Hydrochloric Acid → (2S,4S)-benzyl 2-(5-(4'-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate

HRID 1751651노트

반응식

HRID 1751651 반응식
C([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]([C@@H:29]4[CH2:33][C@H:32]([CH2:34][O:35][CH3:36])[CH2:31][N:30]4[C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])=[N:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])=O)(C)(C)C.Cl.[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:66]([CH3:68])[CH3:67])[C:54]([N:56]1[CH2:60][C@@H:59]([S:61][CH3:62])[CH2:58][C@H:57]1C(O)=O)=[O:55])=[O:51].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[CH3:48][O:49][C:50]([NH:52][C@@H:53]([CH:66]([CH3:68])[CH3:67])[C:54]([N:56]1[CH2:60][C@@H:59]([S:61][CH3:62])[CH2:58][C@H:57]1[C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[NH:28][C:27]([C@@H:29]4[CH2:33][C@H:32]([CH2:34][O:35][CH3:36])[CH2:31][N:30]4[C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])=[N:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:11])=[O:5])=[O:55])=[O:51]

참가 물질

10

반응물 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 67682555HCID 67682555, 화합물HCID 69671862(2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid

생성물 1

HCID 67682446(2S,4S)-benzyl 2-(5-(4'-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate수율 58%

시약·촉매·용매 4

HCID 887Methanol용매HCID 6228Dimethylformamide용매HCID 6344Dichloromethane용매HCID 8857Ethyl Acetate용매

실험 절차

(2S,4S)-benzyl 2-(5-(4′-(2-(tert-butoxycarbonylamino)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (640 mg, 1.02 mmol) was dissolved in DCM (8 mL), MeOH (2 mL) and HCl (4 M in dioxane, 2 mL) was added. The reaction mixture was stirred for 14 h and then concentrated under reduced pressure. The crude residue was treated with (2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxylic acid (324 mg, 1.02 mmol), HATU (388 mg, 1.02 mmol) and DMF (10 mL), then DIPEA (0.9 mL, 5.12 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford (2S,4S)-benzyl 2-(5-(4′-(2-((2S,4S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-(methylthio)pyrrolidine-2-carboxamido)acetyl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidine-1-carboxylate (487 mg, 58%).

후처리

  1. concentrationconcentrated under reduced pressure
  2. waitAfter 1 h
  3. washwashed successively with saturated aqueous NaHCO3 and brine
  4. dry with materialThe organics were dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc)

출처 및 근거

ORD 기록
ord-3a24ab97abb947a1bfa4195a714c69b5
출처 데이터셋
uspto-grants-2015_10
특허 번호
US09156823B2

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