Potassium Carbonate → ethyl 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoate

HRID 1508584노트

반응식

HRID 1508584 반응식
[F:1][C:2]([F:30])([F:29])[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][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.[C:54](=O)([O-])[O-].[K+].[K+]>C1COCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:30])([F:29])[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:38]4[CH:37]=[C:36]([CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:54])=[O:42])[CH:35]=[CH:34][C:33]=4[O:32][CH3:31])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

참가 물질

7

반응물 3

HCID 11430Potassium CarbonateHCID 57576268(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one2회HCID 67036621Methyl 3-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate2회

생성물 1

HCID 131734392ethyl 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoate수율 93.4%

시약·촉매·용매 3

HCID 178454861HCID 178454861, 화합물촉매HCID 962Water용매HCID 8028Tetrahydrofuran용매

실험 절차

A mixture of (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 32) (500 mg, 0.966 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (INTERMEDIATE 2) (370 mg, 1.107 mmol), potassium carbonate (1M aqueous) (3 ml, 3.00 mmol), and 1,1′-bis(di-t-butylphosphino)ferrocene palladium dichloride (94 mg, 0.145 mmol) in THF (5 ml) was stirred at RT under nitrogen overnight. The reaction was diluted with water and extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting EtOAc in hexanes to afford 582 mg of ethyl 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoate. 294 mg (0.456 mmol) of this ester was combined with LiOH (1M aqueous) (1 ml, 1.000 mmol) in THF (2 ml)/EtOH (0.5 ml) and stirred at RT under nitrogen overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic was dried over sodium sulfate and the solvent was evaporated under reduced pressure to afford 267 mg of 3-{3-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl]-4-methoxyphenyl}propanoic acid, 30 mg of which were combined with copper (spatula tip) and piperidine (5 ml, 50.5 mmol) and was heated at 150° C. for 5 hours in a sealed tube. The reaction was concentrated and purified by RP HPLC to afford the title compound. Mass spectrum (ESI) 666.2 (M+1). 1H NMR (500 MHz, CD3OD) (atropisomers) δ 7.96 (s, 1H); 7.88 (s, 2H); 7.30 (d, J=8.7 Hz, 1H); 7.20 (dd, J=2.2, 8.4 Hz, 1H); 7.02 (s, 1H); 6.95 (d, J=8.5 Hz, 1H); 6.73 (d, J=8.5 Hz, 1H); 5.76 (br s, 1H); 4.60 (br s, 1H); 3.49-4.34 (m, 9H); 2.87 (t, J=7.1 Hz, 2H); 2.57 (br s, 2H); 1.61-1.73 (m, 6H); 0.56 (br s, 3H).

후처리

  1. extractionextracted 3 times with ethyl acetate
  2. washThe combined organics were washed with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. customthe solvent was evaporated under reduced pressure
  6. customThe residue was purified by flash column chromatography on silica gel
  7. washeluting EtOAc in hexanes

출처 및 근거

ORD 기록
ord-9feffb6deecc4d2a8586455bf283824b
출처 데이터셋
uspto-grants-2015_12
특허 번호
US09221834B2

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