CN101448799A - Racemisation of enantiomers of nefopam and analogues - Google Patents

Racemisation of enantiomers of nefopam and analogues Download PDF

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CN101448799A
CN101448799A CNA2007800179630A CN200780017963A CN101448799A CN 101448799 A CN101448799 A CN 101448799A CN A2007800179630 A CNA2007800179630 A CN A2007800179630A CN 200780017963 A CN200780017963 A CN 200780017963A CN 101448799 A CN101448799 A CN 101448799A
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tetrahydrochysene
oxazole
benzo
suffering
phenyl
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马克-亨利·穆托
埃尔夫·莱尔米特
安德鲁·道格拉斯·巴克斯特
肯尼思·沃尔特·辛登
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Sosei R&D Ltd
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    • 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

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Abstract

The present invention discloses 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

The racemization of the enantiomorph of nefopam and analogue thereof
Technical field
The present invention relates to racemization and method for recycling, relate in particular to the racemization of the enantiomorph of nefopam and analogue thereof.
Background technology
Nefopam (can hydrochloride form obtain) is the non-narcotic analgesics of central action.Nefopam and analogue thereof are described among GB1148717 and the WO2004/056788.The individual isomer of the nefopam i.e. purposes of (+)-nefopam is disclosed among WO03/105832 and the WO03/105833.In addition, single enantiomer of nefopam analogue and uses thereof is described among the WO2006/095187.
Described in WO2005/056539, (+)-nefopam hydrochloride monohydrate can be prepared by fractionation, square case 1.At present, (-)-nefopam enantiomer does not have clear and definite purposes, and it is used as waste material and abandons.
Scheme 1
Figure A200780017963D00091
Up to now, do not have relevant optically pure nefopam to carry out the evidence of chemical racemization in the document, in the API stability study that this molecule is carried out, do not have any evidence of racemization yet.About the document of the accelerated stability of nefopam molecule shows that it all is chemically unstables under acid and alkaline condition, it may be inappropriate pointing out the racemization that carries out nefopam under these conditions.
Summary of the invention
The present invention is based on the basis that utilizes this discovery of mother liquor of method for splitting shown in the scheme 1.Described mother liquor comprises (-) as the dibenzoyl tartaric acid salt form-nefopam enantiomer of substantial amount.These mother liquors all are dropped in history, but have been found that at the after separating that carries out free base material, by in addition gentle acidic treatment can cause racemization, obtain being recycled to subsequently the material in the method for splitting for example.Improve the efficient of described method for splitting like this and significantly reduced waste material, improved the commercial appeal of this method.
According to the present invention, the racemization method that is used for the compound of the nefopam of single enantiomer or non-racemic mixture form or its analogue comprises makes described compound contact with acid.
Embodiment
The substrate of racemization is the single enantiomer of nefopam or its analogue or the non-racemic mixture of enantiomorph, promptly has the compound of identical ring structure and chiral centre.Analogue is described among GB1148717, WO2004/056788 and the WO2006/095187, and its content is incorporated this paper into by reference at this.
The acid that is used for racemization can be organic compound or mineral compound.Example comprises alkylsulphonic acid and aryl sulfonic acid.Mineral acid for example hydrochloric acid is preferred.Other suitable acid is conspicuous for persons skilled in the art.
Described racemization reaction can be carried out in water and/or organic solvent.For example, alcoholic solvent (for example ethanol or Virahol) can be used as cosolvent.Other suitable solvent is conspicuous for persons skilled in the art.
Described reaction is preferably carried out at 20～80 ℃, more preferably carries out at 50～80 ℃, most preferably carries out at 50～5 ℃.Described reaction needs 6～24 hours usually, and needs at least 12 hours usually.For the acid of rare relatively reaction mixture, low relatively temperature of reaction and/or relatively small amount, described reaction may need high relatively temperature and/or time and may need to stir.Racemic product can be separated by method known to those skilled in the art, for example utilizes isopropanol.
Following embodiment illustrates the present invention.
Embodiment 1
The dilute hydrochloric acid (1.5 times volume) of utilization in ethanol (5 times of volumes) is handled (-)-nefopam free base (obtaining in the mother liquor from method for splitting) even can be caused racemization at low temperatures.The result is presented in the following table.When conversion is when initial ee (enantiomeric excess) 95.6 becomes 80 ℃ 2.4 and 20～25 ℃ 13.0.
Embodiment 2
Handle in the following manner from the mother liquor (WO2005/056539) that splits 300g nefopam racemoid:
The mother liquor of self-forming hydrochloride form places suitable containers and distill out Virahol under vacuum in the future.In described enriched material, add liquid, distill out ethanol under the vacuum from the recrystallization of nefopam dibenzoyl tartaric acid salt.In the future the mother liquor of the initial dibenzoyl tartaric acid salt of self-forming joins in the described enriched material, steams ethanol under the vacuum.In enriched material, add water (100ml) and toluene (300ml).Mixture was heated 1 hour down at 50～55 ℃ at least, at least 1 hour time, add solution of potassium carbonate (50%w/w is in water).Isolate following water layer.Organic layer above water (100ml) cleans also separates following water layer.Distill out toluene under the vacuum and obtain enriched material.The ratio of isomer is 25/75%, and (-)-enantiomorph is preponderated.
Add 36%w/w hydrochloric acid (100ml) down at 40～45 ℃, mixture was heated 12 hours down at 50～55 ℃ at least.The ratio of isomer is 52/48% (promptly being racemic basically).
Adding Virahol (500ml) also distills away to remove excessive hydrochloric acid.Add Virahol (500ml), mixture at least 2 hours time internal cooling to 0～5 ℃, and is placed mixture 2 hours at least.By the racemic nefopam hydrochloride of filtering separation, and with cold Virahol (2 * 20ml) clean and dry.

Claims (18)

1. the racemization method of the compound of a nefopam that is used for single enantiomer or non-racemic mixture form or its analogue, it comprises makes described compound contact with acid.
2. the process of claim 1 wherein that described compound has following formula or its pharmacy acceptable salt:
Figure A200780017963C00021
Wherein
R 1The C that is H, is randomly replaced by F 1-C 6Alkyl, C 3-C 6Cycloalkyl or C 2-C 6Thiazolinyl;
Perhaps R 2And R 3Identical or different, and be selected from H, halogen, CN, CF 3, C 1-C 6Alkyl or OR 1, perhaps R 2And R 3Formation can be 5 yuan or 6 yuan of rings of carbocyclic ring, heterocycle, aromatic series or heteroaromatic, and described heterocycle contains 1～2 heteroatoms that is selected from O, N and S, and described heteroaromatic contains 1～2 heteroatoms that is selected from O and N;
One of W, X, Y and Z are N or CR4, and other each be CH naturally;
R 4Be halogen, CF 3, CN, OR 7, SO 2N (R 6) 2, COR 6, CO 2R 6, CON (R 6) 2, NR 1COR 5, NR 1SO 2R 5, NR 1CO 2R 5, NR 1CON (R 6) 2, randomly by R 4The OC that replaces 1-C 6Alkyl, randomly by R 4The C that replaces 1-C 6Alkyl, randomly by R 4The C that replaces 3-C 6Cycloalkyl, randomly by R 4The C that replaces 2-C 6Thiazolinyl, randomly by R 4The C that replaces 2-C 6Alkynyl, randomly by R 4The aryl that replaces or contain 1～4 heteroatomic 5 yuan or 6 membered aromatic heterocycle that are connected by carbon or nitrogen that is selected from N and O;
R 5Be C 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 3-C 6Cycloalkyl, aryl or heteroaryl;
Each R 6Can be identical or different, each is H, C naturally 1-C 6Alkyl, C 2-C 6Thiazolinyl, C 2-C 6Alkynyl, C 3-C 6Cycloalkyl, aryl or heteroaryl; And
R 7Be aryl or heteroaryl;
Wherein aryl is the phenyl or naphthyl that randomly replaces;
Carbocyclic ring is the saturated alicyclic part with 5 or 6 C atoms;
Heterocycle is the saturated heterocyclic part with 5 or 6 atoms, and described 5 or 6 atoms comprise one or more among N, O and the S; And
Heteroaromatic is the aromatic series of 5 or 6 atoms, and at least one in wherein said 5 or 6 atoms is N, O or S.
3. the method for claim 2, wherein R4 exists and is halogen, CN, OR 7, SO 2N (R 6) 2, COR6, CO 2R 6, CON (R 6) 2, NR 1COR 5, NR 1SO 2R 5, NR 1CON (R 6) 2, by R 4The OC that replaces 1-C 6Alkyl, by R 4The C that replaces 1-C 6Alkyl, randomly by R 4The C that replaces 3-C 6Cycloalkyl, randomly by R 4The C that replaces 2-C 6Thiazolinyl, randomly by R 4The C that replaces 2-C 6Alkynyl, randomly by R 4The aryl that replaces or contain 1～4 heteroatomic 5 yuan or 6 membered aromatic heterocycle that are connected by carbon or nitrogen that are selected from N and O.
4. the method for claim 3, wherein R 4Be Br, CN, CON (R 6) 2, the cycloalkyl or aryl or 5 yuan or 6 membered aromatic heterocycles that randomly replace.
5. each method, wherein R in the claim 2～4 2Be halogen, CN, CF 3, C 1-C 6Alkyl or OR 1
6. each method, wherein R in the claim 2～4 2And R 3Form ring.
7. each method, wherein R in the claim 2～4 2Or R 3Be OR 1
8. the process of claim 1 wherein that described compound is selected from:
9-methoxyl group-5-methyl isophthalic acid-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering (oxazocine),
8-methoxyl group-5-methyl isophthalic acid-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
9-methoxyl group-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-methoxyl group-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
9-methoxyl group-5-methyl isophthalic acid-(4-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering, and
8-methoxyl group-5-methyl isophthalic acid-(4-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering.
9. the process of claim 1 wherein that described compound is selected from:
9-cyano group-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-cyano group-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
9-cyclopropyl-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-cyclopropyl-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
N-(ethanoyl)-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-9-methylamine,
N-(ethanoyl)-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-methylamine,
9-cyclopropyl-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-cyclopropyl-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
9-cyclopropyl-5-methyl isophthalic acid-(4-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-cyclopropyl-5-methyl isophthalic acid-(4-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering, and
9-cyano group-5-methyl isophthalic acid-(4-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering.
10. the process of claim 1 wherein that described compound is selected from:
9-cyano group-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-cyano group-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-9-methane amide,
5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-methane amide,
N-(1,1,1-trimethylammonium methoxycarbonyl)-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-9-methylamine,
N-(1,1,1-trimethylammonium methoxycarbonyl)-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-methylamine,
The 5-methyl isophthalic acid, 9-phenylbenzene-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
The 5-methyl isophthalic acid, 8-phenylbenzene-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
9-(3,5 dimethyl isoxazoles-4-yl)-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-(3,5 dimethyl isoxazoles-4-yl)-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
2-(5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-9-vinyl) methane amide,
2-(5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-vinyl) methane amide,
2-(5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-9-ethyl) methane amide,
2-(5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-ethyl) methane amide,
5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-9-methylamine,
5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-methylamine,
N-(ethanoyl)-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-9-methylamine, and
N-(ethanoyl)-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-methylamine.
11. the process of claim 1 wherein that described compound is selected from:
9-bromo-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-bromo-5-methyl isophthalic acid-phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
9-bromo-5-methyl isophthalic acid-(4-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
8-bromo-5-methyl isophthalic acid-(4-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering,
9-bromo-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering, and
8-bromo-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering.
12. the method for claim 1 is used for racemization single enantiomer (-)-nefopam basically.
13. the method for claim 1 is used for racemization single enantiomer (+)-nefopam basically.
14. the method for claim 1 is used to prepare and is selected from following compound and salt thereof:
(1S)-and 8-cyano group-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering;
(1R)-and 8-cyano group-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering;
(1S)-and 8-cyclopropyl-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering;
(1S)-and 8-cyclopropyl-5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering;
(1S)-and 5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-methane amide;
(1R)-and 5-methyl isophthalic acid-(3-methoxyl group) phenyl-1,3,4,6-tetrahydrochysene-5H-benzo [f]-2,5-oxazole suffering-8-methane amide.
15. each method in the aforementioned claim wherein utilizes mineral acid to carry out described racemization.
16. the method for claim 15, wherein said mineral acid is a hydrochloric acid.
17. each method in the aforementioned claim, wherein be selected from water, organic solvent with and composition thereof solvent in carry out described racemization.
18. be used to prepare the method for individual isomer basically of the compound of nefopam or its analogue, it comprises by each method in the aforementioned claim and splits described racemic compound, separates desired individual isomer and with undesirable material racemization.
CNA2007800179630A 2006-05-17 2007-05-17 Racemisation of enantiomers of nefopam and analogues Pending CN101448799A (en)

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GBGB0609793.5A GB0609793D0 (en) 2006-05-17 2006-05-17 Racemisation and recycling process

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WO2004056788A1 (en) * 2002-12-20 2004-07-08 Arakis Ltd. Benzoxazocines and their use as monoamine-reuptake inhibitors
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