2-bromoethyl carbonochloridate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(2-mercaptobenzoyl)glycinamide (1.05 g, 5.0 mmol) in N,N-dimethylacetamide (DMA, 25 ml) was added 2-bromoethyl chloroformate (1.22 g, 6.5 mmol). The reaction mixture was stirred for 8 h, the solvent was evaporated to dryness, and the residue was triturated with ethyl ether (25 ml. The resulting precipitate was filtered, washed with water and dried over CaCO2, Yield: 89%. 1H NMR (DMSO-d6): 3.71 (t, 1H, CH2), 3.78 (d, 2H, CH2), 3.86 (t, 1H, CH2), 4.45 (t, 1H, CH2), 4.51 (t, 1H, CH2), 7.11 (brs, 1H, NH2), 7.30 (brs, 1H, NH2), 7.36-7.58 (m, 5H, Ar—H, NH2), 8.26 (t, 2H, Py-H), 8.36 (t, 1H, NH), 8.52 (t, 1H, NH), 8.66 (t, 1H, Py-H), 9.12 (d, 21, Py-H). the solvent was evaporated to dryness the residue was triturated with ethyl ether (25 ml The resulting precipitate was filtered washed with water dried over CaCO2, Yield: 89%

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.5 g of (S)-2-O-benzyl-1-O-octadecyl glycerine in 25 ml of dichloromethane is treated with 0.3 ml of pyridine and cooled to 0° C. The solution is treated with 0.2 ml of 2-bromoethyl chloroformate, stirred at room temperature, treated with 10 ml of water and acidified to pH 3 with 1N hydrochloric acid. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on silica gel while eluting with ether/n-hexane (1:1). There is obtained (R)-2-O-benzyl-1-[(2-bromoethoxy)carbonyl]-3-O-octadecylglycerine in the form of an oil. The organic phase is washed with water dried evaporated The residue is chromatographed on silica gel while eluting with ether/n-hexane (1:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5.0 g (14.3 mmol) of 5-(cyanomethyl)-4-(2-methylpropyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example d, above, 8.02 g 2-bromoethyl chloroformate, and 0.3 g benzyltriethylammonium chloride in 125 mL dichloromethane was added 82 mL 50% NaOH. The solution was stirred at room temperature for one hour. The mixture was then poured into ice water and extracted twice with ethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered through silica gel, and concentrated to give 3.2 g of crude dark yellow oil. Chromatography using 50% ethyl acetate in hexanes yielded 2.0 g of the desired product as a light yellow oil, a 56% yield, which crystallized upon standing. m.p. 121°-122° C. extracted twice with ethyl ether The organic layer was washed with brine dried over magnesium sulfate filtered through silica gel concentrated to give 3.2 g of crude dark yellow oil

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5.0 g (14.3 mmol) of 5-(cyanomethyl)-4-(2-methylpropyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylic acid, methyl ester, prepared as in Example d, above, 8.02 g 2-bromoethyl chloroformate, and 0.3 g benzyltriethylammonium chloride in 125 mL dichloromethane was added 82 mL 50% NaOH. The solution was stirred at room temperature for one hour. The mixture was then poured into ice water and extracted twice with ethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, filtered through silica gel, and concentrated to give 3.2 g of crude dark yellow oil. Chromatography using 50% ethyl acetate in hexanes yielded 2.0 g of the desired product as a light yellow oil, a 56% yield, which crystallized upon standing. m.p. 121°-122° C. extracted twice with ethyl ether The organic layer was washed with brine dried over magnesium sulfate filtered through silica gel concentrated to give 3.2 g of crude dark yellow oil

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 272 mg (0.89 mmol) of the compound from Example 101A and 171 μl (0.98 mmol) of N,N-diisopropylethylamine in 3 ml of acetonitrile was admixed dropwise with a solution of 106 μl (0.98 mmol) of 2-bromoethyl chloroformate in 2 ml of acetonitrile. For work-up, after 10 minutes, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added. The organic phase was separated, washed again with saturated aqueous sodium hydrogen carbonate solution, dried over sodium sulphate and freed from the volatile constituents on a rotary evaporator. Drying of the residue in an HV gave 352 mg (82% of theory) of the title compound. The organic phase was separated washed again with saturated aqueous sodium hydrogen carbonate solution dried over sodium sulphate freed from the volatile constituents on a rotary evaporator Drying of the residue in an HV

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 0.5 g of (S)-2-O-benzyl-1-O-octadecyl glycerine in 25 ml of dichloromethane is treated with 0.3 ml of pyridine and cooled to 0° C. The solution is treated with 0.2 ml of 2-bromoethyl chloroformate, stirred at room temperature, treated with 10 ml of water and acidified to pH 3 with 1N hydrochloric acid. The organic phase is washed with water, dried and evaporated. The residue is chromatographed on silica gel while eluting with ether/n-hexane (1:1). There is obtained (R)-2-O-benzyl-1-[(2-bromoethoxy)carbonyl]-3-O-octadecylglycerine in the form of an oil. The organic phase is washed with water dried evaporated The residue is chromatographed on silica gel while eluting with ether/n-hexane (1:1)