Process for the preparation of substituted benzamides
By using a one-pot reaction method, the compounds of formula (II) and formula (III) are reacted with specific solvents and bases at a certain temperature, which solves the problems of low efficiency and high cost in the preparation of pyridyl methylbenzamide derivatives in the prior art and realizes a high-efficiency and low-cost preparation process.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ADAMA MAKHTESHIM LTD
- Filing Date
- 2024-12-24
- Publication Date
- 2026-08-04
AI Technical Summary
Existing methods for preparing pyridylmethylbenzamide derivatives are inefficient, costly, and use toxic and flammable solvents and catalysts, resulting in low yields and metal contamination.
A one-pot reaction method is used, in which compounds having formulas (II) and (III) are reacted with specific solvents and bases at a certain temperature, followed by post-processing, including phase separation and purification, thus avoiding the separation steps of intermediates.
It improves the preparation efficiency of pyridylmethylbenzamide derivatives, reduces waste and costs, avoids the use of toxic solvents, and reduces the risk of metal pollution.
Smart Images
Figure CN122514518A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to an improved reaction for synthesizing a key intermediate having formula (I) for the production of pyridylmethylbenzamide, and a one-pot reaction for the preparation of pyridylbenzamide, particularly fluopyram.
[0002] (I) Background Technology
[0003] Substituted pyridyl methylbenzamide derivatives of formula (VI)
[0004] (VI)
[0005] in
[0006] X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0007] Y is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0008] p is 0-4
[0009] q is 0-5
[0010] Known for its activity against plant pathogenic fungi, fluopyram is widely used in the agricultural industry as a pest control agent. Bayer Ltd. first described fluopyram (2,6-dichloro-N-{[3-chloro-5-(trifluoromethyl)-2-pyridyl]methyl}benzamide) and its family of compounds having formula (V) in EP 1056723. This patent discloses the compounds and their synthesis via substituted 2-(aminomethyl)pyridine substances (a key intermediate in the synthesis). WO1999 / 042447 and WO 2004 / 065359 demonstrate methods for preparing 2-aminomethylpyridine via benzophenone imine derivatives. However, these methods are inefficient, have low yields, and are costly. In particular, the preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester requires the use of high-volume propionitrile, which is expensive, toxic, and highly flammable. This particular method also requires the use of polluting tetrabutylammonium bromide (TBAB).
[0011] Other methods, such as those described in patents WO 2002 / 016322 and WO 2004 / 046114, demonstrate the preparation of substituted 2-(aminomethyl)pyridine derivatives by hydrogenation of the corresponding substituted 2-cyanopyridine material in the presence of a metal catalyst. However, this method results in low yields of the hydrogenation step, the formation of dehalogenation byproducts, and the formation of secondary and tertiary amines that can contaminate the desired primary amine. Furthermore, this method is costly, inefficient, and occasionally leads to metal contamination in the final product.
[0012] In view of the above, there is a need for novel and improved preparation methods for these compounds, and specifically for N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine esters. Summary of the Invention
[0013] This invention relates to a method for preparing compounds having formula (I).
[0014] (I)
[0015] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0016] Z represents halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkylamino, OS(O)2R; where R represents -CH3, -C6H5-CH3;
[0017] p is 0-4
[0018] The method includes making a compound having formula (II) or a salt thereof.
[0019] (II)
[0020] in
[0021] Z represents halogens, substituted C1-C6 alkoxy groups, aryloxy groups, C1-C4 alkylaryloxy groups, benzyloxy groups; OH, C1-C6 alkylamino groups, OS(O)2R; where R represents -CH3 or -C6H5-CH3.
[0022] With compounds having formula (III) or their salts
[0023] (III)
[0024] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0025] U is Cl, Br, F, or I;
[0026] p is 0-4
[0027] The reaction occurs in the presence of the following:
[0028] a) At least one solvent (a) selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic hydrocarbons and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and mixtures thereof.
[0029] (b) At least one polar aprotic solvent (b) selected from the group consisting of: N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixtures thereof.
[0030] c) At least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, C1-C4 sodium alkoxide, C1-C4 potassium alkoxide, and mixtures thereof; and
[0031] d) Optionally, the catalyst (d) is selected from the group consisting of 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and mixtures thereof.
[0032] Another aspect of the present invention relates to a method for preparing compounds having formula (VI).
[0033] (VI)
[0034] in
[0035] X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0036] Y is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0037] p is 0-4
[0038] q is 0-5
[0039] This method uses a compound having formula (I) prepared by: making a compound having formula (II) or a salt thereof.
[0040] (II)
[0041] in
[0042] Z represents halogens, substituted C1-C6 alkoxy groups, aryloxy groups, C1-C4 alkylaryloxy groups, benzyloxy groups; OH, C1-C6 alkylamino groups, OS(O)2R; where R represents -CH3 or -C6H5-CH3.
[0043] With compounds having formula (III) or their salts
[0044] (III)
[0045] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0046] U is Cl, Br, F, or I;
[0047] p is 0-4
[0048] The reaction occurs in the presence of the following:
[0049] a) At least one solvent (a) selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic hydrocarbons and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and mixtures thereof.
[0050] (b) At least one polar aprotic solvent (b) selected from the group consisting of: N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixtures thereof; and
[0051] c) At least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, C1-C4 sodium alkoxide, C1-C4 potassium alkoxide, and mixtures thereof; and
[0052] d) Optionally, the catalyst (d) is selected from the group consisting of 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and mixtures thereof. Detailed Implementation
[0053] definition:
[0054] Before detailing the subject matter of this invention, it may be helpful to provide definitions for 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 this subject matter pertains.
[0055] Throughout this application, the description of different embodiments uses the term "comprising"; however, those skilled in the art will understand that in certain specific cases, the language of "substantially consisting of" or "consisting of" may be used instead to describe embodiments.
[0056] Unless otherwise specified, the term "a / an" as used herein includes both the singular and the plural. Therefore, the terms "a / an" or "at least one" are used interchangeably in this application.
[0057] As used herein, the term "halogen" or "halogenated" refers to one or more halogen atoms, defined as F, Cl, Br, and I. Unless otherwise indicated, the numerical parameters set forth in the following description and appended claims are approximate values and may vary depending on the desired properties sought to be obtained. For a better understanding of this teaching, and in no way to limit its scope, all figures and other numerical values expressing quantities, percentages, or proportions used in the description and claims, unless otherwise indicated, should be understood to be modified in all cases by the term "about".
[0058] At a minimum, each numerical parameter should be interpreted according to the number of significant figures reported and by applying common rounding techniques. In embodiments, the term "about" as used herein specifically includes ±10% of the indicated value within the range. Furthermore, endpoints of all ranges referring to the same component or property herein include endpoints, are independently combinable, and include all intermediate points and ranges.
[0059] As used in this article, the term "carbonyl" refers to the group -C=O.
[0060] As used herein, the term "alkoxy" refers to an alkyl group that is optionally substituted by an oxygen atom attached to a portion of the parent molecule.
[0061] The term "aryloxy group" refers to an aryl group that is optionally substituted by an oxygen atom attached to a portion of the parent molecule.
[0062] As used herein, the term "alkoxycarbonyl" refers to an optionally substituted alkoxy group attached to a portion of the parent molecule via a carbonyl group.
[0063] As used herein, the term "benzyloxy group" refers to the benzyl group C6H5CH2- attached to the parent molecule via an oxygen atom.
[0064] As used herein, the term "alkyl" refers to a group derived from a straight-chain or branched saturated hydrocarbon containing one to six carbon atoms.
[0065] As used herein, the term "one-pot" reaction refers to the possibility of carrying out multiple chemical reactions in a single reaction vessel in one step without separating (e.g., purifying) the intermediates obtained in each chemical reaction. This method reduces the number of synthetic steps, waste, time, and cost.
[0066] As used herein, the term "telescopic process" refers to a series of reactions performed without separating the intermediate product. Specifically, the telescopic process implies multiple transformations (including reaction quenching and other post-processing operations) without directly separating the intermediate. The telescopic solution of the intermediate can be extracted, filtered (provided the desired product is retained in the filtrate), and subjected to solvent exchange, but the intermediate ultimately remains in solution and continues with subsequent transformations.
[0067] As used herein, the term "salt" refers to organic salts such as chlorides, bromides, fluorides, iodides, acetates, bisulfates, phosphates, formates, nitrates, carbonates, etc., or alkali metal salts (if applicable) such as sodium, potassium, calcium, lithium, cesium, magnesium, barium, etc.
[0068] As used herein, the verb “comprising” and its variations as used in this specification and claims are used in their non-limiting sense to mean including items that follow the word, but not excluding items not specifically mentioned.
[0069] As used in this article, the term "granule" broadly refers to grains, microparticles, pellets, or debris.
[0070] This invention relates to a method for preparing compounds having formula (I).
[0071] (I)
[0072] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0073] Z represents halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkylamino, OS(O)2R; where R represents -CH3, -C6H5-CH3;
[0074] p is 0-4
[0075] The method includes making a compound having formula (II) or a salt thereof.
[0076] (II)
[0077] in
[0078] Z represents halogens, substituted C1-C6 alkoxy groups, aryloxy groups, C1-C4 alkylaryloxy groups, benzyloxy groups; OH, C1-C6 alkylamino groups, OS(O)2R; where R represents -CH3 or -C6H5-CH3.
[0079] With compounds having formula (III) or their salts
[0080] (III)
[0081] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0082] U is Cl, Br, F, or I;
[0083] p is 0-4
[0084] The reaction occurs in the presence of the following:
[0085] a) At least one solvent (a) selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic hydrocarbons and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and mixtures thereof.
[0086] (b) At least one polar aprotic solvent (b) selected from the group consisting of: N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixtures thereof; and
[0087] c) At least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, C1-C4 sodium alkoxide, C1-C4 potassium alkoxide, and mixtures thereof; and
[0088] d) Optionally, the catalyst (d) is selected from the group consisting of 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and mixtures thereof.
[0089] The compounds covered by formula (II) are known and can be prepared, for example, according to the procedure disclosed in WO 2004 / 065359.
[0090] The compounds covered by formula (III) are known and can be purchased from multiple chemical suppliers.
[0091] The present invention also relates to a method for preparing compounds having formula (I).
[0092] (I)
[0093] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0094] Z represents halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkylamino, OS(O)2R; where R represents -CH3, -C6H5-CH3;
[0095] p is 0-4
[0096] The method includes making a compound having formula (II) or a salt thereof.
[0097] (II)
[0098] in
[0099] Z represents halogens, substituted C1-C6 alkoxy groups, aryloxy groups, C1-C4 alkylaryloxy groups, benzyloxy groups; OH, C1-C6 alkylamino groups, OS(O)2R; where R represents -CH3 or -C6H5-CH3.
[0100] With compounds having formula (III) or their salts
[0101] (III)
[0102] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0103] U is Cl, Br, F, or I;
[0104] p is 0-4
[0105] The reaction occurs in the presence of a solvent system containing the following components:
[0106] a) At least one solvent (a) selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic hydrocarbons and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and mixtures thereof.
[0107] (b) At least one polar aprotic solvent (b) selected from the group consisting of: N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixtures thereof; and
[0108] c) At least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, C1-C4 sodium alkoxide, C1-C4 potassium alkoxide, and mixtures thereof; and
[0109] d) Catalyst (d), selected from the group consisting of: 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline and mixtures thereof.
[0110] According to the examples, the molar ratio between compound (II) and compound (III) is 1:5 to 5:1.
[0111] According to the examples, the molar ratio between compound (II) and compound (III) is 1:2 to 2:1.
[0112] According to the examples, the molar ratio between compound (II) and compound (III) is from 1:1.1 to 1:1.
[0113] According to the examples, solvent (a) is selected from the group consisting of: aliphatic hydrocarbons (acyclic and cyclic) selected from octane, heptane, hexane, pentane, cyclooctane, cyclopentane, petroleum ether, cyclohexane, and cyclopentane; and chlorinated hydrocarbons selected from carbon tetrachloride, chloroform, 1,2-dichloroethane, and dichloromethane; and aromatic hydrocarbons selected from toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, and trichlorobenzene; and ethers (acyclic and cyclic) selected from diethyl ether, diethylene glycol dimethyl ether (diethylene glycol dimethyl ether), 1,4-dioxane, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), cyclopentylmethyl ether, and methyl-tert-butyl ether; and aliphatic and aromatic esters selected from ethyl acetate, propyl acetate, and butyl acetate; and ketone The alcohols are selected from acetone, 2-butanone, cyclohexanone; and alcohols selected from methanol, ethanol, 1-butanol, 2-butanol, 1-propanol, 2-propanol, tert-butanol, diethylene glycol, glycerol, ethylene glycol; and mixtures thereof.
[0114] According to the examples, solvent (b) is selected from the group consisting of: N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixtures thereof.
[0115] According to the embodiments, the solvent (a) is selected from the group consisting of aromatic hydrocarbon solvents and halogenated aromatic hydrocarbons selected from toluene, benzene, xylene, ethylbenzene, chlorobenzene, dichlorobenzene, trichlorobenzene and mixtures thereof.
[0116] According to the embodiments, solvent (b) is selected from the group consisting of dimethylacetamide, dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and mixtures thereof.
[0117] According to the example, solvent (a) is toluene.
[0118] According to the examples, solvent (a) is xylene.
[0119] According to the examples, solvent (a) is monochlorobenzene.
[0120] According to the examples, solvent (b) is dimethylacetamide.
[0121] According to the examples, solvent (b) is dimethylformamide.
[0122] According to the examples, solvent (b) is N-methylpyrrolidone.
[0123] According to the examples, solvent (b) is dimethyl sulfoxide.
[0124] According to the embodiments, the weight ratio between solvent (a) and solvent (b) is 100:1 to 1:100.
[0125] According to the embodiments, the weight ratio between solvent (a) and solvent (b) is 50:1 to 1:1.
[0126] According to the embodiments, the weight ratio between solvent (a) and solvent (b) is 50:1 to 30:1.
[0127] According to the example, the weight ratio between solvent (a) and solvent (b) is 40:1 w / w.
[0128] According to the examples, the weight ratio between compound (I) and the solvent system is 1:10 to 1:0.5.
[0129] According to the examples, the weight ratio between compound (I) and the solvent system is 1:5 to 1:1.
[0130] According to the examples, the weight ratio between compound (I) and the solvent system is 1:3 to 1:2.
[0131] According to the examples, the alkali (c) 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, butyllithium, sodium hydride, potassium hydride, sodium methoxide, potassium hydroxide, potassium tert-butoxide, and mixtures thereof.
[0132] According to the embodiments, the alkali (c) is selected from the group consisting of potassium hydroxide, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and mixtures thereof.
[0133] According to the examples, the base (c) is potassium carbonate.
[0134] According to the examples, the base (c) is potassium hydroxide.
[0135] According to the examples, the base (c) is sodium carbonate.
[0136] According to the examples, the base (c) is sodium bicarbonate.
[0137] According to the examples, the base (c) is sodium hydroxide.
[0138] According to the embodiments, the alkali (c) may optionally be in the form of granules, flakes, powders and mixtures thereof.
[0139] According to the examples, the alkali (c) is in powder form.
[0140] According to the examples, the weight ratio between compound (I) and base is 1:5 to 1:1.
[0141] According to the examples, the weight ratio between compound (I) and base is 1:3 to 1:1.
[0142] According to the examples, the weight ratio between compound (I) and base is 1:2 to 1:1.
[0143] According to the examples, the catalyst (d) is selected from the group consisting of: trimethylamine, tributylamine, diisopropylamine, tetramethylethylenediamine, pyridine, piperidine, morpholine, proline, L-proline, 4-dimethylaminopyridine, dimethylbenzylamine, quinoline, aniline, imidazole, pyrrole, pyrrolidine, pyrimidine, piperazine, morpholine, N-methylmorpholine, N-ethylpyrrolidine, diisopropylmethylamine, diisopropylethylamine, triallylamine, diallylamine, indole, and mixtures thereof.
[0144] According to the examples, the catalyst (d) is selected from the group consisting of trimethylamine, tributylamine, diisopropylamine, tetramethylethylenediamine, pyridine, 4-dimethylaminopyridine and mixtures thereof.
[0145] According to the examples, the catalyst (d) is 4-dimethylaminopyridine.
[0146] According to the examples, the catalyst (d) is proline or L-proline.
[0147] According to the examples, the catalyst is (d) morpholine.
[0148] According to the examples, the catalyst is (d) piperidine.
[0149] According to the examples, the weight ratio between compound (I) and catalyst is from 1:0.01 to 1:0.2.
[0150] According to the examples, the weight ratio between compound (I) and catalyst is 1:0.02 to 1:0.1.
[0151] According to the examples, the weight ratio between compound (I) and catalyst is 1:0.04 to 1:0.06.
[0152] According to the examples, the molar ratio between the base (c) and the catalyst (d) is 100:1 to 1:100.
[0153] According to the examples, the molar ratio between the base (c) and the catalyst (d) is 50:1 to 1:1.
[0154] According to the examples, the molar ratio between the base (c) and the catalyst (d) is 25:1 to 10:1.
[0155] According to the example, the weight ratio between the base (c) and the catalyst (d) is 20:1.
[0156] According to the examples, compound (II) and compound (III) were contacted in a temperature range of 10°C to 130°C.
[0157] According to the examples, compound (II) and compound (III) were contacted in a temperature range of 60°C to 130°C.
[0158] According to the examples, compound (II) and compound (III) were contacted in a temperature range of 100°C to 120°C.
[0159] According to the embodiments, the reaction mixture is monitored by HPLC analysis, and the process ends when the concentration of formula (II) is between 0-99%, preferably 0-50%, and most preferably, especially when no more than 1% of the compound having formula (II) remains in the reaction medium.
[0160] Finally, the reaction mixture containing the obtained compound of formula (I) is post-processed. This stage may include adding water, adding organic solvent, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying.
[0161] According to the embodiments, the next step in the method can be carried out as a separate process in which compound (I) is separated and purified, or as a combined process (such as a one-pot reaction, a condensation reaction) in which compound (I) is not separated from the process mixture.
[0162] According to an embodiment, the next step in the method is carried out as a one-pot reaction.
[0163] According to the embodiments, the reaction can be carried out in the presence of a phase transfer catalyst selected from the group consisting of: pyridinium hydrochloride, pyridinium acetate, pyridinium trifluoromethanesulfonate, 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 glycol, and mixtures thereof, preferably tetrabutylammonium bromide and mixtures thereof.
[0164] According to the examples, the molar ratio between compound (I) and the phase transfer catalyst is 1:1 to 1:0.0001, preferably 1:0.01 to 1:0.1, and most preferably 1:0.05 to 1:0.01.
[0165] According to another embodiment, a compound having formula (VI)
[0166] (VI)
[0167] in
[0168] X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0169] Y is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0170] p is 0-4
[0171] q is 0-5
[0172] Prepared by a method including the following steps:
[0173] Step a) Preparation of compound (I)
[0174] (I)
[0175] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0176] Z represents halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkylamino, OS(O)2R; where R represents -CH3, -C6H5-CH3;
[0177] p is 0-4
[0178] Compound (I) is prepared by: taking a compound having formula (II) or a salt thereof.
[0179] (II)
[0180] in
[0181] Z represents halogens, substituted C1-C6 alkoxy groups, aryloxy groups, C1-C4 alkylaryloxy groups, benzyloxy groups; OH, C1-C6 alkylamino groups, OS(O)2R; where R represents -CH3 or -C6H5-CH3.
[0182] With compounds having formula (III) or their salts
[0183] (III)
[0184] Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0185] U is Cl, Br, F, or I;
[0186] p is 0-4
[0187] The reaction occurs in the presence of the following:
[0188] a) At least one solvent (a) selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic hydrocarbons and halogenated acyclic hydrocarbons, aromatic hydrocarbons and halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and mixtures thereof.
[0189] (b) At least one polar aprotic solvent (b) selected from the group consisting of: N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixtures thereof; and
[0190] c) At least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, C1-C4 sodium alkoxide, C1-C4 potassium alkoxide, and mixtures thereof; and
[0191] d) Optionally, the catalyst (d) is selected from the group consisting of: 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and mixtures thereof;
[0192] Step b) Preparation of compound (IV)
[0193] (IV)
[0194] in
[0195] X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group;
[0196] p is 0-4
[0197] The preparation is carried out by mixing compound (I) in the presence of an acid and optionally an organic solvent; and step c) contacting compound (IV) or a salt thereof with compound (V) in the presence of an organic solvent and optionally in the presence of a base.
[0198] (V)
[0199] Where q is an integer equal to 1, 2, 3, or 4.
[0200] Y is a halogen and
[0201] q is 0-5
[0202] L is a leaving group, which is selected from C1-C6 alkoxy, OH, halogen, halide, OS(O)2R; where R is -CH3 or -C6H5-CH3.
[0203] The compounds covered by formula (V) are known and can be purchased from multiple chemical suppliers.
[0204] According to the embodiments, the acid in step b) 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.
[0205] According to the embodiments, the molar ratio between compound (I) and acid in step b) is about 1:10 to 1:0.5, preferably about 1:2 to 1:4.
[0206] According to the embodiments, the organic solvent in step b) is selected from the group consisting of: water, dichloromethane, methanol, ethanol, isopropanol, tert-butanol, dimethylformamide, 1,4-dioxane, ethyl acetate, acetonitrile, tetrahydrofuran, acetic acid, toluene, benzene, hexane, cyclohexane, dimethyl sulfoxide, pyridine, piperidine, morpholine, diethyl ether, chloroform, 1,2-dichloroethane, acetone, isopropyl acetate, anisole, etc. N 1-Methyl-2-pyrrolidone, 4-methylmorpholine, nitromethane and mixtures thereof, preferably toluene.
[0207] According to the embodiments, the weight ratio between compound (I) and organic solvent in step b) can be about 1:10 to 10:1, preferably 1:1 to 1:5, and most preferably about 1:2 to 1:4.
[0208] According to an embodiment, in step b), compound (IV) is produced by mixing a compound having formula (I), 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, and most preferably 60°C to 70°C.
[0209] According to the embodiments, the reaction mixture in step b) is stirred for 10 minutes to 5 hours, preferably 0.5 to 3 hours, and most preferably 1 to 2 hours, depending on the reaction progress.
[0210] According to the embodiments, the reaction mixture in step b) is monitored by HPLC analysis, and the reaction ends when the concentration of formula (I) is 0-99%, preferably 0-50%, and particularly when no more than 2.5% of the compound having formula (I) remains in the reaction medium.
[0211] Finally, according to the embodiments, the reaction mixture containing the obtained compound of formula (IV) in step b) is post-treated. This stage may include cooling, adding water, adding organic solvent, stirring, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, washing, purification, pH adjustment, extraction, and drying processes.
[0212] According to the embodiments, the molar ratio between compound (IV) and compound (V) in step c) is 1:5 to 5:1.
[0213] According to the embodiments, the molar ratio between compound (IV) and compound (V) in step c) is 1:2 to 2:1.
[0214] According to the examples, the molar ratio between compound (IV) and compound (V) in step c) is 1:1.1 to 1:1.
[0215] According to the embodiments, the base in step c) is selected from the group consisting of alkali metal and alkaline earth metal hydroxides, alkoxides, carbonates and bicarbonates, and organic primary, secondary and tertiary amines, such as triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, aniline, chloroaniline and mixtures thereof, preferably sodium hydroxide.
[0216] According to the examples, the molar ratio between compound (IV) and base in step c) is about 1:10 to 1:0.5, preferably 1:1 to 1:5, and most preferably about 1:2 to 1:3.
[0217] According to the embodiments, the organic solvent in step c) 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 proton 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.
[0218] According to the embodiments, the weight ratio between compound (IV) and solvent in step c) is about 1:1 to 1:20, preferably 1:1 to 1:5, and most preferably about 1:2 to 1:3.
[0219] According to the embodiments, the alkali in step c) can 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, and most preferably 5% to 10% w / w.
[0220] According to the embodiments, the weight ratio between compound (IV) and the alkaline aqueous solution in step c) can be from about 1:001 to 1:1, preferably from about 1:0.01 to 1:0.5, and most preferably from about 1:0.05 to 1:0.15.
[0221] According to an embodiment, in step c), the compound having formula (IV) is preferably contacted with the compound having formula (V) at an elevated temperature. The preferred temperature range is 0°C to 130°C, more preferably 0°C to 50°C, and most preferably 10°C to 20°C.
[0222] According to the embodiment, the reaction mixture in step c) is stirred for 1 minute to 10 hours, preferably 10 minutes to 5 hours, and most preferably 1 to 2 hours after the addition is completed.
[0223] According to the embodiment, the reaction temperature range of the stirring stage in step c) is 0°C to 130°C, preferably 10°C to 50°C, and most preferably 20°C to 30°C.
[0224] According to the embodiments, the reaction mixture in step c) is monitored by HPLC analysis, and the reaction ends when the concentration of formula (IV) is between 0-99%, preferably 0-50%, and particularly when no more than 0.5% of the compound having formula (IV) remains in the reaction medium.
[0225] Finally, according to the embodiments, the reaction mixture containing the obtained compound of formula (VI) in step c) is post-treated. This stage may include adding water, adding organic solvent, stirring, cooling, heating, phase separation, distillation, precipitation, recrystallization, concentration, filtration, purification, pH adjustment, extraction, and drying.
[0226] Without further detail, it is believed that those skilled in the art will be able to utilize the invention to its fullest extent using the foregoing description. Therefore, the following examples should be interpreted as illustrative only and not as limiting this disclosure in any way.
[0227] Example :
[0228] Example 1: Preparation of 2-((diphenylmethylene)amino)ethyl acetate (compound II) from glycine ethyl ester hydrochloride and benzophenone:
[0229] Toluene (400 mL), glycine ethyl hydrochloride (100 g), and benzophenone (264.24 mL) were charged into a 2 L reactor equipped with a Dean-Stark condenser at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C and maintained at azeotropic reflux for 1 hour. N,N-diisopropylethylamine (DIPEA) (102.37 g) was dissolved in toluene (100 mL) and added dropwise over 2 hours at azeotropic reflux and water extraction at 125°C. The mixture was then vortexed for 3 hours, and the reaction progress was monitored by HPLC. The reaction was terminated when the glycine ethyl hydrochloride content in the reaction mixture was less than 0.5%. The mixture was cooled to 25°C, and water (300 mL) was added. The mixture was stirred, allowed to stand, and the organic layer was separated. The organotoluene layer (810 g, 20%) with the desired ethyl 2-((diphenylmethylene)amino)acetate (85% yield) was transferred to the next step without further processing.
[0230] Example 2: Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0231] A solution of 783 g of toluene containing 20% (162 g) of ethyl 2-((diphenylmethylene)amino)acetate, 12.5 mL of dimethylacetamide (DMAc), 100 g of potassium carbonate, 4.34 g of dimethylaminopyridine (DMAP), and 127.3 g of 2,3-dichloro-5-(trifluoromethyl)pyridine were charged into a 1 L reactor equipped with a Dean-Stark condenser at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C and maintained at azeotropic reflux for 16 hours. Water was extracted and the reaction progress was monitored by HPLC, and the reaction was terminated when compound (III) in the reaction mixture was less than 0.2%. The mixture was cooled to 25°C and water (200 mL) was added. The mixture was stirred, allowed to stand, and the organic layer was separated. The organotoluene layer (883 g, 26.8%) containing the desired product (236.64 g, 91.4% yield) was transferred to the next step without further processing.
[0232] Example 3: Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0233] A toluene solution (1410 mL) of ethyl 2-((diphenylmethylene)amino)acetate (18.3%, 315.84 g), dimethylacetamide (DMAc) (25.0 mL), potassium carbonate (200 g), dimethylaminopyridine (DMAP) (8.85 g, 0.06 equivalent), and 2,3-dichloro-5-(trifluoromethyl)pyridine (258 g) were charged into a 5 L reactor equipped with a Dean-Stark condenser at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 16 hours. Water was extracted and the reaction progress was monitored by HPLC, and the reaction was terminated when compound (III) in the reaction mixture was less than 0.2%. The mixture was cooled to 25°C and water (1000 mL) was added. The mixture was stirred, allowed to stand, and the organic layer was separated. The organotoluene layer (1590 g) containing the desired product (478.6 g, 90.76% yield) was transferred to the next step without further processing.
[0234] Example 4: Preparation of (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methylamine (compound IV) from N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (compound I):
[0235] A toluene layer (883 g) containing N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (compound I) from the previous step was charged into a 1 L reactor equipped with a Dean-Stark condenser. Concentrated HCl (250 mL, 2.5 Vol) was added to the mixture at 25°C, and the mixture was stirred for 5 minutes. The reaction was then heated to 85°C for 4 hours. The reaction was monitored by HPLC, and the reaction was terminated when compound (I) in the reaction mixture was less than 0.5%. The mixture was then heated to azeotropic reflux at 110°C, and water was extracted. The mixture was cooled to 65°C, and methanol (50 mL) was added. The mixture was stirred at 65°C for 30 minutes, and then at 25°C for another 30 minutes. The solid precipitate was filtered and washed with 20% methanol (200 mL) in toluene. The solid was dried under vacuum at 65°C to obtain the desired product with 99% purity (112.5 g, 62% yield, from glycine ethyl ester hydrochloride).
[0236] Example 5: 2,6-Dichloro-N-((3-chloro-5-(trifluoromethyl)pyridin-2-yl)methyl)benzamide (compound V) was prepared by reacting 2,6-dichlorobenzoyl chloride (compound VI) and (3-chloro-5-(trifluoromethyl)pyridin-2-yl)methylamine (compound IV).
[0237] Water (400 mL) and sodium hydroxide (34.7 g) were added to a 1 L reactor. The resulting mixture was cooled to 15°C, and 3-chloro-5-(trifluoromethyl)pyridin-2-yl)methylamine hydrogen chloride (1033.95 g) was added. Then, 2,6-dichlorobenzoyl chloride (91.31 g) was added dropwise, maintaining the temperature between 15°C and 20°C. The mixture was stirred at 25°C for 2 hours. The reaction was monitored by HPLC, and the reaction was terminated when the concentration of compound (VI) in the reaction mixture was less than 0.5%. The precipitate was filtered, washed with water (200 mL), and dried under vacuum. The solid was dissolved in toluene (200 mL) at 25°C and washed with water (200 mL). The mixture was heated to 90°C for 30 minutes and cooled to 5°C for 1 hour. The solid precipitate was collected and filtered. The solid was washed with toluene (50 mL) at 5°C and dried under vacuum to give the desired product (143.6 g, 92% yield).
[0238] Comparison examples:
[0239] Example 6 (with 0.1 equivalents of DMSO and DMAP):Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0240] A 2 L reactor equipped with a Dean-Stark condenser was charged at 25°C with a toluene solution (498 mL) of ethyl 2-((diphenylmethylene)amino)acetate (21.3%, 106 g), dimethyl sulfoxide (DMSO) (70 mL), potassium carbonate (70.7 g), dimethylaminopyridine (DMAP) (6.1 g), and 2,3-dichloro-5-(trifluoromethyl)pyridine (87.5 g) and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 6 hours. Water was extracted and the reaction progress was monitored by HPLC, and the reaction was terminated when compound (III) in the reaction mixture was less than 0.2%. The mixture was cooled to 25°C and water (350 mL) was added. The mixture was stirred, allowed to stand, and the organic layer was separated. The organotoluene layer (593 g) with the desired product (148.8 g, 85.32% yield) was transferred to the next step without further action.
[0241] Example 7 (with 0.05 equivalents of DMSO and DMAP): Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0242] A 2 L reactor equipped with a Dean-Stark condenser was charged at 25°C with a toluene solution (542 mL) of ethyl 2-((diphenylmethylene)amino)acetate (19.8%, 104.3 g), dimethyl sulfoxide (DMSO) (70 mL), potassium carbonate (70.7 g), dimethylaminopyridine (DMAP) (3.0 g), and 2,3-dichloro-5-(trifluoromethyl)pyridine (87.5 g) and stirred for 5 min. The reaction was then heated to azeotropic reflux at 125°C for 12 h. Water was extracted and the reaction progress was monitored by HPLC, and the reaction was terminated when compound (III) in the reaction mixture was less than 0.2%. The mixture was cooled to 25°C and water (350 mL) was added. The mixture was stirred, allowed to stand, and the organic layer was separated. The organotoluene layer (653.6 g) with the desired product (157.5 g, 87.44% yield) was transferred to the next step without further processing.
[0243] Example 8 (without DMAP):Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0244] A solution of 462.8 mL of toluene containing 2-((diphenylmethylene)amino)ethyl acetate (22.0%, 101.8 g), 70 mL of dimethyl sulfoxide (DMSO), 70.7 g of potassium carbonate, and 87.5 g of 2,3-dichloro-5-(trifluoromethyl)pyridine was added to a 2 L reactor equipped with a Dean-Stark condenser at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 24 hours. Water was extracted and the reaction progress was monitored by HPLC, and the reaction was terminated when compound (III) in the reaction mixture was less than 0.2%. The mixture was cooled to 25°C and water (350 mL) was added. The mixture was stirred, allowed to stand, and the organic layer was separated. The organotoluene layer (655.8 g) containing the desired product (148.2 g, 84.40% yield) was transferred to the next step without further processing.
[0245] Example 9 (without DMAP and DMAc): Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0246] 2-((diphenylmethylene)amino)acetate (25 g), toluene (125 mL), potassium carbonate (26.37 g), and 2,3-dichloro-5-(trifluoromethyl)pyridine (20.40 g) were charged into a 500 mL reactor equipped with a Dean-Stark condenser at 25°C and stirred for 5 minutes. Water was extracted, and the reaction was then heated to azeotropic reflux at 125°C for 12 hours. The reaction conditions resulted in a low yield of only 0.25% of the desired product.
[0247] Example 10 (with MCB): Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0248] A 1 L reactor equipped with a Dean-Stark condenser was charged at 25°C with 397 mL of monochlorobenzene (MCB) solution (14.3%, 56.7 g) of ethyl 2-((diphenylmethylene)amino)acetate, potassium carbonate (50.51 g), dimethylaminopyridine (DMAP) (1.14 g), and 2,3-dichloro-5-(trifluoromethyl)pyridine (78.15 g) and stirred for 5 min. Water was extracted, and the reaction was then heated to azeotropic reflux at 135°C for 12 h. The reaction progress was monitored by HPLC. The reaction conditions resulted in a low yield of only 18.98% of the desired product.
[0249] Example 11 (with MCB and DMSO): Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0250] A 1 L reactor equipped with a Dean-Stark condenser was charged at 25°C with 397 mL of monochlorobenzene (MCB) solution of ethyl 2-((diphenylmethylene)amino)acetate (14.3%, 56.7 g), 25 mL of dimethyl sulfoxide (DMSO), 50.51 g of potassium carbonate, 1.14 g of dimethylaminopyridine (DMAP), and 78.15 g of 2,3-dichloro-5-(trifluoromethyl)pyridine, and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 135°C for 6 hours. Water was extracted, and the reaction progress was monitored by HPLC. The mixture was cooled to 25°C, and 250 mL of water was added. The mixture was stirred, allowed to stand, and the organic layer was separated. The organotoluene layer (571 g) containing the desired product (102.78 g, 78.92% yield) was transferred to the next step without further processing.
[0251] Example 12 (using NaOH and toluene): Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0252] Toluene (125 mL), ethyl 2-((diphenylmethylene)amino)acetate (25 g), sodium hydroxide (4.06 g), and 2,3-dichloro-5-(trifluoromethyl)pyridine (20.40 g) were charged into a 500 mL reactor equipped with a Dean-Stark condenser at 25°C and stirred for 5 minutes. The reaction was then heated to azeotropic reflux at 125°C for 6 hours. Water was extracted, and the reaction progress was monitored by HPLC. The reaction conditions resulted in a low yield of only 27.0% of the desired product.
[0253] Example 13 (with NaOH and DMF): Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0254] Dimethylformamide (DMF) (150 mL) and ethyl 2-((diphenylmethylene)amino)acetate (191.5 g) were charged into a 500 mL reactor at 25°C and stirred for 5 min. The reaction was then cooled to 2°C and sodium hydroxide (25.3 g) was added. The reaction was stirred for 2 min and 2,3-dichloro-5-(trifluoromethyl)pyridine (131.55 g) was added, and the mixture was heated to 10°C. The mixture was spontaneously heated to 17°C and stirred for 6 h. The reaction progress was monitored by HPLC. The reaction conditions resulted in a moderate yield of only 51.95% of the desired product.
[0255] Example 14 (with NaOH and NMP): Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0256] N-methylpyrrolidone (NMP) (75 mL) and ethyl 2-((diphenylmethylene)amino)acetate (96.0 g) were charged into a 250 mL reactor at 25°C and stirred for 5 min. The reaction was then cooled to 2°C and sodium hydroxide (12.65 g) was added. The reaction was stirred for 2 min and 2,3-dichloro-5-(trifluoromethyl)pyridine (65.77 g) was added, and the mixture was heated to 10°C. The mixture was then spontaneously heated to 17°C and stirred for 6 h. The reaction progress was monitored by HPLC. The reaction conditions resulted in a moderate yield of only 57.43% of the desired product.
[0257] Example 15 (containing NaOH and DMSO):Preparation of N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycine ethyl ester (Compound I) from ethyl 2-((diphenylmethylene)amino)acetate (Compound II) and 2,3-dichloro-5-(trifluoromethyl)pyridine (Compound III):
[0258] Dimethyl sulfoxide (DMSO) (75 mL) and ethyl 2-((diphenylmethylene)amino)acetate (96.0 g) were charged into a 250 mL reactor at 25°C and stirred for 5 min. The reaction was then cooled to 2°C and sodium hydroxide (12.65 g) was added. The reaction was stirred for 2 min and 2,3-dichloro-5-(trifluoromethyl)pyridine (65.77 g) was added, and the mixture was heated to 10°C. The mixture was then spontaneously heated to 17°C and stirred for 6 h. The reaction progress was monitored by HPLC. The reaction conditions resulted in a moderate yield of only 55.97% of the desired product.
Claims
1. A method for preparing a compound having formula (I). (I) Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; Z represents halogen, C1-C6 alkoxy, aryloxy, C1-C4 alkylaryloxy, benzyloxy; OH, C1-C6 alkylamino, OS(O)2R; where R represents -CH3, -C6H5-CH3; p is 0-4 The method includes applying a compound having formula (II) or a salt thereof. (II) in Z represents halogens, substituted C1-C6 alkoxy groups, aryloxy groups, C1-C4 alkylaryloxy groups, benzyloxy groups; OH, C1-C6 alkylamino groups, OS(O)2R; where R represents -CH3 or -C6H5-CH3. With compounds having formula (III) or their salts (III) Where X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; U is Cl, Br, F, or I; p is 0-4 The reaction occurs in the presence of the following: a) at least one solvent (a) selected from the group consisting of: aliphatic cyclic and acyclic hydrocarbons, halogenated aliphatic cyclic hydrocarbons and halogenated acyclic hydrocarbons, aromatic hydrocarbons, halogenated aromatic hydrocarbons, ethers, aliphatic esters and aromatic esters, ketones, C1-C4 alcohols and mixtures thereof, and (b) At least one polar aprotic solvent (b) selected from the group consisting of: N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixtures thereof; and c) At least one base (c) selected from potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, C1-C4 sodium alkoxide, C1-C4 potassium alkoxide, and mixtures thereof; and d) Optionally, the catalyst (d) is selected from the group consisting of 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline, and mixtures thereof.
2. The method according to claim 1, wherein, The solvent (a) is selected from the group consisting of pentane, hexane, cyclohexane, benzene, toluene, chlorobenzene, dichlorobenzene, trichlorobenzene, dichloromethane, chloroform, tetrachloromethane, acetone, methyl ethyl ketone, cyclohexanone, methanol, ethanol, propanol, butanol, pentanol, hexanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, and the solvent (b) is selected from the group consisting of N-methyl-2-pyrrolidone, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetone, ethyl acetate, dichloromethane, and mixtures thereof.
3. The method according to any one of claims 1-2, wherein, The ratio between solvent (a) and solvent (b) is from 100:1 to 1:
100.
4. The method according to any one of claims 1-3, wherein, The weight ratio of compound (I) to the solvent system is from 10:1 to 1:0.
5.
5. The method according to any one of claims 1-4, wherein, The alkali (c) is selected from the group consisting of potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, and mixtures thereof.
6. The method according to any one of claims 1-5, wherein, The weight ratio between compound (I) and base (c) is 1:5 to 1:
1.
7. The method according to any one of claims 1-6, wherein, The catalyst (d) is selected from the group consisting of: 4-dimethylaminopyridine (DMAP), triethylamine, diisopropylethylamine, pyridine, piperidine, morpholine, proline, L-proline, aniline, p-chloroaniline and mixtures thereof.
8. The method according to any one of claims 1-7, wherein, The weight ratio between compound (I) and catalyst (d) is from 1:0.01 to 1:0.
2.
9. A method for preparing a compound having formula (VI). (WE) in X is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; Y is a halogen, a C1-C4 alkyl group, or a C1-C4 haloalkyl group; p is 0-4 q is 0-5 The method uses a compound having formula (I) prepared by the method according to any one of claims 1-8.
10. The method for preparing a compound having formula (VI) according to claim 9, wherein the method is carried out as a one-pot reaction.