The method of obtaining crystalline mes, crystalline mes 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethyl)benzoyl]benzo(b)difengidramin and method for producing resolutionvideo crystalline 6 - hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl) benzoyl]benzo(b)difengidramin

 

(57) Abstract:

The invention relates to a method for producing crystalline MES or resolutionvideo crystalline 6-hydroxy-2(4-hydroxyphenyl) 3-(4-(2-piperidinoethyl)benzoyl/benzo (b)difengidramin by acylation protected derivative of 2-arylbenzofurans trichloride in the presence or trichromate boron, followed by separation of the crystalline MES, by dissolving the latter in a hot solution containing methanol and water, the concentration of the solution. 7 C. and 4 h.p. f-crystals, 6 PL.

The invention relates to a new chemical process for the production of 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl]benzo[b]-thiophenol.

Overview of methods of preparation of aromatic ketones Dan Gore in Olah, Friedel - Crafts and Related Reactions, 3, Rat 1, Ch ap. XXXI (1964). Typically acyl component and the aromatic substrate is subjected to interaction in the presence of a catalyst of the Lewis acid to obtain an aromatic ketone. Suitable catalysts are Lewis acid for this type of reaction include metalhalide, such as aluminised, aluminumframed, ferric chloride (3), bromide, iron (3) and boron TRIFLUORIDE (see Olah, Friedel - Crafts and Related Reactions, Y, I, Ch ap. II, III and IV, 1963).

In the method described in U.S. patent N 4358593 use specific suitable protective group to obtain 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl] benzo[b] teofanov. Such suitable protective groups are acetyl, acetyl protected, benzoline, alkylsulfonyl and arylsulfonyl group. This patent discloses the use of classical catalysts of the Friedel-crafts reaction of acylation of protected 2-(4-hydrofoil)-6 - hydroxy-benzo[b]teofanov, including the halides of the metals, as luminiare, aluminumframed, zinc chloride, boron TRIFLUORIDE, trichromacy boron, titanium tetrachloride, tetrabromide titanium, are usually in alkaline conditions.

The most useful compound in this series of 2-aryl-3-[4-(2-aminoethoxy)benzoyl] benzo[b] teofanov is 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl]benzo[b]thiophene. This connection, as well as the means of obtaining it, was first disclosed in U.S. patent N 4418068. This connection is a nonsteroidal antiestrogen that can be used to facilitate paralogical States, organs associated with the endocrine system that are dependent on estrogen.

An improved way to obtain 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)benzoyl] benzo[b]teofanov disclosed in U.S. patent N 4380635. These compounds are produced by acylation Friedel-using as catalyst luminiare di-O-methylsiloxane benzo[b]thiophene. The intermediate product of the acylation will demetrious by processing the reaction mixture acylation of a sulfur compound, such as methyl, ethanthiol, diethylsulfide and methionine. Unfortunately, the product of this reaction contains a number of impurities which are difficult to remove from benzothiophene, including (but not limited to, aluminum salts and unpleasant residual smell of thiol or sulfide.

Halide of boron compounds Bahtt and Kulkarni, Synthesis, 249-282, 1983). Trichromacy Bor was previously used for splitting allotropic ethers in benzothiophene compounds (German patent N DE 4117512 AI).

In accordance with the present invention, the authors describe a new method to produce 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl]- benzo[b]teofanov. This method of the invention has several advantages compared to the methods described in the literature. In the method of the present invention use tribromide boron trichloride or boron as catalysts for acylation instead of aluminofluoride. Luminiare difficult to handle, especially on an industrial scale. In addition, acylation and dealkylation required large amounts of aluminofluoride, usually six equivalents. Luminiare leads to the formation of a large number of products that contain aluminum, which is insoluble in the working solvents and are difficult to remove from pharmaceutically active 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl]benzo[b]teofanov. Reactions catalyzed by aluminofluoride, usually represent the reaction in a heterogeneous mixture.

The method of the present invention relates generally to homogeneous mixtures, and under what miniloader, requires the addition of the mercaptan or sulfide for splitting alkylaryl ethers with getting diallylsulfide, have a very unpleasant smell. Such mercaptans or sulfides can be removed by recrystallization, but the result is the solvent of crystallization with smelly impurities.

The method of the present invention eliminates the use of aluminum and malodorous mercaptans and sulfides. Typically, in known methods, a large number of related compounds and a lot of residual aluminum salts in the final product. Representatives of related compounds include 6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b]thiophene, 2-(4-hydroxyphenyl)-6 - methoxy-3-[4-(2-piperidinoethyl) benzoyl]benzo[b]thiophene, 6-hydroxy-3-(4-hydroxybenzoyl)-2-(4-hydroxyphenyl)benzo[b] thiophene, propyl-4-(2-piperidinoethyl)thiobenzoate, methyl-4-(2-piperidinoethyl)-benzoate, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)-benzoyl] -5-[4-(2- piperidinoethyl)benzoyl] benzo[b] thiophene and 6-hydroxy-2-(4-hydroxyphenyl)-3-[4(2-piperidinoethyl)benzoyl] -7- [4-(2-piperidinoethyl)benzoyl]benzo[b] thiophene. By-products of boron can be removed from the final product. In addition, the way the crust is lorataine, the reaction is homogeneous, which allows the use of higher concentrations and to obtain a crystalline solvate, which can easily be distinguished.

The present invention relates to an improved process for the preparation of 2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl] benzo[b] teofanov, which includes the acylation suitably protected starting compound and dealkylation protected phenolic groups to obtain the target product. In accordance with a preferred aspect of the present invention the stage of acylation and dealkylation carried out sequentially in the same reactor. More specifically, the present invention relates to a method for producing crystalline MES compounds of the formula

< / BR>
where R1represents hydrogen or hydroxyl;

R2and R3independently represent C1- C4alkyl, or R2and R3together with the adjacent oxygen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, morpholino;

HX is HCl or HBr, which involves the following stages:

(a) acylation of benzothiophene formula:

< / BR>
where

R4is the volume formula III:

< / BR>
where R6represents chlorine, bromine or hydroxyl;

HX, R2and R3have the previously indicated meanings, in the presence of BX'3where X' is chlorine or bromine;

(b) the dealkylation of one or more phenolic groups due to the interaction with an additional quantity BX'3where X' has the above meanings;

(c) allocation of the crystalline MES.

Another aspect of the present invention are crystalline solvate of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)- benzoyl] benzo[b] difengidramin, which are new products of the method of the invention.

The present invention relates also to new ways of getting resolutional crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)- benzoyl]benzo[b]difengidramin, which includes stages:

(a) acylation of benzothiophene formula II:

< / BR>
where

R4represents C1- C4alkoxy,

R5represents C1- C4alkyl,

allermuir agent of formula (III):

< / BR>
where

R6represents chlorine, bromine or hydroxyl;

HX is HCl or 6Br;

R2and R3together with designdecision phenolic groups of the acylated product from step (a) due to the interaction with an additional quantity BX'3where X' has the above meanings;

(c) allocation of the crystalline MES the compounds of formula (I):

< / BR>
where

R1represents hydroxyl;

HX, R2and R3has the previously indicated meaning;

(d) communicating the specified crystalline MES in methanol or in a mixture of methanol and water with about one equivalent of a base;

(e) an optional extraction solution from stage (d) aliphatic hydrocarbon solvent;

(f) adding about one equivalent of hydrochloric acid to a methanol solution obtained in stage (d) or (e);

(g) allocation resolutionvideo crystalline substance.

In a preferred aspect of the present invention the variables in the above methods have the following values: HX is HCl, BX'3is BCl3, aliphatic hydrocarbon solvent is hexane or heptane, and the base is sodium hydroxide.

The present invention relates also to the second method of obtaining resolutional crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)-benzoyl] benzo[b] difengidramin, which includes - C4alkoxy;

R5represents C1- C4alkyl;

allermuir agent of formula (III):

< / BR>
where

R6represents chlorine, bromine or hydroxyl,

HX is HCl or HBr,

R2and R3together with the adjacent nitrogen atom form piperidine in the presence of BX'3where X' is chlorine or bromine;

(b) the dealkylation of phenolic groups of the acylation product from stage (a) due to the interaction with an additional quantity BX'3where X' has the above meanings;

(c) allocation of the crystalline MES the compounds of formula (I):

< / BR>
where

R1represents hydroxyl;

HX, R2and R3have the previously indicated meanings;

(d) dissolving the specified crystalline MES in a hot solution of methanol in water;

(e) optional filtering the solution from step (d);

(f) concentrating the solution from stage (d) or (e) by distillation;

(g) allocation resolutionvideo crystalline substance.

In a preferred aspect of the present invention the variables in the above methods have the following values: R4is methoxy, R5is methyl, R6- chlorine, HX is HCl, and BX'Lannoy alkyl chain, containing from 1 to 4 carbon atoms. Usually C1- C4alkyl groups include methyl, ethyl, n-propyl and n-butyl. The term "C1- C4alkoxy" represents groups such as methoxy, ethoxy, n-propoxy and n-butoxy. A preferred group of C1- C4alkoxy is methoxy.

The term "molar equivalent" in the sense used here, refers to the number of moles of reagent trechaleidae boron in relation to the number of moles of the original benzothiophene connection. So, for example, three millimole boron trichloride, which interact with one millimoles of benzothiophene, correspond to three molar equivalents boron trichloride.

The term "MES" refers to the Assembly that contains one or more of the molecules of such dissolved compounds as the compound of formula (I) with a solvent molecule. Representatives of the solvate is a solvate formed with methylene chloride, 1,2-dichloroethane, chloroform and 1,2,3-trichlorpropane.

The method of the present invention can be applied to obtain compounds with antiestrogenic and antiandrogenna activity (see U.S. patent N 4418068 and 4133814). Representatives of the compounds of formula (I), brooksi)benzoyl] benzo[b]thiophene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-dimethylaminoethoxy)benzoyl]-benzo[b]thiophene, 6-hydroxy-2-phenyl-3-[4-(2-diethylaminoethoxy)benzoyl] -benzo[b] thiophene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-diethylaminoethoxy)benzoyl]benzo[b]thiophene, 6-hydroxy-2-phenyl-3-[4-(2-diisopropylaminoethyl)benzoyl] benzo[b]thiophene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-diisopropylaminoethyl)- benzoyl]benzo[b] thiophene, 6-hydroxy-2-phenyl-3-[4-(2-di-n - butylaminoethyl)benzoyl]benzo[b] thiophene, 6-hydroxy-2-(4 - hydroxyphenyl)-3-[4-(2-di-n-butyl-aminoethoxy)-benzoyl] benzo[b] thiophene, 6-hydroxy-2-phenyl-3-[4-(2-pyrrolidinone)benzoyl] benzo[b]thiophene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-pyrrolidinone) benzoyl] benzo[b] thiophene, 6-hydroxy-2-phenyl-3-[4-(2-piperidinoethyl)benzoyl] benzo[b] thiophene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b] thiophene, 6-hydroxy-2-phenyl-3-[4-(2-hexamethyleneimino)benzoyl] benzo[b] thiophene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-hexamethyleneimino) benzoyl] benzo[b] thiophene, 6-hydroxy-2-phenyl-3-[4-(2-morpholinoethoxy) benzoyl] -benzo[b] thiophene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-morpholinoethoxy)benzoyl] benzo [b]thiophene.

The preferred products of the claimed methods are the compounds of formula (I) in which R1or hexamethyleneimino group. Representative compounds with such preferred groups include 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-pyrrolidinone)benzoyl] benzo[b] thiophene, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b] thiophene and 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-hexamethyleneimino)-benzoyl] benzo[b] thiophene. The preferred products of the present invention is the compounds of formula (I) in which R2and R3together with the neighboring nitrogen atom to form pyrrolidine or piperidine group. Representative products of this more preferred group of compounds include 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-pyrrolidinone) benzoyl] benzo[b]thiophene and 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b]thiophene. The most preferred product of the present invention is a compound of formula (I) in which R1represents hydroxyl, and R2and R3together with the neighboring nitrogen atom to form piperidino group. Therefore the most preferred compound is 6-hydroxy-2-(4-hydroxyphenyl) -3-[4-(2-piperidinoethyl)benzoyl]benzo[b]thiophene.

Compounds of formulas (II) and (III) the source materials of the present invention can be obtained using standard which is shown in the example of a 1 and depicted in scheme I (see at the end of text).

The compounds of formula (II), where R4represents C1-C4alkoxy, and R5- C1- C4alkyl, can be obtained by first subjecting the interaction of 3-alkyloxybenzoic with 4'-alkoxysilanes in the presence of a strong base. Suitable bases for this transformation include (but are not limited to, potassium hydroxide and sodium hydroxide. The reaction is usually run in ethanol or in a mixture of water and ethanol at a temperature of from about 0 to about 50oC. the Next step is the cyclization of 3-alkoxysilylated. The cyclization is usually lead by heating 3-alkoxysilylated in polyphosphoric acid. Usually, the cyclization is carried out at a temperature of from about 80 to about 120oC, preferably from 85 to 90oC. Benzothiophen formula II is usually purified by recrystallization. For example, if R4is methoxy, and R5- methyl, compound of formula II can be recrystallized from ethyl acetate.

Allerease agent for this method, the compound of formula III, can be obtained as shown in scheme II (see the end of the text), where the variables R2, R3, R6and HX have the previously mentioned meanings and R represents a C16is hydroxide. Suitable for the alkylation of bases include potassium carbonate and sodium carbonate. Suitable for this alkylation solvents are not reactive polar organic solvents, such as methyl ethyl ketone and dimethylformamide. Ester hydrolyzing using standard synthesis methods, for example the reaction of the alkylated intermediate compound with aqueous acid or base. So, for example, ethyl esters are easily hydrolyzed in the reaction with 5 N sodium hydroxide in miscible with water, an organic solvent, for example methanol. As a result, the acidification of the reaction mixture with concentrated hydrochloric acid yields a compound of the formula (III), where R6represents a hydroxyl in the form of a salt is hydrochloride.

The compounds of formula (III), where R6represents chlorine or bromine, can be obtained as a result of haloiding compounds of the formula (III), where R6represents hydroxyl. Suitable Ganoderma agents include oxalicacid, thionyl chloride, thienylboronic, trichromacy phosphorus, triphosgene and phosgene. Preferably, R6was chlorine. Suitable solvents for this reaction are of the same solvent, that and the subsequent acylation reaction. A catalytic amount of dimethylformamide from about 0.05 to about 0.25 equivalents added to the reaction mixture chlorination. If the reaction of lead in 1,2-dichloroethane, the reaction is completed within a period of time from about 2 to 5 hours at a temperature of about 47oC. the compounds of formula (III) in which R6is chlorine, can be stored either in solid form or in solution, or in a mixture with methylene chloride, chlorobenzene, 1,2-dichlorobenzene or 1,2-dichloroethane. It is preferable to conduct the reaction of chlorination and acylation sequentially in the same reactor.

2-aryl-6-hydroxy-3-[4-(2-aminoethoxy)benzoyl][b] tiophene can be obtained by acylation and subsequent dialkylammonium phenolic groups on two different stages or sequentially in the same reactor. Stepwise synthesis is described next. Acylated derivative benzothiophene connection of the formula IV can be obtained, as shown in scheme III (see the end of the text), where R2, R3, R4, R5, R6and HX have the previously indicated meanings.

Usually benzothiophene derivative II acelerou compound of formula (III), using boron trichloride or tribromide boron as rolled is RATAN, 1,2-dichlorobenzene, Brabanthal, chloroform, 1,1, 2,2-tetrachlorethane, 1,2,3-trichlorpropane or torbenson. It is preferable to carry out the acylation in methylene chloride, chlorobenzene or 1,2-dichloroethane. More preferably the stage of acylation in methylene chloride. The rate of acylation of the compounds of formula (II) and the rate of dealkylation of phenolic esters of the formula (II) and (IV) change depending on the choice of solvent, reaction temperature and choice of trihalide boron. Since the compounds of formula (II) contain one or more of unprotected phenolic groups, they are not easy to allievate in such conditions, and the degree of dealkylation should be kept to a minimum.

As trichromacy boron is preferable for the dealkylation of phenolic esters, the preferred trigloides boron to catalyze the acylation is boron trichloride. For reactions with catalyst is boron trichloride in methylene chloride acylation reaction can be conducted at room temperature with minimal dialkylammonium compounds of formulas (II) and (IV).

In other solvents the acylation reaction is carried out at lower temperatures such as -10 to +10oC, in order to minimize the degree of dealkylation in which at least 2 molar equivalents of this reagent, as triploid boron. If Alliluyeva agent use benzoic acid (R6= OH), then typically use five equivalents of trihalide boron. The compound of formula IV can be isolated in the form of a salt, hydrobromide or hydrochloride or free base.

In the stepwise method acylated intermediate compound (compound of formula (IV) dealkylase to obtain the compounds of formula I, as shown in scheme IV (see end of text), where R1, R2, R3, R4, R5and HX have the previously indicated meanings.

The compound of the formula I can be obtained by interaction or cleaners containing hydrochloride hydrobromide salts of the compounds of formula (IV) with tribromide boron or trichloride boron. The preferred trigloides boron for dealkylation is trichromacy Bor. This dealkylation reaction can be conducted in various organic solvents, such as methylene chloride, 1,2-dichloroethane, chloroform, 1,2,2,2-tetrachlorethane, 1,2,3-trichloropropane, 1,2-dichlorobenzene or torbenson. The preferred solvent is 1,2-dichloroethane. If the original connection using salt accession acid, the amount of by-product formed during deal is d, and reagent boron is boron trichloride, the reaction is usually conducted at temperatures from about 55 to about 75oC, obtaining the compound of formula (I) without appreciable removal of aminoaniline group. In such other solvents, such as chloroform, 1,2-dichloroethane, 1,2-dichlorobenzene or torbenson, dealkylation occurs readily at room temperature. For example, if the solvent is 1,2-dichloroethane, the reaction is usually carried out at 25-35oC without appreciable removal of aminoaniline group. To complete the reaction within a reasonable time, usually using four equivalents of reagent-trihalide boron.

It is preferable to obtain the compounds of formula I in the reaction in one reactor, synthesizing them from the compounds of formulas II and III as shown in scheme V (see the end of the text), where R1, R2, R3, R4, R5, R6and HX have the previously indicated meanings.

Benzothiophen the compounds of formula (II) acelerou compound of formula (III) in the presence of boron trichloride or trichromate boron; boron trichloride is preferred for the method "in the same reactor. The reaction can be conducted in such organic solvents as chloroform, methylene chloride, 1,2-dichloroethane, 1,2,3-dichloropropane, 1,1,2,2-taloraan. The reaction is conducted at temperatures from about -10oC to about 10opreferably at 0oC. the Reaction is best conducted at a concentration of benzothiophenes the compounds of formula (II) from about 0.2 M to about 1.0 M. the acylation Reaction is usually completed in approximately 2-8 hours

The acylated benzothiophen the compounds of formula IV into a compound of formula I without isolation. This transformation is carried out, adding more trihalide boron and heating the reaction mixture. It is preferable to add from two to five equivalents of boron trichloride to the reaction mixture, more preferably three molar equivalents. This reaction is carried out at a temperature of about 25-40oC, preferably at 35oC. Usually the reaction is finished after 4-48 hours the Reaction of acylation/dealkylation extinguish with alcohol or mixture of alcohols. Suitable for damping the reaction of the alcohols include methanol, ethanol and isopropanol. Preferably, the reaction mixture acylation/dealkylation to add to 95:5 mixture of ethanol and methanol (3A). 3A ethanol can be room temperature or may be heated to the boiling point, preferably at the boil under reflux.

If the reaction is quenched thus illegal source benzothiophene.

If using BCl3, crystalline product of this process in a single reactor is isolated in the form of MES cleaners containing hydrochloride salt. Such crystalline solvate get in various conditions. Usually the shape of the product obtained in this way is determined by the choice of solvent for the acylation/dealkylation of trihalide boron and treatment conditions. For example, if the solvent acylation/dealkylation is 1,2-dichloroethane, 1,2,3-trichloropropane or torbenson allocated to the crystalline MES containing 1,2-dichloroethane, 1,2,3-trichloropropane or torbenson respectively.

The most preferred MES the compounds of formula (I) is MES 1,2-dichloroethane. This MES receive, conduct the process of acylation/dealkylation "all in one reactor" in 1,2-dichloroethane. If R1is hydroxyl, R2and R3together with the adjacent nitrogen atom form piperidino, and HX is HCl, then MES 1,2-dichloroethane can exist in two different forms. One form of the crystalline MES called crystalline form 1, it turns out, when catalyzed by boron trichloride reaction acylation/dealkylation is th form. This specific crystal is characterized by the diffraction pattern of x-rays, are presented in table. 1.

The number of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b] difengidramin in this crystalline material is about 87.1 percent according to high performance liquid chromatography (BASH), which are disclosed hereinafter. The amount of 1,2-dichloroethane present in the crystalline material is about to 0.55 molar equivalents according to the nuclear magnetic resonance.

Large, analytically pure single crystal of form I of MES 1,2-dichloroethane get for analysis of x-ray diffraction single crystal. Such single crystal get by placing a saturated methanolic solution of 6-hydroxy-2-(4-hydroxyphenyl)-3- [4-(2-piperidino ethoxy)benzoyl] benzo[b] difengidramin in the atmosphere, saturated with 1,2-dichloroethane (see example 8). Get all 8419 reflexes for less than 20 116oand their use for structure determination. According to x-ray diffraction clearly shows that the crystalline material is a MES 1,2-dichloroethane with a ratio of the number of solvent molecules to ravenii data for the diffraction pattern of single crystal, identical to that presented in table. 1, which testifies to the identity of both the solvate.

The second form of the crystalline MES called crystalline form II, similar crystalline form I. This second form is received, quenching metal reaction acylation/dealkylation catalyst is boron trichloride, carried out in 1,2-dichloroethane. In another embodiment, in the reaction of acylation/dealkylation catalyst is boron trichloride, held in 1,2,3-trichlorpropane as solvent, receive 1,2,3-trichlorpropane MES of this form. This particular crystal form is characterized by the diffraction pattern of x-rays, are presented in table. 2.

The number of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b]difengidramin in this crystalline material is about 86,8%. The amount of 1,2-dichloroethane present in the crystalline material is about 6.5% according to gas chromatography.

The following solvated crystalline form referred to as crystalline form III. This particular form is received by way of acylation/dealkylation catalyst trichloride Orme is characterized by the diffraction pattern of x-rays, presented in table. 3.

The number of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b]difengidramin present in the crystalline material is about 80,4% according to HPLC. The amount of chloroform in the crystalline material is approx 0.42 molar equivalents according to proton nuclear magnetic resonance.

The preferred crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl) benzoyl] benzo[b]difengidramin is resolutiona crystalline form. This particular form is preferred for use in the preparation of pharmaceutical compositions, as there is no solvent that can harm the patient. This specific crystal form can be obtained by recrystallization of solvated cleaners containing hydrochloride salt obtained in the method of acylation/dealkylation catalyst is boron trichloride. In a preferred method, recrystallization solvated cleaners containing hydrochloride salt are added to a solution of sodium hydroxide in methanol or in a mixture of methanol and water. At least one equivalent of base is used for dissolution and for obesity solution to facilitate the removal of impurities. The resulting mixture is optionally filtered to remove the activated carbon, if present, and any insoluble impurities. The obtained filtrate optional extracted with aliphatic hydrocarbon solvent used in the reaction of acylation/dealkylation. Stage extraction is necessary in the case when the reaction of acylation/dealkylation are in such aromatic solvent, as torbenson, bramasol or o-dichlorobenzene. The methanol solution is acidified with hydrochloric acid, for example, gaseous or aqueous hydrochloric acid, which causes crystallization of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b]thiophene in the form of resolutional salt of hydrochloric acid. The resulting crystalline suspension pre-stirred at room temperature for about 1 to 2 h to ensure complete crystallization. Resolutionyou crystalline form are filtered, followed by drying in vacuum. This particular crystal form is characterized by the diffraction pattern of x-rays, are presented in table. 4.

The number of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b] difengidramin resolutionvideo crystalline material is the crystallization of certain solvated forms 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl) benzoyl] benzo[b] difengidramin. Usually solvated cleaners containing hydrochloride salt is dissolved in a hot solution (about 50oC to the boiling temperature under reflux) containing methanol and water, where the water is from about 3 to 10 vol.%. The resulting solution can be filtered to remove insoluble impurities. This solution or the filtrate is concentrated by distillation of solvent, getting resolutiony crystalline material. This resolutiony crystalline material produce, using standard techniques, such as filtering and drying. This process of crystallization in hot methanol (water) can be used to obtain resolutiony crystalline forms of some crystalline solvate in which the boiling point of the solvent in the MES less than about 85oC.

Resolutiony crystalline material is more pure than the material produced by the methods described in the above referenced patents. The material obtained by the methods of the present invention, does not contain impurities of aluminum compounds and chlorinated aliphatic hydrocarbon solvents and aromatic solvents. This resolutiona crystalline form of n the following examples further illustrate the present invention. These examples are not intended to limit the invention in any way. All experiments acylation and dialkylamino are under high pressure of dry nitrogen. All solvents and reagents used without purification. Interest is usually expressed as wt.%, with the exception of HPLC solvents, which are calculated as vol.%. Data proton nuclear magnetic resonance (1H NMR) were obtained on a spectrometer Bruker AC - 300 FT MR M with an operating frequency of 300, 135 MHz. The melting temperature is determined using differential scanning calorimeter (DSC) TA device DCS 2920 using a closed cell at heating rate of 2oC/min Diffraction spectrum of x-rays for powders get an x-ray powder diffractometer Siemens D 5000, using copper radiation and Si(Li) detector.

AT the end of the reaction is usually controlled by high performance liquid chromatography (HPLC). The course of the reaction to obtain the acid chloride, the compounds of formula III, where R6represents chlorine, controlled by Bond RX-C8 column (25 cm 4.6 mm B h.D., 5 μm particle size), elwira a mixture of 60 mm phosphate (KH2PO4) and 10 mm octanesulfonate (pH 2,0) acetonitrile (60 : 40). Connection formulas. The reaction is controlled by adding about 0.3 ml of a solution of the acid chloride to 1 ml of methanol HPLC purity. The resulting mixture was intensively shaken and left to react. After 30 minutes add 6 ml of acetonitrile, and then dilute to 100 ml described above eluent.

The completion of the acylation reactions, dealkylation or acylation/dealkylation control using HPLC. Samples of the reaction mixture analyzed using column Bond RX-C8 (25 cm 4.6 mm EXT. D., 5 μm particle size), using as eluent a gradient solvent system, are presented in table. 5.

The reaction mixture was analyzed by diluting 0.1 - 0.2 ml sample to a volume of 50 ml with a mixture of 60 : 40 A/B. Similarly, the mother liquor of precrystallization examined in a similar way, selecting samples.

Number (%) of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl) benzoyl] benzo[b] difengidramin in the crystalline material (purity) is determined in the following way. A sample of the crystalline solid (5 mg) is weighed into a 100 ml volumetric flask and dissolved in a mixture of 70/30 75 mm potassium phosphate buffer (pH 2.0) and acetonitrile. An aliquot of this solution (10 µl) was analyzed by high performance liquid using a gradient solvent system, shown in the table. 6.

The percentage of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] [b] difengidramin in the sample is calculated using the peak area, the slope (m) and intercept (b) calibration curve with the following equation:

< / BR>
The percentage of solvent, such as methanol, ethanol or 1,2-dichloroethane, present in the crystalline material was determined by gas chromatography. A sample of the crystalline sample (50 mg) is weighed into a 10 ml volumetric flask and dissolved in a solution of 2-butanol (0.025 mg/ml) and dimethyl sulfoxide. A sample of this solution is analyzed by gas chromatography using a DBWax column (30 m, 0.53 mm EXT. diameter, particle size 1 micron), at a flow rate of 10 ml/min with a flame ionization detector. The temperature of the column increases from 35 to 230oC for 12 minutes, the Amount of solvent is determined by comparison with the internal standard (2-butanol) using the following formula:

,

where

C - the proportion of solvent in the sample

D - average share of the standard for a specific solvent;

E - the average weight standard;

F - weight of sample (mg);

G - sample volume (10 ml);

H - volume standard (10,000 ml);
oC. to This cold mixture is treated with 4'-methoxybenzylamine (164 g) in several small portions. After complete addition, the mixture cool for another 10 minutes, then allow it to warm to room temperature. After three hours the mixture was concentrated in vacuo, and the residue is treated with water (200 ml). The resulting mixture was treated with ethyl acetate and the phases are separated. The organic phase is washed twice with water, sodium bicarbonate solution twice and also twice with a solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to obtain 202 g (3 methoxybenzylthio)-4-methoxyacetophenone. The crude product is crystallized from methanol and washed with hexane to obtain 158 g of substance. So melting 53oC. 930 g polyphosphate acid is heated to 85oC and treated intermediate product obtained previously (124 g) in small portions over 30 minutes After complete addition, the resulting mixture was stirred at 90oC. after 45 min, the reaction mixture is allowed to cool to room temperature. The resulting mixture was treated with crushed ice, cooling the mixture in an ice bath. The resulting mixture is treated with water (100 ml), resulting in a light>C to obtain 119 g of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene. This crude product is suspended in hot methanol, filtered and washed with cold methanol. The obtained solid material is recrystallized from ethyl acetate (4 l), filtered, washed with hexane and dried in vacuum to obtain 68 g specified in the title compounds. The melting point of 187 - to 190.5oC.

Example of getting a 2. Ethyl-4-(2-piperidinoethyl)benzoate.

A mixture of ethyl-4-hydroxybenzoate (8,31 g), 1-(2-chloroethyl)piperidineacetate (10, 13 g), potassium carbonate (16,59 g) and 60 ml of methyl ethyl ketone heated to 80oC. After one hour, the mixture is cooled to 55oC and treated with an additional amount of 1-(2-chloroethyl)piperidineacetate (0,92 g). The resulting mixture was heated to 80oC. the reaction is monitored by thin layer chromatography (TLC), using plates of silica gel and a mixture of ethyl acetate-(acetonitrile) triethylamine (10:6:1 volume/volume). Add a further portion of 1-(2-chloroethyl)piperidinedione up until the original 4-hydroxybenzoate ester does not react whole. After completion of the reaction, the reaction mixture is treated with water (60 ml) and left to cool down to room temperature the oil is used in the next stage without additional purification.

Example of getting a 3. 4-(2-Piperidinoethyl)benzoic acid hydrochloride.

A solution of the compound obtained in the example of a 2 (about 13,87 g) in 30 ml of methanol, treated with 5 N. sodium hydroxide (15 ml) and heated to 40oC. After 4.5 h add 40 ml of water. The resulting mixture was cooled to 5-10oC and slowly add concentrated hydrochloric acid (18 ml). In the process of acidification crystallizes specified in the title compound. The crystalline product is collected by filtration and dried in vacuum at 40-50oC to obtain 83% of output specified in the title compounds. The melting point 270-271oC.

Example 4. 4-(2-Piperidinoethyl) of benzoyl chloride hydrochloride.

A solution of the compound obtained by the method of example for the preparation of 3 (30,01 g) and 2 ml of dimethylformamide in a 500 ml of methylene chloride is treated with oxalylamino (10.5 ml) for 30-35 minutes After stirring for about 18 h, the reaction mixture was analyzed for completion of the reaction by HPLC. If the mixture still has the original carboxylic acid, add additional oxalicacid. After completion of the reaction, the reaction solution is evaporated to dryness in a vacuum. The residue is dissolved in 200 ml met the treatment specified in the title compounds as solids. Specified in the title compound can be stored in the form of a solid substance or in the form of a 0.2 M solution in 500 ml of methylene chloride.

Example 1. 6-Methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] -benzo[b]difengidramin.

The mixture of compounds obtained by the method of example obtain 1 (8,46 g), and the acid chloride obtained according to the method of example for the preparation of 3 (10.0 g) in 350 ml of methylene chloride is cooled to about 20-25oC. the resulting mixture was treated with boron trichloride (2.6 ml) and everything is mechanically stirred. The reaction is monitored by HPLC, using the earlier analysis. After 85 min according to HPLC in situ output per 6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b]titanovyi standard is 88%.

Example 2. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl]-benzo[b]difengidramin 1,2-dichlorethane MES

(Crystal form I)

A solution of 6-methoxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethyl)-benzoyl] benzo[b]difengidramin (2.0 g) in 20 ml of 1,2-dichloroethane is treated with boron trichloride (2.0 ml). The resulting mixture was stirred at 35oC for 18 hours the Mixture of ethanol and methanol (10 ml 95:5,3 (A) treat the reaction with vsuza the crystal suspension is stirred at 25oC. After an hour, the crystalline product is filtered, washed with cold ethanol (10 ml) and dried at 40oC in a vacuum to obtain 1.78 g specified in the title compounds. Diffraction pattern x-ray powder identical to the picture shown in the table. 1. The melting point of 255oC.

Degree of purity : 80.2 per cent.

1,2-dichloroethane : 7,5% (according to gas chromatography).

Example 3. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl]-benzo[b] triphenylborane methylenchloride MES.

(Crystal form III)

The mixture of compounds obtained by the method of obtaining 1 (7,54 g in 10 ml of methylene chloride, and the acid chloride obtained according to the method of obtaining 4 (140 ml, 0.21 M solution in methylene chloride), placed in a sealed reactor (Hastalloy Parr). The resulting solution was cooled to 0oC and treated with boron trichloride (7.2 ml). The resulting reaction mixture was stirred at room temperature. After 3 h the reaction mixture was cooled in an ice bath for 10 minutes the Second portion of boron trichloride is added to the reaction mixture (4.8 ml) and the resulting mixture is heated to 75oC. After 2.5 h, the reaction mixture is cooled to about 15oC. Hallodri 18oC, getting a solid crystalline substance. It is a solid crystalline substance is removed by filtration, washed with cold methanol (45 ml) and dried in vacuum at 40oC for 18 h to obtain 12.5 g specified in the title compounds. The diffraction pattern of x-rays identical to the picture presented in the table.3.

Melting point: 207oC.

Degree of purity: 81,8 %

Methylene chloride: a 0.4 molar equivalent (according to the1H NMR).

Example 4. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl]-benzo[b]difengidramin 1,2-dichlorethane MES

(Crystal form I)

The mixture of compounds obtained as described in example obtain 3 (15 g), and dimethylformamide (0.2 ml) in 250 ml of 1,2-dichloroethane is cooled to 0oC, of 8.25 ml of phosgene condense in cold funnel, equipped with a jacket (-10oC) and added dropwise to the cold mixture for 2 minutes the resulting mixture is heated to approximately 47oC. After two and a half hours, the reaction mixture was analyzed by HPLC. To complete the reaction may need to add additional phosgene. The excess phosgene is removed by vacuum distillation at 30-32oC and a pressure of 105 to 110 mm RT. Art.

receipt (13,52 g). The resulting solution was cooled to 0oC. boron Trichloride (12,8 ml) condense in a measuring cylinder and added to the cold reaction mixture. After eight hours at 0oC the reaction solution is treated with an additional amount of boron trichloride (12,8 ml). The resulting solution was heated to 30oC. After 15 h, the reaction mixture was monitored by HPLC.

A mixture of ethanol and methanol (125 ml, 95:5, 3A) is heated to boiling under reflux and treated reaction solution obtained earlier, within 60 minutes After complete addition, the flask for reaction acylation/demethylation washed with additional ethanol (30 ml). The resulting suspension is allowed to cool to room temperature with stirring. After one hour at room temperature crystalline product is filtered off, washed it with ethanol (75 ml) and dried at 40oC in a vacuum to obtain 25,9 g specified in the title compounds. Diffraction pattern x-ray powder are presented in table. 1.

Melting point: 261oC.

Degree of purity: 87,1%.

1,2-dichloroethane: to 0.55 molar equivalents (1H NMR).

Example 5. 6-Hydroxy-2-(4-GI is (Crystal form II)

The mixture of compounds obtained as described in example obtain 1 (2,92 g), compounds obtained as described in example 4 (of 3.45 g), 1,2-dichloroethane (52 ml) is cooled to about 0oC. boron Trichloride condense in the cold cylinder (2.8 ml) and add the specified cold mixture. After 8 h at 0oC, the reaction mixture was treated with an additional amount of boron trichloride (2.8 ml). The resulting solution was heated to 35oC. After 16 h the reaction is finished.

30 ml of methanol is treated with the reaction mixture obtained previously, for 20 min, resulting in boiling methanol under reflux. The resulting suspension is stirred at 25oC. After an hour, the crystalline product is filtered, washed with cold methanol (8 ml) and dried at 40oC in a vacuum to obtain 5,14 g specified in the title compound.

Melting point: 225oC.

The diffraction pattern of x-rays is presented in table. 2.

Degree of purity: 86,8%.

1,2-dichloroethane: 6,5% (according to gas chromatography)

Example 6. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethyl)benzoyl]-benzo[b]difengidramin.

The compound obtained is with a solution of sodium hydroxide (0,313 g) in 10 ml of methanol. After complete dissolution the solution was added activated carbon (0,4 Darco G-b0, Aldrich Chem. Co., Inc., Milwankee, WI).

After 30 min, the suspension is filtered through filter paper Whatman No. 1 pre-coated with diatomaceous earth (Hyflo Super Cel, Aldrich Chem Co.). The filter cake is washed with methanol (10 ml). The combined filtrates are treated (drops) 2 N. hydrochloric acid (4 ml). The resulting suspension is stirred for 60 min at room temperature and filtered. The filter cake was washed with cold methanol (14 ml, 0oC) and dried in vacuum at 60oC for about 18 h to obtain 3.0 g off-white free-presupuestos powder. So melting 262oC. Diffraction pattern x-ray powder is the same as presented in table. 4.

Degree of purity: 99.1 per cent.

Related substances: 0,85%.

Example 7. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethyl)benzoyl]-benzo[b]difengidramin 1,2-dichlorethane MES.

(Crystal form I)

A saturated solution of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethyl)benzoyl] -benzo[b] difengidramin get, stirring a suspension of the compound obtained Sabah N-1). Part of the filtrate (20 - 25 ml) placed in a 50 ml Erlenmeyer flask. This flask is placed inside a glass vessel (8.5 cm x 10 cm) containing 1,2-dichloroethane (10 ml). The vessel is sealed, and all this is left at room temperature. After 24 h the individual crystals appear from a methanol solution. These crystals are filtered and dried in vacuum. So melting 273oC.

Crystal structure determined using an automatic diffractometer Siemens R3m/v with monochromatic copper radiator ( = 1,54178). Crystal structure determined using direct methods normal TREF software library SHELXTL PLUS.

Refinement full matrix least squares of deviations is carried out with anisotropic temperature factors for all atoms except hydrogens, which include the computed positions with isotropic temperature factors. The final value of R-factor is 8,02%.

The results of the study of the crystal below.

Characterization of crystals:

Space group C 2/C

Lattice parameters:

a = 20,720 (7)

b = 9,492(2)

c = 28,711(4)

< / BR>
Volume - 5610(2)

Density (calculated) - 1,40 clearly shows that crystalline material is a 1,2-dichlorethane MES with a ratio of 1 : 2 molecules of 1,2-dichloroethane to molecules of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] -benzo[b]difengidramin.

Example 8. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethyl)benzoyl]-benzo[b]difengidramin 1,2,3-trichlorpropane MES.

(Crystal form II)

The mixture of compounds obtained by the method of example obtain 1 (2.70 g), compounds obtained by the method of obtaining 4 (of 3.60 g) and 50 ml of 1,2,3-trichlorpropane mixed with boron trichloride (2.6 ml). After 3 h at 20 - 25oC, the reaction mixture was treated with an additional amount of boron trichloride (2.6 ml). After 18 h, the reaction mixture was treated with tetrahydrofuran (15 ml) and then slowly add methanol (15 ml). After these additions, the reaction mixture was stirred at room temperature. After an hour of solid crystalline substance is filtered off, washed with cold methanol (10 ml) and dried at 50oC in a vacuum to obtain 4,13 g specified in the title compounds. Diffraction pattern x-ray powder identical to the picture presented in the table. 2.

Temperament (1H NMR)

Example 9. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl]- benzo[b]difengidramin chloroformate MES.

(Crystal form III)

Specified in the title compound (4.42 g) are obtained according to the method of example 8 except that the solvent in the reaction is chloroform (50 ml). Diffraction pattern x-ray powder identical to the picture presented in the table. 3.

Melting point: 258oC.

Degree of purity : 80,4%.

Chloroform : 0,42 molar equivalent (1H NMR).

Example 10. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethyl)benzoyl]-benzo[b]difengidramin.

A solution of sodium hydroxide (0,313 g) in 10 ml of methanol diluted with additional methanol (50 ml). This solution is treated with a compound obtained by the method of example 5 (4.0 g). After 45 min at room temperature the resulting solution was filtered (filter paper Whatman No. 1) and the filter paper was washed with methanol (3 ml). The resulting filtrate is treated with 2 G. hydrochloric acid (4 ml) to give a crystalline suspension. After 1.5 h, the crystalline product is filtered off, washed with methanol (5 ml) and dried at 45 s powder identical to the picture, presented in table. 4.

Melting point: 261oC.

Degree of purity : 96.5 per cent.

Example 11. 6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethyl)benzoyl]-benzo[b]difengidramin.

The mixture of compounds obtained by the method of example 4 (50 g) in methanol (1125 ml) and water (60 ml) is heated to boiling under reflux until complete dissolution. The hot solution is filtered (filter paper Whatman No. 1) and the residue is washed with methanol (200 ml). The combined filtrate is concentrated by distillation, removing 1207 ml of distillate. During distillation, crystallization occurs. The resulting suspension is left to cool at room temperature and filtered. The crystalline material was washed with cold (0oC) methanol (170 ml). The resulting material is dried in vacuum at 60oC for about 18 h, lightly blowing with nitrogen to obtain 38,79 g of yellow-brown freely presuposes solids. The diffraction pattern of x-rays identical to the picture presented in the table. 4.

Melting point: 275,6oC.

Degree of purity : 99.4 per cent.

Residual methanol : less than 0.6% (gas chromatography)

Related substances : 0,51% SUP>1is hydrogen or hydroxyl;

R2and R3independently - C1- C4-alkyl or together with the adjacent nitrogen atom form a heterocyclic ring selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, morpholino;

HX is HCl or HBr,

characterized in that (a) benzothiophen General formula II

< / BR>
where R4is hydrogen or C1- C4-alkoxy;

R5- C1- C4-alkyl,

acelerou compound of General formula III

< / BR>
where R6is chlorine, bromine or hydroxyl;

HX, R2and R3have the specified values,

in the presence of BX'3where X' is chlorine or bromine, followed by (b) dialkylammonium one or two phenolic esters of acylated product of stage (a) by interacting with additional quantity BX'3where X' has the specified values, and (c) the allocation of the crystalline MES.

2. The method according to p. 1, wherein R1is hydroxyl, R2and R3together with the adjacent nitrogen atom form the group piperidino, R4- methoxy, R5is methyl, R6- chlorine, HX is HCl, X' is chlorine.

3. The method of obtaining crystalline MES compounds of General formula I

< / BR>
where R1- ECCE nitrogen form a heterocyclic ring, selected from the group consisting of pyrrolidino, piperidino, hexamethyleneimino, morpholino;

HX is HCl or HBr,

characterized in that conduct and dealkylation of one or two phenolic esters of the compounds of General formula IV

< / BR>
where R4is hydrogen or C1- C4-alkoxy;

R5- C1- C4-alkyl;

HX, R2and R3have the specified values;

by interacting with BX'3where X' is chlorine or bromine, and (b) isolation of the crystalline MES.

4. The method according to p. 3, wherein R1is hydroxyl, R2and R3together with the adjacent nitrogen atom form piperidino, R4- methoxy, R5is methyl, HX is HCl, X' is chlorine.

5. Crystalline MES-6-hydroxy-2-(4-hydroxyphenyl)-3[4-(2-piperidinoethyl) benzoyl]benzo(b)difengidramin with 1,2,3-trichlorpropane, in which the ratio of solvent and benzothiophene is 1 : 2 and which has the following picture of the x-ray diffraction obtained with copper radiation source:

The position of the d-lines, - I/I0100

10,4311 - 22,64

8,9173 - of 10.73

8,4765 - 5,31

8,0095 - 50,39

7,3068 - 4,23

6,6094 - 79,23

5,6196 - 22,34

5,4223 - 89,86

5,1959 - 11,81

5,0746 - 74,90

4,8017 - 100,00
,80

3,9880 - of 14.76

3,8863 - 8,17

3,7999 - 42,13

3,7662 - 57,09

3,6738 - 38,58

3,5701 - 18,50

3,5393 - 19,00

3,4622 - 39,57

3,3867 - 5,02

3,3321 - 4,33

3,2686 - 6,79

3,1535 - 14,86

3,0450 - of 13.58

2,9028 - 12,30

2,8302 - 19,59

2,7544 - 12,30

2,6366 - 6,89

2. Crystalline MES-4-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl) benzoyl] benzo [b]difengidramin 1,2-dichloroethane, in which the ratio of solvent and benzothiophene is 1 : 2 and which has the following picture of the x-ray diffraction obtained with copper radiation source:

The position of the d-lines, - I/I0100

10,4311 - 22,64

8,9173 - of 10.73

8,4765 - 5,31

8,0095 - 50,39

7,3068 - 4,23

6,6094 - 79,23

5,6196 - 22,34

5,4223 - 89,86

5,1959 - 11,81

5,0746 - 74,90

4,8017 - 100,00

4,7262 - 57,97

4,6569 - 53,35

4,5378 - 96,75

4,4376 - 10,83

4,3397 - 56,89

4,2782 - 48,23

4,2129 - 40,94

4,1037 - 12,80

3,9880 - of 14.76

3,8863 - 8,17

3,7999 - 42,13

3,7662 - 57,09

3,6738 - 38,58

3,5701 - 18,50

3,5393 - 19,00

3,4622 - 39,57

3,3867 - 5,02

3,3321 - 4,33

3,2686 - 6,79

3,1535 - 14,86

3,0450 - of 13.58

2,9028 - 12,30

2,8302 - 19,59

2,7544 - 12,30

2,6366 - 6,89

7. Crystalline MES 6-hydroxy-2-(4-hydroxyphenyl) -3-[4-(2-piperidinoethyl)benzoyl] benzo[b] type who meet the following picture of the x-ray diffraction, obtained from a copper radiation source:

The position of the d-lines, - I/I0100

16,1265 - 3,80

10,3744 - 8,63

8,3746 - of 5.29

7,9883 - 36,71

7,2701 - 5,06

6,5567 - 70,77

6,2531 - 6,79

5,5616 - 24,05

5,3879 - 100,00

5,0471 - 89,64

4,7391 - 85,96

4,6777 - 39,36

4,6332 - 62,60

4,5191 - 77,56

4,2867 - 36,82

4,2365 - 41,66

4,1816 - 49,60

4,0900 - 11,28

3,9496 - 11,85

3,7869 - 36,25

3,7577 - 56,16

3,6509 - 40,62

3,5751 - 15,65

3,5181 - 21,52

3,4964 - 18,53

3,4361 - 33,60

3,3610 - 6,21

3,3115 - 4,95

3,2564 was 7.36

3,2002 - 3,80

3,1199 - 15,77

3,0347 - 14,84

2,8744 - 9,67

2,8174 - 10,82

2,7363 - 11,51

8. The method of obtaining resolutionvideo crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl) benzoyl] benzo[b] -difengidramin having the following diffraction picture of x-rays obtained from a copper radiation source:

The position of the d-lines, - I/I0100

13,3864 - 71,31

9,3598 - 33,16

8,4625 - 2,08

7,3888 - EUR 7.57

6,9907 - 5,80

6,6346 - 51,04

6,1717 - 29,57

5,9975 - 5,67

5,9135 - 9,87

5,6467 - 38,47

5,4773 - 10,54

5,2994 - 4,74

4,8680 - 4,03

4,7910 - 5,98

4,6614 - 57,50

4,5052 - 5,75

4,3701 - 9,03

4,2516 - 69,99

4,2059 - 57,64

4,1740 - 65,07

4,0819 - to 12.44

3,9673 - 22,53

3,9318 - 100,00

3,87751857 - 8,90

3,1333 - 6,24

3,0831 - 9,43

3,0025 - 12,13

2,9437 - 4,96

2,8642 - 7,70

2,7904 - 11,95

2,7246 - 3,05

2,6652 - 3,32

2,5882 - 7,30

characterized in that (a) benzothiophen General formula II

< / BR>
where R4- C1- C4-alkoxy;

R5- C1- C4-alkyl,

acelerou compound of General formula III

< / BR>
where R6is chlorine, bromine or hydroxyl;

HX is HCl or HBr;

R2and R3together with the adjacent nitrogen atom form piperidine in the presence of BX'3where X' is chlorine or bromine,

then (b) dialkylammonium phenolic esters of the acylation product of stage (a) by interacting with additional quantity BX'3where X' has the value (c) allocation of the crystalline MES compounds of General formula I

< / BR>
where R1is hydroxyl;

HX, R2and R3have the specified values;

(d) interaction of a specified crystalline MES in methanol or in a mixture of methanol and water with about one equivalent of a base; (e) an optional extraction solution from stage (d) aliphatic hydrocarbon solvent; (f) adding about one equivalent of hydrochloric acid to a methanol solution from stage (d) of the action scene, what R4- methoxy, R5is methyl, R6- chlorine, HX is HCl, BX'3- BCl3, aliphatic hydrocarbon solvent is hexane or heptane, the base is sodium hydroxide.

10. The method of obtaining resolutionvideo crystalline 6-hydroxy-2- (4-hydroxyphenyl)-3-[4- (2-piperidinoethyl)benzoyl] benzo[b] difengidramin, which is described in paragraph 8, the diraction pattern of x-rays obtained from a copper radiation source, characterized in that (a) benzothiophen General formula II

< / BR>
where R4- C1- C4-alkoxy;

R5- C1- C4-alkyl,

acelerou compound of General formula III

< / BR>
where R6is chlorine, bromine or hydroxyl;

HX is HCl or HBr;

R2and R3together with the adjacent nitrogen atom form piperidine in the presence of BX'3where X' is chlorine or bromine,

then (b) dialkylammonium phenolic esters of the acylation product from stage (a) by interacting with additional quantity BX'3where X' has the value (c) allocation of the crystalline MES compounds of General formula I

< / BR>
where R1is hydroxyl;

HX, R2and R3have the specified values,

is selected by filtering the solution from step (d); (f) the concentration of the solution from stage (d) or (e) by distillation, and (g) allocation resolutionvideo crystalline substance.

11. The method according to p. 10, wherein R4- methoxy, R5is methyl, R6- chlorine, HX is HCl, and BX'3- BCl3.

 

Same patents:

FIELD: chemistry.

SUBSTANCE: compounds of formula (1) are described, where substitutes are as defined in the formula of invention. Methods of obtaining formula (1) compounds are described, when n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining compounds with fungicide properties.

17 cl, 60 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to thiophene derivatives of formula (I):

where A denotes -CONH-CH2-, -CO-CH=CH-, -CO-CH2CH2-, -CO-CH2-O-, -CO-CH2-NH-, or ; R1 denotes hydrogen, C1-5-alkyl or C1-5-alkoxy; R2 denotes hydrogen, C1-2-alkyl, C1-5-alkoxy, trifluoromethyl or halogen, R3, R31, R32, R33, R34, R4, R5, R6, R7, k, m, n are described in claim 1. The invention also relates to a pharmaceutical composition for preventing or treating diseases and disorders associated with an activated immune system, based on said compounds and to use thereof as therapeutically active compounds for preventing or treating diseases or disorders such as graft rejection, graft versus host reaction and autoimmune syndromes.

EFFECT: improved properties of the compound.

27 cl, 2 tbl, 525 ex

FIELD: medicine.

SUBSTANCE: invention refers to new thiophen derivatives of formula (I), formula (II), formula (III). Formula (I) where R1 means methyl, triflouromethyl or ethyl; R2 means hydrogen; R3 means hydrogen or C1-C4alkyl; R4 means hydrogen or C1-C4alkyl; R5 means hydrogen; R6 means hydrogen; n is equal to 0; m is equal to 0 or 1; and if m is equal to 1, n is also equal to 1; and salts, as well as to complexes of such compounds with a solvent, producing and applying thereof as pharmaceutically active compounds. Formula (II) where R1, R2, R3, R4, R5, R6, n and m have the values specified in cl. 1 for Formula (I), and R7 means hydrogen, methyl, ethyl or tert-butyl; Formula (III) where R1, R2, R3 and R4 have the values specified in cl. 1 for formula (I), and R7 means hydrogen, methyl, ethyl or tert-butyl.

EFFECT: compounds first of all have an effect of immunosuppressive agents.

18 cl, 2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing a compound of general formula VIII of enantiomeric purity min. 80% by a reaction of the compound according to general formula IV with enantiomeric pure 2-hydroxy-4-methyl-2-(trifluoromethyl)pentenoic acid to produce a compound of general formula II to be reduced to prepare a compound for general formula I to be oxidated to form an aldehyde which then reacts with an aromatic amine of formula H2N-Ar to produce a respective imine which is then reduced to prepare a compound described by formula VIII in the enantiomeric pure form. Also, it refers to methods for preparing the compound of formula I, as well as to the compounds of formula I. In general formulas

, ,

, , X1, X2, X3 is specified in fluorine, chlorine, bromine, hydroxy, methoxy, ethoxy, trifluoromethyl, amino whereas the other groups X1, X2, X3 represent a hydrogen atom.

EFFECT: preparing the non-steroid anti-inflammatory drugs.

12 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

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