Oxygen → 1-[(3'-Chloro-2',6'-difluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylic Acid Methyl Ester

HRID 1475775Notes

Reaction equation

HRID 1475775 reaction equation
[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4].[F-].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[Cl:44][C:45]1[C:46]([F:57])=[C:47](B(O)O)[C:48]([F:53])=[CH:49][C:50]=1[O:51][CH3:52].O=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([NH:12][C:13]([C:14]2[CH:15]=[C:16]([C:47]3[C:48]([F:53])=[CH:49][C:50]([O:51][CH3:52])=[C:45]([Cl:44])[C:46]=3[F:57])[C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:23])[CH2:10][CH2:9][CH:8]([CH3:11])[CH2:7][CH2:6]1)=[O:4]

Participants

8

Reactant 5

HCID 977OxygenHCID 522689Potassium FluorideHCID 2734635Tri-tert-butylphosphine tetrafluoroborateHCID 671711241-(3-Bromo-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl esterHCID 866725703-Chloro-2,6-difluoro-4-methoxyphenylboronic Acid

Product 1

HCID 866725711-[(3'-Chloro-2',6'-difluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methyl-cyclohexanecarboxylic Acid Methyl EsterYield 39.9%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Procedure

300 mg of 1-(3-Bromo-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl ester, 36 mg of tris(dibenzylideneacetone)di-palladium(0), 150 mg of KF, 27 mg of tri-tert-butylphosphonium tetrafluoroborate, and 347 mg of 3-Chloro-2,6-difluoro-4-methoxyphenylboronic acid were suspended using 5 ml of anhydrous dioxane and oxygen was removed by passing argon through. Then, 12 mg of N,N-diisopropylethylamine were added and again argon passed through the suspension. Stirring was continued for 24 h at room temperature. The reaction mixture was then filtered and evaporated. The residue was purified by preparative RP HPLC (water/ACN gradient) to yield 150 mg of the title compound, viscous oil.

Workup

  1. customwas removed
  2. additionThen, 12 mg of N,N-diisopropylethylamine were added
  3. filtrationThe reaction mixture was then filtered
  4. customevaporated
  5. customThe residue was purified by preparative RP HPLC (water/ACN gradient)

Sources & evidence

ORD record
ord-a6cfdf19f7614c398074289cf0de505f
Source dataset
uspto-grants-2015_04
Patent number
US09018383B2

Reaction notes

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