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WO1999036390A1 - Purification du tramadol - Google Patents

Purification du tramadol Download PDF

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Publication number
WO1999036390A1
WO1999036390A1 PCT/GB1999/000013 GB9900013W WO9936390A1 WO 1999036390 A1 WO1999036390 A1 WO 1999036390A1 GB 9900013 W GB9900013 W GB 9900013W WO 9936390 A1 WO9936390 A1 WO 9936390A1
Authority
WO
WIPO (PCT)
Prior art keywords
tramadol
preparation
salt
crude
hydrochloride
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
PCT/GB1999/000013
Other languages
English (en)
Inventor
Nicholas Archer
Stewart Cairns
Melville Mitchell
Helen Ogden
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.)
Macfarlan Smith Ltd
Original Assignee
Macfarlan Smith 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 Macfarlan Smith Ltd filed Critical Macfarlan Smith Ltd
Priority to IL13695799A priority Critical patent/IL136957A0/xx
Priority to EP99901000A priority patent/EP1047662A1/fr
Priority to CA002316991A priority patent/CA2316991A1/fr
Priority to KR1020007007604A priority patent/KR20010034010A/ko
Priority to AU20637/99A priority patent/AU744938B2/en
Priority to PL99341712A priority patent/PL341712A1/xx
Priority to NZ505129A priority patent/NZ505129A/en
Priority to SK1035-2000A priority patent/SK10352000A3/sk
Publication of WO1999036390A1 publication Critical patent/WO1999036390A1/fr
Anticipated expiration legal-status Critical
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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to the production of a pharmaceutical product obtained through a process which initially produces a crude base as a mixture of isomers together with side products from which a selected isomer is to be separated.
  • the invention is concerned with the separation and purification of the selected isomer to achieve a substantially increased yield of same.
  • the desired product ( ⁇ ) -trans-2-dimethylaminomethyl-l- (3- methoxyphenyl ) cyclohexanol, (Tramadol) is difficult to isolate by distillation because the mixed geometric cis and trans isomers boil around 138°C - 140°C.
  • the target compound can be obtained through subsequent re-crystallisation steps by converting the crude base to the hydrochloride salt as described in US-A-3, 652, 589 and GB-A-997 , 399.
  • Tramadol hydrochloride as described in GB-A-997,399 involves a Grignard reaction to produce mixed cis-and trans-isomers of 2-dimethylaminomethyl-l- (3- methoxyphenyl) cyclohexanol and side products.
  • the crude mixed isomer base is obtainable by distilling the complex mixture obtained from the Grignard reaction under a high vacuum.
  • the distilled isomer mixture is dissolved in diethyl ether and treated with gaseous hydrogen chloride.
  • the resulting crude mixture of cis- and trans-isomer hydrochlorides is precipitated and filtered. This procedure yields an isomer mixture with a relatively high content of cis-isomer.
  • the isomer mixture is then refluxed with a five-fold volume of moist dioxane, and the resulting suspension is filtered while still hot.
  • the filter cake is boiled once more with dry dioxane and filtered; the residue obtained consists of the target trans hydrochloride.
  • the commercial production of Tramadol is believed to have always followed the process described in GB-A-997,399 but certain disadvantages of the process described have caused the acceptability of such a process to be questioned.
  • One such disadvantage lies in that the solvent used in that process is dioxane which is now considered as an unacceptable toxic compound for which the tolerance set for its residual content in the product is extremely low, of the order of several parts per billion.
  • dioxane is considered to be a health risk which is toxic by inhalation or through skin absorption as a carcinogen, central nervous system depressant and an agent causing necrosis of the liver and kidney. It is also considered to be a hazardous material by its flammability, and ability to form explosive peroxides.
  • Tramadol hydrochloride is obtainable from the Grignard reaction mixture containing the isomers and side products by combining the mixture with a solution of hydrochloric acid in a low molecular weight alcohol or with gaseous hydrogen chloride in the presence of an organic solvent selected from medium molecular weight alcohols, ketones, esters, and ethers or aromatic ethers, to effect the selective precipitation of Tramadol hydrochloride.
  • EP-A-0 778 262 proposes an improved method of purification of Tramadol base reliant again on the use of the hydrochloride for this purpose which is based on treating mixtures otherwise difficult to resolve by simple hydrochloride salt formation in a solvent with acid to selectively dehydrate the unwanted isomer. Subsequently the hydrochloride salt formation allows for better resolution and re-crystallisation. Therefore, this dehydration stage allows resolution of mixtures by hydrochloride formation and re- crystallisation more efficiently than previously.
  • An object of the present invention is to provide a method which obviates or mitigates the aforesaid disadvantages of the prior art methods and does not require the dehydration stage. Disclosure of Invention
  • a process for the preparation of Tramadol according to a Grignard reaction of 2- (dimethylaminomethyl) cyclo- hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, characterised by contacting the crude base with hydrobromic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydrobromide.
  • a process for the preparation of Tramadol according to a Grignard reaction of 2- (dimethylaminomethyl) cyclo- hexanone with the reagent 3-methoxyphenylMgX, where X is a halogen, to obtain the crude base which is then introduced to a solvent, characterised by contacting the crude base with hydriodic acid to form a salt thereof, and subjecting the salt to a re-crystallisation step to obtain the product Tramadol hydriodide .
  • the Grignard reagent mentioned above for use in forming the crude base prior to salt formation may be of the traditional type wherein the halogen "X" is a matter of convenient choice, such as the chloride, bromide or iodide.
  • the bromide is found to be very suitable for the purposes of the invention and is preferred.
  • alcohols such as isopropanol are found to be suitable for the present purpose.
  • the salt is recovered as a precipitate, e.g. by filtering before the re-crystallisation step.
  • the salt forming process from the crude
  • Tramadol free base is operated at very low pH i.e. at about pH 1.0, using acid solutions of about 40 to 60% strength of the appropriate acids, preferably 45 to 50%, especially 48% hydrobromic acid or 47% hydriodic acid.
  • Tramadol hydrobromide or hydriodide can then be readily converted to a preferred pharmaceutically acceptable form for example Tramadol hydrochloride.
  • the product of the purification process is converted to the base, mixed with absolute alcohol, diisopropyl ether and hydrochloride gas. It will be understood that no additional resolution benefits are achieved on converting to the hydrochloride, since a remarkably high resolution is already achieved using the hydrobromide or hydriodide. Therefore, this is simply formation of the hydrochloride salt for sale using a well established method in literature for forming hydrochloride salts of organic compounds in solvent and hydrochloride gas.
  • the advantages offered by this invention are that use of the Tramadol hydrobromide and hydriodide salt dispense with the need for repeated re-crystallisation steps and removes the variations found in the yield and quality associated with the hydrochloride under similar conditions.
  • a high resolution of product can surprisingly be obtained by only one re-crystallisation step.
  • the present invention obtains at least 80% of the desired isomer with no re-crystallisation step whereas the prior art methods only obtain about 50% and that is only obtained by re- crystallising at least two times and still contains circa 2% of unwanted isomer.
  • the fact that the prior art methods require multiple re-crystallisation means that the overall recovery is dramatically reduced, to about 40% in order to achieve a material with an unwanted isomer of ( ⁇ 0.3%) .
  • This invention is applicable in the production of Tramadol which is useful therapeutically as a non-additive analgesic.

Landscapes

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

Abstract

L'invention concerne un procédé pour la purification du tramadol selon une réaction de Grignard entre du 2-(diméthylaminométhyl)cyclo-hexanone et le réactif 3-méthoxyphénylMgX, où X est un halogène, de manière à obtenir la base brute destinée à être introduite dans un solvant. On met en contact ladite base avec un acide bromhydrique ou iodhydrique pour former un sel correspondant. Ensuite, on soumet ledit sel à une phase de recristallisation donnant respectivement un bromhydrate de tramadol ou un iodhydrate de tramadol, produits à partir desquels il est possible d'obtenir une base de tramadol purifiée aux fins de conversion éventuelle sous forme de produit pharmaceutique préféré (par exemple, chlorhydrate de tramadol).
PCT/GB1999/000013 1998-01-14 1999-01-14 Purification du tramadol Ceased WO1999036390A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
IL13695799A IL136957A0 (en) 1998-01-14 1999-01-14 Purification of tramadol
EP99901000A EP1047662A1 (fr) 1998-01-14 1999-01-14 Purification du tramadol
CA002316991A CA2316991A1 (fr) 1998-01-14 1999-01-14 Purification du tramadol
KR1020007007604A KR20010034010A (ko) 1998-01-14 1999-01-14 트라마돌의 정제
AU20637/99A AU744938B2 (en) 1998-01-14 1999-01-14 Purification of tramadol
PL99341712A PL341712A1 (en) 1998-01-14 1999-01-14 Tramadole purification process
NZ505129A NZ505129A (en) 1998-01-14 1999-01-14 Purification of tramadol
SK1035-2000A SK10352000A3 (sk) 1998-01-14 1999-01-14 Čistenie tramadolu

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9800656.2A GB9800656D0 (en) 1998-01-14 1998-01-14 Improved purification process
GB9800656.2 1998-01-14

Publications (1)

Publication Number Publication Date
WO1999036390A1 true WO1999036390A1 (fr) 1999-07-22

Family

ID=10825209

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1999/000013 Ceased WO1999036390A1 (fr) 1998-01-14 1999-01-14 Purification du tramadol

Country Status (12)

Country Link
EP (1) EP1047662A1 (fr)
KR (1) KR20010034010A (fr)
AU (1) AU744938B2 (fr)
CA (1) CA2316991A1 (fr)
GB (1) GB9800656D0 (fr)
HU (1) HUP0100356A3 (fr)
IL (1) IL136957A0 (fr)
NZ (1) NZ505129A (fr)
PL (1) PL341712A1 (fr)
SK (1) SK10352000A3 (fr)
TR (1) TR200002022T2 (fr)
WO (1) WO1999036390A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100342919B1 (ko) * 1999-10-21 2002-07-04 박노중 트랜스체 염산 트라마돌의 분리 제조방법
EP1346978A1 (fr) * 2002-03-21 2003-09-24 Jubilant Organosys Limited Procédé pour la préparation de tramadol chlorohydrate et/ou de tramadol monohydrate
US6649783B2 (en) 2001-10-03 2003-11-18 Euro-Celtique, S.A. Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
DE10236510A1 (de) * 2002-08-09 2004-02-19 Grünenthal GmbH Verfahren zur Herstellung von 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
US7470816B2 (en) 2005-11-14 2008-12-30 Ipac Laboratories Limited Tramadol recovery process
WO2010032254A1 (fr) * 2008-09-22 2010-03-25 Kamud Drugs Pvt . Ltd . Procédé industriel pour la préparation de cis(+m-2-r(diméthylamino)-méthyl-1-(3- méthoxyphényl) cyclohexanol chlorhydrate
WO2014154747A1 (fr) 2013-03-26 2014-10-02 Institut National De La Sante Et De La Recherche Medicale (Inserm) Extraction de tramadol à partir de nauclea latifolia smith
WO2020039456A1 (fr) * 2018-08-20 2020-02-27 Mylan Laboratories Limited Co-cristal de tramadol hbr-célécoxib

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USD828429S1 (en) 2015-02-23 2018-09-11 Samsung Electronics Co., Ltd. Digital camera

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3652589A (en) * 1967-07-27 1972-03-28 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US5414129A (en) * 1992-09-08 1995-05-09 Chemagis, Ltd. Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3652589A (en) * 1967-07-27 1972-03-28 Gruenenthal Chemie 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols
US5414129A (en) * 1992-09-08 1995-05-09 Chemagis, Ltd. Process for the purification of 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol and its salts
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

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100342919B1 (ko) * 1999-10-21 2002-07-04 박노중 트랜스체 염산 트라마돌의 분리 제조방법
US6649783B2 (en) 2001-10-03 2003-11-18 Euro-Celtique, S.A. Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
US6784319B2 (en) 2001-10-03 2004-08-31 Euro-Celtique, S.A. Synthesis of (±)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols
EP1346978A1 (fr) * 2002-03-21 2003-09-24 Jubilant Organosys Limited Procédé pour la préparation de tramadol chlorohydrate et/ou de tramadol monohydrate
WO2003078380A3 (fr) * 2002-03-21 2004-03-11 Jubilant Organosys Ltd Procede de preparation de chlorhydrate de tramadol et/ou de monohydrate de tramadol
DE10236510A1 (de) * 2002-08-09 2004-02-19 Grünenthal GmbH Verfahren zur Herstellung von 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
US7470816B2 (en) 2005-11-14 2008-12-30 Ipac Laboratories Limited Tramadol recovery process
WO2010032254A1 (fr) * 2008-09-22 2010-03-25 Kamud Drugs Pvt . Ltd . Procédé industriel pour la préparation de cis(+m-2-r(diméthylamino)-méthyl-1-(3- méthoxyphényl) cyclohexanol chlorhydrate
WO2014154747A1 (fr) 2013-03-26 2014-10-02 Institut National De La Sante Et De La Recherche Medicale (Inserm) Extraction de tramadol à partir de nauclea latifolia smith
WO2020039456A1 (fr) * 2018-08-20 2020-02-27 Mylan Laboratories Limited Co-cristal de tramadol hbr-célécoxib

Also Published As

Publication number Publication date
HUP0100356A2 (hu) 2002-05-29
PL341712A1 (en) 2001-04-23
TR200002022T2 (tr) 2000-11-21
KR20010034010A (ko) 2001-04-25
EP1047662A1 (fr) 2000-11-02
SK10352000A3 (sk) 2001-02-12
NZ505129A (en) 2001-11-30
HUP0100356A3 (en) 2002-08-28
IL136957A0 (en) 2001-06-14
AU744938B2 (en) 2002-03-07
AU2063799A (en) 1999-08-02
CA2316991A1 (fr) 1999-07-22
GB9800656D0 (en) 1998-03-11

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