Method for synthesis of mandipropamid and derivatives thereof


FIELD: chemistry.

SUBSTANCE: disclosed is a method of producing a compound of formula (I), where N equals 0, and values of substitutes R, R1 are given in claim 1, which involves: (i) esterification of a compound of formula (V) with an alcohol of formula , where m and m' are independently equal to 0 or 1; under the condition that both are not equal to 0 at the same time and values of A are given in claim 1, to obtain a compound of formula (III); (ii) reaction of the compound of formula (III) and a compound of formula (IV) to obtain a compound of formula (II); and (iii) reaction of the compound of formula (II) with L-CH2-C≡CH, wherein L is a leaving group, to form a compound of formula (I); intermediate compounds of formula (II), formula (III) and formula (XII) are also disclosed.

EFFECT: improved method.

15 cl, 19 ex, 1 dwg

 

The present invention relates to a method for antifungal agents derived fenilpropionova ether and a process for the production of some intermediate compounds.

Antifungal drugs derived fenilpropionova ether, which can be obtained according to the present invention, are described, for example, in WO01/87822. These drugs derived fenilpropionova ester corresponds to the formula (A)

including their optical isomers and mixtures of such isomers, in which

RIrepresents hydrogen, alkyl, cycloalkyl or optionally substituted aryl;

RIIand RIIIeach independently represents hydrogen or alkyl;

RIVis alkyl, alkenyl or quinil;

RV, RVI, RVIIand RVIIIeach independently represents hydrogen or alkyl;

RIXrepresents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl; or optionally substituted quinil;

Rxrepresents an optionally substituted aryl, optionally substituted heteroaryl; and

Z represents halogen, optionally substituted aryloxy, optionally substituted alkoxyl, optionally substituted alkenylacyl, optional replacement of the military alkenylacyl, optional substituted killigrew, optionally substituted by allylthiourea, optionally substituted by altertekhnogrupp, optionally substituted by alinytjara, optionally substituted alkylsulfonyl, optionally substituted alkanesulfonyl, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonyl, optionally substituted alkanesulfonyl or optionally substituted alkylsulfonyl.

Different ways to obtain compounds of the above formula (A) described in WO01/87822.

The present invention relates to another alternative and preferred route for the synthesis of fungicides derived fenilpropionova ether of the formula (I)

in which:

R represents quinil;

R1represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkyl-alkyl, phenyl and phenylalkyl, and each of these groups, in turn, contains one or more identical or different halogen atoms; alkoxyl; alkenylacyl; alkyloxy; alkoxyalkyl; halogenoalkanes; alkylthiols; halogenation; alkylsulfonyl; formyl; alkanoyl; hydroxyl; halogen; cyano; nitro-group; an amino group; alkylamino; dialkylamino; carboxyl; alkoxycarbonyl; alkenylbenzenes or alkenylamine is of IMT; and

n is an integer of 0-3.

The terms "alkyl", "alkenyl" or "quinil" as one Deputy, and the other substituent represents a group with 1-8 (2-8 in case alkenyl or quinil) carbon atoms, better 1-6 (or 2-6) and preferably 1-4 (or 2-4) carbon atoms.

Specific examples of R include: ethinyl, prop-1-inyl, prop-2-inyl, but-1-inyl, but-2-inyl, l-methyl-2-butenyl, Gex-1-inyl, l-ethyl-2-butinyl or Oct-1-inyl. Most preferred is prop-2-inyl.

Typical examples R1include: 4-chloro, 4-bromo, 3,4-dichloro, 4 - chloro-3-fluoro, 3-chloro-4-fluoro, 4-methyl, 4-ethyl, 4-propargyloxy, 3-methyl, 4-fluoro, 4-ethynyl, 4-ethinyl, 4-propyl, 4-isopropyl, 4-tert-butyl, 4-ethoxyl, 4-itineracy, 4-phenoxy, 4-methylthiourea, 4-methylsulphonyl, 4-cyano, 4-nitro-group, 4-methoxycarbonyl, 3-bromo, 3-chloro, 2-chloro, 2,4-dichloro, 3,4,5-trichloro, 3,4-debtor, 3,4-dibromo, 3,4-dimethoxy, 3,4-dimethyl, 3-chloro-4-cyano, 4-chloro-3-cyano, 3-bromo-4-methyl, 4-methoxy-3-methyl, 3-fluoro-4-methoxy, 4-chloro-3-methyl, 4-chloro-3-trifluoromethyl, 4-bromo-3-chloro, 4-trifluoromethyl, 4-trifloromethyl, 4-methoxyl. Better when R1is a 3-halogen, 4-halogen, or 3,4-dihalogen; preferably 4-chloro.

When n is 2 or 3, the groups R1may be the same or different. Better n is 1 or 2; preferably 1.

Accordingly, the first version of nastoyascheevremya relates to a method for obtaining compounds of formula (I), as described above, and the method includes:

(i) reaction of compounds of formula (III)

in which R, R1and n are defined above;

m and m' are independently 0 or 1;

in the case when m and m' are both equal to 0, A is alkyl, alkenylphenol or alkenylphenol group (preferably containing up to eight carbon atoms), optionally substituted by one or more groups independently selected from halogen, hydroxyl, alkoxyl, C1-4dialkylamino or cyanopropyl;

when one of m and m' are 0, and the other is 1, A is landiolol, alkantiolsul or alcindoro group containing at least two carbon atoms (preferably up to eight carbon atoms), optionally substituted by one or more groups independently selected from halogen, hydroxyl, alkoxyl, C1-4-dialkylamino or cyanopropyl;

in the case when m and m' are both equal to 1, A is alcantarilla, alcantarilla or alcantarilla group containing at least three carbon atoms (preferably up to eight carbon atoms), optionally substituted by one or more groups independently selected from halogen, hydroxyl, alkoxyl, C1-4-dialkylamino or cyanopropyl;

and in which, if a group contains three or more carbon atoms, one or more atom is in each carbon may optionally be replaced by oxygen atom, provided that at least one carbon atom between two oxygen atoms in the molecule,

with the compound of the formula (IV)

with the formation of the compounds of formula (II)

in which R, R1and n are defined above, and

(ii) reaction of the compound of formula (II)containing the groupingin which L is a leaving group, with formation of compounds of formula (I).

The terms "alcander" and "alcanter" the authors understand alkyl group with two or three free valences, respectively (i.e. there are no two or three hydrogen atoms), preferably free valences at different carbon atoms.

The terms "alcander" and "allentries" the authors understand alkenylphenol group with two or three free valences, respectively, the best free valences at different carbon atoms.

The terms "alcindor" and "allentries" the authors understand alkylamino group with two or three free valences, respectively, the best free valences at different carbon atoms.

Suitable leaving groups L include halogen, alkyl sulphonates, halogenated.sulphonated and optionally substituted arylsulfonate; and preferably, L represents a chlorine or mesilate.

Examples of compounds is the second of the formula (III) include the following compounds:

Stage (i) is best done in the temperature range of 50°-150°C. the Reaction can be carried out in the melt or in the presence of an inert solvent, for example toluene, xylene, chlorobenzene and the like, the reaction Temperature depends on the reactivity of ester. In the case of esters with low reactivity, such as methyl ether, ethyl ether or benzyl ether, you can add alcohol to the high reactivity of type Diethylaminoethanol, ethylene glycol triethanolamine or propargilovyh alcohol or lowering the reaction temperature and to avoid adverse reactions directly to the use of esters of these alcohols. Usually the reaction temperature is 70°-120°C. At higher temperatures produce more by-products.

Stage (ii) is best done in an environment most common polar and non-polar solvents (for example, hydrocarbon type, toluene, xylene, or chlorinated hydrocarbons, including chlorobenzene, or ethers, including THF, dioxane, anisole, or NITRILES, for example acetonitrile, or in mixtures with water in the presence of bases, such as hydroxides of alkali metals, hydroxides of alkaline earth metals or carbonates. It is better if the solvent or the mixture of rastvoritelyami with respect to the compound (II) and the base. The base can be used in a wide range of concentrations, preferably in the range of 1-2 mol per mol of compound (II). Useful phase transfer catalyst type ternary ammonium salts in the range of 0.5 to 10 mol.%. It is better to conduct the reaction in the temperature range 20-150°C, preferably in the range of 50-100°C.

The compound of formula (III) can be obtained from the compounds of formula (V)

;

or from compounds of formula (VI)

or from compounds of formula (VII)

in which R, R1, m, m', n and A are defined above and X is a leaving group. Suitable leaving groups include halogen, such as fluorine, chlorine or bromine, or alkylsulfonate or arylsulfonate.

Accordingly, the second variant of the invention provides a method of obtaining compounds of formula (I)as described above, and the method includes

(i) (a) the esterification of the compounds of formula (V)as described above;

or

(b) reaction of compounds of formula (VI), as described above, with an alcohol of the formulain which A, m and m' are defined above; or

(c) reaction of the above compounds of formula (VII) with an alcohol R-OH, in which R is defined above, with formation of the compound of the above formula (III);

(ii) reaction of the compound of formula (III) with the compound is shown above formula (IV) with the formation of compounds of the above formula (II); and

(iii) reaction of compounds of formula (II)containing the groupin which L is defined above, to form compounds of formula (I).

Stage (i)(a) is best done in the melt or in the presence of an inert solvent, such as toluene, xylene, chlorobenzene, etc. Reaction is accelerated by adding a catalyst, such as sulfuric acid, methanesulfonate acid orp-toluensulfonate. To achieve high conversion formed by the reaction of the water is preferably removed by distillation or decompose chemically, for example, by adding, for example, trimethylol ether orthomorphisms acid. The reaction is best conducted at a temperature of 0°-150°C, preferably in the range of 50°-100°C.

Stage (i)(b) is best done in a solvent such as a hydrocarbon, e.g. hexane, cyclohexane, methylcyclohexane or toluene; in chlorophenothane, for example, dichloromethane or chlorobenzene; in simple ether, for example diethyl,tert-butylmethylether, dioxane or tetrahydrofuran; or in the water. Can also be used as solvent of the alcohol. You can use a mixture of such solvents. The reaction is carried out in the presence of acids, such as organic or inorganic acid such as hydrogen halide, e.g. hydrogen chloride, hydrogen bromide, or such as sulfuric acid is whether phosphoric acid. The reaction is best conducted at a temperature in the range from -80°C to the boiling temperature of the reaction mixture, preferably in the range of 0°-100°C.

Stage (i)(c) is best done in the presence of a base, such as trialkylamine, in the absence of water. The reaction is best conducted in a solvent, for example hydrocarbons, including toluene, xylene, or chlorinated hydrocarbons, such as chlorobenzene, or an ether, such as THF, dioxane, anisole, or amide, such as DMF, in the presence of a base, e.g. potassium carbonate, or alcohol, for example, propargilovyh alcohol. The reaction temperature is 0°-100°C.

Stage (ii) and (iii) are as described above.

The compounds of formula (V) can be obtained from the compounds of formula (VIII)

or the compounds of formula (IX)

or the compounds of formula (X)

in which R1, n, X and Y are defined above, and each may be the same or different and represent alkoxygroup or halogen; C1-4alkoxyl or halogen, preferably methoxy or chlorine.

Accordingly, the third variant of the invention provides a method of obtaining compounds of formula (I)as described above, and the method includes

(i) (a) the reaction of compounds of formula (VIII), as described above, with an alcohol R-OH; or

(b) Rea is of the compounds of formula (IX), as described above, with an alcohol R-OH in the presence of a base; or

(c) reaction of compounds of formula (X), as described above, with an alcohol R-OH and trihalomethanes or trigalogenmetany acid in the presence of a base;

with the formation of the compounds of formula (V)as described above;

(ii) the esterification of the compounds of formula (V) with the formation of the compounds of formula (III)as described above;

(iii) reaction of compounds of formula (III) with the compound of the formula (IV), as described above, with the formation of the compounds of formula (II)as described above; and

(iv) reaction of compounds of formula (II) with the compoundin which L is defined above, to form compounds of formula (I).

Stage (i)(a) is best done in the presence of a base such as a hydroxide of an alkali metal or tertiary amine. It is better to use the base in the ratio of 2 to 10 mol per mol of compound (VIII), preferably 2.5 to 3.5 mol. One mole of base is consumed in the neutralization of the carboxylic acid group of the compound (VIII). The reaction is best done in the temperature range from -50°C to 120°C, preferably in the range from -10°C to 50°C. as a solvent, you can use the alcohol R-OH or an additional solvent, such as aliphatic or aromatic hydrocarbons, halogenated aromatic hydrocarbons, ketones, ethers, N-organic (NMP) or Dima is insulted (DMSO). The reaction is best done in the absence of water.

Stage (i)(b) is carried out in the presence of a base, such as hydroxide of alkali or alkaline earth metal, e.g. sodium hydroxide or potassium hydroxide, sodium alcoholate or potassium, for example, sodium methoxide or nitrogen-containing compounds such as l,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU), l,4-diazabicyclo-[2.2.2]-octane (DABCO) (also known as triethylenediamine). You can also use mixtures of such bases. The reaction is best carried out at temperatures from -80°C to 150°C, preferably in the range of 30-100°C. the Reaction is best conducted in a solvent, for example, in a polar or nonpolar organic solvent, such as hydrocarbons, ethers, amides, for example, DME, diglyme, dioxane, THF, anisole, N-organic, DMSO or alcohol; the alcohol ROH may also be a solvent.

Stage (i)(c) is best done at temperatures from -80°C to 150°C, preferably in the range of 0°-70°C. Trihalomethane are derivatives of methane, in which three hydrogen atoms replaced by identical or different halogen type fluorine, chlorine or bromine. Examples of such trihalomethanes are chloroform, bromoform, chlorodibromomethane or bromodichloromethane. Suitable hydroxide bases include hydroxides of alkali or alkaline earth metals such as sodium hydroxide or hydroxide CA the Oia. The reaction is best carried out in a solvent such as a hydrocarbon, e.g. hexane, cyclohexane, methylcyclohexane or toluene; chloropetalum, for example, dichloromethane or chlorobenzene; a simple ether, for example diethyl ether,tert-butyl methyl ether, dioxane or tetrahydrofuran, or water. You can also use a mixture of solvents. Alcohol and/or trihalomethane can also be used as solvent; in one embodiment, the alcohol R-OH is used as the solvent; in another embodiment, the solvent is trihalomethane.

Stage (ii)-(iv) are as described above.

The connection defined above, of formula (VI) can be obtained from the compounds of formula (XI)

in which R, R1and n are the same as described above, either directly or through the connection of the formula (XII)

in which R, R1and n are the same as above.

Accordingly, a fourth variant of the invention provides a method of obtaining compounds of the above formula (I), and this method includes

(i) (a) the reaction of the compound of the above formula (XI) with tianyoude reagent; or

(b) (i) the reaction of the compound of the above formula (XI) with gloriouse reagent with the formation of the above compounds of formula (XII) and the subsequent reaction of the compound of formula (XII) with Tianyu the relevant reagent;

with the formation of compounds of the above formula (VI).

(ii) reaction of the compound of formula (VI) with an alcohol of the formulain which m, m' and A are defined above, with the formation of the above compounds of formula (III);

(iii) reaction of compounds of formula (III) with the compound of the above formula (IV), with the formation of compounds of the above formula (II); and

(iv) reaction of compounds of formula (II) within which L is defined above, to form compounds of formula (I).

Stage (i)(a) is best done in the presence of Pentecosta acids, such as strong mineral acid, e.g. hydrogen chloride, hydrogen bromide or sulfuric acid, or Lewis sites acids, such as compounds of group III elements, such as boron TRIFLUORIDE, metal salts, e.g. zinc salts, such as chloride of zinc (II)bromide, zinc (II), iron salts such as iron chloride (III), cobalt salts such as cobalt chloride (II), salts of antimony, such as antimony chloride (V), salts of scandium, such as triplet scandium (III)salts of yttrium, such as triplet yttrium (III), India salt, such as chloride, indium (III)salts of lanthanum, such as triplet lanthanum (III)or bismuth salt such as the chloride of bismuth (III)bromide bismuth (III). It is preferable to use the acid in quantities less than stoichiometric. Suitable tianyoude reagents VK is ucaut the hydrogen cyanide, cyanomelana, such as trialkylsilyl, for example, trimethylsilane or similar cyanhydrin. The reaction is preferably carried out in a solvent such as a hydrocarbon, e.g. hexane, cyclohexane, methylcyclohexane or toluene; chloropetalum, for example, dichloromethane or chlorobenzene; a simple ether, for example diethyl,tert-butyl methyl ether, dioxane or tetrahydrofuran; amide, e.g. N,N-dimethylamide, N,N-dimethylacetamide or N-organic. You can also use a mixture of solvents. The reaction is best done in the temperature range from -80°C to 150°C, preferably in the range of 0°-70°C.

Stage (i)(b)(i) is best done at temperatures from -80°C to 100°C, preferably in the range of 0°-25°C. as gloriously reagents is better to use organic chlorides, such as lower alcoholclone, for example, acetylchloride, or chlorides of inorganic acids, for example, thionylchloride, sulfurylchloride or phosphorus oxychloride. You can also use a mixture of gloriously reagents. The reaction is carried out in a suitable solvent such as a hydrocarbon, e.g. hexane, cyclohexane, methylcyclohexane or toluene; chloropetalum, for example, dichloromethane or chlorobenzene; a simple ether, for example diethyl,tert-butyl methyl ether, dioxane or tetrahydrofuran. You can also use a mixture of R is of Stroiteley.

Stage (i)(b)(ii) is carried out in a suitable solvent such as a hydrocarbon, e.g. hexane, cyclohexane, methylcyclohexane or toluene; chloropetalum, for example, dichloromethane or chlorobenzene; a simple ether, for example diethyl,tert-butyl methyl ether, dioxane or tetrahydrofuran; amides, for example N,N-dimethylamide, N,N-dimethylacetamide or N-organic; or water. You can also use a mixture of solvents. Suitable tianyoude reagents include cyanides of metals such as cyanide alkaline or alkaline earth metals such as sodium cyanide or potassium. The reaction is best carried out at temperatures from -50°C to 100°C, preferably 0°-40°C.

Stage (ii)-(iv) are as described above.

The above-described compound of the formula (VII) can be obtained from the compounds of formula (XIII)

in which R1, n and X are the same as described above, and W is halogen, preferably chlorine.

Accordingly, the fifth variant of the invention provides a method of obtaining the above-described compounds of formula (I), and this method includes

(i) reaction of the compound of the above formula (XIII) with an alcohol of the formula

in which A, m and m' are defined above, with formation of the compound of the above formula (VII).

(ii) reaction of the compound of formula (VII) with an alcohol R-OH, what oterom R - same as above, with the formation of the compounds of formula (III)described above;

(iii) reaction of compounds of formula (III) with the compound of the above formula (IV) with the formation of compounds of the above formula (II); and

(iv) reaction of compounds of formula (II) with the compoundin which L is defined above, to form compounds of formula (I).

Stage (i) is best done in the presence of a base, such as trialkylamine, under normal conditions, the reaction of carboxylic acid with alcohol. For example, the solvent may be an alcohol type propargilovyh alcohol, and the reaction temperature may be from -20°C to 150°C, preferably in the range of 0°-60°C.

Stage (ii)-(iv) are as described above.

Compounds of the above formula (VIII) can be obtained from the compounds of formula (XIV)

in which R1and n are defined above.

Accordingly, the sixth variant of the invention provides a method of obtaining compounds of the above formula (I), and this method includes

(i) halogenoalkane compounds of the above formula (XIV) with the formation of compounds of the above formula (VIII);

(ii) reaction of the compound of formula (VIII) with an alcohol R-OH, in which R is defined above, with formation of the compound of the above formula (V);

(iii) the esterification of the compounds of formula (a) with formation of the compound of the above formula (III);

(iv) reaction of compounds of formula (III) with the compound of the above formula (IV) with the formation of compounds defined above, of formula (III); and

(v) reaction of compounds of formula (II) within which L is defined above, to form compounds of formula (I).

Stage (i) can be carried out in the melt or in an inert solvent type acetic acid or most of halogenated aromatic and aliphatic solvents. To accelerate the reaction it is necessary to add the catalyst type red phosphorus, phosphorotrithioite or bromide, phosphorochloridate or bromide, thionyl chloride or tiniversity, phosgene in an amount of 0.01 to 1.0 mole per mole of compound (XIV), preferably in the range of 0.1 to 0.5 mol. Halogenoalkane (XIV) can be done using bromine, chlorine or appropriate succinimide in the temperature range of 50°-200°C, preferably 80°-150°C.

Stage (ii)-(v) can be performed as described above.

Compounds of the above formula (IX) can be obtained from compounds of the above formula (X) or the compounds of formula (XV)

in which R1and n are defined above.

Accordingly, the seventh version of the invention provides a method of obtaining compounds of the above formula (I), and this method includes:

(i) (a) accession trihalomethane-anion to connect the s in the above formula (X); or

(b) attaching trichloraceticaldehyde to the compound of the above formula (XV);

with the formation of compounds of the above formula (IX);

(ii) reaction of the compound of formula (IX) with an alcohol R-OH and trihalomethanes in the presence of a base with the formation of compounds defined above, of formula (V);

(iii) the esterification of the compounds of formula (V) with the formation of compounds of the above formula (III);

(iv) reaction of compounds of formula (III) with the compound defined above, of formula (IV) with the formation of compounds defined above, of formula (II); and

(v) reaction of compounds of formula (II) with the compoundin which L is defined above, to form compounds of formula (I).

Stage (i)(a) is best done in a solvent such as a hydrocarbon, e.g. hexane, cyclohexane, methylcyclohexane or toluene; chloropetalum, for example, dichloromethane or chlorobenzene; a simple ether, for example diethyl,tert-butyl methyl ether, dioxane or tetrahydrofuran; amide, e.g. N,N-dimethylformamide, N,N-dimethylacetamide or N-organic; or water. You can also use a mixture of solvents. Trihalomethane are derivatives of methane, in which the three hydrogen atoms replaced by identical or different halogen type fluorine, chlorine or bromine. Examples of such trihalomethanes are chloroform, brough the product, chlorodibromomethane or bromodichloromethane. You can also use salts of alkaline or alkaline earth metals or trigalogenmetany acids in the presence of appropriate trigalogenmetany acids, such as sodium salt of trichloroacetic acid or potassium salt of trichloroacetic acid in the presence of trichloroacetic acid. The reaction is best done in the temperature range from -80°C to 150°C, preferably in the range of 0-70°C.

Stage (i)(b) is conducted in a suitable solvent such as carbon disulphide; chloropetalum, for example, dichloromethane or chloroform; an aromatic compound, for example, chlorobenzene, dichlorobenzene, trichlorobenzene, nitrobenzene; simple ether, for example diethyl,tert-butyl methyl ether, dioxane or tetrahydrofuran. You can also use a mixture of solvents. Trichloraceticaldehyde are derived acetaldehyde, in which three hydrogen atoms replaced by identical or different halogen atoms, such as fluorine, chlorine or bromine. Examples of such trichloraceticaldehyde are trichloroacetaldehyde, fribromyalgia, chlorodibromomethane or bromochloroacetonitrile. The reaction is best carried out at temperatures in the range from -80°C to 150°C, preferably in the range from -10°C to 70°C.

Stage (ii)-(v) are as described above.

Connection of the particular above formula (XI) are obtained from compounds of the above formula (X).

Accordingly, the eighth variant of the present invention provides a method of obtaining compounds defined above, of formula (I), and this method includes:

(i) reaction of the compound of the above formula (X) with an alcohol R-OH in the presence of acid, with formation of the compound of the above formula (XI);

(ii) (a) the reaction of compounds of formula (XI) with tianyoude reagent; or

(b) (i) the reaction of compounds of formula (XI) with gloriouse reagent to form compounds of the above formula (XII) and then (ii) reaction of the compound of formula (XII) with tianyoude reagent

with the formation of the compound of the above formula (VI).

(iii) reaction of compounds of formula (VI) with an alcohol of the formula

in which A, m and m' are defined above, with formation of the compound of the above formula (III);

(iv) reaction of compounds of formula (III) with the compound of the above formula (IV) with the formation of compounds of the above formula (II); and

(v) reaction of compounds of formula (II) with the compoundin which L is defined above, to form compounds of formula (I).

Stage (i) is conducted in the presence of a suitable solvent such as a hydrocarbon, e.g. hexane, cyclohexane, methylcyclohexane or toluene; chloropetalum, for example, dichloromethane or chlorobenzene; a simple ester, e.g. the measures diethyl,tert-butyl methyl ether, dioxane or tetrahydrofuran. In a preferred embodiment, the alcohol R-OH is used as a solvent. You can also use a mixture of solvents. The reaction is carried out in the presence of acid, such as Pentecosta acid, for example, a strong mineral acid, including hydrogen chloride, hydrogen bromide or sulfuric acid; Lisowska acid, such as compounds of group III elements, such as boron TRIFLUORIDE; salt of the metal, e.g. zinc salts, such as chloride of zinc (II)bromide, zinc (II), iron salts such as iron chloride (III), cobalt salts such as cobalt chloride (II), salts of antimony, such as antimony chloride (V), salt scandium, such as triplet scandium (III)salts of yttrium, such as triplet yttrium (III), India salt, such as chloride, indium (III)salts of lanthanum, such as triplet lanthanum (III)or bismuth salt such as the chloride of bismuth (III)bromide bismuth (III). It is preferable to use the acid in substochiometric quantities. The reaction can also be carried out in the presence of artefiera, such as areavery lower alkylcarboxylic acids and lower alilovic alcohols, for example, triethylorthoformate, triethylorthoformate and triethylorthoformate or triethylorthoformate. It is preferable to use orthoepy, when the reaction products (ester and the alcohol can be removed and the reaction mixture by distillation. The reaction is best carried out at temperatures from -80°C to the boiling temperature of the reaction mixture, preferably in the range of 0°-100°C.

Stage (ii)-(v) are as described above.

Compounds of the above formula (XIII) can be obtained from compounds of formula (XVI)

in which R1, W and n are defined above.

Accordingly, the ninth variant of the invention provides a method of obtaining compounds of the above formula (I), and this method includes:

(i) halogenoalkane compounds of the above formula (XVI) with the formation of compounds of the above formula (XIII);

(ii) reaction of the compound of formula (XIII) with an alcohol of the formula

in which A, m and m' are defined above, with the formation of compounds defined above, of formula (VII).

(iii) reaction of compounds of formula (VII) with an alcohol R-OH, in which R is defined above, with formation of the compound of the above formula (III);

(iv) reaction of compounds of formula (III) with the compound of the above formula (IV) with the formation of compounds of the above formula (II); and

(v) reaction of compounds of formula (II) with the compoundin which L is defined above, to form compounds of formula (I).

Stage (i) is conducted as described in the patent Canada 967978, in the melt or in an inert solvent, such as chlorine the data hydrocarbons or chlorinated aromatic compounds, in the temperature range of 50-150°C.

Stage (ii)-(v) are as described above.

Compounds of formula (IV), (X), (XIV), (XV) and (XVI) are known in this area, and receive them easily accessible for professionals.

Alternatively, the compounds of formula (IV) can be obtained in a new way according to the following reaction scheme:

The methods of the prior art to produce compounds of formula (IVA) are associated with a significant quantity of water flows and/or the use of expensive catalysts; water drains must be processed (by decomposition of cyanide bleach or hydrogen peroxide)that is costly and leads to the effluent still contains toxic components.

In the above scheme, the compound (IVB) is converted into a compound (IVA) by using one of the following ways:

(i) by the reaction of compound (IVB) with a cyanide such as sodium cyanide or potassium (preferably in slight excess) at pH 5-9, preferably 6-7, with a subsequent decrease in pH below 3 or

(ii) by the reaction of compound (IVB) with HCN in an organic or aqueous solvent; or

(iii) by the reaction of compound (IVB) with acetonecyanohydrin in the presence of catalytic amounts of cyanide or a conventional Foundation.

The compound (IVA) then restore using H2/Pd-C and H2SO4/MeOH. In the first method, the H /Pd-C and H2SO4/MeOH added together and the process is carried out through an intermediate compound (IVA"); in the second method, first add H2SO4/MeOH with the formation of the intermediate compound (IVA') and subsequent reduction with H2/Pd-C.

Thus, the following variant of the invention provides a method of producing compound (IV), and this method includes:

(i) reaction of the compound (IVB)

(a) with a cyanide such as sodium cyanide or potassium (preferably in slight excess) at pH 5-9, preferably 6-7, with a subsequent decrease in pH below 3 or

(b) with HCN in an organic or aqueous solvent; or

(c) acetonecyanohydrin in the presence of catalytic amounts of cyanide or regular basis;

with the formation of compound (IVA), and

(ii) the reduction of compound (IVA) using H2/Pd-C and H2SO4/MeOH via an intermediate of the compound (IVA') or (IVA") and its tautomers with the formation of compound (IV).

Intermediate compound (IVA') and (IVA") and his "hydroxylamine" tautomer are also new substances and comprise the following variant of the invention.

Obtaining the compounds of formula (II) from compounds of formula (III) is a new method proposed and accordingly makes the following variant of the present invention.

Many premiato the basic compounds of formula (II), (III), (V), (VI), (VII), (XI) or (XII), especially when R1represents a halogen, for example, 4-chloro, are also new and therefore offer another variant of the invention.

The reaction scheme depicting all possible the reaction described above, is shown in Figure 1.

Hereinafter the invention will be illustrated in the following examples:

Example 1: 1-(Bis-prop-2-Unlocker)-4-chlorobenzene-(4-chlorobenzaldehyde-diprophylline)(compound of formula (XI)

4-Chlorobenzaldehyde (14.3 g) are added to propargilovyh alcohol (56,6 g) and concentrated hydrochloric acid (0.1 ml). The reaction mixture was stirred and heated to 80°C. and Then continuously add triethylorthoformate (11.9 g) for 1 hour. The reaction mixture was stirred at 85°C for 5 hours and some substances are distilled off. The reaction mixture is cooled to room temperature. Addtert-butyl methyl ether (200 ml). The organic phase is washed with 40% solution of acidic sodium sulfite (2 x 200 ml), dried (sodium sulfate) and evaporated. Get 1-(bis-prop-2-Unlocker)-4-chlorobenzene (18,8 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): 2,45 (t, 2H); 4,15 (DD, 2H); 4,3 (DD, 2H); to 5.85 (s, 1H); to 7.35 (d, 2H); was 7.45 (d, 2H).

Example 2: 1-Chloro-4-(chlorpro-2-Unlocker)benzene(compound of formula (XII)

1-(Bis-about the-2-Unlocker)-4-chlorobenzene (11,7 g) are added to acetylchloride (19.9 g) and thionyl chloride (0.2 ml) for 1 hour. Using the periodic cooling support temperature of 20°C. the Reaction mixture was stirred at room temperature for 20 hours. The reaction mixture is evaporated at 20-30°C in vacuum. Get 1-chloro-4-(chloro-prop-2-Unlocker)benzene (13,4 g) in the form of oil.

1H-NMR (CDCl3) δ (ppm): 2,6 (t, 1H); and 4.6 (d, 2H); 6.75 in (s, 1H); to 7.35 (d, 2H); was 7.45 (d, 2H).

Example 3: (4-Chlorophenyl)-prop-2-indexicality(compound of formula (VI)

1-Chloro-4-(chlorpro-2-Unlocker)benzene (13,0 g) are added to a sodium cyanide (3.1 g) in N,N-dimethylformamide (40 ml) for 2 hours at room temperature. The reaction mixture was stirred at room temperature for 3 hours and then poured into water (200 ml)containing sodium hydroxide (4 g). The aqueous phase is extracted withtert-butylmethylamine ether (2 x 200 ml). The organic phase was washed with water (2 x 50 ml), combined, dried (sodium sulfate) and evaporated. Receive (4-chlorophenyl)prop-2-indexicality (9.2 grams), purified flash column chromatography on silica gel using a mixture of ethyl acetate/hexane as the eluate.

1H-NMR (CDCl3) δ (ppm): 2,6 (t, 1H); 4,4 (d, 2H), and 5.5 (s, 1H); of 7.4-7.5 (m, 4H).

Example 4: (4-Chlorophenyl)-prop-2-indexicality(compound of formula (VI)

In the atmosphere of nitrogen trimethylsilylacetamide (3.1 g) are added to br the Ministry of foreign Affairs of bismuth (III) (0,22 g) and 1-(bis-prop-2-Unlocker)-4-chlorobenzene (6.7 g) in dichloromethane (50 ml) at room temperature. The reaction mixture is stirred for 48 hours at room temperature and then poured into 0.5 M hydrochloric acid (50 ml). The organic phase is separated, dried (magnesium sulfate) and evaporated. Get raw (4-chlorophenyl)-prop-2-indexicality (3.7 g) in the form of oil.

1H-NMR (CDCl3) δ (ppm): 2,6 (t, 1H); 4,4 (d, 2H), and 5.5 (s, 1H); of 7.4-7.5 (m, 4H).

Example 5: Methyl ether (4-chlorophenyl)-prop-2-innoxiously acid(compound of formula (III)

A mixture of (4-chlorophenyl)-prop-2-isolatsiooniriba (6.4 g) and 37% hydrochloric acid (12,6 g) in methanol (40 ml) is heated under reflux for 16 hours. The reaction mixture is cooled to room temperature and add water (25 ml). The aqueous phase is extracted with ethyl acetate (2×25 ml). The combined organic phases washed with water (1×25 ml), dried (sodium sulfate) and evaporated. Get the crude methyl ester (4-chlorophenyl)prop-2-innoxiously acid in the form of oil.

1H-NMR (CDCl3) δ (ppm): 2,5 (t, 1H);3,7 (s, 3H); 4,15 (DD, 1H); 4,3 (DD, 1H); 5,2 (s, 1H); 7.3 to 7.5 (m,4H).

Example 6: (4-Chlorophenyl)-prop-2-innoxiously acid(compound of formula (V)

a) a Mixture of potassium hydroxide (23,4 g, content analysis 90%) in propargilovyh alcohol (70 ml) is added to 4-chlorobenzaldehyde (7.2 g) and chloroform (13,4 g) in propargilovyh alcohol (10 ml) for 5 hours at 50°. The reaction mixture was stirred at 50°C for another 3 hours. After cooling to room temperature, add water (150 ml). The resulting mixture was extracted withtert-butylmethylamine ether (150 ml). The organic phase is again extracted with 4M potassium hydroxide (50 ml). The aqueous alkaline extracts are combined and acidified (pH<3) with concentrated hydrochloric acid. The aqueous phase is extracted withtert-butylmethylamine ether (2×150 ml). The combined organic phases, extracted with water (1×100 ml), dried (magnesium sulfate) and evaporated. Receive (4-chlorophenyl)-prop-2-innoxiously acid (7.7 g) in the form of oil, which solidified upon standing.

b) 4-Chlorobenzaldehyde (7.2 g) in propargilovyh alcohol (15 ml) is heated to 50°C. a Mixture of potassium hydroxide (31,2 g, content analysis 90%) in propargilovyh alcohol (150 ml) and the mixture bromoform (13 g) in propargilovyh alcohol (15 ml) are added simultaneously over 1 hour at 50°C. the Reaction mixture was stirred at 50°C for another 5 hours. After cooling to room temperature, add water (150 ml). The resulting mixture was extracted withtert-butylmethylamine ether (150 ml). The organic phase is again extracted with 4M potassium hydroxide (50 ml). The aqueous alkaline extracts are combined and acidified (pH < 3) with concentrated hydrochloric acid. The aqueous phase is extracted withtert-butylmethylamine ether (2×150 ml). The organic phase of Yedinaya, extracted with water (1×100 ml), dried (magnesium sulfate) and evaporated. Receive (4-chlorophenyl)-prop-2-innoxiously acid (10.4 g) in the form of oil, which solidified upon standing.

1H-NMR (CDCl3) δ (ppm): 2,5 (t, 1H); 4,15 (DD, 1H); 4,3 (DD, 1H); 5,2 (s, 1H); 7.3 to 7.5 (m, 4H); of 7.2 to 9.5 (s, ush., 1H).

Example 7: 2,2,2-Trichloro-1-(4-chlorophenyl)ethanol(compound of formula (IX)

A mixture of 4-chlorobenzaldehyde (35.5 g) and trichloroacetic acid (61,5 g) in N,N-dimethylformamide (200 ml) was stirred at 30-35°C. the Sodium salt of trichloroacetic acid (71,5 g) added in portions over 20 minutes Periodically require cooling. The reaction mixture was stirred at 30°C for 2 hours. Blend until the end remains viscous, and it added N,N-dimethylformamide (150 ml). The reaction mixture was poured into water (700 ml). The aqueous phase is extracted with ethyl acetate (600 ml). The organic phase is separated, washed with water (300 ml), dried (magnesium sulfate) and evaporated. Get 2,2,2-trichloro-1-(4-chlorophenyl)ethanol in the form of oil.

1H-NMR (CDCl3) δ (ppm): 4,1 (, ush., 1H); 5,2 (s, 1H); and 7.3 (d, 2H); at 7.55 (d, 2H).

Example 8: 2,2,2-Trichloro-1-(4-chlorophenyl)ethanol(compound of formula (IX)

A mixture of chlorobenzene (1400 g) and trichloroacetaldehyde (384 g) was stirred at 0-2°C. aluminum Chloride (274 g) added in portions in the course of 110 minutes at the same temperature. Mix the period of the Cesky cool. The reaction mixture was stirred at 0-5°C for 5 hours. The reaction mixture was poured into a mixture of ice water (3000 g). The organic phase is separated, washed three times with water (500 g), dried (sodium sulfate) and evaporated. Get 2,2,2-trichloro-1-(4-chlorophenyl)ethanol in the form of oil.

1H-NMR (CDCl3) δ (ppm): 4,1 (, ush., 1H); 5,2 (s, 1H); and 7.3 (d, 2H); at 7.55 (d, 2H).

Example 9: (4-Chlorophenyl)-prop-2-innoxiously acid(compound of formula (V)

To the mixture propargilovyh alcohol (300 g) and 2,2,2-trichloro-1-(4-chlorophenyl)ethanol (501 g) add a 15% solution (1820 g) of sodium hydroxide and propargilovyh alcohol within three hours at 70-75°C. the Mixture is periodically cooled. The reaction mixture was stirred at the same temperature for 3 hours. After distillation, the greater part of the solvent the residue is cooled to room temperature and add a mixture of water with ethyl acetate. The organic phase is again extracted with 2M sodium hydroxide (50 ml). United water-alkaline extract is acidified (pH<3) with concentrated hydrochloric acid. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases, extracted with water, dried (sodium sulfate) and evaporated. Receive (4-chlorophenyl)prop-2-innoxiously acid (10.4 g) in the form of oil.

1H-NMR (CDCl3) δ (ppm): 2,5 (t, 1H); 4,15 (DD, 1H); 4,3 (DD, 1H); 5,2 (s, 1H); 7.3 to 7.5 (m, 4H); of 7.2 to 9.5 (s, ush., 1H).

p> Example 10: 2-(4-Chlorophenyl)-N-[2-(3-methoxy-4-prop-2-injectively)ethyl]-2-prop-2-iniatiated(compound of formula (I)

To a solution of 1 mol of 2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated in 500 ml of toluene added 207 g of potassium carbonate (1.5 mol) and 10 g of tetrabutylammonium bromide. The mixture is heated to 90°C and add to 1.4 mol propargylamine in the form of a 35% solution in toluene for 30 minutes After 3 hours, the conversion of 2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated ends. For dissolution of salts added 500 ml of water and separated from the phase of product in toluene. The toluene is completely evaporated at 80°C/20 mbar and replaced by methanol. The product 2-(4-chlorophenyl)-N-[2-(3-methoxy-4-prop-2-injectively)ethyl]-2-prop-2-iniatiated crystallized from solution upon cooling to 0°C, filtered and washed with 200 ml of methanol at 0°C. the Product is dried at 50°C in vacuum. Get 315 g of 2-(4-chlorophenyl)-N-[2-(3-methoxy-4-prop-2-injectively)ethyl]-2-prop-2-iniatiated with 98% purity according to LC. Melting point =94-96°C.

Example 11: 2-(4-Chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated(compound of formula (II)

To a solution of 1 mol of (4-chlorophenyl)-prop-2-innoxiously acid 2-[2-(4-chlorophenyl)-2-prop-2-indexicality]-these are the new ether ("glycaemia") 500 g of chlorobenzene (obtained from 1 mol of (4-chlorophenyl)prop-2-innoxiously acid) is added to 1.05 mol of 4-(2-amino-ethyl)-2-methoxyphenol ("AE-phenol") and 0.3 mol of Diethylaminoethanol. The reaction mixture is heated to 90-100°C and chlorobenzene is distilled off in vacuum. After stirring for 3-4 hours at 90-100°C the transformation of glycaemia ends. Add 500 g of toluene and 250 ml of water. After stirring for 5 min at 50-70°C, the aqueous phase is separated. To the toluene phase, add 250 ml of water and establish a pH of 0.5-1.0 using 32% aqueous hydrochloric acid solution to remove excess AE-phenol and dimethylaminoethanol. The aqueous phase is separated and the toluene phase 2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated optional add 20 g of bleaching agent Prolith rapid, stirred for 30 min at 50-60°C and then filtered. Toluene filtrate containing the product 2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated exit 92% (according to LC), directly used in the next stage. 2-(4-Chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated can be partially distinguished by crystallization/filtration from toluene solution at -10°C with the release of 224 g (60% per gelcoater). Melting point = 93-95°C.

Example 11a: 2-(4-Chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated(compound of formula (II)

To a solution of 1 mol of (4-chlorophenyl)-prop-2-innoxiously acid 2-[2-(4-chlorophenyl)-2-prop-2-ynyloxy is ethoxy]ethyl ester (glycaemia") 500 g of chlorobenzene (obtained from 1 mol of (4-chlorophenyl)prop-2-innoxiously acid) is added to 1.05 mol of 4-(2-amino-ethyl)-2-methoxyphenol ("AE-phenol") and 0.3 mol of Diethylaminoethanol. The reaction mixture is heated to 90-100°C and chlorobenzene is distilled off in vacuum. After stirring for 3-4 hours at 90-100°C the transformation of glycaemia ends. Add 500 g of toluene and 250 ml of water. After stirring for 5 min at 50-70°C, the aqueous phase is separated. To the toluene phase, add 250 ml of water and establish a pH of 0.5-1.0 using 32% aqueous hydrochloric acid solution to remove excess AE-phenol and dimethylaminoethanol. The aqueous phase is separated and the toluene phase 2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated optional add 20 g of bleaching agent Prolith rapid, stirred for 30 min at 50-60°C and then filtered. To the toluene filtrate add 12% solution of Na2CO3or 50% solution K2CO3and establish a pH of about 8.5-10.5 removal of by-products with acid fragments. The organic layer containing the product 2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated exit 92% (according to LC), directly used in the next stage. 2-(4-Chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated can be partially distinguished by crystallization/filtration from toluene solution at -10°C with the release of 224 g (60% of theory calculated on gelcoater). Melting point = 93-95°C.

Example 12: 2-Hydroxyethyloxy ether (4-chlorophenyl)prop-2-noxiousnet acid or 2-[2-(4-chlorophenyl)-2-prop-2-indexicality]ethyl ester (4-Chlorophenyl)-prop-2-innoxiously acid (compound of formula (III)

To a solution of (4-chlorophenyl)prop-2-innoxiously acid (1 mol) in 600 g of chlorobenzene add 0.75 mol of ethylene glycol and 4 gp-toluenesulfonic acid and heated in vacuum under reflux at 90°-100°C. the Water of reaction is separated from the condensate and chlorobenzene return to the reactor. After 1 hour etherification ends. At the end of distilled 100 g of chlorobenzene. The reaction mixture contains a mixture of mono - and diesters of ethylene glycol, which directly without allocating converted into 2-(4-chlorophenyl)-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-prop-2-iniatiated at the next stage (example 11).

Example 13: Methyl ether (4-chlorophenyl)prop-2-innoxiously acid(compound of formula (III))

To a solution of (4-chlorophenyl)prop-2-innoxiously acid (1 mol) in 500 g of chlorobenzene is added 2 mol of methanol, 1 mol trimethylol ether orthomorphisms acid and 4 gp-toluenesulfonic acid. The mixture is heated to 50-60°C and incubated for 2-3 hours before the end of the esterification of (4-chlorophenyl)prop-2-innoxiously acid. Low-boiling substances such as methanol and methylformate distilled off in vacuum at 50-60°C. the Solution "methyl ester" in chlorobenzene can be directly converted into II in the next stage without selection. After removal of the solvent vacuume get 245 g butter, containing 236 g methyl ester (4-chlorophenyl)prop-2-innoxiously acid (according to the analysis by GLC).

1H-NMR (CDCl3) δ (ppm): 2,5 (C, HC≡); 3,7 (s, OCH3) (4,2+4,3 (2D, CH2); 5,2 (1C, CH); to 7.35(4H, Ar)

Example 14: (4-Chlorophenyl)prop-2-innoxiously acid(compound of formula (V)

Loaded into the reactor with stirring, 500 g of chlorobenzene, 177-187 g of potassium hydroxide 90-95% (3.0 mol) and 112 g propargilovyh alcohol (2 mol). At 15-20°C, add a solution of 1 mole of bromo-(4-chlorophenyl)acetic acid in 800 g of chlorobenzene (or the reaction mixture of 1 mole of bromo-(4-chlorophenyl)acetic acid/carboxylic acid described in example 15a) via addition funnel over 2 hours. The reaction mixture was incubated for 1-2 hours until the conversion of the bromo-(4-chlorophenyl)acetic acid. The reaction mass is diluted with 500 ml of water and set pH 0.5 with hydrochloric acid at 35-40°C. the Aqueous phase is separated from the organic phase of the product and then distilled 800 g of chlorobenzene in vacuum at 90-100°C. the Remaining solution contains chlorobenzene 218 g (4-chlorophenyl)prop-2-innoxiously acid according to LC analysis (yield 97% per bromo-(4-chlorophenyl)acetic acid). A solution of (4-chlorophenyl)prop-2-innoxiously acid in chlorobenzene can be used directly in the next stage.

"Proargi the OIC acid", ie (4-chlorophenyl)prop-2-innoxiously acid, can be partially distinguished by concentration to 50% of the solution and crystallization/filtration at 0°C. to About 170 g (4-chlorophenyl)prop-2-innoxiously acid can be isolated in crystalline form. Melting point =69-70°C.

Example 15: Bromo-(4-chlorophenyl)acetic acid(compound of formula (VIII)

Download under stirring in a reactor with a reflux condenser (connected with the alkaline scrubber) 171 g of 4-chlorophenylalanine acid in 750 g of chlorobenzene and added 41 g of phosphorotrithioite (0.3 mol). The mixture is heated to 100-110°C and via addition funnel is added 280 g of bromine (about 1.75 mol) for 1 hour. The reaction mixture is stirred for 3-4 hours at 110-115°C until complete conversion of 4-chlorophenylalanine acid (control by LC). The reaction mixture is cooled to 50°C and add 100 ml of water. The excess bromine is decomposed with a solution of NaHSO3. In the reaction mixture set pH 1 with aqueous NaOH solution and then the organic product is separated from the aqueous phase. Phase chlorobenzene contains 237 g of bromo-(4-chlorophenyl)acetic acid according to LC analysis (yield =95% (based on 4-chlorophenylalanine acid). "Bracelate", i.e. bromo-(4-chlorophenyl)acetic acid, can be partially distinguished by concentration to 50% of the solution and crystallization/filtration is the situation at 0°C. Approximately 200 g of bromo-(4-chlorophenyl)acetic acid can be isolated in crystalline form. Melting point =92-93°C.

1H-NMR (CDCl3) δ (ppm): 5,3 (s, 1H); to 7.4 (4H, Ar); and 9.7 (1H, OH).

Example 15a: Bromo-(4-chlorophenyl)acetic acid(compound of formula (VIII)

In a reactor with a reflux condenser (connected with the alkaline scrubber) with stirring download 171 g of 4-chlorophenylalanine acid in 400 g of chlorobenzene and heated to 105°C. Added 42 g of thionyl chloride for 30 min at 105-110°C with the formation of partially carboxylic acid. To the reaction mixture add 256 g of bromine (1.6 mol) for 90 min at 105-108°C. the Reaction mixture is stirred for 2-3 hours at 105-108°C until complete conversion of 4-chlorophenylalanine acid (monitoring by HPLC). The excess bromine is distilled off in the form of a mixture of bromine/chlorobenzene at 90°C to achieve a vacuum of 250 mbar and change the color of the reaction mixture from brown to yellow. Distilled bromine can be re-used in the next operation. The reaction mixture containing a mixture of bromo-(4-chlorophenyl)acetic acid and acid chloride, diluted with chlorobenzene to the mass of 800 g, and it can be turned directly into (4-chlorophenyl)prop-2-innoxiously acid according to example 14.

Example 16: Bromo-(4-chlorophenyl)acetylchloride(compound of formula (XIII)

In a reactor with a reflux condenser (connected with the alkaline scrubber) with stirring download 171 g of 4-chlorophenylalanine acid (1 mol) in 600 g of toluene and 7 g of dimethylformamide. The mixture is heated to 50°C and injected under the surface 125 g of phosgene in 2-3 hours. The toluene is completely distilled off in vacuo and to the residue of the acid chloride of 4-chlorophenylalanine acid type 226 g of bromine at 90°C for 1-2 hours. For complete conversion the reaction mixture is stirred for another hour and then pumped to remove excess bromine. The orange residue 290 g contains about 260 g of acid chloride of 4-chlorophenylpiperazine acid (97%, based on a 4-chlorophenylalanine acid), defined in the form of methyl ester by LC.

1H-NMR (CDCl3) δ (ppm): 5,7 (s, 1H); to 7.4 (s, 4H, Ar)

Example 17: Prop-2-injuly ether (4-chlorophenyl)prop-2-innoxiously acid(compound of formula (III)

To a mixture of 70 ml propargilovyh alcohol and 35 ml of N-ethyldiethanolamine add 14 g of bromo-(4-chlorophenyl)acetylchloride for 15 min at 0-5°C with the formation of the compounds of formula VII. Then the reaction mixture is heated to 60°C and stirred at this temperature for 8 hours with the formation of the above compounds of formula (III). The reaction mixture is poured into 400 ml of a mixture of ice/water. Set pH 3 using hydrochloric key is lots and the product is extracted 3 times with diethyl ether (100 ml). The combined extracts dried over MgS4and the solvent is evaporated at 50°C in vacuum. Remains 12 g of a brownish oil.

1H-NMR (CDCl3) δ (ppm): 2,45+2,55 (2C, HC≡); 4,2+4,7 (2kV., CH2); 5,3 (1C, CH); of 7.4 (4H, Ar).

Example 18: 4-(l-Hydroxyacetanilide)-2-methoxyphenol(compound of formula (IVA))

A1.In a 1 l round bottom flask was added 80 g (0,52 EQ), 4-hydroxy-3-methoxybenzaldehyde (compound (IVB), vanillin) in 135 g of water at 5°C. After 2 hours, was added 90 g (0,64 EQ) 35% solution of sodium cyanide and 78 g (0.68 EQ) of 32% hydrochloric acid, simultaneously adjusting the pH between 6.5 and the temperature at 5°C. At the end of the addition the suspension was stirred for 6-8 hours at a pH of 6.5 and 5°C to complete the reaction. Then he set the pH 1-2 using 32% HCl and added to 160 g of methyltert-butyl ether (MTBE) extraction of cyanhydrin in an organic solvent. Two-layer mixture was stirred at room temperature for 1 hour. Then the stirrer was stopped and the layers were separated; the lower aqueous layer was separated and the layer methyl-tert-butyl ether was added 0.8 g (0.01 EQ) Chloroacetic acid to stabilize cyanhydrin before removing the solvent. A solution of methyl-tert-butyl ether drove under reduced pressure at 40-60°C (100-500 mbar) and got 93 g (yield 94%) of compound (IVA) as a yellow oil or crystalline substance.

A2.In a 1 l round bottom flask suspended 100 g (0,64 EQ), 4-hydroxy-3-methoxybenzaldehyde (compound (IVB), vanillin) and 165 g of water at ordinary temperature. Then, the resulting suspension is cooled with active stirring to 15°C and stirred for further 30 minutes Add 130 g (0.8 EQ) of 30% solution of sodium cyanide and 130 g (0.4 EQ) of 30% sulfuric acid in a parallel regulation for 4-6 hours pH level of 6.0-6.5 and the temperature at 15°C. At the end of the supplementation of the reaction mass start stirring until crystallization of the product, and then stirred suspension of 2 hours at pH 6.5 and 15°C to complete the reaction. Then set pH≤1 using about 2 g of 30% sulfuric acid and added 170 g of methyltert-butyl ether (MTBE). The product is extracted in the organic layer under stirring for 1 hour at 25-30°C. thereafter, the stirrer is stopped and the layers are separated, the lower aqueous layer is separated and the layer MTBE was added 1 g (0.01 EQ) Chloroacetic acid to stabilize cyanhydrin before removing the solvent. Solution in MTBE then distilled under reduced pressure at 40-60°C (100-500 mbar) and obtain 112 g (yield 96%) of compound (IVA) as a yellow oil or crystalline residue.

A3. In a 1 l round bottom flask suspended 160 g (1.03 EQ), 4-hydroxy-3-methoxybenzaldehyde (compound (IVB), vanillin) in 160 g of water at room temperature. the ATEM add 4 g of methyl tert-butyl ether (MTBE) and the resulting suspension is cooled with vigorous stirring to 15°C. Then establish pH 7.0 and 7.5 with about 4 g of 10% NaOH. Then to suspension of vanillin/water with stirring to 85 g (1,26 EQ) 40% aqueous solution of HCN within 30-60 minutes At the end of the addition of HCN (if necessary) establish a pH of 6.5 or 20% sulfuric acid, or 10% Paon. Reaction mass quickly brightens, and then it is stirred for 3 hours at 15°C and a pH of 6.0 to 6.5. Usually during the mixing begins crystallization of the product from the clear solution and immediately upon completion of the crystallization, the suspension is stirred for 1-2 hours to complete the reaction.

Then set pH≤1.5 adding approximately 3 g of 20% sulfuric acid and then added 170 g of methyltert-butyl ether (MTBE). The product is extracted in the organic layer under stirring for 1 hour at 25-30°C. thereafter, the stirrer is stopped and the layers are separated, the lower aqueous layer is separated and the layer MTBE was added 1 g (0.01 EQ) Chloroacetic acid to stabilize cyanhydrin before removing the solvent. Then the MTBE solution is distilled under reduced pressure at 40-60°C (100-500 mbar) and get 180 g (yield 96%) of compound (IVA) as a yellow oil or crystalline residue.

B.In a 50 ml round bottom flask with mechanical stirrer, thermometer, reflux condenser with scrubber to absorb the off-gas (1:1 NaOCl:NaOH) has established an inert atmosphere. A solution of HCN in tetrahydrofuran (THF) (17% mass/mass) prepared prior to this experience by known literature methods. To the reactor was added potassium hydroxide (0,026 g, 0.02 EQ) and a solution of hydrogen cyanide in THF (5,02 ml, 1.5 EQ) and then THF (5 ml). Vanilla (of 3.07 g) was dissolved in THF (5 ml) and added to the reactor with stirring for several minutes. The reaction mass was stirred at ambient temperature for 3.5 hours (a small amount of white solid pale yellow liquid) and then analyzed quantitatively by HPLC to determine the output. Conversion of 90%; yield 83%.

C.Into the flask containing 8.5 g of acetonecyanohydrin (1 equiv), in portions added 15.2 g of vanillin (1 EQ) for 1 hour. After stirring for 1 hour was added 0.8 ml of 35% aqueous solution of sodium cyanide (of 0.05 EQ). The mixture stood at room temperature for 5 days and then stubbed out the reaction by adding 75 g of methyltert-butyl ether (MTBE) and 9 g of water. Analysis of the organic layer by HPLC showed that vanillylamide was formed with a yield of 36%, and only the designated component was neproreagirovavshimi vanilla.

Example 19: 4-amino-ethyl-2-methoxyphenol(obtaining the compounds of formula IV via the intermediate compound IVA")

In a 300 ml reactor pressure was placed 30 ml of methanol and 31.1 g of 98% sulfuric KIS is the notes (1.41 equiv). Added a suspension of 3.8 g of the catalyst is 5% palladium on charcoal (0.004 EQ) in 10 ml of methanol, followed by washing with 10 ml of methanol. In the reactor under a pressure of 5 bar of hydrogen at a temperature of 20-25°C were introduced 100 g of a 40% solution of unilinearity in methanol (1 EQ of unilinearity) for 4 h and then washed 15 ml of methanol. Was stirred 20 min, then the pressure dropped and added 75 ml of water. This mixture was stirred at 45°C to dissolve the product and then the catalyst was filtered. The precipitate of the catalyst on the filter is washed with water (3×25 ml), wash water was combined with the mother liquor and got 315 g of a solution containing 10.0% of AE-phenol according to HPLC (yield 86%).

1. The method of obtaining the compounds of formula (I)

in which:
R represents a C2-C8quinil;
R1represents a C1-C8alkyl, C2-C8alkenyl,2-C8quinil,3-C8cycloalkyl,3-C8cycloalkyl-C1-C8alkyl, phenyl and panels1-C8alkyl, and each of these groups, in turn, contains one or more identical or different halogen atoms; C1-C8alkoxyl; C2-C8alkenylacyl; C2-C8alkyloxy; C1-C8alkoxyl1-C8alkyl; Halogens1-C8alcox is l; With1-C8allylthiourea; Halogens1-C8allylthiourea; C1-C8alkylsulfonyl; formyl; alkanoyl; halogen; cyano; nitro-group; C1-C4dialkylamino; carboxyl; C1-C8alkoxycarbonyl; C2-C8alkenylacyl or2-C8alkyloxyalkyl; and n is 1, and the method includes:
(i) the esterification of the compounds of formula (V)

in which R, R1and n are defined above with a
alcohol of the formula

in which m and m' are independently 0 or 1; provided that both are not simultaneously equal to 0;
when one of m and m' are 0, and the other is 1 And represents landiolol, alkantiolsul or alcindoro group containing at least two carbon atoms (and better containing up to eight carbon atoms), optionally substituted by one or more groups independently selected from halogen, hydroxyl, C1-8alkoxyl, C1-4dialkylamino or cyanopropyl;
when m and m1both equal to 1, And represents alcantarilla, alcantarilla or alcantarilla group containing at least three carbon atoms (preferably containing up to eight carbon atoms), optionally substituted by one or more groups independently selected from halogen, hydroxy is and, With1-8alkoxyl, C1-4dialkylamino or cyanopropyl;
and in which, if a group contains three or more carbon atoms, one or more carbon atoms can optionally be replaced by oxygen atom, provided that at least one carbon atom between two oxygen atoms in the molecule, to obtain the compounds of formula (III)

in which R, R1and n are defined above for the compounds of formula (I), in which m, m' and As defined above for the compounds of formula

(ii) reaction of the compound of formula (III) with the compound of the formula (IV)

with the formation of the compounds of formula (II)

in which R, R1and n are defined above, and
(iii) reaction of compounds of formula (II) within which L is a leaving group, with the formation of compounds defined above, of formula (I).

2. The method of obtaining the compounds of formula (I) according to claim 1 in which the compound of formula (V) are obtained by a process comprising (a) reaction of compounds of formula (VIII)

in which R1, n and X are defined above for the compounds of formula (I) according to claim 1, with an alcohol of the formula R-OH in which R is defined above for the compounds of formula (I) according to claim 1; or (b) reaction of compounds of formula (IX)

in which R1and n are defined above for the compounds of formula (VIII), and each Y can be the same or different and represents a C1-C8alkoxygroup or halogen, with the alcohol R-OH, in which R is defined above for the compounds of formula (I), in the presence of a base; or (C) reaction of the compound of formula (X)

in which R1and n are defined above for the compounds of formula (I)with an alcohol R-OH, in which R is defined above for the compounds of formula (I), and trihalomethanes in the presence of a base.

3. The method of obtaining the compounds of formula (I) according to claim 1 in which the compound of formula (VI) are obtained by a method including (i) (a) the reaction of compounds of formula (XI)

in which R, R1and n are defined above for the compounds of formula (I) according to claim 1, tianyoude reagent; or
(b) (i) the reaction of compounds of formula (XI) with gloriouse reagent to form compounds of formula (XII)

in which R, R1and n are defined above,
(ii) followed by reaction of the compound of formula (XII) with tianyoude reagent.

4. The method according to claim 2, in which the compound of formula (VIII) are obtained by a method including
(i) halogenoalkane the compounds of formula (XIV)

in which R1and n are defined above for the compounds of formula (I) according to claim 1.

5. The method of obtaining compounds the Oia formula (I) according to claim 2, which compound of formula (IX) are obtained by a method including (i) (a) accession trihalomethane-anion to the compound of formula (X)

specified in paragraph 2, or (b) attaching trichloraceticaldehyde to the compound of formula (XV)

in which R1and n are defined above for the compounds of formula (I) according to claim 1.

6. The method of obtaining the compounds of formula (I) according to claim 3, in which the compound of formula (XI) are obtained by a process comprising (i) a reaction of the compound of formula (X) according to claim 2 with an alcohol R-OH in the presence of acid to form compounds of formula (XI) according to claim 3.

7. The method according to claim 1, in which R represents ethinyl, prop-1-inyl, prop-2-inyl, but-1-inyl, but-2-inyl, 1-methyl-2-butenyl, Gex-1-inyl, 1-ethyl-2-butinyl or Oct-1-inyl.

8. The method according to claim 7, in which R is a prop-2-inyl.

9. The method according to any one of claims 1 to 8, in which R1is a 4-chloro, 4-bromo, 4-methyl, 4-ethyl, 4-propargyloxy, 3-methyl, 4-fluoro, 4-ethynyl, 4-ethinyl, 4-propyl, 4-isopropyl, 4-tert-butyl, 4-ethoxyl, 4-itineracy, 4-phenoxy, 4-methylthiourea, 4-methylsulphonyl, 4-cyano, 4-nitro-group, 4-methoxycarbonyl, 3-bromo, 3-chloro, 2-chloro, 4-trifluoromethyl, 4-trifloromethyl, 4-methoxyl.

10. The method according to claim 9, in which R1is a 4-chlorine.

11. The method of obtaining the compounds of formula (II) according to claim 1

moreover, the method includes the reaction of the compound of formula (III) according to claim 1

with the compound of the formula (IV)

12. The intermediate compound of formula (II)

formula (III)

or of the formula (XII)

according to claims 1 and 3, respectively.

13. The intermediate compound of formula (XI) according to claim 3, where R1is a 4-chlorine.

14. The intermediate connection section 12, where R1represents a halogen.

15. The intermediate connection 14, where R1is a 4-chlorine.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to new compounds of formula (I) where X is carboxylic acid, carboxylates, carboxylic anhydride, diglyceride, triglyceride, phospholipid, or carboxamides, or to any their pharmaceutically acceptable salt. The invention particularly refers to (4Z, 7Z, 10Z, 13Z, 16Z, 19Z)-ethyl 2-ethyldocosa-4,7,10,13,16,19-hexanoate. The invention also refers to a food lipid composition and to a composition for diabetes, for reducing insulin, blood glucose, plasma triglyceride, for dislipidemia, for reducing blood cholesterol, body weight and for peripheral insulin resistance, including such compounds. Besides, the invention refers to methods for treating and/or preventing diabetes, dislipidemia, peripheral insulin resistance, body weight reduction and/or weight gain prevention, insulin, blood cholesterol, blood glucose and/or plasma triglyceride reduction.

EFFECT: higher clinical effectiveness.

61 cl, 4 tbl, 16 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: method of regioselective obtainment of 1-R1-2-R2-3-acetyl-glycerol derivative of the Formula 1 involves the following stages: Obtainment of 1-R1-3-(protective group)-glycerol of Formula 3 by adding protective group to 3rd position in 1-R1-glycerol of Formula 2; obtainment of 1-R1-2-R2-3-(protective group)-glycerol of Formula 4 by adding R2 group to 2nd position of 1-R1-3-(protective group)-glycerol of Formula 3, where R2 group is added by reaction of R2-OH with 1-R1-3-(protective group)-glycerol in the presence of aprotic organic solvent, catalyst and dehydrating medium; aprotic organic solvent is selected out of group consisting of hexane, heptane, dichloromethane, ethyl acetate, tetrahydrofuran and mixes thereof; dimethylaminopyridine is catalyst; and dicyclohexylcarbodiimide is dehydration medium; simultaneous removal of protective group and acetylation of 1-R1-2-R2-3-(protective group)-glycerol of Formula 4, where protective group removal reaction and acetylation reaction are performed using Lewis acid and acetic anhydride or using acetylation agent; Lewis acid is selected out of group including zink chloride (ZnC2), tin chloride (SnCl2), boron trifluoride diethyl ether (BF3Et2O) and mixes thereof; acetylation agent is selected out of group including acetylchloride, acetylbromide and mixes thereof, where compounds of Formulae 1-4 are racemic or optically active; R1 is palmitic acid group, R2 is linoleic acid group; P is trityl or trialkylsilyl as protective group; alkyl in trialkylsilyl is an alkylic group containing 1-5 carbon atoms, so that if the protective group is trityl then 1-R1-3-(protective group)-glycerol is obtained in the presence of pyridine solvent at 40-60°C or in the presence of nonpolar aprotic organic solvent and organic base within 0°C to room temperature range; nonpolar aprotic organic solvent is selected out of group including pyridine, dichloromethane, tetrahydrofuran, ethyl acetate and mixes thereof; organic base is selected out of group including triethylamine, tributylamine, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU) and mixes thereof, and if the protective group is trialkylsilyl then 1-R1-3-(protective group)-glycerol is obtained in the presence of aprotic organic solvent and organic base within 0°C to room temperature range; aprotic organic solvent is selected out of group including dichloromethane, tetrahydrofuran, ethyl acetate, dimethylformamide and mixes thereof; and organic base is selected out of group including imidazole, triethylamine, and mixes thereof. [Formula 1] , [Formula 2] , [Formula 3] , [Formula 4] .

EFFECT: obtainment of glycerol derivative with high efficiency and output.

8 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I) and their pharmaceutically acceptable salts and esters. In the general formula (I) X means oxygen (O) or sulfur (S) atom; R means hydrogen atom (H) or (C1-C6)-alkyl; R1 means H, -COOR, (C3-C8)-cycloalkyl or (C1-C6)-alkyl, (C2-C6)-alkenyl or (C1-C6)-alkoxyl and each of them can be unsubstituted or comprises substitutes; values of radicals R2, R3, R4, R5 and R6 are given in the invention claim. Also, invention relates to a pharmaceutical composition based on compounds of the general formula (I) and to intermediate compounds of the general formula (II) and the general formula (III) that are used for synthesis of derivatives of indane acetic acid. Proposed compounds effect on the blood glucose level and serum triglycerides level and can be used in treatment of such diseases as diabetes mellitus, obesity, hyperlipidemia and atherosclerosis.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 6 tbl, 6 sch, 251 ex

The invention relates to an improved process for the preparation of ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid, which is an intermediate product, suitable for the synthesis of idebenone - drug nootropic action

The invention relates to ester compounds, method of their production and their use as a means for spooling the fiber

The invention relates to organic chemistry, namely the method of obtaining the ethyl ester of 10-(2,3,4-trimetoksi-6-were) decanoas acid - intermediate, suitable for the synthesis of idebenone - drug nootropic action

The invention relates to compounds of the formula

< / BR>
in which R1and R2each independently represents CNS group containing 1 to 4 carbon atoms, R3- H or acylcarnitine group containing 2 to 5 carbon atoms, R4- CNS group containing 1 to 4 carbon atoms, in free form and also, if such exist, in the form of salt

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing biologically active pluripotential compounds - 2-methyl-4-halogen-phenoxyacetates of tris-(2-hydroxyethyl)-ammonium of general formula given below referred to as chlorocresacin and bromocresacin respectively, by reacting 4-halogen-substituted 2-methyl-phenoxyacetic acid, where the halogen is chlorine or bromine, with triethanolamine. 4-halogen-substituted 2-methyl-phenoxyacetic acid is obtained via chlorination with sulphuryl chloride, where catalyst used is aluminium powder in an ester solution and bromation is carried out using elementary bromine in a glacial acetic acid medium. The obtained compounds have proven to be highly efficient biologically active substances with unique physiological action, for example as biostimulators or adaptogen. The method is characterised by replacement of chlorine gas with sulphuryl chloride which is more suitable for use in preparations. .

EFFECT: method enables to obtain desired products with high degree of purity.

2 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of anionic surfactants, specifically to methods of producing carboxymethylates of oxyethylated alkylphenols used as components of detergents for domestic and industrial purposes - intensification of oil extraction processes by increasing ratio of extraction of oil from oil deposits. The method of producing oxyethylated alkylphenol-based anionic surfactants is realised through condensation of oxyethylated alkylphenols with sodium monochloroacetate in molar ratio 1.0:(0.8-1.0) in nitrogen medium while heating in the presence of an alkaline agent at 45-50°C. The alkaline agent used is crystalline potassium hydroxide taken in molar ratio to the oxyethylated alkylphenol equal to (0.7-1.0):1.0 or its mixture with crystalline sodium hydroxide in the same molar ratio to the oxyethylated alkylphenol. After condensation, a hydrogen ion concentration (pH) regulator is added to the reaction mixture in molar ratio of pH regulator to the oxyethylated alkylphenol equal to (0.01-0.1):1.0 until attaining pH of the reaction mixture of 8.0-9.0. The anionic surfactant is stored without partial decomposition and resin formation for not less than 100 days.

EFFECT: efficient method of producing anionic surfactants.

4 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry of organochlorine compounds, and specifically to an improved method of producing chlorine-substituted aryloxycarboxylic acids through chlorination of acids of general formula

where R1 is H, haloid, C1-C4alkyl, n is an integer ranging from 1 to 3, or salts thereof with subsequent extraction of the end product, wherein the chlorinating agent used is solid calcium hyprochlorite in the absence of solvents, and the process is activated by mechanical action in form of impact or impact-shear loading the mixture of solid reagents.

EFFECT: method increases output and purity of the end product, and also simplifies the process technology.

5 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to perfection of the method of making aryl hydrocarboxylic acids, which are widely used as herbicides. The method involves a stage of obtaining alkali phenolate from reaction of the respective phenol with a hydroxide of an alkali metal, a stage of obtaining salts of monochloroacetic acid from reaction of salts of monochloroacetic acid with the obtained alkali phenolates, with heating and subsequent acidification and separation of aryl hydrocarboxylic acids. The process of obtaining alkali phenolates and salts of monochloroacetic acid is carried out in a solid phase with fine grinding and intense mixing at the same time.

EFFECT: increased output and quality of the end product, as well as simplification of the technology.

6 cl, 7 ex

The invention relates to a method for aryloxyalkanoic acid of General formula I, where X=-C(Et)=C(Et)-; -CH(Et)-CH(Et) - which is used as a source of products to obtain conjugates with proteins in the development of immunochemical methods for the determination of hormones, and also exhibits antioxidant and anti-inflammatory properties
The invention relates to organic synthesis and applies the selection method 2,4-D acid

The invention relates to a method for producing 4-chlorophenoxyacetic or 2,4-dichlorophenoxyacetic acid (2,4-D)

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2,2'-dichlorodiethylformal. The method is realised by reacting ethylene chlorohydrin and paraformaldehyde in the presence of magnesium sulphate or magnesium chloride crystalline salt. 2,2'-dichlorodiethylformal is extracted by salting out the organic phase by saturating with magnesium salt solution. Excess ethylene chlorohydrin is then distilled from the organic phase.

EFFECT: low concentration of ethylene chlorohydrin in synthesis wastes, low expenses on recycling wastes, high environmental safety of production.

4 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of di-(β-chloroethyl)formal, which is the basic material in synthesis of polysulphide oligomers (thiocols), capable of cold curing to obtain sealants with unique properties. Method involves reacting ethylene chlorohydrin with formaldehyde in molar ratio (2.25-2.7):1, in the presence of dry gaseous hydrogen chloride as an acid catalyst with subsequent azeotropic distillation of the reaction water in the presence of 1,2-dichloroethane as a resolving agent.

EFFECT: method enables to obtain an end product with high output and selectivity.

6 cl, 1 tbl, 12 ex

Up!