Process and intermediates for the preparation of Fluensulfone

1. A process for preparing heterocyclic fluoroalkenyl sulfones and their thioether and sulfoxide precursors of the formula:

Cl—R—S(O) n —(CH 2 ) 2 —CF═CF 2   (Formula I′)

wherein R is a heterocyclic five-membered aromatic ring and n is 0, 1 or 2, comprising a step of dehalogenation of a compound of the formula:

Cl—R—S(O) n —(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate B)

wherein X 1 and X 2 are independently halogen atoms, to remove said X 1 and X 2 atoms.

2. A process according to claim 1 , comprising the steps of:

A) alkylating thiol R—SH, wherein R is a heterocyclic five-membered aromatic ring, with a fluorinated haloalkane of the formula L-(CH 2 ) 2 —CFX 1 —CF 2 X 2 in a first organic solvent, wherein L is a leaving group capable of displacement by a thiol group, and X 1 and X 2 are halogen atoms which may be the same or different, to form a thioether having the formula:

R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate A)

B) ring-chlorinating Intermediate A, optionally in a second organic solvent, to produce chlorine-substituted thioether having the formula:

Cl—R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate B)

and optionally oxidizing Intermediate B to its corresponding oxidized form Cl—R—S(O) n —(CH 2 ) 2 —CFX 1 —CF 2 X 2 , wherein n is 1 or 2;

C) dehalogenation of Intermediate B or its oxidized form in a third organic solvent to remove said X 1 and X 2 atoms and produce the compound of Formula I′:

Cl—R—S(O) n —(CH 2 ) 2 —CF═CF 2   (Formula I′)

and optionally oxidizing said compound of Formula I′ in case that n=0 or n=1, to afford the heterocyclic fluoroalkenyl sulfone:

Cl—R—SO 2 —(CH 2 ) 2 —CF═CF 2   (Formula I)

wherein the organic solvents used in consecutive steps are the same or different.

3. A process according to claim 2 , wherein the intermediate B undergoing dehalogenation is the chlorine-substituted thioether of the formula Cl—R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2 , said process comprising:

A) alkylating thiol R—SH to give Intermediate A:

R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate A);

B) ring-chlorinating Intermediate A to produce Intermediate B:

Cl—R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate B)

C) dehalogenation of Intermediate B to remove the X 1 and X 2 halogen atoms and produce a thioether fluorinated alkene of the formula:

Cl—R—S—(CH 2 ) 2 —CF═CF 2   (Intermediate C)

and optionally oxidizing Intermediate C to give the heterocyclic fluoroalkenyl sulfone:

Cl—R—SO 2 —(CH 2 ) 2 —CF═CF 2   (Formula I).

4. A process according to claim 2 , wherein the thiol R—SH is 2-mercaptothiazole:

5. A process according to claim 2 , wherein the fluorinated haloalkane of the formula L-(CH 2 ) 2 —CFX 1 —CF 2 X 2 is Hal-(CH 2 ) 2 —CFX 1 —CF 2 X 2 wherein Hal is halide.

6. A process according to claim 5 , wherein the alkylation step comprises combining 2-mercaptothiazole with a fluorinated haloalkyl halide Hal-(CH 2 ) 2 —CFX 1 —CF 2 X 2 in the first organic solvent in the presence of a base under heating, allowing the reaction to reach completion, collecting a worked-up organic solution and either isolating and optionally purifying Intermediate A from the worked-up organic solution, or carrying the Intermediate A-containing organic solution to the ring-chlorination step.

7. A process according to claim 5 , wherein the fluorinated haloalkyl halide Hal-(CH 2 ) 2 —CFX 1 —CF 2 X 2 is 1,4-dibromo-2-chloro-1,1,2-trifluorobutane.

8. A process according to claim 3 , wherein the ring-chlorination reaction comprises combining Intermediate A:

R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate A)

and a chlorinating agent in the second organic solvent and recovering Intermediate B from a reaction mixture:

Cl—R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate B).

9. A process according to claim 8 , wherein the chlorinating agent is selected from the group consisting of sulfuryl chloride, elemental chlorine, trichloro isocyanuric acid and N-chlorosuccinimide.

10. A process according to claim 8 , wherein the Intermediate A that undergoes the ring-chlorination reaction is of the formula:

to give Intermediate B:

11. A process according to claim 1 , wherein the dehalogenation reaction of Intermediate B of the formula:

Cl—R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate B)

to remove the X 1 and X 2 halogen atoms, comprises using a reducing agent.

12. A process according to claim 11 , wherein the reducing agent is a reducing metal.

13. A process according to claim 12 , wherein the reducing metal is zinc.

14. A process according to claim 11 , wherein Intermediate B that undergoes the dehalogenation reaction is of the formula:

15. A process according to claim 2 , wherein the thiol used is 2-mercaptothiazole that is supplied to the alkylation step (A) in the form of a solution in the first organic solvent, said solution being a worked-up organic solution recovered following a ring closure reaction of chloroacetaldehyde with a dithiocarbamate salt in an acidic aqueous medium to give 4-hydroxy-2-thiazolidinethione, a tautomer or an isomer thereof, dehydrating same to give said 2-mercaptothiazole:

and collecting a worked-up solution of said 2-mercaptothiazole in said first organic solvent.

16. A process according to claim 15 , wherein the first organic solvent is a water-immiscible organic solvent that meets the requirements:

1) The solubility of 2-mercaptothiazole in the first solvent at 25° C. is not less than 5 wt %; AND

2) The solvent is sufficiently inert to at least one chlorinating reagent.

17. A process according to claim 16 , comprising the steps of collecting, after the alkylation step has been completed, a worked-up solution of

in the first organic solvent and carrying said worked-up solution to the ring-chlorination step, such that the first and second organic solvents are identical, whereby the synthesis of 2-mercaptothiazole and subsequent alkylation and chlorination reactions are telescoped.

18. A process according to claim 17 , wherein the first organic solvent is selected from the groups consisting of aliphatic nitriles and ethers of the formula R1-O—R2, wherein R1 is aliphatic ring and R2 is straight or branched alkyl.

19. A process according to claim 18 , wherein the first organic solvent is an aliphatic nitrile which is n-butyronitrile.

20. A process according to claim 15 , wherein the first organic solvent is C4-05 water-immiscible alkanol, the process comprises steps of isolation of the alkylation product and solvent exchange to a second organic solvent prior to the chlorination reaction.

21. A process according to claim 20 , wherein the water immiscible alkanol is 1-pentanol, which is exchanged for halogenated aromatic hydrocarbon prior to chlorination.

22. A process according to claim 3 , further comprising oxidizing Intermediate C.

23. A process according to claim 1 , wherein Fluensulfone is prepared:

24. A process according to claim 2 , wherein the oxidized form of intermediate B of the formula Cl—R—SO 2 —(CH 2 ) 2 —CFX 1 —CF 2 X 2 undergoes dehalogenation, said process comprising:

A) alkylating thiol R—SH to give the thioether

R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate A);

B) ring-chlorinating Intermediate A to produce chlorine-substituted thioether compound of the formula:

Cl—R—S—(CH 2 ) 2 —CFX 1 —CF 2 X 2   (Intermediate B);

C) oxidizing Intermediate B to produce the corresponding oxidized form of Intermediate B, which is sulfone of the formula:

Cl—R—SO 2 —(CH 2 ) 2 —CFX 1 —CF 2 X 2

D) dehalogenation of said oxidized form of Intermediate B to give the heterocyclic fluoroalkenyl sulfone:

Cl—R—SO 2 —(CH 2 ) 2 —CF═CF 2   (Formula I),

wherein organic solvents used in consecutive steps are the same or different.

25. A process according to claim 24 , wherein the intermediate B which undergoes oxidation is:

26. A process according to claim 24 , wherein Intermediate B is oxidized with the aid of an oxidizing agent consisting of the mixture KHSO 5 .0.5KHSO 4 .0.5K 2 SO 4 .

27. A process according to claim 26 , comprising progressively adding the reagent KHSO 5 .0.5KHSO 4 .0.5K 2 SO 4 to a reaction vessel that was previously charged with alkanol and the intermediate B1.

28. A process according claim 25 , wherein the oxidized form of Intermediate B which undergoes dehalogenation is:

29. A process according to claim 24 , wherein the dehalogenation reaction comprises using a reducing metal.

30. A process according to claim 29 , comprising using zinc in tetrahydrofuran, with in-situ activation of said zinc.

31. A compound of the formula

wherein n=0, 1 or 2, or an acid addition salt thereof.

32. A compound according to claim 31 wherein n=0:

33. A compound of the formula:

wherein n=0, 1 or 2, or an acid addition salt thereof.

34. A compound according to claim 33 wherein n=0:

35. A compound according to claim 33 wherein n=2: