The method of obtaining 1,4:3,6-dianhydro-d-sorbitol
(57) Abstract:The invention relates to a method for producing 1,4:3,6-dianhydro-D-sorbitol, which is an intermediate in the production of lekarstvennyh drugs on the basis of its mono - or dinitropropane. The method of obtaining 1,4:3,6-dianhydro-D-sorbitol is dehydration 75-80% of sorbitol solution at an elevated temperature in the presence of an acid catalyst, such as benzosulfimide or sulfuric acid, in the amount of 0.65 to 1.0 wt.% and the process of distillation is conducted using a capillary, through which, if the temperature of the reaction mass in the cube above 130C supplied inert gas (nitrogen, carbon dioxide). The technical result is to increase the output and quality of the target product, as well as reducing heat and energy consumption. table 1. The invention relates to the technology of 1,4:3,6-dianhydro-D-sorbitol (sorbed, isosorbide), which is an intermediate in the production of medicines on the basis of its mono - and dinitropropane, which are used as a vasodilatory action in hypertension, strokes and other diseases.Known methods of dehydration of sorbitol in toluene or xylene in the presence of acid catalysts har ሺ/P>According to these works, the output isosorbide ranges from 8 to 67%.Methods for isolation and purification of isosorbide complex, long and multi-stage. Also known is a method of obtaining isosorbide proposed by P. M. Kochergin with employees (Kochergin P. M., Kuzmicheva So on, Honey. prom. The USSR, 1964, No. 5, S. 29-30. Kochergin P. M., Titkov, P. M. Honey. prom. The USSR, 1959, No. 8, S. 18-20), implemented in Krasnouralsk copper smelting plant in Krasnouralsk the Ekaterinburg region).Currently isosorbide get Krasnouralsk copper smelting plant in GOSNII “Crystal”, Dzerzhinsk, Nizhny Novgorod region) according to the method proposed Khusainova A. R. with employees (Khusainov, A. R., Zyuzin Y. C., Daduh Century BC, Kochergin P. M. a method of obtaining a 1,4:3,6 dianhydro-D-sorbitol. RF patent № 2131434 from 09.04.1990).According to this method, adopted for the prototype, the process of dehydration is carried out with simultaneous separation from the reaction zone of the target product and the reaction water. The reaction is carried out in the presence of catalytic amounts of water 3-10 wt.% and acid catalyst of 0.2-0.6 wt.% p-toluenesulfonic acid, sulfuric or phosphoric acids. The process is carried out at a temperature of 165-C and a pressure of 1.0 to 4.0 kPa.Isosorbide obtained in this way, it turns out viscoplastic the process of obtaining isosorbide due to the exclusion of flammable solvents, increased process safety, increased the yield of the target product to the 78,1%.The disadvantages of the method are the duration of the melting process used food sorbitol; great heat and energy consumption for melting sorbitol; the uneven distribution of the catalyst; the absence of mixing, and hence the unevenness of the boiling point of the reaction mass, overheating, oxidation, which ultimately leads to a significant reduction of yield and quality of the target product.The aim of the present invention is to reduce the time of the technological cycle of dehydration of sorbitol, reducing heat and energy consumption; increasing the yield of the target product and the reduction of its cost, while maintaining its high quality.This goal is achieved:by using as feedstock syrup sorbitol (75-80% solution of sorbitol in water). Syrup of sorbitol is produced in the process of food production of sorbitol. Its cost in terms of 100% of the content of sorbitol 30% below the cost of the final product, because the process of obtaining food sorbitol syrup is time consuming and requires a lot of heat and energy;by using a capillary, primates through capillary inert gas (nitrogen, carbonic acid) eliminates oxidation of the reaction mass, in the apparatus at a high temperature, which in turn increases the yield of the target product;as the acid catalyst, it is recommended to use benzosulfimide, sulfuric acid in the amount of 0.65 to 1.0 wt.%.The technology of the method consists in the following: in an apparatus equipped with a thermometer, capillary, download 110,0 g of sorbitol syrup (75 g in terms of 100%), of 0.48-0.75 g of catalyst. Apparatus connected to the receiver isosorbide, which, in turn, connected through a cooler-condenser with water collection, which is connected via an additional trap to a vacuum pump. With a uniform boiling of the reaction mixture due to the presence of the capillary at a pressure of 1.0 to 4.0 kPa and a temperature of 55-100C distilled water, and when the temperature of the mass s and up through capillary miss inert gas (nitrogen, carbon dioxide) and at a temperature of 160-S is the selection of isosorbide in the form of a light yellow mass. The results of the experiments presented in the table.The use of sampling helps to ensure uniform boiling of the reaction mixture, the introduction of inert gas at a temperature of 130C and above, excluding the oxidation of d is s 1,4:3,6 dianhydro-D-sorbitol by dehydration of sorbitol in the presence of an acid catalyst at elevated temperature, characterized in that the feedstock use 75-80% solution of sorbitol, the process of distillation is carried out with the use of the capillary, when the temperature of the reaction mass in the cube above 130C through capillary supplied inert gas (nitrogen, carbon dioxide) and as the acid catalyst used benzosulfimide or sulfuric acid in the amount of 0.65 to 1.0 wt.%.
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new bis-tetrahydrofuranbenzodioxolyl sulfonamide compounds of the formula (I): , its salts, stereoisomers and racemates that are effective inhibitors of protease activity. Also, invention relates to pharmaceutical preparations, methods for inhibition of retrovirus proteases, in particular, to resistant retrovirus proteases, to many drugs, methods for treatment and prophylaxis of infection or disease associated with retrovirus infection in mammals and to methods for inhibition of retrovirus replication. Invention provides preparing new derivatives of bis-tetrahydrofuranbenzodioxalyl sulfonamides eliciting the valuable pharmaceutical properties.
EFFECT: valuable medicinal properties of compound and composition, improved treatment method.
16 cl, 2 dwg, 3 tbl
FIELD: organic chemistry, medicine, oncology, pharmacy.
SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:
wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.
EFFECT: valuable medicinal properties of compound.
13 cl, 1 dwg, 4 tbl, 16 ex
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to a novel method for preparing 14β-hydroxy-1,4-carbonate-desacetylbaccatin III and intermediate substances used in preparing new derivatives of taxane and possessing an antitumor activity. Method involves the following stages: a) protection of hydroxyls at positions 7 and 10 in 10-desacetylbaccatin III wherein R and R1 are taken among hydrogen atom, (C1-C10)-alkyl or aryl, (C1-C10)-alkyl- or aryl-carbonyl, trichloroacetyl, (C1-C4)-trialkylsilyl; preferably, when R and R1 are similar then they represent trichloroacetyl; when they are different then, preferably, R represents trichloroacetyl and R1 represents acetyl; or R represents triethyl or trimethylsilyl and R1 represents acetyl; b) two-stage oxidation to yield a derivative oxidized to carbonyl at position 13 and hydroxylated at position 14; c) carboxylation of vicinal hydroxyls at positions 1 and 14 to yield 1,14-carbonate derivative; d) reduction of carbonyl at position 13; e) removal of protective groups at positions 7 and 10. Also, invention relates to intermediate substances. Invention provides preparing intermediate substances used in synthesis of taxane.
EFFECT: improved preparing method.
8 cl, 8 ex
FIELD: organic chemistry, chemical technology, medicine.
SUBSTANCE: invention relates to a method for synthesis of new compounds, namely, 1,11-dialkyl-3,5-dihydrofuro-[2',3':3,4]-cyclohepta[c]isochromens of the formula: (Ia-f): wherein (Ia): R means hydrogen atom (H); R1 means hydrogen atom (H); (Ib): R means bromine atom (Br); R1 means hydrogen atom (H); (Ic): R means chlorine atom (Cl); R1 means hydrogen atom (H); (Id): R means hydrogen atom (H); R1 means bromine atom (Br): (Ie): R means hydrogen atom (H); R1 means chlorine atom (Cl); (If): R means methoxy-group (-OCH3); R1 means hydrogen atom. Method involves formation of condensed tetracyclic system as result of the successive recyclization reactions of furan ring of derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol and the secondary cyclization of formed isochromen ketone in boiling of solution containing derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol of the formula: in ethanol medium in the presence of hydrogen chloride alcoholic solution for 15-40 min. Invention provides synthesis of new derivatives of isochromens possessing the potential anti-inflammatory activity.
EFFECT: improved method of synthesis, valuable medicinal properties of compounds.
1 cl, 2 tbl, 5 ex
FIELD: organic chemistry of natural compounds, medicine, oncology.
SUBSTANCE: invention relates to a novel crystalline form of (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)ethylideneoxy]-5,20-epoxy-1-hydroxytax-11-ene-13-yl-(2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate that shows the diffraction picture of roentgen rays in powder with characteristic peaks at diffraction angles (θ)= 6.2o, 10.3o, 10.7, 11.4o and 12.0, and a method for its preparing. Method involves carrying out the crystallization step by using organic solvent chosen from group consisting of ketone type solvent, nitrile solvent type and their mixture, or mixture of said solvent and water. Also, invention relates to an antitumor agent based on the prepared crystalline form. Invention provides the stable quality of a medicinal agent based on its lower hygroscopicity.
EFFECT: improved and valuable properties of compounds.
8 cl, 5 ex
FIELD: organic chemistry, chemical technology, medicine, oncology.
SUBSTANCE: invention relates to a method for isolation of epotilons used in medicine in treatment of cancer diseases. Method for desorption of epotilons A, B, D and/or E from synthetic resin is based on using low-polar or nonpolar solvent chosen from the group comprising (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Used aromatic solvent is chosen from the group including naphthalene, benzene or naphthalene and benzene substituted with one or some substitutes chosen from the following group: (lower)-alkyl, (lower)-alkoxy-group, halogen atom, nitro-group and (lower)-alkoxy-(lower)-alkyl wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Solvent is removed to the required level but up to preparing a dry residue preferably. If necessary, residue is dissolved in mixture alcohol/hydrocarbon in the corresponding volume ratio. Alcoholic phase is evaporated until dry and then alcoholic extract is crystallized from mixture alcohol and hydrocarbon. Then formed crystallized product is dissolved in mixture nitrile/water but preferably in mixture acetonitrile/water taken in the ratio = 2:3 (vol./vol.). Formed solution is applied on column (if necessary, after separation for some distillates) for preparative chromatography in reversed phase followed by elution with mixture nitrile/water, removing nitrile and extraction of an aqueous phase with ester. Ester extract is evaporated and formed product is subjected for crystallization. Method for preparing epotilons A, B, D and/or E from resin or reaction mixture involves the following steps: (a) desorption of epotilons with low-polar or nonpolar solvent chosen from the group including (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents being the desorption step can be repeated up to achievement of the more complete desorption; (b) removal of solvent used in desorption from formed solutions by evaporation; (c) optional crystallization of epotilon(s) after desorption and first of all for crystallization of epotilon B by addition of mixture of alcohol with hydrocarbon and the following evaporation of alcoholic phase until dry and crystallization of epotilon B from the corresponding mixture of solvents; (d) (obligatory step) separation of epotilons by method of chromatography in reversed phase and the following dissolving a residue obtained in previous step in suitable solvent, elution with mixture nitrile/water and removing nitrile from epotilon-containing fractions by evaporation. If necessary, water remained with epotilon is extracted with ester followed by evaporation of epotilon-containing ester phase until dry; (e) optional purification by adsorption chromatography method, and final recrystallization of purified epotilon from corresponding solvents or mixture of solvents. If necessary, in this process between each step formed solutions or suspensions are concentrated, and/or liquid or solid components are separated of one another. Separation of epotilons A and B is carried out by chromatography method based on a mobile layer modeling. Invention provides simplifying methods for preparing large amounts of epotilons for satisfying requirement in these agents.
EFFECT: improved isolating method.
12 cl, 2 ex
FIELD: organic chemistry, medicine, gynecology.
SUBSTANCE: invention relates to novel tetracyclic heterocompounds of the formula (I): wherein X, Y, Z, R1 - R4, n and m has values given in the invention description and used as selective modulating agents for estrogen receptors. Also, invention relates to a method for synthesis of these compounds and pharmaceutical compositions comprising thereof, and their using in treatment and/or prophylaxis of disorders mediated by one or more estrogen receptors. Proposed compounds are useful in treatment and/or prophylaxis of disorders associated with depleting estrogen and comprising such disorders as rush of blood, vaginal dryness, osteopenia and osteoporosis, hormone-dependent cancer and hyperplasia of breast, endometrium, uterus cervix and prostate, endometriosis, uterus fibroma, osteoarthritis that can be used as contraceptive agents both separately and in combination with progestogen or progestogenous antagonist.
EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.
25 cl, 7 tbl, 171 ex
FIELD: organic chemistry, medicine, endocrinology.
SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.
EFFECT: valuable medicinal properties of compounds.
11 cl, 41 tbl, 243 ex
FIELD: organic chemistry, medicine, biochemistry, pharmacy.
SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra 1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.
35 cl, 16 sch, 13 tbl, 43 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to heterocycle-substituted tricyclic compounds of the formula (I): or their pharmaceutically acceptable salts wherein R means hydrogen atom; R1 and R2 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R3 means hydrogen atom; n1 and n2 = 0-3 independently under condition that they both do not mean 0; Het means pyridyl wherein pyridyl is added to B through cyclic carbon atom and it comprises from 1 to 4 substitutes (W) chosen independently from group comprising -NR4R5, -NHCOR26, -NHSO2R16; R21 means aryl and R21 means heteroaryl wherein heteroaryl represents furyl, thienyl, pyridyl, thiazolyl, pyrrolidinyl, azethidinyl; R4 and R5 mean hydrogen atom or alkyl comprising 1-6 carbon atoms, or R4 and R5 mean in common -(CH2)3-, -(CH2)4-, -(CH2)5- or -(CH2)2NR7-(CH2)2- wherein R7 means hydrogen atom or alkyl comprising 1-6 carbon atoms; R8, R, R10 and R11 mean hydrogen atom; B means -(CH2)n4CR12=CR12a(CH2)n5 wherein n4 and n5 = 0-2 independently; R12 and R12a are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R21 means from 1 to 3 substitutes chosen independently from group comprising hydrogen atom, trifluoromethyl, trifluoromethoxy, halogen atom, cyano, alkyl comprising 1-6 carbon atoms, alkoxy group comprising 1-6 carbon atoms, or -CR29(=NOR28); R22 means -COR23, -S(O)R31, -S(O)2R31 or -COOR27; R23 means cycloalkyl comprising 3-7 carbon atoms, (C3-C7)-cycloalkyl-(C1-C6)-alkyl, cycloalkyl comprising 3-7 carbon atoms containing from 1 to 3 substitutes chosen from group comprising halogen atom, (C1-C3)-alkoxy-(C1-C3)-alkyl, hydroxy group and alkoxy group comprising 1-6 carbon atoms, aryl, aryl-(C2-C6)-alkyl; R27 means alkyl comprising 1-6 carbon atoms, phenyl or benzyl; R28 and R29 are chosen independently from group comprising hydrogen atom or alkyl comprising 1-6 carbon atoms; R31 means alkyl comprising 1-6 carbon atoms, halogenalkyl comprising 1-6 carbon atoms, aryl, aryl-(C1-C6)-alkyl. Also, invention relates to pharmaceutical compositions containing these substances and their using for preparing a drug used in treatment of thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, heart failure and cancer.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
10 cl, 11 tbl, 9 ex