Diisopropylethylamine → N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-4-hydroxy-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide

HRID 1014881

반응식

HRID 1014881 반응식
C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H:17]([O:40][Si](C(C)(C)C)(C)C)[C@@H:18]([NH:28][C:29]([C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)C(O)=O)=[O:30])[CH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)=O)(C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](O)CN1C(OC(C)(C)C)=O)[C@@H:57]([NH:67][C:68](=O)[C:69]1C=CC=C(C(=O)N)C=1)[CH2:58][C:59]1[CH:64]=[C:63](F)[CH:62]=[C:61](F)[CH:60]=1)(C(C)(C)C)(C)C.[CH2:92]([N:96]([CH3:108])[C:97](C1C=C(C=CC=1)C(O)=O)=[O:98])[CH2:93][CH2:94][CH3:95].CCN(C(C)C)C(C)C.CN(C([O:125]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=CC=C(C(OC)=O)C=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C>ClCCl>[CH2:92]([N:96]([CH3:108])[C:97](=[O:98])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C@@H:18]([CH2:19][C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[C@H:17]([OH:40])[C@H:68]2[CH2:69][C:58]([OH:125])([C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)[CH2:57][NH:67]2)=[O:30])[CH:32]=1)[CH2:93][CH2:94][CH3:95]

참가 물질

8

반응물 6

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 434527753-(Butyl(methyl)carbamoyl)benzoic acidHCID 673161403-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acidHCID 67316447(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylateHCID 67316674(2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-(methoxycarbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate

생성물 1

HCID 11848528N1-butyl-N3-((1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-((2R)-4-hydroxy-4-phenylpyrrolidin-2-yl)propan-2-yl)-N1-methylisophthalamide

시약·촉매·용매 1

HCID 6344Dichloromethane용매

실험 절차

Step 6 (C): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylate. To a solution of 3-(butyl(methyl)carbamoyl)benzoic acid (Preparation F, 146 mg, 0.62 mmol) in dichloromethane (8 mL) was added Hunig's base (182 mg, 1.41 mmol) to make a clear solution and HATU (250 mg, 0.66 mmol) was then added. After stirring for 30 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-hydroxypyrrolidine-1-carboxylate (Step 6 (B), 230 mg, 0.47 mmol) and the reaction mixture was stirred at rt for 3 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% EtOAc/Hexane step gradient) to give 350 mg of the title compound: 1H NMR (CDCl3, 500 MHz) δ 0.01-0.07 (6H, m), 0.66 (2H, m), 0.83 (9H, s), 1.02 (1H, m), 1.30 (1H, m), 1.38 (9H, s), 1.53 (1H, m), 2.10 (2H, s), 2.60 (1H, m), 2.70 (1H, m), 2.79 (2H, s), 2.89-2.94 (2H, m), 3.09-3.16 (3H, m), 3.43 (1H, brd s), 3.56 (1H, dd, J=5, 10 Hz), 3.97-4.02 (2H, m), 4.16 (1H, brd s), 4.31-4.38 (2H, m), 6.48 (1H, m), 6.65-6.71 (2H, m), 7.25-7.34 (2H, m), 7.56-7.63 (2H, m), 7.83 (1H, s). MS (ESI) (M+H)+ 704.43.

후처리

  1. additionwas then added
  2. stirringthe reaction mixture was stirred at rt for 3 h
  3. customThe crude mixture was purified by silica gel Flash Chromatography (0% to 20% to 40% to 60% EtOAc/Hexane step gradient)

출처 및 근거

ORD 기록
ord-cba2f79668494c8984d798d017a5431b
출처 데이터셋
uspto-grants-2011_07
특허 번호
US07981913B2

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