Process for the preparation of tetraconazole

Abstract

The present invention relates to a new process for the preparation of Tetraconazole or one of its optically active isomers by means of the fluorination of 2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-1-ol.

Claims

1. A process for the preparation of Tetraconazole having formula (I), or one of its optically active isomers: ##STR00004## which comprises reacting the compound 2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-1-ol having formula (II), or one of its optically active isomers, ##STR00005## dissolved or suspended in at least one organic solvent, with tetrafluoroethylene in the presence of water and an inorganic base to form said Tetraconazole having formula (I) or one of its optically active isomers.

2. The process according to claim 1, wherein said water is present in a quantity within the range of 1%-10% by weight of said compound having formula (II).

3. The process according to claim 1, wherein said at least one organic solvent is a polar organic solvent selected from: dimethylsulfoxide, dimethylformamide, N-methylpyrrolidone or mixtures thereof.

4. The process according to claim 1, wherein said at least one organic solvent is an apolar organic solvent.

5. The process according to claim 1, wherein said reaction is carried out in a mixture of solvents which comprises at least one polar organic solvent and at least one apolar organic solvent.

6. The process according to claim 5, wherein the volume ratio between said polar organic solvent and said apolar organic solvent is within the range of 1:1 to 1:20.

7. The process according to claim 6, wherein said polar organic solvent is dimethylsulfoxide and said apolar organic solvent is toluene.

8. The process according to claim 5, wherein said polar organic solvent is dimethylsulfoxide and said apolar organic solvent is toluene.

9. The process according to claim 5, which comprises, after said reaction with tetrafluoroethylene, a phase for separating said polar solvent from said mixture of solvents.

10. The process according to claim 5, wherein the volume ratio between said polar organic solvent and said apolar organic solvent is within the range of 1:2 to 1:10.

11. The process according to claim 5, wherein the volume ratio between said polar organic solvent and said apolar organic solvent is about 1.5.

12. The process according to claim 1 wherein said inorganic base is selected from hydroxides of alkaline metals and mixtures thereof.

13. The process according to claim 12 wherein said inorganic base is selected from sodium hydroxide, potassium hydroxide and mixtures thereof.

14. The process according to claim 1, wherein said inorganic base is present in a quantity ranging from 1% to 10% by weight, with respect to the weight of said compound having general formula (II).

15. The process according to claim 14, wherein said inorganic base is present in a quantity ranging from 2% to 5% by weight, with respect to the weight of said compound having general formula (II).

16. The process according to claim 1, wherein said reaction with tetrafluoroethylene is carried out at a temperature ranging from 10 C. to 5 C.

17. The process according to claim 1, wherein said reaction with tetrafluoroethylene is carried out at a pressure ranging from 1 bar to 1.5 bar.

18. The process according to claim 1, wherein said polar solvent is separated from said mixture of solvents by extraction with water.

19. The process according to claim 1, wherein said water is present in a quantity within the range of 2%-4% by weight of said compound having formula (II).

Description

EXPERIMENTAL PART

Example 1: Preparation of Tetraconazole with Solid KOH

(1) 100.0 grams of 2-(2,4-dichlorophenyl-3-(1H-1,2,4-triazol-1-yl)propan-1-ol are suspended in a mixture of toluene (875 mL) and DMSO (180 mL) in a glass reactor having a volume of 2 liters, equipped with a cooling jacket and mechanical anchor stirrer.

(2) The mass is cooled to a temperature of 10 C. and 4.4 grams of finely ground potassium hydroxide and 2.5 mL of water are added.

(3) A vacuum is established in the reactor up to a residual pressure of about 25 mbar, which is released by feeding gaseous tetrafluoroethylene from a reserve, at a pressure of about 1.1 bar.

(4) The reaction mixture is stirred for about 2 hours at a temperature ranging from 10 C. to 5 C., and is then filtered on a cellulose filter and extracted three times consecutively with aliquots of 200 mL of water, each time separating the organic phase from the aqueous phase.

(5) The organic phase is completely evaporated to obtain a liquid residue of Tetraconazole having a weight of 135 grams and a purity higher than 96% by weight.

(6) The product thus obtained contains from 1% to 1.5% by weight of the main impurity: 1[2-(2,4-dichlorophenyl)propen-2-yl]1H-1,2,4-triazole.

Example 2: Preparation of Tetraconazole with an Aqueous Solution of KOH

(7) 100.0 grams of 2-(2,4-dichlorophenyl-3-(1H-1,2,4-triazol-1-yl)propan-1-ol are suspended in a mixture of toluene (875 mL) and DMSO (180 mL) in a glass reactor having a volume of 2 liters, equipped with a cooling jacket and mechanical anchor stirrer.

(8) The mass is cooled to a temperature of 10 C. and 5.0 grams of an aqueous solution at 50% by weight of potassium hydroxide are added.

(9) A vacuum is established in the reactor up to a residual pressure of about 25 mbar, which is released by feeding gaseous tetrafluoroethylene from a reserve, at a pressure of about 1.1 bar.

(10) The reaction mixture is stirred for about 4 hours at a temperature ranging from 10 C. to 5 C., and is then extracted three times consecutively with aliquots of 200 mL of water, each time separating the organic phase from the aqueous phase.

(11) The organic phase is filtered on a cellulose filter. The organic phase is then completely evaporated to obtain a liquid residue of Tetraconazole having a weight of 133 grams and a purity higher than 96% by weight.

(12) The product thus obtained contains from 1% to 1.5% y weight of the main impurity: 1[2-(2,4-dichlorophenyl)propen-2-yl]1H-1,2,4-triazole.

Example 3

(13) 100.0 grams of 2-(2,4-dichlorophenyl-3-(1H-1,2,4-triazol-1-yl)propan-1-ol are dissolved in 180 mL of DMSO at a temperature of 40 C. 4.4 grams of finely ground potassium hydroxide and 2.5 mL of water are then added. The solution obtained is combined with 875 mL of toluene in a glass reactor having a volume of 2 liters, equipped with a cooling jacket and mechanical anchor stirrer.

(14) The mass is cooled to a temperature of 10 C. and a vacuum is established in the reactor up to a residual pressure of about 25 mbar, which is released by feeding gaseous tetrafluoroethylene from a reserve, at a pressure of about 1.1 bar.

(15) The reaction mixture is stirred for about 4 hours at a temperature ranging from 10 C. to 5 C.

(16) Optionally, instead of anchor stirring, the reactor can be equipped with a recirculation system by means of a pump which continuously removes the reaction mass from the bottom and re-introduces it from above by means of a nozzle, so that it penetrates the liquid and entrain the gas.

(17) The organic phase is extracted three times consecutively with aliquots of 200 mL of water, each time separating the organic phase from the aqueous phase. The organic phase is stirred in the presence of solid sodium bicarbonate and then filtered. The organic phase is completely evaporated to obtain a liquid residue of Tetraconazole having a weight of 135 grams and a purity higher than 96%.

(18) The product thus obtained contains from 1% to 1.5% by weight of the main impurity: 1[2-(2,4-dichlorophenyl)propen-2-yl]1H-1,2,4-triazole.

Example 4: (Comparative): Preparation of Tetraconazole According to the Procedure Described in Bianchi D. Et al. J. Agric. Food Chem 1991, 39, 197-201

(19) 100.0 grams of 2-(2,4-dichlorophenyl-3-(1H-1,2,4-triazol-1-yl)propan-1-ol are dissolved in a mixture of toluene (1250 mL) and DMSO (185 mL) in a glass reactor having a volume of 2 liters, equipped with a mechanical anchor stirrer.

(20) The mass is cooled to a temperature of 5 C. and 11.5 grams of finely ground potassium hydroxide are added.

(21) A vacuum is established in the reactor up to a residual pressure of about 25 mbar, which is released by feeding gaseous tetrafluoroethylene from a reserve, at a pressure of about 1.1 bar.

(22) The reaction mixture is stirred for about 2 hours at a temperature of about 5 C., and is then extracted three times consecutively with cold water, each time separating the organic phase from the aqueous phase.

(23) The organic phase is completely evaporated to obtain a liquid residue of Tetraconazole having a weight of 133 grams and a purity of 92% by weight.

(24) The product thus obtained contains about 5% by weight of the main impurity: 1[2-(2,4-dichlorophenyl) propen-2-yl]1H-1,2,4-triazole.