Ammonium Chloride → N-(4-fluorobenzyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)thiazole-5-carboxamide

HRID 883143Notes

Reaction equation

HRID 883143 reaction equation
[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1.[Cl-].[NH4+]>CN1CCCN(C)C1=O.O1CCCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:19][CH2:18][CH:17]([CH2:35][C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=4)[C:16]3=[O:20])=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 25517Ammonium ChlorideHCID 1230621-(Bromomethyl)-4-(trifluoromethyl)benzeneHCID 2733832Lithium HexamethyldisilazideHCID 16954475HCID 16954475, compound

Product 1

HCID 24801505N-(4-fluorobenzyl)-4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)pyrrolidin-1-yl)thiazole-5-carboxamideYield 41%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent

Conditions

Temperature
-78 °C

Procedure

To a solution of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide (0.13 g, 0.38 mmol) in a mixture of anhydrous tetrahydrofuran and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8/1, v/v) at −78° C. was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL, 0.83 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 minutes, followed by the addition of 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.058 mL, 0.38 mmol) dropwise. The reaction mixture was warmed to −30° C. in 30 minutes. Aqueous saturated ammonium chloride solution (10 mL) was added, followed by extraction with dichloromethane (3×10 mL). The combined organic solutions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexanes (1/1)) to afford the title compound as a white solid (0.075 g, 41%): mp 175-176° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=7.9 Hz, 2H), 7.32-7.24 (m, 4H), 7.01 (t, J=8.9 Hz, 2H), 6.03 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.17-4.04 (m, 1H), 3.91-3.81 (m, 1H), 3.30 (dd, J=13.8, 4.3 Hz, 1H), 3.06-2.99 (m, 1H), 2.85 (dd, J=13.8, 8.9 Hz, 1H), 2.61 (s, 3H), 2.32-2.21 (m, 1H), 1.93-1.83 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.4, 162.3, 155.3, 152.8, 142.4, 133.8, 129.9, 129.6, 129.3, 125.6, 118.6, 115.7, 115.6, 45.9, 44.2, 43.4, 36.2, 24.4, 17.3; MS (ES+) m/z 492.3 (M+1).

Workup

  1. temperatureThe reaction mixture was warmed to −30° C. in 30 minutes
  2. extractionfollowed by extraction with dichloromethane (3×10 mL)
  3. dry with materialThe combined organic solutions were dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue was purified by column chromatography (ethyl acetate/hexanes (1/1))

Sources & evidence

ORD record
ord-984dc17119664f33b32d295143cd15f5
Source dataset
uspto-grants-2012_08
Patent number
US08236835B2

Reaction notes

Loading…