Tetrahydrofuran → 2-[2-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4 fluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol

HRID 1855468Notes

Reaction equation

HRID 1855468 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20](C(OCC)=O)[CH:19]=[C:18]([C:27]3[CH:32]=[CH:31][C:30]([C:33](F)([F:35])F)=[CH:29][CH:28]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C[Mg]Cl.[C:40](=O)([O-])[O-].[Na+].[Na+].[O:46]1[CH2:50][CH2:49]CC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:50]([OH:46])([CH3:49])[CH3:40])[CH:19]=[C:18]([C:27]3[CH:28]=[CH:29][C:30]([CH2:33][F:35])=[CH:31][CH:32]=3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1

Participants

5

Reactant 4

HCID 8028Tetrahydrofuran2×HCID 10340Sodium CarbonateHCID 44192331HCID 44192331, compoundHCID 178418332HCID 178418332, compound

Product 1

HCID 866909022-[2-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4 fluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-olYield 54%

Conditions

Temperature
0 °C

Procedure

To a solution of ethyl 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6-(4-trifluoromethyl-phenyl)-pyrimidine-4-carboxylate (597 mg, 1.2 mmol) in tetrahydro-furane (25 mL) was added at 0° C. over 2 min a 3 M solution of methylmagnesiumchloride in tetrahydrofurane (1.68 mL, 5.04 mmol). The reaction mixture was stirred at 0° C. for 15 min followed by 1.5 h at 20° C. The mixture was poured on saturated sodium carbonate solution (20 mL) and the product was extracted with ethyl acetate (80 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% methanol as eluent. Following a more liopophilic by-product (54 mg, example 175) the title compound was eluted and crystallized from dichloromethane/diethyl ether to give a white solid (314 mg, 54%). MS ISP (m/e): 484.4 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.21 (d, 2H), 7.82 (d, 1H), 7.77 (d, 2H), 7.66 (s, 1H), 7.36 (s, 2H), 7.22 (d, 1H), 7.10 (dd, 1H), 6.90 (s, 1H), 3.90 (s, 3H), 3.84 (br s, 1H), 2.31 (s, 3H), 1.56 (s, 6H).

Workup

  1. waitfollowed by 1.5 h at 20° C
  2. extractionthe product was extracted with ethyl acetate (80 mL)
  3. washThe organic layer was washed with brine (20 mL)
  4. dry with materialdried over sodium sulfate
  5. customevaporated under reduced pressure
  6. customThe residual material was purified by chromatography on silica gel
  7. washwas eluted
  8. customcrystallized from dichloromethane/diethyl ether

Sources & evidence

ORD record
ord-bbfad2b67b22473485cf1d66f73bae69
Source dataset
uspto-grants-2015_02
Patent number
US08962834B2

Reaction notes

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