein
Step a) is carried out in the presence of base and copper iodide as catalyst,
Step b) is carried out in the presence of a reducing agent selected from Pd/C, Raney Nickel, Iron/acid, Iron/Lewis acids, Zinc, SnCl2, Na2S, LiAlH4 and Na2S204 optionally in a solvent,
Step c) is carried out by reacting compound of Formula Ilia with alkyl chloroformate in the presence of a base optionally in a solvent,
Step d) is carried out in the presence of titanium tetrachloride optionally in a solvent.
8. An improved process according to claim 7, wherein the base used in step a) and step c) is selected from organic base or inorganic base. Inorganic base is selected from
NaHCO3, LiOH, NaOH, KOH, KHCO3, LiHCO3, Na2CO3, K2CO3, Li2CO3,
CaCO3, MgCO3, sodium hydride, Potassium tert butoxide, Sodium tert butoxide, magnesium hydroxide, MgH2, Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt, CaH2, Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof. Organic base is selected from pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
9. An improved process according to claim 7, wherein the solvent used in steps b), c) & d) are selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert- butylether, diethylether, diisopropyl ether, l,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylenes, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof. An improved process for the preparation of Clozapine of Formula-I
Figure imgf000025_0001
Formula-I
or its salts, which comprises,
a) Reacting compound of Formula- VI
Figure imgf000026_0001
Formula- VI
with 2-chlorobenzoic acid in DMF, Xylenes or mixture of DMF & Xylenes, in the presence of potassium carbonate and copper iodide as a catalyst to give compound of Formula-V
Figure imgf000026_0002
Formula-V
b) Reducing compound of Formula-V in the presence of a suitable reducing agent in a solvent to give compound of Formula- IV
Figure imgf000026_0003
Formula-IV
c) Cyclizing compound of Formula-IV to give compound of Formula- III
Figure imgf000026_0004
Formula-Ill
d) Reacting compound of Formula-Ill with compound of Formula- II
Figure imgf000026_0005
Formula-II
to give Clozapine or its salts.
PCT/IB2018/056546 2018-06-11 2018-08-28 Novel & improved synthesis of antipsychotic drug WO2019239202A1 (en)

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CN115160239A (en) * 2022-07-08 2022-10-11 山东省分析测试中心 Preparation method of clozapine fine powder

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CN111718302A (en) * 2020-06-15 2020-09-29 江苏慈星药业有限公司 Clozapine intermediate and synthetic method and application thereof
CN115160239A (en) * 2022-07-08 2022-10-11 山东省分析测试中心 Preparation method of clozapine fine powder
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