Derivatives of 3-(piperidinyl-1)-chroman-4,7-diol and 1-(4 - hydroxyphenyl)-2-(piperidinyl-1)-alkanol, pharmaceutical composition and methods of linking nmda receptor

 

(57) Abstract:

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist. The proposed pharmaceutical composition and the method of binding of the NMDA receptor. 8 ozbugday amino acid receptor) derivatives of phenol, corresponding to the formula I below; their pharmaceutically acceptable salts, their pharmaceutical compositions, use of such compounds for the treatment of neurological disorders, including the feeling of causeless anxiety, cerebral ischemia, epilepsy, muscular spasms and paralysis; and to a method of using such compounds for the treatment of degenerative diseases such as Alzheimer's disease, syndrome, Huntington's and Parkinson's disease. In addition, the present invention relates to a method of using such compounds for the treatment of addiction to medicines, migraine headaches and urinary incontinence. The present invention also relates to a method of using such compounds for the treatment of traumatic brain injury.

Excitatory amino acids are an important group of neurotransmitters, which regulate the excitatory neuropterida in the Central nervous system. Glutamic acid and aspartic acid are two endogenous ligand that activates the receptor of the excitatory amino acids (EAA). There are two types of EAA receptors, ionotropic and metabotropic that differ according to the type of signal transduction. There are at least three indiviudal-D - aspartic acid), AMPA (2-amino-3-(5-methyl-3-hydroxyethoxy-4-yl)propanoic acid) and kainic acid receptor. Ionotropic EAA receptors linked to ion channels permeable to sodium and, in the case of NMDA receptors, calcium. Metabotropic receptors linked to phosphoinositide hydrolysis using associated with membrane G-protein activated quisqualate acid, botanova acid and (1S, 3R)-1-aminocyclopentane 1,3 - dicarboxylic acid.

The NMDA receptor is a macromolecular complex consisting of a number of individual binding sites, the closing of an ion channel permeable to sodium ions and calcium. Hansen and Krogsgaard-Larson, d. Res., Rey., 10, 55-94 (1990). There are binding sites for glutamate, glycine and polyamines, as well as a site within the ion channel, where compounds such as phencyclidine (PCP) exert their antagonistic effects.

Competitive NMDA antagonists are compounds that block the NMDA receptor by interacting with glutamatzugaben site. Ability connection-specific competitive contact NMDA glutamate receptor can be determined using the analysis of radioligand binding. Cm. Murphy with al., British J. Pharma is Rys. Cm. Harrison and Simmonds, British.J.Pharmacol., 84, 381-391 (1984).

Examples of specific NMDA antagonists may serve as D-2 - amino-5-phosphonopentanoate acid (D-AP5) and D-2-amino-7 - phosphonopentanoate acid, see Schoepp. with al., J. Neur. Trangm., 85, 131-143 (1991).

Antagonists of neuropterida on NMDA receptors represent a useful therapeutic agents for the treatment of neurological disorders. U.S. patent N 4902695 refers to the number of competitive NMDA antagonists used for the treatment of such neurological disorders as epilepsy, paralysis, anxiety, cerebrally ischemia, muscular spasms and such neurodegenerative disorders as Alzheimer's disease and syndrome Huntington. U.S. patent N 4968878 belongs to another series of competitive NMDA receptor antagonists are used to treat similar neurological disorders and neurodegenerative disorders. In U.S. patent N 5192751 disclosed a method of treating urinary incontinence in a mammal, which consists in applying an effective amount of a competitive NMDA antagonist.

NMDA antagonists also represent therapeutic agents with anticonvulsive, anxioliticescoy, mytechnologylawyer and antipsychotic activities Cm. J. L in the treatment of migraine Canadian Journal of Neurological Science, 19(4), page 487 (1992)); addiction to medicines, Science, 251, page 85 (1992)); and neuropsychiatric diseases associated with AIDS (PIPS, 11, page 1 (1990).

Ifenprodil is a racemic, the so-called dl-Erythro compound meets the following stereochemical formula:

< / BR>
marketed as an antihypertensive agent, the applicability of which is similar to the applicability of a number of close analogues; with Carron al., U.S. patent 3509164; Carron with TCS. Drug Bes., so 21 p. 1992-1993 (1971). Recently it was shown that ifenprodil has antiischemic activity and the ability to block excitatory amino acid receptor; Gotti with TCS. , J. Pharm. Exp. Therap. so 247 p. 1211-21(1988); Carter with al., ibid, page 1222-32 (1988). Cm. also French patent 2546166. The present invention provides for compounds with such a neuroprotective effect significantly and at the same time, low or mild hypotensive action. In addition, the present invention provides compounds with enhanced metabolic stability, which results in neuroprotective effects of these compounds can for a long time not to bring discomfort to patients.

It was reported, Toaletni, for example, in U.S. patent 3924804; and in Japanese Kokai 53-02,474 (CA 89:43498y; Derwent Abs. 14858A) and 53-59,675 (CA 89:146938w; Derwent Abs. 48671A) reported that 1-(4-amino - and hydroxy-alkyl)phenyl)-2-(4-hydroxy-4-callipering)-1-alkanols and alkenone possess analgesic, antigipnoticescoe, psychotropic and anti-inflammatory activities.

Chenard (U.S. patent 5185343 and 5272160) describes compounds of General formula:

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in which Q represents S or CH=CH; X represents H, OH or other aromatic Deputy; R is hydrogen, alkyl, alkenyl or quinil; Y and Y1together, they represent arylmethylene or aralkylamines (or the corresponding epoxy derivative), or Y and Y1individually, have the following meanings - Y is hydrogen or OH, and Y1represents aryl, aralkyl, aaltio or aryloxy; and describes the structurally related 2-(piperidino)alkanols and 2- (pyrrolidino)alkanols which are useful agents for the treatment of disorders of the Central nervous system (CNS).

Butler in EPO 441.506 discloses 3-piperidino-1-chromium-nalinie derivatives corresponding to the formula;

< / BR>
in which A and B together represent-CH2CH2- or separately, each of the radicals A and B is the battle H, OH or halogen; Z1represents H, halogen or alkyl; n is O or 1; and m is O or an integer in the range of 1-6, and indicate that such compounds possess valuable properties in the treatment of CNS disorders.

Summary of the invention.

The present invention relates to compounds of General formula:

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or their pharmaceutically acceptable salts accession acids, in which: (a) R2and R5individually and R1, R2, R3and R4is, independently of one another represent hydrogen, (C1-6) alkyl, halogen, CF3, OH or or7, a R5represents methyl or ethyl; or (b) R2and R5together form the group:

< / BR>
with the formation of rings chroman-4-ol; and each of R1, R3and R4independently from each other, represent hydrogen, (C1-6) alkyl, halogen, CF3, OH or or7; R6represents a group:

< / BR>
R7represents methyl, ethyl, isopropyl or n - propyl; R8represents phenyl optionally substituted by the substituents in the number to three, independently from each other selected from the group consisting of (C1-6) alkyl, halogen Il is P>5considered separately, at least one of the substituents R1, R2, R3and R4is not hydrogen; and (b) if R2and R5considered together, at least one of the radicals R1, R3and R4is not hydrogen.

The present invention particularly relates to compounds corresponding to the formula I, in which R2and R5are individual substituents; R2and R3represent hydrogen; R6represents a group:

< / BR>
a R8represents phenyl, 4-halophenol or 4-triptoreline. Within this group, the invention applies in particular to compounds in which R5- represents methyl with 1R*THAT 2R*the relative stereochemistry:

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Even more interest in the above group are those compounds in which R1and R2independently from each other, represent hydrogen, fluorine or methyl, a, R8is a 4-forfinal, 4-chlorophenyl or 4-triptoreline and especially (1R*THAT 2R*)-1-(4-hydroxy-3-were) -2- (4- (4-forfinal) -4 - hydroxy-piperidine-1-yl-propan-1-ol; (1R*THAT 2R*)-1-(3,5-dimethyl-4 - gidengil) -2- (4- (4-chloro - phenyl) -4-hydroxy-piperidine-1-yl-propan-1-ol; (1R*THAT 2R*)-1- (3, 5-debtor-4-hydroxyphenyl) -2- (4- (4-forfinal) -4 - hydroxy-piperidine-1-yl-propan-1-ol; (1R*THAT 2R*)-1-(3, 5-debtor-4 - hydroxyphenyl) -2- (4- (4-triptoreline) -4-hydroxy - piperidine-1-yl-propan-1-ol. Primarily, the present invention relates to mesilate salts of the compounds listed above.

In addition, the present invention also relates to compounds corresponding to the formula I, in which R2and R5represent individual deputies, a R6is:

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Within this group, the present invention mainly relates to compounds corresponding to the formula I, in which R5represents methyl, with 1R*THAT 2R*the relative stereochemical configuration:

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The present invention also relates to compounds corresponding to the formula I, in which R2and R5represent a generalized Deputy and as a group:

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with the formation of rings chroman-4-ol. Within this group, the invention applies in particular to compounds in which the C-3 and C-4 position of the ring chroman-4-ol have 3R*4S*the relative stereochemical configuration:

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In RA what is a:

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a R8represents phenyl and 4-halophenol.

The present invention also relates to compounds corresponding to the formula I, in which R2and R5form together a group:

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with the formation of rings chroman-4-ol, and C-3 and C-4 position of the specified ring chroman-4-ol have 3R*4S*the relative stereochemical configuration:

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and R6is:

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In addition, the present invention relates to methods for treating paralysis, spinal cord and brain, apoplexy or post-stroke dementia, such degenerative diseases of the Central nervous system like Alzheimer's disease, senile dementia of the Alzheimer's type, syndrome, Huntington's, Parkinson's, epilepsy, amyotrophy lateral sclerosis, pain, dementia associated with AIDS, psychotic state, addiction to drugs, migraine, hypoglycemia, anxiety, incontinence and ischemic situations occur when surgical intervention in CNS surgery, open heart or any other method, in the course of which runs the risk function of the cardiovascular system, and such methods include the application on the specified integral of salt accession acid.

The present invention mainly relates to the above-described method, by which treatment of a mammal suffering from senile dementia type Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophy lateral sclerosis, epilepsy, paralysis, migraine and traumatic disorders of the brain.

Even more, the present invention relates to a method of treatment of migraine, Alzheimer's disease, brain injuries, spinal cord injuries and paralysis.

Most of all, the present invention relates to a method of treating Parkinson's disease, traumatic brain injuries and migraines.

Besides all the above, the present invention relates to pharmaceutical compositions containing a compound according to paragraph 1 and a pharmaceutically acceptable carrier.

Description of the invention

The pharmacologically active compounds of the present invention that meets the above formula I, can be easily obtained.

As a rule, the compounds of formula I are obtained by removing the protective group from the phenolic alcohol intermediate compound. Such phenol-protective group is removed transaprency silyl ethers, such as triisopropyl, tert.-butyl dimethylsilane, triphenylsilane, etc., or benzyl or substituted benzyl ethers. The preferred method of removal of these silyl groups includes the use of 1-1,1 molar equivalents of tetrabutylammonium fluoride or other traditional source of fluoride in the environment such inert reaction solvent like tetrahydrofuran. The reaction is usually carried out at 0-50oC and is best at room temperature to avoid the cost of heating or cooling the reaction mixture and to minimize decomposition of the product in the case of heating. One of the ways to remove benzyl or substituted benzyl ester groups is to implement traditional hydrogenolysis using a catalyst based on a noble metal, such as palladium or Nickel, in an inert solvent, for example, using 10% palladium on coal as a catalyst, preferably at low pressure (for example, 1-10 atmospheres) at temperatures (for example, 20-75oC) and, as a rule, in the environment of such an inert solvent as methanol or ethanol. In another method of hydrogenolysis using ammonium formate as a hydrogen source in the environment ine Ernie solvents for this reaction, hydrogenolysis include ethers, as diethyl ether, tetrahydrofuran or dioxane; lower alcohols such as methanol or ethanol; or a combination of these substances. Especially preferred combination of solvents for this reaction, hydrogenolysis is a mixture of tetrahydrofuran and methanol.

Found in the previous paragraph and elsewhere in the text, the expression "inert at the reaction solvent" refers to any solvent which does not react with the starting materials, reagents, intermediates or reaction products thus resulting undesirable effects on the yield of the target product.

The compounds of formula I, in which the phenolic hydroxy-group is a protected group can also be obtained traditional hydride recovery of alpha-piperidino chroman-4-it, alpha pyrrolidino-chroman-4-or alpha-8-Aza-bicyclo(3.2.1) octanol of chromanone, for example,

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which, as a rule, form a mixture of CIS - and TRANS - isomers, respectively, for example,

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Of course, in specific cases, the mixtures can be dominated by one or other of these CIS - or TRANS-isomers.

Such reactions hydride recovery is performed using the traditional is usual used in excess (for example, mol to mol) in inert in respect to the reaction solvent, such as tetrahydrofuran, at low temperature (for example, -15oC - 75oC. Any protective groups that still remain after recovery of the ketone then removed using the methods described above. Intermediate compounds of type (B) above, in which R2and R5represent the joint Deputy and intermediate compounds of type (D) above, in which R2and R5are individual substituents, usually obtained by the reaction of the corresponding derived monobrom of chromanone with the appropriate substituted piperidine, pyrrolidine or 8-azabicyclo (3.2.1) octane, for example:

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respectively. Specialist in the field of chemistry should be clear that in such a reaction of alpha-bromo group can be replaced by another nucleophile-substituted group, such as chlorine, alkanesulfonyl or arylsulfonate. This reaction is carried out in conditions that are typical for the implementation of nucleophilic substitution. In the case when two such reagent is roughly equivalent availability may apply about their molar equivalents; however, in the case when one ü excess of such more affordable reagent for a more rapid completion of the reaction bimolecular nucleophilic substitution. The above reaction is usually carried out in the presence of at least 1 molar equivalent of a base, such as amine derivative as such, if this substance is readily available, but, as a rule, use a tertiary amine, which is at least comparable in terms of basicity with the nucleophilic amine; and the reaction is carried out in an environment of such an inert solvent as acetonitrile, ethanol, methanol, etc., If desired, the reaction is carried out in the presence of a catalyst by adding the reaction mixture to one molar equivalent or more iodide (e.g., NaI, KI). The reaction temperature is not critical, but typically use several elevated temperatures in order to speed up the completion of the reaction in a shorter time, but the temperature should not be too high so as to avoid undesirable decomposition. Usually, a satisfactory temperature interval is the interval 20-120oC. Specialist in this field should take into account the fact that the use of elevated temperatures it is necessary to carefully monitor the progress of the reaction in order to use the shortest reaction times to minimize decomposition. As the rights of the PA (S), above, in which R2and R5are United by the Deputy, are usually obtained by the reaction of the corresponding derivative of alpha, alpha-dibromo of chromanone with the appropriate substituted piperidine, pyrrolidine or 8-Aza-bicyclo(3.2.1)octane, for example,

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Except that in this reaction using at least one additional molar equivalent of base (neutralization NVG formed during competitive dehydrohalogenation), the conditions of the reaction are similar to those described above for preparing compounds of types (C) and (D) by the reaction of nucleophilic substitution.

The compounds of formula I contain two asymmetric carbon atom, which corresponds to two racemates and four optically active compounds. One such Ruzmetov represents the above-mentioned CIS-isomer, and the other is the TRANS-isomer. Each of these racemates can split into a pair of enantiomers through diastereomeric salt accession acids in the presence of an optically active acid. On the other hand, racemic alcohol is transformed into the corresponding diastereomeric esters or urethanes using an optically active acid or isocyanate. hromatograficheskaja division). Such diastereomeric esters are formed from an alcohol and an optically active acid or isocyanate standard methods, which typically involve the activation of the acid, for example, its use as chloranhydride acid, a mixture of acid anhydride and alkyl formate or such dehydrating agent combinations, as dicyclohexylcarbodiimide. After separation of the resulting diastereomeric esters, for example, by the methods of chromatography and subjected to hydrolysis carried out by conventional methods, for example using an aqueous solution of acid or base to obtain enantiomerically optically active alcohol compounds of formula I. In accordance with the intentions of the applicant, the present invention is not limited to racemic CIS - and TRANS - compounds specifically illustrated below, and covers all of the optically active enantiomers of the compounds of formula I of the present invention.

The term "pharmaceutically acceptable acid additive salt" includes, but is not limited to such salts as the hydrochloride, hydrobromide, hiraide, nitrate, acid sulfate, monopotassium phosphate, mesilate, maleate and succinate. Such salts typically the one molar equivalent, in the environment of the solvent. Those salts which are directly deposited are usually isolated by concentration of the solvent and/or attach nerastvorim agent.

Alpha-halo ketone starting materials required for the synthesis of compounds of the present invention are usually obtained by the reaction of the corresponding galodamadruga with aromatic halide under the reaction conditions for the acylation according to the Friedel-Crafts or other conditions of acylation of aromatics is well known to specialists in this field. In the case when the acyl halide has no halo-substituent in the alpha position to the carbonyl group, carry out the reaction of the reaction product of the specified aromatic acylation under standard conditions of synthesized well-known to specialists in this field. Other starting materials and reagents required for the synthesis of compounds of the present invention, are readily available substances, or issued by the industry in accordance with the information on how to obtain listed in the literature or by methods described in Preparative examples below.

Compounds of the present invention corresponding to the formula I possess neuroprotective act is multi-infarct dementia, such degenerative diseases of the Central nervous system like Alzheimer's disease, senile dementia type Allgamer syndrome Huntington's, Parkinson's, epilepsy, amyotrophy lateral sclerosis, pain syndrome, dementia associated with AIDS, psychotic state, addiction to drugs, migraine, hypoglycemia, anxiety, incontinence and ischemic conditions arising during surgery CNS surgery, open heart or any other intervention, in which the function of the cardiovascular system is exposed to risk, based on its ability to block excitatory amino acid receptors, and thus there is reduced or no significant hypotensive activity. Compounds of the present invention corresponding to the formula I also have extended metabolic stability. Anti-ischemic activity of the compounds of formula I is determined using one or more methods described below.

The research described below is based on the analysis of binding demonstrates the degree of binding of the test compound with N-methyl - D-aspartate (NMDA)receptor. Membranes intended for use in the analysis svyazyvanie the sucrose solution (0.32 m). The volume of the system was increased to 100 ml by adding additional quantities of sucrose solution. The homogenate was centrifuged with a speed of 3000 rpm for 10 minutes. The supernatant (SI) was retained, and the residue after centrifugation resuspendable and homogenized. The volume of the system was increased to 75 ml with sucrose solution (0.32 M). The homogenate was centrifuged with a speed of 3000 rpm for ten minutes, after which the resulting supernatant (S2) was retained, and the residue after centrifugation (P1) is discarded. Supernatant (SI) and (S2) were combined and centrifuged with a speed of 12,000 rpm for 25 minutes. The resulting precipitate after centrifugation (P2) re-suspended in 100 ml of Tris acetate (5 mm, pH 7.4) and then left on ice for at least ten minutes to lysis of cells. The precipitate after centrifugation three times washed with 1.0 ml of Tris acetate (5 mm, pH 7.4) and resuspendable in a minimal volume of Tris acetate) about 2 ml per forebrain, the protein concentration of about 10 mg/ml). Thus obtained membrane was frozen and kept at -20oC. Analysis of binding per se was carried out as follows. Membranes were thawed and quickly homogenized. The residue after centriole connection, the compound of formula I, and then added tritium-labeled ligand. In this case, tritium-labeled ligand (5 nm), which tested the binding was represented by a compound of the formula:

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in which T is an atom of tritium (3N). Nonspecific binding was determined using 100 μm of cold ligand. All the samples were analyzed three times. The tubes were incubated for 20 minutes at 30oC shake a water bath. The contents of each tube were filtered in the presence of the collector cells Brandela (Brandel, 8561 Atlas Drive, Gaithersburg, Maryland, 20877, USA) using a GF/B filter. The sediment on the specified filter was washed for 10 seconds, cooled on ice Tris HCl (5 mm, pH 7.4). The filters were placed in vials was added to scintillation fluid and radioactivity was counted on the counter beta particles. The number of counts per minute (CPM) for nonspecific binding subtracted from the values of CPM in test tubes only with ligands, resulting in estimated specific binding. The CPM values for nonspecific binding subtracted from the values obtained in the test tubes containing the test compound and the obtained values were expressed in percentage of specific swim below in Preparative example 49.

As the preferred methods for the assessment of neuroprotective activity used the methodology proposed by Ismail A. Shalaby with TCS. J. Pharm. and Experimental Therapeutics, 260,925(1992), referenced in the text and which are described below.

Cell culture. (Hippocampal) Hippocampal cells from rat embryos at the age of 17 days (CD, Charles River Breeding Laboratories, Inc., Wilmington, MA) were cultured on PRIMARIA culture tablet (Falcon Co., Lincoln Park, NJ) for 2-3 weeks in serum containing culture medium (minimum supporting medium with nonessential amino acids, containing 2 mm glutamine, 21 mm glucose, penicillin/streptomycin (5000 units each), 10% serum bovine fetus (age 1-7 days) and 10% horse serum (days 1-21)) (with Choi al., 1987). Cells viseable on 96-well titrimetrically the microplate with a density of 80,000 cells per well, 24-hole culture tablets with a density of 250,000 cells per well. The cultures were grown at 37oC in a humidified CO2-incubator with tissue culture containing a mixture of CO2-the air in the ratio of 5:95%. The proliferation negarandeh cells was controlled by the addition of 20 μm uridine and 20 μm 5-fluoro-2-deoxyuridine (Sigma Chemical Co., St. Louis, MO) in the period from the 6th to the 8th day of cultivation (Martin with the tours were assessed on glutamate toxicity within 2-3 weeks after sowing. The culture medium was removed and cultures were washed twice CSS (Chai with al., 1987): NaCl, 12:KCl, 5.4; MgCl2, 0.8; CaCl21.8; glucose, 15; and 4-(2 - hydroxyethyl)-1 - piperazineethanesulfonic, 25 mm (pH 7.4). Then, in such cultures for 15 minutes (37oC was affected by different concentrations of glutamate. After incubation, the culture was thrice washed not contain glutamate CSS and twice with fresh culture medium without serum. Then these cultures were incubated for 20-24 hours in not containing serum culture medium. 2 minutes before and during the 15-min exposure to glutamate was added to the test compound, the compound of formula I. In some experiments indicated compound of formula I was added over different time intervals after exposure to glutamate and subsequent 20-24 hours.

Cell viability was assessed in the usual way after 20 to 24 hours after exposure excitotoxin by measuring the activity of the cytosolic enzyme LDH (Koh and Choi, 1987; Wroblewski and LaDue, 1955). LD activity was determined in the culture medium in each of the 96 wells titrimetrically microplate, 50 μl of the sample medium was added to equal volume of sodium phosphate buffer (0.1 M, pH 7.4) containing 1.32 mm Privata sodium and 2.9 mm NADH. Pohlad is 2 minutes using an automated spectrophotometric titrimetricheskogo microplate reader (Molecular Devices; Menio Park, CA). The velocity of the optical absorption automatically counted using the IBM SOFTMax and used as an index LDH activity.

Morphological assessment of neuronal viability was performed using phase-contrast microscopy. 96-well culture tablets do not allow to obtain good phase - contrast image, so for this purpose was applied to 24 - well plates. In quantitative terms, both cultural planting equally sensitive to glutamate toxicity and demonstrate a 2-3 - fold increase in LDH activity after 24 hours of exposure to 0.1-1.0 mm glutamate.

The reagents. Horse and fetal bovine serum were purchased from firms Hyclone (Logan, UT), and culture medium, glutamine and penicillin with streptomycin - the firm From Gibco. (Grand Island, NY).

The data analysis. Quantitative determination of neurotoxicity were carried out by measurement of LDH activity present in the culture medium after 20-24 hours after exposure to glutamate. Initial experiments confirmed published reports that raise LDH activity in the culture medium correlates with the degradation and degeneration of neurons (Koh and Choi, 1987). Posovremennei the buffer pairs of holes on the same culture plate. To get the index value of LDH activity in cultures treated with glutamate and drug LDH values for the control cultures subtracted from the corresponding values for the treated groups. The data obtained for medicinal treatments, expressed as a percentage increase in LDH induced by 1 mm glutamate (or NMDA) in each experiment. Concentrations of NMDA antagonists, required to achieve 50% increase in LDH caused by excitotoxins (IC50) considered using logarithmically probing analysis of the combined results of three independent experiments. Different groups, processed, compared with the use of twice-diminishing t-test.

Metabolic stability. To determine the in vitro metabolic stability of compounds of the formula I performed the following test microsome assay in human liver. Microsomal incubation mixture contained 1 μm of microsomal P450, NADPH - generating system (0.5 mm NADP+, 4 mm glucose-6-phosphate and 10 units/ml glucose-6-phosphate dehydrogenase), 0.1 M phosphate buffer (pH 7.4), 10 mm MgCl2and 2 μm of the test compound as a substrate in a total volume of 1.4 ml of the Reaction mixture was plaincourault at 37ooC in a water bath with gentle shaking. Aliquots of the incubation mixtures were taken at points corresponding 0,20,40 and 60 minutes, and then transferred into polypropylene tubes for microanalysis containing equal volume of chilled on ice methanol to stop the reaction. The denatured protein was separated by centrifugation and the resulting supernatant was transferred and stored at -20oC for subsequent analysis. The substrate was subjected to quantitative analysis by HPLC method with UV detection. After direct input aliquot (75 μl) of the supernatant into the HPLC, the height of the peak obtained substrate was used for quantitative calculation of the rate of consumption of substrate during incubation, suggesting that the amount of substrate in the initial moment of time is 100%. The half-life period (T0.5) was determined by dividing the 0,693 on K, where K was determined by log-linear regression of the entire incubation period during which the consumption rate of the substrate was subordinated to the kinetic equation of the first order.

Such selective neuroprotective antisemitische and excitatory amino acid blocking activity together with increased metabolic stability reflect the price of the nervous system), as paralysis and traumatic brain damage; Alzheimer's disease, Parkinson's syndrome and Huntington's; not there is a significant potential for competitive undesirable fall in blood pressure. The systematic treatment of such diseases neuroprotective amount of compounds of formula I, dosages are usually 0.02-50 mg/kg/day (0.001-2.5 g/day in a typical human representative of a weight of 50 kg) when used in the form of single or split doses regardless of the route of application. A more preferred dosage interval is 0.15 to 50 mg/kg/day. Naturally, depending on the type of connection and the specific nature of the disease and the treating physician may be prescribed dosage beyond the specified interval. Usually, the preferred route of administration is oral medication. However, in the case of the inability of the patient to swallowing or any other deterioration of oral absorption, the preferred route of application will parenteral method (intramuscular, intravenous or topical application.

Compounds of the present invention is usually used in the form of pharmaceutical composer or diluent. Such compositions typically form in the traditional way using solid or liquid carriers or diluents appropriate method of application.

For oral administration may be tablets containing such eccipienti as sodium citrate, calcium carbonate and secondary acidic calcium phosphate, together with various disintegrators, such as starch, preferably potato or tapioca starch, alginic acid, certain complex silicates, together with binding agents, as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum. In addition, for tabletting is often a very useful application of such lubricating agents, without limiting them as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be used as fillers in soft elastic and hard-filled gelatin capsules; as examples of materials of this type, without limiting them, can lead to lactose or milk sugar and high molecular weight glycols. In cases where oral administration is desired aqueous suspensions and/or elixirs, the main active ingredient moslemi and if so desired, emulsifying and/or suspendresume agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

Further, the present invention is illustrated in the examples, but is not limited to their details.

All reactions in nonaqueous media held for convenience in the atmosphere of nitrogen and, as a rule, to achieve the maximum output. All solvents/thinners were dried according to standard published procedures or acquired in pre-dried form. All of the reaction mixture was subjected to stirring using a magnetic stirrer or mechanical stirrer. NMR spectra were shooting at 300 MHz and expressed in ppm (M. D.). Unless otherwise noted, as a solvent for NMR analysis used CDCl3. IR spectra were recorded in cm-1usually referring only strong signals.

Example 1,

(1R*THAT 2R*)-1-(3-Fluoro-4-hydroxyphenyl)-2-(4-forfinal)-4 - hydroxypiperidine-1-yl)propan-1-ol mesilate.

A mixture consisting of 3-fluoro-4-triisopropylsilane-and-bromopropiophenone (compound of Preparative example 1, 1.19 g, 2.95 mmole), 4-(4-forfinal)-4-hydroxypiperidine (0.864 g, 4.43 mmole) and Tr is stirred at ambient temperature for 64 hours. The solvent was removed under reduced pressure and the residue was distributed between ethyl acetate and water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (1.5 x 3 inches; 3.8 x 7.6 cm), conducting elution as follows: 10% ethyl acetate/hexane (350 ml), lack of product; 20% ethyl acetate/hexane (150 ml), lack of product; 20% ethyl acetate/hexane (450 ml) after 0.437 g (29%) of 1-(3-fluoro-4-triisopropylchlorosilane)-2-(4-(4-forfinal)- 4-hydroxypiperidine-1-yl)-propane-1-it is in the form of a yellow oil, having an NMR spectrum : 7.88 double doublet, J= 2.11 Hz, 1H), 7.81 (doublet, J= 8.5 Hz, 1H), 7.43 (double doublet, J= 5.5, 9 Hz, 1H), 7.00 (triplet, J= 9 Hz, 1H), 6.95 (triplet, J= 8.5 Hz, 1H), 4.05 (Quartet, J= 6.5 Hz, 1H), 2.93-2.72 (multiplet, 2H), 2.72-2.53 (multiplet, 2H), 2.03 (symmetric multiplet, 2H), 1.82-1.58 (multiplet, 3H), 1.35-1.22 (multiplet, 5H), 1.10 (doublet, J = 7 Hz, N).

A mixture of sodium borohydride (0.027 g, 0.717 mmole) and ethanol (10 ml) was stirred for 10 minutes and then was added 1-(3-fluoro-4 - triisopropylchlorosilane)-2-(4-(4-fluoro-phenyl)-4 - hydroxypiperidine-1-yl)-propane-1-he (0.371 g, 0.717 mmole in 10 ml ethanol). The reaction mixture was stirred at

ambient temperatures were and the organic phase was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to separation by the method of flash chromatography on silica gel (0.75 x 3 inch/1.9 x 7.6 cm/ while loading in hexane) with elution by the following method: 10% ethyl acetate/hexane (200 ml), lack of product; 10% ethyl acetate/hexane (100 ml) and 20% ethyl acetate/hexane (200 ml), 0.22 g (59%) of (1R*THAT 2R*)-1-(3-fluoro-4 - triisopropylchlorosilane)-2-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)-propan-1-ol. A sample recrystallized from ether had so pl. 159-160oC.

The product of the reaction described above (0.192 g, 0.37 mmole) was dissolved in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (0.407 ml, 0.407 mmole, 1M tertrahydrofuran ring solution). The reaction mixture was stirred for 30 minutes at ambient temperature and then concentrated. The residue was distributed in a mixture of ethyl acetate-water and separation of the phases. The organic layer was washed with brine, dried over calcium sulfate and concentrated to obtain 0.122 g (91%) of white solid product. The solid is suspended in methanol (6 ml) was added methansulfonate (0.022 ml, 0.34 mmole). The resulting mixture was concentrated at boiling to a volume of 0.5 ml In the cooling obrazovyvaet)-2-(4-(4-forfinal)-4-hydroxypiperidine-1 - yl)-propan-1-ol nelfinavir, which had so pl. 239-241oC. Elemental analysis for C20Y23NO23CH4SO3. Calculated: C Is At 54.89; H, 5.92; N, 3.05. Found: C, 55.17; H, 6.08; N, 3.11.

Example 2.

(1R*THAT 2R*)-1-(4-Hydroxy-3-were)-2-(4-(4-forfinal)-4 - hydropiperoides-1-yl)propan-1-ol mesilate.

A mixture consisting of Z-methyl-4-triisopropylsilane-and - bromopropiophenone (compound of Preparative example 6, 9.17 g, 22.97 mmole), 4-(4-forfinal)-4-hydroxypiperidine (6.73 g, 34.45 mmole) and triethylamine (8.0 ml, 57.43 mmole) in ethanol (180 ml) was heated under reflux for 6 hours. The solvent was removed under reduced pressure and the residue was distributed between ethyl acetate and water. Was phase separation and the organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (column size 3 x 3.5 inch /7,6 x 8.9 cm/ filled in hexane), conducting elution as follows: 10% ethyl acetate/hexane (100 ml), without product; 20% ethyl acetate/hexane (700 ml), without product; 20% ethyl acetate/hexane (1300 ml) and 25% ethyl acetate/hexane (600 ml), 7.66 g (65%) of 1-(3 - methyl-4-triisopropylchlorosilane)-2-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-propane-1-it is in the form of a yellow pen is/hexane and obtained a substance in the form of white crystals with so pl. 78-82oC.

A mixture of sodium borohydride (0.564 g, 14.92 mmole) and ethanol (60 ml) was stirred for 10 minutes and then was added 1-(3-methyl-4-triisopropylchlorosilane)-2-(4-(4- terphenyl)-4-hydroxypiperidine-1-yl)-propane-1-he (7.66 g, 14.92 mmole in 10 ml ethanol), while twice washing with 30 ml portions of ethanol. The reaction mixture was stirred at ambient temperature overnight. Saducees white solid was collected by filtration and dried to obtain 5.72 g (74%) of (1R*THAT 2R*)-1-(3-methyl-4-triisopropylchlorosilane)-2-(4-(4- forfinal-4-hydroxypiperidine-1-yl)-propan-1-ol, which is suitable for further use without further purification and has so pl. 188 - 189oC.

The product of the reaction described above (5.72 g, 11.1 mmole) was dissolved in tetrahydrofuran (150 ml) was added tetrabutylammonium fluoride (12.21 ml, 12.21 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated. The residue was distributed in the system ethyl acetate-water and separation of the phases. The organic layer was concentrated and suspended in methylene chloride. Saducees white solid was collected filtration is piperidine-1 - yl)-propan-1-ol. Sample (0.16 g, 0.447 mmole) was transformed into mesilate salt. The resulting substance suspended in methanol (8 ml) was added methansulfonate (0.029 ml, 0.45 mmole). The resulting mixture was filtered and concentrated; then the residue was recrystallized from ethanol with the formation of 0.152 g (58%) mesilate salt having so pl. 215-216oC. Elemental analysis for C21H25FNO3CH4SO3. Calculated: C, 58.01; H, 6.64; N, 3.07. Found: C, 57.99; H 6.72, N 3.17.

Example 3,

(1R*THAT 2R*)-1-(3,5-Dimethyl-4-hydroxyphenyl)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl)-propan-1-ol mesilate.

A mixture of 3,5-dimethyl-4-triisopropylsilane-and-bromopropiophenone (compound of preparative example 18, 1.50 g, 3.63 mmole), 4-(4-chlorophenyl)-4-hydroxypiperidine (1.00 g, 4.03 mmole) and triethylamine (1.7 ml, 12.2 mmole) in ethanol (30 ml) was heated for 4.5 hours under reflux and then stirred overnight at ambient temperature. The solvent was removed in vacuum under reduced pressure and the residue was distributed in the system ethyl acetate - water. Was phase separation and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to separation by the method of flash XP is her sequence: 10% ethyl acetate/hexane (750 ml) the lack of product; 10% ethyl acetate/hexane (250 ml) and 20% ethyl acetate/hexane (500 ml), education 0.82 g (41%) of 1-(3,5-dimethyl - 4-triisopropylchlorosilane)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl)-propane-1-it is in the form of a yellow foam, which can be used without further purification, this product has the following NMR spectrum: 7.37 (singlet, 2H), 7.36 (AB Quartet, V1-3= 30.5 Hz, J= 8.5 Hz, 4H), 4.15 (Quartet, J= 6.7 Hz, 1H), 2.85 - 2.75 (multiplet, 2H), 2.67-2.53 (multiplet, 1H), 2.31 (singlet, 6H), 2.25-1.97 (multiplet, 2H), 1.74-1.60 (multiplet, 2H), 1.60 (singlet, 1H), 1.50-1.18 (multiplet, 6H), 1.13 (doublet, J= 7.2 Hz, N).

A mixture of sodium borohydride (0.054 g, 1.43 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(3,5 - dimethyl-4-triisopropylchlorosilane)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl>-propane-1-(0.77 g, 1.42 mmole in 25 ml ethanol). The reaction mixture was stirred at ambient temperature overnight. Saducees white solid was collected by filtration and dried to obtain 0.44 g (56%) of (1R*THAT 2R*)-1-(3,5-dimethyl-4-triisopropylsilyl)-2-(4-(4- chlorophenyl)-4-hydroxypiperidine-1-yl)-propan-1-ol, which can be used without additional purification and which has so pl. 211.5-212,5oC.

The product described (0.81 ml, 0.81 mmole), 1M tertrahydrofuran ring solution). The reaction mixture was stirred for 30 minutes at ambient temperature and then concentrated. The residue was distributed between ethyl acetate and water and separation of the phases. The organic layer was washed with brine, dried and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column 1x3 inch of 2.54 x 7.62 cm, filled in hexane), conducting elution in the following sequence: 50% ethyl acetate/hexane (300 ml), lack of product; 50% ethyl acetate/hexane (100 ml)and ethyl acetate (200 ml), 0.247 g (88%) of (1R*THAT 2R*)-1-(3,5-dimethyl-4-hydroxyphenyl)-2-(4-(4- chlorophenyl)-4-hydroxypiperidine-1-yl)propan-1-ol. A sample of this substance (0.24 g, 0.616 mmole) was transformed into its mesilate. The resulting product is suspended in methanol (15 ml) was added methansulfonate (0.040 ml, 0.616 mmole). The resulting mixture was filtered and concentrated; then the residue was recrystallized from a mixture of ethanol/water in a ratio of 9:1 with obtaining 0.228 g (58%) mesilate salt in the form of white crystalline solids having so pl. 202.5-203oC. Elemental analysis for C22H28ClNO3CH4SO3. Calculated: C, 56.84; H, 6.64; N, 2.88. Found: C, 57.01; H, 6.83; oxopiperidin-1-yl)-propan-1-ol.

A mixture of 3,5-dimethyl-4-triisopropylsilane- -bromopropiophenone (compound of Preparative example 18, 1.50 g, 3.63 mmole), 4-(4-forfinal)-4-hydroxypiperidine (0.78 g, 4.00 mmole) and triethylamine (1.0 ml, 7.2 mmole) in ethanol (30 ml) was heated under reflux for 4.5 hours and then stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the residue was distributed in the system ethyl acetate - water. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1x4 inch, 2.H.16 cm, filled in hexane), conducting elution in the following sequence: 10% ethyl acetate/hexane (500 ml), lack of product; 20% ethyl acetate/hexane (500 ml), 0.96 g (50%) 1-(3,5-dimethyl-4-triisopropylchlorosilane)-2-(4-(4-forfinal) -4-hydroxypiperidine-1-yl)-propane-1-it is in the form of an orange foam, which can be used without additional purification, moreover, the resulting product had the following NMR spectrum 7.74 (singlet, 2H), 7.48-7.43 (multiplet, 2H), 7.02 (triplet, J= 8.8 Hz, 2H), 4.15 (Quartet, J= 6.7 Hz, 1H), 2.90-2.77 (multiplet, 3H), 2.68-2.57 (multiplet, 1H), 2.31 (singlet, 6H), 2.28-2.03 (multiplet, 2H), 1.77-1.66 (m is(0.065 g, 1.72 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(3,5 - dimethyl-4-triisopropylchlorosilane)-2-(4-(4-fluoro-phenyl)-4 - hydroxypiperidine-1-yl)-propane-1-he (0.90 g, 1.71 mmole in 25 ml ethanol). The reaction mixture was stirred at ambient temperatures for Saturday and Sunday. Saducees white solid was collected by filtration and dried to obtain 0.365 g (40%) of (1R*THAT 2R*)-1-(3,5-dimethyl-4 - triisopropylchlorosilane)-2-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-propan-1-ol, which is suitable for further use without further purification and has so pl. 186,5-187oC. Elemental analysis for C31H48FNO3Si0.125H2O. Calculated: C, 69.69; H, 9.15; N, 2.62. Found: C, 69.65; H, 9.29; N, 2.57.

The product of the reaction described above (0.31 g, 0.59 mmole) was dissolved in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (0.65 ml, 0.65 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 30 minutes at ambient temperature and then concentrated. The residue was distributed in a mixture of ethyl acetate-water and separation of the phases. The organic layer was washed with brine, dried and concentrated. The residue was subjected to purification by the method of flash chromedome sequence: 50% ethyl acetate/hexane (150 ml), the lack of product; 50% ethyl acetate/hexane (50 ml) and ethyl acetate (200 ml), 0.200 g (91%) of (1R*THAT 2R*)-1-(3,5-dimethyl-4-hydroxyphenyl)-2-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-propan-1-ol. A sample of this product from 0.194 b g, 0.519 mmole) was transformed into mesilate salt. This substance is suspended in methanol (15 ml) was added methansulfonate (0.034 ml, 0.524 mmole). The mixture was filtered and concentrated; then the residue was recrystallized from a mixture of ethanol/water in a ratio of 9: 1 with obtaining mesilate salt in the form of a fine white solid product (0.174 g), having so pl. 179-180oC. Elemental analysis for C22H28FNO3CH3SO30.25 H2O. Calculated: C 58,27; H, 6.91; N, 2.95. Found: C, 58.30; H, 7.24; N, 3.00.

Example 5.

Mesilate (1R*THAT 2R*)-1-(3,5-debtor-4-hydroxyphenyl)-2-(4-(4- chlorophenyl)-4-hydroxypiperidine-1-yl)-propan-1-ol.

A mixture of 3,5-debtor-4-triisopropylsilane- -bromopropiophenone (compound of Preparative example 20, 1.50 g, 3.56 mmole), 4-(4-chlorophenyl)-4-hydroxypiperidine (1.00 g, 4.03 mmole) and triethylamine (1.7 ml, 12.2 mmole) in ethanol (30 ml) was heated under reflux for 4.5 hours and then stirred overnight at ambient temperature. The solvent dallimonti layer was washed with brine, was dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silicagel (column size 1x4 inch, 2.54 x 10.16 cm, filled in hexane), using the following sequence of elution: 10% ethyl acetate/hexane (250 ml), lack of product; 10 % ethyl acetate/hexane (250 ml) and 20% ethyl acetate/hexane (250 ml), 0.79 g (40%) 1-(3,5-debtor-4-triisopropyl-dioxyphenyl)-2-(4-(4- chlorophenyl)-4-hydroxypiperidine-1-yl)-propane-1-it is in the form of an orange foam, which can be used without additional purification, and the resulting product had the following NMR spectrum: 7.73 (paired doublet in a long interval, J= 9.0 Hz, 2H), 7.37 (AB Quartet, V1-3= 26.3 Hz, J= 8.7 Hz, 4H), 4.03 (Quartet, J= 6.8 Hz, 1H), 2.95-2.81 (multiplet, 2H), 2.66-2.61 (multiplet, 2H), 2.17-1.93 (multiplet, 2H), 1.80-1.55 (multiplet, 3H), 1.39-1.21 (multiplet, 5H), 1.12 (doublet, J= 7.2 Hz, N).

A mixture of sodium borohydride (0.058 g, 1.40 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(3,5 - debtor-4-triisopropylchlorosilane)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl)-propane-1-he (0.76 r, 1.38 mmole in 20 ml ethanol). The reaction mixture was stirred at ambient temperatures for Saturday and Sunday. Saducees white solid was collected Flor-phenyl)-4 - hydroxypiperidine-1-yl)-propan-1-ol, which can be used further without additional purification and which has so pl. 192 - 192.5 kgoC. Elemental analysis for C29H42ClF2NO3Si H2O. Calculated: C, 50.65; H, 5.67; N, 2.81. Found: C, 50.94; H, 5.54; N, 2.85.

Example 6.

Mesilate (1R*THAT 2R*)-l-(3,5-dimethyl-4-hydroxyphenyl)-2-(4-(4- triptoreline)-4-hydroxypiperidine-1-yl)-propan-1-ol

A mixture of 3,5-dimethyl-4-triisopropylsilane- -bromopropiophenone (compound of Preparative example 18, 2.00 g, 4.84 mmole), 4-(4-triptoreline)-4-hydroxypiperidine (1.78 g, 7.26 mmole) and triethylamine (1.4 ml, 10.0 mmole) in ethanol (30 ml) was heated under reflux for 7.75 hours and then stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the residue was distributed in the system ethyl acetate - water. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1.5x4 inches, 3.81 x 10.16 cm, filled in hexane), conducting elution in the following sequence: 10% ethyl acetate/hexane (500 ml), without product education; 25% ethyl acetate/hexane (250 ml), 1.39 g (50%) 1-orange foamy product suitable for further use without further purification and has the following NMR spectrum: 7.74 (singlet, 2H), 7.60 (multiplet, 4H), 4.17 (Quartet, J= 6.8 Hz, 1H), 2.92-2.79 (multiplet, 2H), 2.71-2.58 (multiplet, 1H), 2.31 (singlet, 6H), 2.25-2.00 (multiplet, 2H), 1.76-1.65 (multiplet, 2H), 1.41-1.18 (multiplet, 6H), 1.13 (doublet, J= 7.2 Hz, N).

A mixture of sodium borohydride (0.090 g, 2.38 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(3,5 - dimethyl-4-triisopropylchlorosilane)-2-(4- (4-triptoreline)-4-hydroxypiperidine-1-yl)-propane-1-he (1.30 g, 2.25 mmole in 25 ml ethanol). The reaction mixture was stirred at ambient temperature overnight. Saducees white solid was collected by filtration and dried to obtain 0.408 g (31%) of (1R*THAT 2R*)-1-(3,5-dimethyl-4 - triisopropylchlorosilane)-2-(4-(4-trifluoromethyl-phenyl)-4 - hydroxypiperidine-1-yl)-propan-1-ol, which can be used without additional purification and has so pl. 177-177.5oC. Elemental analysis for C32H48F3NO3SiCH4SO31.25 H2O. Calculated: C, 53.18; H, 6.42; N, 2.58. Found: C, 53.18; H 6.63; N, 2.58.

Example 7.

Mesilate (1R*THAT 2R*)-1-(3,5-dichloro-4-hydroxyphenyl)-2-(4-(4- forfinal)-4-hydroxypiperidine-1-yl)-propan-1-ol.

A mixture of 3,5-dichloro-4-triisopropylsilane- - bromopropiophenone (product Preparative is) in ethanol (20 ml) was heated under reflux for 6 hours and then stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the residue was distributed between ethyl acetate and water. Was phase separation and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1x4 inch, 2,h,16 cm, filled in hexane), conducting elution in the following sequence: 10% ethyl acetate/hexane (250 ml), lack of product; 10% ethyl acetate/hexane (350 ml), 0.12 g (10%) 1-(3,5-dichloro-4-triisopropylchlorosilane)-2-(4-(4- forfinal)-4-hydroxypiperidine-1-yl)-propane-1-it is in the form of an orange oil, which was directly used in the next stage.

A mixture of sodium borohydride (0.010 g, 0.26 mmole) and ethanol (1 ml) was stirred for 10 minutes and then was added 1-(3,5 - dichloro-4-triisopropylchlorosilane)-2-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-propane-1-he (0.12 g, 0.211 mmole in 4 ml ethanol). The reaction mixture was stirred over night at room temperature. The mixture was cooled by adding water and concentrated at 40oC. the Residue was distributed in the system ethyl acetate - water and separation of the phases. The organic layer was washed with brine, dried over magnesium sulfate and concentration.9 x 10.16 cm filled in hexane), conducting elution in the following sequence: 10% ethyl acetate/hexane (200 ml), lack of product; 20% ethyl acetate/hexane (200 ml), lack of product; 20% ethyl acetate/hexane (150 ml), 0.033 g (27%) of (1R*THAT 2R*)-1-(3,5-dichloro-4 - triisopropylchlorosilane)-2-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-propan-1-ol as a yellow oil, which can be used further without additional purification.

The product of the reaction described above (0.033 g, 0.058 mmole) was dissolved in tetrahydrofuran (5 ml) was added tetrabutylammonium fluoride (0.060 g, 0.060 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 3 hours at ambient temperature and concentrated. The residue was distributed in the system ethyl acetate-water and separation of the phases. The organic layer was washed with brine, dried and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 0.75 x 3 inch, 1.9 x 7.62 cm, when filling in hexane), conducting elution as follows: 25% ethyl acetate/hexane (200 ml), the absence of reaction product; 50% ethyl acetate/hexane (150 ml) to give 0.014 g (58%) of (1R*THAT 2R*)-1- (3,5-dichloro-4-hydroxyphenyl)-2-(4-(4-fluorine is whether mesilate salt. This substance is suspended in methanol and was added methansulfonate (0.0022 ml, O. 0034 mmole). The mixture was concentrated; then the residue was treated with a mixture of ether/ethanol in a ratio of 20: 1 with obtaining 0.013 g mesilate salt in the form of a white solid having the following NMR spectrum: (D2O/DMSO-d6) 7.70 (AB Quartet, AB Quartet, V1-3= 23.8 Hz, 4H), 7.42 (singlet, 2H), 4.70 (doublet, J= 10.2 Hz, 1H), 3.71-3.50 (multiplet, 4H), 3.37-3.32 (multiplet, 1H), 2.75 (singlet, 3H), 2.60-2.42 (multiplet, 2H), 2.15-2.05 (multiplet, 2H), 1.11 (doublet, J= 6.8 Hz, 3H).

Example 8.

Mesilate (1R*THAT 2R*)-1-(3,5-dichloro-4-hydroxyphenyl)-2-(4-(4- triptoreline)-4-hydroxypiperidine-1-yl)-propan-1-ol.

A mixture of 3,5-dichloro-4-triisopropylsilane- -bromopropiophenone (compound of Preparative example 14, 1.00 g, 2.20 mmole), 4-(4-triptoreline)-4-hydroxypiperidine (0.86 g, 3.26 mmole) and triethylamine (0.62 ml, 4.45 mmole) in ethanol (20 ml) was heated under reflux for 6 hours and then stirred overnight at ambient temperature. The solvent was removed under reduced pressure and the residue was distributed in the system ethyl acetate - water. The phases were separated and the organic layer was washed with brine, dried over sulfate magmas 1x3 inch, 2.54 x 7.62 cm, filled in hexane), conducting elution in the following sequence: 10% ethyl acetate/hexane (250 ml), lack of product; 10% ethyl acetate/hexane (250 ml), 0.18 g (13%) 1-(3,5-dichloro-4 - triisopropylchlorosilane)-2-(4-(4-triptoreline)-4 - hydroxypiperidine-1-yl)-propane-1-it is in the form of an orange oil, which was directly used in the next stage.

A mixture of sodium borohydride (0.012 g, 0.317 mmole) and ethanol (1 ml) was stirred for 10 minutes and then was added 1-(3,5 - dichloro-4-triisopropylsilyl)-2-(4-(4-triptoreline)-4 - hydroxypiperidine-1-yl-propane-1-he (0.18 g, 0.291 mmole in 4 ml ethanol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was cooled with water and concentrated at 40oC. the Residue was distributed in a mixture of ethyl acetate-water and separation of the phases. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 0.75 x 4 inches; 1.9 x 10.16 cm, filled in hexane), conducting elution as follows: 10% ethyl acetate/hexane (200 ml), the absence of reaction product; 20% ethyl acetate/hexane (150 ml), 0.072 g (40%) of (1R*THAT 2R*)-1-(3,5-di oil, which can be used without additional purification.

The product of the reaction described above (0.072 g, 0.116 mmole) was dissolved in tetrahydrofuran (5 ml) was added tetrabutylammonium fluoride (0.120 ml, 0.120 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 3 hours at ambient temperature and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (0.75 x 4 inches; 1.9 x 10.16 cm, filling in hexane), conducting elution as follows: 25% ethyl acetate/hexane (200 ml), the absence of reaction product; 50% ethyl acetate/hexane (100 ml), 0.028 g (52%) of (1R*THAT 2R*)-1-(3,5-dichloro-4 - hydroxyphenyl)-2-(4-(4-triptoreline)-4-hydroxypiperidine-1 - yl)-propan-1-ol as a white solid. A sample of this substance was made in mesilate salt. This substance is suspended in methanol and was added methansulfonate (0.0039 ml, 0.006 mmole). The resulting mixture was concentrated; then the residue was treated with a mixture of ether/ethanol in a ratio of 20:1 with obtaining 0.022 g mesilate salt in the form of a white solid substance having so pl. 208-208.5oC; NMR spectrum (E2Oh, DMSO-d6) 7.49-7.42 (multiplet, 6H), 4.70 (doublet, J= 10.2 Hz, 1H), 3.72-3.47 (multiplet, 4H), 3.36-3.28 (EP 9.

Mesilate (1R*THAT 2R*)-1-(3,5-dichloro-4-hydroxyphenyl)-2-(4-(4- chlorphenyl)-4-hydropiperoides-1-yl)-propan-1-ol.

A mixture of 3,5-dichloro-4-triisopropylsilane- - bromopropiophenone (compound of Preparative example 14, 1.O0 g, 2.20 mmole), 4-(4-chlorophenyl)-4-hydroxypiperidine (0.81 g, 3.26 mmole) and triethylamine (0.93 ml, 6.67 mmole) in ethanol (20 ml) was heated under reflux for 6 hours and then stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the residue was distributed in a mixture of ethyl acetate-water. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1x3 inch, 2.54 x 7.62 cm, filled in hexane), conducting elution in the following sequence: 10% ethyl acetate/hexane (250 ml), the absence of reaction product; 10% ethyl acetate/hexane (250 ml), 0.08 g (b%) of 1- (3,5-dichloro-4-triisopropylchlorosilane)-2-(4-(4-chloro-phenyl)-4 - hydroxypiperidine-1-yl)-propane-1-it is in the form of an orange oil, which was directly used in the next stage.

A mixture of sodium borohydride (0.010 g, 0.26 mmole) and ethanol (1 ml) premieredin-1-yl)-propane-1-he (0.08 g, 0.137 mmole in 4 ml ethanol). The reaction mixture was stirred over night at ambient temperature. The mixture was cooled with water and concentrated at 40oC. the Residue was distributed in the system ethyl acetate-water and separation of the phases. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 0.75 x 4 inches; 1.9 x 10.16 cm, filled in hexane), conducting elution as follows: 10% ethyl acetate/ hexane (200 ml), the absence of reaction product; 20% ethyl acetate/hexane (150 ml), 0.03 g (40%) of (1R*THAT 2R*)-1-(3,5-dichloro-4 - triisopropylchlorosilane)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl)-propan-1-ol as a yellow oil, which you can use without additional purification. The product of the reaction described above (0.030 g, 0.051 mmole) was dissolved in tetrahydrofuran (5 ml) was added tetrabutylammonium fluoride (0.053 ml, 0.053 mmole, 1M tertrahydrofuran ring solution). The reaction mixture was stirred for 3 hours at ambient temperature and then concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 0.75 x 3 inch, 1.9 x 7.62 cm, filled in and; 50% ethyl acetate/hexane (150 ml), 0.009 g (41%) of (1R*THAT 2R*)-1-(3,5-dichloro-4-hydroxyphenyl)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl)-propan-1-ol as a white solid. A sample of this product was converted into its mesilate salt. This substance is suspended in methanol and was added methansulfonate (0.0014 ml, 0.002 mmole). The resulting mixture was concentrated; then the residue was treated with a mixture of ether/ethanol in a ratio of 10: 1 with obtaining 0.0085 g mesilate salt in the form of a white solid substance having so pl. 223-223.5oC; NMR Spectrum (E2O) 7.54-7.46 (multiplet, 6H), 4.70 (doublet, 1H, partially obscured by solvent), 3.74-3.53 (multiplet, 4H), 3.37 (broad doublet, J= 13.2 Hz, 1H), 2.80 (singlet, 3H), 2,60-2,27 (multiplet, 2H), 2.20-2.07 (multiplet, 2H), 1.15 (doublet, J= 6.8 Hz, 3H).

Example 10.

Mesilate (1R*THAT 2R*)-l-(3,5-debtor-4-hydroxyphenyl)-2-(4-(4- forfinal)-4-hydroxypiperidine-1-yl)-propan-1-ol.

A mixture of 4-benzyloxy-3,5-debtor- - bromopropiophenone (compound of Preparative example 22, 1.00 g, 2.82 mmole) and 4-(4-forfinal)-4-hydroxypiperidine (1.1 g, 5.63 mmole) in ethanol (25 ml) was heated under reflux overnight. The solvent was removed under reduced pressure and the residue was distributed system and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1x4 inch, 2.H.16 cm, filled in hexane), conducting elution in the following sequence: 5% ethyl acetate/hexane (500 ml), the absence of reaction product; 15% ethyl acetate/hexane (500 ml), lack of product; 20% ethyl acetate/hexane (250 ml), 0.59 g (45%) of 1-(4-benzyloxy-3,5-differenl)-2-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-propane-1-it is in the form of a bright yellow oil suitable for use without further purification and has the following NMR spectrum: 7.75 (dlina-interval paired doublet, J= 9.2 Hz, 2H), 7.48-7.30 (multiplet, 7H), 7.03 (dlina-interval paired triplet, J= 8.7 Hz, 2H), 5.31 (singlet, 2H), 4.01 (Quartet, J= 6.7 Hz, 1H), 2.93 (double triplet, J= 2.6, 11.2 Hz, 1H), 2.80-2.75 (multiplet, 1H), 2.70-2.60 (multiplet, 2H), 2.18-1.92 (multiplet, 2H), 1.81 - 1.62 (multiplet, 2H), 1.30 (doublet, J= 6.7 Hz, 3H).

A mixture of sodium borohydride (0.050 r, 1.32 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(4-benzyloxy-3,5-differenl)-2-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-propane-1-he (0.55 g, 1.17 mmole in 20 ml ethanol). The reaction mixture was stirred at ambient temperature overnight. The precipitated white solid was collected has shown that the 40oC. the Residue was distributed in the system ethyl acetate - water. Was phase separation and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1x4 inch, 2.H.16 cm), conducting elution in the following sequence: 30% ethyl acetate/hexane (300 ml), obtaining 0.059 g of the product. This method has been 0.399 g (73%) of (1R*THAT 2R*)-1-(4-benzyloxy-3.5 - debtor-phenyl)-2-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)-propan - 1-ol, suitable for further use without additional processing and having so pl. 169-171oC; NMR spectrum: 7.53-7.44 (multiplet, 4H), 7.41-7.30 (multiplet, 3H), 7.06 (long range coupled triplet, J= 8.7 Hz, 2H), 6.92 (long range coupled doublet, J= 8.9 Hz, 2H), 5.27 (singlet, 1H), 5.15 (singlet, 2H), 4.18 (doublet, J= 9.7 Hz, 1H), 3.08 (double triplet, J= 2.3, 11.6 Hz, 1H), 2.71-2.68 (multiplet, 2H), 2.59-2.48 (multiplet, 2H), 2.26-2.01 (multiplet, 2H), 1.83 (broad doublet, J = 13.9 Hz, 2H), 1.58 (singlet, 1H), 0.86 (doublet, J= 6.7 Hz, 3H). The product of the reaction described above (0.34 g, 0.721 mmole) was dissolved in tetrahydrofuran (10 ml) and methanol (10 ml) and ammonium formate (0.45 g, 7.14 mmole) was added 10% palladium on coal (0.19 g). The reaction mixture plumage is stroudley the pad was washed with ethanol and water. The filtrate was concentrated and the residue was distributed in the system ethyl acetate - water. Was phase separation and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated so that the solution does not remain in the product. Layer on the filter from the magnesium sulfate was dissolved in water and the grey solid was filtered, washed with water and dried. Grey solid substance with a weight 0.195 g) was subjected to purification by the method of flash chromatography on silica gel (column size 1x4 inch, 2.H.16 cm). Elution was performed in the following sequence: 50% ethyl acetate/hexane (100 ml), the absence of reaction product; ethyl acetate (200 ml), the absence of reaction product; 10% methanol/ethyl acetate (200 ml), the absence of reaction product; 25% methanol/ethyl acetate (200 ml) and 50% methanol/ethyl acetate (200 ml), 0.097 g (36%) of (1R*THAT 2R*)-1-(3,5-debtor-4 - hydroxyphenyl)-2-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)- propan-1-ol as a white solid. The obtained product was converted into its mesilate salt. This substance is suspended in methanol (10 ml) was added methansulfonate (0.017 ml, 0.262 mmole). The resulting mixture was filtered and concentrated; then the residue was recrystallized from a mixture of ethanol/water in aspect] 239-239,5oC. Elemental analysis for C20H2F3NO3VH4SO3. Calculated: C At 58.82; H, 5.49; N, 2.93. Found: C, 52.80; H, 5.76; N, 2.99.

Example 11.

Mesilate (1R*THAT 2R*)-1-(3,5-debtor-4-hydroxyphenyl)-2-(4-(4- triptoreline)-4-hydroxypiperidine-1-yl)-propan-1-ol.

A mixture of 4-benzyloxy-3,5-debtor- -bromopropiophenone (compound of Preparative example 22, 1.14 g, 3.21 mmole), 4-(4-triptoreline)-4-hydroxypiperidine (0.87 g, 3.55 mmole) and triethylamine (0.90 ml, 6.5 mmole) in ethanol (25 ml) was heated at reflux for 1.75 hours and during the night was stirred at ambient temperature. The solvent was removed under reduced pressure and the residue was distributed in the system ethyl acetate-water. Was phase separation and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (1x4 inch, 2.H.16 cm, filling column in the environment hexane), conducting elution in the following sequence: 15% ethyl acetate/hexane (500 ml), lack of product; 25% ethyl acetate/hexane (250 ml), 1.09 g (65%) of 1-(4 - benzyloxy-3,5-differenl)-2-(4-(4-triptoreline)-4 - hydroxypiperidine-1-yl)-propane-1-it in VI is an NMR spectrum: 7.74 (long range coupled doublet, J= 9.4 Hz, 2H), 7.61 (singlet, 4H), 7.48-7.34 (multiplet, 5H), 5.32 (singlet, 2H), 4.03 (Quartet, J= 5.7 Hz, 1H), 2.95-2.83 (multiplet, 2H), 2.67-2.62 (multiplet, 2H), 2.16-1.98 (multiplet, 2H), 1.81-1.67 (multiplet, 2H), 1.57 (broad singlet, 1H), 1.31 (doublet, J= 6.8 Hz, 3H).

A mixture of sodium borohydride (0.085 g, 2.25 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(4-benzyloxy-3,5-differenl)-2-(4-(4-triptoreline)-4 - hydroxypiperidine-1-yl)-propane-1-he (1.02 g, 1.96 mmole in 30 ml ethanol). The reaction mixture was stirred over night at ambient temperature. The precipitated white solid was collected by filtration and dried to obtain 0.66 g (65%) of (1R*THAT 2R*)-1- (4-benzyloxy-3,5-differenl)-2-(4-(4-triptoreline)-4 - hydroxypiperidine-1-yl)-propan-1-ol, which can be used without additional purification and has so pl. 201-202oC. Elemental analysis for C28H28F5NO30.25 H2O. Calculated: C, 63.93; H, 5.46; N, 2.66. Found: C, 63.98; H, 5.49; N, 2.70.

The product of the reaction described above (0.60 g, 1.15 mmole) was dissolved in tetrahydrofuran (15 ml) and methanol (15 ml) was added ammonium formate (0.73 g, 11.6 mmole) and 10% palladium on coal (0.30 g). The reaction mixture was stirred for 2 hours at the temperature of okrujaushei - water. The phases were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to education 0.517 g (1R*THAT 2R*)-1-(3,5-debtor-4-hydroxyphenyl)-2- (4-(4-triptoreline)-4-hydroxypiperidine-1-yl)-propan-1-ol as a white solid. A sample of this substance (0.50 g, 1.16 mmole) was transformed into its mesilate salt. The resulting substance suspended in methanol (15 ml) was added methanesulfonate (0.75 ml, 1.16 mmole). The mixture was filtered and concentrated; then the residue was recrystallized from a mixture of ethanol/water in a ratio of 9:1 with obtaining mesilate salt in the form of a crystalline white solid (0.475 g) having so pl. 218-219oC. Elemental analysis for C21H22F5NO3CH4SO30.75 H2O. Calculated: C 48,84; H 5,12; N, 2.59. Found: C, 48.88; H, 5.37; N, 2.59.

Example 12.

(1R*THAT 2R*)-1-(3-Fluoro-4-hydroxyphenyl)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl)-propan-1-ol mesilate.

A mixture of 3-fluoro-4-triisopropylsilane- -bromopropiophenone (compound of Preparative example 11), 1.25 g, 3.10 mmole), 4-(4-chlorophenyl)-4-hydroxypiperidine (1.0 g, 4.03 mmole) and triethylamine (1.51 ml, 10.85 mmole) in ethanol (25 ml) was heated with Ob system ethyl acetate - water. Was phase separation and the organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1x3.5 inch 2.H.9 cm, filled with a mixture of 10% ethyl acetate/hexane), conducting elution in the following order: hexane (150 ml), lack of product; 10% ethyl acetate/hexane (350 ml) lack of product; 20% ethyl acetate/hexane (300 ml), 0.535 g (32%) of 1-(3 - fluoro-4-triisopropylsilyl)-2-(4-(4-chlorophenyl)- 4-hydroxypiperidine-1-yl)-propane-1-it is in the form of a yellow oily foam, having the following NMR spectrum: 7.87 (double doublet, J= 2,11.5 Hz, 1H), 7.80 (doublet, J= 8.5 Hz, 1H), 7.39 (doublet, J= 8.5 Hz, 2H), 7.28 (doublet, J= 8.5 Hz, 2H), 6.95 (triplet, J= 8.5 Hz, 1H), 4.07 (Quartet, J = 7 Hz, 1H), 2.95-2.78 (multiplet, 2H), 2.78-2.57 (multiplet, 2H), 2.04 (symmetric multiplet, 2H), 1.78-1.64 (multiplet, 2H), 1.30 (doublet, J= 7 Hz, 3H), 1.10 (doublet, J= 7 Hz, N).

A mixture of sodium borohydride (0.032 g, 0.85 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(3 - fluoro-4-triisopropylsilyl)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl)-propane-1-he (0.454 g, 0.850 mmole in 10 ml ethanol). The reaction mixture was stirred over night at ambient temperature. Oversolicitous)-2-(4-(4-chlorophenyl)-4-chlorophenyl) -4-hydroxypiperidine-1-yl)-propan-1-ol, having the following NMR spectrum: 7.39/AB Quartet, V1-3= 35.2 Hz, J= 8.5 Hz, 4H), 7.06 (double doublet, J= 2,11.5 Hz, 1H), 6.96-6.82 (multiplet, 2H), 5.15 (singlet, 1H), 4.18 (doublet, J= 9.5 Hz, 1H), 3.04 (double triplet, J= 2.5 and 11.5 Hz, 1H), 2.78-2.67 (multiplet, 1H), 2.67 - 2.52 (multiplet, 3H), 2.12 (symmetric multiplet, 2H), 1.80 (distorted doublet, J= 14 Hz, 2H), 1.54 (singlet, 1H), 1.36-1.19 (multiplet, 3H), 1.08 (doublet, J= 7 Hz, N), 0.80 (doublet, J= 6.5 Hz, 3H).

This product also contained about 8% of Erythro diastereoisomer, but it can be used without additional purification.

The product of the reaction described above (0.220 g, 0.41 mmole) was dissolved in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (0.452 ml, 0.45 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 30 minutes at ambient temperature and concentrated. The residue was distributed in the system ethyl acetate - water and separation of the phases. The organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 0.75 x 3.5 inch, 1,9 x 8.4 cm), conducting elution as follows: 5% ethyl acetate/hexane (100 ml), lack of product; 15% ethyl acetate/hexane (200 ml), the absence of the same; 35% ethyl acetate/hexane (200 ml), 0.106 g (68%) of white solid product. The obtained solid is suspended in methanol (4 ml) was added methansulfonate (0.018 ml, 0.28 mmole). The resulting mixture was filtered, and then concentrated by boiling to a volume of 0.5 ml with the addition of a few drops of ethanol. In result of cooling the formed white crystals, which were collected by filtration to obtain 0.084 g (43%) of (1R*THAT 2R*)-1-(3-fluoro-4 - hydroxyphenyl)-2-(4-(4-chlorophenyl)-4 - hydroxypiperidine-1-yl)-propan-1-ol nelfinavir with so pl. 233-235oC. Elemental analysis for C20H23ClFNo3CH4SO3/ Calculated: C, 52.99; H, 5.72; N, 2.94. Found: C, 53.06; H, 5.91; N, 3.03.

Example 13.

Mesilate (1R*THAT 2R*)-1-(3-fluoro-4-hydroxyphenyl)-2-(4-(4- triptoreline)-4-hydroxy-piperidine-1-yl)-propan-1-ol.

A mixture of 3-fluoro-4-triisopropylsilane- - bromopropiophenone (compound of Preparative example 11, 1.35 g, 3.35 mmole), 4-(4-triptoreline)-4-hydroxypiperidine (1.15 g, 4.69 mmole) and triethylamine (1.20 ml, 8.38 mmole) in ethanol (25 ml) was heated under reflux for 4 hours. The solvent was removed under reduced pressure and the residue was distributed in the system ethyl acetate - water. Phase time is was vergili cleaning method flash chromatography on silica gel (column 1x3.5 inches, 2,54 x 8.9 cm, filled with a mixture of 10% ethyl acetate/hexane), conducting elution in the following order: hexane (150 ml), lack of product; 10% ethyl acetate/hexane (350 ml), lack of product; 20% ethyl acetate/hexane (350 ml), 0.841 g (44%) of 1-(3-fluoro-4 - triisopropylchlorosilane)-2-(4-(4-triptoreline)- 4-hydroxypiperidine-1-yl)-propane-1-it is in the form of a yellow oily foam having the following NMR spectrum: 7.88 (double doublet, J= 2, 11.5 Hz, 1H), 7.80 (symmetric multiplet, 1H), 7.60-7.57 (multiplet, 4H), 6.96 (triplet, J= 8.5 Hz, 1H), 4.08 (Quartet, J= 7 Hz, 1H), 3.32 (broad multiplet, 1H), 2.96-2.78 (multiplet, 2H), 2.78-2.56 (multiplet, 2H), 2.08 (symmetric multiplet, 2H), 1.78-1.63 (multiplet, 2H), 1.31 (doublet, J= 7 Hz, 3H), 1.10 (doublet, J= 7 Hz, N).

A mixture of sodium borohydride (0.049 g, 1.30 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(3-fluoro-4 - triisopropylsilyl)-2-(4-(4-triptoreline)-4 - hydroxypiperidine-1-yl)-propane-1-it (0.738 g, 1.30 mmole in 10 ml ethanol), carrying out washing with 5 ml ethanol. The reaction mixture was stirred over night at ambient temperature. The resulting white precipitate was collected by filtration to obtain 0.335 g (45%) of (1R*THAT 2R*)-1-(3-fluoro - 4-triisopropylsilyl)- 2-(4-(4-trifloromethyl is 11.5 Hz, 1H), 6.98-6.84 (multiplet, 2H), 5.13 (singlet, 1H), 4.20 (doublet, J= 9.5 Hz, 1H), 3.06 (symmetric multiplet, 1H), 2.81-2.71 (multiplet, 1H), 2.70-2.50 (multiplet, 3H), 2.15 (symmetric multiplet, 2H), 1.81 (distorted doublet, J= 14 Hz, 2H), 1.59 (singlet, 1H), 1.33-1.19 (multiplet, 3H), 1.08 (doublet, J= 7 Hz, N), 0.81 (doublet, J= 6.5 Hz, 3H). The product also contained about 7% erythroleukaemia, but was suitable for use without additional purification.

The product of the reaction described above (0.300 g, 0.527 mmole) was dissolved in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (0.58 ml, 0.58 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 30 minutes at ambient temperature and then concentrated. The residue was distributed in the system ethyl acetate - water and separation of the phases. The organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (0.75 x 3.5 inch, 1.9 x 8.9 cm), conducting elution as follows: 5% ethyl acetate/hexane (100 ml), lack of product; 15% ethyl acetate/hexane (200 ml), lack of product; 25% ethyl acetate/hexane (200 ml), lack of product; 35% ethyl acetate/hexane (350 ml), 0.156 g (72%) of a white solid product is obtained mixture was filtered and concentrated. The residue was recrystallized from ethanol with education Acting 085 g (32%) of (1R*THAT 2R*)-1-(3-fluoro-4-hydroxyphenyl)-2-(4-(4-triptoreline)-4 - hydroxypiperidine-1-yl)-propan-1-ol nelfinavir with so pl. 155 - 157oC. Elemental analysis for C21H23F4NO3CH4SO3. Calculated: C, 51.86; H, 5.34; N, 2.75. Found: C, 51.94; H, 5.58; N, 2.76.

Example 14

(1R*THAT 2R*)-4-{ 2-(3-(4-Chlorophenylsulfonyl)-8-azabicyclo(3,2,1) Oct-8-yl)-1-hydroxypropyl}-2-were.

A mixture consisting of 3-methyl-4-triisopropylsilane- -bromopropiophenone (compound of Preparative example 6, 1.25 g, 3.14 mmole), 3-(4-chlorophenylsulfonyl)-8-azabicyclo (3,2,1)octane (compound of Preparative example 41, 1.11 g, 4.40 mmole) and triethylamine (1.09 ml, 7.85 mmole) in ethanol (17 ml) was heated under reflux for 16 hours. The solvent was removed under reduced pressure and the residue was distributed between methylene chloride and water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was purified by the method of flash chromatography on silica gel (1x4 inch of 2.54 x 10.16 cm, filled with hexane), conducting elution in the following order: hexane (150 ml), lack of product; 5% ATI g (74%) of 1-(3-methyl-4-triisopropylchlorosilane)-2-{3-(4-chlorophenylsulfonyl) -8-azabicyclo(3,2,1) octane-8-yl}-propane-1-it is in the form of a yellow oil, which is directly used in the next stage.

A mixture of sodium borohydride (0.082 g, 2.18 mmole) and ethanol (10 ml) was stirred for 10 minutes and then was added 1-(3-methyl - 4-triisopropylsilyl)-2 - 3-(4-chlorophenylsulfonyl)-8 - azabicyclo(3,2,1)octane-8-yl-propane-1-he (1.247 g, 2.18 mmole in 5 ml ethanol) when washing with two portions of ethanol with a volume of 5 ml each. The reaction mixture was stirred at ambient temperature overnight and then concentrated. The residue was distributed in the system methylene chloride - water and separation of the phases. The organic phase was washed with brine, dried and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (1x4 inch, 2.H.16 cm), conducting elution in the following sequence: 10% ethyl acetate/hexane (200 ml), lack of product; 20% ethyl acetate/hexane (500 ml), 0.475 g (38%) of (1R*THAT 2R*)-1-(3-methyl-4 - triisopropylchlorosilane)-2-{ 3-(4-chlorophenylsulfonyl)-8 - azabicyclo(3,2,1) octane-8-yl}-propan-1-ol in the form of oil, which had the following NMR spectrum: 7.29,(AB Quartet, V1-3=23 Hz, J= 8.5 Hz, 4H), 7.07 (doublet, J= 2 Hz, 1H), 6.94 (double doublet, J=2.8 Hz, 1H), 6.70 (doublet, J= 8 Hz, 1H), 5.11 (broad singlet, 1H), 4.00 (doublet, J= 8 Hz, 1H), 3.42 (broad singlet, 2H)(multiplet, 8H), 1.34-1.20 (multiplet, 3H), 1.08 (doublet, J= 7 Hz, N), 0.79 (doublet, J = 6.5 Hz, 3H), This product also contained about 10% erythroleukaemia, but it can be used without additional purification. It should be noted that additional elution columns for flash chromatography with 25% ethyl acetate/hexane (250 ml) and 30% ethyl acetate/hexane (200 ml) produces 0.291 g erythroleukaemia in the form of butter.

The product of the reaction described above (0.475 g, 0.828 mmole) was dissolved in tetrahydrofuran (14 ml) was added tetrabutylammonium fluoride (0.91 ml, 0.91 mmole, 1M tertrahydrofuran ring solution). The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated. The residue was distributed in the system methylene chloride and water was the separation of the phases. The organic layer was washed with brine, dried and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (0.H inch, 1.H.62 cm), making subsequent elution method: 200 ethyl acetate/hexane (150 ml) lack of product; 30% ethyl acetate/hexane (200 ml) and 40% ethyl acetate/hexane (300 ml), 0.183 g (52%) of (1R*THAT 2R*)-4-{2-(3-(4- chlorophenylsulfonyl)-8-azabicyclo(3,2,1)Oct-8-yl)-1 - hydroxypropyl} -2-METHYLPHENOL in the form of a white solid propects NMR 7.31 (AB Quartet, V1-3= 19.5 Hz, J= 8.5 Hz, 4H), 7.09 (doublet, J= 2 Hz, 1H), 7.00 (double doublet, J= 2.8 Hz, 1H), 6.68 (doublet, J= 8 Hz, 1H), 5.10 (broad singlet, 2H), 4.02 (doublet, J= 8 Hz, 1H), 3.45 (broad singlet, 1H), 3.30 (symmetric multiplet, 1H), 3.22 (broad singlet, 1H), 2.62 (symmetric multiplet, 1H), 2.23 (singlet, 3H), 1.92-

1.68 (multiplet, 5H), 1,68-1.55V (multiplet, 3H), 0.82 (doublet, J= 6.5 Hz, 3H).

Example 15.

(1R*THAT 2R*)-4-{ 2-(3-(4-Chlorophenylsulfonyl)-8 - azabicyclo(3,2,1) Oct-8-yl)-1-hydroxypropyl}-2,6 - dimethylphenol.

A mixture of 3,5-dimethyl-4-triisopropylsilane- -bromopropiophenone (compound of Preparative example 41, 1.3 g, 3.14 mmole), 3-(4-chlorophenylsulfonyl)-8-azabicyclo (3,2,1)octane (1.11 g, 4.40 mmole) and triethylamine (1.09 g, 7.85 mmole) in ethanol (17 ml) was heated under reflux for 16 hours. The solvent was removed under reduced pressure and the residue was distributed in the system methylene chloride - water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (1x4 inch, 2,h.16 cm, filling in the presence of hexane), conducting chromatography according to the following procedure: hexane (150 ml), lack of product; 5% ethyl acetate/is l-4-triisopropylsilyl)-2-{ 3-(4- chlorophenylsulfonyl)-8-azabicyclo(3,2,1) octane-8-yl} -propane-8-it is in the form of a yellow oil, which is directly used in the next stage.

A mixture of sodium borohydride (0.070 g of 1.86 mmole) and ethanol (10 ml) was stirred for 10 minutes and then was added 1-(3,5 - dimethyl-4-triisopropylchlorosilane)-2 - 3-(4-chlorophenylsulfonyl)- 8-azabicyclo(3,2,1)octane-8-yl-propane-1-he (1.09 g, 2.86 mmole in 5 ml ethanol), carrying out washing 3 portions of 5 ml of ethanol. The reaction mixture was stirred at ambient temperature overnight. The resulting white precipitated product was collected and dried to obtain 0.22 g of erythrophobia (1R*THAT 2R*). The filtrate was concentrated and the residue was distributed in the system methylene chloride - water. The phases were separated and the organic phase was washed with brine, dried and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (1 x 3.5 inch, 2.54 x 8.9 cm), conducting elution as follows: 10% ethyl acetate/hexane (200 ml), lack of product; 20% ethyl acetate/hexane (500 ml), 0.208 g (19%) of (1R*THAT 2R*)-1-(3,5-dimethyl-4-triisopropylchlorosilane)- 2-{ 3-(4-chlorophenylsulfonyl)-8-azabicyclo(3,2,1) octane-8 - yl}-propan-1-ol in the form of oil, having the following NMR spectrum: 7.29 (AB Quartet, V1-3=22.5 Hz, J= 8.5 Hz, 4H), 6.88 (singlet, 2H), 5.08 (broad singlet, 1H), 3.98 (doublet, J= 7.5 the plet, 1H), 2.22 (singlet, 6H), 1.90-1.50 (multiplet, 8H), 1.34-1.20 (multiplet, 3H), 1.08 (doublet, J= 7 Hz, N), 0.80 (doublet, J= 6.5 Hz, 3H). The resulting product contained > 10% erythroleukaemia and it can be used without additional purification. Further elution of the chromatographic column 20% mixture of ethyl acetate/hexane (250 ml) produces erythroleukaemia in the form of oil and the overall yield of retroprojector in this case was 0.346,

The product of the reaction described above (0.196 r, 0.33 mmole) was dissolved in tetrahydrofuran (7 ml) was added tetrabutylammonium fluoride (0.37 ml, 0.37 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated. The residue was redistributed in the system methylene chloride - water and separation of the phases. The organic layer was washed with brine, dried and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 0.H.5 inch 1.9x6.25 cm), conducting elution as follows: 20% ethyl acetate/hexane (140 ml), lack of product; 30% ethyl acetate/hexane (200 ml) and 40% ethyl acetate/hexane (75 ml), 0.144 g (100%) of (1R*THAT 2R*-4-{ 2-(3-(4-chlorophenylsulfonyl)-8-azabicyclo (3,2,1)Oct-8-yl)-1-which of ethyl acetate and the resulting product had so pl. 143-144.5oC; NMR spectrum 7.31 (AB Quartet, V1-3= 19.5 Hz, J= 8.5 Hz, 4H), 6.93 (singlet, 2H), 5.19 (broad singlet, 1H), 4.59 (broad singlet, 1H), 3.98 (doublet, J= 8.5 Hz, 1H), 3.45 (broad singlet, 1H), 3.29 (symmetric multiplet, 1H), 3.22 (broad singlet, 1H), 2.62 (symmetric multiplet, 1H), 2.23 (singlet, 6H), 1.95-1.56 (multiplet, 8H), 0.81 (doublet, J= 6.5 Hz, 3H).

Example 16,

3R*4S*6-Fluoro-3-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)- chroman-4.7-diol.

A mixture of 3,5-dibromo-6-fluoro-7-benzyloxy-chroman-4-it (the compound of Preparative example 31, 0.91 g, 2.12 mmole), 4- (4-forfinal-4-hydroxypiperidine (0.83 g, 4.25 mmole) and triethylamine (0.60 ml, 4.30 mmole) in acetonitrile (30 ml) was stirred overnight at ambient temperature. The resulting yellow precipitate was collected by filtration. The resulting material was purified by the method of flash chromatography on silica gel (column 1x4 inch, 2.54 x 10.16 cm, filled in the presence of methylene chloride) through the elution according to the following procedure: 2% methanol/methylene chloride (200 ml), lack of product; 3% methanol/methylene chloride (100 ml), 0.16 g (16%) 7-benzyloxy-6-fluoro-3-(4-(4 - forfinal)-4-hydroxypiperidine-1-yl)-chromen-4-it, which was used without further purification.

The product of the reaction described above (0.13 g, 0.28 mmole) was dissolved in tetrahydrofuran (6 ml) and methanol (6 ml) and ammonium formate (0.18 g, 2.85 mmole) was added 10% palladium on coal (0.09 g). The reaction mixture was stirred overnight at ambient temperature and then filtered through diatomaceous earth. Filter pad was washed with methanol. The filtrate was concentrated and the residue was intensively stirred with aqueous bicarbonate. Solid (0.057 g) was collected and recrystallized from ethanol to obtain 0.022 g (20%) (3R*4S*)-6-fluoro-3-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)- chroman-4,7-diol in the form of a white solid substance having so pl. 160-161oC. an NMR Spectrum (DMSO-d6): 9.84 (broad singlet, 1H), 7.50 (double doublet, J= 5.6, 8.9 Hz, 2H), 7.11 (triplet, J= 8.9 Hz, 2H), 6.95 (doublet, J= 11.4 Hz, 1H), 6.31 (doublet, J= 7.7 Hz, 1H), 4.90 (broad singlet, 1H), 4.86 (singlet, 1H), 4.62 (singlet, 1H), 4,20 (double doublet, J= et, 2H), 2.57-2.52 (multiplet, 1H, partially obscured by solvent for NMR), 1.96-1.86 (multiplet, 2H), 1.56 (broad doublet, J= 13.4 Hz, 2H).

Example 17,

(3R*4S*)-5-Bromo-6-methyl-3-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-chroman-4,7-diol.

A mixture of 3,3-dibromo-6-methyl-7-triisopropyl - calixarene-4-it 6-methyl-3,3,5-tribromo-7-triisopropyl - similarsame-4-it (the compound of Preparative example 34, 1.0 g), 4-(4-forfinal)-4-hydroxypiperidine (0.79 g, 4.05 mmole) and triethylamine (0.60 ml, 4.30 mmole) in acetonitrile (30 ml) was stirred for 30 minutes at ambient temperature. The precipitate was collected by filtration to obtain 0.188 g of 5-bromo-6-methyl-7-carisopro-persillade-3-(4-(4 - forfinal)-4-hydroxypiperidine-1-yl)-chroman-4-it. The filtrate was subjected to purification by the method of flash chromatography on silica gel (column size 1x4 inch, 2.H.16 cm, filled in hexane), conducting elution in the following sequence: 20% ethyl acetate/hexane (100 ml), 0.115 g of 6-methyl-7 - triisopropylsilane-3-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)- chromen-4-it is in the form of a light yellow solid having so pl. 193-195oC; 20% ethyl acetate/hexane (100 ml) and 40% ethyl acetate/hexane (100 ml), 0.07 g of the mixture; 40% ethyl acetate/hexane (100LASS="ptx2">

A mixture of sodium borohydride (0.11 g , 2.91 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 5-bromo-6 - methyl-7-triisopropylsilyl-3-(4-(4-forfinal) 4 - hydroxypiperidine-1-yl)-chromen-4-one (0.15 g, 0.285 mmole in 10 ml ethanol and 5 ml of tetrahydrofuran). The reaction mixture was stirred at ambient temperature over the weekend. The reaction mixture was cooled with water and concentrated. The residue was treated with water and filtered to obtain 0.14 g of a solid substance having a cream color. The obtained solid was purified by the method of flash chromatography on silica gel (column size 1x3.5 inch 2.H.9 cm, filled with hexane), making subsequent elution method: processing 20% ethyl acetate/hexane (200 ml) and 30% ethyl acetate/hexane (100 ml), lack of product; 30% ethyl acetate/hexane (100 ml) and 50% ethyl acetate/hexane (150 ml), 0.094 g (63%) of (3R*4S*8*)-5-bromo-6-methyl - 7-triisopropylsilyl-3-(4-(4-forfinal)-4-hydroxypiperidine-1 - yl)-chroman-4-ol as a pale yellow solid having so pl. 201-202.5oC. Elemental analysis for C30H43BrFNO4. Calculated: C, 59.20; H, 7.12; N, 2.23. Found: C, 59.30; H, 7.41; N, 2.25.

The product of the reaction described above (0.09 g, 0.17 mmole) was dissolved in recreactional the mixture was stirred overnight at ambient temperature then concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1x3 inch, 2.H.62 cm, filled with hexane), conducting chromatography according to the following procedure: processing a mixture of 20% ethyl acetate/hexane (200 ml), lack of product; 40% ethyl acetate/hexane (200 ml), lack of product; 60% ethyl acetate/hexane (100 ml), lack of product; 60% ethyl acetate/hexane (100 ml), 0.045 g (71%) of (3R*4S*8)-5-bromo-6-methyl - 3-(4-(4-forfinal)-4-guide-oxypiperidine-1-yl)-chroman-4,7-diol in the form of a bright white solid. A sample of this substance was recrystallized from a mixture of ethanol/ether to obtain 0.035 g of product, having so pl. 195.5-196oC. Elemental analysis for C21H23BrFNO4. Calculated: C, 55.76; H, 5.13; N, 3.10. Found: C, 55.70; H, 5.23; N, 3.07.

Example 18.

(3R*4S*)-6-Methyl-3-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)- chroman-4,7-diol.

A mixture of 6-methyl-7-hydroxy-3-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-chromen-4-it (the compound of example 17, 0.30 g, 0.81 mmole), potassium carbonate (0.22 g, 1.59 mmole) and benzyl bromide (0.10 ml, 0.84 mmole) in acetone was heated under reflux for 6 hours. The reaction mixture was concentrated and the residue was distributed in the system ethyl acetate/tetrahydrof layer was washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated to education yellow solid. This solid was treated with ether to obtain 0.31 g (84%) of 7 - benzyloxy-6-methyl-3-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)- chromen-4-she has so pl. 245-245.5oC. Elemental analysis for C28H26FNO4: Calculated: C At 73.19; H, 5.70; N, 3.05. Found: C, 72.87; H, 5.76; N, 3.21.

A mixture of sodium borohydride (0.25 g, 6.61 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 7 - benzyloxy-6-methyl-3-(4-(4-forfinal)-4-hydroxypiperidine-1-yl)- chromen-4-one (0.30 g, 0.653 mmole in 20 ml of ethanol and 15 ml of tetrahydrofuran). The reaction mixture was stirred at ambient temperature overnight. Was added 0.12 g of sodium borohydride and stirring continued over the weekend. The reaction mixture was cooled with water and concentrated. The residue was treated with water and filtered to obtain a solid substance composed of a mixture of starting material and product in the ratio of 2:1. This material was stirred with hot ethanol and filtered. The obtained solid substance was collected and weighed to obtain 0.2 g of the product representing net source material, which can be *)-7-benzyloxy-6-methyl-3-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-chroman-4-ol, having so pl. 201-202oC. This substance is directly used at a later stage.

The product of the reaction described above (0.080 g, 0.173 mmole) was dissolved in tetrahydrofuran (3 ml) and ethanol (3 ml) was added ammonium formate (0.14 g, 2.22 mmole) and 10% palladium on coal (0.06 g). The reaction mixture was stirred over the weekend at ambient temperature and then filtered through diatomaceous earth. The filtration layer was washed with tetrahydrofuran and ethanol. The filtrate was concentrated and the residue was treated with water. Solid (0.045 g) was collected and recrystallized from a mixture of ethanol/ether to obtain 0.030 g (46%) of (3R*4S*3)-6-methyl-3-(4-(4-fluoro-phenyl)-4-hydroxypiperidine-1 - yl)-chroman-4,7-diol in the form of a white solid substance having so pl. 173.5-174oC; NMR spectrum (DMSO-d6) 9.10 (singlet, 1H), 7.37-7.32 (multiplet, 2H), 6.94 (triplet, J= 8.9 Hz, 2H), 6.71 (singlet, 1H), 6.02 (singlet, 1H), 4.69 (singlet, 1H), 4.55 (doublet, J= 4.3 Hz, 1H), 4.43 (broad singlet, 1H), 4.01 (doublet, J= 7.7 Hz, 1H), 3.83 (triplet, J= 10 Hz, 1H), 2.81 (broad doublet, J= 11.2 Hz, 1H), 2.69 (broad doublet, J= 10.8 Hz, 1H), 2.55-2.43 (multiplet, 2H), 1.85 (singlet, 3H), 1.79-1.71 (multiplet, 2H), 1.40 (broad doublet is n-1-yl) -chroman-4,7-diol.

A mixture consisting of 3.3-dibromo-6,8-dimethyl-7-triisopropylchlorosilane-4-it (the compound of Preparative example 28, 0.62 g, 1.22 mmole), 4-(4-forfinal)-4-hydroxypiperidine (0.48 g, 2.46 mmole) and triethylamine (0.68 ml, 4.88 mmole) in acetonitrile (20 ml) was stirred overnight at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated. The residue was distributed in the system ethyl acetate - water. The phases were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to purification by the method of flash chromatography on silica gel (column size 1x3 inch, 2.H.6 cm, filled in hexane), conducting chromatography according to the following procedure: processing a mixture of 10% ethyl acetate/hexane (250 ml), 0.23 g of 3-bromo-n,8-dimethyl-7-triisopropylsilane-3-(4-(4 - forfinal)-4-hydroxypiperidine-1-yl)-chromen-4-it, which was used without further purification.

A mixture of sodium borohydride (0.082 g, 2.17 mmole) and ethanol (3 ml) was stirred for 10 minutes and then added 6,8 - dimethyl-7-triisopropylsilyl-3-(4-(4-forfinal)-4 - hydroxypiperidine-1-yl)-chromen-4-it (0.117 g, 0.217 mmole in 12 ml of ethanol and 3 ml of tetrahydrofuran). The reaction mixture was stirred at a temperature of ltravel obtaining 0.110 g of solid substance. This material was subjected to purification by the method of flash chromatography on silica gel (column size 1x4-inch, 2,h.16 cm, filled in the presence of hexane), conducting chromatography according to the following procedure: processing a mixture of 25% ethyl acetate/hexane (300 ml), lack of product; 25% ethyl acetate/hexane (300 ml), 0.064 g (54%) of (3R*4S*)-6,8-dimethyl-7-triisopropylsilyl-3-(4-(4-forfinal)- 4-hydroxypiperidine-1-yl)-chroman-4-ol in the form of a white solid substance having tons of dps, 198-199oC; NMR spectrum: 7.46 (double doublet, J= 5.5, 8.5 Hz, 2H), 7.04 (triplet, J=8.7 Hz, 2H), 6.95 (singlet, 1H), 4.72 (doublet, J= 2.8 Hz, 1H), 4.38 (double doublet, J= 2.9, 10.4 Hz, 1H), 4.06 (triplet, J= 10.5 Hz, 1H), 3.09 (broad doublet, J= 11.1 Hz, 1H), 2.80 - 2.68 (multiplet, 4H), 2.19 (singlet, 3H), 2.11-2.02 (multiplet, 4H), 1.90-1.76 (multiplet, 3H), 1.38-1.21 (multiplet, 3H), 1.12 (doublet, J= 7.1 Hz, N).

The product of the reaction described above (0.060 g, 0.110 mmole) was dissolved in tetrahydrofuran (5 ml) was added tetrabutylammonium fluoride (0.115 ml, 0.115 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 1.5 hours at ambient temperature and then concentrated. The residue was subjected to evaporative chromatography on silica gel (column size 1x4 inch, 2.H.16 cm, filled with hexane), making suitelocated/hexane (200 ml), the lack of product; 75% ethyl acetate/hexane (400 ml), colorless oil that solidified with the formation of 0.035 g of substance (81%) - (3R*4S*)-6,8-dimethyl-3-(4- (4-forfinal)-4-hydroxypiperidine-1-yl)-chroman-4.7-diol as a white solid. A sample of this product was recrystallized from ethanol-ether to obtain 0.016 g of the product of two fractions, having a melting point 185.5-186oC; NMR spectrum (DMSO-d6) 8.17 (singlet, 1H), 7.52 (double doublet, J= 5.7, 8.7 Hz, 2H), 7.12 (triplet, J=8.9 Hz, 2H), 6.76 (singlet, 1H), 4.86 (singlet, 1H), 4.69 (singlet, 1H), 4.61 (singlet, 1H), 4.29 (broad doublet, J= 7.8 Hz, 1H), 4.02 (triplet, J= 10.5 Hz, 1H), 3.01 (broad doublet, J= 10.7 Hz, 1H), 2.89 (broad doublet, J= 12.4 Hz, 1H), 2.72-2.60 (multiplet, 2H), 2.54-2.49 (multiplet, 1H, partially obscured by solvent for NMR), 2.08 (singlet, 3H), 1.97-1.89 (singlet with overlapping multiplet, 5H), 1.58 (broad doublet, J= 13 Hz, 2H).

Example 20,

(3R*4S*)-6,8-Dimethyl-3-(4-(4-forfinal)-4-hydroxypiperidine - 1-yl)-chroman-4,7-diol.

A mixture of 3-bromo-,8-dimethyl-7-triisopropyl - similarsame-4-it (the compound of Example 19, 0.23 g, 0.54 mmole), 4-(4-forfinal)-4-hydroxypiperidine (0.22 g, 1.12 mmole) and triethylamine (0.3 ml, 2.15 mmole) in acetonitrile (15 ml) was stirred tech. the solid substance was subjected to flash chromatography on silica gel (column size 1x4 inch, 2.H.16 cm, filled in hexane), conducting chromatography according to the following procedure: processing a mixture of 10% ethyl acetate/hexane (100 ml), lack of product; 25% ethyl acetate/hexane (200 ml), 0.065 g (22%) of 6,8-dimethyl-7 - triisopropylsilyl-3-(4-(4-forfinal)-4-hydroxypiperidine-1 - yl)-chromen-4-she has so pl. 226.5-227oC. Elemental analysis for C31H42FNO4. Calculated: C, 68.98; H, 7.84; N, 2.59. Found: C, 69.00; H, 7.94; N Is 2.37. This product was identical to the product selected in the first stage of example 19 and was converted to the target compound using the method of example 19.

Example 21.

(1R*THAT 2R8)-1-(4-Hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4 - phenyl-piperidine-1-yl)-propan-1-ol.

A mixture of 4-benzyloxy - bromo-3-methoxypropiophenone (compound of Preparative example 46, 1.00 g, 2.86 mmole), 4-hydroxy-4-phenylpiperidine (0.60 g, 3.39 mmole) and triethylamine (0.80 ml, 5.74 mmole) in ethanol (30 ml) was heated under reflux for 3.5 hours. The solvent was removed under reduced pressure and the residue was distributed in a mixture of ethyl acetate - water. The phases were separated and the organic layer was washed with brine, dried over sulfate Magadan-1-it is in the form of a light orange foam, which can be used without additional purification and has the following NMR spectrum: 7.76 (double doublet, J= 2, 8.4 Hz, 2H), 7.71 (doublet, J= 2 Hz, 1H), 7.49-7.23 (multiplet, 10H), 6.89 (Doublet, J= 8.4 Hz, 1H), 5.22 (singlet, 2H), 4.16-4.11 (multiplet, 1H), 3.93 (singlet, 3H), 2.94-2.62 (multiplet, 4H), 2.13 (double Quartet, J= 4.3, 12.7 Hz, 2H), 1.78-1.69 (multiplet, 2H), 1.32 (doublet, J= 6.8 Hz, 3H).

A mixture of sodium borohydride (0.10 g, 2.64 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(4-benzyloxy - 3-methoxyphenyl)-2-(4-hydroxy-4-phenyl-piperidine-1-yl)-propane-1-he (1.13 g of 2.54 mmole in 25 ml ethanol). The reaction mixture was stirred over night at ambient temperature. The reaction mixture was cooled with water and concentrated under reduced pressure and a temperature of 40oC. the Residue was distributed in the system ethyl acetate - water. The phases were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to obtain 1.16 g of crude product which is a mixture of (1R*THAT 2R*) and (1R*, 2S*) isomers in a ratio of 5: 1. The resulting mixture was recrystallized from a mixture of ethanol/ether/hexane and then recrystallized from a mixture of ethanol/ether to obtain 0.47 g (41%) of (1R*THAT 2R*)-1-(4-benzo is Alize for C28H33NO4Calculated: C, 75.14; H, 7.43; N, 3.13. Found: C, 75.50; H, 7.33; N, 3.25.

A mixture of the product of the reaction described above (0.40 g, 0.89 mmole) and 10% palladium on coal (0.080 g) in methanol (25 ml) and acetic acid (0.5 ml) was first made at a pressure of 50 lb/in2(3.5 kg/cm2(initial pressure) for 5.5 hours at ambient temperature and then filtered through diatomaceous earth. The filter bed was washed with methanol. The filtrate was concentrated and the residue was distributed in a mixture of ethyl acetate - saturated aqueous solution of bicarbonate. The phases were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The resulting light yellow foam was recrystallized from ethanol to obtain 0.195 g (61%) of (1R*THAT 2R*)-1-(4-hydroxy-3-methoxyphenyl)-2- (4-hydroxy-4-phenyl - piperidine-1-yl)-propan-1-ol as a white solid connections with so 187.5 square-188oC. Elemental analysis for C2H27NO4. Calculated: C, 70.56; H, 7.61; N, 3.92. Found: C, 70.44; H, 8.00; N, 3.78.

Example 22.

(1R*THAT 2R*)-1-(3,4-Dihydroxyphenyl)-2-(4-hydroxy-4-phenyl - piperidine-1-yl)-propan-1-ol.

A mixture of 2-bromo-1-(2,2-diphenyl-benzo(1,3) dioxol - 5-yl)-propane-1-it is connected.04 mmole) in ethanol (50 ml) overnight was heated under reflux. The solvent was removed under reduced pressure and the residue was distributed in the system of the ether - water. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (column size 2x5 inch 5.H.7 cm, filled in hexane), conducting elution as follows: 20% ethyl acetate/hexane (500 ml), was weighed; 50% ethyl acetate/hexane (500 ml), 1.76 g (71%) of 1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-2- (4-hydroxy-4-phenylpiperidine-1-yl)-propane-1-it is in the form of light yellowish-brown foam, which can be used without additional cleaning, having the following NMR spectrum: 7.81 (double doublet, J= 1.7, 8.3 Hz, 1H), 7.70 (doublet, J= 1.6 Hz, 1H), 7.64-7.13 (multiplet, 15H), 6.92 (doublet, J= 8.2 Hz, 1H), 4.07 (Quartet, J= 7.0 Hz, 1H), 3.39-3.27 (multiplet, 1H), 2.94 - 2.59 (multiplet, 3H), 2.30-2.04 (multiplet, 2H), 1.74 (broad triplet, J= 13.2 Hz, 2H), 1.30 (doublet, J= 6.8 Hz, 3H).

A mixture of sodium borohydride (0.15 g, 3.97 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(2,2 - diphenyl-benzo(1,3)dioxan-5-yl)-2-(4-hydroxy-4-phenylpiperidine-1 - yl)-propane-1-he (1.70 g, 3.36 mmole in 20 ml ethanol). The reaction mixture was stirred at ambient temperature over the weekend. Loose white on the t recrystallized from a mixture of ethanol/ether/hexane and then recrystallized from a mixture of ethanol/ethyl acetate/methylene chloride to obtain 1.05 g (61%) of (1R*THAT 2R*)-1-(2,2 - diphenylene(1,3)dioxol-5-yl)-2-(4-hydroxy-4-phenylpiperidine-1 - yl)-propan-1-ol, having so pl. 224-224.5oC. Elemental analysis for C33H33NO4. Calculated: C 78,08; H, 6.55; N, 2.76. Found: C 78.16; H, 6.46; N, 2.72.

A mixture of the product of the reaction described above (1.00 g, 1.97 mmole) and 10% palladium on coal (0.175 g) in methanol (50 ml) and acetic acid (1.0 ml) was first made at a pressure of 50 lb/in2(3.6 kg/cm2) for 5 hours at ambient temperature. Added an additional amount of catalyst (0.18 g) and hydrogenation was continued overnight. The reaction mixture was filtered through diatomaceous earth and the filter bed was washed with methanol. The filtrate was concentrated and the residue was distributed in the system ethyl acetate - saturated aqueous bicarbonate and the mixture was intensively stirred for 1 hour. The phases were separated and the aqueous layer was extracted with ethyl acetate (2x). The combined organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (column size 1x4 inch, 2.H.16 cm), conducting chromatography according to the following procedure: processing a mixture of 20% ethyl acetate/hexane (500 ml), lack of product; 10 is so - and-green solid. The solid is recrystallized from ethanol to obtain (1R*THAT 2R*)--1-(3,4-dihydroxyphenyl)-2-(4 - hydroxy-4-phenyl-piperidine-1-yl)-propan-1-ol in the form of a white solid substance having so pl. 167-168oC. Elemental analysis for C20H25NO40.5 C2H6O. Calculated: C, 68.83; H, 7.70; N, 3.82. Found: C, 68.78; H, 8.05; N, 3.70.

Example 23.

Mesilate (1R*, 2R*)-1-(3-fluoro-4-hydroxyphenyl)-2-(4-hydroxy-4 - phenylpiperidine-1-yl)-propan-1-ol.

A mixture of 3-fluoro-4-triisopropylsilane- - bromopropiophenone (2.0 g, 4.96 mmole), 4-hydroxy-4-phenyl-piperidine (1.1 g, 6.2 mmole) and triethylamine (0.9 ml, 6.5 mmole) in ethanol (25 ml) was heated under reflux for 6.5 hours. The solvent was removed under reduced pressure and the residue was distributed in a mixture of ethyl acetate - water. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (h inch, 2.54 x 15.24 cm, filled in hexane). The reaction product was suirable a mixture of 15% ethyl acetate/hexane to obtain 1.82 g (73%) of 1-(3-fluoro-4-triisopropylchlorosilane)-2- (4-hydroxy-4-phenylpiperidine-1-yl)-propane-1-it is in the form of a yellow oil having the following NMR spectrum: 7.plet, J= 8.5 Hz, 1H), 4.07 (Quartet, J= 7 Hz, 1H), 2.92-2.84 (multiplet, 2H), 2.69-2.64 (multiplet, 2H), 2.23-1.95 (multiplet, 2H), 1.82 -1.70 (multiplet, 2H), 1.38-1.22 (multiplet, 6H), 1.12 (doublet, J= 7 Hz, 18H).

A mixture of sodium borohydride (0.12 g, 3.17 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(3-fluoro-4 - triisopropylchlorosilane)-2-(4-hydroxy-4-phenylpiperidine-1-yl)- propane-1-it (1.41 g, 2.82 mmole in 25 ml ethanol). The reaction mixture was stirred over night at room temperature. The resulting white precipitate was collected by filtration to obtain 0.14 g (10%) of (1R*THAT 2R*)-1-(3-fluoro-4 - triisopropylchlorosilane)-2-(4-hydroxy-4-phenylpiperidine-1-yl)- propan-1-ol, having so pl. 140-141oC. Elemental analysis for C29H44FNO3Si. Calculated: C, 69.42; H, 8.84; N, 2.79. Found: 69.30; H, 9.06; N, 2.84. The filtrate was quickly cooled water and stirred over night. The resulting precipitate was collected, washed with water and dried in the air (1.5 g). This material was recrystallized from ethanol to obtain 0.72 g of additional product resulting in a total output amounted to 0.86 g (61%).

The product of the reaction described above (0.72 g, 1.43 mmole) was dissolved in tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (1.45 ml, 1.45 mm what about the air and then concentrated. To the residue was added ether and water, and after intensive mixing of the collected white solid and the product was air-dried to obtain 0.5 g of free base. The resulting material was transferred into ethanol and was added methansulfonate (0.093 ml, 1.43 mmole). The mixture was concentrated and recrystallized from ethanol to obtain 0.476 g (75%) of (1R*THAT 2R*)-1-(3-fluoro-4-hydroxyphenyl)-2-(4-hydroxy-4 - phenylpiperidine-1-yl)-propan-1-ol nelfinavir with so pl. 198.5 - 199.5oC. Elemental analysis for C20H24FNO3CH4SO3. Calculated: 57,13; H, 6.39; N, 3.17. Found: 57.02; H, 6.45; N, 3.33.

Example 24,

Mesilate (1R*THAT 2R*)-1-(3,5-debtor-4-hydroxyphenyl)-2-(4-hydroxy-4 - phenylpiperidine-1-yl)-propan-1-ol.

A mixture of 3,5-debtor-4-triisopropylsilane- -bromopropiophenone (2.46 g, 5.84 mmole), 4-hydroxy-4-phenyl - piperidine (1.55 g, 8.74 mmole) and triethylamine (1.6 ml, 11.5 mmole) in ethanol (50 ml) was heated under reflux overnight. The solvent was removed under reduced pressure and the residue was distributed in the system ethyl acetate-water. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash chrome is the following method: processing a mixture of 10% ethyl acetate/hexane (250 ml), the lack of product; 10% ethyl acetate/hexane (250 ml) and 20% ethyl acetate/hexane (250 ml) of 1.41 g (47%) of 1-(3,5-debtor-4 - triisopropylchlorosilane)-2-(4-hydroxy-4-phenylpiperidine-1-yl)- propane-1-it is in the form of an orange oil having the following NMR spectrum: 7.73 (long range coupled doublet, J= 9 Hz, 2H), 7.46 (doublet, J= 8.5 Hz, 1H), 7.33 (triplet, J= 7.5 Hz, 2H), 7.27 - 7.21 (multiplet, 1H), 4.00 (Quartet, J= 6.7 Hz, 1H), 2.91 (double triplet, J= 2.5, 13 Hz, 1H), 2.79-2.76 (multiplet, 1H), 2.69-2,60 (multiplet, 2H), 2.19-1.93 (multiplet, 3H), 1.80-1.67 (multiplet, 3H), 1.39-1.27 (multiplet, 6H), 1.10 (doublet, J= 7 Hz, N).

A mixture of sodium borohydride (0.16 g, 4.23 mmole) and ethanol (5 ml) was stirred for 10 minutes and then was added 1-(3,5 - debtor-4-triisopropylchlorosilane)-2-(4-hydroxy - 4-phenylpiperidine-1-yl)-propane-1-he (1.40 g, 2.86 mmole in 20 ml ethanol). The reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture is quickly cooled water and stirred for 4 hours. The resulting white precipitate was collected by filtration and recrystallized from ethanol with the formation of 0.46 g (32%) 1R*THAT 2R*1-(3,5-debtor-4 - triisopropylchlorosilane)- 2-(4-hydroxy-4-phenylpiperidine-1-yl)-propan-1-ol, having the following NMR spectrum: 7.54 (doublet, J= 7.5 Hz, 2H), 7.40 (triplet, J= the years, J= 2.2, 11.7 Hz, 1H), 2.73-2.69 (multiplet, 2H), 2.62-2.51 (multiplet, 2H), 2.30 - 2.06 (multiplet, 2H), 1.90-1.83 (multiplet, 2H), 1.36-1.20 (multiplet, 3H)., 1.10(doublet, J= Hz, D), 0.85 (doublet, J= 6.7 Hz, 3H). Elemental analysis for C29H43F2NO3Si. Calculated: 67.02; H, 8.34; N, 2.69. Found: 66.77; H, 8.58; N, 2.71.

The product of the reaction described above (0.398 g, 0.81 mmole) was dissolved in tetrahydrofuran (13 ml) was added tetrabutylammonium fluoride (0.89 ml, 0.89 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 2 hours at ambient temperature and then concentrated. Added a few drops of a saturated aqueous solution of ammonium chloride and the solvent was removed in a stream of nitrogen. The residue was stirred with saturated aqueous bicarbonate and ethyl acetate and the resulting white solid precipitate was collected and washed with water and ethyl acetate, and then the resulting material was dried to obtain 0.185 g of free base. This free base (0.150 g) suspended in methanol and was added methansulfonate (O. 027 ml, 0.417 mmole). The mixture was filtered, and then concentrated by boiling to a volume of 0.5 ml with addition of ethyl acetate (2 ml). In the cooling and grinding got white crystals, which sabarudin - 1-yl)-propan-1-ol nelfinavir, with so pl. 216-218oC. Elemental analysis for C20H23FNO3CH4SO3. Calculated: C Is At 54.89; H, 5.92; N, 3.05. Found: 54.70; H, 5.90; N, 2.91.

Example 25,

Mesilate (1R*THAT 2R*)-1-(3-methyl-4-hydroxyphenyl)-2-(4-hydroxy-4 - phenyl-piperidine-1-yl)-propan-1-ol.

A mixture of 4-benzyloxy-3-methyl-bromopropiophenone (2.48 g, 7.45 mmole), 4-hydroxy-4-phenylpiperidine (1.1 g, 6.21 mmole) and triethylamine (2.08 ml, 14.9 mmole) in ethanol (17 ml) was heated under reflux for 6 hours. The solvent was removed under reduced pressure and the residue was distributed in the system methylene chloride - water. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (column size 1x4 inch, 2.54 x 10.16 cm, filled in a mixture of 10% ethyl acetate/hexane), conducting chromatography according to the following procedure; processing the mixture of 10% ethyl acetate/hexane (500 ml), lack of product; 20% ethyl acetate/hexane (250 ml), lack of product; 50% ethyl acetate/hexane (400 ml), 2.14 g of crude product. This product was recrystallized from a mixture of ether/hexane to obtain 1.41 g (53%) of 1-(4-benzyloxy-3-were)-2-(4-hydroxy-4-phenylpiperidine-1-yl)-propane-1-it is in the form of TV is -7.20 (multiplet, 10H), 6.92 (doublet, J= 8.5 Hz, 1H), 5.17 (singlet, 2H), 4.14 (Quartet, J= 7 Hz, 1H), 2.95-2.75 (multiplet, 3H), 2.64 (double triplet, J= 2.5, 12hz, 1H), 2.33 (singlet, 3H), 2.22-2.02 (multiplet, 2H), 1.82-1.70 (multiplet, 2H), 1.55 (broad singlet, 1H), 1.33 (doublet, J= 7 Hz, 3H).

A mixture of lithium aluminum hydride (0.246 g, 6.48 mmole) and tetrahydrofuran (45 ml) was cooled to 0oC and immediately added solid 1-(4-benzyloxy-3-were)-2-(4-hydroxy-4 - phenylpiperidine-1-yl)-propane-1-he (1.39 g, 3.24 mmole). The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture is gently and quickly cooled water (0.476 ml) and stirred 4 hours. The suspension was dried over sodium sulfate, filtered through diatomaceous earth and concentrated. The residue was subjected to flash chromatography on silica gel (column size 1x3 inch, 2.H.6 cm, filled in the presence of a mixture of 20% ethyl acetate/hexane), conducting chromatography according to the following procedure: processing a mixture of 20% ethyl acetate/hexane (150 ml), lack of product; 30% ethyl acetate/hexane (250 ml) and 40% ethyl acetate/hexane (250 ml) 0.701 g (50%) 1R*THAT 2R*1-(4-benzyloxy-3 - were)-2-(4-hydroxy-4-phenylpiperidine - 1-yl)-propan-1-ol in the form of a white solid substance having so pl. 162-163oC; NMR spectrum: 7.53-7.26 (m the years, 2H), 4.21 (doublet, J= 9.5 Hz, 1H), 3.08 (symmetric multiplet, 1H), 2.83-2.56 (multiplet, 4H), 2.28 (singlet, 3H), 2.28-2.05 (multiplet, 2H), 1.84 (broad doublet, J= 13.5 Hz, 2H), 1.54 (singlet, 1H), 0.82 (doublet, J= 6.5 Hz, 3H).

The product of the reaction described above (0.69 g, 1.6 mmole) was dissolved in tetrahydrofuran (30 ml) and methanol (30 ml) was added ammonium formate (1.0 g, 16 mmole and 10% palladium on coal (0.15 g). The reaction mixture was stirred for 2 hours at ambient temperature and filtered through diatomaceous earth. The filter layer was washed with ethanol and water. The filtrate was concentrated and the residue was stirred with ethyl acetate and saturated aqueous bicarbonate. The solid precipitate was collected, washed with ether, and dried in air to obtain 0.611 g (100%) 1R*THAT 2R*1-(4-hydroxy-3-were)-2-(4-hydroxy-4-phenylpiperidine - 1-yl)-propan-1-ol as a white solid. This solid was subjected to chromatography on silica gel (column size 1x3 inch, 2.H.6 cm, filled in a mixture of 50% ethyl acetate/hexane), performing a gradient elution starting with a mixture of 50% ethyl acetate/hexane to a mixture of 2% methanol/ethyl acetate. Fractions of product were combined, concentrated and recrystallized from nitromethane to obtain 0.063 g (11.5%) Chistov the N 4.10. Found: 73,60; H, 8.21; N, 4.22. The obtained product was converted into its mesilate salt. This substance is suspended in methanol (few drops) was added methansulfonate (0.010 ml, 0.152 mmole). The resulting mixture was diluted with isopropanol (1 ml) and concentrated to a volume of about 0.25 ml as a result of boiling. Formed upon cooling, the crystals were collected by obtaining mesilate salt in the form of a crystalline white solid (0.053 g) having so pl. 196-197oC.

Example 26.

Mesilate (1R*THAT 2R*)-1-(3,5-dimethyl-4-hydroxyphenyl)-2-(4 - hydroxy-4-phenylpiperidine-1-yl)-propan-1-ol.

A mixture of 4-benzyloxy-3,5-dimethyl - bromo - propiophenone (2,59 g, 7.45 mmole), 4-hydroxy-4-phenylpiperidine (1.1 g, 6.21 mmole) and triethylamine (2.08 ml, 14.9 mmole) in ethanol (15 ml) was heated under reflux for 6 hours. The solvent was removed under reduced pressure and the residue was distributed in the system methylene chloride-water. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (column size 1.5x3.5 inches, 3.8x8.9 cm, filled with 10% ethyl acetate/hexane), conducting elution on sledujuschtschij product; 50% ethyl acetate/hexane (400 ml), 2.16 g (79%) of 1-(4-benzyloxy-3, 5dimethylphenyl)-2-(4-hydroxy-4-phenylpiperidine-1-yl)-propane-1-it is in the form of an orange foam having the following NMR spectrum: 7.82 (singlet, 2H), 7.55-7.21 (multiplet, 10H), 4.87 (singlet, 2H), 4.17 (Quartet, J= Hz, 1H), 2.93-2.78 (multiplet, 3H), 2.66 (double triplet, J= 3.12 Hz, 1H), 2.35 (singlet, 6H), 2.26-2.04 (multiplet, 1.95-1.69 (multiplet, 3H), 1.34 (doublet, J= Hz, 3H). The resulting material contained about 15% of unidentified impurities, but was suitable for further use without additional purification.

A mixture of lithium aluminum hydride (0.257 g, 6.77 mmole) and tetrahydrofuran (45 ml) was cooled to 0oC and immediately added 1- (4-benzyloxy-3, 5dimethylphenyl)-2-(4-hydroxy-4-phenylpiperidine-1 - yl)-propane-1-he (1.50 g, 3.38 mmole). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture is thoroughly cooled by mixing with water (0.487 ml) and was stirred for 4 hours. The suspension was dried in the presence of sodium sulfate, filtered through diatomaceous earth and concentrated. The residue was subjected to flash chromatography on silica gel (column size 1x3 inches, filled with a mixture of 20% ethyl acetate/hexane), conducting chromatography according to the following procedure: 20% utilizer> THAT 2R*1-(4-benzyloxy-3, 5dimethylphenyl)-2-(4-hydroxy-4 - phenylpiperidine-1-yl)-propan-1-ol in the form of a yellow solid having so pl. 133-135oC; NMR spectrum: 7.54-7.48 (multiplet, 4H), 7.47-7.25 (multiplet, 6H), 7.02 (singlet, 2H), 5.23 (singlet, 1H), 4.79 (singlet, 2H), 4.19 (doublet, J= 9.5 Hz, 1H), 3.09 (symmetric multiplet, 1H), 2.81-2.59 (multiplet, 4H), 2.29 (singlet, 6H), 2.30-2.25 (multiplet, 2H), 1.85 (broad doublet, J= 13.5 Hz, 2H), 1.54 (singlet, 1H), 0.84 (doublet, J= 6.5 Hz, 3H).

The product of the reaction described above (1.30 g, 2.92 mmole) was dissolved in tetrahydrofuran (50 ml) and methanol (50 ml) was added ammonium formate (1.8 g, 29 mmole) and 10% palladium on coal (0.3 g). The reaction mixture was stirred for 2 hours at ambient temperature and then filtered through diatomaceous earth. The filtration layer was washed with ethanol and water. The filtrate was concentrated and the residue was distributed in the system containing chloroform, a saturated aqueous solution of bicarbonate and a small amount of acetone. The phases were separated and the organic layer was washed with brine, dried and concentrated to education 0.886 g (86%) 1R*THAT 2R*1-(3,5-dimethyl-4-hydroxyphenyl)-2-(4-hydroxy-4 - phenylpiperidine)-1-yl)-propan-1-ol as a white solid. This product was converted into its m is .52 mmole). The mixture was concentrated and the residue was treated with ether. The remaining solid is recrystallized from isopropanol to obtain 0.273 g (24%) mesilate salt having so pl. 203-204oC. Elemental analysis for C22H29NO3CH3CO30.5 H2O. Calculated: C 59.98; H, 7.44; N, 3.04. Found: 60.10; H 7.63, N 3.13.

Example 27.

1R, 2R 1-(4-Hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenyl - piperidine-1-yl)-propan-1-ol and 1S, 2S 1-(4-hydroxy-3-methoxyphenyl) -2-(4-hydroxy-4-phenyl-piperidine-1-yl)-propan-1-ol.

The product of Example 21 was dissolved in ethanol and separated into its enantiomers by HPLC method (liquid chromatography high resolution) using the following conditions chromatographic separation Column, Hirzel ML; mobile phase; 25% ethanol/75% hexane; ambient temperature (approximately 22oC); detection, UV detector at a wavelength of 215 nm. Under such conditions 1R, 2R 1-(4-hydroxy-3-methoxyphenyl)-2-(4 - hydroxy-4-phenyl-piperidine-1-yl)-propan-1-ol was elyuirovaniya with a retention time of approximately 9.12 min, a 1S, 2S 1-(4-hydroxy-3 - methoxyphenyl)-2-(4-hydroxy-phenyl-piperidine-1-yl)-propan-1-ol was elyuirovaniya with a retention time of approximately 16.26 minutes.

Preparative example 1.

Preparative example 2.

4-Propionyl-2-METHYLPHENOL.

To a mixture of aluminum chloride (51.8 g, 0.388 mmole) and methylene chloride (140 ml) was added chloride propionyl (11.25 ml, 0.129 mol) then was added 2-METHYLPHENOL (7.O g, 64.73 mmole) in methylene chloride (25 ml when washing with 10 ml). The resulting mixture was stirred for 2 hours at ambient temperature and then poured on ice. The phases were separated the Ohm calcium and concentrated on silica gel. The resulting material was subjected to flash chromatography on silica gel (column 3.5x3 inches, 7.6x8.9 cm, conducting chromatography according to the following procedure: treatment with hexane (200 ml), lack of product; 4% ethyl acetate/hexane (1000 ml), lack of product; 8% ethyl acetate/hexane (2000 ml), 8.17 g of 4-propionyl-2 methylenephosphonate in the form of a light yellow oil, having the following NMR spectrum: 7.86 (singlet, 1H), 7.82 (double doublet, J= 2, 8.5 Hz, 1H), 2.98 (Quartet, J= 7 Hz, 2H), 2.65 (Quartet, J= 7.5 Hz, 2H), 2.23 (singlet, 3H), 1.30 (triplet, J= 7.5 Hz, 3H), 1.22 (triplet, J= 7.5 Hz, 3H).

The product of the reaction described above (7.61 g, at 34.57 mmole) was added to a mixture of methanol (100 ml), water (100 ml) and potassium hydroxide (3.88 g, 68.14 mmole) and the resulting mixture was heated for 1.5 hours under reflux. The methanol was removed under reduced pressure and the residue was acidified using 6N model HC1. The aqueous phase was extracted with ethyl acetate. The obtained organic layer was washed with an aqueous solution of bicarbonate, and brine; then it was dried and concentrated to obtain 5.29 g (93%) of 4-propionyl-2 METHYLPHENOL in the form of a white crystalline solid, identical to the material obtained in Preparative example 1.

Preparative example 3,

4 Triisopropylsilyl-3-methylpropiophenone

To SMEs) in dimethylformamide (35 ml) was added chloride triisopropylsilyl (7.44 ml, 34.79 mmole in 15 ml of dimethylformamide with flushing portion 2 ml). The reaction mixture was stirred at ambient temperature for 15 hours, then poured into a mixture of ice with a 1N aqueous solution of lithium chloride. The resulting mixture was extracted with ethyl acetate (3x). The combined organic phase washed with 1 N solution of lithium chloride and brine, dried over calcium sulfate and concentrated to obtain 9.61 g (95%) 4-triisopropylsilyl - 3-methylpropiophenone in the form of a yellow oil, which contained a small amount of impurities silila determined by the NMR method, but which can be used further without additional purification. The resulting product had the following NMR spectrum: 7.80 (doublet, J= 2 Hz, 1H), 7.71 (double doublet, J= 2.5, 8.5 Hz, 1H), 6.80 (Doublet, J= 8.5 Hz, 1H), 2.94 (Quartet, J= 7.5 Hz, 2H), 2.28 (singlet, 3H), 1.33 (symmetric multiplet, 3H), 1.20 (triplet, J= 7.5 Hz, 3H), 1.12 (doublet, J= 7 Hz, N).

Preparative example 4.

4-Benzyloxy-3-methylpropiophenone.

A mixture of benzyl bromide (4.44 ml, 37.34 mmole), potassium carbonate (9.38 g, 67.88 mmole) and 4-propionyl - 2 METHYLPHENOL (compound of Preparative examples 1 and 2, 5.57 g, 33.94 mmole) in acetone (100 ml) was stirred at ambient temperature sty methylene. The phases were separated and the organic phase was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (column 2 & 4 inch, 5.H.16 cm). Conducting chromatography according to the following procedure: processing a mixture of 5% ethyl acetate/hexane (300 ml), head wrap, which was thrown out; 5% ethyl acetate/hexane (500 ml) and 10% ethyl acetate/hexane (600 ml), 8.03 g (93%) of 4-benzyloxy-3-methylpropiophenone in the form of a white crystalline solid, having the following NMR spectrum: 7.83-7.78 (multiplet; 2H), 7.48-7.31 (multiplet, 5H), 6.89 (doublet, J= 8gts, 1H), 5.14 (singlet, 2H), 2.94 (Quartet, J= 7.5 Hz, 2H), 2,31 (singlet, 3H), 1.20 (triplet, J= 7.5 Hz, 3H). The resulting material can be used without additional purification.

Preparative example 5.

4-Benzyloxy-3-methyl-bromopropiophenone.

To a mixture of 4-benzyloxy-3-methylpropiophenone (compound of Preparative example 4, 7.89 g, 31.06 mmole) in carbon tetrachloride (80 ml) was added precapitalism bromide (1.63 ml, 31.68 mmole in 20 ml of carbon tetrachloride with flushing 5 ml) and the characteristic bromine color almost disappeared in contact with the reaction solution. The reaction mixture was stirred for 15 minutes at a temperature ocrt. The phases were separated and the organic layer was washed with an aqueous solution of bicarbonate and brine. The organic layer was dried over calcium sulfate and concentrated to obtain 10.29 g (99.5%) of the desired product as light yellowish-brown solid having so pl. 88.5-89.5oC, suitable for further use without additional processing.

Preparative example 6.

4 Triisopropylsilane-3-methyl-bromopropiophenone.

To a solution of 4-triisopropylsilyl-3-methylpropiophenone (compound of Preparative example 3, 9.35 g, 29.19 mmole) in carbon tetrachloride (100 ml) was bury bromide (1.53 ml, 29.77 mmole in 20 ml of carbon tetrachloride) and characteristic of the bromine color disappeared in contact with the reaction solution. The reaction mixture was stirred for 15 minutes, was added an aqueous solution bisulfate, and the mixture was stirred for 15 minutes. The phases were separated and the organic layer was washed with an aqueous solution of bicarbonate and brine. The organic layer was dried over calcium sulfate and concentrated to obtain 11.65 g (100%) 4-triisopropylsilyl-3-methyl-bromopropiophenone in the form of a light yellow oil, having the following NMR spectrum: 7.86 (doublet, J= 2 Hz, the C, 3H), 1.42-1.27 (multiplet, 3H), 1.13 (doublet, J= 7 Hz, 18H). The resulting material can be used without additional purification.

Preparative example 7.

4-Propionyl-2-terfenol.

To a mixture of aluminum chloride (45.8 g, 0.343 mol) in methylene chloride (140 ml) was added propionyl chloride (10.85 ml, 124.9 mmole) and immediately after this was added 2-terfenol (5.57 ml, 62.44 mmole in 25 ml of methylene chloride with flushing portion 10 ml). The resulting mixture was gently heated for 5 hours under reflux, cooled to ambient temperature and poured on ice. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with an aqueous solution of bicarbonate and brine. The organic layer was dried over calcium sulfate and concentrated to obtain 11.43 g (82%) of 4-propionyl-2-forfinal propionate in the form of a transparent yellowish - brown oil, which was used without characterizing.

The product of the reaction described above (10.76 g, 48.01 mmole) was added to a mixture of methanol (125 ml), water (125 ml) and potassium hydroxide (5.39 g, 56.11 mmole). The reaction mixture was heated under reflux for 2 hours, cooled and the methanol was removed under reduced with davleniya bicarbonate, and brine, dried over calcium sulfate and concentrated to education yellowish-brown solid. This yellowish-brown residue was subjected to flash chromatography on silica gel (column size 2x3 inch 5.H.62 cm, filled in hexane), conducting chromatography according to the following procedure: processing a mixture of 5% ethyl acetate/hexane (800 ml) head fraction, which was thrown out; 10% ethyl acetate/hexane (500 ml), lack of product; 25% ethyl acetate/hexane (1000 ml), 5.56 g (69%) of 4-propionyl-2 terfenol in the form of a white solid substance having so pl. 104-106oC; NMR spectrum: 7.74 (double doublet, J= 2, 9.5 Hz, 1H), 7.71 - 7.68 (multiplet, 1H), 7.05 (triplet, J= 8.5 Hz, 1H), 5.82 (broad singlet, 1H), 2.93 (Quartet, J= 7.5 Hz, 2H), 1.20 (triplet, J= Hz, 3H).

Preparative example 8.

4-Propionyl-2-terfenol.

A mixture of 4-bromo-2-terfenol (1.0 g, 5.24 mmole) in tetrahydrofuran (15 ml) was cooled to -78oC and quickly bury utility (4.6 ml, 11.5 mmole, 2.5 M solution). The reaction mixture was stirred for 12 minutes and was added N-methyl-N - methoxypropionate (compound of Preparative example 9, 0.735 g, 6.28 mmole in 1 ml of tetrahydrofuran with flushing portion 1 ml). The reaction mixture was stirred for 5 minutes at -78oC and then e under reduced pressure. The residue was transferred into methylene chloride and washed with an aqueous solution of ammonium chloride and brine. The organic layer was dried and concentrated. The residue was subjected to flash chromatography on silica gel (column size 1x2.5 inch 2.H.35 cm, filled in hexane), conducting chromatography according to the following procedure: processing a mixture of 10% ethyl acetate/hexane (250 ml), the parent faction, which was thrown out; 20% ethyl acetate/hexane (250 ml), 0.186 g of a yellow crystalline solid, having an NMR spectrum, identical to those given in Preparative example 7.

Preparative example 9.

N-Methyl-N-methoxypropionate.

A mixture of 11.0-dimethyl hydroxylamine hydrochloride (4.43 g, 45.39 mmole) and triethylamine (6.93 ml, 49.71 mmole) in methylene chloride (150 ml) was cooled to 0oC and bury chloride propionyl (3.76 ml, 43.23 mmole in 25 ml of methylene chloride with flushing portion 25 ml). The reaction mixture was allowed to warm to ambient temperature and was stirred over the weekend. The reaction mixture was extracted with water and brine, dried and concentrated to obtain 3.08 g (61%) of N - methyl-N-methoxypropylamine in the form of a yellow oil having the following NMR spectrum: 3.66 (singlet, 3H), 3.16 (singlet, 3 is tough.

Preparative example.10.

4 Triisopropylsilane-3-forpromotion.

A mixture of 4-propionyl-2 terfenol (compound of Preparative example 7, 5.44 g, 32.37 mmole), imidazole (4.41 g, 64.74 mmole) and triisopropylsilyl chloride (7.62 ml, 35.60 mmole) in dimethylformamide (55 ml) was stirred for 15 hours at ambient temperature. The reaction mixture was poured into a mixture of ice with a 1N aqueous solution of lithium chloride. The resulting mixture was extracted with ethyl acetate (3x). The combined organic phase was washed 1N solution of lithium chloride and brine, dried over calcium sulfate and concentrated to obtain 10.5 g (100%) 4-triisopropylsilyl-3-forpromotion in the form of a yellow oil having the following NMR spectrum: 7.75-7.60 (multiplet, 2H), 6.95 (triplet, J= 8 Hz, 1H), 2.92 (Quartet, J= 7 Hz, 2H), 1.25 (symmetric multiplet, 3H), 1.19 (triplet, J= 7.5 Hz, 3H), 1.09 (doublet, J= 7 Hz, N). The resulting material can be used without additional purification.

Preparative example 11.

4 Triisopropylsilane-3-fluoro - bromopropiophenone.

To a solution of 4-triisopropylsilane-3-forpromotion (compound of Preparative example 10, 10.27 g, 31.67 mmole) in carbon tetrachloride (110 ml) prokopiv is how many drops of bromine, a typical solution of bromine solution did not disappear. To initiate the reaction was added one drop of 48% HBr and the resulting mixture was stirred for 5 minutes until the colour disappears. Then bury the residue of a solution of bromine). The resulting mixture was stirred for 15 minutes; then added an aqueous solution of the bisulfite and the reaction mixture was stirred for 15 minutes. The phases were separated and the organic layer was washed with an aqueous solution of bicarbonate and brine. The organic layer was dried over calcium sulfate and concentrated to obtain 11.68 g (91%) 4-triisopropylsilyl-3-fluoro - bromopropiophenone in the form of a yellow oil having the following NMR spectrum: 7.80-7.69 (multiplet, 2H), 6.99 (triplet, J= 8.5 Hz, 1H), 5.20 (Quartet, J=6. 5 Hz, 1H), 1.89 (doublet, J= 6.5 Hz, 3H), 1.28 (symmetric multiplet, 3H), 1.12 (doublet, J= 7 Hz, N). This product can be used further without additional purification.

Preparative example 12.

2.6-Dichloro-4-propenilfenola.

A mixture of 2.6-dichlorophenol (10.10 g, 61.96 mmole) and propionic acid (3.34 ml, 62.58 mmole) in triftoratsetata (50 g) in 24 hours was heated up to 80oC. the Reaction solution was cooled to ambient temperature, poured on ice and the former is om, was dried and concentrated to obtain 8.90 g (66%) of 2,6-dichloro-4-propylaniline in the form of a yellowish-brown solid having so pl. 50-52oC. an NMR Spectrum: 7.89 (singlet, 2H), 6.29 (singlet, 1H), 2.91 (Quartet, J= 7 Hz, 2H), 1.20 (triplet, J= 7 Hz, 3H). The resulting material can be used without additional purification.

Preparative example 13.

3,5-Dichloro-4-triisopropylchlorosilane.

A mixture of 2,6-dichloro-4-propylaniline (compound of Preparative example 12, 8.67 g, 39.59 mmole), imidazole (5.39 g, 79.18 mmole) and chloride triisopropylsilyl (9.32 ml, at 43.56 mmole) in dimethylformamide (90 ml) was stirred for 15 hours at ambient temperature. The reaction mixture was poured into a mixture of ice with a 1N aqueous solution of lithium chloride. The resulting mixture was extracted with ethyl acetate (3x). The combined organic phase was washed 1N solution of lithium chloride and brine, dried over sulfatase calcium and concentrated. The residue was subjected to rapid thin-layer chromatography on silica gel (column size 3x3 inch, 7.H.62 cm, filled in hexane), conducting chromatography according to the following procedure: hexane (200 ml), lack of product; 2% ethyl acetate/hexane (400 ml); the absence of the product; 5 the CSO solids. This material was subjected to distillation on a Kugelrohr at a residual pressure of 1.5 mm RT.article and collected the following fraction: 70oC (the temperature of boiling cube), head wrap, which was rejected; 130oC cast head wrap; 150-170, 3.84 g (26%) of 3,5-dichloro - 4-triisopropylchlorosilane in the form of a white solid containing a small amount of impurities, which was established by NMR, however this substance can be used without additional purification. The sample subjected to another distillation on a Kugelrohr had so pl. 74-76oC; NMR spectrum: 7.98 (singlet, 2H), 2.92 (Quartet, J= Hz, 2H), 1.45 (symmetric multiplet, 3H), 1.21 (triplet, J= 7 Hz, 3H), 1.14 (doublet, J= 7.5 Hz, N).

Preparative example 14.

3,5-Dichloro-4-triisopropylsilane- -bromopropiophenone.

To a solution of 3,5-dichloro-4-triisopropylchlorosilane (compound of Preparative example 13, 3.84 g, 10.23 mmole) in carbon tetrachloride (45 ml) was bury bromine (0.54 ml, 10.48 mmole in 5 ml of carbon tetrachloride). After adding the first few drops of bromine solution added was stopped prior to the initiation of the reaction, as judged by the disappearance of the red color of the solution. Then add a solution of bromine aqueous solution of bisulfite and the mixture was stirred for another 1.5 hours. There was division of the layers and the organic phase was washed with an aqueous solution of bicarbonate and brine. The organic layer was dried over sulfatase magnesium and concentrated to obtain 4.88 g (100%) of 3,5-dichloro-4 - triisopropylsilane- -bromopropiophenone in the form of a pale yellow oil having the following NMR spectrum: 7.95 (singlet, 2H), 5.15 (Quartet, J= 6.7 Hz, 1H), 1.89 (doublet, J= 6.7 Hz, 3H), 1.53-1.42 (multiplet, 3H), 1.15 (doublet, J= 7.4 Hz, N). Shows an NMR spectrum also indicates the presence of small amounts of impurities, however, the product can be used without additional purification.

Preparative example 15.

2,6-Dimethyl-4-propenilfenola.

To a mixture of aluminum chloride (32.0 g, 24 mmole) in methylene chloride (100 ml) was added chloride propionyl (3.56 ml, 20.95 mmole) and then within 5 minutes was added 2,6 - dimethylphenol (5.0 g, 40.93 mmole in 25 ml of methylene chloride). After stirring for 1 hour at ambient temperature was added a second equivalent of chloride propionyl (3.56 ml). The reaction mixture was stirred for 2 hours and then carefully cooled water. The mixture was extracted with ether (3x) and the combined organic phase was washed with an aqueous solution of bicarbonate and brine pinifer propionate in the form of a waxy yellowish brown solid, having the following NMR spectrum: 7.68 (singlet, 2H), 2.95 (Quartet, J= 7.3 Hz, 2H), 2.65 (Quartet, J= 7.5 Hz, 2H), 2.19 (singlet, 6H), 1.32 (triplet, J= 7.6 Hz, 3H), 1.20 (triplet, J= 7.3 Hz, 3H). This product also contained a small amount of impurities according to the NMR spectrum, however, it has been found that such a product can be used without additional purification.

The product of the reaction described above (8.18 g, 34.91 mmole) was added to a mixture of methanol (100 ml), water (100 ml) and potassium hydroxide (3.9 g, 69.5 mmole) and the reaction mixture was heated under reflux for 1 hour. The methanol was removed under reduced pressure and the residue was acidified to pH 4 with 6N HCl. The aqueous phase was extracted with ether. The organic layer was washed with an aqueous solution of bicarbonate (2x), dried over magnesium sulfate and concentrated to obtain 5.4 g (87%) of 2,6-dimethyl-4 - propylaniline in the form of a waxy yellowish-brown solid having the following NMR spectrum: 7.65 (singlet, 2H), 5.47 (singlet, 1H), 2.94 (Quartet, J= 7.3 Hz, 2H), 2.30 (singlet, 6H), 1.21 (triplet, J= 7.3 Hz, 3H).

Preparative example 16.

2,6-Dimethyl-4-propenilfenola.

A mixture of 2,6-dimethylphenol (10.5 g, 85,95 mmole), propionic acid (4.64 ml, 86.81 mmole) and cripto who was agarawala chloroform and the organic phase was washed with an aqueous solution of bicarbonate and brine. The organic layer was dried and concentrated to a state dark orange oily solid. The residue was subjected to distillation on a Kugelrohr at a residual pressure of 1.5 mm RT.article and collected the following fractions: 23-105oC (the temperature of the cube), head wrap, which was rejected; 105-135oC, 11.2 g (73%) of 2,6-dimethyl-4 - propylaniline in the form of a yellowish-white solid, having an NMR spectrum identical to the spectrum given in Preparative example 15.

Preparative example 17.

3,5-Dimethyl-4-triisopropylchlorosilane.

A mixture of 2,6-dimethyl-4-propylaniline (compound of Preparative example 15, 16.30 g, 16.83 mmole), imidazole (2.3 g, 33.8 mmole) and triisopropylsilyl chloride (4.0 ml, 18.7 mmole) in dimethylformamide (30 ml) was stirred overnight at ambient temperature. The reaction mixture was poured on ice and extracted with ether. The organic phase is washed with 1N lithium chloride (2x), water and brine; then the resulting solution was dried over magnesium sulfate and concentrated to obtain 5.62 g (100%) of 3,5-dimethyl-4-triisopropylchlorosilane in the form of a yellow solid having so pl. 87-88.5oC; NMR spectrum: 7.62 (singlet, 2H), 2.94 (Quartet, J= 7.2 s ' example 18.

3,5-Dimethyl-4-triisopropylsilane- -bromopyrene.

To a solution of 3.5-dimethyl-4-triisopropylchlorosilane (compound of Preparative example 17, 5.50 g, 16,44 mmole) in carbon tetrachloride (60 ml) was bury bromide (0.87 g, 16.89 mmole in 15 ml of carbon tetrachloride). After adding the first few drops of a solution of bromine addition was discontinued prior to initiation of the reaction, as evidenced by the disappearance of the red color of the solution. Then add a solution of bromine was resumed (total time add 20 min). The reaction mixture was stirred for 30 minutes, then was added an aqueous solution of bicarbonate and the resulting mixture was stirred for 1 hour. The layers were separated and the organic phase was washed with an aqueous solution of bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated to obtain 7.0 g (100%) of 3,5-dimethyl-4-triisopropylsilane- -bromopropiophenone in the form of an orange solid having the following NMR spectrum: 7.68 (singlet, 2H), 5.28 (Quartet, J= 6.6 Hz, 1H), 2.31 (singlet, 6H), 1.88 (doublet, J= 6.6 Hz, 3H), 1.38-1.27 (multiplet, 3H), 1.13 (doublet, J= 7.2 Hz, N); range13C - NMR: 192.66, 158.87, 132.77, 130.18, 128.61, 126.88, 41.52, 20.40, 18.07, 17.94, 17.70, 14.26, 12.29.

Preparative example 19.

Preparative example 20.

3,5-Debtor-4-triisopropylsilane- -bromopropiophenone.

To a mixture of 3,5-debtor-4-triisopropylchlorosilane (compound of Preparative example 19, 3.0 g, 8.76 mmole) in carbon tetrachloride (35 ml) was bury bromine (0.46 ml, 8.93 mmole in 5 ml of carbon tetrachloride). After adding the first few drops of a solution of bromine added was stopped, waiting for the initiation of synthesized. After 5 minutes was added 1 drop of 48% HBr. If after 5 minutes b is Ali the remaining solution of bromine (20 minutes). The reaction mixture was stirred for 15 minutes and then was added an aqueous solution bisulfate, after which the mixture was stirred for another 30 minutes. The phases were separated and the organic layer was washed with water, aqueous bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and concentrated to obtain 3.26 g (88%) of 3,5-debtor-4-triisopropylsilane- -bromopropiophenone in the form of a white solid having the following NMR spectrum: 7.58 (long interval paired double doublet, J= 1.3, 7.3 Hz, 2H), 5.14 (Quartet, J= 6.7 Hz, 1H), 1.89 (doublet, J= 6.5 Hz, 3H), 1.36-1.20 (multiplet, 3H), 1.11 (doublet, J= 7.4 Hz, N); range13C NMR 190.50, 156.16, 156.09, 152.88, 152.81, 125.99, 113.05, 112.91, 112.82, 112.71, 40.75, 20.05, 17.16, 12.90.

Preparative example 21.

3,5-Debtor-4-benzyloxypropionic.

A mixture of 2,6-debtor-4-propylaniline (Indian Chemicals company, Inc. , P. O. Box 473, Somervil, new Jersey, 08876, USA, 2.5 g, 13.43 mmole), potassium carbonate (3.7 g, 26.8 mmole) and benzyl bromide (1.75 ml, 14.71 mmole) in acetone (40 ml) was stirred overnight at ambient temperature. The resulting mixture was concentrated under reduced pressure and the residue was distributed in a mixture of ether - water. The phases were separated and the organic phase was washed wok was treated with hexane to obtain 1.40 g of the product. The mother liquor was subjected to rapid chromatography on silica gel (column size 1x4 inch, 2,h,16 cm), conducting chromatography according to the following procedure: hexane (200 ml), unweighted benzyl bromide; 20% ethyl acetate/hexane (150 ml), 0.38 g of the product. In the same way received 1.78 g (48%) of 3,5-debtor-4 - benzyloxypropionic in the form of a white solid substance having the following NMR spectrum: 7.56-7.32 (multiplet, 7H), 5.30 (singlet, 2H), 2.91 (Quartet,

J= 7.2 Hz, 2H), 1.21 (triplet, J= 7.1 Hz, 3H).

Preparative example 22.

3,5-Debtor-4-benzyloxy- -bromopropiophenone.

To a solution of 3,5-debtor-4-benzyloxypropionic (compound of Preparative example 21, 1.78 g, 6.44 mmole) in carbon tetrachloride (25 ml) was bury bromine (0.34 ml, 6.60 mmole in 5 ml of carbon tetrachloride). After adding the first few drops of a solution of bromine further addition was suspended prior to the initiation of the reaction, as evidenced by the disappearance of the red color of the solution. Then add a solution of bromine was resumed (total time add 15 min). The reaction mixture was stirred for 1 hour, then was concentrated in a stream of nitrogen. The residue was transferred into ether and washed with an aqueous solution bisulfate, aqueous rest and- - bromopropiophenone in the form of a yellowish oil having the following NMR spectrum: 7.58 (doublet, J = 9 Hz, 2H), 7.47-7.32 (multiplet, 5H), 5.33 (singlet, 2H), 5.11 (Quartet, J= 6.6 Hz, 1H), 1.88 (doublet, J= 6.6 Hz, 3H). According to the NMR spectrum, the product also contained a small amount of substance, however, it was found that the product is suitable for further use without additional purification.

Preparative example 23.

2-Acetoxy-2,6-dimethyl-3,4,5,6-cyclohexadiene-1-it.

To the suspension leads to compounds, which lead (20.0 g, 45.1 mmole) in acetic acid (33 ml) was added 2,6-dimethylphenol, (5.00 g, 40.93 mmole in 27 ml of acetic acid) by the addition over 15 minutes. The reaction mixture was stirred for 2 hours at ambient temperature and gradually formed a homogeneous yellow solution. The resulting mixture was diluted with water and was extracted with chloroform (3x). The combined organic layer was washed with water and brine, dried over calcium sulfate and concentrated to formation of a yellow oil. The residue was subjected to distillation on a Kugelrohr at a residual pressure of 0.4 mm RT.article The material distilled at a temperature of cube 75-85oC (5.69 g) was collected as a yellow oil. The sample in the amount of 3.2 g dopolnitelna chromatography according to the following procedure: hexane (500 ml), the absence of the product; 5% ether/hexane (500 ml) and 10% ether/hexane (250 ml), 1.89 g of 2-acetoxy-2.6 - dimethyl-3,4,5,6-cyclohexadiene-1-it is in the form of bright yellow waxy solid having the following NMR spectrum: 6.80-6.76 (multiplet, 2H), 6.19-6.09 (multiplet, 4H), 2.05 (singlet, 3H), 1.92 (doublet, J= 0.8 Hz, 3H), 1,36 (singlet, 3H).

Preparative example 24.

1,3-Diacetoxy-2,4-xylene.

A mixture of 2-acetoxy-2,6-dimethyl-3,4,5,6-cyclohexadiene-1-she (the compound of Preparative example 23, 0.5 g, 2.77 mmole) in acetic anhydride (1 ml) was cooled to 0oC and added slowly Prilepa on the wall of the bulb apirat boron TRIFLUORIDE (0.075 ml). The reaction mixture was stirred at 0oC for 15 minutes, then the mixture was heated to ambient temperature and was stirred for 1 hour. Was added an aqueous solution of bicarbonate and the mixture was intensively stirred for 30 minutes. The reaction mixture was extracted with ether. The organic phase was washed with brine, dried over magnesium sulfate and concentrated with the formation of 0.59 g (97%) of 1,3-diacetoxy-2,4-xylene in the form of a light yellow oil, having the following NMR spectrum: 7.08 (doublet, J= 8.2 Hz, 1H), 6.87 in (doublet, J= 8.2 Hz, 1H), 2.35 (singlet, 3H), 2.32 (singlet, 3H), 2.15 (singlet, 3H), 1.98 (Singh is lithium aluminum hydride (0.56 g, of 14.76 mmole) in ether (35 ml) was added 1,3-diacetoxy-2,4-xylene (compound of Preparative example 24, of 1.65 g, 7.42 mmole in 40 ml of ether) with a syringe. The resulting mixture was stirred over night; then gently cooled by decahydrate sodium sulfate (excess). The resulting mixture was dried with anhydrous sodium sulfate, filtered and concentrated to obtain 0.62 g (62%) of 1,3-dihydroxy-2,4-xylene in the form of a waxy pale yellow solid having the following NMR spectrum; 6.83 (doublet, J= 8 Hz, 1H), 6.34 (doublet, J= 8.1 Hz, 1H), 4.71 (singlet, 2H), 2.19 (singlet, 3H), 2.17 (singlet, 3H). The product obtained according to the NMR also contained a small amount of impurities, however, it was found that the product can be used without additional purification. The resulting product is somewhat sensitive to the action of air and must be used on the day of fusion.

Preparative example 26.

6,8-Dimethyl-7-hydroxychromone-4-one.

A mixture consisting of 1,3-dihydroxy-2,4-xylene (compound of Preparative example 25, and 0.62 g, 4.49 mmole), 3 - chloropropionic acid (0.49 g, 4.52 mmole) and triftoratsetata (2 ml) was heated for 2.25 hours at 80oC .Reactionary see the back extraction with ether. The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated to obtain 2,4-dihydroxy-3,5 - dimethyl - chloropropiophenone in the form of a red oil.

The product of the reaction described above was added to 50 ml of 2N sodium hydroxide solution, which was pre-cooled to 0oC. the resulting mixture was stirred for 2 hours, then acidified to pH 1-2 with 6N HCl and extracted with ethyl acetate (3x). The combined organic phase was washed with an aqueous solution of bicarbonate and brine, dried over magnesium sulfate and concentrated with the formation of 0.55 g (64% in two stages) of 6,8 - dimethyl-7-hydroxychromone-4-it is in the form of an orange solid having the following NMR spectrum: 7.59 (singlet, 1H), 5.45 (singlet, 1H), 4.52 (triplet, J= 6.4 Hz, 2H), 2.74 (triplet, J= 6.4 Hz, 2H), 2.22 (singlet, 3H), 2.13 (singlet, 3H).

Preparative example 27.

6,8-Dimethyl-7-chemoprophylaxis-4-one.

A mixture of 6.8-dimethyl-7-hydroxychromone-4-it (the compound of Preparative example 26, 0.50 g, 2.60 mmole), imidazole (0.35 g, 5.14 mmole) and triisopropylsilyl chloride (0.61 ml, 2.85 mmole) in dimethylformamide (10 ml) was stirred at ambient temperature overnight. The reaction mixture was diluted in the brine, was dried over magnesium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (column size 1x4 inch, 2.H.16 cm, filled in hexane), conducting elution as follows: 5% ethyl acetate/hexane (100 ml), lack of product; 5% ethyl acetate/hexane (100 ml) and 10% ethyl acetate/ hexane (150 ml), 0.529 g (58%) of 6,8-dimethyl-7-triisopropylchlorosilane-4-it is in the form of waxy lemon-yellow solid having the following NMR spectrum: 7.57 (singlet, 1H), 4.52 (triplet, J= 6.4 Hz, 2H), 2.74 (triplet, J= 6.4 Hz, 2H), 2.21 (singlet, 3H), 2.11 (singlet, 3H), 1.40-1.26 (multiplet, 3H), 1.13 (doublet, J= 7.2 Hz, N). Range13WITH NMR: 191.60, 160.25, 159.93, 125,91, 122.55, 116.15, 115.29, 67.24, 37.52, 17.91, 17.69, 17.38, 14.24, 12.28, 9.97.

The NMR spectrum of this compound was found a small amount of silyl impurity in an amount of 1.06 h/million, however it has been found that such a product can be used for further transformation without further purification.

Preparative example 28.

3,3-Dibromo-6,8-dimethyl-7-triisopropylchlorosilane-4-one.

To a solution of 6,8-dimethyl-7-triisopropylchlorosilane-4-it (the compound of Preparative example 27, 0.50 g, 1.43 mmole) in carbon tetrachloride (10 ml) was bury bromine is ur ambient air, then added an aqueous solution of bicarbonate and the resulting mixture was stirred for another 30 minutes. The phases were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated to obtain 0.64 g (89%) of 3,3-dibromo-6,8 - dimethyl-7-triisopropylchlorosilane-4-it is in the form of an orange solid having the following NMR spectrum: 7.64 (singlet, 1H), 4.68 (singlet, 2H), 2.22 (singlet, 3H), 2.13 (singlet, 3H), 1.38-1.15 (multiplet, 3H), 1.11 (doublet, J =7.3 Hz, 18H). B NMR spectrum was observed the presence of small amounts of impurities. However, the resulting material is suitable for further use without additional purification.

Preparative example 29.

6-Fluoro-7-hydroxychromone-4-one.

A mixture of 1,3-dimethoxybenzene (3.80 ml, 29.0 mmole) and N - ftordezoksianalogov (4.21 g, 29.21 mmole) was heated at 60oC during the night. The mixture was cooled and subjected to rapid chromatography on silica gel (column 2x5 inch 5.H.7 cm, filled in hexane), conducting chromatography according to the following procedure: 3% ethyl acetate/hexane (1000 ml), discarded head wrap; 3% ethyl acetate/hexane (1000 ml) 2.69 g of a mixture in the ratio 2:1, 2.4-dimethoxyphenol and the source material that directly ispolzovanm (11 ml) and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was concentrated and subjected to rapid chromatography on silica gel (column size 2x5 inches, 5.08 x 12.7 cm, filled in hexane), conducting elution as follows: 10% ethyl acetate/hexane (2000 ml), 0.95 g (43%) of 2,4-dihydroxybenzene in the form of a waxy white solid, which was used without further purification.

A mixture consisting of 2,4-dihydroxybenzene (0.15 g, 1.17 mmole) 3-chloropropionic acid (0.13 g, 1.20 mmole) and triftoratsetata (1 ml) was heated for 3 hours to 80oC. the Reaction mixture was poured into water and was extracted with ether (3x). The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated with the formation of 2,4-dihydroxy-5-fluoro - chloropropiophenone in the form of a red solid having the following NMR spectrum: 7.37 (doublet, J= 10.8 Hz, 1H), 6.54 (doublet, J= 7.7 Hz, 1H), 3.87 (triplet, J= 6.8 Hz, 2H), 3.33 (triplet, J= 6.8 Hz, 2H). The resulting product still contained some residual 3-chloropropionic acid, but was suitable for use in subsequent reactions.

The product of the reaction described above was combined with 2N sodium hydroxide solution (15 ml) and was stirred for necrovile with ethyl acetate (3x). The combined organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (column size 1x4 inch, 2.54 x 10.16 cm, filled in hexane), conducting elution as follows: 25% ethyl acetate/hexane (300 ml), lack of product; 25% ethyl acetate/hexane (200 ml), 0.11 g (52% for the last two stages) of 6-fluoro-7-hydroxychromone-4-it is in the form of a white solid substance having so pl. 222-223oC. an NMR Spectrum; 7.61 (doublet, J= 10.3 Hz, 1H), 6.58.(doublet, J= 7.2 Hz, 1H), 5.70-5.58 (multiplet, 1H), 4.51 (triplet, J= 6.5 Hz, 2H), 2.77 (triplet, J= 6.4 Hz, 2H).

Preparative example 30.

Fluoro-7-benzisoxazole-4-one.

A mixture of 6-fluoro-7-hydroxychromone-4-it (the compound of Preparative example 29, 0.93 g, 5.11 mmole), benzyl bromide (0.61 ml, 5.13 mmole), potassium carbonate (1.41 g, 10.2 mmole) in acetone (100 ml) was stirred overnight at ambient temperature. The mixture was cooled, filtered and concentrated to education yellow solid. This residue was recrystallized from ethyl acetate/ether to obtain 1.02 g (73%) of 6-fluoro-7-benzisoxazole-4-it is in the form of two batches of creamy white crystals having so shall reply, J= 6.4 Hz, 2H), 2.75 (triplet, J= 6.4 Hz, 2H). Elemental analysis for C16H13FO2. Calculated: C, 70.58; H, 4.81. Found: C, 70.45; H 4.80.

Preparative example 31.

3,3-Dibromo-6-fluoro-7-benzisoxazole-4-one.

To a mixture of 6-fluoro-7-benzisoxazole-4-it (the compound of Preparative example 30, 0.99 g, 3.64 mmole) in carbon tetrachloride (45 ml) was bury bromine (0.37 ml, 7.18 mmole in 5 ml of carbon tetrachloride). The reaction mixture was stirred over night at room temperature. In the reaction mixture were added water and 87 mg unidentified pink solid was collected by filtration and was thrown out. The phases were separated in the solution of the filtrate and the organic layer was washed with water, aqueous bicarbonate solution and brine, dried over magnesium sulfate and concentrated to obtain, sensitive to the effects of air, the oil that was a mixture of products synthesized and original material (0.93 g). This material was combined with ethyl acetate (100 ml) was added copper bromide (0.6 g, 2.69 mmole) and then the mixture was heated for 4 hours under reflux. Added copper bromide (0.6 g, 2.69 mmole) again and the reaction was continued during the night when heated with reverse Ho is washed with water and brine, was dried over magnesium sulfate and concentrated to obtain 0.91 g of a mixture of 3,3-dibromo-6-fluoro-7-benzisoxazole-4-it products and comprehensive, synthesized. Key distinctive features of the NMR spectrum are signals 7.69 (triplet, J= 9.3 Hz), 7.63-7.32 (multiplet, ), 6.62 (pair of doublets, J= 5.7 and 7 Hz), 5.19 (singlet), 4.70 (singlet). The resulting material was used in crude form for the experiments on the reaction of the combination.

Preparative example 32.

6-Methyl-7-hydroxychromone-4-one.

A mixture consisting of 1,3-dihydroxy-4-methylbenzene (5.0 g, 40.3 mmole), 3-chloropropionic acid (4.38 g, 40,36 mmole) and triftoratsetata (20 g) was heated overnight to 80oC. the Reaction mixture was poured into water and was extracted with a mixture of ether/ethyl acetate sootnoshenii:1 (2x). The combined organic phase was washed with water (2x) and brine, dried over magnesium sulfate and concentrated to education orange resin (7.6 g).

The resin obtained in the reaction described above was combined with 2H sodium hydroxide solution (200 ml) and heated overnight under reflux. The resulting mixture was acidified to pH 1-2 with 6NHCl and was extracted with ethyl acetate (3x). United organicheskoi magnesium and concentrated. The residue was subjected to rapid chromatography on silica gel (column size 1.5-4 inches, 3.8x10.16 cm, filled in hexane), conducting chromatography according to the following procedure: processing a mixture of 10% ethyl acetate/hexane (500 ml); the absence of a product; 20% ethyl acetate/hexane (500 ml), lack of product; 30% ethyl acetate/hexane (500 ml), 3.1 g of a yellow solid. The resulting material was recrystallized from ethyl acetate with the formation of 1.66 g (23% in two stages) of 6-methyl-7-hydroxychromone-4-it is in the form of a light pink solid having so pl. 185 - 186oC; NMR spectrum: 7.66 (singlet, 1H), 6.90 (broad singlet, 1H), 6.38 (singlet, 1H), 4.45 (triplet, J= 6.4 Hz, 2H), 2.73 (triplet, J= 6.4 Hz, 2H), 2.17 (singlet, 3H).

Preparative example 33.

6-Methyl-7-triisopropylchlorosilane-4-one.

A mixture of 6-methyl-7-hydroxychromone-4-it (the compound of Preparative example 32, 1.50 g, 8.42 mmole), imidazole (1.15 g, 16.9 mmole) triisopropylsilyl chloride (2.0 ml, 9.2 mmole) in dimethylformamide (30 ml) was stirred overnight at ambient temperature. The reaction mixture was poured into water and was extracted with ether (2x). The combined organic layer washed with 1N lithium chloride (2x), dried over sulfate low having the following NMR spectrum: 7.64 (singlet, 1H), 6.30 (singlet, 1H), 4.45 (triplet, J=6.4 Hz, 2H), 2.70 (triplet, J= 6.4 Hz, 2H), 2.14 (singlet, 3H), 1.40-1.25 (multiplet, 3H), 1.09 (doublet, J= 7.3 Hz, 18H). The product also contained a small amount of silyl impurity and it was attended by residual dimethylformamide, however, the product can be used in subsequent reactions.

Preparative example 34.

3,3-Dibromo-6-methyl-7-triisopropylchlorosilane-4-one and 6-methyl-3, 3, 5-tribromo-triisopropylchlorosilane-4-one.

To a mixture of 6-methyl-7-triisopropylchlorosilane-4-it (the compound of Preparative example 33, 5.0 g, 8.97 mmole) in carbon tetrachloride (70 ml) for 15 minutes was bury bromide (0.93 ml, 18.05 mmole in 20 ml of carbon tetrachloride). The reaction mixture was stirred for 1 hour at ambient temperature was added an aqueous solution of the bisulphite. The resulting reaction mixture was stirred for 15 minutes; then, place the phase separation and the organic phase was washed with an aqueous solution of bicarbonate and brine, dried over magnesium sulfate and concentrated to education orange oil. This residue was subjected to rapid chromatography on silica gel (column size EN (500 ml), the lack of product; 3% ether/hexane (300 ml), 2,61 g of a mixture of 3,3-dibromo-6-methyl-7-triisopropylchlorosilane - 4-it 6-methyl-3,3,5-tribromo-7-triisopropylchlorosilane-4-it is in the form of a colorless oil (the ratio of these products, approximately 2.5:1). Key distinguishing features of the NMR spectrum for 3,3-dibromo-6-methyl-7 - triisopropylchlorosilane-4-it represent the following values : 7.77 (H at C-5), 6.38 (H at C-8), 4.68 (C-2 methylene groups), 2.19 (C-6 methyl group).

Preparative example 35.

3 Tripterocalyx-8-methyl-8-azabicyclo- (3.2.1)- octane.

According to the (14.2 g, 0.10 mol) was dissolved in methylene chloride (210 ml) and triethylamine (23 ml, 0.16 mol). Chloride trifloromethyl (9.3 ml, 0.12 mol) was bury with such speed, which provided soft boiling methylene chloride. The reaction mixture was stirred at ambient temperature for 1 hour; then it was washed with cold 0.5 N sodium hydroxide solution, water and brine. The organic phase was dried and concentrated to education yellow solid having the following NMR spectrum: 4.88 (triplet, 1H), 3.10-3.05 (multiplet, 2H), 2.94 (singlet, 3H), 2.22 (singlet, 3H), 2.20-2.10 (multiplet, 2H), 2.02-1.88 (multiplet, 6H).

necked round bottom flask, equipped with outboard mechanical stirrer was loaded and stirred sodium hydride (2.02 g, 50.47 mmole, 60% oil dispersion), which was washed from the oil with hexane (2 washes) was added in tetrahydrofuran (225 ml), then were added 4-portifino (4.89 ml, 45,89 mmole in 30 ml of tetrahydrofuran during the flushing portion 20 ml). From the reaction mixture freely allocated hydrogen gas. After cessation of hydrogen evolution was immediately added 3-tripterocalyx-8-methyl-8-azabicyclo- (3,2,1)-octane (compound of Preparative example 35, 9.42 g, at 45.89 mmole) in undiluted solids by washing in 50 ml of tetrahydrofuran. The reaction mixture was heated overnight under reflux and then cooled. The solvent was removed in vacuum under reduced pressure and the residue was transferred into ethyl acetate. The organic phase is washed with water and brine, dried over sulfate, calcium and concentrated to obtain 8.28 g (72%) of 3- (4-perpenicular) -8-methyl-azabicyclo- (3, 2, 1) - octane in the form of a yellowish-brown oil having the following NMR spectrum: 7.38 (double doublet, J= 5.9 Hz, 2H), 6.96 (long range coupled triplet, J= 9 Hz, 2H), 3.22-3.08 (multiplet, 3H), 2.23 (singlet, 3H), 2.02-1.94 (multiplet, 2H), 1.83-1.64 (multiplet, 4H), 1.50 (A-8-(2. 2. 2-trichlorocyanuric) -8-azabicyclo- (3,2,1)-octane.

A mixture of 3-(4-perpenicular)-8-methyl-8 - azabicyclo-(3,2,1)-octane (compound of Preparative example 36, 8.20 g, 32.65 mmole), 2.2.2-trichlorethyl of chloroformiate (4.94 ml, 35,92 mmole) and potassium carbonate (4.96 g, 35.92 mmole) in benzene (140 ml) was heated under reflux overnight. The solvent was removed under reduced pressure and the residue was transferred into ethyl acetate. The organic phase was washed with an aqueous solution of bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (column size 3x4 inches, 7.62 x 10.16 cm), conducting elution in the following sequence: processing hexane (350 ml), lack of product; 10% ethyl acetate/hexane (400 ml) drop head wrap; 10% ethyl acetate/hexane (600 ml), 20% ethyl acetate/hexane (500 ml) and 30% ethyl acetate/hexane (250 ml), 10.32 g (77%) of 3-(4-perpenicular) 8-(2.2.2 - trichlorocyanuric) -8-azabicyclo- (3.2.1) -octane as a white solid substance having so pl. 65-67oC; NMR spectrum: 7.40 (Double doublet, J= 5.5, 9.5 Hz, 2H), 6.98 (long range coupled triplet, J=8.5 Hz, 2H), 4.72 (AB Quartet, V1-3= 60 Hz, J= 12 Hz, 2H), 4.35 (symmetric multiplet, 2H),P> 3- (4-Perpenicular) -8-azabicyclo- (3. 2. 1) -octane. A mixture of 3-(4-perpenicular)-8-(2.2.2 - trichlorocyanuric) -8-azabicyclo- (3. 2. 1) -octane (compound of Preparative example 37, 10.28 g, 24.92 mmole), 48% HB (20 ml) and acetic acid (80 ml) was heated for 78 hours to 110oC. Established the pH of the reaction mixture is equal to 11 by addition of 4N sodium hydroxide solution and extraction was performed methylene chloride. The organic phase was filtered through diatomaceous earth, washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to distillation on a Kugelrohr (110oC (temperature Cuba) residual pressure 1.5 mm RT. Art. ) to give 3.30 g of 3-(4-perpenicular)-8-azabicyclo-(3.2.1)- octane as a yellow oil, having the following NMR spectrum: 7.41 (double doublet, J= 5.5 Hz, 2H), 7.00 (long range coupled triplet, J= 8.5 Hz, 2H), 4.11 (singlet, impurity), 3.55 (broad triplet, J= 3.5 Hz, 2H), 3.24 (symmetric multiplet, 1H), 2.58 (broad singlet, 2H, exchanges with D2Must integrate with 1H), 1.90-1.77 (multiplet, 4H), 1.70-1.51 (multiplet, 4H). This product can be used without additional processing.

Preparative example 39.

3- (4-Chlorophenylsulfonyl) -8-methyl-8-sabicic the model (2. 03 g, 50.91 mmole, 60% suspension in oil) was washed reagent from the oil with hexane (2 washes), then was added tetrahydrofuran (200 ml) and then 4-chlorophenol (6.69 g, 46.28 mmole in 20 ml of tetrahydrofuran). From the reaction mixture freely allocated hydrogen gas. After the evolution of hydrogen was added 3-tripterocalyx-8-methyl - 8-azabicyclo-(3.2.1)-octane (9.5 g, 46.28 mmole in 70 ml of tetrahydrofuran). The reaction mixture was heated under reflux overnight, then cooled and filtered through diatomaceous earth (with flushing ether). The filtrate was concentrated under reduced pressure and the residue was transferred into the ether. The organic phase is washed with water and brine, dried over calcium sulfate and concentrated to obtain 8,08 g (65%) of 3-(4-chlorophenylsulfonyl) -8-methyl-8-azabicyclo- (3.2.1) -octane in the form of a yellowish-brown oil having the following NMR spectrum: 7.42-7.23 (multiplet, 4H), 3.22 (symmetric multiplet, 1H), 3.20-3.11 (multiplet, 2H), 2.24 (singlet, 3H), 2.03-1.97 (multiplet, 2H), 1.82-1,65 (multiplet, 4H), 1.53 (AB Quartet, V1-3= 14.5 Hz, J= 6.5 Hz, 2H).

Preparative example 40.

3- (4-Chlorophenylsulfonyl) -8- (2. 2. 2-trichlorocyanuric) -8-azabicyclo- (3.2.1) -octane.

A mixture of 3-(4-chlorpheniramine potassium (4.58 g, 33.13 mmole) in benzene (150 ml) was heated overnight under reflux. The solvent was removed under reduced pressure and the residue was transferred into ethyl acetate. The organic phase was washed with an aqueous solution of bicarbonate and brine, dried over calcium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (column size 3x4 inches, 7.62 x 10.16 cm), conducting elution in the following sequence: processing hexane (350 ml), lack of product; 10% ethyl acetate/hexane (500 ml), discarded head fraction); 10% ethyl acetate/hexane (500 ml), 20% ethyl acetate/hexane (500 ml) and 30% ethyl acetate/hexane (250 ml), 9.26 g (72%) of 3-(4-chloro-phenylsulfanyl) -8- (2. 2. 2- trichlorocyanuric) -8-azabicyclo-(3.2.1)-octane as a yellow solid, having so pl. 70-71.5oC. an NMR Spectrum: 7.33 (long range coupled doublet, J= 8.5 Hz, 2H), 7.26 (long range coupled doublet, J= 8.5 Hz, 2H), 2.73 (AB Quartet, V1-3=58 Hz, 1 = 12 Hz, 2H), 4.43-4.30 (multiplet, 2H), 3.40 (septet, J= 6 Hz, 1H), 2.10-1.56 (multiplet, 8H).

Preparative example 41.

3- (4-Chlorophenylsulfonyl) -8-azabicyclo- (3,2,1)-octane.

A mixture of 3-(4-chlorophenylsulfonyl)-8-(2.2.2 - trichlorocyanuric) -8-azabicyclo- (3. 2. 1) -octane (8.and was set equal to 11 by addition of 4N sodium hydroxide solution and the mixture was extracted with methylene chloride. The organic phase was filtered through diatomaceous earth, washed with brine, dried over calcium sulfate and concentrated to obtain 3-(4 - chlorophenylsulfonyl)-8-azabicyclo-(3.2.1)-octane as a yellow oil. The product was subjected to distillation on a Kugelrohr (110-130oC (the temperature of the cube), the residual pressure 1.5 mm RT. Art. ) to obtain 4.1 g (79%) of 3- (4-chlorophenylsulfonyl) -8-azabicyclo- (3.2.1)-octane in the form of almost colorless oil, which was hardened and had the following NMR spectrum: 7.30 (multiplet, 4H), 3.54 (broad triplet, J= 3.5 Hz, 2H), 3.32 (symmetric multiplet, 1H), 1.97-1.72 (multiplet, 5H), 1.71-1,52 (multiplet, 4H).

Preparative example 42.

1-(2, 2-Diphenyl-benzo(1,3)dioxol-5-yl)-propane-1-on.

A mixture of 3,4-dihydroxypropane (ICN Biomedicals, Inc., 3300 Hyland Eyv. Costa Mesa, California, 92626, USA, 5.0 g, 30 mmol) and dichlorodiphenylmethane (10.0 ml, 52.1 mmole) was heated for 7 minutes at 170oC. the Reaction mixture was cooled and poured into 1N solution of sodium hydroxide. The resulting mixture was extracted with ether (2x) and the combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (2x5 inch, Iksan (500 ml), 0.84 g of a white solid identified as 2-chloro-1- (2,2-diphenyl-benzene(1,3)dioxol-5-yl)-propane-1-it; 5% ether/hexane (250 ml), 1.9 g of unidentified orange oil; 5% ether/hexane (250 ml), 2.18 g of regenerated dichlorodiphenylmethane; 10% ether/hexane (500 ml), 4.82 g (48%) of 1- (2.2-diphenyl-benzo(1,3)dioxol-5-yl)-propane-1-it is in the form of an orange oil, stiffening when standing. The resulting product had so pl. 69-70.5oC. Elemental analysis for C22H17ClOC3. Calculated: C, 79.98; H, 5.49. Found: C At 80.05; H 5.34.

Preparative example 43.

2-Bromo-1- (2.2-diphenyl-benzo (1.3) dioxol-5-yl) -propane-1 - on.

1- (2, 2-Diphenyl-benzo (I, 3) dioxol-5-yl) -propane-1-he (the compound of Preparative example 42, 4.70 g, 14,23 mmole) was dissolved in carbon tetrachloride (60 ml) and bury bromide (0.74 ml, 14,36 mmole in 10 ml of carbon tetrachloride), the Reaction mixture was stirred at ambient temperature for 30 minutes and then was extracted with saturated aqueous bicarbonate. The organic phase is washed with water and brine, dried over magnesium sulfate and concentrated to obtain 5.58 g (96%) of 2-bromo-1-(2,2-diphenylene(1.3)dioxol-5 - yl)-propane-1-it is in the form of a dark orange oil, having the following range is exploring the example 44.

4-Benzyloxy-3-hydroxypropiophenone.

A mixture of 3,4-dihydroxypropane (ICN Biomedicals. Inc., 3300 Hyland Eyv., Costa Mesa, California, 92626, USA, 2.00 g, 12.0 mmole), benzyl bromide (1.43 ml, 12.0 mmole) and potassium carbonate (3.33 g, 24.1 mmole) in acetone (100 ml) was heated for 24 hours under reflux. The reaction mixture was cooled and filtered. The filtrate was concentrated and the residue was distributed in the system ethyl acetate - 0.25 N hydrochloric acid. The phases were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (1 x 5 inch, 2.H.7 cm, filled in hexane), conducting chromatography according to the following procedure: processing a mixture of 10% ethyl acetate/hexane (500 ml), lack of product; 30% ethyl acetate/hexane (1000 ml), 0.88 g (23%) of 4-benzyloxy-3-hydroxypropiophenone in the form of a white solid having the following NMR spectrum: 7.58-7.52 (multiplet, 2H), 7.44-7.36 (multiplet, 5H), 6.96 (doublet, J= 8.2 Hz, 1H), 5.72 (singlet, 1H), 5.19 (singlet, 2H), 2.94 (Quartet, J= 7.2 Hz, 2H), 1.21 (triplet, J= 7.3 Hz, 3H).

Preparative example 45.

4-Benzyloxy-3-methoxypropiophenone.

A mixture of 4-benzyloxy methyl iodide (0.50 ml, 8.0 mmole) in acetone (50 ml) was heated for 2 hours under reflux and was stirred over the weekend at ambient temperature. The reaction mixture was filtered and the filtrate was concentrated. The residue was distributed in the system of the ether - water. The phases were separated and the organic phase is washed with water and brine, dried over magnesium sulfate and concentrated to obtain 0.88 g (95%) 4-benzoyloxy-3 - methoxypropiophenone in the form of a white solid having the following NMR spectrum: 7. 55 (doublet, J= 2 Hz, 1H), 7.50 (double doublet, J = 2, 8.4 Hz, 1H), 7.44-7.28 (multiplet, 5H), 6.87 (doublet, J = 8.4 Hz, 1H), 5.22 (singlet, 2H), 3.93 (singlet, 3H), 2.93 (Quartet, J= 7.3 Hz, 2H), 1.20 (triplet, J= 7.3 Hz, 3H)

Preparative example 46.

4-Benzyloxy - bromo-3-methoxypropiophenone.

4-Benzyloxy-3-methoxypropiophenone (compound of Preparative example 45, 0.84 g, 3.11 mmole) was dissolved in carbon tetrachloride (20 ml), and within 10 minutes was added bromine (0.16 ml, 3.11 mmole in 5 ml of carbon tetrachloride). The reaction mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was poured into saturated aqueous bicarbonate and was the separation of the phases. The organic layer was washed with water and brine, sustacal to remove residual content of carbon tetrachloride in the product. This method was obtained 1.12 g (100%) 4-benzyloxy - bromo-3-methoxypropiophenone in the form of a waxy light orange solid, having the following NMR spectrum: 7.58-7.54 (multiplet, 3H), 7.42-7.23 (multiplet, 4H), 6.89 (doublet, J= 8.3 Hz, 1H), 5.25-5.21 (multiplet, 3H), 3.93 (singlet, 3H), 1.85 (doublet, J = 6.6 Hz, 3H).

Preparative example 47.

4- (3, 5-Dibromophenyl) -4-hydroxy-piperidine hydrochloride.

A solution of 1,3,5-tribromobenzene (15.75 g, 50.0 mmole) in ether (500 ml) was cooled to -78oC and bury within 30 minutes utility (20.8 ml, 50.0 mmole, 2.4 M solution in hexane). The reaction mixture was stirred for 30 minutes and then for 30 minutes with 20 ml washing with ether, bury 1-tert. - butyloxycarbonyl-4-one (5.0 g, 25 mmole per 100 ml of ether). The reaction mixture was stirred for 2 hours at -78oC then cooled with water and allowed to warm to room temperature. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (column size 4x4 inches, 10.H.16 cm), conducting elution in the following sequence: processing a mixture of 1% ethyl acetate/hexane (1000 ml), the absence of a product; is Anzola; 10% ethyl acetate/hexane (1000 ml), lack of product; 15% ethyl acetate/hexane (2000 ml), the lack of product; 20% ethyl acetate/hexane (2000 ml), 6.76 g (62%) of 4-(3,5-dibromophenyl) -4-hydroxy-1-tert.-butyloxycarbonyl in the form of a light yellow foam having the following NMR spectrum: 7.56 (multiplet, 3H), 4.06 (broad doublet, J= 13 Hz, 2H), 3.21 (triplet, J= 13 Hz, 2H), 1.93 (double triplet, J = 4,5, 13 Hz, 2H), 1.80 (singlet, 1H), 1.68 (doublet, J= Hz, 2H), 1,48 (singlet, N). It was found that the resulting product has a purity of 88% and contaminated with 12% of 1-tert.-butyloxycarbonyl 4-it is an NMR spectrum, the triplets at 3.71 and 2.44). This material can be used without additional purification.

The product of the reaction described above (6.76 g, 15.5 mmole) was dissolved in ether (150 ml) was added dioxane saturated with HCl (15 ml). The resulting mixture was stirred for 30 minutes at ambient temperature, then was cooled to 0oC and in the solution for 3 minutes, was barbotirovany gaseous HCl. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. Nitrogen gas was barbotirovany through the mixture to remove gaseous HCl and the resulting precipitate was filtered to obtain 3.27 g of a cream solid. The filtrate is again necydalis HCl was repeated three times with an 0.45 g of the product. In this way received 5.45 g (94%) of 4-(3.5-dibromo-phenyl)-4-hydroxypiperidine hydrochloride in the form of a cream solid. The resulting material was used without additional purification.

Preparative example 48.

(1R*THAT 2R*)-1-(4-Hydroxyphenyl)-2-(4-(3,5-dibromophenyl)-4 - hydroxypiperidine-1-yl) -propan-1-ol.

A mixture of 4-triisopropylsilane - bromo - propiophenone (3.0 g, 7.79 mmole), 4- (3, 5-dibromophenyl) -4 - hydroxypiperidine hydrochloride (compound of Preparative example 47, 2.89 g, 7.79 mmole) and triethylamine (3.26 ml, 23.4 mmole) in ethanol (200 ml) was heated overnight under reflux. The solvent was removed under reduced pressure and the residue was distributed in a mixture consisting of ethyl acetate and water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (column size 2x4 inches, 5.08 x 10.16 cm), conducting chromatography according to the following procedure: treatment with 1% solution of ethyl acetate/hexane (500 ml), lack of product; 5% ethyl acetate/hexane (300 ml), unweighted source ketone; 5% ethyl acetate/hexane (700 ml) and 15% ethyl acetate/hexane (300 ml), lack of product; 15% ethylacetate-it is in the form of a crisp white foam, having the following NMR spectrum: 8.03 (doublet, J= Hz, 2H), 7.57-7.53 (multiplet, 3H), 6.92 (doublet, J= 8.5 Hz, 2H), 4.14 (Quartet, J=7 Hz, 1H), 2.85 (double doublet, J= 2, 9.5 Hz, 2H), 2.77-2.70 (multiplet, 1H), 2,60 (double triplet, J= 2.5 and 11.5 Hz, 1H), 2.13-1.92 (multiplet, 2H), 1.74-1.56 (multiplet, 3H), 1.32 (doublet, J= 7 Hz, 3H), 1.36-1.18 (multiplet, 3H), 1.12 (doublet, J= Hz, N).

Chilled on ice, the mixture of sodium borohydride (0.21 g, 5.56 mmole) and ethanol (50 ml) was stirred for 10 minutes and then bury within 15 minutes, 1-(4-triiso-propertylistener) - 2- (4- (3, 5-dibromophenyl) -4-hydroxypiperidine-1-he (3.55 g, 5.56 mmole in 50 ml ethanol). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. Added an additional amount of sodium borohydride (0.10 g) and the reaction mixture was stirred for b hours. A white precipitate was collected and washed with ethanol and then received the product in the amount of 0.84, the Filtrate was treated with sodium borohydride (0.10 g) and stirred over night. A white precipitate was collected and washed with ethanol to obtain the product in the amount of 2.56, United sediment (3.40 g) was recrystallized from ethanol to obtain 3.0 g (84%) of (1R*THAT 2R*) -1- (4-triisopropylchlorosilane) -2- (4- (3, 5-dibromophenyl)-4-g is C29H43Br2NO3Si. Calculated: C 54,29; H, 6.76; N, 2.18. Found: C, 54.17; H 6,50; N 2.35.

The product of the reaction described above (0.53 g, 0.827 mmole) was dissolved in tetrahydrofuran (20 ml) was added tetrabutylammonium fluoride (1.25 ml, 1.25 mmole, 1M solution in tetrahydrofuran). The reaction mixture was stirred for 1 hour at ambient temperature and then concentrated. The residue was subjected to rapid chromatography on silica gel (column size 1.5 x 3 inches, 3.81 x 7.62 cm), conducting chromatography according to the following procedure: processing a mixture of 26% ethyl acetate/hexane (600 ml), unweighted head fraction, 25% ethyl acetate/hexane (200 ml), lack of product; 25% ethyl acetate/hexane (200 ml) and 50% ethyl acetate/hexane)800 ml), 0.20 g (50%) of (1R*THAT 2R*)-1-(4-hydroc-Setenil) -2- (4- (3. 5-dibromophenyl) - 4-hydroxypiperidine-1-yl) -propan-1-ol in the form of a white solid substance having so PL 232-234oC. Elemental analysis for C20H23Br2NO3. Calculated: C At 49.51; H, 4.78; N, 2.89. Found: C, 49.77; H, 4.58; N, 2.76.

Preparative example 49.

1R*THAT 2R*1- (4-Hydroxyphenyl) -2- (4- (3, 5-detritivores) -4 - hydroxypiperidine-yl) -propan-1-ol.

To a solution of (1R*THAT 2R*)-1-(4-hydroxyphenyl)-2-(4-(3,5- dibromoneopentyl 10% palladium on coal (0.013 g) and triethylamine (0.015 ml). The reaction mixture was three times degirolami mode of freezing/thawing and then it worked gaseous tritium (15 curies) for 6 hours at ambient temperature. The reaction mixture was filtered through diatomaceous earth and the filter layer was thoroughly washed with methanol (3 ml). The filtrate was concentrated. The residue was diluted with methanol (1 ml) and concentrated to remove the labile tritium impurities. This process of dilution/evaporation was repeated three times. The residue was dissolved in ethanol (20 ml) and filtered through a TeflonTMsyringe filter with receive activity 913 mCi. The whole party was purified by chromatography on silica gel (column size 2.5x8 cm), carrying out elution with ethyl acetate to obtain 156 mCi (1R*THAT 2R*)-1-(4-hydroxyphenyl)-2-(4-(3, 5-detritivores)-4 - hydroxypiperidine-yl)-propan-1-ol, having a radiochemical purity > 98% and specific activity 42.8 Ci/mmol.

Preparative example 50.

3,5-Dimethyl-4-hydroxypropiophenone.

A mixture of 2,6-dimethylphenol (10.5 g, 85.9 mmole), propionic acid (4.64 ml, 86.8 mmole) and reformersglossary (59%) was heated for 48 hours up to 80oC. the Reaction mixture was cooled, lane is carbonate and brine, was dried and concentrated to a dark oily solid. This material was subjected to distillation on a Kugelrohr in the range of 105-135oC (residual pressure 1.5 mm RT. Art., the temperature of the cube) to obtain 11.2 g (73%) of 3,5-dimethyl-4 - hydroxypropiophenone in the form of a solid substance having the following NMR spectrum: 7.63 (singlet, 2H), 5.30 (singlet, 1H), 2.92 (Quartet, J= 7.5 Hz, 2H), 2.27 (singlet, 6H), 1.18 (triplet, J= 7.5 Hz, 3H).

Preparative example 51.

4-Benzyloxy-3,5-dimethylpropylene.

A mixture consisting of 3, 5-dimethyl-4-hydroxypropiophenone (11.2 g, 62.9 mmole), benzyl bromide (8.23 ml, 69.2 mmole) and potassium carbonate (17,4 g, 125.8 mmole) in acetone (200 ml) was stirred over night. The resulting mixture was filtered and the solvent was removed. The residue was distributed in a mixture of ethyl acetate - water. The phases were separated and the organic layer was washed with brine, dried over calcium sulfate and concentrated. The residue was subjected to rapid chromatography on silica gel (column size, 2.5 x 3.5 inches, 6.H.9 cm, filled in hexane), conducting elution as follows: 5% ethyl acetate/hexane (700 ml), the lack of product; 7% ethyl acetate/hexane (400 ml) and 10% ethyl acetate/hexane (1500 ml), 15.33 g (91%) of 4-benzyloxy-3,5 - dimethylpropanamide, 5H), 4.83 (singlet, 2H), 2.95 (Quartet, J= 7.5 Hz, 2H), 2.32 (singlet, 6H), 1.20 (triplet, J = 7.5 Hz, 3H).

Preparative example 52.

4-Benzyloxy - bromo - 3,5-dimethylpropylene.

To a solution of 4-benzyloxy-3,5-dimethylpropylene (15.19 g, 56.6 mmole) in carbon tetrachloride (160 ml) was bury bromide (2.98 ml, 57.8 mmole in 40 ml of carbon tetrachloride). The reaction mixture was stirred for 15 min after adding and then added an aqueous solution of sodium sulfite and the mixture was stirred for another 30 minutes. The phases were separated and the organic layer washed with saturated aqueous bicarbonate and brine, dried and concentrated to obtain 19.55 g (99%) 4-benzyloxy - bromo-3,5-dimethylpropylene in the form of a yellow solid, suitable for use without further purification and has the following NMR spectrum: 7.72 (singlet, 2H), 7.52-7.30 (multiplet, 5H), 5.27 (Quartet, J= 6.5 Hz, 1H), 4.85 (singlet, 2H), 2.33 (singlet, 6H), 1.88 (doublet, J= 6.5 Hz, 3H).

1. Derivatives of 3-(piperidinyl-1)-chroman-4,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)-alkanol General formula I

< / BR>
or its pharmaceutically acceptable salt accession acid,

in which (a) R2and R5taken in individual p is)-alkyl, halo, HE or or7and R5represents methyl; or (b) R2and R5are taken together to represent a group

< / BR>
forming a ring chroman-4-ol, and R1, R3and R4each independently represent hydrogen, (C1- C6)-alkyl, halo, HE or or7;

R6represents a group

< / BR>
R7represents methyl;

R8represents phenyl, optionally substituted by halo or CF3;

X represents S;

provided that (a) when R2and R5taken separately, at least one of R1, R2, R3and R4are not hydrogen; and (b) when R2and R5taken together, at least one of R1, R3and R4are not hydrogen.

2. Connection on p. 1, in which R2and R5taken separately, R2and R3represent hydrogen, R6are a group of

< / BR>
and R8represent phenyl, 4-halophenol or 4-triptoreline.

3. Connection on p. 2, in which R5represents methyl, with 1R*THAT 2R*the relative stereochemistry of the form

< / BR>
4. Connection on p. 3, kotorogo, 4-chlorophenyl or 4-triptoreline.

5. Connection on p. 4, in which each of R1and R4represents fluorine, and R8is a 4-forfinal.

6. Connection on p. 4, in which R1and R4represent fluorine, and R8- 4-chlorophenyl.

7. Connection on p. 4, in which R1and R4represents fluorine, and R8is a 4-triptoreline.

8. Connection on p. 4, in which R1represents hydrogen, R4represents methyl, and R8is a 4-forfinal.

9. Connection on p. 4, in which R1and R4represent methyl, and R8is a 4-forfinal.

10. Connection on p. 1, in which R2and R5taken in isolation, and R6represents a

< / BR>
11. Connection on p. 10, in which R5represents methyl, with 1R*THAT 2R*the relative stereochemistry of the form

< / BR>
12. Connection on p. 1, in which R2and R5are taken together to represent a group

< / BR>
forming a ring chroman-4-ol.

13. Connection on p. 12, in which the C-3 and C-4 position of the specified ring 4-chroman-4-ol have 3R*fight

< / BR>
and R8represents phenyl or 4-halophenol.

15. Connection on p. 13, in which R6represents a

< / BR>
16. Connection on p. 3, which is (1R,2R)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidine-1-yl)-propan-1-ol.

17. Connection on p. 3, which is (1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperidine-1-yl)-propan-1-ol.

18. Mutilata salt compounds on p. 1 of the formula I, in which each of R1and R4represents fluorine, and R8is a 4-forfinal.

19. Mutilata salt compounds on p. 1 of the formula I, in which R1and R4represent fluorine, and R8represents 4-chlorophenyl.

20. Mutilata salt compounds on p. 1 of the formula I, in which R1and R4represents fluorine, and R8is a 4-formationl.

21. Mutilata salt compounds on p. 1 of the formula I, in which R1represents hydrogen, R4represents methyl, and R8is a 4-forfinal.

22. Mutilata salt compounds on p. 1 of the formula I, in which R1and R4represent methyl, and R8is, trichosis the fact that the impact of implementing an effective amount of the compounds under item 1 or its pharmaceutically acceptable salt.

24. Pharmaceutical composition having the properties of NMDA antagonist, including an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a connection on p. 1 or its pharmaceutically acceptable acid additive salt.

 

Same patents:

The invention relates to new derivatives of 1-phenyl-3-azabicycloalkanes-2-ones, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents

The invention relates to new derivatives of 2-azabicyclo-[2.2.1]hept-5-ene-2-acetic acid of General formula

-CH2-Y where R3-R8hydrogen or C1-4alkyl,

Y means a group СOOR, CON(R1)2or CN, where R and R1independently of one another denote hydrogen or C1-4alkyl, which can be used as intermediates in the synthesis of N-phosphonomethylglycine known herbicide and plant growth regulator

The invention relates to new derivatives of railmachine-(endo)-N-[(8-methyl-8-azabicyclo-3,2,1-Octan-3-yl) amino]-carbonyl]-2-(cyclopropylmethoxy)benzamide or its salt

The invention relates to a method for producing 6-fluoro-1,2-benzisothiazole formula

(I) where R is a hydrogen atom, a lower alkyl or a group of the formula

orwhere R1means-Cho or - CN, namely, that on-halogenoalkane derivative of the formula:

where R has the above meanings, is subjected to the interaction with R3SH, where R3- benzyl, environment aprotic organic solvent, with the formation of the compounds of formula

(III)where R and R3have the specified values, which are subjected to interaction with a halogenation agent to obtain the corresponding sulfanilamide formula

(IV)Subjected to interaction obtained sulfanilamide with ammonia in the compounds of the formula

(I)

Polucheniya pharmaceutically active compounds, which can be used, for example, as antipsychotic agents and as inhibitors of reuptake of serotonin

The invention relates to new derivatives of 2-azabicyclo(2,2,1) hept-5-ene-2-acetic acid formulaCH2-Y where R3-R8is hydrogen or C1-C4-alkyl,

Y means a group COOR, CON(R1)2or CN, where R and R1- independently of one another denote hydrogen or C1-C4-alkyl, which can be used as intermediates in the synthesis of N-phosphonomethylglycine known herbicide and plant growth regulator

The invention relates to new fluorine-containing organic compounds, more specifically to an amine derivative having biological activity

The invention relates to new derivatives of piperidine and piperazine of the formula I

< / BR>
where Ind is unsubstituted or one - or twofold substituted by Oh, OA, CN, Hal, COR2or CH2R indol-3-ilen balances;

R1is unsubstituted or once substituted with CN, CH2OH, CH2OA or COR2benzofuran-5-yl, 2, 3-dihydrobenzofuran-5-yl-, chroman-6-yl, chroman-4-one-6-yl, 3-chromen-6-yl or chromen-4-one-6-yl;

Q-CmH2m;

Z is N or CR3;

A is alkyl with 1-6 C-atoms;

Hal is F, Cl, Br or I;

R2-OH, OA, NH2, NHA or NA2;

R3Is H, OH or OA;

m is 2, 3 or 4,

and their physiological acceptable salts

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds

The invention relates to stereoisomerism forms of Itraconazole (X=CL) and saperconazole (X= F), which can be represented by the formula CIS-(I) that are listed in the text of the description, their pharmaceutically acceptable acid additive salt forms, and methods of producing these stereoisomeric forms and their complexes with cyclodextrin derivatives and pharmaceutical compositions containing the above-mentioned complexes with anti-fungal activity

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine
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