Dimethylformamide → (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

HRID 928469Notes

Reaction equation

HRID 928469 reaction equation
[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]([NH2:27])=O)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CN(C)C=O.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>[Cl-].[Na+].O.C(OCC)(=O)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24][C:25]#[N:27])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 6420Trichloroacetyl chlorideHCID 8471TriethylamineHCID 59420152(R)-(4-(1-(3-Amino-1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate

Product 1

HCID 59420145(R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalateYield 70.2%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
2.5 °C

Procedure

Method A. To a 50 mL round bottom flask equipped with a stir bar and the nitrogen inlet was charged (R)-(4-(1-(3-amino-1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-11, 413 mg, 0.942 mmol), N,N-dimethylformamide (DMF, 10 mL, 129 mmol) and triethylamine (TEA, 0.525 mL, 3.77 mmol, 4.0 equiv) at room temperature. The resulting mixture was then cooled to 0-5° C. in an ice bath before trichloroacetyl chloride (0.315 mL, 2.82 mmol, 3.0 equiv) was added drop wise via a syringe at room temperature. The resulting reaction mixture was stirred at 0-5° C. for 90 min. When TLC and HPLC showed that the reaction was deemed complete, the reaction mixture was treated with ethyl acetate (EtOAc, 25 mL) and 20% aqueous brine (20 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (EtOAc, 2×25 mL). The combined organic extracts were washed with 20% aqueous brine (35 mL), dried over magnesium sulfate (MgSO4), filtered, and concentrated under reduced pressure. The residual brown oily crude product was purified by flash chromatography (SiO2, 0 to 50% ethyl acetate/hexane gradient elution) to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-12, 278 mg, 396.1 mg theoretical, 70.2% yield) as the light oil, which was solidified upon standing at room temperature in vacuum. For (R)-12: achiral purity (99.1 area % by HPLC detected at 220 nm); chiral purity (99.6 area % by chiral HPLC; 99.2% ee); 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.84 (s, 1H), 8.78 (s, 1H), 8.39 (s, 1H), 7.74 (d, 1H, J=3.7 Hz,), 7.11 (d, 1H, J=3.8 Hz), 6.23 (s, 2H), 4.53 (ddd, 1H, J=9.9, 9.6, 4.2 Hz), 3.26 (dd, 1H, J=17.4, 9.9 Hz), 3.19 (dd, 1H, J=17.2, 4.3 Hz), 2.41 (m, 1H), 1.87-1.13 (m, 8H), 1.07 (s, 9H); C23H28N6O2 (MW, 420.51), LCMS (EI) m/e 421.4 (M++H).

Workup

  1. customTo a 50 mL round bottom flask equipped with a stir bar
  2. additionwas added drop wise via a syringe at room temperature
  3. customThe resulting reaction mixture
  4. customThe two layers were separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (EtOAc, 2×25 mL)
  6. washThe combined organic extracts were washed with 20% aqueous brine (35 mL)
  7. dry with materialdried over magnesium sulfate (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residual brown oily crude product was purified by flash chromatography (SiO2, 0 to 50% ethyl acetate/hexane gradient elution)

Sources & evidence

ORD record
ord-07fb4523248c47828ae63f5c27a50ffa
Source dataset
uspto-grants-2016_03
Patent number
US09290506B2

Reaction notes

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