Methods of obtaining derivatives 4a,5,9,10,11,12-hexahydro-6n - benzofuro(3a,3,2-ef)(2)benzazepine and intermediate compounds

 

(57) Abstract:

Describes how to obtain new derivatives 4A, 5, 9, 10, 11, 12 - hexahydro-6N-benzofuro(3A, 3, 2-EF) (2) benzazepine General formula selected from the group consisting of (I) and (II) or their salts, where the values of the substituents specified in paragraph 1 of the formula. The method consists in the interaction (R2O)2C6H2(CHO)(X1) (III) with compound (IV) obtained when this product condensation restore, cyclist, exposing its interaction with the substrate and oxidant. Thus obtained compound of General formula (I) in which Y1and Y2together represent = O (ketone), recover L - selectride, K - selectride, KS - selectride and LS - selectride to compounds of General formula (I) in which Y represents hydroxy, and a racemic compound of General formula (I) in which R4selected from the group consisting of hydrogen, lower alkyl or aralkyl, separated by crystallization with a chiral acid to the corresponding enantiomers. The technical result - the development of a way to reproduce large quantities specified in the title compounds with improved outputs as separate stages and throughout the process, as well as roizvodnykh 4A,5,9,10,11,12-hexahydro-6H-benzofuro/3a,3,2-ef//2/benzazepine General formula (I)

< / BR>
or its salts, where R2, R4X1X2, Y1, Y2identical or different and denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxy - or alkoxygroup; lowest, if necessary, branched and, if necessary, replaced, for example, at least one halogen alkyl group, a lower, if necessary branched alkenylphenol group; lower, if necessary branched alkylamino group; if necessary, substituted aryl, aracelio or aryloxyalkyl group, the alkyl chain of which, if necessary, branched and aromatic nucleus which, if necessary substituted; formyl, and unsubstituted or substituted by one or more halogen, linear or branched alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl, or Y1and Y2together represent =O and where A stands for a benzene nucleus, if necessary one or more times substituted by at least one of the lowest, if necessary, a branched alkyl group; at least one lower, if necessary the alkyne group; at least one lower if need extensive alkoxygroup; fluorine, chlorine, bromine, iodine or more identical or different halogen, at least one substituted with one halogen or two or more identical or different halogen alkyl group, such as chlorochilon and trifluoromethyl; at least one, if necessary substituted aranceles group and/or at least one hydroxy-group; primary, secondary or tertiary amino group, a nitro-group, a nitrile group, alkylaminocarbonyl, killingray, aldehyde group, carboxyl group, all derivatives of carboxyl groups, for example esters, inorganic salts, the halides.

The invention relates further to a method for producing derivatives of 4a, 5,9,10,11,12-hexahydro-6H-benzofuro/3a, 3,2-ef//2/benzazepine General formula (II)

< / BR>
where R2, R4X1X2, Y1and Y2and A have the above in formula (I) values, Z-denotes organic anion pharmaceutically acceptable acid, for example, tartrate, lactate, citrate, acetate, maleinate, or inorganic anion, such as fluoride, chloride, bromide, iodide, sulfate, phosphate, chlorate, R< a branched alkyl, alkenyl, aryl, aralkyl, alkylaryl, arylcarbamoyl or aralkylamines, and unsubstituted or substituted by one or more halogen, linear or branched allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, arylsulfonyl, aralkylamines.

Preferred meanings of the substituents R1-R6X1X2, Y1, Y2are

R1, R2, R3, R6: hydrogen, unsubstituted and substituted by one or more halogen, linear or branched alkyl, alkenyl, aryl, aralkyl, alkylaryl, arylcarbamoyl, aralkylamines or any combination of these residues;

X1X2: H, F, Cl, Br, J-, tert-butyl, as well as any combination;

Y1, Y2: H, O-R6and Y1and Y2= O

R4, R5: named for R1, R2, R3, R4preferred values, and unsubstituted and substituted by one or more halogen, linear or branched allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, arylsulfonyl, aralkylamines.

Galantamine is a found mainly in plants of the type Avego inhibitor of acetylcholinesterase and the resulting use it when Alzheimer's disease. To date galantamine produce several kilograms per year and costs over $ 30,000 per kilogram of Caucasian snowdrops Galanthus Woronoyi. Synthesis of galantamine in principle known from the late sixties, however, was used long uneconomical methods with low overall output.

Synthesis of some compounds of the above General formulas (I) and (II) are known and described in the literature. Thus, N-(3-hydroxy-4-methoxyphenyl)-N-methyl-4-hydroxyphenylethylamine was cyclically using various oxidants to derivatives navedena (Naroden is a precursor of galantamine, but already has inherent galantamine cyclic structure (D. H. R. Barton, G. W. Kirby, Proc.Chem.Soc. 392, 1960, D. H. R. Barton, G. W. Kirby, J. Chem.Soc. 806, 1962), and output, usually below 1% of theoretical. The structure was proved, however, to get galantamine in pharmaceutically interesting quantities could not.

Optimal methods (primarily (T. Kametani, T. Yamaki, H. Yagi, K. Fukumoto, J. Chem.Soc. 2602, 1969, J. Chem.Soc.Chem. Comm. 25, 1969) describe the cyclization of derivatives of N-methylbenzamide, respectively phenylacetamide with the yield up to 40%, but low output makes it impossible for industrial use. Further, the literature describes celecia (Edinen Zentar po Chimia Sophia, DE 2945 161 800604, CA, 94, 15945b), microbiological, enzymatic (J. Shewczyk, A. H. Lewin, F. I. Carroll, J. Het.Chem.25,1809, 1988), and biomimetic methods (K. Shimizu, K. Tomioka, S. Yamada, K. Koga, Heterocycles 8, 277, 2977, K. Shimizu, K. Tomioka, S. Yamada, K. Koga, Chem.Pharm. Bull 26, 3765, 1978). In the literature (R. A. Holton, M. P. Sibi, W. S. Murphy, J. Am.Chem.Soc. 110, 314, (1988)) retrieves navedena from isovanillin with 44% overall yield, however, the use of equimolar amounts of triptoreline palladium, as well as trifenatate thallium makes this synthesis uneconomical. Obtained in this way (+/-) narogin (R. A. Holton, M. P. Sibi, W. S. Murphy, J. Am.Chem. Soc. 110, 314 (1988), enrich the desired (-) narodnom and using L-selectride transferred with good access to galantamine.

Proposed synthesis (J. Shewczyk, A. H. Lewin, F. I. Carroll, J. Het.Chem. 25, 1809, 1988), which describes the oxidative cyclization of 21%, but there is no separation of enantiomers. It is also known recovery bromo-navedena using LiAlH4in tetrahydrofuran with the formation of a mixture 53-31 diastereomers (+/-) galantamine and (+/-) of aphelenchida.

The objective of the invention is to develop a way to reproducibly obtain large quantities specified in the title compounds with improved outputs as separate stages, and sicilie the claims relate to preferred variants of carrying out the invention. In particular, suitable according to the invention were the following techniques.

Replacement of halogenated solvents such as chloroform, toluene. Halogenated solvents in the present time because of their toxicity, difficulties in recycling and environmental risk hardly even used as technical solvents. Toluene, on the contrary, does not have these disadvantages.

Processing by extraction requires organic solvents. The invention allows to optimize the majority of stages that the product of the reaction for the most part can be obtained in crystalline form from the solution. Thereby largely eliminating the need for phase chromatographic purification or extraction.

The invention further allows to improve the parameters to reproduce the output in a very narrow interval, and to determine the purity of the main product and the content of by-products after these reactions. The methods according to the invention provide improved and reproducible output as separate stages, and the total output. Incidentally, the invention provides a method in which bromfieldii vosstanovit diastereoselective high yield (for example, 85%) to obtain N-dimethylpropanolamine, which by N-methylation by the Eschweiler-Clarke and dibromononane can be transferred to (+/-) galantamine. In this method, the reaction product (+/-) epiglottis not been able to find chromatographic methods. Galantamine and galantamine derivatives can be obtained by the method according to the invention on an industrial scale through not described in the literature intermediate products.

The methods according to the present invention, which is substantially superior to the prior art in respect to yield and purity of the products obtained and which can be carried out on an industrial scale, can be represented, for example, as follows: For the synthesis of derivatives 4a,5,9,10,11,12-hexahydro-6H-benzofuro/3a,3,2-ef//2/benzazepine General formula (I)

< / BR>
or its salts, where R2, R4X1X2, Y1and Y2the same or different and denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxy - or alkoxygroup, lowest, if necessary, branched and, if necessary, substituted alkyl group, a lower, if necessary branched alanovoy group, the lowest, if necessary, branched alginovu group, if neobhodimosti branched and aromatic nucleus which, if necessary, replaced, formyl group, and unsubstituted or substituted by one or more halogen, linear or branched alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl and Y1, Y2together may denote a =O (ketone)

and

where A stands for a benzene nucleus, if necessary one or more times substituted by at least one of the lowest, if necessary, a branched alkyl group, at least one of the lowest, if necessary, the branched alkinoos group, at least one of the lowest, if necessary, branched alkyne group, at least one lower if need extensive alkoxygroup, fluorine, chlorine, bromine, iodine or more identical or different Halogens, at least once a substituted alkyl group, such as chlorochilon and trifluoromethyl, at least one, if necessary, replaced aranceles group, at least one hydroxy-group, primary, secondary or tertiary amino group, a nitro-group, a nitrile group, alkylamino or aryl is p ethers, inorganic salts, halides, perform a process comprising a stage of condensation with subsequent restoration, N-formirovanie or the introduction of the N-protective group, bromination (which can be done already at the stage of isovanillin according to the General scheme), oxidative cyclization, recovery, depending on the type of reducing agent is also N-methylation and dibromononane, and the separation of optical isomers. If necessary, some of the mentioned stages of the method can be excluded.

The object of the present invention is also receiving salts listed in the title compounds.

Compounds of General formula (I) can be converted into salts with organic and inorganic acids, for example, mineral acids such as hydrochloric and Hydrobromic acid, sulfuric acid and phosphoric acid, perchloric acid, or pharmaceutically acceptable organic acids such as lactic acid, substituted and unsubstituted tartaric acid, acetic acid, salicylic acid, citric acid, benzoic acid, beta-naphthoic acid, adipic acid, etc.

The methods according to the invention partially lead to pruchten formula

< / BR>
N-dimethylpropanolamine formula

< / BR>
N-dimethylaminopropylamine formula

< / BR>
The subject invention also is obtaining salts of substituted derivatives 4a,5,9,10,11,12-hexahydro-6H-benzofuro/3a,3,2-ef//2/benzazepine General formula (II)

< / BR>
in which R2, R4X1X2, Y1and Y2and A have the above in formula (I) values, Z represents an organic anion pharmaceutically acceptable acid, for example, tartrate, lactate, citrate, acetate, maleinate, etc. or inorganic anion, such as fluorine ion, chlorine, bromine or iodine, sulfate or phosphate or chromate, R5denotes a hydrogen atom, a lower linear or branched alkyl residue, an aryl or branched in the alkyl chain or unbranched Uralkaliy remnant, according to the method described above as an example.

Obtained according to the invention compounds and their salts have at least two asymmetric center and therefore exist in several stereoisomeric forms. The invention includes the separation of the resulting diastereomers, a racemate, respectively in optically pure antipodes, as well as mixtures thereof.

The above stages can be conducted in of the compounds of General formula (I) and (II) receive substituted derivatives of General formula (V), in which R4denotes H, subjecting the condensation of the compound of General formula (III) in which R1and R2denote hydrogen, lower linear or branched alkyl or branched in the alkyl chain or unbranched aryl, respectively aralkyl and alkylaryl, arylcarbamoyl and aralkylamines or General (R1=R2=- CH2-) alkyl group, or a combination of these residues, X1represents H, fluorine, chlorine, bromine, iodine, tert-butyl, with tyramine or substituted by tyramine (R3denotes a lower linear or branched alkyl, aryl or branched in the alkyl chain or unbranched aralkyl and alkylaryl, arylcarbamoyl and aralkylamines). You can proceed as follows.

Equimolar solution of compounds (III) and (IV) in toluene, xylene or benzene, or mixtures of these solvents with higher alcohols, preferably toluene and n-butanol, at a ratio of from 9:1 to 1:9, preferably 1:1, at a concentration of from 1 to 30%, is subjected to the interaction at the temperature of reflux distilled and separated water. The solvent is then separated by distillation and more than 95% recovered, the residue is dissolved in alcohol, for example methanol, ethanol, n-propanol, isopropyl the om in methanol, at a concentration of from 1 to 30% and restore, adding portions from 0.6 to 5 equivalents, preferably from 0.65 to 0.7 equivalent of reducing agent such as sodium borohydride, Lamborghini sodium, LiAlH4and their mixtures, but mainly sodium borohydride 4 in the form of a powder or granulate at a temperature of from -30oC to the temperature of reflux distilled. The product of the condensation of (V) is filtered by output from 80% to 85% in the form of a first fraction of the alcohol solution. The concentration of alcohol solution by distillation up to 15-30% of the volume and filtering the 2nd fraction increases output up to 90-95% of theory. Alternatively, the reaction solution may be poured on the water, while precipitated crystalline product (V), and after separation and drying receive the product with the yield up to 95%.

2. N-formirovanie, respectively, the N-protective group

The original connection for the oxidative cyclization of formula (V) in which R4denotes formyl, and unsubstituted or substituted by one or more halogen, linear or branched aralkyl, alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl get vzaimoreklamy, halides, azegami, carbonates or other reactive derivatives of these protective groups.

In particular, the compound of General formula (V), where R4denotes H, may be subjected to interaction in solvents such as tetrahydrofuran, dioxane, dimethylformamide, toluene, xylene, or mixtures of these solvents, ethyl formate, taken in an amount of from equimolar to 50-fold molar, and catalytic amounts of formic acid (0.001 to 1 equivalent) at a temperature of from 0oC to the temperature of reflux distilled to obtain compounds of General formula (V), where R4indicates CHO. In this method, the solvent is removed by vacuum distillation, the residue after distillation is crystallized by batch addition of water and ice and get the product after filtering with the release of above 90% and more than 95%.

3. Bromination

If compounds of General formula (V) in which R1, R2and R3denote the lower linear or branched alkyl, aryl, aralkyl, alkylaryl, arylcarbamoyl, aralkylamines, X1X2denote H, R4denotes formyl, and unsubstituted or substituted by one or more halogen, linear or rasvet oxycarbonyl, alkylsulfonyl, aralkylamines, arylsulfonyl, with a content of from 90 to 100 % in mixtures of solvents are halogenated hydrocarbons such as chloroform or methylene chloride, alcohols (methanol, ethanol, methylglycol, ethylglycol, ethylene glycol, n-propanol, isopropanol) at a ratio of from 9:1 to 1:9, preferably from 3:2 to 2:3, as well as of pure alcohols (methanol, ethanol, methylglycol, ethylglycol, ethylene glycol, n-propanol, isopropanol and their mixtures with each other, preferably ethanol/methylglycol, at a ratio of from 9:1 to 1:9, preferably from 3:2 to 2:3 with a water content of from 0 to 5%, preferably from 0 to 0.2%, at temperatures from -80 to +60oC, preferably from -40 to 0oC, at a concentration of from 0.5 to 20 g/100 ml of solvent is subjected to interaction with 1.0 to 3.0, preferably from 1.4 to 1.7 equivalents brainwashes agent obtained by adding elemental bromine in these solvents at a concentration of from 1 to 90%, preferably from 2 to 10%, while adding brainwashes agent is from 10 minutes to 4 hours, preferably from 15 to 30 minutes after a reaction time of 0.5 to 24 hours, preferably from 30 to 60 minutes after treatment (concentration by distillation up to 10-25% volume and pouring in 10-50-KRA is where X1means Br.

The intermediate compounds of formula (V) in which X1denotes Br, R4represents CHO or multi-brominated intermediates.

Path 1 (see General scheme): when bromirovanii compound of formula (V), where X1X2denote H and R4indicates CHO, in accordance with work instructions to receive, for example, 82% of the product, 6% of the educt, 8% by-product, in which X2denotes Br, and 5% vysokoobrazovannogo product (high performance liquid chromatography HPLC Lichrosorb RP 18, 5 μm, 300/4 mm in solvent MeOH/H2O 6:4 at 280 nm). When changing a method of synthesized also changes and the relationship of these products (for the most part, an increasing share of visbreaking products). After oxidative cyclization in the educt find, along with the desired compound of General formula (I), where X1denotes Br, R4indicates CHO and Y1, Y2denote O, in an amount corresponding to the amount of compounds of General formula (V) in which X1X2each represent Br, R4indicates CHO (HPLC, Lichrosorb Si 60, 10 μm, 300/4 mm, solvent system: CHCl3:MeOH 95:5 at 254 nm) and emit using preparationtime vysokopetrovsky narogin (X1=X2=Br) or restore to galantamine or singled out using preparative chromatography.

Path 2 (see General scheme). Based on paratroopa aldehyde 6-bromo-isovanillin can be obtained by condensation of N-formirovanie compound of formula (V) in which X1denotes Br, R4indicates CHO, without vysokoobrazovannyh products.

4. Oxidative cyclization of

For the oxidative cyclization of compounds of General formula (V) in which R2denotes hydrogen, a lower branched or linear alkyl, aryl or branched in the alkyl chain or unbranched aralkyl and alkylaryl, arylcarbamoyl and aralkylamines or a combination of these residues, X1represents H, fluorine, chlorine, bromine, iodine, tert-butyl, R4denotes formyl, and unsubstituted or substituted by one or more halogen, linear or branched aralkyl, alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl, R3denotes hydrogen to compounds of General formula (I) in which R2, R4X1have the above value, Y1, Y24, KMnO4, FeCl3, potassium ferricyanide, H2O2preferably the potassium ferricyanide, in the amount of 4 to 10 equivalents, preferably 5.5 to 6 equivalents, if necessary with addition of catalysts phase transfer, such as the aliquot or crown ether, as well as ascorbic acid, CuCI2or triperoxonane acid, at temperatures from -40oC to the temperature of reflux distilled mainly from 50 to 80oC, and fast or portions of the addition of the educt in the form of a solid, solution or suspension in a solvent, preferably in the form of a solid substance, with a duration of response of 10 minutes on the second, and the homogenizer, if necessary, in the atmosphere of inert gas, for example, N2, CO2, argon, mainly in argon atmosphere. In the subsequent processing by filtration, phase separation and vacuum distillation, toluene phases get the crude product with the release of 5-65%, which distinguish by cleaning the cyclization product with the release of 5-50%.

5. Recovery

To restore the compounds of General formula (I) in which R2denotes a lower linear or branched alkyl, aryl, aralkyl, alkylaryl, arylcarbamoyl, aralkylamines, X1X2denote fluorine, chlorine, bromine, iodine, tert-butyl, R4denotes formyl, and unsubstituted or substituted by one or more halogen, linear or branched aralkyl, alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl, and Y1, Y2indicate On the type panarodea, you can work with a hydride reagent such as DiBAL-H, DiBAL-H/ZnCl2, Al-isopropylate, Red-Al, K-selectride, L-selectride, KS-selectride, LS-selectride, Li-tri-tert-butoxy-AlH, Li-triethoxy-AlH, 9-BBN, superseded, NaBH4, Zn(BH4)2, AlH3Oia reductant in equimolar amounts or in excess to the original product or, on the contrary, by adding the original product to the reducing agent in an inert solvent, such as diethyl ether, tetrahydrofuran, dioxane, toluene, xylene, benzene, at temperatures from -50oC to the temperature of reflux distilled. After alkaline (mainly NH4OH), respectively sour (mainly 2 N. HCl) processing and subsequent extraction with solvents, such as toluene, xylene, benzene, ethyl acetate, ether, chloroform or methylene chloride, the crude product is purified chromatographically and, if necessary, allocate the diastereomers, or raw foods directly subjected to further interactions.

In particular, the recovery bromo-N-formylmorpholine (in contrast to the method described by W. C. Shien, J. A. Carlson, J. Org.Chem. 59, 5463-5465, (1994), where use Norwegen) L-selectride or K-selectride selectively receive after purification on a chromatographic columns the diastereoisomer of N-dimethylpropanolamine with the release of 70-85% of theory. Chromatographic methods were unable to detect an EPI-N-dimethylpropanolamine.

N-dimethylpropanolamine transferred to bronholitin N-methylation, for example, by boiling from 10 minutes to several hours in the 5-50 - fold excess of formic acid and Bodmin, for example, heating for 1 to 10 hours at the temperature of reflux distilled from 5-50-fold excess of formic acid and triethylamine in the presence of 0.1-15% palladium catalyst on charcoal with the removal of bromine. Yield: 70-80% of theoretical.

The reaction can be carried out without isolation and purification of intermediate products.

Restoring doctow by Li-tri-tert-butoxy-AlH allows to obtain a mixture of N-dimethylpropanolamine and epidemiologically in the ratio of 1:1.

When restoring via DiBAL-H receive 43% of bragantina and 41% of epibromohydrin.

Recovery by Li-AlH/anhydrous H2SO4also results in bronholitin and epibromohydrin in the ratio of 1:1.

When restoring, you can work as specified below.

To restore the compounds of General formula (I) in which R2denotes alkyl, X is Br, R4indicates CHO, X2denotes H, Y1, Y2represent = O (ketone), educt is dissolved in a solvent, for example tetrahydrofuran, dioxane or other ethers, primarily in tetrahydrofuran, in concentrations of from 0.1 to 20 g/100 ml by heating. C is mainly 3.5 equivalent L-selectride, mainly in the form of a 1-molar solution in tetrahydrofuran, stirring, conduct the reaction at 0-20oC from 20 minutes to 48 hours, preferably within 1 hour. The complex formed with the reducing agent is destroyed by adding water and ammonium hydroxide, and distilled off the excess organic solvent by heating in vacuum up to a maximum of 30oC. Extraction with solvents, such as ether (e.g. diethyl ether), ethyl acetate, butyl acetate, chloroform, methylene chloride, toluene, benzene or xylene allows to obtain N-dimethylpropanolamine to the outputs of the crude product from 90 to 100% of theoretical.

For monomethylamine N-dimethylpropanolamine a solution of N-dimethylpropanolamine in 5-30-fold molar excess of formic acid and aqueous formaldehyde solution (37%) is heated with an organic solvent or without it for 10 minutes to 2 hours, mostly 15 to 20 minutes, until the temperature of the reflux distilled.

For dibromononane of bragantina or epibromohydrin bromo-, respectively epibromohydrin heated in 5-50-fold molar excess of formic acid and triethylamine with an organic solvent or in the presence of 0.1-15% palladium catalysate reflux distilled.

To restore the compounds of General formula (I) in which R2denotes alkyl, X1denotes Br, R4indicates CHO, X2denotes H, Y, Y2represent = O (ketone), educt is suspended in an inert organic solvent, for example benzene, toluene or xylene, mainly toluene in a concentration of from 0.1 to 20 g/100 ml and at a temperature of from -50oC to the temperature of reflux distilled is added dropwise from 3 to 5 equivalents, mainly 3.5 equivalent of DiBAL-H in the form mainly of a 1.5-molar solution in toluene. Then stirred at this temperature for 20 minutes to 12 hours, mostly between 30 minutes to 1.5 hours, the resulting complex is destroying water and ammonium hydroxide, extracted with toluene and the crude product (90-100% of theory) separated through column chromatography (silica gel, acetone/hexane 1:1) 43% of bragantina and 41% of epibromohydrin.

6. Separation of optical isomers

For the separation of chiral 4a, 5,9,10,11,12-hexahydro-6N-benzofuro/3A, 3,2-ef//2/benzazepine General formula (I), (Y1=H, HE; Y2=OH; HE), in which A, R2, R4X1X2have the above values, enantiomerically-pure antipodes can be used FR the new type (compounds of General formula (I), in which Y and Y2indicate together =O (ketone) by fractionated crystallization is carried out in such a way that the solution or suspension of a mixture of optical isomers in the 5-50-fold amount of solvent, for example, water, methanol, ethanol, propanol, isopropanol, acetone or mixtures of these solvents, preferably methanol, is mixed with an equimolar amount or excess of the chiral acid (unsubstituted, substituted one or more times (+) or (-) tartaric acid, citric acid, lactic acid, alpha-methoxyphenylacetic acid, campocologno acids and their derivatives, preferably di-p-tolyl-(+) tartaric acid), dissolved in one of the above solvents, the solution is injected seed crystal, obtained from natural derivative (-) galantamine and chiral organic acids, for example, di-p-tolyl-(+) tartaric acid, and maintained at a temperature from -40 to +20oC, preferably at 0oC for 2-24 hours or longer, filtered and the resulting crystals are dried, then mixed with an excess of NH4OH and extracted with an organic solvent, such as chloroform, methylene chloride, ethyl acetate, butyl acetate, diethyl ether, tert-Besut distillation of the solvent corresponding derivative (-)-galantamine.

This way, by concentrating the mother liquor, adding in excess of NH4OH, extraction with an organic solvent (as described above) and evaporation receive subsequent fraction galantamine, of which a similar way using chiral organic acids, such as di-p-tolyl-(-) tartaric acid can be obtained derivative (+) galantamine.

The products obtained according to the invention can be purified using conventional in the chemistry of ways, for example by means of fractional distillation, crystallization or chromatography.

Known /W. C. Shieh and J. A. Carlson, J. Org. Chem. 1994, 59, 5463-5465/ that (-)galantamine is a selective inhibitor of acetylcholinesterase and enhances cholinergic function and can be considered as the treatment of persons suffering from Alzheimer's disease.

To obtain a pure enantiomer (-) galantamine is proposed to mix (+/-)norwegin in solution with a catalytic amount of seed crystals of (-) navedena or (+) galantamine and left to crystallize. The solution containing (+/-) narogin, distilled (- )norwegin in the form of white crystals. For translation (-) navedena restoration (-) galantamine pretem diastereoselective crystallization, restore stereospecific L-selectride at -78oC with almost 99% yield up to (-)galantamine. For the two-stage method (crystallization and recovery) are known to 90% of total output transformations of racemic navedena in (-)galantamine. On receipt of (+/-) navedena known method (R. A. Holton, M. P. Sibi, W. S. Murphy, J. Am. Chem. Soc. 110, 314 (1988)), which requires a stoichiometric amount of palladium and thallium.

The disadvantage of this method is, among other things, that the restoration should be carried out in the described conditions at -78oC. furthermore, it describes only aluminosilicate (285 mg of educt), which is obtained in a 200-fold amount of solvent and chromatography purified using system CH2Cl2/methanol (6:1).

At the end of the description describes the scheme of the reaction according to the claimed methods.

According to one variant of the method according to the invention, it is possible to obtain norwegin based on cyklinowanie compounds of General formula (I) in which Y1, Y2means = O (ketone), by introducing a cyclic Catala as a protective group (Y1, Y2denote substituted or unsubstituted cyclic ketal or thioketal, naprilene Catalinas protective group. The racemic narogin (or the compound of General formula (I) in which Y1, Y2represent = O (ketone) may be enriched by the addition of catalytic amounts of (+)galantamine or (-)navedena, obtaining (-)navedena with an enantiomeric purity of more than 98%.

The advantage of this method according to the invention is that the undesired enantiomer can be translated into the desired enantiomer.

In the same way by adding catalytic amounts of (-)galantamine or (+)navedena the racemic norwegin can be enriched in (+) norwegin. Enriched norwegin translate L-selectride with a good yield in pure enantiomeric galantamine, and by appropriate processing can be obtained either free base or directly to the hydrobromide. Crystallization hydrobromide allows you to get galantamine hydrobromide content enantiomer over 99%. The determination is carried out by measuring the rotation angle of the polarization plane and the quantification of the enantiomers by microcapillary electrophoresis in chiral electrolyte.

The above stages can be carried out as an example as follows.

1, Y2represent =O (ketone), X1denotes Br, and R1indicates CHO, in solvents, such as benzene, toluene, xylene, but mainly toluene, together with 1-30-fold amount of diols, such as ethylene glycol, propylene glycol, or developed, such as 1,3-citypaper, in the presence of catalytic amounts of p-toluenesulfonic acid or concentrated sulfuric acid or other acid is heated for several hours in the water separator to the temperature of reflux distilled. Then cooled, diol phase (dithiolene phase) is separated, extracted with toluene and pariva Toloraya phase, allocate the received ketal (thioketal).

8. Restoration, removal of protective groups

Purified or crude ketal (thioketal) of General formula (I) (mainly so X1denotes Br, and R4indicates CHO), restore using LiAlH4and subsequent removal of Catalinas group is transferred to norwegin. For example, propylenglykolether compounds of General formula (I) is dissolved in tetrahydrofuran, mixed with 3-5-fold stoichiometric amount of LiAlH4and heated for 12 hours at the temperature of reflux distilled. It also allows, if necessary, to produce Simeon, filtering and extragere with ethyl acetate, get catalizadores compound of General formula (I) Narodnogo type. Heating the crude product in acid, mainly in 2 N. hydrochloric acid, and Podlachia through NH4OH, get the compound of General formula (I) Narodnogo type with good yield (approx. 80%). If you mix with LiAlH4at a temperature of from -10 to 0oC for 2 hours, then to hydrolyze NH4OH and extracted with ethyl acetate, you can get metalizowany N-dimethylpyridin. Compared with the recovery of L-selectride formed intermediate compound of General formula (I) in which R4denotes CH2Is IT that when hydrolysis decomposes and gives N-demethylase connection. Processing it in 2 N. HCl, you can remove catalog group and get the connection type dimethylpyridine. Alkylation of O-protected or unprotected connections dimethylpyridine or the introduction of the N-protective group and cleavage Of the protective groups, if present, gives variously substituted Narodny General formula (I) in which Y1and Y2represent =O (ketone), R4denotes a substituted or unsubstituted alkyl, alkenyl, quinil, aryl, aralkyl, accordingly any using Zn/CaCl2you get N-substituted compounds of the type navedena.

If a compound of General formula (I) in which Y1and Y2denote ethylenglykolether, heat with LiAlH4in tetrahydrofuran 12 hours at the temperature of reflux distilled, formed respectively metalizowany norwegin. If educt be heated 24 hours at the temperature of reflux distilled (65-68oC), the cyclic structure Catala is opened and the product is obtained in which Y1denotes-CH2-CH2HE and Y2denotes H, which, however, can also be transferred brief heating in acid, mainly 2 N. HCl, connection type navedena.

Interestingly, the recovery with LiAlH4at 0oC leads to the formation of dimethylpyridine, at 45oC - education of nurodykite, when 70oC and for 48 hours to education hydroxyethylamide ether galantamine and 45-75oC and subsequent treatment with hydrochloric acid (splits ketal) to education navedena.

Recovery catalizadores compounds of General formula (I) in which X1denotes Br, R4indicates CHO, using Zn/CaCl2leads to the recovery of bromine, to the elimination of Catalina is ormula (I), in which Y1, Y2represent = O (ketone), R4denotes CH3is heated in a solvent such as water, methanol, ethanol, n-propanol, butanol, etilenglikol, ethylene glycol or mixtures of these solvents with 1-30% triethylamine or similar grounds to the temperature of reflux distilled, mixed with optically pure compounds, for example, (+) - galantamine or (-)narodnom. For (-) navedena used, for example, either (+)galantamine, or (-)narogin, for (+) navedena used, for example, (-)galantamine or (+)norwegin and slowly stepped cooled.

Preferably stirred for from one to 14 days at 40oC, then cooled to 0 to 20oC, separating the precipitated optically enriched crystals and determined by microcapillary electrophoresis content enantiomer, which is more than 98%. Thus, for example, for navedena the rotation angle of the polarization plane of light reaches 405-407o(20oC= 1/CHCl3). Define by microcapillary electrophoresis in chiral electrolyte gives the value of the content of more than 98% of the enantiomer.

10. Recovery

Pure enantiomeric compound Narodnogo type (Y1, Ythe collective in pure enantiomeric compound galantamine type (Y1or Y2denote IT). Treatment of aqueous HBr allows to obtain the corresponding hydrobromide galantamine content enantiomer above 99% when 87-95% of theory.

11. The removal of bromine

The compound of General formula (I) in which X1denotes Br, dissolved in 5-50-fold amount of solvent, such as water, methanol, ethanol, n-propanol, isopropanol, n-butanol butanol or mixtures thereof, mainly 70% ethanol, add 1-5-fold amount of powdered zinc and 1-10 times the amount of CaCl2and mix. Later on average approx. 1-2 hours the solid is filtered off, the solution evaporated and chromatographic (silica gel 60, solvent, e.g. acetone), getting 80-85% dibromononane product.

Unlike described by W. C. Shieh J. Org.Chem. 1994, 59, 5463-5465 method was able to improve the way so that it can be implemented on an industrial scale. For example, the educt in powder form preferably added to 1-molar solution of L-selectride in tetrahydrofuran at room temperature, stirred for one hour, mixed with methanol and evaporated. Isolated in ethanol (e.g., 5-30-fold amount) and podkisst aqueous HBr, get Hydrobromic which partially leads to the production of new compounds, accordingly, the formation of new compounds as intermediates.

Assigned to these compounds rooms are also used in the schemes of reactions, which are given at the end of the description.

Another variant of the method of obtaining racemic compounds Narodnogo type, according to the invention, lies in the fact that the compound of General formula (Ia)

< / BR>
in which R2, R4X1X2have the meanings indicated in the General formula (I), Z1and Z2denote O, S, N and Y1, Y2represent =O (ketone), obtained by oxidative cyclization of compounds of General formula (Va)

< / BR>
in which R1, R2, R3, R4X1X2have the meanings indicated in the General formula (V), Z1and Z2denote O, S, n

Then translate the same as the above stage 7 in ketal, or thioketal, or cyclic ketal, or cyclic thioketal, restore a reducing agent, such as LiAlH4similar to the above stage 8), isolated in the form of ketala or thioketal or translate preferably acidic hydrolysis into the corresponding connection Narodnogo type. The reaction scheme is shown in the overview "Synthese von Narwedin uber Benzazepinon-Typ (Z
< / BR>
in which R2, R4X1X2, Z1and Z2have the meanings indicated in the General formula (Ia) and R7corresponds applied to obtain Catala alcohol or thiol, for example, -O-CH2CH(CH3)-HE (propylene glycol residue).

When restoring the compounds of General formula (Ia) in which R2, R4X1X2have listed in the General formula (I) values, Z1, Z2denote O, S, N and Y1, Y2represent = O (ketone), L-selectride get compound of formula (Ia) in which Y1IT denotes, and Y2denotes H.

The recovery of the compounds of formula (Ia) in which Y1, Y2represent =O, using LiAlH4gives a mixture of galantamine type (Y1= HE, Y2= N) and aprehentions type (Y1= H, Y2= HE) in a ratio of about 5:3, and X1X2= Br to restore X1X2= H and Z = O restore to Z = H2.

Described variant of the method partially leads to the production of new compounds:

< / BR>
< / BR>
< / BR>
Below are examples of the implementation of the methods according to the invention.

Example 1

N-(4-hydroxyphenethyl)-(3-hydroxy-4-methoxy)benm 5-liter vessel with double walls suspended to 217.5 g (1,43 mole) of isovanillin and 200 g (1,45 mole) tiramina 2.5 l of toluene/n-butanol (1:1) and heated with the Department of water to the temperature of reflux distilled. After 4 hours the solvent is distilled off in vacuum, the residue is collected in 2.5 l of methanol and the clear solution is mixed with 25 g of NaBH4(of 0.66 mol). The reaction mixture was stirred at 0oC, the precipitation is filtered off, washed with methanol and dried.

Output: 332,3 g (85.1%) are

Melting point: 176-178oC

Molecular weight: C16H19NO3: 273,32.

Example 2

N-(4-hydroxyphenethyl)-(6-bromo-3,4-dimethoxy)benzylamine (General formula (V) in which R3=R4= X2=H, R1=R2=Me, X1=Br)

In a 100-ml round bottom flask suspended of 2.45 g (10 mmol) of 6-bromo-3,4-dimethoxybenzaldehyde and 1,37 (10 mmol) of tiramina in 50 ml of toluene/n-butanol (1:1) and heated with the Department of water to the temperature of reflux distilled. After 3 hours, the solvent is distilled off in vacuum, the residue is collected in 50 ml of methanol and the clear solution is mixed with 0.8 g of NaBH4. The reaction mixture is stirred for 4 hours at 0oC, the solvent is distilled off in vacuum, the residue is collected in 100 ml of CH2Cl2and the organic phase is washed twice with water (2 x 10 ml of water). The organic phase is dried over Na2SO4, filtered and the solvent is removed under vacuum. The remainder chromatographic on 150 g of silica gel in a mixture of hexane:ethyl is : 333,23.

Example 3

N-(4-hydroxyphenethyl)-(4-methoxy-3-methoxyethoxy)benzylamine (General formula (V) in which R1=MeOCH2O, R2=Me, X1X1=X2=X3=X4=R3=R4=X2=H)

In a 100-ml round bottom flask suspended 0,83 g (4.2 mmole) of 4-methoxy-3-methoxysalicylaldehyde /16-17/ and 0.55 g (4.0 mmole) of tiramina in 50 ml of a mixture of toluene/n-butanol (1: 1) and heated with the Department of water to the temperature of reflux distilled. After 4 hours the solvent is distilled off in vacuum, the residue is collected in 50 ml of methanol and the clear solution is mixed with 0.35 g NaBH4. The reaction mixture is stirred for 4 hours at 0oC, the solvent is distilled off in vacuum, the residue is collected in 100 ml of CH2Cl2and the organic phase is washed twice with water (2 x 10 ml of water). The organic phase is dried over Na2SO4, filtered and the solvent is removed under vacuum. The remainder chromatographic on 65 g of silica gel in a mixture of hexane:ethyl acetate (7:3).

Yield: 1.12 g (of 83.4 %) of viscous oil

Molecular weight: C18H23NO4: 317,37.

Example 4

N-(4-hydroxyphenethyl)-(6-bromo-3-hydroxy-4-methoxy)benzylamine (General formula (V) in which R1=R3=R4=H, X2=H, R2=Me, X1=Br)

Method 1:

In a 50 ml in 20 ml of a mixture of toluene/n-butanol (1:1) and heated with the Department of water to the temperature of reflux distilled. After 90 minutes, the solvent is distilled off in vacuum, the residue is collected in 20 ml of methanol and the clear solution is mixed with 0.33 g of NaBH4. The reaction mixture is stirred for 4 hours at 0oC, the solvent is distilled off in vacuum, the residue is collected in 50 ml of CH2Cl2and the organic phase is washed twice with water (2 x 10 ml of water). The organic phase is dried over Na2SO4, filtered and the solvent is removed under vacuum. The remainder chromatographic on 60 g of silica gel in a mixture of ethyl acetate:methanol in the ratio(97:3) - (95:5).

Output: 1,43 g (93,8%).

Method 2:

In a 1-liter round bottom flask suspended 53,38 g (231 mmol) of 6-bromo-4-methoxy-3-hydroxybenzaldehyde /18/ and 31.7 g (231 mmol) of tiramina in 530 ml of a mixture of toluene/n-butanol (1:1) and heated with the Department of water to the temperature of reflux distilled. After 90 minutes, the solvent is distilled off in vacuum, the residue is collected in 350 ml of methanol and the suspension is mixed with 12 g of NaBH4. The reaction mixture is stirred 1 hour at 0oC and added dropwise to 3 l of ice water. After 30 minutes of stirring the precipitated product is filtered, washed twice with water (2 x 10 ml of water) and dried in a drying Cabinet at 60oC.

Output: to 70.2 g (86,3%)

Melting point: 122-125oC.

Molecules is 554,48 s; 3200-3370 br.

1H-NMR (DMSO-d6): 7,0-6,60 (m, 6H), 6.73 x (m, 2H); of 3.77 (s, 3H), 2,75-of 2.58 (m, 4H), 2,88 (s, 20H).

13NMR (CDCl3+DMSO-d6): 155,46 s, 147,28 s, of 145.95 s, 130,56 s, 129,68 s, 129,12 2d, 116,93 d, 115,61 d, 114,99 2d, 110,95 s, 55,85 q, 51,76 t, 50,16 t, 34,50 t.

Example 5

N-(4-hydroxyphenethyl)-(4-methoxy-3-tert-BUTYLCARBAMATE)benzylamine (General formula (V) in which R1=Me3CO.,

R2=Me, X1=X2=R3-R4H)

In a 50 ml round bottom flask suspended 3,63 g (of 16.5 mmole) (4-methoxy-3-tert-BUTYLCARBAMATE) (benzaldehyde and of 2.06 g (15 mmol) of tiramina in 32 ml of a mixture of toluene/n-butanol (1:1) and heated with the Department of water to the temperature of reflux distilled. After 3 hours, the solvent is distilled off in vacuum, the residue is collected in 32 ml of methanol and transparent solution is mixed from 1.32 g of NaBH4. The reaction mixture is stirred for 4 hours at 0oC, the solvent is distilled off in vacuum, the residue is collected in 50 ml of CH2Cl2and the organic phase is washed twice with water (2 x 10 ml of water). The organic phase is dried over Na2SO4, filtered and the solvent is removed under vacuum. The remainder chromatographic on 140 g of silica gel in a mixture of ethyl acetate:methanol in the ratio(9:1) - (8:2).

Yield: 1.7 g (28.8%) of a viscous oil.

Molecular weight: C1
=R3=X1=X2=H, R2=Me, R4=CHO)

A 10-liter 3-necked flask (drip funnel, the reflux condenser, bubble counter, the venting tube) load 370 g (of 1.35 mmole) of compound V (R1=R3=R4=X1=X2=H, R2=Me), 5 l technical dioxane and 370 ml technical dimethylformamide. An addition funnel filled with a mixture of 1100 ml (13,66 mole) HCOOEt and 10 ml of HCOOH, the suspension is stirred in an argon atmosphere with magnetic stirrer and heated to boiling. The inside temperature of the flask rises from 100 to 103oC, and the suspension becomes homogeneous. To this solution for 20-30 minutes, add a solution from a dropping funnel. The internal temperature is reduced to 87-89oC. the Cloudy reaction mixture is stirred for 4 hours at the temperature of reflux distilled. The solvent is removed in vacuo and the residue portions mixed with 8 l of ice water. The precipitated crystals filtered, washed with water three times (3 x 2 l water) and dried in vacuum for 12 hours.

Output: 360,5 (88,6%)

Melting point: 144-148oC

Molecular weight: C17H19NO4: 301,33.

Example 7

N-formyl-N-(4-hydroxyphenethyl)-(6-bromo-3,4-dimethoxy)-benzylamine (General formula (V the funnel, the reflux condenser, bubble counter, the venting tube) boil the mixture 4,53 g (12.2 mmole) of compound V (R3= R4=X2=H, X1=Br, R1=R2=Me), 100 ml technical dioxane, 10.0 ml (122,0 mmole) HCOOEt and 0.1 ml of HCOOH under reflux. After 68 hours the solvent is removed in vacuum and the residue is crystallized from 40 ml of MeOH.

Output: 3,61 g (75%)

Melting point: 160-162oC.

Molecular weight: C18H20BrNO4: 394,24.

Example 8

N-formyl-N-(4-hydroxyphenethyl)-(4-methoxy-3-tert-BU-tinkerbelle) benzylamine (General formula (V) in which R1=Me3CO., R2=Me, X1=X2=R3=H, R4=CHO)

In a 500-ml 3-necked flask boil a mixture of 1.7 g (4.7 mmole) of the compound of formula V (R1Me3CO., R2=Me, X1=X2=R3=R4=H), 7.5 ml of technical dioxane, 7.5 ml HCOOEt and one drop of HCOOH under reflux. After 15 hours the solvent is removed in vacuo and the residue chromatographic on 30 g of SiO2using AcOEt.

Yield: 1.5 g (81,8%) oil

Molecular weight: C22H27NO5: 385,44.

1H-NMR (CDCl3): 8,20 and 7,80 (2s, 1H), 7,16-to 6.80 (m, 7H), 4,30 (d, 2H), of 3.78 (s, 3H), at 3.35 (m, 2H), 2,70 (m, 2H), to 1.38 (s, 9H).

13C-NMR (CDCl

Example 9

N-formyl-N-(4-hydroxyphenethyl)-(6-bromo-3-hydroxy-4-methoxy) benzylamine (General formula (V) in which R1=R3=X2=H, X1=Br, R2=Me, R4=CHO)

Method 1:

In a 500-ml 3-necked flask (drip funnel, the reflux condenser, bubble counter, the venting tube) boil a mixture of 27 g (76,6 mmole) of the compound (V) (R1= R3=R4=X2=H, X1=Br, R2=Me), 300 ml of technical dioxane, 30,0 ml (or 37.2 mmole) HCOOEt and 0.1 ml of HCOOH under reflux. After 72 hours the solvent is removed in vacuum and the residue is crystallized from 50 ml of chloroform.

Output: 23,95 g (82.3 per cent)

Method 2:

300 g of compound (V) (R1=R3=X1=X2=H, R2=Me, R4=CHO) is dissolved in 2000 ml of anhydrous ethanol and 2000 ml of methylglycol (water less than 0.1%) by heating to 40oC, then cooled to -20oC for 15 minutes was added dropwise 14 ml of bromine in 1000 ml of a mixture of ethanol/methylglycol (1:1), so that the temperature does not exceed -20oC. and Then stirred for 30 minutes at -20oC, and the solution was concentrated to approx. 1000 ml and with vigorous stirring, poured into 30 liters of water with ice. 4 hours and stirred at 0oC, isolated and dried colorless crystalline substance in vacuum (60/BR> Molecular weight: C17H18BrNO4: 380,22.

Example 10

N-formyl-N-(4-hydroxyphenethyl)-(4-methoxy-3-methoxy-methoxy) benzylamine (General formula (V), in which

R1=MeOCH2O, R2=Me, X1=X2=R3=H, R4=CHO)

In a 50 ml 3-necked flask (drip funnel, the reflux condenser, bubble counter, the venting tube) boil the mixture of 4.9 g (15.4 mmole) of the compound (V) (R1= MeOCH2O, R1=Me, X1=X2=R3=R4=H), 60 ml HCOOEt, one drop of HCOOH under reflux. After 18 hours the solvent is removed in vacuo and the residue crystallized from AcOEt/hexane.

Output: 3,95 g (74%)

Melting point: 102-104oC.

Molecular weight: C19H23NO5: 345,38.

1H-NMR (CDCl3): 8,23 and 7,83 (2s, 1H), 7,05-6,70 (m, 7H), 5,20 (s, 2H), 4,46, and 4,28 (2s, 2H), a 3.87 (s, 3H), 3,52 (s, 3H), 3,38 (m, 2H), 2,70 (m, 2H).

13C-NMR (CDCl3): 163,20 and 162,86 d; 155,41 and 155,05 s; 149,53 and 149,30 s; 146,53 and 146,33 s; 129,66 and 129,59 s; 129,52 d; 128,56 and 128,02 s; 122,40 d; 121,64 d; 118,71 d; 115,88 d; 115,60 and 115,33 d; 111,75 d; 95,39 t; 56,13 q; 55,79 q; 51,44 and 48,62 t; 45,10 and 43,71 t; 33,72 and 32,27 t.

Example 11

4A, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-formyl-6H-benzofuro /3a, 3,2-ef//2/benzazepin-6-(General formula (I) in which R2=Me, R4=CHO, X1= and K2CO3add in the 70oC immediately 120 g (0,316 mole) of pulverized into fine powder of compound (V) (R1=R3=X2=H, X1=Br, R2=Me, R4=CHO). Then the reaction mixture is intensively stirred at the same temperature for 30 minutes with the connection of the homogenizer, and precipitates of insoluble product. The reaction mixture is filtered, the organic phase is dried over Na2SO4, filtered and the solvent is removed in vacuum.

Output: to 59.6 g (49.9 percent)

If cyclization is used educt, obtained according to example 9, method 2, after separation by column chromatography (silica gel 60, CHCl3/MeOH (1-5%)) receive a by-product of General formula (I) in which R2=CH3X1=X2=Br, R4=CHO, Y1,Y2=O with 6% yield.

1H-NMR (CDCl3): 8,23 (d, 1H), 7,30 (s, 1H), 6,98 (s, 1H), 5,85-3,95 (m, 3H), 4,70 (s, 1H), 3,80 (s, 3H), at 3.35 (m, 2H), 2.95 and (m, 1H), 2,15 (m, 2H).

13C-NMR (CDCl3+ d6): 185,31 + 185,25 s, 162,43 and 161,43 d; 147,12 and 146,84 s; 144,61 and 144,37 s; 142,33 and 141,97 d; 129,27 and 129,13 s; 126,62 and 126,40 s; 123,40 and 123,25 s; 116,67 and 116,46 d; 114,27 and 112,74 s; 87,00 and 86,86 d; 56,01 q; 52,38 and 51,55 s; 46,18 and 45,80 t; 40,58 t; 37,68 and 36,86 t; 34,26 t.

Example 12

(4,6)-4A, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6N-benzofuro /3A, 3,2-ef//2/benzene
Method 1:

In a 1-liter 3-necked flask is charged with 4.6 g (121,21 mmole) LiAlH4in 80 ml of absolute tetrahydrofuran and cooled to 0oC. To this suspension within 5 minutes added dropwise under vigorous stirring of 7.36 g (19,47 mmole) of the compound (V) (R1=H, R4=CHO, X1=Br, Y1,Y2=0) in 460 ml of absolute tetrahydrofuran, stirred for 1 hour and boiled for 21 hours under reflux. The reaction mixture was then transferred into a 1-liter odnogolosy flask and remove the solvent in vacuo. The residue is mixed with water and with 2 n HCl solution was adjusted pH to 1. The reaction solution is shaken and heated until then, until you dissolve the precipitate. Then use 2 N. NaOH pH adjusted to 9, a cloudy solution is mixed with ethyl acetate, shake well and loose precipitate is filtered off. The organic phase is separated and the aqueous phase extracted with ethyl acetate. The combined organic phases are dried over Na2SO4filter and remove the solvent in vacuo. The residue is chromatographically purified (300 g SiO2, CHCl3:MeOH 97:3 to 95:5) to give colorless crystals.

Output: 2,23 g (40,03%)

Method 2:

To a suspension of 240 mg (6.3 mmole) LiAlH4in 4 ml of absolute tetrahydrofuran was added drop=HE) in 4 ml of anhydrous tetrahydrofuran, stirred for 1 hour at room temperature and then 23 hours at the temperature of reflux distilled. The reaction mixture was then cooled to 0oC, the excess reducing agent is decomposed with water, diluted with 50 ml ethyl acetate and 50 ml (CC) NH4OH. After shaking the precipitation is filtered, the organic phase is separated and the aqueous phase washed with ethyl acetate. The combined organic phases are dried over Na2SO4filter and remove the solvent in vacuo. The residue is chromatographically purified (25 g SiO2, CHCl3:MeOH 99:1 to 96:4) to give 140 mg (49%) of compound (I) (R2=R4=Me, X1=X2=Y2=H, Y1=HE).

Method 3:

To a suspension of 100 mg (of 0.27 mmole) of the compound (I) (R2=R4=Me, X1=Br, X2=H= Y2= H, Y1= OH) and 10 mg of 10% Pd/C in 3 ml of Et3N is added dropwise 1.0 ml HCOOH. After 2.5 hours stirring at the temperature of reflux distilled Pd/C is filtered off through celite, the solvent is removed in vacuum and the residue is collected in CH2Cl2. The organic solution is washed twice with saturated solution of NH4Cl, once with water, dried over Na2SO4and the solvent evaporated in vacuum. The residue is separated in a chromatographic column (9 g SiO2, CHCl3:MeOH=95: 5)>/P>Melting point: 119-121oC.

Molecular weight: C17H21NO3: 287,34.

Example 13

(4,6)- 4A,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-6N - benzofuro/3A, 3,2-ef//2/benzazepin-6-ol (bronholitin) (General formula (I) in which R2=R4=Me, X1=Br, X2=Y2=H, Y1=HE) and

(4,6)- 4A, 5,9,10,11,12-hexahydro-1-bromo-3 - methoxy-11-methyl-6N-benzofuro/3A, 3,2-ef//2/benzazepin-6-ol (epibromohydrin) (General formula (I) in which R2=R4=Me, X1=Br, X2=Y1=H, Y2=OH)

To a suspension of 8.0 g (21 mmol) of the compound (V) (R2=Me, R4=CHO, X1=Br, X2=H, Y1, Y2= O) in 150 ml of toluene is added dropwise 10 ml (36 mmol) of a 1.5 M solution of DIBAL-H in toluene at 0oC. the Reaction mixture is stirred for 1 hour at room temperature, the residue of the reducing agent is decomposed with water and then add 12 ml of concentrated NH4OH. After 20 minutes stirring at room temperature the precipitation is filtered off. The organic phase is separated and the aqueous phase is washed with 50 ml of toluene. The combined organic phases are dried over Na2SO4filter and remove the solvent in vacuo. The residue (7.7 g) is separated in a chromatographic column.

(20,7 %) of compound (I) (R2=R4=Me, X1=Br, X2=Y1=H, Y2=HE).

Data bragantino (compound (I) in which:

R2=R4=Me, X1=Br, X2=Y2=H, Y1=IT):

Molecular weight: C17H19BrNO3: 365,23.

IR (KBr): 689,03 m; 778,57 m; 839,86 m; 989,86 m; 1050,66 s; 1212,43 s; 1279,87 s; 1434,08 s; 14,72 s; 1613,99 s; 2667,39 m; 3370-3778 br.

1H-NMR (CDCl3): 6,9 (s, 1H), 6,06 (m, 2H), 4,6 (d, 1H), 4,15 (t, 1H), 3,92 (d, 1H), 3,82 (s, 3H), 3,24 (m, 1H), 2,98 (dt, 1H), 2,68 (dd, 1H), 2,42 (s, 3H), of 2.05 (m, 2H), 1,60 (dt, 1H).

13C-NMR (CDCl3): 145,32 s; 144,00 s; 133,96 s; 127,95 d; 127,68 s; 126,51 d; 126,51 d; 114,22 s; 88,56 d; 61,58 d; 58,56 t; 55,95 q; 53,26 t; 48,56 s; 42,06 q; represented 33.47 per t; 29,69 t.

Data epibromohydrin (compound (I) in which: R2=R4=Me, X1= Br, X2=Y1=H, Y2=IT):

Molecular weight: C17H19BrNO3: 365,23.

IR (KBr): 667,95 w; 752 m; 836,68 m; 1040,31 s; 1208,39 s; 12,82 m; 1435,25 m; 1485,72 m; 1512,94 w; 1558,27 w; 1615,19 m; 1667,14 w.; 2943,24 w; 3360-3575 br.

1H-NMR (CDCl3): of 6.65 (s, 1H), 5,96 (AB, 2H), 4,69 (d, 1H), 4,28 (d, 1H), 3,90 (d, 1H), 3,83 (s, 1H), 3,25 (m, 1H), 2.95 and (m, 1H), 2,85 (dt, 1H), a 2.36 (s, 3H), 2,15 (td, 1H), 1.69 in (m, 2H).

13C-NMR (CDCl3+ DMSO-d6): 145,84 s; 143,49 s; 133,89 s; 133,14 d; 126,12 s; 124,35 d; 115,04 s; 113,01 s; 88,26 d; 61,10 d; 57,44 t; 55,58 q; of 52.84 t; 47,86 s; 41,20 q; 33,35 t; 31,43 t.

Example 14

(4,6)- 4a,5,9,10,11,12-hexahydro-3-meth =Me, X1=X2=Y1=H, Y2=IT)

To a suspension of 240 mg (6.3 mmole) LiAlH4in 4 ml of absolute tetrahydrofuran was added dropwise at 0oC a solution of 365 mg (1.0 mmole) of the compound (I) (R2=R4= Me, X1=Br, X2=Y1=OH, Y2=OH) in 4 ml of anhydrous tetrahydrofuran, stirred for 1 hour at room temperature and then 23 hours at the temperature of reflux distilled. The reaction mixture was then cooled to 0oC, the excess reducing agent is decomposed with water, diluted with 50 ml ethyl acetate and 50 ml of concentrated NH4OH. After shaking the precipitation is filtered, the organic phase is separated and the aqueous phase washed with ethyl acetate. The combined organic phases are dried over Na2SO4filter and remove the solvent in vacuo. The residue is purified by column chromatography (25 g of SiO2, HCl3:MeOH 99:1 to 96:4).

Yield: 140 mg (49%) of compound (I) R2=R4=Me, X1=X2=Y1=H, Y2=OH).

Melting point: 199-201oC.

Molecular weight: C17H21NO3: 287,34.

Example 15

(4,6)- 4A, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-ol (N-demethyl bronholitin) (General formula (I), to the R2=Me, R4=CHO, X1=Br, X2= H, Y1=Y2=O) in 200 ml of tetrahydrofuran is added dropwise within 30 minutes, add 100 ml (100 mmol) of 1M solution of L-selectride at 0oC. After 60 minutes of stirring at 0oC the formed complex is decomposed with water and the reaction mixture is mixed with 100 ml of 25% aqueous solution of NH4OH. After 30 minutes stirring at room temperature the solvent is concentrated to half volume in vacuo, transferred into a funnel to shake, mixed with 100 ml of 25% aqueous solution of NH4OH and extracted three times with methylene chloride (2 x 200 ml of CH2Cl2). The combined organic phases are dried over Na2SO4filter and remove the solvent in vacuo. The residue is chromatographically purified (650 g SiO2silica gel, the solvent CCHCl3:MeOH 95:5 to 9:1) to give a colorless foam.

Output: 7,3 g (75.8 per cent)

Molecular weight: C16H18BrNO3: 352,21

IR(KBr): 748,19 m; 793,11 m; 828,59 m; 927,62 w; 991,65 w; 1058,8 s; 1214,79 s; 1281,61 s; 14,29 s; 1488,49 s; 1571, 11 w; 1616,51 s; 2912,36 s; 3280-3420 br.

UV(MeOH):max225,0 and 297,5 nm.

1H-NMR (CDCl3): 6,85 (s, 1H), 6,02 (AB, 2H), 4.53-in (s, 1H), 4,81 and 4,48 (AB, 2H), 4,10 (m, 1H), of 3.78 (s, 3H), up 3.22 (m, 2H), 2.63 in (dd, 1H), to 2.29 (s, br, 2H), 2,00 (m, 1H), 1,78 (m, 2H).

13C-NMR (CDCl3

(4,6)- 4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-ol (N-dimethylpropanediamine (General formula (I) in which R2=Me, X1=Br, R4=X2=Yy=H, Y1=OH)

(4,6)- 4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-ol (N-dimethylaminopropylamine) (General formula (I) in which R2=Me, X1=Br, R4=X2=Y1=H, Y2=IT)

To a suspension of 1.0 g (2.6 mmole) of the compound (I) (R2=Me, R4=CHO, X1=Br, X2= H, Y1= Y2=O) in 5 ml of tetrahydrofuran is added dropwise within 30 minutes add 3.0 g (11.8 mmole) of LiAlH (tert-4O)3in 15 ml of tetrahydrofuran at 0oC. After 30 minutes stirring at 0oC, the reaction mixture is refluxed. Formed after 22-hour boiling the complex is decomposed with water and the reaction mixture is mixed with 10 ml of 25% aqueous solution of NH4OH. After 30 minutes stirring at room temperature the solvent is concentrated to half volume in vacuo, was transferred to a funnel to shake, mixed with 10 ml of 25% aqueous solution of NH4OH and extracted three times with methylene chloride (2 x 200 ml of CH2Cl2). The combined organic phases are dried over Na2SO4actuarialy CHCl3:MeOH 95:5 to 9: 1 to 8:2) to give two products:

300,0 mg (32.2 per cent) N-dimethylpropanediamine (General formula (I) in which R2=Me, X1=Br, R4=X2=Y2=H, Y1=HE) as a colourless foam and

270 mg (29,0%) N-dimethylpropanediamine (General formula (I) in which R2=Me, X1=Br, R4=X2=Y1=OH, Y2=HE) as a colourless foam.

Data on N-dimethylaminopropylamine:

Molecular weight: C16H18BrNO3: 352,21.

IR(KBr): 781,60 w; 834,28 w; 976,63 w; 1050,28 m, 1179,73 m; 1211,87 m; 1280,07 m; 1435,24 m; 1486,10 m; 1616, 37 m; 2923,54 w; 3700-2900 mbr.

1H-NMR (CDCl3): 6,86 (s, 1H), of 5.92 (AB, 2H), 4,56 (m, 2H), 4,50, and is 3.82 (AB, 2H), 3,80 (s, 3H), of 3.28 (m, 2H), 2,52 (m, 1H), 2,20-to 1.70 (m, 3H).

13C-NMR (CDCl3): 146,73 s; 143,91 s; 134,10 s; 132,17 s; 132,17 d; 131,48 d; 126,34 d; 115,34 d; 112,44 s; 88,51 d; 62,81 d; 56,10 q; 52,34 t; 49,25 s; 46,82 t; 40:52 t; 32,07 t.

Example 17

(4,6)- 4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-ol (N-dimethylpropanolamine) (General formula (I) in which R2=R4=Me, X1=Br, X2=Y2=H, Y1=IT)

Method 1:

To a solution of 2.0 g (5.6 mmole) of the compound (I) (R2=Me, X1=Br, R4=X2=Y2=H, Y1= OH) in 20 ml of H2O add 5 ml of 89% HCOOH, 5 ml of 37% CH2O and boiling the th NH4OH and extracted three times with methylene chloride (3 x 20 ml of CH2Cl2). The combined organic phases are dried over Na2SO4, filtered and the solvent evaporated in vacuum. The residue is chromatographically purified (150 g SiO2silica gel, CHCl3:MeOH 97:3 to 95:5) to give a colorless foam.

Yield: 2.0 g (96,4%).

Method 2:

To a suspension of 10 g (26,4 mmole) of the compound (I) (2=Me, R5=CHO, X1=Br, X2=H, Y1= Y2= O) in 200 ml of tetrahydrofuran is added dropwise within 30 minutes, add 100 ml (100 mmol) of 1 M solution of L-selectride at 0oC. After 60 minutes of stirring at 0oC the formed complex is decomposed with water and the reaction mixture is mixed with 100 ml of 25% aqueous solution of NH4OH. After 30 minutes stirring at room temperature the solvent is concentrated to half volume in vacuo, transferred into a funnel to shake, mixed with 100 ml of 25% aqueous solution of NH4OH and extracted three times with methylene chloride (2 x 200 ml of CH2Cl2). The combined organic phases are dried over Na2SO4, filtered and the solvent evaporated in vacuum. To the residue are added 50 ml of H2About 30 ml of 98% HCOOH, 30 ml of 37% aqueous solution of CH2O and the reaction mixture is boiled with obdi extracted with methylene chloride (3 x 200 ml of CH2Cl2). The combined organic phases are dried over Na2SO4, filtered and the solvent evaporated in vacuum. The residue is chromatographically purified (600 g SiO2silica gel, CHCl3:MeoH 9:1 to 8:2) to give a colorless foam.

Yield: 6.4 g (66.2 per cent).

Example 18

Optical separation of (+/-)galantamine

A solution of 500 mg (+/-)galantamine (1,74 mmole) of the compound (I) (R2=R4=Me, X1= X2= Y2= H, Y1= HE) in 1.0 ml MeOH mixed at room temperature with a solution 672,2 mg (1,74 mmole) of (+)di-p-toluyl-D-tartaric acid in 4 ml of MeOH. After 24-hour incubation in the refrigerator precipitated crystalline precipitate is filtered off and washed with MeOH. The mother liquor save for the other isomer. By recrystallization from EtOH receive 450 mg (-)galantamine-(+)di-p-toluoyltartaric (compound (II, R2=R4=Me, R5=X1=X2= Y2= H, Y1= OH, Z=(+)di-p-toluoyltartaric), melting point: 182-184oC. the Free base is recovered from the salt by using CHCl3/NH4OH. ()D= 101,80o.

The methanol mother liquor is evaporated, the Foundation allocate using CHCl3/NH4OH, dissolved in 0.5 ml MeOH and mixed with a solution of 215 mg (0,55 IMO the Ute and washed with MeOH. By recrystallization from EtOH get 242 mg (+)galantamine-(-)di-p-toluoyltartaric (compound (II) in which R2=R4=Me, R5=X1=X2=Y2=H, Y1=OH, z=(-)di-p-toluoyltartaric), melting point: 144-148oC. the Sol was transferred to the free base using CHCl3/NH4OH. ()D= +98,9o.

Example 19

4A, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-formyl-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-atlantal (General formula (I) in which R2=Me, R4= CHO, X1=Br, X2=H, Y1,Y2=-O-(CH2)22-O-)

5.0 g of compound (I) in which R2=Me, R4=CHO, Z1=Br, X2=H, Y1,Y2=O, 10.0 g of ethylene glycol and 0.05 g of p-toluenesulfonic acid are heated in 100 ml of toluene at room temperature the mixture dwuhfazna) with vigorous stirring to a temperature of reflux distilled (starting approx. with the 90oC the mixture is homogeneous) and boiled for 2 hours with water separation. After cooling, the phases are separated (and the toluene phase is the upper phase), etilenglikolevye phase is twice extracted with toluene (2 x 200 ml toluene), United toluene phase is shaken out twice with a solution of NaHCO3(2 x 50 ml), dried over Na2SO3and evaporated.

Output: 5,40 g the zhonka 1.0 g (60 g of silica gel 60, CHCl3/1-2% MeOH) receive: 0,62 g of a colorless foam, which was crystallized from ethyl acetate.

Melting point: 212-214oC.

Molecular weight: C19H20BrNO5: 422,28.

1H-NMR (CDCl3): to 8.12 (d, H), 6.87 in (s, H), the 6.06 (t, N) 5,72 (d, H), 5,64 (d, H/2), 5,11 (d, H/2), 4,54 (b, N), 4,48 (d, H/2), or 4.31 (d, H/2), 3,50-4,10 (m, 6H), 3,82 (s, 3H), 2,65 (d, H), and 2.27 (d, H), 1,74 is 2.10 (m, 2H).

1C-NMR (CDCl3C): 162,40; 161,65; 147,08; 144,81; 144, 55; 132,14; 131,96; 127,68; 127,48; 115,68; 115,43; 126,71; 126,44; 113,12;m, 111,59; 102,04; 87,07; 86,90; 65,14; 64,23; 55,88; 51,43; 46,11; 48,41; 40,67; 39,27; 35,96; 32,94.

Example 20

4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-formyl-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-propranolol (General formula (I) in which R2=Me, R4=CHO, X1=Br, X2=H, Y1,Y2= -O-CH2-CH(C3)-O-)

100 g of the compound (I) in which R2=Me, R4=CHO, X1=Br, X2=H, Y1,Y2=O, 100 g of propylene glycol and 0.5 g of H2SO4heated in 800 ml of toluene at room temperature the mixture dwuhfazna) with vigorous stirring to a temperature of reflux distilled (starting approx. with the 90oC the mixture is homogeneous) and boiled for 14 hours with water separation. After cooling, the phases are separated (and the toluene phase is the upper phase), propylene glycol phase double-ek is (2 x 50 ml), dried over Na2SO4and evaporated.

Output: 115,3 g of a yellowish foam (100% of theory, counting on crude product), which during the night crystallizes. When chromatographicaliy on a column of 1.0 g (60 g of silica gel 60, CHCl31-2% MeOH) receive: 0,80 g of a colorless foam, which was crystallized from ethyl acetate.

Melting point: 170-171oC.

Molecular weight: C20Q22BrNO5: 436,28.

1H-NMR (CDCl3): to 8.12 (d, N), to 6.88 (s, H), 5,96-6,17 (m, H), of 5.75 (dd, H), of 5.68 (d, H/2), 5,10 (d, H/2), 4,53 (b, H), 4,48 (d, H/2), or 4.31 (d, H/2), 3,12-to 4.38 (m, 5H), 3,82 (s, 3H), 2,56 is 2.80 (m, H), of 2.05 to 2.35 (dd, H), 1,83-2,05 (m, 2H), 1,22 to 1.47 (m, 3H).

1C-NMR (CDCl3): 162,48; 161,72; 147,17; 144,89; 144, 64; 132,16; 129,04; 128,51; 128,57; 127,82; 127,70; 127,61; 115,70; 115,48; 127,09; 126,77; 126,5; 113,20; 111,66; 102, 38; 102,22; 87,25; 87,07; 73,38; 72,46; 71,67; 71,41; 71,23; 70,55; 70,28; 55,92; 51,52; 46,18; 48,43; 40,77; 39:29; 36,07; 35,97; 34,58; 33,68; 33,44; 33,13; 18,68; 17,59; 17,45.

Note (NMR1diastereoisomers): as a result of the introduction of additional (+/-) propylene group of the chiral center is the formation of diastereomers, which cause the splitting of the signal in addition to splitting, due to the formyl group.

Example 21

4A, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6N-benzofuro-/3A, 3, 2-ef//2/benzazepin-6-atlantal (the overall shape of the 2.0 g of the compound (I), in which R2=Me, R4=CHO, X1=Br, X2=H, Y1,Y2=O-(CH2)2-O-, suspended in 50 ml of anhydrous tetrahydrofuran, cooled to 0oC for 5 minutes is added dropwise 20 ml of LiAlH4/diethyl ether (1 M) and heated to room temperature. Stirred for 12 hours at the temperature of reflux distilled (45-52oC), cooled, added dropwise 3 ml of a mixture of tetrahydrofuran with water (2:1), alkalinized 50 milliliters of NH4OH (25%) and extracted four times with ethyl acetate (4 x 50 ml EtOAc). The organic phase is dried over Na2SO4and evaporated.

Yield: 1.52 g of a yellowish oil (92.9% of theory).

When chromatographicaliy on a column (80 g silica gel 60, EtOAc/MeOH 8:2) gain of 0.82 g of colorless crystals.

Molecular weight: C12H23NO4: 329,40.

1H-NMR (CDCl3): of 1.65 (ddd, 1H), 2,10 (ddd, 1H), 2,15 (dd, 1H), 2.40 a (s, 3H), 2,65 (dd, 1H), 3,05 (ddd, 1H), 3,20 (ddd, 1H), 3,60 (d, 1H), 3,80 (s, 3H), 3,90-of 4.05 (m, 4H), 4,10 (d, 1H), 4,55 (dd, 1H), 5,65 (d, 1H), x 6.15 (d, 1H), 6,55, 6,60 (2xd, 2H).

13C-NMR (CDCl3): 33,2 (t) 33,8 (t) 41,7 (q) 47,8 (t) 53,8 (s) of 55.5 (q), 60,2 (t), 64,0, 65,0 (2x t) 87,1 (d) 102,5 (s), 110,9 (d), 121, 1million (d), 125,9 (d), 128,7 (s), 128,9 (s), 131,8 (d), 143,8 (s), 146,5 (s).

Example 22

4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6N-benzofuro/3A, 3,2-ef//2/benzazepin-6H2-CH2-OH, Y2=N)

1.0 g of the compound (I) in which R2=Me, R4=CHO, X1=Br, X2=H, Y1,Y2= O-(CH2)2-O-, dissolved in 25 ml of tetrahydrofuran, cooled to 0oC, for 5 minutes, add dropwise 9 ml of LiAlH4/tetrahydrofuran (1M) and stirred for 30 minutes at 0oC. and Then for 48 hours heat up to the temperature of reflux distilled, cooled, added dropwise 25 ml of NH4OH (25%), extracted four times with ethyl acetate (4 x 20 ml EtOAc). The organic phase is dried over Na2SO4and evaporated.

Output: 0,76 g yellowish oil (92.9% of theory).

When chromatographicaliy on a column (40 g silica gel 60, CHCl3/2-7% MeOH) gain of 0.62 g of a colorless foam.

Molecular weight: (C19H24NO4): 330,40.

1H-NMR (CDCl3): of 1.52 (dd, H), of 1.85 (td, H) of 2.10 (dt, H) to 2.35 (s, 3H), 2,82 (d, H), to 3.02 (d, H), 3,20 (d, H, D20 exchange), 3,24 (d, H), 3,53-and 3.72 (m, 5H), of 3.78 (s, 3H), of 3.94 (t, H), 4,10 (d, H), 4,54 (b, H), 5,94 (d, H), from 6.22 (d, H) 6,33 (d, H), is 6.61 (d, H).

13C-NMR (CDCl3): 26,50; 34,35; 41,57; 48,01; 53,57; 55,72; 60,17; 61,78; 68,42; 49,48; 86,85; 111,06; 121,22; 124,60; 128,95; 129,21; 131,86; 143,88; 146,15.

Example 23

4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-dimethyl-6N-benzofuro/3A, 3,2-ef//2/benzazepin-6-atlantal (General formula (I) in which R< where R2=Me, R4=CHO, X1=Br, X2=H, Y1,Y2= O-(CH2)2-O-, dissolved in 10 ml of tetrahydrofuran, cooled to 0oC for 5 minutes is added dropwise 0.3 ml of LiAlH4/tetrahydrofuran (1M) and stirred for 30 minutes at 0oC. an Excess of tetrahydrofuran is evaporated, the residue is collected in 10 ml of NH4OH (25%) and extracted three times with ethyl acetate (3 x 10 ml of EtOAc). The organic phase is dried over Na2SO4and evaporated.

Output: 0,13 g of oily product raw.

When chromatographicaliy in column (5 g silica gel 60, CHCl3/2-7% MeOH) to obtain 80 mg of a colorless foam (77,9 % of theory).

Molecular weight: (C18H20BrNO4): 394,27.

1H-NMR (CDCl3): PC 6.82 (s, N), 6,16 (d, H), 5,67 (d, N) 4,55 (b, H), 4,48 (d, N), 3,84-4,08 (m, 5H), of 3.78 (s, 3H), 3.04 from-3,37 (m, 2H), 2,62 (bd, N), of 2.15 (dd, H), 1.70 to 1,95 (m, 3H).

13C-NMR (CDCl3): 146,69; 144,00; 133,07; 131,29; 129,00; 112,16; 126,30; 115,25; 102,37; 87,28; 65,11; 64,17; 55,78; 52,46; 49,02; 40,13; 33,06.

Example 24

4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-benzyl-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-atlantal (General formula (I) in which R2=Me, R4= CH2-Ph, X1=Br, X2=H, Y1,Y2= -O-CH2-CH2-HE)

250 mg (0,63 mmole) of the compound (I) in which R22SO4) and evaporated.

Yield: 260 mg (84.7 % of theory) of colorless crystals.

Melting point: 118-119oC.

Thin layer chromatography (DC): EtOAc:MeOH = 9:1.

Molecular weight: (C25H26BrNO4): 484,39.

1H-NMR (CDCl3; d(ppm)): 1,65 (ddd, 1H), 2.05 is-is 2.30 (m, 2H), 2,65 (dd, 1H), 3.00 and-3,30 (m, 2H), 3,70 (s, 2H), 3,80 (s, 3H), 3,90-4,20 (m, 5H), 4,35 (dd, 1H), 4,60 (ddd, 1H), 5,70 (d, 1H), and 6.25 (d, 1H), 6,85 (s, 1H), 7,25-7,30 (m, 5H).

13C-NMR (CDCl3, d(ppm)): 33,1 (d), and 33.4 (t), 48,5 (s), 50,7 (t) and 55.8 (q), is 56.4 (t) 56,9 (t), 64,2, 65,1 (2t), 87,4 (d), to 102.3 (s), 113,6 (s), 115,6 (d), 126,6, 128,2, 128,9 (3 d), 127,1 (d), 3,1 (s), 137,9 (s), 144,2 (s), 146,3 (s).

Example 25

4a,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-dimethyl-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-(General formula (I) in which R2=Me, R4=H, X1=Br, X2=H, Y1,Y2=O) (=N-dimethylpyridin)

250 mg (0,63 mmole) of the compound (I) in which R2=Me, R4=H, X1=Br, X2=H, YoC. Then add 20 ml of concentrated ammonia, a short heat up, the reaction mixture is cooled and receive the precipitate, which is isolated and at the 50oC (20 mm) dry.

Yield: 130 mg (58,6% of theory) of colorless crystals.

Melting point: 173-174oC.

Thin layer chromatography (DC): EtOAc:MeOH = 8:2.

Molecular weight: (C16H16BrNO3): 350,21.

1H-NMR (DMSO-d6, d(ppm)): 1,90-of 2.15 (m, 2H), 2,75 (dd, 1H), 2,95 (dd, 1H), 3,10-to 3.35 (m, 2H, in), 3.75 (s, 3H), 3,90 (d, 1H), and 4.40 (d, 1H), 4,55 (dd, 1H), 5,90 (d, 1H), 6.90 to (s, 1H), 7,05 (d, 1H).

13C-NMR (DMSO-d6, d(ppm)): 36,3 (d) 37,0 (t) 45,6 (s) 49,5 (t) 51,3 (t) of 55.9 (q), 87,6 (d) 112,5 (s), 116,0 (d), 126,6 (d), of 129.6 (s), 132,0 (s), 143,7 (s), 144, 8mm (d), 146,6 (s), 194,0 (s).

Example 26

4a, 5,9,10,11,12-hexahydro-3-methoxy-11-dimethyl-6N-benzofuro/, 3,2-ef//2/benzazepin-6-(General formula (I) in which R2=Me, R4=H, X1=X2=H, Y1,Y2=O)

Example 27

4a, 5,9,10,11,12-hexahydro-3-methoxy-11-benzyl-6N-benzofuro /3A, 3,2-ef//2/benzazepin-6-(General formula (I) in which R2=Me, R4=CH2-Ph, X1=X2= H, Y1,Y2=O)

Example 28

4a, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6N-benzofuro /3A, 3,2-ef//2/ benzazepin-6-propranolol (General formula (I) in which R2 loaded in an argon atmosphere in a pre-dried 4-liter mnogogolovy the flask through an addition funnel add 800 ml of tetrahydrofuran, and the temperature rises with the rapid foaming approximately 45oC (depends on water content in tetrahydrofuran and the reaction flask). Then within 15 minutes added dropwise a suspension of 114 g of compound (I) in which R2=Me, R4=CHO, X1=bromo, X2=H, Y1,Y2= -P-CH2-CH(CH3)-O- (raw) in 400 ml of tetrahydrofuran, and the temperature rises to the temperature of reflux distilled (CA. 65-68oC). Then heated for 10 hours under mechanical stirring at a temperature of reflux distilled, cooled and added dropwise, while cooling, add 100 ml of water in 100 ml of tetrahydrofuran.

Take 10 ml, alkalinized with NH4OH, extracted with ethyl acetate (3 x 20 ml) and obtain after evaporation of the oily product.

When chromatographicaliy 0.17 g in column (5 g silica gel 60, CHCl3/3-5% MeOH) to obtain 0.1 g of a colorless foam.

Molecular weight: (C20H25NO4): 343,42.

1H-NMR (CDCl3): 6,60 (dd, 2H), 6,16 (dt, H), of 5.68 (dd, H), 4,55 (m, H), of 4.38-4,00 (m, 3H), of 3.80 (s, 3H), 3,68-2,95 (m, 4H), 2,78-2,60 (m, H), 127,44; 126,92; 126,12; 126,02; 121,16; 111,05; 110,90; 110,77; 102,87; 102,73; 87,23; 73,15; 72,24; 71,43; 71,12; 70,44; 70,17; 60,28; 55,59; 55,53; 55,45; 53,83; 47,87; 47,80; 47,75; 41,80; 41,70; 34,84; 33,95; 33,66; 33,37; 18,66; 17,62; 17,43.

Note (NMR, diastereomers): as a result of the introduction of additional (+/-)propylene group of the chiral center is the formation of diastereomers, which cause the splitting of the signal in addition to splitting, due to the formyl group.

Example 29

4A, 5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6N-benzofuro /3A, 3,2-ef//2/ benzazepin-6-he, Norwegen (General formula (I) in which R2=Me, R4I= CH3X1=X2=H, Y1,Y2=O)

of 37.5 g of LiAlH4loaded in an argon atmosphere in a pre-dried 4-liter mnogogolovy the flask through an addition funnel enter 800 ml of tetrahydrofuran, and the temperature rises with the rapid foaming approximately 45oC (depends on the water content of tetrahydrofuran and the reaction flask). Then within 15 minutes added dropwise a suspension of 114 g of compound (I) in which R2=Me, R4=CHO, X1=bromo, X2=H, Y1,Y2= -O-CH2-CH(CH3)-O- (raw) in 400 ml of tetrahydrofuran, and the temperature rises to the temperature of reflux distilled (CA. 65-adut and dropwise, when cooled, add 100 ml of water in 100 ml of tetrahydrofuran.

Then pH was adjusted to a value of 0-1 using 1.25 l 2 N. model HC1 and 60 ml of concentrated HCl and stirred for 30 minutes at 60oC, after which the content is transferred into a 5-liter separating funnel, cover with 1 litre layer of ethyl acetate (EtOAc) and brought to pH 10 with NH4OH (approx. 250 ml) and extracted. The aqueous phase is again extracted with one liter of ethyl acetate + 300 ml of tetrahydrofuran, and then the precipitate is filtered over celite and extracted twice with ethyl acetate (2 x 500 ml). The combined organic phases are dried over Na2SO4and evaporated.

Output: 64,8 g (86.9 % of theory, counting on crude product) of yellow crystals.

Molecular weight: 285,32 (C17H19NO3).

Thin layer chromatography (DC): CHCl3/MeOH (5%).

Melting point: 189-192oC.

Example 30

(-) Norwegin

122,4 g (+/-)navedena heated in a mixture of 1.9 l EtOH (96%) and triethylamine (9:1) at the temperature of reflux distilled until a homogeneous solution. Then slowly cooled and add at 68oC 4.0 g (-)navedena and within 7 days stirred at 40oC. Then cooled to room temperature, widely the t with a mixture of 200 ml of ethanol (96%) and triethylamine (9:1) to the temperature of reflux distilled and the method above is mixed with 0.4 g (-)navedena and within 7 days stirred at 40oC. Cool, sucked off and dried, obtaining (-) narogin (fraction II).

Output:

fraction I: 98,6 g of colorless crystals (80,5 % of theory).

fraction II: 7,4 g (6.0 % of theory).

The rotation angle of the polarization plane:

fraction I: ()18= -407o(=1,5/CHCl3)

fraction II: ()18= -401o(=1,5/CHCl3).

Molecular weight: C17H19NO3(285,32)

Melting point: 189-192oC

Example 31

(-) Galantamine

98,6 g (-)navedena added at room temperature portions 1 l L-selectride in tetrahydrofuran (1 M) and stirred for 1 hour. Slowly added dropwise 100 ml of MeOH, turbid solution is evaporated to dryness and added to 3 liters of ethanol (96 %). Aqueous 60% solution of HBr in EtOH (1:1) from the aqueous phase is acidified to pH 1 and incubated over night at 0oC. the Precipitated crystals are separated and dried.

Output: 120,1 g (94.5% of theory).

The rotation angle of the polarization plane: ()18= -88o(or=1.5/H2O)

Molecular weight: C17H21NO3HBr (368,25)

Melting point: 244-247oC.

Example 32

3-benzoyloxy-N-4-(benzyloxyphenyl)-6-bromo-4-methoxy-N-methylbenzamide (General formula (Va) in which R3+ SOCl2. The resulting chloranhydride acid are placed in 150 ml of CHCl3.

14.24 from g O-benzyl-N-methyltyramine dissolved in 60 ml of CHCl3then add 100 ml of 2 N. NaOH. To a biphasic mixture with vigorous stirring at room temperature add the dissolved acid chloride acid and stirred over night. Then the phases are separated. The organic phase is washed with water, dried over Na2SO4and evaporated. The oil obtained is recrystallized from 250 ml of ethanol.

Output: 27,76 g (83% of theory) of colorless crystals.

Thin layer chromatography (DC): petroleum ether/EtOAc (25:75).

1H-NMR (CDCl3): Because of amides appear two conformer (rotamer) 2,69+3,12 (2s, 1.5 H), 2,95+3,21 (2t, 1H), 3,75 (t, 1H), 3,9 (s, 3H), 4,96-5,14 (m, 4H), 7,1-of 7.48 (m, 16H).

13C-NMR (CDCl3): 32,26; 36,55; 32,48; 33,39; 48,75; 52,34; 56,14; 70,92; 71,10; 112,82; 113,05; 114,77; 115,69; 127,23; 128,47; 129,73; 129,78.

Example 33

6-Bromo-3-hydroxy-N-(4-hydroxyphenethyl)-4-methoxy-N-methylbenzamide (General formula (Va) in which R1=R3=H, R2=R4=CH3X1=Br, X2=H, Z1=O, Z1
, R3=benzyl, R2=R4=CH3X1=Br, X2= H, Z1=O, Z2=H2) is heated with 50 ml of ethanol and 21.6 ml of HBr to 60oC and stirred for 9 hours. The solution is slowly poured onto 1 l of ice water and recrystallization stirred for 9 hours. The precipitate was separated, washed with water and dried.

Output: 3,23 g (95,22 % of theory) of colorless crystals.

Thin layer chromatography (DC): CHCl3:MeOH = 9:1.

Melting point: 162-166oC.

1H-NMR (CDCl3/DMSO): due to amide appear two isomers. 2,49+2,81 (2s, 1.5 H), is 3.08+3,42 (2t, 1H), the 3.65 (s, 3H), to 6.43 and 6.6 (m, 4H), 6,72 (s, IH), to 6.88 (s, IH), 8,31-8,59 (b, 2H).

13C-NMR (CDCl3/DMSO): 32,08+33,52, 32,36+54, 48,91+ 52,49, 55,92, 113,97, 114,39, 115,43+115,28, 129,44+129,30, 168,61+168,97.

Example 34

4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl-12-oxo-6N-benzofuro /3A, 3,2-ef//2/ benzazepin-6-(General formula (Ia) in which R2=R4= CH3X1=Br, X2=H, Y1,Y2=O, Z1=O, Z2=H2)

40,5 g hexacyanoferrate potassium (III) (123 mol) and 18 g K2CO3(0,13 mol) was dissolved in 2.7 l of toluene and 180 ml of water and heated to 60oC. Then adding 9.0 g of 6-bromo-3-hydroxy-N-(4-hydroxyphenethyl)-4-methoxy-N-methylbenzamide (total>H) (0,024 mol). The reaction mixture is strongly mechanically stirred. The resulting polymer is filtered off through celite. The aqueous phase is separated, the toluene phase is washed with saturated NaCl, dried over Na2SO4and evaporated.

Crude yield: 5,39 g (60,22 % of theory) of a yellowish oil.

1.8 g chromatographic (100 g of silica gel, solvent system: CHCl3: MeOH = 98:2).

Yield: 1.13 g (37.8% of theory) of colorless crystals.

Thin layer chromatography (DC): CHCl3:MeOH = 95:5

Melting point: 218-222oC.

1H-NMR (CDCl3): 1,92+2,48 (dd, 2H), 2,75+3,1 (dd, 2H), 3,34+3,82 (dd, 2H), 3,91 (s, 3H), of 4.83 (t, 1H), 5,9-6,0+6,3-6,39 (dd, 2H), 7,11 (s, 1H).

13C-NMR (CDCl3/DMSO): 34,00, 36,44+36,58, 48,44, 48,55, 56,31, 89,15, 113,88, 118,55, 122,84, 125,84, 129,35, 145,60, 146,02, 146,61, 164,57, 192,93.

Example 35

4a, 5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11 - methyl-12-oxo-6N-benzofuro/3A, 3,2-ef//2/ benzazepin-6,6 - propylenglykolether (General formula (Ia) in which R2=R4=CH3X1=B, X2=H, Y1,Y2= O-CH2CH(CH3)O-, Z1=O, Z2=H2)

1 g of educt (12) (0,0026 mole), 50 ml toluene, 2 ml of propylene glycol and 0.1 g p-toluenesulfonic acid is boiled for 4 hours under reflux with a trap for water the main objective of the evaporator.

Output: 0,92 g 79,75 % of theory.

0.9 g of the product chromatographic through 50 g of silica gel in the solvent system CH2Cl2:MeOH = 99:1.

fraction 1: 0.34 g of colorless foam (30,1 % of theory).

fraction 2: 0,19 g of a colorless foam,

fraction 3: 0.17 g of colorless foam.

Thin layer chromatography (DC): CHCl3:MeOH = 95:5.

Fraction 1:

1H-NMR (CDCl3): to 6.95 (s, 1H), 5,38-the ceiling of 5.60 (m, 2H), with 4.64 (m, 1H), 4,15 (m, 1H), 3,80 (s, 3H), 3,35-4,10 (m, 2H), 3,10 (s, 3H), of 3.00 (dd, H), 2,85 (dd, H), of 2.15 to 2.35 (m, 2H), 1.70 to 1,95 (m, 2H), 1,12-1,25 (m, 3H).

Fraction 2:

1H-NMR (CDCl3): 0,96-1,1 (m, 3H), 1.18 to 1.32 to (m, 3H), 1,40-1,71 (m, 2H), 1.85 to (b, H), 1,90-of 2.20 (m, 2H), 2,35-of 2.66 (m, 2H), 2,70-2,82 (m, H), 3,10 (s, 3H), 3,20 (b, H), 3,42-3,81 (m, 6N), 3,85 (s, 3H), was 4.02 (m, H), 4,20 (m, H), 4,50 (bd, H), 7,05 (s, H).

Fraction 3:

1H-NMR (CDCl3): 0,95-1,1 (m, 3H), of 1.20 and 1.35 (m, 3H), 1,51-1,72 (m, H), 1,82 (b, H), 1,80-2,12 (m, 3H), 2,30 of 2.68 (m, 2H), 3,12 (s, 3H), 3,20 of 3.75 (m, 7H), 3,83 (s, 3H), 3.96 points - to 4.15 (m, H), 4,22 (m, H) to 4.52 (bd, H), 7,07 (s, H).

Example 36

Narogin (General formula (Ia) in which R2=R4=CH3X1=X2=H, Y1,Y2=O, Z1= Z2=H2)

0.35 g 4A,5,9,10,11,12-hexahydro-1-bromo-3-methoxy-11-methyl - 12-oxo-6N-benzofuro/3A, 3,2-ef//2/benzazepin-6,6 - propilenglikolstearat (General formula (Ia) in which R2=R4=CH3X1=Br, X2= g LiAlH4in 20 ml of anhydrous tetrahydrofuran and stirred overnight at room temperature. Mixed with 20 ml of 2 N. HCl, stirred for 30 minutes at 40oC, alkalinized with concentrated NH4OH and extracted with ethyl acetate (4 x 30 ml). After drying over Na2SO40and evaporation of the organic phase obtain 0.21 g of a yellowish oil, which chromatographic (15 g of silica gel, CHCl3/MeOH 98:2) to give 0.14 g (61,2% of theory navedena in the form of colorless crystals.

Thin layer chromatography (DC): CHCl3/MeOH (95:5).

Example 37

The reduction of compound (12) L-selectride to compounds of General formula (Ia) in which R2=R4=CH3X1=Br, X2=H, Y1=HE, Y2=H, Z1=O, Z2=H2< / BR>
1 g of educt (12) (0,0026 mole) dissolved in 50 ml of anhydrous tetrahydrofuran, then added to 7.93 ml L-selectride (0,0079 mol = 3 equivalent) and stirred for three hours at room temperature. The solution is acidified with 10 milliliters of 2 N. HCl, neutralized with 5 milliliters of NH4OH and extracted three times with ethyl acetate, dried over Na2SO4and evaporated (rotary evaporator).

Yield: 1.07 g (106,47% of theory).

Product chromatographic (50 ml of silica gel, the system is UB>:MeOH = 95:5

Melting point: 75,2 - 80oC.

1H-NMR (CDCl3): of 1.65 and 1.80 (m, N), 1,95-2,17 (m, N), 2,19-of 2.38 (dt, N), 2,65 (dm, N), 3,13-up 3.22 (m, H) and 3.15 (s, 3H), 3,70-3,88 (m, 3H), 3,85 (s, 3H), of 4.12 (m, H), 4,70 (b, N), of 5.50 (d, H), 5,88 (dd, H), was 7.08 (s, H).

13C-NMR (CDCl3): 29,64, 33,91, 38,01, 48,13, 48,63, 56,12, 60,59, 89,68, 113,47, 117,78, 123,08, 126,20, 130,64, 131,90, 144,61, 146,02, 164,94.

Explanation of abbreviations used in the present description

DIBAL-H: diisobutylaluminium

Red-AlR: sodium bis-(2-methoxyethoxy)-aluminum hydride

SuperhydrideR: Li-triethylborohydride

9-BBN: 9-borabicyclo(3.3.1)nonan

L-Selektride: lithium tri-sec-butylborane (Aldrich)

K-Selektride: potassium-three-second-butylbromide (Aldrich)

LS-Selektride: Li-tricarbonate (Aldrich)

KS-Selektride: potassium tricarbonate (Aldrich):

Aliquat: 3-methyltrioctylammonium

THF: tetrahydrofuran

DMF: dimethylformamide

EtOAc: ethyl acetate

Example 38

(4a,8a)- 4A, 5,9,10,11,12)-hexahydro-1-bromo-3-methoxamine(6N)- benzofuro-[3A, 3,2-ef] [2] benzazepin-6,2-1,3-dioxolane-11 - carboxaldehyde (st10):

< / BR>
10.0 g (of 26.5 mmole) st8 together with 20 g of ethylene glycol and 2000 ml of toluene in the presence of 0.1 ml of concentrated sulfuric acid was heated on a water separator under reflux. After 24 hours Dalwallinu saturated aqueous solution of sodium bicarbonate, dried over Na2SO4, filtered and evaporated and receive 11.1 g (99% of theory.) colorless crystals with a melting point 192-193oC connection st10.

Thin layer chromatography (DC): ethyl acetate:methanol= 99:1

1H-NMR (CDCl3; (ppm)) of 1.75 is 2.10 (m, 2H, H-9/9'); 2,15 (dd, 1H, H-5, J(5,5')= to 16.5 Hz); to 2.65 (dd, 1H, H-5', J(5,5')=to 16.5 Hz); of 3.60 (ddd, 1H, H-10), of 3.80 (s, 3H, OCH3); 3,90 - 4,10 (m, 5H, H-10', O-CH2-CH2-O), 4,30 (d, 1H, H-12Konf.AI , J(12,12')=17,8 Hz), 4,50 (d, 1H, H-12Konf.B), 4,55 (b, 1H, H-4a), 5,10 (d, 1H, H-12'Konf.AI , J(12,12')= 17,8 Hz); the 5.65 (d, 1H, H-12'Konf.B); 5,70 (d, 1H, H-8); 6,10 (t, 1H, H-7), 6,85 (s, 1H, H-2); 8,10, 8,15 (2*s, 1H, CHOKonf.AB)

13C-NMR (CDCl3; (ppm)): 32,9 (t, C-5); 36,0 (t, C-9); 39,3, 40,7 (2*t, C-10Konf.A/B); 48,4 (s, C-8a); 46,1, 51,4 (2*t, 0,12Konf.A/B); 55,9 (q, OCH3); 64,2, 65,1 (2*t, O-CH2-CH2-O); 86,9, 87,1 (2*s, C-4aKonf.A/B); 102,0 (s, c-6), 111,6 (d, C-2); 115,4, 115,7 (2*d, C-8Konf.A/B); 126,4 (s, C-12a); a 126.7 (s, C-1); 127,5, 127,7 (2*t, C-7Konf.A/B); 132,0, 132,1 (2*s, C-12bKonf.A/B); 144,6, 144, 8mm (2*s, C-3aKonf.A/B); 147,1 (s, C-3), 161,6, 162,4 (2*s, CHOKonf.A/B)

C19H20BrNO5(JOS 1520) 422,28 g/mol

theory. C 54,04 H 4,77 N 3,32

practical use. C 54,26 H 4,94 N 3,12

Example 39

(4a,8a)0 g (21.3 mmole) of the compound st10 suspended in 100 ml of absolute tetrahydrofuran, at a temperature of from -15 up to a maximum of -10oC gain of 28.4 ml (25,6 mmole) of 0.9 N. solution sociallyengaged in diethyl ether and stirred at this temperature. After 20 minutes the following was added dropwise 10 ml of 0.9 N. solution sociallyengaged in diethyl ether and stirred for further 20 minutes at a temperature of from -15 to -10oC. Then hydrolyzing with 15 ml of a mixture of tetrahydrofuran:water at a ratio of 2:1, the solution is concentrated and the residue is placed in 200 ml of water, then extracted three times each time with 100 ml of ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, evaporated and receive 6,53 g (78% of theory.) colorless crystals with a melting point 81-84oC connection st11a.

Thin layer chromatography (DC): CHCl3:MeOH = 95:5 ethyl acetate:methanol= 9:1

1H-NMR (CDCl3; (ppm)): 1,70 - 1,85 (b, 1H tauscht D2O, NH); 1,80 - 2,00 (m, 2H, H-9/9'); 2,15 (dd, 1H, H-5, J(5,5')= to 15.4 Hz); to 2.65 (dd, 1H, H-5', J(5,5')= to 15.4 Hz); 3.15 in (ddd, 1H, H-10); 3,30 (ddd, 1H, H-10'); of 3.80 (s, 3H, OCH3); 3,85 - 4,10 (m, 5H, H-10'/12, OCH2CH2O); 4,50 (d, 1H, H-12', J(12,12')= 16,1 Hz); 4,60 (dd, 1H, H-4A), the 5.65 (dd, 1H, H-8, J(7,8)= 9,8 Hz); x 6.15 (dd, 1H, H-7, J(7,8)= 9,8 Hz); 6,85 (s, 1H, H-2)

Example 40
>/BR>< / BR>
Method A:

Perform General stages of detachment etilenglikolevykh protective groups. 5.0 g of educt (connection st11a, R1=Br, R2=H) is dissolved in 100 ml of 2 N. hydrochloric acid and heated for 30 minutes at 100oC. After cooling, alkalinized with concentrated aqueous ammonia, the product is sucked off and dried at 50oC and 20 mbar, and/or the aqueous phase is extracted three times each time with 50 ml of ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over Na2SO4, filtered, evaporated. By thin-layer chromatography (DC): CDCl3:MeOH = 9:1 ethyl acetate:methanol= 8:2 with the connection st19 exit 91% of theoretical in the form of colorless crystals with a melting point 173-174oC.

Method B

9.0 g (21.3 mmole) of the compound st10 suspended in 100 ml of absolute tetrahydrofuran, at temperatures from -25 up to a maximum of -20oC gain of 28.4 ml (25,6 mmole) of 0.9 N. solution sociallyengaged in diethyl ether and stirred at this temperature. After 20 minutes the following was added dropwise 10 ml (9.0 mmole) of 0.9 N. solution sociallyengaged in diethyl ether and stirred for further 20 minutes at a temperature of from -25 to -20o
2
SO4, filtered, evaporated and receive 6,53 g (78% of theory.) colorless crystals with a melting point 173-174oC connection st19.

Thin layer chromatography (DC): CHCl3:MeOH = 95:5 ethyl acetate:methanol= 9:1

1H-NMR (CDCl3; (ppm)): (ppm)): 1,90 - of 2.15 (m, 2H, H-9/9'), 2,75, 2,95 (AB, 2H, H-5/5', J(5,5')= 16,0 Hz); 3,10 - to 3.35 (m, 2H, H-10/10'); of 3.75 (s, 3H, O-CH3); 3,90 (d, 1H, H-12, J(12,12')= to 16.4 Hz); however, 4.40 (d, 1H, H-12', J(12,12')= to 16.4 Hz); 455 (dd, 1H, H-4a), 5,90 (d, 1H, H-8, J(7,8)= to 10.7 Hz); 6.90 to (s, 1H, H-2); 7,05 (d, 1H, H-7, J(7,8)= 10,7 Hz)

1C-NMR (CDCl3; (ppm)): (ppm)):) 36,3 (t, C-5); 37,0 (t, C-9); 45,6 (s, C-8a); 49,5 (t, C-10); 51,3 (t, C-12); 55,9 (q, OCH3); 87,9 (d, C-4a); 112,5 (s, C-1); 116,0 (d, C-8), 126,6 (d, C-7); of 129.6 (s, C-12a), 132,0 (s, C-12b); 143,7 (s, C-3a); 144,8 (d, C-2); 146,6 (s, C-H)

C16H16BrNO30,4 H2O (JOS1522) 357,43 g/mol

theory. C 53,77 H 4,74 N 3,92

practical use. C 53,63 H A 4.86 N 4,17.

1. The method of obtaining derivatives 4A, 5, 9, 10, 11, 12-hexahydro-6N-benzofuro (3A, 3, 2-EF) (2) benzazepine General formula selected from the group consisting of

Y1and Y2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, alkoxygroup, or together represent =O (ketone);

And denotes a benzene ring core, substituted if necessary at least once alkoxygroup, fluorine, chlorine, bromine or iodine;

Z is a pharmaceutically acceptable anion of an organic acid or inorganic anion;

R5selected from the group consisting of hydrogen, formyl, alkyl, aralkyl, alkylcarboxylic or allyloxycarbonyl,

characterized in that

(A) compound of formula III

< / BR>
where R1and R4selected from the group consisting of hydrogen, alkyl, aralkyl, alkylcarboxylic;

X1selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine and tertiary butyl;

(B) condensation with a compound of General formula IV

< / BR>
where R3selected from the group consisting of hydrogen, aralkyl or alkylsulphonyl,

to compounds of General formula V

< / BR>
the resulting condensation product (Schiff base) vosstanavlivaete group;

(C) the compound obtained of General formula V cyclist, exposing its interaction with the substrate and the oxidant;

(D) thus obtained compound of General formula I, in which Y1and Y2together represent =O (ketone), recover L-selectride, K-selectride, KS-selectride or LS-selectride to compounds of General formula I, in which Y1denotes hydroxy, and a racemic compound of General formula I, in which R4selected from the group consisting of hydrogen, alkyl, alkenyl, or aralkyl, separated by crystallization with a chiral acid to the corresponding enantiomers.

2. The method of obtaining derivatives 4A, 5, 9, 10, 11, 12-hexahydro-6N-benzofuro (3A, 3,2-ef) (2) benzazepine General formula selected from the group consisting of

< / BR>
and

< / BR>
or their salts,

where R2, R4X1and X2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, lower alkyl, aralkyl, formyl, alkylcarboxylic, allyloxycarbonyl;

Y1and Y2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, alkoxygroup, or together represent =O (ketone);

And indicates benzol is or iodine;

Z is a pharmaceutically acceptable anion of an organic acid or inorganic anion;

R5selected from the group consisting of hydrogen, formyl, alkyl, aralkyl, alkylcarboxylic or allyloxycarbonyl,

characterized in that

(A) compound of formula III

< / BR>
where R1and R2selected from the group consisting of hydrogen, alkyl, aralkyl or alkylsulphonyl,

X1selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine and tertiary butyl;

(B) condensation with a compound of General formula IV

< / BR>
where R3selected from the group consisting of hydrogen, alkyl, aralkyl to compounds of General formula V

< / BR>
the resulting condensation product (Schiff base) restore, and if R4is hydrogen, the compound of General formula V, if necessary, introduce the N-protective group;

(C) thus obtained compound of General formula V cyclist, exposing its interaction with the substrate and the oxidant,

(D) thus obtained compound of General formula I, in which Y1and Y2together represent = O (ketone), restore DIBAL, REDAL or superherodom to compounds of General formula I, forming diastereomerism way racemic compound of General formula I, in which R4selected from the group consisting of hydrogen, alkyl, or aralkyl, separated by crystallization with a chiral acid to the corresponding enantiomers.

3. The method of obtaining derivatives 4A, 5, 9, 10, 11, -hexahydro-6N-benzofuro (3A,3,2-ef) (2) benzazepine General formula selected from the group consisting of

< / BR>
and

< / BR>
or their salts,

where R2, R4X1and X2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, alkoxy, lower alkyl, aralkyl, formyl, alkylcarboxylic or allyloxycarbonyl;

Y1and Y2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, bromine or iodine, or together represent =O (ketone);

And denotes a benzene ring core, substituted if necessary, at least once alkoxygroup, fluorine, chlorine, bromine, iodine;

Z is a pharmaceutically acceptable anion of an organic acid or inorganic anion;

R5selected from the group consisting of hydrogen, formyl, alkyl, aralkyl, alkylcarboxylic or allyloxycarbonyl, characterized in that

(A) the total connection f is arbonia;

X1selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine and tertiary butyl;

(B) condensation with a compound of General formula IV

< / BR>
where R3selected of the group consisting of hydrogen or aralkyl,

to compounds of General formula V

< / BR>
the resulting condensation product (Schiff base) restore, and if R4is hydrogen, the compound of General formula V if necessary, introduce the N-protective group;

(C) thus obtained compound of the formula V cyclist, exposing its interaction with the substrate and the oxidant;

(D) thus obtained compound of General formula I, in which Y1and Y2together represent = O (ketone), transferred to ketal or thioketal, thus obtained ketal or thioketal restore, formed in the connection type nurodykite catalog or thioketal group split, the racemic compound of General formula I, in which R4selected from the group consisting of hydrogen, alkyl, or aralkyl, translated by chiral initiated crystallization into the corresponding enantiomers and thus obtained enantiomers restore L-selectride, K-selectride, KS-celek-hexahydro-6N-benzofuro (3A, 3,2-ef) (2) benzazepine General formula selected from the group consisting of

< / BR>
and

< / BR>
or their salts,

where R2, R4X1and X2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, iodine, hydroxy, alkoxy, lower alkyl, formyl, alkylcarboxylic or allyloxycarbonyl;

Y1and Y2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, alkoxygroup, or together represent =O (ketone);

And denotes a benzene ring core, substituted if necessary at least once lower alkyl, lower alkene, lower Alcina, alkoxygroup, fluorine, chlorine, bromine or iodine;

Z is a pharmaceutically acceptable anion of an organic acid or inorganic anion;

R5selected from the group consisting of hydrogen, formyl or alkyl, aralkyl, alkylcarboxylic, arylcarbamoyl, allyloxycarbonyl,

characterized in that the compound of General formula Va

< / BR>
where R1, R2, R3, R4X1X2are specified in paragraph 1 values and where Z1and Z2represent =O, S, N, and if R4is hydrogen, the compound of General formula Va in eastview with the substrate and the oxidant,

< / BR>
(D) thus obtained compound of General formula I, in which Y1and Y2together represent = O (ketone), transferred to ketal or thioketal, thus obtained ketal or thioketal restore, formed in the connection type nurodykite catalog or thioketal group split, the racemic compound of General formula I, in which R4selected from the group consisting of hydrogen, alkyl, or aralkyl, translated by chiral initiated crystallization into the corresponding enantiomers and thus obtained enantiomers restore L-selectride, K-selectride, KS-selectride or LS-selectride to compounds of General formula I.

5. The method according to one of paragraphs.1-4, characterized in that the reaction of condensation (stage b) is carried out at a temperature of reflux distilled and, if necessary, separating the formed water.

6. The method according to one of paragraphs.1-5, characterized in that the recovery obtained at the stage In the condensation product (Schiff's base) conduct a reducing agent selected from the group consisting of sodium borohydride, potassium borohydride, cyanoborohydride sodium, Li Al H4and mixtures thereof.

7. The method according to one of paragraphs.1-6, characterized in that castaeda of sodium bicarbonate, potassium carbonate, NaOH, KOH and pyridine.

8. The method according to one of paragraphs.1-7, characterized in that on the stage With a compound of General formula V or Va is subjected to interaction with an oxidant selected from the group consisting of Pb(OAc)4, KMnO4, ferric chloride, potassium ferricyanide and H2O2.

9. The method according to one of paragraphs.1-8, characterized in that the interaction on stage is carried out in a solvent selected from the group consisting of toluene and xylene.

10. The method according to one of paragraphs.3-9, characterized in that at stage D, the compound of General formula I or Ia where Y1and Y2together represent =O (ketone), transferred to ketal or thioketal, subjecting the compound of General formula I or Ia interaction with a compound selected from the group consisting of an alcohol R6- OH and thiol, R6- SH, where R6selected from the group consisting of alkyl, alkenyl, aryl, aralkyl, alkylcarboxylic, arylcarbamoyl and aralkylamines, and R6if necessary substituted by at least one halogen.

11. The method according to one of paragraphs.3-9, characterized in that at stage D, the compound of formula I or Ia where Y1and Y2together represent =O (ketone), transferred to ketal or thioketal, podoydem R6is specified in the letter of 10 values.

12. The method according to p. 11, characterized in that in stage D for education Catala interaction is carried out with propylene glycol.

13. The method according to one of paragraphs.3-12, characterized in that ketal or thioketal restore a reducing agent selected from the group consisting of sodium borohydride, potassium borohydride, cyanoborohydride sodium, LiAlH4L-selectride, DIBAL, REDAL, selectride, KS-selectride, LS-selectride, superseded, 9-DBH, Zn/CaCl2and mixtures thereof.

14. The method according to p. 13, characterized in that the reducing agent is LiAlH4.

15. The method according to one of paragraphs.1-14, characterized in that the compound is a Quaternary ammonium salt of General formula II.

16. The method according to p. 15, characterized in that Z is selected from the group consisting of tartrate, lactate, citrate, acetate, maleinate, fluoride, chloride, bromide, iodide, sulfate, phosphate and chlorate.

17. The method according to p. 16, wherein R1, R2and R3selected from the group consisting of hydrogen, alkyl, or alkylcarboxylic.

18. The method according to one of paragraphs.1-16, wherein R4and R5selected from the group consisting of hydrogen, formyl, alkyl, arilas> selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine and tert-butyl.

20. The method according to one of paragraphs.1-19, characterized in that the nitrogen in the compound of General formula (V) or (Va) before oxidation protects the introduction of compounds selected from the group consisting of formyl, aralkyl or alkylcarboxylic.

21. The method according to p. 20, wherein introducing formyl group, subjecting the compound of General formula (V) or (Va) interaction with 1-50-fold molar amount of ethylformate in the presence of catalytic amounts of formic acid.

22. The method according to one of paragraphs.1-21, characterized in that the compound of General formula (V), where R1, R2and R3selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, alkylcarboxylic; X1denotes bromine; X2denotes hydrogen and R4selected from the group consisting of hydrogen, formyl, aralkyl, alkylcarboxylic or allyloxycarbonyl, subjecting the compound of General formula V

< / BR>
where R4indicates CHO, and X1denotes hydrogen, interaction with brainwashin agent.

23. The method according to one of paragraphs.1-22, characterized in that cyclist compound of General formula V

< / BR>
where R2SEL is dust, consisting of hydrogen, fluorine, chlorine, bromine, iodine and tert-butyl;

R4selected from the group consisting of hydrogen, formyl, aralkyl, alkylcarboxylic or alkoxycarbonyl;

R3denotes hydrogen,

to compounds of General formula I, where R2, R4and X1have the above meanings, X2denotes hydrogen or bromine, Y1and Y2together represent =O (ketone), subjecting the interaction with the substrate and oxidant.

24. The method according to p. 23, characterized in that the oxidative cyclization is carried out in the presence of tetraalkylammonium, such as aliquat, crown corks ester, ascorbic acid, copper chloride or triperoxonane acid or mixtures thereof.

25. How dibromononane compounds of General formula I, characterized in that the compound of General formula I

< / BR>
where X1denotes bromine,

R2, R4and X2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, bromine or iodine, lower alkyl, aralkyl, formyl, alkylcarboxylic or allyloxycarbonyl;

Y1and Y2the same or different and selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, alkoxy, or together with oboznachaiushchaia, fluorine, chlorine, bromine or iodine,

for dibromononane subjected to interaction with a mixture consisting of (a) formic acid, triethylamine and palladium on charcoal, or b) a metal powder of zinc and CaCl2in alcohol.

26. The method of producing compounds of the type N-dimethylpropanolamine and N-dimethylaminopropylamine, characterized in that the restoring compound of General formula I

< / BR>
where R2- alkyl;

X1- bromine;

R4- SNO;

X2is hydrogen;

Y1and Y2represent =O (ketone),

A - benzene nucleus substituted if necessary at least once alkoxygroup, fluorine, chlorine, bromine or iodine.

27. The method according to p. 27, characterized in that as the reductant used DIBAL-H, REDAL or superseded, L-selectride, selected, KS-selected or LS-selectride.

28. The method according to one of paragraphs.1-24, wherein the chiral acid is selected from the group consisting of dibenzoyltartaric acid, di-p-Dalwallinu acid, tartaric acid, citric acid, camphor acid, campanulas acid, camphorsulfonic acid or almond acid.

29. The method according to p. 30, characterized in that acid.

30. The method according to one of paragraphs.3-29, where Y1-Y2selected from the group consisting of OR6and OR6-O, X1denotes bromine, and R4indicates CHO.

31. A compound selected from the group consisting of

and bragantina formula

< / BR>
b) epibromohydrin formula

< / BR>
in) N-dimethylpropanolamine formula

< / BR>
g) N-dimethylaminopropylamine formula

< / BR>
D) bromo-N-formyl-Norwegen-propilenglikolstearat formula

< / BR>
(e) Norwegen-propilenglikolstearat formula

< / BR>
W) bromo-N-formyl-Norwegen-etilenglikolya formula

< / BR>
C) Norwegen-etilenglikolya formula

< / BR>
and) 0-(2-hydroxyethyl)galantamine formula

< / BR>
K) bromo-N-demethyl-Norwegen-etilenglikolya formula

< / BR>
l) bromo-N-benzyl-Norwegen-etilenglikolya formula

< / BR>
m) bromo-N-demethyl-navedena formula

< / BR>
n)

< / BR>
o)

< / BR>
Priority points:

21.10.94. - PP.1, 2, 5, 6, 7, 8, 9,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 25A, 26, 27 (all except REDAL), 28, 29, (+ di...), 31A, b, C, g;

07.06.95. - PP.3, 4, 10, 11, 12, 13, 14, 27 (REDAL), 29 (di...), 30, 31-d-m

on the date of filing of application PP.B, 31N,O.

 

Same patents:

The invention relates to compounds of formula (1)

< / BR>
in which

R1is a hydrogen atom;

R2is a hydrogen atom, (C3-C12) alkenylboronic, (C3-C12)cycloalkylcarbonyl, (C3-C12)cycloalkylcarbonyl, (C3-C12)alkylcarboxylic, (C3-C12)cycloalkyl (C1-C12)alkylcarboxylic, pyridyloxy, morpholinoethoxy or tetrahydropyranyloxy, halogen(C1-C6)alkylsulfonate, (C1-C6)alkylsilane;

R3is a hydrogen atom or halogen;

R4is a hydrogen atom or a (C1-C6)alkyl, or geometric, optical or stereoisomers, or pharmaceutically acceptable additive salts, which are useful for the treatment of various memory disorders characterized by a decrease cholinergic function such as Alzheimer's disease

The invention relates to a derivative of galantamine, in particular a derivative of galantamine General formula (II)

< / BR>
in which R1represents hydrogen, (C1-C12)alkylsulphonyl, (C1-C12)alkoxycarbonyl, mono-(C1-C12)alkylaminocarbonyl or di-(C1-C12)alkylaminocarbonyl; R2represents a mono-(C1-C18)alkylaminocarbonyl or di-(C1-C8)alkylaminocarbonyl group; R3represents hydrogen or halogen; or pharmaceutically acceptable acid additive salts

The invention relates to compounds of the formula

< / BR>
where

R1is hydrogen, (C1C12) alkylsulphonyl, (C1-C12) alkoxycarbonyl,

R2- (C1-C12) alkylcarboxylic-, (C1-C12) alkoxycarbonyl-, hydroxy-, (C1-C6) alkoxycarbonyl (C1-C6) alkoxy or hydroxy (C1-C10) alkoxy - and phenylcarbonylamino, where the phenyl part is unsubstituted or substituted C1-C6the alkyl or trifluoromethyl

The invention relates to compounds corresponding to the following formula I:

< / BR>
where R1- represents a group of formula

< / BR>
where n = 1 or 2, R3represents hydroxyl, lower alkoxygroup, aryl (lower) alkoxygroup, amino group, lower alkylamino or di (lower alkyl) amino group, R4represents hydrogen, lower alkyl or aryl (lower) alkyl , R5represents hydrogen, lower alkyl, aryl (lower) alkyl or lower alkylsulphonyl, R6represents hydrogen or lower alkyl, provided that when R6is lower alkyl, then R6replaces one of the methylene hydrogen atoms, R2represents a group of formula

< / BR>
where X is hydrogen, halogen, lower alkyl or lower alkoxygroup,

R7represents lower alkyl or aryl (lower) alkyl,

R8represents hydrogen or lower alkyl,

R9represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl (lower) alkyl, formyl, lower alkyl carbonyl, aryl (lower alkyl) carbonyl Il is kilcarbery,

R11represents hydrogen, lower alkyl or aryl (lower) alkyl,

and such compounds are applicable for alleviating various memory disorders, characterized by a cholinergic deficit such as disease Alzheimer

The invention relates to new chemical compound, specifically to 5H-3,4,6,7-tetrahydro-10-methoxy-5-methyl-6-(1', 1'-dioxide)-3'- metalorigin-4'-methoxy-benzo[B] thiophene-7 yl)-furo-[4.3.2

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of galantamine hydrobromide, which includes a method of purifying galantamine through precipitation of galantamine hydrobromide from a mixture of alkaloids obtained from Amaryllidaceae plants which contain galantaminem, with subsequent treatment of hydrobromide with an alkali, extraction and crystallisation of galantamine using a solvent of general formula , in which R1 is hydrogen or methyl, and R2 is selected from n-butyl, isobutyl, fluoro-butyl and tert-butyl.

EFFECT: obtained pure galantamine can be used to obtain galantamide hydrobromide suitable for pharmaceutical applicaion using a conventional method.

11 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess qualities to estrogen modulators, of general formula (1) or its pharmaceutically acceptable salt, where R1 represents hydrogen atom or (C1-C6)alkyl, -SO2NR7R8, phenyl (C1-C3)alkyl or (C1-C3)alkyl, substituted with 5-8-member heterocyclic radical, containing nitrogen atom; R2 and R3 each independently represents hydrogen atom or hydroxyl, halogen atom or (C1-C6)alkoxy; X represents O, S, SO, SO2 or NR4; R4 represents hydrogen atom or (C1-C6)alkyl, phenyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted with 5-8-member saturated heterocyclic radical, containing one nitrogen atom, or group -COR7, -CO2R7 or -SO2NR7R8, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom or phenyl(C1-C3)alkoxy; Y represents direct bond, -(CR10R11)n- or -R10C=CR11-; R7 and R8 each independently represents hydrogen atom or (C1-C6)alkyl group; R10 and R11 each independently represent hydrogen atom or cyano, or group CONR7R8; n equals 1 or 2; A represents (C3-C12)cycloalkyl or phenyl, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom, (C1-C3)alkyl, (C1-C3)alkoxy; when X represents NR4, Y and R2 together with containing them indazole cycle can also form 1H-pyrano[4,3,2-cd)indazole; on condition that: 1) when X represents O, S or NR4, R1 represents hydrogen atom or (C1-C6)alkyl, and Y stands for direct bond, then A is not optionally substituted phenyl; 2) when X represents O, R1O represents 6-OH or 6-OCH3, Y represents direct bond and A represents cyclopeptyl, then (R2, R3) or (R3, R2) are different from (H, CI) in position 4, 5; 3) when X stands for O, R1O represents 6-OH, R2 and R3 represent H, and Y represents CH=CH, then A is not phenyl or methoxyphenyl; 4) when X represents SO2, A represents phenyl and R1O represents 5-or 6-OCH3, then (R2, R3) or (R3, R2) are different from (H, OCH3) in position 6- or 5-, compound not being one of the following: 3-phenyl-5-(phenylmethoxy)-1H-indazole; n-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5]isoxazole; 3-(4-chlorphenylmethyl)-6-hydroxy-7-(n-propyl)-benz[4,5]isoxazole; 6-hydroxy-3-(2-phenylethyl)-7(n-propyl)-benz[4,5]isoxazole; 3-cyclopropyl-6-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5|isoxazole; 3-cyclohexylmethyl-6-hydroxy-3-phenylmethyl-7-propyl-benz[4,5]isoxazole. Invention also relates to pharmaceutical composition, application and method of prevention and treatment of disease, where modulation of estrogen receptors is required.

EFFECT: obtaining novel compounds, which possess qualities of estrogen receptors modulators.

18 cl, 7 dwg, 8 tbl, 97 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing highly pure 4a,5,9,10,11,12-hexahydro-6H-benzofuro[3a,3,2-en][2]benzazepine, as well as derivatives thereof of formula I and II , produced from racemic bromonarwedine which is debrominated during catalysis with palladium. The invention involves treatment of the reaction mixture, which takes place in the presence of oxygen or peroxides, such that the palladium catalyst is converted to an insoluble, easily separated form. The following reactions take place via reduction of enantiomerically pure narwedine to enantiomerically pure galantamine, which is then alkylated or dealkylated so as to achieve the corresponding substitution in the nitrogen ring atom. Through subsequent purification such as recrystallisation, residual content of palladium lower than 5 ppm is achieved, which enables direct use as pharmaceutical raw material.

EFFECT: improved method.

6 cl, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to azoloazine salts of compounds of a fluoroquinolone line of formulae 4a-c , 5a-c , 7a-b and 8a-b , possessing antibacterial and antiviral properties. The claimed compounds can be applied for the creation of a medication for the emergency prevention and treatment of infections, caused by pathogens of both the bacterial and viral origin, including especially dangerous ones. In general formulae 4 and 5 R=CH3, R1=C2H5; R=H, R1=C2H5; R=C2H5, R1=cyclo-C3H7, in formulae 7 and 8 R=H (7a, 8a); R=CH3 (7b, 8b).

EFFECT: increased efficiency of the compound application.

8 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzopyran derivatives of formula or

or their pharmaceutically acceptable salts, where R1 and R2 independently represent a hydrogen atom or a C1-6alkyl group, R3 is a hydroxyl group, R4 is a hydrogen atom, m is an integer ranging from 1 to 4, n is an integer ranging from 0 to 4, V is a single bond, CR7R8 or NR9, R5 is a hydrogen atom, R6 is a hydrogen atom, C1-6alkyl group, C3-8cycloalkyl group, C3-8cycloalkenyl group, amino group, C1-6alkylamino group, C6-14aryl group, C2-9heteroaryl group or C2-9heterocyclic group, A is a 5- or 6-member ring condensed with a benzene ring, and the ring can contain an oxygen atom, a nitrogen atom or a sulphur atom numbering from 1 to 3 or separately, or combined, the number of unsaturated bonds in the ring equals 1, 2 or 3, including the unsaturated bond in the condensed benzene ring, carbon atoms in the ring can represent carbonyl or thiocarbonyl.

EFFECT: compounds can be used as antiarrhythmic agents.

47 cl, 1 tbl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds, specifically to 4-substituted-3-(1-alkyl-2-chloro-1H-indol-3-yl)furan-2,5-diones of general formula I , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R3=phenyl, naphthyl, 2-phenyl-1-ethenyl, thienyl, furyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, synthesis method thereof and use as compounds capable of photochemical generation of stable fluorophores of formula II, which can be used, for instance in information storage systems, particularly as photosensitive components of material for three-dimensional recording and storage of information. The invention also relates to novel 4,5-substituted-6-alkyl-1H-furo[3,4-c]carbazole-1,3(6H)diones of general formula II , where R1=H, C1-C6 alkyl; R2=H, C1-C6 alkyl, C1-C6 alkoxy; R4=H, R5=phenyl, R4, R5=benzo, naphtho, thieno, furo, pyrrolo, benzothieno, benzofuro, indolo, method for synthesis of said compounds and use as fluorophores.

EFFECT: obtaining novel compounds and possibility of using said compounds as fluorophores.

14 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing an optically active chromene oxide compound of formula or formula where R5, R6, R7, R8, R9, R10 and A are as described in the claim, and the absolute configuration of carbon atoms, denoted by *, denotes (R) or (S), which includes asymmetric epoxidation of a chromene compound of formula or formula with an oxidant in a solvent using optically active titanium complexes of formula formula formula and formula where R1, R2, R3 and R4 are defined in the claim, as a catalyst for asymmetric oxidation of the optically active chromene compound with high enantioselectivity and high chemical output.

EFFECT: efficient method of producing an optically active chromene oxide compound, which is an important intermediate compound used to produce a benzopyran compound, which is effective in treating arrhythmia.

18 cl, 26 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds able to prevent the extracellular release of inflammatory cytokines. Proposed compounds including their diastereomeric forms and their pharmaceutically acceptable salts correspond to the formula: wherein R means: (a) -O[CH2]kR3 or (b) -NR4aR4b; R3 means a substituted or unsubstituted (C1-C4)-alkyl, a substituted or unsubstituted phenyl wherein substitutes are taken among halogen atom, cyano-group, trihalidemethyl, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein R3 means hydrogen atom each among R4a and R4b means independently hydrogen atom or (C1-C4)-alkyl-CO- or benzo(1,3)dioxol; index k has a value from 0 to 5; each among R4a and R4b means independently: (a) hydrogen atom or (b) -[C(R5aR5b)2]mR6 wherein each Ra means hydrogen atom, and R5b means hydrogen atom, linear or branched (C1-C)-alkyl; R6 means vinyl, the group -OR7, -CO2R7, cyclic (C3-C)-alkyl, unsubstituted phenyl or phenyl substituted with (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, -NR4aR4b, -O[CH2]kR3 wherein each among R3, R4a and R4b means independently hydrogen atom, or unsubstituted 6-membered nitrogen-containing heteroaryl; R7 means hydrogen atom, water-soluble cation or (C1-C4)-alkyl; index m has a value from 0 to 5. Also, invention relates to a pharmaceutical composition comprising the effective dose of compounds corresponding to abovementioned formula, and to a method for inhibition of extracellular release of inflammatory cytokines.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 1 sch, 6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds with pharmacological activity to sigma-receptor, and more specifically to pyrazole derivatives of formula (I) in which radicals and symbols have the values defined in cl. 1 of the patent claim; to a method for preparing such compounds; to a pharmaceutical composition containing them and to their application for manufacturing a medicinal agent for treatment and prevention of a sigma-receptor mediated disease or a condition, particularly for treatment of psychotic illness, such as depression, anxiety or schizophrenia, and neuropathic or inflammatory pain, including allodynia and/or hyperalgesia.

EFFECT: improved clinical effectiveness.

11 cl, 2 dwg, 1 tbl, 112 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) or pharmaceutically acceptable salts thereof where R1 and R2 together denote a group selected form groups of formula (III-1): , where R9 denotes 1) a lower alkyl group, optionally substituted with a halogen atom or lower alkoxy group, 2) an aryl group, 3) an aralkyl group, 4) a heteroarylalkyl group, 5) a heteroaryl group, where the aryl, aralkyl, heteroarylalkyl and heteroaryl groups can be substituted with a halogen atom, lower alkyl group, optionally substituted with a lower alkoxy group or 1-3 halogen atoms, lower alkoxy group, optionally substituted with 1-3 halogen atoms, cyano group, hydroxy group, alkylsulphonyl group, cycloalkylsulphonyl group, aryl group, heteroaryl group, alkylaminocarbonyl group, alkanoyl amino group, alkyl amino group or dialkylamino group; R10 denotes a lower alkyl group, optionally substituted with 1-3 halogen atoms, or a lower alkylsulphonyl group; X9-X12 denotes a carbon atom or a nitrogen atom, where the carbon atom can be independently substituted with a lower alkyl group, optionally substituted with a halogen atom or a lower alkoxy group, lower alkoxy group, optionally substituted with a halogen atom, or a cyano group or a halogen atom; R3 denotes a) a group of formula (II-1): (ii-U where R4 and R5, taken together with a nitrogen atom, form a 5- or 6-member monocyclic ring, where the monocyclic ring may contain a substitute in form of a lower alkyl group, m1 equals 3; or b) a group of formula (II-2): , where R6 denotes a lower alkyl group or cycloalkyl group; m2 equals 1 or 2; X1-X4 all denote carbon atoms, or one of X1-X4 denotes a nitrogen atom and the rest denote carbon atoms; and where "heteroaryl" in each case relates to a 5- or 6-member aromatic ring containing 1-3 heteroatoms selected from a nitrogen atom, oxygen atom and a sulphur atom. The invention also relates to a histamine H3 receptor antagonist or inverse agonist, as well as a preventive or medicinal agent.

EFFECT: obtaining novel biologically active compounds, having histamine H3 receptor antagonist or inverse agonist activity.

11 cl, 8 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula (I) or to its salt or ester in which radicals and symbols have the values presented in claim 1. These compounds are ACC inhibitors.

EFFECT: production of compounds to be applied as a therapeutic agent for various ACC-related disorders such as bacony liver, hyperlipidemia, obesity and diabetes.

13 cl, 48 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): or to their pharmaceutically acceptable derivatives selected from a group consisting of pharmaceutically acceptable salts and esters; in which: R1, R2, R3, R4, R5, R6, R7, R8a, R8b, R8c and R8d are such as presented in the patent claim 1. The invention also refers to compounds of formula (I), to a compounds selected from a group, to a pharmaceutical composition, to methods of treating, to a method of decreasing the plasma cholesterol level in a patient, to a method of modulating cholesterol metabolism, catabolism, synthesis, absorption, re-absorption, secretion or excretion in a mammal, to a method of modulating farnesoid X receptor activity, to a compound representing 3-(3,4-difluorobenzoyl)-1,1-dimethyl-1,2,3,6-tetrahydroazepino [4,5-b]indole-5-isopropylcarboxamide, to a composition, to a method of reducing the risk of an onset or a recurrence, to a method of modulating triglyceride metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal, and also to a method of modulating bile acid metabolism, catabolism, synthesis, absorption, re-absorption, secretions or excretion in a mammal.

EFFECT: preparation of the new biologically active compounds showing possessing nuclear receptor activity.

73 cl, 76 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula

, where X1, X2, Y, R1a, R1b, R2a, R2b, A1, A2, A3 and A4 have the values specified in the description, which are vanilloid receptor subtype 1 (VR1) antagonists.

EFFECT: preparing a pharmaceutical composition on the basis of the compounds of formula 1 and developing methods of managing pain, neurotic pain, allodynia, inflammation or inflammatory disease associated pain, inflammatory hyperalgesia, bladder hyperactivity and urine incontinence.

22 cl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula I where A is such as given in the invention formula, R is selected from the group consisting of H and C1-6 alkyl, n and p each is independently selected from 0, 1 and 2, on condition that n + p = 2; Y represents -O- or -S-; R1, R2, R3, R4 in each position are independently selected from H and C1-6 alkyl; R5 is selected from the group consisting of -C(O)-CH2-indol-3-yl, -C(O)-(CH2)2-indol-3-yl, -C(O)-(CH2)3-indol-3-yl, trans -C(O)-(CH=CH)-indol-3-yl, -SO2-4-fluorophenyl, -C(O)-CH(n-propyl)2, -C(O)-(4-hydroxy-3,5-di-tert-butylphenyl), -C(O)-CH(NH2)-CH2-indol-3-yl and -C(O)-CH2CH3; and R6 represents H. Invention also relates to pharmaceutical composition for modulation of muscarinic receptor M1, containing formula I compounds, and methods of treating disease or state, curable by modulator of muscarinic receptor M1.

EFFECT: formula I compounds as modulators of muscarinic receptor M1.

33 cl, 1 tbl, 27 ex

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