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

HRID 705564Notes

Reaction equation

HRID 705564 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 temperatures 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-5128e8bc32474a2e9b3da441f2930280
Source dataset
uspto-grants-2015_11
Patent number
US09174970B2

Reaction notes

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