Process for the preparation of Difenoconazole Background of the invention

The present invention encompasses the preparation of Difenoconazole from 2-(4-(4-chloro phenoxy)-2-chlorophenyl)-2-(bromomethyl)-4-methyl-l,3-dioxalane in an industrially advantageous method.

The present invention also involves the acylation of l-chloro-3-(4-chlorophenoxy)benzene to generate l-[2-chloro-4-(4-chlorophenoxy)phenyl] ethanone which is an important intermediary stage in the preparation of Difenoconazole in an industrially advantageous method.

The present invention also involves preparation of 2-(4-(4-chlorophenoxy)-2-chlorophenyl)-2-(bromomethyl)-4-methyl-l,3-dioxalane, another crucial intermediate for the preparation of Difenoconazole yet again in an industrially advantageous method.

Detailed Description of the invention

Difenoconazole is a systemic fungicide with a novel broad-range activity protecting the yield and crop quality by foliar application or seed treatment, provides long-lasting preventive and curative activity against Ascomycetes, Basidiomycetes and Deuteromycetes.

The objective of the present invention is the preparation of Difenoconazole in an industrially advantageous method.

Another objective of the present invention is preparation of l-[2-chloro-4-(4-chlorophenoxy)phenyl] ethanone, an important intermediate for the preparation of Difenoconazole in an industrially advantageous method.

Yet another objective of the present invention is the preparation of 2-(4-(4-chloro phenoxy)-2-chlorophenyl)-2-(bromomethyl)-4-methyl-l,3-dioxalane, another crucial intermediate for the preparation of Difenoconazole yet again in an industrially advantageous method.

In the first aspect of the invention, the inventors provide a novel process for the preparation of 1-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone II US 3065205 describes the acylation of diphenyl ether with an acid chloride in presence of aluminum chloride in nitrobenzene as solvent at a temperature range of 50-125°C. This process suffers from the drawback that aluminum chloride was used in excess.

US 4474990 describes the reaction of diphenyl ether with acetic anhydride and acetyl chloride. In this process, HF was used as catalyst for the acylation. Usage of HF needs special material of construction for the manufacturing equipment and hence is not an industrially viable process.

It is known that acylation of diphenyl ether can be obtained with acetic anhydride using macro porous cation exchange resins as catalyst (cf. Chemical Engineering Science, 2008, 58, 2573). This process variant too has its own disadvantage. The reusability studies demonstrated that the resin activity falls in subsequent reactions due to blocking of pores by larger products, particularly diacylated derivatives rendering some pore networks ineffective.

While all of the above other acylation process are effective to varying degrees, they suffer certain deficiencies, particularly when scaled up for commercial procedure.

Thus there is a need in the art for an industrially applicable, simple and facile synthesis of the 1-[2-chloro-4-(4-chlorophenoxy)phenyl] ethanone, an important intermediate for the preparation of Difenoconazole.

The present inventors describes an acylation reaction of l-chloro-3-(4-chlorophenoxy)benzene using acetyl chloride in the presence of aluminium chloride. The novel reaction thus has the advantage that it can be carried without using HF and acetic anhydride; and wherein aluminium chloride is used in a molar ratio.

The reaction is carried out in solvents like dichloromethane, carbon-di-sulfide, toluene, xylene, dimethylsulfoxide and 1,2-dichloroethane wherein 1,2-dichloroethane is the most preferred solvent.

In the second aspect of the invention, the inventors report a novel process for the preparation of 2-(4-(4-chlorophenoxy)-2-chlorophenyl)-2-(bromomethyl)-4-methyl-1,3-dioxalane, another crucial intermediate for the preparation of Difenoconazole.

US 3575999 describes the preparation of ketal derivatives of imidazoles. The procedure describes the reaction of ethanone with bromine in presence of dioxane-ether mixture. The resultant intermediate after solvent evaporation was reacted with excess glycol in toluene.

Likewise US 4503059 describes the preparation of 1,3-dioxacyclopentane. The procedure describes the reaction of ethanone with 3-chloropropan-l,2-diol in toluene wherein the reaction work up involves excess glycol.

The present invention involves initial reaction of the l-(4-(4-chlorophenoxy)-2-chlorophenyl ethanone with 1,2-propanediol to obtain the intermediate 2-(4-(chlorophenoxy)-2-chlorophenyl)-2,4-dimethyl-l,3-dioxalane of formula III.

In the process of the present invention, cyclohexane is used as solvent in the above stage. Whereas in the prior art toluene is used as solvent. In the current process, 1,2-propanediol is used in excess. The advantage of using cyclohexane solvent in this process is that 1,2-propanediol can be recovered after the reaction is completed and can be reused. If toluene is used as solvent, recovery of 1,2-propanediol is not possible.

In the subsequent stages 2-(4-(chlorophenoxy)-2-chlorophenyl)-2,4-dimethyl-l,3-dioxalane is brominated by bromine to generate bromodioxalone 2-(4-(4-chloro phenoxy)-2-chlorophenyl)-2-(bromomethyl)-4-methyl-1,3-dioxalane IV.

Another aspect of the invention is the preparation of Difenoconazole I by reacting bromodioxalone 2-(4-(4-chlorophenoxy)-2-chlorophenyl)-2-(bromomethyl)-4-methyl-1,3-dioxalane IV with potassium salt of 1,2,4-triazole in DMSO.

GB 2098607 discloses a process for preparing Difenoconazole by allowing bromodioxalane derivative to react with 1, 2, 4-triazole. This process suffers from the draw-back that it requires extended reaction times.

The present invention involves the reaction of bromodioxalone 2-(4-(4-chloro phenoxy)-2-chlorophenyl)-2-(bromomethyl)-4-methyl-l,3-dioxalane IV with potassium salt of 1,2,4-triazole. The reaction can be carried out at temperatures greater than 150° C, preferably between 160° C and 165° C.

The reaction is performed in solvents like N.N-dimethyl formamide, chloroform, toluene, benzene, JV-methylpyrrolidone dimethylsufoxide (DMSO) and mixture of solvents such as toluene and butanol wherein DMSO is the most preferred solvent.

Thus by using the potassium salt of 1,2,4-triazole instead of sodium salt and by increasing the reaction temperature, the reaction times has reduced drastically from 30 hrs to 6 hrs. When DMSO is used as solvent, effluent quantity is reduced by recovering DMSO. Using the process according to the invention, Difenoconazole I can be prepared in high yield and in a relatively short reaction times.

Examples

Example 1: l-[2-chloro-4-(4-chlorophenoxy)phenyl] ethanone II 950 ml of 1,2-dichloroethane and 238.8 g of l-chloro-3-(4-chlorophenoxy)benzene were taken in the RB flask, cooled to 15° C. AlCl3 was added slowly followed by acetyl chloride in 1-2 hour at 13-15° C and maintained for 1 hour. After completion of the reaction, confirmed by GC, the reaction mixture was cooled by suspending in ice by stirring for 30 min. The organic layer was separated and washed with 350 ml of water and 350 ml of 5% NaHCO3 and then with 350 ml of water. The total aqueous layer was extracted with 100 ml of 1,2-dichloroethane followed by washing with 50 ml of water. The organic layer is concentrated under vacuum to obtain l-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone (276 g, yield, 93.8%, purity by GC, 95.5%).

Example 2: 2-(4-(chlorophenoxy)-2-chlorophenyl)-2,4-dimethyl-l,3-dioxalane III 276 g of l-[2-chloro-4-(4-chlorophenoxy)phenyl]ethanone, 1028 ml of cyclohexane, 127.2 g of 1,2-propanediol and 10 g of p-Toluenesulphonic acid were added in RB flask attached with dean & stark apparatus for moisture removal. Reaction mixture was heated and refluxed at 85° C for 6 hours. After the completion of reaction, confirmed by GC, the reaction mass was cooled to room temperature and organic layer was separated. 1,2-propanediol was recovered from organic layer. The organic layer was washed twice with 600 ml of water and dried with anhydrous sodium sulfate. The organic layer can be taken directly for bromination (purity by GC, 94.6%).

Example 3: Bromodioxalone 2-(4-(4-chloro phenoxy)-2-chlorophenyl)-2-(bromo methyl)-4-methyl-l,3-dioxalane IV 2-(4-(chlorophenoxy)-2-chlorophenyl)-2,4-dimethyl-l,3-dioxalane prepared by the above process and p-toluenesulphonic acid (2.5 g) were taken in 4 neck RB flask. The mixture was cooled to 28° C while stirring. Bromine was added in a period of 1 hour and stirring continued for 1 hour more at 27-28° C. After the completion of reaction, confirmed by GC, 500 ml of water was added and stirred for 30 min. Organic layer was separated and washed with 300 ml of 1.5% NaOH and then washed twice with 500 ml of water to neutralize completely. Cyclohexane was recovered completely under vacuum to obtain product bromodioxalone (385 g, yield, 94.3%, purity by GC, 94%).

Example 4: Preparation of Difenoconazole I 1,2,4 triazole (77.4 g), KOH (70.2 g) and toluene (400 ml) are added in 4 neck RB flask. The reaction mixture is heated for 6 hours at the reflux temperature (105-114° C) using dean & stark apparatus to remove moisture. Excess water and toluene were removed. The reaction mixture was cooled down to 70° C followed by addition of bromodioxalane IV. The above mixture was dissolved in DMSO and heated to 160-165° C. The remaining toluene was distilled and maintained for 4 hours at 160-165° C. After the completion of reaction, confirmed by GC, the reaction mass was cooled to room temperature followed by filtration and washing with DMSO. DMSO was distilled off from the filtrate under vacuum. After the addition of 1000 ml of water to the residue the mixture was extracted twice with 160 ml of toluene. The organic layer was washed twice with 175 ml of water. Toluene was removed under reduced pressure below 70° C. The mass was cooled; where by 305 g of crude product was obtained (305 g, yield, 80.3%, purity by HPLC, 85 to 87%). The crude mass was crystallized with suitable solvent to obtain pure Difenoconazole I.

We Claim:

1. A process for the preparation of Difenoconazole by reacting 2-(4-(4-chlorophenoxy)-2-chlorophenyl)-2-(bromomethyl)-4-methyl-l,3-dioxalane with potassium salt of 1,2,4-triazole in DMSO at higher temperatures.

2. The process of claim 1 wherein the reaction temperature is greater than 150°C.

3. The process of any preceding claim wherein the reaction temperature is 160 - 165°C.