An improved procedure for the preparation of 3-carbometfaoxy-4-oxotetrahydrothiopyran, 2- and 4-carbomethoxy-3-oxotetrahydrothiophene

Abstract

An improved procedure for the preparation of the title compounds 1-3 has been developed. Direct condensation of methyl 3-mercaptopropionate with methyl acrylate using sodium hydride as a base gave compound 1 in good yield. The reaction of methyl thioglycolate and methyl acrylate at 0 °C gave compound 2 as the major product whereas at lower temperature (−40 °C) isomer 3 was found as the major product. The condensation reactions of methyl thioglycolate with methyl methacrylate and crotonate were also carried out.

Development of a Practical Process for the Synthesis of PDE4 Inhibitors

“…The combined organic layer was washed with water twice (24 L per wash) and concentrated under reduced pressure by distillation to give 7.45 kg (95.8% weight by assay; 44.6 mol) of 5 in 89.8% yield. The spectral data of 5 are consistent with literature values. , …”

“…These results suffered the drawbacks of releasing an equivalent of ethanethiol or utilizing undesirable diazo compounds, both of which are potential issues for large scale synthesis. However, as we also observed, the use of ordinary diesters like 4 for the base promoted Dieckmann condensation is reported to occur without selectivity to afford a mixture of difficult to separate regioisomers. , Similarly, the TiCl 4 -mediated regioselective formation of 5 from 4 in the presence of Et 3 N gave numerous impurities arising from chlorination and dehydrohalogenation as reported by Deshmukh and co-workers. In addition, the workup procedure resulted in the formation of vast quantities of solids that had to be laboriously removed.…”

“…However, the undesired regioisomer (7) could only be removed by silica gel chromatography or high vacuum distillation (eq 1) making this approach undesirable for multikilo scale synthesis. 6 To solve the above limitations, we evaluated a number of reported literature procedures for the synthesis of similar compounds.…”

“…Initially, 5 was obtained from 4 under strongly basic conditions (sodium hydride, DME) at low temperature (−40 °C) resulting in the desired product along with varying amounts of the undesired regioisomer 7 . However, the undesired regioisomer ( 7 ) could only be removed by silica gel chromatography or high vacuum distillation (eq ) making this approach undesirable for multi-kilo scale synthesis . To solve the above limitations, we evaluated a number of reported literature procedures for the synthesis of similar compounds. …”

“…12 This new process completely eliminated the strong stench associated with both the synthesis of 8 and the liberation of ethanethiol upon its hydrolysis. In addition, the overall cost of the drug substance was significantly reduced and the new process (eq 2) provided a stable, easy-to-purify, solid intermediate (6), eliminating the complications associated with the transport or storage of crude and noncrystalline 5.…”