Methyl Carbamate → {1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

HRID 417708Notes

Reaction equation

COC(=O)N.[CH3:6][O:7][C:8](=[O:52])[NH:9][CH:10]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[NH:22][C:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][C:39]([C:42]5[NH:43][C:44]([CH:47]6[CH2:51][CH2:50][CH2:49][NH:48]6)=[N:45][CH:46]=5)=[CH:38][CH:37]=4)[CH:32]=3)[CH:27]=2)=[CH:24][N:25]=1)=[O:15])[CH:11]([CH3:13])[CH3:12].[CH3:53][O:54][C:55]([NH:57][C@@H:58]([C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[O:68][CH3:69])[C:59](O)=[O:60])=[O:56].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:52])[NH:9][CH:10]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[C:21]1[NH:22][C:23]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:36]4[CH:41]=[CH:40][C:39]([C:42]5[NH:43][C:44]([CH:47]6[CH2:51][CH2:50][CH2:49][N:48]6[C:59](=[O:60])[CH:58]([NH:57][C:55]([O:54][CH3:53])=[O:56])[C:62]6[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=6[O:68][CH3:69])=[N:45][CH:46]=5)=[CH:38][CH:37]=4)[CH:32]=3)[CH:27]=2)=[CH:24][N:25]=1)=[O:15])[CH:11]([CH3:13])[CH3:12]

Participants

Conditions

Temperature: 0 °C

Procedure

{1-[2-(5-{6-[4-(2-{1-P-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester. To a solution of {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester (0.04 g, 0.05 mmol) and (S)-Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid (0.02 g, 0.08 mmol, 1.5 equiv.) in CH2Cl2 (0.5 mL) was added K3PO4 (0.03 g, 0.15 mmol, 3 equiv.). The slurry was cooled to 0° C. and COMU (0.03 g, 0.06 mmol, 1.25 equiv.) and the reaction was stirred at 0° C. for 1 hour. The slurry was diluted with CH2Cl2 and filtered. The filtrate was concentrated and the crude product was purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide {1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.02 g, 50%) as a white powder. LCMS-ESI+: calc'd for C48H52N8O7: 852.4 (M+). Found: 853.6 (M+H+). 1H-NMR: 400 MHz, (acetone-d6) δ: (Mixture of rotomers) 10.96-11.01 (m, 2H), 8.29 (s, 1H), 8.07 (s, 1H), 7.73-7.89 (m, 7H), 7.35-7.48 (m, 4H), 7.33 (t, 1H), 7.05 (d, 1H), 6.96 (t, 1H), 6.36 (d, 1H), 5.91 (d, 1H), 5.21-5.26 (m, 3H), 4.29 (t, 1H), 3.90 (s, 3H), 3.78-3.93 (m, 2H), 3.60 (s, 3H), 3.58 (s, 3H), 3.30 (q, 2H), 2.59-2.65 (m, 2H), 2.36 (m, 1H), 1.90-2.21 (m, 6H), 0.85-0.93 (m, 6H).

Workup

filtrationfiltered
concentrationThe filtrate was concentrated
customthe crude product was purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid))

Sources & evidence

ORD record: ord-1696c0ec0ecd41e4a5f112f802ca1873
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08088368B2

Reaction notes

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