Chlorotrimethylsilane → 2-[2-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile

HRID 1778442Notes

Reaction equation

HRID 1778442 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30](=[O:34])[CH2:31][C:32]#[N:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:35][C:36]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)([CH3:39])[CH:37]=O.N1CCCC1.[Si](Cl)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3[C:30]([C:31](=[CH:37][C:36]([CH3:39])([N:40]3[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]3)[CH3:35])[C:32]#[N:33])=[O:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12

Participants

6

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 31268PyrrolidineHCID 900010212-Methyl-2-(4-methylpiperazin-1-yl)propanalHCID 900011903-[2-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile

Product 1

HCID 1317323722-[2-[[4-Amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrileYield 14.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a mixture of 3-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidin-1-yl]-3-oxo-propanenitrile (100.6 mg, 0.220 mmol) and 2-methyl-2-(4-methylpiperazin-1-yl)propanal (118.2 mg, 0.660 mmol) in DCM (5 mL) in an ice bath was added pyrrolidine (0.11 mL, 1.32 mmol) and TMS-Cl (0.11 mL, 0.880 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was loaded on silca gel plate, purified by MeOH:CH2Cl2 to obtain 2-[2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile (19 mg) as a white powder. LC-MS (ES, m/z): 610 [M+H]

Workup

  1. customThe ice bath was removed
  2. customThe crude reaction mixture
  3. custompurified by MeOH

Sources & evidence

ORD record
ord-35d0224698be4bfd96ea11db11fd0e4b
Source dataset
uspto-grants-2016_02
Patent number
US09266895B2

Reaction notes

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