AU2002250962A1 - Process for the preparation of mesylates of piperazine derivatives - Google Patents
Process for the preparation of mesylates of piperazine derivativesInfo
- Publication number
- AU2002250962A1 AU2002250962A1 AU2002250962A AU2002250962A AU2002250962A1 AU 2002250962 A1 AU2002250962 A1 AU 2002250962A1 AU 2002250962 A AU2002250962 A AU 2002250962A AU 2002250962 A AU2002250962 A AU 2002250962A AU 2002250962 A1 AU2002250962 A1 AU 2002250962A1
- Authority
- AU
- Australia
- Prior art keywords
- formula
- group
- mesylate
- compound
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Description
Process for 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)amine. This reactive ester derivative is obtained by reacting the substituted di(hydroxyethyl)amine compound with a sulfonylhalide of the general formula R1SO2-Hal, wherein R1 represents alkyl or aryl, and Hal 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.
The present invention relates to a novel process for the preparation of the mesylate of compounds having the formula (1)
X-N / \ N-Y (1)
by reacting an amine of the formula (2)
X-NH2 (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 oxo 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, cycloalkyl (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)
and Y has the above meanings.
Especially the invention relates to the preparation of mesylates of compounds having formula (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 the reactive ester of a compound having formula (3) by reacting it with methanesulfonic 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 particularly 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 formula (1), together with its interesting pharmacological 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 bioavaiiabiiity 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 condensor 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 stirring 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 0 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 (12)
1. Process for the preparation of piperazine derivatives, characterized in that the mesylate of compounds having the formula (1)
X-N N-Y (1 )
\ i
by reacting an amine of the formula (2)
X-NH, (2)
with a compound of the formula (3)
and methanesulfonic anhydride, in which formulae X represents a group of the formula (4)
wherein
Ri is hydrogen or fluoro
R2 is hydrogen, alkyl (1-4 C), alkoxy (1-4 C) or an oxo 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, cycloalkyl (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 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.
5. 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 benzyl group is prepared.
6. 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.
7. Mesylate of a compound having formula (1) wherein the symbols have the meanings given in claim 1.
8. Mesylate as claimed in claim 7 wherein the symbols have the meanings given in claim 2.
9. Mesylate as claimed in claim 8, wherein the symbols have the meanings given in claim 3.
10. 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.
11. Mesylate as claimed in claim 9 of the compound having formula (1 ) wherein X is the group having formula (6) and Y is benzyl.
12. Mesylate as claimed in claim 9 of the compound having formula (1) wherein X is the group having formula (6) and Y is methyl.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01200534 | 2001-02-16 | ||
| EP01200534.4 | 2001-02-16 | ||
| PCT/EP2002/001666 WO2002066449A2 (en) | 2001-02-16 | 2002-02-14 | Process for the preparation of mesylates of piperazine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2002250962A1 true AU2002250962A1 (en) | 2003-02-27 |
| AU2002250962B2 AU2002250962B2 (en) | 2006-08-24 |
Family
ID=8179894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002250962A Ceased AU2002250962B2 (en) | 2001-02-16 | 2002-02-14 | Process for the preparation of mesylates of piperazine derivatives |
Country Status (35)
| Country | Link |
|---|---|
| US (1) | US7030241B2 (en) |
| EP (1) | EP1362040B1 (en) |
| JP (1) | JP4328528B2 (en) |
| KR (2) | KR100859106B1 (en) |
| CN (1) | CN1176079C (en) |
| AR (1) | AR034206A1 (en) |
| AT (1) | ATE284875T1 (en) |
| AU (1) | AU2002250962B2 (en) |
| BG (1) | BG66101B1 (en) |
| BR (1) | BR0205683A (en) |
| CA (1) | CA2422703C (en) |
| CZ (1) | CZ301780B6 (en) |
| DE (1) | DE60202261T2 (en) |
| DK (1) | DK1362040T3 (en) |
| DZ (1) | DZ3489A1 (en) |
| ES (1) | ES2230481T3 (en) |
| HK (1) | HK1059934A1 (en) |
| HR (1) | HRP20030610B1 (en) |
| HU (1) | HUP0400772A3 (en) |
| IL (1) | IL153509A (en) |
| IS (1) | IS2417B (en) |
| ME (1) | MEP37508A (en) |
| MX (1) | MXPA03002359A (en) |
| MY (1) | MY130687A (en) |
| NO (1) | NO324460B1 (en) |
| NZ (1) | NZ524632A (en) |
| PL (1) | PL208363B1 (en) |
| PT (1) | PT1362040E (en) |
| RS (1) | RS51126B (en) |
| RU (1) | RU2272036C2 (en) |
| SI (1) | SI1362040T1 (en) |
| SK (1) | SK286143B6 (en) |
| UA (1) | UA75390C2 (en) |
| WO (1) | WO2002066449A2 (en) |
| ZA (1) | ZA200301590B (en) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7435738B2 (en) | 2003-08-18 | 2008-10-14 | Solvay Pharmaceuticals, Inc. | Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate) |
| AR045362A1 (en) * | 2003-08-18 | 2005-10-26 | Solvay Pharm Bv | STABLE CRYSTALLINE FORM OF BIFEPRUNOX MESILATE (MONOMETANSULFONATE 7- [4 - ([1,1- BIFENIL] -3- ILMETIL) -1- PIPERAZINIL] - 2- (3H) -BENZOXAZOLONA |
| US7405216B2 (en) * | 2004-08-18 | 2008-07-29 | Solvay Pharmaceuticals, B.V. | Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate) |
| US7423040B2 (en) * | 2005-02-18 | 2008-09-09 | Irene Eijgendaal | Stable crystalline form of bifeprunox mesylate, dosage forms thereof and methods for using same |
| US7964604B2 (en) * | 2005-02-18 | 2011-06-21 | Solvay Pharmaceuticals B.V. | Bifeprunox mesylate maintenance dose compositions and methods for using the same |
| US20070275977A1 (en) * | 2006-05-02 | 2007-11-29 | Van Aar Marcel P | N-oxides of pyridylmethyl -piperazine and -piperidine derivatives |
| US8106056B2 (en) | 2006-06-16 | 2012-01-31 | Solvay Pharmaceuticals B.V. | Combination preparations comprising bifeprunox and a dopamine agonist |
| US7786126B2 (en) * | 2006-06-16 | 2010-08-31 | Solvay Pharmaceuticals B.V. | Combination preparations comprising SLV308 and a dopamine agonist |
| WO2008025781A1 (en) | 2006-08-31 | 2008-03-06 | Solvay Pharmaceuticals B.V. | Bifeprunox doses for treating schizophrenia |
| US20080132520A1 (en) * | 2006-08-31 | 2008-06-05 | Winsemius Antje A | Compositions, kits and methods for administering a titration schedule comprising bifeprunox compounds |
| US20090068290A1 (en) * | 2006-08-31 | 2009-03-12 | Michel Bourin | Bifeprunox doses for treating schizophrenia |
| EP2249838A4 (en) | 2008-02-05 | 2012-05-02 | Harbor Biosciences Inc | Pharmaceutical solid state forms |
| WO2011023796A1 (en) | 2009-08-31 | 2011-03-03 | Abbott Healthcare Products B.V. | Bifeprunox for treating addiction |
| UY32934A (en) | 2009-10-12 | 2011-05-31 | Abbott Healthcare Products Bv | PARDOPRUNOX MONOHIDRATE |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0190472B1 (en) * | 1984-12-21 | 1989-07-12 | Duphar International Research B.V | New pharmaceutical compositions having anti-psychotic properties |
| ATE81975T1 (en) * | 1984-12-21 | 1992-11-15 | Duphar Int Res | MEDICATIONS WITH PSYCHOTROPIC EFFECTS. |
| JPH0344383A (en) * | 1989-07-12 | 1991-02-26 | Ihara Chem Ind Co Ltd | Production of 5-trifluoromethyl-2-halomethylbenzothiazoles |
| JP3044383B2 (en) * | 1990-05-22 | 2000-05-22 | コニカ株式会社 | Method for producing nitrogen-containing 6-membered ring compound |
| JP3989554B2 (en) * | 1996-03-29 | 2007-10-10 | デユフアー・インターナシヨナル・リサーチ・ベー・ブイ | Piperazine and piperidine compounds |
| SE9702799D0 (en) * | 1997-07-25 | 1997-07-25 | Astra Ab | New compounds |
| UA71590C2 (en) * | 1998-11-13 | 2004-12-15 | Duphar Int Res | Piperazine and piperidine derivatives |
| US7435738B2 (en) * | 2003-08-18 | 2008-10-14 | Solvay Pharmaceuticals, Inc. | Stable crystalline form of bifeprunox mesylate (7-[4-([1,1′-biphenyl]-3-ylmethyl)-1-piperazinyl]-2(3H)-benzoxazolone monomethanesulfonate) |
-
2002
- 2002-02-12 AR ARP020100460A patent/AR034206A1/en active IP Right Grant
- 2002-02-14 PT PT02719858T patent/PT1362040E/en unknown
- 2002-02-14 CZ CZ20030697A patent/CZ301780B6/en not_active IP Right Cessation
- 2002-02-14 DZ DZ023489A patent/DZ3489A1/en active
- 2002-02-14 HU HU0400772A patent/HUP0400772A3/en unknown
- 2002-02-14 CN CNB028016858A patent/CN1176079C/en not_active Expired - Fee Related
- 2002-02-14 MX MXPA03002359A patent/MXPA03002359A/en active IP Right Grant
- 2002-02-14 SK SK309-2003A patent/SK286143B6/en not_active IP Right Cessation
- 2002-02-14 UA UA2003098528A patent/UA75390C2/en unknown
- 2002-02-14 AT AT02719858T patent/ATE284875T1/en active
- 2002-02-14 RS YUP-644/03A patent/RS51126B/en unknown
- 2002-02-14 JP JP2002565965A patent/JP4328528B2/en not_active Expired - Fee Related
- 2002-02-14 BR BR0205683-6A patent/BR0205683A/en not_active Application Discontinuation
- 2002-02-14 US US10/468,098 patent/US7030241B2/en not_active Expired - Fee Related
- 2002-02-14 WO PCT/EP2002/001666 patent/WO2002066449A2/en active IP Right Grant
- 2002-02-14 EP EP02719858A patent/EP1362040B1/en not_active Expired - Lifetime
- 2002-02-14 PL PL369330A patent/PL208363B1/en unknown
- 2002-02-14 KR KR1020037000026A patent/KR100859106B1/en not_active IP Right Cessation
- 2002-02-14 ES ES02719858T patent/ES2230481T3/en not_active Expired - Lifetime
- 2002-02-14 SI SI200230061T patent/SI1362040T1/en unknown
- 2002-02-14 ME MEP-375/08A patent/MEP37508A/en unknown
- 2002-02-14 IL IL153509A patent/IL153509A/en not_active IP Right Cessation
- 2002-02-14 CA CA2422703A patent/CA2422703C/en not_active Expired - Fee Related
- 2002-02-14 MY MYPI20020505A patent/MY130687A/en unknown
- 2002-02-14 DE DE60202261T patent/DE60202261T2/en not_active Expired - Lifetime
- 2002-02-14 DK DK02719858T patent/DK1362040T3/en active
- 2002-02-14 NZ NZ524632A patent/NZ524632A/en not_active IP Right Cessation
- 2002-02-14 KR KR1020087015071A patent/KR101000733B1/en not_active IP Right Cessation
- 2002-02-14 RU RU2003105902/04A patent/RU2272036C2/en not_active IP Right Cessation
- 2002-02-14 AU AU2002250962A patent/AU2002250962B2/en not_active Ceased
-
2003
- 2003-02-26 ZA ZA200301590A patent/ZA200301590B/en unknown
- 2003-04-15 NO NO20031754A patent/NO324460B1/en not_active IP Right Cessation
- 2003-07-17 IS IS6876A patent/IS2417B/en unknown
- 2003-07-28 HR HR20030610A patent/HRP20030610B1/en not_active IP Right Cessation
- 2003-08-13 BG BG108090A patent/BG66101B1/en unknown
-
2004
- 2004-04-22 HK HK04102835A patent/HK1059934A1/en not_active IP Right Cessation
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