TW201808904A - 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 for preparing Bai Ke Lie   

The present invention relates to a method for preparing becquerel, in particular to a method for preparing a specific crystalline form of becquerel.

The compound 2-chloro-N- (4'chloro [1,1'biphenyl] -2-yl) -3-pyridylcarboxamide having the general name of becquerel has the structural formula I:

Becogli is a fungicide of carboxyamide group and acts as a succinate dehydrogenase inhibitor (SDHI), a respiratory inhibitor of mitochondria. Carboximide compounds of this class and their activities are first described in US 4,001,416 and US 5,330,995.

Buclacre is active as a fungicide, and it is now commercially available as a series of formulations for the treatment of fungal infections and the resulting diseases.

US 7,087,239 relates to crystalline hydrates of nicotinic acid aniline and / or benzanilide derivatives. US 7,087,239 specifically exemplifies the synthesis and recovery of the hydrate of becquerel. The hydrate is obtained by first preparing the anhydrous product of becquerel, which is obtained as a solution in hot xylene at the end of the synthesis process. After cooling, white clematis crystallized from the solution and dried in an oven under vacuum. The anhydrous substance is pointed out 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 anhydrous substance in tetrahydrofuran (THF) in a solvent at 40 ° C and adding the resulting solution to water. The precipitate was separated from the resulting mixture by filtration and dried to produce the white hydrate monohydrate. The crystalline modification of becquerel anhydrate disclosed in US 7,087,239 is referred to herein as crystalline modification I of becquerel.

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

We have found that it is difficult to grind the crystalline variant of Becquerel Anhydrous disclosed in US 7,087,239 in water. Therefore, it is not a simple task to directly formulate the crystalline variant of Becquerel into the desired formulation that requires grinding and / or grinding processes. 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 Formulations in which the active compound is present in dispersed form, such as water suspensions, water-dispersible oil suspensions, concentrated suspension emulsions or water suspensions for seed treatment. Before being formulated into an aqueous suspension, crystalline variants of becquerel need to be hydrated.

US 7,501,384 discloses the so-called novel crystalline variants of Becquerel anhydrous. The crystalline modification disclosed in US 7,501,384 is referred to herein as the crystalline modification II of Becquerel. In US 7,501,384, it is proposed that the crystalline modification II of Becquerel is more suitable for manufacturing various formulations, otherwise these formulations require a long grinding / grinding process.

US 7,501,384 describes that the crystalline modification II of becquerel can be prepared by a method comprising: a) dissolving the anhydrous substance of the crystalline modification I of becquerel in a polar organic solvent or aromatic hydrocarbon; and b ) By cooling the solvent, the anhydrous substance of the crystalline modification II of becquerel was precipitated.

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

US 7,501,384 describes the crystalline modification II of becquerel, 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 the crystalline modification II of Becquerel using Siemens' single crystal diffractometer are given in US 7,501,384:     

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

FTIR spectroscopy can be used to record IR spectra.

It would be a significant advantage if an improved preparation method of crystalline variant II of becquerel anhydrate can be provided, especially a method suitable for commercial scale application and having a reproducible high yield of variant II product . Preferably, the method is simple to operate and easy to control.

Surprisingly, it has now been found that the formation of high-yield crystalline variant II of becquerel anhydrate occurs at elevated temperatures. In contrast, the lower temperature leads to the formation of crystal variant I of becquerel anhydrate. Specifically, when precipitating becquerel from the solvent system, it was unexpectedly found that the precipitation of becquerel in the solvent system at a low temperature mainly or only produced the crystalline modification I of the becquerel anhydrous, however, increasing the solvent The temperature of the system and the precipitation of solid becquerel preferentially produce a crystalline II variant of becquerel anhydrate.

Fig. 1 is an IR spectrum of crystalline modification II of the anhydrous form of Becquerel; and Fig. 2 is an IR spectrum of crystalline modification I of the anhydrous form of Becquerel.

Therefore, in a first aspect, the present invention provides a method for preparing crystalline modification II of becquerel anhydrate, the method comprising providing a becquerel solution in an organic solvent system, heating the solution to an elevated temperature, and From the solution, a solid bequerol is precipitated, wherein the elevated temperature is sufficient to preferentially form crystalline modification II of the bequerol anhydrous.

In the present invention, an elevated temperature is used to form crystalline modification II of Becquerel anhydrous. As mentioned above, this increased temperature leads to the preferential formation of crystalline variant II of becquerel anhydrate compared to lower temperatures.

The method of the present invention uses Becquerel starting material. The white clergy starting material is a solution of white clergy in an organic solvent system. Any suitable organic solvent system for becquerel can be used to form the becquerel starting material described in this specific example. The solvent system may be a single organic solvent or a mixture of two or more solvents. Suitable solvents include polar organic solvents and aromatic hydrocarbons. Preferred polar organic solvents are alcohols, including polyhydric alcohols such as ethylene glycol, 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 a polyhydric alcohol, such as ethylene glycol. Examples of suitable ethylene 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, amyl ketone and hexanone. The ketones may be linear, branched or cyclic, such as alkyl acetone and cyclohexanone.

Examples of suitable ethers are C ₃ to C ₈ ethers, preferably C ₃ to C ₆ ethers. Such ethers may 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 preferred 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 A combination of ketones, one or more ethers (eg 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 in order to ensure the maximum productivity of the anhydrous product of becquerel. 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.

Beacillide solution can be formed in any suitable manner. For example, the solution can be formed by dissolving other forms of Beklee than solid crystalline modification II in an organic solvent system. Alternatively, becoclamide can be synthesized in the presence of an organic solvent. Suitable methods for synthesizing becquerel in solution in organic solvents are known in the art. US 7,087,239 discloses a suitable synthetic route for the preparation of becquerel.

The method of the present invention includes precipitating solid white clectin from a solution of white clin in an organic solvent. The solution is heated to an elevated temperature. This elevated temperature is higher than the ambient temperature or room temperature, and is the temperature at which precipitation preferentially produces crystalline modification II of becquerel anhydrate. Any suitable elevated temperature can be used. Preferably, the elevated temperature is lower than the boiling point of the Becquerel solution.

A suitable elevated temperature can be determined by analyzing the precipitated Becquerel material, in particular whether the temperature is high enough to precipitate the Becquerel Anhydrous Modification II.

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., the precipitation of bacilli from a solution in an organic solvent produces a solid bacilli 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, becoxel is precipitated from the solution. In experiments, it has been found that, after heating to a temperature of 65 ° C., precipitation of solid bequere from a solution in an organic solvent results in the formation of crystalline modification II of 100% by weight of bequere anhydrous.

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

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

It is preferable to use an elevated temperature ranging from 30 ° C to 130 ° C, more preferably from 35 ° C to 120 ° C, even more preferably from 40 ° C to 110 ° C, and still more preferably 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 even more preferably from 60 ° C to 80 ° C. A temperature from 60 ° C to 70 ° C is particularly preferred, where a temperature of about 65 ° C results in the formation of a variant II of substantially 100% by weight of white clematis anhydrous.

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

Alternatively, after heating the solution to an elevated temperature, the precipitation of becoclide from the solution may be performed at a temperature below the elevated temperature. In particular, the precipitation of the white claire material from the organic solvent can be achieved by cooling the saturated solution of white claire in the solvent from an elevated temperature to a lower temperature at which solid white claire precipitation occurs.

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

The cooling can be performed continuously, stepwise, or a combination thereof.

The precipitation of the bequere product can be carried out in an organic solvent in the presence of the seed crystals of bequere, preferably in the presence of seed crystals of crystalline modification II of bequere anhydrous.

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

The precipitation of Becquerel Crystal Modification II can be carried out using any suitable apparatus. Suitable devices are known in the art and are commercially available.

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

The following specific examples are used to describe the embodiments of the present invention for illustrative purposes only.

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

Examples

Example 1

According to the following general reaction scheme for the preparation of Bacrine:

Prepare the Bclectin solution in xylene 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 homogeneous solution was obtained. A solution of 349 g (1.984 mol) of 2-chloro-3-nicotinyl chloride 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 was heated to an elevated temperature of 95 ° C over a period of 4 to 5 hours. Hydrogen chloride (HCl) produced by the reaction was removed by an external scrubber and absorption by a spray tower using water and alkali solution. The reaction mixture was maintained 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, which resulted in the precipitation of a solid white claire material, and the solution was removed by filtration. Traces of xylene were removed from the precipitate by vacuum drying in an oven.

Using Bruker (a Bruker) model Tensor 37 spectrometer (recording wavelength of 550 to 4000cm ^-1, having the highest resolution of 4cm ^-1 of 16 scans) using column material Hornbeck infrared (IR) spectrometry recovered. Analysis showed that the solid product was crystalline modification II of becquerel anhydrate.

Example 2

750 g of toluene was charged into the reaction vessel under a nitrogen atmosphere. At room temperature, 335 g of 2-chloronicotinic acid was added with stirring. To this mixture, 35 g of dimethylformamide (DMF) was added, and the resulting reaction mixture was slowly heated to 40 ° C with stirring. 300g of sulfenyl chloride was added within 1 hour. 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 at 60 ° C. for 4 to 5 hours until a complete reaction of the acid occurred (monitored by HPLC). Thereafter, excess sulfenyl chloride is 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) with stirring. At 45 ° C., 400 g of 4′-chlorobiphenyl-2-amine was added to this homogeneous mixture over a period of 30 to 45 minutes, and the mixture was further stirred for 4 to 5 hours to complete the reaction. The mixture was quenched by adding water and stirring for an additional 2 to 3 hours.

The organic layer was separated and maintained at an elevated temperature of 60 ° C. The mixture was filtered to remove insoluble impurities. The mixture was finally cooled to 10 to 15 ° C with slow stirring. The solid was separated by filtration and dried to obtain 450 to 480 g of white clematis.

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

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 homogeneous 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 was heated to an elevated temperature of 95 ° C over a period of 4 to 5 hours. Hydrogen chloride (HCl) produced by the reaction was removed by an external scrubber and absorption by a spray tower using water and alkali solution. The reaction mixture was further maintained at the same elevated temperature with stirring for a period of from 2 to 3 hours to remove all traces of all HCl.

The resulting mixture was seeded with seed crystals of Crystalline Modification II of Becquerel Anhydrous, resulting in precipitation of a solid material, which was collected by filtration. Traces of xylene were removed from the precipitate by vacuum drying in an oven.

Using Bruker (a Bruker) model Tensor 37 spectrometer (recording wavelength of 550 to 4000cm ^-1, having the highest resolution of 4cm ^-1 16 scans), the solid material employed infrared (IR) spectrometry collected. Analysis showed that the solid product was crystalline modification II of becquerel anhydrate.

Example 4

The carbonyl intermediate of chloronicotinic acid was prepared according to the procedure described in Example 2 and reacted with 400 g of 4'-chlorobiphenyl-2-amine to obtain a crude becquerel product. The product was repeatedly washed with tetrahydrofuran (THF) and diluted with 850 g of isopropanol. The resulting solution was 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 isolated by filtration and drying.

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

In order to study the effect of temperature on the solid white clematis material obtained in the process, the procedure of Example 1 was repeated, in which solid white clematis was precipitated from a 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 white clergy anhydrous precipitated from the organic solvent depends on the temperature of the white clergy solution precipitated therefrom. Specifically, the precipitation of xylene heated to a temperature of 65 ° C. produced a crystalline modification II of 100% becquerel anhydrous. In contrast, the precipitation of the xylene solution heated to just 30 ° C produced only 10% to 20% of the crystalline variant II of the white kleeline anhydrate, at which the main form of the white kleeline anhydrate Crystalline modification I.

Claims (27)

    A method for preparing crystalline modification II of becquerel anhydrate, the method comprising providing a becquerel solution in an organic solvent system, heating the solution to an elevated temperature, and precipitating solid becquerel from the solution This elevated temperature is sufficient to preferentially form crystalline modification II of Becquerel anhydrous.         The method as described in item 1 of the patent application scope, wherein the solvent system includes a polar organic solvent, an aromatic hydrocarbon, or a mixture thereof.         The method as described in item 2 of the patent application scope, wherein the polar organic solvent is selected from alcohols, ketones, ethers, esters, amides, and mixtures thereof.         The method as described in item 3 of the patent application, wherein the alcohol is a linear or branched aliphatic alcohol or an alicyclic alcohol.         The method according to item 4 of the patent application scope, wherein the alcohol is selected from ethanol, propanol, butanol, cyclohexanol, ethylene glycol, and diethylene glycol.         The method as described in item 3 of the patent application scope, wherein the ketone is selected from acetone, methyl ethyl ketone, amyl ketone and hexanone.         The method as described in item 3 of the patent application, wherein the ether is selected from dioxane and tetrahydrofuran.         The method as described in item 3 of the patent application, wherein the ester is selected from ethyl acetate and methyl acetate.         The method as described in item 3 of the patent application scope, wherein the amide is dimethylformamide.         The method as described in item 2 of the patent application scope, wherein the aromatic solvent is selected from benzene, toluene and xylene.         The method as described in any of the foregoing patent applications, wherein the solvent system is substantially free of water.         The method as described in any one of the aforementioned patent applications, wherein the solution can be formed by dissolving other forms of Bekleet in addition to the solid crystalline modification II in an organic solvent system.         The method according to any one of items 1 to 11 of the patent application range, wherein the solution is formed by synthesizing becloxil in the presence of an organic solvent system.         The method as described in any of the foregoing patent applications, wherein the elevated temperature is below the boiling point of the solution.         The method as described in any of the foregoing patent applications, wherein the elevated temperature is at least 45 ° C.         The method as described in item 15 of the patent application range, wherein the elevated temperature is at least 55 ° C.         The method as described in item 16 of the patent application range, wherein the elevated temperature is at least 65 ° C.         The method as described in any of the foregoing patent applications, wherein the elevated temperature is below 100 ° C.         The method as described in item 18 of the patent application range, wherein the elevated temperature is less than 85 ° C.         The method as described in item 19 of the patent application range, wherein the elevated temperature is from 55 ° C to 85 ° C.         A method as described in any one of the foregoing patent applications, wherein solid becquerel precipitation occurs at this elevated temperature.         A method as described in any one of the aforementioned patent applications, wherein the precipitation of solid becquerel occurs at a temperature below the elevated temperature.         The method as described in any of the foregoing patent applications, wherein the precipitation is aided by adding seed crystals to the solution.         The method as described in item 23 of the patent application scope, in which the seed crystals are crystals of crystalline modification II of the Baicale anhydrous.         The method as described in any of the foregoing patent applications, wherein the method is carried out in batches or in a continuous manner.         A method of preparing crystalline modification II of becquerel anhydrate substantially as described above.         A fungicidal formulation, the fungicidal formulation comprising the crystalline modification II of becquerel anhydrate prepared by the method described in any of the aforementioned patent applications.