One-Step Synthesis of 3-Thioacetylsulfolane

Abstract

A one-step synthesis of (S)-3-thioacetylsulfolane is described. Reaction of 3-sulfolene with thiolacetic acid in the presence of AIBN or Ph₃SiSH under basic conditions gave racemic 3-thioacetylsulfolane in 30-32% yield. Enantiomerically pure (S)-3-thioacetylsulfolane was obtained by chiral chromatography.

Key words

3-sulfolane - butadiene sulfone - thioacetic acid - thioacetylsulfolane

References and Notes

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4

The prodrug ester undergoes in vivo hydrolysis to release sulopenem as the active drug substance.

16

A 1-liter three-necked round-bottomed flask equipped with mechanical stirring, heating mantle, glycol condenser, and bleach scrubber under nitrogen atmosphere was charged with butadiene sulfone (15.0 g, 127 mmol), toluene, (12 mL/g), and 2,2′-azobisisobutyronitrile (10.43 g, 63.5 mmol). Thioacetic acid (21.77 g, 286 mmol) was added via syringe. The mixture was then heated at 100 ˚C for 15 h. A sample by HPLC verified the reaction was done. The toluene was removed on a rotovap (30 mmHg, 65 ˚C). The resulting dark red viscous oil was dissolved in EtOAc (100 mL) and washed successively with sat. NaHCO₃ solution (100 mL; pH check of aqueous layer showed 8.0) and sat. NaCl solution (100 mL). The organic phase was then stirred with MgSO₄ powder (75 g) for 1 h. Darco G-60 activated carbon (15 g) was added to the slurry and stirred for additional 1 h. The slurry was filtered over silica gel 60 (100 g), and washed with EtOAc (4 × 100 mL). The combined filtrate and wash were concentrated to an oil, then diluted with EtOAc (15 mL) and hexanes (75 mL). After stirring for 30 min, the product started to crystallize. The resulting slurry was stirred for 1 h at 20-25 ˚C, filtered and air dried to give rac-8 (7.42 g, 35.2 mmol, 30%); mp 68.2-70.6 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 4.09-4.18 (m, 1 H), 3.53 (dd, J = 8.0, 14.0 Hz, 1 H), 3.20-3.33 (m, 1 H), 3.05-3.14 (m, 1 H), 2.96 (dd, J = 8.0, 14.0 Hz, 1 H), 2.54-2.63 (m, 1 H), 2.36 (s, 3 H), 2.15-2. 27 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 193.8, 56.1, 51.5, 37.4, 30.5, 29.1. MS: m/z = 195.08 [M + H]⁺, 152.04. HRMS: m/z [M + H]⁺ calcd for C₆H₁₁O₃S₂: 195.0150; found: 195.0137.

18

2.48 g (90% yield) of (S)-8 was obtained from 5.5 g of rac-8 in a typical laboratory chiral chromatographic separation.

19

The scale-up was performed in a contract research organization facility, where the process safety evaluation was completed. Due to the inherent risk of scaling up radical chemistry, it is recommended that process safety be thoroughly examined when considering running this reaction.