Acryloyl chloride → HCID 86677232, compound

HRID 1842616Notes

Reaction equation

HRID 1842616 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]3[CH:24]=[C:25]([NH2:38])[C:26]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][C:28]=3[O:29][CH3:30])[N:16]=2)=[CH:7]1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.O>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]3[C:28]([O:29][CH3:30])=[CH:27][C:26]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[C:25]([NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH:24]=3)[N:16]=2)=[CH:7]1

Participants

7

Reactant 3

HCID 13140Acryloyl chlorideHCID 81531DiisopropylethylamineHCID 86677233HCID 86677233, compound2×

Product 1

HCID 86677232HCID 86677232, compoundYield 15.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Acryloyl chloride (0.025 mL, 0.30 mmol) was added dropwise to N′-[4-(1H-indol-3-yl)-5-methylpyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 12, 135 mg, 0.30 mmol) and DIPEA (0.090 mL, 0.33 mmol) in CH2Cl2 (10 mL) and DMF (2 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 2 h. then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and extracted with CH2Cl2 (40 mL). The resulting organic solution was washed with sat. Na2CO3 (20 mL) and then sat. brine (20 mL). The solution was then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-5% 7M methanolic ammonia in CH2Cl2 gave crude product. Further purification by preparative HPLC (Waters SunFire column, 5μ it silica, 19 mm diameter, 100 mm length), eluting with decreasingly polar mixtures of water (containing 0.1% formic acid) and CH3CN, followed by HPLC (Waters XBridge Prep C18 OBD column, 5μ it silica, 19 mm diameter, 100 mm length), eluting with decreasingly polar mixtures of water (containing 1% NH3) and CH3CN, gave the title compound (23 mg, 15%) as a white solid; 1H NMR: 2.26 (3H, s), 2.37 (3H, s), 2.48-2.57 (4H, m), 2.87 (4H, t), 3.84 (3H, s), 5.70 (1H, d), 6.18 (1H, dd), 6.59 (1H, dd), 6.87 (1H, s), 7.05 (1H, dd), 7.15 (1H, t), 7.44 (1H, d), 7.83 (1H, s), 7.98 (1H, d), 8.22 (1H, s), 8.34 (1H, d), 8.49 (1H, s), 8.97 (1H, s), 11.68 (1H, s); m/z: ES+ MH+ 498.60.

Workup

  1. temperatureto warm to r.t
  2. extractionextracted with CH2Cl2 (40 mL)
  3. washThe resulting organic solution was washed with sat. Na2CO3 (20 mL)
  4. dry with materialThe solution was then dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customPurification by FCC
  7. washeluting with 1-5% 7M methanolic ammonia in CH2Cl2
  8. customgave crude product
  9. customFurther purification by preparative HPLC (Waters SunFire column, 5μ it silica, 19 mm diameter, 100 mm length)
  10. washeluting with decreasingly polar mixtures of water (containing 0.1% formic acid) and CH3CN
  11. washeluting with decreasingly polar mixtures of water (containing 1% NH3) and CH3CN

Sources & evidence

ORD record
ord-7592098b766b4183a877ead074da6cea
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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