Process for the preparation of Verapamil hydrochloride

Patent metadata

Field	Value
Publication number	US-10144703-B2
Application number	US-201615570821-A
Country	US
Kind code	B2
Filing date	May 10, 2016
Priority date	May 12, 2015
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

A process for the preparation of 5-(3,4-dimethoxyphenylethyl) methyl-amino-2-(3,4-dimethoxyphenyl)-2-isopropyl valeronitrile, which is known as Verapamil is described. A process for improving the purity of verapamil and therefore of its hydrochloride represented as the compound of formula I, by efficient removal of the impurities formed, affording a product of purity greater than 99% is described.

First claim

We claim:

1. A process for the preparation of verapamil hydrochloride represented as a compound of formula I,

comprising the steps of:
a) reacting compound of formula II

 with chlorobromopropane, using a quaternary ammonium salt as a phase transfer catalyst in the presence of a base and a solvent to yield compound of formula III,

b) reacting the compound of formula III, obtained in step (a) with the compound of formula IV,

 in the presence of a base and a solvent followed by reaction with an acetylating agent to yield compound of formula V, and

c) reacting the compound of formula V, obtained in step (b) using hydrochloric acid in isopropyl alcohol to prepare the corresponding hydrochloride salt represented as the compound of formula I

2. The process according to claim 1 , wherein the quaternary ammonium salt phase transfer catalyst used in step (a) is selected from the group consisting of tricaprylyl methyl ammonium chloride (Aliquat 336), tetra-n-butylammonium bromide, benzyltriethylammonium chloride (TEBA), cetyltrimethylammonium bromide, cetylpyridinium bromide, N-benzylquininium chloride, tetra-n-butylammonium chloride, tetrabutylammonium bromide (TBAB), tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium chloride, hexadecyltriethylammonium chloride, tetramethylammonium chloride, hexadecyltrimethylammonium chloride, and octyltrimethylammonium chloride or combinations thereof.

3. The process according to claim 1 , wherein the phase transfer catalyst used in step (a) of claim 1 is tetrabutylammonium bromide.

4. The process according to claim 1 , wherein the base used in step (a) is an inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; or combinations thereof in a solvent.

5. The process according to claim 4 , wherein the base used in step (a) of claim 1 is sodium hydroxide in water as solvent.

6. The process according to claim 1 , wherein in step (a), the reaction is carried out at room temperature range of 20° C. to 35° C. for 2 h to 8 h.

7. The process according to claim 1 , wherein in step (b), the base used is a metal amide.

8. The process according to claim 1 , wherein in step (b), the base used is sodium amide.

9. The process according to claim 1 , wherein in step (b), the reaction with base and solvent is carried out at a temperature maintained between 0° C. to 80° C. for 2 h to 6 h.

10. The process according to claim 1 , wherein in step (b), the reaction with base and solvent is followed by an acetic acid wash to remove a dimer formed as impurity

11. The process according to claim 1 , wherein in step (b), the solvent used is toluene.

12. The process according to claim 1 , wherein in step (b), the acetylating agent is selected from acetyl chloride or acetic anhydride.

13. The process according to claim 1 , wherein in step (b), the acetylating agent is acetic anhydride used in a catalytic amount ranging from 0.05 equivalents to 0.5 equivalents.

14. The process according to claim 1 , wherein in step (b), the reaction with acetylating agent is carried out at a temperature maintained from 0° C. to 50° C. for 2 h to 6 h.

15. The process according to claim 1 , wherein the use of acetic anhydride acetylates the N-desmethyl and the O-desmethyl derivatives of verapamil obtained as impurities, which facilitates easy removal of these impurities due to selective crystallisation of verapamil hydrochloride resulting in a purity of the compound of formula I greater than 99%.

Assignees

• Piramal Entpr Ltd

Inventors

• Krishnamurthy Dhileep Kumar
• Gharpure Milind
• Somisetti Narender Rao
• Rajappa Murali
• Aareddy Rajshekar
• Kasireddy Damodhar

Classifications

• C07C253/30 Primary

  by reactions not involving the formation of cyano groups · CPC title

• C07C255/43

  the carbon skeleton being further substituted by singly-bound oxygen atoms · CPC title

• C07C2531/02

  containing organic compounds or metal hydrides · CPC title

• C07C213/08

  by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups · CPC title

• C07C217/60

  linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring · CPC title