Dimethyl Sulfoxide → {3-[2-(3-Chlorophenyl)-2,2-difluoroethylamino]-6-cyano-2-fluorophenyl}acetic acid ethyl ester

HRID 1987058Notes

Reaction equation

HRID 1987058 reaction equation
CCN(C(C)C)C(C)C.C(OC(=O)[CH:14]([C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22](F)[C:21]=1[F:29])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.CS(C)=O.[Cl:35][C:36]1[CH:37]=[C:38]([C:42]([F:46])([F:45])[CH2:43][NH2:44])[CH:39]=[CH:40][CH:41]=1>C([O-])(O)=O.[Na+]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:20]1[C:25]([C:26]#[N:27])=[CH:24][CH:23]=[C:22]([NH:44][CH2:43][C:42]([C:38]2[CH:39]=[CH:40][CH:41]=[C:36]([Cl:35])[CH:37]=2)([F:45])[F:46])[C:21]=1[F:29])[CH3:19]

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 81531DiisopropylethylamineHCID 577226982-(3-Chlorophenyl)-2,2-difluoroethan-1-amineHCID 577227202-(6-Cyano-2,3-difluorophenyl)malonic acid diethyl ester

Product 1

HCID 57722713{3-[2-(3-Chlorophenyl)-2,2-difluoroethylamino]-6-cyano-2-fluorophenyl}acetic acid ethyl esterYield 64.1%

Reagents, catalysts & solvents 1

HCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of DIPEA (1.38 mL, 7.9 mmol), 2-(6-cyano-2,3-difluorophenyl)malonic acid diethyl ester (1.35 g, 6.00 mmol), as prepared in the preceding step, and DMSO (1.7 mL) was added 2-(3-chlorophenyl)-2,2-difluoroethylamine (1.44 g, 7.51 mmol), as prepared in Example 2d. The reaction was stirred under argon at 110° C. for 69 h and then allowed to cool to room temperature. The mixture was diluted with saturated NaHCO3 (15 mL) and extracted with ether (2×15 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel (3:1 hexane/EtOAc) to afford the title compound (1.525 g, 64%) as a tan crystalline solid. 1H NMR (300 MHz, CDCl3) δ 7.51-7.41 (m, 2H), 7.40-7.36 (m, 2H), 7.30 (dd, J=8.6 Hz, 1.3 Hz, 1H), 6.63 (t, J=8.2 Hz, 1H), 4.67 (br, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.84 (d, J=2.0 Hz, 2H), 3.81 (dt, J=13.3 Hz, 6.9 Hz, 2H), 1.29 (t, J=7.1 Hz, 3H). LC/MS (ESI) calcd for C21H20ClF3N3O2 (MH+.MeCN) 438.1. found 438.2.

Workup

  1. customas prepared in Example 2d
  2. temperatureto cool to room temperature
  3. extractionextracted with ether (2×15 mL)
  4. dry with materialThe combined organic layers were dried (Na2SO4)
  5. concentrationconcentrated
  6. customThe residue was purified by flash chromatography on silica gel (3:1 hexane/EtOAc)

Sources & evidence

ORD record
ord-1f65a06f11be4765a64c8aeb6ab920fb
Source dataset
uspto-grants-2009_06
Patent number
US07550474B2

Reaction notes

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