3-Oxo-azetidine-1-carboxylic acid tert-butyl ester → tert-butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate

HRID 626844노트

반응식

HRID 626844 반응식
Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:29])[C:19]([C:27]#[N:28])=[C:20]4[C:26]=3[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.O=[C:31]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32]1.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[C:26]4[O:25][CH2:24][CH2:23][N:22]([CH:31]5[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:34]5)[CH2:21][C:20]=4[C:19]([C:27]#[N:28])=[C:18]([Cl:29])[CH:17]=3)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12

참가 물질

6

반응물 3

HCID 15194043-Oxo-azetidine-1-carboxylic acid tert-butyl esterHCID 5003444Sodium cyanoborohydrideHCID 866975369-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride

생성물 1

HCID 86697538tert-butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate수율 35.7%

시약·촉매·용매 2

HCID 887Methanol용매HCID 8857Ethyl Acetate용매

반응 조건

온도
60 °C

실험 절차

9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (0.030 g, 0.078 mmol) was dissolved in methanol (3.0 mL), and the tert-butyl 3-oxoazetidine-1-carboxylate (0.027 g, 0.16 mmol) and then sodium cyanoborohydride (0.0098 g, 0.16 mmol) were added. The reaction was heated to 60° C. for 3 hrs and then allowed to cool to room temperature. The reaction was diluted with ethyl acetate and washed with brine. The organic layer dried over magnesium sulfate and concentrated to give the crude product as an amber oil. The oil was purified by prep HPLC on a C-18 column eluting water:acetonitrile gradient at pH 10 to give tert-butyl 3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]azetidine-1-carboxylate (0.015 g, 35%). LCMS calculated for C26H32ClN8O3 (M+H)+: m/z=539.2; found: 539.2.

후처리

  1. temperatureto cool to room temperature
  2. washwashed with brine
  3. dry with materialThe organic layer dried over magnesium sulfate
  4. concentrationconcentrated
  5. customto give the crude product as an amber oil
  6. customThe oil was purified by prep HPLC on a C-18 column
  7. washeluting water

출처 및 근거

ORD 기록
ord-0a631bac2b7d4f02bc4338127c1a9517
출처 데이터셋
uspto-grants-2016_04
특허 번호
US09309251B2

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