CHEMBRDG-BB 4010237

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: The procedure is as in Example 29 for the preparation of ethyl (4-methylbenzylthio)acetate, starting with 1-chloromethyl-4-trifluoromethylbenzene (9.8 g), a 2M ethanolic solution of sodium ethylate (25 cc) and ethyl 2-mercaptoacetate (6.1 g) in ethanol (120 cc). Ethyl (4-trifluoromethylbenzylthio)acetate (12.2 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.

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

Procedure: By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-(trifluoromethyl)benzyl chloride (760 mg, 3.92 mmole), 510 mg (50% yield) of 5-(4-(trifluoromethyl)benzyl)aminosalicylic acid was obtained as a white solid.: mp>188° C. (decompose). in Synthesis Example 1

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

Procedure: To an ice-cold solution of 2-amino-2-methyl-1-propanol (21.4 g, 240 mmol) and triethylamine (16.8 mL, 120 mmol) in THF was added dropwise 4-trifluoromethyl benzyl chloride (25.0 g, 120 mmol). After the addition, the reaction mixture was stirred at 0° C. for 30 mins and then stirred at ambient temperature for 8 hrs. The precipitate was removed by filtration and the filtrate was concentrated by evaporating the solvent under reduced pressure. The resulting residue was treated dropwise with thionyl chloride with vigorous stirring at 0° C. After complete addition, the reaction mixture was further stirred at ambient temperature for 1 hr. Ether was poured into the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in water and the aqueous solution was hydrolyzed with 10% (w/v) NaOH. The aqueous phase was extracted three times with ether, and the combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex/EtOAc=5/1) to yield the title compound (25.4 g, 87%). After the addition stirred at ambient temperature for 8 hrs The precipitate was removed by filtration the filtrate was concentrated by evaporating the solvent under reduced pressure The resulting residue was treated dropwise with thionyl chloride with vigorous stirring at 0° C After complete addition the reaction mixture was further stirred at ambient temperature for 1 hr Ether was poured into the reaction mixture the precipitate was collected by filtration The precipitate was dissolved in water The aqueous phase was extracted three times with ether the combined organic layer was washed with brine dried over anhydrous MgSO4 concentrated under reduced pressure The crude residue was purified by column chromatography (Hex/EtOAc=5/1)

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

Procedure: To an ice-cold solution of 2-amino-2-methyl-1-propanol (21.4 g, 240 mmol) and triethylamine (16.8 mL, 120 mmol) in THF was added dropwise 4-trifluoromethyl benzyl chloride (25.0 g, 120 mmol). After the addition, the reaction mixture was stirred at 0° C. for 30 mins and then stirred at ambient temperature for 8 hrs. The precipitate was removed by filtration and the filtrate was concentrated by evaporating the solvent under reduced pressure. The resulting residue was treated dropwise with thionyl chloride with vigorous stirring at 0° C. After complete addition, the reaction mixture was further stirred at ambient temperature for 1 hr. Ether was poured into the reaction mixture and the precipitate was collected by filtration. The precipitate was dissolved in water and the aqueous solution was hydrolyzed with 10% (w/v) NaOH. The aqueous phase was extracted three times with ether, and the combined organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The crude residue was purified by column chromatography (Hex/EtOAc=5/1) to yield the title compound (25.4 g, 87%). After the addition stirred at ambient temperature for 8 hrs The precipitate was removed by filtration the filtrate was concentrated by evaporating the solvent under reduced pressure The resulting residue was treated dropwise with thionyl chloride with vigorous stirring at 0° C After complete addition the reaction mixture was further stirred at ambient temperature for 1 hr Ether was poured into the reaction mixture the precipitate was collected by filtration The precipitate was dissolved in water The aqueous phase was extracted three times with ether the combined organic layer was washed with brine dried over anhydrous MgSO4 concentrated under reduced pressure The crude residue was purified by column chromatography (Hex/EtOAc=5/1)