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Hydrochloric Acid → methyl {(2S,3R)-3-methoxy-1-[(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate

HRID 1431826
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1431826
[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]1[C:33]2[C:38]([CH2:39][O:40][C:27]=1[CH:26]=3)=[CH:37][C:36]([C:41]1[NH:45][C:44]([C@@H:46]3[CH2:50][C@H:49]([CH3:51])[CH2:48][N:47]3C(OC(C)(C)C)=O)=[N:43][CH:42]=1)=[CH:35][CH:34]=2)=[O:11])[CH:7](C)[CH3:8])=[O:4].Cl.[CH3:60][O:61][C@H:62]([CH3:72])[C@H:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64](O)=[O:65].CN([C:76]([O:80]N1N=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.CO.CCOC(C)=O.CN(C=O)C.CO>[CH3:76][O:80][C@H:7]([CH3:8])[C@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C:10]([N:12]1[CH2:16][C@@H:15]([CH2:17][O:18][CH3:19])[CH2:14][C@H:13]1[C:20]1[NH:24][C:23]2[C:25]3[C:30]([CH:31]=[CH:32][C:22]=2[N:21]=1)=[CH:29][C:28]1[C:33]2[C:38]([CH2:39][O:40][C:27]=1[CH:26]=3)=[CH:37][C:36]([C:41]1[NH:45][C:44]([C@@H:46]3[CH2:50][C@H:49]([CH3:51])[CH2:48][N:47]3[C:64](=[O:65])[C@H:63]([C@@H:62]([CH3:72])[O:61][CH3:60])[NH:67][C:68]([O:70][CH3:71])=[O:69])=[N:43][CH:42]=1)=[CH:35][CH:34]=2)=[O:11]
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Komponenten

10

Edukt 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 59540170(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acidHCID 178495664HCID 178495664, Verbindung

Produkt 1

HCID 178495663methyl {(2S,3R)-3-methoxy-1-[(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamateAusbeute 34,1 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 887MethanolLösungsmittelHCID 6228DimethylformamideLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 21584119Ethylacetate methanolLösungsmittel

Versuchsvorschrift

Tert-butyl (2S,4S)-2-[5-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-valyl]-4-(methoxymethyl)pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-methylpyrrolidine-1-carboxylate (174 mg, 0.24 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 5 h and then concentrated under reduced pressure. The crude residue was treated with ((2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (92 mg, 0.48 mmol), HATU (182 mg, 0.48 mmol) and DMF (5 mL), then DIPEA (0.31 mL, 2.4 mmol) was added dropwise. After 35 min, the mixture was diluted with 10% MeOH/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 HPLC to afford methyl {(2S,3R)-3-methoxy-1-[(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidin-1-yl]-1-oxobutan-2-yl}carbamate (72 mg, 34%). LCMS-ESI+: calculated for C46H56N8O10: 880.41; observed [M+1]+: 882.39. 1H NMR (CD3OD): 8.558 (s, 1H), 8.123-7.572 (m, 7H), 5.436-5.391 (dd, 1H, J=7.2, 3.6 Hz), 5.252 (s, 2H), 5.220 (m, 1H), 4.493-4.444 (m, 2H), 4.287-4.206 (m, 2H), 3.756-3.256 (m, 21H), 2.834 (m, 1H), 2.717-2.621 (m, 2H), 2.500 (m, 1H), 2.150 (m, 1H), 1.882 (m, 1H), 1.208 (d, 3H, J=6.4 Hz), 1.159-1.099 (m, 6H).

Aufarbeitung

  1. concentrationconcentrated under reduced pressure
  2. waitAfter 35 min
  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 HPLC

Quellen und Nachweise

ORD-Eintrag
ord-6f4c5c67f2cc48449f93e3a7a45e059b
Quelldatensatz
uspto-grants-2015_01
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08940718B2

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