HU204514B - Process for producing (azolyl-phenoxy-methyl)-keton derivatives - Google Patents

Abstract

The application relates to a process for the preparation of azolylether ketones of the general formula I, in which R<1> represents chlorine, bromine, phenyl, alkyl having from 1 to 3 carbon atoms or nitro, R<2> represents alkyl having from 1 to 4 carbon atoms, phenyl or phenyl substituted by chlorine, A represents the grouping = CH- or represents a nitrogen atom, and n represents 0, 1, 2 or 3, where ether ketones of the general formula IV, in which R<1>, R<2> and n have the abovementioned meanings, are reacted, at a temperature of 80-140@C, with equimolar quantities, or at most with a 25 mol% excess, of a halogenating agent, preferably sulphuryl chloride, the haloether ketones, obtained in this way or by any other method, of the general formula II, in which R<1>, R<2> and n have the abovementioned meanings, and X represents chlorine or bromine, are reacted with azoles of the general formula III, in which A has the abovementioned meaning, in a molar ratio of 1:2 at a temperature of 100-180@C, and the azolylether ketones are isolated from the reaction mixture by washing with water or with organic solvents, or by separation.

Description

The process of the present invention relates to the preparation of (azolylphenoxymethyl) ketones. According to the invention, the (phenoxymethyl) ketone is chlorinated with sulfuryl chloride in a solvent-free medium, and the resulting (phenoxychloromethyl) ketone is condensed with azole to form the (azolylphenoxymethyl) ketone. recovering from the reaction mixture.

The (azolylphenoxy) -ethyl clones can be used as active ingredients in fungicidal compositions.

In the literature, azolylphenoxymethyl ketones such as 1- (1,2,4-triazol-1-yl) -1- (4-chlorophenoxy) -3,3-dimethylbutane-2 on (German Patent Publication No. 2201063) primarily serves as an active ingredient in antifungal agent against powdery mildew.

In the present state of the art, (azolylphenoxymethyl) ketones can be prepared by the following general methods:

a) condensation of phenoxyhalomethyl ketone and azole in a solvent medium in the presence of an acid scavenger,

b) condensation of phenoxyhydroxymethyl ketone and azole in a solvent medium in the presence of a water-binding agent,

(c) condensation of phenoxyhydroxymethyl ketone with diazolyl ketone and diazolyl ketone in a solvent medium (Methods (a) to (c) in German Patent Publication No. 2201063),

d) condensation of azolyl halomethyl ketone in the presence of an acid scavenger with phenol in a solvent medium (U.S. Patent No. 2,937,595),

(e) reaction of diphenoxymethyl ketone with azolyl hydrochloride (German Patent Publication No. 2201063),

f) Reaction of 1,2,4-triazole with phenol and dichloromethyl-tert-butyl ketone in a solvent (German Patent Publication No. 2406,665).

The starting materials used in the above solutions are phenol, halomethylketone, halogenating agent and azole. These reactions can be conducted by condensing the (halomethyl) ketone with an azole and then halogenating the (azolylmethyl) ketone and then reacting it with phenol (method d). However, the yield of the reaction is less than 60%.

The reaction is carried out in a better yield when the (halomethyl) ketone is first condensed with phenol and then the ² -phenoxymethyl ketone is halogenated and the resulting (phenoxyhalomethyl) ketone is condensed with azole (method a). In the first solutions, each reaction was performed in different solvents. Although the solvent quality is optimal for the reaction, the reaction time is very long. Partly because of this, and partly because of the solvent change, these processes are particularly heat intensive.

According to the procedure disclosed in German Patent Specification No. 2,720,868, 4-chlorophenol in the presence of potassium carbonate is refluxed in 1-chloro-3,3-dimethyl-butan-2-one in an acelonic solution for 5 to 20 hours. The resulting phenoxymethyl ketone derivative is chlorinated in carbon tetrachloride with sulfuryl chloride for 15 hours.

The chlorinated product is condensed with 1,2,4-triazole 6 again in acetone in the presence of potassium carbonate acid scavenger. Reaction time is again 15 hours. Total reaction time was 50 hours, 87% yield.

In another embodiment of the above process (German Patent Publication No. 2201063 5), the final step uses a large excess of 1,2,4-triazole as an acid scavenger.

Although the condensation partner is a more reactive bromine derivative, the reaction time in acetonitrile is 48 hours.

The above disadvantage is mitigated by the solution disclosed in Hungarian Patent Application No. 176,059. The complete reaction sequence is carried out in the same solvent without recovering the intermediates. According to embodiments 5, 1.2 kg (9.4 moles) of 4-chlorophenol and 1.25 kg (9 moles) of potassium carbonate in 3 kg of toluene are heated to 90 ° C and added at this temperature for 1 hour. 1.2 kg (9 mol) of 1-chloro-3,3-dimethylbutan-2-one. The reaction mixture is refluxed for 6 hours, while the reaction mixture is stirred for approx. 100 ml of water are azeotropically distilled off. The reaction mixture was then cooled to 40 ° C and water (6 kg) was added. The slurry is stirred until the solids dissolve and the phases are separated. The organic phase is dried by azeotropic distillation, then cooled to 30-35 ° C and treated with 1.2 kg (9 mol) of sulfuryl chloride at this temperature for 6 hours.

The reaction mixture was stirred for a further 3 hours at 35 ° C and then 200 ml of toluene was removed in vacuo. The reaction mixture is then treated with 1.3 kg (18.8 mol) of 1,2,4-triazole and stirred at 95 ° C for 6 hours. At the end of the reaction, the toluene solution was diluted to 20-30 ° C and dissolved in water-soluble by-products with 2.5 kg water.

»After separation, the organic phase is washed twice with 1.5 kg to 1.5 kg of 5% sodium hydroxide and then with 1.5 kg of water. Finally, the solvent is distilled off to give the final product, 97% 1- (4-chlorophenoxy) -1- (1,2,4-thiazol-1-yl) 3,3-dimethylbutan-2-one , yield 88%.

¹ This process is still quite time and heat consuming.

It is our discovery that the (azolylphenoxymethyl) ketone derivatives of formula I wherein

R ² is C 1 -C 4 alkyl, phenyl or monohalogen phenyl, n is 0,1,2 or 3,

R ¹ when n is 1 is chloro or bromo, C 1-3 alkyl, phenyl or nitro, and when n is 2 or 3, chloro

A is a nitrogen atom or a methine group, prepared by reacting a compound of formula (IV). (phenoxymethyl) ketone, where R ¹ , R ² and n are as defined above, is chlorinated with up to 25% by weight of sulfuryl chloride at 70-90 ° C in a solvent-free medium, i.e. a melt, and the resulting compound (II) (phenoxychloromethyl) ketone - wherein R ¹ , R ² and n are as defined above, X is at least 100% excess azole of formula (III) in a chlorine melt at 100-140 ° C - wherein A is a 2 above

They are condensed to form the target compound of formula (I).

The recovery of the target product by the methods defined by the physico-chemical properties of the substances formed during the reaction is as follows:

a) dissolving the target product from the triazole hydrochloride in an organic solvent,

b) dissolving the triazole hydrochloride from the target product with water

c) removing the triazole hydrochloride from the melt,

d) separating the melt of the components

According to the present invention, a toluene solution of a phenoxymethylketone of formula (IV), in particular 1 (4-chlorophenoxy) -3,3-dimethylbutan-2-one, the toluene was boiled at 118 ° C.

The residue, which is a melt, is cooled to 70 ° C and chlorinated with sulfuryl chloride at this temperature by adding the sulfuryl chloride to the melt for 1 hour.

The reaction is complete at this temperature within 1 hour. The melt was blown with nitrogen to remove dissolved gases and traces of unreacted sulfuryl chloride. Subsequently, the melt temperature is raised by about 30 ° C and azole of formula (III) - where A is as defined above - is added. The azole is used in an excess of at least 100% because it is not only a condensation partner but also an acid scavenger.

The condensation reaction with azole is heat-generating, so that the reaction temperature rises to 130-140 ° C without any external intervention.

At the end of the condensation reaction, the melt was dissolved in toluene and most of the triazole hydrochloride by-product was removed by filtration. The target product is recovered from the toluene solution by known methods.

The preparation thus proceeds extremely rapidly, with a total of 3 hours of chlorination, triazole addition, addition and reaction time.

No side reactions occur and the final product is formed in good quality. Due to the solvent-free condition, on the one hand, smaller masses need to be heated with a smaller temperature difference and, on the other hand, the solvent is not heated for 6 hours. The shorter reaction time reduces the otherwise natural heat loss. This results in significant thermal energy savings.

A further advantage is that while the solvent process operates in a 40-45% solution, i.e., more than half of the reaction vessel is filled with an inert solvent, the process can double the reactor charge.

Combined with this, a shorter reaction time, together with the absence of solvent, results in about ten times as many descriptions as the same unit volume.

The following examples illustrate the present invention.

Example 1

Process for the preparation of 1- (4-chlorophenoxy) -1- (1,2,4-triazol-1-yl) -3,3-dimethylbutan-2-one in a 4 L 3 neck flask equipped with a stirrer With a thermometer and a dropping funnel, mole (2040 g) of 1- (4-chlorophenoxy) -3,3-dimethylbutan-2-one was weighed and heated to 65-70 ° C. Sulfuryl chloride (9.5 mol, 1282 g) was added over 1/2 hour by introducing the chlorinating agent to the bottom of the melt. The temperature was maintained at 70 ° C and stirred for 1/2 hour after addition. The dried nitrogen gas was then blown through the system for 1/4 hour and then heated to 100 ° C. The dropping funnel was replaced with a solid feeder and 18 mol (1242 g) of 1,2,4-triazole was added over 10 minutes.

The temperature rises to 120-125 ° C. The melt is stirred for 1 hour at this temperature and the target product is recovered in known manner.

2586 g of product are obtained with a purity of 95.5% (determined by gas chromatography), 93% yield. M.p. 79-80 ° C.

Example 2

Procedure for the preparation of 1- (2,4-dichlorophenoxy) -1- (imidazole) -3,3-dimethylbutan-2-one in a 4-L 3-necked flask equipped with a stirrer, thermometer, addition funnel, 1- (2,4-Dichlorophenoxy) -3,3-dimethylbutan-2-one (9 mol, 2349 g) was heated to 65 ° C. Moles (1350 g) of sulfuryl chloride are added over 1/2 hour by passing the chlorinating agent to the bottom of the melt. The temperature was maintained at 70 ° C, stirred for an additional hour, and then the residual sulfuryl chloride and dissolved gases were removed under vacuum (6.67 kPa). To the resulting melt, which was heated to 100 ° C over 10 minutes, 18 moles (1224 g) of imidazole were added while the temperature rose to 130 ° C.

After addition, the temperature is adjusted to 140 ° C and stirred for 1 hour, and the product is opened in a manner known per se.

3056 g of 91% (GC) product are obtained, yield 94.5%. 94-95 ° C.

Example 3

Procedure for the preparation of 1- (4-nitrophenoxy) -1- (1,2,4-triazol-1-yl) -3,3-dimethylbutan-2-one in a 4 L flask equipped with a thermometer 9 M (2133 g) of 1- (4-nitrophenoxy) -3,3-dimethylbutan-2-one was added via a funnel and heated to 80 ° C. Sulfuryl chloride (10 moles, 1350 g) was added over 1/2 hour, then heated to 90 ° C and stirred for 1 hour.

The residual sulfuryl chloride and dissolved gases were removed under vacuum (6.67 kPa) and then heated to 100 ° C and treated with 1,2,4-triazole (18 mol, 1242 g). After adjusting the temperature to 140 ° C and stirring for 1 hour, the resulting target product is recovered in a manner known per se.

2707 g of 95% target product (GC) are obtained, yield

94%. Mp 145 ° C.

HU 204514 A

l. spreadsheet

Compounds of formula (I) prepared by the process of the present invention

number Example R ¹ n THE R ² M.p. First First 4-Br 1 N C (CH ₃ ) ₃ 88-91 Second 1 4-CH ₃ 1 N C (CH ₃ ) ₃ 80 Third 1 4-C (CH ₃ ) ₂ 1 N C (CH ₃ ) ₃ 75 4th 1 H 0 N c ₆ h ₅ 63-68 5th 1 2,4-¾ 2 N 4-C 1 -C ₆ H ₄ 100-105 6th 3 4-NO ₂ 1 N C (CH ₃ ) ₃ 145 7th 3 2,4,5-Cl ₃ 3 N C (CH ₃ ) ₃ 140-143 8th 2 2,4-¾ 2 CH C (CH ₃ ) ₃ 68-70 9th 2 4-C1 1 CH C (CH ₃ ) ₃ 94-95 10th 3 4 CgHj- 1 N C ₅ H _His 62-70

The advantages of our procedure are summarized below:

- the preparation of (azolylphenoxymethyl) ketone can be accomplished in a quicker, simpler, less time-consuming manner;

- the production volume requirement of the production equipment is lower than that used in prior art processes.

Claims (1)

Process (Azolyl-phenoxymethyl) -ketone derivatives of formula (I) - wherein R ² is C 1 -C 4 alkyl, phenyl or monohalophenyl, n is 0,1,2 or 3, Does R ¹ Mean In? when n is 1 then chlorine or bromine, C 1-3 alkyl, phenyl or nitro, and if n is 2 or 3 then chlorine, A is a phenoxychloride of formula (H) for the preparation of a nitrogen atom or a methine group from a (phenoxymethyl) ketone derivative of formula (IV) wherein R ¹ and R ² have the meanings given above by sulfonyl chloride formation. -methyl) ketone derivative wherein R ¹ and R ² are as defined above, n is as defined above, X is chlorine, and the azole of formula (D ¹ ) wherein A is as defined above. The phenoxymethyl ketone derivative of formula (II) is chlorinated at 70-90 ° C in a solvent-free medium with up to 25% by weight of excess sulfuryl chloride to form the phenoxychloromethyl ketone derivative of formula (H) At 100-140 ° C, is condensed with at least 100% excess azole of formula (III) and the resulting (azolyl-phenoxymethyl) -ketou derivative of formula (I) is obtained in a manner known per se. yerjük.