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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 1185946
Notes
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Reaction equation

HRID 1185946 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>[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]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 62657Potassium Phosphate, TribasicHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 66620752(1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 66620764(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

Product 1

HCID 66620650[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 esterYield 24%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

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

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

Sources & evidence

ORD record
ord-5cd08f701ec248ea9f3782da300ebaf0
Source dataset
uspto-grants-2014_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08669234B2

Reaction notes

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