Patent Watch

January 2, 2012

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Modify reaction conditions to improve an anesthetic synthesis. In these two patents, O. Pacheco and co-inventors report processes for preparing sevoflurane (3), an inhalation anesthetic, and its precursor sevochlorane (2). They summarize earlier processes used to prepare 3, many of which have low selectivity or give poor yields. Their synthesis of 3 begins with fluoro alcohol 1, which was also used in earlier processes that had incomplete reactions or used highly toxic reagents.

In the first patent, the inventors describe the synthesis of 2 by treating 1 with HCHO and a chlorinating agent such as SOCl2 in the presence of H2SO4. HCHO is generated from 1,3,5-trioxane or paraformaldehyde. After the reaction mixture is neutralized, 2 is treated with KF to produce 3 (Figure 1).

The purity of 2 and the reaction selectivity depend on the proportions of HCHO and SOCl2 relative to 1; both reagents are usually used in excess. The reaction is carried out by adding H2SO4 to the mixture of 1, SOCl2, and the HCHO precursor. The chlorinating agent ClSO3H is formed in situ. The reaction initially forms several byproducts, shown in Figure 2.

As the reaction proceeds, byproducts 46 are converted to 2 by reacting with ClSO3H. According to the inventors, this result contradicts reports of earlier processes that used 1 as the starting material, which stated that these byproducts reduce the yield of 2.

Ether byproduct 7 is an extremely carcinogenic, volatile compound that is formed when HCHO contacts ClSO3H. Although 7 is rapidly hydrolyzed, its production is a potential major health hazard. Monitoring its concentration in and around the process site is essential because of its volatility. Analysis of the crude reaction mixture from the production of 2 showed levels of 7 as high as 0.5%.

The mixture is neutralized with base, and 2 is recovered in 80% yield. GC analysis showed that the product is 99.3% pure, with 0.04% 1, 0.3% 4, and 0.4% of 5 and 6.

The second patent describes the use of KI to improve the rate and conversion of the reaction of intermediate 2 and KF to form 3. Several experiments show the effect of KI and solvent on this reaction. Adding substoichiometric amounts of KI reduces the reaction time and the quantity of KF needed. The inventors, however, recommend using a slight excess of KF to shift the reaction equilibrium toward 3.

The solvents examined include sulfolane, DMF, glycols and their ethers or esters, and mixtures of mono- and diglycerides (MDG) with medium chain lengths. In all cases, the conversion of 2 to 3 was >97%. In an example in which MDG is the solvent, 3 is recovered in 76% yield and >99% purity after fractional distillation.

The overall process gives high yields but produces an extremely hazardous byproduct that requires careful methods for monitoring and control. (Cristalia Produtos Quimicos Farmaceuticos [Itapira, Brazil]. US Patent 8,039,678, Oct. 18, 2011, and US Patent 8,044,247, Oct. 25, 2011; Keith Turner)

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