Process for preparation of sulfonyl pyrazolones

Abstract

The invention relates to a method for preparing sulfonyl pyrazolone compound of Formula (IV) with substantially less undesired toxic impurity, Formula (IV), wherein these compounds are used as active ingredients in agricultural field, especially as an herbicidal compound. The process for preparation of compound of Formula (IV) comprises reacting the compound of Formula (III), with a catalytic amount of cyanide source and a base followed by mixing with an oxidizing reagent and acidifying the mixture to obtain the compound of Formula (IV).

Description

[0001] PROCESS FOR PREPARATION OF SULFONYL PYRAZOLONES

[0002] Field of the Invention:

[0003] The invention relates to a novel process for preparation of sulfonyl pyrazolone compound of Formula (IV) with substantially less undesired toxic impurity, wherein these compounds are used as active ingredients in agricultural field, especially as an herbicidal compound.

[0004] Background of the Invention:

[0005] Sulfophenyl pyrazolone is an organic compound widely used in the agricultural field, such as a pyrasulfotole herbicide. The herbicide is used for post-emergent control of various broadleaved weeds.

[0006] US 6,420,317 patent discloses the process for the preparation of benzoylpyrazoles compounds by rearrangement of corresponding enol esters in which the rearrangement is conducted in the presence of acetone cyanohydrin and triethylamine. The drawback of this process is that solid material separation takes place from the reaction mixture with a significant concentration of cyanide ions. Such handling on the industrial scale makes this process dangerous. Moreover, after product filtration, washing and drying, part of the cyanide impurities is also present in the final product.

[0007] Therefore, the processes described in the prior art have limitation such as challenges of handling the reaction mixture, product and mother liquor due to contamination of cyanide ion as well as difficulty of the purification of the product to avoid undesired cyanide level. It makes the prior art process uneconomical, and use of excessive reagent for purification also makes the prior art process less efficient. Thus, there is still a need for a process that obviates the shortcomings associated with the known processes.

[0008] Hence, there is a need to develop an effective process for the preparation of sulfonyl pyrazolone compound of Formula (IV), with higher yield and efficiency, is therefore desirable.

[0009] Summary of the Invention:

[0010] The present invention provides a process for the preparation of compound of Formula (IV) wherein,

[0011] R1is methyl or ethyl;

[0012] R2is trifluoromethyl;

[0013] R3is hydrogen, methyl or ethyl;

[0014] R4is methyl, ethyl or n-propyl;

[0015] R5is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl which is mono- or poly-substituted by halogen, phenyl sulfonyl which is monosubstituted by methyl or halogen, benzyl which is substituted by halogen, nitro, methyl or methoxy or benzoylmethyl which is mono- or polysubstituted by halogen, nitro, methyl or methoxy; and n is 0, 1, or 2; from a compound of Formula (III) wherein the process comprises the steps of: a) treating the compound of Formula (III) with a catalytic amount of cyanide source and a base, b) mixing the reaction mixture of step (a) with an oxidizing reagent; and c) acidifying the reaction mixture of step (b) with an acid to obtain a compound of Formula (IV).

[0016] In another aspect, the present invention provides a process for the preparation of a compound of Formula (IV) wherein the process comprises the steps of: al) reacting a compound of Formula (I) with a compound of Formula (II) in presence of a base to obtain a compound of Formula (III); wherein,

[0017] R1is methyl or ethyl;

[0018] R2is trifluoromethyl;

[0019] R3is hydrogen, methyl or ethyl;

[0020] R4is methyl, ethyl or n-propyl;

[0021] R5is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkyl sulfonyl which is mono- or poly-substituted by halogen, phenyl sulfonyl which is monosubstituted by methyl or halogen, benzyl which is substituted by halogen, nitro, methyl or methoxy or benzoylmethyl which is mono- or polysubstituted by halogen, nitro, methyl or methoxy and n is 0, 1, or 2; a) treating the compound of Formula (III) obtained in step (al) with a catalytic amount of a cyanide source and a base; b) mixing the reaction mixture of step (a) with an oxidizing reagent; and c) acidifying the reaction mixture of step (b) with an acid to obtain a compound of Formula (IV).

[0022] In an aspect, the compound of Formula (IV) is 5 -hydroxy- 1,3 -dimethyl- 1H- pyrazol-4-yl 2- (methylsulfonyl)-4-(trifluoromethyl)phenyl ketone.

[0023] In another aspect, the compound of Formula (III) is 1,3 -dimethyl- 1H- pyrazol-5-yl 4- trifluoromethyl-2-(methylsulfonyl)benzoate.

[0024] In yet another aspect, the compound of Formula (I) is 2-(m ethyl sulfonyl)-4- (trifluoromethyl)benzoyl chloride.

[0025] In a further aspect, the compound of Formula (II) is 2,5-dimethyl-2,4-dihydro-3H- pyrazol-3- one. In an aspect, the process of the present invention provides that the base is an organic or an inorganic base. The inorganic base is selected from the group comprising sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium phosphate and mixtures thereof. The organic base is selected from the group comprising a tertiary amine, N-substituted imine, aromatic amine and mixtures thereof.

[0026] In a preferred aspect, the process of the present invention provides that the base is a tertiary amine such as triethylamine.

[0027] In an aspect, the process of the present invention provides that the base and the compound of Formula (III) is present in a molar ratio of about 1 : 1 to 2: 1.

[0028] In another aspect, the process of the present invention provides that the base and the compound of Formula (I) is present in a molar ratio of about 2: 1 to 4: 1.

[0029] In yet another aspect, the process of the present invention provides that the cyanide source is a cyanohydrin of a methyl alkyl ketone having from 1-4 carbon atoms in the alkyl group, benzaldehyde cyanohydrin; a cyanohydrin of a C2-C5aliphatic aldehyde, hydrogen cyanide and mixtures thereof.

[0030] In a preferred aspect, the process of the present invention provides that the cyanide source is a cyanohydrin of a methyl alkyl ketone having from 1-4 carbon atoms in the alkyl group such as acetone cyanohydrin.

[0031] In yet another aspect, the process of the present invention provides that the cyanide source and the compound of Formula (III) is present in a molar ratio of about 1 : 5 to 1 : 50.

[0032] In a further aspect, the process of the present invention provides that the oxidizing reagent is hydrogen peroxide, sodium hypochlorite, chlorine and mixtures thereof.

[0033] In an aspect, the process of the present invention provides that the oxidizing reagent and the cyanide source is present in a molar ratio of about 1.5: 1 to 5: 1.

[0034] In another aspect, the process of the present invention provides that the acid is hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, chloric acid, hydrobromic acid and mixtures thereof.

[0035] In a further aspect, the process of the present invention provides that the compound of Formula (IV) contains the cyanide ions at the concentration below 5 ppm, preferably below 1 ppm. In a preferred aspect, the present invention provides the process for the preparation of 5- hydroxy- 1,3 -dimethyl- l / / -pyrazol-4-yl 2-(methylsulfonyl)-4-(trifluoromethyl)phenyl ketone by rearrangement of l,3-dimethyl- 1H- pyrazol-5-yl 4-trifluoromethyl-2- (methylsulfonyl)benzoate in which the rearrangement is conducted in the presence of a catalytic amount of acetone cyanohydrin, triethylamine, and mixing the reaction mixture with a solution of hydrogen peroxide. The reaction mixture is treated with a concentrated acid to obtain the 5-hydroxy-l,3-dimethyl- 1H- pyrazol-4-yl 2-(m ethyl sulfonyl)-4-

[0036] (trifluoromethyl)phenyl ketone.

[0037] Description of the Invention:

[0038] For the sake of clarity, specific terminology is resorted to in describing the embodiments of the invention. However, it is not intended that the invention be limited to the specific terms so selected, and it is to be understood that each specific term includes all technical equivalents that operate in a similar manner to accomplish a similar purpose.

[0039] It will be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. As used in this specification, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, the reference to “a compound” includes one or more of such compounds.

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one ordinarily skilled in the art to which the invention pertains. Although other methods and materials similar to or equivalent to those described herein can be used in the practise of the present invention, the preferred materials and methods are described herein.

[0041] As used herein, the term “or” means “and / or”. It will be further understood that the terms “comprises”, “comprising”, “includes”, “including”, or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition or a method that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such a method.

[0042] Throughout the application, descriptions of various embodiments use the term “comprising”.

[0043] However, it will be understood by one of skill in the art that in some specific instances, an embodiment can alternatively be described using the language “consisting essentially of’ or “consisting of.”

[0044] As used herein the term “mol” or “molar” refers to the quantity of a substance that reacts with an arbitrary quantity (usually one mole) of another substance in a particular chemical reaction.

[0045] Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, each numerical parameter should at least be construed considering the number of reported significant digits and by applying ordinary rounding techniques.

[0046] In addition, the endpoints of all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges.

[0047] The terms used in compounds of Formula (I), (II), (III), (IV), either alone or in combine with other terms, represent the following groups:

[0048] • Alkyl refers to linear chain alkyl or branch chain alkyl for example, methyl, ethyl, n- propyl or isopropyl, n-butyl, iso butyl, t-butyl or 2-butyl, pentyls, hexyls, such as n- hexyl, isohexyl and 1,3 -dimethylbutyl.

[0049] • “Sulfonyl” refers to a functional group in which the sulfur atom has four substituents, two of which are double bonded oxygen atoms. The sulfonyl moiety can be represented as -S(O)2- .

[0050] • Halogen by itself or as part of a substituent refers to a chlorine, bromine, iodine, or fluorine atom.

[0051] • If a group is polysubstituted by radicals, this is to be understood as meaning that this group is substituted by one or more identical or different of the radicals mentioned.

[0052] As used herein, the term “base” is meant a substance which acts as a base yet whose strength or activity as a base lie between that of strong bases such as hydroxides (which could cause hydrolysis of the enol ester) and that of weak bases such as bicarbonates (which would not function effectively). Bases suitable for use in 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. As used herein, the term “catalytic amount” refers to the amount of catalyst that is less than stoichiometric compared to the reactants.

[0053] As used herein, the term “cyanide source” refers to a substance or substances which under the rearrangement conditions consists of or generates hydrogen cyanide and / or cyanide anion.

[0054] As used herein, the term “oxidizing reagent” refers to a reagent whose oxidation potential is high enough to carry out the cyanide oxidation in the reaction mass without significantly effecting any undesired reactions. Suitable oxidants include hydrogen peroxide and the like.

[0055] As used herein, the term “acid” refers to any substance that can lower the pH of a solution.

[0056] As used herein, the term “substantially less undesired toxic impurity” refers to the level of toxic impurity of cyanide is very less or in negligible amount.

[0057] As used herein the term “about” refers to and includes the values shown and the range before and after those values. In certain embodiments, the term “about” refers to ± 10%, ± 5%, or ± 1% of the values shown.

[0058] As used herein, the term “batch process” refers to a chemical process that involves a series of operations on a separate, identifiable item or parcel of material, in which the product comes out in groups and not continuously. As used herein, the term “multistep batch process” refers to a chemical process that involves a process carried out in a telescopic manner without isolation of intermediates produced during the synthesis.

[0059] All ranges are inclusive. As used throughout the specification, the following abbreviations are applied: °C = Centigrade or min.= minutes or h = hours.

[0060] Sulfophenyl pyrazolone compound such as a pyrasulfotole herbicide is widely used in agricultural field. The pyrasulfotole herbicide is used for post-emergent control of various broad-leaved weeds.

[0061] The present invention provides the process for the preparation of compound of Formula (IV) wherein,

[0062] R1is methyl or ethyl;

[0063] R2is trifluoromethyl;

[0064] R3is hydrogen, methyl or ethyl;

[0065] R4is methyl, ethyl or n-propyl;

[0066] R5is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl which is mono- or poly-substituted by halogen, phenyl sulfonyl which is monosubstituted by methyl or halogen, benzyl which is substituted by halogen, nitro, methyl or methoxy or benzoylmethyl which is mono- or polysubstituted by halogen, nitro, methyl or methoxy; and n is 0, 1, or 2; from a compound of Formula (III) wherein the process comprises the steps of: a) treating the compound of Formula (III) with a catalytic amount of cyanide source and a base, b) mixing the reaction mixture of step (a) with an oxidizing reagent and; c) acidifying the reaction mixture of step (b) with an acid to obtain a compound of Formula (IV).

[0067] In an embodiment, the present invention provides a process for the preparation of compound of Formula (IV) wherein,

[0068] R1is methyl or ethyl;

[0069] R2is trifluoromethyl;

[0070] R3is hydrogen, methyl or ethyl;

[0071] R4is methyl, ethyl or n-propyl;

[0072] R5is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl which is mono- or poly-substituted by halogen, phenyl sulfonyl which is monosubstituted by methyl or halogen, benzyl which is substituted by halogen, nitro, methyl or methoxy or benzoylmethyl which is mono- or polysubstituted by halogen, nitro, methyl or methoxy and n is 0, 1, or 2; by rearrangement of the compound of Formula (III) in which the rearrangement is conducted in the presence of a) a catalytic amount of cyanide source and a base, b) mixing the reaction mixture of step (a) with an oxidizing reagent and; c) acidifying the reaction mixture of step (b) with an acid to obtain the compound of Formula (IV).

[0073] In another embodiment, the present invention provides a process for the preparation of a compound of Formula (IV) wherein the process comprises the steps of: al) reacting a compound of Formula (I)

[0074] Formula (I) with a compound of Formula (II)

[0075] Formula (II) in presence of a base to obtain a compound of Formula (III); wherein,

[0076] R1is methyl or ethyl;

[0077] R2is tritluoromethyl;

[0078] R3is hydrogen, methyl or ethyl;

[0079] R4is methyl, ethyl or n-propyl;

[0080] R5is hydrogen, (C1-C6yalkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl which is mono- or poly-substituted byhalogen, phenylsulfonyl which is monosubstituted by methyl or halogen, benzyl which is substituted by halogen, nitro, methyl or methoxy or benzoylmethyl which is mono- or polysubstituted by halogen, nitro, methyl or methoxy; and n is 0, 1, or 2; a) treating the compound of Formula (III) obtained in step (al) with a catalytic amount of a cyanide source and a base; b) mixing the reaction mixture of step (a) with an oxidizing reagent; and c) acidifying the reaction mixture of step (b) with an acid to obtain a compound of Formula (IV).

[0081] In a preferred embodiment, the present invention provides a process for the preparation of a compound of Formula (IV) wherein the process comprises the following steps: al) reacting a compound of Formula (I)

[0082] Formula (I) with a compound of Formula (II)

[0083] Formula (II) in presence of a base to obtain the compound of Formula (III);

[0084] wherein,

[0085] R1is methyl or ethyl;

[0086] R2is trifluoromethyl;

[0087] R3is hydrogen, methyl or ethyl;

[0088] R4is methyl, ethyl or n-propyl;

[0089] R5is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkyl sulfonyl which is mono- or poly-substituted by halogen, phenyl sulfonyl which is monosubstituted by methyl or halogen, benzyl which is substituted by halogen, nitro, methyl or methoxy or benzoylmethyl which is mono- or polysubstituted by halogen, nitro, methyl or methoxy and n is 0, 1, or 2. a) treating the compound of Formula (III) obtained in step (al) with a catalytic amount of a cyanide source and a base; b) mixing the reaction mixture of step (a) with an oxidizing reagent; and c) acidifying the reaction mixture of step (b) with an acid to obtain a compound of Formula (IV).

[0090] In an embodiment, the process of the present invention is a multistep batch process for the preparation of compound of Formula (IV) that is carried out by telescopic manner without isolation of intermediates such as compound of Formula (III) produced during the synthesis.

[0091] In another embodiment, the process of the present invention is a batch process for the preparation of compound of Formula (IV) that is carried out by isolation of the intermediate such as compound of Formula (III) produced during the synthesis.

[0092] In another embodiment, the compound of Formula (I) wherein R1is methyl and R2is trifluoromethyl. In a further embodiment, the compound of Formula (I) is 2-(methylsulfonyl)- 4-(trifluoromethyl)benzoyl chloride. In yet another embodiment, the compound of Formula (II) wherein R3is methyl and R4is methyl. In an embodiment, the compound of Formula (II) is 2,5-dimethyl-2,4-dihydro-3JT- pyrazol-3-one.

[0093] In another embodiment, the compound of Formula (III) wherein R1is methyl, R2is trifluoromethyl, R3is methyl and R4is methyl. In a preferred embodiment, the compound of Formula (III) is l,3-dimethyl-1H- pyrazol-5-yl 4-trifluoromethyl-2-(methylsulfonyl)benzoate.

[0094] In an embodiment, the process of the present invention provides the purity of the compound of Formula (III) is at least 90%, at least 95%, at least 98%, or at least 99%.

[0095] In yet another embodiment, the compound of Formula (IV) wherein R1is methyl, R2is trifluoromethyl, R3is methyl, R4is methyl and R5is hydrogen. In a preferred embodiment, the compound of Formula (IV) is 5 -hydroxy- 1,3 -dimethyl- 1H- pyrazol -4-yl 2-(m ethyl sulfonyl)-4- (trifluoromethyl)phenyl ketone.

[0096] In another embodiment, the process of the present invention provides the purity of the compound of Formula (IV) is at least 90%, at least 95%, at least 98%, or at least 99%.

[0097] In an embodiment, the present invention provides a process for the preparation of 5-hydroxy- 1,3 -dimethyl- 1H- pyrazol-4-yl 2-(m ethyl sulfonyl)-4-(trifluoromethyl)phenyl ketone by reacting the 2,5-dimethyl-2,4-dihydro-3H -pyrazol-3-one and 2-(m ethyl sulfonyl)-4- (trifluoromethyl)benzoyl chloride in presence of triethylamine base to form 1,3-dimethyl- 1H- pyrazol-5-yl 4-trifluoromethyl-2-(methylsulfonyl)benzoate. It undergoes in the rearrangement process which is conducted in the presence of a catalytic amount of acetone cyanohydrin, triethylamine and mixing the reaction mixture with a solution of hydrogen peroxide. The reaction mixture is treated with a concentrated acid to obtain the 5-hydroxy- l ,3-dimethyl- l / / - pyrazol-4-yl 2-(methylsulfonyl)-4-(trifluoromethyl)phenyl ketone.

[0098] The compound of Formula (IV) contains substantially less undesired toxic impurity of cyanide ions. In an embodiment, the compound of Formula (IV) contains the cyanide ions at the concentration below 50 ppm. In another embodiment, the compound of Formula (IV) contains the cyanide ions at the concentration below 40 ppm. In a further embodiment, the compound of Formula (IV) contains the cyanide ions at the concentration below 30 ppm. In yet another embodiment, the compound of Formula (IV) contains the cyanide ions at the concentration below 20 ppm. In an embodiment, the compound of Formula (IV) contains the cyanide ions at the concentration below 10 ppm. In a preferred embodiment, the compound of Formula (IV) contains the cyanide ions at the concentration below 5 ppm. In a more preferred embodiment, the compound of Formula (IV) contains the cyanide ions at the concentration below 1 ppm.

[0099] The compound of the Formula (I) and compound of Formula (II) reacts in presence of a base to form the compound of Formula (III). A solution in an organic solvent of a base and the compound of Formula (II) is added to the solution in the organic solvent of the compound of Formula (I) at a temperature of about 15 °C to 35 °C within the time period from about 2 to 3 hours. The reaction mixture is cooled to 0 °C to 5 °C and filtered to collect the cake. The cake is rinsed 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 an ambient temperature for certain time-period and filtered to obtain compound of Formula (III).

[0100] The term “organic solvent” refers to organic molecule capable of at least partially dissolving another substance (i.e., the solute). Organic solvents may be liquids at room temperature. Examples of organic solvents that may be used for the present 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 oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., , toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., chlorobenzene, , 1,2-di chloroethane, di chloromethane, , etc.), ester solvents (e.g., ethyl acetate, isopropyl acetate, etc.), acetonitrile. In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents. In a preferred embodiment, the organic solvent is used in the process of the present invention is chlorobenzene.

[0101] The term “rinsed” or “washing” can be used interchangeably and it refers to the process of purifying a solid mass (e.g., crystals) by passing a liquid over and / or through the solid mass, as to remove undesirable soluble matter. The process includes passing a solvent, such as distilled water or an organic solvent, over and / or through a precipitate obtained from filtering, decanting, or a combination thereof.

[0102] The bases used in the process of the present invention is an organic or an inorganic base. The inorganic base is selected from the group comprising sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium phosphate and mixtures thereof. The organic base is selected from the group comprising a tertiary amine such as tri-C1-C6alkylamine, N-substituted imine, aromatic amine and mixtures thereof. In a further embodiment, the base used in the process of the present invention is tri-C1-C6alkylamine such as triethylamine.

[0103] In a preferred embodiment, the present invention provides a process for the preparation of 5- hydroxy- 1,3 -dimethyl- l / / -pyrazol-4-yl 2-(methylsulfonyl)-4-(trifluoromethyl)phenyl ketone by rearrangement of l,3-dimethyl- 1H- pyrazol-5-yl 4-trifluoromethyl-2- (methylsulfonyl)benzoate in which the rearrangement is conducted in the presence of a catalytic amount of acetone cyanohydrin, triethylamine, and mixing the reaction mixture with a solution of hydrogen peroxide. The reaction mixture is treated with a concentrated acid to obtain the 5-hydroxy-l,3-dimethyl-lJ / -pyrazol-4-yl 2-(m ethyl sulfonyl)-4- (trifluoromethyl)phenyl ketone.

[0104] The rearrangement in the process of the present invention is carried out in the presence of a cyanide source or substances which under the rearrangement conditions consists of or generates cyanide ion. Preferred cyanide sources are cyanohydrins of methyl alkyl ketones having from 1-4 carbon atoms in the alkyl groups, such as acetone or methyl isobutyl ketone cyanohydrins; cyanohydrins of benzaldehyde or of C2-C5aliphatic aldehydes such as acetaldehyde, propionaldehyde, etc., cyanohydrins; and hydrogen cyanide itself. Among cyanohydrins the preferred cyanide source is acetone cyanohydrin.

[0105] In a preferred embodiment, the cyanide source and the compound of Formula (III) is present in a molar ratio of about 1 : 5 to 1 : 50, preferably in a ratio of about 1 : 20.

[0106] The preferred base for the rearrangement reaction is tri-C1-C6alkylamine, such as tri ethylamine. The molar ratio of the base and the compound of Formula (III) is about 1 : 1 to 2: 1, preferably in a ratio of about 1.2: 1. The molar ratio of the base and the compound of Formula (I) is about 2: 1 to 4: 1, preferably in a ratio of about 2.5: 1.

[0107] If acetone cyanohydrin is used as a cyanide source than cyanohydrin dissociates during the reaction under basic conditions and the real catalyst of the process is cyanide ion as shown below: The problem associated with the prior art process as mentioned in the background of the present invention is that during the product separation and purification, a significant concentration of cyanide ions in the reaction mixture makes this process dangerous. A portion of the cyanide ions was also found in the finished product after the product was filtered, washed, and dried. Cyanide ions in this product is an important contaminant, the quantity of which is capped by regulatory authorities at 50 parts per million. There are situations when further purifying steps are required to reach this level.

[0108] The process of the present invention solves this problem by using an oxidizing agent that oxidize the cyanide ions remain in the process after the rearrangement reaction without any effect on the yield and quality of the product bringing to the very low level of toxic impurity of cyanide ions. In an embodiment, the oxidizing reagent used in the oxidation reaction may be a common oxidizing reagent, known to a person skilled in the art.

[0109] In another embodiment, the oxidizing agent is selected from the group comprising hydrogen peroxide, sodium hypochlorite, chlorine and mixtures thereof. In a further embodiment, the oxidizing agent is present in a molar ratio to the cyanide source of about 1.5: 1 to 5: 1, preferably in a ratio of about 3: 1.

[0110] If hydrogen peroxide is used as an oxidizing agent in the process of the present invention than the result was achieved by oxidation of the cyanide ion in the reaction mixture as follows:

[0111] In an embodiment, in the final step of the rearrangement process of the present invention, the acidification of the reaction mixture with an acid to precipitate the compound of Formula (IV) takes place. The acid is used to acidify the reaction mixture to pH in the range from about 1 to 3, preferably 2.

[0112] In yet another embodiment, the acid is selected from the group comprising 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.

[0113] The process according to the present invention is generally carried out under atmospheric pressure. However, it is also possible to carry out the process according to the invention under elevated or reduced pressure. In an embodiment, the process for preparing sulfonyl pyrazolone compound of Formula (IV) may be conducted at a pressure from about 1 bar to about 10 bar. In another embodiment, the process may be conducted at a pressure from about 1 bar to about 5 bar. In yet another embodiment, the process for preparing sulfonyl pyrazolone compound of Formula (IV) may be conducted at atmospheric pressure. In a further embodiment, the process may be conducted at about 10 bars. In certain embodiments, it may be preferred that the process is conducted at pressures less than atmospheric pressure. For example, the process may be carried out at 0.7 bar, 0.75 bar, 0.8 bar, 0.9 bar or 0.95 bar.

[0114] The present process is advantageous in that it is significantly safer for industrial implementation, makes possible to get qualified product with low level of cyanide impurity by strait crystallization of the compound of Formula (IV) from reaction mixture and does not demand additional purification / re-crystallization of the final material. These advantages make the process highly efficient.

[0115] The progress of the reaction of synthesis of the compound of Formula (III) and the compound of Formula (IV) can be monitored using any suitable method, which can include, for example, chromatographic methods such as, e.g., high performance liquid chromatography (HPLC), thin layer chromatography (TLC), and the like. In yet another embodiment, the compound of Formula (III) or compound of Formula (IV) can be isolated from the reaction mixture by any conventional technique well-known in the art. Such isolation techniques can be selected, without limitation, from the group consisting of extraction, crystallization, or precipitation by concentration, cooling or antisolvent addition; filtration; centrifugation, and a combination thereof, followed by drying.

[0116] In yet another embodiment, the compound of Formula (III) and the compound of Formula (IV) can be optionally purified by any conventional technique well-known in the art. Such purification techniques can be selected, without limitation, from the group consisting of precipitation, crystallization, extraction, slurring, washing in a suitable solvent, filtration through a packed-bed column, dissolution in an appropriate solvent, re-precipitation by addition of a second solvent in which the compound is insoluble, and a combination thereof.

[0117] The following examples illustrate the practice of the present invention in some of its embodiments but should not be construed as limiting the scope of the present invention. From consideration of the specification and examples, other embodiments will be apparent to one skilled in the art. It is intended that the specification, including the examples, be considered exemplary only without limiting the scope and spirit of the present invention.

[0118] An exemplary experimental procedure for producing sulfonyl pyrazolone compound of Formula (IV) is described as follows:

[0119] Example 1:

[0120] Synthesis of 1.3-d im ethyl- l / / -pyrazol-5-yl 2-(methylsulfonyl)-4-trifluoromethyl benzoate: ( y )

[0121] 273.7g of chlorobenzene and 57.8g (0.5 mol) of 2,5-dimethyl-2,4-dihydro-3H -pyrazol-3-one were added to the four-necked flask. Azeotropic dehydration was conducted under vacuum until no water droplets were observed in the condensate, maintaining a pressure of -0.090 to - 0.095Mpa at temperatures of 60 °C to 65 °C. 55.9 g (0.55 mol) of triethylamine was added into the mixture, resulting in the formation of a solution of 2,5-dimethyl-2,4-dihydro-37 / -pyrazol-

[0122] 3-one in chlorobenzene and triethylamine, yielding approximately 387.4g.

[0123] The solution of 2,5-dimethyl-2,4-dihydro-3H -pyrazol-3-one in chlorobenzene and triethylamine was added dropwise into the solution of 140.4 g (0.49 mol) of 2- (methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride in 281 g chlorobenzene at a temperature range of 20 °C to 30°C within a 2 hour duration. The mixture was kept at 20 °C to 30°C for 1 hour until the presence of 2-(m ethyl sulfonyl)-4-(trifluoromethyl)benzoyl chloride was less than 1.0 area % on HPLC. The temperature was lowered to 0 °C to 5°C, followed by filtration to collect the resulting cake.

[0124] The collected cake was rinsed with 41.1g of cold chlorobenzene to obtain wet solid (approximately 298.8 g). Approximately 298.8 g of the 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% aqueous hydrochloric acid and stirred for 1.0 hour at temperatures ranging from 25 °C to 30 °C. The product was filtered and wet solid was dried at temperatures of 60 °C to 65 °C, producing l,3-dimethyl-1H- pyrazol-5-yl 4-trifluoromethyl-2-(methylsulfonyl)benzoate as an off-white solid, weighing 172.0 g (Purity 97%, 0.46 mol). Yield 94%.

[0125] Example 2:

[0126] Synthesis of 5-hydroxy-l .3-diniethyl-l / / -pyrazol-4-yl 2-(methylsulfonyl)-4- (trifluoromethyl)phenyl ketone:

[0127] 344.1 g of chlorobenzene and 172.0 g (0.46 mol) of l,3-dimethyl-1H- pyrazol-5-yl 4- trifluoromethyl-2-(methylsulfonyl)benzoate were combined in the four-necked flask. Azeotropic dehydration was carried out under vacuum until no water droplets were observed in the condensate, maintaining a pressure of -0.09 to -0.095Mpa at temperatures ranging from 60 °C to 65°C. 56.2 g (0.55 mol) of triethylamine and 2.0 g (0.02 mol) of acetone cyanohydrin were added into the mixture. The mixture was maintained at 60 °C to 65°C for about 6 hours until 1 ,3 -di methyl - 177-pyrazol -5-yl 4-trifluoromethyl-2-(methylsulfonyl)benzoate reduced to less than 0.5 area % on HPLC.

[0128] 206.5 g of water was added into the mixture at the temperature 60 to 65°C. pH of aqueous phase is about 9. 7.9 g (0.07 mol) of 30% solution of hydrogen peroxide was added into the mixture and the mixture was held for 2 hours at 60 °C to 65 °C. The mixture was acidified to a pH close to 1 with 58.7 g (0.3 mol) of 50% aqueous solution of sulfuric acid to precipitate the desired product.

[0129] 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 within a span of 3 hours. Subsequently, the mixture was filtered to collect the resulting cake. The collected cake was rinsed with 86.0 g of cold water and 86.0 g of cold chlorobenzene to obtain wet solid. The substance was dried at temperatures ranging from 75 °C to 85 °C. The end product was 5-hydroxy-l,3-dimethyl-1H- pyrazol-4-yl 2- (methyl sulfonyl)-4-(trifluoromethyl)phenyl ketone, acquired as an off-white solid, weighing 153.3g (Purity 98%, 0.415 mol). Yield 90%. Content of cyanide ions below 1 ppm.

[0130] Example 3:

[0131] Synthesis of 5-hydroxy-l .3-diinethyl-l / / -pyrazol-4-yl 2-(methylsulfonyl)-4-

[0132] (trifluoromethyl)phenyl ketone:

[0133] 1140 g of chlorobenzene and 286.8 g (1.05 mol) of 4-trifluoromethyl-2- (methylsulfonyl)benzoic acid were added to a four-necked flask. Azeotropic dehydration was carried out under vacuum until no water droplets were observed in the condensate, maintaining a pressure of -0.09 to -0.095Mpa at a temperature ranging from 60 °C to 65 °C.

[0134] 1.6 g (0.02 mol) of dimethylformamide as a catalyst were added to the reaction mixture and 151 g (1.26 mol) of thionyl chloride were fed dropwise during about 3 hours to the reaction mixture at a temperature of 60°C to 65 °C. The reaction mixture was held for about 4 hours until concentration of 4-trifluoromethyl-2-(methylsulfonyl)benzoic acid was reduced below 1.0 area % on HPLC. The prepared solution of 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride was concentrated by distilling off about 286 g of chlorobenzene under vacuum of - 0.09 to -0.095Mpa at temperatures ranging from 60 °C to 80 °C. A solution of 295 g (1.03 mol) of 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride in about 1000 g of chlorobenzene was prepared and kept at the temperature 60 °C to 65 °C to prevent precipitation for the next step of the synthesis.

[0135] 858 g of chlorobenzene and 120.1 g (1.05 mol) of 2,5-dimethyl-2,4-dihydro-3H-pyrazol-3-one was added to a four-necked flask. Azeotropic dehydration was conducted under vacuum until no water droplets were observed in the condensate, maintaining a pressure of -0.090 to - 0.095Mpa at temperatures of 60 °C to 65 °C. 268.3 g (2.62 mol) of triethylamine was added into the reaction mixture.

[0136] A solution of 295g (1.03 mol) of 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride in about 1000 g of chlorobenzene, previously produced and maintained at a temperature of about 60 °C to 65°C was fed to this reaction mixture by maintaining the temperature below 65 °C. After the feeding 4.5 g (0.05 mol) of acetone cyanohydrin were added into the reaction mixture.

[0137] The mixture was stirred at 60 °C to 65°C for 8 hours until concentration of 1,3 -dimethyl- \H- pyrazol-5-yl 4-trifluoromethyl-2-(methylsulfonyl)benzoate will be less than 0.5 area% on HPLC.

[0138] At the end of reaction to the mixture 800 g of water and 19.4 g (0.15 mol) of 30 % solution of hydrogen peroxide were added and the reaction mixture was stirred at 60 °C to 65 °C for 2 hours. The reaction mixture was acidified to the pH close to 1 with 189 g (0.95 mol) of 50 % sulfuric acid to precipitate the desired product at 60 °C to 70 °C.

[0139] 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 within a span of 3 hours. Subsequently, the mixture was filtered to collect the resulting cake. The collected cake was rinsed with 228 g of cold water and 228 g of cold chlorobenzene to obtain wet solid. The substance was dried at temperatures ranging from 75 °C to 85 °C. The end product was 5-hydroxy-l,3-dimethyl-1H- pyrazol-4-yl 2- (methylsulfonyl)-4-(trifluoromethyl)phenyl ketone, acquired as an off-white solid, weighing 316.7g (Purity 98.5%, 0.862 mol). Yield 82.0%. Content of cyanide ions below 1 ppm. Example 4 (Comparative):

[0140] Synthesis of 5-hydroxy-l .3-dimethyl-l / / -pyr:izol-4-yl 2-(methylsulfonyl)-4- (trifluoromethyl)phenyl ketone:

[0141] 1140 g of chlorobenzene and 286.8 g (1.05 mol) of 4-trifluoromethyl-2- (methylsulfonyl)benzoic acid were added to a four-necked flask. Azeotropic dehydration was carried out under vacuum until no water droplets were observed in the condensate, maintaining a pressure of -0.09 to -0.095Mpa at a temperature ranging from 60 °C to 65 °C.

[0142] 1.6 g (0.02 mol) of dimethylformamide as a catalyst were added to the reaction mixture and 151 g (1.26 mol) of thionyl chloride were fed dropwise during about 3 hours to the reaction mixture at a temperature of 60°C to 65 °C. The reaction mixture was held for about 4 hours until concentration of 4-trifluoromethyl-2-(methylsulfonyl)benzoic acid was reduced below 1.0 area % on HPLC. The prepared solution of 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride was concentrated by distilling off about 286 g of chlorobenzene under vacuum of - 0.09 to -0.095Mpa at temperatures ranging from 60 °C to 80 °C. A solution of 295 g (1.03 mol) of 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride in about 1000 g of chlorobenzene was prepared and kept at the temperature 60 °C to 65 °C to prevent precipitation for the next step of the synthesis.

[0143] 858 g of chlorobenzene and 120.1 g (1.05 mol) of 2,5-dimethyl-2,4-dihydro-3H-pyrazol-3-one were added to a four-necked flask. Azeotropic dehydration was conducted under vacuum until no water droplets were observed in the condensate, maintaining a pressure of -0.090 to - 0.095Mpa at temperatures of 60 °C to 65 °C. 268.3 g (2.62 mol) of triethylamine was added into the reaction mixture.

[0144] A solution of 295g (1.03 mol) of 2-(methylsulfonyl)-4-(trifluoromethyl)benzoyl chloride in about 1000 g of chlorobenzene, previously produced and maintained at a temperature of about 60 °C to 65°C was fed to this reaction mixture by maintaining the temperature below 65 °C. After the feeding 4.5 g (0.05 mol) of acetone cyanohydrin were added into the reaction mixture.

[0145] The mixture was stirred at 60 °C to 65°C for 8 hours until concentration of 1,3 -dimethyl- \H- pyrazol-5-yl 4-trifluoromethyl-2-(methylsulfonyl)benzoate will be less than 0.5 area% on HPLC.

[0146] At the end of reaction to the mixture 800 g of water were added and the reaction mixture was stirred at 60 °C to 65 °C for a few minutes. The reaction mixture was acidified to the pH close to 1 with 189 g (0.95 mol) of 50 % solution of sulfuric acid to precipitate the desired product at 60 °C to 70 °C.

[0147] 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 within a span of 3 hours. Subsequently, the mixture was filtered to collect the resulting cake. The collected cake was rinsed with 228 g of cold water and 228 g of cold chlorobenzene to obtain wet solid. The substance was dried at temperatures ranging from 75 °C to 85 °C. The end product was 5-hydroxy-l,3-dimethyl-1H- pyrazol-4-yl 2- (methylsulfonyl)-4-(trifluoromethyl)phenyl ketone, acquired as an off-white solid, was prepared in amount 317.8 g (Purity 98.3%, 0.863 mol). Yield 82.2%. Content of cyanide ions 218 ppm.

Claims

We Claim:

1. A process for the preparation of compound of Formula (IV)wherein,R1is methyl or ethyl;R2is trifluoromethyl;R3is hydrogen, methyl or ethyl;R4is methyl, ethyl or n-propyl;R5is hydrogen, (C1-C6)-alkylcarbonylmethyl, (C1-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkyl sulfonyl which is mono- or poly-substituted by halogen, phenyl sulfonyl which is monosubstituted by methyl or halogen, benzyl which is substituted by halogen, nitro, methyl or methoxy or benzoylmethyl which is mono- or polysubstituted by halogen, nitro, methyl or methoxy and n is 0, 1, or 2; from a compound of Formula (III)wherein the process comprises the steps of: a) treating the compound of Formula (III) with a catalytic amount of cyanide source and a base, b) mixing the reaction mixture of step (a) with an oxidizing reagent; and c) acidifying the reaction mixture of step (b) with an acid to obtain a compound of Formula (IV).

2. The process as claimed in claim 1, wherein the base is an organic or an inorganic base.

3. The process as claimed in claim 2, wherein the inorganic base is selected from the group comprising sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium phosphate and mixtures thereof.

4. The process as claimed in claim 2, wherein the organic base is selected from the group comprising a tertiary amine, N-substituted imine, aromatic amine and mixtures thereof.

5. The process as claimed in claim 4, wherein the organic base is tri ethylamine.

6. The process as claimed in claim 2, wherein the base and the compound of Formula (III) is present in a molar ratio of about 1 : 1 to 2: 1.

7. The process as claimed in claim 1, wherein the cyanide source is a cyanohydrin of a methyl alkyl ketone having from 1-4 carbon atoms in the alkyl group, benzaldehyde cyanohydrin; a cyanohydrin of a C2-C5aliphatic aldehyde, hydrogen cyanide and mixtures thereof.

8. The process as claimed in claim 7, wherein the cyanide source is acetone cyanohydrin.

9. The process as claimed in claim 1, wherein the cyanide source and the compound of Formula (III) is present in a molar ratio of about 1 :5 to 1 : 50.

10. The process as claimed in claim 1, wherein the oxidizing reagent is hydrogen peroxide, sodium hypochlorite, chlorine and mixtures thereof.

11. The process as claimed in claim 1, wherein the oxidizing reagent and the cyanide source is present in a molar ratio of about 1.5: 1 to 5 : 1.

12. The process as claimed in claim 1, wherein the acid is hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, chloric acid, hydrobromic acid and mixtures thereof.

13. The process as claimed in claim 1, wherein the compound of Formula (IV) contains the cyanide ions at the concentration below 5 ppm.

4. A process for the preparation of a compound of Formula (IV)wherein the process comprises the steps of: al) reacting a compound of Formula (I)with a compound of Formula (II)in presence of a base to obtain a compound of Formula (III);wherein,R1is methyl or ethyl;R2is tritluoromethyl;R3is hydrogen, methyl or ethyl;R4is methyl, ethyl or n-propyl;R3is hydrogen, (Cj-C6)-alkylcarbonylmethyl, (Cj-C4)-alkylsulfonyl, phenylsulfonyl, benzyl, benzoylmethyl, (C1-C3)-alkylsulfonyl which is mono- or poly-substituted by halogen, phenylsulfonyl which is monosubstiiuted by methyl or halogen, benzyl which is substituted by halogen, nitro, methyl or methoxy or benzoylmethyl which is mono- or poly ubstituted by halogen, nitro, methyl or methoxy: and n is 0, 1, or 2; a) treating the compound of Formula (III) obtained in step (al) with a catalytic amount of a cyanide source and a base; b) mixing the reaction mixture of step (a) with an oxidizing reagent; and c) acidifying the reaction mixture of step (b) with an acid to obtain a compound of Formula (IV).

15. The process as claimed in claim 14, wherein the base is an organic or an inorganic base.

16. The process as claimed in claim 15, wherein the inorganic base is selected from the group comprising, sodium carbonate, sodium bicarbonate, sodium phosphate, potassium carbonate, potassium bicarbonate, potassium phosphate and mixtures thereof.

17. The process as claimed in claim 15, wherein the organic base is selected from the group comprising a tertiary amine, N-substituted imine, aromatic amine and mixtures thereof.

18. The process as claimed in claim 17, wherein the organic base is triethylamine.

19. The process as claimed in claim 14, wherein the base and the compound of Formula (I) is present in a molar ratio of about 2: 1 to 4: 1.

20. The process as claimed in claim 14, wherein the cyanide source is, a cyanohydrin of a methyl alkyl ketone having from 1-4 carbon atoms in the alkyl group, benzaldehyde cyanohydrin; a cyanohydrin of a C2-C5aliphatic aldehyde, hydrogen cyanide and mixtures thereof.

21. The process as claimed in claim 20, wherein the cyanide source is acetone cyanohydrin.

22. The process as claimed in claim 14, wherein the cyanide source and the compound of Formula (I) is present in a molar ratio of about 1 : 5 to 1 : 50.

23. The process as claimed in claim 14, wherein the oxidizing reagent is hydrogen peroxide, sodium hypochlorite, chlorine and mixtures thereof.

24. The process as claimed in claim 14, wherein the oxidizing reagent and the cyanide source is present in a molar ratio of about 1.5 : 1 to 5 : 1.

25. The process as claimed in claim 14, wherein the acid is hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, chloric acid, hydrobromic acid and mixtures thereof.

26. The process as claimed in claim 14, wherein the compound of Formula (IV) contains the cyanide ions at the concentration below 5 ppm.