Lithium Hydroxide → {4'-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acid

HRID 631914Notes

Reaction equation

HRID 631914 reaction equation
C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[N:20][N:21]([CH3:35])[C:22]=3[NH:23][C:24]([O:26][C@@H:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH3:28])=[O:25])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)C.[OH-].[Li+]>C1COCC1>[CH3:35][N:21]1[C:22]([NH:23][C:24]([O:26][C@@H:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28])=[O:25])=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:36])=[O:3])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)[N:19]=[N:20]1

Participants

4

Reactant 2

HCID 3939Lithium HydroxideHCID 71500376{4'-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acid ethyl ester

Product 1

HCID 71453960{4'-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acidYield 90.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

[5-(4-Bromo-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (from Example 1, 120 mg, 0.30 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)acetate (130 mg, 0.45 mmol), X-PHOS (43 mg, 0.09 mmol), palladium acetate (10 mg, 0.045 mmol) and potassium phosphate (190 mg, 0.90 mmol) were combined in 5 mL of toluene. Deionized water (1 mL) was added and the mixture was degassed with argon for 2 minutes. The mixture was sealed and stirred at 100° C. for 2 hrs. The mixture was extracted with ethyl acetate and water, washed with brine and dried. Solvents were evaporated and the residue was purified by ISCO flash column chromatography (12 g silica gel, 0% to 70% ethyl acetate in hexanes) to give {4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acid ethyl ester as an amorphous powder (70 mg, 48.3% yield). LC/MS calcd for C28H28N4O4 (m/e) 484.0, obsd 485.1 (M+H); 1H-NMR (400 MHz, CDCl3) δ ppm 1.31 (t, J=7.2 Hz, 3H), 1.53-1.76 (m, 3H), 3.69 (s, 2H), 3.95 (s, 3H), 4.21 (q, J=7.2 Hz, 2H), 5.93 (m, 1H), 6.40 (br s, 1H), 7.31-7.49 (m, 7H), 7.56-7.66 (m, 4H), 7.80 (d, J-6.8 Hz, 2H). {4′-[1-Methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acid ethyl ester (60 mg, 0.124 mmol) was dissolved in 3 mL of THF and lithium hydroxide solution (0.5 N, 1.0 mL) was added. The mixture was stirred at room temperature for 3 hrs. TLC indicated complete consumption of the starting material. The mixture was concentrated and dissolved in water (8 mL). The clear solution was treated with hydrochloric acid (1N, 0.6 mL). The mixture was filtered and the white solid was dried to give {4′-[1-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-1H-[1,2,3]triazol-4-yl]-biphenyl-4-yl}-acetic acid (51 mg, 90.2% yield). LC/MS calcd for C26H24N4O4 (m/e) 456.0, obsd 457.0 (M+H); 1H-NMR (400 MHz, DMSO-d6) ppm 1.12-1.32 (m, 0.6H), 1.59 (br, 2.4H), 3.64 (s, 2H), 3.89 (s, 3H), 5.80 (br m, 1H), 6.96-7.54 (m, 7H), 7.61-7.74 (m, 4H), 7.80 (d, J=7.6 Hz, 2H), 9.54 and 9.95 (br s, 1H), 12.38 (br s, 1H).

Workup

  1. customconsumption of the starting material
  2. concentrationThe mixture was concentrated
  3. dissolutiondissolved in water (8 mL)
  4. additionThe clear solution was treated with hydrochloric acid (1N, 0.6 mL)
  5. filtrationThe mixture was filtered
  6. customthe white solid was dried

Sources & evidence

ORD record
ord-0d267ccce88e4c68aa1d937b3df1fba9
Source dataset
uspto-grants-2016_04
Patent number
US09321738B2

Reaction notes

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