Yield:300383-07-7 52%

Reaction Conditions:

in acetonitrile at 0 - 20;

Steps:

A.2; F.2

Step 2: Synthesis of 4-Methyl-3-(piperidine-l-sulfonyl)-benzoic acid; To a suspension of 8 g (34.2 mmol) 3-chlorosulfonyl-4-methyl-benzoic acid in acetonitrile (160 mL) was added dropwise 10.1 mL (103 mmol, 3 equ.) of piperidine at 0 ⁰C. The reaction was stirred at 0 ⁰C for 0.5 h, then allowed to warm to room temperature and stirred until completion. The reaction was concentrated under reduced pressure to l/8th of the volume. The residue was dissolved in IM aqueous NaOH solution (50 mL) and washed with TBME (2 x 50 mL). The basic aqueous layer was cooled in an ice-bath and acidified with 2M aqueous HCl solution to pH 1-2. This acidic aqueous layer was then extracted with TBME (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 5.0 g of 4-methyl-3 -(piperidine- 1 -sulfonyl)-benzoic acid.; Step 2: Synthesis of 4-Methyl-3-(piperidine-l-sulfonyl)-benzoic acid; To a suspension of 8 g (34.2 mmol) 3-chlorosulfonyl-4-methyl-benzoic acid in acetonitrile (160 mL) was added dropwise 10.1 niL (103 mmol, 3 equ.) of piperidine at 0 °C. The reaction was stirred at 0 ⁰C for 0.5 h, then allowed to warm to room temperature and stirred until completion. The reaction was concentrated under reduced pressure to l/8th of the volume. The residue was dissolved in IM aqueous NaOH solution (50 mL) and washed with TBME (2 x 50 mL). The basic aqueous layer was cooled in an ice-bath and acidified with 2M aqueous HCl solution to pH 1-2. This acidic aqueous layer was then extracted with TBME (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford 5.0 g of 4-methyl-3 -(piperidine- 1 -sulfonyl)-benzoic acid.

References:

WO2008/98025,2008,A1 Location in patent:Page/Page column 20; 21; 49-50