Potassium Carbonate → 4'-(3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3'-fluoro-4-biphenylcarboxylic Acid

HRID 525218Notes

Reaction equation

HRID 525218 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.OB(O)[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[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:28]5[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=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

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 3121834-Carboxyphenylboronic AcidHCID 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 682610804'-(3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3'-fluoro-4-biphenylcarboxylic Acid

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Procedure

A microwave vial was charged with 4-(4-bromo-2-fluorophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.29 mmol), 4-(dihydroxyboranyl)benzoic acid (0.32 mmol), PdCl2(dppf) (0.015 mmol), a solution of K2CO3 (0.73 mmol) in water (1 mL), and 1,4-dioxane (3 mL). The vial was purged with nitrogen, sealed and irradiated in a microwave reactor for 30 min at 130° C. (pressure ˜3-4 bar). Analysis of the crude reaction by LCMS indicated ˜80% conversion to desired product. Re-subjection of the reaction to the microwave at 130° C. for 30 min did not progress the reaction any further as judged by LCMS. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO (3 mL), filtered through a syringe filter, and purified by reverse phase HPLC (10-90% acetonitrile/water+0.1% TFA). The appropriate product fractions were concentrated to remove a majority of the acetonitrile, leaving an aqueous suspension of product which was collected by filtration and dried to constant weight to provide the title product (38 mg, 0.084 mmol, 29% yield) as an off-white solid. MS(ES)+ m/e 451.0 [M+H]+.

Workup

  1. customThe vial was purged with nitrogen
  2. customsealed
  3. customirradiated in a microwave reactor for 30 min at 130° C. (pressure ˜3-4 bar)
  4. customAnalysis of the crude reaction by LCMS

Sources & evidence

ORD record
ord-b426885f45b64518954b38e5c15fd705
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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