Process for the preparation of metformin

Patent metadata

Field	Value
Publication number	US-11465964-B2
Application number	US-201916967781-A
Country	US
Kind code	B2
Filing date	Feb 5, 2019
Priority date	Feb 7, 2018
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The present invention relates to an improved process for the preparation of metformin hydrochloride, an important drug in the first line treatment of Type II Diabetes.

First claim

The invention claimed is:

1. A process comprising preparing metformin HCl by
(a) continuously feeding dimethylammonium chloride, dicyanodiamide, 0.001 to 50% by weight based on the total weight of dimethylammonium chloride and dicyanodiamide present of an additive that increases the reaction selectivity and/or the viscosity of the melted mixture, which additive is sodium chloride, celite, silica, or a blend of two or more thereof, and optionally water in an amount up to 20% by weight and optionally metformin HCl in an amount up to 50% by weight, each based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture, to a reactor under continuous stirring and under continuous heating the mixture to a temperature in the range from 70° C. to 250° C.;
(b) cooling the reacted mixture and collecting crystalline metformin HCl obtained,
said process being run in one continuous reactor or in a combination of continuous reactors in series.

2. The process according to claim 1 , wherein metformin HCl is present in an amount of 5 to 10% by weight based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture.

3. The process according to claim 1 , wherein in (a) the mixture is heated to a first temperature in the range from 70° C. to 120° C., which temperature is maintained for a certain time, and then heated in to a second temperature in the range from 120° C. to 250° C., which temperature is maintained for a certain time.

4. The process according to claim 1 , wherein the process is run in a combination of continuous reactors in series.

5. The process according to claim 4 run in a combination of continuous reactors in series wherein in (a) the mixture is heated in a first reactor to a first heating temperature in the range from 70° C. to 120° C., which temperature is maintained for a certain time, then heated in a second reactor to a second heating temperature in the range from 110° C. to 160° C., which temperature is maintained for a certain time and then heated in a third reactor to a third temperature in the range from 140° C. to 250° C., which temperature is maintained for a certain time.

6. The process according to claim 5 , wherein the sum of all times at which the heating temperature(s) is/are maintained for a certain time ranges from 0.1 minutes to 10 hours.

7. The process according to claim 5 , wherein the first heating temperature is maintained for 0.1 min to 2 hours and the second heating temperature is maintained for 0.1 min to 3 hours and the third heating temperature is maintained for 0.1 min to 5 hours.

8. The process according to claim 1 , wherein the continuous reactor is a continuous stirred tank reactor, a single or twin-screw extruder, a single or twin-screw kneader or a combination of continuous stirred tank reactors, single or twin-screw extruders and single or twin-screw kneaders.

9. The process according to claim 1 , wherein dimethylammonium chloride and dicyanodiamide are present in the mixture to each other in a molar ratio of from 1.0 to 2.0:1.

10. The process according to claim 1 , wherein the mixture processed in (a) contains water, in an amount up to 10% by weight, based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture.

11. The process according to claim 2 , wherein the additive is celite.

12. The process according to claim 10 , wherein the mixture comprises as additive about 1% celite by weight, based on the total weight of dimethylammonium chloride and dicyanodiamide present in the mixture.

13. The process according to claim 1 , comprising preparing a solution of dimethylammonium chloride containing 20 to 50% water by weight and concentrating such solution to 0.1 to 20% water by weight, based on the total weight of dimethylammonium chloride and water, and feeding the resultant concentrated solution of dimethylammonium chloride in (a).

Assignees

• Merck Patent Gmbh

Inventors

• Correia Camille
• Poli Renaud
• Gerbaut Serge
• Dittmann Marc
• Maillard David
• Haertner Sebastian

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07C279/26

  X and Y being nitrogen atoms, i.e. biguanides · CPC title

• C07C277/08 Primary

  of substituted guanidines · CPC title