Acryloyl chloride → N-(2-{3-Dimethylaminoazetidin-1-yl}-4-methoxy-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

HRID 1842654Notes

Reaction equation

HRID 1842654 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:36])[CH2:9]1>C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:36][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1

Participants

4

Reactant 2

HCID 13140Acryloyl chlorideHCID 866772974-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine2×

Product 1

HCID 86677296N-(2-{3-Dimethylaminoazetidin-1-yl}-4-methoxy-5-{[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamideYield 46%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of acryloyl chloride (22.5 mg, 0.25 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 139, 108 mg, 0.25 mmol) in CH2Cl2 (12 mL), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while being cooled by the bath, was then allowed to warm to r.t. and was then stirred for 1 h. The mixture was then diluted with CH2Cl2 and washed with sat. NaHCO3, brine and was then dried (MgSO4). Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (56 mg, 46%) as a brown solid after trituration with diethyl ether; 1H NMR: 1.75-1.82 (2H, m), 1.90-1.97 (2H, m), 2.08 (6H, s), 2.98-3.09 (3H, m), 3.54 (2H, t), 3.85 (3H, s), 3.93 (2H, t), 4.09 (2H, t), 5.69 (1H, dd), 6.18-6.25 (2H, m), 6.49 (1H, dd), 6.95 (1H, d), 7.70 (1H, s), 7.89 (1H, s), 8.03 (1H, s), 8.26 (1H, d), 9.24 (1H, s); m/z: ES+ MH+ 489.63.

Workup

  1. temperaturewas cooled in an ice/water bath
  2. temperaturewhile being cooled by the bath
  3. stirringwas then stirred for 1 h
  4. washwashed with sat. NaHCO3, brine
  5. dry with materialwas then dried (MgSO4)
  6. customPurification by FCC
  7. washeluting with 0-5% 7N methanolic ammonia in CH2Cl2

Sources & evidence

ORD record
ord-85928c00298141ffbe2a5a9f2a440692
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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