There is described a method of reducing polymer tar build-up in the production of methyl methacrylate and/or methacrylic acid by the acetone cyanohydrin process. In the method a stabiliser is contacted with the amide stage reaction medium. The stabiliser includes a hydrocarbon moiety capable of donating a labile hydrogen atom to a methacrylamide derivative capable of reaction with said labile hydrogen atom under the conditions in the said medium. The method herein is especially useful for the continuous production of methyl methacrylate and/or methacrylic acid.

The present invention relates to TRPV1 modulator compounds of formula (I) or their pharmaceutically, veterinary or cosmetically acceptable salts, or their stereoisomers or mixtures thereof, wherein m is an integer selected from 1 to 3; R.sup.1, R.sup.2, R.sup.6 and R.sup.6′ are independently selected from H, (C.sub.1-C.sub.8)alkyl, unsaturated (C.sub.2-C.sub.8)hydrocarbon, and (C.sub.3-C.sub.6)cycloalkyl, being these groups optionally substituted; R.sup.3 is hydrogen or halogen; R.sup.4 is selected from H, (C.sub.1-C.sub.8)alkyl, unsaturated (C.sub.2-C.sub.8)hydrocarbon, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.6-C.sub.12)aryl, and (C.sub.5-C.sub.12)heteroaryl, being these groups optionally substituted; and R.sup.5 is selected from (C.sub.3-C.sub.28)alkyl, unsaturated (C.sub.3-C.sub.28)hydrocarbon, (C.sub.6-C.sub.12)aryl, and (C.sub.5-C.sub.12)heteroaryl, being these groups optionally substituted. It also relates to a process for their preparation, to pharmaceutical, veterinary or cosmetic compositions containing them, and to their pharmaceutical, veterinary and cosmetic applications. ##STR00001##

The present invention relates to TRPV1 modulator compounds of formula (I) or their pharmaceutically, veterinary or cosmetically acceptable salts, or their stereoisomers or mixtures thereof, wherein m is an integer selected from 1 to 3; R.sup.1, R.sup.2, R.sup.6 and R.sup.6′ are independently selected from H, (C.sub.1-C.sub.8)alkyl, unsaturated (C.sub.2-C.sub.8)hydrocarbon, and (C.sub.3-C.sub.6)cycloalkyl, being these groups optionally substituted; R.sup.3 is hydrogen or halogen; R.sup.4 is selected from H, (C.sub.1-C.sub.8)alkyl, unsaturated (C.sub.2-C.sub.8)hydrocarbon, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.6-C.sub.12)aryl, and (C.sub.5-C.sub.12)heteroaryl, being these groups optionally substituted; and R.sup.5 is selected from (C.sub.3-C.sub.28)alkyl, unsaturated (C.sub.3-C.sub.28)hydrocarbon, (C.sub.6-C.sub.12)aryl, and (C.sub.5-C.sub.12)heteroaryl, being these groups optionally substituted. It also relates to a process for their preparation, to pharmaceutical, veterinary or cosmetic compositions containing them, and to their pharmaceutical, veterinary and cosmetic applications. ##STR00001##

Disclosed herein is a method for preparing a 2-arylmalonic acid derivative. In this method, a cyclohexadiene compound is used as a raw material, and sequentially undergoes an isomerization reaction, a halogenation reaction in the presence of a halogenating agent and a dehydrohalogenation-aromatization reaction to obtain a 2-arylmalonic acid derivative (3). An intermediate for preparing the 2-arylmalonic acid derivative (3) and use of the intermediate are also disclosed.

##STR00001##

Disclosed herein is a method for preparing a 2-arylmalonic acid derivative. In this method, a cyclohexadiene compound is used as a raw material, and sequentially undergoes an isomerization reaction, a halogenation reaction in the presence of a halogenating agent and a dehydrohalogenation-aromatization reaction to obtain a 2-arylmalonic acid derivative (3). An intermediate for preparing the 2-arylmalonic acid derivative (3) and use of the intermediate are also disclosed.

##STR00001##

A method of producing an N,N-disubstituted amide of the present invention is a method of reacting a nitrile with an alcohol in the presence of a catalyst, wherein the nitrile is a compound represented by R.sup.1CN (R.sup.1 represents an alkyl group having 10 or less carbon atoms or an aryl group having 10 or less carbon atoms), wherein the alcohol is a compound represented by R.sup.2OH (R.sup.2 represents an alkyl group having 10 or less carbon atoms), wherein the catalyst is a metal salt represented by MXn (M represents a metal cation having an oxidation number of n, X represents a monovalent anion including a substituted sulfonyl group represented by —S(═O).sub.2—R.sup.3 (R.sup.3 represents a hydrocarbon group having 10 or less carbon atoms or a group in which some or all of hydrogen atoms in the hydrocarbon group are substituted with fluorine atoms), and n represents an integer of 1 to 4), a substituent bonded to a carbon atom in a carbonyl group of the N,N-disubstituted amide is R.sup.1, and two substituents bonded to nitrogen atoms in an amide group are both R.sup.2.

A method of producing an N,N-disubstituted amide of the present invention is a method of reacting a nitrile with an alcohol in the presence of a catalyst, wherein the nitrile is a compound represented by R.sup.1CN (R.sup.1 represents an alkyl group having 10 or less carbon atoms or an aryl group having 10 or less carbon atoms), wherein the alcohol is a compound represented by R.sup.2OH (R.sup.2 represents an alkyl group having 10 or less carbon atoms), wherein the catalyst is a metal salt represented by MXn (M represents a metal cation having an oxidation number of n, X represents a monovalent anion including a substituted sulfonyl group represented by —S(═O).sub.2—R.sup.3 (R.sup.3 represents a hydrocarbon group having 10 or less carbon atoms or a group in which some or all of hydrogen atoms in the hydrocarbon group are substituted with fluorine atoms), and n represents an integer of 1 to 4), a substituent bonded to a carbon atom in a carbonyl group of the N,N-disubstituted amide is R.sup.1, and two substituents bonded to nitrogen atoms in an amide group are both R.sup.2.

A method of producing an N,N-disubstituted amide of the present invention is a method of reacting a nitrile with an alcohol in the presence of a catalyst, wherein the nitrile is a compound represented by R.sup.1CN (R.sup.1 represents an alkyl group having 10 or less carbon atoms or an aryl group having 10 or less carbon atoms), wherein the alcohol is a compound represented by R.sup.2OH (R.sup.2 represents an alkyl group having 10 or less carbon atoms), wherein the catalyst is a metal salt represented by MXn (M represents a metal cation having an oxidation number of n, X represents a monovalent anion including a substituted sulfonyl group represented by —S(═O).sub.2—R.sup.3 (R.sup.3 represents a hydrocarbon group having 10 or less carbon atoms or a group in which some or all of hydrogen atoms in the hydrocarbon group are substituted with fluorine atoms), and n represents an integer of 1 to 4), a substituent bonded to a carbon atom in a carbonyl group of the N,N-disubstituted amide is R.sup.1, and two substituents bonded to nitrogen atoms in an amide group are both R.sup.2.

A process for preparing methyl methacrylate (MMA) and/or methacrylic acid (MAS) having improved yield, involves amidation, conversion, and hydrolysis/esterification. Especially high yields are obtained during the amidation and in the subsequent so-called conversion.

A process for preparing methyl methacrylate (MMA) and/or methacrylic acid (MAS) having improved yield, involves amidation, conversion, and hydrolysis/esterification. Especially high yields are obtained during the amidation and in the subsequent so-called conversion.