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KR840002836A - Flutroline and preparation of intermediates useful for preparing the same - Google Patents

Flutroline and preparation of intermediates useful for preparing the same Download PDF

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KR840002836A
KR840002836A KR1019820005645A KR820005645A KR840002836A KR 840002836 A KR840002836 A KR 840002836A KR 1019820005645 A KR1019820005645 A KR 1019820005645A KR 820005645 A KR820005645 A KR 820005645A KR 840002836 A KR840002836 A KR 840002836A
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fluorophenyl
fluoro
tetrahydro
pyrido
indole
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사전트 마젯트(외 2) 스테판
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윌리암 데이비스 헌
화이자 인코포레이티드
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Priority claimed from US06/331,494 external-priority patent/US4510308A/en
Priority claimed from US06/425,151 external-priority patent/US4477669A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

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Description

플루트롤린 및 이를 제조하는데 유용한 중간체의 제조방법.Flutroline and methods of preparing intermediates useful for preparing the same.

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음As this is a public information case, the full text was not included.

Claims (22)

(a) 1,1-디(p-플루오로페닐)우레아를 단계(a)의 반응불황성 용매 내에서 (C1-C4)알킬 차아염소산염으로 염소화하여 제1중간체인 3-클로로-1,1-디(p-플루오로페닐)우레아를 생성하는 단계, (b) 상기 중간체인 3-클로로우레아를 단계(b)의 반응 불활성 용매 내에서(C1-C3)알콕시화물의 알칼리 금속염과 작용시킴으로써 재배열시켜 제2중간체임 2-(C1-C3)카르브알콕시-1,1-디(p-플루오로페닐)히드라진을 생성하는 단계, (c) 상기 중간체인 카르브알콕시히드라진을 단계(c)의 불환성 반응용매 중에서 염기 존재하의 물로 가수분해 및 카르복시이탈시켜서 제3 중간체인 1,1-디(p-플루오로페닐)히드라진을 생성하는 단계(d) 상기 중간체인 1,1-디(p-플루오로페닐)히드라진을 단계 (d)의 불활성 반응용매 중에서 강산존재하에 N-카르보벤조옥시-4-피페리돈으로 응축시키고, 전체 반응 생성물인 2-키르보벤조옥시-8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 회수하는 단계로 구성됨을 특징으로 하는 2-카르보벤조옥시-8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 제조하는 방법.(a) Chlorinated 1,1-di (p-fluorophenyl) urea with (C 1 -C 4 ) alkyl hypochlorite in the reaction inert solvent of step (a), 3-chloro-1 Producing, 1-di (p-fluorophenyl) urea, (b) alkali metal salt of (C 1 -C 3 ) alkoxide in the reaction inert solvent of step (b) with the intermediate 3-chlorourea Rearrangement by reaction with a second intermediate to produce 2- (C 1 -C 3 ) carbalkoxy-1,1-di (p-fluorophenyl) hydrazine, (c) carbalkoxy as the intermediate Hydrolysis and carboxylation of hydrazine with water in the presence of a base in the acyclic reaction solvent of step (c) to produce a third intermediate, 1,1-di (p-fluorophenyl) hydrazine (d) the intermediate 1 , 1-di (p-fluorophenyl) hydrazine is condensed with N-carbobenzooxy-4-piperidone in the presence of a strong acid in the inert reaction solvent of step (d), 2-kerbobenzooxy-8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole as a sieve reaction product Recovering 2-carbobenzooxy-8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3] -b] method of making indole. 제1항에 있어서, (C1-C4)알킬 차아열소산염이 t-부틸차아염소산염이고, 알콕시화물의 알칼리금속염이 메톡시화나트륨이며 제2의 중간체가 2-카르보메톡시-1,1-(p-디페닐)히드라진이며, 강산이 염산임을 특징으로 하는 제조방법.The method of claim 1, wherein the (C 1 -C 4 ) alkyl hypotherite is t-butyl hypochlorite, the alkali metal salt of the alkoxide is sodium methoxylate and the second intermediate is 2-carbomethoxy-1,1- (p-diphenyl) hydrazine, wherein the strong acid is hydrochloric acid. 제1항 또는 2항에 있어서, 상기 2-카르보벤조옥시-8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 불활성 반응용매 내, 0-75°에서 정확히 1몰당량의 2-(p-플루오로페닐)-5-히드록시테트라히드로푸란의 존재하에서 귀금속 촉매를 통해 수소화시켜 플루트롤린을 생성하는 단계가 추가됨을 특징으로 하는 제조방법.The method of claim 1 or 2, wherein the 2-carbobenzooxy-8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4, 3-b] indol was hydrogenated through a noble metal catalyst in the presence of exactly 1 molar equivalent of 2- (p-fluorophenyl) -5-hydroxytetrahydrofuran at 0-75 ° in an inert solvent to yield flutroline Method for producing characterized in that the step of adding. 제3항에 있어서, 상기 귀금속이 팔라듐이며 수소압력이 2내지 8기압임을 특징으로 하는 제조방법.The method according to claim 3, wherein the precious metal is palladium and the hydrogen pressure is 2 to 8 atmospheres. 제1항 또는 2항에 있어서, 상기 2-카르보벤조옥시-8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 0-75℃에서 귀금속 촉매를 통해 수소화시켜 8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드록-1H-피리도[4,3-b]인돌을 생성하는 단계로 추가됨을 특징으로 하는 제조방법.The method of claim 1 or 2, wherein the 2-carbobenzooxy-8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4, 3-b] indole is hydrogenated through a noble metal catalyst at 0-75 ° C. to yield 8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydroxy-1H-pyrido [4 , 3-b] is added to produce an indole. 제5항에 있어서, 상기 귀금속이 팔라듐이며 수소의 압력이 2-8기압임을 특징으로 하는 제조방법.The method of claim 5, wherein the precious metal is palladium and the pressure of hydrogen is 2-8 atm. 제5항 또는 6항에 있어서, 상기 8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 환원제 존재하, 불활성 반응용매 내에서 동몰량 이상의 2-(p-플루오로페닐)-5-드히록시테트라히드로푸란과 접촉시켜 플루트롤린을 제조하는 단계가 추가됨을 특징으로 하는 제조방법.7. The method of claim 5 or 6, wherein the 8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole is reduced as a reducing agent. In the presence of an equimolar amount of 2- (p-fluorophenyl) -5-dehydroxytetrahydrofuran in the inert reaction solvent, in the presence of an inert reaction solvent. 제7항에 있어서, 상기 환원제가 시안화보톤산나트륨 또는 수소와 귀금속 촉매의 유효촉매량임을 특징으로 하는 제조방법.8. The method according to claim 7, wherein the reducing agent is an effective catalyst amount of sodium cyanide borate or hydrogen and a noble metal catalyst. 제5항 또는 6항에 있어서 반응 불활성 극성 유기 용매중의 상기 8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 동몰량 이상의 일반식 HC=CCHOH(p-FC6H4)인 아세틸렌성 화합물 및 이아세틸렌성 화합물에 관하여 촉매 유효량의 염화제일구리 또는 브롬화 제일구리 존재하, 동몰량의 포름알데히드로 응축시키고, 이어서 그 결과 생성된 응축 생성물을 약 15-75℃의 불활성 반응 유기 용매 내에서 촉매 유효량의 귀금속 촉매 존재하 약 75psig에 달하는 수소압력으로 수소화시켜 플루트롤린을 제조하는 단계가 추가됨을 특징으로 하는 제조방법.The 8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3] according to claim 5 or 6 in a reaction inert polar organic solvent. -b] an equimolar amount of formaldehyde in the presence of a catalytically effective amount of cuprous chloride or cuprous bromide with respect to an acetylenic compound having an equimolar amount or more of the general formula HC = CCHOH (p-FC 6 H 4 ) and an acetylenic compound And condensation of the resulting condensation product with a hydrogen pressure of up to about 75 psig in the presence of a catalytically effective amount of a noble metal catalyst in an inert reaction organic solvent at about 15-75 ° C. to produce flutroline. The manufacturing method to make. 제5항 또는 6항에 있어서, 상기 8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H 피리도[4,3-b]인돌과 4-(p-플루오로페닐)-테트라히드로-2-푸란온은 불활성 반응용매 중에서 65-125℃로 반응시켜 8-플루오로-5-(p-플루오로페닐)2-[4-(p-플루오로페닐)-4-히드록시부티릴]-2,3,4,5-테트라히드록-1H-피리도[4,3-b]인돌을 제조하는 단계가 추가됨을 특징으로 하는 제조방버.7. The method of claim 5 or 6, wherein the 8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H pyrido [4,3-b] indole and 4- (p-fluorophenyl) -tetrahydro-2-furanone was reacted at 65-125 ° C. in an inert reaction solvent to give 8-fluoro-5- (p-fluorophenyl) 2- [4- (p-fluoro Chlorophenyl) -4-hydroxybutyryl] -2,3,4,5-tetrahydroxy-1H-pyrido [4,3-b] indole is prepared. 제10항에 있어서, 상기 8-플루오로-5-(p-플루오로페닐)-2-[4-(p-플루오로페닐)-4-히드록시부티릴]-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 반응 불활성 용매 내, 80-110℃에서 비스-(2-메톡시에톡시)알루미늄 수소화물의 나트륨으로 환원시킴으로써 플루트롤린을 제조하는 단계가 추가됨을 특징으로 하는 제조방법.The method of claim 10, wherein the 8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydroxybutyryl] -2,3,4,5 Fluteroline is prepared by reducing tetrahydro-1H-pyrido [4,3-b] indole with sodium bis- (2-methoxyethoxy) aluminum hydride at 80-110 ° C. in a reaction inert solvent. Method of manufacturing, characterized in that the step is added. 2-카르보벤조옥시-8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 반응 불활성 용매 내, 0-75℃에서 정확히 1몰 당량의 2-(p-플루오로페닐)-5-히드록시테트라히드로푸란 존재하에서 귀금속 촉매를 통해 수소화시키는 단계로 구성됨을 특징으로 하는 플루트롤린 제조방법.2-carbobenzooxy-8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole in a reaction inert solvent And hydrogenating through a noble metal catalyst in the presence of exactly 1 molar equivalent of 2- (p-fluorophenyl) -5-hydroxytetrahydrofuran at 0-75 ° C. 제12항에 있어서, 상기 귀금속이 필라듐이며 수소 압력이 2-8기압임을 특징으로 하는 제조방법.13. The process according to claim 12, wherein the precious metal is filadium and the hydrogen pressure is 2-8 atmospheres. 8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 환원제 존재하에 불활성 반응용매 중에서 동몰량 이상의 2-(-플루오로페닐)-5-히드록시테트라히드로푸란과 접촉시키는 단계로 구성됨을 특징으로 하는 플루트롤린 제조방법.8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole in an inert reaction solvent in the presence of a reducing agent of at least 2 equivalents A method for producing fluthroline, comprising contacting with-(-fluorophenyl) -5-hydroxytetrahydrofuran. 제14항에 있어서, 상기 환원제가 시아노보론산나트륨 또는 수소와 유효촉매량의 귀금속 촉매임을 특징으로 하는 제조방법.The production method according to claim 14, wherein the reducing agent is sodium cyanoboronate or hydrogen and a noble metal catalyst having an effective catalyst amount. 반응 불황성 극성 유기용매 중의 8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 동몰량 이상의 일반식 HC≡CHOH(p-FC6H4)인 아세틸렌성 화합물 및 아세틸렌성 화합물에 관하여 유효촉매량의 염화제일구리 또는 브롬화제일구리 존재하의 동몰량의 포름알데히드로 응축시키는 단계, 그런 연후에 그 결과 생성된 응축 생성물을 약 15-75℃의 반응 불활성 유기 용매 내에서 유효촉매량의 귀금속 촉매 존재하에 약 75psig에 달하는 수소압력으로 수소화시키는 단계로 구성됨을 특징으로 하는 플루트롤린 제조방법.Equivalent to or greater than equimolar amount of 8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole in the reaction slack polar organic solvent Condensation of an equimolar amount of formaldehyde in the presence of an effective catalyst amount of cuprous chloride or cuprous bromide with respect to the acetylenic compound and the acetylenic compound of the formula HC≡CHOH (p-FC 6 H 4 ); And hydrogenating the condensed product at a hydrogen pressure of about 75 psig in the presence of an effective catalyst amount of a noble metal catalyst in a reaction inert organic solvent at about 15-75 ° C. 8-플루오로-5-(p-플루오로페닐)-2-[4-(p-플루오로페닐)-4-히드록시부티릴]-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 비스-(2-메톡시에톡시)알루미늄 수소화물의 나트륨염으로 불활성 반응 용매 중에서 80-110℃로 환원시키는 단계로 구성됨을 특징으로 하는 플루트롤린 제조방법.8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydroxybutyryl] -2,3,4,5-tetrahydro-1H-pyri A method for producing fluthroline, characterized by reducing the [[4,3-b] indole to the sodium salt of bis- (2-methoxyethoxy) aluminum hydride in an inert reaction solvent at 80-110 [deg.] C. 제17항에 있어서, 8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 불황성 용매 내, 65-125℃에서 4-(p-플루오로페닐)테트라히도로-2-푸란온과 반응시킴으로써 8-플루오로-5-(p-플루오로페닐)-2-[4-(p-플루오로페닐)-4-히드록시부티릴-]2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌을 제조하는 단계가 추가됨을 특징으로 하는 제조방법.18. The process of claim 17, wherein 8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole is dissolved in an inert solvent, 8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluoro by reacting with 4- (p-fluorophenyl) tetrahydrodo-2-furanone at 65-125 ° C Preparing a phenyl) -4-hydroxybutyryl-] 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole. 1,1-디(p-플루오로페닐)우레아.1,1-di (p-fluorophenyl) urea. 2-카르보벤조옥시-8-플루오로-5-(p-플루오로페닐)-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌.2-carbobenzooxy-8-fluoro-5- (p-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole. 8-플루오로-5-(p-플루오로페닐)-2-[4-(p-플루오로페닐)-4-히드록시-2-부틴일-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydroxy-2-butynyl-2,3,4,5-tetrahydro-1H -Pyrido [4,3-b] indole 8-플루오로-5-(p-플루오로페닐)-2-[4-(p-플루오로페닐)-4-히드록시부티릴]-2,3,4,5-테트라히드로-1H-피리도[4,3-b]인돌8-fluoro-5- (p-fluorophenyl) -2- [4- (p-fluorophenyl) -4-hydroxybutyryl] -2,3,4,5-tetrahydro-1H-pyri Degree [4,3-b] indole ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
KR1019820005645A 1981-12-17 1982-12-16 Flutroline and preparation of intermediates useful for preparing the same Abandoned KR840002836A (en)

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US06/331,494 US4510308A (en) 1981-12-17 1981-12-17 Process for preparing carboline derivatives
US33419581A 1981-12-24 1981-12-24
US334195 1981-12-24
US41515282A 1982-09-30 1982-09-30
US415152 1982-09-30
US06/425,151 US4477669A (en) 1982-09-30 1982-09-30 Processes and intermediates useful in the preparation of flutroline
US331494 1989-03-31
US425151 1989-10-20

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