Processes And Intermediates For The Preparation Of {1-(Ethylsulfonyl)-3-[4-(7h-Pyrrolo[2,3-D]Pyrimidin-4-Yl)-1h-Pyrazol-1-Yl]Azetidin-3-Yl}AcetonitrileThe present invention provides processes and intermediates for the preparation of {1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3- yl}acetonitrile: (I)One kind is used to prepare { 1- (ethylsulfonyl) -3- [4- (7h- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1h- pyrazoles -1- base] azetidine -3- bases acetonitrile (i) method, methods described comprises the steps：i) be coupled aza-cyclobutane -3-alcohol hydrochloride (2) and ethyl sulfonic chloride with produce 1- ethylsulfonyls azetidine- 3- alcohol (3)；ii) in the presence of nitroxyl reagent, oxidising agent and acid under oxygen atmosphere by 1- ethylsulfonyls azetidine- (3) aerobic oxidation of 3- alcohol is into 1- (ethylsulfonyl) azetidine -3- ketone (4)；or will with tcca and catalytic azanol reagent 1- ethylsulfonyls aza-cyclobutane -3-alcohol (3) is oxidized to 1- (ethylsulfonyl) azetidine -3- ketone (4)；iii 1- (ethylsulfonyl) azetidine -3- ketone (4)) is made to be reacted with phosphonate reagent to prepare in the presence of alkali compound (1)；iv) crystallize optionally [1- (ethylsulfonyl) azetidine -3- subunits] acetonitrile (1)；v) optionally 4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -1h- is protected with nitrogen-protecting group pyrazoles (5)；vi) make in the presence of non-nucleophilic base [1- (ethylsulfonyl) azetidine -3- subunits] acetonitrile (1) and 4- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -1h- pyrazoles (5) coupling with obtain 1- (ethylsulfonyl) - 3- [4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) -1h- pyrazol-1-yls] azetidine -3- base } acetonitrile (ii)；vii) optionally make 1- (ethylsulfonyl) -3- [4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolans alkane - 2- yls) -1h- pyrazol-1-yls] azetidine -3- bases } acetonitrile (ii) crystallization；viii chloro- 7h- pyrrolo-es [2,3-d] pyrimidines (7a) of 4- optionally) are protected with nitrogen-protecting group；ix) in the presence of alkali using pd (ii) catalyst will 1- (ethylsulfonyl) -3- [4- (4,4,5,5- tetramethyl -1, 3,2- dioxaborolan alkane -2- bases) -1h- pyrazol-1-yls] azetidine -3- bases } acetonitrile (ii) and the chloro- 7h- pyrroles of 4- simultaneously [2,3-d] pyrimidine (7a) or 4- chlorine pyrrolo- [2,3-d] pyrimidine -7- t-butyl formates (7b) coupling are coughed up to provide { 1- (ethyls sulfonyl) -3- [4- (7h- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1h- pyrazol-1-yls] azetidine -3- bases } acetonitrile (i) or 4- { 1- [3- (cyano methyl) -1- (ethylsulfonyl) azetidine -3- bases] -1h- pyrazoles -4- bases } -7h- pyrrolo-es [2,3-d] pyrimidine -7- t-butyl formates (iii)；x) optionally by 4- { 1- [3- (cyano methyl) -1- (ethylsulfonyl) azetidine -3- bases] -1h- pyrazoles -4- base } -7h- pyrrolo-es [2,3-d] pyrimidine -7- t-butyl formates (iii) deprotection is into { 1- (ethylsulfonyl) -3- [4- (7h- pyrroles cough up simultaneously [2,3-d] pyrimidine-4-yl) -1h- pyrazol-1-yls] azetidine -3- bases } acetonitrile (i)；withxi { 1- (ethylsulfonyl) -3- [4- (7h- pyrrolo-es [2,3-d] pyrimidine-4-yl) -1h- pyrazoles -1-) are optionally made base] azetidine -3- bases } acetonitrile (i) crystallization.
｛1-(에틸술포닐)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일｝아세토니트릴의 제조를 위한 방법 및 중간체본 발명은 {1-(에틸술포닐)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴 (I)의 제조를 위한 방법 및 중간체를 제공한다.[이미지]{1-(에틸술포닐)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴 (I)의 제조 방법이며,i) 아제티딘-3-올 히드로클로라이드 (2)를 에탄술포닐 클로라이드와 커플링시켜 1-에틸술포닐아제티딘-3-올 (3)을 수득하는 단계;ii) 1-에틸술포닐아제티딘-3-올 (3)을 산소 분위기 하에 니트록실 시약, 산화 시약 및 산의 존재 하에 1-(에틸술포닐)아제티딘-3-온 (4)으로 호기성 산화시키는 단계; 또는 1-에틸술포닐아제티딘-3-올 (3)을 TCCA 및 촉매량의 옥사암모늄 시약에 의해 1-(에틸술포닐)아제티딘-3-온 (4)으로 산화시키는 단계;iii) 1-(에틸술포닐)아제티딘-3-온 (4)을 염기의 존재 하에 포스포네이트 시약과 반응시켜 화합물 (1)을 제조하는 단계;iv) 임의로 [1-(에틸술포닐)아제티딘-3-일리덴]아세토니트릴 (1)을 결정화하는 단계;v) 임의로 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸 (5)를 질소 보호기에 의해 보호하는 단계;vi) [1-(에틸술포닐)아제티딘-3-일리덴]아세토니트릴 (1) 및 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸 (5)을 비-친핵성 염기의 존재 하에 커플링시켜 {1-(에틸술포닐)-3-[4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴 (II)을 수득하는 단계;vii) 임의로 {1-(에틸술포닐)-3-[4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴 (II)을 결정화하는 단계;viii) 임의로 4-클로로-7H-피롤로[2,3-d]피리미딘 (7a)을 질소 보호기에 의해 보호하는 단계;ix) {1-(에틸술포닐)-3-[4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴 (II)을 염기의 존재 하에 Pd(II) 촉매를 사용하여 4-클로로-7H-피롤로[2,3-d]피리미딘 (7a) 또는 tert-부틸 4-클로로피롤로[2,3-d]피리미딘-7-카르복실레이트 (7b)와 커플링시켜 {1-(에틸술포닐)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴 (I) 또는 tert-부틸 4-{1-[3-(시아노메틸)-1-(에틸술포닐)아제티딘-3-일]-1H-피라졸-4-일}-7H-피롤로[2,3-d]피리미딘-7-카르복실레이트 (III)를 수득하는 단계;x) 임의로 tert-부틸 4-{1-[3-(시아노메틸)-1-(에틸술포닐)아제티딘-3-일]-1H-피라졸-4-일}-7H-피롤로[2,3-d]피리미딘-7-카르복실레이트 (III)를 {1-(에틸술포닐)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴 (I)로 탈보호하는 단계; 및xi) 임의로 {1-(에틸술포닐)-3-[4-(7H-피롤로[2,3-d]피리미딘-4-일)-1H-피라졸-1-일]아제티딘-3-일}아세토니트릴 (I)을 결정화하는 단계를 포함하는 방법.