Acryloyl chloride → N-{5-[(5-Cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[3-dimethylaminoazetidin-1-yl]-4-methoxyphenyl}prop-2-enamide

HRID 1842648Notes

Reaction equation

HRID 1842648 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:33]2[CH2:36][CH:35]([N:37]([CH3:39])[CH3:38])[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[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[C:17]([C:29]#[N:30])=[CH:16][N:15]=2)[CH:12]=1>C(Cl)Cl.CO>[C:29]([C:17]1[C:18]([C:20]2[CH:21]=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:31][CH3:32])=[CH:9][C:8]([N:33]3[CH2:36][CH:35]([N:37]([CH3:38])[CH3:39])[CH2:34]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:30]

Participants

5

Reactant 2

HCID 13140Acryloyl chlorideHCID 866772872-{[5-Amino-4-(3-dimethylaminoazetidin-1-yl)-2-methoxyphenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile2×

Product 1

HCID 86677286N-{5-[(5-Cyano-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-2-[3-dimethylaminoazetidin-1-yl]-4-methoxyphenyl}prop-2-enamideYield 89%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

A solution of acryloyl chloride (0.025 mL, 0.31 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 2-{[5-amino-4-(3-dimethylaminoazetidin-1-yl)-2-methoxyphenyl]amino}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-5-carbonitrile (Intermediate 122, 136 mg, 0.30 mmol) in CH2Cl2 (15 mL), which was cooled in an ice bath to approximately 0° C. The mixture was stirred for 1 h, and was then diluted with iii CH2Cl2 (50 mL) and methanol (to fully dissolve suspension). This solution was then washed with sat. NaHCO3 (100 mL) which had been diluted with water (10 mL). The aqueous wash solution was then extracted with CH2Cl2 (2×50 mL) and 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 (136 mg, 89%) as a yellow solid; 1H NMR: 2.10 (6H, s), 3.05-3.13 (1H, m), 3.62 (2H, t), 3.74 (3H, s), 4.00 (2H, s), 5.67 (1H, d), 6.17 (1H, d), 6.27 (1H, s), 6.45 (1H, dd), 7.16 (1H, br s), 7.25 (1H, s), 7.42 (1H, br s), 7.95 (1H, br s), 8.68 (1H, s), 8.87 (1H, br s), 8.91 (1H, s), 9.28 (1H, s), 9.32 (1H, br s); m/z: ES+ MH+ 510.18.

Workup

  1. washThis solution was then washed with sat. NaHCO3 (100 mL) which
  2. additionhad been diluted with water (10 mL)
  3. extractionThe aqueous wash solution was then extracted with CH2Cl2 (2×50 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

Sources & evidence

ORD record
ord-e1f08ecc754f4a439b44e46d253c061c
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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