Acryloyl chloride → Osimertinib

HRID 1842637Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1842637
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[CH2:8][CH2:9][N:10]([CH3:37])[C:11]1[C:12]([NH2:36])=[CH:13][C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[C:15]([O:17][CH3:18])[CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:38][N:7]([CH3:6])[CH2:8][CH2:9][N:10]([CH3:37])[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[CH:23]=[CH:22][N:21]=2)=[CH:13][C:12]=1[NH:36][C:1](=[O:4])[CH:2]=[CH2:3]

Komponenten

5

Edukt 3

HCID 13140Acryloyl chlorideHCID 81531DiisopropylethylamineHCID 78358313Mutated EGFR-IN-12×

Produkt 1

HCID 71496458OsimertinibAusbeute 39,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel3×

Versuchsvorschrift

A solution of acryloyl chloride (34.5 mg, 0.38 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred mixture of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 170 mg, 0.38 mmol) and DIPEA (0.073 mL, 0.42 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH2Cl2 (25 mL) and washed with sat.NaHCO3 (50 mL). The aqueous washes were extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (75 mg, 39%) as a cream solid after trituration with diethyl ether; 1H NMR: 2.21 (6H, s), 2.29 (2H, t), 2.72 (3H, s), 2.89 (2H, t), 3.86 (3H, s), 3.92 (3H, s), 5.77 (1H, dd), 6.27 (1H, dd), 6.43 (1H, dd), 7.04 (1H, s), 7.15 (1H, t), 7.20-7.27 (2H, m), 7.53 (1H, d), 7.91 (1H, s), 8.24 (1H, d), 8.33 (1H, d), 8.68 (1H, s), 9.14 (1H, s), 10.22 (1H, s); m/z: ES+ MH+ 500.42.

Aufarbeitung

  1. temperaturewas cooled in an ice/water bath
  2. washwashed
  3. extractionThe aqueous washes were extracted with CH2Cl2 (2×25 mL)
  4. dry with materialThe combined organic solutions were dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customPurification by FCC
  7. washeluting with 0-4% 7N methanolic ammonia in CH2Cl2

Quellen und Nachweise

ORD-Eintrag
ord-1beb7b3a3f8b4fe1ba58ae7bd2bbc417
Quelldatensatz
uspto-grants-2015_02
Patentnummer
US08946235B2

Notizen zur Reaktion

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