The method of obtaining piperidinylmethyl-tripterocalyx cyclic ethers

 

(57) Abstract:

The invention relates to a new method of obtaining diastereomeric mixture piperidinylmethyl-tripterocalyx cyclic ethers of the formulae Ia and Ib and their pharmaceutically acceptable salts, where R1is C1-C6the alkyl, R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl, R3is hydrogen or halogen; m = 0, 1 or 2, in which said mixture is enriched compound of formula Ia. The described method lies in the interaction of a mixture of compounds Ia and Ib with an acid of formula HX, which is selected from the group consisting of (S)-(+)-almond acid, D-(-)-tartaric acid, di-p-toluoyl-D-tartaric acid and other acids, crystallization HX salt diastereomeric mixture of products from its solution, processing the resulting mixture of compounds Ia and Ib, which is enriched compound of formula Ia. The use of certain specified above acids to separate diastereomeric mixture allows to achieve a high degree diastereomeric purity (>95%). The invention relates also to a mixture of compounds Ia and Ib, enriched Ia, and to intermediate compounds used in the new method of obtaining diastereomeric mixture piperidinecarbonitrile cyclic esters of formulas Ia and Ib:

< / BR>
< / BR>
and their pharmaceutically acceptable salts,

where R1is C1-6by alkyl;

R2is C1-6by alkyl, halogen, C1-6the alkyl or phenyl or substituted phenyl;

R3is hydrogen or halogen;

m means zero, one, or two.

In addition, the present invention also relates to a method for diastereomeric mixture of compounds of formulas Ia and Ib and their pharmaceutically acceptable salts, enriched compound of formula Ia. The method according to the present invention allows selective crystallization to allocate diastereomeric mixture of compounds of formulas Ia and Ib, in which the proportion of compounds of the formula Ia to Ib is greater than 90:10.

In addition, the present invention relates to new methods for obtaining the compounds of formula II:

< / BR>
intermediate compounds useful for preparing compounds of formulas Ia and Ib. In addition, the present invention is directed also to other new intermediate compounds useful in the method of obtaining a mixture of compounds of formulas Ia and Ib. The present invention also relates to a new method of purification of some intermediate compounds for use in methods according to the invention.

Diastereomeric mixture of compounds of formulas Ia and Ib and the method of obtaining diastereomeric mixtures are described in international patent publication WO 99/25714, published may 27, 1999. This source relates to methods of obtaining diastereomeric mixture using methods other than the methods of the present invention, and it is included as a source in its entirety. The present invention provides a more practical, more direct and gives a greater output of the method of obtaining a mixture of diastereomers of compounds of formulas Ia and Ib, highly enriched compound of formula Ia, with new ways of synthesis.

Brief description of the invention

The present invention relates to a method of obtaining a mixture with the almost acceptable salts, where

R1is C1-6by alkyl;

R2is C1-6by alkyl, halogen, C1-6the alkyl or phenyl or substituted phenyl;

R3is hydrogen or halogen;

m means zero, one or two;

includes stage (A1) of the interaction of a mixture of compounds of formulas Ia and Ib:

< / BR>
< / BR>
with an acid of formula HX, where HX is selected from the group consisting of (S)-(+)-almond acid, D-(-)-tartaric acid, di-p-toluoyl-D-tartaric acid, ((1R)-endo, anti)-(+)-3-bromkamfora-8-sulfonic acid, Hinn acid, acetic acid and Hydrobromic acid, with formation of a mixture of diastereoisomeric compounds of formulas Va and Vb, respectively, enriched by the presence of the compounds of formula Va:

< / BR>
< / BR>
(b1) providing opportunities HX salt of the mixture of the diastereomeric product stage (A1) to crystallize from solution in an appropriate solvent; and

(C1) processing the resulting mixture of compounds obtained from step (b1), base.

The most preferred embodiment of the invention is a case where the acid HX stage (A1) is (3)-(+)-almond acid. The preferred embodiment of the invention is such that when the corresponding facilitate, isopropylacetate, methyl tert-butyl ether, diisopropyl ether, toluene, acetonitrile, acetone, water and mixtures of any of the above solvents. In the preferred embodiment an appropriate solvent phase (A1) is ethanol. The preferred embodiment of the invention is such that when the substrate stage (C1) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.

The present invention also relates to the production of pharmaceutically acceptable salts of a mixture of compounds of formulas Ia and Ib, highly enriched compound of formula Ia, which includes the processing of the mixture of compounds Ia and Ib, which is enriched in one of the diastereomeric compounds of the formula Ia, proton acid H+Y-where the anion Y-selected from the group consisting of hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarata, gluconate, saharat, benzoate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) spans the mules VIa:

< / BR>
where n is determined by the inherent characteristics of the form of compounds Ia and Ib, when they complex with a specific acid WELL, and n is an integer from one to two. The method according to the invention also relates to the production of hydrates of the compounds of formulas VIa and VIb, which is between zero and three water molecules may be associated with each molecule of the compounds of formulas VIa and VIb, and these hydrates are formed at the stage of the compounds of formulas Ia and Ib are processed proton acid.

The preferred embodiment of the invention is that used proton acid is hydrochloric acid, and n is 2. The preferred embodiment of the invention is when the obtained ratio of compounds VIa and VIb is 90:10 or higher. The preferred embodiment of the invention, is obtained when the ratio of compounds VIa and VIb is 98:2 or above.

The present invention also relates to a method for producing compounds of formulas Ia and Ib, enriched by the presence of the compounds of formula Ia, optionally including the stage of interaction of the compounds of formula III:

< / BR>
with the compound of the formula IV:

< / BR>
in prisutstvie is owenii of the invention, the reducing agent is selected from the group consisting of triacetoxyborohydride sodium, cyanoborohydride sodium and sodium borohydride. In a more preferred embodiment of the invention regenerating agent is triacetoxyborohydride sodium.

The present invention relates also to a method for producing compounds of formulas Ia and Ib, enriched by the presence of the compounds of formula Ia, optionally including stage formirovaniya the compounds of formula II:

< / BR>
where R1, R2and R3have the meanings defined above; m is 0, 1 or 2, with hexamethylenetetramine in the presence of acid to form compounds of formula III. In the preferred embodiment of the invention, the acid in the reaction of formirovaniya is triperoxonane acid, glazirovalnoy acid, acetic acid or hydrochloric acid. The most preferred acid is triperoxonane acid.

The present invention also relates to a method for producing compounds of formulas Ia and Ib, enriched by the presence of the compounds of formula Ia, in which the compound of formula II:

< / BR>
in which R1, R2and R3have the meanings defined above; m is 0, 1 or 2, get a method, comprising the stage of:

(A2) mutual is aetsa (C1-C6) alkyl or phenyl, in the presence of a fluoride source to form compounds of formula VIII:

< / BR>
(b2) removing silyl protective groups of the product of stage (A2) by treatment with base or fluoride source to form compounds of formula IX:

< / BR>
(C2) hydrolysis difficult ester group of the product of stage (b2) in the presence of a base to form compounds of formula X:

< / BR>
and (d2) the reaction of cyclization ring of the product of stage (C2) in the presence of a base and an activating agent selected from the group consisting of methanesulfonanilide, methanesulfonamido anhydride, p-toluensulfonate, p-toluensulfonate anhydride and triftormetilfullerenov anhydride.

In a more preferred embodiment of the present invention, the source of fluorine on stage (A2) is selected from the group consisting of cesium fluoride, potassium fluoride and fluoride of alkylamine. The preferred fluoride of alkylamine is tetrabutylammonium fluoride. In the most preferred embodiment of the invention a source of fluoride on stage (A2) is cesium fluoride. Preferred solvents for the stage (A2) are dimethylformamide, dimethylacetamide, toluene, dimethylformamide.

On stage (b2) is preferred bases are sodium hydroxide or potassium hydroxide, and the preferred fluoride sources include tetrabutylammonium fluoride, cesium fluoride, complex hydrofluoric acid-pyridine and hydrofluoric acid. The preferred fluoride source is tetrabutylammonium fluoride. Preferred solvents for the stage (b2) are tetrahydrofuran, diisopropyl ether, acetonitrile, methyl tert-butyl ether, dichloromethane and toluene. The most preferred solvent for the stage (b2) is tetrahydrofuran.

Preferred bases on stage (C2) are sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. The preferred Foundation stage (C2) is sodium hydroxide. Preferred solvents for the stage (C2) include water, tetrahydrofuran, methanol, ethanol, isopropanol, 1,4-dioxane and a combination of any of these solvents. The most preferred solvent for the stage (C2) is a mixture of water and tetrahydrofuran.

On stage (d2), the most preferred activating agent is methanesulfonanilide, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate. The most preferred base for the stage (d2) is triethylamine. Preferred solvents for the stage (d2) are dichloromethane, tetrahydrofuran, toluene, diisopropyl ether and methyl tert-butyl ether. The most preferred solvent for the stage (d2) is dichloromethane.

The present invention relates also to a method for producing compounds of formulas Ia and Ib, enriched by the presence of the compounds of formula Ia, in which the compound of formula II:

< / BR>
in which R1, R2and R3have the meanings defined above; m is 0, 1 or 2; obtained by the method comprising the steps:

(A3) the interaction of the compounds of formula XI:

< / BR>
with the alcohol of formula R1OH in the presence of acid, where R1has the values defined above, to form compounds of formula XII:

< / BR>
(b3) the interaction of the product of stage (A3) with the compound of the formula CF3SiR43where R4is (C1-C6) alkyl or phenyl, with the formation of compounds of formula XIII:

< / BR>
(C3) the interaction of the product of stage (b3) with a fluoride source to obtain a lactone of the formula in the presence of a Lewis acid to obtain the compounds of formula XV:

< / BR>
and (E3), the interaction of the product of stage (d3) with a regenerating agent, optionally in the presence of a Lewis acid to obtain the compounds of formula II.

According to another preferred embodiment of the invention the acid stage (A3) is selected from the group consisting of sulfuric acid, hydrochloric acid, Hydrobromic acid, triperoxonane acid and methanesulfonic acid. The most preferred acid for the stage (A3) is sulfuric acid.

On stage (b3) preferred fluoride sources are cesium fluoride, potassium fluoride and the fluoride of alkylamine, such as tetrabutylammonium fluoride. The preferred fluoride source is cesium fluoride. Preferred solvents for the stage (b3) are dimethylformamide, dimethylacetamide, dichloromethane and tetrahydrofuran. The most preferred solvent for the stage (b3) is dimethylformamide.

The preferred fluoride sources for the stage (C3) is tetrabutylammonium fluoride, cesium fluoride, complex hydrofluoric acid and pyridine and hydrofluoric acid. The preferred fluoride source for the stage (C3) is the fluoride tetapi, acetonitrile, methyl tert-butyl ether, dichloromethane and toluene. The most preferred solvent for the stage (C3) is tetrahydrofuran.

Preferred reducing agents for the stage (d3) are sodium borohydride complex of borane and tetrahydrofuran, a complex of borane and dimethyl sulfide, DIBORANE, lithium borohydride, calcium borohydride, alumoweld lithium hydride diisobutylaluminum, L-selectride and-selected. The most preferred regenerating agent is sodium borohydride. The preferred Lewis acid for the stage (d3) is a complex of boron TRIFLUORIDE and diethyl ether. Preferred solvents for the stage (d3) are tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and dimethoxyethane. The most preferred solvent for the stage (d3) is tetrahydrofuran.

Preferred reducing agents for the stage (E3) are triethylsilane or triphenylsilane in the presence of a Lewis acid such as athirat of boron TRIFLUORIDE or triperoxonane acid, preferably triperoxonane acid. Preferred solvents for the stage (E3) are dichloromethane, dichloroethane and chloroform. Most oploschenii on stage (E3), the compound of formula XIV is treated with a catalyst, such as platinum, platinum oxide or palladium hydroxide, preferably platinum, in a solvent such as methanol, ethanol or isopropanol, preferably ethanol, in an atmosphere of hydrogen, optionally under pressure higher than atmospheric pressure.

The present invention relates also to a method for producing compounds of formulas Ia and Ib, enriched by the presence of the compounds of formula Ia, in which the compound of formula III:

< / BR>
clear the way, including the stage (A4) the formation of the hydrazone with the reaction of compounds of formula III with a hydrazone of the formula XVI:

< / BR>
in the presence of acid gives the compound of formula XVII:

< / BR>
and (b4) hydrolysis of the product of stage (A4) by treatment with a reagent selected from the group consisting of chloride copper (II) iodide, copper (II) acetate copper (II), copper sulfate, sulfuric acid, acetic acid and hydrochloric acid.

The preferred acid for the stage (A4) include acetic acid, sulfuric acid, hydrochloric acid, methanesulfonate acid and p-toluensulfonate acid. The most preferred acid for the stage (A4) is acetic acid. Preferred solvents for the stage (A4) are methanol, ethanol, isopropanol, tet the I stage (A4) is a mixture of methanol and water.

The most preferred reagent for the stage (b4) is the chloride copper (II). Preferred solvents for the stage (b4) are tert-butyl alcohol, methanol, ethanol, isopropanol, tetrahydrofuran, water and a mixture of any of the above solvents. The most preferred solvent for the stage (b4) is a mixture of tert-butyl alcohol and water.

In addition, the present invention encompasses methods of obtaining pharmaceutical compositions of compounds of formula Ia or Ib or their pharmaceutically acceptable salts. The method of obtaining such a pharmaceutical composition includes the addition of a mixture of compounds of formula Ia and Ib, or their pharmaceutically acceptable salts to a pharmaceutically acceptable carrier or diluent.

The present invention relates to new intermediate compounds used in the method of the invention, including, but not limited to, compounds of formulae VII, IX, XIII, XIV, XV and XVII and their salts.

The term "alkyl", used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having a normal, branched or cyclic groups, and combinations thereof.

The term "substituted phenyl", as used what stiteler(s), such as halogen, hydroxy, (C1-C6) alkyl or (C1-C6) alkoxy.

The term "halo" or "halogen" used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine.

The term "suitable solvent" or "diluent" as used here, unless otherwise specified, means an environment that serves to dissolve the concrete of the specified substance(C), the compound(s) or reagent(s) to form a uniformly dispersed mixture of the substances or compounds at the molecular or ionic level.

The term "proton acid used to obtain the acid additive salts of the compounds of the method of the present invention is of such acids which form non-toxic acid additive salts, i.e. salts containing pharmacologically acceptable anions, such salts as the hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-aftout)).

The term "enriched" as used here, the RA over the other or other components in the mixture.

The term "enriched" as used here, unless otherwise specified, means the predominance in the ratio of at least 90:10 one particular compound or isomer over the other or other components in the mixture. Unless otherwise stated, this invention relates to all optical isomers, tautomers and stereoisomers of any of the compounds described herein.

The term "pharmaceutically acceptable salt", as used here, unless otherwise specified, refers to an acid additive salts of proton acids, as defined here, or the hydrate of the acid additive salt.

Detailed description of the invention

Diastereomer mixture piperidinecarbonitrile cyclic ethers of the formulae Ia and Ib, highly enriched compound of formula Ia can be obtained in accordance with the new method presented in reaction scheme 1 (see the end of the description). New ways to obtain critical intermediate in obtaining piperidinecarbonitrile cyclic esters of compounds of formula II can be carried out in accordance with schemes 2 and 3 (see the end of the description). A new method of purification of a key intermediate in the method according to scheme 1, t and n have the meanings above.

Stage 1 scheme 1 is formirovanie. The compound of formula II is treated with hexamethylenetetramine in the presence of acid, such as triperoxonane acid, glicerina acid, acetic acid or hydrochloric acid, preferably triperoxonane acid, optionally in a solvent such as dichloromethane, dichloroethane, heptane or nitromethane, preferably without solvent, at temperatures between 0 and 100oC, preferably at 70oSince, during the period of time between 10 minutes and 24 hours, preferably 3 hours, followed by addition of water to obtain the compounds of formula III. At this point, the compound of formula III can be purified according to the method of the invention, as shown in the following scheme 4, before stage 2.

Stage 2 in figure 1 is a restorative blend. The aldehyde of formula III is treated with an amine of the formula IV or its salt in the presence of a reducing agent, such as triacetoxyborohydride sodium, cyanoborohydride sodium or sodium borohydride, preferably triacetoxyborohydride sodium in a solvent such as dichloromethane, dichloroethane, tetrahydrofuran, toluene, acetic acid, diisopropyl ether or methyl tert-butyl e is eriod time between 30 min and 24 h, preferably 3 hours, to obtain a mixture of compounds of formulas Ia and Ib.

Stage 3 scheme 1 represents the formation of salts. The mixture of compounds Ia and Ib is treated with acid of the formula HX, such as (S)-(+)-mandelic acid, D-(-)-tartaric acid, di-p-toluoyl-D-tartaric acid, ((1R)-endo,anti)-(+)-3-bromkamfora-8-sulfonic acid, Hinn acid, acetic acid, Hydrobromic acid, preferably (S)-(+)-mandelic acid, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate isopropylacetate, methyl tert-butyl ether, diisopropyl ether, toluene, acetonitrile, acetone, water or a mixture of the above solvents, preferably ethanol, at temperatures between -20 and 70oC, preferably at room temperature, over a period of time between 30 minutes and 48 hours, preferably 18 hours, to obtain a mixture of compounds of formulas Va and Vb, which is enriched compound of formula Va. Stage 3 allows you to select a mixture of compounds of formulas Va and Vb, in which the proportion of compounds of the formula Va to Vb are higher than 70:30, and mostly 80:20 or higher.

Stage 4 in figure 1 represents the formation of an acid additive salt. The mixture of compounds of formulas Va and Vb, highly enriched compound VN, potassium carbonate or potassium bicarbonate, in water in the presence of co-solvent, such as toluene, diisopropyl ether, methyl tert-butyl ether, ethyl acetate or dichloromethane, preferably diisopropyl ether, at temperatures between 0 and 40oC, preferably at room temperature, over a period of time between 10 minutes and 48 hours, preferably 18 hours, to obtain a mixture of compounds of formulas Ia and Ib, which is enriched compound of formula Ia. The ratio of compounds Ia and Ib obtained at this stage, stage 4, 70:30 or higher, but mostly 80:20 or higher. This mixture is treated with a proton acid HY, defined above, preferably hydrochloric acid, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, diisopropyl ether, water and a mixture of the above solvents, preferably a mixture of methanol and water, at temperatures between 0 and 60oC, preferably at room temperature, over a period of time between 1 and 48 hours, preferably 18 hours, to obtain a mixture of compounds of formulas VIa and VIb, which vysokoobogashchennyj compound of formula VIa, and where n has a value as defined above. Stage 4 allows you to select a mixture of compounds of formulas VIa and VIb, in which the ratio is connected to the ing in higher proportions.

Stage 1 scheme 2 is the acylation arena, which proceeds with the protection of the alcohol according to the method similar to a known method (Sternberg, E. D.; Vollhardt, K. P. C. , J. Org. Chem. 1984, 49, 1574-1583). Arenas formula XVIII is treated allermuir agent of the formula R2(C=O)-X', where R2has the values defined above, and X' is halogen, R2(C=O)-O -, or other appropriate group in allerease agent, as is known to experts in this field, in the presence of acid, such as tribromide aluminum, trichloride aluminum, tin tetrachloride, titanium tetrachloride or polyphosphoric acid, preferably tribromide aluminum, in a solvent such as dichloromethane, dichloroethane, nitromethane, nitrobenzene, carbon disulfide or chlorobenzene, preferably dichloromethane, at temperatures between -20 and 125oC, preferably between 0 and 20oSince, during the period of time between 10 minutes and 10 hours, preferably about 1 hour, to obtain the compounds of formula VII.

Stage 2 figure 2 represents the accession triptorelin group to the ketone using a modification of the known method (Prakash, G. K. S.; Krishnamurti R.; Olah, G. A., J. Am. Chem. 1989, 111, 393-395). The ketone of formula VII is treated with a compound of the formula CF3SiR43where R4oC, preferably at room temperature over a period of time between 10 minutes and 18 hours, preferably 45 minutes, to obtain the compounds of formula VIII.

Stage 3 scheme 2 is removing protection from alcohol. The compound of formula VIII is treated with a reagent such as sodium hydroxide, potassium hydroxide or fluoride source such as tetrabutylammonium fluoride, cesium fluoride, complex hydrofluoric acid-pyridine or hydrofluoric acid, preferably tetrabutylammonium fluoride, in a solvent such as tetrahydrofuran, diisopropyl ether, acetonitrile, methyl tert-butyl ether, dichloromethane or toluene, preferably tetrahydrofuran, at temperatures between -40 and 60oC, preferably at room temperature, over a period of time between 5 min and 5 h, preferably 1 h to obtain the compounds of formula IX.

Stage 4 in scheme 2 is the hydrolysis of ester. The compound of formula IX about ONAT potassium, the potassium bicarbonate, preferably sodium hydroxide, in a solvent such as water, tetrahydrofuran, methanol, ethanol, isopropanol, 1,4-dioxane, or a combination of the abovementioned solvents, preferably a mixture of water and tetrahydrofuran, at temperatures between 0 and 75oC, preferably at room temperature, over a period of time between 1 and 48 hours, preferably 12 hours, to obtain the compounds of formula X.

Stage 5 figure 2 is a cyclization. The compound of formula X is treated with an activating agent such as methanesulfonate, methanesulfonyl anhydride, p-toluensulfonate, p-toluensulfonyl anhydride or triftormetilfullerenov anhydride, preferably methanesulfonate, and a base, such as triethylamine, diisopropylethylamine, 2,6-lutidine, pyridine, sodium hydroxide, potassium hydroxide, cesium carbonate or potassium carbonate, preferably triethylamine, in a solvent such as dichloromethane, tetrahydrofuran, toluene, diisopropyl ether or methyl tert-butyl ether, preferably dichloromethane, at temperatures between -40 and 75oC, preferably between 0oC and room temperature, over a period of time between 1 and 48 hours, preferably 12 hours, with probative allermuir agent of the formula R2(C=O)-X', where R2has the values defined above, and X' is halogen, R2(C=O)-O -, or other appropriate group in allerease agent, known to specialists in this field, in the presence of acid, such as tribromide aluminum, trichloride aluminum, tin tetrachloride, titanium tetrachloride or polyphosphoric acid, preferably tribromide aluminum, in a solvent such as dichloromethane, dichloroethane, nitromethane, nitrobenzene, carbon disulfide or chlorobenzene, preferably dichloromethane, at temperatures between -20 and 125oC, preferably between 0 and 20oSince, during the period of time of 10 minutes and 10 hours, preferably about 1 hour, to obtain the compounds of formula XI.

Stage 2 in figure 3 is esterification. Carboxylic acid of formula XI is treated with an alcohol of formula R1OH, where R1has the values defined above, in the presence of acid, such as sulfuric acid, hydrochloric acid, Hydrobromic acid, triperoxonane acid or methansulfonate acid, preferably sulfuric acid, at temperatures between 0 and 100oC, preferably at room temperature, over a period of time between 10 minutes and 48 hours, preferably 16 hours, with getting the tone using a modification of the known method (Prakash, G. K. S.; Krishnamurti R.; Olah, G. A., J. Am. Chem. Soc. 1989, 111, 393-395). The ketone of formula XII is treated with a compound of the formula CF3SiR43where R4has the values defined above, in the presence of a fluoride source, such as cesium fluoride, potassium fluoride or fluoride of alkylamine, such as tetrabutylammonium fluoride, preferably cesium fluoride, in the presence of a solvent, such as dimethylformamide, dimethylacetamide, dichloromethane or tetrahydrofuran, preferably dimethylformamide, at temperatures between -78 and 50oC, preferably at 0oSince, during the period of time between 10 minutes and 18 hours, preferably 7 hours, to obtain the compounds of formula XIII.

Stage 4 in figure 3 is lactoridaceae. The compound of formula XIII is treated with fluoride source such as tetrabutylammonium fluoride, cesium fluoride, complex hydrofluoric acid-pyridine or hydrofluoric acid, preferably tetrabutylammonium fluoride, in a solvent such as tetrahydrofuran, diisopropyl ether, acetonitrile, methyl tert-butyl ether, dichloromethane or toluene, preferably tetrahydrofuran, at temperatures between -40 and 60oC, preferably at room temperature, over a period of time between what Stanovlenie of the lactone.

The compound of formula XIV is treated regenerating agent such as sodium borohydride complex of borane-tetrahydrofuran complex of borane-dimethyl sulfide, DIBORANE, lithium borohydride, calcium borohydride, alumoweld lithium hydride diisobutylaluminum, L-selectride or-selected, optionally in the presence of a Lewis acid such as a complex of boron TRIFLUORIDE-diethyl ether, preferably sodium borohydride, in the presence of a complex of boron TRIFLUORIDE-diethyl ether, in a solvent such as tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether or dimethoxyethane, preferably tetrahydrofuran, at a temperature of between -78 and 60oC, preferably between 0oC and room temperature, over a period of time between 30 minutes and 48 hours, preferably 16 hours, to obtain the compounds of formula XV.

Stage 6 in figure 3 is the recovery. The compound of formula XV is treated regenerating agent, such as triethylsilane or triphenylsilane, in the presence of a Lewis acid such as athirat of boron TRIFLUORIDE or triperoxonane acid, preferably triperoxonane acid, in a solvent such as dichloromethane, dichloroethane or chloroform, preferably dichloramine between 5 min and 5 h, preferably 2 hours, to obtain the compounds of formula II. An alternative compound of formula XV is treated regenerating agent, i.e. a catalyst, such as platinum, platinum oxide or palladium hydroxide, preferably platinum, in a solvent such as methanol, ethanol or isopropanol, preferably ethanol, in an atmosphere of hydrogen, optionally under pressure, at a temperature between room temperature and 100oC, preferably at room temperature, over a period of time between 1 and 48 hours, preferably 5 hours, to obtain the compounds of formula II.

Alternative compound III can be cleaned by derivatization. Stage 1 in figure 4 is a hydrazone formation. The compound of formula III is treated with a hydrazone of the formula XVI with an acid, such as acetic acid, sulfuric acid, hydrochloric acid, methanesulfonate acid or p-toluensulfonate acid, preferably acetic acid, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, water or a mixture of any of the abovementioned solvents, preferably a mixture of methanol and water, at temperatures between 0 and 110oWith, preferably by boiling under reflux, during the period of lying which is the hydrolysis of the hydrazone. The compound of formula XVII is treated with a reagent, such as chloride copper (II) iodide copper (II) acetate copper (II), copper sulfate, sulfuric acid, acetic acid or hydrochloric acid, preferably the chloride copper (II), in a solvent such as tert-butyl alcohol, methanol, ethanol, isopropanol, tetrahydrofuran, water or a mixture of any of the abovementioned solvents, preferably a mixture of tert-butyl alcohol and water, at temperatures between 0 and 110oC, preferably at 70oSince, during the period of time between 30 min and 10 h, preferably 2.5 h, to obtain the compounds of formula III.

Obtain other compounds of the present invention, are not specifically described in the above-mentioned experimental section can be performed using combinations of the reactions described above that will be familiar to specialists in this field.

In each of the reactions discussed or illustrated in schemes 1-4 above, pressure is not a critical factor, if not stated otherwise. Generally preferred pressure is from about 0.9 atmospheres to about 2 atmospheres and ambient pressure, i.e., about 1 atmosphere, which is a matter of convenience.

Intermediate compounds of the invention, referenced visionary forms; this invention relates to all optical and stereoisomers of these intermediate compounds, and their mixtures.

This invention also relates to labeled isotopes compounds identical to those listed for formulae Ia and Ib or pharmaceutically acceptable salts, but given the fact that one or more atoms replaced them by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H,3H,13C,14C,15N18OH,17OH,31P, 32R35S18F and36Cl, respectively.

Compounds of the present invention, their prodrugs and pharmaceutically acceptable salts of these compounds or these prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are covered by the scope of the invention. Some labeled isotopes of the compounds of the present invention, for example, such that incorporate radioactive isotopes, such asusing fabric. Especially preferred are trithiolane, i.e. 3H and carbon-14, i.e.14With, isotopes due to the simplicity of their production and the ability to detect. In addition, the substitution of heavier isotopes such as deuterium, i.e.2H, may provide some therapeutic benefits as a result of higher metabolic stability, for example, increased half-life in vivo or requirements reduced dosage, and therefore in some circumstances it may be preferable.

Labeled isotopes of the compounds of formulas Ia and Ib of the present invention and their prodrugs can usually be obtained by using the procedures given here by replacing unlabeled isotope reagents readily available isotope-labeled reagents.

Activity, methods of testing activity, dosages, dosage forms, routes of administration and background information relating to the compounds of formulas Ia and Ib, presented in international patent publication WO 99/25714, published may 27, 1999 Piperidinecarbonitrile cyclic ethers, obtained by using the methods of the present invention, have shown considerable activity against tie is characterized by the presence of an excess of activity of the specified substance P. Such conditions include cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, Central nervous system disorders, inflammatory diseases, vomiting, incontinence, pain, migraine, sunburn and diseases, disorders and conditions caused by Helicobacter pylori infection, in mammals, especially in humans. For the treatment of vomiting these compounds may preferably be used in combination with an antagonist of 5-HT3.

Active piperidinecarbonitrile cyclic ethers of the formulae Ia and Ib can be entered mammal orally, parenterally (e.g. intravenously, subcutaneously or intramuscularly) or by local. These compounds can be administered in single or in combination with pharmaceutically acceptable carriers or diluents one of the ways listed above, and you can enter as a single or multiple doses. Compounds obtained by the methods of the invention, it is possible to enter in a wide variety of different drug doses, for example, combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, pellets, lozenges, hard candies, powders, sprays, creams, salves, suppositories, jellies, GE is a CAREER

The present invention is illustrated by the following examples. However, it is clear that the invention is not limited to the specific details of these examples.

Example 1

< / BR>
2-(2-Acetyl-5-methoxyphenyl)-ethyl ester acetic acid

This compound was obtained by using a modification of a known procedure (Sternberg, E. D. , Vollhardt, K. P. C., J. Org. Chem. 1984, 49, 1574-1583). To a solution of tribromide aluminum (43,8 g, 164 mmol) in dichloromethane (70 ml) at 0oWith slowly added acetylmuramic (14.6 ml, 197 mmol). The reaction mixture was heated to 15oWith and within 45 minutes was added 2-(3-methoxyphenyl)-ethanol (10.0 g, to 65.7 mmol) in dichloromethane (20,0 ml). The reaction mixture was stirred for one hour and then poured into ice (100 ml). To the mixture was added 1N aqueous solution of hydrochloric acid (100 ml). The organic layer was separated and the aqueous layer was extracted with dichloromethane (100 ml). The combined organic extracts washed with 1N aqueous solution of sodium hydroxide (100 ml), dried over magnesium sulfate, filtered through celite, concentrated to obtain 2-(2-acetyl-5-methoxyphenyl)-ethyl ester of acetic acid in the form of oil (14.8 g, 95%).1H NMR (300 MHz, Dl3) was 2.05 (s, 3), at 2.59 (s, 3), 3,29 (t, 2, J=6,9), with 3.89 (s, 3), 4,33 (t, 2, J=6,9), for 6.81 (d, 1, J=2,5), cent to 8.85 (DD, 1, J= 8674, 1604, 1567, 1358, 1239, 1037 cm-1. Analysis. Calculated for C13H16O4: 66,09; N 6,83. Found: 65,71; N 7,21.

Example 2

< / BR>
2-[5-Methoxy-2-(2,2,2-Cryptor-1-methyl-1-trimethylsilyloxy)-phenyl] -ethyl ester acetic acid

To a solution of 2-(2-acetyl-5-methoxyphenyl)-ethyl ester acetic acid (12.5 g, to 52.9 mmol) and cesium fluoride (0,964 g 6,35 mmol) in dimethylformamide (75 ml) at 0oWith slowly added triftormetilfullerenov (10,2 ml of 69.0 mmol). The reaction mixture was stirred for 45 min, after which the analysis of GC/MS and HPLC showed the absence of starting material. For the purposes of the characteristics of the reaction mixture was poured into water and was extracted with methyl tert-butyl ether (100 ml). The organic layer was washed with water (2 x 75 ml) and brine (50 ml), dried over magnesium sulfate, filtered and concentrated, obtaining 2-[5-methoxy-2-(2,2,2-Cryptor-1-methyl-1-trimethylsilyloxy)-phenyl] -ethyl ester of acetic acid in the form of crude oil.1H NMR (300 MHz, D13) to 0.19 (s, 9), of 1.93 (s, 3), 2,10 (s, 3), 3,23-to 3.33 (m, 1), 3,42-to 3.52 (m, 1), 3,83 (s, 3), 4.26 deaths-4,32 (m, 2), 6,77 (DD, 1, J=8,9, 2,8), 6,86 (d, 1, J= 2,9), 7,32 (d, 1, J=8,9). 13With NMR (100 MHz, D13) 2,03, 21,03, 24,64, 32,86, 55,11, 65,54, 78,90 (kV, J=30,3), 111,26, 117,44, 125,70 (kV, J=287), 129,56, 129,79, 139,77, 159,17, 171,09. IR 2961, 1741, 1610, 1383, 1286, 1255, 11 6,53.

Example 3

< / BR>
2-[5-Methoxy-2-(2,2,2-Cryptor-1-hydroxy-1-methylethyl)-phenyl] -ethyl ester acetic acid

To the crude reaction mixture described in example 2, containing a solution of 2-[5-methoxy-2-(2,2,2-Cryptor-1-methyl-1-trimethylsilyloxy)-phenyl] -ethyl ester of acetic acid was added tetrabutylammonium fluoride (52,9 ml of 1.0 M solution in tetrahydrofuran, to 52.9 mmol). The reaction mixture is stirred for one hour, after which the analysis of GC/MS and HPLC showed the absence of starting material. For the purposes of the characteristics of the reaction mixture was poured into water and was extracted methyl tert-butyl ether (75 ml). The organic layer was washed with water (75 ml) and brine (50 ml), dried over magnesium sulfate, filtered and concentrated giving the crude oil.1H NMR (400 MHz, Dl3) to 1.82 (s, 3), a 2.01 (s, 3), 2,98-of 3.06 (m, 2), 3,55 (dt, 1, J= 13,7, 6,8), 3,79 (s, 3), 4,27-4,32 (m, 2), 6.73 x-6,77 (m, 2), 7,28 (d, 1, J= 8,5).13With NMR (100 MHz, CDCl3) 20,92, 25,50, 34,16, 55,10, 66,49, 76,67 (kV, J= 30,3), 111,55, 118,25, 126,02 (kV, J=286), 128,67, 129,56, 139,70, 159,20, 171,32. IR 3453, 1720, 1610, 1249, 1161, 1134, 1038 cm-1. Analysis. Calculated for C14H17F3O4: 54,90; N 5,59. Found: 55,03; N 5,85.

Example 4

< / BR>
1,1,1-Cryptor-2-[2-(2-hydroxyethyl)-4-methoxyphenyl]-propan-2-ol

To the crude of the reaction is an ester of acetic acid, was added 1N aqueous solution of sodium hydroxide (75,0 ml, 75 mmol). The reaction mixture was allowed to warmed to room temperature and was stirred for 12 hours. The reaction mixture was poured into water (75 ml) and was extracted with methyl tert-butyl ether(150 ml). The organic layer was washed with water (75 ml) and brine (75 ml), dried over magnesium sulfate and concentrated to oil. To the crude oil was added hexane (20 ml) and methyl tert-butyl ether (4 ml) and the precipitate was becoming solid. The mixture was mixed for 30 min and filtered, giving 1,1,1-Cryptor-2-[2-(2-hydroxyethyl)-4-methoxyphenyl] -propan-2-ol (7,3 g, 52% overall yield from 2-(2-acetyl-5-methoxy-phenyl)-ethyl ester of acetic acid). So pl. 110-111oS.1H NMR (300 MHz, D13) to 1.83 (s, 3), only 2.91 (dt, 1, J=13,7, 3,9), 3,76 (DDD, 1, J= 13,7, 9,3, 4,4), 3,85 (C, 3), 3,85-3,93 (m, 1), 4,08 (dt, 1, J=9,3, 3,7), 6,80-6,83 (m, 2), 7,38 (d, 1, J=8,4).13With NMR (100 MHz, D13) 26,01, 36,12, 55,19, 64,13, 76,52 (kV, J=28,9), 111,47, 117,43, 125,99 (kV, J=287), 129,69, 129,94, 140,86, 159,55. IR 3395, 3162, 1610, 1513, 1467, 1248, 1157, 1087, 1046 cm-1. Analysis. Calculated for C12H15F3ABOUT3: 54,54; N 5,72. Found: 54,65; N 5,70.

Example 5

< / BR>
6-Methoxy-1-methyl-1-triftormetilfosfinov

To a solution of 1,1,1-Cryptor-2-[2-(2-hydroxyethyl)-4-methoxyphenyl]-propan-2-ol (5,0 shall ulali dropwise methanesulfonanilide (1,61 ml, to 20.8 mmol). The reaction mixture was allowed to warmed to room temperature and was stirred for 12 hours. The formation of 2-[5-methoxy-2-(2,2,2-Cryptor-1-hydroxy-1-methylethyl)-phenyl] -ethyl ester methanesulfonic acid was quick and his disappearance was monitored by HPLC (retention time of 4.5 min, column Bond Rx-C64,H mm, 40oC, 50% SN3SP/50% (0,2% Et3N, 0.1% aqueous solution of N3RHO4at pH 3.2, buffer), 1 ml/min). At the end of the reaction the mixture was poured into 1N aqueous solution of hydrochloric acid (30 ml) and was extracted with dichloromethane (20 ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated, giving 6-methoxy-1-methyl-1-triftormetilfosfinov in the form of oil (3,40 g, 73%).1H NMR (300 MHz, D13) was 1.69 (s, 3), 2,85-2,90 (m, 2), 3,85 (s, 3), 3,90-3,98 (m, 1), 4,14-is 4.21 (m, 1), 6,72 (d, 1, J=2,6), 6,85 (DD, 1, J=8,7, 2,6), 7,31 (d, 1, J=8,7). 13With NMR (100 MHz, D13) 23,25, 29,42, 55,19, 61,37, 76,10 (kV, J= 27,4), 112,84, 113,43, 124,85, 125,96 (kV, J=289), 127,86, 136,49, 158,98. IR 2946, 2839, 1738, 1611, 1505, 1162, 1137, 1101 cm-1. Analysis. Calculated for C12H13F3ABOUT2: 58,54; N, 5,32. Found: 58,27; N 5,35.

Example 6

< / BR>
(2-Acetyl-5-methoxyphenyl)-acetic acid

To a solution of tribromide aluminum (57.6 g, 216 mmol) in dichloromethane (90 ml) at 0oFrom medl is 7.9 g, 108 mmol) in dichloromethane (20,0 ml). The reaction mixture was stirred for one hour and then poured into ice (100 ml). The organic layer was separated and added a 1N aqueous solution of sodium hydroxide (100 ml). A two-phase mixture was intensively stirred for 90 min and the layers were separated. The organic layer is discarded and the aqueous layer was added concentrated hydrochloric acid until then, until it reached a pH value of 1. In the sludge precipitated solid substance, it is filtered and dried in air, yielding (2-acetyl-5-methoxyphenyl)-acetic acid (16,8 g, 75%). So pl. 153 to 155oS.1H NMR (300 MHz, D13) of 2.68 (s, 3), 3,91 (s, 3), to 3.92 (s, 2), 6,92-to 6.95 (m, 2), 7,88 (d, 1, J= 9,5).13With NMR (100 MHz, D13) 28,33, 41,43, 55,46, 112,54, 118,26, 129,17, 133,08, 136,94, 162,65, 174,80, 200,96. IR 3435, 1704, 1663, 1609, 1568, 1258 cm-1. Analysis. Calculated for C11H12O4: 63,45; N. OF 5.81. Found: 63,35; N 5,46.

Example 7

< / BR>
Methyl ether (2-acetyl-5-methoxyphenyl)-acetic acid

To a solution of (2-acetyl-5-methoxyphenyl)-acetic acid (5,00 g of 24.0 mmol) in methanol (50 ml) was added concentrated sulfuric acid (1.0 ml). The reaction mixture was stirred at room temperature for 16 hours, after which it was concentrated to small volume. We use the Loy were dried over magnesium sulfate, filtered and concentrated to an oil, which solidified upon standing, giving methyl ether (2-acetyl-5-methoxyphenyl)-acetic acid (4,70 g, 88%). So pl. 74-76oS.1H NMR (300 MHz, D13) of 2.58 (s, 3), 3,74 (s, 3), with 3.89 (s, 3), of 3.95 (s, 2), is 6.78 (d, 1, J=2,6), 6,89 (DD, 1, J=8,7, 2,6), 7,89 (d, 1, J= 8,6).13With NMR (75 MHz, CDCl3) 29,65, 42,35, 53,11, 56,69, 113,17, 120,00, 130,52, 134,39, 138,90, 163,54, 173,23, 200,35. IR 1739, 1665, 1605, 1568, 1321, 1247, 1165 cm-1. Analysis. Calculated for C12H14ABOUT4: 65,85; H 6,35. Found: 64,87; N 6,44.

Example 8

< / BR>
Methyl ester of [5-methoxy-2-(2,2,2-Cryptor-1-methyl-1-trimethylsilyloxy)-phenyl]-acetic acid

To a solution of methyl ester (2-acetyl-5-methoxyphenyl)-acetic acid (2.00 g, 9,00 mmol) and cesium fluoride (96.0 mg, 0,632 mmol) in dimethylformamide (12 ml) at 0oWith slowly added triftormetilfullerenov (1.73 ml, 11.7 mmol). The reaction mixture was stirred at 0oWith over 7 hours. To characterize the reaction mixture was poured into water and was extracted with methyl tert-butyl ether (50 ml). The organic layer was washed with water (2 x 75 ml) and brine (50 ml), dried over magnesium sulfate, filtered and concentrated, yielding the methyl ester of [5-methoxy-2-(2,2,2-Cryptor-1-methyl-1-trimethylsilyloxy)-phenyl] -J=17,0), 6,74-6,77 (m, 2), 7,29 (d, 1, J=9,1).13With NMR (100 MHz, D13) 1,87, 24,25, 39,32, 51,75, 55,12, 78,67 (kV, J= 30,3), 111,97, 118,30, 125,70 (kV, J=286), 129,50, 129,57, 136,10, 159,17, 172,81. IR 2956, 1745, 1611, 1577, 1467, 1436, 1290, 1256, 1166, 1092, 989, 863, 847 cm-1. Analysis. Calculated for C16H23F3O4Si: 52,73; N 6,36. Found: From 52.84; H 6,36.

Example 9

< / BR>
6-Methoxy-1-methyl-1-triftormetilfosfinov-3-one

To the crude reaction mixture described in example 8, containing a solution of methyl ester [5-methoxy-2-(2,2,2-Cryptor-1-methyl-1-trimethylsilyloxy)-phenyl]-acetic acid, was added tetrabutylammonium fluoride (9,00 ml of 1.0 M solution in tetrahydrofuran, of 9.00 mmol). The reaction mixture was stirred for 1 hour, after which it was poured into water (50 ml) and was extracted with methyl tert-butyl ether (50 ml). The organic layer was washed with water (50 ml) and brine (30 ml), dried over magnesium sulfate, filtered and concentrated, giving 6-methoxy-1-methyl-1-triftormetilfosfinov-3-one in the form of oil (1.26 g, 54%).1H NMR (400 MHz, CDCl3) 1,89 (s, 3), 3,71 (d, 1, J= 20,6), 3,79 (s, 3), with 3.89 (d, 20,8), of 6.65 (d, 1, J=1,5), 6,85-6,89 (m, 1), 7,29 (d, 1, J=8,7).13With NMR (100 MHz, CDCl3) 21,45, 34,32, 55,33, 83,01 (kV, J=30,3), 112,21, 113,88, 120,57, 124,68 (kV, J=285,7), 127,73, 132,18, 160,75, 167,45. IR 1765, 1614, 1509, 1322, 1301, 1274, 1259, 1183, 1101, 997, 813 cm-1. Analysis. Calculated the XI-1-methyl-1-triftormetilfosfinov-3-ol

To a solution of 6-methoxy-1-methyl-1-triftormetilfosfinov-3-one (1.50 g, USD 5.76 mmol) in tetrahydrofuran (30 ml) at 0oWith added sodium borohydride (0,240 g, 6,34 mmol), then the complex of boron TRIFLUORIDE-diethyl ether (0,992 g, 8,07 mmol). The reaction mixture was heated to room temperature and was stirred overnight. The reaction mixture was added to water (75 ml) and was extracted with methyl tert-butyl ether (75 ml). The layers were separated and the organic layer was washed 1N aqueous solution of hydrochloric acid (50 ml), dried over magnesium sulfate, filtered and concentrated, giving 6-methoxy-1-methyl-1-triftormetilfosfinov-3-ol in the form of oil and a mixture of a and b anomers (1.19 g, 79%). The data for the main diastereoisomer.1H NMR (400 MHz, D13) of 1.74 (s, 3), 2,85 (DD, 1, J=15,7, 4,3), 2,88-2,99 (m, 1), 3,11 (DD, 1, J=15,7, 3,2), of 3.80 (s, 3), 5,63 (t, 1, J=3,7), 6,69 (d, 1, J= 2,7), PC 6.82 (DD, 1, J=8,7, 2,7), 7,22-7,27 (m, 1).13With NMR (100 MHz, D13), (the data for the identified signals of the main diastereoisomer) 24,52, 35,46, 55,16, 90,71, 113,11, 113,98, 125,22, 127,57, 132,98, 159,59. IR 3439, 2949, 1735, 1613, 1506, 1166, 1141, 1070 cm-1.

Example 11

< / BR>
6-Methoxy-1-methyl-1-triftormetilfosfinov

To a solution of 6-methoxy-1-methyl-1-triftormetilfosfinov-3-ol (at 8.36 g, 31.9 per mmol) dichloromethane was stirred at room temperature for 2 h and was poured into 1N aqueous solution of sodium hydroxide (250 ml). The organic layer was separated and washed with 1N aqueous solution of sodium hydroxide (100 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated, giving 6-methoxy-1-methyl-1-triftormetilfosfinov in the form of oil (to 6.88 g, 88%).1H NMR (300 MHz, CDCl3) was 1.69 (s, 3), 2,85-2,90 (m, 2), 3,85 (s, 3), 3,90-3,98 (m, 1), 4,14-is 4.21 (m, 1), 6,72 (d, 1, J=2,6), 6,85 (DD, 1, J=8,7, 2,6), 7,31 (d, 1, J=8,7).13With NMR (100 MHz, D13) 23,25, 29,42, 55,19, 61,37, 76,10 (kV, J= 27,4), 112,84, 113,43, 124,85, 125,96 (kV, J=289), 127,86, 136,49, 158,98. IR 2946, 2839, 1738, 1611, 1505, 1162, 1137, 1101 cm-1. Analysis. Calculated for C12H13F3ABOUT2: 58,54; N, 5,32. Found: 58,27; N 5,35.

Example 12

< / BR>
6-Methoxy-1-methyl-1-triftormetilfosfinov-7-carbaldehyde

To hexamethylenetetramine (31,3 g, 223 mmol) was added triperoxonane acid (400 ml) and the mixture was heated to 70oC for 90 minutes Then the reaction mixture for 40 min, the solution was added 6-methoxy-1-methyl-1-triftoratsetofenona (50.0 g, 203 mmol) in triperoxonane acid (100 ml). The solution was stirred for 3 hours and was added water (450 ml). The reaction mixture was stirred for 16 hours, cooled to room temperature and was poured into methyl tert-butyl ether (500 ml). The organic layer was separated and washed with water (3 x 300 ml). Institutions and sodium as long while pH did not rise to 10 (500 ml). The organic layer was separated, washed with water (200 ml), dried over magnesium sulfate, filtered and concentrated, giving 6-methoxy-1-methyl-1-triftormetilfosfinov-7-carbaldehyde in the form of oil (54,2 g of a mixture of 12:1 regioisomers, 97%).1H NMR (400 MHz, D13) 1,71 (s, 3), 2,95 (dt, 2, J=2,6, 5,3), 3,90-3,97 (m, 1), of 3.97 (s, 3), 4,19 (dt, 1, J=11,2, 5,6), for 6.81 (d, 1, J=1,2), of 10.4 (s, 1).13With NMR (75 MHz, D13) 23,07, 29,98, 55,73, 60,83, 76,03 (kV, J=27,4), 111,81, 112,50, 123,65, 125,32, 125,64 (kV, J=287), 127,06, 160,89, 188,92. IR 1683, 1616, 1498, 1296, 1271, 1163, 1149, 1120, 1096, 874 cm-1. Analysis. Calculated for C13H13F3ABOUT3: 57,13; N. OF 5.05. Found: 56,94; N 4,78.

Example 13

< / BR>
N'-1-[(E)-1-(6-methoxy-1,1-dimethyl-3,4-dihydro-1H-isochroman-7-yl)methylidene]-4-methyl-1-benzosulfimide

To a solution of crude 6-methoxy-1-methyl-1-triftormetilfosfinov-7-carbaldehyde (54,2 g, 198 mmol) obtained in example 12, in methanol (542 ml) was added p-toluensulfonate (36,9 g, 198 mmol) followed by 2% aqueous solution of acetic acid (81,3 ml). The reaction mixture was heated to boiling under reflux for 90 min and cooled to room temperature. In the sludge precipitated solid, which was filtered, giving N'-1-[(E)-1-(6-methoxy-1,1-dimethyl-3,4-dihydro-1H-isochroman-7-yl) , =0,7), is 2.44 (s, 3), 2,85-2,89 (m, 2), of 3.84 (s, 3), 3,93 (dt, 1, J=11,2, 5,6), 4,16 (dt, 1, J=11,2, 5,6), of 6.65 (s, 1), 7,33 (d, 2, J=8,1), 7,79 (d, 1, J=1,2), 7,89 (d, 2, J=8,4), 8,13 (s, 1).13With NMR (75 MHz, CDCl3) 21,48, 23,07, 29,50, 55,47, 60,99, 76,02 (kV, J=27,4), 110,91, 120,45, 124,74, 125,04, 125,72 (kV, J=287), 127,95, 129,45, 134,97, 138,97, 143,34, 144,22, 157,04. IR 3223, 1623, 1505, 1417, 1325, 1289, 1275, 1172, 1157, 1123, 1098, 918, 658 cm-1. Analysis. Calculated for C20H21F3N2ABOUT4S: 54,29; N 4,78; N 6,33. Found: 54,34; N To 4.73; N 6,37.

Example 14

< / BR>
6-Methoxy-1-methyl-1-triftormetilfosfinov-7-carbaldehyde

A mixture of copper chloride (II) (52.7 g, 309 mmol) and N'-1-[(E)-1-(6-methoxy-1,1-dimethyl-3,4-dihydro-1H-isochroman-7-yl)methylidene] -4-methyl-1-benzosulfimide (45,5 g, 103 mmol) in tert-butyl alcohol (910 ml) and water (228 ml) was heated to 70oC for 2.5 hours. The reaction mixture was cooled to room temperature, concentrated to approximately 300 ml and poured into methyl tert-butyl ether (500 ml) and water (500 ml). The mixture was stirred for 15 min and filtered. The filtrate was poured into methyl tert-butyl ether (200 ml) and the layers were separated. The organic layer was washed with water (4 x 250 ml), dried over magnesium sulfate, filtered and concentrated, giving 6-methoxy-1-methyl-1-triftormetilfosfinov-7-carbaldehyde in the form of oil, which hardened when St, 1, J=11,2, 5,6), for 6.81 (d, 1, J=1,2), of 10.4 (s, 1).13With NMR (75 MHz, D13) 23,07, 29,98, 55,73, 60,83, 76,03 (kV, J=27,4), 111,84, 112,50, 123,65, 125,32, 125,64 (kV, J=287), 127,06, 160,89, 188,92. IR 1683, 1616, 1498, 1296, 1271, 1163, 1149, 1120, 1096, 874 cm-1. Analysis. Calculated for C13H13F3O3: 57,13; N. OF 5.05. Found 56,94; N 4,78.

Example 15

< / BR>
(S)-(+)-Mandelate (2S, 3S)-[(1R)-6-methoxy-1-methyl-1-triftormetilfosfinov-7-ylmethyl]-(2-phenylpiperidine-3-yl)-amine

Triacetoxyborohydride sodium (to 11.61 g of 54.8 mmol) was added in one portion to a cooled on a water bath) suspension of 6-methoxy-1-methyl-1-triftormetilfosfinov-7-carbaldehyde (7.51 g, a 27.4 mmol) and dimenticata (2S-3S)-2-phenylpiperidine-3-ylamine (13.8 g, 28.7 mmol) in dichloromethane (150 ml). Within 15 minutes most of the initial substances were dissolved, and shortly thereafter began a slow precipitation of the product. The reaction mixture was stirred for 2.5 h at room temperature, cooled to 0oC and slowly added 1N aqueous solution of sodium hydroxide (150 ml). The layers were separated, the aqueous layer (pH 9) was extracted with dichloromethane (50 ml). The combined organic extracts were mixed for one hour with 1N aqueous solution of sodium hydroxide (100 ml), the layers were separated and the organic layer was washed with water (50 ml completely white foam was dried in vacuum, giving 11,08 g (93%) of crude product. S-(+)almond acid (of 7.55 g of 49.6 mmol) dissolved in ethanol (100 ml) was added to a solution of a mixture of diastereoisomers (6-methoxy-1-methyl-1-triftormetilfosfinov-7-ylmethyl)-(2-phenylpiperidine-3-yl)-amine (10,78 g of 24.8 mmol) in ethanol (300 ml) at room temperature. The mixture was stirred, and began crystallization. After stirring overnight the mixture was filtered, giving of 4.66 g (32%) of (S)-(+)-mandelate (6-methoxy-1-methyl-1-triftormetilfosfinov-7-ylmethyl)-(2-phenylpiperidine-3-yl)-amine as a mixture of diastereoisomers (ratio of 81:19 to the results of HPLC analysis).1H NMR (400 MHz, D13), (presents the data for the main diastereoisomer) 1,42-of 1.64 (m, 2), of 1.53 (s, 3), 1,72-to 1.79 (m, 1), 1,94-to 1.98 (m, 1), 2,46-2,89 (m, 4), 3,15 of 3.28 (m, 3), of 3.45 (s, 3), 3,47-of 3.78 (m, 1), 3,92-of 3.97 (m, 2), 4,27 (Shir.S., 1), to 4.52 (s, 1), of 6.66 (s, 1),? 7.04 baby mortality-7,19 (m, 4), 7,27 was 7.36 (m, 7).13With NMR (100 MHz, D13) 16,99, 22,53, 25,96, 28,58, 45,05, 45,46, 53,52, 53,95, 55,08, 60,61, 61,86, 73,25, 75,54 (kV, J=28,2), 110,36, 126,02, 126,27, 126,32, 126,42, 126,55, 127,01, 127,43, 127,57, 128,27, 135,04, 137,83, 143,16, 156,51, 174,59. IR 3441, 1576, 1358, 1160, 1136, 1098, 1038, 775, 756, 698 cm-1. Analysis. Calculated for C32H37F3N2ABOUT5: 65,52; N 6,36; N 4,78. Found: 65,55; N 6,03; N 4,84.

Example 16

< / BR>
The dihydrochloride (2S,3S)-[(1R)-6-methoxy-1-methyl-1-triftormetilfosfinov-7-ilmatieteen-3-yl)-amine (2.25 g of a mixture of diastereoisomers 81:19, of 3.84 mmol) was stirred over night in diisopropyl ether (23 ml) and 1N aqueous sodium hydroxide solution (23 ml). The layers were separated and the organic layer was washed with water (20 ml) and brine (20 ml). The organic layer was concentrated to a crude waxy solids and was added methanol (15 ml). The solution was mixed at room temperature and was added dropwise a 1.5 N aqueous solution of hydrochloric acid (5.0 ml). Immediately to precipitate the dihydrochloride, and the white suspension stirred overnight at room temperature, was filtered and was dried in vacuum, yielding the dihydrochloride (6-methoxy-1-methyl-1-triftormetilfosfinov-7-ylmethyl)-(2-phenylpiperidine-3-yl)-amine (1,282 g, 66%) as a mixture of diastereoisomers 96:4. The ratio of diastereoisomers could be improved by crystallization from methanol/water (75/25).1H NMR (400 MHz, D2O), (presents the data for the main diastereoisomer) of 1.52 (s, 3), 1,80-of 1.92 (m, 2), 1,95-of 2.50 (m, 1), 2,21-of 2.26 (m, 1), 2,63-a 2.71 (m, 2), 3.04 from-3,11 (m, 1), to 3.36 (s, 3), 3,45-to 3.49 (m, 1), 3,65-3,81 (m, 3), 3,90-of 3.96 (m, 1), 4.09 to (d, 1, J=13,5), 6,46 (s, 1), 6,98-7,07 (m, 3), 7.23 percent-7,25 (m, 2), 7,30 (m, 1, J=7,5). IR 2958, 1457, 1377, 1143, 749, 692 cm-1. Analysis. Calculated for C24H31Cl2F3N2ABOUT2: 56,81; N 6,16; Cl 13,97; N 5,52. Found: 56,69; N. Of 6.31; Cl 14,13; N 5, is rmula Ia, and their pharmaceutically acceptable salts,

where R1is C1-6the alkyl,

R2is C1-6by alkyl, halogen, C1-6the alkyl or phenyl or substituted phenyl;

R3is hydrogen or halogen;

m = 0, 1, or 2;

includes stage

(A1) the interaction of a mixture of compounds of formulas Ia and Ib

< / BR>
< / BR>
with an acid of formula HX, where HX is selected from the group consisting of (S)-(+)-almond acid, D-(-)-tartaric acid, di-p-toluoyl-D-tartaric acid, ((1R)-endo, anti)-(+)-3-bromkamfora-8-sulfonic acid, Hinn acid, acetic acid and Hydrobromic acid with the formation of diastereomeric mixture of compounds of formulas Va and Vb, respectively

< / BR>
< / BR>
(b1) crystallization HX salt diastereomeric mixture product stage (A1) of its solution in an appropriate solvent,

(C1) processing the resulting mixture of compounds obtained in stage (b1), the base with a mixture of compounds Ia and Ib, which is enriched compound of formula Ia.

2. The method according to p. 1, further comprising processing the mixture of compounds Ia and Ib, which is enriched compound of formula Ia

< / BR>
< / BR>
proton acid H+Y-where the anion Y-selected from the group which logo citrate, tartrate, bitartrate, succinate, maleate, fumarata, gluconate, saharat, benzoate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate and 1,1'-methylene-bis-(2-hydroxy-3-naphthoate), with formation of a mixture of compounds VIa and VIb, highly enriched kislotoupornoj salt diastereomeric the compounds of formula VIa

< / BR>
< / BR>
where n is an integer from 1 to 2.

3. The method according to p. 2, wherein the proton acid is hydrochloric acid, and n = 2.

4. The method according to p. 1, further comprising the stage of interaction of the compounds of formula III

< / BR>
in which R1is C1-6by alkyl;

R2is C1-6by alkyl, halogen, C1-6the alkyl or phenyl or substituted phenyl;

m = 0, 1, or 2;

with the compound of the formula IV

< / BR>
in which R3is hydrogen or halogen;

in the presence of a reducing agent with the formation of diastereomeric mixture of compounds of formulas Ia and Ib

< / BR>
< / BR>
5. The method according to p. 4, in which the reducing agent is chosen from the group consisting of triacetoxyborohydride sodium, cyanoborohydride sodium and sodium borohydride.

6. The method according to p. 1, in which the acid HX in stage (A1) is (S)-(+)-almonds is salt,

in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl;

R3is hydrogen or halogen;

m = 0, 1, or 2,

and the ratio of the compounds of formula Ia and Ib is 90: 10 or higher.

8. The mixture according to p. 7, in which a ratio of 98: 2 or above.

9. The mixture of compounds of formulas Va and Vb,

< / BR>
< / BR>
highly enriched compound of formula Va,

in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl;

R3is hydrogen or halogen;

m = 0, 1, or 2;

HX is selected from the group consisting of (S)-(+)-almond acid, D-(-)-tartaric acid, di-p-toluene-D-tartaric acid, ((1R)-endo, anti)-(+)-3-bromkamfora-8-sulfonic acid, Hinn acid, acetic acid and Hydrobromic acid.

10. The mixture under item 9, in which HX is (S)-(+)-almond acid.

11. The method according to p. 1, further comprising a stage of formirovaniya the compounds of formula II

< / BR>
in which R1is C1-C6the alkyl is th phenyl;

R3is hydrogen or halogen;

m = 0, 1, or 2,

by reaction with hexamethylenetetramine in the presence of acid to form compounds of formula III

< / BR>
12. The method according to p. 11 in which the acid is selected from the group consisting of triperoxonane acid, glazirovalnoy acid, acetic acid and hydrochloric acid.

13. The method according to p. 1, in which the compound of formula II

< / BR>
in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl;

R3is hydrogen or halogen;

m = 0, 1, or 2;

get in the way, including the stage

(A2) the interaction of the compounds of formula VII

< / BR>
with the compound of the formula CF3SiR34in which R4is alkyl or phenyl, in the presence of a fluoride source to form compounds of formula VIII

< / BR>
(b2) removing silyl protective groups of the product of stage (A2) by treatment with base or fluoride source to form compounds of formula IX

< / BR>
(C2) hydrolysis of the ester group of the product of stage (b2) in the presence of a base with the formation of compound forms timireysevo agent, selected from the group consisting of methanesulfonanilide methanesulfonate anhydride p-toluensulfonate, p-toluensulfonate anhydride and triftormetilfullerenov anhydride.

14. The method according to p. 13, in which the fluoride source at a stage (A2) selected from the group consisting of fluoride, cesium fluoride and potassium fluoride of alkylamine.

15. The method according to p. 1, in which the compound of formula II

< / BR>
in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl;

R3is hydrogen or halogen;

m = 0, 1, or 2,

get in the way, including the stage

(A3) the interaction of the compounds of formula XI

< / BR>
with the alcohol of formula R1HE is in the presence of acid, where R1has the values defined above, to form compounds of formula XII

< / BR>
(b3) the interaction of the product of stage (A3) in the presence of a fluoride source with the compound of the formula CF3SiR34in which R4is C1-C6the alkyl or phenyl, with the formation of compounds of formula XIII

< / BR>
(C3) the interaction of the product of stage (b3) with fluoride and ustanavlivaushee agent optionally in the presence of a Lewis acid to obtain the compounds of formula XV

< / BR>
and (E3), the interaction of the product of stage (d3) with a regenerating agent, optionally in the presence of Lewis acid.

16. The method according to p. 1, further comprising a stage of purification of the compounds of formula III

< / BR>
in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl, halogen, C1-C6the alkyl or phenyl or substituted phenyl;

m = 0, 1, or 2,

includes stage (A4) formation of hydrazone by the reaction of compounds of formula III with a hydrazone of the formula XVI

< / BR>
in which R1has the values defined above, in the presence of acid to obtain the compounds of formula XVII

< / BR>
and (b4) hydrolysis of the product of stage (A4) by treatment with a reagent selected from the group consisting of chloride copper (II) iodide, copper (II) acetate copper (II), copper sulfate, sulfuric acid, acetic acid and hydrochloric acid.

17. The compound of formula VIII

< / BR>
in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl;

R4is C1-C6by alkyl;

m = 0, 1, or 2.

18. The compound of formula IX

< / BR>
in which R1is C1-C6by alkyl;

in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl;

R4is C1-C6by alkyl;

m = 0, 1, or 2.

20. The compound of formula XIV

< / BR>
in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl;

m = 0, 1, or 2.

21. The compound of formula XV

< / BR>
in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl;

m = 0, 1, or 2.

22. The compound of formula XVII

< / BR>
in which R1is C1-C6by alkyl;

R2is C1-C6by alkyl;

m = 0, 1 or 2.

 

Same patents:

The invention relates to a new substance having the properties of an inhibitor of corrosion-mechanical fracture (CMR) low-alloy steels in hydrogen sulfide-containing saline environments

The invention relates to the chemistry of organosilicon compounds, in particular to a method for the preparation of 3-[N,N-bis(2-hydroxy-3-methacryloxypropyl)amino]propyl (triethoxy)silane of the formula:

< / BR>
The specified connection is used for finishing glass fiber in composite fiberglass, used as structural materials, products, sanitary equipment, etc

The invention relates to the chemistry of organosilicon compounds, in particular to methods for fenilatsetilenov, and can be used to obtain polyphenylsiloxane resins, varnishes and enamels, widely used in national economy
The invention relates to the chemistry of organosilicon compounds, in particular to methods for organoalkoxysilanes, and can be used to obtain silicone fluids and resins of various types

The invention relates to a method of sililirovanie carbohydrates in liquid ammonia

The invention relates to a new crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chromane hydrofolate, method thereof, pharmaceutical compositions on the basis and method of reducing or preventing the rarefaction of bone, including the introduction to the patient an effective amount of the specified new connection

The invention relates to a new method of producing compounds of the formula I

< / BR>
where a represents a C1-C6is alkyl, aryl, mono - or Disaese F, Cl, Br, och3C1-C3-alkyl or benzyl, - inhibitors of 5-lipoxygenase, are useful for the treatment or relief of inflammatory diseases, Allergy and cardiovascular diseases

The invention relates to new derivatives of barbituric acid and a pharmaceutical composition having activity of inhibiting metalloprotease

The invention relates to substituted chromalusion (thio)ureas of the formula (I):

< / BR>
where R (1) denotes hydrogen, alkyl with 1-4 C-atoms, alkoxy with 1-4 C-atoms, fluorine, chlorine, bromine, iodine, CF3, NH2, NH-alkyl with 1-4 C-atoms, N(alkyl)2with 1-4 C-atoms in the same or different alkyl residues, or S-alkyl with 1-4 C-atoms;

R (2a) denotes hydrogen or alkyl with 1 or 2 C-atoms;

R (2b) and R (2d), which are identical or different, denote hydrogen, alkyl with 1 or 2 C-atoms not substituted phenyl, substituted phenyl, unsubstituted benzyl or substituted phenyl residue, benzyl, and as the substituents in the phenyl residues are up to three identical or different substituents selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

R (2c) and R (2e), which are identical or different, denote hydrogen or alkyl with 1 or 2 C-atoms;

R (3) denotes hydrogen, alkyl with 1,2,3 or 4 C-atoms, cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, CH2-cycloalkyl with 3, 4, 5 or 6 C-atoms in the ring, or CF3;

Q represents (CH2)n;

where n = 1 or 2;

Z denotes serousily, selected from the group consisting of hydrogen, halogen, alkyl with 1 or 2 C-atoms, alkoxyl with 1 or 2 C-atoms;

or

A denotes the residue of a saturated or unsaturated lactam of the formula:

< / BR>
where B denotes albaniles or alkylene with 3, 4, 5 or 6 C-atoms, which is unsubstituted or substituted by up to three identical or different alkyl groups with 1, 2, 3 or 4 C-atoms;

or

A denotes the residue of a bicyclic system of the formula:

< / BR>
< / BR>
< / BR>
< / BR>
and their physiologically acceptable salts

The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, to prevent thrombosis
Up!