Benzyl ((3R,4R)-4-fluoropyrrolidin-3-yl)carbamate → benzyl ((3R,4R)-4-fluoro-1-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)carbamate

HRID 928165Notes

Reaction equation

HRID 928165 reaction equation
F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]2[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=2)[N:3]=1.[F:21][C@@H:22]1[CH2:26][NH:25][CH2:24][C@H:23]1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[NH3:3].[CH2:30]([O:29][C:28](=[O:37])[NH:27][C@H:23]1[C@H:22]([F:21])[CH2:26][N:25]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[N:3]=2)[CH2:24]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1

Participants

4

Reactant 2

HCID 96884550Benzyl ((3R,4R)-4-fluoropyrrolidin-3-yl)carbamateHCID 1180736162-fluoro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine

Product 2

HCID 222AmmoniaHCID 118084953benzyl ((3R,4R)-4-fluoro-1-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)carbamateYield 82%

Conditions

Temperature
100 °C

Procedure

To the above solution of crude 2-fluoro-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine was added benzyl [(3R,4R)-4-fluoropyrrolidin-3-yl]carbamate (238 mg, 1 mmol). The resulting solution was heated at 100° C. (block temperature) and stirred for 14 hr. After cooling, the volatiles were removed and the residue was purified via flash chromatography (eluting with a gradient of 100% heptane to 100% ethyl acetate and then to 10% ammonia (7 N in methanol-90% ethyl acetate) to give the title compound as a light yellow solid (402 mg, 82% yield (over 2 steps)). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.62 (s, 1 H) 7.98 (s, 1 H) 7.91 (s, 1 H) 7.80 (d, J=5.75 Hz, 1 H) 7.71 (s, 1 H) 7.27-7.41 (m, 5 H) 4.98-5.30 (m, 3 H) 4.55-4.68 (m, 1 H) 4.16-4.34 (m, 1 H) 3.76-3.96 (m, 6 H) 3.64-3.71 (m, 1 H) 1.50 (d, J=6.72 Hz, 6 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −178.93 (br. s., 1F). m/z (APCI+) for C24H28FN9O2 494.2 (M+H)+. Chiral purity was determined as below (using racemic sample to compare):

Workup

  1. temperatureAfter cooling
  2. customthe volatiles were removed
  3. customthe residue was purified via flash chromatography (
  4. washeluting with a gradient of 100% heptane to 100% ethyl acetate

Sources & evidence

ORD record
ord-07ca75765a544daeb64f5753c146651c
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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