TWI733869B - Process for preparing boscalid - Google Patents

Abstract

A process for preparing the crystalline modification II of the anhydrate of boscalid is provided, the process comprising providing a solution of boscalid in an organic solvent system, heating the solution to an elevated temperature, and precipitating solid boscalid from the solution, the elevated temperature being sufficient to preferentially form the crystalline modification II of the anhydrate of boscalid.

Description

Method of preparing Bekley

The present invention relates to a method for preparing buckle, and particularly to a method for preparing a specific crystalline form of buckle.

The compound 2-chloro-N-(4'chloro[1,1'biphenyl]-2-yl)-3-pyridinecarboxamide with the common name Bekley has the structural formula I:

Bakelite is a fungicide for the carboxamide group and acts as a succinate dehydrogenase inhibitor (SDHI), that is, a respiratory inhibitor of mitochondria. Carboximine compounds of this type and the activities of these compounds were first described in US 4,001,416 and US 5,330,995.

Becquel is active as a fungicide, and it is now commercially available in a series of formulations for treating fungal infections and the diseases they produce.

US 7,087,239 relates to crystalline hydrates of nicotinic acid aniline and/or benzaniline derivatives. US 7,087,239 specifically exemplifies the synthesis and recovery of the hydrate of Becquerie. The hydrate is obtained by first preparing an anhydrate of Becquerère, which is obtained as a solution in hot xylene at the end of the synthesis process. After cooling, the white Klei crystallized from the solution and dried in an oven under vacuum. The anhydrous is indicated to have the following physical properties:

Molecular weight [g/mol]: 343.2

Melting point [℃] (DSC): 145.2

Density [g/mol]: 1.42

X-ray reflection (2θ degrees): 18; 22.5; 9.5; 6

Cu-Kα

IR absorption [cm ^-1 ]: 1650

Water content [%]: <1

US 7,087,239 discloses that the hydrate can be formed by dissolving the anhydrate in tetrahydrofuran (THF) in a solvent at 40°C and adding the resulting solution to water. The precipitate was separated from the resultant mixture by filtration and dried to produce the monohydrate of Beakley. The crystalline modification of Bekley anhydride disclosed in US 7,087,239 is referred to herein as crystalline modification I of Bekley.

US 7,241,896 relates to a method for the production of 2-halogen-pyridine-formamide, which discloses and exemplifies the preparation of Becquerie. In these examples, Becquerie was synthesized by reacting 2-chloro-3-nicotinyl halide II and 2-(4-chlorophenyl)aniline in a solvent system (specifically xylene). After extraction with a sodium carbonate solution, the organic solution was steadily cooled to crystallize the white Klebsiella.

We have found that it is difficult to grind the crystalline modification of the buckle anhydride disclosed in US 7,087,239 in water. Therefore, it is not a simple task to directly formulate the crystalline modification of Becquerie into the desired formulation that requires a grinding and/or grinding process. Such formulations are, for example, granules, capsule granules, tablets, water-dispersible granules, water-dispersible tablets, wettable powders or wettable powders for seed treatment, powder formulations, and wherein Formulations in which the active compound is present in dispersed form, for example, aqueous suspensions, water-dispersible oil suspensions, suspension emulsions or aqueous seed treatment suspensions. Before being formulated into an aqueous suspension, the crystalline modification of Becquerie needs to be hydrated.

US 7,501,384 discloses the so-called novel crystalline modification of Becquel anhydride. The crystalline modification disclosed in US 7,501,384 is referred to herein as Bakelite's crystalline modification II. It is proposed in US 7,501,384 that Becquerie's crystalline modification II is more suitable for the manufacture of various formulations, which would otherwise require a long grinding/grinding process.

US 7,501,384 describes that the crystalline modification II of Becquerie can be prepared by the following method, which comprises: a) dissolving the anhydrate of the crystalline modification I of Becquerie in a polar organic solvent or an aromatic hydrocarbon; and b ) Precipitating the anhydrate of the crystalline modification II of Becquerie by cooling the solvent.

The alternative method of preparing the crystalline modification II of Becquerie disclosed in US 7,501,384 includes: a) heating the crystalline modification I of Becquerie to above 150°C until melting; and b) by adding the crystalline modification of Becquerie Seed crystals of body II to cool the melt.

US 7,501,384 describes the crystalline modification II of Becquerie, which has the following properties:

Molecular weight [g/mol]: 342

Melting point [℃] (DSC): 147.2

Heat of fusion [J/g] (DSC): 106

Density [g/cm ³ ]: 1.457

Characteristic IR band [cm ^-1 ]: 868, 917, 1675

The key parameters and unit cell matrix obtained from the crystallographic study of Becquerie’s Crystal Modification II using Siemens’ single crystal diffractometer are given in US 7,501,384:

The parameters shown above have the following meanings: a, b, c = the edge length of the unit cell; α, β, γ = the corresponding angle; and Z = the number of molecules in the unit cell.

FTIR spectroscopy can be used to record IR spectra.

It would be a significant advantage if an improved preparation method for the crystalline modification II of Beclet anhydride can be provided, especially a method suitable for commercial-scale applications with reproducible and high yield of the modification II product. . Preferably, the method is simple to operate and easy to control.

Unexpectedly, it has now been discovered that the formation of crystalline modification II of the bucklean anhydride in high yield occurs at elevated temperatures. In contrast, the lower temperature leads to better formation of the crystal modification I of Becquel anhydride. Specifically, when precipitating Beakley from a solvent system, it was unexpectedly found that the precipitation of Beakley in the solvent system at low temperatures mainly or only produced the crystalline modification I of Beakley anhydrous, while increasing the solvent The temperature of the system and the precipitation of solid bacillus preferentially produce the crystalline II variant of baccladium anhydrate.

Fig. 1 is the IR spectrum of the crystalline modification II of Becquel’s anhydrate; and Fig. 2 is the IR spectrum of the crystalline modification I of Becquel’s anhydrate.

Therefore, in a first aspect, the present invention provides a method for preparing the crystalline modification II of Beklitz anhydride, the method comprising providing a Beklell solution in an organic solvent system, heating the solution to an elevated temperature, and From this solution, a solid beakley was precipitated, wherein the elevated temperature was sufficient to preferentially form crystalline modification II of the beakley anhydrous.

In the present invention, the elevated temperature is used to form the crystalline modification II of Becquel anhydride. As mentioned above, this increased temperature results in the preferential formation of crystalline modification II of Becquel anhydride compared to lower temperatures.

The method of the present invention uses Beckert starting material. The starting material of Beikelie is a solution of Beikelie in an organic solvent system. Any organic solvent system suitable for Beakley can be used to form the Beakley starting material described in this embodiment. The solvent system can be a single organic solvent or a mixture of two or more solvents. Suitable solvents include polar organic solvents and aromatic hydrocarbons. The preferred polar organic solvents are alcohols, including polyols, such as glycols, ketones, ethers, esters, amides and mixtures thereof.

Examples of suitable alcohols are C ₁ to C ₈ alcohols, preferably C ₁ to C ₅ alcohols. The alcohol may be a linear or branched fatty alcohol, more preferably ethanol, propanol and butanol. The alcohol may be an alicyclic alcohol, such as cyclohexanol. The solvent may contain polyols, such as ethylene glycol. Examples of suitable glycols are monoethylene glycol and polyethylene glycol, preferably ethylene glycol and diethylene glycol.

Examples of suitable ketones are C ₃ to C ₈ ketones, preferably C ₃ to C ₆ ketones, more preferably acetone, methyl ethyl ketone, pentanone and hexanone. The ketones can be linear, branched or cyclic, such as alkylacetone and cyclohexanone.

Examples of suitable ethers are C ₃ to C ₈ ethers, preferably C ₃ to C ₆ ethers. These ethers can be linear, branched or cyclic, such as dioxane and tetrahydrofuran.

Examples of suitable esters are C ₃ to C ₈ esters, preferably C ₃ to C ₆ esters, more preferably ethyl acetate and methyl acetate.

Examples of suitable amides are C ₃ to C ₈ amides, preferably C ₃ to C ₆ amides, and more preferably dimethylformamide.

Suitable aromatic solvents are benzene, toluene and xylene. Xylene is a better solvent.

Suitable solvents are known in the art and are commercially available.

A mixture of solvents can be used as the solvent system. For example, the organic solvent may include aromatic solvents (such as benzene, xylene or toluene) or cyclic alkanes (such as cyclohexene) and one or more aliphatic or alicyclic alcohols (such as cyclohexanol), one or more Combinations of ketones, one or more ethers (e.g. cyclic ethers such as tetrahydrofuran) or one or more amides.

The organic solvent used in the method of the present invention is preferably substantially free of water, so as to ensure the maximum productivity of the anhydrate of Becquel. The organic solvent may contain up to 0.4% by weight of water, which can be absorbed by the solvent in the atmosphere. Most preferably, the organic solvent does not contain water.

The Beakley solution can be formed in any suitable way. For example, the solution can be formed by dissolving other forms of Becquerie other than solid crystal modification II in an organic solvent system. Alternatively, Becquel can be synthesized in the presence of an organic solvent. Suitable methods for synthesizing Beakley in solution in organic solvents are known in the art. US 7,087,239 discloses a suitable synthetic route for the preparation of Beakley.

The method of the present invention involves precipitating a solid bacillus from a solution of bacillus in an organic solvent. The solution is heated to an elevated temperature. This elevated temperature is higher than ambient temperature or room temperature, and is the temperature at which the precipitation preferentially produces crystalline modification II of bucklean anhydride. Any suitable elevated temperature can be used. Preferably, the elevated temperature is lower than the boiling point of the Becquerie solution.

The appropriate elevated temperature can be determined by analyzing the precipitated Beakley material, in particular whether the temperature is high enough to allow the Beakley anhydrous variant II to precipitate.

The elevated temperature is preferably at least 35°C, more preferably at least 40°C, and still more preferably at least 45°C. In experiments, it has been found that after heating to a temperature of 45° C., precipitation of white kraft from a solution in an organic solvent produces a solid white kraft material containing crystalline modification II in an amount of 30% by weight.

More preferably, after heating to a temperature of at least 50°C, still more preferably at least 55°C, and still more preferably still at least 60°C, the beakley is precipitated from the solution. In experiments, it has been found that after heating to a temperature of 65°C, precipitation of solid white crepe from a solution in an organic solvent leads to the formation of 100% by weight crystalline modification II of white crepe anhydride.

As mentioned above, the elevated temperature is preferably lower than the boiling point of the solution of the organic solvent and Becquerie starting material. This elevated temperature is also lower than the melting point of crystalline modification II of Becquerie anhydride.

The upper limit of this elevated temperature will depend on the particular solvent or solvent system used. The elevated temperature is preferably lower than 140°C, more preferably lower than 130°C, still more preferably lower than 120°C, and still more preferably still lower than 110°C. In a preferred embodiment, the solid Becquel starting material is heated to less than 100°C, more preferably less than 90°C, still more preferably less than 85°C, more preferably still low At an elevated temperature of 80°C.

It is preferable to use an elevated temperature in the range from 30°C to 130°C, more preferably from 35°C to 120°C, still more preferably from 40°C to 110°C, and more preferably still from 45°C to 100°C, wherein the preferred temperature range is from 50°C to 90°C, more preferably from 55°C to 85°C, and still more preferably from 60°C to 80°C. Temperatures from 60°C to 70°C are particularly preferred, wherein a temperature of about 65°C results in the formation of substantially 100% by weight of Becquerel anhydride variant II.

Any suitable technique can be used to carry out the precipitation of the Becquerie material from the organic solvent. Precipitation of Beakley from solution can be carried out at elevated temperature. For example, the precipitation can be carried out by, for example, by evaporation, for example, by removing the organic solvent at an elevated temperature under reduced pressure.

Alternatively, after the solution has been heated to an elevated temperature, the precipitation of beakley from the solution can be performed at a temperature lower than the elevated temperature. In particular, it is possible to realize the precipitation of the white kraft material from the organic solvent by cooling the saturated solution of white krafter in the solvent from an elevated temperature to a lower temperature at which solid white kraft precipitation occurs.

As a further alternative, the method may use a combination of the above-mentioned techniques, that is, the precipitation of the solid beakley material may be started at an elevated temperature, and then the solution may be cooled, for example, to precipitate additional solids.

Cooling can be performed continuously, stepwise, or in a combination thereof.

The precipitation of the Bekrief product can be carried out in an organic solvent in the presence of seed crystals of Bekrief, preferably in the presence of seed crystals of the crystal modification II of Bekrief anhydride.

The method of the present invention can be carried out batchwise or in a continuous manner.

Any suitable device can be used to carry out the precipitation of Beakley Crystal Modification II. Suitable devices are known in the art and are commercially available.

In another aspect, the present invention provides a fungicidal formulation comprising the crystalline modification II of Becquel anhydride prepared by the method described above.

The embodiments of the present invention are described by the following specific examples for illustrative purposes only.

In the following examples, unless otherwise stated, percentages are percentages by weight.

Instance

Example 1

The Becquerie was prepared according to the following general reaction scheme:

The Becquerie solution in xylene was prepared as follows:

396 g (1.944 mol) of 2-amino-4'-chlorobiphenyl in 311 g of xylene was charged into the reaction vessel, and the mixture was stirred until a uniform solution was obtained. 349 g (1.984 mol) of 2-chloro-3-nicotinyl chloride solution in 233 g of xylene was added to the reaction vessel, and the resulting mixture was allowed to heat to 30°C.

The resulting mixture is heated to an elevated temperature of 95°C over a period of 4 to 5 hours. Use an external scrubber and use water and alkali solution to absorb and remove the hydrogen chloride (HCl) generated by the reaction through a spray tower. The reaction mixture was kept at the same elevated temperature with stirring for a further 30 minutes to remove all traces of all HCL. Thereafter, the reaction mixture was cooled to 30°C with slow stirring over a period of 5 to 7 hours.

Finally, the solution was cooled to room temperature, resulting in the precipitation of solid bacillus material, and the solution was removed by filtration. Traces of xylene were removed from the precipitate by vacuum drying in an oven.

Using a Bruker model Tensor 37 spectrometer (recording wavelength of 550 to 4000 cm ^-1 , 16 scans with a maximum resolution of 4 cm ^-1 ), infrared (IR) spectroscopy was used to analyze the recovered Beikelie material. The analysis showed that the solid product was the crystalline modification II of Becquel anhydride.

Example 2

750 g of toluene was charged into the reaction vessel under a nitrogen atmosphere. 335 g of 2-chloronicotinic acid was added with stirring at room temperature. 35 g of dimethylformamide (DMF) was added to the mixture, and the resulting reaction mixture was slowly heated to 40°C under stirring. Add 300 g of sulfite chloride in a period of 1 hour. The hydrogen chloride (HCl) and sulfur dioxide (SO ₂ ) released by the reaction are removed by washing. Thereafter, the reaction mass was kept under a nitrogen atmosphere and maintained at 60°C for 4 to 5 hours until complete acid reaction (monitored by HPLC) occurred. After that, excess thiol chloride was removed under reduced pressure at 60°C to 75°C. The resulting mixture was cooled to room temperature.

The cooled mixture was diluted with 500 g of toluene and 200 g of triethylamine (TEA) under stirring. At 45°C, 400 g of 4'-chlorobenzidine-2-amine is added to this homogeneous mixture within 30 to 45 minutes, and the mixture is stirred for another 4 to 5 hours to complete the reaction. The mixture was quenched by adding water and stirring for another 2 to 3 hours.

The organic layer was separated and maintained at an elevated temperature of 60°C. The mixture is filtered to remove insoluble impurities. The mixture was finally cooled to 10°C to 15°C under slow stirring. The solid was separated by filtration and drying to obtain 450 to 480 g of Beak Lie.

The solid product was analyzed by IR spectroscopy as in Example 1, which showed that the solid product was the crystalline modification II of the anhydride of Becleter.

Example 3

792 g (3.888 mol) of 2-amino-4'-chlorobiphenyl in 622 g of xylene was charged into the reaction vessel, and the mixture was stirred until a uniform solution was obtained. A solution of 698 g (3.968 mol) of 2-chloro-3-nicotinyl chloride in 466 g of xylene was added to the reaction vessel, and the resulting mixture was allowed to heat to a temperature of 30°C.

The resulting mixture is heated to an elevated temperature of 95°C over a period of 4 to 5 hours. Use an external scrubber and use water and alkali solution to absorb and remove the hydrogen chloride (HCl) generated by the reaction through a spray tower. The reaction mixture was kept at the same elevated temperature with stirring for a further period of from 2 to 3 hours to remove all traces of HCl.

The resulting mixture was inoculated with seed crystals of crystalline modification II of Bekley anhydride, which resulted in the precipitation of solid material, which was collected by filtration. Traces of xylene were removed from the precipitate by vacuum drying in an oven.

Using Bruker model Tensor 37 spectrometer (recording wavelength from 550 to 4000 cm ^-1 , 16 scans with a maximum resolution of 4 cm ^-1 ), infrared (IR) spectroscopy was used to analyze the collected solid materials. The analysis showed that the solid product was the crystalline modification II of Becquel anhydride.

Example 4

According to the procedure described in Example 2, 375 g of the carbonyl intermediate of chloronicotinic acid was prepared, and reacted with 400 g of 4'-chlorobenzidine-2-amine to obtain the crude Becquerie product. The product was washed repeatedly with tetrahydrofuran (THF) and diluted with 850 g of isopropanol. The resulting solution is heated to 60°C and maintained at this temperature for 2 to 3 hours.

The resulting mixture was cooled to obtain a solid precipitate. The solid was separated by filtration and drying.

The solid product was analyzed by IR spectroscopy as in Example 1, which showed that the solid product was the crystalline modification II of Becquel anhydride.

In order to study the effect of temperature on the solid bacclair material obtained in the method, the procedure of Example 1 was repeated in which solid bacclair was precipitated from the xylene solution maintained in a different elevated temperature range before cooling.

The results are summarized in the table below.

From the results summarized in the above table, it can be seen that the form of the bacillus claret anhydride precipitated from the organic solvent depends on the temperature of the bacillus claret solution from which the precipitation is carried out. Specifically, the precipitation from xylene heated to a temperature of 65° C. produced 100% crystalline modification II of the white crepe anhydride. In contrast, from the precipitation of the xylene solution heated to just 30°C, only 10% to 20% of the crystalline modification II of the white creline anhydride was produced. Crystal Modification I.

Claims (23)

A method for preparing the crystalline modification II of Beak Lite anhydride, the method comprising providing a Beak Lite solution in an organic solvent system, heating the solution to an elevated temperature, and precipitating a solid Beak Lite from the solution , The elevated temperature is sufficient to preferentially form crystalline modification II of the buckle anhydride, wherein the elevated temperature is at least 35°C and less than 140°C, and wherein the precipitation of solid buckleite occurs at the elevated temperature . The method described in item 1 of the scope of the patent application, wherein the solvent system comprises a polar organic solvent, an aromatic hydrocarbon or a mixture thereof. The method described in item 2 of the patent application, wherein the polar organic solvent is selected from alcohols, ketones, ethers, esters, amides, and mixtures thereof. The method described in item 3 of the scope of the patent application, wherein the alcohol is a linear or branched aliphatic alcohol or a cycloaliphatic alcohol. The method described in item 4 of the scope of patent application, wherein the alcohol is selected from ethanol, propanol, butanol, cyclohexanol, ethylene glycol and diethylene glycol. The method according to item 3 of the scope of patent application, wherein the ketone is selected from acetone, methyl ethyl ketone, pentanone and hexanone. The method described in item 3 of the scope of patent application, wherein the ether is selected from dioxane and tetrahydrofuran. The method described in item 3 of the scope of patent application, wherein the ester is selected from ethyl acetate and methyl acetate. The method described in item 3 of the scope of patent application, wherein the amide is dimethylformamide. The method described in item 2 of the scope of patent application, wherein the aromatic solvent is selected from benzene, toluene and xylene. The method according to any one of items 1 to 10 in the scope of the patent application, wherein the solvent system is substantially free of water. Such as the method described in any one of items 1 to 10 in the scope of the patent application, wherein the method can be The other forms listed in addition to the solid crystal modification II are dissolved in an organic solvent system to form the solution. The method according to any one of items 1 to 10 in the scope of the patent application, wherein the solution is formed by synthesizing Beakley in the presence of an organic solvent system. The method according to any one of items 1 to 10 in the scope of the patent application, wherein the elevated temperature is lower than the boiling point of the solution. The method according to any one of items 1 to 10 in the scope of the patent application, wherein the elevated temperature is at least 45°C. The method described in item 15 of the scope of patent application, wherein the elevated temperature is at least 55°C. The method described in item 16 of the scope of the patent application, wherein the elevated temperature is at least 65°C. The method according to any one of items 1 to 10 in the scope of the patent application, wherein the elevated temperature is lower than 100°C. The method described in item 18 of the scope of patent application, wherein the elevated temperature is less than 85°C. The method described in item 19 of the scope of the patent application, wherein the elevated temperature is from 55°C to 85°C. The method described in any one of items 1 to 10 in the scope of the patent application, wherein the precipitation is aided by adding seed crystals to the solution. The method described in item 21 of the scope of patent application, wherein the seed crystals are the crystals of the crystal modification II of Bekley anhydride. The method according to any one of items 1 to 10 in the scope of the patent application, wherein the method is carried out in batches or in a continuous manner.

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