Method for preparing amido acid ester

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

 

The present invention relates to an improved process for the preparation of ester of amicability of amino acids. More specifically, the present invention relates to a process for the preparation of ester of amicability, useful as an intermediate product for agrochemical preparation of amino acids (the source material) easily at low cost from the point of view of industrial production.

Background of the invention

The known method on the basis of the mixed anhydride of carboxylic acids for the reaction of the acid group amicability derived from amino acids (the source material), with another amine (Nobuo Izumiya et al., "Synthesis Chemistry Series - Peptide Synthesis", pp.126-129, Oct. 30, 1970, Maruzen K.K.).

In this method, first, the amino group [amino acids interacts with a complex ester chlorocarbonic acid, to synthesize amide; then the carboxyl group interacts with the amide complex air chlorocarbonic acid to obtain a mixed anhydride of carboxylic acids; and the mixed anhydride of carboxylic acid is reacted with the appropriate amine to synthesize the desired product.

However, in the method, since in the presence of water, the formation of the anhydride of carboxylic acids is slow, the second reaction should be carried out in non-aqueous system using a non-water-containing solvent; a poet who amide, synthesized in an aqueous solvent in the first reaction should degidrirovanii; moreover, the second reaction should be carried out in a nonaqueous system, as described above; accordingly, the method has the problem, consisting in the fact that it is difficult for industrial use.

Moreover, required for synthesizing the amide stage dehydration decreases performance per unit of time, etc. and requires a longer time to heat the reaction system, leading to decomposition of the desired product, etc. and the subsequent reduction of output; hence, the above] the traditional method also has a problem with the cost.

The present invention aims to provide a method of obtaining a complex ester of amicability, useful as an intermediate product for agrochemical funds from amino acids (the source material) easily at low cost from the point of view of industrial production.

Description of the invention

The above aim is achieved by the following inventions[1] - [9].

[1] a method of obtaining a complex ester of amicability represented by the following General formula (7):

where a represents a substituted or unsubstituted lower alkylenes group, substituted or unsubstituted cycloalkenyl group, samisen the Yu or unsubstituted Allenova group, substituted or unsubstituted cycloalkylcarbonyl group or a substituted or unsubstituted Aracinovo group; R1represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aracelio group, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclic alkyl group; and R3represents a hydrogen atom or a lower alkyl group, including interaction, in the presence of water, amino acids, represented by the following General formula (1):

where a has the same sign as given above, with a complex ether, halogenated carboxylic acids represented by the following General formula (2):

where R1has the same sign as given above, and X represents a halogen atom to obtain the amide compounds represented by the following General formula (3):

where a and R1have the same designations as given above, then the interaction of the amide compounds with a complex ether, halogenated carboxylic acids, represented the following General formula (4):

where R2represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aracelio group, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclic alkyl group; and X represents a halogen atom, with the receipt in the system of the mixed anhydride of carboxylic acids represented by the following General formula (5):

where A, R1and R2have the same designations as given above, and the interaction of the mixed anhydride of carboxylic acids with amine compound represented by the following General formula (6) or its salt:

where R3has the same sign as given above, Het is a substituted or unsubstituted heterocyclic group.

[2] a method of obtaining a complex ester of amicability according to claim 1, where the amino acid represented by the General formula (1), is dissolved in water and subjected to interaction with a complex ether, halogenated carboxylic acids represented by the General formula (2).

[3] the Method of obtaining of ester amido is islote according to claim 1, where the interaction of the amide compounds represented by General formula (3), complex ether halogenated carboxylic acid represented by the General formula (4), carried out in a reaction system containing water or a mixture of water - organic solvent.

[4] the Method of obtaining complex ester amicability according to claim 1, where the interaction of the mixed anhydride of carboxylic acids represented by the General formula (5), with the amine compound represented by the General formula (6)or its salt is carried out in the reaction system containing water or a mixture of water - organic solvent.

[5] a method of obtaining a complex ester of amicability according to claim 1, where every stage is carried out in one tank (single reactor).

[6] a method of obtaining a complex ester of amicability according to claim 1, where the amino acid represented by the General formula (1)is a valine, and ester chlorocarbonic acid represented by the General formula (2)is isopropylcarbonate.

[7] a method of obtaining a complex ester of amicability according to claim 6, where all the stages is carried out in one tank (single reactor).

[8] a method of obtaining a complex ester of amicability according to claim 1, where the amino acid represented by the General formula (1)is optically active valine, and amine represented by the General formula (6)is optically active 1-(6-fermentation-2-yl)ethylamine.

[9] Pic is b produce complex ester amicability of claim 8, where every stage is carried out in one tank (single reactor).

Studies have been conducted to achieve the above goals. As a result, it has been unexpectedly discovered that ester of amicability can be obtained in a single tank (single reactor) in the presence of water, adding to the amino acid (obtained in the form of an aqueous solution of its alkali metal salts) ester chlorocarbonic acid to obtain an amide compound, as necessary, neutralizing present in excess alkali by the acid, adding to it an organic solvent (e.g. toluene) and a catalytic amount of tertiary amine to convert the reaction system in a two-phase system, then subjecting the interaction of the amide compound with a complex ester chlorocarbonic acid in the presence of water to obtain a mixed anhydride of carboxylic acid in the reaction system in the presence of water, and subjecting the interaction of the mixed anhydride of carboxylic acids with amine compound corresponding to the desired product (when the amine compound is in the form of a salt, such as hydrochloride, sulfonate or the like, also add alkali); and, in addition, when used raw materials [for example, the amino acid represented by the above General formula (1), and the amine compound represented by the above General form of the Oh (6)] are optically active compounds it is possible to synthesize optically active ester of amicability, in which the optical purity of the source materials being stored. The above studies led to the final design of the present invention.

The preferred method of carrying out the invention

The method according to the present invention is described in detail below.

First, describes the terms used in this description.

Used in the description, the term "substituted or unsubstituted" means that the next term, the group may be unsubstituted or substituted, e.g. by halogen atoms, including fluorine atom, chlorine atom, bromine atom and iodine atom (hereinafter, the "halogen atoms" have the same notation as above, if it is not otherwise defined, and this applies to other substituents); C1-6the lower alkyl groups are straight or branched chain, including methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group and n-hexoloy group; a hydroxyl group; a lower CNS groups [(lower alkyl)-O - group, where the alkyl part is the above-mentioned lower alkyl group, including a methoxy group, ethoxypropan, n is ropaccigo, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, n-pentyloxy and n-hexyloxy; lower alkoxycarbonyl groups [(lower alkoxy)-CO - group], CNS where the part is above the lower CNS group; carbamoyl group [NH2-CO-]; and lower alkylcarboxylic groups [(lower alkyl)-NH-CO - group, where the alkyl part is the above-mentioned lower alkyl group.

Substituted or unsubstituted lower Allenova group belongs to C1-6alkalinous group with a straight or branched chain which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, isobutilene group, sec-butylene group, a tert-butylene group, n-Panteleeva group and n-hexylene group.

Substituted or unsubstituted cycloalkenes group belongs to C3-6cycloalkanones group, which can be the t to be substituted, for example, by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include cyclopropylamino group, cyclopentenone group and cyclohexylthio group.

Substituted or unsubstituted Allenova group refers to Allenova group (for example, phenylene, naphthylene or antanimena), which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include fenelonov group, 1-Neftyanoy group, 2-Neftyanoy group and 1-entrylevel group.

Substituted or unsubstituted cycloalkylcarbonyl group belongs to C1-6alkalinous group with a straight or branched chain, substituted C3-6cycloalkyl group which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alcox the carbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include cyclopropylmethanol group, cyclopropylamino group, cyclohexylamino group and cyclopropylacetylene group.

Substituted or unsubstituted Arakelova group refers to Aracinovo group (for example, basileiou group or phenylethylene group), which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include basileiou group or phenylethylene group.

Substituted or unsubstituted lower alkyl group refers to C1-6alkyl group with straight or branched chain which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. In quality the ve specific examples include methyl group, ethyl group, n-sawn group, isopropyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow group, n-hexoloy group, hydroxymethylene group, hydroxyethylene group, methoxymethyl group, ethoxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, carbamoylmethyl group, methylcarbamoylmethyl group, ethylcarbodiimide group, methylcarbamoylmethyl group and ethylcarbodiimide group.

Substituted or unsubstituted cycloalkyl group is a C3-6cycloalkyl group which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include cyclopropyl group, ferricopiapite group, chlorocyclopropane group, bromocyclopropane group, godzillatron group, methylcyclopropyl group, ethylcyclopropane group, hydroxyisopropyl group, methoxycyclohexene group, etoxisclerol group, methoxycarbonylpropionyl group, ka is amorticarrying group, methylcarbamoylmethyl group, cyclobutyl group, fertilisation group, chlorcycloguanil group, bromocyclobutane group, godzillatron group, methylcyclobutene group, ethylcyclopentadienyl group, hydroxyisobutyryl group, methoxyisobutyl group, amoxicillinno group, methoxycarbonylamino group, carbamoylmethyl group, methylcarbamoylmethyl group, cyclobutenyl group, fertilematerial group, chlorcycloguanil group, bromocyclobutane group, hadziconstantinou group, methylcyclopentadienyl group, ethylcyclopentadienyl group, hydroxylcontaining group, methoxycyclohexyl group, amoxicillinonline group, methoxycarbonylamino group, carbamoylmethyl group, methylcarbamoylmethyl group, cyclopentyloxy group, porcelaindoll group, chlorocyclopentane group, bromocyclopentane group, itselemental group, methylcyclopentadienyl group, ethylcyclopentadienyl group, hydroxycyclopent group, methoxycyclohexyl group, amoxicillinno group and tsiklogeksilnogo group.

Substituted or unsubstituted aryl group refers to an aryl group such as phenyl group, Tomilina group, Xili the other group, cominella group, diphenylene group, naftalina group, antanella group or the like, which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include phenyl group, o-florfenicol group, m-florfenicol group, p-florfenicol group, chloraniline group, m-chloraniline group, p-chloraniline group, bromperidol group, m-bromperidol group, p-bromperidol group, itfinally group, m-itfinally group, p-itfinally group, taillow group, m-taillow group, p-taillow group, kalilou group, m-kalilou group, p-kalilou group, -colaninno group, m-colaninno group, p-colaninno group, hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl, metoksifenilny, m-metoksifenilny, p-metoksifenilny, carbamoylphenoxy, m-carbamoylphenoxy, p-carbamoylphenoxy, methylcarbamoylmethyl, m-methylcarbamoylmethyl, p-methylcarbamoylmethyl, 1-naftalina group, 2-naftalina group and 1-antrasilina group.

Substituted or unsubstituted who Clausiliidae group belongs to C 1-6alkyl group with straight or branched chain, substituted C3-6cycloalkyl, which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include cyclopropylmethyl group, portilloportilloanniea group, chlorocyclopropane group, bromocyclopropane group, godzillatron group, methylcyclopentadienyl group, 1,1-dimethylcyclopropane group, 1,2-dimethylcyclopropene group, hydroxyisopropyl group, methoxycarbonylmethyl group, amoxicillinminocycline group, methoxycarbonylpropionyl group, methylcarbamoylmethyl group, cyclopropylethyl group, cyclohexylmethyl group and cyclopropylamino group.

Substituted or unsubstituted kalkilya group refers to Uralkaliy group (for example, benzyl group, 1-phenylethylene group, 2-phenylethylene group, 1-phenylpropanol group, 2-phenylpropanol group, 3-phenylpropene group or naphthylmethyl group), which can be C Medina, for example, by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples include benzyl group, o-performatrin group, m-performatrin group, p-performatrin group, 2,3-differenetly group, 2,4-differenetly group, 2,5-differenetly group, 3,4-differenetly group, 2,3,4-triterpenols group, 2,3,5-triterpenols group, 3,4,5-triterpenols group, chlorpheniramine group, m-chlorpheniramine group, p-chlorophenylglycine group, 2,3-dichlorophenylamino group, 2,4-dichlorophenylamino group, 2,5-dichlorophenylamino group, 3,4-dichlorophenylamino group, 2,3,4-trichloromethyl group, 2,3 A 5-trichloromethyl group, 3,4,5-trichloromethyl group, brompheniramine group, m-brompheniramine group, p-brompheniramine group, idenlily group, m-idenlily group, p-idenlily group, phenylethylene group, methylphenylethyl group, m-methylphenylethyl group, p-methylphenylthio group, 2,3-dimethyltrimethylene group, 2,4-di is ethylvanillin group, 2,5-dimethyltrimethylene group, 2-ethylenediamino group, 3-ethylenediamino group, 4-ethylenediamino group, o-(n-propyl) phenylmethylene group, m-(n-propyl) phenylmethylene group, p-(n-propyl)phenylmethylene group, o-(isopropyl)phenylmethylene group, m-(isopropyl) phenylmethylene group, n-(isopropyl)phenylmethylene group, hydroxytrimethylene group, m-hydroxytrimethylene group, p-hydroxytrimethylene group, methoxypolyethylene group, m-methoxyphenethyl group, p-methoxyphenylalanine group, o-ethoxyphenylurea group, m-ethoxyphenylurea group, p-ethoxyphenylurea group, methoxycarbonylmethyl group, m-methoxycarbonylmethyl group, p-methoxycarbonylmethyl group, carbamoylmethyl group, m-carbamoylmethyl group, p-carbamoylmethyl group, methoxycarbonylmethyl group, m-methoxycarbonylmethylene group and p-methoxycarbonylmethylene group.

Substituted or unsubstituted heterocyclic group refers to a 5 - to 10-membered mono - or condensed heterocyclic ring having in the ring at least one heteroatom selected from oxygen, nitrogen and sulfur, such as Peregrina group, pyridazine group, piramidalnaya group, piratininga the group, trainline group, Pernilla group, dioxinlika group, Taanilinna group, gitanilla group, furilla group, oxalanilide group, dioxopregna group, thienyl group, oxazoline group, isoxazolyl group, thiazolidine group, isothiazolinone group, benzoperylene group, kumarila group, benzothiazoline group, indolizinyl group, benzoxazolyl group, benzothiazolyl group, chromadorina group, hyalinella group, chinadaily group, khinoksalinona group or the like, a ring which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples of such a substituted or unsubstituted heterocyclic group, you can specify pyridyloxy group, 2-perpillou group, 4-chloropyridine group, 2,4-dichloropyrimidine group, 4-bromopyridine group, 4-impirically group, 2-methylpyridyl group, 4-ethylpyridine group, 2-hydroxypyridine group, 2-methoxypyridine group, 2-carbamoylethyl group, 2-methylcarbamoylmethyl group, pyridazinyl group pyramidalnou group, personilnya group, 1,3,5-triazinyl group α-pyranyloxy group β-pyranyloxy group, 1,4-dianilino group, follow group, oxalanilide group, doxofylline group, thienyl group, oxazolidinyl group, isoxazolyl group, thiazolidine group, isothiazolinone group, benzofuranyl group, coumaranyl group, benzothiazoline group, indolizinyl group, benzoxazolyl group, benzothiazolyl group, 2-fermentatively group, 4-fermentatively group, 5-fermentatively group, 6-fermentatively group, 7-fermentatively group, 2H-romanello group, 4H-romanello group, hyalinella group, chinazolinei group and khinoksalinona group.

Substituted or unsubstituted heterocyclic alkyl group refers to C1-6alkyl group with straight or branched chain, substituted 5 - to 10-membered heterocyclic ring having in a loop, at least one heteroatom selected from oxygen, nitrogen and sulfur (examples of the cycle are Peregrina group, pyridazine group, piramidalnaya group, piratininga group, trainline group, Pernilla group, dioxinlika group, Taanilinna group, gitanilla group, furilla group, oxalanilide group, dioxopregna group, Tamilnadu, oxazolidine group, isoxazolyl group, thiazolidine group, isothiazolinone group, benzoperylene group, kumarila group, benzothiazoline group, indolizinyl group, benzoxazolyl group, benzothiazolyl group, chromadorina group, hyalinella group, chinadaily group, khinoksalinona group), ring which may be substituted, e.g. by halogen atoms, lower alkyl groups, hydroxy-group, the lower alkoxygroup, lower alkoxycarbonyl groups, carbamoyl group and lower alkylcarboxylic groups. The position of each substituent and the position of each connection can be anything. As specific examples of the substituted or unsubstituted heterocyclic alkyl groups you can specify 2-pyridylmethyl group, 4-pyridylmethyl group, 2-ftorpirimidinu group, 2,4-littorelletalia group, 4-chloropyridinyl group, 2-bromopyrogallol group, 2-iteratively group, 2-methylergometrine group, 4-methylergometrine group, 2-hydroxypropylamino group, 2-methoxypolyethylene group, 2-carbamoylmethyl group, 4-methylcarbamoylmethyl group, 3-pyridinylmethyl group, 2-pyrimidinemethanol group, 2-personilnya group, 2-(1,3,5-triazinyl)methyl the group α-feast of the-2-yl-methyl group, Thian-2-yl-methyl group, 1,4-dition-2-yl-methyl group, 2-furylmethyl group, dioxolan-2-yl-methyl group, 2-thienylmethyl group, oxazol-2-yl-methyl group, isoxazol-3-yl-methyl group, a thiazol-2-yl-methyl group, isothiazol-3-yl-methyl group, benzofuran-2-yl-methyl group, kumaran-2-yl-methyl group, benzothiophen-2-yl-methyl group, benzothiophen-3-yl-methyl group, benzothiophen-4-yl-methyl group, benzothiophen-5-yl-methyl group, benzothiophen-6-yl-methyl group, benzothiophen-7-yl-methyl group, indolin-1-yl-methyl group, benzoxazol-2-yl-methyl group, Binational-2-yl-methyl group, 4-fermentational-2-yl-methyl group, 5-fermentational-2-yl-methyl group, 6-fermentation-2-yl-methyl group, 7-fermentation-2-yl-methyl group, benzothiazol-4-yl-methyl group, benzothiazol-5-yl-methyl group, benzothiazol-6-yl-methyl group, benzothiazol-7-yl-methyl group, 2H-chromen-2-yl-methyl group, 4H-chromen-2-yl-methyl group, quinoline-2-yl-methyl group, hinzelin-2-yl-methyl group, cinoxacin-2-yl-methyl group, 1-(2-pyridyl)ethyl group, 1-(2-perperidis)ethyl group, 1-(2,4-liftability)ethyl group, 1-(2-chloropyridin)ethyl group, 1-(2-bromopyridin)ethyl group, 1-(2-impirical)ethyl group, 1-(2-methylpyridyl)ethyl group is, 1-(2-ethylpyridine)ethyl group, 1-(2,4-diethylphenyl)ethyl group, 1-(2-hydroxypyridine)ethyl group, 1-(3-hydroxypyridine)ethyl group, 1-(2-methoxyphenyl)ethyl group, 1-(4-ethoxycarbonylphenyl)ethyl group, 1-(2-carbamoylethyl)ethyl group, 1-(2-methylcarbamoylmethyl)ethyl group, 1-(3-pyridil)ethyl group, 1-(2-pyrimidyl)ethyl group, 1-(4-pyrimidyl)ethyl group, 1-(2-pyrazinyl)ethyl group, 1-(2-(1,3,5-triazinyl)ethyl group, 1-(α-Piran-2-yl)ethyl group, 1-(β-Piran-2-yl)ethyl group, 1-(β-Piran-3-yl)ethyl group, 1-(β-Piran-4-yl)ethyl group,, 1-(dioxane-2-yl)ethyl group, 1-(Thian-2-yl)ethyl group, 1-(1,4-dition-2-yl)ethyl group, 1-(2-furyl)ethyl group, 1-(oxolan-2-yl)ethyl group, 1-(dioxolan-2-yl)ethyl group, 1-(2-thienyl)ethyl group, 1-(oxazol-2-yl)ethyl group, 1-(isoxazol-3-yl)ethyl group, 1-(thiazol-2-yl)ethyl group, 1-(isothiazol-3-yl)ethyl group, 1-(benzofuran-2-yl)ethyl group, 1-(coumaran-2-yl) ethyl group, 1-(benzothiophen-2-yl)ethyl group, 1-(indolin-1-yl)ethyl group, 1-(benzoxazol-2-yl)ethyl group, 1-(benzothiazol-2-yl)ethyl group, 1-(4-fermentational-2-yl)ethyl group, 1-(5-fermentational-2-yl)ethyl group, 1- (6-fermentation-2-yl)ethyl group, 1-(7-fermentation-2-yl)ethyl group, 1-(benzothiazol-4-yl)ethyl) - Rev. ing group, 1-(benzothiazol-5-yl)ethyl group, 1-(benzothiazol-6-yl)ethyl group, 1-(benzothiazol-7-yl)ethyl group, 1-(2N-chromen-2-yl)ethyl group, 1-(4H-chromen-2-yl)ethyl group, 1- (chinolin-2-yl)ethyl group, 1-(hinzelin-2-yl)ethyl group, 1-(cinoxacin-2-yl)ethyl group, 2-(2-pyridyl)ethyl group, 2-(2-perperidis)ethyl group, 2-(2,4-liftability)ethyl group, 2-(2-chloropyridin)ethyl group, 2-(2-bromopyridin)ethyl group, 2-(2-impirical)ethyl group, 2-(2-methylpyridyl)ethyl group, 2-(4-ethylpyridine)ethyl group, 2-(2-hydroxypyridine)ethyl group, 2-(2-methoxyphenyl)ethyl group, 2-(2-ethoxycarbonylphenyl)ethyl group, 2-(2-carbamoylethyl)ethyl group, 2-(2-methylcarbamoylmethyl)ethyl group, 2-(3-pyridil)ethyl group, 2-(4-pyridil)ethyl group, 2-(4-pyrimidyl)ethyl group, 2-(2-pyrazinyl)ethyl group, 2-(2-(1,3,5-triazinyl)ethyl group, 2-(α-Piran-2-yl)ethyl group, 2-(β-Piran-2-yl)ethyl group, 2-(β-Piran-3-yl)ethyl group, 2-(β-Piran-4-yl)ethyl group, 2-(Thian-2-yl)ethyl group, 2-(1,4-dition-2-yl)ethyl group, 2-(2-furyl)ethyl group, 2-(oxolan-2-yl)ethyl group, 2-(dioxolane-2-yl)ethyl group, 2-(2-thienyl)ethyl group, 2-(oxazol-2-yl)ethyl group, 2-(isoxazol-3-yl)ethyl group, 2-(thiazol-2-yl)ethyl group, 2-(iodiesel-3-yl)ethyl group, 2-benzofuran-2-yl)ethyl group, 2-(coumaran-2-yl)ethyl group, 2-(benzothiophen-2-yl)ethyl group, 2-(indolin-1-yl)ethyl group, 2-(benzoxazol-2-yl)ethyl group, 2-(benzothiazol-2-yl)ethyl group, 2-(4-fermentational-2-yl)ethyl group, 2-(5-fermentational-2-yl)ethyl group, 2-(6-fermentation-2-yl)ethyl group, 2-(7-fermentation-2-yl)ethyl group, 2-(benzothiazol-4-yl)ethyl group, 2-(benzothiazol-5-yl)ethyl group, 2-(benzothiazol-6-yl)ethyl group, 2-(benzothiazol-7-yl)ethyl group, 2-(2H-chromen-2-yl)ethyl group, 2-(4H-chromen-2-yl)ethyl group, 2-(chinolin-2-yl)ethyl group, 2-(hinzelin-2-yl)ethyl group and 2-(cinoxacin-2-yl)ethyl group.

The following is a description of the method according to the present invention.

First, it describes the response of the amino acids represented by the General formula (1), complex ether halogenated carboxylic acid represented by the General formula (2).

In this reaction the amino acid represented by the General formula (1), is dissolved in water in the form of its salt with an alkaline metal and subjected to interaction, in the presence of water, with a complex ether, halogenated carboxylic acids represented by the General formula (2)to convert the amino group of the amino acids represented by the General formula (1), amide.

In this reaction, used as starting material amino acid, represented the military General formula (1), can be any compound represented by the General formula (1). If the connection has one or more asymmetric carbon atoms, the compound may be a single pure optical isomer or mixture (e.g., racemic modification) of any proportions of the individual optical isomers, or a mixture of diastereomers. In this reaction, the configuration of the source material is maintained even after completion of the reaction. As specific examples of the amino acids represented by the General formula (1), you can specify glycine, alanine, β-alanine, valine, Norvaline, leucine, norleucine, isoleucine, serine, threonine, methionine, phenylalanine, tyrosine, γ-aminobutyric acid, Anthranilic acid and p-aminobenzoic acid. In this case, represented by the General formula (1) amino acid is known or can be obtained, for example, by the method described in "JIKKEN CALLED KOZA (4™ EDITION), compiled by THE CHEMICAL SOCIETY OF JAPAN, Vol. 22, ORGANIC SYNTHESIS IV, ACID-AMINO ACID PEPTIDE, PP.193-309".

Used in the reaction, ester, halogenated carboxylic acids represented by the General formula (2)may be any compound represented by the General formula (2). As specific examples of ester, halogenated carboxylic acids represented by the General formula (2), you can specify esters chlorocarbonate acids such as methylcarbonate, ethylchloride, n-propylparaben, isopropylcarbonate, n-butylcarbamoyl, isobutylparaben, n-intelilitent, isobutylparaben, neopentylglycol, cyclohexylcarbonyl and the like. In this case, ester, halogenated carboxylic acids represented by the General formula (2)is known or can be obtained, for example, by the method described in "Lasurewskii; Forostjam et al., 29 (1959) 3498; engl. Ausg., etc.".

In this reaction the amount of ester, halogenated carboxylic acids represented by the General formula (2)is 0.8 to 10 mol, preferably 1.0 to 3.0 moles per mole of the amino acids represented by the General formula (1). Water as a reaction solvent is used in an amount of 0.01 to 10 liters, preferably 0.1 to 5 liters per mole of the amino acids represented by the General formula (1).

In this reaction the amino acid represented by the General formula (1), prepared in advance in the form of an aqueous solution of its salt with an alkaline metal, using an aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like. Specifically, it can be performed by dissolving the amino acid represented by the General formula (1), in an aqueous solution of alkali metal hydroxide. In this case, an aqueous solution of alkali metal hydroxide used in such a quantity is as, to lye was 1-10 mol, preferably 2-3 mol per mol of the amino acids represented by the General formula (1).

In this reaction to aqueous salt solution of an alkali metal and amino acids represented by the General formula (1)add ester, halogenated carboxylic acids represented by the General formula (2). Ester, halogenated carboxylic acids represented by the General formula (2), preferably is added dropwise at a temperature of from -20 to 80°C, preferably from 0 to 50°in order to suppress the decomposition of ester, halogenated carboxylic acids.

The reaction after adding dropwise a complex ether, halogenated carboxylic acids represented by the General formula (2), carried out at a temperature from -20 to 80°C, preferably from 0 to 50°With 10 hours or less, preferably 2 hours or less.

The following describes the reaction of the thus obtained amide compounds represented by General formula (3), complex ether halogenated carboxylic acid represented by the General formula (4), to obtain a mixed anhydride of carboxylic acid represented by the General formula (5).

In this reaction, the amide compound represented by the General formula (3), is subjected to the interaction with a complex ether, halogenated carboxylic acids, n is redstavleny General formula (4), in water or a mixture of water-organic solvent to obtain a mixed anhydride of carboxylic acid represented by the General formula (5).

In this reaction as used as source material amide compounds represented by General formula (3), it is possible to use the reaction mixture obtained in the preceding reaction between the amino acid represented by the General formula (1), and a complex ether, halogenated carboxylic acids represented by the General formula (2), by itself in the same reactor and there is no need to allocate obtained in the preceding reaction, the reaction product.

Used in the reaction, ester, halogenated carboxylic acids represented by the General formula (4)may be any compound represented by the General formula (4). As specific examples of ester, halogenated carboxylic acids represented by the General formula (4), you can specify esters chlorocarbonic acid, such as methylcarbonate, ethylchloride, n-propylparaben, isopropylcarbonate, n-butylcarbamoyl, isobutylparaben, n-intelilitent, isobutylparaben, neopentylglycol, cyclohexylcarbonyl and the like; and esters bromocarbons acid, such as methylparaben, ethylbromide, n is ropivacaine, isopropylcarbonate, n-butylparaben, isobutylparaben, n-antibracket, isopentylamine, pointerpoint, cyclohexylcarbonyl and the like. The amount of ester, halogenated carboxylic acids represented by the General formula (4)may be from 0.5 to 10 mol, preferably from 0.8 to 2.0 mol per mol of the amino acids represented by the General formula (1)used as the starting material.

When carrying out the reaction, an aqueous solution of alkali metal salt and the amide compounds represented by General formula (3), if necessary, neutralize the acid, such as hydrochloric acid, sulfuric acid or the like; to this may be added an organic solvent, miscible or immiscible with water, such as aromatic hydrocarbons (e.g. toluene, xylene, ethyl benzene or chlorobenzene), esters (e.g. methyl acetate or ethyl acetate), a simple ether (e.g. diethyl ether, tert-butyl methyl ether or dioxane), aliphatic hydrocarbons (e.g. pentane, n-hexane or cyclohexane), ketone (e.g. methyl isobutyl ketone), a nitrile (e.g. acetonitrile), aprotic polar solvent (e.g., sulfolan, dimethylimidazolidine, dimethylformamide or dimethylacetamide). The amount used of the organic dissolve the El, if it is used, is from 0.05 to 10 liters, preferably from 0.1 to 5 liters per mole of the amino acids represented by the General formula (1).

In this reaction, ester, halogenated carboxylic acids represented by the General formula (4), add to the reaction system containing the amide compound represented by the General formula (3). In this case, ester, halogenated carboxylic acids represented by the General formula (4), preferably is added dropwise at a temperature of from -20 to 100°C, preferably from -5 to 30°to suppress the decomposition of ester, halogenated carboxylic acids.

The reaction after adding dropwise a complex ether, halogenated carboxylic acids represented by the General formula (4), is carried out at a temperature of from -20 to 100°C, preferably from -5 to 30°C for no more than 10 hours, preferably not more than 3 hours.

The reaction proceeds in the system that does not contain any tertiary amine, as described previously. However, the use of tertiary amine as a catalyst is preferred for smooth reaction. As specific examples suitable for use tertiary amines, it is possible to specify dimethylbenzylamine, triethylamine, tributylamine and pyridine. Dimethylbenzylamine is preferred. sportwave amount of tertiary amine is from 0.001 to 5 mol, preferably from 0.05 to 2 mol per mole of the amino acids represented by the General formula (1).

The following describes the obtaining of ester of amicability represented by the General formula (7), by reacting the thus obtained mixed anhydride of carboxylic acids represented by the General formula (5), with the amine compound represented by the General formula (6).

In this reaction, the mixed anhydride of carboxylic acids represented by the General formula (5), reacts with the amine compound represented by the General formula (6), in the system containing water or a mixture of water-organic solvent, whereby receive ester of amicability represented by the General formula (7), which is assumed to be obtained by the method according to the present invention.

In the reaction as a mixed anhydride of carboxylic acid represented by the General formula (5)used as the starting material, it is possible to use the reaction mixture obtained in the previous reaction between the amide compound represented by the General formula (3), and a complex ether, halogenated carboxylic acids represented by the General formula (4), by itself in the same reactor and there is no need to allocate the reaction product obtained in the preceding reaction.

In the preceding reaction, when using an organic solvent, n is miscible with water, the water layer can be removed by separation of the phases in order, for example, to give the opportunity to use a reactor having a capacity as small as possible per mole of starting material; in this case, the reaction between the compound (5) and compound (6) proceeds in an organic solvent.

Used in the reaction of the amine compound represented by the General formula (6)may be any compound represented by the General formula (6). When the amine compound (6) has one or more asymmetric carbon atoms, the compound can be a single optical isomer, or a mixture of any proportions of the individual optical isomers (for example, racemic modification), or a mixture of diastereomers. You can also use an acid additive salt. As specific examples of the amine compounds represented by the General formula (6), or its acid salt additive, you can specify (R)-1-(6-fermentation-2-yl)ethylamine, (S)-1-(6-fermentation-2-yl)ethylamine (thiophene-2-yl)methylamine, (R,S)-1-(4-methylfuran-3-yl)ethylamine, (R,S)-1-(5-methoxyazobenzene-6-yl)Propylamine, (R,S)-1-(4-chloropyridin-2-yl)ethylamine, (R,S)-1-personalaties, (4,6-dimethoxypyrimidine-2-yl)methylamine, (R,S)-1-(2H-pyrrol-3-yl)ethylamine, personilities, (indol-1-yl)methylamine, (chinolin-2-yl)methylamine, 2-methoxycarbonylbenzyl, 4-ethoxycarbonylmethylene-carbamoylmethyl; inorganic salts of the above amine compounds represented by the General formula (6), such as hydrochloride, sulfate, bisulfite salt, sodium phosphate, monopotassium phosphate salt of sodium, carbonate, bicarbonate salt is sodium and the like; organic acid salts of the above amine compounds represented by the General formula (6), such as acetate, citrate, methanesulfonate, triftorbyenzola, bansilalpet, p-toluensulfonate, p-chlorobenzenesulfonate and the like. The amount of such compound is from 0.5 to 10 mol, preferably from 0.5 to 2 mol per mole of the amino acids represented by the General formula (1).

In this case, for example, the above-mentioned (R)-1-(6-fermentation-2-yl)ethylamine can be obtained by adding the alkali metal salt of the corresponding derivative of 2-aminothiophenol in acid to lower the pH of salt to 6 or less, and then subjecting the interaction of the resulting derivative 2-aminothiophenol with the corresponding amino acid-N-carboxyanhydrides (see patent application of Japan No. 2000-100466).

When the reaction of the amine compound represented by the General formula (6), used in the form of its acid salt additive, an acid additive salt is converted into the free amine compound represented by the General formula (6)by adding alkali to the reaction system. As the E. lye, used to do this, you can specify, for example, sodium hydroxide and potassium hydroxide. The alkali can be added to the reaction system in the form of an aqueous solution containing from 1%to 100%, preferably from 10 to 50% of alkali. The amount of alkali is 1 mol or more, preferably 1 mol per mol of acid additive salts of amine compounds represented by the General formula (6).

The reaction can be conducted by adding the amine compounds represented by the General formula (6), in the system containing the mixed anhydride of carboxylic acid represented by the General formula (5), in a system containing water or a mixture of water-organic solvent, or in a system containing an organic solvent, if in the previous reaction using an organic solvent, immiscible with water, and after the previous reaction, the aqueous layer was removed by separation of the phases, and then stirring the resulting mixture. The reaction temperature is from -20 to 100°C, preferably from 0 to 50°and the duration of the reaction is 10 hours or less, preferably 0.5 to 5 hours.

After completion of the reaction the desired product according to the present method, i.e. an ester of amicability represented by the General formula (7), is in the dissolved form in the organic phase of the reaction mixture; therefore, the reaction mixture is subjected to sec the of phases in the usual way, the separated organic phase, optionally washed with water and dried, and then the organic solvent in the organic phase is distilled to isolate the desired product. Alternatively, the reaction mixture is subjected to separation of the phases, and subjected to distillation to remove the organic solvent contained in the reaction mixture, and to obtain the aqueous suspension of the desired product, and the suspension is filtered to select the desired product.

The method of the present invention is described more specifically below by Comparative Example and Examples.

Comparative Example

40 ml of water and 30 g (0,296 mol) of 36% hydrochloric acid are placed in a 300-ml reaction flask and cooled to 3°C. To this solution are added dropwise at a temperature of 2-5°under stirring to 48.0 g (0,056 mol) of an aqueous solution of potassium salt of 2-amino-5-portifino, followed by stirring for 1 hour. The resulting mixture has a pH 5,23. To this solution was added 9.7 g (0,051 mol) of the monohydrate of p-toluenesulfonic acid and 15 ml of tetrahydrofuran, followed by stirring for 30 minutes. Then at 0°add to 8.1 g (by 0.055 mol) of D-alanine-N-carboxyanhydride (purity: 78,3%). Aging is carried out at a temperature of 15-20°C for 18 hours. The resulting crystals are collected and dried at 60°receiving 16,6 is [2-(6-fermentational)]ethylamine-4-methylbenzenesulfonate (purity: 93.5 per cent). The output is the 82,8% relative to the potassium salt of 2-amino-5-portifino.

Example 1

16,1 g (0,092 mole) of 23% sodium hydroxide, 10 ml of water and 4.7 g (0.04 mol) of L-valine is placed in a 300-ml reaction flask and stirred at room temperature for 30 minutes. To this solution are added dropwise 5.9 g (0,048 mol) of isopropylcarbonate at room temperature, followed by stirring for 1 hour. The resulting mixture is neutralized with concentrated hydrochloric acid. To this solution add 100 ml of toluene and 0.06 g (of 0.0004 mol) N, N-dimethylaminobenzylidene. Then dropwise at room temperature is added 4.7 g (of 0.038 mol) of isopropylcarbonate, and then stirred for 1 hour. After that add 14.0 g (of 0.038 mol) of (R)-1-(6-fermentation-2-yl)]ethylamine-4-methylbenzenesulfonate (purity: 97,4%, optical purity: 99.2% of it)obtained in the above Comparative example. Next dropwise at room temperature added 15.2 g (of 0.038 mol) of 10% sodium hydroxide, and then stirred for 2 hours. Add 50 ml of water; the resulting mixture is heated to 70°and subjected to separation of the phases; the toluene layer washed with 50 ml of hot water and remove the solvent, obtaining 13,0 g (yield: 89.7%) the isopropyl [(S)-1-[(R)-1-(6-fermentation-2-yl)]ethylcarbamate]-2-methylpropyl]carbamate (purity: 97,2, the share obtained the desired substance in the four diastereomers: 99,2%).

Example 2

16,1 g (0,092 mol) of 23% sodium hydroxide, 10 ml of water and 4.7 g (0.04 mol) of L-valine is placed in a 300-ml reaction flask and stirred at room temperature for 30 minutes. To this solution are added dropwise 5.9 g (0,048 mol) of isopropylcarbonate at room temperature, followed by stirring for 1 hour. The resulting mixture is neutralized with concentrated hydrochloric acid. To this solution add 50 ml of toluene and 0.06 g (of 0.0004 mol) N, N-dimethylaminobenzylidene. Then dropwise at room temperature is added 4.7 g (of 0.038 mol) of isopropylcarbonate, and then stirred for 1 hour. Then added dropwise a solution of 7.5 g (of 0.038 mol) of (R)-1-(6-fermentation-2-yl]ethylamine (purity: 98,3%, optical purity: 99,0%), dissolved in 50 ml of toluene obtained in the above Comparative example, followed by stirring at room temperature for 2 hours. Add 50 ml of water; the resulting mixture is heated to 70 °and subjected to separation of the phases; the toluene layer washed with 50 ml of hot water and remove the solvent, obtaining a 13.4 g (yield: 92.4 per cent) isopropyl[ (S)-1-[ (R)-1-(6-fermentation-2-yl)]ethylcarbamate]-2-methylpropyl]carbamate (purity: 96,3%, the share received wish what about the substances in the four diastereomers: 98,5%),

Industrial applicability

The present invention provides a method of obtaining a complex ester of amicability, useful as an intermediate product for the production of agrochemical product, easily at low cost from the point of view of industrial production. This method proceeds even in the presence of water and it can be done in one tank (one reactor), if necessary.

When used raw materials [for example, the amino acid represented by the General formula (1), and the amine compound represented by the General formula (6)] are optically active compounds, it is possible to synthesize optically active ester of amicability without a significant decrease in the optical purity of the starting materials and therefore preserving their optical purity. Therefore, the present method can also be used to obtain the intermediate compounds to optically active agrochemical product. Thus, this method has a very high industrial value.

1. A method of obtaining a complex ester of amicability represented by the following General formula (7):

where a represents a substituted or unsubstituted lower alkylenes group, substituted or unsubstituted cycloalkenyl group, zameshano is or unsubstituted Allenova group, substituted or unsubstituted cycloalkylcarbonyl group or a substituted or unsubstituted Aracinovo group;

R1represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aracelio group, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclic alkyl group;

R5represents a hydrogen atom or a lower alkyl group, including interaction, in the presence of water, amino acids, represented by the following General formula (1):

where a has the same designation as shown above,

with a complex ether, halogenated carboxylic acids represented by the following General formula (2):

where R1has the same sign as given above;

X represents a halogen atom,

getting amide compounds represented by the following General formula (3):

where a and R1have the same designations as given above,

then vzaimodeistviyami amide complex ether halogenated carboxylic acid, represented by the following General formula (4);

where R2represents a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted cycloalkenyl group, substituted or unsubstituted aracelio group, a substituted or unsubstituted heterocyclic group, or substituted or unsubstituted heterocyclic alkyl group;

X represents a halogen atom, with the receipt in the system of the mixed anhydride of carboxylic acids represented by the following General formula (5):

where A, R1and R2have the same designations as given above,

and the interaction of the mixed anhydride of carboxylic acids with amine compound represented by the following General formula (6):

where R3has the same sign as given above;

Het represents a substituted or unsubstituted heterocyclic group.

2. A method of obtaining a complex ester of amicability of claim 1, wherein the amino acid represented by the General formula (1), is dissolved in water and subjected to interaction with complex halogenated ether ka is oil acids, represented by the General formula (2).

3. A method of obtaining a complex ester of amicability according to claim 1, in which the interaction of the amide compounds represented by General formula (3), complex ether halogenated carboxylic acid represented by the General formula (4), carried out in a reaction system containing water or a mixture of water - organic solvent.

4. A method of obtaining a complex ester of amicability according to claim 1, in which the interaction of the mixed anhydride of carboxylic acids represented by the General formula (5), with the amine compound represented by the General formula (6)or its salt is carried out in the reaction system containing water or a mixture of water - organic solvent.

5. A method of obtaining a complex ester of amicability according to claim 1, in which all stages are conducted in a single reactor.

6. A method of obtaining a complex ester of amicability according to claim 1, in which the amino acid represented by the General formula (1)is a valine and ester chlorocarbonic acid represented by the General formula (2)is isopropylcarbonate.

7. A method of obtaining a complex ester of amicability according to claim 6, in which all stages are conducted in a single reactor.

8. A method of obtaining a complex ester of amicability according to claim 1, in which the amino acid represented by the General formula (1)is optically active valine and amine represented by General what armoloy (6), is optically active 1-(6-fermentation-2-yl)ethylamine.

9. A method of obtaining a complex ester of amicability of claim 8, in which all stages are conducted in a single reactor.



 

Same patents:

The invention relates to new derivatives of asola General formula I, where R1and R2the same or different, each represents hydrogen, cycloalkyl and so forth, or R1and R2forming (a) a condensed ring, (b) or (C), which may be optionally substituted substituted lower alkyl, amino group and the like; R3, R6, R7, R8the same or different, each represents a hydrogen atom, and so on; R4represents a cyano, tetrazolyl, -COOR9and so on; R5represents a hydrogen atom or lower alkyl; D represents optionally substituted lower alkylene; X and Z are the same or different, each represents oxygen or sulfur, Y is-N= or-CH=; A is-B is-O-, -S-B-, -B-S - or-In-; represents the lowest alkylene or lower albaniles; n = 2

The invention relates to a method for producing derivatives of General formula (I), which allows to improve the yield of these products

The invention relates to the field exitlinks acids, in particular to the intermediate compounds - derivatives of 1-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(A) where R1-C1-C6-alkyl, and the method of obtaining derivatives complex alilovic esters of 4-oxo-3H-phthalazine-1-acetic acid of General formula

< / BR>
(I) where R1-C1-C6-alkyl, R2and R3may be the same or different and represent a hydrogen atom, chlorine or trifluoromethyl, which are inhibitors oldselected

FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

The invention relates to a new method of obtaining simple diaminopropionic ether or simple gidroksiaminopirimidinov ester by the interaction of dipropyleneglycol with ammonia and hydrogen at 150-190oC and at a pressure of 75-250 bar in the presence of Nickel-copper-chromium catalyst containing 35-58 mol.% Nickel, 10 to 30 mol.% copper and 12-55 mol.% chromium

The invention relates to a new methyl-isopropyl[(3-n-propoxyphene)ethyl]amine of formula I, where R1represents n-propyl, R2is methyl, R3- isopropyl, or its pharmaceutically acceptable salts, which have the properties of a topical local anaesthetics and can be used to produce medicines used for local anesthesia

The invention relates to a method for producing derivatives benzothiophenes formula I, including the interaction of amerosport formula (II) or its salt with the compound of the formula (III) or its reactive derivative, the oxidation of the resulting product in the presence of 2,2,6,6-tetramethylpiperidine-1-oxide and then liaising with ridom in the conditions of a Wittig reaction with subsequent optional unprotect

The invention relates to the production of intermediates for macroheterocyclic compounds visa and sacroiliac

The invention relates to organic chemistry, in particular to a method for producing 2,5-N,N'-(dimethylaminomethyl)-1,4-hydroquinone, which can be used as a starting product for the production of biologically active compounds

FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

FIELD: industrial organic synthesis.

SUBSTANCE: invention provides improved 2,7-bis[2-(diethylamino)ethoxy]fluorenone dihydrochloride production process comprising stages of sulfurization of fluorenone followed by neutralization of obtained reaction mass, isolation of purified fluorenone-2,7-disulfonic acid disodium salt, "alkaline melting" of this salt in presence of sodium nitrate to form 4.4'-dihydroxydiphenyldicarboxylic acid, cyclization to form 2,7-dihydroxyfluorene and alkylation thereof. More specifically, 2,7-dihydroxyfluorene obtained in cyclization stage is converted into alkali metal salt and toluene solution of 2-diethylaminoethyl chloride is added to preheated aqueous solution of the above salt at molar ratio 1:(3-5), preferably 1:4, to form 2,7-bis[2-(diethylamino)ethoxy]fluorenone, which is then treated with concentrated aqueous hydrochloric acid at molar ratio 1:(3.5-4), preferably 1:3.5.

EFFECT: increased yield and improved quality of product, and simplified process.

3 cl, 3 dwg, 4 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 3,4'-diamino-4-R-benzophenones of the general formula: wherein R means Cl, Br, F, -CH3, -OCH3,

that are used as intermediate product in synthesis of azo dyes useful for staining protein fibers and possessing the unique indices of thermal stability. Method involves steps for nitration reaction of substituted benzophenones with potassium nitrate in concentrated H2SO4, nucleophilic replacing halogen (wherein R means Cl) in interaction with O- and N-nucleophilic compounds in dimethylsulfoxide (DMSO) medium in the presence of K2CO3 and reduction of 3,4'-dinitro-4-R-benzophenones. The nitration reaction of synthesized benzophenones is carried out at temperature 20oC for 5 h in the mole ratio 4'-nitro-4-R-benzophenone : KNO3 = 1.0:1.15. Nucleophilic replacing halogen is carried out at temperature 40-60oC for 1-5 h in the mole ratio substrate : nucleophilic compound = 1.0:1.05, and reduction of dinitrobenzophenones is carried out with SnCl2 x 2H2O in 18% HCl medium, in the mole ratio 3,4'-dinitro-4-R-benzophenone : SnCl2 x 2H2O = 1:6, at temperature 20oC for 0.15 h. Invention provides decreasing cost of synthesis, reducing time and temperature in carrying out the process, enhancing purity and yield of end products.

EFFECT: improved method of synthesis.

4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of continuous production of alkylamino(meth)acrylamide of formula (C) by reacting a formula (B) compound with a formula (A) compound in the presence of a re-esterification catalyst in the presence of at least one polymerisation inhibitor in a continuous re-esterification installation. Reacting substances are continuously fed into the corresponding reactor (1) and the alcohol formed from the reaction is continuously removed in form of an azeotropic mixture of methanol and methyl(meth)acrylate (13) (mixture of ethanol and ethylacrylate 13, respectively) using a distillation column (2). The reaction mixture is constantly fed from the reactor into the distillation column (3) or, respectively, into evaporator (5). Highly volatile components (A, B, methanol or, respectively, ethanol) and a very small part of amide end product (C) are tapped from the head of the column and returned to the reactor. Amide end products (C) together with catalyst and polymerisation inhibitor, as well as heavy by-products are tapped from the bottom of the column. Material flow (15) from the bottom of the distillation column (3) is continuously taken for distillation to obtain pure end product.

EFFECT: improved quality of product, high efficiency and output.

15 cl, 1 tbl, 1 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: improved method of producing 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one dihydrochloride, known as thylorone or amixine, and used as an immunostimulating and antiviral agent, involves treating 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one in methylene chloride with hydrogen chloride in gaseous state of in form of hydrochloric acid, preferably in molar ratio 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one : hydrochloric acid equal to 1:2.05-3.0. A solution of 2,7-bis[2-(diethylamino)ethoxy]fluoren-9-one dihydrochloride in methylene chloride is obtained, which is cooled to temperature not below minus 12C to obtain a suspension and then filtered and dried. The filtered residue is dried in inert gas or air at temperature from 90 to 110C or in a vacuum, as a rule. Completion of salt formation is usually controlled from increase in temperature of the reaction mass and its stabilisation to a value between 32 and 34C, as well as from the pH value, which must not be higher than 4.0. The filtered residue is dried in an inert gas or air, at temperature from 90 to 110C or in a vacuum, as a rule.

EFFECT: simplification of the process due to exclusion of inflammable solvents and obtaining a product of high quality with high output.

6 cl, 1 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing and aminophenol compound of formula (1) , where each of R1 and R2, which can be identical or different, are a hydrogen atom, C1-C6 alkyl group, which can be substituted with phenyl, or phenyl; R1 and R2 together with the neighbouring nitrogen atom can form a 5- or 6-member heterocyclic group, selected from piperidinyl and piperazinyl; the heterocyclic group can be substituted with one substitute selected from hydroxyl group, C1-C6 alkyl group and phenoxy group, which can have a C1-C6 alkoxy group, substituted with 1-3 halogen atoms. The method involves reacting a cyclohexanedione compound of formula (2) with a amine compound of formula (3) , where R1 and R2 assume values given above, in neutral or basic conditions.

EFFECT: wider range of use of the compound.

8 cl, 4 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of 4-(dimethylamino)-1-alkyl-1-methyl-2-alkyn-1-ols of general formula (1): where R=C2H5, C4H9, C6H13, which are substances with physiological activity, particularly cholinolytic properties. The method involves reacting 3-alkyl-3-methyl-1-alkyn-3-ols with N,N,N1,N1-tetramethylmethanediamine in the presence of a copper monochloride catalyst in molar ratio 3-alkyl-3-methyl-1-alkyn-3-ol: N,N,N1,N1-tetramethylmethanediamine: CuCl=10:(10-12):(0.4-0.6) in an argon atmosphere at temperature 50-90C and atmospheric pressure, predominantly at 80C, for 3-5 hours. Output of 4-(dimethylamino)-1-alkyl-1-methyl-2-alkyn-1-ols (1) is 84-96%.

EFFECT: method increases output of products.

1 cl, 3 dwg, 1 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2-[(dimethylamino)methyl]phenol used in the food industry and medicine, as well as lubrication and engine oil additives, corrosion inhibitors for different types of steel, stabilisers of motor car and rocket fuel, monomers, plastic and different types of rubbers. The method involves reacting phenol with N,N,N,N-tetramethylmethylenediamine. The reaction is carried out in the presence of a copper (I) chloride catalyst in molar ratio phenol: N,N,N,N-tetramethylmethylenediamine: CuCl=10:(10-11):(0.2-0.4) at atmospheric pressure, mainly at temperature of 50C for 3.5-4.5 hours.

EFFECT: increased selectivity of the process and output of the desired product, reduced reaction temperature.

1 cl, 2 dwg, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the given invention, there is offered a method for preparing a compound of formula , where Y is specified of CH3, CH2OH, CH2CH2OH, CH2Br and Br; involving the stages: (1) reaction of the compound of formula where OX represents hydroxy or O-M+ where M+ represents cation chosen of Li+, Na+ and K+ and Y is such as specified above; with trans-cynnamaldehyde , with a secondary amine compound added; then (2) acid treatment of a product from the previous stage to prepare a compound of formula (I). The aforesaid method can be used for preparing tolterodine and fezoterodine which are effective in treating the hyperactive urinary bladder. There are also declared compounds of formulae V, VI and VII.

EFFECT: development of the effective method for preparing the compound.

25 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing amido acid ester that is useful as an intermediate substance in synthesis of agrochemical preparation. Invention relates to amido acid ester represented by compound of the general formula (7): wherein A represents substituted or free lower alkylene group, and so on; R1 represents substituted or free lower alkyl group, and so on; R3 represents hydrogen atom or lower alkyl group. Method for preparing amido acid ester involves interaction of amino acid represented by compound of the general formula (1): in presence of water with halogenated carboxylic acid ester represented by compound of the general formula (2): wherein X represents halogen atom with formation of amide represented by compound of the formula (3): Then amide compound interacts with halogenated carboxylic acid ester represented by compound of the general formula (4): wherein R2 represents substituted or free lower alkyl group, and so on; X represents halogen atom with preparing carboxylic acid mixed anhydride represented by compound of the general formula (5): Then carboxylic acid mixed anhydride interacts with amine compound represented by compound of the general formula (6): A, R1 and R3 have the same values as given above; Het represents substituted of free heterocyclic group. Invention provides reducing economic indices of the process.

EFFECT: improved preparing method.

9 cl, 2 ex

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