methyl 1,1-dioxo-1,2-thiazolidine-3-carboxylate

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

Procedure: Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (781 mg) described in Preparation Example 108 and 1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (580 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (41 mg) was obtained.

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

Procedure: Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (781 mg) described in Preparation Example 108 and 1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (580 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (41 mg) was obtained.

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

Procedure: To a stirred solution of 1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (Intermediate 1, 0.200 g, 1.10 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.450 g, 3.20 mmol) at room temperature under nitrogen. The reaction mixture was cooled to 0° C. and 3-cyano benzyl bromide (available from Aldrich; 0.240 g, 1.22 mmol) was added into the reaction mixture slowly and followed by the addition of tetra-n-butylammonium (0.025 g, 0.07 mmol). The reaction was completed in 5 h at room temperature as monitored by silica TLC. The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (3×15 mL), dried over sodium sulfate and concentrated under reduced pressure to provide crude material, which was purified by silica gel column chromatography (100-200 mesh) using a gradient of 20-30% ethyl acetate/hexanes to give 2-(3-cyano-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (0.170 g, 56%). washed with water (3×15 mL) dried over sodium sulfate concentrated under reduced pressure to provide crude material, which was purified by silica gel column chromatography (100-200 mesh)

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

Procedure: 3-Bromomethyl-benzaldehyde (2.44 g, 12.3 mmol) and cesium carbonate (9.08 g, 27.9 mmol) were added to a solution of a 4:3 mixture of 1,1-dioxo-isothiazolidine-3-carboxylic acid methyl ester and 1,1-dioxo-isothiazolidine-3-carboxylic acid ethyl ester (Intermediate 7 Step 2; 2.01 g, 10.8 mmol) in N,N-dimethylformamide (60 mL). The mixture was stirred at room temperature for 20 h and then dichloromethane (100 mL) was added. Saturated aqueous ammonium chloride solution (25 mL) was added followed by 1 M hydrochloric acid to bring the pH to 2-3. The two layers were separated and the organic layer was washed twice with brine. The solution was dried over sodium sulfate, and filtered. Celite was added and the solvents were evaporated under reduced pressure. The residue (containing the mixture of crude products coated onto Celite) was purified using flash chromatography (Analogix SF40-240 g Si), eluting with 30-70% ethyl acetate/hexanes to give 2-(3-formyl-benzyl)-1,1-dioxo-1λ6 isothiazolidine-3-carboxylic acid ethyl ester (first eluting peak; 1.26 g, 37%) and 2-(3-formyl-benzyl)-1,1-dioxo-1λ6 isothiazolidine-3-carboxylic acid methyl ester (second eluting peak; 1.69 g, 53%). The two layers were separated the organic layer was washed twice with brine The solution was dried over sodium sulfate filtered Celite was added the solvents were evaporated under reduced pressure The residue (containing the mixture of crude products coated onto Celite) was purified eluting with 30-70% ethyl acetate/hexanes