A NOVEL PROCESS FOR THE PREPARATION OF 4-(2-CHLOROPHENYL)-2-ETHYL-9-METHYL-6H-THIENO[3 2-f][1 2 4]TRIAZOLO[4 3-a][1 4]DIAZEPINE (ETIZOLAM)

Field of the Invention
This invention  in general relates to a process for preparing 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (Etizolam). More particularly  the present invention provides a novel economical process for the preparation of highly pure 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (Etizolam) of Formula-I.

Background of the Invention
Etizolam  4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine  is known to treat anxiety disorder and as an unrivalled treatment for depression. Etizolam is also being extensively explored for the treatment of insomnia and short term treatment of panic attacks.

Etizolam and its intermediates are disclosed in various references including US Patent No. 3 904 641. The preparation of Etizolam as disclosed in US ‘641 is as depicted in scheme-1.

Scheme 1:

In the above scheme  5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepin-2(3H)-one (Formula- II) is reacted with phosphorus pentasulphide in presence of solvents like Tetrahydrofuran (THF)  Dimethylformamide (DMF)  Pyridine and recrystallised in ethanol and chloroform to produce 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepine-2(3H)-thione (Formula-III)  followed by treatment with hydrazine hydrate to produce 5-(2-chlorophenyl)-7-ethyl-2-hydrazono-2 3-dihydro-1H-thieno[2 3-e][1 4]diazepine (Formula-IV). Compound of Formula-IV is treated with orthoacetate to give 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine  Etizolam (Formula-I)

According to another embodiment given in the above patent  Etizolam (Formula-I) is synthesized from 5-(2-chlorophenyl)-7-ethyl-2-hydrazono-2 3-dihydro-1H-thieno[2 3-e][1 4]diazepine (Formula-IV) by treating compound of Formula IV with acetimino ethyl ether hydrochloride or acetamidine hydrochloride in presence of acid like sulphuric acid or base like 2-methyl imidazole respectively  in the solvent like chloroform followed by recrystallization in the mixture of ligroin and acetone.

The main drawback in above said process is the use of highly flammable liquid ligroin and ethyl orthoacetate  where  such flammable liquids are difficult to handle at industrial scale.

CA 2 012 411 & US 4 968 794 disclose the process for the preparation of hydrazine diazepine derivatives wherein oxodiazepines are converted to their respective thio-diazepines by treating oxodiazepines with P2S5 in diglyme. Moreover reaction is carried out in presence of base which is followed by conversion of thio diazepines to their respective hydrazine derivatives by reacting thione derivatives with hydrazine hydrate in solvents like THF.

EP 0 268 242  discloses process for preparation of diazepine analogues. The process involves preparation of thione intermediate by treating oxodiazepines with Lawesson’s reagent in the solvent like toluene at temperature range of 38-48oC  followed by treating thione so obtained with hydrazine hydrate at ice cooled low temperature. The different diazepine analogues are prepared from their respective hydrazine-diazepine intermediate by cyclization process which is performed in suitable solvent in the presence of acetic acid and acetic anhydride.

Here  sulfurisation process involves use of expensive reagent like Lawesson’s reagent which results in increase in the cost of production at commercial scale. Moreover  acetic anhydride is toxic and flammable liquid and according to Occupational Safety and Health Administration (OSHA) permissible exposure limits (PEL) for acetic anhydride is 5 ppm which is difficult to maintain when used at large scale.

Patent US 3 849 405  reported a process for preparing the intermediate 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepin-2(3H)-one of Formula-II as per scheme 2  using 2-amino-N-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)acetamide (Formula-VI) or (2-amino-5-ethylthiophen-3-yl)(2-chlorophenyl)methanone (Formula-VII) as the starting materials. The process involves cyclization of 2-aminoacetamido-3-o-chloro benzoyl-5-ethylthiophene (Formula-VI) in presence of benzene  acetic acid and pyridine under reflux for 10h followed by recrystallization in toluene to give Formula-VIII.

According to another embodiment  Formula-VII is treated with ethyl glycinate hydrochloride in presence of pyridine as solvent under reflux conditions for 20h. Further purification by conventional method like silica gel-chromatography is required to get pure compound of Formula-II.

Scheme 2:

The above mentioned patent also discloses preparation of compound of Formula-VI and analogues in multiple steps through formation and isolation of intermediates like iodoacetamido and azidoacetamido compounds.

The drawbacks of the above mentioned processes are requiring more operations to obtain oxodiazepine derivatives; synthesis of intermediates like azide compound requires critical parameters and requiring the use of column chromatography for purification of compound of Formula-II  consequently making process uneconomical at commercial scale.

Patent DE 2940737  describes another strategy for the preparation of triazole-benzodiazepines of compound of Formula-XII; as revealed in Scheme 3.

Wherein R1  R2 are each independently hydrogen  or alkyl group; R3 is hydrogen  halogen  or alkyl group; and R4 and R5 are each independently hydrogen or halogen.

Scheme 3:

The process involves reacting Formula-IX with hydroxylamine in presence of KI to produce cyclised compound of Formula-X  which on dehydration give Formula-XI. The compound of Formula-XI when reacted with PCl5 or PBr3 or TPP produces triazole-benzodiazepine of Formula-XII.

The synthetic method disclosed herein involves  use of very toxic and environmentally hazardous chemical like mercuric oxide  which when working in large scale makes the process environmentally unfriendly. Additionally  above said process is tedious as well as expensive.

US 3 872 089  discloses different approach for the preparation of compound of Formula-XIX  wherein R3 is halophenyl.

According to the above patent  Formula-XIX is prepared starting from nitrile compound of Formula-XIII as described in scheme-4.

Scheme-4:

According to above patent  nitrile compound of Formula-XIII  when treated with methyl magnesium bromide followed by hydrolysis obtained compound of Formula-XIV or Formula-XV  which on treatment with Br2 in chloroform in presence of AlCl3 or diazomethane and hydrogen bromide respectively  produces compound of Formula-XVI. The bromide derivative XVI is further treated with sodium and nitrile source  acetonitrile (ACN) in solvent like benzene followed by hydrolysis to obtain compound of Formula-XVII through an imine intermediate XVIa. The compound so obtained when further condensed with a-mercaptoacetaldehyde in solvent at 50oC for 15h obtained cyclised product of Formula-XVIII which is further converted to oxodiazepine of Formula-XIX in multiple steps.

The disadvantage of the above mentioned method is that multiple isolation steps are necessary to get desired oxo-diazepine derivatives which ultimately results into increase in production cost.

CN101648939  discloses preparation of compound of Formula-II by reacting compound of Formula-XX

with a mixture of hydrazine hydrate in methanol or ethanol at 20-80oC to give 2-amino-N-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)acetamide (Formula-XXI)

Compound of Formula-XXI is then cyclised using toluene and silica gel to give 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepin-2(3H)-one of Formula-II.

The processes disclosed in the prior art involves time consuming reaction steps as well as use of reagents which are difficult in handling and involves tedious workups. The processes include multiple steps for extraction and isolation and time consuming purification processes to obtain the desired derivatives  which results into wastage of material  thus making synthetic route lengthy  low yielding  expensive and uneconomical. Moreover  the processes mentioned in the prior art are suitable only at small scale as most of them require use of hazardous chemicals consequently making process toxic to environment and unsuitable for large-scale production.

Therefore  there is a need to provide a cost effective and ecologically friendly process for producing triazol-benzodiazepine derivatives  such as Etizolam of high purity and yield for human consumption. To meet the increasing demand  there exists a need to develop a simple and efficient  commercially and economically viable process for large scale industrial manufacturing of Etizolam.

Object and Summary of the Invention
It is the principal object of the present invention to improve upon limitations in the prior art by providing a process for producing 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (Etizolam) which is employed for the treatment of anxiety and depression.

It is another object of the present invention to provide a commercially viable  economical and environmentally friendly process for preparing 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine of Formula-I  wherein the process employs minimal reaction  extraction and purification steps.

It is yet another object of the present invention  to provide simple and safe process for the preparation of 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine of Formula-I at industrial scale employing user friendly  cost efficient and non-hazardous raw materials.

The above and other objects of the present invention are further attained and supported by the following embodiments described herein. However  the described embodiments are in accordance with the best mode of practice and the scope of the invention is not restricted to the described embodiments herein after.

In accordance with one embodiment of the present invention there is provided a process for producing 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepinem (Etizolam) of Formula-I.

The said process comprises the steps of:
a) reacting 2-chlorobenzonitrile compound of Formula (i)

with acetonitrile in presence of base and solvent  to obtain 3-(2-chlorophenyl)-3-oxopropanenitrile of Formula (ii)
 
b) cyclization of compound of Formula (ii) with butaldehyde and sulphur in presence of base and organic solvent to obtain (2-amino-5-ethylthiophen-3-yl)(2-chlorophenyl) methanone of Formula (iii)
 
c) one-pot reaction of N-phthaloyl glycine of Formula (v) with in situ coupling of acid chloride intermediate with compound of Formula (iii) in presence of acid and organic solvent(s) 

followed by addition of base  to give N-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-2-(1 3-dioxoisoindolin-2-yl)acetamide of Formula (vi)
 
d) one-pot cyclization of compound of Formula (vi) to 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepin-2(3H)-one of Formula (vii) without the isolation of intermediates

by reacting compound of Formula (vi) with hydrazine hydrate and acid in protic solvent like isopropyl alcohol (IPA) 
e) sulfurization of compound of Formula (vii) with phosphorus pentasulfide in absence of base to give 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepine-2(3H)-thione of Formula (viii)
 
f) converting compound of Formula (viii) to hydrazine derivative; 5-(2-chlorophenyl)-7-ethyl-2-hydrazono-2 3-dihydro-1H-thieno[2 3-e][1 4]diazepine of Formula (ix)

by reacting compound of Formula (viii) with hydrazine hydrate in presence of suitable organic solvent 
g) subjecting the resultant compound of Formula (ix) to cyclization by treating with acid in suitable solvent to obtain crude compound  Etizolam of Formula-I  and
h) treating crude Etizolam with solvent at elevated temperature to get pure compound of Formula-I with purity above 99.8%.

Furthermore  according to the process of the present invention  the process for the preparation of Etizolam further comprises reacting a compound of Formula (iv) wherein R1  and R2 are selected independently from hydrogen or amine protecting group  R3 is hydrogen or (C1-C6)-alkyl group 

with phthalic anhydride  to obtain a compound of Formula (v)  in presence of base and low-toxic solvent.

Detailed Description of the Invention
While the invention will now be described in detail in connection with certain embodiments  so that various aspects thereof may be more clearly understood and appreciated  it is not intended to limit the invention to these particular embodiments.

The method described herein further provides substantial benefits relative to previously used or suggested production methods of prior art and the starting materials  intermediates  liquid media are relatively easier to handle and to dispose off  if necessary.

According to the aspect of present invention  there is provided a novel process for preparing a compound represented by Formula-I 

which comprises the steps of:
a) reacting 2-chlorobenzonitrile compound of Formula (i)

with acetonitrile in presence of base and solvent  to obtain 3-(2-chlorophenyl)-3-oxopropanenitrile of Formula (ii)
 
b) cyclization of compound of Formula (ii) with butaldehyde and sulphur in presence of base and organic solvent to obtain (2-amino-5-ethylthiophen-3-yl)(2-chlorophenyl) methanone of Formula (iii)
 
c) one-pot reaction of N-phthaloyl glycine of Formula (v) with in situ coupling of acid chloride intermediate with compound of Formula (iii) in presence of acid and organic solvent(s) 

followed by addition of a base  to give N-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-2-(1 3-dioxoisoindolin-2-yl)acetamide of Formula (vi)
 
d) one-pot cyclization of compound of Formula (vi) to 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepin-2(3H)-one of Formula (vii) without the isolation of intermediates

by reacting compound of Formula (vi) with hydrazine hydrate and acid in protic solvent like isopropyl alcohol 
e) sulfurization of compound of Formula (vii) with phosphorus pentasulfide in absence of base to give 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepine-2(3H)-thione of Formula (viii)
 
f) converting compound of Formula (viii) to hydrazine derivative; 5-(2-chlorophenyl)-7-ethyl-2-hydrazono-2 3-dihydro-1H-thieno[2 3-e][1 4]diazepine of Formula (ix)

by reacting compound of Formula (viii) with hydrazine hydrate in presence of suitable organic solvent 
g) subjecting the resultant compound of Formula (ix) to cyclization by treating with acid in suitable solvent to obtain crude compound  Etizolam of Formula-I  and
h) treating crude Etizolam with a solvent at elevated temperature to get pure compound of Formula-I with purity above 99.8%.

Furthermore  according to the process of the present invention  the process for the preparation of Etizolam further comprises reacting a compound of Formula (iv) wherein R1  and R2 are selected independently from hydrogen or amine protecting group  R3 is hydrogen or (C1-C6)-alkyl group 

with phthalic anhydride  to obtain a compound of Formula (v)  in presence of base and low-toxic solvent.

The base used in the step a) is selected from a weak base like hydroxides  carbonates  bicarbonates  or a strong base like alkali and alkaline earth metals. Preferably  the base used in step a) is a strong base. Most preferably  the strong base is an alkali metal selected from sodium or potassium metal. The solvent used in step a) is selected from polar and non-polar solvents like C1-C4 alcohol  amides  sulfoxides  ketones  ethers  esters  halogenated or non-halogenated hydrocarbons or mixtures thereof. The preferred solvent is non-halogenated hydrocarbons like toluene  xylene  cyclohexane  cycloheptane  and more preferred solvent is toluene. The reaction step a) is carried out at a temperature range of 25-150oC  preferably at 90-125oC.

The cyclization reaction of compound of Formula (ii) as in step b) can be performed according to the teachings known to those skilled in the prior art  such as those described in Heterocycles  31(7)  1241-4  1990 and US 2010/0317709.

The base used in step b)  is selected from organic and inorganic base. The base used in step b) is organic base which is selected from amine like triethyl amine (TEA)  di-isopropyl ethyl amine  tributylamine  pyridine or dimethyl aniline. The more preferred base is triethylamine and diisopropyl ethylamine. The solvent used in step b) is selected from organic solvent such as amide  sulfoxide  chlorinated solvent  C1-C4 alcohol  hydrocarbons  most preferably selected from Dimethylformamide (DMF)  dimethyl sulfoxide (DMSO)  N-methyl pyrrolidine (NMP)  Dimethylacetamide (DMAc) or mixture thereof. It is contrary to the prior art process that sequential addition of reagents  base and solvent resulted into the isolation of (2-amino-5-ethylthiophen-3-yl)(2-chlorophenyl) methanone of Formula (iii) with high yields (up to 90%) whereas process mentioned in the prior art is a one-shot addition process with poor isolation yields.

In a preferred embodiment the one pot process of reaction of Formula (v)  as in step c)  with compound of Formula (iii) could be performed in presence of an acid like COCl2  SOCl2  PCl5  preferably SOCl2  in at least one non-polar solvent and one hydrocarbon solvent  in presence of at least one base. The reaction could proceed at ambient temperature. According to the present invention  the acid chloride intermediate formed in the reaction is in situ coupled with compound of Formula (iii) without isolation.

The base used in step c) is inorganic base. The inorganic base is selected from the group consisting of carbonate  a hydroxide  or a (C1-C4)-alkoxide of an alkali metal or alkaline earth metal. More preferably base is sodium or potassium carbonate.

The organic solvent (s) used in step c) is at least one non-polar solvent and one hydrocarbon solvent wherein  non-polar solvent is selected from tetrahydrofuran  diethyl ether  di-isopropyl ether  dioxane or cumene or mixture thereof. More preferably dioxane or tetrahydrofuran is used. The most preferred non-polar solvent is dioxane. Hydrocarbon solvent is selected from o-xylene  m-xylene  p-xylene  toluene  cyclohexane  or cycloheptane. More preferred hydrocarbon solvent is toluene or xylene.

The reaction step c) is carried out at a temperature range of 25-120oC. Preferably  the temperature range is 70-100oC.

In a further preferred embodiment the two synthetic steps (deprotection and cyclization)  in step d); are performed in one-pot without isolation of the amide intermediate by reacting compound of Formula (vi) with hydrazine hydrate and acid like acetic acid. The solvent used in the step d) is protic solvent like isopropyl alcohol.

The reaction step d) is carried out at a temperature range of 50 to 100oC. Preferably the temperature range is 70-85oC.

In other preferred embodiment  the sulfurization of compound of Formula (vii) is carried out in absence of base by reacting compound of Formula (viii) with P2S5 in solvent like C1-C2 alcohol  ethylene glycol or inert solvents like diglyme  toluene  xylene  tetrahydrofuran  dioxane or mixture thereof. More preferred solvent is diglyme. The sulfurization reaction is carried out at a temperature range of 30 to 100oC. Preferably the temperature range is 30-60oC. Compound of Formula (viii) is isolated by quenching the reaction mass with inorganic base like carbonates  bicarbonates  hydroxides  alkoxides of alkaline or alkaline earth metal. More preferably  bicarbonates like sodium or potassium bicarbonate are used.

The conversion of compound of Formula (viii)  according to step f)  to its respective hydrazine derivative can be performed according to the teachings known to those skilled in the prior art  such as those described in Arzneimittel-Forschung  28(7)  1153-8  1978; DE2229845  US 3 904 641 and US 3 987 052.

The organic solvent used in step f) is C1-C4 alcohol like methanol. The temperature range is between 30 and 100oC. Preferably the temperature range is 40-50oC.

The cyclization reaction for obtaining 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (Etizolam) is performed in presence of acid like trimethyl orthoacetate.

The molar ratio of trimethyl orthoacetate used in step g) is 1.0 to 9.0 of the compound of Formula (ix). The preferred molar ratio of trimethyl orthoacetate is 1.5 to 5.0 of the compound of Formula (ix).

The solvent used in step g) is selected from inert solvent like toluene  xylene  tetrahydrofuran  cyclohexane  mesitylene  dioxane  or halogenated solvent like chloroform  protic solvent like C1-C3 alcohol  esters or mixtures thereof. The most preferred solvent is toluene  o-xylene  m-xylene  p-xylene  cyclohexane  ethylacetate or mixture thereof.

Step g) is carried out at a temperature range of 20 to 100oC. Preferably the temperature range is 40-50oC. Resulting 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (Etizolam) is converted to pure Etizolam with or without isolation. Etizolam could be purified using methods like recrystallization with solvent like ketone  ester  hydrocarbon  halogenated solvent  ether or mixture thereof. Recrystallization process is performed at a temperature range of 50 to 150oC. Preferably the recrystallization process is performed at 60 to 90oC.

In the preferred embodiment  recrystallization is performed in solvents like acetone  diethyl ether  chloroform  dichloromethane  methyl ethyl ketone  cyclohexane  ethyl acetate or mixtures thereof. Desired Etizolam is obtained with purity above 99.8%.

Moreover  synthesis of compound of Formula (v) is carried out by reacting compound of Formula (iv) with phthalic anhydride in presence of a base at a temperature range of 60 to 170oC. The preferred temperature range is 110 to 140oC 

wherein R1  R2 and R3 are as defined above. The base used in synthesis of intermediate of Formula (v) is organic base like amine  preferably triethylamine.

In the present invention  the low-toxicity organic solvent (s)  used in the synthesis of intermediate of Formula (v)  is selected from xylene  acetonitrile (ACN)  N-methyl pyrrolidine (NMP)  anisole  ethylene glycol  tert-butyl methyl ether  ethyl acetate  dimethyl sulfoxide (DMSO)  ethyl formate or mixture thereof. More preferred solvent is xylene viz. o-xylene  m-xylene or p-xylene.

Further  the present invention is illustrated in detail by way of the following examples. The examples are given herein for illustration of the invention and are not intended to be limiting thereof.

Example 1
Preparation of 3-(2-chlorophenyl)-3-oxopropanenitrile
[Formula (ii)]
Charged 55g (2.39mol) of sodium metal to 750ml of toluene under inert conditions and stirred under heating at 90-105oC  followed by addition of 150g (1.09mol) of 2-chloro benzonitrile  100.0g (2.45mol) of acetonitrile in 350ml of toluene. Stirred the reaction mass under heating at 110oC for 1hour. Reaction mixture was cooled to 10oC and the pH was adjusted to 1.0-2.0 by hydrochloric acid. Stirred the reaction mass at 30-35oC  separated the toluene layer  which was then concentrated at 50-55oC to get 160g of 3-(2-chlorophenyl)-3-oxopropanenitrile. (HPLC purity: 94%).

Example 2
Preparation of 2-amino-5-ethylthiophen-3-yl)(2-chlorophenyl) methanone
[Formula (iii)]
To a solution of 148.6g (0.827mol) of 3-(2-chlorophenyl)-3-oxopropanenitrile of Formula (ii) in 450ml of Dimethylformamide (DMF) was added 33.0g of sulphur powder and stirred the solution for 30 min. Added 83.6g (0.827mol) of triethyl amine (TEA) at 10oC followed by slow addition of 65.66g (0.91mol) of n-butaldehyde at 10oC. Stirred the resulting reaction mixture under heating at 50 to 55oC for 3.0-4.0 hours. Reaction mass was cooled to 25-30oC followed by addition of 1000ml of water and 800ml of toluene. Separated the toluene layer and concentrated at 40-60oC to get 228g of 2-amino-5-ethylthiophen-3-yl)(2-chlorophenyl) methanone. (HPLC Purity: 96%).

Example 3
Preparation of N-phthaloyl glycine
[Formula (v)]
To the solution of 300g (2.02mol) of Phthalic anhydride in 1500ml of xylene  added 152.0g (2.02mol) of compound of Formula (iv) (wherein R1  R2  and R3 are hydrogen) followed by addition of 15ml of triethyl amine (TEA) at RT. Heated the reaction mass to reflux and removed the water from the reaction mass. The reaction mass was being cooled to RT and solid compound of Formula (v) was collected by filtration. Wet solid compound so obtained was dried in vacuum oven at 90oC to get 415g of N-phthaloyl glycine. (HPLC purity: 99.23%).

Example 4
Preparation of N-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-2-(1 3-dioxoisoindolin-2-yl)acetamide
[Formula (vi)]-ONE-POT PROCESS
Heated the solution of 155.3g (0.756mol) of N-phthaloyl glycine of Formula (v) in 466ml of toluene at 35oC and added 359.76g (3.024mol) of thionyl chloride at 35-40oC and stirred the reaction mixture under heating at 75-80oC for 1.5-2.0 hours. After completion of reaction  distilled out thionyl chloride to completion and only 60-80% of toluene was concentrated under vacuum (200-40mbar). Cooled the resulting reaction mixture to RT and added in situ to 228.4g (0.584mol) of 2-amino-5-ethylthiophen-3-yl)(2-chlorophenyl) methanone of Formula (iii) dissolved in 450ml of 1 4-dioxane. Stirred the reaction mass at RT and added 103.9g (0.750 mol) of potassium carbonate and stirred the reaction mass at RT for 5.0hours. Distilled out 1 4-dioxane under vacuum at 60oC and to the residue was added 500ml of water. Filtration was carried out to obtain the solid -which was  in turn  washed with water and then dried in vacuum oven to get 219g of N-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-2-(1 3-dioxoisoindolin-2-yl)acetamide. (HPLC purity 99%).

Example 5
Preparation of 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepin-2(3H)-one
[Formula (vii)]-ONE-POT PROCESS
To the solution of 219g (0.487mol) of N-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-2-(1 3-dioxoisoindolin-2-yl)acetamide in 1750ml of isopropyl alcohol was added 34.0g (0.6818mol)of hydrazine hydrate at 40-50oC over 2.0 hours. Stirred the reaction mixture under heating at 68-75oC for 5-6 hours. After completion of reaction  cooled the reaction mass to 30oC and filtered off the solid cake. Washed the solid cake so obtained with 50ml of isopropyl alcohol (IPA). Collected both the isopropyl layers and 50-60% of IPA was distilled out under reduced pressure at 60oC. To this solution was added 292.2g (4.87mol) of acetic acid at RT followed by stirring under heating at 68-75oC for 3-4 hours. After completion of reaction  concentrated the reaction mixture at 50oC under vacuum and added 150 ml of toluene and stirred for 2.0 hours. Filtered off the solid substance (first crop of the desired compound) and washed the solid substance with 150 ml of toluene. Washed the filtrate with hydrochloric acid and washed the resulting aqueous solution with toluene and then  added solid potassium carbonate to adjust the pH of the aqueous layer to 7.0-8.0. Extracted the compound in dichloromethane and concentrated under reduced pressure to obtain a solid compound (second crop). Both crops of the desired compound were then collected and dried to get 100g of 5-(2-chlorophenyl)-7-ethyl-1H-thieno [2 3-e][1 4]diazepin-2(3H)-one. (HPLC purity: 96%).

Example 6
Preparation of 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepine-2(3H)-thione
[Formula (viii)]
To the solution of 88.0g (0.288mol) of 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepin-2(3H)-one in 440 ml of diglyme was added 707g (0.314mol) of phosphorus pentasulphide at 40oC in 1.0 hour and stirred the reaction mixture under heating at 50-55oC for 4-5 hours. After completion of reaction  cooled the reaction mixture to room temperature and reaction was quenched by addition of 2000ml of 6% sodium bicarbonate solution. Stirred the resulting reaction mixture at room temperature for 30 min. Filtration was carried out to obtain wet cake which  in turn  was washed with 500ml of water and then dried in vacuum oven at 80oC to get 75g of 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepine-2(3H)-thione. (HPLC purity: 96%).

Example 7
Preparation of 5-(2-chlorophenyl)-7-ethyl-2-hydrazono-2 3-dihydro-1H-thieno[2 3-e][1 4]diazepine
[Formula (ix)]
To the solution of 65.0g (0.230mol) of 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepine-2(3H)-thione in 520ml methanol was added 14g (0.280mol) of hydrazine hydrate at 35oC and stirred the reaction mass under heating at 40oC for 1-2 hours. After completion of reaction  reaction mass was cooled to 10oC and filtration was carried out to get solid mass which was then dried in vacuum oven at 80oC to get 56g of 5-(2-chlorophenyl)-7-ethyl-2-hydrazono-2 3-dihydro-1H-thieno[2 3-e][1 4]diazepine. (HPLC purity: 98%).

Example 8
Preparation of 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (ETIZOLAM)
[Formula (I)]
To the solution of 56.3g (0.178mol) of 5-(2-chlorophenyl)-7-ethyl-2-hydrazono-2 3-dihydro-1H-thieno[2 3-e][1 4]diazepine in 230ml of toluene was added 64.16g (0.534mol) of trimethyl orthoacetate and stirred the reaction mixture under stirring at 55-60oC for 4-5 hours. After completion of reaction  toluene and trimethyl orthoacetate were distilled out at 55oC under vacuum. To the crude mass so obtained was added 700 ml of ethyl acetate and stirred the resulting mixture under heating at 65-80oC till clear solution was obtained. Added activated charcoal and stirred the reaction mixture for 30 min. Filtration was carried out to remove charcoal through 10g of celite bed and washed the residue with 100ml of ethyl acetate. The hot ethyl acetate layer was then cooled to 10-15oC and stirred for 30 min. Filtered the solid cake so formed to get the 42g of 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (ETIZOLAM). (HPLC purity: 99.9%).

We Claim:

1. A process for producing 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (Etizolam) of Formula-I
 
the process comprising the steps of:
a) reacting 2-chlorobenzonitrile compound of Formula (i)

with acetonitrile in presence of a base and a solvent  to obtain 3-(2-chlorophenyl)-3-oxopropanenitrile of Formula (ii)
;
b) cyclization of compound of Formula (ii) with butaldehyde and sulphur in presence of a base and an organic solvent to obtain (2-amino-5-ethylthiophen-3-yl)(2-chlorophenyl) methanone of Formula (iii)
;
c) one-pot reaction of N-phthaloyl glycine of Formula (v) with in situ coupling of acid chloride intermediate with compound of Formula (iii) in presence of an acid and an organic solvent(s) 

followed by addition of a base  to give N-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-2-(1 3-dioxoisoindolin-2-yl)acetamide of Formula (vi)
;
d) one-pot cyclization of compound of Formula (vi) to 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepin-2(3H)-one of Formula (vii) without the isolation of intermediates

by reacting compound of Formula (vi) with hydrazine hydrate and acid in a protic solvent;
e) sulfurization of compound of Formula (vii) with phosphorus pentasulfide to give 5-(2-chlorophenyl)-7-ethyl-1H-thieno[2 3-e][1 4]diazepine-2(3H)-thione of Formula (viii)
;
f) converting compound of Formula (viii) to hydrazine derivative 5-(2-chlorophenyl)-7-ethyl-2-hydrazono-2 3-dihydro-1H-thieno[2 3-e][1 4]diazepine of Formula (ix)

by reacting compound of Formula (viii) with hydrazine hydrate in presence of an organic solvent;
g) subjecting the resultant compound of Formula (ix) to cyclization by treating with an acid in a solvent to obtain crude compound  Etizolam of Formula-I; and
h) treating said crude Etizolam with a solvent at an elevated temperature to obtain the compound of Formula-I with purity above 99.8%.

2. The process according to claim 1  wherein said base used in step (a) is selected from a weak base or a strong base.

3. The process according to claim 2  wherein said weak base is selected from the group consisting of hydroxides  carbonates  or bicarbonates  and the strong base is selected from alkali metals or alkaline earth metals.

4. The process according to claim 3  wherein the base used in step (a) is an alkali metal selected from sodium or potassium metal.

5. The process according to claim 1  wherein the solvent used in step (a) is selected from the group consisting of C1-C4 alcohol  amides  sulfoxides  ketones  ethers  esters  halogenated or non-halogenated hydrocarbons and mixtures thereof.

6. The process according to claim 5  wherein said solvent used in step (a) is non-halogenated hydrocarbons selected from toluene  xylene  cyclohexane or cycloheptane.

7. The process according to claim 1  wherein the base used in step (b) is amine  selected from triethyl amine  di-isopropyl ethyl amine  tributylamine  pyridine or dimethyl aniline.

8. The process according to claim 1  wherein the solvent used in step (b) is an organic solvent  selected from the group consisting of amide  sulfoxide  chlorinated solvent  C1-C4 alcohol  and hydrocarbons.

9. The process according to claim 1  wherein the organic solvent used in step (c) is at least one non-polar solvent and one hydrocarbon solvent.

10. The process according to claim 9  wherein said non-polar solvent used in step (c) is selected from tetrahydrofuran  diethyl ether  di-isopropyl ether  dioxane  cumene or mixture thereof  and hydrocarbon solvent is selected from o-xylene  m-xylene  p-xylene  toluene  cyclohexane or cycloheptane.

11. The process according to claim 1  wherein the acid used in step (c) is selected from COCl2  SOCl2  or PCl5.

12. The process according to claim 1  wherein the base used in step (c) is an inorganic base.

13. The process according to claim 1  wherein the steps (c) and (d) are carried out without isolation of intermediates.

14. The process according to claim 1  wherein the protic solvent used in step (d) is isopropyl alcohol.

15. The process according to claim 1  wherein the sulfurization in step (e) is carried out in absence of a base.

16. The process according to claim 1  wherein the organic solvent used in step f) is selected from C1-C4 alcohol.

17. The process according to claim 1  wherein the acid used in step (g) is trimethyl orthoacetate.

18. The process according to claim 17  wherein said trimethyl orthoacetate used in step (g) is in a molar ratio of 1.0 to 9.0 of the compound of Formula (ix).

19. The process according to claim 1  wherein the solvent used in step (g) is selected from an inert solvent  halogenated solvent  protic solvent or mixtures thereof.

20. The process according to claim 1  wherein in step (h)  the crude Etizolam is treated with a solvent  selected from acetone  diethyl ether  ethylacetate  dichloromethane  chloroform  methyl ethyl ketone  cyclohexane or mixtures thereof  at an elevated temperature of 50 to 150oC.

21. The process according to claim 1  wherein the compound of Formula (v) is prepared by reacting a compound of Formula (iv)  wherein R1  R2 are selected independently from hydrogen or amine protecting group  R3 is hydrogen or (C1-C6)-alkyl group 

with phthalic anhydride in presence of a base and a low-toxic solvent at a temperature in a range of from 60oC to 170oC to obtain the compound of Formula (v).

22. The process according to claim 21  wherein the low-toxic solvent is selected from xylene  acetonitrile  N-methyl pyrrolidine  anisole  ethylene glycol  tert-butyl methyl ether  ethyl acetate  dimethyl sulfoxide  ethyl formate or mixture thereof.

A NOVEL PROCESS FOR THE PREPARATION OF 4-(2-CHLOROPHENYL)-2-ETHYL-9-METHYL-6H-THIENO[3 2-f][1 2 4]TRIAZOLO[4 3-a][1 4]DIAZEPINE (ETIZOLAM)

ABSTRACT OF THE INVENTION

Disclosed herein is a less expensive and commercially viable process for the preparation of 4-(2-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3 2-f][1 2 4]triazolo[4 3-a][1 4]diazepine (Etizolam) of Formula-I.