WO2001096306A1 - Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer - Google Patents
Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer Download PDFInfo
- Publication number
- WO2001096306A1 WO2001096306A1 PCT/EP2001/006552 EP0106552W WO0196306A1 WO 2001096306 A1 WO2001096306 A1 WO 2001096306A1 EP 0106552 W EP0106552 W EP 0106552W WO 0196306 A1 WO0196306 A1 WO 0196306A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- enantiomer
- acid
- piperidone
- solution
- alkyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
Definitions
- the invention relates to a process which can be used on an industrial scale for the dynamic enantiomer separation of piperidone derivatives of the general formula (1)
- R 1 , R 2 R 3 and n can have the meaning given in the description and the claims, with simultaneous in situ racemization of the unreacted enantiomer.
- R 2 and R 3 each represent a methyl group
- R 4 is hydrogen, C 1 -C 6 -alkyl, halogen, hydroxy, a benzoyl radical bonded via oxygen or an alkylcarbonyl radical having a straight-chain or branched lower alkyl radical having 1 to 6 carbon atoms, the alkyl radical optionally being substituted by one or more halogen atoms which may be identical or different from one another, nitro , Cyano, amino, mono- or disubstituted amino with CC 8 -alkyl, where the alkyl radicals can be the same or different, -NH-acyl- (CC 8 -alkyl), wherein acyl is benzoyl or an alkylcarbonyl radical with a straight-chain or branched lower alkyl radical has 1 to 6 carbon atom (s), the alkyl radical optionally having one or more halogen atom (s) which may be identical or different from one another, may be substituted, or a radical which can be converted into one of the radicals listed above by simple
- benzomorphane derivatives which e.g. can be used in the treatment of neurodegenerative diseases and brain ischemia, such as heart attack or brain stroke.
- German published patent application DE 195 28 472 describes a process which is essential for the invention, in which the desired enantiomer is obtained from the solution of a mixture of enantiomeric 3,3-dimethyl-4-piperidones by reaction with a suitable organic acid, e.g. Tartaric acid, as salt, e.g. as tartrate, fails.
- a suitable organic acid e.g. Tartaric acid
- salt e.g. as tartrate
- the present invention therefore aims at a process for the enantiomer separation of piperidone derivatives of the general formula (1)
- Rt is C 1 -C 8 alkyl, preferably C r C 6 alkyl, which can be straight-chain or branched and is optionally mono- to polysubstituted, aryl, which can be mono- or polysubstituted, preferably optionally substituted Phenyl or naphthyl, particularly preferably a radical of the general formula
- heteroaryl preferably pyridine, where the heterocycle with one to
- Ring belonging carbon atom or originating from the methylene bridge is linked to the chiral center, R 2 and R 3 , which may be the same or different, CC 6 alkyl, which may be straight-chain or branched, preferably methyl or ethyl, particularly preferably methyl; R 4 independently of one another methoxy, ethoxy, isopropyloxy, halogen, hydroxy, CC 6 alkyl, which can be partially or completely halogenated, such as trifluoromethyl, amino, nitro, cyano, benzoyl, CC 6 alkyl carbonyl, preferably methoxy; n denotes 0, 1, 2 or 3, preferably 1, and m denotes 0, 1, 2 or 3, preferably 0 or 1,
- a solution of an optically active organic acid optionally with the addition of catalytic amounts of a sulfonic acid, e.g. Toluene or camphorsulfonic acid, presented at a certain temperature in a suitable solvent.
- a solution of the enantiomer mixture of the piperidone derivative (1) is slowly added to this temperature-controlled solution.
- the optically active organic acid, the solvent or solvent mixture and also the reaction temperature are selected such that the desired enantiomer of the piperidone derivative (1) crystallizes out as the salt of the optically active acid, while the other enantiomer remains dissolved and racemizes under the reaction conditions.
- the desired enantiomer is continuously simulated and precipitated in a dynamic process until equilibrium is established.
- the process according to the invention for dynamic enantiomer separation of piperidone derivatives is thus characterized in that a) an optically active acid and, if appropriate, catalytic amounts of a sulfonic acid are dissolved in a suitable solvent and the temperature of this solution is controlled, b) a solution of the piperidone is slowly added to this solution.
- a) an optically active acid and, if appropriate, catalytic amounts of a sulfonic acid are dissolved in a suitable solvent and the temperature of this solution is controlled
- a solution of the piperidone is slowly added to this solution.
- Derivative metered in so that the desired enantiomer crystallizes out as a salt of the organic acid used while at the same time the undesired isomer racemizes in solution and the portion of the desired enantiomer thus formed likewise precipitates as a salt in a dynamic process
- the salt of the desired enantiomer Termination of the crystallization is thus characterized in that a)
- Suitable organic acids for precipitating the desired enantiomer are (+) - or (-) - ditoluoyl tartaric acid or (+) - or (-) - dibenzoyl tartaric acid.
- the reaction is optionally carried out in the presence of catalytic amounts of p-toluenesulfonic acid or camphorsulfonic acid.
- the reaction can be carried out, for example, in solvents such as acetone, acetonitrile, methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate, water, toluene, methylcyclohexane, n-butyl acetate or mixtures thereof.
- solvents such as acetone, acetonitrile, methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl acetate, water, toluene, methylcyclohexane, n-butyl acetate or mixtures thereof.
- Acetonitrile or acetone are preferably used.
- (+) - piperidone (1a) is precipitated and thus enriched, for example, by the reaction with (+) - ditoluoyl tartaric acid or (+) - dibenzoyl tartaric acid.
- (+) - ditoluoyl-tartaric acid or (+) - dibenzoyl-tartaric acid gives the opposite enantiomer, namely the (-) - piperidone (1 b).
- R 2 and R 3 each denote methyl and n 1, characterized in that the desired (R) - (+) - enantiomer is precipitated as the salt thereof by reaction with (+) - ditoluoyltartaric acid and at the same time in the dissolved (S) - (- ) Enantiomeric epimerization of the chiral center takes place by heating to a temperature of approximately 30-75 ° C, particularly preferably to 50-65 ° C. Acetonitrile, acetone or mixtures thereof, preferably acetonitrile, can be used as the solvent.
- Also preferred according to the invention is a process which leads to a piperidone of the general formula (1a) or (1b) with an enantiomeric excess of> 95% ee, particularly preferably of> 97% ee.
- a mixture of the enantiomeric piperidone derivatives of the general formula (1) is in an inert solvent, e.g. Acetonitrile, dissolved and slowly added to a solution of a suitable tartaric acid derivative, preferably (+) - ditoluoyltartaric acid, preheated to about 35 to 75 ° C., preferably to 50 to 65 ° C., in the same solvent.
- a suitable tartaric acid derivative preferably (+) - ditoluoyltartaric acid
- the mixture is stirred at the same temperature for a further 0.5 to 36 hours until no more precipitate appears to form.
- the crystals are filtered off with suction and the residue is washed with the cold solvent.
- the desired enantiomer is obtained in the form of the salt of the organic acid, from which the base can be released with the aid of known processes.
- the acid can be recovered in very good yields by simple extraction.
- the enantiomer separation of piperidone derivatives according to the invention by crystallization with simultaneous racemization of the undesired enantiomer can start from the free base of the formula (1), which can also be used as an up to 20% contaminated crude product, or from an acid addition salt precipitated for purification with a Mineral acid, such as a hydrochloride or hydrobromide, are carried out after the base has been released.
- a Mineral acid such as a hydrochloride or hydrobromide
- Alkyl means, both when it is alone and in combination with other radicals, a straight-chain or branched alkyl radical with the specified number of carbon atoms, such as eg Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl or n-hexyl.
- Aryl means an aromatic hydrocarbon radical with up to 10 carbon atoms, such as phenyl or naphthyl; Heteroaryl stands for a mono- or bicyclic aromatic radical with up to 10 ring atoms which, in addition to carbon, has one or more heteroatoms which are selected independently of one another from the group formed by N, O and S, e.g. Pyridine or furan.
- Halogen means fluorine, chlorine or bromine.
- 150 g (0.53 mol) of 2 - (- methoxyphenyl) methyl-3,3-dimethyl-4-piperidonium hydrochloride are first added to 320 ml of water. After adding 150 ml of toluene, a pH of 12.8 is set using 47.5 ml (0.53 mol) of sodium hydroxide solution (45% in water). The mixture is stirred with thorough mixing of the phases at room temperature for about 40 minutes, allowed to settle and the water phase is separated off. The organic phase is washed with 40 ml of water and then concentrated to dryness.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA 2409614 CA2409614C (en) | 2000-06-16 | 2001-06-09 | Separation of the enantiomers of piperidone derivatives with simultaneous racemisation in situ of the unwanted enantiomer |
AU2001270563A AU2001270563A1 (en) | 2000-06-16 | 2001-06-09 | Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer |
EP01949395A EP1305287A1 (en) | 2000-06-16 | 2001-06-09 | ENANTIOMER SEPARATION OF PIPERIDONE DERIVATIVES WITH SIMULTANEOUS i IN SITU /i RACEMIZATION OF THE UNWANTED ENANTIOMER |
JP2002510449A JP2004503539A (en) | 2000-06-16 | 2001-06-09 | Separation of Enantiomers of Piperidone Derivatives with In Situ Simultaneous Racemization of Undesired Enantiomers |
MXPA02012301A MXPA02012301A (en) | 2000-06-16 | 2001-06-09 | Enantiomer separation of piperidone derivatives with simultaneous in situ. |
KR1020027016915A KR100863922B1 (en) | 2000-06-16 | 2001-06-09 | Separation of the desired enantiomer of piperidone derivatives with simultaneous in situ racemization of the undesired enantiomer |
IL15308501A IL153085A0 (en) | 2000-06-16 | 2001-06-09 | Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer |
IL153085A IL153085A (en) | 2000-06-16 | 2002-11-26 | Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10029851A DE10029851A1 (en) | 2000-06-16 | 2000-06-16 | Optical resolution of 2-substituted 4-piperidone derivatives, for use as pharmaceutical intermediates, by simultaneous formation of salt with optically active acid and racemization |
DE10029851.6 | 2000-06-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001096306A1 true WO2001096306A1 (en) | 2001-12-20 |
Family
ID=7646064
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2001/006552 WO2001096306A1 (en) | 2000-06-16 | 2001-06-09 | Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1305287A1 (en) |
JP (1) | JP2004503539A (en) |
KR (1) | KR100863922B1 (en) |
AR (1) | AR028957A1 (en) |
AU (1) | AU2001270563A1 (en) |
CA (1) | CA2409614C (en) |
DE (1) | DE10029851A1 (en) |
IL (2) | IL153085A0 (en) |
MX (1) | MXPA02012301A (en) |
WO (1) | WO2001096306A1 (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996009290A1 (en) * | 1994-09-23 | 1996-03-28 | Chiroscience Limited | Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof |
DE19528472A1 (en) * | 1995-08-03 | 1997-02-06 | Boehringer Ingelheim Kg | New process for the production of norbenzomorphan of an intermediate stage in the production of pharmaceutically valuable benzomorphan derivatives, in particular of (-) - (1R, 5S, S "R) -3'-hydroxy-2- (2-methoxypropyl -) - 5.9.9 -trimethyl-6.7 benzomorphan |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0736724B2 (en) * | 1992-08-07 | 1995-04-26 | 株式会社スリオンテック | Seeding and raising seedling sheet using ultraviolet curing adhesive and method for producing the same |
-
2000
- 2000-06-16 DE DE10029851A patent/DE10029851A1/en not_active Ceased
-
2001
- 2001-06-09 CA CA 2409614 patent/CA2409614C/en not_active Expired - Fee Related
- 2001-06-09 AU AU2001270563A patent/AU2001270563A1/en not_active Abandoned
- 2001-06-09 WO PCT/EP2001/006552 patent/WO2001096306A1/en active Application Filing
- 2001-06-09 KR KR1020027016915A patent/KR100863922B1/en not_active IP Right Cessation
- 2001-06-09 MX MXPA02012301A patent/MXPA02012301A/en active IP Right Grant
- 2001-06-09 JP JP2002510449A patent/JP2004503539A/en active Pending
- 2001-06-09 EP EP01949395A patent/EP1305287A1/en not_active Withdrawn
- 2001-06-09 IL IL15308501A patent/IL153085A0/en active IP Right Grant
- 2001-06-15 AR ARP010102869A patent/AR028957A1/en not_active Suspension/Interruption
-
2002
- 2002-11-26 IL IL153085A patent/IL153085A/en not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996009290A1 (en) * | 1994-09-23 | 1996-03-28 | Chiroscience Limited | Racemisation and asymmetric transformation processes used in the manufacture of levobupivacaine and analogues thereof |
DE19528472A1 (en) * | 1995-08-03 | 1997-02-06 | Boehringer Ingelheim Kg | New process for the production of norbenzomorphan of an intermediate stage in the production of pharmaceutically valuable benzomorphan derivatives, in particular of (-) - (1R, 5S, S "R) -3'-hydroxy-2- (2-methoxypropyl -) - 5.9.9 -trimethyl-6.7 benzomorphan |
Also Published As
Publication number | Publication date |
---|---|
CA2409614C (en) | 2008-08-05 |
MXPA02012301A (en) | 2003-04-25 |
DE10029851A1 (en) | 2001-12-20 |
IL153085A (en) | 2008-11-26 |
AU2001270563A1 (en) | 2001-12-24 |
IL153085A0 (en) | 2003-06-24 |
KR20030016288A (en) | 2003-02-26 |
AR028957A1 (en) | 2003-05-28 |
EP1305287A1 (en) | 2003-05-02 |
JP2004503539A (en) | 2004-02-05 |
CA2409614A1 (en) | 2001-12-20 |
KR100863922B1 (en) | 2008-10-17 |
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