Acryloyl chloride → N-{4-Methoxy-2-[8-methyl-2,8-diazaspiro[3.4]octan-2-yl]-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

HRID 1842664Notes

Reaction equation

HRID 1842664 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)[CH:28]=[CH:27][N:26]=1>C(Cl)Cl.CO>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=34)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:15][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:17]2)[CH:13]=1

Participants

5

Reactant 2

HCID 13140Acryloyl chlorideHCID 866773174-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N'-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine2×

Product 1

HCID 86677316N-{4-Methoxy-2-[8-methyl-2,8-diazaspiro[3.4]octan-2-yl]-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamideYield 52%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution of acryloyl chloride (0.766 mL, 0.77 mmol, 1.0 M in CH2Cl2) was added dropwise over 10 minutes to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 162, 333 mg, 0.73 mmol) in CH2Cl2 (6 mL), which was cooled in an ice/CH3OH bath. The mixture was then stirred for 0.5 h, then diluted with 10% CH3OH in CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-10% methanolic ammonia in CH2Cl2 gave the title compound (193 mg, 52%) as an beige solid after trituration with diethyl ether; 1H NMR: 1.69 (2H, dt), 2.03-2.08 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.65 (2H, d), 3.83 (3H, s), 3.94 (2H, d), 5.68 (1H, dd), 6.19 (1H, dd), 6.25 (1H, s), 6.47 (1H, dd), 7.06 (1H, td), 7.19 (1H, d), 7.44 (1H, dd), 7.67 (1H, s), 7.98 (1H, s), 8.29 (1H, d), 8.47 (1H, d), 8.75 (1H, s), 8.78 (1H, d), 9.25 (1H, s); m/z: ES+ MH+ 511.34.

Workup

  1. temperaturewas cooled in an ice/CH3OH bath
  2. washThe resulting solution was washed with sat. NaHCO3
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customPurification by FCC
  6. washeluting with 1-10% methanolic ammonia in CH2Cl2

Sources & evidence

ORD record
ord-da0548d1707d4d22ad6d690e75523667
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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