(22)-6b-methoxy-3a,5-cyclo-5a-cholestan-24-one-22-ol as an intermediate in the synthesis of (22r,23r)-3b-acetoxy-22,23 - isopropylidenedioxy-24-metalholic-5-ene
(57) Abstract:Use: as an intermediate product in the synthesis of rototiller plants - brassinolide). The inventive product (22 x )-6 b-methoxy-3 a , 5-cyclo-5 a-cholestan-24-one-22-ol, yield 90%. BF C28H47O3. Reagent 1: (22 )-6 b-methoxy-3 a , 5-cyclo-5 a-pregnan-20-formyl. Reagent 2: methyltriphenylphosphonium in the presence of utility and isobutyronitrile. Reagent 3: hydrogen gas on the Raney Nickel in the presence of boric acid. Output increased 2.5 times since the simplified schema of the target product. The invention relates to new chemical compound, specifically to (22 )-6-methoxy-3,5-cyclo-5-cholestan-24-one-22-Olu formula I,
which is an intermediate substance to obtain (22R, 23R)-3 - acetoxy-22,23-isopropylidenedioxy-24-metalholic-5 - ene of formula II;
Compound II is a well-known synthetic precursor hormone brassinolide) III, which is found in very low concentrations in some plants and is the most active of the new class of natural hormones - steroids, and therefore can be used in agriculture as a growth promoter, plant /1/. His synthesis of the methoxy-24-methyl - 5-cholestan-22,23,26-triol (IV):
It is obtained from (20S)-6-methoxy-20-formyl-3 , 5-cyclo-5-pregnane (V) in seven stages with the release of 21% in the General scheme /3/:
____< / BR>____ ____< / BR>IVAttach 2-liliputana to (20S)-22-aldehyde (V) receive fullcarbon in the form of a mixture of two isomers (VI) and (VII), one of which (VI) after chromatographic separation oxidized with N-bromosuccinimide and get lactol (VIII) as a mixture of two isomers, which is then transformed into a mix - and-ethoxyethyl esters (IX) and (X) with the release of 96% in the ratio of 3:1. Main isomer (IX), the selected chromatographic process lithium dimethylcarbinol, and the resulting ketone (XI) is subjected to the action of sitedisability and under the conditions that leads to bis-methylated product (XII) with a yield of 84%. The restoration of the keto group of compound (XII) detribalized get the alcohol (XII) with a yield of 92%, the treatment of which 10% HCl and subsequent recovery of lithium aluminum hydride leads to the desired triol (IV) yield 81%.The use of triol (IV) to obtain the compound (II) includes the following stages:
< / BR>_____ The compound (IV) is heated in acetic acid and obtain the corresponding 3-acetoxy-5-ene (96%), which after processing p-toluensulfonate in acetone leads to and is cholest-5-ene (II) sequential processing methanesulfonamido in pyridine, recovering the resulting ester with lithium aluminum hydride and acetylation with a total yield of 80%.The total number of stages in obtaining predecessor brassinolide) (II) under the scheme of the aldehyde (V) is equal to 9, with a total yield of about 12%.The disadvantage of using triol (IV) as an intermediate product to obtain the compound (II) is a multi-stage process, its complexity, and not a high yield.The aim of the invention is to simplify the process of obtaining (22R,23R)-3-acetoxy-22,23-isopropylidenedioxy-24-IU-TileList-5-ene (II) of the aldehyde (V) and the reduction in the number of stages.This goal is achieved by the described compound (22 )-6-methoxy-3 , 5-cyclo-5-cholestan-24-one-22-I (I). The described compound (I) is obtained from the 20-aldehyde (V) in two stages according to the scheme:
< / BR>The aldehyde (V) is subjected to the action of the Wittig reagent and the resulting steroid olefin by 1,3-dipolar cycloaddition of isobutyronitrile turn in isoxazolin (XV) c output 90% recovery splitting on the Raney Nickel transform in the inventive connection-within (I) with the release of 95%.It should be noted that the inventive compound (I) is used on the aspects of chromatographic separation epimeres. The transformation of the claimed compound (I) in the well-known synthetic precursor of brassinolide) (II) is carried out according to the scheme:
II-Within (I) the alkylate methyllithium, the resulting secondary alcohol is oxidized by the reagent Carreta (CrO3.Py) and dehydration by treatment with p-TsOH. Get inceton (XVI) with a total yield of 80% . Restoring eketone (XVI) diisobutylaluminium, epoxidation m-chloramben - sainoi acid and disclosure of epoxide aluminum hydride leads to diolo (XVII) with a yield of 60%. Last by boiling in acetic acid and treatment p-toluensulfonate in acetone converted into the target compound (II) with a yield of 90% . Thus, (22R,23R)-3-acetoxy-22,23-isopropylidenedioxy-24-metalholic-5-ene (II) receive from the aldehyde (V) under this scheme using the described compounds (I) in 5 stages with the release of 37%.P R I m e R 1. Obtaining (22)-6-methoxy-3 ,5-cyclo-5-cholestan-24-one-22-ol.To the suspension to 13.09 g (36.6 mmol) of methyltriphenylphosphonium in dry ether (150 ml) is added in an argon atmosphere at room temperature of 14.8 ml of a 2.25 M solution of utility. Stirred for 2 h and add 11,47 g (33.3 mmol) of the 20-aldehyde (V) in dry THF. The mixture is boiled for 5 hours Then filtered, dried over Na2SO4, the sid, obtained from 8,96 g (66,6 mmol) N-chlorosuccinimide in 300 ml of chloroform, to 0.12 ml of pyridine and 5,78 g (66,6 mmol) of oxime samalanga aldehyde. After a few minutes add 7,12 g (a 56.6 mmol) of triethylamine in chloroform for 6 hours, the Reaction mixture was stirred at room temperature for 24 h and the solvent evaporated. The residue is treated with water and extracted with ether. The ether solution is passed through a filter with alumina, the solvent is evaporated. Received 12,78 g (90%) of (20S,5' )-20-(3'-isopropylthiazole-5-yl)-6-meth - oxy-3 ,5-cyclo-5-pregnane (XV).PMR-spectrum (200 MHz, M. D.): 0,42 m (1H, cyclop.), 0.65 m (1H, Cyclops. ), of 0.71 (3H,18-Me), of 0.87 (3H, J = 7 Hz, 21-Me), a 1.01 (3H, 19-Me), 1,15 d (6N, J = 7 Hz, 26-and 27-IU), 2,63 DD (1H, J1= 16 Hz, J2=8 Hz, C23-N), 2,71 Sept. (1H, J = 7 Hz, C25-N), 2,78 m (1H, C6-N), 2,94 DD (1H, J1= 16 Hz, J2= 11 Hz, C23-N) to 3.33 (3H, OMe), 4,67 m (1H, C22-H); IR spectrum (film, cm-1): 1620, 1100.Mass spectrum (m/z): 427 /M/+, 412/M-Me)+, 395/M-MeOH)+, 372.To a well stirred in ethyl alcohol the Raney Nickel type of 18.6 g (300 mmol) of boric acid and 12,35 g (29 mmol) of isoxazoline (XV). The reaction mixture was kept at room temperature and stirring in an atmosphere of hydrogen for 7 hours Then provide water and dried over Na2SO4. The solvent is evaporated to 2/3 of its volume and the residue is passed through a filter with silica gel. After evaporation of the solvent receive 11,84 g (95% ) (22 )-6-methoxy-3 ,5-cyclo-5-cholestan-24-one-22-ol (I). PMR-spectrum (200 MHz , M. D.): 0,44 m (1H, cyclop.), 0.65 M (1H, cyclop.), to 0.74 (3H, 18-Me), 0.95 (3H, J = =7 Hz, 21-Me), of 1.02 (3H, 19-Me), 1,11 d (6N, J = 7 Hz, 26-and 27-IU), 2,41 DD (1H, J1= 17 Hz, J2= 10 Hz, C23-N), 2,54 DD (1H, J1= 17 Hz, J2= 3 Hz, C23-H), 2.63 in Sept. (1H, J = 7 Hz, C23-N), 2,78 m (1H, C6-N) to 3.33 (3H, OMe), 4.10 m (1H, C22-N).IR spectrum (film, cm-1): 3510, 1710, 1100.Mass spectrum (m/z) 430/M/+, 415/M-Me/+,398/M-MeOH/+, 397/M-Me-H2O/+, 375, 329.P R I m m e R 2. Receipt of (22R,23R)- 3-acetoxy-22,23-isopropylidenedioxy - 24-metalholic-5-ene (II).To a solution of br11.01 g (25.5 mmol) is within (I) in 350 ml of absolute ether in an argon atmosphere is added dropwise 150 ml of 1.0 N. the ether solution metallice, maintaining a temperature of 0-5aboutC. Stirred the reaction mixture for 2 hours and add ammonium chloride, water, and extracted with ether. Dried over Na2SO4, evaporated, the residue is dissolved in 145 ml of methylene chloride and add 1.2 g of reagent Carreta. The solution was stirred at room temperature and evaporated. The residue is dissolved in 300 ml of anhydrous benzene, add a catalytic amount of para-toluenesulfonic acid and calcium chloride. The reaction mixture is heated to boiling and boil for 5-10 minutes Then the reaction mixture is cooled and passed through a layer of aluminum oxide evaporated. Get 8,67 g (80% ) 24-methyl-6-methoxy-3 ,5-cyclo-5-cholesterol-23-ene-22-she (XVI). IR spectrum (KBr, cm-1): 1680, 1620, 1040.Mass spectrum (m/z): 426/M/+, 384/M-MeOH/+.PMR-spectrum (200, MHz , M. D.): 0,44 m and 0.65 m (2N, cyclop.), 0,70 (3H, 18-Me), of 1.02 (3H, 19-Me), 1.07 (6N, J = 7 Hz, 26-and 27-IU), 1,11 d (3H, J = 7 Hz, 21-Me), 2,08 D. (3H, J = =1.5 Hz, 28-Me), to 3.33 (3H, OMe), 6,06 Shire. (1H, C23-N).To mix the solution 5,112 g (0.012 mol) of the ketone (XVI) in 50 ml of THF in a stream of argon add 38 g of 86% of DIBAH in THF at -78aboutC. the Reaction mixture is stirred for 30 min and gently poured upon cooling in an ice bath in a mixture of methanol and petroleum ether. The resulting suspension is stirred for 1 h, evaporated the solvent, add 200 ml of water and extracted with methylene chloride, washed with a solution of NH4Cl and NaHCO3, dried over Na2SO4. To the resulting solution was poured a solution of 2.40 g (0.014 mol) of meta-chlormadinone acid in 25 ml of methylene chloride. The reaction dare and filtered through a layer of aluminum oxide. The solvent is evaporated. The residue is dissolved in ether and poured to aluminum hydride prepared from 0.34 g LiAlH4and 0.31 AlCl3in ether at room temperature. Stirred for 1 h and treated with 150 ml of 50% AcOH, extracted with ethyl acetate, the extracts washed with a solution of NaHCO3, water, dried over Na2SO4, evaporated. The residue is subjected to column chromatography on silica gel (eluent-hexane-ether). Get 3,21 g (60%) of (22R,23R,24S)-22,23-dihydroxy-24-methyl-6-methoxy-3 ,5-cyclo-5-cholestan (XVII).PMR-spectrum (200 MHz , M. D.): 0,82 (3H, 18-Me), was 1.04 (3H, 21-Me), was 1.06 (3H, 19-Me), 1,11 d (3H, 28-Me), 1.16 and 1.20 of, 2 d (6N, 27 and 28 IU), 2,78 m (1H, 6-H), 3.33 and m (3H, OMe), 4,91-5,41 (2H, 22-H and 23-H).IR spectrum (film, cm-1): 3450. Mass spectrum (m/z): 446/M/+, 431/M-Me/+, 414/M-MeOH/+.2.37 g (5 mmol) of diol (XVII) is dissolved in 50 ml of acetic acid and boiled for 0.5 hours After cooling, the reaction mixture was poured into sodium hydrogen carbonate solution and extracted with ether, washed with water, dried over Na2SO4and evaporated. The residue is dissolved in acetone (50 ml), add a few crystals of p-toluene - sulfonic acids and boil for 2 hours, the Reaction mixture was poured into a solution of potassium carbonate and extracted with ether, dried over Na2SO4IR spectrum (KBr, cm-1): 1735, 1250.PMR-spectrum (200 MHz , M. D.): 0,80 (3H, 18-Me), of 1.03 (3H, 21-Me), was 1.06 (3H, 19-Me), 1.13 (3H, 28-Me), 1,17 l and 1.29 d (6N, 26 and 27 IU), 1,34 with and 1.52m (6N, IU-acetone. protection), 3,90 was 4.42 (2H, 22-H and 23-H), 4.59 (1H, 3-H), 5,38 m (1H, 6-H).Mass spectrum (m/z): 514/M/+, 454/M-AcOH/+.Thus, the use of the inventive substances (1) as an intermediate of synthesis of (22R, 23R)-3-acetoxy-22,23 - isopropylidenedioxy-24-metalholic-5-ene (II) of the aldehyde (V) allows platitudinal the transition to the target product, which is stage 4 less, compared with the scheme using analog (IV) to increase output by 2.5 times and to simplify the scheme, excluding the hard work of separating mixtures of epimeres in some cases. (22 )-6-methoxy-3 ,5-cyclo-5-cholestan-24-one-22-ol of the formula
< / BR>as an intermediate in the synthesis of (22R,23R)- 3-acetoxy-22,23-isopropylidenedioxy-24-metalholic-5-ene.
cholesterol (Chs)< / BR>testosterone (TS)which can be used as source reagents for solid-phase synthesis of steroid derivatives of oligonucleotides and their analogues
FIELD: organic chemistry, steroids, medicine, pharmacy.
SUBSTANCE: invention relates to 3-methylene-steroid derivative of the general formula (1):
wherein R1 means hydrogen atom (H), or in common with R3 it forms β-epoxide; or R1 is absent in the presence of 5-10-double bond; R2 means (C1-C5)-alkyl; R3 means βH, βCH3 or in common with R1 it forms β-epoxide; either R3 is absent in the presence of 5-10-double bond; R4 means hydrogen atom, lower alkyl; Y represents [H, H], [OH, H], [OH, (C2-C5)-alkenyl], [OH, (C2-C5)-alkynyl] or (C1-C6)-alkylidene, or =NOR5 wherein R5 means hydrogen atom (H), lower alkyl; dotted lines represent optional double bond. Compound can relate also to its prodrug used for treatment of arthritis and/or autoimmune diseases.
EFFECT: valuable medicinal properties of compounds, improved method for treatment.
38 cl, 1 tbl, 18 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention represents new derivatives of 17,20-dihydrofusidic acid of the formula (Ia)
wherein Q1 and Q2 are similar or different and mean -CO-, -CHOH-, -CHRO- wherein R means (C1-C4)-alkyl; Q3 means -CH2-; Y means hydrogen atom (H); A means -O- or -S-; R1 means (C1-C4)-alkyl, (C2-C4)-olefin, (C1-C6)-acyl, (C3-C7)-cycloalkylcarbonyl, benzoyl. These derivatives are used in pharmaceutical compositions for treatment of infectious diseases, in particular, in composition for topical applying for treatment of infectious diseases of skin and eyes.
EFFECT: valuable medicinal properties of compounds.
22 cl, 7 tbl, 41 ex
FIELD: organic chemistry, chemistry of steroids.
SUBSTANCE: invention relates to a new method for synthesis of 6β-formyl-B-norcholestane-3β,5β-diol of the formula (I): by constricting six-membered B-ring of cholesterol. Method involves photooxidation of cholesterol with air oxygen at irradiation by visible light in the presence of porphyrine photosensibilizing agent immobilized on low-molecular fraction of copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-5-methyl-6-sulfonylfluoride octene-1 in the mass ratio porphyrine photosensibilizing agent : cholesterol = 1:(12-15). As porphyrine photosensibilizing agent 5,10,15,20-tetraphenylporphyrine can be used. Method shows technological simplicity, it doesn't require rigid conditions and provides the high yield of the end product.
EFFECT: improved preparing method.
2 cl, 3 ex
FIELD: medicinal industry, sterols.
SUBSTANCE: invention relates, in particular, to the improved method for producing sterols - lanosterol and cholesterol from wooly fat that can be used in preparing medicinal and cosmetic preparations. Method is carried out by alkaline hydrolysis of raw, extraction of unsaponifiable substances, removal of solvent and successive isolation of lanosterol and cholesterol. Alkaline hydrolysis of raw is carried out with a mixture of ethanol, sodium hydroxide, pyrogallol and water at temperature 70°C for 4 h at stirring in the following ratio of components: raw : ethanol : sodium hydroxide : pyrogallol : water = 100.0:(300.0-350.0):(30.0-35.0):(0.01-0.05):(7.5-12.0), respectively, with the indicated mixture with addition of toluene in the following ratio: raw : ethanol : sodium hydroxide : pyrogallol : toluene : water = 100.0:(220.0-255.0):(30.0-38.0):(0.05-0.12):(100.0-137.0):(2.5-7.0), respectively, and lanosterol is isolated by precipitation from mixture of methylene chloride and ethanol in the ratio = 1:1. Before removal of solvent unsaponifiable substances are extracted at temperature 50°C for 2-3 h at stirring. Invention provides increasing yield of the end product, enhancing qualitative indices and reducing cost of production.
EFFECT: improved producing method.
2 cl, 3 ex
SUBSTANCE: polyaminosteroid branched derivatives of general formula I are described, where R1 is saturated or unsaturated C2-C10alkyl (conjugated or branched) or methyl, R2 is COOH or branched polyamine fragments, R3 is H, OR19, where R19 is H or C1-6acyl, R4 is H, R5 is H, CH3, R6 is H, CH3, R7=R8=R9=H, R10 is H, CH3, R11 is OH,-OSO3, - O-acyl, -(Z)n-(NR-Z)p-N(R)2, Z is linear hydrocarbon diradical, n=0, 1, p=1, R-H, C1-6alkyl, C1-6aminoalkyl, possibly substituted by C1-6alkyl, R12=R13=R15=H, R16 is H, OH, R17 is H, R18 is H, CH3, possible double bond. Compounds possess bactericidal activity and can be used for prevention of bacterial infections.
EFFECT: production of polyaminosteroid derivatives, possessing bactericidal activity which can be used for prevention of bacterial infections.
27 cl, 31 ex, 1 tbl, 2 dwg
SUBSTANCE: claimed invention describes paroxetine cholate or salt of cholic acid derivative and composition, which contains paroxetine and cholic acid or its derivative. Also described is pharmaceutical composition for treatment of depressive states, containing paroxetine salt or composition. Pharmaceutical composition can be part of peroral medication, swallowed without water, on form of disintegrating in mouth paroxetine tablet.
EFFECT: obtaining paroxetine cholate or salt of cholic acid derivative, which can be used in pharmacology.
19 cl, 38 ex, 12 tbl
SUBSTANCE: invention refers to synthesis of biologically active substances, in particular specifically, to improved method of producing 2,3-monoacetonide 20-hydroxyecdysone of formula found in very small amounts in some plants, e.g. Rhaponticum carthamoides. Method is implemented by interaction of 20- hydroxyecdysone (1.0 g, 2.08 mmole) and acetone with phosphomolybdic acid (PMA) added. As suspension is effected by mother compound in PMA acetone (0.3 g, 0.16 mmole), after 5 min homogenisation of reaction mixture is observed to be steamed by neutralisation with 0.1% sodium hydrocarbonate solution with following ethyl acetate and chromatography extraction of the end product, thus resulting in isolation of the end 2,3-monoacetonide 20- hydroxyecdysone of 32% yield.
EFFECT: method is highly selective and single-stage.
2 cl, 1 ex
SUBSTANCE: claimed invention relates to novel fusidic acid derivatives of general formula [I], where X represents halogen, trifluoromethyl, C1-C7alkyl, substituted with phenyl, C2-C9alkenyl, optionally substituted with C1-C7alkyl, halogen or phenyl, phenyl, optionally substituted with one or two similar or different substituents, selected from group consisting of halogen, C1-C7alkyl, C2-C9alkenyl, phenyl, C1-C6alkoxy, nitro, C1-C6alkyltio, trifluoromethyl and cyano; or X represents naphtyl; Y and Z both represent hydrogen or together with bond C-17/C-20 form double bond between C-17 and C-20 or together represent methylene and form cyclopropane ring in combination with C-17 and C-20; A represents O, S or S(O); B represents C1-6alkyl, C2-6alkenyl, C1-6acyl, phenyl or benzoyl, where C1-6alkyl is optionally substituted with one or more halogens, hydroxy, C2-6alkenyl, phenyl, C1-4heteroaryl or C1-6alkoxy; Q1 represents -(CHOH)-, or -(CHW)-, where W represents halogen or azido; Q2 represents -(CHOH)-; to their pharmaceutically acceptable salts and easily hydrolysed esters and to pharmaceutical compositions, including said derivatives, as well as to their application in therapy.
EFFECT: application in therapy.
31 cl, 127 ex, 5 tbl
FIELD: production processes.
SUBSTANCE: invention refers to wood working and wood chemical industries. Birch bark is broken down, mixed with liquid, the mixture is held at temperature higher than mixture freezing temperature, then triterpene compounds are separated from lingo-adipic residue with the following filtration and drying. Birch bark is additionally broken down by method of impact-abrasing and/or abrasing effect till obtaining birch bark flour. Birch bark flour is mixed with liquid with density of 0.999-0.958 kg/m3. Mixture is held for 0.1-10 hours and then separated by flotation to hydrophobic and hydrophilous fraction. Solution remaining after separation is condensed and dried. Obtained hydrophobic fraction - mixture of triterpene compounds - is exposed to recrystallisation in ethanol with activated charcoal and then betuline, solution of triterpene compounds in ethanol and mixture of triterpene and polyphenol compounds at carbon matrix is obtained. Or triterpene compounds mixture is separated to fractions in carbon-dioxide extractor and betuline, dry mixture of triterpene and polyphenol compounds are obtained. Hydrophilous fraction - lingo-adipic flour - is separated from liquid and dried out.
EFFECT: increase of environmental safety and method effectiveness.
6 cl, 4 ex, 3 dwg
SUBSTANCE: present invention presents a preparation to reduce insulin resistance. The preparation contains 3-O-v-D-glucopyranosyl-4-methylergost-7-ene-3-ole, or an extract made with using an organic solvent, or an extract made with using hot water, or a drained liquid of a plant of Liliaceae family, or fraction thereof which contains this compound as an active component.
EFFECT: production of the preparation which is suitable for inhibition of adipocytokine production, particularly adipocytokine which cause insulin resistance, and for prevention of pathological conditions caused by insulin resistance, or simplification of clinical course of said pathological conditions.
9 cl, 3 ex