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Synlett 2011(8): 1117-1120  
DOI: 10.1055/s-0030-1259953
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© Georg Thieme Verlag Stuttgart ˙ New York

Efficient and Scalable Synthesis of Pyridine Sulfonamides

Takashi Emura*, Hitoshi Yoshino, Kazutaka Tachibana, Takuya Shiraishi, Akie Honma, Akemi Mizutani, Terushige Muraoka
Research Division, Chugai Pharmaceutical Co. Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
Fax: +81(550)875326; e-Mail: emuratks@chugai-pharm.co.jp;
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Publication History

Received 13 January 2011
Publication Date:
18 April 2011 (online)

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Abstract

Short-step and scalable transformations from 2,6-dibromopyridine to 6-bromopyridine-2-sulfonamide by means of halogen-metal exchange and subsequent reaction with sulfuryl chloride followed by amidation are established. Application of the method for the synthesis of various pyridine sulfonamides is also described.

Key words

sulfonyl chlorides - sulfonamides - pyridines - Grignard reaction - large-scale synthesis

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12

Large-Scale Preparations of Sulfonamide 2: n-BuLi (1.6 M, 737 mL), n-Bu2Mg (2.0 M, 1176 mL), and THF (70 mL) were charged into a nitrogen-filled reaction vessel at r.t. After cooling at -11 ˚C, a solution of 2,6-dibromopyridine (700 g, 2.95 mol) in THF (2.7 L) was added dropwise over 1 h and 40 min and the mixture was stirred at -10 ˚C for 1 h. The resulting mixture was added to a solution of SO2Cl2 (364 mL, 4.53 mol) in toluene (2.8 L) at -12 ˚C over 1 h and 15 min and the mixture was stirred for 20 min. To the reaction mixture was added H2O (2.8 L) over 40 min. After removal of the aqueous layer, the organic phase was dried over MgSO4 (180 g). The mixture was filtered and concentrated affording the crude sulfonyl chloride 5a (736.5 g). To a solution of the sulfonyl chloride (713 g) in EtOAc (2.1 L) at 0 ˚C was added a solution of HN(PMB)2 (571.2 g, 2.22 mol) and Et3N (385 mL, 2.76 mol) in EtOAc (2.1 L), and the mixture was stirred for 1 h and 10 min. The crude product obtained by extraction and concentration was purified by crystallization from EtOH and H2O giving the sulfonamide 2 (855.8 g, 64%).

13

General Procedure: n-BuLi (2.3 M, 0.139 mL) and n-Bu2Mg (1.0 M, 0.321 mL) were charged into a nitrogen-filled reaction tube at r.t. A solution of halopyridine (0.8 mmol) in THF (0.76 mL) was added dropwise to the n-Bu3MgLi solution at -10 ˚C and the mixture was stirred at
-10 ˚C for 1 h. The resulting mixture was added to a solution of SO2Cl2 (0.096 mL, 1.2 mmol) in toluene (0.76 mL) at -10 ˚C and the mixture was stirred for 10 min. After allowing the temperature of the reaction mixture to rise to 10 ˚C, Et2NH (0.414 mL, 4.0 mmol) was added and the mixture was stirred for 30 min. Extraction and purification by silica gel chroma-tography afforded the product.