Potassium Acetate → [1-(6-{5-[6-(4-(2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2-methoxy-ethoxy)-pyrrolidin-2-yl]-3H-imidazol-4-yl)-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 79896Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:33])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:13][CH:12]1[C:21]1[NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH3:57][O:58][C:59](=[O:90])[NH:60][CH:61]([C:65]([N:67]1[CH:73]([C:74]2[NH:75][C:76]([C:79]3[CH:88]=[CH:87][C:86]4[C:81](=[CH:82][CH:83]=[C:84](Br)[CH:85]=4)[CH:80]=3)=[CH:77][N:78]=2)[CH2:72][C:69]2([CH2:71][CH2:70]2)[CH2:68]1)=[O:66])[CH:62]([CH3:64])[CH3:63]>O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:57][O:58][C:59](=[O:90])[NH:60][CH:61]([C:65]([N:67]1[CH:73]([C:74]2[NH:75][C:76]([C:79]3[CH:88]=[CH:87][C:86]4[C:81](=[CH:82][CH:83]=[C:84]([C:29]5[CH:28]=[CH:27][C:26]([C:23]6[NH:22][C:21]([CH:12]7[CH2:13][CH:14]([O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:15][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:33])[CH:6]([CH3:8])[CH3:7])=[N:25][CH:24]=6)=[CH:31][CH:30]=5)[CH:85]=4)[CH:80]=3)=[CH:77][N:78]=2)[CH2:72][C:69]2([CH2:71][CH2:70]2)[CH2:68]1)=[O:66])[CH:62]([CH3:64])[CH3:63]

Participants

Conditions

Temperature: 90 °C

Procedure

A mixture of {1-[2[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2-methoxy-ethoxy)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (169 mg), bis(pinacolato)diboron (107 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (24 mg) and potassium acetate (95 mg) in 1.6 mL of dioxane was heated to 90° C. for 1.5 hour. (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (170 mg) in 1 mL of dioxane and 2M tripotassium phosphate (565 μl) were added and stirred at 90° C. for overnight. The mixture was purified by a preparative HPLC (10-60% MeCN—H2O; 0.1% formic acid modifier) to afford the title product (119 mg, 41%). 1H NMR (DMSO-d6, 400 MHz) δ: 8.20-8.10 (m, 2H), 7.90-7.68 (m, 6H), 7.60-7.55 (m. 2H), 7.33-7.30 (m, 2H), 5.18 (m, 1H), 5.07 (m, 1H), 4.44 (m, 1H), 4.04-3.69 (m, 6H), 3.80-3.38 (m, 5H), 3.30 (m, 9H), 2.71 (m, 1H), 2.40-1.90 (m, 5H), 0.90-0.79 (m, 12H), 0.70-0.54 (m, 4H); MS (ESI) m/z 889.5 [M+H]+.

Workup

customThe mixture was purified by a preparative HPLC (10-60% MeCN—H2O; 0.1% formic acid modifier)

Sources & evidence

ORD record: ord-8055aac3099a48c28d32fe09e6efcc70
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08841278B2

Reaction notes

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