# US 8,541,578 B2 · Process for the production of n-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide

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- Number: US 8,541,578 B2
- Document ID: US8541578B2
- Status: Granted
- Kind: B2
- Application number: 10/518,887
- Filed: 2003-06-19
- Published: 2005-10-27
- Granted: 2013-09-24
- Earliest claimed: 2002-06-24
- Assignees: Janssen Pharmaceutica NV
- Applicants: Michel Joseph Maurice André Guillaume; Jozef Ludo Jan Cuypers; Ivan Joseph Maria Vervest; Stefan Marcel Herman Leurs; Dirk De Smaele
- Inventors: Michel Joseph Maurice André Guillaume; Jozef Ludo Jan Cuypers; Ivan Joseph Maria Vervest; Stefan Marcel Herman Leurs; Dirk De Smaele
- Web page: https://patentgrep.com/patent/US8541578B2

## CPC

- C07D 295/15: to an acyclic saturated chain
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a novel process, suitable for industrial exploitation for the production of N-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide, also known as N-lidocaine, obtained from the reaction of piperazine with N-haloacetyl-2,6-xylidine. The process comprises the consecutive steps a) through f) a) reacting piperazine with N-haloacetyl-2,6-xylidine in a molar ratio between about 1/1 and about 6/1 in an aqueous solvent in which has been dissolved an equimolar amount of HCl; b) separating the solid formed in step a) from the reaction mixture; c) neutralizing the filtrate; d) extracting the filtrate with a solvent which is not or only to a small extent miscible with the aqueous solvent mentioned in step a); e) crystallizing the N-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide from the solvent mentioned in step d) and f) separating the solid obtained in step e) from the solvent mentioned in step d).

## Claims

### Claim 1

Process for the production of N-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide, obtained from the reaction of piperazine with N-haloacetyl-2,6-xylidine, characterized in that the process comprises the subsequent steps a) through f):
a) reacting piperazine with N-haloacetyl-2,6-xylidine in a molar ratio of piperazine to N-haloacetyl 2,6-xylidine between about1/1 and about 6/1 in an aqueous solvent in which has been dissolved in an about equimolar amount of HCl relative to the molar amount of piperazine;
b) separating the solid formed in step a) from the reaction mixture by filtration to create a filtrate;
c) neutralizing the filtrate;
d) extracting the filtrate with a solvent which is not or only slightly miscible with the aqueous solvent mentioned in step a);
e) crystallizing the N-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide from the solvent mentioned in step d); and
f) separating the solid obtained in step e) from the solvent mentioned in step d).

### Claim 2 (depends on 1)

Process according to claim 1 in which N-haloacetyl-2,6-xylidine is N-chloroacetyl-2,6-xylidine.

### Claim 3 (depends on 1)

Process according to claim 1, characterized in that the molar ratio in step a) is about 3/1 piperzine to N-haloacetyl-2,6-xylidine.

### Claim 4 (depends on 1)

Process according to claim 1, characterized in that solvent for extraction (step d) and crystallization (step e) is toluene.

### Claim 5 (depends on 1)

Process according to claim 1, characterized in that the separation method in step f) is filtration.

### Claim 6

Process for the production of N-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide, obtained from the reaction of piperazine with N-chloroacetyl-2,6-xylidine, characterized in that the process comprises the subsequent steps a) through f):
a) reacting piperazine with N-chloroacetyl-2,6-xylidine at about 80° C. in water in a molar ratio of about 3/1, piperzine to N-haloacetyl-2,6-xylidine, the reaction mixture also containing an equimolar amount of HCl relative to the molar amount of piperzine;
b) filtering the reaction mixture at about 60° C.;
c) neutralizing the filtrate up to a pH equal to about 10;
d) extracting the filtrate with toluene at about 70° C.;
e) crystallizing the N-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide from toluene; and
f) filtering the solid N-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide.