1-Bromo-4,5-difluoro-2-methoxybenzene → (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone

HRID 1371641Notes

Reaction equation

HRID 1371641 reaction equation
Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.CON(C)[C:20]([C:22]1[C:23]([NH2:31])=[N:24][C:25]([S:28][CH2:29][CH3:30])=[N:26][CH:27]=1)=[O:21]>CCCCC.O1CCCC1.O1CCCC1>[NH2:31][C:23]1[C:22]([C:20]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[O:10][CH3:11])=[O:21])=[CH:27][N:26]=[C:25]([S:28][CH2:29][CH3:30])[N:24]=1

Participants

6

Reactant 3

HCID 27362621-Bromo-4,5-difluoro-2-methoxybenzeneHCID 119748325-Pyrimidinecarboxamide, 4-amino-2-(ethylthio)-N-methoxy-N-methyl-HCID 178418339Butyllithium

Product 1

HCID 11974838(4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 21183376Pentane tetrahydrofuranSolvent

Conditions

Temperature
-72 °C

Procedure

A solution of 2-bromo-4,5-difluoro-anisole (1.95 g, 8.75 mmol, Astatech) in a mixture of pentane/tetrahydrofuran (5 mL/17 mL) was cooled to −72° C. and treated with n-butyl lithium (2.5 M in hexane, 3.6 mL, 9.0 mmol). After stirring for 10 minutes, a solution of 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (0.78 g, 3.21 mmol, Example 1) in tetrahydrofuran (3 mL) was added. The temperature was slowly raised to −35° C. for ˜2 hours. The reaction was quenched at −35° C. with 5% aqueous ammonium chloride solution and the mixture was diluted with ethyl acetate/hexane (100 mL). The organic phase was separated, washed with 1:1 water/saturated aqueous sodium chloride solution and dried (Na2SO4). The residue after solvent removal was purified by HPLC chromatography (Waters Prep 500 eluting with 35% ethyl acetate/hexane) to give, in approximately 1:1 ratio, the two positional isomers (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone identical to material prepared in Example 102, and (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone as a white solid after evaporation. HRMS, observed: 326.0772; Calcd for M+: 326.0770.

Workup

  1. temperatureThe temperature was slowly raised to −35° C. for ˜2 hours
  2. customThe reaction was quenched at −35° C. with 5% aqueous ammonium chloride solution
  3. additionthe mixture was diluted with ethyl acetate/hexane (100 mL)
  4. customThe organic phase was separated
  5. washwashed with 1:1 water/saturated aqueous sodium chloride solution
  6. dry with materialdried (Na2SO4)
  7. customThe residue after solvent removal
  8. customwas purified by HPLC chromatography (Waters Prep 500 eluting with 35% ethyl acetate/hexane)
  9. customto give, in approximately 1:1 ratio
  10. customthe two positional isomers (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone identical to material prepared in Example 102, and (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone as a white solid after evaporation

Sources & evidence

ORD record
ord-bc4b501cc735403d8591f27668f496d9
Source dataset
uspto-grants-2007_01
Patent number
US07157455B2

Reaction notes

Loading…