Water → 2-((trans)-3-amino-4-fluoropyrrolidin-1-yl)-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine

HRID 928166Notes

Reaction equation

HRID 928166 reaction equation
[F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:8]=2)[CH2:4][C@H:3]1[NH:26]C(=O)OCC1C=CC=CC=1.C([O-])=O.[NH4+].O>C(O)C>[NH2:26][C@H:3]1[C@H:2]([F:1])[CH2:6][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:8]=2)[CH2:4]1

Participants

5

Reactant 3

HCID 962WaterHCID 2723923Ammonium formateHCID 118084953benzyl ((3R,4R)-4-fluoro-1-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)carbamate

Product 1

HCID 1180736782-((trans)-3-amino-4-fluoropyrrolidin-1-yl)-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amineYield 96%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A mixture of benzyl ((3R,4R)-4-fluoro-1-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)carbamate (390 mg, 0.8 mmol), ammonium formate (514 mg, 8 mmol) in ethanol (20 mL) was degassed for 3 min and 10%-Pd/C (50 mg) was then added. The reaction was stirred and heated to gentle reflux for 45 min. The catalyst was removed by filtration and washed well with ethanol (40 mL). The combined liquors were concentrated to give a residue, which was taken into water (5 mL) and extracted with DCM-isopropanol (9:1, 2×70 mL). The combined organic extracts were washed with saturated NaHCO3 (5 mL), dried over Na2SO4 and evaporated to give the title compound as a light yellow solid (272 mg, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (s, 1 H) 8.00 (s, 2 H) 7.90 (s, 2 H) 7.73 (s, 1 H) 4.89-5.08 (m, 1 H) 4.56-4.66 (m, 1 H) 3.86-4.00 (m, 1 H) 3.81-3.85 (m, 3 H) 3.58-3.80 (m, 3 H) 3.53 (d, J=11.13 Hz, 1 H) 1.51 (d, J=6.72 Hz, 6 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −177.42 (s, 1F). m/z (APCI+) for C16H22FN9 360.2 (M+H)+. Chiral purity was determined as below (using racemic sample to compare):

Workup

  1. customwas degassed for 3 min
  2. addition10%-Pd/C (50 mg) was then added
  3. temperatureheated
  4. temperatureto gentle reflux for 45 min
  5. customThe catalyst was removed by filtration
  6. washwashed well with ethanol (40 mL)
  7. concentrationThe combined liquors were concentrated
  8. customto give a residue, which
  9. extractionextracted with DCM-isopropanol (9:1, 2×70 mL)
  10. washThe combined organic extracts were washed with saturated NaHCO3 (5 mL)
  11. dry with materialdried over Na2SO4
  12. customevaporated

Sources & evidence

ORD record
ord-38afd8a6515d4ec7a42db82ecfb48ea3
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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