EP1187804A1 - Procede de separation des bases diastereo-isomeres de 2- (dimethylamino)methyl]-1-(3-methoxy-phenyl)-cyclohexanol - Google Patents

Procede de separation des bases diastereo-isomeres de 2- (dimethylamino)methyl]-1-(3-methoxy-phenyl)-cyclohexanol

Info

Publication number
EP1187804A1
EP1187804A1 EP99931139A EP99931139A EP1187804A1 EP 1187804 A1 EP1187804 A1 EP 1187804A1 EP 99931139 A EP99931139 A EP 99931139A EP 99931139 A EP99931139 A EP 99931139A EP 1187804 A1 EP1187804 A1 EP 1187804A1
Authority
EP
European Patent Office
Prior art keywords
trans
water
mixture
isomer
cyclohexanol
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.)
Ceased
Application number
EP99931139A
Other languages
German (de)
English (en)
Inventor
Bernhard Akteries
Michael Finkam
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.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
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 Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP1187804A1 publication Critical patent/EP1187804A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives

Definitions

  • the invention relates to a process for the purification and diastereoisomer separation of 2- [(dimethylammo) methyl J -1- (3-methoxyphenyl) cyclohexanol.
  • the tramadol hydrochloride, CA-No 36282-47-n ( ⁇ ) -trans-2- [(diethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol hydrochloride is as
  • CONFIRMATION OPY highly effective analgesic has been on the market for a long time.
  • WO 99/03820 describes a process for the production of pure cis-tramadol hydrochloride (here ice because it is named after the IUPAC nomenclature), in which a monohydrate of the corresponding cis-tramadol base is obtained from the G ⁇ gnard bases by adding water and is separated.
  • the trans / cis isomer ratio of the diastereomeric base mixtures to be separated is usually 80:20 and larger in all previously known processes. According to DE-OS 4 330 240 and US 5,414,129, for example, it is 86:14. However, it is also of interest to separate the desired trans isomer from mixtures which contain the diastereomeric bases in an unfavorable isomer ratio, in order, for example, to be able to work up G ⁇ gnard reaction mixtures obtained under different reaction conditions or else mother liquors. Mother liquors, which are formed after a first precipitation of the desired isomer, still contain the diastereomeric bases in a trans / cis isomer ratio of about 50:50.
  • the object of the invention is therefore to develop a process which, without primary salt formation, separates the diastereomers from a diastereomeric base mixture of 2- [(dimethylammo) methyl] -1- (3-methoxyphenyl) cyclohexanol over a wide range of the isomer ratio enables.
  • the subject of the invention is a process for the separation of the diastereomeric bases of 2- [(dimethylammo) methyl] -1- (3-methoxyphenyl) cyclohexanol by treatment with water in at least stoichiometric amounts to complete conversion of the bases and subsequent separation of the precipitated hydrate of the trans diastereomer, which is characterized in that a base mixture with an isomer ratio of trans to ice below 80:20, preferably from 60:40 to 75:25, is used.
  • contaminated diastereomeric base mixtures they are preferably dissolved in a water-miscible organic solvent or solvent mixture before the reaction with water, solvents from the group of alcohols, ketones, esters, ethers, low molecular weight polyalcohols or aromatic hydrocarbons being used.
  • the organic solvent or solvent mixture is preferably used in a volume ratio to water of 10: 2 to 10: 5.
  • the water-miscible organic solvents used are preferably C ] __8 alcohols, C3_g ketones, C2-8 esters, aliphatic, aromatic, open-chain and cyclic C ⁇ g ethers, C2-g polyalcohols or Cg-g Aromatics.
  • the separated hydrate crystals of the trans-diastereomer are then washed with a mixture of the organic solvent and water in a volume ratio of 10: 2 to 10: 5 and then dried.
  • the water is used in at least stoichiometric amounts for the complete conversion of the bases.
  • the water and also the solvent or solvent mixture can be used in a wide mixing ratio with the diastereomeric base mixture.
  • the diastereomers can be separated over a wide temperature range, as long as it is ensured that the reaction mixture does not freeze out at low temperatures.
  • the temperature of the reaction mixture is preferably kept below the melting point of the base hydrate.
  • the process according to the invention is characterized in that the diastereomeric base mixture forms a hydrate under the conditions described above and this hydrate, namely the trans-diastereomer, is preferably precipitated and thus easy separation of the diastereomers is possible.
  • the process offers the advantages over the previously described procedures that the diastereomer separation can take place without salt formation (eg via the hydrochloride), that undesirable decomposition products are simply and effectively avoided by the formation of the base hydrate and that a later salt formation with a Variety of acids is possible directly via the base level. Above all, however, it offers the possibility of separating diastereomeric base mixtures whose trans / cis isomer ratio deviates greatly from the usual ratio after the Grignard reaction. It is particularly suitable for processing mother liquors.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de séparation des bases diastéréo-isomères de 2-[(diméthylamino)méthyl]-1-(3-méthoxy-phényl)-cyclohexanol, cette séparation desdites bases diastéréo-isomères se faisant par la formation d'un hydrate de base.
EP99931139A 1999-06-22 1999-06-22 Procede de separation des bases diastereo-isomeres de 2- (dimethylamino)methyl]-1-(3-methoxy-phenyl)-cyclohexanol Ceased EP1187804A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1999/004325 WO2000078705A1 (fr) 1999-06-22 1999-06-22 Procede de separation des bases diastereo-isomeres de 2-[(dimethylamino)methyl]-1-(3-methoxy-phenyl)-cyclohexanol

Publications (1)

Publication Number Publication Date
EP1187804A1 true EP1187804A1 (fr) 2002-03-20

Family

ID=8167340

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99931139A Ceased EP1187804A1 (fr) 1999-06-22 1999-06-22 Procede de separation des bases diastereo-isomeres de 2- (dimethylamino)methyl]-1-(3-methoxy-phenyl)-cyclohexanol

Country Status (11)

Country Link
US (1) US6521792B2 (fr)
EP (1) EP1187804A1 (fr)
JP (1) JP2003502400A (fr)
AU (1) AU4775699A (fr)
CA (1) CA2375234A1 (fr)
CZ (1) CZ20014669A3 (fr)
HK (1) HK1045301A1 (fr)
HU (1) HUP0201464A3 (fr)
MX (1) MXPA01013145A (fr)
SK (1) SK19002001A3 (fr)
WO (1) WO2000078705A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6579805B1 (en) * 1999-01-05 2003-06-17 Ronal Systems Corp. In situ chemical generator and method
DE10108308A1 (de) * 2001-02-21 2002-08-29 Gruenenthal Gmbh Verfahren zur Isolierung und Reinigung von (1RS,2RS)-2[(Dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol
EP1346978A1 (fr) * 2002-03-21 2003-09-24 Jubilant Organosys Limited Procédé pour la préparation de tramadol chlorohydrate et/ou de tramadol monohydrate
US7375035B2 (en) * 2003-04-29 2008-05-20 Ronal Systems Corporation Host and ancillary tool interface methodology for distributed processing
US7429714B2 (en) 2003-06-20 2008-09-30 Ronal Systems Corporation Modular ICP torch assembly
EP1785412A1 (fr) * 2005-11-14 2007-05-16 IPCA Laboratories Limited Procédé de récuperation de Tramadol

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3830934A (en) * 1967-07-27 1974-08-20 Gruenenthal Chemie Analgesic and antitussive compositions and methods
IL103096A (en) * 1992-09-08 1996-12-05 Chemagis Ltd Process for purification 2 -]) Dimethylamino (methyl-1-) 3-methoxycinyl (cyclohexanol and its salts.
IL116281A (en) * 1995-12-07 1999-06-20 Chemagis Ltd Process for the purification of (rr,ss)-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol and its salts
IL119121A (en) * 1996-08-22 2000-11-21 Chemagis Ltd Process for the purification of (RR-SS)-2-dimethylaminomethyl-1-(3-methoxyphenyl)cyclohexanol hydrochloride
CN1151122C (zh) * 1997-07-15 2004-05-26 拉辛斯基有限公司 反胺苯环醇及其盐以及它们的制备方法
US5877351A (en) * 1997-12-24 1999-03-02 Wyckoff Chemical Company, Inc. Preparation and purification process for 2- (dimethylamino) methyl!-1-(3-methoxphenyl)-cyclohexanol and its salts
GB9800657D0 (en) * 1998-01-14 1998-03-11 Macfarlan Smith Ltd Improved purification process

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0078705A1 *

Also Published As

Publication number Publication date
HK1045301A1 (zh) 2002-11-22
US20020091287A1 (en) 2002-07-11
AU4775699A (en) 2001-01-09
SK19002001A3 (sk) 2002-05-09
JP2003502400A (ja) 2003-01-21
MXPA01013145A (es) 2002-06-04
HUP0201464A3 (en) 2003-02-28
CA2375234A1 (fr) 2000-12-28
US6521792B2 (en) 2003-02-18
WO2000078705A1 (fr) 2000-12-28
CZ20014669A3 (cs) 2002-05-15
HUP0201464A2 (hu) 2002-12-28

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