Process for preparation of substituted benzamides

Abstract

The present invention relates to novel intermediates for the preparation of pyridylmethylbenzamides via substituted hydroxyiminopyridines or acetaminopyridines and to innovative processes for the preparation thereof. In particular, the present invention discloses the total synthesis of fluopicolide fungicides. Disclosed is the preparation of the main substance of fluopicolide synthesis via two different synthesis routes including two novel substances, in particular substituted pyridin-2-yl methylamine or a salt thereof.

Description

Technical field:

[0001] The present invention relates to novel key intermediates for preparing pyridylmethylbenzamides and corresponding preparation methods thereof. In general, the present invention relates to novel methods for preparing pyridylmethylbenzamides, in particular fluopyram. Background technology: Background of the Invention

[0003] Substituted pyridylmethylbenzamide derivatives having formula (VIII)

[0004]

[0005] in

[0006] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0007] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0008] p is 0-4

[0009] q is 0-5

[0010] It is well known for its anti-plant pathogenic fungal activity and is widely used in the agricultural industry as a pesticide. Bayer Ltd. first described fluopyram (2,6-dichloro-N-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]methyl}benzamide) and its compound family with formula (VIII) in EP 1056723. In this patent, the synthesis of compounds and substituted 2-(aminomethyl)pyridine derivatives (key intermediates in the synthesis) is disclosed. WO1999 / 042447 and WO 2004 / 065359 show a method for preparing 2-aminomethylpyridine via benzophenone imine derivatives. However, the method has low economic efficiency, low yield and high cost.

[0011] WO 2002 / 016322 and WO 2004 / 046114 show the preparation of substituted 2-(aminomethyl)pyridine derivatives by hydrogenation of the corresponding substituted 2-cyanopyridine derivatives in the presence of a metal catalyst. However, this method results in a low yield in the hydrogenation step, the formation of dehalogenated by-products and the formation of secondary and tertiary amines which may contaminate the desired primary amine. In addition, the method is expensive, inefficient and occasionally results in metal contamination in the final product.

[0012] Improvements in the preparation of these compounds are necessary to allow for economical commercial operation. In view of this, the present invention provides a convenient, cost-effective route for the preparation of substituted 2-(aminomethyl)pyridine derivatives and their corresponding pyridylmethylbenzamides. Summary of the invention:

[0013] The present invention relates to a compound having formula (I),

[0014]

[0015] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0016] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0017] p is 0-4

[0018] And more specifically relates to a compound having formula (Ia)

[0019]

[0020] The present invention also relates to a method for preparing a compound having formula (I)

[0021]

[0022] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0023] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0024] p is 0-4

[0025] The method comprises subjecting a compound having formula (II) or a salt thereof to

[0026]

[0027] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0028] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0029] p is 0-4

[0030] The reaction is carried out with a nitrite selected from the group consisting of sodium nitrite, potassium nitrite, ammonium nitrite and mixtures thereof in the presence of an acid, optionally in the presence of a solvent, optionally in the presence of a phase transfer catalyst.

[0031] Another aspect of the present invention relates to a method for preparing a compound having formula (II) or a salt thereof

[0032]

[0033] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0034] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0035] p is 0-4

[0036] The method comprises subjecting a compound having formula (III) or a salt thereof to

[0037]

[0038] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0039] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0040] p is 0-4

[0041] In the presence of an acid and / or with an alkali metal halide, the acid is selected from the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, the alkali metal halide is selected from the group comprising sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide.

[0042] Furthermore, the present invention relates to a process for preparing a compound having formula (III) or a salt thereof

[0043]

[0044] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0045] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0046] p is 0-4

[0047] The method comprises subjecting a compound having formula (IV) to

[0048]

[0049] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0050] p is 0-4

[0051] With a compound having formula A

[0052]

[0053] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0054] The reaction is carried out in the presence of a base and a phase transfer catalyst.

[0055] The present invention also relates to a method for preparing a compound having formula (II) or a salt thereof

[0056]

[0057] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0058] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0059] p is 0-4

[0060] The method comprises treating a compound having formula (III) or a salt thereof

[0061]

[0062] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0063] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0064] p is 0-4

[0065] Heating at 60°C-180°C at a pressure of 1-32 bar.

[0066] The present invention further provides a method for preparing a compound having formula (V) or a salt thereof

[0067]

[0068] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0069] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0070] p is 0-4

[0071] The method comprises subjecting a compound having formula (I) to

[0072]

[0073] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0074] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0075] p is 0-4

[0076] With hydrogen in the presence of a metal catalyst, optionally in the presence of an acid.

[0077] Another aspect of the present invention relates to a method for preparing a compound having formula (VI) or a salt thereof

[0078]

[0079] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0080] p is 0-4

[0081] The method comprises a) preparing a compound having formula (V) according to the above method, and b) further reacting the obtained compound having formula (V) with an acid, optionally in the presence of an organic solvent.

[0082] The present invention further provides a method for preparing a compound having formula (VIII)

[0083]

[0084] in

[0085] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0086] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0087] p is 0-4

[0088] q is 0-5

[0089] The method comprises reacting a compound having formula (VI) prepared according to the above method with a compound having formula (VII)

[0090]

[0091] where q is an integer equal to 1, 2, 3 or 4,

[0092] Y is halogen and

[0093] L is a leaving group selected from C1-C6 alkoxy, OH, halogen, hydrogen, OS(O)2R--wherein R is -CH3, -C6H5-CH3;

[0094] q is 0-5

[0095] The reaction is carried out in the presence of an organic solvent, optionally in the presence of a base.

[0096] The present invention further relates to a process for preparing compounds having formula (VIII)

[0097]

[0098] in

[0099] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0100] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0101] p is 0-4

[0102] q is 0-5

[0103] The method uses a compound having formula (I)

[0104]

[0105] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0106] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0107] p is 0-4

[0108] Another aspect of the present invention relates to a compound having formula (XI),

[0109]

[0110] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0111] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0112] p is 0-4

[0113] And more specifically relates to a compound having formula (XIa),

[0114]

[0115] The present invention further provides a process for preparing a compound of formula (XI),

[0116]

[0117] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0118] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0119] p is 0-4

[0120] The method comprises subjecting a compound having formula (IX) to

[0121]

[0122] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0123] p is 0-4

[0124] and a compound having formula (X)

[0125]

[0126] Where Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0127] The reaction is carried out in the presence of an organic solvent, optionally in the presence of a base and optionally in the presence of a phase transfer catalyst.

[0128] In addition, the present invention provides a method for preparing a compound having formula (VI) or a salt thereof

[0129]

[0130] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0131] p is 0-4

[0132] The process comprises preparing a compound of formula (XI) according to the process described above, optionally in the presence of an organic solvent, with an acid.

[0133] Another aspect of the present invention relates to a method for preparing a compound having formula (VIII)

[0134]

[0135] in

[0136] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0137] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0138] p is 0-4

[0139] q is 0-5

[0140] The method comprises reacting a compound having formula (VI) prepared according to the above method with a compound having formula (VII)

[0141]

[0142] where q is an integer equal to 1, 2, 3 or 4,

[0143] Y is halogen and

[0144] L is a leaving group selected from C1-C6 alkoxy, OH, halogen, hydrogen, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0145] q is 0-5

[0146] The reaction is carried out in the presence of an organic solvent, optionally in the presence of a base.

[0147] In particular, the present invention relates to a method for preparing a compound having formula (VIII)

[0148]

[0149] in

[0150] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0151] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0152] p is 0-4

[0153] q is 0-5

[0154] The method uses a compound having formula (XI)

[0155]

[0156] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0157] Where Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0158] p is 0-4 Specific implementation method:

[0159] definition:

[0160] Before explaining the present subject matter in detail, it may be helpful to provide definitions of certain terms used herein. 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 the present subject matter belongs.

[0161] Throughout this application, descriptions of various embodiments use the term "comprising"; however, those skilled in the art will appreciate that in some specific cases, the language of "consisting essentially of" or "consisting of" may be used alternatively to describe the embodiments.

[0162] Unless otherwise specifically stated, the terms "a / an" as used herein include the singular and the plural. Therefore, the terms "a / an" or "at least one" can be used interchangeably in this application.

[0163] As used herein, the term "halogen" or "halo" refers to one or more halogen atoms, which are defined as F, Cl, Br and I. Unless indicated to the contrary, the numerical parameters set forth in the following specification and the appended claims are approximate values, which may vary depending on the desired properties sought to be obtained. For a better understanding of the present teachings, and in no way limiting the scope thereof, all numbers expressing quantities, percentages or ratios and other numerical values ​​used in the specification and claims should be understood as being modified in all cases by the term "about", unless otherwise indicated.

[0164] At least, each numerical parameter should at least be interpreted according to the number of reported significant figures and by applying ordinary rounding techniques. In the embodiments, the term "about" used herein specifically includes ±10% of the indicated value within the range. In addition, the endpoints of all ranges involving the same component or characteristic herein include the endpoints, are independently combinable, and include all intermediate points and ranges.

[0165] As used herein, the term "carbonyl" refers to the group -C=O.

[0166] The term "alkoxy," as used herein, refers to an optionally substituted alkyl group attached to the parent molecular moiety through an oxygen atom.

[0167] The term "aryloxy" refers to an optionally substituted aryl group attached to the parent molecular moiety through an oxygen atom.

[0168] The term "alkoxycarbonyl," as used herein, refers to an optionally substituted alkoxy group attached to the parent molecular moiety through a carbonyl group.

[0169] As used herein, the term "benzyloxy" refers to a benzyl C6H5CH2- group attached to the parent molecular moiety through an oxygen atom.

[0170] As used herein, the term "alkyl" refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six carbon atoms.

[0171] As used herein, the term "telescopic process" refers to performing several reactions without isolating the intermediate products. In particular, the telescopic process implies performing multiple transformations (including reaction quenching and other post-processing operations) without directly isolating the intermediates. Telescopic solutions of intermediates can be extracted, filtered (as long as the desired product remains in the filtrate), and solvent exchanged, but the intermediates ultimately remain in solution and continue to be subjected to subsequent transformations.

[0172] As used herein, the term "salt" refers to an organic salt such as chloride, bromide, fluoride, iodide, acetate, bisulfate, phosphate, formates, nitrates, carbonates, and the like, or an alkali metal salt (if applicable) such as sodium, potassium, calcium, lithium, cesium, magnesium, barium, and the like.

[0173] As used herein, the term "E / Z isomers" refers to compounds that have the same chemical formula but differ in geometry from one another.

[0174] The present invention relates to a novel compound having the general formula (I):

[0175]

[0176] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0177] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0178] p is 0-4

[0179] The compounds of formula (I) according to the present invention may exist in both E / Z forms and any mixtures thereof.

[0180] In one embodiment, the present invention represents a novel compound having formula (Ia):

[0181]

[0182] The compounds of formula (Ia) according to the present invention may exist in both E / Z forms and any mixture thereof.

[0183] In another embodiment, the present invention provides a method for preparing a compound having formula (I)

[0184]

[0185] The method makes a compound having formula (II) or a salt thereof

[0186]

[0187] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0188] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0189] p is 0-4

[0190] reacting with a nitrite, optionally in the presence of a solvent, optionally in the presence of an acid, optionally in the presence of a phase transfer catalyst.

[0191] According to an embodiment, the nitrite may be selected from the group consisting of sodium nitrite, potassium nitrite, calcium nitrite, lithium nitrite, ammonium nitrite and mixtures thereof, preferably sodium nitrite.

[0192] According to an embodiment, the molar ratio between compound (II) and nitrite may be about 1:10 to 10:1, preferably about 1:1 to 1:5, and most preferably 1:1 to 1:1.5.

[0193] According to an embodiment, the organic solvent is selected from the group consisting of: aliphatic hydrocarbons (acyclic and cyclic) such as octane, heptane, hexane, pentane, cyclooctane, cyclopentane, petroleum ether, cyclohexane, cyclopentane, chlorinated hydrocarbons such as carbon tetrachloride, chloroform, 1,2-dichloroethane, dichloromethane, optionally substituted aromatic hydrocarbons such as toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, ethers (acyclic and cyclic) such as diethyl ether, diethylene glycol dimethyl ether (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), cyclopentyl methyl ether, methyl-tert-butyl ether, aliphatic and aromatic esters such as ethyl acetate, nitriles such as acetonitrile, benzonitrile, ketones such as acetone, 2-butanone, alcohols such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol, polar aprotic solvents like dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, water, and mixtures thereof.

[0194] According to an embodiment, the molar ratio between compound (II) and the organic solvent may be about 1:20 to 10:1, preferably 1:0.5 to 1:5, most preferably about 1:3 to 1:5.

[0195] According to an embodiment, the acid is selected from the group consisting of organic acids C1-C6 carboxylic acids, acetic acid, propionic acid, formic acid, benzoic acid, citric acid, glutamic acid, malonic acid, tartaric acid, phthalic acid, barbituric acid, cinnamic acid, glutaric acid, caproic acid, malic acid, folic acid, trifluoroacetic acid, ascorbic acid, glutamic acid, benzyl acid, lactic acid, p-toluenesulfonic acid, inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, nitric acid, and mixtures thereof.

[0196] According to an embodiment, the molar ratio between compound (II) and the acid may be about 1:20 to 10:1, preferably about 1:1 to 1:5, most preferably about 1:3 to 1:5.

[0197] According to an embodiment, the phase transfer catalyst is selected from the group consisting of ammonium salts or polyethers, and the ammonium salts or polyethers are selected from the group consisting of pyridinium hydrochloride, pyridinium acetate, pyridinium triflate, pyridinium hydrobromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetraethylammonium bromide, tetraethylammonium chloride, tetraethylammonium hydrogen sulfate, tetraethylammonium iodide, tetramethylammonium bromide, tetramethylammonium chloride, tetramethylammonium hydrogen sulfate, tetramethylammonium iodide, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium hydrogen sulfate, tetrapropylammonium iodide, tetraoctylammonium bromide, tetraoctylammonium chloride, tetraoctylammonium hydrogen sulfate, tetraoctylammonium iodide, crown ethers, polyethylene glycols and mixtures thereof, preferably tetrabutylammonium bromide.

[0198] According to an embodiment, the molar ratio between compound (II) and the phase transfer catalyst may be about 1:1 to 1:0.0001, preferably about 1:0.01 to 1:0.1, and most preferably about 1:0.05 to 1:0.01.

[0199] According to an embodiment, the compound of formula (II) is contacted with the nitrite at a temperature interval of 10° C. to 130° C. A preferred temperature interval is 15° C. to 50° C., more preferably 15° C. to 25° C.

[0200] According to an embodiment, the nitrite can be added to the mixture of compound (II) as a solid or as an aqueous solution. In the case where the nitrite is added to the mixture of compound (II) as an aqueous solution, the weight ratio between the aqueous solution and the mixture of compound (II) can be 10:1 and 1:10 w / w, preferably 0.5:1 to 2:1, most preferably 1:1 w / w.

[0201] According to an embodiment, the reaction mixture is stirred for 1 minute to 10 hours, preferably 1 to 2 hours, depending on the progress of the reaction. According to an embodiment, the reaction temperature range is 0°C to 130°C, preferably 0°C to 50°C, most preferably 10°C to 20°C.

[0202] According to an embodiment, the reaction mixture is monitored by HPLC analytical method and the process is terminated when the concentration of the compound of formula (II) is between 0-99%, preferably 0-50%, most preferably, in particular when no more than 1% of the compound of formula (II) remains in the reaction medium.

[0203] Finally, the reaction mixture containing the obtained compound of formula (I) is post-treated. This stage may include adding water, adding organic solvents, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction and drying processes.

[0204] In another embodiment, the present invention provides a method for preparing a compound having formula (II) or a salt thereof by a two-step reaction,

[0205]

[0206] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0207] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0208] p is 0-4

[0209] The two-step reaction can be carried out as a separate process or a combined process (e.g., one-pot reaction, telescoping reaction), preferably in a one-pot reaction process. The intermediate formed in the above process can be separated from the reaction mixture, or the process can be continued without separating the intermediate.

[0210] According to an embodiment, the first step provides a method for preparing a compound having formula (III) or a salt thereof,

[0211]

[0212] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0213] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0214] p is 0-4

[0215] The method allows a compound having formula (IV) to be

[0216]

[0217] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0218] p is 0-4

[0219] With a compound having formula A

[0220]

[0221] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0222] The reaction is carried out in the presence of a base, an organic solvent and a phase transfer catalyst.

[0223] According to an embodiment, compound (A) is selected from the group consisting of methyl malonate, ethyl malonate, propyl malonate, hexyl malonate, cyclohexyl malonate, benzyl malonate, chloromethyl malonate, chloroethyl malonate, chloropropyl malonate, chlorohexyl malonate, chlorocyclohexyl malonate, chlorobenzyl malonate, bromomethyl malonate, bromoethyl malonate, bromopropyl malonate, bromohexyl malonate, bromocyclohexyl malonate, bromobenzyl malonate, malonic acid and mixtures thereof, preferably methyl malonate or ethyl malonate.

[0224] According to an embodiment, the molar ratio between compound (IV) and malonic acid or alkyl malonate can be about 1:10 to 10:1, preferably 2:1 to 1:2, and most preferably about 1:1 to 1:1.5. According to an embodiment, the base is selected from the group consisting of aluminum hydroxide, calcium hydroxide, calcium hydroxide, iron (II) hydroxide, lithium hydroxide, potassium hydroxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, trimethylamine, tributylamine, diisopropylamine, tetramethylethylenediamine, pyridine, dimethylbenzylamine, quinoline, aniline, imidazole, pyrrole, pyrrolidine, pyrimidine, piperidine, piperazine, morpholine, N-methylmorpholine, N-ethylpyrrolidine, diisopropylmethylamine, diisopropylethylamine, triallylamine, diallylamine, indole, butyllithium, sodium hydride, potassium hydride and mixtures thereof, preferably potassium bicarbonate.

[0225] According to an embodiment, the molar ratio between compound (IV) and the base may be about 1:10 to 10:1, preferably 2:1 to 1:5, most preferably about 1:1 to 1:3.

[0226] According to an embodiment, the organic solvent is selected from the group consisting of: aliphatic hydrocarbons (acyclic and cyclic) such as octane, heptane, hexane, pentane, cyclooctane, cyclopentane, petroleum ether, cyclohexane, cyclopentane, chlorinated hydrocarbons such as carbon tetrachloride, chloroform, 1,2-dichloroethane, dichloromethane, substituted or unsubstituted aromatic hydrocarbons such as toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene, all ethers (acyclic and cyclic) such as diethyl ether, diglyme (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), Tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), cyclopentyl methyl ether, methyl-tert-butyl ether, all aliphatic and aromatic esters such as ethyl acetate, nitriles such as acetonitrile, benzonitrile, ketones such as acetone, 2-butanone, alcohols such as methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol, polar aprotic solvents like dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, water, and mixtures thereof, preferably a mixture of dimethyl sulfoxide and toluene.

[0227] According to an embodiment, the w / w ratio between compound (IV) and the organic solvent may be about 1:20 to 20:1, preferably about 1:1 to 1:10, most preferably about 1:3 to 1:5.

[0228] According to an embodiment, the phase transfer catalyst is selected from the group consisting of ammonium salts or polyethers, and the ammonium salts or polyethers are selected from the group consisting of pyridinium hydrochloride, pyridinium acetate, pyridinium triflate, pyridinium hydrobromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetraethylammonium bromide, tetraethylammonium chloride, tetraethylammonium hydrogen sulfate, tetraethylammonium iodide, tetramethylammonium bromide, tetramethylammonium chloride, tetramethylammonium hydrogen sulfate, tetramethylammonium iodide, tetrapropylammonium bromide, tetrapropylammonium chloride, tetrapropylammonium hydrogen sulfate, tetrapropylammonium iodide, tetraoctylammonium bromide, tetraoctylammonium chloride, tetraoctylammonium hydrogen sulfate, tetraoctylammonium iodide, crown ethers, polyethylene glycols and mixtures thereof, preferably tetrabutylammonium bromide.

[0229] According to an embodiment, the molar ratio between compound (IV) and the phase transfer catalyst can be about 1:1 to 1:0.0001, preferably about 1:0.1 to 1:0.001, and most preferably about 1:0.05 to 1:0.01.

[0230] According to an embodiment, compound (III) is produced by mixing a compound having formula (IV), malonic acid or a malonic ester derivative and a base in an organic solvent, and heating the mixture to a temperature range of 20°C to 130°C, preferably 50°C to 110°C, and most preferably 80°C to 100°C.

[0231] According to an embodiment, the reaction mixture is stirred for 1 to 10 hours, preferably 1 to 10 hours, most preferably 5 to 7 hours, depending on the progress of the reaction.

[0232] According to the embodiments, the reaction mixture is monitored by HPLC analysis and is terminated when the concentration of the compound of formula (IV) is between 0-99%, preferably 0-50%, most preferably, in particular when no more than 1% of the compound of formula (IV) remains in the reaction medium.

[0233] Finally, the reaction mixture containing the obtained compound of formula (III) is post-treated. This stage may include cooling, adding water, adding an organic solvent, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, washing, purification, pH adjustment, extraction and drying processes.

[0234] According to an embodiment, the second step, as accomplished in a one-pot process, comprises a method for preparing a compound having formula (II) or a salt thereof,

[0235]

[0236] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0237] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0238] p is 0-4

[0239] According to an embodiment, the compound having formula (II) is prepared by providing the following reaction method: a compound having formula (III) or a salt thereof

[0240]

[0241] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl,

[0242] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0243] p is 0-4

[0244] In the presence of an acid and / or with an alkali metal halide

[0245] According to an embodiment, the acid in the above method is selected from the group consisting of sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, nitric acid and mixtures thereof, preferably hydrochloric acid.

[0246] According to an embodiment, the w / w ratio between compound (III) and the acid may be about 1:0.5 to 1:10, preferably 1:0.5 to 1:5, most preferably about 1:1 to 1:2.

[0247] According to an embodiment, the alkali metal halide is selected from the group consisting of sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide, most preferably sodium chloride or potassium chloride.

[0248] According to an embodiment, the w / w ratio between compound (III) and the alkali metal halide may be about 1:0.1 to 1:10, preferably 1:0.5 to 1:5, most preferably about 1:1.5 to 1:2.5.

[0249] According to an embodiment, compound (II) is produced by mixing a compound having formula (III) with an acid and heating the mixture to a temperature interval of 20°C to 130°C, preferably 100°C to 130°C, most preferably 120°C to 130°C.

[0250] According to the embodiments, the reaction mixture is stirred for 1 to 10 hours, preferably 5 to 10 hours, most preferably 8 to 9 hours, depending on the progress of the reaction.

[0251] According to the embodiments, the reaction mixture is monitored by HPLC analysis and is terminated when the concentration of the compound of formula (III) is between 0-99%, preferably 0-50%, in particular when no more than 2.5% of the compound of formula (III) remains in the reaction medium.

[0252] Finally, the reaction mixture containing the obtained compound of formula (II) is post-treated. This stage may include cooling, adding water, adding an organic solvent, stirring, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, decantation, washing, purification, pH adjustment, extraction and drying processes.

[0253] According to an alternative embodiment of the method for preparing a compound having formula (II) or a salt thereof,

[0254]

[0255] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0256] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0257] p is 0-4

[0258] The method comprises treating a compound having formula (III) or a salt thereof

[0259]

[0260] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0261] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0262] p is 0-4

[0263] Heating at an elevated temperature between 60°C and 200°C, preferably 120°C to 180°C, most preferably 140°C to 160°C, and at a pressure between 1 and 32 bar, preferably 15-25 bar, most preferably 19-23 bar.

[0264] According to the embodiments, the reaction mixture is monitored by HPLC analysis and is terminated when the concentration of the compound of formula (III) is between 0-99%, preferably 0-50%, in particular when no more than 1% of the compound of formula (III) remains in the reaction medium.

[0265] In another embodiment of the present invention, a method for preparing a compound having formula (VI) or a salt thereof via a two-step reaction is described.

[0266]

[0267] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0268] p is 0-4

[0269] The two-step reaction can be carried out as separate processes or as a combined process (eg, one-pot reaction, telescopic reaction), preferably as a one-pot reaction.

[0270] According to an embodiment, the first step provides a method for preparing a compound having formula (V) or a salt thereof,

[0271]

[0272] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0273] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0274] p is 0-4

[0275] The method comprises subjecting a compound having formula (I) to

[0276]

[0277] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0278] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0279] p is 0-4

[0280] With hydrogen in the presence of a metal catalyst, optionally in the presence of an acid.

[0281] According to an embodiment, the metal catalyst is selected from the group comprising zinc, iridium, nickel, palladium, platinum, rhodium or ruthenium, cobalt, tin, iron, Raney nickel or a metal salt selected from the group consisting of ferric chloride, ferric nitrate, nickel chloride, nickel bromide, Grubbs catalyst and mixtures thereof.

[0282] According to an embodiment, the w / w ratio between compound (I) and the catalyst may be about 1:1 to 1:0.0001, preferably 1:0.005 to 1:0.5, most preferably about 1:0.05 to 1:0.15.

[0283] According to an embodiment, optionally in the presence of a C1-C4 carboxylic acid selected from the group consisting of acetic acid, propionic acid, butyric acid, lactic acid, formic acid, citric acid, oxalic acid, malic acid, tartaric acid and mixtures thereof, preferably acetic acid.

[0284] According to an embodiment, the w / w ratio between compound (I) and the C1-C4 carboxylic acid may be about 1:10 to 1:0.5, preferably 1:10 to 1:1, most preferably about 1:8 to 1:2.

[0285] According to an embodiment, optionally in the presence of hydrogen at a pressure between 4-20 bar, preferably 8 to 16 bar, most preferably about 10-15 bar.

[0286] According to an embodiment, compound (V) is produced by mixing a compound having formula (I) with optionally an acid and optionally hydrogen at a temperature interval of 20°C to 130°C, preferably 50°C to 100°C, most preferably 70°C to 80°C.

[0287] According to the embodiments, the reaction mixture is stirred for 1 to 10 hours, preferably 5 to 10 hours, most preferably 5 to 8 hours, depending on the progress of the reaction.

[0288] According to the embodiments, the reaction mixture is monitored by HPLC analysis and is terminated when the concentration of the compound of formula (I) is between 0-99%, preferably 0-50%, in particular when no more than 1% of the compound of formula (I) remains in the reaction medium.

[0289] Finally, the reaction mixture containing the obtained compound of formula (V) is post-treated. This stage may include cooling, adding water, adding an organic solvent, stirring, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, washing, purification, pH adjustment, extraction and drying processes.

[0290] According to an embodiment, the second step comprises a method for preparing a compound having formula (VI) or a salt thereof

[0291]

[0292] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0293] p is 0-4

[0294] The method comprises subjecting a compound having formula (V) to

[0295]

[0296] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0297] Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0298] p is 0-4

[0299] The reaction is carried out in the presence of an acid, optionally in the presence of an organic solvent.

[0300] According to an embodiment, the acid is selected from the group consisting of sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, nitric acid and mixtures thereof, preferably hydrochloric acid.

[0301] According to an embodiment, the molar ratio between compound (V) and the acid may be about 1:10 to 1:0.5, preferably about 1:2 to 1:4.

[0302] According to an embodiment, the organic solvent is selected from water, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, dimethylformamide, 1,4-dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, diethyl ether, chloroform, 1,2-dichloroethane, acetone, isopropyl acetate, anisole, N-methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane and a mixture thereof, preferably toluene.

[0303] According to an embodiment, the w / w ratio between compound (V) and the organic solvent may be about 1:10 to 10:1, preferably 1:1 to 1:5, most preferably about 1:2 to 1:4.

[0304] According to an embodiment, compound (VI) is produced by mixing a compound having formula (V), an acid and an organic solvent, and heating the resulting mixture to a temperature of 20°C to 130°C, preferably 50°C to 100°C, most preferably 60°C to 70°C.

[0305] According to an embodiment, the reaction mixture is stirred for 10 minutes to 5 hours, preferably 0.5 to 3 hours, most preferably 1 to 2 hours, depending on the progress of the reaction.

[0306] According to the examples, the reaction mixture is monitored by HPLC analysis and the reaction is terminated when the concentration of the compound of formula (V) is 0-99%, preferably 0-50%, in particular when no more than 2.5% of the compound of formula (V) remains in the reaction medium.

[0307] Finally, the reaction mixture containing the obtained compound of formula (VI) is post-treated. This stage may include cooling, adding water, adding an organic solvent, stirring, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, washing, purification, pH adjustment, extraction and drying processes.

[0308] According to another embodiment, the compound of formula (VIII) is the well-known fungicide compound fluopyram having the following formula:

[0309]

[0310] in

[0311] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0312] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0313] p is 0-4

[0314] q is 0-5

[0315] The compound is prepared by a process providing the following steps: a) preparing compound (VI) as described above via a compound having formula (I), b) reacting compound (VI) with a compound having formula (VII) in the presence of an organic solvent, optionally in the presence of a base.

[0316]

[0317] where q is an integer equal to 1, 2, 3 or 4,

[0318] Y is halogen and

[0319] L is a leaving group selected from C1-C6 alkoxy, OH, halogen, halide, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0320] q is 0-5

[0321] According to an embodiment, the base is selected from the group comprising alkali metal and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates and organic primary, secondary and tertiary amines, such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, chloroaniline and mixtures thereof, preferably sodium hydroxide.

[0322] According to an embodiment, the molar ratio between compound (VI) and the base can be about 1:10 to 1:0.5, preferably 1:1 to 1:5, and most preferably about 1:2 to 1:3.

[0323] According to an embodiment, the organic solvent is selected from the group consisting of aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, ethers, aliphatic and aromatic esters, nitriles, ketones, C1-C4 alcohols, n-alkyl protic and aprotic polar solvents such as dichloromethane, chloroform, pyridine, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof, preferably toluene.

[0324] According to an embodiment, the w / w ratio between compound (VI) and the solvent may be about 1:1 to 1:20, preferably 1:1 to 1:5, most preferably about 1:2 to 1:3.

[0325] According to embodiments, the base may be added as a solid or as an aqueous solution between 1% and 60% w / w, preferably as an aqueous solution of about 2% to 20% w / w, most preferably 5% to 10% w / w.

[0326] According to an embodiment, the w / w ratio between compound (VI) and the aqueous base solution may be about 1:001 to 1:1, preferably about 1:0.01 to 1:0.5, most preferably about 1:0.05 to 1:0.15.

[0327] According to an embodiment, the compound of formula (VII) is preferably contacted with the compound of formula (VI) at elevated temperature. The preferred temperature interval is 0°C to 130°C, preferably 0°C to 50°C, most preferably 10°C to 20°C.

[0328] According to the embodiment, after the addition is complete, the reaction mixture is stirred for 1 minute to 10 hours, preferably 10 minutes to 5 hours, most preferably 1 to 2 hours.

[0329] According to an embodiment, the reaction temperature during the stirring stage is in the range of 0°C to 130°C, preferably 10°C to 50°C, and most preferably 20°C to 30°C.

[0330] According to the embodiments, the reaction mixture is monitored by HPLC analysis and is terminated when the concentration of the compound of formula (VI) is between 0-99%, preferably 0-50%, in particular when no more than 0.5% of the compound of formula (VI) remains in the reaction medium.

[0331] Finally, the reaction mixture containing the obtained compound of formula (VIII) is post-treated. This stage may include adding water, adding organic solvents, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction and drying processes.

[0332] In another embodiment, the present invention relates to a novel derivative having the general formula (XI)

[0333]

[0334] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0335] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0336] p is 0-4

[0337] And more specifically relates to a compound having formula (XIa),

[0338]

[0339] According to an embodiment, the present invention provides a method for preparing a compound having formula (VI) or a salt thereof via a two-step reaction,

[0340]

[0341] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0342] p is 0-4

[0343] The two-step reaction can be carried out as separate processes or as a combined process (eg, one-pot reaction, telescopic reaction), preferably as a one-pot reaction.

[0344] According to an embodiment, the first step comprises a method for preparing a compound having formula (XI)

[0345]

[0346] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0347] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0348] p is 0-4

[0349] The method allows a compound having formula (IV) to be

[0350]

[0351] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0352] p is 0-4

[0353] and a compound having formula (X)

[0354]

[0355] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0356] The reaction is carried out in the presence of an organic solvent, optionally in the presence of a base, and optionally in the presence of a phase transfer catalyst.

[0357] According to an embodiment, the molar ratio between compound (IV) and compound (X) may be about 1:10 to 10:1, preferably 1:0.5 to 1:5, most preferably about 1:1 to 1:2.

[0358] According to an embodiment, the base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium alkoxide, potassium alkoxide, potassium tert-butoxide, sodium hydride, potassium hydride, butyl lithium, lithium diisopropylamide, aniline, p-chloroaniline and mixtures thereof, preferably potassium carbonate.

[0359] According to an embodiment, the molar ratio between compound (IV) and the base may be about 1:5 to 0.5:1.0, preferably about 1:1 to 1:5, and most preferably about 1:1.5 to 1:2.5.

[0360] According to an embodiment, the organic solvent is selected from dichloromethane, chloroform, pyridine, water, tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, dimethylacetamide and mixtures thereof, preferably dimethyl sulfoxide.

[0361] According to an embodiment, the w / w ratio between compound (IV) and the solvent may be about 1:20 to 1:0.1, preferably about 1:1 to 1:10, most preferably about 1:3 to 1:5.

[0362] According to an embodiment, the phase transfer catalyst is selected from the group consisting of quaternary ammonium salts, phosphonium salts, polyethers and mixtures thereof, such as benzyltriethylammonium chloride, methyltridecanoylammonium chloride, methyltributylammonium chloride and methyltrioctylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, crown ethers, polyethylene glycol and mixtures thereof, preferably tetra-n-butylammonium bromide.

[0363] According to an embodiment, the molar ratio between compound (IV) and the phase transfer catalyst can be about 1:1 to 1:0.0001, preferably 1:0.25 to 1:0.025, and most preferably about 1:0.15 to 1:0.05.

[0364] According to an embodiment, the second step provides a method for preparing a compound having formula (VI) or a salt thereof,

[0365]

[0366] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0367] p is 0-4

[0368] The method comprises subjecting a compound having formula (XI)

[0369]

[0370] wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0371] Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0372] p is 0-4

[0373] The reaction is carried out in the presence of an acid, optionally in the presence of an organic solvent.

[0374] According to an embodiment, the acid is selected from the group consisting of sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hydrochloric acid, hydrobromic acid, nitric acid and mixtures thereof, preferably hydrochloric acid.

[0375] According to an embodiment, the molar ratio between compound (XI) and the acid may be about 1:10 to 1:0.5, preferably about 1:1 to 1:10, most preferably about 1:4 to 1:6.

[0376] According to an embodiment, the organic solvent is selected from water, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, dimethylformamide, 1,4-dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, diethyl ether, chloroform, 1,2-dichloroethane, acetone, isopropyl acetate, anisole, N-methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane and a mixture thereof, preferably toluene.

[0377] According to an embodiment, the w / w ratio between compound (XI) and the organic solvent may be about 1:10 to 10:0.1, preferably 1:10 to 1:1, most preferably about 1:5 to 1:1.

[0378] According to an embodiment, compound (VI) is produced by mixing a compound having formula (XI), an acid and an organic solvent, and heating the mixture to a temperature range of 0°C to 130°C, preferably 50°C to 120°C, most preferably 100°C to 115°C.

[0379] According to an embodiment, the reaction mixture is stirred for 10 minutes to 20 hours, preferably 5 to 15 hours, most preferably 12 to 15 hours, depending on the progress of the reaction.

[0380] According to the embodiments, the reaction mixture is monitored by HPLC analysis and is terminated when the concentration of the compound of formula (XI) is 0-99%, preferably 0-50%, in particular when no more than 2.0% of the compound of formula (XI) remains in the reaction medium.

[0381] Finally, the reaction mixture containing the obtained compound of formula (XI) is post-treated. This stage may include cooling, adding water, adding an organic solvent, stirring, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, washing, purification, pH adjustment, extraction and drying processes.

[0382] According to another embodiment, the compound having formula (VIII),

[0383]

[0384] in

[0385] X is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0386] Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0387] p is 0-4

[0388] q is 0-5

[0389] Prepared by a process comprising the steps of: a) preparing compound (VI) as described above via a compound of formula (XI), b) reacting compound (VI) with a compound of formula (VII) in the presence of an organic solvent, optionally in the presence of a base.

[0390]

[0391] where q is an integer equal to 1, 2, 3 or 4,

[0392] Y is halogen and

[0393] L is a leaving group selected from C1-C6 alkoxy, OH, halogen, halide, OS(O)2R; wherein R is -CH3, -C6H5-CH3;

[0394] q is 0-5

[0395] According to an embodiment, the base is selected from the group comprising alkali metal and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates and organic primary, secondary and tertiary amines, such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, chloroaniline and mixtures thereof, preferably sodium hydroxide.

[0396] According to an embodiment, the molar ratio between compound (VI) and the base can be about 1:10 to 1:0.5, preferably 1:1 to 1:5, and most preferably about 1:2 to 1:3.

[0397] According to an embodiment, the organic solvent is selected from the group consisting of aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, ethers, aliphatic and aromatic esters, nitriles, ketones, C1-C4 alcohols, n-alkyl protic and aprotic polar solvents such as dichloromethane, chloroform, pyridine, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof, preferably toluene.

[0398] According to an embodiment, the w / w ratio between compound (VI) and the solvent may be about 1:1 to 1:20, preferably 1:1 to 1:5, most preferably about 1:2 to 1:3.

[0399] According to the embodiment, the base may be added as a solid or as a 1% to 60% w / w aqueous solution, preferably as a 2% to 20% w / w, most preferably 5% to 10% w / w aqueous solution.

[0400] According to an embodiment, the w / w ratio between compound (VI) and the aqueous base solution may be about 1:001 to 1:1, preferably about 1:0.01 to 1:0.5, most preferably about 1:0.05 to 1:0.15.

[0401] According to an embodiment, the compound of formula (VII) is preferably contacted with the compound of formula (VI) at elevated temperature. The preferred temperature interval is 0°C to 130°C, preferably 0°C to 50°C, most preferably 10°C to 20°C.

[0402] According to the embodiment, after the addition is complete, the reaction mixture is stirred for 1 minute to 10 hours, preferably 10 minutes to 5 hours, most preferably 1 to 2 hours.

[0403] According to an embodiment, the reaction temperature during the stirring stage is in the range of 0°C to 130°C, preferably 10°C to 50°C, and most preferably 20°C to 30°C.

[0404] According to the embodiments, the reaction mixture is monitored by HPLC analysis and is terminated when the concentration of the compound of formula (VI) is between 0-99%, preferably 0-50%, in particular when no more than 0.5% of the compound of formula (VI) remains in the reaction medium.

[0405] Finally, the reaction mixture containing the obtained compound of formula (VIII) is post-treated. This stage may include adding water, adding organic solvents, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction and drying processes.

[0406] Examples:

[0407] Example 1: Preparation of methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (Compound II) from 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound IV) via dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (Compound III):

[0408] At 25 ℃, toluene (180mL), potassium carbonate (138g), dimethylaminopyridine (2.82g) and tetra-n-butylammonium bromide (7.46g) were loaded into a 1L reactor equipped with a dean-stark condenser, and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 115 ℃ for 30 minutes to 1 hour. 3mL of water was collected, and heating was continued until no water was detected and collected. The mixture was cooled to 85 ℃, and dimethyl malonate (77.7g) and dimethyl sulfoxide (120mL) were added dropwise, followed by dropwise addition of compound (IV) (100g). The mixture was heated to 100 ℃ for 6 hours. The reaction process was monitored by HPLC, and the compound (IV) in the reaction mixture was less than 1.5% when it was terminated. The mixture was cooled to 25 ℃, and pH was adjusted by concentrated HCl (160mL). The solid particles were filtered and washed twice with toluene (200mL). Toluene was distilled off to obtain compound (III) in dimethyl sulfoxide. The mixture is acidified by concentrated HCl so that the pH is adjusted to 2.5. The mixture is heated to 115 ℃ and continues for 16 hours. The reaction process is monitored by HPLC, and the compound (III) in the reaction mixture is less than 1.5% when finishing. The mixture is cooled to 25 ℃, and water (400mL) is added, and toluene (200mL) is added subsequently. The mixture is stirred, and the sedimentation and organic layer are separated. The water layer is washed with toluene (200mL) again, and the organic phase is merged. Toluene is distilled, to obtain (% w / w) 109g of the oily crude product containing compound (II) (75%-77% productive rate).

[0409] Example 2: Preparation of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (Compound III) from 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound IV):

[0410] At 25 ° C, N-methyl-2-pyrrolidone (300mL), potassium carbonate (142g) were loaded into a 1L reactor equipped with a condenser, and stirred for 5 minutes. 2,3-dichloro-5-(trifluoromethyl)pyridine (100g) was loaded into the reactor, and the mixture was stirred for 15 minutes. Dimethyl malonate (77.3g) was loaded into the reactor, and the mixture was stirred for 15 minutes. The reaction was then heated to 75 ° C for 1 hour. The temperature was raised to 90 ° C for another 9h. The reaction progress was monitored by HPLC, and the reaction mixture was terminated when the compound (IV) was less than 1.5%. The mixture was cooled to 25 ° C, and the pH was adjusted by concentrated HCl (160mL). The solid particles were filtered and washed twice with N-methyl-2-pyrrolidone (200mL). N-methyl-2-pyrrolidone was distilled off to obtain an oily crude product containing compound (III) (92% yield).

[0411] Example 3: Preparation of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (Compound III) from 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound IV):

[0412] Toluene (700mL), potassium carbonate (136g), dimethyl malonate (78.3g), tetra-n-butylammonium bromide (7.4g) and dimethylaminopyridine (2.8g) were loaded into a 2L reactor equipped with a condenser at 25°C, and stirred for 5 minutes. 2,3-dichloro-5-(trifluoromethyl)pyridine (103g) was loaded into the reactor, and the mixture was stirred for 15 minutes. The reaction was then heated to 115°C for 14 hours. The reaction process was monitored by HPLC, and the compound (IV) in the reaction mixture was terminated when it was less than 1.5%. The mixture was cooled to 25°C, and the pH was adjusted by concentrated HCl (160mL). The solid particles were filtered and washed twice with toluene (200mL). Toluene was distilled off to obtain an oily crude product containing compound (III) (91% yield).

[0413] Example 4: Preparation of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (Compound III) from 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound IV):

[0414] At 25 ° C, N, N-dimethylacetamide (150mL), potassium carbonate (96g), dimethyl malonate (77.4g), tetra-n-butylammonium bromide (7.4g) and dimethylaminopyridine (2.8g) were loaded into a 1L reactor equipped with a condenser, and stirred for 5 minutes. 2,3-dichloro-5-(trifluoromethyl)pyridine (100g) was loaded into the reactor, and the mixture was stirred for 15 minutes. The reaction was then heated to 90 ° C for 8 hours. The reaction progress was monitored by HPLC, and the reaction mixture was terminated when the compound (IV) was less than 1.5%. The mixture was cooled to 25 ° C, and the pH was adjusted by concentrated HCl (160mL). The solid particles were filtered and washed twice with N, N-dimethylacetamide (200mL). N, N-dimethylacetamide was distilled off to obtain an oily crude product containing compound (III) (93% yield).

[0415] Example 5: Preparation of dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (Compound III) from 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound IV):

[0416] At 25 ℃, in the 0.25L reactor equipped with reflux condenser, charge compound (IV) (25g), dimethyl malonate (19.4g), potassium carbonate (34g), dimethylaminopyridine (0.7g) and tetra-n-butylammonium bromide (1.88g), and stir 5 minutes.Then react and be heated to azeotropic reflux at 85 ℃ and continue 3 hours.Monitor reaction process by HPLC, and finish when compound (IV) in reaction mixture is less than 1.5%.Obtain viscous oily residue, to obtain compound (III) of 72% productive rate.

[0417] Example 6: Preparation of methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (Compound II) from dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (Compound III):

[0418] At 25 ℃, in the 0.250L reactor equipped with reflux condenser, charge compound (III) (20g), dimethyl sulfoxide (40mL) and 30% sodium chloride aqueous solution (25mL), and stir for 5 minutes.Then the reaction is heated to 110 ℃ and continues for 24 hours.Monitor the reaction process by HPLC, and finish when the compound (III) in the reaction mixture is less than 2.0%.The mixture is cooled to 25 ℃, and water (100mL) is added.Organic compound is extracted twice with toluene (100mL).Distill out toluene, to obtain the viscous oily residue with 80% compound (II) (the productive rate of compound (II) is 94%).

[0419] Example 7: Preparation of methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (Compound II) from dimethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (Compound III):

[0420] At 25 ℃, compound (III) (10 g) and dimethyl sulfoxide (20 mL) were loaded into a 0.250 L autoclave reactor and stirred for 5 minutes. The reaction was then heated to 145 ℃ for 7 hours. The reaction progress was monitored by HPLC and the reaction mixture was terminated when the compound (III) was less than 1.5%. A viscous oily residue was obtained to obtain a 62% productive rate of compound (II).

[0421] Example 8: Preparation of methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-(hydroxyimino)acetate (Compound I) from methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (Compound II):

[0422] At 25 ℃, 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl acetate (107g), acetic acid (100mL) and water (30mL) are loaded into 1L reactor, and stirred for 5 minutes.The mixture is cooled to 10 ℃, and a solution of sodium nitrite (35.72g) in water (40mL) is added dropwise, keeping the temperature below 25 ℃.The mixture is stirred for 2 hours at 15 ℃.The reaction process is monitored by HPLC, and the compound (II) in the reaction mixture is less than 1.5% when it ends.Water (350mL) is added, and the mixture is cooled to 5 ℃.Solid is filtered, washed with water (100mL) and dried under vacuum, to obtain solid compound (I) (97% yield).

[0423] Example 9: Preparation of methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-(hydroxyimino)acetate (Compound I) from methyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)acetate (Compound II):

[0424] At 25 ℃, 1L reactor was charged with 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl acetate (20 g), acetic acid (100 mL), water (30 mL) and tetra-n-butylammonium bromide (2.54 g), and stirred for 5 minutes. The mixture was cooled to 10 ℃, and a solution of sodium nitrite (35.72 g) in water (40 mL) was added dropwise, keeping the temperature below 25 ℃. The mixture was stirred for 2 hours at 15 ℃. The reaction process was monitored by HPLC, and the compound (II) in the reaction mixture was less than 1.5% and ended. Water (350 mL) was added, and the mixture was cooled to 5 ℃. The solid was filtered, washed with water (100 mL) and dried under vacuum to obtain solid compound (I) (97% yield).

[0425] Example 10: Preparation of (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Compound VI) from 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-(hydroxyimino)acetic acid methyl ester (Compound I) via 2-amino-2-(3-chloro-5-trifluoromethyl)pyridin-2-yl)acetic acid methyl ester (Compound V)

[0426] Into 1L autoclave reactor, load 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-(hydroxyimino) methyl acetate (20g), acetic acid (200mL) and Raney nickel (2g).Autoclave is closed and heated to 75 ℃ for 8 hours.Reaction process is monitored by HPLC, and when the compound (I) in the reaction mixture is less than 1.5%, it ends.Mixture is filtered and washed with acetic acid (40mL).Filtrate is distilled, and concentrated HCl (20mL), water (10mL) and toluene (30mL) are loaded into residue.Mixture is heated to 65 ℃ and stirred for 2 hours.Mixture is cooled to 5 ℃, and solid precipitate is filtered, washed with toluene (20mL) and dried under vacuum, to obtain the solid product (85% yield) of 12g compound (VI).

[0427] Example 11: Preparation of (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methanamine hydrochloride (Compound VI) from 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-(hydroxyimino)acetic acid methyl ester (Compound I) via 2-amino-2-(3-chloro-5-trifluoromethyl)pyridin-2-yl)acetic acid methyl ester (Compound V)

[0428] 1L autoclave reactor was charged with 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-(hydroxyimino)acetic acid methyl ester (70 g), acetic acid (200 mL), and stirred at 10 ° C for 10 minutes. Zinc powder (40.8 g) was added at 10 ° C, and the mixture was stirred for 2 hours. The reaction progress was monitored by HPLC, and the reaction mixture was terminated when the compound (I) was less than 0.5%. The mixture was filtered and washed with acetic acid (50 mL). The filtrate was distilled, and concentrated HCl (20 mL) was loaded into the residue. The mixture was heated to 100 ° C and stirred for 5 hours. The reaction progress was monitored by HPLC, and the reaction mixture was terminated when the compound (V) was less than 0.5%. Water was distilled from the solution, and the oily residue was dissolved in toluene (150 mL). The mixture was cooled to 5 ° C, and the solid precipitate was filtered. The solid residue was washed with toluene (50 mL) and dried under vacuum to obtain 46.5 g of a solid product of Compound (VI) (83% yield).

[0429] Example 12: Preparation of (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methylamine hydrochloride (Compound VI) from 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound IV) and diethyl acetamidomalonate (Compound X) via diethyl 2-acetamido-2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)malonate (Compound XI)

[0430] 2,3-dichloro-5-(trifluoromethyl)pyridine (100g), diethyl 2-acetamidomalonate (106.7g), potassium carbonate (130.6g), tetra-n-butylammonium bromide (14.8g) and dimethyl sulfoxide (400mL) were loaded into a 2L reactor, and the resulting mixture was heated to 80°C for 13 hours. The reaction process was monitored by HPLC, and the reaction mixture was terminated when the compound (IV) was less than 2.0%. The mixture was cooled to 25°C, and water (1000mL) and toluene (500mL) were loaded. Thereafter, the mixture was stirred for 20 minutes, and the organic layer was separated. The water layer was washed with toluene (200mL), and the organic phase was combined. The organic phase was washed with water (200mL) and separated. Toluene was distilled to obtain an oily residue. Concentrated HCl (307g) was loaded, and the mixture was heated to 105°C for 15 hours. The reaction process is monitored by HPLC, and the compound (XI) in the reaction mixture is less than 0.5% when finishing. The mixture is cooled to 65 ℃ and distilled to a lower volume. The mixture is further cooled to 25 ℃, and toluene (200mL) is loaded. The mixture is heated to 70 ℃ and lasts for 1 hour. The mixture is cooled to 5 ℃ and lasts for 1 hour, and the solid is filtered, washed with toluene (100mL) and vacuum dried, to obtain a solid product (63% yield) of 73g compound (VI).

[0431] Example 13: Preparation of 2,6-dichloro-N-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide (Compound VIII) from 2,6-dichlorobenzoyl chloride (Compound VII) and (3-chloro-5(trifluoromethyl)pyridin-2-yl)methanamine (Compound VI)

[0432] Water (400mL) and sodium hydroxide (34.7g) were loaded into a 1L reactor, the resulting mixture was cooled to 15°C, and 3-chloro-5-(trifluoromethyl)pyridin-2-yl)methylamine hydrochloride (1033.95g) was loaded. Then, 2,6-dichlorobenzoyl chloride (91.31g) was loaded dropwise, keeping the temperature between 15°C. Toluene (10mL) was used to wash any residue on the reactor. The mixture was stirred at 25°C for 2 hours. The reaction progress was monitored by HPLC, and the compound (VI) in the reaction mixture was terminated when it was less than 0.5%. The solid was filtered, washed with water (200mL) and dried under vacuum. The solid was dissolved in toluene (200mL) and washed with water (200mL) at 25°C. The mixture was heated to 90°C for 30 minutes and cooled to 5°C for 1 hour. The solid was filtered, washed with toluene (50 mL) at 5°C and dried under vacuum to give 143.6 g of a solid product of compound (VIII) (92% yield).

Claims

1. A compound having formula (I) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4.

2. A compound having formula (Ia) 3. A method for preparing a compound having formula (I) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 The method comprises subjecting a compound having formula (II) or a salt thereof wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 reacting with a nitrite selected from the group comprising sodium nitrite, potassium nitrite, ammonium nitrite and mixtures thereof in the presence of a solvent, optionally in the presence of an acid and optionally in the presence of a phase transfer catalyst.

4. The method according to claim 3, wherein: The nitrite is sodium nitrite.

5. The method according to claim 3, wherein: The solvent is selected from the group consisting of aliphatic cyclic and non-cyclic hydrocarbons, halogenated aliphatic cyclic and non-cyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, ethers, aliphatic and aromatic esters, nitriles, ketones, C1-C4 alcohols, n-alkylpyrrolidones, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof.

6. The process according to claim 3, which is carried out in the presence of an acid selected from the group consisting of acetic acid, formic acid, chloroacetic acid, dichloroacetic acid, trifluoroacetic acid, carboxylic acids, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, hydrochloric acid and mixtures thereof.

7. The method according to claim 3, wherein the method is carried out in the presence of a phase transfer catalyst selected from quaternary ammonium salts, phosphonium salts, crown ethers, polyethers and mixtures thereof, wherein the phase transfer catalyst is selected from the group consisting of benzyltriethylammonium chloride, methyltridecanoylammonium chloride, methyltributylammonium chloride and methyltrioctylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, crown ethers, polyethylene glycol, polypropylene glycol and mixtures thereof.

8. A method for preparing a compound of formula (II) or a salt thereof, wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 The method comprises subjecting a compound having formula (III) or a salt thereof wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 Reacting with an acid and / or with an alkali metal halide, the acid being selected from the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, and the alkali metal halide being selected from the group consisting of sodium chloride, potassium chloride, lithium chloride, sodium bromide, potassium bromide, lithium bromide.

9. A method for preparing a compound of formula (III) or a salt thereof wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 The method comprises subjecting a compound having formula (IV) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 With a compound having formula A Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; The reaction is carried out in the presence of a base and a phase transfer catalyst, and optionally in the presence of a solvent.

10. The method according to claim 9, wherein: The base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium C1-C4 alcoholate, potassium C1-C4 alcoholate, potassium tert-butoxide, sodium hydride, potassium hydride, butyl lithium, lithium diisopropylamide, aniline, p-chloroaniline and mixtures thereof.

11. The method according to claim 9, wherein the method is carried out in the presence of a phase transfer catalyst selected from quaternary ammonium salts, phosphonium salts, crown ethers, polyethers and mixtures thereof, wherein the phase transfer catalyst is selected from the group consisting of benzyltriethylammonium chloride, methyltridecanoylammonium chloride, methyltributylammonium chloride and methyltrioctylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, crown ethers, polyethylene glycol, polypropylene glycol and mixtures thereof.

12. A method for preparing a compound of formula (II) or a salt thereof, wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 The method comprises treating a compound having formula (III) or a salt thereof wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 Heating at 60°C-180°C under high pressure of 1-32 bar.

13. A method for preparing a compound of formula (V) or a salt thereof, wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 The method comprises subjecting a compound having formula (I) to wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 The reaction is carried out in the presence of a metal catalyst, optionally in the presence of hydrogen, optionally in the presence of a carboxylic acid.

14. The method according to claim 13, wherein: The metal catalyst is selected from the group comprising zinc, iridium, nickel, palladium, platinum, rhodium or ruthenium, cobalt, tin, iron, Raney nickel or the corresponding salts selected from the group consisting of chlorides, bromides, iodides, nitrates and mixtures thereof.

15. The method according to claim 13, which is carried out in the presence of a C1-C4 carboxylic acid selected from the group consisting of acetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, lactic acid, formic acid, citric acid, oxalic acid, uric acid, malic acid, tartaric acid and mixtures thereof.

16. A method for preparing a compound of formula (VI) or a salt thereof, wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 The process comprises a) preparing a compound of formula (V) according to any one of claims 13 to 15, and b) further reacting the obtained compound of formula (V) with an acid, optionally in the presence of an organic solvent.

17. The method according to claim 16, wherein: The acid is selected from the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid and mixtures thereof.

18. The method according to claim 16, which is carried out in the presence of an organic solvent selected from the group consisting of water, halogenated aliphatic cyclic and non-cyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, dimethylformamide, 1,4-dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, diethyl ether, chloroform, 1,2-dichloroethane, 1-chlorobenzene, 1,2-dichlorobenzene, 1,3,5-trichlorobenzene, acetone, isopropyl acetate, anisole, N-methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane, and mixtures thereof.

19. A method for preparing a compound having formula (VIII) in X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 q is 0-5 The method comprises reacting a compound having formula (VI) prepared according to claim 16 with a compound having formula (VII) where q is an integer equal to 1, 2, 3 or 4, Y is halogen and L is a leaving group selected from C1-C6 alkoxy, OH, halogen, hydrogen, OS(O)2R; wherein R is -CH3, -C6H5-CH3; q is 0-5 The reaction is carried out in the presence of an organic solvent, optionally in the presence of a base.

20. The method according to claim 19, wherein: The base is selected from the group comprising alkali metal and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates and organic primary, secondary and tertiary amines, such as triethylamine, diisopropylethylamine, pyridine, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, p-chloroaniline and mixtures thereof.

21. The method according to claim 19, which is carried out in the presence of an organic solvent selected from the group consisting of aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic and acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, ethers, aliphatic and aromatic esters, nitriles, ketones, C1-C4 alcohols, n-alkyl protic and aprotic polar solvents such as dichloromethane, chloroform, pyridine, water, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, water and mixtures thereof.

22. A method for preparing a compound having formula (VIII) in X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 q is 0-5 The method uses a compound having formula (I) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z is C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy, optionally halogen-substituted; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4.

23. A compound having formula (XI) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4.

24. A compound having formula (XIa) 25. A method for preparing a compound having formula (XI) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4 The method comprises subjecting a compound having formula (IX) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 and a compound having formula (X) Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; The reaction is carried out in the presence of an organic solvent, in the presence of a base and optionally in the presence of a phase transfer catalyst.

26. The method according to claim 25, wherein: The base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium alkoxide, potassium alkoxide, potassium tert-butoxide, sodium hydride, potassium hydride, butyl lithium, lithium diisopropylamide, aniline, p-chloroaniline and mixtures thereof.

27. The method according to claim 25, which is carried out in the presence of an organic solvent selected from the group consisting of dichloromethane, chloroform, pyridine, water, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, dimethylacetamide and mixtures thereof.

28. The method according to claim 25, which is carried out in the presence of a phase transfer catalyst selected from the group consisting of quaternary ammonium salts, phosphonium salts, crown ethers, polyethers and mixtures thereof, wherein the phase transfer catalyst is selected from the group consisting of benzyltriethylammonium chloride, methyltridecanoylammonium chloride, methyltributylammonium chloride and methyltrioctylammonium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium fluoride, crown ethers, polyethylene glycol and mixtures thereof.

29. A method for preparing a compound of formula (VI) or a salt thereof, wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 The process comprises preparing a compound of formula (XI) according to claim 25, and b) further reacting the obtained compound of formula (XI) with an acid, optionally in the presence of an organic solvent.

30. The method of claim 29, wherein: The acid is selected from the group consisting of trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid and mixtures thereof.

31. The method according to claim 29, which is carried out in the presence of an organic solvent selected from the group consisting of water, halogenated aliphatic cyclic and non-cyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, dichloromethane, methanol, ethanol, propanol, isopropanol, tert-butanol, dimethylformamide, 1,4-dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, diethyl ether, chloroform, 1,2-dichloroethane, 1-chlorobenzene, 1,2-dichlorobenzene, 1,3,5-trichlorobenzene, acetone, isopropyl acetate, anisole, N-methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane and mixtures thereof.

32. A method for preparing a compound having formula (VIII) in X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 q is 0-5 The method comprises reacting a compound having formula (VI) prepared according to claim 29 with a compound having formula (VII) where q is an integer equal to 1, 2, 3 or 4, Y is a halogen, and L is a leaving group selected from C1-C6 alkoxy, OH, halogen, hydrogen, OS(O)2R; wherein R is -CH3, -C6H5-CH3; q is 0-5 The reaction is carried out in the presence of an organic solvent, optionally in the presence of a base.

33. The method of claim 32, wherein: The base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, chloroaniline, and mixtures thereof.

34. The method according to claim 32, which is carried out in the presence of an organic solvent selected from the group consisting of dichloromethane, chloroform, pyridine, water, tetrahydrofuran, dimethylformamide, ethyl acetate, toluene, 1,4-dioxane, diethyl ether, isopropyl acetate, methanol, ethanol, acetonitrile, dimethylacetamide and mixtures thereof.

35. A method for preparing a compound having formula (VIII) in X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Y is halogen, C1-C4 alkyl or C1-C4 haloalkyl; p is 0-4 q is 0-5 The method uses a compound having formula (XI) wherein X is halogen, C1-C4 alkyl or C1-C4 haloalkyl; Z 1 , Z 2 Independently, optionally halogen-substituted C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, halogen, C1-C6 alkylamino, OS(O)2R; wherein R is -CH3, -C6H5-CH3; p is 0-4.

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