Potassium Phosphate, Tribasic → [1-(6-{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}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 417733Notes

Reaction equation

[CH3:1][O:2][C:3](=[O:30])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]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+].[CH3:54][O:55][C:56](=[O:87])[NH:57][CH:58]([C:62]([N:64]1[CH:70]([C:71]2[NH:72][C:73]([C:76]3[CH:85]=[CH:84][C:83]4[C:78](=[CH:79][CH:80]=[C:81](Br)[CH:82]=4)[CH:77]=3)=[CH:74][N:75]=2)[CH2:69][C:66]2([CH2:68][CH2:67]2)[CH2:65]1)=[O:63])[CH:59]([CH3:61])[CH3:60].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Pd](Cl)Cl>[CH3:54][O:55][C:56](=[O:87])[NH:57][CH:58]([C:62]([N:64]1[CH:70]([C:71]2[NH:72][C:73]([C:76]3[CH:85]=[CH:84][C:83]4[C:78](=[CH:79][CH:80]=[C:81]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:30])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:82]=4)[CH:77]=3)=[CH:74][N:75]=2)[CH2:69][C:66]2([CH2:68][CH2:67]2)[CH2:65]1)=[O:63])[CH:59]([CH3:61])[CH3:60]

Participants

Conditions

Temperature: 85 °C

Procedure

(1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.10 g, 0.24 mmol), bis(pinacolato)diboron (0.073 g, 0.29 mmol), Palladium dichloride (dppf) (0.018 g, 0.024 mmol), and potassium acetate (0.071 g, 0.72 mmol) were suspended in 1,4-dioxane (1.2 mL) and degassed with argon for 30 minutes. The suspension was heated at 85° C. for 2 hours. The mixture was cooled, (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 (0.182 g, 0.346 mmol) and aqueous potassium phosphate (2M, 0.84 mL, 0.84 mmol) was added. The mixture was returned to heat for 16 hours at which time, Palladium(tetrakis)triphenylphosphine (0.014 g, 0.012 mmol) was added. The reaction was heated for an additional 4 hours. Upon completion, the crude reaction mixture was concentrated in vacuo and filtered through a Pd scavenging cartridge (Polymer Labs, PL-Guanidine MP SPE). The resulting slurry was diluted in DMF and purified by reverse phase HPLC (15-40% acetonitrile: water; 0.1% formic acid modifier), and lyophilized giving [1-(6-{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}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.048 g, 24%) as a white solid.

Workup

customdegassed with argon for 30 minutes
temperatureThe mixture was cooled
additionwas added
temperatureThe reaction was heated for an additional 4 hours
customUpon completion, the crude reaction mixture
concentrationwas concentrated in vacuo
filtrationfiltered through a Pd scavenging cartridge (Polymer Labs, PL-Guanidine MP SPE)
additionThe resulting slurry was diluted in DMF
custompurified by reverse phase HPLC (15-40% acetonitrile: water; 0.1% formic acid modifier)

Sources & evidence

ORD record: ord-b0f10da76c2943e89a301f70e5691a4b
Source dataset: uspto-grants-2012_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08088368B2

Reaction notes

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