FOAM 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 OF PREPARING LOPRAZOLAM MESYLATE"
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
I. The fol lowing specification describes the invention.

AN IMPROVED PROCESS OF PREPARING LOPRAZOLAM MESYLATE
FIELD OF THE INVENTION:
The present invention relates to an improved process of preparing Loprazolam mesylate comprises reacting a compound of structural formula II with an alkyl chloroformate compound of structural formula III to get a compound of structural formula IV and then converting compound of structural formula IV into Loprazolam mesylate compound of structural formula I.

BACKGROUND OF THE INVENTION:
Loprazolam mesylate is chemically (Z)-6-(2-chlorophenyl)-2, 4-dihydro-2-[(4-methyl-l-piperazinyl) methylene]-8-nitro-lH-imidazo [], 2-a] [1. 4] benzodiazepin-1-one methanesulphonates monohydrate and is known from U.S.Patent No. 4.044,142. Loprazolam mesylate is represented by compound of structural formula I.


Loprazolam is indicated for the short-term treatment of insomnia including difficulty in falling asleep and/or frequent nocturnal awakenings and has been approved in European countries.
U.S.Patent No. 4.044.142 discloses a process of preparing Loprazolam compound of structural formula XII as mentioned below in scheme no. I.

The prior art also discloses a process of preparing Loprazolam compound of structural formula I as mentioned below in scheme no. II.


The prior art processes for preparing Loprazolam involves the use of 8-nitro-l, 2-dihydro-6-(o-chlorophenyl)-lH. 4H-imidazo [1, 2-a] [1.4] benzodiazepine 1-one compound of structural formula VIII. which is very difficult to remove and thus produces low quality Loprazolam with low yield.
Additionally the process for the preparation of 8-nitro-l. 2-dihydro-6-(o-chlorophenyl)-l H, 4H-imidazo [1, 2-a] [1.4] benzodiazepin-1-one compound of structural formula VIII involves the use of dicyclocarbodiimide (DCC) chemical reagent, which is carcinogenic substance and generates environmentally hazardous toxic substance.
Additionally, the prior art processes involve the prepartion of Loprazolam mesylate compound of structural formula I by reacting Loprazolam compound of structural formula XIJ with methane sulfonic acid in a mixture of methanol and methylene dichloride solvent, which produces methyl ester of methane sulphoinc acid as a genotoxic impurity, which is also very difficult to remove in ppm level.
Accordingly it'is an object of the present invention to solve the problems associated with the prior art and provides an efficient process. The process provides obvious benefits with respect to economics and convenience to operate on a commercial scale.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process of preparing Loprazolam mesylate compound of structural formula I comprising the steps of:
a. reacting a compound of structural formula II with an alkyl chloroformate compound of
structural formula III to get a compound of structural formula IV,


wherein R1 is a C1-C4 alkyl group
b. reacting a compound of structural formula IV with a compound of structural formula V
to get a compound of structural formula VI,

wherein R2 and R3 is a C1-C4 alkyl group
c. reacting a compound of structural formula VI with 1-methylpiperazine to get
Loprazolam compound of structural formula XII and

d. optionally converting Loprazolam compound of structural formula XII into Loprazolam mesylate compound of structural formula I in ketonic solvent.


A second aspect of the present invention is to provide a process of preparing Loprazolam mesylate compound of structural formula 1 comprises reacting a compound of structural formula II with an alkyl chlor oformate compound of structural formula III to get a compound of structural formula IV and then converting compound of structural formula IV into Loprazolam mesylate compound of structural formula I.
A third aspect of the present invention is to provide a novel intermediate compound of structural formula IV.

wherein R1 is a C1-C4 alkyl group
A fourth aspect of the present invention is to provide a process of preparing Loprazolam mesylate compound of structural formula 1 characterized by the conversion of a novel intermediate compound of structural formula IV into Loprazolam mesylate compound of structural formula I.


Another aspect of the present invention is to provide a process of preparing Loprazolam mesylate compound of structural formula I as depicted in scheme no. III.

Another aspect of the present invention is to provide substantially pure Loprazolam mesylate compound of structural formula 1 prepared by the use of a novel intermediate compound of structural formula IV.

Another aspect of the present invention is to provide a process of preparing substantially pure Loprazolam mesylate compound of structural formula I comprise reacting Loprazolam compound of structural formula XII with methane sulfonic acid in ketonic solvent.
The term "substantially pure Loprazolam mesylate compound of structural formula I" refer herein describe the Loprazolam mesylate compound of structural formula I having less than 0.1% weight/weight of 8-nitro-l. 2-dihydro-6-(o-chlorophenyl)-lH. 4H-imidazo [1, 2-a] [1, 4] benzodiazepin-1-one compound of structural formula VIII.
DETAIL DESCRIPTION OF THE INVENTION:
The reaction of a compound of structural formula II with an alkyl chloroformate compound of structural formula III may be carried out in the presence of organic base in chlorinated hydrocarbon solvents.
The examples of organic base may include but not limited to tri ethyl amine, diisopropyl amine. diethyl amine, methyl ethyl amine or diisobutyl amine.
The examples of chlorinated hydrocarbon solvents may include dichloromethane. dichloroethane, carbon tetrachloride or chloroform.
The reaction of a compound of structural formula II with an alkyl chloroformate compound of structural formula III may be carried out at a temperature in the range of-5°C to 35°C for a period of 30 minutes to 8 hours.
The reaction of a compound of structural formula IV with a compound of structural formula V may be carried out in the presence of organic base in chlorinated hydrocarbon solvents at a temperature in the range of 20°C to 35°C for a period of 15 minutes to 1 hour.

The compound of structural formula VI may be isolated by concentrating the solution of a compound of structural formula VI in chlorinated hydrocarbon solvents under reduced pressure followed by crystallizing in ketonic solvents.
The examples of ketonic solvents may include but not limited to acetone, methyl isobutyl ketone, methyl ethyl ketone, diethyl ketone, diisopropyt ketone or dibutyl ketone.
The compound of structural formula VI may be isolated by the steps of filtration, centrifugation, washing, drying and the combination thereof.
The compound of structural formula VI may be dried at a temperature in the range of 40°C to 60°C under reduced pressure for a period of 1 hour to 12 hours.
The reaction of a compound of structural formula VI with 1-methylpiperazine may be carried out in aromatic hydrocarbon solvents.
The examples of aromatic hydrocarbon solvents may include toluene, xylene or cresol.
The reaction of a compound of structural formula VI with 1-methylpiperazine may be carried out at a temperature in the range of 30°C to 100°C for a period of 2 hours to 12 hours.
The Loprazolam compound of structural formula XII may be isolated by filtering reaction mixture followed by slurrifying in chlorinated hydrocarbon solvents and ketone solvents.
The slurrification of Loprazolam compound of structural formula XII in chlorinated hydrocarbon solvents and ketone solvents may be carried out at a temperature in the range of 0°C to 30°C for a period of 15 minutes to 1 hour.
The reaction of Loprazolam compound of structural formula XII with methane sulfonic acid may be carried out in a mixture of ketonic solvent and water.

The Loprazolam mesylate compound of structural formula 3 may be further slurrified in ketonic solvents at a temperature in the range of 0°C to 30°C for a period of 15 minutes to 1 hour.
The Loprazolam mesylate compound of structural formula I may be isolated by the steps of filtration, centrifugation. washing, drying and the combination thereof.
The Loprazolam mesylate compound of structural formula I may be dried at a temperature in the range of 60°C to ] 00°C for a period of 5 hours to J 5 hours.
In the following section one preferred embodiment has been described by way of example to illustrate the process of the invention. However, it is not intended in any way to limit the scope of the present invention.
Example 1: Preparation of Loprazolam mesylate compound of structural formula I
Step a: Preparation of 6-(2-chlorophcnyl)-2, 4-dihydro-2-[(dimethylamino) methylene]-8-
nitro-lH-imidazo-[], 2-a] [1,4] benzodiazepin-1-one.
The solution of compound of structural formula II (30.3Kg) in methylene chloride (45L) was added triethyl amine (13.44L) and ethyl chloroformate (6.1L) at 0-5°C. The resulting reaction mixture was stirred for 4 hours at 25-30°C. The organic layer was separated, washed with water (75L) and dried over anhydrous sodium sulfate (5Kg). The organic layer containing 2-[5-(2-chlorophenyl)-7-nitro-3H-benzo[e][l,4]diazepin-2-ylamino]acetic (ethyl carbonic) anhydride was added triethyl amine (12L) and dimethyl acetal dimethylformamide (12L) at 25-30°C and resulting reaction mixture was stirred for 30 minutes. The organic layer was separated, washed with water (75L), dried over anhydrous sodium sulfate (5Kg) and concentrated under reduced pressure to get crude 6-(2-chlorophenyl)-2,4-dihydro-2-[(dimethylamino)methylene]-8-nitro-lH-imidazo-[1.2-a][1.4]benzodiazepin-l-one. The crude 6-(2-chlorophenyl)-2. 4-dihydro-2-[(dimethylamino) methy]ene]-8-ni1ro-]H-imidazo-[l, 2-a] [1, 4] benzodiazepin-1-one was recrystallized in acetone (30L) to get title compound.

Yield: 7Kg
Purity; 98.0% (By HPLC)
Step b: conversion of 6-(2-chIorophenyJ)-2, 4-dihydro-2-f(dimethyIamino) methyIene]-8-nitro-lH-imidazo-[l, 2-a] [1, 4] benzodiazepin-1-one into Loprazolam compound of structural formula XII
The 6-(2-chlorophenyl)-2. 4-dihydro-2-[(dimethylamino) methylene]-8-nitro-lH-irnidazo-[1, 2-
a] [1. 4] benzodiazepin-1-one (7Kg) was added to the solution of N-methylpiperazine (10L) in
toluene (58.5L) at 25-30°C and resulting reaction mixture was initially refiuxed for 2 hours and
then stirred at 25-30°C for 2 hours. The resulting solids were filtered, slurried in methylene
chloride (70L) and acetone- (35L) to get title compound.
Yield: 5Kg
Purity: 99.0% (By HPLC)
Step c: Conversion of Loprazolam compound of structural formula XII into Loprazolam mesylate compound of structural formula I
The solution of Loprazolam compound of structural formula XII (5Kg) in acetone (75L) was added a solution of methanesulfonic acid (0.768L) in acetone (25L) in 30 minutes at 25-30°C. The resulting reaction mixture was added water (15L) and then it was stirred for 1 hour at 25-30°C. The resulting solids were filtered, slurried in acetone (66L) and dried initially at 40 - 45°C for 1.0 hour and then at 80°C for 8 hours. The dried Loprazolam mesylate compound of structural formula I was micronized and again dried at 80°C for 8 hours. Yield: 4.7Kg Purity: 99.8 % (By HPLC)

WE CLAIM:
1. A process of preparing Loprazolam mesylate compound of structural formula I comprising the steps of:
a. reacting a compound of structural formula II with an alkyl chloroformate compound of
structural formula III to get a compound of structural formula IV.

wherein R1 is a C1-C4 alkyl group
b. reacting a compound of structural formula IV with a compound of structural formula V
to get a compound of structural formula VI.

wherein R2 and R3 is a C1-C4 alkyl group
c. reacting a compound of structural formula VI with I -methylpiperazine to get
Loprazolam compound of structural formula XII and

d. optionally converting Loprazolam compound of structural formula XII into Loprazolam mesylate compound of structural formula I in ketonic solvent.

2. A process of preparing Loprazolam mesylate compound of structural formula I comprises reacting a compound of structural formula II with an alkyl chloroformate compound of structural formula III to get a compound of structural formula IV and then converting compound of structural formula IV into Loprazolam mesylate compound of structural formula I.

4. A process of preparing Loprazolam mesylate compound of structural formula I characterized by the conversion of a novel intermediate compound of structural formula IV into Loprazolam mesylate compound of structural formula I.

5, A process of preparing Loprazolam mesylate compound of structural formula I as depicted in scheme no. III.

6. Substantially pure Loprazolam mesylate compound of structural formula I prepared by the use of a novel intermediate compound of structural formula IV.

7. A process of preparing substantially pure Loprazolam mesylate compound of structural
formula 1 comprise reacting Loprazolam compound of structural formula XII with methane
sulfonic acid in ketonic solvent.
8. The process according to claim no. 1 or 2 wherein reaction of a compound of structural formula II with an alky! chloroformate compound of structural formula III is carried out in the presence of organic base in chlorinated hydrocarbon solvents at a temperature in the range of 20°C to 35°C for a period of 15 minutes to 1 hour.
9. The process according to claim no 8 wherein chlorinated hydrocarbon solvents is selected from the group comprising of dichloromethane, dichloroethane, carbon tetrachloride or chloroform and organic base is selected from the group comprising of triethyl amine, diisopropyl amine, diethyl amine, methyl ethyl amine or diisobutyl amine.
10. The process according to claim no. 7 wherein "substantially pure Loprazolam mesylate
compound of structural formula I" describe the Loprazolam mesylate compound of structural
formula I having less than 0.1% weight/weight of 8-nitro-l. 2-dihydro-6-(o-chlorophenyl)-lH.
4H-imidazo [1, 2-a] [1,4] benzodiazepin-1-one compound of structural formula VIII and ketonic
solvents is selected from the group comprising of acetone, methyl isobutyl ketone, methyl ethyl
ketone, diethyl ketone, diisopropyl ketone or dibutyl ketone.