MX2008014432A

MX2008014432A - Racemisation of enantiomers of nefopam and analogues.

Info

Publication number: MX2008014432A
Application number: MX2008014432A
Authority: MX
Inventors: Andrew Douglas Baxter; Kenneth Walter Sinden; Marc-Henri Mouton; Herve Lhermitte
Original assignee: Sosei R & D Ltd
Priority date: 2006-05-17
Filing date: 2007-05-17
Publication date: 2008-12-18
Also published as: CA2652250A1; EP2027099A2; AU2007251332A1; JP2009538281A; WO2007132255A2; BRPI0711836A2; GB0609793D0; WO2007132255A3; IL195199A0; CN101448799A; KR20090023603A

Abstract

A process for the racemisation of a compound which is nefopam or an analogue thereof in the form of a single enantiomer or non-racemic mixture, which comprising contacting the compound with an acid.

Description

RACEMIZATION OF NEFOPAM AND ANALOG ENANTIZERS Field of the Invention This invention relates to a racemization and recycling process, and in particular to the racemization of nefopam and the like. Background of the Invention Nefopam (available as the hydrochloride) is a non-narcotic analgesic that acts centrally. Nefopam and analogs are described in GB1148717 and in WO2004 / 056788. The utility of a single isomer of nefopam, ie, (+) - nefopam, is disclosed in WO03 / 105832 and WO03 / 105833. In addition, individual enantiomers that are nefopam analogs and their use are described in WO2006 / 095187. The hydrochloride monohydrate of (+) - nefopam can be manufactured by resolution, as described in WO2005 / 056539; see Scheme 1. Currently there is no defined use for the (-) -enantiomer of nefopam which is discarded as waste material. Scheme 1 9 C "H, 9NO. HCI. H, 0 [307,811 There is no evidence in the literature that optically pure nefopam undergoes chemical racemization nor is there any evidence of racemization in API stability studies carried out on the molecule to date. The literature related to the stress stability of the nefopam molecule indicates that it is chemically unstable under both acidic and alkaline conditions, suggesting that it would not be appropriate to attempt the racemization of nefopam under these conditions. Brief Description of the Invention The present invention is based upon a discovery of the usefulness of the mother liquors of the resolution process shown in Scheme 1, which contains enriched amounts of the (-) - nefopam enantiomer such as the dibenzoyltartrate salt. These mother liquors have historically been discarded, but it has been discovered that the isolation of the free base material followed by the treatment of still mild acid results in racemization to the material that can be subsequently recycled, for example in the resolution process. This improves the efficiency of the resolution process and dramatically reduces waste materials, increasing the commercial attractiveness of the process. According to the present invention, a process for the racemization of a compound that is nefopam or an analogue thereof in the form of a single enantiomer or non-racemic mixture, comprises contacting the compound with an acid. Description of the Invention The racemization substrate is a single enantiomer or non-racemic mixture of enantiomers, of nefopam or an analog, that is, a compound having the same cyclic structure and chiral center. Analogs are described in the documents GB1148717, WO2004 / 056788 and WO2006 / 095187, the content of each of which is incorporated in the present by reference. The acid used for the racemization can be an organic or inorganic compound. Examples include alkyl and aryl-susonic acids. Preferably it is a mineral acid such as hydrochloric acid. Other suitable acids will be readily apparent to one of ordinary skill in the art. The racemisation reaction can be carried out in water and / or an organic solvent. For example, an alcohol solvent, for example ethanol or isopropanol, can be used as a cosolvent. Other suitable solvents will be readily apparent to one of ordinary skill in the art. The preferred reaction is carried out at 20 to 80 ° C, more preferably 50 to 80 ° C, and much more preferably 50 to 5 ° C. The reaction typically takes 6 to 24 hours, and usually requires at least 12 hours. For relatively dilute reaction mixtures, relatively low reaction temperatures and / or relatively low amounts of acid, the reaction may require relatively high temperature and / or time, and may require agitation. The racemic product can be isolated by methods known to those skilled in the art; for example, dilution with isopropanol. The following Examples illustrate the invention.

Example 1 The treatment of the free base of (-) - nefopam, obtained from the mother liquors of the resolution process, in ethanol (5 volumes) with dilute hydrochloric acid (1.5 volumes) results in racemization even at low temperature. The results are shown in the following table. The conversion was from an ee (initial enantiomeric excess) of 95.6, to 2.4 to 80 ° C and to 13.0 to 20-25 ° C. EXAMPLE 2 The mother liquors of the resolution of 300 g of nefopam racemate (WO2005 / 056539) were treated as follows: The mother liquors of the hydrochloride salt formation were charged to a suitable vessel and the isopropanol was distilled under vacuum . To the concentrate were added the liquors of the recrystallization of the dibenzoyl tartrate salt of nefopam and the ethanol was distilled under vacuum. To the concentrate, the mother liquors of the initial dibenzoyl tartrate salt formation were added and the ethanol was distilled under vacuum. Water (100 ml) and toluene (300 ml) were added to the concentrate. The mixture was heated to 50-55 ° C for at least 1 hour and a solution of potassium carbonate (50% w / w in water) was added for at least 1 hour. The lower aqueous layer was separated. The upper organic layer was washed with water (100 ml) and the lower aqueous layer was separated. He Toluene was distilled under vacuum to leave a concentrate. The isomer ratio was 25/75% in favor of the (-) -enantiomer. Hydrochloric acid at 36% w / w (100 ml) was added at 40-45 ° C and the mixture was heated at 50-55 ° C for at least 12 hours. The isomer ratio was 52/48% (i.e., essentially racemic). Isopropanol (500 ml) was added and distilled to remove excess hydrochloric acid. Isopropanol (500 ml) was added and the mixture was cooled to 0-5 ° C for at least 2 hours and the mixture was maintained for at least 2 hours. The racemic nefopam hydrochloride was isolated by filtration, washed with cold isopropanol (2 x 20 ml) and dried.

Claims

CLAIMS 1. A process for the racemization of a compound that is nefopam or an analogue thereof in the form of a single enantiomer or non-racemic mixture, characterized in that it comprises contacting the compound with an acid.
2. A process according to claim 1, characterized in that the compound has the formula wherein Ri is H, Ci-C6 alkyl optionally substituted with F, C3-C6 cycloalkyl or C2-C6 alkenyl, 'whether R2 and R3 are the same or different and are H, halogen, CN, CF3, Ci-C6 alkyl or 0RX, or R2 and R3 form a five or six membered ring which can be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from 0, N and S), aromatic or heteroaromatic (containing 1- 2 heteroatoms selected from 0 and N); one of, X, Y and Z is N or CR4 and the others are each one CH; R4 is halogen, CF3, CN, 0R7, S02N (R6) 2, COR6, C02R6, CON (R6) 2, NR1COR5, NRXS02R5, NRiC02R5, NRiCON (R6) 2, O-C1-C6 alkyl optionally substituted with R4, C 1 -C 6 alkyl optionally substituted with R 4, C 3 -C 6 cycloalkyl optionally substituted with R 4, C 2 -C 6 alkenyl optionally substituted with R 4, C 2 -C 5 alkynyl optionally substituted with R 4, aryl optionally substituted with R 4, or an aromatic heterocycle of five or six members containing 1-4 heteroatoms selected from N and 0, linked either through carbon or nitrogen; R5 is Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl; each of R6 (which may be the same or different) is H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl; and R7 is aryl or heteroaryl; wherein aryl is an optionally substituted phenyl or naphthyl group; carbocyclic is a saturated alicyclic moiety having 5 or 6 C atoms; heterocyclic is a saturated heterocyclic moiety having 5 or 6 atoms including one or more of N, O and S; and heteroaromatic is aromatic of 5 or 6 atoms of the which at least one is N, O or S; or a pharmaceutically acceptable salt thereof.
3. A process according to claim 2, characterized in that R4 is present and is halogen, CN, 0R7, S02N (R6) 2, COR6, C02R6, CON (R6) 2, RICORB, N RÍSOZ RS, RxCON (R6) 2 O-Ci-C6 alkyl substituted with R4, Ci-C5 alkyl substituted with R4, C3-C6 cycloalkyl optionally substituted with R, C2-Ce alkenyl optionally substituted with R4, C2-C6 alkynyl optionally substituted with R4, aryl optionally substituted with R4, or a five or six membered aromatic heterocycle containing 1-4 heteroatoms selected from N and O, linked either through carbon or nitrogen.
4. A process according to claim 3, characterized in that R4 is Br, CN, CON (R6) 2, optionally substituted cycloalkyl or aryl, or a five or six membered aromatic heterocycle.
5. A process according to any of claims 2 to 4, characterized in that R2 is halogen, CN, CF3, Ci-C6 alkyl or ORi.
6. A process according to any of claims 2 to 4, characterized in that R2 and R3 form a ring.
7 A process according to any of claims 2 to 4, characterized in that R2 or R3 is ORi.
8. A process according to claim 1, characterized in that the compound is selected from 9-methoxy-5-methyl-l, 3,4, 6-tetrahydro-5H-benz [f] -2,5-oxazocine 8- methoxy-5-methyl-l, 3,4, 6-tetrahydro-5H-benz [f] -2,5-oxazocin 9-methoxy-5-methyl-l- (3-methoxy) phenyl-1,3,4 , 6-tetrahydro-5H-benz [f] -2,5-oxazocin 8-methoxy-5-methyl-l- (3-methoxy) phenyl-1,3,4,6-tetrahydro-5H -benz [f] -2,5-oxazocin 9-methoxy-5-methyl-1- (4-methoxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5 -oxazocine and 8-methoxy-5-methyl-1- (4-methoxy) phenyl-1, 3,4, β-tetrahydro-5H-benz [f] -2,5-oxazocine.
9. A process according to claim 1, characterized in that the compound is selected from 9-cyano-5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz- [ f] -2,5-oxazocine 8-cyano-5-methyl-1- (3-methoxy) phenyl-1,3, 6-tetrahydro-5H-benz [f] -2,5-oxazocine 9- cyclopropyl-5-methyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-cyclopropyl-5-methyl-1-phenyl-1,3, 4,6-tetrahydro-5H-benz [f] -2,5-oxazocine N- (acetyl) -5-methyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-9-methylamine N- (acetyl) -5-methyl- l-phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-methylamine 9-cyclopropyl-5-methyl-1- (3-methoxy) phenyl-1, 3, 4, 6-tetrahydro-5Ji-benz [f] -2,5-oxazocin 8-cyclopropyl-5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazozine 9-cyclopropyl-5-methyl-1- (4-methoxy) phenyl-1, 3,4,6-tetrahydro-5-yf-benz [f] -2,5-oxazocine 8- Cyclopropyl-5-methyl-1- (4-methoxy) phenyl-1, 3,4,6-tetrahydro-5-tf-benz [f] -2,5-oxazocine and 9-cyano-5-methyl-1- (4 -methoxy) phenyl-1,3,4,6-tetrahydro-5-fluo-benz [f] -2,5-oxazocine.
10. A process according to claim 1, characterized in that the compound is selected from 9-cyano-5-methyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2, 5 -oxazocin 8 -cyano-5-methyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 5-methyl-1-phenyl-1, 3,4, 6-tetrahydro-5H-benz [f] -2,5-oxazocin-9-carboxamide 5-methyl-l-phenyl-l, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine -8-carboxamide N- (1,1,1-trimethylmethoxycarbonyl) -5-methyl-1-phenyl- , 3,4, 6-tetrahydro-5H-benz [f] -2,5-oxazocin-9-melamine N- (1,1,1-trimethylmethoxycarbonyl) -5-methyl-1-phenyl-, 3,4 , 6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-methylamine 5-methyl-l, 9-diphenyl-1,3,6,6-tetrahydro-5H-benz [f], 5-oxazocine 5-methyl-l, 8-diphenyl-1,3,4,6-tetrahydro-5H-benz [f], 5-oxazocin 9- (3, 5-dimethylisoxazol-4-yl) -5-methyl-l- phenyl-1, 3, 6-tetrahydro-5H-benz [f] -2,5-oxazocine 8- (3, 5-dimethylisoxazol-5-yl) -5-methyl-1-phenyl-1, 3, 4, 6-tetrahydro-5H-benz [f] -2,5-oxazocin 2- (5-methyl-1-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin- 9-ethenyl) carboxamide 2- (5-methyl-l-phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-ethenyl) carboxamide 2- (5-methyl) -l-phenyl-1, 3,4, 6-tetrahydro-5H-benz [f] -2) 5-oxazocin-9-ethyl) carboxamide 2- (5-methyl-1-phenyl-1, 3,4, 6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-ethyl) carboxamide 5-methyl-1-phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2.5 oxazocine-9-methylamine 5-methyl-phenyl-1, 3, 4, 6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-methylamine N- (acetyl) -5-methyl-l-phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2, 5-oxazocin-9-methylamine and N- (acetyl) -5-methyl-l-phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-methylaraine.
11. A process according to claim 1, characterized in that the compound is selected from 9-bromo-5-methyl-1-phenyl-1, 3, 4, 6-tetrahydro-5H-benz- [f] -2, 5-oxazocine 8-bromo-5-methyl-l-phenyl-1,3,4,6-tetrahydro-5H-benz- [f] -2,5-oxazocine 9-bromo-5-methyl-1- (4 -methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin 8-bromo-5-methyl-1- (4-methoxy) phenyl-1,3,4, 6-tetra-hydro-5H-benz [f] -2,5-oxazocin 9-bromo-5-methyl-1- (3-methoxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -oxazocine and 8-bromo-5-methyl-1- (3-methoxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine.
12. A process according to claim 1, characterized in that it is to racemize the (-) - nefopam enantiomer substantially alone.
13. A process in accordance with the claim 1, characterized in that it is to racemize the (+) - nefopam enantiomer substantially alone.
14. A process according to claim 1, characterized in that it is for the preparation of a compound selected from (1 S) -8-cyano-5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5 H -benz [f] -2,5-oxazocine; (1f?) -8-cyano-5-methyl-1- (3-methoxy) phenyl-1, 3,4,6-tetrahydro-5H-benz [f] -2,5-oxa zozine; (1S) -8-cyclopropyl-5-methyl-1- (3-methoxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; (1 S) -8-cyclopropyl-5-methyl-1- (3-methoxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocine; (1S) -5-methyl-1- (3-methoxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-carboxamide; (1R) -5-methyl-l- (3-methoxy) phenyl-1,3,4,6-tetrahydro-5H-benz [f] -2,5-oxazocin-8-carboxamide; and the salts thereof.
15. A process according to any preceding claim, characterized in that the racemization is carried out using a mineral acid.
16. A process according to claim 15, characterized in that the mineral acid is hydrochloric acid.
17. A process according to any preceding claim, characterized in that the racemization is carried out in a solvent selected from water and organic solvents and mixtures thereof.
18. A process for the manufacture of the isomer substantially solely of a compound that is nefopam or a analogous thereof, characterized in that it comprises the resolution of the racemic compound, isolation of the desired single isomer and racemization of the undesired material by a process according to any preceding claim.