Potassium Phosphate, Tribasic → 1-{4'-[5-((R)-1,2-dimethyl-propoxycarbonylamino)-1-methyl-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester

HRID 631918Notes

Reaction equation

HRID 631918 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:22])[C:12]=2[NH:13][C:14](=[O:21])[O:15][C@@H:16]([CH:18]([CH3:20])[CH3:19])[CH3:17])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([C:37]3([C:40]([O:42][CH3:43])=[O:41])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:43][O:42][C:40]([C:37]1([C:34]2[CH:35]=[CH:36][C:31]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:9]=[N:10][N:11]([CH3:22])[C:12]=4[NH:13][C:14]([O:15][C@H:16]([CH3:17])[CH:18]([CH3:20])[CH3:19])=[O:21])=[CH:4][CH:3]=3)=[CH:32][CH:33]=2)[CH2:39][CH2:38]1)=[O:41]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 71264507Methyl 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropane-1-carboxylateHCID 118061596(R)-3-Methylbutan-2-yl 4-(4-bromophenyl)-1-methyl-1H-1,2,3-triazol-5-ylcarbamate

Product 1

HCID 1180622341-{4'-[5-((R)-1,2-dimethyl-propoxycarbonylamino)-1-methyl-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl esterYield 76.6%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
95 °C

Procedure

(R)-3-Methylbutan-2-yl 4-(4-bromophenyl)-1-methyl-1H-1,2,3-triazol-5-ylcarbamate (101.4 mg. 0.28 mmol), methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate (108 mg, 0.36 mmol), X-Phos (39.5 mg, 0.083 mmol), palladium acetate (9.3 mg, 0.041 mmol), and potassium phosphate tribasic (176 mg, 0.83 mmol) were combined in toluene (6 mL). To this mixture was added degassed water (1.5 mL) and the mixture was stirred at 95° C. for 2 hrs until it became black. LC/MS indicated no more starting material. The mixture was extracted with ethyl acetate and water. The organic layer was washed with brine and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (12 g silica gel, 5% to 65% ethyl acetate in hexanes) to give a pale yellow solid as 1-{4′-[5-((R)-1,2-dimethyl-propoxycarbonylamino)-1-methyl-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester (97.8 mg, 76.6% yield). LC/MS calcd for C26H30N4O4 (m/e) 462, obsd 463.2 (M+H).

Workup

  1. additionTo this mixture was added
  2. customdegassed water (1.5 mL)
  3. extractionThe mixture was extracted with ethyl acetate and water
  4. washThe organic layer was washed with brine
  5. customdried
  6. customSolvents were evaporated
  7. customthe residue was purified by ISCO flash column chromatography (12 g silica gel, 5% to 65% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-4e045f724bc144db82df8bfa860ff191
Source dataset
uspto-grants-2016_04
Patent number
US09321738B2

Reaction notes

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