Potassium Carbonate → Methyl 5'-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylthio)pyrimidin-5-yl]-2'-fluoro-4'-methoxy-2-methylbiphenyl-4-carboxylate

HRID 604687Notes

Reaction equation

HRID 604687 reaction equation
[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][C:34]=1[C:50]1[CH:55]=[CH:54][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:52][C:51]=1[CH3:60].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Cl-].[Na+].O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:36]4[C:37]([O:39][CH3:40])=[CH:38][C:33]([F:32])=[C:34]([C:50]5[CH:55]=[CH:54][C:53]([C:56]([O:58][CH3:59])=[O:57])=[CH:52][C:51]=5[CH3:60])[CH:35]=4)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 57576287(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one2×HCID 67057767Methyl 2'-fluoro-4'-methoxy-2-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate

Product 1

HCID 86627638Methyl 5'-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylthio)pyrimidin-5-yl]-2'-fluoro-4'-methoxy-2-methylbiphenyl-4-carboxylate

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 57417360Sodium chloride; waterSolvent

Procedure

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylthio)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 38, 158.7 mg, 0.299 mmol), methyl 2′-fluoro-4′-methoxy-2-methyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-carboxylate (144 mg, 0.359 mmol), K2CO3 (0-329 mL, 0.658 mmol), 1,1′-bis(diphenylphosphino) ferrocene-palladium dichloride dichloromethane adduct (36.7 mg, 0.045 mmol) and 1,4-dioxane (7 mL) were sealed in a microwave vessel and subjected to microwave irradiation at 140° C. for 20 min. LCMS trace of aliquot indicated completion of reaction. The reaction crude was combined with Crude-D1 and Crude-D2. The combined crude mixture was worked up with brine, extracted with EtOAc, dried (Na2SO4), filtered and evaporated to afford a dark mixture. The resulting dark mixture was purified by flash chromatography (SiO2, Biotage 40M cartridge). The column was eluted with a EtOAc/hexanes gradient mixture (0% to 30%). Related fractions were pooled and evaporated into 256 mg of yellow glass. TLC and LCMS trace indicated this yellow glass was not pure. The yellow glass was purified by preparative TLC (silica gel) developed with a EtOAc/hexanes mixture (30% EtOAc/hex, v/v) to give a yellow glass of 175 mg. This yellow glass was further purified by preparative TLC (silica gel, EtOAc/CH2Cl2, 2.5%, v/v) to give a yellow glass as the titled compound. LCMS calc.=723.16; found=724.03 (M+H)+.

Workup

  1. customirradiation at 140° C. for 20 min
  2. customLCMS trace of aliquot indicated completion of reaction
  3. customThe reaction crude
  4. extractionextracted with EtOAc
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. customevaporated
  8. customto afford a dark mixture
  9. customThe resulting dark mixture was purified by flash chromatography (SiO2, Biotage 40M cartridge)
  10. washThe column was eluted with a EtOAc/hexanes gradient mixture (0% to 30%)
  11. customevaporated into 256 mg of yellow glass
  12. customThe yellow glass was purified by preparative TLC (silica gel)
  13. customto give a yellow glass of 175 mg
  14. customThis yellow glass was further purified by preparative TLC (silica gel, EtOAc/CH2Cl2, 2.5%, v/v)

Sources & evidence

ORD record
ord-2cb336fbd2ec4dd4943d29324c3e3f2e
Source dataset
uspto-grants-2011_03
Patent number
US07910592B2

Reaction notes

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