Process for the preparation of sulfonyl pyrazolones

Abstract

This invention relates to a method for preparing sulfonylpyrazolinone compounds of formula (IV) with substantially reduced undesirable toxic impurities, wherein these compounds are used as active ingredients in the agricultural field, particularly as herbicides. The method for preparing compounds of formula (IV) comprises reacting a compound of formula (III) with a catalytic amount of a cyanide source and a base, followed by mixing with an oxidizing agent and acidifying the mixture to obtain the compound of formula (IV).

Description

Technical Field

[0001] This invention relates to a novel method for preparing sulfonylpyrazolinone compounds of formula (IV) with substantially reduced unwanted toxic impurities.

[0002]

[0003] These compounds are used as active ingredients in agriculture, especially as herbicides. Background Technology

[0004] Sulfophenylpyrazolone is an organic compound widely used in agriculture, such as the sulfonylurea herbicide sulfonylurea. This herbicide is used for post-emergence control of various broadleaf weeds.

[0005] US Patent 6,420,317 discloses a method for preparing benzoylpyrazole compounds by rearranging the corresponding enol esters, wherein the rearrangement is carried out in the presence of acetone cyanohydrin and triethylamine. A disadvantage of this method is the separation of solid materials from a reaction mixture containing a significant concentration of cyanide ions. This process, carried out on an industrial scale, makes the method hazardous. Furthermore, after filtration, washing, and drying of the product, some cyanide impurities remain in the final product.

[0006] Therefore, the methods described in the prior art have limitations, such as the challenges of handling the reaction mixture, product, and mother liquor due to cyanide ion contamination and the difficulty in purifying the product to avoid undesirable cyanide levels. This makes the prior art methods uneconomical, and the use of excess reagents for purification also makes them inefficient. Therefore, there is still a need for a method that eliminates the drawbacks associated with known methods.

[0007] Therefore, there is a need to develop an efficient method for preparing sulfonylpyrazolinone compounds of formula (IV) with higher yield and efficiency, and such a method is desirable. Summary of the Invention

[0008] This invention provides a method for preparing a compound having formula (IV) from a compound having formula (III).

[0009]

[0010] in,

[0011] R 1 It is methyl or ethyl;

[0012] R 2 It is trifluoromethyl;

[0013] R 3 It is hydrogen, methyl, or ethyl;

[0014] R 4 It is methyl, ethyl, or n-propyl;

[0015] R 5 It is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl monosubstituted or polysubstituted with halogen, phenylsulfonyl monosubstituted with methyl or halogen, benzyl substituted with halogen, nitro, methyl or methoxy, or benzoylmethyl monosubstituted or polysubstituted with halogen, nitro, methyl or methoxy; and

[0016] n is 0, 1, or 2;

[0017]

[0018] The method includes the following steps:

[0019] a) Treat compounds having formula (III) with a catalytic amount of cyanide source and base;

[0020] b) Mix the reaction mixture from step (a) with the oxidizing agent; and

[0021] c) Acidify the reaction mixture of step (b) to obtain a compound having formula (IV).

[0022] In another aspect, the present invention provides a method for preparing compounds having formula (IV),

[0023]

[0024] The method includes the following steps:

[0025] a1) To make compounds having formula (I)

[0026]

[0027] With compounds having formula (II)

[0028]

[0029] The reaction is carried out in the presence of a base to obtain a compound having formula (III);

[0030]

[0031] in,

[0032] R 1 It is methyl or ethyl;

[0033] R 2 It is trifluoromethyl;

[0034] R 3 It is hydrogen, methyl, or ethyl;

[0035] R 4 It is methyl, ethyl, or n-propyl;

[0036] R 5 It is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl monosubstituted or polysubstituted with halogen, phenylsulfonyl monosubstituted with methyl or halogen, benzyl substituted with halogen, nitro, methyl or methoxy, or benzoylmethyl monosubstituted or polysubstituted with halogen, nitro, methyl or methoxy, and

[0037] n is 0, 1, or 2;

[0038] a) The compound having formula (III) obtained in step (a1) is treated with a catalytic amount of cyanide source and base;

[0039] b) Mix the reaction mixture from step (a) with the oxidizing agent; and

[0040] c) Acidify the reaction mixture of step (b) to obtain a compound having formula (IV).

[0041] On one hand, the compound having formula (IV) is 5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone.

[0042] In another respect, the compound having formula (III) is 1,3-dimethyl-1H-pyrazole-5-yl-4-trifluoromethyl-2-(methylsulfonyl)benzoate.

[0043] In another aspect, the compound having formula (I) is 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride.

[0044] In another respect, the compound having formula (II) is 2,5-dimethyl-2,4-dihydro-3H-pyrazol-3-one.

[0045] In one aspect, the method of the present invention specifies that the base is an organic base or an inorganic base. The inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium phosphate, and mixtures thereof. The organic base is selected from the group consisting of tertiary amines, N-substituted imines, aromatic amines, and mixtures thereof.

[0046] In a preferred aspect, the method of the present invention specifies that the base is a tertiary amine, such as triethylamine.

[0047] In one aspect, the method of the present invention specifies that the base and the compound having formula (III) are present in a molar ratio of about 1:1 to 2:1.

[0048] In another aspect, the method of the present invention specifies that the base and the compound having formula (I) are present in a molar ratio of about 2:1 to 4:1.

[0049] In another aspect, the method of the present invention specifies that the cyanide source is a cyanohydrin of a methyl alkyl ketone having 1-4 carbon atoms in an alkyl group, benzaldehyde cyanohydrin; a cyanohydrin of a C2-C5 aliphatic aldehyde, hydrogen cyanide, and mixtures thereof.

[0050] In a preferred aspect, the method of the present invention specifies that the cyanide source is a cyanohydrin of a methyl alkyl ketone having 1-4 carbon atoms in an alkyl group, such as acetone cyanohydrin.

[0051] In yet another aspect, the method of the present invention specifies that the cyanide source and the compound having formula (III) are present in a molar ratio of about 1:5 to 1:50.

[0052] In another aspect, the method of the present invention specifies that the oxidizing agent is hydrogen peroxide, sodium hypochlorite, chlorine, or a mixture thereof.

[0053] In one aspect, the method of the present invention specifies that the oxidizing agent and the cyanide source are present in a molar ratio of about 1.5:1 to 5:1.

[0054] In another aspect, the method of the present invention specifies that the acid is hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, chloric acid, hydrobromic acid, and mixtures thereof.

[0055] In another aspect, the method of the present invention specifies that the compound having formula (IV) contains cyanide ions at a concentration of less than 5 ppm, preferably less than 1 ppm.

[0056] In a preferred aspect, the present invention provides a method for preparing 5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone by rearranging 1,3-dimethyl-1H-pyrazole-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone, wherein the rearrangement is carried out in the presence of catalytic amounts of acetone cyanohydrin, triethylamine, and mixing of the reaction mixture with a hydrogen peroxide solution. The reaction mixture is then treated with a concentrated acid to obtain 5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone. Detailed Implementation

[0057] For clarity, specific terminology is used in describing embodiments of the invention. However, it is not intended to limit the invention to the specific terminology chosen so far, and it should be understood that each specific term includes all technical equivalents that operate in a similar manner to achieve a similar purpose.

[0058] It should be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. Unless the context clearly specifies otherwise, as used in this specification, the singular forms “a / an” and “the” include plural referents. Thus, for example, references to “compound” include one or more such compounds.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although other methods and materials similar to or equivalent to those described herein may be used in the practice of this invention, preferred materials and methods are described herein.

[0060] As used herein, the term “or” means “and / or”. It will be further understood that the terms “comprise / comprising,” “include / including,” or any other variations thereof are intended to cover non-exclusive inclusion, subject to any expressly indicated limitations. For example, a composition or method that includes a list of elements is not necessarily limited to those elements, but may include other elements not expressly listed or inherent to the method.

[0061] Throughout this application, the descriptions of various embodiments use the term "comprising". However, those skilled in the art will understand that in certain specific circumstances, the language "substantially consisting of" or "consisting of" may be used to describe embodiments.

[0062] As used in this article, the term "mol" or "molar" refers to the amount of one substance that reacts with any amount (usually one mole) of another substance in a specific chemical reaction.

[0063] Therefore, unless otherwise indicated, the numerical parameters listed in the following specification and appended claims are approximate values ​​and may vary depending on the desired characteristics sought to be obtained. At a minimum, each numerical parameter should be interpreted taking into account the number of significant figures reported and by applying common rounding techniques.

[0064] Furthermore, the endpoints of all ranges involving the same component or property in this document include endpoints, are independently combinable, and include all intermediate points and ranges.

[0065] In compounds having formulas (I), (II), (III), and (IV), the terms used (alone or in combination with other terms) denote the following groups:

[0066] • Alkyl refers to straight-chain alkyl or branched alkyl, such as methyl, ethyl, n-propyl or isopropyl, n-butyl, isobutyl, tert-butyl or 2-butyl, pentyl, hexyl such as n-hexyl, isohexyl and 1,3-dimethylbutyl.

[0067] • "Sulfonyl group" refers to the functional group in which the sulfur atom has four substituents, two of which are double-bonded oxygen atoms. The sulfonyl group can be represented as -S(O)2-.

[0068] • Halogen itself, or as part of a substituent, refers to chlorine, bromine, iodine, or fluorine atoms.

[0069] • If a group is substituted by a radical, this should be understood to mean that the group is substituted by one or more of the same or different radicals mentioned.

[0070] As used herein, the term "base" means a substance that acts as a base, but whose strength or activity as a base lies between that of a strong base such as hydroxides (which may cause hydrolysis of enol esters) and that of a weak base such as bicarbonates (which do not function effectively). Bases suitable for this embodiment include both organic bases (such as tertiary amines) and inorganic bases (such as alkali metal carbonates, bicarbonates, and phosphates). Suitable tertiary amines include trialkylamines, such as triethylamine. Suitable inorganic bases include potassium carbonate and trisodium phosphate.

[0071] As used in this article, the term "catalytic amount" refers to the amount of catalyst that is less than the stoichiometric amount of reactants.

[0072] As used herein, the term "cyanide source" refers to one or more substances that, under rearrangement conditions, consist of or generate hydrogen cyanide and / or cyanide anions.

[0073] As used herein, the term "oxidizing agent" refers to an agent whose oxidation potential is high enough to carry out cyanide oxidation in the reactants without significantly affecting any undesirable reaction. Suitable oxidizing agents include hydrogen peroxide, etc.

[0074] As used in this article, the term "acid" refers to any substance that can lower the pH of a solution.

[0075] As used in this article, the term “substantially reduced unwanted toxic impurities” refers to cyanide toxic impurities at very low or negligible levels.

[0076] As used herein, the term "about" refers to and includes the values ​​shown and the ranges before and after these values. In some embodiments, the term "about" refers to ±10%, ±5%, or ±1% of the values ​​shown.

[0077] As used herein, the term "batch method" refers to a chemical method involving a series of operations performed on a single, identifiable item or batch of material, wherein the product is produced as a group rather than continuously. As used herein, the term "multi-step batch method" refers to a chemical method involving a method performed in a cascade manner without separating intermediates generated during synthesis.

[0078] All ranges are inclusive. As used throughout this instruction manual, the following abbreviations shall apply: °C = degrees Celsius, or min. = minutes, or h = hours.

[0079] Sulfophenylpyrazolone compounds, such as sulfonylurea herbicides, are widely used in agriculture. Sulfonylurea herbicides are used for post-emergence control of various broadleaf weeds.

[0080] This invention provides a method for preparing a compound having formula (IV) from a compound having formula (III).

[0081]

[0082] in,

[0083] R 1 It is methyl or ethyl;

[0084] R 2 It is trifluoromethyl;

[0085] R 3 It is hydrogen, methyl, or ethyl;

[0086] R 4 It is methyl, ethyl, or n-propyl;

[0087] R 5 It is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl monosubstituted or polysubstituted with halogen, phenylsulfonyl monosubstituted with methyl or halogen, benzyl substituted with halogen, nitro, methyl or methoxy, or benzoylmethyl monosubstituted or polysubstituted with halogen, nitro, methyl or methoxy; and

[0088] n is 0, 1, or 2;

[0089]

[0090] The method includes the following steps:

[0091] a) Treat compounds having formula (III) with a catalytic amount of cyanide source and base;

[0092] b) Mix the reaction mixture from step (a) with the oxidizing agent; and

[0093] c) Acidify the reaction mixture of step (b) to obtain a compound having formula (IV).

[0094] In the embodiments, the present invention provides a method for preparing a compound having formula (IV) by rearranging a compound having formula (III).

[0095]

[0096] in,

[0097] R 1 It is methyl or ethyl;

[0098] R 2 It is trifluoromethyl;

[0099] R 3 It is hydrogen, methyl, or ethyl;

[0100] R 4 It is methyl, ethyl, or n-propyl;

[0101] R 5 It is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl monosubstituted or polysubstituted with halogen, phenylsulfonyl monosubstituted with methyl or halogen, benzyl substituted with halogen, nitro, methyl or methoxy, or benzoylmethyl monosubstituted or polysubstituted with halogen, nitro, methyl or methoxy, and

[0102] n is 0, 1, or 2;

[0103]

[0104] This rearrangement occurs under the following conditions:

[0105] a) Catalytic amounts of cyanide source and base;

[0106] b) Mix the reaction mixture from step (a) with the oxidizing agent; and

[0107] c) Acidify the reaction mixture of step (b) to obtain a compound having formula (IV).

[0108] In another embodiment, the present invention provides a method for preparing a compound having formula (IV),

[0109]

[0110] The method includes the following steps:

[0111] a1) To make compounds having formula (I)

[0112]

[0113] With compounds having formula (II)

[0114]

[0115] The reaction is carried out in the presence of a base to obtain a compound having formula (III);

[0116]

[0117] in,

[0118] R 1 It is methyl or ethyl;

[0119] R 2 It is trifluoromethyl;

[0120] R 3 It is hydrogen, methyl, or ethyl;

[0121] R 4 It is methyl, ethyl, or n-propyl;

[0122] R 5 It is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl monosubstituted or polysubstituted with halogen, phenylsulfonyl monosubstituted with methyl or halogen, benzyl substituted with halogen, nitro, methyl or methoxy, or benzoylmethyl monosubstituted or polysubstituted with halogen, nitro, methyl or methoxy; and

[0123] n is 0, 1, or 2;

[0124] a) The compound having formula (III) obtained in step (a1) is treated with a catalytic amount of cyanide source and base;

[0125] b) Mix the reaction mixture from step (a) with the oxidizing agent; and

[0126] c) Acidify the reaction mixture of step (b) to obtain a compound having formula (IV).

[0127] In a preferred embodiment, the present invention provides a method for preparing a compound having formula (IV).

[0128]

[0129] The method includes the following steps:

[0130] a1) To make compounds having formula (I)

[0131]

[0132] With compounds having formula (II)

[0133]

[0134] The reaction is carried out in the presence of a base to obtain a compound having formula (III);

[0135]

[0136] in,

[0137] R 1 It is methyl or ethyl;

[0138] R 2 It is trifluoromethyl;

[0139] R 3 It is hydrogen, methyl, or ethyl;

[0140] R 4 It is methyl, ethyl, or n-propyl;

[0141] R 5 It is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl monosubstituted or polysubstituted with halogen, phenylsulfonyl monosubstituted with methyl or halogen, benzyl substituted with halogen, nitro, methyl or methoxy, or benzoylmethyl monosubstituted or polysubstituted with halogen, nitro, methyl or methoxy, and

[0142] n is 0, 1, or 2;

[0143] a) The compound having formula (III) obtained in step (a1) is treated with a catalytic amount of cyanide source and base;

[0144] b) Mix the reaction mixture from step (a) with the oxidizing agent; and

[0145] c) Acidify the reaction mixture of step (b) to obtain a compound having formula (IV).

[0146] In the embodiments, the method of the present invention is a multi-step intermittent method for preparing compounds having formula (IV), which is carried out in a condensed manner without separating intermediates (such as compounds having formula (III)) generated during synthesis.

[0147] In another embodiment, the method of the present invention is an intermittent method for preparing compounds having formula (IV), which is carried out by isolating intermediates (such as compounds having formula (III)) generated during synthesis.

[0148] In another embodiment, a compound having formula (I), wherein R 1 It is methyl and R 2 It is trifluoromethyl. In another embodiment, the compound having formula (I) is 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride.

[0149] In yet another embodiment, a compound having formula (II), wherein R 3 It is methyl and R 4 It is methyl. In the examples, the compound having formula (II) is 2,5-dimethyl-2,4-dihydro-3H-pyrazol-3-one.

[0150] In another embodiment, a compound having formula (III), wherein R 1 It is methyl, R 2 It is trifluoromethyl, R 3 It is methyl and R 4 It is methyl. In a preferred embodiment, the compound having formula (III) is 1,3-dimethyl-1H-pyrazole-5-yl-4-trifluoromethyl-2-(methylsulfonyl)benzoate.

[0151] In the embodiments, the method of the present invention specifies that the purity of the compound having formula (III) is at least 90%, at least 95%, at least 98%, or at least 99%.

[0152] In yet another embodiment, a compound having formula (IV), wherein R 1 It is methyl, R 2 It is trifluoromethyl, R 3 It is methyl, R 4 It is methyl and R 5 It is hydrogen. In a preferred embodiment, the compound having formula (IV) is 5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone.

[0153] In another embodiment, the method of the present invention specifies that the purity of the compound having formula (IV) is at least 90%, at least 95%, at least 98%, or at least 99%.

[0154] In the embodiments, the present invention provides a method for preparing 5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone, the method comprising: reacting 2,5-dimethyl-2,4-dihydro-3H-pyrazole-3-one and 2-(methanesulfonyl)-4-(trifluoromethyl)benzoyl chloride in the presence of a triethylamine base to form 1,3-dimethyl-1H-pyrazole-5-yl 4-trifluoromethyl-2-(methanesulfonyl)benzoate. This involves a rearrangement process carried out in the presence of a catalytic amount of acetone cyanohydrin, triethylamine, and mixing the reaction mixture with a hydrogen peroxide solution. The reaction mixture is then treated with a concentrated acid to obtain 5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone.

[0155] Compounds having formula (IV) contain a substantially reduced amount of undesirable cyanide ion toxic impurities. In one embodiment, the compound having formula (IV) contains cyanide ions at a concentration of less than 50 ppm. In another embodiment, the compound having formula (IV) contains cyanide ions at a concentration of less than 40 ppm. In yet another embodiment, the compound having formula (IV) contains cyanide ions at a concentration of less than 30 ppm. In still another embodiment, the compound having formula (IV) contains cyanide ions at a concentration of less than 20 ppm. In an embodiment, the compound having formula (IV) contains cyanide ions at a concentration of less than 10 ppm. In a preferred embodiment, the compound having formula (IV) contains cyanide ions at a concentration of less than 5 ppm. In a more preferred embodiment, the compound having formula (IV) contains cyanide ions at a concentration of less than 1 ppm.

[0156] A compound having formula (I) and a compound having formula (II) react in the presence of a base to form a compound having formula (III). A solution of the base and a solution of the compound having formula (II) in an organic solvent is added to a solution of the compound having formula (I) in an organic solvent at a temperature of about 15°C to 35°C for a period of about 2 to 3 hours. The reaction mixture is cooled to 0°C to 5°C and filtered to collect a filter cake. The filter cake is washed with a cold organic solvent to obtain a wet solid, and the wet solid is mixed with water. The mixture is acidified and stirred at ambient temperature for a period of time and filtered to obtain a compound having formula (III).

[0157] The term "organic solvent" refers to an organic molecule capable of at least partially dissolving another substance (i.e., a solute). Organic solvents can be liquids at room temperature. Examples of organic solvents that can be used in this invention include, but are not limited to, hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oil, etc.), as well as aromatic hydrocarbon solvents (e.g., toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., chlorobenzene, 1,2-dichloroethane, dichloromethane, etc.), ester solvents (e.g., ethyl acetate, isopropyl acetate, etc.), and acetonitrile. In some embodiments, the organic solvent can be formed by a combination of two or more organic solvents. In a preferred embodiment, the organic solvent used in the method of this invention is chlorobenzene.

[0158] The terms "rinsing" or "washing" are used interchangeably, and they refer to the process of purifying a solid substance by passing a liquid through and / or through it to remove unwanted soluble impurities. This process includes passing a solvent (such as distilled water or an organic solvent) through and / or through a precipitate obtained from filtration, decantation, or a combination thereof.

[0159] The base used in the method of the present invention is an organic base or an inorganic base. The inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium phosphate, and mixtures thereof. The organic base is selected from the group consisting of tertiary amines such as tri-C1-C6 alkylamines, N-substituted imines, aromatic amines, and mixtures thereof. In another embodiment, the base used in the method of the present invention is a tri-C1-C6 alkylamine, such as triethylamine.

[0160] In a preferred embodiment, the present invention provides a method for preparing 5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone by rearranging 1,3-dimethyl-1H-pyrazole-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone, wherein the rearrangement is carried out in the presence of catalytic amounts of acetone cyanohydrin, triethylamine, and mixing of the reaction mixture with a hydrogen peroxide solution. The reaction mixture is then treated with a concentrated acid to obtain 5-hydroxy-1,3-dimethyl-1H-pyrazole-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone.

[0161] The rearrangement in the method of the present invention is carried out in the presence of a cyanide source or a substance that is composed of or generates cyanide ions under rearrangement conditions. Preferred cyanide sources are cyanohydrins of methyl alkyl ketones having 1-4 carbon atoms in the alkyl group, such as acetone or methyl isobutyl ketone cyanohydrin; cyanohydrins of benzaldehyde or C2-C5 aliphatic aldehydes, such as acetaldehyde, propionaldehyde, etc.; and hydrogen cyanide itself. Among cyanohydrins, acetone cyanohydrin is a preferred cyanide source.

[0162] In a preferred embodiment, the cyanide source and the compound having formula (III) are present in a molar ratio of about 1:5 to 1:50, preferably in a ratio of about 1:20.

[0163] Preferred bases for rearrangement reactions are tri-C1-C6 alkylamines, such as triethylamine. The molar ratio of the base to a compound having formula (III) is about 1:1 to 2:1, preferably about 1.2:1. The molar ratio of the base to a compound having formula (I) is about 2:1 to 4:1, preferably about 2.5:1.

[0164] If acetone cyanohydrin is used as the cyanide source, the cyanohydrin dissociates under basic conditions during the reaction, and the actual catalyst for this method is the cyanide ion, as shown below:

[0165]

[0166] As mentioned in the background of this invention, a problem associated with prior art methods is that the significant concentration of cyanide ions in the reaction mixture during product separation and purification makes this method hazardous. Even after filtering, washing, and drying the product, a portion of cyanide ions was found in the final product. Cyanide ions in this product are a significant contaminant, with regulatory agencies limiting their concentration to 50 parts per million. There are situations where additional purification steps are required to achieve this level.

[0167] The method of the present invention addresses this problem by using an oxidizing agent that oxidizes the cyanide ions remaining in the method after the rearrangement reaction, without affecting the yield and quality of the product, thereby resulting in very low levels of toxic cyanide ion impurities. In the embodiments, the oxidizing agent used in the oxidation reaction can be a common oxidizing agent known to those skilled in the art.

[0168] In another embodiment, the oxidant is selected from the group consisting of hydrogen peroxide, sodium hypochlorite, chlorine, and mixtures thereof. In yet another embodiment, the oxidant is present with a cyanide source in a molar ratio of about 1.5:1 to 5:1, preferably about 3:1.

[0169] If hydrogen peroxide is used as the oxidant in the method of the present invention, the result is achieved by oxidizing the cyanide ions in the reaction mixture as follows:

[0170]

[0171] In an embodiment, in the final step of the rearrangement process of the present invention, the reaction mixture is acidified with an acid to precipitate the compound having formula (IV). The acid is used to acidify the reaction mixture to a pH in the range of about 1 to 3, preferably 2.

[0172] In yet another embodiment, the acid is selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, chloric acid, hydrobromic acid, and mixtures thereof. In a preferred embodiment, the acid is an aqueous solution of sulfuric acid.

[0173] The method according to the invention is generally carried out at atmospheric pressure. However, it is also possible to carry out the method according to the invention at elevated or decreased pressures. In an embodiment, the method for preparing a sulfonylpyrazolone compound having formula (IV) can be carried out at a pressure of about 1 bar to about 10 bar. In another embodiment, the method can be carried out at a pressure of about 1 bar to about 5 bar. In yet another embodiment, the method for preparing a sulfonylpyrazolone compound having formula (IV) can be carried out at atmospheric pressure. In yet another embodiment, the method can be carried out at about 10 bar. In some embodiments, it may be preferred that the method be carried out at a pressure less than atmospheric pressure. For example, the method can be carried out at 0.7 bar, 0.75 bar, 0.8 bar, 0.9 bar, or 0.95 bar.

[0174] The advantage of the method of the present invention lies in its significantly greater safety for industrial implementation, making it possible to obtain a qualified product with low levels of cyanide impurities by directly crystallizing a compound having formula (IV) from the reaction mixture without requiring additional purification / recrystallization of the final material. These advantages make the method highly efficient.

[0175] The progress of the synthetic reaction of compounds having formula (III) and compounds having formula (IV) can be monitored using any suitable method, which may include, for example, chromatographic methods such as high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), etc. In yet another embodiment, compounds having formula (III) or compounds having formula (IV) can be separated from the reaction mixture using any conventional techniques well known in the art. Such separation techniques may be selected from, but are not limited to, the group consisting of: extraction, crystallization, or precipitation by concentration, cooling or antisolvent addition, filtration, centrifugation, and combinations thereof, followed by drying.

[0176] In yet another embodiment, compounds having formula (III) and compounds having formula (IV) may optionally be purified using any conventional technique well known in the art. Such purification techniques may be selected from, but are not limited to, the group consisting of: precipitation, crystallization, extraction, slurrying, washing in a suitable solvent, filtration through a packed bed column, dissolution in a suitable solvent, reprecipitation by adding a second solvent in which the compound is insoluble, and combinations thereof.

[0177] The following examples illustrate the practice of the invention in some of its embodiments, but should not be construed as limiting the scope of the invention. Other embodiments will be apparent to those skilled in the art from consideration of this specification and the examples. This specification (including the examples) is intended to be considered exemplary only and not to limit the scope and spirit of the invention.

[0178] An exemplary experimental procedure for producing sulfonylpyrazolinone compounds having formula (IV) is described below:

[0179] Example 1:

[0180] Synthesis of 1,3-dimethyl-1H-pyrazole-5-yl 2-(methanesulfonyl)-4-trifluoromethyl benzoate:

[0181]

[0182] 273.7 g of chlorobenzene and 57.8 g (0.5 mol) of 2,5-dimethyl-2,4-dihydro-3H-pyrazole-3-one were added to a four-necked flask. Azeotropic dehydration was carried out under vacuum at 60°C to 65°C until no water droplets were observed in the condensate, while maintaining a pressure of -0.090 to -0.095 MPa. 55.9 g (0.55 mol) of triethylamine was added to the mixture, resulting in the formation of a solution of 2,5-dimethyl-2,4-dihydro-3H-pyrazole-3-one in chlorobenzene and triethylamine, with a yield of approximately 387.4 g.

[0183] A solution of 2,5-dimethyl-2,4-dihydro-3H-pyrazole-3-one in chlorobenzene and triethylamine was added dropwise to a solution of 140.4 g (0.49 mol) of 2-(methanesulfonyl)-4-(trifluoromethyl)benzoyl chloride in 281 g of chlorobenzene over a 2-hour period at a temperature range of 20°C to 30°C. The mixture was maintained at 20°C to 30°C for 1 hour until the presence of 2-(methanesulfonyl)-4-(trifluoromethyl)benzoyl chloride was less than 1.0% by area on HPLC. The temperature was then lowered to 0°C to 5°C, followed by filtration to collect the resulting filter cake.

[0184] The collected filter cake was washed with 41.1 g of cold chlorobenzene to obtain a wet solid (approximately 298.8 g). Approximately 298.8 g of wet solid and 410.5 g of water were added to another four-necked flask. The mixture was acidified to pH 6 to 7 with approximately 3.0 g of 30% hydrochloric acid aqueous solution and stirred for 1.0 h at a temperature ranging from 25°C to 30°C. The product was filtered and the wet solid was dried at a temperature ranging from 60°C to 65°C to yield 1,3-dimethyl-1H-pyrazol-5-yl-4-trifluoromethyl-2-(methanesulfonyl)benzoate as a grayish-white solid, weighing 172.0 g (97% purity, 0.46 mol). Yield: 94%.

[0185] Example 2:

[0186] Synthesis of 5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone:

[0187]

[0188] 344.1 g of chlorobenzene and 172.0 g (0.46 mol) of 1,3-dimethyl-1H-pyrazole-5-yl-4-trifluoromethyl-2-(methanesulfonyl)benzoate were combined in a four-necked flask. Azeotropic dehydration was carried out under vacuum at temperatures ranging from 60°C to 65°C until no water droplets were observed in the condensate, while maintaining a pressure of -0.09 to -0.095 MPa. 56.2 g (0.55 mol) of triethylamine and 2.0 g (0.02 mol) of acetone cyanohydrin were added to the mixture. The mixture was maintained at 60°C to 65°C for approximately 6 hours until the area of ​​1,3-dimethyl-1H-pyrazole-5-yl-4-trifluoromethyl-2-(methanesulfonyl)benzoate was reduced to less than 0.5% on HPLC.

[0189] 206.5 g of water was added to the mixture at a temperature of 60°C to 65°C. The pH of the aqueous phase was approximately 9. 7.9 g (0.07 mol) of 30% hydrogen peroxide solution was added to the mixture, and the mixture was maintained at 60°C to 65°C for 2 hours. The mixture was then acidified with 58.7 g (0.3 mol) of 50% sulfuric acid aqueous solution to a pH close to 1 to precipitate the desired product.

[0190] The mixture was then heated to 80°C to 90°C until the product was completely dissolved. The mixture was cooled to 0°C to 5°C over a 3-hour span. Subsequently, the mixture was filtered to collect the resulting filter cake. The collected filter cake was washed with 86.0 g of cold water and 86.0 g of cold chlorobenzene to obtain a wet solid. The substance was dried at a temperature ranging from 75°C to 85°C. The final product was 5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone, obtained as a grayish-white solid, weighing 153.3 g (98% purity, 0.415 mol). Yield: 90%. Cyanide ion content: less than 1 ppm.

[0191] Example 3:

[0192] Synthesis of 5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone:

[0193]

[0194] 1140 g of chlorobenzene and 286.8 g (1.05 mol) of 4-trifluoromethyl-2-(methanesulfonyl)benzoic acid were added to a four-necked flask. Azeotropic dehydration was carried out under vacuum at temperatures ranging from 60°C to 65°C until no water droplets were observed in the condensate, while maintaining a pressure of -0.09 to -0.095 MPa.

[0195] 1.6 g (0.02 mol) of dimethylformamide was added to the reaction mixture as a catalyst, and 151 g (1.26 mol) of thionyl chloride was fed dropwise into the reaction mixture over a period of approximately 3 hours at a temperature of 60°C to 65°C. The reaction mixture was maintained for approximately 4 hours until the concentration of 4-trifluoromethyl-2-(methanesulfonyl)benzoic acid decreased to less than 1.0 area % on HPLC. The prepared solution of 2-(methanesulfonyl)-4-(trifluoromethyl)benzoyl chloride was concentrated by distilling off approximately 286 g of chlorobenzene under a vacuum of -0.09 to -0.095 MPa at a temperature ranging from 60°C to 80°C.

[0196] A solution of 295 g (1.03 mol) 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride in about 1000 g chlorobenzene was prepared and kept at a temperature of 60°C to 65°C to prevent precipitation for the next step of the synthesis.

[0197] 858 g of chlorobenzene and 120.1 g (1.05 mol) of 2,5-dimethyl-2,4-dihydro-3H-pyrazole-3-one were added to a four-necked flask. Azeotropic dehydration was carried out under vacuum at 60°C to 65°C until no water droplets were observed in the condensate, while maintaining a pressure of -0.090 to -0.095 MPa. 268.3 g (2.62 mol) of triethylamine was added to the reaction mixture.

[0198] By maintaining a temperature below 65°C, a solution of 295 g (1.03 mol) of 2-(methanesulfonyl)-4-(trifluoromethyl)benzoyl chloride in approximately 1000 g of chlorobenzene, previously generated and maintained at a temperature of approximately 60°C to 65°C, was fed into this reaction mixture. Following the feed, 4.5 g (0.05 mol) of acetone cyanohydrin was added to the reaction mixture.

[0199] The mixture was stirred at 60°C to 65°C for 8 hours until the concentration of 1,3-dimethyl-1H-pyrazole-5-yl-4-trifluoromethyl-2-(methylsulfonyl)benzoate on HPLC was less than 0.5 area.

[0200] At the end of the reaction, 800 g of water and 19.4 g (0.15 mol) of 30% hydrogen peroxide solution were added to the mixture, and the reaction mixture was stirred at 60°C to 65°C for 2 hours. The reaction mixture was then acidified to a pH close to 1 with 189 g (0.95 mol) of 50% sulfuric acid at 60°C to 70°C to precipitate the desired product.

[0201] The mixture was then heated to 80°C to 90°C until the product was completely dissolved. The mixture was cooled to 0°C to 5°C over a 3-hour span. Subsequently, the mixture was filtered to collect the resulting filter cake. The collected filter cake was washed with 228 g of cold water and 228 g of cold chlorobenzene to obtain a wet solid. The substance was dried at a temperature ranging from 75°C to 85°C. The final product was 5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone, obtained as a grayish-white solid, weighing 316.7 g (purity 98.5%, 0.862 mol). Yield 82.0%. The cyanide ion content was less than 1 ppm.

[0202] Example 4 (Comparison):

[0203] Synthesis of 5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone:

[0204]

[0205] 1140 g of chlorobenzene and 286.8 g (1.05 mol) of 4-trifluoromethyl-2-(methanesulfonyl)benzoic acid were added to a four-necked flask. Azeotropic dehydration was carried out under vacuum at temperatures ranging from 60°C to 65°C until no water droplets were observed in the condensate, while maintaining a pressure of -0.09 to -0.095 MPa.

[0206] 1.6 g (0.02 mol) of dimethylformamide was added to the reaction mixture as a catalyst, and 151 g (1.26 mol) of thionyl chloride was fed dropwise into the reaction mixture over a period of approximately 3 hours at a temperature of 60°C to 65°C. The reaction mixture was maintained for approximately 4 hours until the concentration of 4-trifluoromethyl-2-(methanesulfonyl)benzoic acid decreased to less than 1.0 area % on HPLC. The prepared solution of 2-(methanesulfonyl)-4-(trifluoromethyl)benzoyl chloride was concentrated by distilling off approximately 286 g of chlorobenzene under a vacuum of -0.09 to -0.095 MPa at a temperature ranging from 60°C to 80°C.

[0207] A solution of 295 g (1.03 mol) 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride in about 1000 g chlorobenzene was prepared and kept at a temperature of 60°C to 65°C to prevent precipitation for the next step of the synthesis.

[0208] 858 g of chlorobenzene and 120.1 g (1.05 mol) of 2,5-dimethyl-2,4-dihydro-3H-pyrazole-3-one were added to a four-necked flask. Azeotropic dehydration was carried out under vacuum at 60°C to 65°C until no water droplets were observed in the condensate, while maintaining a pressure of -0.090 to -0.095 MPa. 268.3 g (2.62 mol) of triethylamine was added to the reaction mixture.

[0209] By maintaining a temperature below 65°C, a solution of 295 g (1.03 mol) of 2-(methanesulfonyl)-4-(trifluoromethyl)benzoyl chloride in approximately 1000 g of chlorobenzene, previously generated and maintained at a temperature of approximately 60°C to 65°C, was fed into this reaction mixture. Following the feed, 4.5 g (0.05 mol) of acetone cyanohydrin was added to the reaction mixture.

[0210] The mixture was stirred at 60°C to 65°C for 8 hours until the concentration of 1,3-dimethyl-1H-pyrazole-5-yl-4-trifluoromethyl-2-(methylsulfonyl)benzoate on HPLC was less than 0.5 area.

[0211] At the end of the reaction, 800 g of water was added to the mixture, and the reaction mixture was stirred at 60°C to 65°C for several minutes. The reaction mixture was then acidified to a pH close to 1 with 189 g (0.95 mol) of 50% sulfuric acid solution at 60°C to 70°C to precipitate the desired product.

[0212] The mixture was then heated to 80°C to 90°C until the product was completely dissolved. The mixture was cooled to 0°C to 5°C over a 3-hour span. Subsequently, the mixture was filtered to collect the resulting filter cake. The collected filter cake was washed with 228 g of cold water and 228 g of cold chlorobenzene to obtain a wet solid. The substance was dried at a temperature ranging from 75°C to 85°C. The final product was 5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl 2-(methanesulfonyl)-4-(trifluoromethyl)phenyl ketone, obtained as a grayish-white solid, prepared in an amount of 317.8 g (purity 98.3%, 0.863 mol). Yield 82.2%. Cyanide ion content 218 ppm.

Claims

1. A method for preparing a compound having formula (IV) from a compound having formula (III), in, R 1 It is methyl or ethyl; R 2 It is trifluoromethyl; R 3 It is hydrogen, methyl, or ethyl; R 4 It is methyl, ethyl, or n-propyl; R 5 It is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl monosubstituted or polysubstituted with halogen, phenylsulfonyl monosubstituted with methyl or halogen, benzyl substituted with halogen, nitro, methyl or methoxy, or benzoylmethyl monosubstituted or polysubstituted with halogen, nitro, methyl or methoxy, and n is 0, 1, or 2; The method includes the following steps: a) Treat the compound having formula (III) with a catalytic amount of cyanide source and base; b) Mix the reaction mixture from step (a) with the oxidizing agent; and c) Acidify the reaction mixture of step (b) to obtain a compound having formula (IV).

2. The method as described in claim 1, wherein, The base is an organic base or an inorganic base.

3. The method as described in claim 2, wherein, The inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium phosphate, and mixtures thereof.

4. The method of claim 2, wherein, The organic base is selected from the group consisting of tertiary amines, N-substituted imines, aromatic amines and mixtures thereof.

5. The method of claim 4, wherein, The organic base is triethylamine.

6. The method of claim 2, wherein, The base and the compound having formula (III) are present in a molar ratio of about 1:1 to 2:

1.

7. The method of claim 1, wherein, The cyanide source is a cyanohydrin of a methyl alkyl ketone having 1-4 carbon atoms in the alkyl group, benzaldehyde cyanohydrin; a cyanohydrin of a C2-C5 aliphatic aldehyde, hydrogen cyanide, and mixtures thereof.

8. The method of claim 7, wherein, The cyanide source is acetone cyanohydrin.

9. The method of claim 1, wherein, The cyanide source and the compound having formula (III) are present in a molar ratio of about 1:5 to 1:

50.

10. The method of claim 1, wherein, The oxidizing agent is hydrogen peroxide, sodium hypochlorite, chlorine, or a mixture thereof.

11. The method of claim 1, wherein, The oxidizing agent and the cyanide source are present in a molar ratio of about 1.5:1 to 5:

1.

12. The method of claim 1, wherein, The acid is hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, chloric acid, hydrobromic acid, or mixtures thereof.

13. The method of claim 1, wherein, The compound having formula (IV) contains cyanide ions at a concentration of less than 5 ppm.

14. A method for preparing a compound having formula (IV), The method includes the following steps: a1) To make compounds having formula (I) With compounds having formula (II) The reaction is carried out in the presence of a base to obtain a compound having formula (III); in, R 1 It is methyl or ethyl; R 2 It is trifluoromethyl; R 3 It is hydrogen, methyl, or ethyl; R 4 It is methyl, ethyl, or n-propyl; R 5 It is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl monosubstituted or polysubstituted with halogen, phenylsulfonyl monosubstituted with methyl or halogen, benzyl substituted with halogen, nitro, methyl or methoxy, or benzoylmethyl monosubstituted or polysubstituted with halogen, nitro, methyl or methoxy; and n is 0, 1, or 2; a) Treat the compound having formula (III) obtained in step (a1) with a catalytic amount of cyanide source and base; b) Mix the reaction mixture from step (a) with the oxidizing agent; and c) Acidify the reaction mixture of step (b) to obtain a compound having formula (IV).

15. The method of claim 14, wherein, The base is an organic base or an inorganic base.

16. The method of claim 15, wherein, The inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium phosphate, and mixtures thereof.

17. The method of claim 15, wherein, The organic base is selected from the group consisting of tertiary amines, N-substituted imines, aromatic amines and mixtures thereof.

18. The method of claim 17, wherein, The organic base is triethylamine.

19. The method of claim 14, wherein, The base and the compound having formula (I) are present in a molar ratio of about 2:1 to 4:

1.

20. The method of claim 14, wherein, The cyanide source is a cyanohydrin of a methyl alkyl ketone having 1-4 carbon atoms in the alkyl group, benzaldehyde cyanohydrin; a cyanohydrin of a C2-C5 aliphatic aldehyde, hydrogen cyanide, and mixtures thereof.

21. The method of claim 20, wherein, The cyanide source is acetone cyanohydrin.

22. The method of claim 14, wherein, The cyanide source and the compound having formula (I) are present in a molar ratio of about 1:5 to 1:

50.

23. The method of claim 14, wherein, The oxidizing agent is hydrogen peroxide, sodium hypochlorite, chlorine, or a mixture thereof.

24. The method of claim 14, wherein, The oxidizing agent and the cyanide source are present in a molar ratio of about 1.5:1 to 5:

1.

25. The method of claim 14, wherein, The acid is hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, chloric acid, hydrobromic acid, or mixtures thereof.

26. The method of claim 14, wherein, The compound having formula (IV) contains cyanide ions at a concentration of less than 5 ppm.

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