Trifluoroacetic acid → N-[2-[[[(4-Fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-(methoxymethyl)-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N',N'-trimethyl-ethanediamide

HRID 75731

反応式

HRID 75731 の反応式
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH2:21][CH2:22][C:17]([CH2:32][O:33]S(C5C=CC(C)=CC=5)(=O)=O)([CH2:18][CH2:19]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48].[C:49](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.F[B-](F)(F)F.C[O+](C)C.CC1C=CC=CN=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[C:14]3[C:20]4([N:23]([CH3:31])[C:24](=[O:30])[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])[CH2:19][CH2:18][C:17]([CH2:32][O:33][CH3:49])([CH2:22][CH2:21]4)[CH2:16][N:15]3[C:44](=[O:47])[C:45]=2[OH:46])=[O:11])=[CH:4][C:3]=1[CH3:48]

参加物

7

反応物 5

HCID 6422Trifluoroacetic acidHCID 79752-MethylpyridineHCID 988982,6-Di-tert-butyl-4-methylpyridineHCID 2735153Oxonium, trimethyl-, tetrafluoroborate(1-) (1:1)2 回HCID 86674319N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N',N'-trimethyl-ethanediamide

生成物 1

HCID 67960341N-[2-[[[(4-Fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-(methoxymethyl)-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N',N'-trimethyl-ethanediamide収率 3.79%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

To a solution of N-[2-[[[(4-fluoro-3-methylphenyl)methyl]amino]carbonyl]-6,7,8,9-tetrahydro-3-hydroxy-7-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-4-oxo-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl]-N,N′,N′-trimethyl-ethanediamide, Intermediate 28, (100 mg, 0.161 mmol) in CH2Cl2 (10 mL) was added 2,6-di-tert-butyl-4-methylpyridine (166 mg, 0.807 mmol) and trimethyloxonium tetrafluoroborate (48.5 mg, 0.807 mmol) and the mixture was stirred at room temp for 16 h. Another 5 equiv each of methylpyridine and trimethyloxonium tetrafluoroborate were added and the mixture was stirred at room temp for 5 h. The reaction was quenched by addition of 1N KHSO4 (30 mL) and stirred for 10 min and extracted with CH2Cl2 (25 mL×2). The combined extracts were dried, filtered and concentrated. The crude material was then dissolved in CH2Cl2 (1 mL) and treated with TFA (1 mL, 12.98 mmol) at room temp for 16 h. The mixture was concentrated in vacuuo and purified by preparative HPLC to afford the title compound (3.5 mg, 6.12 mmol, 3.79% yield) as a thick film. 1H NMR (500 MHz, CDCl3) δ: 12.15 (1H, br. s.), 9.59 (1H, br. s.), 7.24-7.27 (1H, m), 7.17-7.23 (1H, m), 6.90-6.97 (1H, m), 4.71 (1H, d, J=15.6 Hz), 4.58-4.65 (1H, m), 4.43-4.48 (1H, m), 3.51 (1H, d, J=15.6 Hz), 3.39-3.45 (1H, m), 3.20 (2H, d, J=5.8 Hz), 3.05 (3H, s), 3.02 (3H, s), 3.00 (3H, s), 2.27 (3H, d, J=1.8 Hz), 2.08-2.12 (3H, m), 1.76-1.83 (1H, m), 1.66-1.74 (2H, m), 1.38-1.49 (1H, m). LCMS (M+H)=544.5.

後処理

  1. stirringthe mixture was stirred at room temp for 5 h
  2. customThe reaction was quenched by addition of 1N KHSO4 (30 mL)
  3. stirringstirred for 10 min
  4. extractionextracted with CH2Cl2 (25 mL×2)
  5. customThe combined extracts were dried
  6. filtrationfiltered
  7. concentrationconcentrated
  8. dissolutionThe crude material was then dissolved in CH2Cl2 (1 mL)
  9. concentrationThe mixture was concentrated in vacuuo
  10. custompurified by preparative HPLC

出典と根拠

ORDレコード
ord-d29c2e97953849d588aeb51b5cdebb36
出典データセット
uspto-grants-2014_09
特許番号
US08835411B2

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