Potassium Carbonate → (1-{7-[5-(4'-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 79982Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:39])[NH:4][CH:5]([C:9]([N:11]1[CH:18]([C:19]2[NH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)=[CH:22][N:23]=2)[CH2:17][C:13]2([CH2:16][CH2:15][CH2:14]2)[O:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:40][O:41][C:42](=[O:67])[NH:43][CH:44]([C:48]([N:50]1[CH2:54][CH2:53][CH2:52][CH:51]1[C:55]1[NH:56][C:57]([C:60]2[CH:65]=[CH:64][C:63](Br)=[CH:62][CH:61]=2)=[CH:58][N:59]=1)=[O:49])[CH:45]([CH3:47])[CH3:46].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:39])[NH:4][CH:5]([C:9]([N:11]1[CH:18]([C:19]2[NH:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:63]4[CH:64]=[CH:65][C:60]([C:57]5[NH:56][C:55]([CH:51]6[CH2:52][CH2:53][CH2:54][N:50]6[C:48](=[O:49])[CH:44]([NH:43][C:42]([O:41][CH3:40])=[O:67])[CH:45]([CH3:47])[CH3:46])=[N:59][CH:58]=5)=[CH:61][CH:62]=4)=[CH:26][CH:25]=3)=[CH:22][N:23]=2)[CH2:17][C:13]2([CH2:14][CH2:15][CH2:16]2)[O:12]1)=[O:10])[CH:6]([CH3:7])[CH3:8]

Participants

Conditions

Temperature: 85 °C

Procedure

To a solution of [2-methyl-1-(7-{5-[4-(4,4,5,5-tetramethyl [1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-oxa-6-azaspiro[3.4]octane-6-carbonyl)-propyl]-carbamic acid methyl ester (81 mg, 0.15 mmol), (1-{2-[5-(4-bromophenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (81 mg, 0.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol) in 1,2-dimethoxyethane (3.0 mL) was added a solution of potassium carbonate (2M in water, 0.300 mL, 0.60 mmol). The resulting mixture was degassed for 15 minutes with a stream of argon and then heated to 85° C. for 3 hours. After cooling to room temperature, the reaction was filtered through a palladium scavenging column (STRATOSPHERES™ PL-Guanidine MP SPE+, Part #: PL3514-CM89) and the solids were rinsed with methanol. The filtrate was concentrated and purified by flash chromatography (0%-5% methanol/dichloromethane). The resulting residue was repurified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H) to yield (1-{7-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (35 mg, 30%). LCMS-ESI+: calculated for C42H52N8O7: 780.40; observed [M+1]+: 781.29. 1H-NMR: 400 MHz, (CD3OD) δ: 7.82-7.72 (m, 4H), 7.69-7.65 (m, 4H), 7.38 (s, 1H), 7.32 (s, 1H), 6.99-6.90 (m, 2H), 5.47-5.42 (m, 1H), 5.20-5.16 (m, 1H), 4.75-4.68 (m, 1H), 4.226-4.21 (m, 1H), 4.03-3.96 (m, 1H), 3.91-3.85 (m, 1H), 3.71-3.48 (m, 7H), 3.00-2.94 (m, 1H), 2.78-2.71 (m, 1H), 2.61-1.90 (m, 10H), 1.83-1.73 (m, 1H), 1.00-0.86 (m, 12H) ppm.

Workup

customThe resulting mixture was degassed for 15 minutes with a stream of argon
temperatureAfter cooling to room temperature
filtrationthe reaction was filtered through a palladium scavenging column (STRATOSPHERES™ PL-Guanidine MP SPE+, Part #: PL3514-CM89)
washthe solids were rinsed with methanol
concentrationThe filtrate was concentrated
custompurified by flash chromatography (0%-5% methanol/dichloromethane)
customThe resulting residue was repurified by preparative reverse phase HPLC (Gemini, 15 to 50% ACN/H2O+0.1% HCO2H)

Sources & evidence

ORD record: ord-c409a6241e7e4860a0bf01e24ebe1e4a
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08841278B2

Reaction notes

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