EP2027099A2 - Racemisation of enantiomers of nefopam and analogues - Google Patents

Racemisation of enantiomers of nefopam and analogues

Info

Publication number
EP2027099A2
EP2027099A2 EP07732871A EP07732871A EP2027099A2 EP 2027099 A2 EP2027099 A2 EP 2027099A2 EP 07732871 A EP07732871 A EP 07732871A EP 07732871 A EP07732871 A EP 07732871A EP 2027099 A2 EP2027099 A2 EP 2027099A2
Authority
EP
European Patent Office
Prior art keywords
oxazocine
tetrahydro
benz
methyl
phenyl
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.)
Withdrawn
Application number
EP07732871A
Other languages
German (de)
French (fr)
Inventor
Marc-Henri Mouton
Hervé LHERMITTE
Andrew Douglas Baxter
Kenneth Walter Sinden
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sosei R&D Ltd
Original Assignee
Arakis Ltd
Sosei R&D Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Arakis Ltd, Sosei R&D Ltd filed Critical Arakis Ltd
Publication of EP2027099A2 publication Critical patent/EP2027099A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/22—Eight-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • This invention relates to a racemisation and recycling process, and in particular to the racemisation of enantiomers of nefopam and analogues.
  • Nefopam (available as the hydrochloride) is a centrally acting nonnarcotic analgesic. Nefopam and analogues are described in GB1148717 and in WO2004/056788. The utility of a single isomer of nefopam, i.e. (+)-nefopam, is disclosed in WO03/105832 and WO03/105833. Further, single enantiomers that are analogues of nefopam, and their use, are described in WO2006/095187. (+)-Nefopam hydrochloride monohydrate may be manufactured by resolution, as described in WO2005/056539; see Scheme 1. There is currently no defined use for the (-)-enantiomer of nefopam which is discarded as waste material.
  • the present invention is based on a finding of the utility of the mother liquors of the resolution process shown in Scheme 1 , which contain enriched quantities of the (-)-nefopam enantiomer as the dibenzoyltartrate salt.
  • These mother liquors have historically been discarded, but it has been discovered that isolation of the free base material followed by even mild acid treatment results in racemisation to material that can subsequently be recycled, e.g. into the resolution process. This improves the efficiency of the resolution process and dramatically reduces the waste materials, enhancing the commercial attractiveness of the process.
  • a process for the racemisation of a compound is nefopam or an analogue thereof in the form of a single enantiomer or non-racemic mixture, comprises contacting the compound with an acid.
  • the racemisation substrate is a single enantiomer or non-racemic mixture of enantiomers, of nefopam or an analogue, i.e. a compound having the same cyclic structure and chiral centre. Analogues are described in GB1148717,
  • the acid that is used for racemisation may be an organic or inorganic compound.
  • examples include alkyl and aryl-suphonic acids. It is preferably 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 may be carried out in water and/or an orgnic solvent.
  • an alcoholic solvent e.g. ethanol or isopropanol
  • suitable solvents will be readily apparent to one of ordinary skill in the art.
  • the reaction is preferably carried out at from 20 to 80 0 C, more preferably
  • the reaction typically takes 6 to 24 hours, and usually requires at least 12 hours.
  • relatively low reaction temperatures and/or relatively low amounts of acid the reaction may require relatively high temperature and/or time, and may require stirring.
  • the racemic product may be isolated by procedures known to those skilled in the art; for example, dilution with isopropanol. The following Examples illustrate the invention.
  • Example 1 Treatment of (-)-nefopam free base, obtained from the mother liquors of the resolution process, in ethanol (5 volumes) with dilute hydrochloric acid (1.5 volumes) results in racemisation even at low temperature. Results are shown in the following Table. Conversion was from an initial ee (enantiomeric excess) of
  • the upper organic layer was washed with water (100 ml) and the lower aqueous layer separated.
  • the toluene was distilled out under vacuum to leave a concentrate.
  • the isomer ratio was 25/75% in favour of the (-)-enantiomer.

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

Racemisation of Enantiomers of Nefopam and Analogues Field of the Invention
This invention relates to a racemisation and recycling process, and in particular to the racemisation of enantiomers of nefopam and analogues. Background of the Invention
Nefopam (available as the hydrochloride) is a centrally acting nonnarcotic analgesic. Nefopam and analogues are described in GB1148717 and in WO2004/056788. The utility of a single isomer of nefopam, i.e. (+)-nefopam, is disclosed in WO03/105832 and WO03/105833. Further, single enantiomers that are analogues of nefopam, and their use, are described in WO2006/095187. (+)-Nefopam hydrochloride monohydrate may be manufactured by resolution, as described in WO2005/056539; see Scheme 1. There is currently no defined use for the (-)-enantiomer of nefopam which is discarded as waste material.
Scheme 1
C17H19NO HCI [289 8] C17H19NO [253 34] C18H14O8 [358 30]
I) EtOH ii) Recryst EtOH
C17H19NO HCI H2O [307 81]
There is no evidence in the literature that optically pure nefopam is subject to chemical racemisation nor is there any evidence of racemisation in the API stability studies carried out on the molecule to date. Literature relating to stress stability of the nefopam molecule indicates that it is chemically labile under both acid and alkaline conditions, suggesting that it would not be appropriate to attempt racemisation of nefopam under these conditions. Summary of the Invention
The present invention is based on a finding of the utility of the mother liquors of the resolution process shown in Scheme 1 , which contain enriched quantities of the (-)-nefopam enantiomer as the dibenzoyltartrate salt. These mother liquors have historically been discarded, but it has been discovered that isolation of the free base material followed by even mild acid treatment results in racemisation to material that can subsequently be recycled, e.g. into the resolution process. This improves the efficiency of the resolution process and dramatically reduces the waste materials, enhancing the commercial attractiveness of the process.
According to the present invention, a process for the racemisation of a compound 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 racemisation substrate is a single enantiomer or non-racemic mixture of enantiomers, of nefopam or an analogue, i.e. a compound having the same cyclic structure and chiral centre. Analogues are described in GB1148717,
WO2004/056788 and WO2006/095187, the content of each of which is incorporated herein by reference.
The acid that is used for racemisation may be an organic or inorganic compound. Examples include alkyl and aryl-suphonic acids. It is preferably 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 may be carried out in water and/or an orgnic solvent. For example, an alcoholic solvent, e.g. ethanol or isopropanol, may be used as a cosolvent. Other suitable solvents will be readily apparent to one of ordinary skill in the art.
The reaction is preferably carried out at from 20 to 800C, more preferably
50 to 8O0C, and most 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 stirring. The racemic product may be isolated by procedures known to those skilled in the art; for example, dilution with isopropanol. The following Examples illustrate the invention.
Example 1 Treatment of (-)-nefopam free base, obtained from the mother liquors of the resolution process, in ethanol (5 volumes) with dilute hydrochloric acid (1.5 volumes) results in racemisation even at low temperature. Results are shown in the following Table. Conversion was from an initial ee (enantiomeric excess) of
95.6, to 2.4 at 80°C and to 13.0 at 20-25°C. Example 2
The mother liquors from the resolution of 300 g of nefopam racemate (WO2005/056539) were treated in the following manner:
The mother liquors from the formation of the hydrochloride salt formation were charged to a suitable vessel and the ispropanol distilled out under vacuum.
To the concentrate were added the liquors from the recrystalisation of the nefopam dibenzoyl tartrate salt and the ethanol distilled out under vacuum. To the concentrate were added the mother liquors form the initial dibenzoyl tartrate salt formation and the ethanol distilled out under vacuum. Water (100 ml) and toluene (300 ml) were added to the concentrate. The mixture was heated at 50-
55°C for at least 1 hour and a solution of potassium carbonate (50% w/w in water) was added over 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 separated. The toluene was distilled out under vacuum to leave a concentrate. The isomer ratio was 25/75% in favour of the (-)-enantiomer.
36% w/w hydrochloric acid (100 ml) was added at 40-450C and the mixture heated at 50-550C for at least 12 hours. The isomer ratio was 52/48% (i.e. essentially racemic). lsopropanol (500 ml) was added and distilled out to remove excess hydrochloric acid, lsopropanol (500 ml) was added and the mixture cooled to 0 -
5°C over at least 2 hours and the mixture held 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 racemisation of a compound which is nefopam or an analogue thereof in the form of a single enantiomer or non-racemic mixture, which comprises contacting the compound with an acid.
2. A process according to claim 1 , wherein the compound has the formula
wherein
Ri is H, CrC6 alkyl optionally substituted with F, C3-C6 cycloalkyl or C2-C6 alkenyl; either R2 and R3 are the same or different and are H, halogen, CN, CF3, CrC6 alkyl or ORi, or R2 and R3 form a five or six-membered ring which may be carbocyclic, heterocyclic (containing 1-2 heteroatoms selected from O, N and S), aromatic or heteroaromatic (containing 1-2 heteroatoms selected from O and N) ; one of W, X, Y and Z is N or CR4 and the others are each CH;
R4 is halogen, CF3, CN, OR7, SO2N(Re)2, COR6, CO2R6, CON(R6)2, NR1COR5, NRiSO2R5, NR1CO2R5, NR1CON(Re)2, OC1-C6 alkyl optionally substituted with R4, C1-C6 alkyl optionally substituted with R4, C3-C6 cycloalkyl optionally substituted with R4, C2-C6 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;
R5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl or heteroaryl; each R6 (which may be the same or different) is H, CrC6 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 which at least one is N, O or S; or a pharmaceutically acceptable salt thereof.
3. A process according to claim 2, wherein R4 is present and is halogen, CN, OR7, SO2N(Re)2, COR6, CO2R6, CON(R6)2, NR1COR5, NR1SO2R5, NR1CON(Re)2, OC1-C6 alkyl substituted with R4, C1-C6 alkyl substituted with R4, C3-C6 cycloalkyl optionally substituted with R4, C2-C6 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, wherein 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 of any of claims 2 to 4, wherein R2 is halogen, CN, CF3, C1-C6 alkyl or OR1.
6. A process according to of any of claims 2 to 4, wherein R2 and R3 form a ring.
7. A process according to any of claims 2 to 4, wherein R2 or R3 is OR1.
8. A process according to claim 1 , wherein the compound is selected from 9-methoxy-5-methyI-1-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine 8-methoxy-5-methyl-1-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine 9-methoxy-5-methyI-1-(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]- 2,5-oxazocine
8-methoxy-5-methyl-1-(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-
2,5-oxazocine
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 ,3,4,6-tetrahydro-5H-benz[f]- 2,5-oxazocine.
9. A process according to claim 1 , wherein the compound is selected from 9-cyano-5-methyl-1-(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[fJ-2,5- oxazocine
8-cyano-5-methyl-1-(3-methoxy)phenyM A4,6-tetrahydro-5H-benz[f]-2,5- oxazocine
9-cyclopropyl-5-methyl-1-phenyl-1 A4,6-tetrahydro-5H-benz[f]-2,5- oxazocine 8-cyclopropyl-5-methyl-1-pheny[-1 ^4,6-tetrahydro-5H-benz[f]-2,5- oxazocine
Λ/-(acetyl)-5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine-9-methylamine
Λ/-(acetyl)-5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine-8-methylamine θ-cyclopropyl-δ-methyl-i-β-methoxyJphenyl-I benz[f]-2 , 5-oxazocine δ-cyclopropyl-S-methyl-i-β-methoxyJphenyl-I .SAβ-tetrahydro-SH- benz[f]-2 , 5-oxazocine 9-cyclopropyl-5-methyl-1-(4-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H- benz[f]-2 , 5-oxazocine
8-cyclopropyl-5-methyl-1-(4-methoxy)phenyl-1 ^4,6-tetrahydro-5H- benz[f]-2, 5-oxazocine and
9-cyano-5-methyl-1-(4-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine.
10. A process according to claim 1 , wherein the compound is selected from 9-cyano-5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine 8-cyano-5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2, 5-oxazocine 5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine-9- carboxamide
5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine-8- carboxamide
/V-(1 ,1 ,1-trimethylmethoxycarbonyl)-5-methyl-1 -phenyl- 1 ,3,4,6-tetrahydro- 5H-benz[f]-2,5-oxazocine-9-methylamine Λ/-(1 ,1 ,1-trimethylmethoxycarbonyl)-5-methyl-1 -phenyl- 1 ,3,4,6-tetrahydro- 5H-benz[f]-2,5-oxazocine-8-methylamine
5-methyl-1 ,9-diphenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine
5-methyl-1 ,8-diphenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine 9-(3,5-dimethylisoxazol-4-yl)-5-methyl-1 -phenyl-1 ,3,4,6-tetrahydro-5H- benz[f]-2,5-oxazocine
8-(3,5-dimethylisoxazol-4-yl)-5-methyl-1 -phenyl-1 ,3,4, 6-tetrahydro-5H- benz[f]-2,5-oxazocine
2-(5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine-9- ethenyl)carboxamide
2-(5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine-8- ethenyl)carboxamide
2-(5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2)5-oxazocine-9- ethyl)carboxamide 2-(5-methyl-1 -phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine-8- ethyl)carboxamide
5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f|-2,5-oxazocine-9- methylamine
5-methyM -phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5-oxazocine-8- methylamine
N-(acetyl)-5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine-9-methylamine and
Λ/-(acetyl)-5-methyl-1-phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine-8-methylamine.
11. A process according to claim 1 , wherein the compound is selected from θ-bromo-δ-methyl-i-phenyl-I .S^.Θ-tetrahydro-SH-benzCfl^.S-oxazocine
8-bromo-5-methyl-1-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- oxazocine 8-bromo-5-methyl-1-(4-methoxy)phenyl-1,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine θ-bromo-δ-methyl-I^S-methoxyJphenyl-I.S^.δ-tetrahydro-δH-benzffl^.S- oxazocine and
8-bromo-5-methyI-1-(3-methoxy)phenyl-1,3,4,6-tetrahydro-5H-benz[f]- 2,5-oxazocine.
12. A process according to claim 1 , for racemising substantially single enantiomer (-)-nefopam.
13. A process according to claim 1 , for racemising substantially single enantiomer (+)-nefopam.
14. A process according to claim 1 , for the preparation of a compound selected from
(1 S)-8-cyano-5-methyl-1 -(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H- benz[f]-2 , 5-oxazocine ;
(1R)-8-cyano-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;
(1 S)-8-cyclopropyl-5-methyl-1-(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H- benz[f]-2, 5-oxazocine; (1 S)-5-methyl-1-(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine-8-carboxamide;
(1 f?)-5-methyl-1 -(3-methoxy)phenyl-1 ,3,4,6-tetrahydro-5H-benz[f]-2,5- oxazocine-8-carboxamide; and the salts thereof.
15. A process according to any preceding claim, wherein the racemisation is carried out using a mineral acid.
16. A process according to claim 15, wherein the mineral acid is hydrochloric acid.
17. A process according to any preceding claim, wherein the racemisation is carried out in a solvent selected from water and organic solvents and mixtures thereof.
18. A process for the manufacture of substantially single isomer of a compound which is nefopam or an analogue thereof, which comprises resolution of the racemic compound, isolating the desired single isomer, and racemisation of the unwanted material by a process according to any preceding claim.
EP07732871A 2006-05-17 2007-05-17 Racemisation of enantiomers of nefopam and analogues Withdrawn EP2027099A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0609793.5A GB0609793D0 (en) 2006-05-17 2006-05-17 Racemisation and recycling process
PCT/GB2007/001849 WO2007132255A2 (en) 2006-05-17 2007-05-17 Racemisation of enantiomers of nefopam and analogues

Publications (1)

Publication Number Publication Date
EP2027099A2 true EP2027099A2 (en) 2009-02-25

Family

ID=36660334

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07732871A Withdrawn EP2027099A2 (en) 2006-05-17 2007-05-17 Racemisation of enantiomers of nefopam and analogues

Country Status (11)

Country Link
EP (1) EP2027099A2 (en)
JP (1) JP2009538281A (en)
KR (1) KR20090023603A (en)
CN (1) CN101448799A (en)
AU (1) AU2007251332A1 (en)
BR (1) BRPI0711836A2 (en)
CA (1) CA2652250A1 (en)
GB (1) GB0609793D0 (en)
IL (1) IL195199A0 (en)
MX (1) MX2008014432A (en)
WO (1) WO2007132255A2 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2311749T3 (en) * 2002-12-20 2009-02-16 SOSEI R&D LTD. BENZOXAZOCINAS AND ITS USE AS INHIBITORS OF THE RECOVERY OF MONOAMINE.
GB0328871D0 (en) * 2003-12-12 2004-01-14 Arakis Ltd Resolution process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007132255A2 *

Also Published As

Publication number Publication date
AU2007251332A1 (en) 2007-11-22
CA2652250A1 (en) 2007-11-22
WO2007132255A3 (en) 2008-01-24
CN101448799A (en) 2009-06-03
KR20090023603A (en) 2009-03-05
JP2009538281A (en) 2009-11-05
BRPI0711836A2 (en) 2011-12-13
MX2008014432A (en) 2008-12-18
GB0609793D0 (en) 2006-06-28
WO2007132255A2 (en) 2007-11-22
IL195199A0 (en) 2009-08-03

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