N-Methylbutylamine → N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N1,5-dimethylisophthalamide

HRID 20962ノート

反応式

HRID 20962 の反応式
[Si]([O:8][C@H:9]([C@H:40]1[CH2:44][C@@H:43]([O:45][CH2:46][CH2:47][CH3:48])[CH2:42][N:41]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:39])[C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([C:29]([N:31]2[CH2:35]C[CH2:33][C@@H:32]2COC)=[O:30])[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.[C:56](NC1C=C(C=C(C)C=1)C(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)=O)(=O)[C:57]1C=CC=CC=1.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=C(C)C=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCCC>ClCCl>[CH2:32]([N:31]([CH3:35])[C:29](=[O:30])[C:24]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([C:21]([NH:20][C@@H:10]([CH2:11][C:12]2[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=2)[C@H:9]([OH:8])[C@H:40]2[CH2:44][C@@H:43]([O:45][CH2:46][CH2:47][CH3:48])[CH2:42][NH:41]2)=[O:39])[CH:23]=1)[CH2:33][CH2:56][CH3:57]

参加物

8

反応物 6

HCID 8068N-MethylbutylamineHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 593468483-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acidHCID 67316523(2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylateHCID 67316677(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-methylbenzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

生成物 1

HCID 68494235N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R,4R)-4-propoxypyrrolidin-2-yl)propan-2-yl)-N1,5-dimethylisophthalamide収率 85%

試薬・触媒・溶媒 1

HCID 6344Dichloromethane溶媒

実験手順

Step 9 (A): (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 26 mg, 0.037 mmol) in dichloromethane (1 mL) was added Hunig's base (15 mg, 0.114 mmol) to make a clear solution and HATU (19 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added methylbutylamine (5 mg, 0.057 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient) to give 24 mg of the title compound (85% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.06 (3H, s), 0.72-0.97 (15H, m), 1.12 (1H, m), 1.36-1.53 (11H, m), 1.61 (1H, m), 1.78 (2H, s), 2.05 (1H, m), 2.19 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.91-2.95 (3H, m), 3.04 (1H, s), 3.21 (1H, m), 3.27-3.36 (3H, m), 3.50 (1H, m), 3.76 (1H, m), 3.98 (1H, m), 4.03-4.06 (1H, m), 4.10-4.12 (1H, m), 4.56 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.29 (1H, d, J=10 Hz), 7.64 (1H, s), 7.71 (1H, s), 8.03 (1H, brd s). MS (ESI) (M+H)+ 760.61.

後処理

  1. additionwas then added
  2. stirringthe reaction mixture was stirred at rt for 6 h
  3. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient)

出典と根拠

ORDレコード
ord-067ed83a01104cd4bc194bfb19931e73
出典データセット
uspto-grants-2010_06
特許番号
US07745470B2

反応ノート

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