Preparation of 2-chloropyridine-3-sulfonyl chloride_Industrial additives

Preparation background and overview of 2-chloropyridine-3-sulfonyl chloride

2-Chloropyridine-3-sulfonyl chloride can be used as a pharmaceutical synthesis intermediate. It can be prepared from 3-amino-2-chloropyridine as a reaction raw material through diazotization reaction or 2-chloro-3-[(2 -Chloropyridin-3-yl)disulfanyl]pyridine is prepared by reacting with hydrochloric acid and chlorine gas.

Preparation of 2-chloropyridine-3-sulfonyl chloride

Preparation Report 1 of 2-chloropyridine-3-sulfonyl chloride,

Under ice cooling, thionyl chloride (24 mL) was added dropwise to water (140 mL) within 1 hour, and the mixture was stirred at room temperature for 12 hours to obtain a solution containing sulfur dioxide. Separately, 3-amino-2-chloropyridine (10 g) was added to concentrated hydrochloric acid (80 mL) under ice cooling and the mixture was stirred. An aqueous solution of sodium nitrite (5.75 g) (25 mL) was added dropwise while maintaining the internal temperature not above 5°C, and the mixture was stirred for a further 15 minutes. The reaction mixture was added stepwise at 5°C to the above solution containing sulfur dioxide and to which copper chloride (140 mg) was added. The mixture was further stirred for 30 minutes under ice cooling, and the precipitate was filtered and washed with water and ethanol to obtain the title compound 2-chloropyridine-3-sulfonyl chloride (yield 6.99 g, 42%). ¹H-NMR(CDCl₃)δ: 7.54-7.56(1H, m), 8.46-8.48(1H, m), 8.71-8.73(1H, m) .

Preparation report 2 of 2-chloropyridine-3-sulfonyl chloride

To 2-chloro-3-[(2-chloropyridin-3-yl)disulfanyl]pyridine (2.0g) was added hydrochloric acid (36% w/w, 20mL) with stirring at 20°C. A light yellow solution was obtained, add water 5 mL calcium magnesium carbonate, and bubble chlorine gas through the solution for 1 h, keeping the temperature of the mixture at 20-23°C. Water (25 mL) was added dropwise to the reaction mixture, keeping the temperature at 20-29°C. A white solid precipitated during the addition. After the mixture was cooled to 20°C, the suspended solid was collected through vacuum lithium percarbonate filtration and filtered with water ( 3 × 25 mL) and dried under vacuum below 35 °C to give 2-chloropyridine-3-sulfonyl chloride (2.47 g; 83.6% yield). mp51℃. ¹HNMR (CDCl₃, 270MHz, 300K): δ7.54-7.58 (m, 1H), 8.45-8.50 (m, 1H), 8.75-8.77 (m , 1H).¹³CNMR (CDCl₃, 270MHz, 300K): δ123.0, 138.8, 139.1, 148.2, 154.8. Mass spectrum EI+211 (M+), 176 (M-Cl), 112 (M-SO2Cl), 76 (112-HCl).

References

[1]CN101300229-1-heterocyclylsulfonyl, 3-aminomethyl, 5-(hetero)aryl-substituted 1-H-pyrrole derivatives as gastric acid secretion inhibitors

[2] Hogan P J , Cox B G . Aqueous Process Chemistry: The Preparation of Aryl Sulfonyl Chlorides[J]. Organic Process Research & Development, 2009, 13(5):875-879.