Process and intermediates for the preparation of Fluensulfone

#Fluensulfone, a powerful nematicide belonging to the class of heterocyclic fluoroalkenyl sulfones, has the following chemical structure:

#Fluensulfone [chemical name: 5-chloro-2-[(3,4,4-trifluoro-3-buten-1-yl)sulfonyl]thiazole] is commercially available on the market as an emulsifiable concentrate formulation. It was first reported in EP 1200418, Example 3, where it was prepared via the two-step synthesis depicted below:

#It is seen that the synthesis consists of chlorination of a compound of Formula III {chemically named 2-[(3,4,4-trifluoro-3-buten-1-yl)thio]thiazole} to add a chlorine atom to the aromatic ring, followed by oxidation of the chlorine-bearing sulfide of Formula II to create the sulfonyl group, arriving at Fluensulfone. Thus, the direct precursor of Fluensulfone is the compound of Formula II. Its chemical name is 5-chloro-2-[(3,4,4-trifluoro-3-buten-1-yl)thio]thiazole. Hereinafter it is sometimes named “Intermediate C1”.

#FIGS. 1A and 1B show chromatogram and mass spectrum, respectively, according to an example.

#FIGS. 2A, 2B and 2C show 1HNMR, 13CNMR and 19FNMR spectra, respectively, according to an example.

#FIGS. 3A and 3B show chromatogram and mass spectrum, respectively, according to another example.

#The inventors have now found that heterocyclic fluoroalkenyl sulfones bearing halogen atoms on the heterocyclic ring, such as Fluensulfone, are accessible via a synthetic pathway that does not require the use of the mixed haloalkene of Formula V. The alkylation of the heterocyclic thiol (IV) is achieved with the aid of a mixed haloalkane in lieu of the mixed haloalkene (V), for example, with 1,4-dibromo-2-chloro-1,1,2-trifluorobutane (BrCH2—CH2—CFCl—CF2Br) to form the corresponding sulfide (thioether). The alkylation reaction is followed by chlorination, to attach a chlorine atom exclusively to the heterocyclic ring absent a competing carbon-carbon double bond. Only later the necessary carbon-carbon double bond is introduced to the molecule, through a dehalogenation (e.g., reduction) reaction that creates the terminal carbon-carbon double bond. As to the oxidation step that converts the sulfide to a sulfonyl group, it may take place either following the chlorination or the dehalogenation steps. It is of note that the oxidized form does not lend itself to chlorination. Hence the synthesis may be accomplished through routes that differ from one another in the order of steps; the chief requirement placed on the process is that the chlorination step precedes the dehalogenation (reduction) step. The alternative routes of the process, Route 1 and Route 2, are illustrated by the reaction scheme depicted below (where the aforementioned 1,4-Dibromo-2-chloro-1,1,2-trifluorobutane was used in the alkylation step of the 2-mercaptothiazole starting material), alongside Route 3 which failed on the chlorination step:

#The synthetic pathway according to Route 1 is preferred; it is shown below, where the arrows 1, 2, 3 correspond to the alkylation (coupling), chlorination and dehalogenation (reduction) steps, respectively. The most preferred key intermediates, through which the synthesis of Route 1 passes, are named Intermediate A1, B1 and C1, respectively:

#The efficiency of the process set forth above is further enhanced by telescoping steps, namely, by carrying a reaction mixture or worked-up solution from one step directly to the following step, without isolation of an intermediate product or exchange of solvent. In a multistep reaction it is often necessary to replace the solvent when advancing from one step to the next one. A series of tests reported below indicates that the synthetic pathway is amenable to telescopic design, starting with the synthesis of the 2-mercaptothiazole (IV), as described below, and moving on to the alkylation (1) and chlorination (2) using the same solvent. The solvent of choice meets two major requirements: (i) good solubilization capacity for 2-mercaptothiazole, say, not less than 10 wt %; and (ii) sufficient inertness to chlorination. Below are provided tests that can serve for solvent selection for use in a telescopic process. However, the process of the invention is not limited to a telescopic design; the process may be carried out with the isolation of one or more intermediates, their purification and exchange of solvents between the process steps. For example, synthesis of 2-mercaptothiazole (IV) and the alkylation step (1) can be telescoped, followed by solvent exchange before the chlorination step (2).