Process and intermediates for the preparation of Fluensulfone

Patent metadata

Field	Value
Publication number	US-11634397-B2
Application number	US-201917280146-A
Country	US
Kind code	B2
Filing date	Sep 26, 2019
Priority date	Sep 26, 2018
Publication date	Apr 25, 2023
Grant date	Apr 25, 2023

Abstract

The invention provides a process for preparing heterocyclic fluoroalkenyl sulfones and their thioether and sulfoxide precursors of the formula: Cl—R—S(O)n—(CH2)2—CF═CF2 (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—(CH2)2—CFX1—CF2X2 (Intermediate B), wherein X1 and X2 are independently halogen atoms, to remove said X1 and X2 atoms. Also included are novel intermediate compounds.

First claim

The invention claimed is:

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

Assignees

• Adama Makhteshim Ltd

Inventors

• Zell Thomas
• Cohen Shlomi

Classifications

• C07D277/36 Primary

  Sulfur atoms · CPC title

• C07D277/32 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title