Phosgene → (R)-2-amino-6-chloro-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one

HRID 2074176Notes

Reaction equation

HRID 2074176 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C@H:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:21].[C:22](Cl)(Cl)=[O:23]>C1COCC1.C1(C)C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]2[C:3]([NH:21][C:22](=[O:23])[N:9]2[C@H:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[O:13][CH2:12][CH2:11]2)=[C:2]([Cl:1])[N:7]=1

Participants

5

Reactant 2

HCID 6371Phosgene2×HCID 57612657(R)-6-chloro-N4-(8-fluorochroman-4-yl)pyrimidine-2,4,5-triamine

Product 1

HCID 57612682(R)-2-amino-6-chloro-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-oneYield 80%

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8028TetrahydrofuranSolvent3×

Procedure

To a solution of (R)-6-chloro-N4-(8-fluorochroman-4-yl)pyrimidine-2,4,5-triamine (0.9 g, 2.91 mmol) in 900 mL of anhydrous THF at −78° C. under Ar was added dropwise, over 20 min, a solution of phosgene in THF (2.6 mL of a 20% solution of phosgene in toluene, 4.94 mmol, 1.7 equiv., diluted with 26 mL of anhydrous THF). The reaction mixture was left to gradually warm up to room temperature over 16 h. It was purged with air for 30 min. The solvent was then removed in vacuo, and the residue was taken in ethyl acetate/saturated aqueous NaHCO3. The layers were separated, and the aqueous layer extracted with ethyl acetate three times. The combined organic extracts were put together, dried (anhydrous Na2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica gel, gradual elution with 6/1 to 4/1 methylene chloride/ethyl acetate) to give 0.78 g (80% yield) of the desired product as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 7.13-7.06 (m, 1H), 6.90-6.82 (m, 1H), 6.75-6.72 (m, 1H), 5.92-5.82 (m, 1H), 4.80-4.73 (m, 1H), 4.50-4.42 (m, 1H), 3.20-3.05 (m, 1H), 2.42-2.30 (m, 1H); MS (EI) m/z 336.3 (MH)+.

Workup

  1. waitThe reaction mixture was left
  2. customIt was purged with air for 30 min
  3. customThe solvent was then removed in vacuo
  4. customThe layers were separated
  5. extractionthe aqueous layer extracted with ethyl acetate three times
  6. dry with materialdried (anhydrous Na2SO4)
  7. customthe solvent removed in vacuo
  8. customThe residue was purified by flash chromatography (silica gel, gradual elution with 6/1 to 4/1 methylene chloride/ethyl acetate)

Sources & evidence

ORD record
ord-658a66bf40264490a8cd357fdcaa5f7e
Source dataset
uspto-grants-2011_04
Patent number
US07919490B2

Reaction notes

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