DESC:A PROCESS FOR THE PREPARATION OF DIPHENOXYLATE HYDROCHLORIDE

FILED OF THE INVENTION

The present invention relates to an improved process for the preparation of diphenoxylate hydrochloride of the formula (I) by condensing 4-Bromo-2,2-diphenylbutanenitrile ( II) and Ethyl 4-phenylpiperidine-4-carboxylate (III) in aqueous medium under basic conditions in the presence of a catalyst. This invention also relates to an improved method for purification of the diphenoxylate hydrochloride.

BACKGROUND OF THE INVENTION

A process for the preparation of Diphenoxylate hydrochloride, an opioid agonist used for the treatment of diarrhea that acts by slowing intestinal contractions and peristalsis allowing the body to consolidate intestinal contents and prolong transit time, thus allowing the intestines to draw moisture out of them at a normal or higher rate and therefore stop the formation of loose and liquid stools.

Diphenoxylate hydrochloride is chemically known as ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride having the structural formula (I), marketed as Lomotil ®, is an opioid agonist used for the treatment of diarrhea.

The method described in the US patent 1959/2898340 by the condensation of 4-Bromo-2,2-diphenylbutanenitrile ( II) and Ethyl 4-phenylpiperidine-4-carboxylate (III) in xylene at 100-120°C for 24 hrs followed by treatment with gaseous hydrogen chloride.

In the method described in the US1974/3847926, diphenoxylate hydrochloride is provided by the reaction of 4-Bromo-2,2-diphenylbutanenitrile ( II) with Ethyl 4-phenylpiperidine-4-carboxylate (III) in the presence of sodium carbonate using water and N,N-dimethyl formamide as a mixture solvent at reflux temperature for 12 hours at atmospheric pressure. The hydrochloride salt formation was carried out with concentrated hydrochloric acid after isolation of the diphenoxylate in a mixture of tetrahydrofuran and n-heptane followed by crystallization from isopropyl alcohol.

The method described in the US1978/4086234, by the condensation of (II) and (III) in the presence of potassium iodide and potassium hydrogen carbonate in deionized water under a nitrogen atmosphere, then following the same workup procedure as described in the US1974/3847926.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for the preparation of ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride by the condensation of 4-Bromo-2,2-diphenylbutanenitrile ( II) with Ethyl 4-phenylpiperidine-4-carboxylate (III) in aqueous medium in the presence of a inorganic base and a catalytic amount of potassium iodide. The isolation of the free base followed by the formation of hydrochloride salt with concentrated hydrochloric acid in isopropyl alcohol at 25°-85°C. Filtered the material at 10°C followed by washing with water and isopropyl alcohol to get the product with high purity without any further recrystallization.

DETAILED DESCRIPTION OF EMBODIMENTS
The present invention is an improved process for the preparation of diphenoxylate hydrochloride of the formula (I) comprising the following steps:

Preparation of ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate by the reaction of 4-Bromo-2,2-diphenylbutanenitrile ( II) with Ethyl 4-phenylpiperidine-4-carboxylate (III) in a solvent of water in presence of a water miscible inorganic base and a catalytic amount of potassium iodide.

Isolation of the ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate free base using ethyl acetate.

Formation of the ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride by the reaction of ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate with hydrochloric acid at room temperature in isopropyl alcohol.

After completion of the reaction, heated the reaction mixture to reflux for 1hour and then filtered the solid at room temperature, washed with water and isopropyl alcohol to get the ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride.

The starting materials of this invention II and III are prepared according to the literature method. The present invention is illustrated with the following examples.

EXPERIMENTAL DETAILS
Example-1

A mixture of 4-Bromo-2,2-diphenylbutanenitrile (53.43gm) and Ethyl 4-phenylpiperidine-4-carboxylate (41.7gm) charged in a four neck 1000 ml round bottom flask along with deoxygenated water (333 ml) and potassium iodide (6.44) and heated the reaction mixture to 50°C and stirred the reaction mixture at 50°C for 30 min. Then charged 22.6 gm of sodium carbonate into the reaction mixture. Heated the reaction mixture to reflux for 4-6 hour. After completion of the reaction, cooled the reaction mixture to 25°C and added 666 ml of ethyl acetate into the reaction mixture. Separated the organic layer and then distilled out the ethyl acetate layer in Rota vapor at 40°C under vacuum to get the diphenoxylate. Yield: 95%.

Example-2
Dissolved 101.6 gm of diphenoxylate free base in 2020 ml of isopropyl alcohol at 25°C and then charged 123.1 ml of concentrated hydrochloric acid to the reaction mixture for 30 min. and then stirred the reaction mixture at the same temperature for another 1hour. As the reaction proceeds, the product will be precipitates out as white color solid. After complete formation of the salt, heated the reaction mixture to 85°C for 1 hour. Cooled the reaction mixture to 25°C then to 10°-15°C slowly. Filtered the product, washed with water (200 ml) followed by isopropyl alcohol (200 ml). Dried the product at 60°C under vacuum for 4 hour. Yield: 103 gm, (94%) with HPLC: 99%.

CLAIMS:WE CLAIM,

1. A process for the preparation of diphenoxylate hydrochloride of the formula (I) using sodium carbonate and a catalytic amount of potassium iodide in aqueous medium, process steps comprising of:

a. Preparation of ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate by the reaction of 4-Bromo-2,2-diphenylbutanenitrile ( II) with Ethyl 4-phenylpiperidine-4-carboxylate (III) in a solvent of water in presence of a water miscible inorganic base and a catalytic amount of potassium iodide.

b. Isolation of the ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate free base using ethyl acetate.

c. Formation of the ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate hydrochloride by the reaction of ethyl 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxylate with hydrochloric acid at room temperature in isopropyl alcohol.

2. A process for the preparation of diphenoxylate hydrochloride of the formula (I) as claimed in claim 1, where in the use of isopropyl alcohol in the salt formation reaction gives the product with 99.5% purity by HPLC without any further crystallization.