Hydrochloric Acid → 2-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester

HRID 1751455Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1751455
C(OC([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46]([O:48][CH2:49][C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[O:47])=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C.Cl.[CH3:57][O:58][C:59]([NH:61][CH:62]([CH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1)[C:63]([OH:65])=O)=[O:60].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.CO>[CH2:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][CH:41]1[C:38]1[NH:37][C:36]([C:31]2[CH:30]=[CH:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([C:17]5[NH:16][C:15]([CH:9]6[CH2:10][C:11]([F:14])([F:13])[CH2:12][N:8]6[C:63](=[O:65])[CH:62]([NH:61][C:59]([O:58][CH3:57])=[O:60])[CH:66]6[CH2:71][CH2:70][O:69][CH2:68][CH2:67]6)=[N:19][CH:18]=5)=[CH:21][CH:22]=4)[CH:27]=3)[CH:32]=2)=[CH:40][N:39]=1)=[O:47])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1

Komponenten

8

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 585162412-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acidHCID 69675276HCID 69675276, Verbindung

Produkt 1

HCID 696753852-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl esterAusbeute 46 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

To a solution of 2-[5-(4-{6-[2-(1-Benzyloxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (0.25 g, 0.34 mmol) in CH2Cl2 (3.5 mL) and MeOH (0.25 mL) was added HCl (in dioxanes, 4 M, 1.7 mL, 7.8 mmol). The solution was stirred at room temperature for 2.5 h and concentrated to dryness. The resulting solid was slurried in CH2Cl2 (3 mL) and DMF (1 mL). Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid (0.11 g, 0.50 mmol), HATU (0.15 g, 0.40 mmol), and DIPEA (0.3 mL, 1.7 mmol) were added. The resulting solution was stirred at room temperature for 18 h. The solution was diluted with CH2Cl2 and washed with saturated sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 2→20% MeOH in CH2Cl2), followed by preparative HPLC (Gemini, 15→50% MeCN in H2O (0.1% TFA)) to provide 2-(5-{6-[4-(2-{4,4-Difluoro-1-[2-methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester (0.13 g, 46%). LCMS-ESI+: calc'd for C47H47F2N7O6: 843.36 (M+); Found: 844.78 (M+H+).

Aufarbeitung

  1. concentrationconcentrated to dryness
  2. stirringThe resulting solution was stirred at room temperature for 18 h
  3. washwashed with saturated sodium bicarbonate
  4. dry with materialThe organic layer was dried over Na2SO4
  5. concentrationconcentrated
  6. customThe crude oil was purified by column chromatography (SiO2, 2→20% MeOH in CH2Cl2)

Quellen und Nachweise

ORD-Eintrag
ord-3dca7d248d0b44d3860eafbf5a6ed75b
Quelldatensatz
uspto-grants-2015_10
Patentnummer
US09156823B2

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