The method of obtaining r(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3 - phenyl-3-cyclohexen-1-yl)methyl]pyrid ina or its pharmaceutically acceptable salts, intermediate compounds and methods for their preparation

 

(57) Abstract:

Describes improved platitudinal way to obtain R-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl) methyl] pyridine from 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid. In addition, ways in which separation of the stereoisomers of 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid using cinchonidine to obtain (S)-5-oxo-3-phenyl-3-cyclohexenecarboxylic acid or a-chymotrypsin for the selective hydrolysis of the n-butyl ester 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid to obtain (S)-5-oxo-3-phenyl-3-cyclohexenecarboxylic acid. Describes and other valuable intermediate compounds used in the proposed methods of production. The method uses inexpensive source materials and is suitable for large-scale synthesis. 11 C. and 28 C.p. f-crystals.

In U.S. patent N 5314896, which is here referred to, describes a number of tools acting on the Central nervous system. It also describes pharmaceutically acceptable salts of these compounds.

The compounds mentioned in the above U.S. patent, useful as dopaminergic funds. As dopaminergic means these substances are useful for the treatment of plectrohyla menstruation and sexual dysfunction. They are also useful as antihypertensive agents. Especially valuable protivopsychoticheskogo means is (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1 - yl)methyl] pyridine.

The methods described in U.S. patent N 5314896, being extremely inefficient in terms of overall output and time-consuming, very useful to perform multiple substitutions on the aryl group in the cyclohexane ring and the variation of substitution in the amine portion of the molecule. In the stage of dehydration during synthesis were also isomers of 2,3-cyclohexene, which could be separated by chromatography for biological testing. In addition, obtaining salt 1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1 - yl)methyl] pyridine with (R)-(-)-1,1-binaphthyl-2,2'-diyl-phosphate with subsequent recrystallization and isolation of the free base has led to (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen - 1-yl)methyl] pyridine, which was evaluated biologically.

It also describes several other ways to obtain (R)-(+)-1,2,3,6 - tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl] pyridine and related compounds. So, Johnson S. J., and others, 206-I national Conference of the American Chemical Society, H is result intramolecular cyclization according to Wittig, where the starting compound is an irritant and lacrimator and the procedure requires the separation of intermediate racemic Yong-acid with the loss of more than 50% of the substance. In addition, Johnson and others and Wustrov D. and others, Tetrahedron Letters 35:61 (1994), described the methodology desoxyribose ketone when using triethylsilane and lithium perchlorate in diethyl ether reagents are not suitable for large-scale synthesis. Wright J., and others, 206-I national Conference of the American Chemical Society, Chicago, Illinois, August 1993, MEDI, outlined the path of the desired connection, requiring separation of the stereoisomers of intermediate compounds, which leads to more than 50% loss of the desired intermediate. Downing D. M., and others, 208-I national Conference of the American Chemical Society, Washington, D. C., August 1994, MEDI-178, and Downing, D. M., and others, 206-I national Conference of the American Chemical Society, Chicago, Illinois, August 1993, MEDI - 173, presented different approaches to the desired connection involving multiple chromatography and repeated separation of stereoisomers, which lead to the exit of less than 50% at the stage of separation. Finally, Wise, L. D., and others, 208-I national Conference of the American Chemical Society, Washington is easemera to obtain (R)-(+)-1,2,3,6 - tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine.

These synthetic methods have allowed to establish the structural constraints for the activity in biological use. However, they are not suitable for large-scale production methods because they involve multiple chromatographic operations, inefficient separation of the intermediate compounds, use of harmful reagents and result in low overall yield.

The object of the present invention is an improved method of obtaining (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen - 1-yl)methyl] pyridine, as described above, when using a new synthesis. Next, we unexpectedly found that particularly valuable dopaminergic agent, maleate (R)-(+)-1,2,3,6-tetrahydro-4-phenyl - 1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine, can be obtained from the new intermediate compounds with fewer stages without chromatography, without a loss of more than 50% of the substances in division (RS)-a mixture of 1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3 - cyclohexen-1-yl)methyl] pyridine and with higher yields than in previous methods. In addition, the present method uses inexpensive source materials and is suitable for large-scale synthesis.

Brief description of the invention

Thus, p and its pharmaceutically acceptable salts, including

stage (a) treating racemic compounds of formula VIII

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cinchonidine in a solvent to obtain compounds of formula VII

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stage (b) treatment of compounds of formula VII in a solvent to obtain after acidification of the compounds of formula VI

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stage (C) treatment of compounds of formula VI, a compound of formula V

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in the presence of reagent combinations and solvent in order to obtain the compounds of formula IV

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stage (d) treatment of compounds of formula IV regenerating reagent in a solvent to obtain a mixture of compounds of formula IlI and formula IIIB

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stage (d) processing the mixture of compounds of formula IlI and formula IIIB with a mixture of zinc chloride and laborgerate sodium in the solvent, and then a solution of carboxylic acid in a solvent to obtain compounds of formula II

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stage (e) treatment of compounds of formula II regenerating agent representing a metal hydride, in a solvent to obtain compounds of formula I;

stage (f) and, if desired, converting the compounds of formula I to a corresponding pharmaceutically acceptable salt of the addition of acid, the OI salt, the resulting accession acid, compound of formula I using conventional methods.

The second aspect of the present invention is a method of obtaining the compounds of formula VI

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including

stage (a) treating racemic compounds of formula VIII

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cinchonidine in a solvent to obtain compounds of formula VII

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and stage (b) treatment of compounds of formula VII in a solvent to obtain after acidification of the compounds of formula VI.

The third aspect of the present invention is a method of obtaining the compounds of formula VI

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includes treatment of the racemic compounds of formula IX

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in the solvent at a pH of about 5 using a-chymotrypsin order to obtain, after separation of unreacted ether complex and acidification of the compounds of formula VI.

The fourth aspect of the present invention is a method for obtaining compounds of formula II

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including

stage (a) treating racemic compounds of formula VIII

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cinchonidine in a solvent to obtain compounds of formula VII

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stage (b) treatment of compounds of formula VII in the implementation of the formula VI with compounds of formula V

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in the presence of reagent combinations and solvent in order to obtain the compounds of formula IV

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stage (d) treatment of compounds of formula IV regenerating agent in a solvent to obtain a mixture of compounds of formula IlI and formula IIIB

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and stage (d) processing the mixture of compounds of formula IIIA and formula IIIB with a mixture of zinc chloride and laborgerate sodium in the solvent, and then a solution of carboxylic acid in a solvent to obtain compounds of formula II.

The fifth aspect of the present invention is a method of obtaining compounds of formula IlI and formula IIIB

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including

stage (a) treating racemic compounds of formula VIII

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cinchonidine in a solvent to obtain compounds of formula VII

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stage (b) treatment of compounds of formula VII in a solvent to obtain after acidification of the compounds of formula VI

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stage (C) treatment of compounds of formula VI with compounds of formula V

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in the presence of reagent combinations and solvent in order to obtain the compounds of formula IV

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and the stage (g) treatment of compounds of formula IV regenerating agent in solvent C which is a method of obtaining the compounds of formula IV

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including

stage (a) treating racemic compounds of formula VIII

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cinchonidine in a solvent to obtain compounds of formula VII

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stage (b) treatment of compounds of formula VII in a solvent to obtain after acidification of the compounds of formula VI

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stage (C) treatment of compounds of formula VI, a compound of formula V

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in the presence of reagent combinations and solvent in order to obtain the compounds of formula IV.

The seventh aspect of the present invention is a new intermediate compound of formula IlI or formula IIIB

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suitable for obtaining compounds of formula II, which in turn suitable for receiving protivopsychoticheskogo the compounds of formula I.

The eighth aspect of the present invention is a new intermediate compound of formula IV

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can be used to produce compounds of formula IlI or formula IIIB, which in turn can be used to produce compounds of formula II, the latter in turn suitable for receiving protivopsychoticheskogo the compounds of formula I.

The ninth aspect of the present invention is a new intermediate compound forms which the compounds of formula IlI or formula IIIB, which in turn can be used to produce compounds of formula II, which in turn suitable for receiving protivopsychoticheskogo the compounds of formula I.

The tenth aspect of the present invention is a new intermediate compound of formula VII

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The eleventh aspect of the present invention is a new intermediate compound of formula IX

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can be used to produce compounds of formula VI, which in turn can be used to produce compounds of formula IV, which in turn can be used to produce compounds of formula IlI or formula IIIB, which in turn can be used to produce compounds of formula II, the latter in turn suitable for receiving protivopsychoticheskogo the compounds of formula I.

Detailed description of the invention

In this invention the term "alkyl" means a hydrocarbon group with a normal or branched chain, containing from 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-amyl, n-hexyl and the like groups.

"Alkali metal" means a metal of group IA of the periodic table of elements and includes, for example, lithium, three is for example, hydrochloric acid, Hydrobromic acid, sulfuric acid and the like acid.

"Carboxylic acid" means an organic acid, which comprises, for example, acetic acid, propionic acid, butyric acid, trimethyloxonium acid and the like acid.

"Mixing metal" means reducing agent, which includes litebrite, detribalized, calibrite and similar borhydride.

"Reducing agent representing the metal hydride" means reducing agent which restores amides of carboxylic acids and which includes alumoweld lithium, bis(2-methoxyethoxy)alumoweld sodium and the like.

"Apparatus" means a reaction system with a fridge, allowing you to fend off the solvent.

"Reactor" means a reaction system with a fridge, allowing you to return the solvent directly into the reaction system.

The compound of the formula I are capable of further accession acids to form pharmaceutically acceptable salts. All of these forms are within the scope of the present invention.

Pharmaceutically acceptable salts of the compounds of formula I, obtained when s is, for example, hydrochloric, nitric, phosphoric, sulfuric, Hydrobromic, itestosterone, phosphoric and the like acids, and salts obtained when using non-toxic organic acids, such as aliphatic mono - and dicarboxylic acids, phenylsilane alcamovia acid, hydroxyalkanoate acid, arcangioli acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.

These salts include, therefore, sulfate, persulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, hydrogen phosphate, dihydrophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, kaprilat, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, bansilalpet, toluensulfonate, phenyl acetate, citrate, lactate, maleate, tartrate, methanesulfonate and the like. Also discusses salts of amino acids, as, for example, arginate and the like and gluconate, galacturonic (see, for example, Berge S. M., and others , "Pharmaceutical salts", Journal of Pharmaceutical Science. 66:1 - 19 (1977).

To obtain these basic salts of the compounds with the acid substance in the form of a free base is subjected to interaction with the base can be regenerated in the interaction of salt with the base and the allocation of free base accepted way. Substances in the form of free bases differ from their respective salt in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free bases from the point of view of the purposes of the present invention.

As previously shown in U.S. patent N 5314896, compound of formula I is useful as dopaminergic funds, as determined using methodology known to those studies. The compound of formula I possesses activity typical of protivopsychoticheskogo tools.

The method described by the present invention in its first aspect is a new, improved, economical, and commercially feasible method of obtaining protivopsychoticheskogo means of formula I. the Process of obtaining according to the present invention is presented in scheme I (see the end of the description).

The compound of formula VIII is obtained from benzoylacrylic acid using a modification of the method described Julia S. and Y. Bonnet. Bull. Soc. Chim., 1354-1364 (1957).

Thus, the compound of formula VIII is dissolved in a solvent, for example alcohol containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl sleep is the boiling point of the solvent, and the resulting solution was treated with a suspension or solution cinchonidine in the same solvent, to obtain a salt with cinchonidine formula VII. If necessary, salt to achieve a higher enantiomeric purity is subjected to recrystallization from an alcohol containing 1 to 4 carbon atoms, such as, for example, methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like. Compound of formula VII is dissolved in a solvent, for example in alcohol containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like, at a temperature of from about 25oC to a temperature of about the boiling point of the solvent. The suspension or solution is subjected to treatment with an aqueous solution of alkali metal hydroxide, such as caustic soda, caustic potash and the like, to form a salt of the alkali metal compounds of the formula VI. The alcohol is removed by vacuum distillation and partially replaced by water, the crystalline cinchonidine return when filtering. The aqueous filtrate containing salt of an alkali metal compound of the formula VI, processed by an excess of solution of mineral acid, cooled and filtered receive the connection f is the standard. The compound of formula VI is subjected to drying in a vacuum at a temperature of from about 55oC to 80oC for approximately 24 to 48 hours to a moisture content of less than 0.2%.

The compound of formula VI is subjected to processing reagent combinations, such as a reagent or reagents that activate the acid, as, for example, carbonyldiimidazole or 1-(3-dimethylaminopropyl)-3 - ethylcarbodiimide, hydrate of 1-hydroxybenzotriazole and triethylamine and the like. The activated acid was processed compound of formula V, 4-phenyl-1,2,3,6-tetrahydropyridine or hydrochloride 4-phenyl-1,2,3,6-tetrahydropyridine and triethylamine in an inert solvent, such as acetonitrile, tetrahydrofuran and the like. The amide formation occurs at a temperature of from about 0oC to a temperature of about the boiling point of the solvent for about 3 to 24 hours. The reaction is stopped with addition of an aqueous solution of bicarbonate, carbonate or hydroxide of an alkali metal, for example sodium bicarbonate, sodium carbonate, sodium hydroxide and the like. The compound of formula IV is extracted with an inert water-immiscible solvent, such as toluene, diethyl ether, tert-butyl methyl ether and the like. The solution is washed with the focus and instead of solvent added alcohol, containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like. The solution is cooled to a temperature of from about -5oC to 25oC and the compound of formula IV is isolated by filtration. The compound of formula IV can be dried in the vacuum, if it must be stored, or used wet in the next reaction.

The compound of formula IV is dissolved in a solvent, for example, in alcohol containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like or their aqueous mixtures, and add reducing agent, such as a metal borohydride, such as detribalized and others like him, in the form of solid or solution. The mixture is stirred for about 3 to 24 hours at a temperature of between approximately 15oC and 35oC. was Added an aqueous solution of ammonium chloride and the mixture is cooled to about 0 to 5oC. a Mixture of compounds of formulas IlI and IIIB is isolated by filtration and dried in vacuum at a temperature of from about 25oC to 55oC to a water content less than 0.2%.

Compounds of formula IlI and IIIB mixed with anhydrous zinc chloride, lamborghini.com sodium we, as, for example, acetic acid, propionic acid, butyric acid, trimethylarsine acid and the like, in an inert solvent, such as, for example, hexane, heptane, tetrahydrofuran and the like at a reaction temperature from about 25oC to 35oC. the Mixture is stirred for from about 6 to 24 hours and added an aqueous solution of ammonium chloride. The compound of formula II is filtered through the enclosed filter and the solid residue washed with water. The solid is dissolved in a solvent such as, for example, tetrahydrofuran, tert-butyl methyl ether or hot alcohol containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like, for removing substances from a closed filter. The solvent is removed by distillation and, if the solvent was not the alcohol, instead add alcohol containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like. The solution is cooled to a temperature of about 0 to 5oC and is isolated by filtering the compound of formula II. The compound of formula II is dried in vacuum until the solvent content less than 0.1%.

The compound of formula II suspender the new ether and the like, and process regenerating reagent, representing a metal hydride, such as, for example, alumoweld lithium and the like, in an inert solvent, such as tetrahydrofuran and the like at a temperature of from about 25oC to 55oC for about 3 to 4 hours. The solution is cooled to about 20 - 25oC. Add a certain amount of water in tetrahydrofuran, and then a certain amount of a saturated aqueous solution of sodium sulfate. The resulting suspension is heated to approximately 50 - 60oC and inorganic salts removed by filtration. The inert solvent is distilled off in a vacuum and instead add alcohol containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like. Can also be used acetonitrile. The solvent is then distilled off in vacuum and again instead add alcohol containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like. The solution is cooled to about 0 to 5oC and stirred for at least 2 hours. The compound of formula I is isolated by filtration.

The compound of formula I is dissolved in a minimum amount selavy alcohol and the like, at about the boiling temperature of the solvent. The solution process pharmaceutically acceptable acid, such as a suspension or solution of maleic acid in alcohol containing 1 to 4 carbon atoms, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol and the like. The solution is cooled to about 0 to 5oC and stirred for at least 2 hours. Salt of the compounds of formula I with maleic acid is isolated by filtration. Salt of the compounds of formula I with maleic acid is dried in a vacuum at a temperature of about 25 - 35oC for about 16 to 24 hours.

The method according to this invention in its third aspect is a new, improved, economical and commercially viable alternative method of obtaining the compounds of formula VI. Set the pH of a solution of racemic compound of formula IX

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in a solvent, such as water, approximately 5 using acid, such as dilute hydrochloric acid, and the like. The mixture is then subjected to treatment with chymotrypsin and supported by about pH 5 by addition of base, such as dilute sodium hydroxide and the like, when the ambient temperature is approximately 2.09 days. The reaction zakancivaetsa 50% of the racemic complex ester of the formula IX. Preferably the reaction is carried out in water at a pH of about 5 using dilute hydrochloric acid and dilute sodium hydroxide at ambient temperature to about 2.09 days. Unreacted ester is extracted and the salt of the acid with the alkaline metal is subjected to treatment with acid to obtain the compound of formula VI.

The compound of formula IX is obtained from the compounds of formula VIII

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the reaction with n-butyl alcohol in the presence of acid, such as sulfuric acid and the like, at temperatures from room temperature up to about 100oC for approximately 18 to 24 hours, the result is a compound of formula IX. Preferably the reaction is carried out using sulfuric acid at a temperature of about 50 - 55oC for about 22 hours.

The following limitiruyuschie example illustrates preferred by the inventors of the method of obtaining the compounds according to the invention.

Example 1. Maleate (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl - 3-cyclohexen-1-yl)methyl]pyridine

Stage A: Obtaining (S)-5-oxo-3-phenyl-3-cyclohexenecarboxylic acid

Method a: Method using cinchonidine

In the apparatus with a capacity of 400 l load 50.0 kg (231.4 mole) of 5-oxo-3-feie. The substance in the apparatus is heated to 70 - 75oC, the soluble substance. Charged to the reactor 50.0 kg (170 moles) cinchonidine and 275 l of isopropyl alcohol and begin mixing. The substance in the reactor is heated to 50 to 75oC to get moving easily transportable suspension. Suspension/solution is passed from reactor apparatus containing a solution of 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid. Charged to the reactor 31 l of isopropyl alcohol for cleaning. Wash the alcohol from the reactor is passed into the apparatus. Now you have finished the complete dissolution. The contents of the apparatus is cooled to 50 - 55oC over 1 hour. The temperature for the device is determined during the 50oC at least 2 hours. The temperature for the device is determined during the 40oC, at least 1 hour. The temperature for the device is determined during the 25oC, at least 10 hours. The contents of the apparatus is cooled to 0 to 5oC and stirred for at least 2 hours. The solid product from the apparatus is filtered on a centrifuge and the mother liquor is sent to the reactor for the regeneration of the substance. This is done in order to extract cinchonidine and (R)-5-oxo-3-phenyl-3-cyclohexanecarbonyl acid. Acupuncture is sent to the reactor for the regeneration of the substance. In the apparatus with a capacity of 200 l load obtained wet sludge from the centrifuge. In the apparatus with a capacity of 200 l load 50 kg of ethyl alcohol, 2B. The mixture is stirred and heated to boiling for about 15 minutes. The slow stirring and the temperature for the device is determined during the 25oC. Stirring is continued at least for 8 hours. The contents of the apparatus is cooled to 0 to 5oC and stirred for at least 2 hours. The solid product from the apparatus with a capacity of 200 l of filtered on a centrifuge and the mother liquor is sent to the reactor for regeneration. In the apparatus with a capacity of 200 l load 4 kg of ethanol, 2V, which is used for washing the precipitate. Wash the alcohol is sent to the reactor for regeneration. Approximately 10 g of solids is withdrawn from the centrifuge and the free acid is isolated by acidification with hydrochloric acid, extraction (twice) with ethyl acetate and concentration of the extract in a rotary evaporator. The resulting product analyzed by chiral high-performance liquid chromatography (HPLC). If the ratio of S:R is not greater than 99:1, recrystallization from ethanol, 2B, will give the opportunity to reach this level.

The salt from the centrifuge is loaded into the apparatus with a capacity of 400 l 67 kg the Mixture is stirred for about 1 hour at 20 25oC, the apparatus load 120 l of water. The alcohol is distilled off under vacuum with stirring at a temperature of 30 - 35oC to considerably reduce the speed of distillation. The contents of the apparatus is cooled to 20 to 25oC. In the apparatus serves nitrogen and the distillate is poured. The regenerated solid cinchonidine of the apparatus is subjected to filtering in the centrifuge. The filtrate is sent to the reactor. The regenerated cinchonidine washed on the centrifuge 20 l of water and the wash water is sent to the reactor. Wet regenerated cinchonidine send in a vacuum shelf dryer and dried at 35 5oC at least 24 hours at the highest possible vacuum. The regenerated cinchonidine can be re-used. The solution of sodium salt of the product in the reactor is treated with stirring 13 kg 37% chemically pure hydrochloric acid. the pH of the suspension test with indicator paper. the pH should be from 1.5 to 2.0. If the pH is above 2.0, add an additional 37% of chemically pure hydrochloric acid. The resulting suspension apparatus is stirred for about 1 hour and cooled to 5 to 10oC. (S)-5-Oxo-3-phenyl-3-cyclohexanecarbonyl acid of the apparatus is filtered on a centrifuge. The filtrate is poured. In the apparatus load 20 l of water and its ipakenyrob acid send in a vacuum shelf dryer and dried at 65 5oC at least 24 hours at the highest possible vacuum. Receive a 20 kg (S)-5-oxo-3-phenyl-3-cyclohexenecarboxylic acid in the form of solids from white to pale yellow; so pl. 111 - 113oC (uncorrected).

200 MHz1H NMR (deuterochloroform): 2.3 - 2.95 (m, 4H), 2.96 - 3.45 (m, 3H), 6.45 (s, 1H), 7.25 - 7.65 (m, 5H), 10.0 - 10.8 (ush. s, 1H).

Analysis by chiral HPLC: S-enantiomer 99.24%, the retention time of 26.9 minutes, R-enantiomer 0.76%, the retention time of 20.9 minutes

Conditions of chiral HPLC:

Column: Chiralpak AD, 250 x 4.6 mm

Flow rate: 1.0 ml/min

Mobile phase: 900 hexane/100 isopropanol/1 formic acid (o/o)

Wavelength: 254 nm

The injected volume: 20 l

Concentration of sample: 10.0 mg/10 ml in isopropanol

Retention time: the S-enantiomer 25-27 minutes, R-enantiomer 20-21 minutes

Column after use store in hexane/isopropanol (900:100) (o/o).

The effluent from the reactor for regeneration is passed into the apparatus. In the apparatus loaded with stirring 11.2 kg caustic soda, 50%, 100 l of water. The solvents are mixed and subjected to distillation in vacuum at 30 - 35oC as long as the speed of distillation is not significantly slowed down. The contents of the apparatus of the OHL is natural cinchonidine of the apparatus is filtered on a centrifuge and the mother liquor is sent to the reactor. The regenerated cinchonidine washed on the centrifuge 20 l of water and the wash water is sent to the reactor. Wet regenerated cinchonidine passed in a vacuum shelf dryer and dried at 35 5oC for at least 24 hours at the highest possible vacuum. The filtrate (solution of sodium salt of predominantly (R)-5-oxo-3-phenyl-3-cyclohexenecarboxylic acid) from the reactor is passed into the apparatus. In the apparatus loaded with stirring, 15 kg of chemically pure 37% hydrochloric acid. The resulting suspension apparatus is stirred for about 1 hour and cooled to 5 to 10oC. Solid (R)-5-oxo-3-phenyl-3-cyclohexanecarbonyl acid of the apparatus is filtered on a centrifuge. The filtrate is poured. In the apparatus load 20 l of water, which is used for washing the filter cake. The filtrate is poured. Wet (R)-5-oxo-3-phenyl-3-cyclohexanecarbonyl acid is passed into a vacuum shelf dryer and dried at 80 5oC at least 24 hours at the highest possible vacuum. The substance may be subjected to racemization in the compound of formula VIII from the sample And using standard techniques.

Method B: Method of using a-chymotrypsin

1 g of n-butyl ether 5-oxo-3-phenyl-3-cyclohexanecarbonyl Chillout approximately 80 ml of water and the mixture is stirred. Bring the pH of the mixture to 5.0 using dilute hydrochloric acid. To this solution was added 0.1 g ( 10% by weight) -chymotrypsin and washed with 20 ml water. The PH of the reaction mixture support at 5 by adding dilute sodium hydroxide solution, carrying out control using a laboratory pH meter. The reaction is carried out at ambient temperature. The reaction is stopped after 2.09 days, for example, when the consumption base is 90 - 100% of theoretical amount required for hydrolysis of 50% of the racemic mixture.

The ratio of (R)-ester to (S)-ether is 94:6.

The desired (S)-5-oxo-3-phenyl-3-cyclohexanecarbonyl acid is obtained upon acidification with diluted hydrochloric acid. The solid precipitate is filtered and dried in vacuum at 80 5oC at least 24 hours at the highest possible vacuum.

Stage B: Obtaining (S)-1,2,3,6-tetrahydro-1-[(5-oxo-3-phenyl-3 - cyclohexenyl)carbonyl]-4-phenylpyridine

Method AND

In the apparatus with a capacity of 400 l load 6.0 kg (27.8 mol) of (S)-5-oxo-3-phenyl-3-cyclohexenecarboxylic acid, 4.1 kg (30.3 mol) of hydrate of 1-hydroxybenzotriazole, 7.0 kg (31.6 mole) of the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 6.2 kg (33.4 mol)

the hydrochloride of 4-phenyl-1,2,3,6-tetrahydropyridine and the (45.5 mol) of triethylamine at a rate of about 0.3 kg/minute. The temperature of the mixture loaded support at 15 - 20oC. the Mixture in the apparatus is stirred for at least 6 hours and allow it to warm to ambient temperature.

In a reactor with a capacity of 200 l load 60.0 l of water and 4.0 kg (47.6 mole) of sodium bicarbonate and begin mixing. Aqueous sodium bicarbonate solution is passed from the reactor into the machine. In the apparatus load 80 l of water, and then 90.0 l of toluene. The mixture in the apparatus is stirred for at least 30 minutes and left for phase separation. The lower aqueous phase is drained from the apparatus into the reactor. In the apparatus load 50.0 kg of water. The mixture in the apparatus is stirred for at least 30 minutes and left for phase separation. The lower aqueous phase is drained from the apparatus into the reactor. Charged to the reactor toluene (30.0 l), the mixture in the reactor is stirred for 30 minutes and left for phase separation. The lower aqueous phase is poured into the system for chemical waste. Toluene phase from the reactor is passed into the apparatus. Charged to the reactor 50 l of water and 6.8 kg (65.7 mol) of chemically pure 37% hydrochloric acid. Diluted hydrochloric acid is passed from the reactor into the machine with a capacity of 400 liters of Aqueous hydrochloric acid extract is poured into the system for chemical waste. Charged to the reactor 40.0 l of water and 4.0 kg of chloride on the E. 20 minutes and leave for phase separation. The lower aqueous phase is poured from the apparatus in a system for chemical waste. The upper toluene phase containing the product from the apparatus with a capacity of 400 l is passed into the apparatus with a capacity of 200 l (for convenience, by distillation). Apparatus with a capacity of 200 l is intended for vacuum distillation in a reactor with a capacity of 200 L. the Temperature for a refrigerator set at 5 - 10oC and the solution concentrated to a volume of 20 5 l Temperature in the unit content is maintained below the 60oC. the Distillate was poured. In the unit load 30 kg of ethyl alcohol, 2B. The solution in the apparatus is cooled to 0 to 5oC and incubated for at least 2 hours. The solid product from the apparatus filtered on a centrifuge, directing the filtrate to the reactor. The product containing residues of alcohol and toluene, placed in a vacuum shelf dryer and dried at 40 5oC for at least 24 hours at the highest possible vacuum. The filtrate is passed from the reactor into the machine. The device is intended for vacuum distillation in the reactor. The filtrate is evaporated to 5 5 l Solution passed into the bottle with a capacity of 20 L. of Distillate is poured. The concentrated filtrate is cooled at 0, 5oC within 24 - 48 hours. The solid product is filtered on a Buechner funnel. Product content the highest possible vacuum. The dry product is placed in a lined plastic drums and store in a dry place at temperatures below 35oC.

Get 8.4 kg first portion of the product and 0.6 kg of the second portion of the product.

The product, (S)-1,2,3,6-tetrahydro-1-[(5-oxo-3-phenyl-3 - cyclohexenyl)carbonyl]-4-phenylpyridine, is a solid substance with a color from the not quite white to pale yellow; so pl. 137 - 141oC (uncorrected).

200 MHz1H NMR (deuterochloroform): 2.62 (m, 2H), 2.89 (m, 2H), 3.00 (m, 1H), 3.74 (m, 1H), 3.88 (m, 1H), 3.91 (m, 1H), 4.30 (m, 2H), 6.04 (m, 2H), 6.14 (s, 1H), 7.23 - 7.60 (m, 10H).

Method B

(S)-5-Oxo-3-phenyl-3-cyclohexanecarbonyl acid, 24.0 kg (111.1 mole), is loaded into the apparatus with a capacity of 200 l with 150.0 kg of acetonitrile. In a separate reactor download 20.0 kg (123.5 mole) of carbonyldiimidazole and 100.0 kg of acetonitrile. The solution in the reactor is cooled to 20 5oC. Solution of carbonyldiimidazole slowly passed from the reactor into the machine. The temperature of the contents of the apparatus is maintained at 25 5oC. was charged To the reactor 50.0 kg of acetonitrile, washed, and all passed from the reactor into the machine. The temperature of the mixture in the apparatus support at 20 - 30oC for 3 to 4 hours. The mixture in the apparatus is cooled to 10 to 15oC under stirring. In the apparatus sachlage to transfer substances are washed with 50.0 kg of acetonitrile and wash acetonitrile is sent to the device. In the unit load 12.0 kg (118.6 mole) of triethylamine, using a metering pump at a rate of about 1.0 kg/minute. The temperature of the contents of the support apparatus at 20 - 25oC. (If the use of the hydrochloride of 4-phenyl-1,2,3,6-tetrahydropyridine, download 24 kg of triethylamine). The mixture in the apparatus is stirred for at least 6 hours. The temperature of the contents of the device rises to the ambient temperature. Charged to the reactor 500 l of water and 10 kg (119 moles) of sodium bicarbonate, the mixture is stirred. An aqueous solution of sodium bicarbonate from the reactor slowly loaded into the apparatus. In the apparatus load 500 l of toluene. The mixture in the apparatus is stirred for about 30 minutes and left for phase separation. The lower aqueous phase from the device is passed into the reactor. In the apparatus load 200 l of water. The mixture in the apparatus is stirred for at least 15 minutes and leave for phase separation. The lower aqueous phase from the device is passed into the reactor. Charged to the reactor 100 l of toluene. The mixture in the reactor is stirred for about 15 minutes and left for phase separation. The lower aqueous phase from the reactor is poured. The upper toluene phase from the reactor is passed into the apparatus. Charged to the reactor 300 l of water, 12 kg of 37% chemically pure hydrochloric acid and the mixture is stirred. Diluted with water Solae 15 minutes and leave for phase separation. The lower aqueous phase from the apparatus poured. Charged to the reactor 300 l of water and 20 kg of sodium chloride. An aqueous solution of sodium chloride from the reactor is directed into the apparatus, the mixture is stirred for about 20 minutes and left for phase separation. The lower aqueous phase from the apparatus poured. The upper toluene phase containing the product from the apparatus to transmit portions in the smaller apparatus for distillation under vacuum. The smaller the device is intended for distillation under vacuum, and the solution in it is concentrated to a volume of about 60 5 l Temperature loaded in the apparatus, the reaction mixture is maintained below 65oC. the Distillate was poured. In the apparatus load 120 kg of ethyl alcohol, 2B. The solution in the apparatus is cooled to 0 to 5oC and incubated for at least 2 hours. The solid product from the apparatus filtered on a centrifuge. The filtrate is sent to the reactor. In the unit load 50 kg of ethyl alcohol, 2B. The mixture in the apparatus is stirred for at least 10 minutes and wash liquid is directed from the apparatus to the precipitate in the centrifuge. The filtrate is sent to the reactor. A solid product from a centrifuge transferred into a shelf dryer and, if necessary, is dried in vacuum. The product is usually used in the next stage wet. The filtrate is passed from the reactor into the machine. Will stereodivergent distillation to a volume of 10 l 50 The distillate is poured. The solution in the apparatus is cooled to 0 to 5oC for at least 2 hours. The solid product from the apparatus is filtered on a centrifuge. The filtrate is sent to the reactor. In the unit load 30 kg of ethyl alcohol, 2B. The mixture in the apparatus is stirred for at least 10 minutes and wash liquid is directed from the apparatus to the precipitate in the centrifuge. The filtrate was poured. A solid product from a centrifuge is placed in a shelf dryer and dried under vacuum, if necessary. The product is typically used in the next stage wet.

Stage: Obtaining (S)-1,2,3,6-tetrahydro-1-[(5-hydroxy-3 - phenyl-3-cyclohexenyl)carbonyl]-4-phenylpyridine

(S)-1,2,3,6-Tetrahydro-1-[(5-oxo-3-phenyl-3-cyclohexenyl)carbonyl] - 4-phenylpyridine, 8.4 kg (23.5 mole), is loaded into the apparatus with a capacity of 200 l with 30 kg of ethyl alcohol, 2B. The mixture in the apparatus is cooled to 15 5oC. was charged To the reactor 1.2 kg (32.4 mole) of detribalized and 30 kg of ethyl alcohol, 2B. The contents of the reactor is passed into the apparatus. The temperature of the mixture in the apparatus of the support 5 at 20oC. was charged To the reactor 15 kg of ethyl alcohol, 2B. Ethanol in the reactor is stirred for at least 3 minutes and passed into the apparatus. Suspension in a stirred apparatus, at least within 12 hours. The temperature is destroying 30 l of water and 5 kg (92.5 mole) of ammonium chloride. The ammonium chloride solution is directed from the reactor in the apparatus, using a metering pump at a rate of about 0.3 l/minute. If foaming occurs, reduce or slow down the addition to the disappearance of the foam. The solution in the apparatus is cooled in a nitrogen atmosphere to 0 5oC for at least 2 hours. The solid product from the apparatus is filtered on a centrifuge. The filtrate was poured. The wet product is passed into a vacuum shelf dryer and dried at 40 5oC for at least 24 hours at the highest possible vacuum.

Output (S)-1,2,3,6-tetrahydro-1-[(5-hydroxy-3-phenyl-3 - cyclohexenyl)carbonyl] -4-phenylpyridine is 6.38 kg (the first portion of the product) and 0.3 kg (the second portion of the product), the resulting product is a solid substance with a color from white to pale yellow; so pl. 162 - 167oC (uncorrected).

200 MHz1H NMR (deuterochloroform): 1.75 (m, 2H), 2.62 (m, 2H), 3.16 (m, 1H), 3.21 (m, 2H), 3.73 (m, 2H), 3.79 (m, 1H), 4.25 (m, 2H), 4.28 (m, 1H), 6.03 (s, 1H), 6.17 (m, 1H), 7.26 - 7.42 (m, 10H).

Assay (HPLC): 96.2% of the peak area (main isomer) and 1.7% of the peak area (minor isomer).

The HPLC conditions:

Column: YMC-AQ, C185 m, 250 x 4.6 mm

Flow rate: 1.5 ml/minute

Mobile phase: 600 acetonitrile/400 Resto mobile phase

*Solution A: 5.75 g sour one-deputizing ammonium phosphate dissolved in 1 l of water with purity for HPLC, add 6 ml of triethylamine and bring the pH to 3.0 using 85% phosphoric acid.

Stage G: Obtaining (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3 - phenyl-3-cyclohexenyl)carbonyl]pyridine

In the scrubber load 750 l of water and 300 kg of caustic soda, 50%. The scrubber must be connected with all parts of the equipment to remove for security purposes emitted during the process of hydrogen cyanide.

In the apparatus with a capacity of 400 l load 8.4 kg (23.4 mol) of (S)-1,2,3,6-tetrahydro-1-[(5-hydroxy-3-phenyl-3-cyclohexenyl)carbonyl] - 4-phenylpyridine, 3.8 kg (27.9 mol) of chloride of zinc, 3.5 kg (55.7 mol) of laborgerate sodium and 70 kg of heptane. The mixture in the apparatus of the mix. In a reactor with a capacity of 80 l load 15 kg of tetrahydrofuran and 5 kg (83.3 mole) of glacial acetic acid. The temperature is loaded in the apparatus support mixture at 25 5oC. a Solution of glacial acetic acid in tetrahydrofuran is passed from the reactor into the machine. The mixture in the apparatus is stirred for at least 6 hours at 25 5oC. In a reactor with a capacity of 80 l load 30 l of water and 5.3 kg (99 moles) of ammonium chloride and start paramashiva the awn about 1 liter/minute. The temperature is loaded in the apparatus of the mixture support 5 at 20oC. the Mixture in the apparatus is stirred for at least 30 minutes. Charged to the reactor 20 l of water and 3.6 kg (34.8 mol) of concentrated 37% hydrochloric acid.

Diluted hydrochloric acid is passed from the reactor into the machine using a metering pump at a rate of about 0.5 l/min. The temperature is loaded in the apparatus of the mixture support 5 at 20oC. the Mixture in the apparatus is stirred for at least 2 hours.

The apparatus used for distillation under vacuum with the application running under vacuum scrubber system. The solution is concentrated to a volume of approximately 350 50 HP Temperature is loaded into the apparatus a mixture of support below the 50oC. the Distillate, a mixture of heptane and tetrahydrofuran, and pour. Charged to the reactor 200 l of water.

Note: the Filtrate contains hydrogen cyanide, and the pair may contain hydrogen cyanide.

Sealed filter to separate the liquid droplets is tested before use in the manometer pressure nitrogen 1.0545 kg/cm2. Any pressure drop should not exceed 0.0703 kg/cm2the gauge over a period of 15 minutes. In other words, fix the leak and re-Prov l of tetrahydrofuran. The contents of the stirred apparatus and heated to 40 5oC. About 300 l of warm tertrahydrofuran ring solution is directed from the apparatus in a sealed filter. The product filter re-suspended and heated to 40 5oC, using water with a temperature of about 50oC in the jacket for coolant. The content is stirred and maintained at this temperature for at least 30 minutes.

Filter Poll is inserted at the entry gate of the device to remove any small particles. Warm tetrahydrofuran with the dissolved product of the above-mentioned filter is passed through the filter of the Poll in the apparatus. The rest of the warm tertrahydrofuran ring solution from the first apparatus to transmit the encapsulated filter. Content filter re-suspended and heated to 40 5oC using the shirt in water with a temperature of about 50oC. the Mixture is stirred and maintained at this temperature for at least 30 minutes. Warm tetrahydrofuran with the dissolved product is passed from the sealed filter through the filter of the Poll in the apparatus. Sealed filter was washed with 50 l of tetrahydrofuran through the spray nozzle. Wash tetrahydrofuran is directed through the filter Poll and tubing in the apparatus. Apparatus in which the od vacuum scrubber system. The solution is concentrated to a volume of approximately 60 20 L. the temperature of the contents in the apparatus of the support below the 50oC. In the apparatus with a concentrated solution of the product load 150 kg of absolute ethanol. In the apparatus conduct the distillation under vacuum. The solution is concentrated to a volume of approximately 60 20 L. the temperature of the contents of the device support below the 50oC. In the apparatus load 300 kg of absolute ethanol. The distillate, consisting of tetrahydrofuran and ethyl alcohol is poured. The mixture in the apparatus is stirred for about 1 hour at 75 5oC. the Solution in the apparatus is cooled in a nitrogen atmosphere to 0 5oC and incubated for at least 2 hours. The solid product from the apparatus is filtered on a centrifuge. The filtrate is sent to the reactor with a capacity of 80 litres per machine load 15 kg of ethyl alcohol, 2B. The mixture in the apparatus is stirred for at least 3 minutes and the wash liquid is passed from the apparatus to a centrifuge, while directing the filtrate to the reactor with a capacity of 80 liters of the Effluent from the reactor is passed into the apparatus with a capacity of 200 liter apparatus conduct the distillation under vacuum. The solution is evaporated to a volume of approximately 15 5 L. the temperature of the contents of the device support below 40 5oC. the Solution is passed into the bottle with a capacity of 20 liter Bottle with SPS send in a vacuum shelf dryer and dried at 40 5oC for at least 24 hours at the highest possible vacuum.

Output (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3 - cyclohexenyl)carbonyl] pyridine is 4 kg (the first portion of the product) and 0.5 kg (the second portion of the product), the resulting product is a solid substance with a color from white to pale yellow; so pl. 142 - 147oC (uncorrected).

200 MHz1H NMR (deuterochloroform): 1.91 (m, 2H), 2.37 (m, 2H), 2.52 - 2.61 (m, 1H), 3.77 (m, 2H), 3.88 (s, 1H), 4.24 (m, 2H), 5.29 (m, 2H), 6.04 (c, 1H), 6.14 (m, 2H), 7.23 - 7.42 (m, 10H).

Stage D: Obtaining (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3 - phenyl-3-cyclohexen-1-yl)methyl]pyridine

Capacity with absolute ethyl alcohol and placed in cold storage for future use for leaching. In the apparatus with a capacity of 200 l load 4.0 kg (at 11.64 mol) of (R)-(+)-1,2,3,6-tetrahydro - 4-phenyl-1-[(3-phenyl-3-cyclohexenyl)carbonyl] pyridine. In the apparatus load 44.4 kg of anhydrous tert-butyl methyl ether (containing less than 0.02% water).

In the apparatus load 16.6 kg (18 moles) of 1 M solution of lithium aluminum hydride in tetrahydrofuran at a feed rate of 0.1 to 0.5 kg/minute and the pressure of argon is less 0.8436 kg/cm2. The temperature is loaded in the apparatus of the mixture support at 30 - 45oC. This reaction is successful PR is the addition of stop, if the temperature rises above 45oC. is Cooled to a temperature below 45oC and resume addition.

Upon completion of addition, the supply line of lithium aluminum hydride was washed with approximately 5 kg of tetrahydrofuran. The washing solution is added to the apparatus. The mixture in the apparatus is stirred at 30 - 45oC for 3 to 4 hours. The mixture in the apparatus is cooled to 20 to 25oC. In glass bottles, placed in a metal canister, prepare a solution of 1.27 kg of water at 4.4 kg of tetrahydrofuran. A solution of 1.27 kg of water at 4.4 kg of tetrahydrofuran is loaded into the device using a metering pump from a speed of 0.05 - 0.1 l per hour to reduce foaming, then adding just complete solution at a speed of 0.1 - 0.5 l per hour. Prepare a saturated solution of sodium sulfate in water by mixing 1 kg of sodium sulfate with 5 kg of water in a glass bottle, placed in a metal canister. If the whole sulphate sodium has dissolved, add more sodium sulfate, there is some nerastvorimaya number. In the apparatus load 4 kg of saturated sodium sulfate solution using a metering pump with a rate of 0.1 - 0.5 l per hour. The temperature of the contents of the device up to 40 - 45oC. Suspe the capacity of 400 HP In the apparatus load 20 l of tetrahydrofuran (for washing) and heated to 40 - 45oC. Leaching tetrahydrofuran is directed through the filter into the reactor with a capacity of 400 liters Temperature solution of the product in the reactor support at 40 - 45oC.

The solution is passed into the apparatus and most of the solvent is distilled off under vacuum. Add absolute ethanol and most of the solvent is distilled off under vacuum. Add absolute ethanol and the solution is cooled to -10oC - 0oC for 1 to 2 hours, (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3 - cyclohexen-1-yl)methyl] pyridine is isolated by centrifugation. Separated by centrifugation the precipitate was washed with cold absolute ethanol and dried in vacuum. Store as well as the maleate.

Stage E: Getting maleate (R)-(+)-1,2,3,6-tetrahydro-4-phenyl - 1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine

A solution of the product in tetrahydrofuran after stage D is passed into the apparatus and subjected to distillation under vacuum. The temperature of the contents in the support apparatus at 25 - 75oC. In the apparatus load 100 l of absolute ethanol and most of the ethanol and tetrahydrofuran is distilled off in vacuum. Temperature maintain remaut to a gentle boil. In a reactor with a capacity of 200 l load 1.74 kg (15 mol) of maleic acid and 15.8 kg of absolute ethanol. The resulting suspension is stirred in the reactor and the temperature of the mixture support at 60 - 65oC. a solution of the product in ethanol was added to a solution of maleic acid or an alternative solution of maleic acid are added to a solution of the product in ethyl alcohol in a reactor with a capacity of 400 l and through the reactor purge argon.

The temperature of the contents of the reactor support at 50 - 55oC and stirred for 1 to 2 hours. Inorganic impurities are removed by filtration. In the reactor make, if necessary, diluted a little of the pure product.

The contents of the reactor is cooled to 35 - 40oC and stirred for 1 to 2 hours. The contents of the reactor is cooled to -10oC - -5oC and stirred for 1 to 2 hours. The solid product is separated in a centrifuge and the filtrate is sent to the reactor with a capacity of 400 liters was charged To the reactor 15.8 kg of cold absolute ethanol, which is then washed precipitate in the centrifuge. The filtrate is sent to the reactor with a capacity of 400 liters of Wet product with traces of ethyl alcohol is passed into a vacuum shelf dryer and dried at 30 5oC.

The second portion of the product:

The effluent from the reactor is passed into the apparatus. The filtrates evaporated in vacuum until the solution level is below the level of the agitator. In the apparatus load is the amount of absolute ethanol, so it was enough for mixing, and cooled the contents to a temperature of -10 to -5oC. the Distillate was poured. The solid product from the apparatus filtered on a centrifuge and the filtrate is poured. In a reactor with a capacity of 200 l load 8 kg of cold absolute ethanol. This leaching alcohol sent for washing the precipitate in the centrifuge, the filtrate is poured. Product with traces of alcohol send in a vacuum shelf dryer and dried at 30 to 5oC for at least 24 hours at the highest possible vacuum.

The dry product is placed in plastic bags lined inside double polyethylene, protected from moisture drums. The product is stored at temperatures below 35oC in a dry place.

Output Malcha) and 0.6 kg (the second portion of the product), the resulting product is a solid white or off-white in color.

200 MHz1H NMR (deuterochloroform): 1.65 - 1.80 (m, 1H), 1.93 - 2.05 (m, 1H), 2.05 - 2.25 (m, 4H), 2.25 - 4.20 (m, 9H), 6.0 (m, H), 6.08 (m, 1H), 6.15 (s, 2H), 7.15 - 7.45 (m, 10H); signals acidic protons maleic acid not observed.

Analysis (HPLC) (Area %): HPLC: not less than 98%.

Retention time (min) Area %

23.2 - 99.52

Impurities (HPLC Area %): Not more than 0.5% each

Retention time (min) Area %

6.50 - 0.04

6.90 - 0.28

9.40 - 0.01

11.50 - 0.06

18.50 - 0.07

21.0 - 0.01

21.50 - 0.01

Total impurities: 0.48%

Not more than 2.0%

Conditions of HPLC

Column: YMC-AQ, C18, 5 m, 250 x 4.6 mm

Flow rate: 1.5 ml/minute

Mobile phase: 350 acetonitrile/650 solution AND*(o/o)

Wavelength: 214 nm

The injected volume: 20 l

Concentration of sample: 5.0 mg/25 ml in mobile phase

*Solution A: 5.75 g sour one-deputizing ammonium phosphate dissolved in 1 l of water with purity for HPLC, add 6 ml of triethylamine and bring the pH to 3.0 using 85% phosphoric acid.

Titration of maleic acid: 26.00% (average of the two values)

theoretical value 26.05%

wearing according to chiral HPLC:HPLC:

Retention time (min) Area% Ratio

12.6 - not determ.(-)

Enantiomer (the limit of detection of 0.03%)

33.2 - 99.96%

Conditions:

Column: Chiralcel OJ, 250 x 4.6 mm

Flow rate: 1.0 ml/minute

Mobile phase: - 700 hexane/300 isopropyl alcohol (o/o)

Wavelength: 254 nm

The injected volume: 20 l

Concentration of sample: 10.0 mg/25 ml isopropyl alcohol (ultrasonic action for dissolution)

Preparation of starting compounds

Example A. 5-Oxo-3-phenyl-3-cyclohexanecarbonyl acid

In the apparatus with a capacity of 800 l load 53.9 kg (306 moles) 3-benzoylacrylic acid. In the apparatus with a capacity of 800 l load 41 kg (315 moles) of the ethyl ester of acetoacetic acid. In the apparatus load 150 l of water. Begin stirring the contents of the apparatus. In the apparatus load 56 kg (1475 moles) of 50% aqueous sodium hydroxide, and then 20 l of water. The resulting solution is stirred and the temperature of the contents of the support apparatus at 45 - 50oC for 16-18 hours after addition of caustic soda. The solution in the apparatus is then boiled for 20 - 24 hours ( 100oC). In a reactor with a capacity of 800 l load 140 liters of water and 90.6 kg (1100 moles) of concentrated hydrochloric acid, and then 20 l of water and begin agitation. R is batusim under atmospheric pressure. The cooled solution of the system (25 - 40oC) was added to diluted hydrochloric acid solution in the reactor at a rate of about 2 to 4 l/minute. In the apparatus load 100 l of water, which is passed into the reactor. Obtained in the reactor, the suspension is stirred at 25 - 40oC for 2 to 4 hours. The solid product from the reactor is filtered on a centrifuge. Charged to the reactor 100 liters of water and this water-washed precipitate in the centrifuge. Royal solutions and wash water is poured. In the apparatus load 100 l of water, this water is sent for washing the filter cake and the filtrate is poured. The wet precipitate of the product from the centrifuge is returned to the apparatus, then there fill in 400 l of water and the suspension is stirred for 2 to 4 hours. The solid product is filtered on a centrifuge. The apparatus and the filter cake washed with 200 l of water. The filtrate was poured. Wet 5-oxo-3-phenyl-3-cyclohexanecarbonyl acid send in a vacuum shelf dryer and dried at 80 5oC for at least 24 hours at the highest possible vacuum, receive 62.5 kg solids with color from the not quite white to pale yellow; so pl. 140 - 160oC (average of two determinations). The dried product is stored in drums lined with IsNot - 0.8 (ush.s, 1H).

Example B. n-Butyl ether 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid

A mixture of 5-oxo-3-phenyl-3-cyclohexenecarboxylic acid (example A) (216 g) and n-butyl alcohol (500 g) is treated with concentrated sulfuric acid (10 ml) under stirring. The mixture was kept at ambient temperature for 18 hours, heated at 50 - 55oC for 1 to 2 hours and then leave to cool. The solution is evaporated in vacuo to a residue in the form of oil. Oil poured into an excess of a saturated solution of sodium carbonate and extracted with toluene. Toluene extract is passed through a layer of silica gel and evaporated under reduced pressure at a temperature of 90 - 95oC. Receive the product in the form of oil; so bales. 150 - 155oC at 0. 01 mm RT. senior Purity according to HPLC is 96.9%, the impurity in the product is toluene.

200 MHz1H NMR (deuterochloroform): 0.87 - 1.1 (t, 3H), 1.1 - 1.8 (complex multiplet, 4H), 2.5 - 3.2 (complex multiplet, 4H), 2.5 - 3.2 (complex multiplet, 5H), 4.0 - 4.15 (t, 2H), 6.3 - 6.5 (s, 1H), 7.2 - 7.7 (complex multiplet, 5H).

1. The method of obtaining the compounds of formula I

< / BR>
and its pharmaceutically acceptable salts, including the stage of (a) processing of racemic compounds of formulas is to prepare the compounds of formula VII in a solvent to obtain after acidification of the compounds of formula VI

< / BR>
stage (C) treatment of compounds of formula VI, a compound of formula V

< / BR>
in the presence of reagent combinations and solvent in order to obtain the compounds of formula IV

< / BR>
stage (d) treatment of compounds of formula IV regenerating reagent in a solvent to obtain a mixture of compounds of formula IIIA and formula IIIB

< / BR>
stage (d) processing the mixture of compounds of formula IIIA and formula IIIB with a mixture of zinc chloride and laborgerate sodium in the solvent, and then a solution of carboxylic acid in a solvent to obtain compounds of formula II

< / BR>
stage (e) treatment of compounds of formula II regenerating agent representing a metal hydride, in a solvent to obtain compounds of formula I; a phase (W) and, if desired, converting the compounds of formula I to a corresponding pharmaceutically acceptable salt of the addition of acid, using conventional methods, and, if so required, the transformation of the corresponding pharmaceutically acceptable salts, obtained by attaching acid, compound of formula I using conventional methods.

2. A way of getting under item 1, where the solvent at the stage (a) is serpolette under item 1, where the Foundation stage (b) is a hydroxide of an alkali metal.

5. A way of getting under item 4, where the base is sodium hydroxide.

6. A way of getting under item 1, where the solvent at the stage (b) is methyl alcohol.

7. A way of getting under item 1, where the reagent combination in stage (C) is selected from the group consisting of: carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrate (1-hydroxy-benzotriazole and triethylamine.

8. A way of getting under item 7, where the reagent combination is carbonyldiimidazole.

9. A way of getting under item 1, where the solvent at the stage (C) is selected from the group consisting of acetonitrile, and tetrahydrofuran.

10. The way of getting p. 9, where the solvent is acetonitrile.

11. A way of getting under item 1, where the regenerating reagent on stage (d) is a metal borohydride.

12. The method of obtaining on p. 11, where the regenerating reagent is detribalized.

13. A way of getting under item 1, where the solvent at the stage (d) is selected from the group consisting of alcohol and aqueous alcohol.

14. The way of getting p. 13, where the solvent is ethyl alcohol.

16. A way of getting under item 15, where the solvent is heptane.

17. A way of getting under item 1, where the carboxylic acid in stage (d) is selected from the group consisting of glacial acetic acid, propionic acid, butyric acid and trimethylhexanoic acid.

18. The way of getting p. 17, where the carboxylic acid is glacial acetic acid.

19. A way of getting under item 1, where the carboxylic acid in stage (d) is added in the form of a solution in a solvent selected from the group consisting of hexane, heptane and tetrahydrofuran.

20. A way of getting under item 19, where the solvent is tetrahydrofuran.

21. The way of getting p. 1 wherein the regenerating agent representing a metal hydride, at stage (e) is alumoweld lithium.

22. A way of getting under item 1, where the solvent at the stage (e) is tetrahydrofuran.

23. A way of getting under item 1, where the compound of the formula I is maleate (R)-(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl] pyridine.

24. The method of obtaining the compounds of formula VI

< / BR>
comprising a phase (a) processing of racemic compounds of formula VIII

< / BR>
cinchonidine solvent in the solvent in order to obtain after acidification of the compounds of formula VI.

25. The way of getting p. 24, where the solvent at the stage (a) is alcohol.

26. The way of getting p. 25, where the solvent is isopropyl alcohol.

27. The way of getting p. 24, where the Foundation stage (b) is a hydroxide of an alkali metal.

28. The way of getting p. 27, where the base is sodium hydroxide.

29. The way of getting p. 24, where the solvent at the stage (b) is methyl alcohol.

30. The method of obtaining the compounds of formula VI

< / BR>
includes treatment of the racemic compounds of formula IX

< / BR>
in the solvent at a pH of about 5 using a-chymotrypsin order to obtain, after separation of unreacted ether complex and acidification of the compounds of formula VI.

31. The way of getting 30 p. where the solvent is water.

32. The method of obtaining the compounds of formula II

< / BR>
comprising a phase (a) processing of racemic compounds of formula VIII

< / BR>
cinchonidine in a solvent to obtain compounds of formula VII

< / BR>
stage (b) treatment of compounds of formula VII in a solvent to obtain after acidification of the compounds of formula VI

< / BR>
stage (C) processing soedineniya the compounds of formula IV

< / BR>
stage (d) treatment of compounds of formula IV regenerating reagent in a solvent to obtain a mixture of compounds of formula IIIA and formula IIIB

< / BR>
and stage (d) processing the mixture of compounds of formula IIIA and formula IIIB with a mixture of zinc chloride and laborgerate sodium in the solvent, and then a solution of carboxylic acid in a solvent to obtain compounds of formula II.

33. The method of obtaining compounds of formula IIIA and formula IIIB

< / BR>
comprising a phase (a) processing of racemic compounds of formula VIII

< / BR>
cinchonidine in a solvent to obtain compounds of formula VII

< / BR>
stage (b) treatment of compounds of formula VII in a solvent to obtain after acidification of the compounds of formula VI

< / BR>
stage (C) treatment of compounds of formula VI, a compound of formula V

< / BR>
in the presence of reagent combinations and solvent in order to obtain the compounds of formula IV

< / BR>
and the stage (g) treatment of compounds of formula IV regenerating reagent in a solvent to obtain a mixture of compounds of formula IIIA and formula IIIB.

34. The method of obtaining the compounds of formula IV

< / BR>
comprising a phase (a) processing VII

< / BR>
stage (b) treatment of compounds of formula VII in a solvent to obtain after acidification of the compounds of formula VI

< / BR>
and stage (C) treatment of compounds of formula VI, a compound of formula V

< / BR>
in the presence of reagent combinations and solvent in order to obtain the compounds of formula IV.

35. The compound of formula IX

< / BR>
36. A compound selected from the group consisting of compounds of formula IIIA and formula IIIB

< / BR>
37. The compound of formula IV

< / BR>
38. The compound of formula VI

< / BR>
39. Compound of formula VII



 

Same patents:

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or the individual is

The invention relates to new compounds 1,2,5,6-tetrahydropyridine number of General formula

(I) where Z is oxygen or sulfur;

R is hydrogen or C1-3-alkyl; when Z stands for oxygen, R1is a halogen, amino group, acetylamino or-O-R2where R2is4-6-alkyl or C6-quinil; Z, meaning sulfur, R1is halogen, C1-8-alkyl, C6-alkenyl straight chain, cyclopropylmethyl, benzyloxypropionic, morpholino-, 4-methylpiperidino - or 4-hexylamino or a group-O-R2where R2linear or branched C3-6alkenyl,3-6-quinil, cyclopropylmethyl, -R3-O-R4or-R3-O-R4-O-R5where each of R3, R4and R5means1-4-alkyl, or R1represents a group S-R2where R2linear C2-8-alkyl, or their pharmaceutically acceptable salts

The invention relates to a new process for the preparation of esters cyclopropanecarbonyl acid of the formula I

< / BR>
where R is the ester residue, split in neutral or acid medium and which WITH1-18the alkyl possibly substituted with halogen or benzyl radical, possibly substituted on the tops of the aromatic ring by one or more halogen atoms, or a radical of formula (a) -(g),

< / BR>
where R2Is h or methyl;

R3- aryl;

R4- CN, N.;

R5- fluorine, chlorine, bromine or hydrogen;

R6, R7, R8, R9is hydrogen or methyl;

S/1 symbolizes tetrahedrite

The invention relates to the production of compounds which are useful as intermediates for obtaining spirotaenia derivatives of glutarimide, especially in connection with a registered brand name candoxatril and systematic name /S/-CIS-4-/1-[2-/5-intenrational/-3-/2-methoxyethoxy/propyl] -1 - cyclopentanecarboxylic/-1 cyclohexanecarbonyl acid

The invention relates to the field of organic chemistry, namely to new chemical compound gross formula

< / BR>
where x= CF2or bond, the sum n + m + C 3 10

How prelinlinary // 2051143

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing acylated 1,3-dicarbonylic compounds used as agrochemicals or intermediate products in manufacturing agrochemicals. Also, invention describes a method for preparing tautomeric forms of acylated 1,3-dicarbonylic compounds. Method involves the arrangement reaction of the corresponding enol ester and this rearrangement reaction is carried out in the presence of alkaline metal azide. Method provides eliminating the requirement in expensive isolating process of catalyst/reagent in systems for waste treatment.

EFFECT: improved preparing method.

7 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 5-[(4-chlorophenyl)methyl]-2,2-dimethylcyclopentanone. Method involves interaction of 1-[(4-chlorophnyl)methyl]-3-methyl-2-oxocyclopentane carboxylic acid methyl ester or 1-[(4-chlorophenyl)methyl]-3-methyl-2-oxocyclopentane carboxylic acid ethyl ester with sodium hydride and methyl halide wherein amount of sodium hydride is 1.0-1.3 mole per one mole of corresponding ester and amount methyl halide used is 1.0-1.3 mole per one mole of the parent ester followed by hydrolysis of synthesized 1-[(4-chlorophenyl)methyl]-3,3-dimethyl-2-oxocyclopentane carboxylic acid methyl ester or 1-[(4-chlorophenyl)methyl]-3,3-dimethyl-2-oxocyclopentane carboxylic acid ethyl ester. Prepared compound is used for synthesis of agricultural or garden fungicide methconazole.

EFFECT: improved preparing method.

8 cl, 5 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of 1-hydroxy-2,3-[60]fullerocyclopentanecarboxylic acid ethyl ester of formula 1 , wherein n = 1-2. Claimed method includes reaction of fullerene[60] (C60) with triethylaluminum (AlEt3) in C60:AlEt3 molar ratio of 1:(25-35) in presence of Cp2ZrCl2 as catalyst in amount of 15-25 mol.% based on C60 in argon atmosphere, in toluene medium under atmospheric pressure and at room temperature for 8 hours followed by addition to reaction mass at -15°C copper chloride (CuCl) catalyst in amount of 15-20 mol % based on C60 and oxalic acid diethyl ester (EtO2C-CO2Et) in equimolar amount in relation to AlEt3. Further reaction mass is agitated at room temperature followed by hydrolysis of reaction mass.

EFFECT: method for production of 1-hydroxy-2,3-[60]fullerocyclopentanecarboxylic acid ethyl ester with high yield.

1 tbl, 1 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of 3-n-alkyl-1-hydroxycyclopentane-n-alkylcarboxylates of formula , wherein R is n-C5H11, n-C6H13, and n-C8H17; R' is C2H5, n-C4H9. Claimed method includes alpha-olefin reaction with triethyl aluminum in presence of catalyst in argon atmosphere at room temperature and normal pressure in hexane for 8 h followed by addition to reaction mass at -15°C copper chloride and oxalic acid dialkyl ester as catalyst. Then reaction mass is agitated at room temperature for 8-10 h. After reaction mass hydrolysis target product yield is 70-92 %. Compounds of present invention are useful in production of paint-vehicle materials, bioactive substances, etc.

EFFECT: method of increased yield.

1 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention concerns organic chemistry, particularly method of obtaining 6-hydroxyspiro[3,4]octane-6-alkylcarboxylates (1), R=C2H5, n-C4H9, where methylenecyclobutane undergoes interaction with triethylaluminum (AlEt3) in the presence of zirconacene dichloride catalyst Cp2ZrCl2 at molar ratio of methylenecyclobutane:AlEt3:Cp2ZrCl2=10:(12-16):(0.5-0.9), in argon atmosphere at room temperature and atmospheric pressure in hexane for 4 hours, with further addition of copper bromide catalyst (CuBr) in amount of 10-14 molar % in respect of methylenecyclobutane, and dialkyl ether of oxalic acid thrice exceeding amount of AlEt3, to reaction mass at -15C, followed by stirring of reaction mass at room temperature with further acid hydrolysis of reaction mass.

EFFECT: 6-hydroxyspiro[3,4]octane-6-alkylcarboxylates applicable in fine organic synthesis and production of paint coating materials and bioactive substances, with total 76-95% output of end product after reaction mass hydrolysis.

1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts possessing anti hiv-activity, to the pharmaceutical composition thereof and to the method of HIV-integrase inhibition. formula (A) where R1 is selected from the group consisting of the hydrogen and halogen; R2 is selected from the group consisting of the hydrogen and OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is COOR9; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.

EFFECT: claimed compounds possess anti HIV-activity.

5 cl, 6 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to high-molecular weight compounds, particularly to aromatic copolyesters,

,

where n=1, 5, 10, 20. or m=1-100. Said compounds are obtained through a reaction between oligosulphones based on diane or phenolphthalein with polycondensation degree equal to 1, 5, 10, 20 and diacyl chlorides of terephthaloyl-di(p-oxybenzoates) through acceptor-catalytic polycondensation in chlorinated organic solvents.

EFFECT: copolyesters have high value of intrinsic viscosity, thermal stability and heat resistance and can be used as heat resistant construction materials.

2 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: method involves mixing starting low-sulphur diesel fuel with a product of re-esterification of plant oil with an aliphatic alcohol - butyl ether of rape-seed oil acids obtained in the presence of concentrated sulphuric acid. The starting diesel fuel is preferably mixed with butyl ether of rape-seed oil acids in weight ratio between 99:1 and 95:5. Antioxidant additive Agidol-12 is additionally added to the said mixture in amount of 0.1 wt %.

EFFECT: obtaining diesel fuel with higher lubricating power.

3 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to methods for preparing macrolides, e.g. compounds of formula (IV) and intermediate compounds of formula (V):

and , wherein R1-R12 have the values specified in the description.

EFFECT: compounds of formula V are valuable for treating inflammatory or immune disorders, and treating cancer.

12 cl, 12 dwg, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula III or to its pharmaceutically acceptable salts, in which: R1 and R2 are independently selected from group, consisting of: (a) H, (b) (C2-C6)alkyl, (c) C1-C6 alkyl, interrupted by one or more groups -O-, (d) (C0-C3)alkyl-(C3-C7)cycloalkyl and (e) (CH2)nQ, where n=1-2 and where Q stands for aromatic ring system, which has from 5 to 6 ring atoms C, and Q can be independently substituted with groups up to 3 in number, selected from halogen, on condition that R1 and R2 simultaneously do not stand for H, and each alkyl of R1 and R2 can be independently substituted with one or more groups, selected from group, consisting of halogen, hydroxy, cyano, CF3 or C1-C4 alkyl, or R1 and R2 together with carbon, to which they are attached, form 3-7-member cycloalkyl or 6-member heterocycloalkyl ring, including one oxygen atom and which in case of necessity carries C1-C4 alkyl substituent, or R1 and R2 together with carbon, to which they are connected, form 3-7-member cycloalkyl ring, substituted with R20 and R21, and R20 and R21 together with carbon or carbons, to which they are connected, form 3-7-member cycloalkyl ring; R6 stands for C1-C6 alkyl; each R7 independently stands for C1-C6 alkyl; Y stands for -O-; R4 is selected from group, consisting of: (a) (C0-C3)alkyl-(C3-C7)cycloalkyl, (b) trifluoroethyl, and (c) trifluoropropyl; Z stands for phenyl or bicyclic ring system, which has 9 ring atoms, independently selected from C, N, O and S, on condition that not more than 3 ring atoms in any single ring differs from C, and said ring system can carry to 3 substituents, independently selected from group, consisting of R6, CF3 and SR6; and R5 is selected from group, consisting of NO2, NH2, F, Cl, Br, CN, SR6, S(O)2N(R7)2 and (C1-C4)alkyl, and each alkyl can be independently substituted with one or more halogens or CF3. Invention also relates to pharmaceutical composition for treatment of neurodegenerative disorder or improvement of cognitive function, containing therapeutically effective quantity of said compound; as well as to method of treatment of neurodegenerative disorder, for instance Alzheimer's disease, or improvement of cognitive function.

EFFECT: compounds act as modulators of gamma-secretase.

31 cl, 14 tbl, 3147 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention covers new compounds of formula I or its salts suitable for pharmacology: , where R1 is selected from phenyl, pyridyl, thienyl, difurylglyoxal, imidazolyl, pyrrolyl and thiazolyl; R2, R3 and R4 independently are d-zalkyl or halogenated C1-zalkyl; and R5 is hydrogen. And also new intermediate compounds formula III: , where R2, R3 and R4 independently are C1-3alkyl or halogenated C1-6alkyl; and R5 is hydrogen. Invention also covers method of production of compound formula I and their applications.

EFFECT: production of new biologically active compounds.

12 cl, 9 ex, 2 tbl

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