Diisopropylethylamine → N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamide

HRID 1014875

反応式

HRID 1014875 の反応式
[Si]([O:8][C@H:9]([CH:33]1[CH2:37][CH:36]([O:38]CCC)[CH2:35][N:34]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24](C(OC)=O)[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.[CH3:49][O:50][C:51]([C:53]1[CH:54]=[C:55]([CH:59]=CC=1)C(O)=O)=O.CCN([CH:68]([CH3:70])[CH3:69])C(C)C.C[N:72]([C:74]([O:78]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C>ClCCl.CN(C=O)C.C(OCC)(=O)C>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:74]([N:72]3[CH2:59][CH2:55][CH2:54][C@@H:53]3[CH2:51][O:50][CH3:49])=[O:78])[CH:23]=2)[C@H:9]([OH:8])[C@H:33]2[CH2:37][C@@H:36]([O:38][CH2:70][CH2:68][CH3:69])[CH2:35][NH:34]2)[CH:13]=[C:14]([F:19])[CH:15]=1

参加物

9

反応物 5

HCID 81531DiisopropylethylamineHCID 6018803-(Methoxycarbonyl)benzoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67316024(2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 67316673tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

生成物 1

HCID 59346852N-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamide収率 88%

試薬・触媒・溶媒 3

HCID 6228Dimethylformamide溶媒HCID 6344Dichloromethane溶媒HCID 8857Ethyl Acetate溶媒

実験手順

Step 1 (B): 2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(methoxycarbonyl)benzoic acid (450 mg, 2.5 mmol) in dichloromethane (20 mL) and DMF (5 mL) was added Hunig's base (646 mg, 5.01 mmol) to make a clear solution and HATU (1.08 g, 2.84 mmol) was then added. After stirring for 20 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 1 (A), 900 mg, 1.67 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (200 mL) was added and the mixture was washed with H2O, dried and concentrated. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% to 80% EtOAc/Hexane step gradient) to give 1.02 g of the title compound (88% yield for 2 steps): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.06 (3H, s), 0.84 (9H, s), 0.86-0.89 (3H, m), 1.52 (9H, s), 2.00-2.05 (2H, m), 2.20 (1H, d, J=15 Hz), 2.68 (1H, dd, J=10, Hz), 2.92 (1H, m), 3.27-3.37 (3H, m), 3.76 (1H, dd, J=5, 10 Hz), 3.91 (3H, s), 3.99 (1H, s), 4.07-4.12 (2H, m), 4.64 (1H, m), 6.59 (1H, m), 6.78 (2H, d, J=5 Hz), 7.46-7.49 (1H, m), 8.08 (1H, d, J=10 Hz), 8.12 (1H, d, J=5 Hz), 8.29 (1H, brd s), 8.56 (1H, s). MS (ESI) (M+H)+ 691.33.

後処理

  1. additionwas then added
  2. stirringthe reaction mixture was stirred at rt overnight
  3. washthe mixture was washed with H2O
  4. customdried
  5. concentrationconcentrated
  6. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% to 80% EtOAc/Hexane step gradient)

出典と根拠

ORDレコード
ord-12b0370fa13348fc8beae71797c2392f
出典データセット
uspto-grants-2011_07
特許番号
US07981913B2

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