WO2003004502A1 - Procede de preparation de derives de tetrahydrothieno[3,2-c]pyridine - Google Patents

Procede de preparation de derives de tetrahydrothieno[3,2-c]pyridine Download PDF

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Publication number
WO2003004502A1
WO2003004502A1 PCT/CA2002/001017 CA0201017W WO03004502A1 WO 2003004502 A1 WO2003004502 A1 WO 2003004502A1 CA 0201017 W CA0201017 W CA 0201017W WO 03004502 A1 WO03004502 A1 WO 03004502A1
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WO
WIPO (PCT)
Prior art keywords
formula
compound
thienyl
methyl
chlorophenylglycinate
Prior art date
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PCT/CA2002/001017
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English (en)
Inventor
Stephen E. Horne
Gamini Weeratunga
Bogdan M. Comanita
Jaipal Reddy Nagireddy
Laura Kaye Mcconachie
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Brantford Chemicals Inc.
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 Brantford Chemicals Inc. filed Critical Brantford Chemicals Inc.
Priority to EP02745008A priority Critical patent/EP1404681A1/fr
Publication of WO2003004502A1 publication Critical patent/WO2003004502A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention refers to a new process for the synthesis of tetrahydrothieno[3,2-c]pyridine derivatives, in particular 5-o-chlorobenzyl-4,5,6,7- tetrahydothieno[3,2-c]pyridine and racemic or enantiomerically enriched methyl ⁇ -(4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate, and intermediates thereof.
  • Structure 1 known as Ticlopidine, is an antithrombotic drug with platelet aggregation inhibiting properties as disclosed in US 4,051,141 and US 4,127,580.
  • the dextrorotatory enantiomer (Structure 2), bearing the International Non- Proprietary name (INN) Clopidogrel, has the absolute configuration S and is a commercially significant drug with excellent antithrombotic and platelet aggregation inhibiting activity as disclosed in US 4,847,265.
  • the enantiomerically enriched compound can be prepared by means of enantioselective synthesis or starting from a racemic mixture of enantiomers in conjunction with a resolution process.
  • a known process for the preparation of racemic Clopidogrel 2 is based on the nucleophilic displacement of racemic ⁇ -halophenylacetic acid derivatives 3 by 4,5,6,7-tetrahydrothieno[3,2c]pyridine 4 as described in US 4,529,596 and US 5,132,435 (Scheme 1).
  • the enantiomerically enriched clopidogrel is obtained through the resolution of the racemic mixture of methyl ⁇ -(4,5,6,7-tetrahydro-5-thieno[3,2- c]pyridyl)-o-chlorophenylacetate 2 with R-camphorsulfonic acid as described in US 4,847,265 and US 5,132,435.
  • Racemic clopidogrel can also be prepared starting with the Strecker synthesis of ⁇ -(2-thienyl)ethylamino-o-chlorophenylacetonitrile 6 as shown in Scheme 2. Hydrolysis of the nitrile followed by esterification leads to methyl ⁇ -(2- thienyl)ethylamino-o-chlorophenylacetate 8. This in turn generates the tetrahydrothieno[3,2-c]pyridine bicyclic system by reacting with a formylating agent (e.g. paraformaldehyde) under acidic conditions. The process is disclosed in WO 98/51682, WO 98/51689 and WO 98/51681. Scheme 2
  • dextrorotatory clopidogrel can be obtained starting from enantiomerically enriched (R)-sulphonyloxyacetic ester derivatives 11 and 4,5,6,7-tetrahydrothieno[3,2c]pyridine 4 as disclosed in WO 99/18110.
  • the same publication documents the reaction of the methyl (R)- ⁇ -tosyloxy-o- chlorophenylacetate 11 with 2-(2-thienyl)ethylamine 12 to result in methyl (S)- ⁇ - (2-(2-thienyl)ethylamino-o-chlorophenylacetate 8. This in turn generates enantiomerically enriched clopidogrel by reaction with a formylating reagent under acidic conditions. (Scheme 4). Scheme 4
  • the present invention provides an improved process for the preparation of a racemic and enantiomerically enriched 4,5,6,7-tetrahydrothieno[3,2-c]pyridines of general formula I
  • the compound of the general formula I is prepared (Scheme 6) by reducing the compound of formula II with suitable reducing agents, known to those skilled in the art, to a mixture of diastereoisomeric compounds of formula III which are reacted with formaldehyde or any chemical equivalent thereof to yield the compound of formula IV.
  • the compound of formula IV is further rearranged in a suitable solution to produce the compound of formula V which upon reduction (by a suitable reducing agent) provides an enantiomerically enriched or racemic mixture of tetrahydrothieno[3,2-c]pyridine of formula I.
  • X can be hydrogen, carboxyl, alkoxycarbonyl, aryloxycarbonyl, nitrile or carbamoyl of formula
  • Ri and R 2 can be individually or simultaneously hydrogen, alkyl or part of a heterocyclic structure; Y can be hydroxyl, alkanoyloxy, aroyloxy, as well as carbonate derivatives of formula -OCOOR3 or carbamate derivatives of formula -
  • R3 can be substituted or unsubstituted alkyl or aryl
  • R4 and R5 can be individually or simultaneously substituted or unsubstituted alkyl, aryl or cycloalkyl
  • Z can be hydrogen, halogen, alkyl, aryl, aryloxy or alkoxy group.
  • the compound of formula II in its racemic or enantiomerically enriched form is obtained through the reaction of a racemic or enantiomerically enriched primary amine of general formula
  • LG is a leaving group such as halogen, arysulphonyloxy, aryloxy, sulphonate, alkyloxy and its derivatives or activated aryl.
  • Other obvious synthetic chemical equivalents of the phenylglycine counterpart, such as various salts as well as aliphatic or aromatic esters, amides, nitrile or free carboxyl group are also included in the present invention.
  • the reaction may be carried out in an aromatic solvent (e.g. toluene and the like), polar aprotic solvents (e.g.
  • polar protic solvents e.g. methanol, ethanol, propanol, butanol, n-butanol, isobutanol, n-propanol, isopropanol, and the like
  • polar protic solvents e.g. methanol, ethanol, propanol, butanol, n-butanol, isobutanol, n-propanol, isopropanol, and the like
  • the process according to one aspect of the present invention improves the previously reported synthesis of ticlopidine and extends the scope of the synthetic sequence to the structurally related clopidogrel.
  • 2-bromoacetylthiophene 18 and methyl o- chlorophenylglycinate 19 can be prepared according to known literature procedures as reported in Bull. Chem. Soc. Jpn. 60, 1159 and J. Am. Chem. Soc. 1999, 121, 4284 respectively. Racemic or enantiomerically enriched methyl 2-o- chlorophenylglycine 19 reacts with 2-bromoacetylthiophene 18 in the presence of a base which acts as an acid scavenger.
  • novel compounds of formulae 22, 21 and 20 which can be made as a racemic or diasteromeric mixture with set configuration at the carbon adjacent to the nitrogen, as well as its enantiomers either as free base or its salts with Bronstead and Lewis acids.
  • Specific compounds arising from the preparation of formulae 22, 21 and 20 include:
  • Methyl N-2-(2-thienyl)-2-oxoethyl)-o-chlorophenylglycinate (20) (5.4 g, 16.6 mmol) was dissolved in methanol and treated with sodium borohydride (0.69 g, 18.3 mmol). The reaction is allowed to stir at room temperature over the night and treated with 2N hydrochloric acid to acidic pH. Most of the methanol is evaporated under vacuum and then the remaining aqueous solution partitioned between methylene chloride and 5% sodium hydroxide.
  • Methyl N-(2-(2-thienyl)-2-hydoxyethyl)-2-o-chlorophenylglycinate (21) (2.5 g, 7.6 mmol) was dissolved in ethanol and treated with 37% formaline (1.85 g, 22.8 mmol), then heated at 40°C over the night under nitrogen. The ethanol is evaporated under vacuum and the residual water was removed by azeotropic distillation with toluene to provide 2.3 g of desired product as a mixture of diastereoisomers.
  • Methyl N-(2-(2-thienyl)-2-oxoethyl)-2S-o-chlorophenylglvcinate (20) Methyl(S)-o-chlorophenylglycinate (6.5g, 0.032 mol) was dissolved in toluene and treated with potassium carbonate (6.62 g, 0.048 mol) and 2- bromoacetylthiophene (7.2 g 0.035) mol. DMF was added to the reaction mixture and the content was stirred under nitrogen at room temperature. When the whole quantity of aminoester is consumed, the reaction mixture is partitioned between toluene and water and the aqueous layer back extracted several times with toluene. The combined organic phase is extracted with brine, then with 2 N HC1.
  • the aqueous phase was treated with sodium bicarbonate solution to basic pH and extracted with toluene. After the concentration of the toluene solution one obtains
  • Methyl N-(2-(2-thienyl)-2-oxoethyl)-2S-o-chlorophenylglycinate (20) (6.2 g, 19 mmol) was dissolved in methanol and treated in portions with sodium borohydride (0.79 g, 21 mmol) to keep the temperature below 10°C. The reaction is allowed to stir at room temperature for two hours and treated with 2N hydrochloric acid to acidic pH. Most of the methanol is evaporated under vacuum and then the remaining aqueous solution partitioned between methylene chloride and aqueous sodium bicarbonate.
  • Methyl N-(2-(2-thienyl)-2-hydoxyethyl)-2S-o-chlorophenylglycinate (21 ) was dissolved in ethanol and treated with 37% formaline (4.08 g, 50.4 mmol), then heated at 40°C under nitrogen. After four hours, the ethanol is evaporated under vacuum and the residual water was removed by azeotropic distillation with toluene to provide 5.6 g of desired product as a mixture of diastereoisomers.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne un procédé de préparation de dérivés de tétrahydrothiéno[3,2-c]pyridine de formule générale (I), ou leur sels pharmaceutiquement acceptables, dans laquelle: X représente hydrogène, carboxyle, alcoxycarbonyle, aryloxycarbonyle, nitrile, ou carbamoyle de formule (a), dans laquelle: R1 et R2 peuvent être séparément ou conjointement hydrogène, alkyle ou une partie d'une structure hétérocyclique; Z peut être hydrogène, halogène, un groupe alkyle, aryle, aryloxy ou alcoxy. Le procédé comprend les étapes suivantes: (a) la réduction du composé de formule (II) avec des agents de réduction appropriés afin d'obtenir un composé de formule (III); (b) la réaction du composé de formule (III) avec du formaldéhyde ou tout équivalent chimique de celui-ci afin d'obtenir un composé de formule (IV); (c) le réarrangement du composé de formule (IV) afin de produire le composé de formule (V), dans laquelle Y est hydroxyle, alcanoyloxy, aroyloxy, des dérivés de carbamate ou de carbonate; et (d) la réduction du composé de formule (V) afin d'obtenir le composé de formule (I).
PCT/CA2002/001017 2001-07-06 2002-07-05 Procede de preparation de derives de tetrahydrothieno[3,2-c]pyridine WO2003004502A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP02745008A EP1404681A1 (fr) 2001-07-06 2002-07-05 Procede de preparation de derives de tetrahydrothieno 3,2-c]pyridine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CA2,352,520 2001-07-06
CA 2352520 CA2352520C (fr) 2001-07-06 2001-07-06 Synthese de derives de tetrahydrothieno-[3,2-c]-pyridine

Publications (1)

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WO2003004502A1 true WO2003004502A1 (fr) 2003-01-16

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CA (1) CA2352520C (fr)
WO (1) WO2003004502A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006137628A1 (fr) * 2005-06-23 2006-12-28 Hanmi Pharm. Co., Ltd. Procédé de préparation de clopidogrel et intermédiaires utilisés dans ce procédé
WO2007094006A1 (fr) * 2006-02-13 2007-08-23 Lee Pharma Limited Procédé de synthèse de la forme 1 du clopidogrel bisulfate
WO2008046792A1 (fr) * 2006-10-17 2008-04-24 Adamed Sp. Z O.O. FORME CRISTALLINE DE L'ACÉTATE RACÉMIQUE DE MÉTHYL-α-(2-CHLOROPHÉNYL)-2-(6,7-DIHYDROTHIÉNO[3,2-C]PYRIDIN-5(4H)), SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2424278A1 (fr) * 1978-04-24 1979-11-23 Parcor Procede de preparation de thieno(2,3-c) et thieno(3,2-c)pyridines
US4529596A (en) * 1982-07-13 1985-07-16 Sanofi, S.A. Thieno [3,2-c] pyridine derivatives and their therapeutic application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2424278A1 (fr) * 1978-04-24 1979-11-23 Parcor Procede de preparation de thieno(2,3-c) et thieno(3,2-c)pyridines
US4529596A (en) * 1982-07-13 1985-07-16 Sanofi, S.A. Thieno [3,2-c] pyridine derivatives and their therapeutic application

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CORRAL ET AL.: "N-Substituted 2-amino-1-(2-thienyl)ethanols as beta-adrenergic blocking agents", J. MED. CHEM., 1973, pages 882 - 885, XP002216488 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006137628A1 (fr) * 2005-06-23 2006-12-28 Hanmi Pharm. Co., Ltd. Procédé de préparation de clopidogrel et intermédiaires utilisés dans ce procédé
US7652140B2 (en) 2005-06-23 2010-01-26 Hanmi Pharm. Co., Ltd Method of preparing clopidogrel and intermediates used therein
US7763730B2 (en) 2005-06-23 2010-07-27 Hanmi Pharm. Co., Ltd Method preparation clopidogrel and intermediates used therein
WO2007094006A1 (fr) * 2006-02-13 2007-08-23 Lee Pharma Limited Procédé de synthèse de la forme 1 du clopidogrel bisulfate
WO2008046792A1 (fr) * 2006-10-17 2008-04-24 Adamed Sp. Z O.O. FORME CRISTALLINE DE L'ACÉTATE RACÉMIQUE DE MÉTHYL-α-(2-CHLOROPHÉNYL)-2-(6,7-DIHYDROTHIÉNO[3,2-C]PYRIDIN-5(4H)), SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION

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Publication number Publication date
CA2352520A1 (fr) 2003-01-06
EP1404681A1 (fr) 2004-04-07
CA2352520C (fr) 2007-10-02

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