EP1841774A1 - PROCÉDÉ DE SYNTHÈSE DU 5,6-DIHYDRO-4-(S)-(ÉTHYLAMINO)-6-(S)MÉTHYL-4H-THIÉNO[2,3b]THIOPYRAN-2-SULFONAMIDE-7,7-DIOXYDE HCI - Google Patents

PROCÉDÉ DE SYNTHÈSE DU 5,6-DIHYDRO-4-(S)-(ÉTHYLAMINO)-6-(S)MÉTHYL-4H-THIÉNO[2,3b]THIOPYRAN-2-SULFONAMIDE-7,7-DIOXYDE HCI

Info

Publication number
EP1841774A1
EP1841774A1 EP04816672A EP04816672A EP1841774A1 EP 1841774 A1 EP1841774 A1 EP 1841774A1 EP 04816672 A EP04816672 A EP 04816672A EP 04816672 A EP04816672 A EP 04816672A EP 1841774 A1 EP1841774 A1 EP 1841774A1
Authority
EP
European Patent Office
Prior art keywords
formula
compound
solvent
acid
group
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.)
Withdrawn
Application number
EP04816672A
Other languages
German (de)
English (en)
Inventor
Mukund Keshao Gurjar
Madhusudan Nagorao Deshmukh
Vincent Paul
Venkatasubramaniam Radhakrishnan USV Ltd. TARUR
DhananjayGovind USV Ltd. SATHE
SantoshPratap USV Ltd. PARDESHI
Sanjay Janardhan USV Ltd. NAIK
Tushar Anil USV Ltd. NAIK
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.)
USV Pvt Ltd
Original Assignee
USV Pvt 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 USV Pvt Ltd filed Critical USV Pvt Ltd
Publication of EP1841774A1 publication Critical patent/EP1841774A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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 relates to an improved process for the preparation of 5,6- dihydro-4-(S)-(ethylamino)-6-(S)methyl-4H-thieno[2,3b]thiopyran-2-sulphonamide-7,7- dioxide hydrochloride commonly known as Dorzolamide Hydrochloride.
  • This compound is described in US Patent 4,797,413 as an agent to reduce intraoccular pressure by inhibiting carbonic anhydrase enzyme.
  • EP O 296 879 describes the synthesis of Dorzolamide Hydrochloride starting from thiophene-2-thiol as depicted in scheme 2 and 3 Scheme 2
  • the object of present invention is to provide an improved process for commercial manufacture of 5,6-dihydro-4-(S)-(ethylammo)-6-(S)methyl-4H-thieno[2,3b]thiopyran-2- sulphonamide-7,7-dioxide hydrochloride commonly known as Dorzolamide Hydrochloride starting from stable 2-bromo thiophene.
  • Another object of the invention is to provide an improved process for Dorzolamide hydrochloride preparation, which is less time consuming involving fewer steps and increases the product efficiency.
  • Another object of the invention is to provide a process for Dorzolamide hydrochloride manufacture, which avoids use of expensive catalyst.
  • Another object of the invention is to provide a process for Dorzolamide hydrochloride manufacture, which avoids the use of expensive reagents.
  • Another object of the invention is to provide a process for Dorzolamide hydrochloride manufacture, which is industrially feasible.
  • the present invention provides a process for preparing 5,6-dihydro-4- (S)-(ethylamino)-6-(S)methyl-4H-thieno[2,3b]thiopyran-2-sulphonamide-7,7-dioxide hydrochloride of formula (I),
  • the organic solvent is selected from the group consisting of ethers, cyclic ethers and aromatic hydrocarbon.
  • the organic solvent used in step (a) is tetrahydrofuran.
  • step (a) is carried out in the presence of a base selected from the group consisting of organic alkylamine and pyridine.
  • the base is trialkyl amine.
  • the base is triethyl amine.
  • X is a halo selected from the group consisting of Cl, Br and I.
  • step (a) is carried out at a temperature in the range of0 o C to 70°C.
  • the organic solvent is an aprotic non-polar solvent.
  • the aprotic non-polar solvent used is a chlorinated solvent such as MDC.
  • the Lewis acid is selected from the group consisting OfAlCl 3 , ZnCl 2 and SnCl 4 and more preferably SnCl 4 .
  • sulfonyl chloride of formula XX is dissolved in an organic solvent selected from the group consisting of ether and ketone.
  • the organic solvent is tetrahydrofuran.
  • the sulfonyl chloride of formula XX is dissolved in an organic sovlent and then treated with ammonia followed by chlorination with a chlorinating agent selected from the group consisting OfPOCl 3 , PCl 5 , PCl 3 , SOCl 2 and more preferably SOCl 2 and in the presence of a chlorination solvent selected from the group consisting of CHCl 3 , MDC, and EDC, preferably MDC.
  • a chlorinating agent selected from the group consisting OfPOCl 3 , PCl 5 , PCl 3 , SOCl 2 and more preferably SOCl 2
  • a chlorination solvent selected from the group consisting of CHCl 3 , MDC, and EDC, preferably MDC.
  • step (d) reduction is effected using sodium borohydride in the presence of a solvent and at a temperature in the range of O 0 C to 40 0 C.
  • the solvent is a lower aliphatic alcohol and more preferably methanol.
  • step (e) compound of formula VI is oxidised with sodium perborate in presence of acetic acid at 20°C to 70°C.
  • step (f) the Ritter reaction of compound of formula VII is effected in a strong acid with acetonitrile at 10 0 C to 40°C.
  • the strong acid is selected from the group consisting of sulfuric acid and a mixture of concentrated sulfuric acid and fuming sulfuric acid.
  • step (g) reduction is effected using borane dimethylsulfide complex in an organic solvent selected from ether and cyclic ether.
  • the organic solvent used in step (g) is tetrahydrofuran.
  • the organic solvent is selected from the group consisting of a ketone, an ester, a dipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon and aromatic hydrocarbon.
  • the ester is ethyl acetate.
  • the acid used for salt formation in step (h) is a mineral acid selected from the group consisting of HCl, H 2 SO 4 , HNO 3 , and HBr more preferably HCl dissolved in a lower aliphatic alcohol.
  • the acid used for salt formation in step (h) is ethanolic HCl.
  • the organic solvent used for recrystallization is selected from the group consisting of a ketone, an ester, a dipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon or aromatic hydrocarbon, preferably an ester, lower aliphatic alcohol or mixture thereof, more preferably ethyl acetate, ethanol or mixture thereof.
  • the compound of formula X is rsolved using di-p-toluyl-L-tartarate and di-p-toluyl-D-tartarate.
  • the invention provides a process for preparing 5,6-dihydro-4-(S)-(ethylamino)-6- (S)methyl-4H-thieno[2,3b]thiopyran-2-sulphonamide-7,7-dioxide hydrochloride of formula (I), comprising of nine steps, as depicted in scheme 4 below: Scheme 4
  • ⁇ XVUl in X of formula II is a halo -Cl, -Br, -I preferably -Br.
  • the organic solvents are ethers, cyclic ethers and aromatic hydrocarbon but preferably cyclic ethers and more preferably THF.
  • the base is an organic alkylamine or pyridine, preferably trialkyl amine and more preferably triethyl amine.
  • the organic solvents are aprotic non-polar solvents, preferably chlorinated solvents and more preferably MDC.
  • Lewis acids are AlCl 3 , ZnCl 2 , SnCl 4 and more preferably SnCl 4 .
  • the chlorination agent is selected from POCl 3 , PCl 5 , PCl 3 , SOCl 2 and more preferably SOCl 2 .
  • Chlorination solvents are preferably selected from CHCl 3 , MDC, and EDC, more preferably MDC.
  • the organic solvent for dissolving sulfonyl chloride is an ether or a ketone, preferably ether and more preferably THF.
  • the organic solvent is lower aliphatic alcohol and more preferably methanol.
  • the organic solvents are ethers, cyclic ethers, preferably cyclic ethers and more preferably THF.
  • Preparation of compound of formula X by converting the compound of formula IX to its acid addition salt in a solvent followed by recrystallisation of the enriched salt from an organic solvent or a mixture of solvents as shown in scheme 12.
  • the organic solvent is a ketone, an ester, a dipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon or aromatic hydrocarbon, preferably an ester and more preferably ethyl acetate.
  • the acid used for salt formation is a mineral acid like HCl, H 2 SO 4 , HNO 3 , HBr more preferably HCl dissolved in lower aliphatic alcohol preferably ethanol.
  • the acid used for salt formation is most preferably ethanolic HCl.
  • the organic solvent for recrystallization is a ketone, an ester, a dipolar aprotic solvent, lower aliphatic alcohol, aliphatic hydrocarbon or aromatic hydrocarbon, preferably an ester, lower aliphatic alcohol or mixture thereof, more preferably ethyl acetate, ethanol or mixture thereof.
  • the process of manufacturing Dorzolamide hydrochloride by the present invention comprises use of 2-bromo thiophene as a starting material avoiding use of unstable thiophene-2-thiol.
  • the process of the said invention requires less number of steps since sulfonamide of formula IV is prepared directly from compound of formula III avoiding isolation of sulfonic acid X. This eliminates the use of an expensive catalyst.
  • the process of invention uses cheap, commercially available sodium perborate as an oxidizing agent, thus making the process more economical.
  • the process of the said invention makes use of hydrochloride salt formation as a means to separate cis:trans isomer thus avoiding industrially cumbersome column chromatography.
  • the salt was then treated with a saturated solution of sodium bicarbonate and mixture extracted with ethyl acetate.
  • the organic extract were dried, filtered and concentrated to dryness to yield (3.2gm) of freebase.
  • the hydrochloride salt was prepared from 5.6 N HCl ethanol and crystallized from methanol- isopropanol to yield (2.83 gm) of (+) isomer, SOR 8.23 (C 0.9 methanol) M.P. 283 -285 0 C.
  • the combine mother liquor was treated with saturated solution of sodium bicarbonate and mixture extracted with ethyl acetate.
  • the organic extracts were dried, filtered and concentrated to dryness.

Landscapes

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

Abstract

La présente invention concerne un procédé amélioré pour la préparation du chlorhydrate de 5,6-dihydro-4-(S)-(éthylamino)-6-(S)-méthyl-4H-thiéno[2,3b]thiopyran-2-sulfonamide-7,7-dioxyde de formule (I), généralement connu sous le nom de Dorzolamide Chlorhydrate, et pouvant être employé pour réduire la pression intra-oculaire en inhibant l'enzyme anhydrase carbonique.
EP04816672A 2004-12-28 2004-12-28 PROCÉDÉ DE SYNTHÈSE DU 5,6-DIHYDRO-4-(S)-(ÉTHYLAMINO)-6-(S)MÉTHYL-4H-THIÉNO[2,3b]THIOPYRAN-2-SULFONAMIDE-7,7-DIOXYDE HCI Withdrawn EP1841774A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000420 WO2006070387A1 (fr) 2004-12-28 2004-12-28 PROCÉDÉ DE SYNTHÈSE DU 5,6-DIHYDRO-4-(S)-(ÉTHYLAMINO)-6-(S)MÉTHYL-4H-THIÉNO[2,3b]THIOPYRAN-2-SULFONAMIDE-7,7-DIOXYDE HCI

Publications (1)

Publication Number Publication Date
EP1841774A1 true EP1841774A1 (fr) 2007-10-10

Family

ID=34960556

Family Applications (1)

Application Number Title Priority Date Filing Date
EP04816672A Withdrawn EP1841774A1 (fr) 2004-12-28 2004-12-28 PROCÉDÉ DE SYNTHÈSE DU 5,6-DIHYDRO-4-(S)-(ÉTHYLAMINO)-6-(S)MÉTHYL-4H-THIÉNO[2,3b]THIOPYRAN-2-SULFONAMIDE-7,7-DIOXYDE HCI

Country Status (5)

Country Link
EP (1) EP1841774A1 (fr)
AU (1) AU2004326111A1 (fr)
BR (1) BRPI0419257A (fr)
MX (1) MX2007007923A (fr)
WO (1) WO2006070387A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060173068A1 (en) * 2005-01-18 2006-08-03 Judith Aronhime Amorphous and crystalline forms of dorzolamide hydrochloride and processes of making same
CN103415524B (zh) * 2011-03-10 2015-11-25 Zach系统股份公司 不对称还原方法
ITMI20121165A1 (it) * 2012-07-03 2014-01-04 Zach System Spa Processo di riduzione asimmetrica
CN111233887A (zh) * 2018-11-28 2020-06-05 武汉武药科技有限公司 一种盐酸多佐胺中间体的合成工艺

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4863922A (en) * 1984-12-12 1989-09-05 Merck & Co., Inc. Substituted aromatic sulfonamides as antiglaucoma agents, compositions and use
US5157129A (en) * 1990-04-18 1992-10-20 Merck & Co., Inc. Enantiospecific synthesis of s-(+)-5,6-dihydro-4-(r-amino)-4h-thieno(2,3-b)thiopyran-2-sulfonamide-7,7-dioxide
TW265343B (fr) * 1993-03-22 1995-12-11 Merck & Co Inc

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006070387A1 *

Also Published As

Publication number Publication date
BRPI0419257A (pt) 2008-05-06
WO2006070387A1 (fr) 2006-07-06
AU2004326111A1 (en) 2006-07-06
MX2007007923A (es) 2007-11-14

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