KR960010634A - 3-[4-(2-아미노에톡시) 벤조일]-2-아릴-6-하이드록시벤조[b]티오펜의 합성법 - Google Patents

3-[4-(2-아미노에톡시) 벤조일]-2-아릴-6-하이드록시벤조[b]티오펜의 합성법 Download PDF

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KR960010634A
KR960010634A KR1019950030210A KR19950030210A KR960010634A KR 960010634 A KR960010634 A KR 960010634A KR 1019950030210 A KR1019950030210 A KR 1019950030210A KR 19950030210 A KR19950030210 A KR 19950030210A KR 960010634 A KR960010634 A KR 960010634A
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chloro
crystalline
formula
hydroxyl
solvate
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스미스 라벨 엘리자베쓰
더글라스 루크 웨인
맥네일 맥길 Iii세 존
스콧 밀러 랜덜
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피터 지. 스트링거
일라이 릴리 앤드 캄파니
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Priority claimed from US08/308,325 external-priority patent/US5629425A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Abstract

본 발명은 2-알릴-6-하이드록시-3-[4-(2-아민페녹시)벤조일]벤조[b]티오펜을 제조하는 신규한 화학적 방법에 관한 것이다. 본발명은 또한 6-하이드록시-2-(4-하이드록시페닐)-3-[4-하이드록시페닐)-3-[4-(2-피페리디노에톡시)벤조일]벤조[b]티오펜 하이드로클로라이드의 결정질 용매화물에 관한 것이다.

Description

3-[4-(2-아미노에톡시)벤조일]-2-2아릴-6-하이드록시벤조[b]티오펜의 합성법
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음

Claims (12)

  1. (a) BX'3의 존재하에 하기 일반식(Ⅱ)의 벤조티오펜을 하기 일반식(Ⅲ)의 아실화제로 아실화시키는 단계; (b) 추가의 BX'3와 반응시킴으로써 (a)단계의 아실화 생성물의 페놀성 기 하나 이상을 탈알킬화시키는 단계; 및 (c) 결정질 용매화물을 단리하는 단계를 포함하는 하기 일반식(Ⅰ)의 화합물의 결정질 용매화물을 제조하는 방법.
    상기 식에서, R1은 수소 또는 하이드록실이고, R2및 R3은 독립적으로 C1-C4알킬이거나, 또는 R2또는 R3은 인접한 질소원자와 함께 피롤리디노, 헥사메틸렌이미노 및 모폴리노로 이루어진 군으로부터 선택된 페테로환상 고리를 형성하며, HX는 CHl 또는 HBr이고, R4는 수소 또는 C1-C4알콕시이고, R5는 C1-C4알킬이며, R6은 클로로, 브로모 또는 하이드록실이며, X'은 클로로 또는 브로모이다.
  2. 제항에 있어서, R1아 하이드록실이고, R2및 R3이 인접한 질소원자와 함께 피페리디노기를 형성하며, R4가 메톡시이고, R5가 메틸이고, R6이 클로로이며, HX가 HCl이며, X'이 클로로인 방법.
  3. (a) BX'3과 반응 시킴으로써 하기 일반식(Ⅳ)의 화합물의 페놀성 기 하나 이상ㅇ르 탈알킬화시키는 단계; 및 (b) 결정질 용매화물을 단리하는 단계를 포함하는 하기 일반식(Ⅰ)의 화합물을 제조하는 방법;
    상기 식에서, R1은 수소 또는 하이드록실이고, R2및 R3은 독립적으로, C1-C4알킬이거나, 또는 R2와 R3은 인접한 질소원자와 함께 피롤리디노, 피레리디노, 헥사메틸렌이미노 및 모폴리노로 이루어진 군으로부터 선택된 헤테로환상 고리를 형성하며, HX는 HCl또는 HBr 이고, R4는 수소 또는 C1-C4알콕시이며, R5는 C1-C4알킬이고, X'은 클로로 또는 브로모이다.
  4. 제3항에 있어서, R1이 하이드록실이고, R2와 R3이 인접한 질소원자와 함꼐 피페리디노기를 형성하고, R4가 메톡시이며, R5라 메틸이며, HX가 HCl이며, X'이 클로로인 방법.
  5. 구리산을 사용하여 얻은 하기 X-선 회절 패턴을 나타내는, 6-하이드록시-2(4-하이드록시페닐)-3-[4-(2-피페리디노에톡시)벤조일]벤조[b]티오펜 하이드로클로라이드의 결정질 용매화물;
  6. 제5항에 있어서, 1,2-디클로로에탄 용매화물 또는 1,2,3-트리클로로프로판 용매 화물인 결정질 용매화물.
  7. 구리선을 사용하여 얻은 하기 X-선 회절 패턴을 나타내는, 6-하이드록시-2-(4-하이드록시페닐)-3-[4-(2-피페리디노에톡시)벤조일]벤조[b]티오펜 하이드로클로라이드의 결정질 용매화물;
  8. 제7항에 있어서, 1,2-디클로로에탄 용매화물인 결정질 용매화물.
  9. (a) BX'3의 존재하에 하기 일반식(Ⅱ)의 벤조티오펜을 하기 일반식(Ⅲ)의 아실화제로 아실화시키는 단계; (b) 추가의 BX'3과 반응기킴으로써 (a)단계의 아실화 생성물의 페놀성 기를 탈알킬화시키는 단계: (c)하기 일반식(Ⅰ)의 화합물의 결정질 용매화물을 단리시키는 단계: (d) 메탄올중 또는 메탄올과 물의 혼합물중 상기 결정질 용매화물을 약 1당량의 염기와 반응시키는 단계 : (e) (d) 단계로부터의 용액을 지방족 탄화수소 용매로 임의적으로 추출하는 단계; (f) (d) 또는 (e) 단계로부터의 메탄올 용액에 약 1당량의 염산을 첨가하는 단계 : 및 (g) 비용매화 결정질 화합물을 단리하는 단계를 포함하는, 구리선을 사용하여 얻은 하기 X-선 회절패턴을 실질적으로 나타내는 비용매화 결정길 6- 하이드록시-2-(4-하이드록시페닐)-3-[4-(2-피페리디노에톡시)벤조일]벤조[b] 티오펜 하이드로클라이드를 제조하는 방법;
    상기 식에서, R1은 하이드록실이고, R2와 R3은 인접한 질소원자와 함께 피페리디노기를 형성하며, R4는 C1-C4알콕시이고, R5는 C1-C4알킬이고, R6은 클로로, 브로모 또는 하이드록실이고, HX는 HCl 또는 HBr이며, X'은 클로로 또는 브로모이다.
  10. 제9항에 있어서, R4가 메톡시이고, R5가 메틸이고, R6이 클로로이고, HX가 HCl이며, BX'3이 BCl3이며, 지방족 탄화수소 용매가 헥산 또는 헵탄이며, 염기가 수산화나트륨인 방법.
  11. (a) BX'3의 존재하에 하기 일반식(Ⅱ)의 벤조티오펜을 하기 일반식(Ⅲ)의 아실화제로 아실화시키는 단계; (b)추가의 BX'3과 반응시킴으로써 (a) 단계의 아실화 생성물의 페놀성 기를 탈알킬화시키는 단계; (c) 하기 일반식(Ⅰ)의 화합물의 결정질 용매화물을 단리하는 단계;(d) 메탄올 및 물을 포함하는 뜨거운 용액에 상기 결정질 용매화물을 용해시키는 단계; (e) (d) 단계로부터 용액을 임의적으로 여과하는 단계;(f) (d) 또는 (e) 단계로부터의 용액을 증류에 의해 농축시키는 단계; 및 (g) 비용매화 결정질 화합물을 단리하는 단계를 포함하는, 구리선을 사용하여 얻은 하기 X-선 회절 패턴을 실질적으로 나타내는 비용매화 결정질 6-하이드록시-2-(4-하이드록시페닐)-3-[4-(2-피페리디노에톡시)벤조일]벤조[b]티오펜 하이드로클로라이드를 제조하는 방법.
    상기 식에서, R1은 하이드록실이고, R2와 R3은 인접한 질소원자와 함께 피페리디노기를 형성하고, R4는 C1-C4알콕시이고, R<SP는 C1-C4알킬이고, R6은 클로로, 브로모 또는 하이드록시이며, HX는 HCl 또는 HBr이며,X'은 클로로 또는 브로모이다.
  12. 제11항에 있어서, R4가 메톡시이고, R5가 메틸이고, R6이 클로로이며, HX가 HCl이고, BCl3인 방법.
    ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
KR1019950030210A 1994-09-19 1995-09-15 3(4-(2-아미노에톡시)벤조일)-2-아릴-6-하이드록시벤조(b)티오펜의합성법 KR100381346B1 (ko)

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US08/308325 1994-09-19
US08/308,325 1994-09-19
US08/308,325 US5629425A (en) 1994-09-19 1994-09-19 Haloalkyl hemisolvates of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-piperidinoethoxy)-benzoyl]benzo[b]thiophene
US42791495A 1995-04-26 1995-04-26
US08/427,914 1995-04-26
US08/427914 1995-04-26

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KR960010634A true KR960010634A (ko) 1996-04-20
KR100381346B1 KR100381346B1 (ko) 2004-04-13

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KR1019950030209A KR100367376B1 (ko) 1994-09-19 1995-09-15 신규한비용매화결정질6-하이드록시-2-(4-하이드록시페닐)-3-[4-(2-피페리디노에톡시)벤조일]벤조[b]티오펜하이드로클로라이드
KR1019950030210A KR100381346B1 (ko) 1994-09-19 1995-09-15 3(4-(2-아미노에톡시)벤조일)-2-아릴-6-하이드록시벤조(b)티오펜의합성법

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