Acetonitrile → N-(2-{(3R)-3-Dimethylaminopyrrolidin-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 1842652Notes

Reaction equation

HRID 1842652 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:38])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:37])[CH2:9]1.CC#N>C(Cl)Cl>[CH3:38][N:7]([CH3:6])[C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=45)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:37][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1

Participants

5

Reactant 3

HCID 6342AcetonitrileHCID 13140Acryloyl chlorideHCID 866773454-[(3R)-3-Dimethylaminopyrrolidin-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 89414684N-(2-{(3R)-3-Dimethylaminopyrrolidin-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 42.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Procedure

A solution of acryloyl chloride (32 mg, 0.36 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-[(3R)-3-dimethylaminopyrrolidin-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 134, 152 mg, 0.34 mmol) in CH2Cl2 (15 mL), which was cooled in an ice/water bath. The solution was stirred for 10 minutes while cooled by the ice bath, and was then allowed to warm to r.t. then stirred for 1 h. The mixture was then diluted with CH2Cl2 and washed with sat. NaHCO3 and then brine. The organic solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave crude product (100 mg) as a beige solid after trituration with diethyl ether. CH3CN (˜3 mL) was then added to the crude product and the resulting slurry was stirred at 50° C. for 4 h. After cooling to r.t. the suspended solid was collected by filtration, washed with CH3CN and dried at 45° C. overnight to give the title compound (72 mg, 42%) as a yellow solid; 1H NMR: 1.68-1.81 (3H, m), 1.89-1.98 (2H, m), 2.03-2.11 (1H, m), 2.17 (6H, s), 2.66-2.74 (1H, m), 3.00-3.05 (2H, m), 3.13-3.21 (3H, m), 3.31-3.38 (1H, m), 3.86 (3H, s), 4.09 (2H, t), 5.70 (1H, dd), 6.21 (1H, dd), 6.48-6.56 (2H, m), 6.96 (1H, d), 7.72 (1H, s), 8.03 (2H, d), 8.27 (1H, d), 9.30 (1H, s); m/z: ES+ MH+ 503.67.

Workup

  1. temperaturewas cooled in an ice/water bath
  2. stirringthen stirred for 1 h
  3. washwashed with sat. NaHCO3
  4. dry with materialThe organic solution was then dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customPurification by FCC
  7. washeluting with 0-5% 7N methanolic ammonia in CH2Cl2
  8. customgave crude product (100 mg) as a beige solid after trituration with diethyl ether
  9. stirringthe resulting slurry was stirred at 50° C. for 4 h
  10. temperatureAfter cooling to r.t. the suspended solid
  11. filtrationwas collected by filtration
  12. washwashed with CH3CN
  13. customdried at 45° C. overnight

Sources & evidence

ORD record
ord-ea7197dad21c4b95a695c6a599e300cf
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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