Acryloyl chloride → N-(5-{[5-Cyano-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

HRID 1842636노트

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HRID 1842636 반응식
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[CH:9][C:10]([O:31][CH3:32])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:29]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]

참가 물질

5

반응물 3

HCID 13140Acryloyl chloride2회HCID 81531DiisopropylethylamineHCID 866772682-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile2회

생성물 1

HCID 86677267N-(5-{[5-Cyano-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide수율 21.6%

시약·촉매·용매 1

HCID 8028Tetrahydrofuran용매

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온도
0 °C

실험 절차

Acryloyl chloride (0.100 mL, 1M in THF, 0.1 mmol) was added dropwise to a fine slurry of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1H-indol-3-yl)pyrimidine-5-carbonitrile (Intermediate 99, 47 mg, 0.10 mmol) and DIPEA (0.027 mL, 0.16 mmol) in THF (2 mL) at −10° C. over a period of 2 minutes under N2. The mixture was then stirred at 0° C. for 10 minutes then allowed to warm to r.t. over 20 minutes. The mixture was then cooled again to −10° C. and further acryloyl chloride (0.06 mL, 1M in THF, 0.06 mmol) was added dropwise. The mixture was stirred at 0° C. for a further 10 minutes, then allowed to warm to r.t. over 20 minutes. The mixture was then concentrated in vacuo and the resulting reside was dissolved in CH2Cl2 (2 mL). This solution was washed with sat. NaHCO3 (1 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1.5-7% 7N methanolic ammonia in CH2Cl2 gave a residue that was washed with CH3OH (0.1 mL) and dried in air to give the title compound (11 mg, 20%) as a cream crystalline solid; 1H NMR: 2.28 (3H, s), 2.54-2.65 (4H, m), 2.93 (4H, s), 3.75 (3H, s), 5.71 (1H, d), 6.18 (1H, d), 6.64 (1H, dd), 6.91 (2H, m), 7.18 (1H, s), 7.47 (1H, d), 8.02 (1H, s), 8.52 (1H, s), 8.67 (1H, s), 9.04 (1H, s), 9.40 (1H, s), 11.99 (1H, s); m/z: ES+ MH+ 509.

후처리

  1. temperatureto warm to r.t. over 20 minutes
  2. temperatureThe mixture was then cooled again to −10° C.
  3. stirringThe mixture was stirred at 0° C. for a further 10 minutes
  4. temperatureto warm to r.t. over 20 minutes
  5. concentrationThe mixture was then concentrated in vacuo
  6. dissolutionthe resulting reside was dissolved in CH2Cl2 (2 mL)
  7. washThis solution was washed with sat. NaHCO3 (1 mL)
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. customPurification by FCC
  11. washeluting with 1.5-7% 7N methanolic ammonia in CH2Cl2
  12. customgave a residue that
  13. washwas washed with CH3OH (0.1 mL)
  14. customdried in air

출처 및 근거

ORD 기록
ord-c60db0dfc3a446cb9aa2f76276269c73
출처 데이터셋
uspto-grants-2015_02
특허 번호
US08946235B2

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