Potassium Carbonate → (1-{7-[5-(4'-{2-[6-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4]oct-7-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 72039Notes

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:70])[NH:43][CH:44]([C:48]([N:50]1[CH:57]([C:58]2[NH:59][C:60]([C:63]3[CH:68]=[CH:67][C:66](Br)=[CH:65][CH:64]=3)=[CH:61][N:62]=2)[CH2:56][C:52]2([CH2:55][CH2:54][CH2:53]2)[O:51]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>[CH3:40][O:41][C:42](=[O:70])[NH:43][CH:44]([C:48]([N:50]1[CH:57]([C:58]2[NH:59][C:60]([C:63]3[CH:68]=[CH:67][C:66]([C:27]4[CH:26]=[CH:25][C:24]([C:21]5[NH:20][C:19]([CH:18]6[CH2:17][C:13]7([CH2:14][CH2:15][CH2:16]7)[O:12][N:11]6[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:39])[CH:6]([CH3:7])[CH3:8])=[N:23][CH:22]=5)=[CH:29][CH:28]=4)=[CH:65][CH:64]=3)=[CH:61][N:62]=2)[CH2:56][C:52]2([CH2:55][CH2:54][CH2:53]2)[O:51]1)=[O:49])[CH:45]([CH3:47])[CH3:46]

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-{7-[5-(4-bromophenyl)-1H-imidazol-2-yl]-5-oxa-6-aza-spiro[3.4]octane-6-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (60 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) in 1,2-dimethoxyethane (2.0 mL) was added a solution of potassium carbonate (2M in water, 0.250 mL, 0.50 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 preparative reverse phase HPLC (Gemini, 15 to 51% ACN/H2O+0.1% HCO2H) to yield (1-{7-[5-(4′-{2-[6-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-oxa-6-aza-spiro[3.4]oct-7-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 (26 mg, 26%). LCMS-ESI+: calculated for C44H54N8O8: 822.41; observed [M+1]+: 823.43. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78-7.75 (m, 4H), 7.68-7.65 (m, 4H), 7.38 (s, 2H), 6.94-6.89 (br, 2H), 5.47-5.42 (m, 2H), 4.74-4.68 (br, 2H), 3.66 (s, 6H), 3.00-2.94 (m, 2H), 2.78-2.71 (m, 2H), 2.61-2.53 (m, 2H), 2.49-2.40 (m, 2H), 2.38-2.30 (m, 2H), 2.22-2.09 (m, 4H), 2.00-1.90 (m, 2H), 1.84-1.75 (m, 2H), 0.98 (d, J=6.8 Hz, 6H), 0.88 (d, J=6.7 Hz, 6H) 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 preparative reverse phase HPLC (Gemini, 15 to 51% ACN/H2O+0.1% HCO2H)

Sources & evidence

ORD record: ord-76cffe56b50445b8b6dfbf1b9cf970a0
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08822430B2

Reaction notes

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