3-(chloromethyl)benzoyl chloride

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:

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: 0.6 ml of 3-chloromethylbenzoyl chloride is added dropwise, at 0° C., to 1.6 g of the compound of Example 4 dissolved in 10 ml of anhydrous pyridine. After 2 hours at 0° C., methanol is added to hydrolyze the excess acid chloride and the organic phase is diluted with methylene chloride. This is then washed with 2N hydrochloric acid, with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride and dried over anhydrous sodium sulphate. The organic solvent is evaporated off and the product is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent, to give the expected product. This is then washed with 2N hydrochloric acid, with saturated aqueous sodium bicarbonate with saturated aqueous sodium chloride and dried over anhydrous sodium sulphate The organic solvent is evaporated off the product is purified on a column of silica a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent

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

Procedure: The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (0.300 g, 1.13 mmol), Et3N (0.17 mL, 1.2 mmol), 3-(chloromethyl)benzoyl chloride (0.13 mL, 1.13 mmol), CH2Cl2 (5.0 mL), acetonitrile (5.0 mL), acetone cyanohydrin (0.05 mL, 0.5 mmol), Et3N (0.35 mL, 2.5 mmol), glacial acetic acid (6.0 mL), sodium cyanoborohydride (0.50 g, 7.9 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 4/1 hexane/ethyl acetate to 3/2 hexane/ethyl acetate) to provide a solid (0.118 g, 135°-137° .C). 1H NMR (400 MHz, DMSO-d6) δ 11.211 (s, 1 H), 7.418-7.280 (m, 10 H), 7.088 (d, 1 H, 7.5 Hz), 6.975 (t, 1 H, J=7.5 Hz), 6.689 (s, 1 H), 6.513 (d, 1 H, J=7.5 Hz), 4.498 (s, 2 H), 3.540 (s, 2 H), 3.447 (s, 2 H). Purification to provide a solid (0.118 g, 135°-137° .C)

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

Procedure: 2-Amino-5-chloro-benzoic acid methyl ester (1.5 g) was dissolved in anhydrous methylene chloride (25 ml). Pyridine (1.4 ml) and 3-(chloromethyl)benzoyl chloride (1.4 ml) were added dropwise to the solution at 0° C., and the mixture was then stirred at room temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was then washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure to precipitate crystals. The precipitated crystals were collected by filtration through Kiriyama Rohto and were washed with ether to give 5-chloro-2-(3-chloromethyl-benzoylamino)-benzoic acid methyl ester as a useful intermediate (2.4 g, yield 90%). After the completion of the reaction distilled water was added at room temperature, and the mixture was subjected to separatory extraction with chloroform The organic layer was then washed with saturated brine was dried over sodium sulfate was then concentrated under the reduced pressure to precipitate crystals The precipitated crystals were collected by filtration through Kiriyama Rohto were washed with ether

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

Procedure: The resultant compound of Example 70 (769 mg, 1.04 mmol) was combined with 3-(chloromethyl) benzoyl chloride (395 mg, 2.09 mmol) and pyridine (165 mg, 2.09 mmol) in 10 mL of freshly distilled methylene chloride. The reaction mixture was stirred at ambient temperature under nitrogen for approximately 65 h and then diluted with 150 mL of chloroform. The chloroform solution was washed with 75 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (1.59 g) was taken up in ~10 mL of methylene chloride and applied to a 1.5×45 cm column of 40 mesh silica gel. The column was eluted @~5 p.s.i. sequentially with 200 mL of methylene chloride, 200 mL of 0.5% methanol in methylene chloride and 200 mL of 1% methanol in methylene chloride to give 275 mg (30% yield) of the title compound; FAB MS M/Z: 889 (M+H)+. The 300 MHz 1H NMR spectrum was consistent with the assigned structure. The chloroform solution was washed with 75 mL of water dried over anhydrous magnesium sulfate filtered concentrated under reduced pressure The column was eluted @~5 p.s.i