Water → 2-[6-Amino-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid Methyl Ester

HRID 385370Notes

Reaction equation

HRID 385370 reaction equation
[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:22])=[C:12](Br)[CH:11]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].O>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.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:10]1[CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[C:13]([NH2:22])=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:5][CH:6]1[CH2:9][CH2:8][CH2:7]1

Participants

8

Reactant 4

HCID 962WaterHCID 25953Cesium fluorideHCID 27343894-(Trifluoromethyl)phenylboronic acidHCID 57995592HCID 57995592, compound

Product 1

HCID 579956032-[6-Amino-5-(2,2,2-trifluoro-ethoxy)-4'-trifluoromethyl-biphenyl-3-yl]-3-cyclobutyl-propionic acid Methyl EsterYield 104.5%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2-[4-amino-3-bromo-5-(2,2,2-trifluoro-ethoxy)-phenyl]-3-cyclobutyl-propionic acid methyl ester (13.8 g, 29.6 mmol) in DME (anhydrous, 100 mL) under argon atmosphere were added 4-trifluoromethylphenylboronic acid (6.8 g, 35.8 mmol), CsF (11 g, 72.3 mmol), and Pd(PPh3)4 (3.4 g, 2.94 mmol). The reaction mixture was refluxed for 18 h (oil bath, 100° C.). On the next day, a mixture water and EtOAc (100 mL/100 mL) was added and the layers were separated. The organic phase was dried over MgSO4 and evaporated to give a crude yellow oil, which was purified by a short silica gel column chromatography by use of Heptane-EtOAc (4:1) to give the product (14.7 g, 94%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.70 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.0 Hz, 2H), 6.78 (dd, J=9.6, 1.4 Hz, 2H), 4.43 (q, J=8.0 Hz, 2H), 3.95 (br s, 2H), 3.66 (s, 3H), 3.39 (t, J=7.7 Hz, 1H), 2.25-2.07 (m, 2H), 2.03-1.91 (m, 2H), 1.88-1.75 (m, 3H), 1.69-1.52 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 174.6, 144.8, 133.1, 129.2, 128.6, 126.3, 125.7 (q, 3JCF=3.6 Hz), 123.8, 123.3 (q, 1JCF=277.6 Hz), 111.4, 66.5 (q, 1JCF=35.4 Hz), 52.0, 49.0, 40.9, 34.1, 28.3, 28.1, 18.5.

Workup

  1. customthe layers were separated
  2. dry with materialThe organic phase was dried over MgSO4
  3. customevaporated
  4. customto give a crude yellow oil, which
  5. customwas purified by a short silica gel column chromatography by use of Heptane-EtOAc (4:1)

Sources & evidence

ORD record
ord-e57e971f866a499cb05820b9dbedef76
Source dataset
uspto-grants-2013_02
Patent number
US08367863B2

Reaction notes

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