trans-2-Phenyl-1-cyclopropanecarbonyl chloride → trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2-phenyl-1-cyclopropanecarboxamide

HRID 432465

Reaction equation

HRID 432465 reaction equation
[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=2)=[C:16]([F:45])[CH:15]=1>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=[C:22]([C:17]3[C:16]([F:45])=[CH:15][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:19]([O:20][CH3:21])[CH:18]=3)[C:30]=12

Participants

5

Reactant 2

HCID 13656trans-2-Phenyl-1-cyclopropanecarbonyl chloride2×HCID 178488236HCID 178488236, compound

Product 1

HCID 20817217trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2-phenyl-1-cyclopropanecarboxamideYield 88.3%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6344DichloromethaneSolvent

Procedure

trans-2-Phenyl-1-cyclopropanecarbonyl chloride (32 mg, 0.176 mmol) in dichloromethane (0.3 mL) was added to a solution of trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.176 mmol) in pyridine (1.5 mL) at 0° C. After 5 minutes the ice-water bath was removed and the reaction mixture was stirred at room temperature for 3 hours. More trans-2-phenyl-1-cyclopropanecarbonyl chloride (32 mg, 0.176 mmol) was added to ensure the reaction went to completion. Solvent was evaporated and the residue was purified by flash column chromatography to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2-phenyl-1-cyclopropanecarboxamide (93 mg, 88%). 1H NMR (DMSO-d6) δ 1.35 (m, 1H), 1.50 (m, 3H), 1.98 (m, 6H), 2.19 (s, 3H), 2.37-2.68 (m, 11H), 3.87 (s, 3H), 4.64 (m, 1H), 7.09 (m, 1H), 7.21 (m, 3H), 7.31 (m, 2H), 8.21 (m, 2H), 9.82 (m, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+ =599.3, Rt=1.97 min.

Workup

  1. customAfter 5 minutes the ice-water bath was removed
  2. customSolvent was evaporated
  3. customthe residue was purified by flash column chromatography

Sources & evidence

ORD record
ord-6d787465c31142bbb6fe7ca31177b964
Source dataset
uspto-grants-2003_12
Patent number
US06660744B1

Linked notes

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