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

HRID 1778429Notes

Reaction equation

HRID 1778429 reaction equation
[CH3:1][C:2]([N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)([CH3:5])[CH:3]=O.N1CCCC1.[Si](Cl)(C)(C)C.[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[N:30]([CH2:47][C@@H:48]3[CH2:52][CH2:51][CH2:50][N:49]3[C:53](=[O:57])[CH2:54][C:55]#[N:56])[N:31]=[C:32]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:35][C:34]=3[F:46])[C:25]=12>CC#N.C(Cl)Cl.O>[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[N:30]([CH2:47][C@@H:48]3[CH2:52][CH2:51][CH2:50][N:49]3[C:53]([C:54](=[CH:3][C:2]([CH3:5])([N:6]3[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[CH3:1])[C:55]#[N:56])=[O:57])[N:31]=[C:32]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:35][C:34]=3[F:46])[C:25]=12

Participants

8

Reactant 4

HCID 6397ChlorotrimethylsilaneHCID 31268PyrrolidineHCID 86714506(S)-3-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrileHCID 900010212-Methyl-2-(4-methylpiperazin-1-yl)propanal

Product 1

HCID 1236017872-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrileYield 71%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 2-methyl-2-(4-methylpiperazin-1-yl)propanal (108.3 mg, 0.6400 mmol) in MeCN (6 mL), was added pyrrolidine (0.11 mL, 1.27 mmol). The reaction mixture was cooled to 0° C., followed by the addition TMS-Cl (0.11 mL, 0.85 mmol). The ice bath was removed and the mixture stirred for 10 min before adding 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (100 mg, 0.210 mmol). The mixture was stirred for 3 h at room temperature, checking progress by TLC and LC-MS. To the mixture was added 15 ml water and extracted with dichloromethane. The combined organic layer was washed by brine, dried over by Na2SO4, filtered, and evaporated. The residues was loaded on TLC plate and purified using MeOH:CH2Cl2=9:100 to get pure product 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-4-methyl-4-(4-methylpiperazin-1-yl)pent-2-enenitrile (93 mg, 0.1491 mmol, 70.30 2% yield) as a light yellow powder. LC-MS (ES, m/z): 625 [M+H].

Workup

  1. customThe ice bath was removed
  2. stirringThe mixture was stirred for 3 h at room temperature
  3. extractionextracted with dichloromethane
  4. washThe combined organic layer was washed by brine
  5. dry with materialdried over by Na2SO4
  6. filtrationfiltered
  7. customevaporated
  8. custompurified

Sources & evidence

ORD record
ord-205199ebbc05427bba492e24e2d46f56
Source dataset
uspto-grants-2016_02
Patent number
US09266895B2

Reaction notes

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