Hydrochloric Acid → 2-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acid

HRID 1930125Notes

Reaction equation

HRID 1930125 reaction equation
[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2].[F:21][C:22]([F:43])([F:42])[C:23]1[CH:24]=[C:25]([CH2:37][C:38]([O:40]C)=[O:39])[CH:26]=[CH:27][C:28]=1OS(C(F)(F)F)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+].Cl>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:28]3[CH:27]=[CH:26][C:25]([CH2:37][C:38]([OH:40])=[O:39])=[CH:24][C:23]=3[C:22]([F:21])([F:42])[F:43])=[CH:12][CH:11]=2)[C:7]([CH3:19])=[N:6][C:5]=1[CH3:20])(=[O:3])[NH2:2]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 10340Sodium CarbonateHCID 433294Lithium ChlorideHCID 59627665Methyl 2-(3-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)phenyl)acetate2×HCID 596277414-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid2×

Product 1

HCID 498472452-(4'-(6-Carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acidYield 55.9%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
85 °C

Procedure

A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)phenylboronic acid (Intermediate 5-1; 278 mg, 1.02 mmol) and methyl 2-(3-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)phenyl)acetate (Intermediate 5-2; 300 mg, 0.82 mmol) and sodium carbonate (0.666 mL, 1.33 mmol), tetrakis(triphenylphosphine)palladium(0) (58.7 mg, 0.05 mmol) and lithium chloride (60.8 mg, 1.43 mmol) in DME (20 mL) was degassed and then stirred at 85° C. for 17 hours. The reaction mixture was The reaction mixture was acidified with 2M HCl and evaporated. The precipitate was collected by filtration, washed with water (20 mL) and dried under vacuum to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acid (197 mg, 55.9%) as a brown solid, which was purified by flash silica chromatography, elution gradient 0 to 6% MeOH in DCM. Failed to purify material so was further purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-(trifluoromethyl)biphenyl-4-yl)acetic acid (197 mg, 55.9%) as a white solid.

Workup

  1. customevaporated
  2. filtrationThe precipitate was collected by filtration
  3. washwashed with water (20 mL)
  4. customdried under vacuum

Sources & evidence

ORD record
ord-d2d0a841b31c456c882b0b42102665d2
Source dataset
uspto-grants-2012_05
Patent number
US08188092B2

Reaction notes

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