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WO2019035775A1 - Procédé de préparation de tapentadol et de ses intermédiaires - Google Patents

Procédé de préparation de tapentadol et de ses intermédiaires Download PDF

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Publication number
WO2019035775A1
WO2019035775A1 PCT/SK2018/000005 SK2018000005W WO2019035775A1 WO 2019035775 A1 WO2019035775 A1 WO 2019035775A1 SK 2018000005 W SK2018000005 W SK 2018000005W WO 2019035775 A1 WO2019035775 A1 WO 2019035775A1
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WO
WIPO (PCT)
Prior art keywords
reaction
salt
compound
prepared
mixture
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Ceased
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PCT/SK2018/000005
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English (en)
Inventor
Dušan BERKEŠ
Jozef MARKUS
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Saneca Pharmaceuticals AS
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Saneca Pharmaceuticals AS
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Priority to EA202090197A priority Critical patent/EA202090197A1/ru
Priority to EP18769245.4A priority patent/EP3713911A1/fr
Publication of WO2019035775A1 publication Critical patent/WO2019035775A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • 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
    • 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
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/72—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present disclosure relates to a new method for the preparation of tapentadol in the form of a base or its hydrogen chloride, whic involves the preparation of a salt (III.) from a mixture of diastereomers (H) by crystallization-induced asymmetric transformation (CIAT) with a high degree of diastereoselectivity through oxo-enol tautomeric equilibrium of covalent!y linked diastereomers, shifted towards the desired diastereomer without the use of chiral resolution wit c iral earboxyl acids.
  • the desired derivative (III) is isolated from the mixture by simple filtration in high yield and high diastereomeric purity.
  • (R)-phenySethylamine as a chirality mediator leads to the generation of the required stereogenie centre at the ot-posiiion to carbonyl and at the same time it enables a simple analytical cheek of the process as well as of subsequent stereoselective transformations without the use of chiral HPLC. This solution thus enables to increase the yield of this step of synthesis and subsequently also the total yield of tapentadol synthesis.
  • the originator's and others' synthesis preferably uses the Mannich reaction from the appropriate 3-substxtuted propiophenone, formaldehyde and dimethylarnine under acidic conditions.
  • cleavage of the racemic mixture of Mannich salts with enantiomerieaHy pure acid is used.
  • the enanliomerically pure Mannich base is subjected to the diastereoselective Grignard reaction, in which the content of the undesired diastereomer needs to be cheeked. Its elimination by crystallization leads to yield losses and requires more demanding analytical instrumentation for the checking of undesired raeemization (chiral HPLC). Equally less stereodiscriminating ⁇ , ⁇ -dimethyIamino group lowers the diastereoselectivity of this reaction stage (addition of ethylmagnesium halide to the carbonyl group of the Mannich base), which lowers the total yield and increases the labour intensity of purifying ' this intermediate of tapentadol synthesis.
  • the object of the present invention is a new method for tapentadol synthesis, whether in the form of a base or its salt, which involves the process of preparing diastereomerically and enantiottierically highly enriched Mannich salts (III) with covalently linked chirality mediator— (S)-phenylethylamine via the process of crystallization-induced asymmetric transformation (CIAT), which represents a transformation of an equilibrating mixture of two or more diastereomers in the reaction mixture by crystallization of one of them under reactio conditions.
  • chirality mediator— (S)-phenylethylamine via the process of crystallization-induced asymmetric transformation (CIAT), which represents a transformation of an equilibrating mixture of two or more diastereomers in the reaction mixture by crystallization of one of them under reactio conditions.
  • the synthesis of tapeniadol thus preferably begins from the propiophenone of oramla (I)
  • This reaction known as the Mannich reaction takes place in a suitable solvent or without a solvent, it uses formalin, parafonnaldehyde or 1 ,3,5-trioxane as a formaldehyde source and a suitable acid.
  • a polar aprotie solvent such as acetonitriie, aliphatic alcohols or lower aliphatic earboxyl acids may be used as a solvent.
  • the reaction preferably takes place without the use of a solvent in the presence of concentrated hydrochloric acid at a temperature of 50-85 °C.
  • a mixture of diastereomers (II) is obtained in the form of a base after the alkalization of a reaction mixture in a diastereomeric ratio close to 1 : 1.
  • a strong acid HX such as hydrochloric acid, bydrobrornie acid, sulphuric acid, preferably hydrochloric acid
  • suitable solvent system effective equilibration between the Mannich salt diastereomers, however, takes place through oxo-enol tautomeric equilibrium, as indicated in the diagram
  • the equilibrium is shifted towards the desired salt (10) by stirring and its elimination from the reaction mixture in a suitable solvent or solvent mixture.
  • the final product is isolated from the reaction mixture by simple filtration in high yield and high diastereomeric purity.
  • the solvents used in this asymmetric transformation can be selected from aliphatic ketones, aliphatic alcohols, , ethers, non-pola aromatic hydrocarbons or mixtures thereof,
  • the object of the present disclosure represents a new method for tapentadol synthesis, which uses diastereomerically pure Mannich salt (III) prepared by CiAT and involves the following steps;
  • bases are selected from the hydroxides or carbonates of alkali metals:
  • the organic solvent is selected from toluene, MTBE,. 2- mefhyltetrahydrofuran, methyl isobutyl ketone or methyl cyclopentyl ether.
  • Fig. 1 Crystalline structure of Mannich salt III (X - CI)
  • aminium chloride (III) (83%) (d.r. 99:1) is obtained.
  • the catalyst is filtered off, washed with 2-methylietrahydiOfuran (100 ml), and the filtrate is subsequently concentrated at a temperature of 50 °C and a pressure of lO mbars,
  • a solution of sodium hydroxide (30.6 g, 0.765 mol) in water (300 ml) is added, and the mixture is extracted using methyl isobutyi ketone (2 x 500 ml).
  • the combined extracts are partially concentrated at a temperature of 70 °C and a pressure of 100 mbars.
  • Hydrogen chloride (12,3 g, 0.337 mol) is introduced to the residue while stirring at a temperature of 10 °C.

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

Abstract

La présente invention concerne un procédé de préparation de tapentadol sous forme d'une base ou de son chlorure d'hydrogène, ledit procédé implique la préparation d'un sel (III) à partir d'un mélange de diastéréomères (II) au moyen d'une transformation asymétrique induite par cristallisation (CIAT) par l'intermédiaire d'un équilibre tautomérique oxo-énol de diastéréomères liés de manière covalente, décalés vers le diastéréoisomère souhaité sans utilisation de résolution chirale avec des acides carboxyliques chiraux.
PCT/SK2018/000005 2017-08-18 2018-08-14 Procédé de préparation de tapentadol et de ses intermédiaires Ceased WO2019035775A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EA202090197A EA202090197A1 (ru) 2017-08-18 2018-08-14 Способ получения тапентадола и его промежуточных соединений
EP18769245.4A EP3713911A1 (fr) 2017-08-18 2018-08-14 Procédé de préparation de tapentadol et de ses intermédiaires

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SK81-2017A SK812017A3 (sk) 2017-08-18 2017-08-18 Spôsob prípravy tapentadolu a jeho medziproduktov
SKPP00081-2017 2017-08-18

Publications (1)

Publication Number Publication Date
WO2019035775A1 true WO2019035775A1 (fr) 2019-02-21

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PCT/SK2018/000005 Ceased WO2019035775A1 (fr) 2017-08-18 2018-08-14 Procédé de préparation de tapentadol et de ses intermédiaires

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EP (1) EP3713911A1 (fr)
EA (1) EA202090197A1 (fr)
SK (1) SK812017A3 (fr)
WO (1) WO2019035775A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119176758A (zh) * 2024-11-26 2024-12-24 苏州盛迪亚生物医药有限公司 一种固载催化制备他喷他多或其可药用盐的方法
CN119192000A (zh) * 2024-11-26 2024-12-27 苏州盛迪亚生物医药有限公司 连续流反应制备他喷他多或其可药用盐的方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008012047A1 (fr) 2006-07-24 2008-01-31 Grünenthal GmbH Procédé d'élaboration de (1r,2r)-3-(3-diméthylamino-1-éthyl-2-méthyl-propyl)-phénol
WO2008012283A1 (fr) * 2006-07-24 2008-01-31 Janssen Pharmaceutica Nv Préparation de (2r,3r)-3-(3-méthoxyphényl)-n,n,2-triméthylpentanamine
EP2049464A1 (fr) 2006-07-24 2009-04-22 Grünenthal GmbH Élaboration de 3-ý(1r,2r)-3-(diméthylamino)-1éthyl-2-méthylpropyl¨phénol
WO2011067714A1 (fr) 2009-12-01 2011-06-09 Archimica Srl Nouveau procédé de préparation de tapentadol et de ses intermédiaires
CN102320984A (zh) 2011-07-25 2012-01-18 江苏恩华药业股份有限公司 (r)-3-(3-甲氧基苯基)-n,n,2-三甲基戊-3-烯-1-胺的制备方法
WO2013111161A2 (fr) 2012-01-10 2013-08-01 Msn Laboratories Limited Procédé de préparation de dérivés de 3-aryl-2-méthyl-propanamine et de ses polymorphes
WO2014005546A1 (fr) 2012-07-06 2014-01-09 江苏恩华药业股份有限公司 Procédé de préparation de chlorhydrate de tapentadol et composés destinés à la préparation de chlorhydrate de tapentadol

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008012047A1 (fr) 2006-07-24 2008-01-31 Grünenthal GmbH Procédé d'élaboration de (1r,2r)-3-(3-diméthylamino-1-éthyl-2-méthyl-propyl)-phénol
WO2008012283A1 (fr) * 2006-07-24 2008-01-31 Janssen Pharmaceutica Nv Préparation de (2r,3r)-3-(3-méthoxyphényl)-n,n,2-triméthylpentanamine
EP2046724A1 (fr) 2006-07-24 2009-04-15 Grünenthal GmbH Procédé d'élaboration de (1r,2r)-3-(3-diméthylamino-1-éthyl-2-méthyl-propyl)-phénol
EP2049464A1 (fr) 2006-07-24 2009-04-22 Grünenthal GmbH Élaboration de 3-ý(1r,2r)-3-(diméthylamino)-1éthyl-2-méthylpropyl¨phénol
WO2011067714A1 (fr) 2009-12-01 2011-06-09 Archimica Srl Nouveau procédé de préparation de tapentadol et de ses intermédiaires
CN102320984A (zh) 2011-07-25 2012-01-18 江苏恩华药业股份有限公司 (r)-3-(3-甲氧基苯基)-n,n,2-三甲基戊-3-烯-1-胺的制备方法
WO2013111161A2 (fr) 2012-01-10 2013-08-01 Msn Laboratories Limited Procédé de préparation de dérivés de 3-aryl-2-méthyl-propanamine et de ses polymorphes
WO2014005546A1 (fr) 2012-07-06 2014-01-09 江苏恩华药业股份有限公司 Procédé de préparation de chlorhydrate de tapentadol et composés destinés à la préparation de chlorhydrate de tapentadol

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANDERSON, N., ORG. PROCESS RES. DEV., vol. 9, 2005, pages 800 - 813
P.P. GRACZYK; O. ZBROJKIEWITZ; S. NERDINGER, TETRAHEDRON: ASYMMETRY, vol. 28, no. 3, 2017, pages 387 - 400

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119176758A (zh) * 2024-11-26 2024-12-24 苏州盛迪亚生物医药有限公司 一种固载催化制备他喷他多或其可药用盐的方法
CN119192000A (zh) * 2024-11-26 2024-12-27 苏州盛迪亚生物医药有限公司 连续流反应制备他喷他多或其可药用盐的方法
CN119176758B (zh) * 2024-11-26 2025-05-09 苏州盛迪亚生物医药有限公司 一种固载催化制备他喷他多或其可药用盐的方法

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Publication number Publication date
EA202090197A1 (ru) 2020-05-27
SK812017A3 (sk) 2019-03-01
EP3713911A1 (fr) 2020-09-30

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