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

HRID 2405403Notes

Reaction equation

HRID 2405403 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:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([OH:33])=[O:32].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][CH:34]=[C:30]([C:31]([OH:33])=[O:32])[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 27339573-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 682610084'-(3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-3'-fluoro-3-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), 3-(dihydroxyboranyl)benzoic acid (0.29 mmol), PdCl2(dppf) (0.015 mmol), a solution of K2CO3 (0.733 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. 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 (product did not crash out). The mixture was adjusted to pH˜12 with 1N aq NaOH and partitioned with ethyl acetate. The aqueous layer was separated and adjusted to pH˜2 with 1N aq HCl, causing a gummy precipitate to form which was collected by filtration and dried to constant weight to provide the title product (39 mg, 0.087 mmol, 30% yield) as a tan 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-2e858b4fcd1d4ae1b9e979481a50fa62
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

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