S)-N-(5-((R)-2--피라졸로[1,5-A]피리미딘-3-일)-3-히드록시피롤리딘-1-카르복사미드의 제조 방법

• Main Authors: JIANG YUTONG, ANDREWS STEVEN W, REYNOLDS MARK, EARY CHARLES TODD, HACHE BRUNO, JUENGST DERRICK, HAAS JULIA, SPENCER STACEY
• Format: Patent
• Language: Korean
• Published: 12.04.2019
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

페닐(5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)-3,3a-디히드로피라졸로 [1,5-a]피리미딘-3-일)카르바메이트 또는 유사한 유도체(화학식 13)를 (S)-피롤리딘-3-올(화학식 14)과 반응시키는 것에 의한, (S)-N-(5-((R)-2-(2,5-디플루오로페닐) 피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-일)-3-히드록시피롤리딘-1-카르복사미드 (화학식 I) 또는 그의 염의 제조 방법. (R)-5-(2-(2,5-디플루오로페닐) 피롤리딘-1-일) -3-니트로피라졸로[1,5-a]피리미딘(화학식 11)의 (R)-5-(2-(2,5-디플루오로페닐) 피롤리딘-1-일)피라졸로[1,5-a]피리미딘-3-아민(화학식 12)으로의 환원에 의한, 페닐(5-((R)-2-(2,5-디플루오로페닐)피롤리딘-1-일)-3,3a-디히드로피라졸로[1,5-a] 피리미딘-3-일)카르바메이트(화학식 13) 또는 유사한 유도체의 제조 방법. (R)-N-((R)-1-(2,5-디플루오로페닐)-3-(1,3-디옥산-2-일)프로필)-2-메틸프로판-2-술핀아미드 (화학식 19)를 산 및 환원제로 처리하는 것에 의한, (R)-2-(2,5-디플루오로페닐) 피롤리딘(R)-2-히드록시숙시네이트 (화학식 10)의 제조 방법. (S)-N-(5-((R)-2-(2,5-디플루오로페닐)-피롤리딘-1-일)-피라졸로[1,5-a]피리미딘-3-일)-3-히드록시피롤리딘-1-카르복사미드는, 예를 들어 암 치료를 위한 티로신 키나제(TRK) 억제제이다. Process for preparing (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (formula I) or a salt thereof by reacting phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate or a similar derivative (formula 13) with (S)-pyrrolidin-3-ol (formula 14).Process for preparing phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate (formula 13) or a similar derivative by reduction of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine (formula 11) to (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (formula 12).Process for preparing (R)-2-(2,5-difluorophenyl)pyrrolidine(R)-2-hydroxysuccinate (formula 10) by treating (R)-N-((R)-1-(2,5-difluorophenyl)-3-(1,3-dioxan-2-yl)propyl)-2-methylpropane-2-sulfinamide (formula 19) with an acid and a reducing agent.(S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-l-yl)-pyrazolo[l,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, is a tyrosin kinase (TRK) inhibitor for trearing e.g. cancer.