The method of obtaining (22r,s)- 1617th-butylidenedioxy - 11, 21-dihydroxypregna-1,4-diene-3,20-dione
(57) Abstract:Usage: in medicine, in particular in the synthesis of known anti-inflammatory and anti-allergic drug. The inventive product (22R, S)- 16, 17-butylidenedioxy - 11, 21-dihydroxypregna-1,4-diene-3.2 0-dione, the angle of rotation at 25°C (+)100 (0.2, dichloromethane). mol.m. 430. Reagent 1: 11, 16, 17 21-tetrahydroxypregna-1,4-diene-3,20-dione. Reagent 2: butanal. Process conditions: in the midst of acetonitrile in the presence of p-toluenesulfonic acid. The reaction is stopped by adding water and aqueous sodium bicarbonate. The recrystallization lead from methylene chloride and methanol by the addition of ligroin, hexane, cyclohexane or heptane, and the recrystallization in methanol and water. 2 C. p. F.-ly. The invention relates to a new manufacturing process (22R, S)-16, 17 butylidenedioxy-11, 21-dihydroxypregna-1,4 - diene-3,20 - dione(budezonida)
(I) by reaction 11, 16, 17, 21-tetrahydroxypregna-1,4-diene - 3,20-dione (16-hydroxyprednisolone)
(II) butanal CH3CH2CH2SNO in the environment of a solvent in the presence of an acid catalyst.In accordance with a known process, the essence of which is disclosed in  budesonide is produced by the reaction of 16-hydrox allocate by dilution of the reacted mixture in methylene chloride, neutralization by washing in aqueous potassium carbonate and water and evaporation of the solvent followed by crystallization from ether-ligroin. Then the product was purified by chromatography, for example, the installation of "Sephadex". The main disadvantages of dioxane lie in its ability to penetrate the protective coating on the skin to form peroxide. Another disadvantage of the known process is the use of perchloric acid is a strong oxidizer, resulting in its use as a catalyst affects the deterioration of the quality of the selection of the reaction product, and this complicates and increases the cost of subsequent cleaning process and processing of the product.The purpose of the invention is to create a new process, which is a more qualitative evolution reaction product and provide a simpler and more economical processing and purification of the product.The objective is achieved by the process according to the invention is carried out in acetonitrile, and the catalyst used p-toluensulfonate.The combination of less basic (compared to dioxane solvent of acetonitrile and amenites, for example n-toluenesulfonic acid gives better the second process, uses dioxane and perchloric acid.According to a preferred embodiment of this invention the reaction is stopped by adding water and adjusting properly the pH of the reaction mixture. This can be done by adding to water water carbonate hydrogenating sodium. After that, the product crystallizes. The crystals are filtered off, dissolved in methylene chloride and methanol, and then crystallized by adding a suitable hydrocarbon type naphtha, hexane, cyclohexane or heptane, receiving the crude product, which is then recrystallized in methanol with water in order to obtain pure budezonida.The manufacturing process budezonida according to the invention consists, therefore, of the two stages.Stage 1. Production of crude budezonida.16-hydroxyprednisolone reacts with butanal in acetonitrile. As the catalyst added n-toluensulfonate acid. The reaction mixture was diluted with water and aqueous carbonate hydrogenating sodium. After cooling down to 5-15aboutWith the crystallized product is filtered and washed with water. Then a wet or dry environment filtrate is dissolved in chloride. Add methanol and precipitated the resulting crude budesonide by adding naphtha or other suitable hydrocarbon (e.g. hexane, heptane or cyclohexane), after which the crude budesonide filtered.Stage 2. Producing pure budezonida.The crude budesonide dissolved in methanol at a temperature of about 60aboutC. the Solution is filtered through a dense filter and crystallized product by adding water. After cooling to a temperature of 5-20aboutWith, filtration and washing in methanol-water, budesonide dried in a vacuum at a temperature of 40-45aboutC. This process easier, much cheaper and less dangerous to health than the known process.Working example. The reaction is performed in nitrogen atmosphere. of 15.4 g of n-toluensulfonate acid are dissolved in 200 ml of acetonitrile. To the solution was added 50.0 g 16-hydroxyprednisolone and 17.6 ml of butanol. The temperature is increased to 25aboutC. After 30 min dissolves most of the material. Shortly thereafter, the product begins to crystallize. After 3 h the reaction is stopped by adding 75 ml of a saturated aqueous solution of carbonate hydrogenating sodium, resulting crystallized product. Visionscope pressure 40-65), receiving crude budesonide.The crude budesonide will recrystallized from methanol-water, getting clean budesonide ratio of isomers A B1 1 (determined by liquid chromatography high pressure), 25100,0about(0,2; CH2Cl2); M+430 (theoretical value 430,5). The method of obtaining (22R,S) - 16, 17 butylidenedioxy - 11, 21-dihydroxypregna-1,4-diene-3,20-dione of the formula
< / BR>interaction 11, 16, 17, 21-tetrahydroxypregna-1,4-diene-3,20-dione of the formula
< / BR>with butanal CH3CH2CH2CHO in the environment of a solvent in the presence of a catalyst, wherein the reaction is carried out in the acetonitrile using as catalyst p-toluenesulfonic acid.2. The method according to p. 1, characterized in that the reaction is stopped by adding water and adjusting the pH of the reaction mixture by adding, for example, sodium hydrogen carbonate in water.3. The method according to p. 1 or 2, characterized in that the obtained upon termination of the reaction, the crystals of the target product is filtered off, dissolved in methylene chloride and methanol, and then crystallized by adding a hydrocarbon type of naphtha, hexane, cyclohexane or heptane, receiving the crude product with
FIELD: organic chemistry, steroids, pharmacy.
SUBSTANCE: invention relates to a new type of selective estrogens comprising steroid structure of the general formula (I) with nonaromatic ring A and free of bound hydroxyl group at carbon atom 3 wherein R1 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R2 means hydrogen atom (H), α-(C1-C4)-alkyl, α-(C2-C4)-alkenyl or α-(C2-C4)-alkynyl; R3 means hydrogen atom (H) or (C1-C4)-alkyl at position 16 of steroid structure; R4 means ethynyl; R5 means hydrogen atom (H), (C1-C3)-alkyl or (C2-C3)-acyl; R6 means (C1-C5)-alkyl, (C2-C5)-alkenyl, (C2-C5)-alkynyl being each of that is substituted optionally with chlorine or fluorine atom; dotted line means the optional double bond. Compounds of the formula (I) elicit the selective affinity to ERα-receptors.
EFFECT: valuable properties of compounds and composition.
4 cl, 3 sch, 1 tbl, 8 ex
FIELD: organic chemistry, chemical technology, pharmacy.
SUBSTANCE: invention describes the improved method for preparing flumetasone (6α,9α-difluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione), flumetazone 21-acetate or its 17-carboxyl-androstene analogue of the formula (I) . Method involves interaction of benzoyl chloride with compound of the formula (II) in pyridine medium of its mixture with N,N'-dimethylacetamide to prepare 3-enol ester of the formula (IIIa) and it's the following interaction with 1-(chloromethyl)-4-fluoro-1,4-diazonium-bicyclo[2.2.2]octane-bis(tetrafluoroborate) in acetonitrile medium and water to prepare compound of the formula (IIIb) and the following removing the protective group in compound of the formula (IIIb) at the position C3 in medium of aqueous metabisulfite and ammonia to prepare compound of the formula (IV) . After the fluorination reaction of 9,11-epoxy group in compound of the formula (IV) using HF flumetasone 21-acetate is prepared followed by the selective hydrolysis with KOH in methanol (CH3OH) medium in the presence or absence of H2O2 to prepare compound of the formula (I) or flumetasone, respectively.
EFFECT: improved preparing method.
3 cl, 5 ex
SUBSTANCE: invention relates to methods for isolation and purification of triterpene glucosides from vegetable raw, in particular, saponins from beet and waste in sugar manufacturing, in particular, from beet pulp. Method involves alkaline extraction of raw at temperature 80°C for 8 h followed by settling. Granulated anion-exchange resin AV-17-2P in OH-form is used as a sorbent, and desorption process of sorbent is carried out with 70% ethanol. Invention can be used in food, pharmaceutical and cosmetic industry.
EFFECT: improved preparing method.
2 cl, 1 ex
FIELD: organic chemistry, steroids, chemical technology.
SUBSTANCE: invention describes a method for preparing 3-keto-7α-alkoxycarbonyl-substituted ▵4,5-steroid of the formula (I): wherein is taken among or R3 means hydrogen atom (H), lower alkyl, lower alkoxy-group or cyano-group (CN); R21 means hydrogen atom (H) or alkyl; R26 means (C1-C4)-alkyl; R8 and R9 form in common heterocyclic ring system. Method involves interaction of an alkylating agent with 4,5-dihydro-5,7-lactone steroid of the formula (II): wherein R18 means (C1-C4)-alkyl or R18O-group taken in common form O,O-oxyalkylene bridge or keto-group and R3, R8 and R9 have above given values in the presence of a base. Compounds of the formula (I) are used as intermediate compounds in improved methods for synthesis of epoxymexerone.
EFFECT: improved preparing method.
56 cl, 42 tbl, 30 sch, 5 dwg, 89 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to compounds of the formula (I): wherein R represents (C3-C6)-cycloalkyl possibly substituted with (C1-C4)-alkyl, or benzofuranyl, naphthyl, benzothiophenyl, benzooxadiazolyl, or phenyl possibly substituted with one or some substitutes. Also, invention describes methods for preparing compound of the formula (I). Indicated compounds are useful as pharmaceutical preparations possessing with anti-inflammatory properties.
EFFECT: valuable medicinal properties of compounds and preparations.
12 cl, 1 tbl, 107 ex
FIELD: organic chemistry, steroids, labeled compounds.
SUBSTANCE: invention relates to highly labeled analog of physiologically active compound, i. e. to 9α-fluoro-16α-hydroxyprednisolon [3H]-acetonide highly labeled with tritium of the formula (I): . The highly tritium-labeled compound of the formula (I) is necessary for investigation of active non-labeled analog.
EFFECT: valuable properties of compound.
2 cl, 1 ex
FIELD: organic chemistry, steroids, medicine, pharmacy.
SUBSTANCE: invention describes compounds of the formula (I) , their pharmaceutically acceptable salts, solvates, stereoisomers wherein in each case R1 and R2 mean independently hydrogen atom, possibly substituted alkyl, aryl, heteroalkyl wherein heteroatom means nitrogen atom, heteroaryl wherein a heteroatom means nitrogen, oxygen or sulfur atom; or R1 and R2 in common with N-atom to which they are bound can form a heterocyclic structure as a moiety of organic group comprising 6-12 carbon atoms and comprising optionally 1-6 heteroatoms chosen from nitrogen and oxygen atoms; R3 and R4 mean hydrogen atom or a protective group under condition that R and/or R4 represents part of the hydroxyl protective group; № from 1 to 17 mean carbon atoms wherein C-atoms at № 1, 2, 4, 11, 12, 15 and 16 can be substituted with two from R5 groups; C17-atom can be substituted with one of the following groups: =C(R5)(R5), =C=C(R5)(R5) or two from groups - R5 and -OR6; C-atoms at № 5, 8, 9, 10, 13 and 14 can be substituted with group R5 wherein R means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, (C1-C6)-halogenalkyl; R6 means H, protective group, such as -OR6-protected OH-group wherein the group -OR6 can form cyclic protective structure for vicinal -OH groups. Proposed compounds can be components of pharmaceutical composition and useful in treatment and/or prophylaxis of different states including inflammation, asthma, allergic disease, chronic obstructive pulmonary disease, allergic dermatitis, solid neoplasms, ischemia and cardiac arrhythmia.
EFFECT: improved treatment method, valuable medicinal properties of substances and pharmaceutical composition.
53 cl, 10 tbl, 24 ex
FIELD: organic chemistry, steroids, chemical technology.
SUBSTANCE: invention relates to novel effective methods for synthesis of 9,11-epoxy-17α-hydroxy-3-oxopregn-4-ene-7α,21-dicarboxylic acid, γ-lactone, methyl ester (eplerenone). Also, invention describes novel intermediate compounds of the general formula (I): wherein R1 means hydrogen atom (H), -COR4 wherein R4 means (C1-C6)-alkyl, (C1-C6)-alkoxy-group; R3 means (C1-C)-alkyl; Z1 means compound of the formula wherein -O-COR4 is at α-position; Z2 means -CH-, or Z1 and Z2 form in common a double bond; Q means compounds of formulas .
EFFECT: improved methods of synthesis.
28 cl, 3 sch, 17 ex
FIELD: organic chemistry, steroids.
SUBSTANCE: invention discloses derivatives of steroid sapogenins of the general formula (I): wherein R means alkylcarbonyl, alkoxycarbonyl substituted possibly with amino-group and others under condition that R is not acetyl and R is not ethoxycarbonyl if C3 is in S and C25 in R-configurations simultaneously; R is nor succinyl if C3 and C25 are in S-configuration simultaneously, or C3 R(α) or S(β), and C25 in R-configuration. Also, invention discloses using these compounds in treatment of cognitive dysfunction, noncognitive neurodegeneration, noncognitive neuromuscular degeneration and loss of receptors in absence of cognitive, nervous and neuromuscular insufficiency. Also, invention discloses methods for synthesis of these compounds, treatment and pharmaceutical composition containing thereof.
EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical compositions.
30 cl, 2 tbl, 5 dwg, 16 ex
SUBSTANCE: invention discovers derivatives of 5β-sapogenin and pseudo sapogenin of general formula or , where in general formula I or II: R1 R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R15 if available-H, independently R1 and R13-OH or R3-OH, =O or OR, where R - optionally substituted alkyl; lower acyl optinally substituted with carbamonyl or amino or lower alkoxycarbamonyl; lower alkoxycarbamonyl; R14 lower alkyl, optionally double bond with the exception of smylagenin and those compounds of formula I where simultaneously R1= R2= R4= R5= R6= R7= R8=R9= R10= R11= R12= R13=H, R3=β OH, R14=CH3, and methyl in C20 condition has α-orientation and C25 has S-configuration.
EFFECT: compounds increases muscarine receptor number and are useful for enhancement of human or animal cognitive function.
12 cl, 17 ex, 5 dwg, 21 tbl