FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"An improved process for the preparation of substituted 3-(Acetyloxy)-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one"
Centaur Pharmaceutical Private Limited, an Indian Company, having its Registered Office at Centaur House, Near Grand Hyatt, Shanti Nagar, Vakola, Santacruz (East), Mumbai- Maharashtra, 400055, India
1. The following specification describes the invention.
Technical field of the invention:
The present invention relates to a process for the preparation of substituted 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l>4-benzodiazepin-2-one? the compound represented by structural formula (I) which is used as a key intermediate for the synthesis of substituted 7-Chloro-3-hydroxy-5-phenyl-lH-l,4-benzodiazepin-2(3H)-one? the compound represented by structural formula (II) such as Lorazepam, Lormetazepam, Temazepam and Oxazepam.


Wherein R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like and R2 represents hydrogen or chlorine.
Background of the invention:
7-Chloro-3-hydroxy-5-phenyl-lH-l,4-benzodiazepin-2(3H)-one, the compound represented by following formula II, disclosed in US3197467 and widely used in a variety of indications such as alcohol dependence, seizures, anxiety disorders, panic, agitation, and insomnia.

Wherein R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like and R2 represents hydrogen or chlorine.
The examples of 7-Chloro-3-hydroxy-5-phenyl-1H-l,4-benzodiazepin-2(3H)-one, the compound represented by structural formula (II) include Lorazepam, Lormetazepam, Temazepam and Oxazepam.

3-(Acetyloxy)-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one the compound represented by following formula I is an intermediate used for synthesis of 7-Chloro-3-hydroxy-5-phenyl-lH-l,4-benzodiazepin-2(3H)-one, the compound represented by structural formula II and is first disclosed in Belgium patent number BE621819.

Wherein R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like and R2 represents hydrogen or chlorine.
Crotian patent HR20000802A discloses the synthesis of the intermediate represented by structural formula (F) which is used for the synthesis of Oxazepam and Lorazepam; by acetoxylation reaction of 3-position of 1,4-Benzodiazepine ring (IF). The reaction involves iodine catalyzed acetoxylation in glacial acetic acid in the presence of potassium acetate using potassium peroxydisulphate as a stoichiometric oxidant at elevated temperature (65-90°C) as depicted in Scheme I.


Further said reference disclosed that all iodination reactions are actually reversible. Therefore the suitable iodide removing agent must be present in the reaction which eliminates iodides from equilibrium by oxidation (back to iodine). The said reference discloses the use of manganese dioxide, potassium and ammonium peroxydisulphate, calcium hypochlorite, nitrous acid (NaNO2/AcOH), and peroxide-based oxidants such as Na2CO3.5H2O2, (H2N)2CO.H2O2, and NaNO2.4H2O can be used as oxidants. However the yield of 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I obtained by using the process disclosed in said reference is very poor, i.e.61%. Further the commercial use of iodine and oxidants is not industrially worthwhile.
Accordingly there is a need to develop a simple, economic, safe and industrially viable process of preparing 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by following formula I which does not involve the use of iodine and oxidants and providing substantially pure 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by following formula I with high yield.
The inventors of the present invention have now found that the compound of formula I can be obtained in good yield and purity through an improved process by acetylation reaction of the compound of formula III using halogenating agent such as Bromine, N-bromosuccinimide 1, 3-dibromo-5, 5-dimethyl hydantoin (DBDMH), Chlorine, N-chlorosuccinimide and acetylating agent to provide the compound of formula I.
Object of the invention:
i. An object of the present invention is to provide a new, simple, economic and safe
process for preparation of 3 -(Acetyloxy)-7-chloro-1,3 -dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, the compound represented by following formula L


Wherein R1 represents hydrogen or C1to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like and R2 represents hydrogen or chlorine
ii. Another object of the present invention is to provide an improved process for
producing 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I from acetylation of the compound of formula III using halogenating agent such as Bromine, N-bromosuccinimide 1, 3-dibromo-5, 5-dimethyl hydantoin (DBDMH), Chlorine, N-chlorosuccinimide and acetylating agent to provide the compound of formula I.
iii. Another object of the present invention is to provide an improved process for
producing 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I from the compound of formula III avoiding use of iodine and oxidants and there by rendering the process industrially viable.
Summary of the invention:
In accordance with the aspect of the present invention is to provide a process for preparation of 3-(Acetyloxy)-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, the compound represented by structural formula I comprising the reaction of the compound represented by structural formula III with halogenating reagent and acetylation using acetylating agent to

provide 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I.
The process for producing the compound of formula I is depicted in Scheme-II herein below:

Another aspect of the present invention is to provide a process for preparation of 7-chloro-5-(2-chlorophenyl)-3-acetoxy-l,3-dihydro-l,4-benzodiazepin-2-one, the compound represented by following formula IV comprising the reaction of the compound represented by following formula V with halogenating reagent and acetylation using acetylating agent to provide 7-chloro-5-(2-chlorophenyl)-3-acetoxy-l,3-dihydro-l,4-benzodiazepin-2-one, the compound represented by following formula IV which is used as an intermediate for synthesis of Lorazepam.
The process for producing the compound of formula IV is depicted in Scheme-Ill herein below:


Yet another aspect of the present invention is to provide a process for preparation of 7-Chloro-l,3-dihydro-3-acetoxy-l-methyl-5-phenyl-l,4-benzodiazepin-2-one, the compound represented by following formula VI comprising the reaction of the compound represented by following formula VII with halogenating reagent and acetylation using acetylating agent to provide 7-Chloro-l,3-dihydrp-3-acetoxy-l-methyl-5-phenyl-l,4-benzodiazepin-2-one, the compound represented by following formula VI which is used as an intermediate for synthesis of Temazepam.
The process for producing the compound of formula VI is depicted in Scheme-IV herein below:

Further aspect of the present invention is to provide a process for preparation of 7-Chloro-5-(2-chlorophenyl)-3-acetoxy-1 -methyl-1H-benzo[e][1,4]diazepin-2(3H)-one, the compound represented by following formula VIII comprising the reaction of the compound represented by following formula IX with halogenating reagent and acetylation using acetylating agent to provide 7-Chloro-5-(2-chlorophenyl)-3-acetoxy-l-methyl-lH-benzo[e][l,4]diazepin-2(3H)-one, the compound represented by following formula Vlll which is used as an intermediate for synthesis of Lormetazepam.
The process for producing the compound of formula VIII is depicted in Scheme-V herein below:


Further aspect of the present invention is to provide a process for preparation of 7-Chloro-3-hydroxy-5-phenyl-l,3-dihydro-l,4-benzodiazepin-2-one, the compound represented by following formula X comprising the reaction of the compound represented by following formula XI with halogenating reagent and acetylation using acetylating agent to provide 7-Chloro-5-phenyl-3-acetoxy-l-methyl-lH-benzo[e][l,4]diazepin-2(3H)-one, the compound represented by following formula X which is used as an intermediate for synthesis of Oxazepam.
The process for producing the compound of formula X is depicted in Scheme-VI herein below:

Detail description of the invention:
The compound represented by structural formula (III) can be obtained as per process disclosed in US3197467.

A first aspect of the present invention is to provide a process for preparation of 3-(Acetyloxy)-7-
chloro-1,3-dihydro-S-phenyl-2H-1,4-benzodiazepin-2-one, the compound represented by
structural formula I.

Wherein
R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like and R2 represents hydrogen or chlorine
comprises,
Reacting the compound represented by structural formula (III)

Wherein

R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl and like and R2 represents hydrogen or chlorine

with halogenating agent such as Bromine, N-bromosuccinimide 1, 3-dibromo-5, 5-dimethyl hydantoin (DBDMH), Chlorine, N-chlorosuccinimide and acetylating agent in the presence of acetic acid to obtain 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I.
The acetylating agent used is selected from the group consisting of sodium acetate, potassium acetate, and acetic anhydride.
The acetylation reaction can be carried out at a temperature ranging from 25°C to 85°C.
3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I can be isolated from the reaction mass by involving steps of, filtration, washing, drying.
3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodia2epin-2-one, the compound represented by structural formula I can be further purified by crystallization.
The solvent used for crystallization is selected from halogenated hydrocarbon such as chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, dichloromethane, tetrachloroethylene, 1,1,1-trichloroethane, Alcohols such as methanol, 2-Propanol, 1-butanol ; Esters such as ethyl acetate, methyl acetate, butyl acetate and ketone such as acetone and mixture thereof
The examples of 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I can include but not limited to following compound represented by structural formula IV, VI, VIII or X which is used as intermediate for synthesis of Lorazepam, Temazepam, Lormetazepam and Oxazepam respectively.



The yield of compound represented by structural formula IV, VI, VIII or X obtain as per process of the present invention is above 85% and purity is above 99%.
Examples:
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
Example-l: Preparation of 7-Chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydro-lH-benzo[e] [1,4] diazepin-3-yl acetate compound represented by structural formula IV (intermediate of Lorazepam)
To a solution of 7-Chloro-5-(2-chlorophenyl)-l,3-dihydro-2H-benzo[e][l,4]diazepin-2-one (10.0 gm) in glacial acetic acid (50.0 ml), sodium acetate (9.8 gm) and bromine (3 ml) were added at room temperature. The suspension was heated to 55-60°C with stirring and maintained for 3 hours.The suspension was then cooled to 10-15°C, filtered and washed with glacial acetic acid (20 ml). Wet solid was crystallized in MDC and dried at 60-65°C under vacuum to get 7-Chloro-5-(2-chlorophenyl)-2-oxo-2,3-dihydro-lH-benzo[e] [1,4] diazepin-3-yl acetate.
Yield: 10.35gm [86%]; purity: 99.2%.
Example-2: Preparation of 7-Chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e]
[l,4]diazepin-3-yl acetate compound represented by structural formula X (intermediate of Oxazepam)

To a solution of 7-Chloro-5-phenyl-l,3-dihydro-2H-benzo[e][l,4]diazepin-2-one (10 gm) in glacial acetic acid (50 ml), Sodium acetate (9.8 gm) and bromine (3 ml) was added at room temperature. The suspension was heated to 55-60°C with stirring and maintained at this temperature for 3 hours.The suspension was cooled to 10-15°C, filtered and washed with glacial acetic acid (20 ml). Wet solid was crystallized in MDC and dried at 60-65°C under vacuum to get 7-Chloro-2-oxo-5-phenyl-2,3-dihydro-lH-benzo[e] [l,4]diazepin-3-yl acetate.
Yield: 10.56gm [87%]; purity: 99.5%.
Example-3: Preparation of 7-Chloro-l-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e] [l,4]diazepin-3-yl acetate compound represented by structural formula VI (intermediate of Temazepam)
To a solution of 7-Chloro-l-methyl-5-phenyl-l,3-dihydro-2H-benzo[e][l,4]diazepin-2-one (10 gm) in glacial acetic acid (50 ml), Sodium acetate (9.8 gm) and bromine (3 ml) was added at room temperature. The suspension was heated to 55-60°C with stirring and maintained at this temperature for 3 hours. The suspension was cooled to 10-15°C, filtered and washed with glacial acetic acid (20 ml). Wet solid was crystallized in MDC and dried at 60-65°C under vacuum to get 7-Chloro-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-benzo[e] [l,4]diazepin-3-yl acetate Yield: 10.71gm [89%]; purity: 99.4%.
Example-4: Preparation of 7-ChIoro-5-(2-chlorophenyl)-3-acetoxy-1-methyl-lH-benzo[e][1,4]diazepin-2(3H)-one compound represented by structural formula VIII (intermediate of Lormetazepam)
To a solution of 7-Chloro-l-methyl-5-(2-chlorophenyl)-l,3-dihydro-2H-benzo[e][l,4]diazepin-2-one (10 gm) in glacial acetic acid (50 ml), Sodium acetate (9.8 gm) and bromine (3 ml) was added at room temperature. The suspension was heated to 55-60°C with stirring and maintained at this temperature for 3 hours. The suspension was cooled to 10-15°C, filtered and washed with glacial acetic acid (20 ml). Wet solid was crystallized in MDC and dried at 60-65°C under

vacuum to get pure 7-Chloro-l-methyl-2-oxo-5-phenyl-2,3-dihydro-lH-benzo[e] [l,4]diazepin-3-yl acetate
Yield: 10.04 gm [89%]; purity: 99.2%.

We claim:
1. A process for preparation of substituted 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by following formula I,

Wherein
R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl
and like and R2 represents hydrogen or chlorine
Comprising,
reacting the compound represented by structural formula (III)

Wherein
R1 represents hydrogen or C1 to C4 alkyl substituents such as methyl, ethyl, propyl, butyl
and like and R2 represents hydrogen or chlorine
with halogenating agent such as Bromine, N-bromosuccinimide l,3-dibromo-5,5-
dimethyl hydantoin (DBDMH), Chlorine, N-chlorosuccinimide and acetylating agent in

the presence of acetic acid to obtainsubstituted3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I.
2. The process as claimed in claim (1) wherein acetylating agent used is selected from the group consisting of sodium acetate, potassium acetate, and acetic anhydride.
3. The process as claimed in claim (1) wherein the reaction can be carried out at a temperature ranging from 25 °C to 85 °C.
4. The process as claimed in claim (1) wherein substituted 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I can be further purified by crystallization.
5. The process as claimed in claim (4) wherein solvent used for crystallization is selected from halogenated hydrocarbon such as chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, dichloromethane, tetrachloroethylene, 1,1,1 -trichloroethane, Alcohols such as methanol, 2-Propanol, 1-butanol ; Esters such as ethyl acetate, methyl acetate, butyl acetate and ketone such as acetone and mixture thereof.
6. The process as claimed in claim (4) wherein solvents used for the crystallization is selected from the group consisting of halogenated hydrocarbon such as chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, chlorinated fluorocarbons, dichloromethane, tetrachloroethylene, 1,1,1-trichloroethane.
7. The process as claimed in claim (1) wherein examples of substituted 3-(Acetyloxy)-7-chloro-l,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one, the compound represented by structural formula I can include but not limited to following compound represented by structural formula IV, VI, VIII or X.