Piperidine → tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(methyl)carbamate

HRID 409119Notes

Reaction equation

HRID 409119 reaction equation
[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[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.[CH3:36][N:37]([C:45]([CH3:49])([CH3:48])[CH:46]=O)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:49][C:45]([N:37]([CH3:36])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:46])[CH3:48])[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 3

HCID 8082PiperidineHCID 71757843tert-butyl N-methyl-N-(2-methyl-1-oxopropan-2-yl)carbamateHCID 86714506(S)-3-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile

Product 1

HCID 86714505tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(methyl)carbamateYield 18.3%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (236 mg, 0.5 mmol, 1 equiv) and tert-butyl methyl(2-methyl-1-oxopropan-2-yl)carbamate (2.01 g, 10 mmol, 20 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4A molecular sieves. The resulting mixture was stirred for 6 h at 110° C. The solids was filtered out, the filtrate was diluted with 50 mL of EA, washed with brine, dried over Na2SO4, concentrated. The residue was purified on silica gel column (EA to EA/MeOH 10/1) to give 60 mg of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(methyl)carbamate as white solid.

Workup

  1. filtrationThe solids was filtered out
  2. additionthe filtrate was diluted with 50 mL of EA
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated
  6. customThe residue was purified on silica gel column (EA to EA/MeOH 10/1)

Sources & evidence

ORD record
ord-ea9ea201610245ecb0b0141b64ffa68b
Source dataset
uspto-grants-2014_06
Patent number
US08759358B1

Reaction notes

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