Diphenyl carbonate → [5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl ester

HRID 1500011Notes

Reaction equation

HRID 1500011 reaction equation
[F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[H-].[Na+].[C:20](=O)([O:28]C1C=CC=CC=1)[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCOC(C)=O>C1COCC1>[C:22]1([O:21][C:20](=[O:28])[NH:17][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[N:4]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1

Participants

6

Reactant 4

HCID 7597Diphenyl carbonateHCID 8857Ethyl AcetateHCID 24758Sodium hydrideHCID 578185745-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-amine

Product 1

HCID 57818876[5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl esterYield 21%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred mixture of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (0.20 g, 0.84 mmol) in dry THF (3 mL) at ice-bath temperature was added NaH (0.034 g of 60 wt. % suspension in mineral oil, 0.84 mmol). When bubbling ceased, the resulting mixture was transferred (dropwise) via cannula to an ice-cold, stirred mixture of diphenyl carbonate (1.8 g, 8.4 mmol) in dry THF (5 mL). The mixture was stirred overnight, poured into EtOAc, and washed with saturated aq. NH4Cl solution followed by brine solution. The EtOAc layer was separated, dried over Na2SO4, filtered, and evaporated. The crude material was purified on silica gel using a gradient of EtOAc and hexanes to give 0.063 g (21%) of [5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl]carbamic acid phenyl ester as a white solid: mp 129-131° C.; 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J=2.3 Hz, 1H), 7.43 (m, 5H), 7.30-7.20 (m, 2H), 7.02 (t, J=8.6 Hz, 2H), 5.38 (s, 2H); HPLC-MS (ESI) m/z 358 (M+H)+.

Workup

  1. customWhen bubbling
  2. stirringThe mixture was stirred overnight
  3. washwashed with saturated aq. NH4Cl solution
  4. customThe EtOAc layer was separated
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. customevaporated
  8. customThe crude material was purified on silica gel using a gradient of EtOAc and hexanes

Sources & evidence

ORD record
ord-92795e8ba4274f1bb8215349c4ef7b4f
Source dataset
uspto-grants-2015_12
Patent number
US09204653B2

Reaction notes

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