Acryloyl chloride → N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{3-dimethylaminoazetidin-1-yl}-4-methoxyphenyl)prop-2-enamide

HRID 1842646노트

반응식

HRID 1842646 반응식
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH2:29])[CH:15]=2)=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1

참가 물질

5

반응물 3

HCID 13140Acryloyl chlorideHCID 81531DiisopropylethylamineHCID 86677283N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine2회

생성물 1

HCID 86677282N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-2-{3-dimethylaminoazetidin-1-yl}-4-methoxyphenyl)prop-2-enamide

시약·촉매·용매 1

HCID 6344Dichloromethane용매3회

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온도
0 °C

실험 절차

A solution of acryloyl chloride (0.057 mL, 0.70 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of N-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 118, 310 mg, 0.67 mmol) and DIPEA (0.127 mL, 0.73 mmol) in CH2Cl2 (40 mL), which was cooled in an ice/water bath to 0° C. The mixture was stirred while in the ice/water bath for 1 h and was then allowed to warm to r.t. The mixture was then held at r.t. for 18 h, and was then diluted with CH2Cl2 (100 mL). This solution was then washed with sat. NaHCO3 (200 mL) and the aqueous wash solution was extracted with CH2Cl2 (2×100 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound together with an impurity (172 mg, 50%) as a pale yellow solid. 120 mg of this material was purified by crystallisation from CH3CN to give the title compound (85 mg, 0.164 mmol) as a yellow solid without evidence of the impurity by NMR analysis. The mother liquors from the crystallization and a further impure fraction from the FCC (containing a 75:25 mixture of product:starting material) were combined, concentrated in vacuo and was purified by crystallisation from CH3CN to give more of the title compound (40 mg, 12%) as a tan solid; 1H NMR: 2.09 (6H, s), 3.03-3.12 (1H, m), 3.58 (2H, t), 3.78 (3H, s), 3.96 (2H, t), 5.66 (1H, dd), 6.16 (1H, dd), 6.25 (1H, s), 6.46 (1H, dd), 7.07 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 7.48 (1H, s), 8.24 (1H, s), 8.27-8.31 (1H, br s), 8.31 (1H, s), 8.46 (1H, d), 9.22 (1H, s), 11.79 (1H, s); m/z: ES+ MH+ 518.23.

후처리

  1. temperatureto warm to r.t
  2. washThis solution was then washed with sat. NaHCO3 (200 mL)
  3. extractionthe aqueous wash solution was extracted with CH2Cl2 (2×100 mL)
  4. dry with materialThe combined organic solutions were dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customPurification by FCC
  7. washeluting with 0-5% 7N methanolic ammonia in CH2Cl2

출처 및 근거

ORD 기록
ord-fb84c9215b1a4b59972394f7acfc60fa
출처 데이터셋
uspto-grants-2015_02
특허 번호
US08946235B2

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