Derivatives of hydroquinone in free form or in the form of salts, methods for their preparation, derivatives of piperidine and methods for their production

 

(57) Abstract:

Usage: in medicine as intermediates for receiving antidepressants. The inventive products - derivatives of hydroquinone f-ly I, where R4is lower alkyl and R1- OH, halogen, -P(O)(R5)(R6or P+(R7)(R8R9X-, M is methylene, R2- H or a group of the formula 2, R3-H, halogen, or R1- OH, or lower CNS group, M is carbonyl, R2Is H and R3- halogen, R5and R6lowest CNS group, R7, R8and R9- phenyl, X-anion halomonadaceae acid, Y is the group - C(O) R10- lower alkyl group. Reagent 1 connection f-crystals 3, which halogenous, restore and subjected to interaction with connection f-ly 4. Products - derivatives of piperidine f-crystals 5, where X5- halogen or the group X7- O, where X7- lower alkanesulfonyl or alkoxycarbonyl, X6- lower alkoxygroup, alkenylacyl, benzyloxy. 10 C. and 16 h.p. f-crystals.

The invention relates to a process for the production of piperidine derivatives or their pharmaceutically acceptable salts exhibiting antidepressant activity, for example, to the synthesis Brovarone; 4-chlorocarbonyl-1-benzyloxycarbonylamino or its salt as an intermediate product to obtain the derivatives of piperidine with antidepressant activity, as well as the new N-alalim derivative of piperidine or their salts.

A method of obtaining derivatives of piperidine, in particular, Brofaromine, of the formula:

< / BR>
(R4CH3)

which is carried out usually within 8 h scheme A1 A8 provided in the end of the description.

Under this scheme, form 4-methoxyphenol on Reimer-Tiemann (A1) and then bromilow (A2). The obtained 3-bromo-5-methoxysalicylaldehyde then condensed with 4-chloromethylpyridine (A3). The obtained 4-(7-bromo-5-methoxybenzophenone-2-yl)-pyridine-N was identified in up to N-methyl-1,2,5,6-tetrahydropyridine (A5) and hydronaut to 1-methyl-4-(7-bromo-5-methoxybenzophenone-2-yl)-piperidine (A6). These will then demetrious by entering into interaction with a complex ether of halogenarenes acid in the formation of the corresponding complex ester of 4-(7-bromo-5-methoxybenzophenone-2-yl)-piperidine-1-carboxylic acid (A7), which finally split up Brofaromine (A8).

This method has certain disadvantages. If you come from a 4-methoxyphenol only achieved a total output Brovar the om-5-methoxysalicylaldehyde stage A1 and A2 (yield 45% of theory). Its subsequent conversion into Brofaromine (stage A3-A8) expensive and goes with large losses due to mnogostadiinost and due to the fact that at the stage A6 get up to 10% of unwanted product dibromononane, which can be removed with difficulty by repeated recrystallization (exit 27.4% of theory). This is primarily due to the fact that the output stage of the cyclocondensation A3 may not exceed 45% of theory. Subsequent hydrogenation of 1-methyl-4-(7-bromo-5-methoxybenzophenone-2-yl)-1,2,5,6-tetrahydropyridine and subsequent demethylation of 1-methyl-4-(7-bromo-5-methoxybenzophenone-2-yl)piperidine (A6-A8) is the yield of only 6% of theory.

The aim of the invention is to develop environmentally friendly and cost-effective method of obtaining derivatives of the formula XII, preferably Brofaromine, which partially or completely devoid of the disadvantages of this method.

This method, already on the basis of 5-bromosalicylaldehyde, in particular, upon receipt Brofaromine allows to increase the output from 27.4% to 62% of theoretical.

For the implementation of new ways of getting the piperidine derivatives or pharmacologically acceptable salts include new compounds and methods for their receipt is where R4denotes lower alkyl and R1denotes either a hydroxyl group, halogen, a group of the formula-P(=O)(R5)(R6)(1a), or a group of the formula P+(R7)(R8R9X-(1b), M is methylene, R2denotes hydrogen or a group of the formula

< / BR>
and R3denotes hydrogen or halogen, or R1denotes a hydroxyl group or a lower CNS group, M denotes a carbonyl, R2denotes hydrogen and R3denotes halogen, R5and R6represent the lowest CNS group, R7, R8and R9denote phenyl group, X-denotes the anion kaleidotrope acid, Y represents a group of formula -(C=O)-(1e) and R10indicates the lowest CNS group, provided that in the compound I, where R1refers to a group 1b, where R7, R8, R9correspondingly represent unsubstituted phenyl group, and X-denotes bromide ion, M denotes methylene, R2denotes hydrogen and R4denotes methyl, R3is not hydrogen, and provided that the compound I where R1denotes a hydroxyl group, M denotes a methylene, R2denotes hydrogen and R4denotes methyl or ethyl, R1refers to a group 1b. Unsuitable for pharmaceutical applications salts can be used, for example, for separation, purification of free compounds of formula I and their pharmaceutically applicable salts.

The term "lower", unless nothing else, mean residues, which contain up to 7, especially up to 4 carbon atoms.

Lower alkyl represents a C1-C4-alkyl, i.e. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl or tert.-butyl; and further covers the C5-C7-alkyl, i.e. corresponding pentelenyi, sexily and Gately remains.

Lowest alkoxyl represents a C1-C4-alkoxyl, i.e. methoxy, ethoxy, propyloxy, isopropoxy, bucalossi, isobutoxy, Deut.-butylochki or tert. -Butylochka; then covers C5-C7-CNS, i.e. corresponding pentyloxy, hexyloxy and heptyloxy remnants.

Lower alkenylacyl is, for example, allyloxy; phenyl-(lower alkenyl)-hydroxy denotes, for example, 3-phenylprop-2-enyloxy.

Halogen is especially chlorine or bromine, next, fluorine or iodine.

N, N-di-(lower alkyl)-amino is a balance, where both N-residue are the same or different and, depending on the circumstances, have specified above in the definition of the lower alkyl is as N,N-dimethylamino, N,N-diethylamino, N,N-diisopropylamino, N-butyl-N-methylamino, N,N-diphenhydamine or N-pentyl-N-methylamino.

Halogen-(lower alkyl) contains compared with the lower alkyl on one of its C atoms one, two or three identical or different halogen atoms instead of hydrogen atoms and represents a balance, where lower alkyl has the above when determining the lower alkyl is, and the halogen has the above when determining the halogen is as trifluoromethyl, trichloromethyl, 2,2,2-triptorelin or 3,3,3-cryptochromes.

(Lower alkane)-sulfonyl represents a C1-C4- alkanesulfonyl as methanesulfonyl, econsultancy, propanesulfonyl, butanesulfonyl or tert.-butanesulfonyl, and then covers the C5

Halogen-(lower alkane)-sulfonyl contains compared with the lowest alkanesulfonyl on one of its C atoms one, two or three identical or different halogen atoms instead of hydrogen atoms and represents a balance, where (lower alkane)-sulfonyl is specified above in the definition (lower alkane)-sulfonyl value, and the halogen has the above when determining the halogen is as trifloromethyl, trichloromethylsulfuryl, 2,2,2-cryptgethashparam or 3,3,3-cryptobranchoidea.

Anions halogenation acid (halide-ions) are particularly chloride or bromide ion, and fluoride and iodide ion.

Anions (lower)alkanesulfonyl (lower alkanesulfonyl-ion) have a value lower alkanesulfonyl mentioned above, in particular, mean sulfonate ion, econsultant-ion, propanesulfonate-ion, butanesulfonate-ion or tert.-butanesulfonate ion.

Preferred are compounds selected from the group:

3-bromo-2-hydroxy-5-methoxybenzyloxy alcohol;

[(3-bromo-2-hydroxy-5-methoxyphenyl)methyl]triphenylphosphonium;

[(3-bromo-2-hydroxy-5-methoxyphenyl)methyl]triphenylphosphonium;

[(2-hydroxy-5 methoxyphenyl)methyl]triphenylphosphonium
3-bromo-2-hydroxy-5-methoxybenzamide;

complex dimethyl [3-bromo-2-hydroxy-5-methoxyphenyl)methyl]phosphonic acid;

methyl ester 3-bromo-2-hydroxy-5-methoxybenzoic acid.

Especially among the compounds of the invention specified in the preferred examples of compounds of formula I in free form or in salt form.

Another object of the invention is a method of obtaining compounds of formula 1:

< / BR>
where R4denotes a lower alkyl group, R1is a group of formula P+(R7)(R8)9X-(1b), M is methylene, R2denotes a group of the formula

< / BR>
and R3denotes halogen, R7, R8and R9denotes a phenyl group, X-denotes the anion kaleidotrope acid, Y represents a group of formula (C=O) (1e) and R10indicates the lowest CNS group in free form or in salt form, concluding that

a) compound of the formula

< / BR>
where R1means hydroxyl or lower alkoxy, and R4means lower alkyl, or a salt of this compound halogenous in the meta-position with respect to the group R1- C(=O)-, provided that when R1-C(=O)- group means carboxypropyl, last < / BR>
where X1indicates the lowest alkoxycarbonyl, R3denotes a lower alkyl group, or a salt of this compound, group, X1restore in hydroxymethylene,

c) in the resulting compound of the formula

< / BR>
hydroxymethylene group transferred to kaleidotile,

d) the compound obtained of the formula

< / BR>
where X2denotes halogen, R3denotes halogen and R4denotes a lower alkyl group, is subjected to the interaction with the compound of the formula

< / BR>
or a salt of this compound with the acid H-X, where X, R7, R8and R9have the meanings indicated in formula I,

f) the compound obtained of the formula

< / BR>
where X4denotes a group of formula-P+(R7)(R8R9X-(1b), M is methylene, R3denotes halogen and R4denotes a lower alkyl group, and R7, R8, R9and X-have the meanings indicated in formula I, is treated with a compound of the formula

< / BR>
or a salt of this compound, where X5represents halogen or a group of the formula X7-O-, in which X7denotes the lower alkanesulfonyl, lower alkoxycarbonyl group or a group of the formula

< / BR>
and RObedinenie formula I, separated and/or obtained according to the invention the free connection transferred to salt or obtained according to the invention the salt is transferred into the corresponding free compound.

The object of the invention is also another way to get a hydroquinone of the formula I

< / BR>
where R4denotes a lower alkyl group, R1denotes a group of formula P+(R7)(R8R9X-(1b), M is methylene, R2denotes a group of the formula

< / BR>
and R3denotes halogen, R7, R8and R9denote phenyl group, X-denotes the anion kaleidotrope acid, Y represents a group of formula (C=O) (1e) and R10indicates the lowest CNS group in free form or in salt form, concluding that

b) the compound of formula III

< / BR>
where R3denotes halogen and R4denotes a lower alkyl group, or a salt of this compound is subjected to interaction with paraformaldehyde or trioxane,

c) in the resulting compound of the formula

< / BR>
oxymethylene group transferred to kaleidotile group

d) the compound obtained of the formula

< / BR>
where X2denotes halogen, R3means R> or a salt of this compound with an acid HX, where X, R7, R8and R9have the meanings indicated in formula I,

f) the compound obtained of the formula

< / BR>
where X4denotes a group of formula-P+(R7) (R8R9X-(1b), M is methylene, R3denotes halogen and R4denotes a lower alkyl group, and R7, R8, R9and X-have the meanings indicated in formula I, is subjected to the interaction with the compound of the formula

< / BR>
or a salt of this compound, where X5denotes a halogen or a group of the formula X7-O-, in which X7denotes the lower alkanesulfonyl, lower alkoxycarbonyl group, lower alkanoyloxy group or a group of the formula

< / BR>
and R10and Y have the meanings indicated in formula I, and optionally the compound obtained was transferred into another compound of formula I, define and/or obtained according to the invention the free connection transferred to salt or obtained according to the invention the salt is transferred into the corresponding free compound.

The object of the invention is also a method of obtaining derivatives of hydroquinone of the formula I

< / BR>
where R4indicates the lowest alkiline the flax, R2denotes a group of the formula

< / BR>
and R3denotes halogen, R7, R8and R9denote phenyl group, X-denotes the anion kaleidotrope acid, Y represents a group of formula -(C= O)- (1e) and R10indicates the lowest CNS group in free form or in salt form, namely, that

e) a compound of the formula

< / BR>
where X4denotes a group of formula-P+(R7)(R8R9X-(1b), M is methylene and R4denotes a lower alkyl group, halogenous in metabologia in relation to the group of X4-M

f) the compound obtained of the formula

< / BR>
where X4denotes a group of formula-P+(R7)(R8R9X-(1b), M is methylene, R3denotes halogen and R4denotes a lower alkyl group, and R7, R8, R9and X-have the meanings indicated in formula I, is subjected to the interaction with the compound of the formula

< / BR>
or a salt of this compound, where X5denotes a halogen or a group of the formula X7-O-, in which X7indicates the lowest alkanesulfonyl group, lower alkoxycarbonyl group, lower alkanoyloxy group or a group of the formula

The above reaction with obtaining new source of substances which, respectively, are intermediate products, carried out by analogy with the reactions and ways of getting known the source of substances which are intermediate products. When not mention certain conditions, apply the appropriate conventional tools such as catalysts, condensing means, and means for solvolysis and/or solvents, respectively, solvents, and reaction conditions, such as temperature and pressure, and, if necessary, inert gases.

Halogenoalkane compounds of the formula II according to the stage of the method (a) is carried out, for example, by treatment with elementary halogen, in particular bromine, preferably in an organic solvent, for example, aliphatic alcohol, particularly in the lower alkanol, such as methanol, ethanol, propanol, isopropanol. Halogenoalkane preferably carried out at normal or slightly reduced t is 0-20oC. When using carboxylic acids II carboxyl group is usually tarifitsiruetsya to the corresponding (lower alkoxy)-carbonyl group.

Source materials for stage method (a) is known.

The interaction of compounds of formula III with paraformaldehyde or trioxane method according to the stage b) is carried out, for example, in the presence of an acidic condensing agent, such as a weak Lewis acid, especially in the presence of anhydrous boric acid. It is derived preferably in situ, by azeotropic distillation with the solvent which forms with water azeotropic mixture, for example, toluene. Preferably operate at elevated temperatures, for example, in the temperature range from about 60oC to about 120oC, in particular at about 80-100oC.

Restoring formyl, carboxyl, respectively lower alkoxycarbonyl X1in the compounds of the formula IV is preferably carried out by treatment with a complex hydride of two small metals, for example, socialogical or especially detribalized. Preferably operate in a simple ether, such as aliphatic or cycloaliphatic simple ether, for example, OfficeScan alcohol, as in the lower alkanol, for example, methanol or ethanol, at a regular or preferably slightly lower temperature, for example, in the temperature range from approximately 0oC to about 40oC, in particular at about 5-20oC.

Educt of the formula III and the compounds of formula IV, where X1denotes formyl, known; educt of the formula IV, where X1denotes carboxyl or lower alkoxycarbonyl, preferably get on stage method a).

Turning oximetry in halogenmethyl according to the stage of the method (c) carried out in the usual way, for example, treatment with a halogen acid, a salt, or in particular bromatologia acid, or a precursor of galgenwaard. As such use, for example, ammonium halides such as ammonium bromide, or for use at a later stage (d)

preferably the halides of phosphonium, such as the compounds of formula HP+(R7)(R8R9X-. Preferably working in an organic solvent, such as aliphatic carboxylic acid or its lower alkilany ester or a nitrile, for example, acetic acid, ethyl acetate or acetonitrile. The choice of the substances of the formula V, where R3denotes halogen and R4denotes methyl or ethyl, are known; other compounds of formula V can be obtained, for example, according to stage b).

The interaction of the intermediate products of the formula VI with compounds VIIc according to the stage of method d) perform the usual way.

The interaction of compounds of the formula VI with compounds of the formula VIIc is carried out preferably in the presence of an organic solvent or diluent, as a complex ether (lower alkane) carboxylic acid or nitrile (lower alkane) carboxylic acids as ethyl acetate or acetonitrile, if necessary while heating, for example, in the temperature range from about 30oC to about 100oC, preferably at about 40-80oC.

In the preferred combining stage c) and (d) the way of the intermediate product of formula VI receive in situ from the corresponding compounds of formula V by treatment with a halogen acid, such as hydrogen chloride, or use the connection formula VIIc in the form of a halogen salt, and without allocating enter into interaction next.

Halogenoalkane compounds of the formula VIII according to the stage of the method (e) is carried out, for example, abrabopa alcohol, especially in the lower alkanol, such as methanol, ethanol, propanol, isopropanol.

The interaction of the compounds of formulas IX and X according to stage f) is carried out preferably in the presence of a basic condensing agent, such as nitrogen-containing organic base, as aromatic nitrogen-containing base, such as pyridine or quinoline, or an aliphatic amine, in particular tri-(lower alkyl)amine like triethylamine, preferably in an organic solvent, for example, in a complex ester of the lower alkenylboronic acid or nitrile lower alkenylboronic acid as ethyl acetate or acetonitrile, if necessary while heating, for example, in the temperature range from about 20oC to about 100oC, preferably at 40-80oC. X5means as halogen usually chlorine or bromine, (lower alkoxy)carbonyloxy preferably ethoxy - or tert.-butoxycarbonylamino.

Obtained according to the method of connection in the usual manner can be converted to other compounds of formula I.

The salts can be converted into the free compounds, for example, by treatment with base, as hydroskin alkali metal, a carbonate of the metal is lots as the inorganic acid, e.g. hydrogen chloride, or another of the above acid forming salt.

The salts in a known manner can be converted to other salts: salts with an acid, for example, by treatment with a suitable metal salt, as salt is a sodium, barium or silver, another acid in a suitable solvent in which the resulting inorganic salt is insoluble and thus stands out from the reaction mass, and basic salts by separating the acids, forming salts, the transfer of the base to another salt.

The compounds of formula I, including their salts, can also be obtained in the form of a hydrate or of a solvate with used for crystallization solvent.

The resulting mixture of diastereoisomers and racemates, using differences in physico-chemical properties, in a known manner can be divided into the pure diastereoisomers, respectively, of the racemates, for example by chromatography and/or fractional crystallization.

Resulting racemates further, known methods can be divided into the optical antipodes, for example by recrystallization from an optically active solvent, with the aid of microorganisms or by introducing into the interaction obtained secuestro obtained compounds of the formula I acid, basic or functionally modifiable groups treated with optically active acid, base or an optically active alcohol, turning in a mixture of diastereoisomeric salts, functional derivatives, respectively, as esters, divide them into the diastereoisomers from which the desired enantiomer can be distinguished in the usual way. Suitable for this purpose, bases, acids, alcohols are, for example, optically active alkaloid bases, as strychnine, cinchonine or brucine, or D - or L-(1-phenyl) ethylamine, 3-pipecolic, ephedrine, amphetamine, and normal synthetically derived bases, optically active carboxylic or sulfonic acids, as Hinn acid or D - or L-tartaric acid, D - or L-di-o-toluylene acid, D-or L-malic acid, D - or L-mandelic acid, or D - or L-camphorsulfacid respectively, optically active alcohols, as borneol or D - or L-(1-phenyl)-ethanol.

The invention relates also to those variants of the method, according to which originate from the obtained at any stage of the method as an intermediate product of the connection and provide the missing stage or use the original substance in the form of a salt or, as a rule, get it n the PU 1b, where R7, R8and R9denote unsubstituted phenyl and X-denotes bromine, M denotes methylene, R2denotes hydrogen, R4denotes methyl and R3denotes hydrogen, can be used to obtain the compounds of formula XI and XII.

The object of the invention is 4-chlorocarbonyl-1-benzyloxy-carbonitriding or its salt as intermediates for producing compounds of General formula:

< / BR>
where X6means lower alkoxy, lower alkenylacyl or benzyloxy, or compounds of the formula

< / BR>
where

R3denotes halogen, and R4denotes a lower alkyl group, or their salts.

The object of the present invention is new derivatives of piperidine derivatives of the formula XV

< / BR>
where

X5denotes a halogen or a group of the formula X7-O-, in which X7denotes the lower alkanesulfonyl, lower alkoxycarbonyl group or a group of the formula

< / BR>
where X6denotes the lower alkoxygroup, lower alkenylacyl or benzyloxy provided that X6is not benzyloxypropionic, if X5denotes chlorine, and salt.

Preferred compounds of formula XV, where X6
denotes the lower alkoxygroup, or their salts.

The most preferred compounds of formula XV, selected from the group:

4-chlorocarbonyl-1-ethoxycarbonylpyrimidine,

4-chlorocarbonyl-1-allyloxycarbonyl,

1-etoxycarbonyl-4-methanesulfonanilide,

1-etoxycarbonyl-4-isobutylacetophenone,

1-etoxycarbonyl-4-pivaloyloxymethyl, and

angerin 1,1'-bis(etoxycarbonyl)piperidine-4-carboxylic acid.

The invention also relates to a method for production of piperidine derivatives of the formula

< / BR>
where X5represents halogen or a group of the formula X7-O-, in which X7denotes the lower alkanesulfonyl, lower alkoxycarbonyl group of the formula

< / BR>
where X6denotes the lower alkoxygroup, lower alkenylacyl or benzyloxy provided that X6is not benzyloxypropionic, if X5denotes chlorine, and their salts, which consists in the fact that the compound of formula XVIII

< / BR>
where Y and R10have the specified values, or a salt of this compound is subjected to interaction with thionylchloride, lower alkanesulfonyl or complex Avodat into another compound of formula XV, and/or obtained according to the invention the free connection transferred to salt, or obtained according to the invention the salt is transferred into the corresponding free compound.

This halogen usually denotes chlorine or bromine; (lower alkane)-sulfonyl means, for example, C1-C4- alkanesulfonyl, such as methane - or econsultancy; lower alkanoyl is, for example, C1-C7-alkanoyl as acetyl, propionyl, butyryl or pivaloyl; (lower alkoxy)-carbonyl, for example, C1- C4-alkoxycarbonyl as methoxycarbonyl, etoxycarbonyl, propylenecarbonate, isopropoxycarbonyl, butyloxycarbonyl, isobutylacetate, Deut.-butyloxycarbonyl or tert.- butyloxycarbonyl; lower alkoxy means, for example, C1- C4-alkoxy like methoxy, ethoxy, propyloxy, isopropoxy, bucalossi, isobutoxy, Deut.-butylochki or tert.-butylochki; lower alkenylacyl means in particular allyloxy and phenyl-(lower alkoxy)-, preferably benzyloxy.

The invention, for example, refers to those compounds of formula XV, where X5denotes a halogen or a group of the formula X7-O-, in which X7means (lower alkane)-sulfonyl or (lower alkoxy)-carbonyl, and X6

The compounds of formula XV were specially synthesized to obtain the compounds of formula XII.

According to the invention provides methods of making compounds XII with antidepressant activity.

The first method of obtaining the piperidine derivatives of formula XII

< / BR>
where R3is halogen and R4is a lower alkyl group, or their pharmaceutically acceptable salts using a derivative of hydroquinone, is that

g1) connection formulas

< / BR>
where R1denotes a hydroxyl group or a lower alkoxygroup and R4denotes a lower alkyl group, or a salt of this compound halogenous by processing elementary halogen in the lower alkanol in the meta-position with respect to the group R1-C(=O)-, provided that when R1-C(=O)- means carboxypropyl, last atrificial in the lower alkoxycarbonyl group. In the resulting compound of the formula

< / BR>
where X1indicates the lowest alkoxycarbonyl group, R3is halogen and R4denotes a lower alkyl group, or a salt of this compound, restore group X1in hydroxymethyl.

The compound obtained formulyatsii kaleidotrope acid of the formula HX2the compound of the formula VIIc

< / BR>
where R7, R8and R9denote phenyl group, or a salt of the compounds of formula VIIc with kaleidotrope acid of the formula HX2,

h) the compound obtained of the formula

< / BR>
subjected to interaction with the compound of the formula

< / BR>
or a salt of this compound, where X5denotes a halogen or a group of the formula X7-O-, in which X7denotes the lower alkanesulfonyl, or lower alkoxycarbonyl group, or a group of the formula

< / BR>
and X6denotes the lower alkoxygroup, lower alkenylacyl or benzyloxy,

i) the compound obtained of the formula

< / BR>
cyclist into the corresponding compound of the formula

< / BR>
and

j) from this compound otscheplaut group of the formula-C(=O)-X6and if necessary, the resulting free compound was transferred to salt with acid or obtained salt with the acid is transferred into the free compound or another salt of the acid.

The object of the invention is also a method of obtaining the piperidine derivatives of the formula XII:

< / BR>
where R3denotes halogen and R4denotes a lower alkyl group, and their pharmaceutically acceptable salts on the basis ol the AET halogen and R4denotes a lower alkyl group, or a salt of this compound is treated with paraformaldehyde or trioxane and the compound obtained of the formula

< / BR>
where R3denotes halogen and R4denotes a lower alkyl group, is subjected to the interaction in the presence of kaleidotrope acid of the formula HX2with the compound of the formula VIIc

< / BR>
where R7, R8and R9denote phenyl group, or a salt of compounds of formula VIIc and kaleidotrope acid of the formula HX2.

h) the compound obtained of the formula

< / BR>
subjected to interaction with the compound of the formula

< / BR>
or a salt of this compound, where X5denotes a halogen or a group of the formula X7-O-, in which X7denotes the lower alkanesulfonyl, lower alkoxycarbonyl group or a group of the formula

< / BR>
and X6denotes the lower alkoxygroup, lower alkenylacyl or optionally substituted lower alkyl group, lower alkoxygroup, halogen or nitro-group familyschool alkoxygroup,

i) the compound obtained of the formula

< / BR>
cyclist into the corresponding compound of the formula

< / BR>
and

j) from this compound otscheplaut gr obtained salt with the acid is transferred into the free compound or another salt with acid.

Another way to get the piperidine derivatives of formula XII

< / BR>
where R3denotes halogen and R4denotes a lower alkyl group, and their pharmaceutical acceptable salts based on a derivative of hydroquinone will lie in the fact that

g3), the compound of the formula

< / BR>
where R4denotes a lower alkyl group, and where R7, R8and R9denote phenyl group, halogenous by processing elementary halogen in the lower alkanol in the meta-position relative to group of the formula R7(R8)- (R9)P+CH2,

h) the compound obtained of the formula

< / BR>
where R3denotes halogen, is subjected to the interaction with the compound of the formula

< / BR>
or a salt of this compound, where X5denotes a halogen or a group of the formula X7-O-, in which X7denotes the lower alkanesulfonyl, lower alkoxycarbonyl group or a group of the formula

< / BR>
and X6denotes the lower alkoxygroup, lower alkenylacyl or optionally substituted lower alkyl, lower alkoxyl, halogen or nitro-group is phenyl-lower alkoxygroup,

i) the compound obtained of the formula

< / BR>
cyclist to appropriate the supplies received free connection is transferred to the salt with acid or obtained salt with the acid is transferred into the free compound or into another salt with acid.

In more detail, the method can be described by the scheme B1 B5 at the end of the description.

It is also possible embodiments of the methods by combining the stages of method b), c)+(d) and (f) according to the schemes of C1-C3, D1, D3, E1, E4, listed at the end of the description.

Upon receiving (3-bromo-2-hydroxy-5-methoxybenzyl)-phosphonylated. This allows you to do without big losses available when using aldehydes, and thus to increase the output from 34.5% from theory to 37.9% from theory of schema (C1-C3), 41.8% of theory (D1-D3), respectively 50.2% of theory (E1-E4).

On the basis of 4-methoxyphenol, according to the invention can easily achieve the following outputs Brofaromine-hydrochloride:

diagram B1-B5: 27,8% the scheme C1-C3, B3-B5: 29,0%

diagram D1-D3, B3-B5: 32.0% and schema E1-E4, B3-B5: 38.4% of

The implementation of the reactions according to the method carried out by analogy with the reactions and the formation of initial substances, which are intermediate products of the formula III-IX, generally as described above in driven upon receipt of the compounds of formula I embodiments, method a)-e). Thus, unless otherwise stated, apply normal, depending on the circumstances, auxiliary tools, such as catalysts, condensing agents, as well as means for solvolysis and/or restoreobject, inert gases.

According to a variant of the method W) spend processing of compounds of formulas III, respectively XIII, with halogen, for example, as described above in the embodiment, method a), respectively, d); restoration of compounds of formula IV, as well as the interaction of the compounds of formula III with paraformaldehyde or trioxane carried out as described above in the embodiment, method b), and the interaction of the compounds of formulas V and VIIc carried out, for example, as described above in the embodiment of method d).

The interaction of the compounds of formulas XIV and XV according to a variant of the method (h) is carried out, for example, in the same way as described above for option method f).

The cyclization according to a variant of the method (h) is conducted, for example, in the presence of a basic condensing agent, a carbonate of alkali metal, such as potassium carbonate, in a complex ester or nitrile lower alanovoy acid as acetonitrile, preferably at deposition formed as by-product halide of phosphonium due supplements aliphatic hydrocarbon, C5-C10- alkane, such as hexane, to the solution of crude product in analiticheskoy hydrocarbon like toluene.

Cleavage of the group-C(= O)-X6according to a variant of the m potassium ethylene glycol.

The invention also relates to such variants of the above-described method, according to which originate from the obtained at any stage of the method as an intermediate product connection and spend the missing stage or use source material in the form of salt or especially get in the reaction conditions.

A reagent that introduces the remainder of X5are, for example, halogenation means, such as galodamadruga oxygen acids of sulfur or phosphorus, as thionyl chloride, thienylboronic phosphorus or pentachloride phosphorus, or compounds of formula X7-X5(XIX), where X5and X7have the above values, as appropriate (lower alkane)-sulphonylchloride [XV; X7(lower alkane)-sulfonyl; X5halogen] galodamadruga lower alkanovykh acids, respectively, anhydrides of lower alkanovykh acids [XV; X7lowest alkanoyl; X5halogen or-OX7] or lower alkalemia esters of halogenarenes acid [XV; X5halogen]

Interaction is usually, for example, in the presence of a basic condensing agent, as a tertiary organic nitrogen bases as pyridine, or an aliphatic, or cycloaliphatic alifaticheskimi hydrocarbon, as toluene or dichloromethane, in a temperature range from about -25oC to about 50oC, preferably at 0-25oC.

Example 1. Suspension 81,8 g of 2-bromo-4-methoxyphenol and 24.9 g of boric acid in 55 ml of toluene is refluxed with a water separator until then, until there is more water to stand out (about 12 hours). Then a thin light brown suspension is cooled to 90oC for 40 minutes servings mixed with 13 g of paraformaldehyde. The mixture is additionally stirred for 1 h at 90oC, after subsequent cooling to 70oC is mixed with 100 ml of water, then cooled to 20oC and using concentrated sodium hydroxide solution set pH 8.5. The brown suspension is stirred for 30 min and with concentrated sulfuric acid to establish a pH of 2.5. Obtained after extraction of the residue on the filter is washed twice with 50 ml ethyl acetate. The combined filtrates are well mixed and the organic phase is separated and evaporated. The remaining oily residue chromatographic on silica gel using a mixture of toluene with ethyl acetate (4:1) as solvent. The thus obtained 3-bromo-2-hydroxy-5-methoxybenzyloxy alcohol has Rf- value of 0.3; vigor>C for 1 h portions mixed with 18 g of Bromhead sodium. The resulting suspension is adjusted to a pH of 2.5 with sulfuric acid (10%) and the mixture was concentrated in vacuo to a volume of 500 ml Add 200 ml of ethyl acetate, separate the organic phase, the aqueous phase is extracted with twice 100 ml of ethyl acetate, the combined organic phases are washed with water, dried over sodium sulfate and evaporated. The obtained oily residue is crystallized from toluene. Thus obtained 3-bromo-2-hydroxy-5 - methoxybenzyloxy alcohol in the form of colorless crystals [so pl. 76oC; IR spectrum (KBr): 3500, 3280, 2930, 1580, 1470, 1425, 1285, 1235, 1190, 1165, 1125, 1060, 1050, 1040 cm-1.1H-NMR (360 MHz, CDCl3): 2,40 (br.s, 1H, CH2OH); 3,75 ('s. 3H, OCH3); 4,74 ('s. 2H, CH2OH); 6,34 (br.s, 1H, OH); of 6.73 (d, 1H); 6,97 (d, 1H) ppm] yield 91% of theory.

Example 3. In a solution of 459 g of triphenylphosphane and 387 g of 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol in 600 ml of ethyl acetate in 40-60oC for 30 min miss 67 g florodora. Then stirred for 5 h at 75oC, and the product after 30 min begins to crystallize. Cooled to 0oC, stirred for another hour and then at this temperature crystallized sucked off. Get thus [(3-bromo-2-hydroxy-5-methoxyphenyl)methyl]-t 1565, 1440, 1420, 1330, 1260, 1225, 1150 cm-1.1H-NMR (360 MHz, CH3OH - d4); 3,50 (s, 3H, OCH3); 4,84 (d, 2H, CH2P+); of 6.49 (dd, 1H); 7,05 (dd, 1H); to 7.61-to 7.77 (m, 12H); 7,88 (m, 3H) ppm; yield 89% of theory.

Example 4. To a solution of 50 g of [(2-hydroxy-5-methoxyphenyl)methyl]- triphenylphosphonium in 1 l of methanol at 5oC for 1.5 h was added dropwise 16 g of bromine. Then the solution was concentrated in vacuo at 20oC to a volume of 130 ml, for 2 h, add 250 ml of ethyl acetate, the resulting yellow suspension is stirred for 2 h at 0oC, slightly yellow crystals are sucked off and recrystallized from methanol. Thus get [(3-bromo-2-hydroxy-5-methoxyphenyl)methyl] -triphenylphosphonium in the form of colorless crystals (so pl. 259oC); IR-spectrum (KBr): 2875, 1585, 1565, 1415, 1325, 1200, 1165, 1150 cm-1.1H-NMR (360 MHz, DMSO-d6):of 3.43 (s, 3H, OCH3); to 5.03 (d, 2H, CH2P+); 6.42 per (dd, 1H); was 7.08 (dd, 1H); to 7.61-7,80 (m, 12H); a 7.92 (m, 3H); 9,00 (br.s, 1H, OH) ppm; yield 76% of theory.

Example 5. In a solution of 49.8 g of 2-hydroxy-5-methoxybenzamido alcohol and 115, 8mm g of triphenylphosphine in 150 ml of acetonitrile at 40-60oC for 30 min miss 18 g florodora. Then stirred for 5 h at 75oC, and the product after about 30 min starts crystallizes the E. Get thus [(2-hydroxy-5-methoxyphenyl)methyl]-triphenylphosphonium in the form of colorless crystals (so pl. 270oC) (decomposition); IR-spectrum (KBr): 2990, 1585, 1395, 1295, 1240, 1145, 995 cm-1.1H-NMR (360 MHz, CH3OH-d4): 3,47 (s, 3H, OCH3); 4,74 (d, 2H, CH2P+); 6,40 (dd, 1H); 6.73 x (m, 1H); 7,56 - 7,72 (m, 12H); 7,87 (m, 3H) ppm; yield 78% of theory.

Example 6. To a solution of 35 g of [(2-hydroxy-5-methoxyphenyl)methyl]- triphenylmethylchloride in 700 ml of methanol and 5oC for 1.5 h was added dropwise 13 g of bromine. The solution was concentrated in vacuo at 20oC to a volume of 110 ml, for 2 h add 220 ml of ethyl acetate, stirred the resulting yellow suspension for 2 h at 0oC, sucked off faintly yellow crystals and recrystallized from methanol. Get a mixture of colorless crystals (so pl. 210oC), which according to the title AgNO3consists of 22.4 wt. [(3-bromo-2-hydroxy-5-methoxyphenyl)methyl] triphenylmethylchloride and 77.6 wt. [(3-bromo-2-hydroxy-5-methoxyphenyl)methyl] triphenylphosphonium; yield 76% of theory.

Example 7. The solution 578,2 g of 4-carboxy-1-ethoxycarbonylpyrimidine in 1200 ml of toluene is first mixed with 1.0 g of N,N-dimethylformamide and then when 68-70oC for 2 h with 369,0 g of thionyl chloride. Mix asomatos temperature in a high vacuum. Thus obtained 4-chlorocarbonyl-1-ethoxycarbonylpyrimidine in the form of slightly yellow oil [product content by NaOH and AgNO3-title: 98% IR spectrum (film): 2969, 2870, 1790, 1695, 1470, 1435, 1300, 1230, 1130, 960, 765 cm-1] The product is distilled without decomposition at so Kip. 98-98oC (0,08-0,09 Torr); the yield after distillation in 94.7% of theory.

Example 8. In a similar manner as described in example 7, from 4-carboxy-1-benzyloxycarbonylamino receive a 4-chlorocarbonyl-1-benzyloxycarbonylation.

Example 9. In a similar manner as described in example 7, from 4-carboxy-1-allyloxycarbonyl receive a 4-chlorocarbonyl-1-allyloxycarbonyl.

Example 10. In a dry flask sulfonation at 20oC in 150 ml of toluene is dissolved and 24.1 g (120 mmol) of 4-carboxy-1-ethoxycarbonylpyrimidine. Then cooled to 0oC for 5 min add to 13.8 (120 mmol) of methanesulfonamide. Then for 15 min at 0oC add a solution of 12.1 g (120 mmol) of N-methylmorpholine in 50 ml of toluene, leave much to be mixed even following 30 min at 20oC, filtered usageprice hydrochloride N-methylmorpholine in the absence of moisture. The resulting yellowish solution of 1-etoxycarbonyl-4 - methanesulfonyl Example 11. In a similar manner as described in example 10, by introducing into the interaction of 4-carboxy-1-ethoxycarbonylpyrimidine with revalorisation get 1-etoxycarbonyl-4 - pivaloyloxymethyl.

Example 12. In a dry flask sulfonation at 20oC in 120 ml of dichloromethane is dissolved with 27.7 g (138 mmol) of 4-carboxy-1 - ethoxycarbonylpyrimidine. After cooling to -10oC for 5 minutes and add a solution 18,48 g (138 mmol) of isobutyl ether of Harborview acid in 15 ml of dichloromethane. After stirring for 5 min and cooling to -10oC for 15 min add 13,96 g (138 mmol) of triethylamine, dissolved in 15 ml of dichloromethane. Mix yet a further 30 min at 0oC and the resulting clear, light yellow solution of 1-etoxycarbonyl-4 - isobutyleneisoprene use in the next stage. In order to exclude the mixture of solvents at a later stage (see example 18), dehydrated dichloromethane, you can drive off in vacuum and the oily residue is dissolved in anhydrous acetonitrile.

Example 13. In a similar manner as described in examples 7, 10 or 11, by introducing into the interaction of 4-carboxy-1 - ethoxycarbonylpyrimidine 4-chlorocarbonyl-1 is Example 14. In the absence of air for 43.9 g of 4-chlorocarbonyl-1 - ethoxycarbonylpyrimidine dissolved in 250 ml anhydrous acetonitrile (degassed) and the solution is mixed with 53.4 g of [(3-bromo-2-hydroxy-5 - methoxyphenyl)methyl]-triphenylmethylchloride. To the resulting suspension at 25-30oC for 30 min was added dropwise 20 g of pyridine. The mixture is refluxed for 5 h, then hydrolyzing with 100 ml of sodium carbonate solution (15%), separate the organic phase, wash it successively with 100 ml of 1N hydrochloric acid and 100 ml of water, it is evaporated in vacuum and the remaining oily residue is dissolved in 50 ml of dichloromethane. To this solution under vigorous stirring at 20oC for 30 min was added dropwise 200 ml of ethyl acetate, while the crystallized product. The resulting suspension of crystals was concentrated to a volume of 150 ml on a rotary evaporator in a weak vacuum and then stirred for 2 h at 0oC. After extraction and drying receive [(3-bromo-2-[(1 - ethoxycarbonylpyrimidine-4-yl)carbonyloxy] -5-methoxyphenyl)methyl]- triphenylmethylchloride (so pl. 196oC); IR-spectrum (KBr): 3415, 3060, 2855, 2780, 1600, 1565, 1385, 1270, 1190, 1165 cm-1;1H-NMR (360 MHz, CDCl3):of 1.28 (t, 3H, CO2CH2CH3); to 1.45 (m, 2H); to 1.75 (m, 2H); of 2.58 (m, 1H); 2,8; ,54-7,87 (m, 15H) ppm; yield 66% of theory.

Example 15. To a suspension of 50 g of 3-bromo-2-hydroxy-5-methoxybenzamido alcohol in 300 ml of anhydrous acetic acid at room temperature for 30 min miss 20 g Pomodoro. Stirred an additional 5 h at room temperature and the resulting solution is evaporated. Subcortically oily residue, which upon standing at room temperature slowly crystallized crystallized by adding a small amount of activated carbon from a mixture of ethyl acetate with cyclohexane (5:1). Thus obtained 3-bromo-2-hydroxy-5 - methoxybenzylamine [1H-NMR (360 MHz, CDCl3:of 3.75 (s, 3H, OCH3); a 4.53 (s, 2H, CH2Br); the 5.45 (s, 1H, OH); 6,85 (d, 1H); 7,00 (d, 1H) ppm]

Example 16. to 20.0 g of 3-bromo-2-hydroxy-5-methoxybenzylamine mixed with 8.8 g of trimethylphosphine and the mixture is heated with stirring 3 h at 140oC (according to TLC complete metamorphosis). The oil obtained using a mixture of toluene with ethyl acetate (4: 1) as solvent is filtered through a small amount of silicagel. Thus receive the dimethyl ether [(3-bromo-2-hydroxy-5-methoxyphenyl)methyl] -phosphonic acid [1H - NMR (360 MHz, CDCl3):3,20 (d, 2H, CH2P, 2JP-H= 21 Hz); 3,70 (s, SIU 20 g of milled potassium carbonate (anhydrous) in 100 ml of acetonitrile in the absence of air at 25-30oC for 30 min make 50 g of [(3-bromo-2-[(1 - ethoxycarbonylmethyl-4 - yl)carbonyloxy]-5-methoxyphenyl)methyl] triphenylmethylchloride. The mixture is stirred for 2 h at room temperature, then mixed with 80 ml of water and acidified with concentrated hydrochloric acid to pH=1.0 in. The organic phase is separated and evaporated, the oily residue is treated with 50 ml of toluene and 20oC for 1 h, mixed with 100 ml of hexane, and the basic amount [about 90% of the content according to HPLC (liquid chromatography high pressure):90% of the formed triphenylphosphine will soon become crystallized. The suspension of the crystals are sucked off and the residue on the filter is washed twice with 40 ml of a mixture of hexane with toluene (3:2). After evaporation of the combined filtrate and chromatography of the residue on silica gel using a mixture of toluene with ethyl acetate (2:1) as solvent to obtain 4-(7-bromo-5-methoxybenzophenone-2-yl)-1-ethoxycarbonylpyrimidine (so pl. 85oC);1H-NMR (360 MHz, CDCl3):of 1.28 (t, 3H, CO2CH2CH3); 1.69 in (m, 2H); of 2.09 (m, 2H); 2.95 and (m, 3H); of 3.80 (s, 3H, OCH3); to 4.16 (q, 2H, CO2CH2CH3); 4,14-of 4.35 (br.m, 2H); 6,36 (s, 1H); 6.90 to (d, 1H); 7,00 (d, 1H) ppm; output 90 from theory.

Example 18. To a suspension of 105 g of [(3-bromo-2-hydroxy-5-methoxyphenyl) IU the air at 25-30oC for 1.5-2 h was added dropwise 49 g of 4-chlorocarbonyl-1 - ethoxycarbonylpyrimidine. Stirred for 30 min at 25-30oC, then mixed with 350 ml of water and acidified with concentrated hydrochloric acid to pH=1.0 in. The organic phase is separated and evaporated. The oily residue is dissolved in 160 ml of toluene and for 1 h at 20oC is mixed with 250 ml of hexane, and the crystallized main number (about 80% of the content according to HPLC: 85%) formed triphenylphosphine. The suspension of the crystals are sucked off and the residue on the filter is washed twice with 40 ml of a mixture of hexane with toluene (3:2). The combined filtrate is evaporated and the oily residue chromatographic on silica gel using a mixture of toluene with ethyl acetate (2:1) as solvent. Get the 4-(7-bromo-5-methoxybenzophenone-2-yl)-1 - ethoxycarbonylpyrimidine, which is identical to the product obtained in example 10. Yield 86% of theory.

Example 19. The solution to 45.9 g of methyl ester of 2-hydroxy-5 - methoxybenzoic acid in 125 ml of heptane at 20oC for 30-45 min with stirring was added dropwise for 43.9 g of bromine. The reaction mixture is then stirred for 3-4 h, then diluted with 100 ml of water, stirred for another hour and then mixed with 295 ml of heptane practical phase is extracted with twice in 114 ml of water and cooled to -20oC. thus Receive the methyl ester of 3-bromo-2-hydroxy-5-methoxybenzoic acid. The yield of 82.5% of theory.

Example 20. To a solution of 8 g of sodium borohydride in 280 ml of tetrahydrofuran at 20oC for 1 h under stirring was added dropwise a solution of 57 g of methyl ester of 3-bromo-2-hydroxy-5 - methoxybenzoic acid in 110 ml of tetrahydrofuran. The reaction mixture was stirred following 2.5 h and hydrolyzing with 105 ml of 2n hydrochloric acid and set pH=2,5. The aqueous phase is separated. The organic phase is shaken out three times with 90 ml of a solution of sodium chloride (10%), evaporated on a rotary evaporator, diluted with 100 ml of toluene, concentrated on a rotary evaporator to 100 g, at 60oC for 30 min add to heated to 70-80oC suspension of up 55.1 g of triphenylphosphine, 8.8 g of hydrogen chloride and 42 ml of toluene. The reaction mixture was stirred next 7 hours and then cooled to 0.-5oC. the Resulting crystallized filtered, washed 4 times in 40 ml of toluene and dried in high vacuum. Get thus [(3-bromo-2-hydroxy - 5-methoxyphenyl)methyl]-triphenylphosphonium, which is identical to the product obtained according to example 3; yield 79% of theory.

Example 21. 7.6 g of 4-(7-bromo-5-methoxybenzophenone-2-yl)-1 - ethoxycarbonylethyl solution with vigorous stirring heated for 18 h at 160oC. the Reaction mixture is cooled to 100oC, diluted with 80 ml of toluene and then cooled to 20oC. the Reaction solution is extracted twice with 1000 ml of water and then four times with 200 ml of 10% solution methansulfonate in the water. Methanesulfonanilide the solution is brought to pH=12 by adding 30% sodium hydroxide solution and shaken with 1000 ml of chloroform, the chloroform solution is dried over sodium sulfate, filtered and evaporated. After crystallization from ethyl acetate to obtain 4-(7-bromo-5-methoxybenzophenone-2-yl)-piperidine with so pl. 149-152oC. From the base by treating a methanol solution of hydrochloric acid and recrystallization from a mixture of methanol with ether to obtain the hydrochloride of 4-(7-bromo-5-methoxybenzophenone-2-yl)-piperidine with so pl. 242-243oC.

1. Derivatives of hydroquinone General formula I

< / BR>
where R4lower alkyl;

R1or hydroxyl group, halogen, a group of the formula Ia

-P(=O)(R5)(R6)

or a group of formula Ib

-P+(R7)(R8R9X-;

M methylene;

R2hydrogen or a group of the formula Id

< / BR>
R3hydrogen or halogen

or

R1hydroxyl group or a lower CNS group;

PA;

R7R9phenyl group;

X-anion halomonadaceae acid;

The Y group of formula Ie

-(C=O)-

R10lower CNS group,

provided that in the compound I, where R1a group of the formula Ib, R7R9correspondingly represent unsubstituted phenyl group, and X-ion bromide, M is methylene, R2the hydrogen and R4is methyl, R3is not hydrogen, and provided that the compound I where R1hydroxyl group, M is methylene, R2the hydrogen and R4methyl or ethyl, R3is not hydrogen,

in free form or in salt form.

2. Connection on p. 1, representing 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol.

3. Connection on p. 1 representing [(3-bromo-2-hydroxy-5-methoxyphenyl)methyl]-triphenylmethylchloride.

4. Connection on p. 1 representing [(3-bromo-2-hydroxy-5-methoxyphenyl)methyl]-triphenylphosphonium.

5. Connection on p. 1 representing [(2-hydroxy-5-methoxyphenyl)methyl]-triphenylmethylchloride.

6. Connection on p. 1 representing [(3-bromo-2-[(1-ethoxycarbonylmethyl-4-yl)carbonyloxy-5-methoxyphenyl)methyl]- triphenylmethylchloride.

7. Conn is engaged in a complex of dimethyl ether [(3-bromo-2-hydroxy-5 - methoxyphenyl)methyl]phosphonic acid.

9. Connection on p. 1 represents methyl ester 3-bromo-2-hydroxy-5 - methoxybenzoic acid.

10. The way to obtain hydroquinone derivatives of the General formula I

< / BR>
where R4lower alkyl group;

R1a group of the formula Ib

-P+(R7)(R8R9X-;

M methylene;

R2a group of the formula Id

< / BR>
R3halogen;

R7R9phenyl group;

X-anion halomonadaceae acid;

The Y group of formula Ie

-(C=O)-

R10lower CNS group,

in free form or in salt form, wherein a) a compound of formula II

< / BR>
where R1hydroxyl or lower alkoxyl;

R4lower alkyl,

or a salt of this compound halogenous in the meta-position with respect to the group R1-C(= O)-, and R1-C(=O) must be in the form of lower alkoxycarbonyl group; (b) in the resulting compound of formula IV

< / BR>
where X1lowest alkoxycarbonyl;

R3halogen;

R4lower alkyl group,

or a salt of this compound, group, X1restore in hydroxymethylene; (C) in the resulting compound of formula V

< / BR>
Hydra is halogen;

R3halogen;

R4lower alkyl group,

subjected to interaction with the compound of the formula VIIc

< / BR>
or a salt of this compound with the acid H-X, where X, R7R9have the meanings specified for formula I; f) the compound obtained of the formula IX

< / BR>
where X4a group of the formula Ib

-P+(R7)(R8R9X-;

M methylene;

R3halogen;

R4lower alkyl group;

R7R9and X-have the meanings specified for formula I,

is treated with a compound of the formula X

< / BR>
or a salt of this compound,

where X5halogen or a group of the formula X7-O-in which X7lowest alkanesulfonyl, lower alkoxycarbonyl group, or a group of the formula Ha

< / BR>
where R10and Y have the meanings stated for formula I,

and, if necessary, the compound obtained was transferred into another compound of formula I, separating and/or obtained according to the invention the free connection transferred to salt, or obtained according to the invention the salt is transferred into the corresponding free compound.

11. The method of obtaining derivatives of hydroquinone of the formula I

< / BR>
where R4R>
M methylene;

R2a group of the formula Id

< / BR>
where R3halogen;

R7R9phenyl group;

X-anion halomonadaceae acid;

The Y group of formula Ie

-(C=O)-

R10lower CNS group,

in free form or in salt form, wherein (b) the compound of formula III

< / BR>
where R3halogen;

R4lower alkyl group,

or a salt of this compound is subjected to interaction with paraformaldehyde or trioxane; (C) in the resulting compound of formula V

< / BR>
oxymethylene group transferred to kaleidotile group; (d) the compound obtained of the formula VI

< / BR>
where X2halogen;

R3halogen;

R4lower alkyl group,

subjected to interaction with the compound of the formula VIIc

< / BR>
or a salt of this compound with an acid HX, where X, R7R9have the meanings specified for formula I; f) the compound obtained of the formula IX

< / BR>
where X4a group of the formula Ib

-P+(R7)(R8R9X-;

M methylene;

R3halogen;

R4lower alkyl group;

R7R9and X-have the meanings specified for formula I,<>
halogen or a group of the formula X7-O-, in which X7lowest alkanesulfonyl, lower alkoxycarbonyl group, lower alcoolica group, or a group of the formula Ha

< / BR>
where R10and Y have the meanings stated for formula I,

and, if necessary, the compound obtained was transferred into another compound of formula I, separating and/or obtained according to the invention the free connection transferred to salt, or obtained according to the invention the salt is transferred into the corresponding free compound.

12. The method of obtaining derivatives of hydroquinone of the formula I

< / BR>
where R4lower alkyl group;

R1a group of the formula Ib

-P+(R7)(R8R9X-,

where M is methylene;

R2a group of the formula Id

< / BR>
where R3halogen;

R7R9phenyl group;

X-anion halomonadaceae acid;

The Y group of formula Ie

-(C=O)-

R10lower CNS group,

in free form or in salt form, characterized in that e) the compound of formula VIII

< / BR>
where X4a group of the formula Ib

-P+(R7)(R8R9X-;

M methylene;

R4lower alcalali IX

< / BR>
where X4a group of the formula Ib

-P+(R7)(R8R9X-;

M methylene;

R3halogen;

R4lower alkyl group;

R7R9and X-have the meanings specified for formula I,

subjected to interaction with the compound of the formula X

< / BR>
or a salt of this compound,

where X5halogen or a group of the formula

X7-O-,

in which X7lowest alkanesulfonyl, lower alkoxycarbonyl group, lower alcoolica group, or a group of the formula Ha

< / BR>
where R10and Y have the meanings stated for formula I,

and, if necessary, the compound obtained was transferred into another compound of formula I, separating, and/or obtained according to the invention the free connection transferred to salt, or obtained according to the invention the salt is transferred into the corresponding free compound.

13. Derivatives of piperidine of formula XV

< / BR>
where X5halogen or a group of the formula X7-O-, in which X7lowest alkanesulfonyl, lower alkoxycarbonyl group, or a group of the formula XVa

< / BR>
where X6lowest alkoxygroup lowest alkenylacyl or benzyloxy, pinene by p. 13 formula XV, where X5halogen or a group of the formula X7-O-, in which X7lowest alkanesulfonyl or lower alkoxycarbonyl group;

X6lowest alkoxygroup,

and their salts.

15. Connection on p. 13, which represents a 4-chlorocarbonyl-1-ethoxycarbonylpyrimidine.

16. Connection on p. 13, which represents a 4-chlorocarbonyl-1-allyloxycarbonyl.

17. Connection on p. 13, which represents a 1-etoxycarbonyl-4-methanesulfonanilide.

18. Connection on p. 13, which represents a 1-etoxycarbonyl-4-isobutylacetophenone.

19. Connection on p. 13, which represents a 1-etoxycarbonyl-4-pivaloyloxymethyl.

20. Connection on p. 13, which represents an anhydride 1,1'-bis(etoxycarbonyl)piperidine-4-carboxylic acid.

21. The method of obtaining the piperidine derivatives of formula XV

< / BR>
where X5halogen or a group of the formula X7-O-, in which X7lowest alkanesulfonyl, lower alkoxycarbonyl group of the formula XVa

< / BR>
X6lowest alkoxygroup lowest alkenylacyl or benzyloxy, provided that X6not so the
where Y and R10have the specified values,

or a salt of this compound is subjected to interaction with thionylchloride, lower alkanesulfonyl or complex lower alkilany halogen-substituted ether formic acid and, if necessary, the compound obtained was transferred into another compound of formula XV, and/or obtained according to the invention the free connection transferred to salt, or obtained according to the invention the salt is transferred into the corresponding free compound.

22. 4-Chlorocarbonyl-1-benzyloxycarbonylamino or its salt as an intermediate for preparing compounds of formula XI

< / BR>
where X6ness.alkoxy, NISS.alkenylacyl or benzyloxy,

or compounds of formula XII

< / BR>
where R3halogen;

R4lower alkyl group,

or their salts.

23. The method of obtaining the piperidine derivatives of formula XII

< / BR>
where R3halogen;

R4lower alkyl group,

pharmaceutically acceptable salts based on a derivative of hydroquinone, wherein g1), the compound of formula III

< / BR>
where R1hydroxyl group or a lower alkoxygroup;

R4lower alkyl group,

Genie with respect to the group R1-C(=O), and carboxypropyl R1-C(=O), if available, tarifitsiruetsya in the lower alkoxycarbonyl group in the resulting compound of formula IV

< / BR>
where X1lower alkoxycarbonyl group;

R3halogen;

R4lower alkyl group,

or a salt of this compound group X1restore the hydroxymethyl obtained compound of the formula V

< / BR>
where R3halogen;

R4lower alkyl group,

process in the presence of halomonadaceae acid of the formula HX2the compound of the formula VII

< / BR>
where R7R9is a phenyl group,

or salt of the compounds of formula VII acid, and halomonadaceae acid of the formula HX2; (h) the compound obtained of the formula XIV

< / BR>
subjected to interaction with the compound of the formula XV

< / BR>
or a salt of this compound,

where X5halogen or a group of the formula X7-O-, in which X7lowest alkanesulfonyl, or lower alkoxycarbonyl group, or a group of the formula XV

< / BR>
X6lowest alkoxygroup lowest alkenylacyl or benzyloxy; (i) the compound obtained of the formula XVI

< / BR>
cyclist in the corresponding connection formue free connection transferred to salt accession acid or received salt accession acid is transferred into the free compound or another salt accession acid.

24. The method of obtaining the piperidine derivatives of formula XII

< / BR>
where R3halogen;

R4lower alkyl group,

and their pharmaceutically acceptable salts based on a derivative of hydroquinone, wherein g2), the compound of formula III

< / BR>
where R3halogen;

R4lower alkyl group,

or a salt of this compound is treated with paraformaldehyde or trioxane and the compound obtained of the formula V

< / BR>
where R3halogen;

R4lower alkyl group,

subjected to interaction in the presence of halomonadaceae acid of the formula HX2with the compound of the formula VIIc

< / BR>
where R7R9phenyl group,

or with a salt of the accession of the acid to the compound of formula VIIc and halomonadaceae acid of the formula HX2; (h) the compound obtained of the formula XIV

< / BR>
subjected to interaction with the compound of the formula XV

< / BR>
or a salt of this compound,

where X5halogen or a group of the formula X7-O-, in which X7lowest alkanesulfonyl, lower alkoxycarbonyl group, or a group of the formula XV

< / BR>
X6lowest alkoxygroup lowest alkenylacyl or in some cases neoba alkoxygroup; i) the compound obtained of the formula XVI

< / BR>
cyclist into the corresponding compound of formula XVII

< / BR>
j) from this compound otscheplaut group of the formula-C(=O)-X6and if necessary, the resulting free compound was transferred to salt accession acid or received salt accession acid is transferred into the free compound or into another salt accession acid.

25. The method of obtaining the piperidine derivatives of formula XII

< / BR>
where R3halogen;

R4lower alkyl group,

and their pharmaceutically acceptable salts based on a derivative of hydroquinone, wherein g3), the compound of formula XIII

< / BR>
where R4lower alkyl group;

R7R9phenyl group,

halogenous by processing elementary halogen in the lower alkanol in the meta-position relative to group of the formula R7(R8)(R9)P+CH2; (h) the compound obtained of the formula XIV

< / BR>
where R3halogen,

subjected to interaction with the compound of the formula XV

< / BR>
or a salt of this compound,

where X5halogen or a group of the formula X7-O-, in which X7lowest alkanesulfonyl, lower alkoxycarbonyl is in some cases optionally substituted lower alkyl, lowest alkoxyl, halogen or nitro-group failness.alkoxygroup; (i) the compound obtained of the formula XVI

< / BR>
cyclist into the corresponding compound of formula XVII

< / BR>
and (j) of this compound otscheplaut group of the formula-C(=O)-X6and if necessary, the resulting free compound was transferred to salt accession acid or received salt accession acid is transferred into the free compound or into another salt accession acid.

26. The method according to any of paragraphs.23 to 25, characterized in that is used as a compound of formula XV, where X5halogen, lower alkanesulfonyl or lower alkoxycarbonyl group and X6- lower alkoxygroup, or a salt of this compound.

 

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