1,2-Dichloroethane → 4-(2-chloro-5-fluoropyrimidin-4-yl)-N-[1-(3-chlorophenyl)-2-hydroxyethyl]-benzamide

HRID 968695Notes

Reaction equation

HRID 968695 reaction equation
CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=2)=[CH:6][CH:5]=1.[Li+].[OH-].[CH2:21]([Cl:24])[CH2:22]Cl.[CH:25]1C=CC2N(O)N=NC=2[CH:30]=1.CC[N:37](CC)CC.[CH2:42]1[CH2:46][O:45][CH2:44][CH2:43]1>O.C(OCC)(=O)C>[Cl:17][C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([NH:37][CH:42]([C:43]3[CH:30]=[CH:25][CH:22]=[C:21]([Cl:24])[CH:44]=3)[CH2:46][OH:45])=[O:18])=[CH:9][CH:8]=2)[C:15]([F:16])=[CH:14][N:13]=1

Participants

9

Reactant 6

HCID 111,2-DichloroethaneHCID 3939Lithium HydroxideHCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 85941984Methyl 4-(2-Chloro-5-fluoro-4-pyrimidinyl)benzoate

Product 1

HCID 865926124-(2-chloro-5-fluoropyrimidin-4-yl)-N-[1-(3-chlorophenyl)-2-hydroxyethyl]-benzamideYield 55%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-(2-chloro-5-fluoropyrimidin-4-yl)-benzoic acid methyl ester (0.3 g, 1.13 mmol) in 4 mL of THF was added a solution of LiOH (0.378 g, 9.0 mmol) in 4 mL of H2O and stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate (10 mL) to remove any byproduct. The aqueous layer was acidified to pH=3 with 6N HCl and the resulting precipitate filtered. To a suspension of these solids in 5 mL of DMF was added EDC (0.26 g, 1.36 mmol), HOBt (0.229 g, 1.70 mmol), and Et3N (0.236 mL, 1.70 mmol) and stirred for 10 minutes. (S)-(+)-3-chlorophenyl glycinol (0.353 g, 1.70 mmol) was added and the reaction stirred overnight. After 18 hours, the reaction was diluted with ethyl acetate and washed with 1N HCl, NaHCO3, saturated NaCl. The organic layer was concentrated and the residue purified by chromatography (Silica, 40% ethyl acetate in hexanes) to afford 4-(2-chloro-5-fluoropyrimidin-4-yl)-N-[1-(3-chlorophenyl)-2-hydroxyethyl]-benzamide (0.15 g, 55%) as a white solid. 1H NMR (CDCl3, 500 MHz): 8.40 (d, 1H), 8.15 (d, 2H), 7.90-7.95 (m, 2H), 7.32 (s, 1H), 7.22-7.29 (m, 2H), 7.05-7.08 (m, 1H), 5.18-5.22 (m, 1H), 3.95-4.00 (m, 2H), 1.80 (s, 2H). LCMS: ES+=406.

Workup

  1. extractionThe reaction mixture was extracted with ethyl acetate (10 mL)
  2. customto remove any byproduct
  3. filtrationthe resulting precipitate filtered
  4. additionTo a suspension of these solids in 5 mL of DMF
  5. stirringstirred for 10 minutes
  6. stirringthe reaction stirred overnight
  7. waitAfter 18 hours
  8. washwashed with 1N HCl, NaHCO3, saturated NaCl
  9. concentrationThe organic layer was concentrated
  10. customthe residue purified by chromatography (Silica, 40% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-ef99b3d07cd843bd8a614ed92789f06b
Source dataset
uspto-grants-2007_12
Patent number
US07304071B2

Reaction notes

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