Field of the Invention:
The present invention relates to a new process for the preparation of 2,1,3 -Benzoxadiazole - 4 -Carboxaldehyde, a key intermediate for the preparation of 4-(4 -Benzofurazanyl ) - 1 ,4-dihydro-2,6, dimethyl-3, 5-pyridinedicarbonylic acid methyl 1-methyl ethyl ester known as Isradipine.
Back ground of the invention:
Swiss. Pat. No. CH 661270 discloses a process for the manufacture of 2, 1, 3 -Benzoxadiazole - 4 - carboxaldehyde which starts from 2,1,3-Benzoxadiazole, which was metalated using butyl lithium and Diisopropylamine in THF. The metalated intermediate was then formylated using N,N-Dimethylformamide to get 2,1,3-Benzoxadiazole- 4-Carboxaldehyde. This process consists of low temperature reactions (-78°C) and also tediaous work-up which includes purification step.
Gasco etal; European Journal of medicinal chemistry (1996), 31(1), 3-10 described a process for the preparation of 2,1,3 - Benzoxadiazole - 4 - carboxaldehyde started with 4- methyl - 2,1,3 - Benzoxadiazole. In which 4 - methyl - 2,1,3 - benzoxadiazole was brominated by using N-bromosuccinamide in presence of peroxide to give 4-bromomethyl -2,1,3-Benzoxadiazole, which was hydrolysed with carbonate to yield 2,1,3- benzoxadiazole-4 yl-methanol. Oxidiation of 2,1,3 -Benzoxadiazole-4-yl-methanol using activated MnO2 gives 2,1,3-1 benzoxadiazole- 4-carboxaldehyde. This process creates more effluent problem with activated MnO2 and also the non- availability of the commercial quantities of consistent quality activated MnO2
WO 2003/000305 discloses a process in which, 2,1,3- benzoxadiazole- 4-carboxaldehyde is prepared from 2,l,3-benzoxadiazole-4-yl-methanol by oxidation using pyridinium chlorochromate (PCC) as oxidant. This process involves the handling of PCC in plant scale which is unsafe.

Summary of the invention:
The main object of the present invention is to provide an improved process for producing 2,1,3-Benzoxadiazole-4- Carboxaldehyde.
Another object of the invention is to provide an economic process for preparing 2,1,3-Benzoxadiazole-4- Carboxaldehyde with out using hazardous chemicals.

Detailed description of the invention:
In accordance with the present invention 2,l,3-Benzoxadiazole-4- Carboxaldehyde is prepared by
• Bromination of 4 - methyl - 2, 1,3- Benzoxadiazole with N-Bromosuccinamide
in the presence of peroxide gives 4 - bromomethyl-2,1,3 -Benzoxadiazole
• Treating 4 - bromomethyl-2,1,3-Benzoxadiazole with hexamethylene tetramine (hexamine) to get quaternary hexamine salt
• Hydrolysis of quaternary hexamine salt with hot aqueous hydrochloric acid to get 2,1,3-Benzoxadiazole-4- Carboxaldehyde.
The reaction scheme can be expressed as follows.


In a specific embodiment, the present invention provides a process for the preparation of 2,l,3-Benzoxadiazole-4- Carboxaldehyde, which involves
a) Heating 4 - Bromomethyl Benzofuroxan and Hexamine in a mixture of acetic acid and DM water to 60° - 100°C preferably 80°-90°C;
b) Maintaining the reaction mass for about 1 to about 4 hours preferably 2-3 hours
c) Cooling the reaction mass to about 60° - 65°C
d) Adding hydrochloric acid over a period of 30min at 60° - 65°C
e) Cooling the reaction mass to about 20° - 40°C preferably 25°-30°C:
0 Extracting the reaction mass with an organic solvent preferably MDC g) Washing the MDC layer with 5 % Na2 C03 followed by DM water h) Evaporating the MDC to get residue
i) Dissolving the residue in cyclohexane and slowly cooling to 0-10°C, j) Filtering the reaction mass and drying the product at 35-40°C to get 2,1,3-Benzoxadiazole-4- Carboxaldehyde.
The present invention is further illustrated by the following example.
Example: Preparation of 2,13 - Benzoxadiazole - 4 -Carboxaldehyde
4 - Bromomethyl Benzofuroxan (20g) is added to a mixture of 50 ml. acetic acid and 50 ml. DM Water at room temperature and stirred for 15 min. To the reaction mixture Hexamine (2.6 g) is added and heated to a temperature of about 90°C and Maintained for 2-2 Vz hrs. Reaction completion is checked by TLC and cooled the reaction mass to 60-65°C. HC1 (35 ml) is added slowly over a period of 25min. at 60-65° C and stirred for 15 min at 60-65°C. Reaction mass is cooled to 25 - 30°C and extracted the reaction mass with MDC (2 x 100 ml.) MDC layer is washed with DM Water (2 x 60 ml) and 60 ml.
5 % Na2 CO3 .Again MDC layer is washed with 60 ml. 5% DM water and distilled of MDC below 55°C. To the obtained crude Cyclohexane (300 ml) is added and maintained at reflux for 1.0 hr. Slowly cooled the mass to room temperature and finally to 0-5°C and

maintained 1.0 hr. at 5° C. The precipitated product is filtered, washed with cyclohexane (30ml) and dried at 35-40°C to get 2,l,3-Benzoxadiazole-4- Carboxaldehyde.
Out put: 4.1 gm (Purity: 96.35 % by HPLC)

We claim;
1. An improved process for the preparation of 2,l,3-Benzoxadiazole-4- Carboxaldehyde
comprising steps
a. Treating 4-bromomethyl-2,l,3-Benzoxadiazole with hexamethylene tetramine
(hexamine) to get quaternary hexamine salt
b. Hydrolysis of quaternary hexamine salt to get 2,l,3-Benzoxadiazole-4-
Carboxaldehyde.
2. The process as claimed in claim-1, wherein step a) is carried out in a mixture of acetic
acid and DM water
3. The process as claimed in claim-1, wherein step a) is carried out at 60° - 100°C
preferably 80°-90°C
4. The process as claimed in claim-1, wherein in step b) hydrolysis is carried out with
hydrochloric acid
5. The process as claimed in claim-1, wherein in step b) hydrolysis is carried out at
60°- 65°C
6. The process as claimed in claim-1, wherein the final product is crystallized in
cyclohexane
7. The process as claimed in claim-1, wherein the final product is isolated at 0-10°C,
preferably at 5°C