Title of Invention

AN IMPROVED PROCESS FOR PREPARATION OF BENZODIAZEPINE DERIVATIVES

Abstract

An improved process for preparation of benzodiazepine derivatives such as clobazam, tetrazaepam and clotiazepam is presented.The process comprises a N-methylation of compound formula-II in biphasic solvent system in presence of phase transfer catalyst to produce formula-I. (The spiral line indicate the side that is attached to the benzodiazepine nucleus) And X is carbon or nitrogen atom. Y is carbon or nitrogen or carbonyl group. Zis,

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION "AN IMPROVED PROCESS FOR PREPARATION OF BENZODIAZEPINE DERIVATIVES" 2. APPLICANT (S) (a) NAME: Centaur Pharmaceuticals Pvt. ltd. (b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956 (c) ADDRESS: Centaur Pharmaceuticals Pvt. ltd. CentaurHouse,shantiNagar,Vakola, Santacruz(e)Mumbai400055. TelNo.+91-22-66499144 Fax No. +91-22-66499108/112. 2. PREAMBLE TO THE DESCRIPTION 3. The following specification particularly describes the invention and the manner in which it is to be performed AN IMPROVED PROCESS FOR PREPARATION OF BENZODIAZEPINE DERIVATIVES FIELD OF INVENTION An improved process mainly concern with the method of preparation and isolation of pharmaceutically active benzodiazepine derivatives such as clobazam, tetrazepam and clotiazepam etc.Furthermore, theses derivatives containing ring chlorine atom or atoms and to functional derivatives thereof. These Pharmaceutically active agent are short acting drugs in the benzodiazepine class used to treat anxiolytic, anticonvulsant and muscle relaxant. BACKGROUND OF INVENTION Benzodiazepine derivatives such as clobazam, tetrazepam and clotiazepam are marketed for therapeutic indications like anxiolytic, anticonvulsant and muscle relaxant. The general scheme for preparation of the benzodiazepine derivatives is as follows: (The spiral Line indicate the side that is attached to the benzodiazepine nucleus) And X is carbon or nitrogen. Y is carbon or nitrogen or carbonyl group. Z is, From above mentioned general scheme, it appears that there is a common strategy for synthetic preparation of the benzodiazepine derivatives involves N-methylation benzodiazepine ring as a common step. The benzodiazepine moiety (Formula-II) required for synthesis can be prepared from corresponding suitable benzophenone derivatives which is commonly described in the literature. The synthesis of benzodiazepine involves a common step N-methylation and formation of pharmaceutically active benzodiazepine derivatives from benzodiazepine derivatives (formula-II).The formation of benzodiazepine derivatives and its N-methylation forms a common synthetic step in various pharmaceutically active benzodiazepine derivatives such as clobazam, tetrazepam and clotiazepam etc. The preparation of Tetrazepam is disclosed in US-3426014, in which 7-chloro-5-(l -cyclohexenyl)-2-oxo-2,3-dihydro- 1H benzo(f) diazepine-1,4 is methylated with sodium methoxide as base and methyl iodide as methylating agent in dry dimethyl formamide. The Tetrazepam is isolated from from reaction mixture by extracting with ethyl acetate. As per US-3551412, N-methylation of 7-chloro-5-(l -cyclohexenyl)-2-oxo-2,3-dihydro- 1H benzo(f) diazepine-1,4 is carried out in anhydrous dimethyl formamide as a solvent media using sodium methoxide as base and methyl iodide as a methylating reagent to produce clobazam with yield 52%. The drawback of this process is the usage of expensive methylating agent like methyl iodide and moderate yield of 52%.Further, maintenance of anhydrous condition may be the limiting factor on large scale preparation. As per US3984398 methylation of 1-phenyl -8-chlorol,2A5,tetrahydro-2,4-dioxo-3H-l-5-bezodiazepine is carried out by acting methyl chloride in presence of sodium ethanolate fallowed by recrystallization in 50% ethanol or isopropanol to gives l-phenyl-5- methyl -8-chlorol,2,4,5,tetrahydro-2,4-dioxo-3H-l-5-bezodiazepine. In similar way alkylation i.e. butylation is carried out in anhydrous ethanol and sodium by using n-butyl bromide as alkylation reagent. From commercial point of view, above said preparation can generate industrial waste on large scale due to aqueous dimethyl formamide. Hence there is need for cost effective and commercially viable process for preparation of benzodiazepine derivatives such as clobazam, tetrazepam and clonazepam. In our embodiment N-methylation carried out in biphasic solvent system such as methylene chloride and alkaline water (5.2 % sodium hydroxide solution) in presence of phase transfer catalyst like tetra butyl ammonium bromide which gives good yield about 80-85% compare to yield reported in prior art. In another embodiment the reagent used for N-methylation purpose is dimethyl sulphate which is cheap and readily available methylating agent. The present invention provides a process which is devoid of the use of expensive and hazardous reagent, and critical reaction parameters. Also, the solvent used as reaction medium is recovered after completion of reaction which makes the process environment friendly and commercially viable. OBJECT OF INVENTION The main object of said invention is to provide a commercially suitable process which involves convenient operation parameters, use of non hazardous regents and solvents for the preparation of benzodiazepine derivatives such as clobazam, tetrazepam and clotiazepam.Other object of said invention is to provide cost effectiveness due to high yield over the existing prior art. SUMMARY OF INVENTION This invention mainly directed to industrially feasible and environment friendly process for the preparation of benzodiazepine derivatives such as clobazepam, tetrazepam and clonazepam etc. In this N-methylation is carried out under milder conditions and also it avoids the use of highly toxic reagents. This method offer distinct advantages over prior art used for the preparation of benzodiazepine derivatives which involves simple reaction parameters with ease of isolation and solvent used can be recovered,. Hence by reduce the generating waste. Importantly the present method is industrially applicable and cost effective due to good yield i.e. 80-85% . The preparation of benzodiazepine derivatives involves the following common synthetic step: (The spiral line indicate the side that is attached to the benzodiazepine nucleus) And X is carbon or nitrogen atom. Y is carbon or nitrogen or carbonyl group. Zis, More specifically, in an embodiment the intermediate 7-chloro-5-phenyM ,5-dihydro -3H-l,5-benzodiazepine-2,4-dione (Clobazam intermediate) in biphasic solvent system such as methylene chloride and aqueous alkali is treated with dimethyl sulphate in presence tetra butyl ammonium bromide as phase transfer catalyst. The reaction carried out at temperature 25-30°C for 4-5 hours and after completion of reaction aqueous phase extracted with methylene chloride and combine extracted organic layer is washed with water . Finally concentrated under vacuum to get crude 7-chloro-l- methyl -5-phenyl-l,5-dihydro-3H-l,5~benzodiazepine-2,4-dione (crude clobazam) in solid form. Furthermore Crude 7-chloro-l- methyl -5-phenyl-l,5-dihydro-3H-l,5-benzodiazepine-2,4-dione (crude clobazam)stirred at room temperature in aliphatic ester solvent to produce a pure clobazam (title compound). In an another embodiment 7-Chloro-5-(cycIohex-l-enyl)-l,3-dihydro-2H- 1,4-benzodiazepin-2-one (tetrazepam intermediate) in biphasic solvent system such as methylene chloride or toluene and aqueous alkali treated with dimethyl sulphate in presence of phase transfer catalyst like tetra butyl ammonium bromide . The reaction carried out at tempreture 25-30°C for 4-5 hours and after completion of reaction aqueous phase extracted with methylene chloride or toluene and combine extracted methylene chloride or toulene with organic layer furthermore washed by water . Finally distilled out organic layer and added cyclohexane with stirring to produce crude 7-Chloro-5-(l-cycIohexen-l-enyl)-l,3-dihydro-l-methy-2H-l,4-benzodiazepin-2-one (crude tetrazepam) in solid form. Furthermore crude 7-Chloro-5-(l-cyclohexe-l-enyl)-l- methyl-l,3-dihydro-2H-l,4-benzodiazepin-2-one (crude tetrazepam) stirred at room temperature in methanol or isopropanol to produce a pure tetrazepam (title compound). In an another embodiment the intermediate 5-o-Chlorophenyl-7-ethyI-l,3-dihydro- 2H-thieno[2,3-e][l,4]diazepin-2-one (Clotiazepam intermediate) in biphasic solvent system such as methylene chloride and alkaline water treated with dimethyl sulphate in prescence of phase transfer catalyst like tetra butyl ammonium bromide . The reaction carried out at temperature 25-35°C for 4-5 hours and after completion of reaction aqueous phase extracted with methylene chloride or toluene and combine extracted methylene chloride or toluene with organic layer furthermore extracted organic layer by water respectively. Finally distilled out organic layer and added cyclohexane with stirring to produce crude 5-o-Chlorophenyl-7-ethyI-l,3-dihydro-2H- thieno[2,3-e][l,4]diazepin-2-one (crude clotiazepam) in solid form.Furthermore crude 5-o- Chlorophenyl-7-ethyI-I,3-dihydro-2H-thieno[2,3-e][l,4]diazepin-2-one (crude clotiazepam)stirred at room temperature in aliphatic ester solvent to produce a pure clotiazepam(title compound). According to present invention the preparation of benzodiazepine derivatives involves steps of: Step-I The benzodiazepine derivatives (formula-II) in biphasic solvent system such as methylene chloride or toluene and aqueous alkali treated with dimethyl sulphate in prescence of phase transfer catalyst like tetra butyl ammonium bromide to produce benzodiazepine derivatives. The reaction carried out at temperature 25-35°C for 4-5 hours and after completion of reaction aqueous phase extracted with methylene chloride or toluene and combine organic layer. Finally distilled out organic layer and added water with stirring to produce crude benzodiazepine derivatives in solid form. Step-II Crude benzodiazepine derivatives stirred at room temperature in aliphatic ester and alcohols to produce pure benzodiazepine derivatives (title compound). DETAILS DESCRIPTION OF INVENTION While the invention will now be described in detail in connection with certain preferred and optional embodiments, so that the various aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to theses particular embodiments. This improved process for preparation of benzodiazepine derivatives carried out in two steps which has been depicted as follows: (The spiral line indicate the side that is attached to the benzodiazepine nucleus) And X is carbon or nitrogen atom. Y is carbon or nitrogen or carbonyl group. Zis, The benzodiazepine derivatives preferably carried out in biphasic solvent system such as methylene chloride or toluene and aqueous alkali (5.2 % sodium hydroxide solution) in presence of phase transfer catalyst such as tetra butyl ammonium bromide. The molar ratio for formula-II to methylation reagent like dimethyl sulphate is in at least 1:0.5 but preferably in ratio 1: 1.28 The molar ratio of formula-II to phase transfer catalyst like tetra butyl ammonium bromide is in at least 36:0.5 but preferably in ratio 36:1 and N-methylation reaction carried out normally at 10-35°C but preferably 25-30 °C for 4-5 hours. The sodium hydroxide concentration is 1-20% W/V but preferably 5to 6 % W/V . The reaction mass (after completion of reaction) is separated and aqueous layer extracted by methylene chloride or toluene and combined organic layer furthermore washed with water. Distilled out methylene chloride or toluene completely and added water in 1:7.5 proportions at room temperature and stirred for 1-2 hours for complete precipitation to get crude solid of compound. The dry cake obtained from above said N-methylation reaction is slugged in aliphatic ester solvent like ethyl acetate or alcohols at least for 1 hour to get pure form of title compound. In an embodiment of present invention, the intermediate 7-chloro-5-phenyl-l,5-dihydro-3H-l,5-benzodiazepine-2,4-dione (Clobazam intermediate) in biphasic solvent system such as methylene chloride and alkaline water treated with dimethyl sulphate in presence of phase transfer catalyst like tetra butyl ammonium bromide . The reaction carried out at temperature 25-35°C for 4-5 hours and after completion of reaction aqueous phase extracted with methylene chloride and combined organic layer is washed with water .Finally distilled out organic layer and added water with stirring to produce crude 7-chloro-l-methyl-5-phenyl-l,5-dihydro-3H-l,5-benzodiazepine-2,4-dione (crude clobazam) in solid form. Furthermore Crude 7-chloro-l-methyl-5-phenyl-l,5-dihydro-3H-l,5-benzodiazepine-2,4-dione (crude clobazam)stirred at room temperature in aliphatic ester solvent to produce a pure clobazam (title compound). In an another embodiment 7-ChIoro-5-(cyclohex-l-enyl)-l,3-dihydro-2H- l,4-benzodiazepin-2-one (tetrazepam intermediate) in biphasic solvent system such as methylene chloride or toluene and aqueous alkali treated with dimethyl sulphate in presence of phase transfer catalyst like tetra butyl ammonium bromide . The reaction is carried out at temperature 25-35°C for 4-5 hours and after completion of reaction aqueous phase extracted with methylene chloride or toluene and combined organic layer is washed with water . Finally distilled out organic layer and added cyclohexane with stirring to produce crude 7-Chloro-5-(1-cyclohexen-l- enyl)-1,3-dihydro-l-mehty-2H-1,4-benzodiazepin-2-one (crude tetrazepam) in solid form. Furthermore crude 7-Chloro-5-( 1 -cyclohexen-1 -enyl)-1,3-dihydro-1 -mehty-2H-l ,4- benzodiazepin-2-one (crude tetrazepam) stirred at room temperature in methanol or isopropyl alcohol or ethanol solvent to produce a pure tetrazepam (title compound). In an another embodiment the intermediate 5-o-Chlorophenyl-7-ethyl-l,3-dihydro-2H-thieno[2,3-e][l54]diazepin-2-one (Clotiazepam intermediate) in biphasic solvent system such as methylene chloride or toluene and aqueous alkali treated with dimethyl sulphate in presence of phase transfer catalyst like terra butyl ammonium bromide . The reaction carried out at temperature 25-35°C for 4-5 hours and after completion of reaction aqueous phase extracted with methylene chloride or toluene and combined organic layer is washed with water .Finally distilled out organic layer and added water with stirring to produce crude 5-o-ChIorophenyl-7-ethyI-l,3-dihydro-2H-thieno[2,3-e][l,4]diazepin-2-one (crude clotiazepam) in solid form.Furthermore crude5-0-Chlorophenyl-7-ethyI-l,3-dihydro-2H-thieno[2,3-e][ls4]diazepin-2-one (crude dotiazepam)stirred at room temperature in aliphatic ester solvent to produce a pure clotiazepam(title compound). Thus from our preferred embodiment ,the N-methylation of benzodiazepine derivatives are carried out in biphasic solvent system in presence of phase transfer catalyst which exert a good yield and purity as well as ease in isolation of final product. Furthermore the N-methylation reagent like dimethyl sulphate is redially available for large scale of preparation. Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following examples are given to illustrate the present invention. It should be understood that the invention is not to be limited to the specific conditions or details described in this example. Example-I General preparation of benzodiazepine derivatives The following general scheme and reaction conditions illustrate the formation of benzodiazepine derivatives: (The spiral line indicate the side that is attached to the benzodiazepine nucleus) And X is carbon or nitrogen atom. Y is carbon or nitrogen or carbonyl group. Zis, Charged benzodiazepine derivatives (formula-II) 1 mole in 2600 ml biphasic solvent system such as methylene chloride or toluene and aqueous alkali treated with 1.28 moles of dimethyl sulphate in presence of phase transfer catalyst like tetra butyl ammonium bromide 0.027 mole. The reaction carried out at temperature 25-35°C for 4-5 hours and after completion of reaction separate the layers and aqueous phase extracted with methylene chloride or toluene and combined organic layer is washed by water . Finally distilled out organic layer is added with water with stirring to produce crude benzodiazepine derivatives in solid form.Crude benzodiazepine derivatives stirred at room temperature in aliphatic ester or alcohols to produce pure benzodiazepine derivatives (title compound). Example-II Preparation of Clobazam. Charged 7-chloro-5-phenyl-l,5-dmydro-3H-l,5-benzodiazepine-2,4-dione (Clobazam intermediate) (84 gms) and methylene chloride (425 ml)in a 1.0 Ltr RB flask.Added tetrabutyl ammonium bromide (2.55 gms) to the reaction mixture .Cooled the reaction mixture to 10°C and added sodium hydroxide solution 18.75 gm in 360 ml water through thr dropping funnel to maintain temperature between 10-15°C within 30-60 minutes. Stirred the reaction mixture and at 10-15°C for 30 minutes and added dimethyl sulphate 34 ml through the dropping funnel at 10-15 °C within 30-45 minutes. Stirred the reaction mixture at 10-15°C for 30 minutes and raised the temperature of reaction mixture to 25-35°C and stirred the reaction mixture for 4-5 hours at 25-35°C .At the end of reaction separated the methylene chloride layer and extracted the aqueous phase with methylene chloride 200 ml. Combined the methylene chloride layer was washed by water . Distilled out methylene chloride and added 600 ml water, cooled the reaction mixture to room temperature and stirred for 1-2 hours .The solid precipitate were filtered and washed with water 50 ml finally dried the the crude product in oven at 60-70°C for 6-8 hours.Crude product obtained from above said steps added ethyl acetate to produce pure clobazam. Yield = 75-85%. Example-Ill Preparation of tetrazepam Charged 7-Chloro-5-(cyclohex-1 -enyl)-1,3 -dihydro-2H-1,4-benzodiazepin-2-one (tetrazepam intermediate) (84 gms) and toulene (425 ml)in a 1.0 Ltr RB flask.Added tetrabutyl ammonium bromide (2.55 gms) to the reaction mixture .Cooled the reaction mixture to 10°C and added sodium hydroxide solution 18.75 gm in 360 ml water through the dropping funnel to maintain temperature between 10-15°C within 30-60 minutes. Stirred the reaction mixture and at 10-15°C for 30 minutes and added dimethyl sulphate 34 ml through the dropping funnel at 10-12 °C within 30-45 minutes. Stirred the reaction mixture at 10-15°C for 30 minutes and raised the temperature of reaction mixture to 25-35°C and stirred the reaction mixture for 4-5 hours at 25-35°C .At the end of reaction separated the toluene layer and extracted the aqueous phase with toluene 200 ml. Combined the toluene layer was washed by 200 ml water respectively. Distilled out toluene at 55°C added cyclohexane 5 parts, cooled the reaction mixture to room temperature and stirred for 1-2 hours .The crude product is isolated by filtration. The crude product is further recrystallized from methanol: water followed by 5 parts of methanol to produce pure tetrazepam. Yield = 75-85%. ExampIe-IV Preparation of Clotiazepam Charged5-o-Chlorophenyl-7-ethyl-l,3-dihydro-2H-thieno[2,3-e][l,4]diazepin-2one (Clotiazepam intermediate) (89.27 gms) and methylene chloride (425 ml)in a 1.0 Ltr RB flask. Added tetrabutyl ammonium bromide (2.55 gms) to the reaction mixture .Cooled the reaction mixture to 10°C and added caustic solution 18.75 gm in 360 ml water through the dropping funnel to maintain temperature between 10-15°C within 30-60 minutes. Stirred the reaction mixture and at 10-15°C for 30 minutes and added dimethyl sulphate 34 ml through the dropping funnel at 10-15 °C within 30-45 minutes. Stirred the reaction mixture at 10-15°C for 30 minutes and raised the temperature of reaction mixture to 25-35°C and stirred the reaction mixture for 4-5 hours at 25-35°C .At the end of reaction separated the methylene chloride layer and extracted the aqueous phase with methylene chloride 200 ml . Combined the methylene chloride layer was washed by water .Distilled out methylene chloride and added 600 ml water, cooled the reaction mixture to room temperature and stirred for 1-2 hours .The solid precipitate were filtered and washed with water 50 ml finally dried the the crude product in oven at 60-70°C for 6-8 hours.Crude product obtained from above said steps added ethyl acetate to produce pure clotizepam. Yield -75-85%. Although presently preferred embodiments of the invention have been specifically described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the various embodiments shown and described herein may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law. What is claimed is: 1) An improved process for preparation of benzodiazepine derivatives of formula -I (The spiral line indicate the side that is attached to the benzodiazepine nucleus) And X is carbon or nitrogen atom. Y is carbon or nitrogen or carbonyl group. Zis, The process comprising N-methylation of formula-II Using dimethyl sulphate in prescence of phase transfer catalyst such as tetrabutyl ammonium bromide in aqueous alkali and methylene chloride or toulene as a biphasic solvent media to produce compound formula-I. 2) The process of claim 1, wherein the reagent used for N-methylation of compound formula -II is dimehtyl sulphate in mole ratio 1:2 but preferably to 1:1.28 against formula-II. 3) The process of claim 1, where the N-methylation of formula-II is carried out in biphasic system; methylene chloride or toulene: aqueous alkali at temperature 25-35°C for 4-5 hours to produce formula-I. 4) The process of claim 1, further comprising the steps of: a) Separation of layers and extraction by water to organic layer b) Distillation of organic layer completely which furthermore addition of water or cyclohexane at room temperature to precipitate out formula-I in crude form. 5) The process of claim 1, wherein further comprising: Treating dry cake obtained from the N-methylation of formula-II with solvent selected from aliphatic ester solvent such as ethyl acetate or alcohols such as methanol or ethanol at room temperature to produce pure Formula-I. 6) The process of claim 1, wherein molar ratio of said formula-H to phase transfer catalyst; tetra butyl ammonium bromide is at least 36:0.5 mole but preferably 36:1. mole. 7) The process of claim 1, wherein said process is used for manufacture of clobazam, tetrazepam and clotiazepam about yield 75-85% and purity above 99%. 8) The process of claim 1, wherein said formula -I is selected from group consisting of clobazam, tetrazepam and clotiazepam.

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