Dimethylformamide → N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide

HRID 1752981Notes

Reaction equation

HRID 1752981 reaction equation
O.[F:2][C:3]1[CH:29]=[CH:28][C:6]([O:7][C:8]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[O:11])=[C:5]([CH3:30])[CH:4]=1.CN(C)C=O.[Cl:36][C:37](OCCl)=O>ClCCl.C(OCC)(=O)C>[Cl:36][CH2:37][N:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[C:9]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:25])[F:26])=[CH:23][C:8]=2[O:7][C:6]2[CH:28]=[CH:29][C:3]([F:2])=[CH:4][C:5]=2[CH3:30])=[CH:14][C:15]1=[O:19]

Participants

6

Reactant 3

HCID 6228DimethylformamideHCID 62754Chloromethyl chloroformateHCID 1181266202-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide monohydrate2×

Product 1

HCID 118126598N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamideYield 48.8%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A sample of 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide monohydrate (9a) (6.0 g, 14.7 mmol) was dehydrated under vacuum at 65° C. A solution of anhydrous 2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (9a) (5.0 g, 12.31 mmol) and N,N-dimethylformamide (10.0 mL) in dichloromethane (50.0 mL) was stirred at room temp., chloromethyl chloroformate (1.64 ml, 18.46 mmol) was added and the solution was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, dried with anhydrous sodium sulfate, filtered and evaporated to dryness. The resulting oil was purified by column chromatography (40 g silica, 20-100% EtOAc in Hexanes), product fractions were pooled and evaporated to give N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide (3.26 g, 7.168 mmol) that was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.66-7.58 (m, 1H), 7.28-7.19 (m, 1H), 7.10 (dd, J=7.7, 2.0 Hz, 2H), 6.98 (s, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.50 (dd, J=7.6, 2.3 Hz, 1H), 5.79 (s, 2H), 2.16 (s, 3H) ppm.

Workup

  1. customwas dehydrated under vacuum at 65° C
  2. washwashed with saturated aqueous sodium bicarbonate, brine
  3. dry with materialdried with anhydrous sodium sulfate
  4. filtrationfiltered
  5. customevaporated to dryness
  6. customThe resulting oil was purified by column chromatography (40 g silica, 20-100% EtOAc in Hexanes), product fractions
  7. customevaporated

Sources & evidence

ORD record
ord-57f397aec2bd4ab48ec452123094e8f1
Source dataset
uspto-grants-2015_10
Patent number
US09163042B2

Reaction notes

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