Formic Acid → N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide

HRID 1712830ノート

反応式

HRID 1712830 の反応式
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:22])([F:21])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)[NH2:9])=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26].[CH:28](OC(=O)C)=[O:29].C(OC(=O)C)(=O)C.C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][C:17]([F:21])([F:22])[CH:18]([F:20])[F:19])[CH:13]=[C:12]([F:23])[CH:11]=2)[NH:9][CH:28]=[O:29])=[CH:4][C:3]=1[O:24][CH:25]([CH3:27])[CH3:26]

参加物

6

反応物 4

HCID 284Formic AcidHCID 7918Acetic AnhydrideHCID 75269Acetic-formic anhydrideHCID 59458943(4-Fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanamine

生成物 1

HCID 86613065N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide収率 85%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

To a solution of (4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methanamine (2.8 g, 7.1 mmol) in CH2Cl2 (30 mL) at 0° C. was added acetic formic anhydride (2.8 mL, formed by heating a 2:1 v/v ratio of acetic anhydride and formic acid at 60° C. for 2 h). The reaction mixture was allowed to warm to room temperature and stirred for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by ISCO (120 g silica gel column, 0 to 60% EtOAc/hexane over 60 min gradient) to give N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide (2.56 g, 85% yield) as a colorless oil. LCMS: RT=1.99 min [M+H] 422.0 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm). To a solution of N-((4-fluoro-3-isopropoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)formamide (225 mg, 0.53 mmol) in THF (2 mL) at 0° C. was added Et3N (0.4 mL, 2.9 mmol) followed by phosphorous oxychloride (74 μL, 0.80 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction mixture was diluted with ice water (15 mL) and extracted with Et2O (3×15 mL). The combined organic layers were washed with sat. NaCl (20 mL), dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by ISCO (12 g silica gel column, 0-50% EtOAc/hexane over 30 min) to yield 1-fluoro-4-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(isocyano)methyl)-2-isopropoxybenzene (143 mg, 67% yield) as a pale yellow oil. LCMS: RT=2.13 min [M−NC] 377 (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.07-7.13 (1H, m), 6.91-7.03 (4H, m), 6.84-6.86 (1H, m), 5.78-6.04 (1H, m), 5.82 (1H, s), 4.54 (1H, ddd, J=11.97, 6.15, 6.04 Hz), 1.35 (6H, t, J=5.05 Hz).

後処理

  1. customformed
  2. concentrationThe reaction mixture was concentrated under reduced pressure
  3. customthe residue was purified by ISCO (120 g silica gel column, 0 to 60% EtOAc/hexane over 60 min gradient)

出典と根拠

ORDレコード
ord-e0a22c49f6bb4e0aace5ecf02d5a27ca
出典データセット
uspto-grants-2010_09
特許番号
US07790770B2

反応ノート

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