Tetrahydrofuran → methyl 3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoate

HRID 529729ノート

反応式

HRID 529729 の反応式
[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4Br)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59])=[CH:52][C:51]=1B1OC(C)(C)C(C)(C)O1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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].O>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:55]4[C:50]([O:49][CH3:48])=[CH:51][CH:52]=[C:53]([CH2:56][CH2:57][C:58]([O:60][CH3:61])=[O:59])[CH:54]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

参加物

8

反応物 4

HCID 8028TetrahydrofuranHCID 62657Potassium Phosphate, TribasicHCID 67036621Methyl 3-(4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate2 回HCID 86682295(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-[2-bromo-5-(trifluoromethyl)phenyl]tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-3-one

生成物 1

HCID 71526552methyl 3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoate収率 90.9%

試薬・触媒・溶媒 3

HCID 167845palladium(II) acetate触媒HCID 12976736Bis(ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane);iron(2+)触媒HCID 962Water溶媒

反応条件

温度
62 °C

実験手順

To Intermediate B2 (30 mg, 0.044 mmol) was added THF (2 mL), water (0.1 mL), tribasic potassium phosphate (45.3 mg, 0.213 mmol), methyl 3-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (51.3 mg, 0.16 mmol) (Intermediate H), palladium(II) acetate (1.2 mg, 5.34 mmol), and 1,1′-bis(di-tert-butylphosphino)ferrocene (2.53 mg, 5.34 μmol). The system was flushed with nitrogen gas and was heated at 62° C. overnight. The reaction was diluted with ethyl acetate:hexanes (1:2, 10 mL) and was partitioned with water (10 mL). The organic was dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC to yield methyl 3-[2′-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanoate (27 mg, 0.04 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 1.2:1 ratio. 1H NMR (500 MHz, CDCl3) δ7.87 (s, 1H), 7.81 (s, 2H), 7.75 (s, 1H, major rotamer), 7.73 (s, 1H, minor rotamer) 7.6 (m, 1H) 6.8-7.3 (m, 4H), 6.06 (d, J=7.9 Hz, 1H, major rotamer), 6.06 (d, J=7.9 Hz, 1H, major rotamer), 6.01 (d, 1H, minor rotamer), 5.12 (m, 1H, major rotamer), 4.98 (m, 1H, minor rotamer), 4.1 (m, 1H), 3.84 (s, 3H, major rotamer), 3.68 (s, 3H), 3.67 (s, 3H) 3.62 (s, 3H, minor rotamer), 2.9 (m, 2H), 2.6 (m, 2H), 0.9-1.7 (m, 4H). MS ESI calc'd. for C32H27F9NO5 [M+H]+ 676.2, found 676.4. RTA (95% HS): 296 nM

後処理

  1. customThe system was flushed with nitrogen gas
  2. additionThe reaction was diluted with ethyl acetate:hexanes (1:2, 10 mL)
  3. customwas partitioned with water (10 mL)
  4. dry with materialThe organic was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude product was purified by reverse phase HPLC

出典と根拠

ORDレコード
ord-5033a65e38414d709efa5cb683a1e2dd
出典データセット
uspto-grants-2016_05
特許番号
US09346825B2

反応ノート

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