Hydrochloric Acid → [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 72005Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 72005
C(OC([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]6[NH:36][C:37]([CH:40]7[CH2:46][C:43]8([CH2:45][CH2:44]8)[CH2:42][N:41]7[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=6)=[CH:31][CH:30]=5)[CH:25]=4)[CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:58][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.[CH:60]1([CH:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64]([OH:66])=O)[CH2:62][CH2:61]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CO.C(Cl)Cl>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:48]([C:47]([N:41]1[CH:40]([C:37]2[NH:36][C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:24]4[CH:23]=[CH:22][C:21]5[C:26](=[CH:27][CH:28]=[C:19]([C:16]6[NH:15][C:14]([CH:13]7[CH:12]8[CH2:58][CH:9]([CH2:10][CH2:11]8)[N:8]7[C:64](=[O:66])[CH:63]([CH:60]7[CH2:61][CH2:62]7)[NH:67][C:68]([O:70][CH3:71])=[O:69])=[N:18][CH:17]=6)[CH:20]=5)[CH:25]=4)=[CH:30][CH:31]=3)=[CH:39][N:38]=2)[CH2:46][C:43]2([CH2:45][CH2:44]2)[CH2:42]1)=[O:57])[CH:49]([CH3:51])[CH3:50]

Komponenten

8

Edukt 5

HCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59166361Cyclopropyl-methoxycarbonylamino-acetic acidHCID 666203703-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl]-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

Produkt 1

HCID 66620456[1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl esterAusbeute 59,6 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittel

Versuchsvorschrift

To a slurry of 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.05 g, 0.06 mmol) in MeOH (0.1 mL) was added HCl in dioxanes (4 M, 0.6 mL). The resulting solution was stirred at room temperature for 1 hour and the concentrated to dryness. Cyclopropyl-methoxycarbonylamino-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) and CH2Cl2 (0.6 mL) were then added, followed by HATU (0.03 g, 0.08 mmol, 1.25 equiv.) and NMM (0.05 mL, 0.45 mmol, 5 equiv.). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 49%) as a white powder. LCMS-ESI+: calc'd for C48H54N8O6: 838.4 (M+). Found: 839.9 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotomers) 8.22 (s, 2H), 7.81-7.96 (m, 10H), 7.63 (d, 1H), 7.29 (d, 1H), 5.18 (t, 1H), 4.56 (d, 1H), 3.96 (t, 1H), 3.74 (m, 1H), 3.51 (s, 6H), 3.12 (t, 1H), 2.48 (s, 1H), 1.93-2.29 (m, 6H), 1.58-1.77 (m, 5H), 0.85 (d, 3H), 0.80 (d, 3H), 0.58 (m, 4H), 0.34 (m, 1H), 0.26 (m, 1H), 0.03 (m, 1H), −0.12 (m, 1H).

Aufarbeitung

  1. concentrationthe concentrated to dryness
  2. stirringThe resulting solution was stirred at room temperature for 18 hours
  3. concentrationThe reaction mixture was concentrated
  4. custompurified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid))

Quellen und Nachweise

ORD-Eintrag
ord-373736ce9b9d42f48e1fe508964bcb82
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08822430B2

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