Title of Invention	A PROCESS FOR THE PREPARATION OF MESYLATES OF PIPERAZINE DERIVATIVES AND THE MESYLATES PREPARED THEREBY
Abstract	The present invention relates to the mesylates of a group of piperazine derivatives and to a process for the preparation of these mesylates in an economic way in the high yield and of high purity. According to the process of the invention the synthesis of the piperazine ring and the mesylate formation are combined in a single reaction step. The invention relates to the mesylate of compounds of the formula (I) wherein X is a bicyclic heterocyclic phenyl group and Y is methyl, ethyl (optionally substituted with fluorine), cycloalkyl (3- 7C) methyl, benzyl or m-phenyl benzyl.

Title of Invention

A PROCESS FOR THE PREPARATION OF MESYLATES OF PIPERAZINE DERIVATIVES AND THE MESYLATES PREPARED THEREBY

Abstract

The present invention relates to the mesylates of a group of piperazine derivatives and to a process for the preparation of these mesylates in an economic way in the high yield and of high purity. According to the process of the invention the synthesis of the piperazine ring and the mesylate formation are combined in a single reaction step. The invention relates to the mesylate of compounds of the formula (I) wherein X is a bicyclic heterocyclic phenyl group and Y is methyl, ethyl (optionally substituted with fluorine), cycloalkyl (3- 7C) methyl, benzyl or m-phenyl benzyl.

Full Text	Process far the preparation of mesylates of piperazine derivatives. The present invention relates to a new process for the preparation of mesylates of piperazine derivatives. It is described in Japanese patent No. 3,044.383 that piperazine derivatives can be obtained by reaction of a primary amine with a reactive ester of a substituted di(hydroxyethyl)am!ne. This reactive ester derivative is obtained by reacting the substituted di(hydroxyethyi)amine compound with a suifonylhalide of the general fomaula R1SOs-Hal, wherein R1 represents alkyl or aryl, and Ha! is a halogen atom. Using this process hydrochloric or hydrobromic acid addition salts of the desired piperazine derivatives are obtained. To obtain the corresponding mesylate the obtained salt has to be converted into the free base, from which the desired mesylate can be prepared-by using methane sulfonic acid. It has now been found that the mesylates of such piperazine derivatives can be obtained directly in an economic way in high yield and high purity according to the process of the invention. and methanesulfonic anhydride, in which formulae X represents a group of the formula (4) wherein - Ri is hydrogen orfluoro - R2 is hydrogen, alkyl (1-4 C). alkoxy (1-4 C) or an 0x0 group, - A represents a heterocyclic group of 5-7 ring atoms wherein 1-3 heteroatoms from the group O, N and S are present, - Y is methyl, ethyl, ethyl substituted with one or more fluorine atoms, cycloalkyi (3-7 C) methyl optionally substituted with one or more fluorine atoms, or a group of the formula (5) wherein Z is hydrogen, phenyl, phenyl substituted with 1-3 substituents from the group hydroxy, halogen, alkyl (1-4 C), alkoxy (1-4 C) or cyano, and R3 is hydrogen or 1-3 substituents from the group halogen, hydroxy, alkyl (1-4 C) or alkoxy (1-4 C). Preferably the invention relates to the preparation of mesylates of compounds having formula (1) wherein X is the group having formula (6) Especially the invention relates to the preparation of mesylates of compounds having fomiula (1) wherein X is the group having formula (6), and Y represents m-phenyl benzyl, benzyl or methyl. According to the process of the invention the synthesis of the piperazine ring and the mesylate formation are combined In one single step which is of great advantage. The formation of thejeactive ester of a compound having formula (3) by reacting it with methanesuifonic anhydride is preferably carried out in the presence of a base such as triethyl amine. This reaction can be carried in an organic solvent at temperatures between 0 and 150 ° C, preferably at reflux temperature. Suitable solvents are for example mono chlorobenzene and methyl ethyl ketone. The starting compounds having formula (2) and (3) are either known compounds, or can be prepared in the same manner as structurally related known compounds. The mesylates of the compounds having formula (1) are novel compounds. A number of free bases, hydrochloric acid addition salts and fumarates of such compound are known already. The invention also relates to the novel mesylates of the compounds having formula (1). The invention especially relates to mesylates of compounds having formula (1) wherein X is the group of the formula (6) and Y has the above meanings. More especially the invention relates to mesylates of compounds having formula (1) wherein X is the group having formula (6) and Y represents m-phenylbenzyl, benzyl or methyl. The invention particulariy relates to the mesylates of the compound having formula (1) wherein X is the group having formula (6) and Y represents the group m-phenyl benzyl. The hydrochloric acid addition salt of the compounds having fonnula (1), together with its interesting phannacological properties are known from WO 97/36893. A disadvantage of this known HCI-salt is the poor solubility thereof in water. At 25 ° C the solubility after 2,4, 8 and 24 hours respectively is between 0.18 and 0.20 mg/ml. It has now been found that the mesylate of this compound is about 8-10 times better soluble in water, i.e. 1.7 mg/ml at 25 ° C. This higher solubility is of great importance since it results in a better bioavaiiability of the active compound. The invention is illustrated in the following example. Example A solution of 27.14 g (100 mmol) of di(hydroxyethyl) m-phenyl benzyl amine in 150 ml of methyl ethyl ketone (MEK) is charged under nitrogen into a 1000 ml round bottomed flask equipped with a thermometer, reflux condenser and mechanical stirrer. An amount of 42.50 g (240 mmol) of methanesulfonic anhydride is dissolved at room temperature while stirring. The reaction mixture is cooled to 0-5 ° C, and 44.77 g (440 mmol) of triethylamine in 50 ml of MEK is added dropwise in 30-45 min. keeping the temperature below 10 ° C. Another 40 ml of MEK is added while stirring for 15 min. at 0-5 ° C. In 10-25 min. 23.08 g (240 mmol) of methanesulfonic acid in 30 ml of MEK is added dropwise while maintaining tHe temperature below 10 ° C. After rinsing with 30 ml of MEK while stining for 15 min. cooling is stopped, and 15.01 g (100 mmol) of the compound having formula (2) wherein X is the group of formula (6) is added. The mixture is rinsed with 130 ml of MEK, and warmed at 20-25 ° C for 1 hour. The clear solution is filtered into another flask and washed with 60 ml of MEK. The mixture is heated till reflux and about 60 ml of MEK is distilled off. Reflux is continued for 8-24 hours and 140 ml of MEK are added. Then 150 ml of water/MEK are distilled off and the mixture is cooled to 0-5 ° C and stirred at this temperature for another 2 hours. The product, i.e. the desired mesylate, is filtered, washed twice with 75 ml of cold MEK (0-5 ° C), and dried at 50 ° C-(100 mbar) under nitrogen. Yield 33.3 g; melting range 263 -275° C. In a similar manner the mesylates of the compounds having formula 1 wherein 1) X is the group of formula (6) and Y is benzyl 2) X is the group of formula (6) and Y is methyl have been prepared. Claims 1. Process for the preparation of piperazine derivatives, characterized in that the mesylate of compounds having the formula (1) by reacting an amine of the formula (2) with a compound of the formula (3) and methanesulfonic anhydride, in which formulae X represents a group of the formula (4) wherein - R1 is hydrogen or fluoro - R2 is hydrogen, alkyl (1-4 C), alkoxy (1-4 C) or an 0x0 group, - A represents a heterocyclic group of 5-7 ring atoms wherein 1-3 het'eroatoms from the group O, N and S are present, - Y is methyl. ethyl, ethyl substituted with one or more fluorine atoms, cycloalky! (3-7 C) methyl optionally substituted with one or more fluorine atoms, or a group of the formula (5) wherein Z is hydrogen, phenyl, phenyl substituted with 1-3 subst¡tuents form the group hydroxy, halogen, alkyl (1-4 C), alkoxy (1-4 C) or cyano, and R3 is hydrogen or 1-3 substituents from the group halogen, hydroxy, alkyl (1-4 C) or alkoxy (1-4 C). 2. Process according to claim 1. characterized in that the mesylate of a compound having formula (1) wherein X is the group of the formula (6) and Y has the meanings given in claim 1 is prepared. 3. Process as claimed in claim, 2 characterized in that the mesylate of the compound of the formula (1) wherein Y represents m-phenyl benzyl, benzyl or methyl is prepared. 4. Process as claimed in claim 3, characterized in that the mesylate of the compound having formula (1) wherein X represents the group having formula (6) and Y is the group m-phenyl benzyl is prepared. Process as claimed in claim 3, characterized in that the mesylaíe of the compound having fonriula (1) wherein × represents the group having formula (6) and Y is the benzyl group is prepared. Process as claimed in claim 3, characterized in that the mesylate of the compound having formula (1) wherein X represent the group having formula (6) and Y is methyl is prepared. Mesylate of a compound having formula (1) wherein the symbols have the meanings given in claim 1. Mesylate as claimed in claim 7 wherein the symbols have the meanings given in claim 2, Mesylate as claimed in claim 8, wherein the symbols have the meanings given in claim 3. Mesylate as claimed in claim 9 of the compound having formula (1) wherein X is the group having formula (6) and Y is m-phenyl benzyl, Mesylate as claimed in claim 9 of the compound having formula (1) wherein X is the group having formuía (6) and Y is benzyl. Mesylate as claimed in claim 9 of the compound having formula (1) wherein X is the group having formula (6) and Y is methyl 13. A process for the preparation of piperazine derivatives substantially as herein described and exemplified.

Full Text

Process far the preparation of mesylates of piperazine derivatives.
The present invention relates to a new process for the preparation of mesylates of piperazine derivatives.
It is described in Japanese patent No. 3,044.383 that piperazine derivatives can be obtained by reaction of a primary amine with a reactive ester of a substituted di(hydroxyethyl)am!ne. This reactive ester derivative is obtained by reacting the substituted di(hydroxyethyi)amine compound with a suifonylhalide of the general fomaula R1SOs-Hal, wherein R1 represents alkyl or aryl, and Ha! is a halogen atom. Using this process hydrochloric or hydrobromic acid addition salts of the desired piperazine derivatives are obtained. To obtain the corresponding mesylate the obtained salt has to be converted into the free base, from which the desired mesylate can be prepared-by using methane sulfonic acid.
It has now been found that the mesylates of such piperazine derivatives can be obtained directly in an economic way in high yield and high purity according to the process of the invention.

and methanesulfonic anhydride, in which formulae X represents a group of the formula
(4)
wherein
- Ri is hydrogen orfluoro
- R2 is hydrogen, alkyl (1-4 C). alkoxy (1-4 C) or an 0x0 group,
- A represents a heterocyclic group of 5-7 ring atoms wherein 1-3 heteroatoms from the group O, N and S are present,
- Y is methyl, ethyl, ethyl substituted with one or more fluorine atoms, cycloalkyi (3-7 C) methyl optionally substituted with one or more fluorine atoms, or a group of the formula (5)
wherein Z is hydrogen, phenyl, phenyl substituted with 1-3 substituents from the group hydroxy, halogen, alkyl (1-4 C), alkoxy (1-4 C) or cyano, and R3 is hydrogen or 1-3 substituents from the group halogen, hydroxy, alkyl (1-4 C) or alkoxy (1-4 C).
Preferably the invention relates to the preparation of mesylates of compounds having formula (1) wherein X is the group having formula (6)

Especially the invention relates to the preparation of mesylates of compounds having fomiula (1) wherein X is the group having formula (6), and Y represents m-phenyl benzyl, benzyl or methyl.
According to the process of the invention the synthesis of the piperazine ring and the mesylate formation are combined In one single step which is of great advantage.
The formation of thejeactive ester of a compound having formula (3) by reacting it with methanesuifonic anhydride is preferably carried out in the presence of a base such as triethyl amine. This reaction can be carried in an organic solvent at temperatures between 0 and 150 ° C, preferably at reflux temperature. Suitable solvents are for example mono chlorobenzene and methyl ethyl ketone. The starting compounds having formula (2) and (3) are either known compounds, or can be prepared in the same manner as structurally related known compounds.
The mesylates of the compounds having formula (1) are novel compounds. A number of free bases, hydrochloric acid addition salts and fumarates of such compound are known already. The invention also relates to the novel mesylates of the compounds having formula (1).
The invention especially relates to mesylates of compounds having formula (1) wherein X is the group of the formula (6)

and Y has the above meanings.
More especially the invention relates to mesylates of compounds having formula (1) wherein X is the group having formula (6) and Y represents m-phenylbenzyl, benzyl or methyl.
The invention particulariy relates to the mesylates of the compound having formula (1) wherein X is the group having formula (6) and Y represents the group m-phenyl benzyl.

The hydrochloric acid addition salt of the compounds having fonnula (1), together with its interesting phannacological properties are known from WO 97/36893. A disadvantage of this known HCI-salt is the poor solubility thereof in water. At 25 ° C the solubility after 2,4, 8 and 24 hours respectively is between 0.18 and 0.20 mg/ml.
It has now been found that the mesylate of this compound is about 8-10 times better soluble in water, i.e. 1.7 mg/ml at 25 ° C. This higher solubility is of great importance
since it results in a better bioavaiiability of the active compound. The invention is illustrated in the following example.
Example
A solution of 27.14 g (100 mmol) of di(hydroxyethyl) m-phenyl benzyl amine in 150 ml of methyl ethyl ketone (MEK) is charged under nitrogen into a 1000 ml round bottomed flask equipped with a thermometer, reflux condenser and mechanical stirrer. An amount of 42.50 g (240 mmol) of methanesulfonic anhydride is dissolved at room temperature while stirring. The reaction mixture is cooled to 0-5 ° C, and 44.77 g (440 mmol) of triethylamine in 50 ml of MEK is added dropwise in 30-45 min. keeping the temperature below 10 ° C. Another 40 ml of MEK is added while stirring for 15 min. at 0-5 ° C. In 10-25 min. 23.08 g (240 mmol) of methanesulfonic acid in 30 ml of MEK is added dropwise while maintaining tHe temperature below 10 ° C. After rinsing with 30 ml of MEK while stining for 15 min. cooling is stopped, and 15.01 g (100 mmol) of the compound having formula (2) wherein X is the group of formula (6) is added. The mixture is rinsed with 130 ml of MEK, and warmed at 20-25 ° C for 1 hour. The clear solution is filtered into another flask and washed with 60 ml of MEK. The mixture is heated till reflux and about 60 ml of MEK is distilled off. Reflux is continued for 8-24 hours and 140 ml of MEK are added. Then 150 ml of water/MEK are distilled off and the mixture is cooled to 0-5 ° C and stirred at this temperature for another 2 hours. The product, i.e. the desired mesylate, is filtered, washed twice with 75 ml of cold MEK (0-5 ° C), and dried at 50 ° C-(100 mbar) under nitrogen. Yield 33.3 g; melting range 263 -275° C. In a similar manner the mesylates of the compounds having formula 1 wherein
1) X is the group of formula (6) and Y is benzyl
2) X is the group of formula (6) and Y is methyl have been prepared.

Claims
1. Process for the preparation of piperazine derivatives, characterized in that the
mesylate of compounds having the formula (1)

by reacting an amine of the formula (2)

with a compound of the formula (3)

and methanesulfonic anhydride, in which formulae X represents a group of the formula (4)

wherein
- R1 is hydrogen or fluoro
- R2 is hydrogen, alkyl (1-4 C), alkoxy (1-4 C) or an 0x0 group,

- A represents a heterocyclic group of 5-7 ring atoms wherein 1-3 het'eroatoms from the group O, N and S are present,
- Y is methyl. ethyl, ethyl substituted with one or more fluorine atoms, cycloalky! (3-7 C) methyl optionally substituted with one or more fluorine atoms, or a group of the formula (5)

wherein Z is hydrogen, phenyl, phenyl substituted with 1-3 subst¡tuents form the group hydroxy, halogen, alkyl (1-4 C), alkoxy (1-4 C) or cyano, and R3 is hydrogen or 1-3 substituents from the group halogen, hydroxy, alkyl (1-4 C) or alkoxy (1-4 C).
2. Process according to claim 1. characterized in that the mesylate of a compound
having formula (1) wherein X is the group of the formula (6)

and Y has the meanings given in claim 1 is prepared.
3. Process as claimed in claim, 2 characterized in that the mesylate of the compound of the formula (1) wherein Y represents m-phenyl benzyl, benzyl or methyl is prepared.
4. Process as claimed in claim 3, characterized in that the mesylate of the compound having formula (1) wherein X represents the group having formula (6) and Y is the group m-phenyl benzyl is prepared.

Process as claimed in claim 3, characterized in that the mesylaíe of the
compound having fonriula (1) wherein × represents the group having formula (6) and Y is the benzyl group is prepared.
Process as claimed in claim 3, characterized in that the mesylate of the compound having formula (1) wherein X represent the group having formula (6) and Y is methyl is prepared.
Mesylate of a compound having formula (1) wherein the symbols have the meanings given in claim 1.
Mesylate as claimed in claim 7 wherein the symbols have the meanings given in claim 2,
Mesylate as claimed in claim 8, wherein the symbols have the meanings given in claim 3.
Mesylate as claimed in claim 9 of the compound having formula (1) wherein X is the group having formula (6) and Y is m-phenyl benzyl,
Mesylate as claimed in claim 9 of the compound having formula (1) wherein X is the group having formuía (6) and Y is benzyl.
Mesylate as claimed in claim 9 of the compound having formula (1) wherein X is the group having formula (6) and Y is methyl

13. A process for the preparation of piperazine derivatives substantially as herein described and exemplified.

Documents:

548-chenp-2003 abstract granted.pdf

548-chenp-2003 claims granted.pdf

548-chenp-2003 description (complete) granted.pdf

548-chenp-2003-claims.pdf

548-chenp-2003-correspondnece-others.pdf

548-chenp-2003-correspondnece-po.pdf

548-chenp-2003-description(complete).pdf

548-chenp-2003-form 1.pdf

548-chenp-2003-form 18.pdf

548-chenp-2003-form 3.pdf

548-chenp-2003-pct.pdf

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Patent Number

225621

Indian Patent Application Number

548/CHENP/2003

PG Journal Number

52/2008

Publication Date

26-Dec-2008

Grant Date

19-Nov-2008

Date of Filing

16-Apr-2003

Name of Patentee

SOLVAY PHARMACEUTICALS B.V.

Applicant Address

C J VAN HOUTENLAAN 36, NL-1381 CP WEESP,

Inventors:

#	Inventor's Name	Inventor's Address
1	AAR, MARCEL, P.M. VAN, C.J	VAN HOUTENLAAN 36, NL-1381 CP WEESP,
2	SCHOUTEN, STEFANUS, J, C.J	VAN HOUTENLAAN 36, NL-1381 CP WEESP,
3	ZORGDRAGER, JAN	VAN HOUTENLAAN 36, NL-1506 TH WEESP,
4	HESLINGA, MICHIEL, C, C.J	VAN HOUTENLAAN 36, NL-1381 CP WEESP,

PCT International Classification Number

C07D 263/58

PCT International Application Number

PCT/EP02/01666

PCT International Filing date

2002-02-14

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	01200534.4	2001-02-16	EUROPEAN UNION