Trimethylsilylacetylene → (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-6-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate

HRID 2175661Notes

Reaction equation

HRID 2175661 reaction equation
[NH2:1][C:2]1[C:3]2[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][CH:12]=3)=[C:9](Br)[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:37]([Si:39]([CH3:42])([CH3:41])[CH3:40])#[CH:38]>C1(C)C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:3]2[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][CH:12]=3)=[C:9]([C:38]#[C:37][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:8]([C@@H:25]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1

Participants

5

Reactant 2

HCID 66111TrimethylsilylacetyleneHCID 86719380(R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate

Product 1

HCID 86719399(R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-6-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of (R)-tert-butyl 3-(4-amino-6-bromo-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (9) (200 mg, 0.36 mmol), ethynyltrimethyl silane (184 mg, 1.87 mmol), Pd(PPh)3Cl2 (26 mg, 0.036 mmol), CuI (17 mg, 0.087 mmol) and TEA (0.26 mL, 1.87 mmol) in toluene (5 mL) was sealed in a microwave vile and purged with N2 three times. The resulting mixture was heated at 80° C. for 2 hr before diluted with EA (20 mL) and water (20 mL). The layers were separated. The organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by flash chromatography (silica gel, 0 to 100% EA in PE) to afford (R)-tert-butyl 3-(4-amino-5-(4-phenoxyphenyl)-6-((trimethylsilyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (110). The product was then dissolved in MeOH (5 mL) and KF was added to the solution. The resulting mixture was stirred at r.t. for 30 min and then concentrated in vacuo. The residue was diluted with DCM (10 mL) and water (10 mL). The layers were separated. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to afford (R)-tert-butyl 3-(4-amino-6-ethynyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (111) (70 mg, 39% yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 496.1.

Workup

  1. customwas sealed in a microwave vile
  2. custompurged with N2 three times
  3. additionbefore diluted with EA (20 mL) and water (20 mL)
  4. customThe layers were separated
  5. washThe organic phase was washed with brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. customto give the crude product which
  9. customwas purified by flash chromatography (silica gel, 0 to 100% EA in PE)

Sources & evidence

ORD record
ord-f7ad4d3cbf794d04997473daca558586
Source dataset
uspto-grants-2015_06
Patent number
US09062058B2

Reaction notes

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