Acryloyl chloride → N-[2-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl]prop-2-enamide

HRID 1842663Notes

Reaction equation

HRID 1842663 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH2:39])[CH2:11][CH2:12]2)[CH2:8]1>C1COCC1.C(Cl)Cl>[CH3:6][N:7]1[CH2:14][C@@H:13]2[C@@H:9]([N:10]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][C:24]4[N:29]=[C:28]([C:30]5[CH:31]=[N:32][N:33]6[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=56)[CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[NH:39][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11][CH2:12]2)[CH2:8]1

Participants

5

Reactant 2

HCID 13140Acryloyl chlorideHCID 866773154-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine2×

Product 1

HCID 86677314N-[2-[(3aR,6aR)-5-Methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-4-methoxy-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl]prop-2-enamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-15 °C

Procedure

A solution of acryloyl chloride (13 mg, 0.14 mmol) in THF (1 mL) was added dropwise to a stirred solution of 4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 160, 100 mg, 0.13 mmol) in THF (3 mL), which was cooled in an ice/CH3OH bath to approximately −15° C. The mixture was stirred for 1 h and allowed to warm to −0° C. The mixture was then diluted with CH2Cl2 (50 mL) and the resulting solution was washed with sat. NaHCO3 (50 mL). The aqueous solution was further extracted with CH2Cl2 (2×25 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo onto silica. Patrial purification by FCC, eluting with 0-3.5% 7N methanolic ammonia in CH2Cl2 provided some of the title compound. Further purification by FCC, eluting with 0-1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (33 mg, 49%) as a yellow solid; 1H NMR: 1.77 (1H, s), 1.94-2.15 (1H, m), 2.10 (3H, s), 2.29 (1H, d), 2.39-2.48 (1H, m), 2.87 (1H, s), 3.11-3.20 (1H, m), 3.33-3.42 (2H, m), 3.81 (3H, s), 4.26-4.34 (1H, m), 5.68 (1H, dd), 6.18 (1H, dd), 6.53 (1H, dd), 6.67 (1H, s), 7.04 (1H, td), 7.21 (1H, d), 7.36-7.43 (1H, m), 8.03 (1H, s), 8.08 (1H, s), 8.30 (1H, d), 8.42 (1H, d), 8.73-8.79 (2H, m), 9.41 (1H, s); m/z: ES+ MH+ 511.16.

Workup

  1. temperatureto warm to −0° C
  2. washthe resulting solution was washed with sat. NaHCO3 (50 mL)
  3. extractionThe aqueous solution was further extracted with CH2Cl2 (2×25 mL)
  4. dry with materialthe combined organic solutions were dried (MgSO4)
  5. concentrationconcentrated in vacuo onto silica
  6. customPatrial purification by FCC
  7. washeluting with 0-3.5% 7N methanolic ammonia in CH2Cl2

Sources & evidence

ORD record
ord-606800f86e854ac6930c817635461707
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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