Potassium Carbonate → HCID 67376178, compound

HRID 2405375Notes

Reaction equation

HRID 2405375 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([F:25])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].O.C(O)(C(F)(F)F)=O.Br[C:58]1[CH:59]=[C:60]([CH:69]=[CH:70][CH:71]=1)[C:61]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:62].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:67]5[CH:66]=[CH:65][CH:64]=[C:63]([C:61]([C:60]6[CH:69]=[CH:70][CH:71]=[CH:58][CH:59]=6)=[O:62])[CH:68]=5)=[CH:3][C:4]=4[F:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1

Participants

8

Reactant 6

HCID 11430Potassium CarbonateHCID 705483-BromobenzophenoneHCID 517044Potassium AcetateHCID 2733548Bis(pinacolato)diboraneHCID 22392675Trifluoroacetic acid waterHCID 673758864-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Product 1

HCID 67376178HCID 67376178, compound

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

In a sealed microwave vial under nitrogen, a mixture of 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (124 mg, 0.303 mmol), bis(pinacolato)diboron (81 mg, 0.318 mmol), potassium acetate (89 mg, 0.909 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12.37 mg, 0.015 mmol) in 1,4-dioxane (2.5 mL) was stirred at 100° C. in an oil bath for 1 h. The reaction was cooled to room temperature. Analysis by LCMS showed complete conversion to the boronic ester intermediate (boronic ester cleavage to acid also observed on LCMS due to water/TFA conditions). 3-Bromobenzophenone (79 mg, 0.303 mmol) and 2M aq potassium carbonate (0.45 mL, 0.909 mmol) were added to the reaction mixture. The resultant reaction mixture was stirred at 100° C. in an oil bath for 1 h. The reaction was cooled to room temperature. The reaction mixture was then transferred to a separatory funnel and the layers were separated. The aqueous layer was adjusted to pH˜5 using 1N aq HCl and then extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-5% methanol/ethyl acetate) provided the desired product as a white solid, which was dried in a vacuum oven (70° C.) overnight. The solid was further purified by reverse phase HPLC (10-80% acetonitrile/water+0.1% NH4OH). The desired product was dissolved in acetonitrile (2 mL) and water (10 mL), frozen, and lyophilized over the weekend. The solid was further dried in a vacuum oven (70° C.) overnight to give the title compound as a white solid (72 mg, 46%). MS(ES)+ m/e 511.1 [M+H]+.

Workup

  1. temperatureThe reaction was cooled to room temperature
  2. customThe resultant reaction mixture
  3. stirringwas stirred at 100° C. in an oil bath for 1 h
  4. temperatureThe reaction was cooled to room temperature
  5. customThe reaction mixture was then transferred to a separatory funnel
  6. customthe layers were separated
  7. extractionextracted with ethyl acetate (2×50 mL)
  8. dry with materialdried over MgSO4
  9. concentrationconcentrated in vacuo
  10. customPurification of the residue by silica gel chromatography (0-5% methanol/ethyl acetate)

Sources & evidence

ORD record
ord-15d5dfde21b04115acb11a1fbf64d851
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

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