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

HRID 2175644Notes

Reaction equation

HRID 2175644 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.[CH3:37]B(O)O.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[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]([CH3:37])[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

6

Reactant 3

HCID 75806TricyclohexylphosphineHCID 139377Methylboronic Acid2×HCID 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 86719381(R)-tert-butyl 3-(4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylateYield 84.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °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) (375 mg, 0.70 mmol), methyl boronic acid (417 mg, 6.96 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), tricyclohexyl phosphine (PCy3) (39 mg, 0.14 mmol) and K3PO43H2O (556 mg, 2.09 mmol) in toluene (10.0 mL) was sealed in microwave tube. The reaction was purged with N2 before heated at 120° C. by microwave for 30 min. Another portion of methyl boronic acid (417 mg, 6.96 mmol) was introduced and the reaction was continued for additional 30 min. After cooled down to r. t., the reaction mixture was partitioned between DCM and water. The layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by column chromatographic (silica gel, 50% ethyl acetate in a mixture of petroleum ether and DCM (1:1)) to afford (R)-tert-butyl 3-(4-amino-6-methyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (10) (286 mg, 70% yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 486.3.

Workup

  1. customwas sealed in microwave tube
  2. customThe reaction was purged with N2
  3. temperatureAfter cooled down
  4. custom, the reaction mixture was partitioned between DCM and water
  5. customThe layers were separated
  6. extractionThe aqueous phase was extracted with DCM
  7. washThe combined organic layers were washed with brine
  8. dry with materialdried over Na2SO4
  9. concentrationconcentrated under reduced pressure
  10. customto give the crude product which
  11. customwas purified by column chromatographic (silica gel, 50% ethyl acetate
  12. additionin a mixture of petroleum ether and DCM (1:1))

Sources & evidence

ORD record
ord-bb9212c2d6484e70acdbc1c8b4a281b5
Source dataset
uspto-grants-2015_06
Patent number
US09062058B2

Reaction notes

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