HK1183303A - Process for preparing pyridinamines and novel polymorphs thereof - Google Patents

Description

Process for preparing pyridinamines and novel polymorphs thereof

The application is a divisional application of Chinese patent application with the application number of 200680043978.X, the application date of 2006, 11/23.3, and the name of the invention of a method for preparing pyridylamine and a novel polymorphic form thereof.

Technical Field

The present invention relates to the synthesis of pyridinamines, and more particularly to an improved synthesis of N-phenylpyridinamines, such as-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam), a pesticide. The present invention relates to novel crystalline polymorphs of fluazinam, processes for their preparation, compositions containing the polymorphs and their use as pesticides.

Background

Certain pyridinamines having pesticidal activity are useful against harmful organisms such as insects, mites, fungi, bacteria and rodents. For example, compounds having rodenticidal activity are disclosed in US patent US4,140,778, and compounds having pesticidal activity are disclosed in US3,965,109 and US3,926,611.

U.S. patent No. 4,331,670 discloses and claims protection of N-pyridinamines having specific substituents on the pyridine ring. These compounds are effective for combating insects, mites, fungi, bacteria and rodents which are harmful to the storage of industrial products, seeds and fruits and for controlling the growth of pests in agricultural and horticultural crops and upland areas. One of these compounds, fluazinam, is currently marketed for the treatment of sclerotinia rot, a major disease of lettuce, caused by two kinds of soil-borne fungi: sclerotinia sclerotiorum and sclerotinia sclerotiorum. Fluazinam and other fungicides such as boscalid (boscalid), fenhexamid (fenhexamid) and fludioxonil (fludioxonil) also show efficacy against crop diseases other than lettuce caused by sclerotinia sclerotiorum and sclerotinia sclerotiorum.

It has also been known that 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) contributes to container-seeded aucubaceae plants protection from southern blight, a detrimental hot day disease that can adversely affect flowering trees, shrubs, and herbaceous ornamentals for nursery and greening purposes.

Fluazinam has a broad-spectrum antibacterial effect and exhibits a good preventive effect on plant diseases. Fluazinam shows good activity against Botrytis cinerea which is resistant to benzimidazole and/or dicarboximide. The field test shows that the fluazinam has excellent activity in resisting phytophthora solani (phytophthora infestan). Fluazinam has also been shown to significantly reduce the number of mites by repeated treatments on the field. (ACS Symposium Series1995584, 443-8).

The contents of U.S. patent No. 4,331,670, which is incorporated herein by reference in its entirety, discloses a coupling process for preparing a pyridylamine such as fluazinam in the following manner.

The reaction uses THF or DMF as solvent, giving reported yields of 75% and 22%, respectively. The aforementioned solvents cause the reaction to suffer from a number of adverse effects. For example, THF is a flammable, non-safe solvent with a low flash point and is a source of peroxide formation; and thus its large-scale application is greatly limited. Furthermore, aprotic solvents such as THF and DMF are miscible with water and contain significant amounts of water in the azeotrope used for recycle. The presence of water reduces the yield of the reaction, on the one hand due to incomplete consumption of the reactants and on the other hand due to the formation of hydrolysis by-products. For example, one competing side reaction is the formation of a by-product of formula (4) from compound (1A) in the presence of water. This reaction significantly reduces the yield of the final product.

Furthermore, the processes of the prior art comprise very cumbersome work-up steps involving extraction into a third solvent, ethyl acetate and purification in silica gel, which are not suitable for large-scale production. These complex purification steps are necessary to remove the large amounts of impurities formed in the reaction, such as the above mentioned hydrolysates, as well as to remove the tar formed at a temperature accelerated above 40 ℃ and the two reactants (1A) and (2A) not consumed completely, mainly due to less than 8.2% w/v of the reactants passing to the solvent to react under dilute conditions.

To date, there is no simple method for purifying fluazinam that can be used for large-scale production of high-purity fluazinam. Neither is it known that fluazinam is in the form of a crystalline polymorph. There is therefore a great need in the art for efficient processes for the preparation and purification of fluazinam and other pyridinamines which overcome the disadvantages and drawbacks of the prior art.

Disclosure of Invention

The present invention relates to an improved process for the synthesis of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) and other pyridinamines, using methyl isobutyl ketone (MIBK) as the reaction solvent. The process of the present invention overcomes the disadvantages of the prior art by reducing side reactions such as hydrolysis, eliminates the need for difficult and laborious purification methods, and provides higher yields of pure product. In another aspect, the present invention relates to novel crystalline polymorphic forms of fluazinam, and mixtures of these polymorphs. The invention also provides processes for preparing the novel polymorphs and pesticidal compositions containing the polymorphs, and methods of using the polymorphs as pesticides against organisms harmful to agricultural and horticultural crops.

As noted herein, applicants of the present invention have unexpectedly found that the use of MIBK as a reaction solvent for the preparation of fluazinam and other pyridinamines provides a more efficient process which reduces labor intensity and greatly improves the yield and purity of the pyridinamine product. This represents a significant improvement over the prior art processes using THF and DMF as solvents. First, the chemical yield increased from 22% using DMF and 75% using THF to about 98%. Furthermore, the process of the present invention allows for easier and easier reprocessing steps by replacing the laborious column purification steps with simple crystallization steps.

Without wishing to be bound by any particular mechanism or theory, it is believed that the advantages resulting from the several advantageous properties of MIBK include: 1) easy recycling and improved safety; 2) lower water content (1.6%) of recycled solvent compared to THF water content (5%); 3) low water solubility and 4) reduced sensitivity to temperature fluctuations. The low water solubility of MIBK minimizes the amount of water present in the reaction process, thereby reducing the amount of hydrolysis byproducts and increasing yield. Reduced sensitivity to temperature fluctuations is important, especially because the reaction is strongly exothermic and produces large amounts of tar at high temperatures.

Furthermore, one disadvantage in the prior art processes is the incomplete consumption of both reactants (1A) and (2A), mainly due to the fact that the reaction is carried out in diluted conditions (less than 8.2 weight/volume (w/v) of reactants versus solvent). In particular, when a solvent such as THF, DMF or other water-soluble solvent is used, the reaction cannot be performed under a concentrated condition because a high concentration of water generated in the reaction and present in the reactant increases the amount of hydrolysis by-products, thereby decreasing the yield. This phenomenon was not observed when MIBK was used as a solvent, mainly due to its low water solubility. In fact, applicants have unexpectedly found that the more concentrated the reaction, the less hydrolysis reactions are observed. The use of MIBK thereby allows the reaction to be carried out under more concentrated conditions, greatly increasing the efficiency of the reaction.

The term "reactant to solvent ratio" as used herein refers to the total weight of reactants of formulae a and B (or formulae 1 and 2 or formulae 1A and 2A) per unit volume of solvent in the reaction mixture, expressed as weight percent per unit volume (W/V). In one embodiment, the reactant to solvent ratio is at least about 10%. Preferably, the reactant to solvent ratio is at least about 25%, more preferably at least about 40% weight/volume (W/V).

Accordingly, it is an object of the present invention to provide a novel process for preparing a pyridylamine compound represented by structural formula (I).

Wherein X is a trifluoromethyl group, a halogen atom, C₁-C₆Alkyl radicals or C₁-C₆An alkoxy group; n is an integer from 0 to 4, R is a hydrogen atom or an acetyl group; y is a hydrogen atom, a halogen atom, C₁-C₆Alkoxy radical, C₁-C₆A thioalkyl (thioalkyl) group, an alkylthio group, a hydroxy group, an azido group, a phenoxy group or a phenoxy group in which the phenyl group is substituted by a hydroxy group; and Z₁，Z₂And Z₃Are each a trifluoromethyl group or a nitro group.

According to the process of the present invention, these pyridinamines are synthesized by reacting a compound of formula (A) with a compound of formula (B) in the presence of a base, wherein X, Y, Z in formulae (A) and (B)₁，Z₂，Z₃And n is as defined above, and one of U and W is an amino group and the other is a leaving group, such as halogen, alkylsulfonyl, arylsulfonyl, wherein MIBK is used as a reaction solvent.

In one embodiment, MIBK is used as the pure solvent. The term "pure solvent" as used herein means at least about 98% pure. In another embodiment, the MIBK is at least about 99% pure. In another embodiment, the MIBK is at least about 99.5% pure. In another embodiment, the MIBK is at least about 99.8% pure. In another embodiment, recycled MIBK containing less than about 2% water is used. In a preferred embodiment, a cyclic azeotrope containing 1.6% aqueous MIBK is used.

In another embodiment, the present invention provides a process for preparing a pyridylamine, referred to as fluazinam, represented by formula (3) by reacting a compound of formula (1) with a compound of formula (2) wherein one of U and W is an amino group and the other is a leaving group, selected from halogen, alkylsulfonyl and arylsulfonyl, in the presence of a base, using MIBK as a reaction solvent.

The process is carried out in a base, preferably selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, hydrides, alkaline earth metal hydroxides and alkaline earth metal carbonates.

In a preferred embodiment, the base is potassium hydroxide or sodium hydroxide.

In another embodiment, the present invention provides a process for preparing a pyridylamine, referred to as fluazinam, represented by formula (3) by reacting a compound of formula (1A) with a compound of formula (2A) using MIBK as a reaction solvent.

The process is carried out in a base, preferably selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, hydrides, alkaline earth metal hydroxides and alkaline earth metal carbonates.

In a preferred embodiment, the base is potassium hydroxide or sodium hydroxide.

It is another object of the present invention to provide a process for purifying a compound represented by formula (I), which comprises the step of crystallizing the compound from a solvent or a mixture of solvents. It is preferred to use an organic solvent or a mixture of organic solvents for the crystallization. The preferred organic solvent in the crystallization step is ethanol.

Still another object of the present invention is to provide a method for purifying fluazinam, which comprises the step of crystallizing the compound from a solvent or a mixture of solvents. The preferred organic solvent in the crystallization step is ethanol. As contemplated herein, the crystallization process described herein may result in the formation of novel polymorphic forms of fluazinam, or mixtures thereof. These polymorphic forms or mixtures therefore also form part of the present invention.

Thus, from another aspect, the present invention provides a novel polymorph form of fluazinam, and a method for preparing the same. In one embodiment, the present invention provides a novel crystalline polymorph form of fluazinam, referred to as "form I". Form I has an X-ray powder diffraction pattern substantially as shown in figure 1, with characteristic peaks (expressed in degrees 2 Θ (+/-0.2 ° θ)) at one or more of the following positions: 8.7, 10, 12.0, 13.7, 14.5, 17.4, 18.5, 19.7, 21.8, 22.9, and 30.2. Form I also has a peak density at 3000cm as shown in FIG. 2^-1In the infrared spectrum of about 3390cm^-1With characteristic peaks in the vicinity. Form I also has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 3, which is characterized by a major endothermic peak at about 115.5 ℃ when scanned using a differential scanning calorimeter at a rate of 10 ℃ per minute. Form I is generally crystallized in the form of prisms, such as the typical large yellow prisms described herein.

In another embodiment, the present invention provides a novel crystalline polymorph form of fluazinam, referred to as "form II". Form II has an X-ray powder diffraction pattern substantially as shown in fig. 4, with characteristic peaks (expressed in degrees 2 Θ (+/-0.2 ° θ)) at one or more of the following positions: 7.4, 10.4, 13.4,15.1, 18.95, 20, 20.4, 21.05, 21.3, 22.2, 24.9, 27.15, 28.6 and 30.5. Form II also had a peak density at 3000cm as shown in FIG. 5^-1Has an infrared spectrum of about 3375cm^-1With characteristic peaks in the vicinity. Form II also has a DSC profile substantially as shown in figure 6, characterized by a major endothermic peak at about 109 ℃ when scanned using a differential scanning calorimeter at a rate of 10 ℃ per minute. Form II is usually crystallized as needles, typically as bright yellow needles.

In another embodiment, the present invention provides a mixture of polymorphic form I and form II of fluazinam. The mixture has an X-ray powder diffraction pattern substantially as shown in FIG. 7, at 3000cm substantially as shown in FIG. 8^-1And a DSC plot substantially as shown in figure 9, scanned at a rate of 10 ℃ per minute using a differential scanning calorimeter.

In another aspect, the present invention provides a process for preparing novel polymorphs of fluazinam form I and form II, and a process for preparing a mixture of polymorphs.

In one embodiment, the fluazinam of form I can be prepared by: crystallizing fluazinam from a solvent selected from the group consisting of ethanol, acetonitrile, dichloromethane and n-hexane; and isolating the resulting crystals. In a preferred embodiment, the process comprises preparing a solution of the compound in one or more of the above-mentioned solvents, preferably by heating until complete dissolution, cooling the solution until crystallisation occurs, and then isolating the crystals.

In another embodiment, the fluazinam of form I and form II can be prepared by crystallizing the fluazinam from diethyl ether using different crystallization conditions. To prepare form I, fluazinam is dissolved in diethyl ether, preferably at room temperature, and the flask is exposed to the environment to allow the solvent to evaporate slowly. Crystallization, typically in the shape of large yellow prisms, begins to occur gradually and then the crystals are isolated. To prepare form II, the compound was also dissolved in ether as described above, but the solvent was allowed to evaporate rapidly from the flask. This results in the formation of crystals, usually bright yellow needles, which are then isolated.

In another embodiment, form II can be prepared by preparing an ethanolic solution of fluazinam in the manner described above for form I. However, rather than precipitating the product by cooling, the solution is exposed to the environment, causing some of the solvent to slowly evaporate. Crystals, usually bright yellow needles, gradually begin to appear and are then isolated.

In another embodiment, the mixture of form I and form II is prepared by crystallizing fluazinam from a solvent selected from the group consisting of isopropanol, n-hexane, and toluene, and then isolating the resulting crystals. In a preferred embodiment, the process comprises preparing a solution of fluazinam in one or more of the above-mentioned solvents, preferably by heating until complete dissolution, cooling the solution until crystallisation occurs, and isolating the crystallisation.

Mixtures of form I and form II may also be prepared by dissolving fluazinam in a solvent in which the compound is soluble, adding an anti-solvent, and isolating the resulting crystals. In a preferred embodiment, the solvent is acetone. In another preferred embodiment, the anti-solvent is water.

In another aspect, the present invention provides pesticidal compositions comprising the novel crystalline polymorph, which are useful for controlling and combating pests such as insects, mites, fungi and bacteria which grow in agricultural and horticultural crops and highland. In one embodiment, the composition comprises crystalline polymorph form I fluazinam; and an acceptable adjuvant (adj uvant). In another embodiment, the composition comprises crystalline, polymorphic form II fluazinam; and acceptable adjuvants. In another embodiment, the composition comprises a mixture of crystalline polymorphic form I and form II fluazinam; and acceptable adjuvants.

The invention also relates to methods of combating insects, acarines, fungi and bacteria by contacting the insects, acarines, fungi and bacteria or exposing them to an effective amount of a composition of the invention.

The invention also relates to a method for protecting crops and upland comprising the industrial products thus obtained, such as seeds and fruits, by applying to the crops or products an effective dose of the composition of the invention.

Further embodiments and full scope of applicability of the present invention will become apparent from the detailed description given hereinafter. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art.

Drawings

Figure 1 is an X-ray powder diffraction pattern of fluazinam form I.

FIG. 2 is an FT IR spectrum (at 3000 cm) of fluazinam form I^-1Range of (d).

Figure 3 is a Differential Scanning Calorimetry (DSC) profile of fluazinam form I.

Figure 4 is an X-ray powder diffraction pattern of fluazinam form II.

FIG. 5 is an FT IR spectrum (at 3000 cm) of fluazinam form II^-1Range of (d).

Figure 6 is a Differential Scanning Calorimetry (DSC) profile of fluazinam form II.

Figure 7 is an X-ray powder diffraction pattern of a mixture of fluazinam form I and form II.

FIG. 8 is a FT IR spectrum (at 3000 cm) of a mixture of fluazinam form I and form II^-1Range of (d).

Fig. 9 is a Differential Scanning Calorimetry (DSC) profile of a mixture of fluazinam form I and form II.

Detailed Description

In one aspect, the present invention relates to an improved process for the synthesis of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) and other pyridinamines using methyl isobutyl ketone (MIBK) as the reaction solvent. The process of the present invention overcomes the disadvantages of the prior art by reducing side reactions such as hydrolysis, eliminates the need for difficult and laborious purification methods, and provides a pure product in high yield.

Without wishing to be bound by any particular mechanism or theory, it is believed that water is a negative role in the coupling reaction between compound a and compound B, although it is required in the reprocessing step of the reaction, particularly when the product is isolated by acidification. In particular, it is believed that water can lead to incomplete consumption of reactants by generating hydrolysis byproducts. There are three different sources of water introduction: 1) water produced stoichiometrically by neutralizing the liberated hydrochloric acid; 2) solid inorganic bases such as KOH and NaOH used in the reaction contain 10-15% water; 3) water is introduced using recycled water-miscible solvents such as THF, DMF and DMSO as azeotropes with the water.

To avoid these problems, the prior art reactions in THF or DMF are carried out under extremely dilute conditions in order to minimize the concentration of water. However, this results in a significant reduction in reaction yield and efficiency.

As noted herein, applicants screened several solvents with different water solubilities as reaction solvents for synthesizing fluazinam and other pyridinamines according to the protocol described above. Table 1 shows the physical parameters of several test solvents.

Table 1: physical parameters of several useful solvents

Applicants have surprisingly found that MIBK is an excellent solvent for the coupling reaction. MIBK was distilled as a 76% solvent azeotrope. However, due to its lower water solubility, it separated into two layers upon standing, the organic-rich layer contained about 98.40% MIBK, while the water-rich layer contained about 1.6% MIBK. MIBK is the only solvent studied that has a significantly different water content in its azeotrope (24%) than in its recycled solvent (1.6%).

Without wishing to be bound by any particular mechanism or theory, one may appreciate the advantages of MIBK as a reaction solvent, at least in part, due to its unique properties, including its low water solubility and low water content in the recycled solvent.

MIBK was found to be the best solvent to overcome the problem of excessive water generation by allowing only a minimal amount of "available water" to interfere with the reaction. The low water solubility of MIBK, which shields the reaction from excess water, enables it to be used in more concentrated systems. This is most desirable to improve both chemical and volumetric yields on a large scale. Indeed, the chemical yield improved from 75% to 98% and the volumetric yield (i.e., reactant to solvent ratio) improved from 8.2% to at least about 40% w/v.

Another advantage of using MIBK is the known much lower sensitivity of MIBK to temperature fluctuations than other solvents. This is important because the reaction is strongly exothermic and produces large amounts of tar at high temperatures. Reprocessing can also be made easier by using MIBK as a solvent by simple crystallization instead of column purification.

It is therefore an object of the present invention to provide a novel process using a solvent which is very effective in preparing a pyridylamine compound represented by structural formula (I).

Wherein X is a trifluoromethyl group, a halogen atom, C₁-C₆Alkyl radicals or C₁-C₆An alkoxy group; n is an integer of 0, 1, 2, 3 or 4, R is a hydrogen atom or an acetyl group; y is a hydrogen atom, a halogen atom, C₁-C₆Alkoxy radical, C₁-C₆A thioalkyl group, a hydroxyl group, an azido group, a phenoxy group or a phenoxy group in which the phenyl group is substituted with a hydroxyl group; and Z₁，Z₂And Z₃Independently a trifluoromethyl group or a nitro group.

According to the process of the present invention, these pyridinamines are synthesized by reacting a compound of formula (A) with a compound of formula (B) in the presence of a base, wherein X, Y, Z in formulae (A) and (B)₁，Z₂，Z₃And n is as defined above and one of U and W is an amino group and the other is a leaving group selected from halogen, alkylsulfonyl, arylsulfonyl, wherein MIBK is used as a reaction solvent. In one embodiment, MIBK is used as the pure solvent. In another embodiment, a recycled azeotrope containing about 1.6% MIBK in water is used.

The term "C₁-C₆An alkyl group "as used herein alone or as part of another group refers to a straight, branched or cyclic (e.g., cycloalkyl), saturated or unsaturated (e.g., alkenyl, alkynyl) group, the latter only when the number of carbon atoms in the alkyl chain is greater than or equal to 2, and may include mixed structures. Examples of saturated alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, hexyl, and the like. Examples of alkenyl groups include vinyl, allyl, butenyl, and the like. Examples of alkynyl groups include ethynyl, propynyl, and the like. Examples of cycloalkyl groups include cyclopropyl, cyclobutylAnd cyclopentyl, cyclohexyl, and the like.

C₁-C₆The alkyl group may be unsubstituted or substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, aryloxy, alkylaryloxy, heteroaryloxy, oxo (oxo), cycloalkyl, phenyl, heteroaryl, heterocyclyl, naphthyl, amino, alkylamino, arylamino, heteroarylamino, dialkylamino, diarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, acyl, acyloxy, nitro, carboxy, carbamoyl, amido (carboxamide), cyano, sulfonyl, sulfonamido, sulfinyl, sulfonamido, mercapto, C₁-C₆Thioalkylarylthio, or C₁-C₆An alkylsulfonyl group. Any substituent may be unsubstituted or further substituted by any of the foregoing substituents.

The term "aryl" as used herein alone or as part of another group refers to aromatic ring systems containing from 6 to 14 ring carbon atoms. The aryl ring may be monocyclic, bicyclic, tricyclic, and the like. Non-limiting examples of aryl groups are phenyl, naphthyl groups include 1-naphthyl and 2-naphthyl, and the like. The aryl group may be unsubstituted or substituted with one or more of the alkyl substituents described above.

The term "C₁-C₆Alkoxy "as used herein alone or as part of another group means C as described above attached to an oxygen atom₁-C₆An alkyl group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, and the like. The term "phenoxy" as used herein alone or as part of another group refers to a phenyl group attached to an oxygen atom. C₁-C₆The alkoxy or phenoxy group may be unsubstituted or substituted with one or more of the foregoing alkyl substituents.

The term "C₁-C₆Thioalkyl "as used herein alone or as part of another group means with a sulfur atomCoupled as above C₁-C₆Alkyl group of (1). Non-limiting examples of thioalkyl groups are thiomethyl, thioethyl, thio-n-propyl, thioisopropyl, thio-n-butyl, thio-t-butyl and the like. C₁-C₆The thioalkyl groups of (a) may be unsubstituted or substituted with one or more of the alkyl substituents described above.

The term "trifluoromethyl" as used herein alone or as part of another group means CF₃A group. The term "hydroxy" as used herein alone or as part of another group means an OH group. The term "halogen" or "halo" as used herein alone or as part of another group refers to chloro, bromo, fluoro and iodo. The term "azido" as used herein alone or as part of another group means N₃A group. The term "acetyl" as used herein alone or as part of another group denotes COCH₃A group. The term "nitro" as used herein alone or as part of another group denotes NO₂A group. The term "amino" as used herein alone or as part of another group denotes NH₂A group. The term "sulfonyl", used herein alone or as part of another group, denotes-S (O)₂-. Alkylsulfonyl refers to a sulfonyl group to which an alkyl group such as those described above is attached. Arylsulfonyl means a sulfonyl group to which is attached an aryl group as described above.

In another embodiment, the present invention also provides a method for preparing fluazinam represented by formula (3) by reacting a compound of formula (1) with a compound of formula (2) wherein one of U and W is an amino group and the other is a leaving group selected from halogen, alkylsulfonyl, arylsulfonyl, in the presence of a base, wherein MIBK is used as a reaction solvent.

The process of the invention is carried out in a base. Preferably, the base is selected from the group consisting of alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., sodium bicarbonate, sodium carbonate, potassium carbonate), hydrides (e.g., sodium hydride, potassium hydride), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide) and alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate). The preferred base is potassium hydroxide or sodium hydroxide.

Preferably, the reactant to solvent ratio is greater than about 10% w/v. More preferably, the reactant to solvent ratio is greater than about 25% w/v, and most preferably, the reactant to solvent ratio is greater than about 40% w/v. This is an advantage over prior art processes which result in incomplete reaction of reactants (a) and (B) under dilute reaction conditions (reactant to solvent ratio of less than 8.2% w/v) and thus reduced yields.

In another embodiment, the present invention provides a process for the preparation of pyridylamine, known as fluazinam, represented by formula (3), by reacting a compound of formula (1A) with a compound of formula (2A), using MIBK as reaction solvent.

The process of the invention is carried out in a base. Preferably, the base is selected from the group consisting of alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., sodium bicarbonate, sodium carbonate, potassium carbonate), hydrides (e.g., sodium hydride, potassium hydride), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide) and alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate). The preferred base is potassium hydroxide or sodium hydroxide.

Preferably, the reactant to solvent ratio is greater than about 10% w/v. More preferably, the reactant to solvent ratio is greater than about 25% w/v, and most preferably, the reactant to solvent ratio is greater than about 40% w/v. This is an advantage over prior art processes which result in incomplete reaction of reactants (a) and (B) under dilute reaction conditions (reactant to solvent ratio of less than 8.2% w/v) and thus reduced yields.

Preferred solvents in this new process are pure MIBK (e.g., at least about 98% pure) or recycled MIBK containing less than 2% water. The water content is preferably less than about 1.9%, more preferably less than about 1.75%, and most preferably less than about 1.6%. In a preferred embodiment, a recycled azeotrope containing about 1.6% MIBK in water is used. The low water solubility characteristic of MIBK allows the reaction to proceed under more concentrated conditions, significantly increasing the efficiency of the reaction.

Generally, the temperature of the reaction is maintained at about 0-20 ℃ or less for about the first hour due to the exothermic nature of the coupling reaction. The reaction may then be allowed to warm to room temperature (about 25-30 deg.C) and stirred at this temperature until the reaction is complete, typically from about 2-3 hours to about 24 hours. Reprocessing (work-up) involves acidification, for example by addition of acids like HCl or H2SO 4. A two-phase mixture is formed. The organic layer is then separated and the product is isolated after evaporation of the solvent.

The purification of the compound of formula (I) is accomplished by crystallizing the mixture from a solvent or a mixture of solvents, preferably from an organic solvent or a mixture of organic solvents. Thus, in one embodiment, the invention provides a process for purifying a compound of formula (I) by crystallizing the mixture from a solvent or a mixture of solvents. In one embodiment, the compound of formula (I) is fluazinam represented by structural formula (3). The preferred organic solvent in the crystallization step is ethanol. Suitable grades of ethanol include 80-100% ethanol. The ethanol may be wet or dry.

Crystallization can be accomplished as is known in the art, for example, by mixing the desired compound in an appropriate amount of solvent or solvent mixture, heating to dissolve it, and cooling to precipitate the product. Alternatively, the compound is dissolved in one solvent and a second, insoluble or slightly soluble solvent is added until precipitation occurs. The reaction may also be seeded with a suitable compound seed to induce precipitation, as is known in the art.

As contemplated herein, the crystallization process described herein may result in the formation of one or more novel polymorphic forms of fluazinam, or mixtures thereof. Thus, in another aspect, the present invention is generally directed to novel polymorphic forms of fluazinam, referred to herein as "polymorphic form I" and "polymorphic form II", and mixtures of said polymorphs. The invention also provides processes for preparing the novel polymorph and pharmaceutical compositions containing the polymorph, and methods of using the polymorph for combating organisms harmful to agricultural and horticultural crops.

The solid is present in amorphous or crystalline form. In the case of crystalline forms, the molecules are arranged in the form of a three-dimensional lattice. When a compound is recrystallized from a solution or slurry, it may crystallize in a different spatial lattice arrangement, a property known as "polymorphism", and each different crystal form known as a "polymorph". The different polymorphic forms of a known substance may differ from one another in one or more physical properties, such as solubility and dissociation, true density, crystal shape, compaction behavior, flowability, and/or solid state stability. When a chemical species exists in two (or more) polymorphic forms, the unstable form typically converts to a thermodynamically more stable form over a sufficient period of time at a temperature. When this conversion is not rapid, the thermodynamically unstable form is referred to as a "metastable" form. In general, the stable form has the highest melting point, the lowest solubility and the greatest chemical stability. However, under normal storage conditions, the metastable form may have sufficient chemical and physical stability to enable its use in commercial form. Moreover, while the metastable form is less stable, it may have more favorable properties than the stable form, such as better styling ability, improved water dispersibility, and the like.

For fluazinam, no known crystalline form exists. After extensive experiments, the inventors of the present application found two new crystalline forms of fluazinam, referred to as form I and form II. The two forms have different spectral characteristics, as shown by their significantly different Differential Scanning Calorimetry (DSC) profiles, X-ray diffraction patterns, and Infrared (IR) spectra.

Form I

In one embodiment, the present invention provides a novel crystalline polymorph form of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam), referred to as "form I". This new, surprising polymorph is characterized, for example, by DSC, X-ray powder diffractogram and/or infrared spectrum.

For example, as shown in fig. 1, form I has an X-ray powder diffraction pattern with characteristic peaks (expressed in degrees 2 θ (+/-0.2 ° θ)) at one or more of the following positions: 8.7, 10, 12.0, 13.7, 14.5, 17.4, 18.5, 19.7, 21.8, 22.9, and 30.2. The X-ray powder diffraction was carried out on a Philips powder diffractometer PW1050/70 operating at 40kV and 30mA, using CuKa radiation (wavelength equal to that of the X-ray powder diffraction)) And a diffractive light graphite monochromator. A typical theta-2 theta scan ranges from 3-35 deg. 2 theta, with a step size of 0.05 deg., and a timing of 0.5 seconds per step.

The sample was ground using an agate bowl and pestle. The resulting powder was then pressed into a 20mm by 15mm deep void of an aluminum sample holder.

Also, as shown in FIG. 2 (only 3000cm is shown)^-1In a range of 3390 cm), form I also has a molecular weight of at least one of^-1An Infrared (IR) spectrum with characteristic peaks nearby is a Fourier transform infrared (FT-IR) spectrometer Reacti R using a Mettler Toledo Autochem (ATR method, MCT detector)^TM1000 diamond window, Durasample1I R^TMMeasured by a sampler. Diamond sensor with standard ZnSe optical condenserAnd (3) charring. The powder sample was compressed in the sample preparation device and measured at 4cm^-1256 scans are performed.

Furthermore, as shown in FIG. 3, form I also has a Differential Scanning Calorimetry (DSC) profile with 821 when using Mettler Toledo^eThe module, when measured by DSC, is characterized by a major endothermic peak at about 115.5 ℃. During the measurement at a scan rate of 2 and/or 10 ℃ per minute, the weighed sample (2-4mg) was washed with a stream of nitrogen. A40. mu.L standard crucible of aluminum was used. Using STAR^eThe software completes the evaluation. As used herein, "about 115.5" means from 114 ℃ to 117 ℃. In this regard, it will be appreciated that the endotherm measured by a particular differential scanning calorimeter depends on a number of factors, including the rate of heating (i.e., the scan rate), the calibration standard used, the calibration instrument, the relative humidity, and the chemical purity of the test sample. Thus, the endotherm measured by the prescribed DSC instrument may vary as much as. + -. 1.5 ℃.

Form I is generally crystallized in the form of prisms, such as the typical large yellow prisms described herein.

In another aspect, the present invention provides a process for the preparation of the novel polymorphic form I of fluazinam. Form I can be prepared by dissolving fluazinam in a suitable amount of solvent or solvent mixture, heating to dissolve it, and then cooling to precipitate the product. Alternatively, fluazinam is dissolved in a fluazinam-soluble solvent and a second solvent in which the compound is insoluble or sparingly soluble (antisolvent) is added until precipitation occurs. The reaction may also use form I seeds as seeds to induce precipitation, as is known in the art.

The fluazinam starting material used to prepare form I can be any form of fluazinam, including fluazinam prepared according to US patent US4,331,670, amorphous fluazinam, form II fluazinam, mixtures of form I and form II fluazinam, or any other fluazinam known in the art.

For example, in one embodiment, form I can be prepared by crystallizing fluazinam from a solvent selected from the group consisting of ethanol, acetonitrile, dichloromethane, and n-hexane, and isolating the resulting crystals. In a preferred embodiment, the process comprises preparing a solution of fluazinam in one or more of the aforementioned solvents, preferably by heating until dissolution is complete, and then cooling the solution until crystallization occurs. Generally, it is sufficient to cool the solution at room temperature (defined herein as about 20 ℃ to about 25 ℃), however, the solution may be cooled to lower temperatures, such as 0 ℃, 5 ℃,10 ℃, 15 ℃, and the like. The crystals may then be isolated by any convenient method known in the art, such as filtration, centrifugation, and the like.

Form I can also be prepared by crystallizing fluazinam from diethyl ether, dissolving fluazinam in diethyl ether, preferably at room temperature, and leaving the flask partially open for slow evaporation of the solvent. Gradually, crystallization begins, usually in the form of large yellow prisms, which are then separated in a conventional manner. Generally, only a portion of the solvent is volatilized before crystallization begins to occur, e.g., about 10-90% of the solvent that is volatilized into the air, resulting in the occurrence of form I crystals.

Form II

In another embodiment, the present invention provides a novel crystalline polymorph form of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam), referred to as "form II". This new, surprising polymorph is characterized, for example, by DSC, X-ray powder diffractogram and/or infrared spectrum.

For example, as shown in fig. 4, form II has an X-ray powder diffraction pattern with characteristic peaks (expressed in degrees 2 θ (+/-0.2 ° θ)) at one or more of the following positions: 7.4, 10.4, 13.4, 15.1, 18.95, 20, 20.4, 21.05, 21.3, 22.2, 24.9, 27.15, 28.6 and 30.5. The X-ray powder diffraction was measured as described above.

Also, as shown in FIG. 5 (only 30 is shown)00cm^-1In a range of about 3375 cm), form II also has a molecular weight of about 3375cm^-1An Infrared (IR) spectrum with characteristic peaks nearby was measured using a fourier transform infrared (FT-IR) spectrometer as described above.

Furthermore, as shown in fig. 6, form II also has a Differential Scanning Calorimetry (DSC) profile, which is characterized by the appearance of a major endothermic peak near about 109 ℃ (form II becomes liquid) when a single regression system is employed. The curve further shows the endotherm at about 115.5 ℃ resulting from the conversion of the crystal to form I. This curve was measured using a differential scanning calorimeter as described above. As used herein, "about 109 ℃ C" means from about 107.5 ℃ to about 110.5 ℃.

Form II is usually crystallized as needles, typically as bright yellow needles.

In another aspect, the present invention provides a process for preparing the novel polymorphic form II of fluazinam. Form II may be prepared by dissolving fluazinam in a suitable amount of solvent or solvent mixture, heating to dissolve it and then cooling to precipitate the product. Alternatively, fluazinam is dissolved in a soluble solvent and a second compound insoluble or slightly soluble solvent (antisolvent) is added until precipitation occurs. The reaction may also use form II seeds as seeds to induce precipitation, as is known in the art.

The fluazinam starting material for preparing form II may be any form of fluazinam, including fluazinam prepared according to US patent US4,331,670, amorphous fluazinam, form I fluazinam, a mixture of form I and form II fluazinam, or any other fluazinam known in the art.

For example, form II can also be prepared by crystallizing fluazinam from diethyl ether, dissolving fluazinam in diethyl ether, preferably at room temperature, and rapidly evaporating the solvent. This results in the formation of crystals, usually in the form of bright yellow needles, which are then isolated in a conventional manner.

Form II can also be prepared by preparing an ethanolic solution of fluazinam; a solution of fluazinam in ethanol was prepared in the manner as described above for preparation of form I. However, instead of precipitating the product by cooling, the solution is exposed to the environment, so that part of the solvent slowly evaporates. Gradually, crystals begin to appear, usually in the form of bright yellow needles, which are then isolated. Generally, only a portion of the solvent is volatilized before crystallization begins to occur, e.g., about 10-90% of the solvent that is volatilized into the air, resulting in the occurrence of form II crystals.

Mixtures of form I and form II

In another embodiment, the present invention provides a mixture of polymorph form I and form II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam).

The mixture has an X-ray powder diffraction pattern substantially as shown in figure 7. Moreover, the mixture also had a general appearance as in FIG. 8 (only 3000cm is shown)^-1Range of (d) in a spectrum. Moreover, the mixture also had a differential DSC thermal scan profile substantially as shown in figure 9, measured using a differential scanning calorimeter as described above.

The fluazinam starting material used to prepare the mixture of form I and form II may be any form of fluazinam, including fluazinam prepared according to US patent US4,331,670, amorphous fluazinam, form I fluazinam, form II fluazinam, or any other fluazinam known in the art.

The mixture of form I and form II can be prepared simply by mixing the polymorph of form I and the polymorph of form II to obtain a mixture. However, the mixture may also be prepared by crystallizing fluazinam from a solvent selected from the group consisting of isopropanol, n-hexane and toluene, and separating the resulting crystals. In a preferred embodiment, the process comprises preparing a solution of fluazinam in one or more of the above-mentioned solvents, preferably by heating until dissolution is complete, cooling the solution until crystallization occurs, and isolating the crystals. Generally, it is sufficient to cool the solution to room temperature, however, the solution may be cooled to lower temperatures, such as 0 ℃, 5 ℃,10 ℃, 15 ℃, and the like.

Mixtures of form I and form II may also be prepared by dissolving fluazinam in a solvent in which the compound is soluble, adding an anti-solvent, and isolating the resulting crystals. In a preferred embodiment, the solvent is acetone. In another preferred embodiment, the anti-solvent is water.

Composition and application

Fluazinam is known to have excellent performance against harmful organisms such as insects, mites, fungi and bacteria, for example, its excellent antifungal and antibacterial effects for controlling the propagation of harmful fungi and bacteria on stored industrial products, seeds and fruits, such as Aspergillus sp, Gibberella sp, and Penicillium sp.

Fluazinam is also very effective in controlling the growth of pests on agricultural and horticultural crops and upland plants, such as, for example, Plutella Xylostella (Plutella Xylostella), cabbage moth (Mamestra brassica) and prodenia litura (Spodoptera litura); like hemiptera cicada (Nephotettix cincticeps) and laodelphax striatellum (Delphacodesstriatella); like the Coleoptera Callosobruchus chimensis and the ladybug (Epilachna virginioticpututa); like Musca domestica (Musca domestica) and Culexopipiens pallens; mites like Tetranychus urticae (Tetranychus urticae) and Tetranychus gossypii (Tetranychus tetratorius) and Tetranychus citrina (Pannychus citri); fungi and bacteria on plants such as Pyricularia oryzae (Pyricularia oryzae), Rhizoctonia solani (Rhizoctonia solani), cucumber colletotrichum anthracnose (Colletotrichum lagenarium), Pseudomonas aeruginosa, melon powdery mildew (Sphaerotheca fuliginosa), potato late blight (Phytohthoras), Diaporthe citri (Diaporter citri), tomato early blight (Alternaria solani), apple scab (Venturia inaelitis), Plasmopara viticola (Plasmopara viticola), Botrytis cinerea (Botrytis cinerea), Puccinia tritici (Puccinia recondita) and Sclerotium sclerotiorum (Sclerotium sclerotium).

Fluazinam also has excellent performance in controlling various harmful organisms, in particular fungi, which are harmful to agricultural and horticultural plants.

Thus, in one embodiment, the present invention also provides compositions comprising the novel crystalline polymorph for controlling and combating the growth of pests, such as insects, mites, fungi and bacteria, on agricultural and horticultural crops and upland plants. In one embodiment, the composition comprises a crystalline polymorph of form I of fluazinam; and acceptable adjuvants. In another embodiment, the composition comprises a form II crystalline polymorph of fluazinam and an acceptable adjuvant. In another embodiment, the composition comprises a mixture of form I and form II crystalline polymorphs of fluazinam; and acceptable adjuvants.

The invention also provides a method of combating insects, acarines, fungi and bacteria comprising administering to the insects, acarines, fungi and bacteria an effective amount of a composition of the invention.

The invention also relates to a method for protecting crops and upland plants, including the protection of industrial products derived therefrom, such as seeds and fruits, by administering to the crop or the product an effective amount of a composition of the invention.

The concentration of the fluazinam polymorph used in the composition of the present invention depends on the pest as the target, the application method, and the form of the composition and the dosage of the active ingredient. The concentration is not critical and typically ranges from about 1 to 10,000ppm, preferably from about 20 to 2,000 ppm.

The compositions may be prepared in various forms, for example dusts, wettable powders, emulsifiable concentrates, inert emulsions, oil solutions, aerosols, etc., together with adjuvants as agricultural compositions. The composition may be used diluted to an appropriate concentration or undiluted.

Suitable adjuvants include powder carriers such as talc, kaolin, bentonite, diatomaceous earth, silica, clay and starch; liquid diluents such as water, xylene, toluene, dimethyl sulfoxide, dimethylformamide, acetonitrile, and ethanol; emulsifying dispersants, surfactants such as sodium alkylbenzenesulfonate, polyoxyethylene alkylaryl ether, sodium naphthalenesulfonate formaldehyde concentrate, ether calcium sulfate, polyoxyethylene alcohol dodecylphenylene ether, polyoxyethylene lauryl ether, polyoxyethylene fatty acid ester, sodium alkylsulfate, sulfate salt of polyoxyethylene alkylaryl ether, dialkyl sulfosuccinate salt and the like.

The concentration of the active ingredient in the acaricide, fungicide or bactericide composition is usually 5 to 80 wt.% in the state of an oily concentrate, 0.5 to 30 wt.% in the state of dust, and 5 to 60 wt.% in the state of a wettable powder. It is also possible to combine other agricultural additives such as other insecticides, acaricides, and/or plant growth regulators. Sometimes synergistic effects are found. Other agricultural additives include organophosphates, carbamates, dithio (or thio) carbamates, organochlorines, dinitriles, organic or organometallic compounds, antibiotic compounds, substituted diphenyl ethers, ureas, triazines, benzoylureas, pyrethroids, imines and benzimidazoles and more specifically benzoylureas such as N- (2, 6-difluorobenzoyl) -N' - (p-chlorobenzoyl) urea; pyrethroid insecticides such as α -cyano-3-phenoxybenzyl-2- (4-chlorobenzene) isovalerate; imine fungicides such as N- (3, 5-dichlorobenzene) -1, 2-dimethylcyclopropane-1, 2-dicarboximide; benzimidazoles as fungicides such as methyl-1- (butylcarbamoyl) -2-carbamic acid benzimidazole; thiocarbamic acid fungicides are, for example, S-ethyl N- (3-dimethylpropylamino) thiocarbamic acid hydrochloride. Dithiocarbamic acid bactericides such as manganese vinylbisdithiocarbamates; urea fungicides are, for example, 2-cyano-N- (ethylcarbonylamino) -2- (methoxyamino) acetamide.

The following examples are intended to illustrate specific embodiments of the present invention in more detail. But should not be construed as limiting the broad scope of the invention. Those skilled in the art can readily devise various changes and modifications of the basic principles disclosed herein without departing from the spirit and scope of the invention.

Experimental part:

the following abbreviations are used herein:

ACP-2-amino-3-chloro-5-trifluoromethylpyridine

CAN-acetonitrile

CNB-2, 4, -dichloro-3, 5-dinitrobenzotrifluoride

DMF-dimethylformamide

DMSO-dimethyl sulfoxide

EtOH-ethanol

MEK-methyl ethyl ketone

MIBK-methyl isobutyl ketone

THF-tetrahydrofuran

Example 1 solvent Effect

As shown in the following scheme, fluazinam is prepared by coupling compounds 1A and 2A in several organic solvents. 1.5 g of (1), 2.5 g of (2) -excess 5%, 1.5 g of KOH-3 equivalents, dissolved in 10ml of organic solvent, are introduced into a 25ml round-bottomed flask with magnetic stirring. The mixture was stirred at 30 ℃ and samples were continuously withdrawn until the reaction was terminated.

Table 2 shows the effect of various solvents on fluazinam synthesis in pure and azeotrope form.

Table 2: effect of various solvents in pure and azeotrope form

a is the total impurities identified in the reaction, except impurity 4.

b is the percentage of hydrolysis by-products 4.

c is unreacted reactant 1A.

d ═ unreacted reactant 2A.

The results show that:

MIBK performs in both pure and wet form in excess of other solvents, both yield and purity.

MIBK is the only solvent whose azeotrope properties do not detract from its pure solvent properties.

3. All solvents except MIBK showed a higher tendency to form hydrolysis product 4 under the form of an azeotrope.

DMF and DMSO exhibit an unusually high degree of impurities and are therefore unsuitable for this method.

Example 2 Synthesis procedure (0.3mol Scale)

Starting materials 1A, CNB, and 2A, ACP, were synthesized by:

starting materials 1A

Starting materials 2A

Synthesis of fluazinam

To a three-neck oil ring reactor equipped with a thermometer and a condenser were added the following reactants in sequence: 60 g ACP (═ 0.3mol), 95 g CNB powder (3% mol excess) and 340 g MIBK azeotrope (1.6% water) and cooled to 20-25 ℃.

Still at low temperature, 70 grams of KOH (═ 3.5mol equivalents) were added in 10 grams per 20 minutes sequence, while preventing the temperature from rising above 30 ℃. The mixture was further stirred after addition (at room temperature 25-30 ℃) until there was no further consumption of the reactants therein (as measured by HPLC).

The mixture was acidified by adding 400 g of 5% hydrochloric acid and the mixture was washed with 400 g of 5% sodium chloride solution. After the aqueous layer of the biphasic mixture was acidified, the organic phase was separated off with a funnel and the solvent was evaporated to dryness under vacuum.

The crude product obtained was a yellow fluazinam product of about 150 g, with a purity of about 95% and a chemical yield of about 98%.

The crude product was crystallized in hot ethanol to obtain about 140 g of a yellow powdery product with a purity higher than 98% with an overall yield of 90%.

EXAMPLE 3 preparation of form I fluazinam

2 g of fluazinam are heated in 10 g of ethanol until complete dissolution. The solution was then cooled to room temperature. The yellow crystals were filtered off and dried in an oven at 40 ℃. The crystals are form I fluazinam.

Example 4 preparation of form I fluazinam

15 g of fluazinam and 10 g of acetonitrile are heated until complete dissolution. Then cooled to room temperature. The yellow crystals were filtered off and dried at 40 ℃. The crystals are form I fluazinam.

EXAMPLE 5 preparation of form I fluazinam

2 g of fluazinam are dissolved in 10 g of dichloromethane by gentle heating on a hot plate. The hot solution was stirred on a hot plate until crystals were obtained. The yellow crystals were filtered off and dried at 40 ℃. The crystals are form I fluazinam.

Example 6 preparation of form I fluazinam

2 g of fluazinam and 30 g of n-hexane are heated until complete dissolution. The solution was then cooled to room temperature, the crystals were filtered off and dried at 40 ℃. The crystals are form I fluazinam.

Example 7 preparation of form I fluazinam

2 g of fluazinam are dissolved in 10 g of diethyl ether at room temperature. Slow evaporation of the solvent (leaving the flask partially open at room temperature) resulted in the appearance of large yellow prisms. The crystals were filtered off and dried at 40 ℃. The crystals are form I fluazinam.

Example 8 preparation of form II fluazinam

2 g of fluazinam are dissolved in 10 g of diethyl ether as described in example 5. The solvent was quickly evaporated from the flask and bright yellow needles appeared to crystallize. The crystals were collected from the flask and dried at 40 ℃. The crystals are form II fluazinam.

Example 9 preparation of form II fluazinam

2 grams of fluazinam were dissolved in 10 grams of ethanol with heating as described in example 1, except that the flask was left open and part of the ethanol was volatilized from the solution. Crystallization was faster and bright yellow needles appeared on the bottom of the flask. The crystals were filtered and dried at 40 ℃. The crystals are form II fluazinam.

Example 10 preparation of a mixture of form T and form II fluazinam

3 grams of fluazinam and 10 grams of isopropanol were heated until completely dissolved. The solution was slowly cooled to room temperature. The yellow crystals were filtered and dried at 40 ℃. The crystals are a mixture of fluazinam form I and form II.

Example 11 preparation of a mixture of form I and form II fluazinam

6 g of fluazinam and 6 g of toluene are heated until complete dissolution. The solution was cooled from the ice water bath to 0 ℃. The crystals were filtered and dried at 40 ℃. The crystals are a mixture of fluazinam form I and form II.

Example 12 preparation of a mixture of form I and form II fluazinam

10 g of fluazinam are dissolved in 10 g of acetone at room temperature. A few drops of water were added as anti-solvent. Crystallization occurs immediately. The crystals were filtered and dried at 40 ℃. The crystals are a mixture of fluazinam form I and form II.

While particular embodiments of the present invention have been illustrated and described, the present invention is not limited to the embodiments described herein. Various modifications, changes, variations, substitutions and alterations will be apparent to those skilled in the art without departing from the spirit and scope of the invention as described.

Claims (64)

1. A crystalline polymorph form I of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam).
2. 2. The crystalline polymorph of claim 1, wherein the polymorph has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 Θ (+/-0.20 ° θ) at about 8.7, 10, 12.0, 13.7, 14.5, 17.4, 18.5, 19.7, 21.8, 22.9, and 30.2.
3. 3. The crystalline polymorph of claim 1, wherein the polymorph exhibits an X-ray powder diffraction pattern substantially as shown in figure 1.
4. 4. The crystalline polymorph of claim 1, wherein the polymorph has an Infrared (IR) spectrum at about 3390cm^-1Has characteristic peaks.
5. 5. The crystalline polymorph of claim 1, wherein the polymorph is at 3000cm^-1An Infrared (IR) spectrum of the range substantially as shown in figure 2.
6. 6. The crystalline polymorph of claim 1, wherein the polymorph exhibits a single major endothermic peak at about 115.5 ℃ when measured using a Differential Scanning Calorimeter (DSC) at a scan rate of 10 ℃ per minute.
7. 7. The crystalline polymorph of claim 1, wherein the polymorph has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 3.
8. 8. The crystalline polymorph of claim 1 in the form of a prism.
9. A crystalline polymorph form II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam).
10. 10. The crystalline polymorph of claim 9, wherein the polymorph has an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2 Θ (+/-0.20 ° θ) at about 7.4, 10.4, 13.4, 15.1, 18.95, 20, 20.4, 21.05, 21.3, 22.2, 24.9, 27.15, 28.6, and 30.5.
11. 11. The crystalline polymorph of claim 9, wherein the polymorph exhibits an X-ray powder diffraction pattern substantially as shown in figure 4.
12. 12. The crystalline polymorph of claim 9, wherein the polymorph has an Infrared (IR) spectrum at about 3375cm^-1Has characteristic peaks.
13. 13. The crystalline polymorph of claim 9, wherein the polymorph is at 3000cm^-1An Infrared (IR) spectrum of the range is substantially as shown in figure 5.
14. 14. The crystalline polymorph of claim 9, wherein the polymorph exhibits a major endothermic peak at about 109 ℃ when measured using a Differential Scanning Calorimeter (DSC) at a scan rate of 10 ℃ per minute.
15. 15. The crystalline polymorph of claim 9, wherein the polymorph has a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 6.
16. 16. The crystalline polymorph of claim 1 in the form of needles.
17. A mixture of polymorphic form I and form II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam).
18. 18. The mixture of claim 17 having an X-ray powder diffraction pattern substantially as shown in figure 7.
19. 19. The mixture of claim 17 having a particle size of at 3000cm^-1An Infrared (IR) spectrum of the range is substantially as shown in figure 8.
20. 20. The mixture of claim 17, having a Differential Scanning Calorimetry (DSC) profile substantially as shown in figure 9.
21. 21. A process for preparing a crystalline polymorph form I of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) comprising the steps of crystallizing the compound from a solvent and isolating the resulting crystal, wherein the solvent is selected from the group consisting of ethanol, acetonitrile, dichloromethane, and N-hexane.
22. 22. The method of claim 21, comprising the steps of:

    i. preparing a solution of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine in a solvent, wherein the solvent is selected from the group consisting of ethanol, acetonitrile, dichloromethane, and N-hexane;

    cooling the solution to allow formation of crystals of the compound; and

    isolating the crystals.
23. 23. The method of claim 21, wherein step a) is performed by heating, and wherein the solution obtained in step a) is cooled to room temperature.
24. 24. A process for preparing a crystalline polymorph form I of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) comprising preparing a solution of said compound in diethyl ether; slowly volatilizing the solvent; and then separating the obtained crystals.
25. 25. The method of claim 24, wherein the solvent is volatilized by exposing the solution to the environment.
26. 26. A process for preparing a crystalline polymorph form II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) comprising preparing a solution of said compound in diethyl ether; rapidly volatilizing the solvent; and then separating the obtained crystals.
27. 27. A process for the preparation of crystalline polymorph form II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) comprising the steps of preparing a solution of said compound in ethanol, volatilizing a portion of the ethanol, and then separating the resulting crystals.
28. 28. The method of claim 27, wherein the ethanol is volatilized by exposing the solution to the environment.
29. 29. A process for the preparation of a mixture of crystalline polymorphic forms I and II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) comprising the steps of crystallizing the compound from a solvent selected from the group consisting of isopropanol, N-hexane and toluene and isolating the resulting crystals.
30. 30. The method of claim 29, comprising the steps of:

    i. preparing a solution of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine in a solvent, wherein the solvent is selected from the group consisting of isopropanol, N-hexane and toluene;

    cooling the solution to allow formation of crystals of the compound; and

    isolating the crystals.
31. 31. The method of claim 30, wherein step a) is accomplished by heating, and wherein the solution resulting from step a) is cooled to room temperature.
32. 32. A process for the preparation of a mixture of crystalline polymorphic forms I and II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) comprising the steps of dissolving the compound in a solvent in which the compound is soluble, adding an anti-solvent, and isolating the resulting crystals.
33. 33. The method of claim 32, wherein the solvent is acetone.
34. 34. The method of claim 32, wherein the anti-solvent is water.
35. 35. A composition for combating insects, acarines, fungi and bacteria comprising the crystalline polymorph form I of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine according to any one of claims 1 to 8; and acceptable adjuvants.
36. 36. A composition for combating insects, acarines, fungi and bacteria comprising the crystalline polymorph form II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine according to any one of claims 9 to 16; and acceptable adjuvants.
37. 37. A composition for combating insects, acarines, fungi and bacteria comprising a mixture of the crystalline polymorphs form I and form II of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine according to any one of claims 17 to 20; and acceptable adjuvants.
38. 38. A method for combating insects, acarines, fungi and bacteria comprising administering to the insects, acarines, fungi or bacteria an effective amount of a composition according to any of claims 35 to 37.
39. 39. A method for protecting a crop from pests selected from the group consisting of insects, acarids, fungi and bacteria, comprising administering to the crop an effective amount of a composition according to any one of claims 35 to 37.
40. 40. A process for preparing a pyridylamine compound represented by the structure of formula (I),

    wherein

    X is a trifluoromethyl group, a halogen atom, C₁-C₆Alkyl radicals or C₁-C₆An alkoxy group;

    n is an integer of 0 to 4;

    r is a hydrogen atom or an acetyl group;

    y is a hydrogen atom, a halogen atom, C₁-C₆Alkoxy radical, C₁-C₆A thioalkyl group, a hydroxyl group, an azido group, a phenoxy group or a phenoxy group in which the phenyl group is substituted with a hydroxyl group;

    and

    Z₁，Z₂and Z₃Independently a trifluoromethyl group or a nitro group, which process comprises reacting a compound of formula (A) with a compound of formula (B) in the presence of a base,

    wherein X, Y, Z in the formulae (A) and (B)₁，Z₂，Z₃And n is as defined above; one of U and W is an amino group and the other is a leaving group selected from the group consisting of halogen, alkylsulfonyl and arylsulfonyl, wherein methyl isobutyl ketone (MIBK) is used as a reaction solvent.
41. 41. The process of claim 40 wherein the compound of formula (I) is 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam), represented by the structure of formula (3):
42. 42. the process of claim 40 wherein the base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, hydrides, alkaline earth metal hydroxides and alkaline earth metal carbonates.
43. 43. The method of claim 42, wherein the base is potassium hydroxide or sodium hydroxide.
44. 44. The method of claim 40 wherein the solvent is pure MIBK.
45. 45. The process of claim 40 wherein the solvent is a recycled azeotrope containing about 1.6% MIBK in water.
46. 46. The method of claim 40, further comprising the step of isolating the compound of formula (1) by: an aqueous acid solution is added to form a mixture containing an organic layer and an aqueous layer, and the compound of formula (1) is separated from the organic layer.
47. 47. The process of claim 40, further comprising the step of purifying the compound of formula (1) by crystallization from a solvent or mixture of solvents.
48. 48. The process of claim 47, wherein the crystallization solvent is ethanol.
49. 49. The method of claim 40, wherein the reactant to solvent ratio is greater than about 10% w/v.
50. 50. A process for purifying a compound represented by the structure of formula (I),

    wherein

    X is a trifluoromethyl group, a halogen atom, C₁-C₆Alkyl radicals or C₁-C₆An alkoxy group;

    n is an integer of 0 to 4;

    r is a hydrogen atom or an acetyl group;

    y is a hydrogen atom, a halogen atom, C₁-C₆Alkoxy radical, C₁-C₆A thioalkyl group, a hydroxyl group, an azido group, a phenoxy group or a phenoxy group in which the phenyl group is substituted with a hydroxyl group; and

    Z₁，Z₂and Z₃Independently a trifluoromethyl group or a nitro group;

    the method comprises the step of crystallizing the compound from a solvent or a mixture of solvents.
51. 51. The process of claim 50 wherein the crystallization solvent is ethanol.
52. 52. A process for preparing 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) represented by the structure of formula (3):

    the process comprising reacting a compound of formula (1) with a compound of formula (2) in the presence of a base,

    wherein one of U and W is an amino group and the other is a leaving group selected from the group consisting of halogen, alkylsulfonyl and arylsulfonyl, wherein methyl isobutyl ketone (MIBK) is used as a reaction solvent.
53. 53. The method of claim 52, wherein the compound of formula (1) is according to formula (1A) and the compound of formula (2) is according to formula (2A):
54. 54. the process of claim 53 wherein the base is selected from the group consisting of alkali metal hydroxides, alkali metal carbonates, hydrides, alkaline earth metal hydroxides and alkaline earth metal carbonates.
55. 55. The method of claim 54, wherein the base is potassium hydroxide or sodium hydroxide.
56. 56. The method of claim 52 wherein the solvent is pure MIBK.
57. 57. The process of claim 52 wherein the solvent is a recycled azeotrope containing about 1.6% MIBK in water.
58. 58. The method of claim 52, further comprising the step of isolating fluazinam by: an aqueous acid solution is added to form a mixture containing an organic layer and an aqueous layer, and fluazinam is separated from the organic layer.
59. 59. The method of claim 52, further comprising the step of purifying fluazinam by crystallization from a solvent or mixture of solvents.
60. 60. The process of claim 59, wherein the crystallization solvent is ethanol.
61. 61. A process as set forth in claim 52 wherein the reactant to solvent ratio is greater than about 10% w/v.
62. 62. A process for the purification of 3-chloro-N- (3-chloro-5-trifluoromethyl-2-pyridinyl) - α, α, α -trifluoro-2, 6-dinitro-p-toluidine (fluazinam) comprising the step of crystallizing said compound from a solvent or a mixture of solvents.
63. 63. The process of claim 62 wherein the crystallization solvent is ethanol.
64. 64. A method for preparing fluazinam represented by the structure of formula (3),

    the process comprising reacting a compound of formula (1) with a compound of formula (2) in the presence of a base,

    wherein methyl isobutyl ketone (MIBK) is used as a reaction solvent.