The way to obtain 6-oxa-8-isanalogous steroid estrogens
(57) Abstract:Usage: as a lipid-lowering means and as an intermediate product in the synthesis of analogues of steroidal estrogens. The inventive product-6-oxa-8-sanalog steroid estrogens f-ly I, where R1= CH3C2H5C3H7; R2- H, CH3; R3= H, CH3; R4, R5= 0,
; n = 0;1. Reagent 1: 6-oxa-1,3,5(10),8,14-astreinte. Reagent 2: hydrogen over Raney Nickel. Reaction conditions: benzene at 80 - 110oC, a pressure of 10 to 15 MPa, the output 48,69%. Connection structure of f-crystals I:
The invention relates to the synthesis of biologically active analogues of steroid hormones, specifically to obtain 6-oxa-8-isanalogous steroid estrogens, having hypolipidemic activity and which intermediate compounds for the synthesis of other classes of substances.Known only large-scale method of obtaining 6-oxa-8-isanalogous steroid estrogens catalytic hydrogenation of the corresponding 6-oxa-1,3,5(10),8,14-extrapontine in the presence of Pd/C (prototype).The disadvantage of this method of production is the low yield of the target compounds due to the low the fir 6-oxa-8-isooctane obtained from the corresponding extrapontine with the release of 15% and methyl ether 18-methyl-6-oxa-8-isooctane with a yield of about 13% (in the latter case, an additional disadvantage is the multistage process).The purpose of the invention to develop a method of obtaining 6-oxa-8-isanalogous of steroid oestrogens from the corresponding 6-oxa-1,3,5(10),8,14-extrapontine, which greatly improve the yield of the target compounds.The objective is achieved by using as a catalyst of Raney Nickel, the hydrogenation reaction is carried out in benzene at 80-110aboutC and a pressure of 10-15 MPa.P R I m e R 1. Synthesis of methyl ester of 6-oxa-8-isooctane (II).< / BR>To a solution 3,49 g of 3-methoxy-6-oxa-1,3,5(10),8,14-astreinte-17-she (I) in 260 ml of benzene is added 5 g of freshly prepared Raney Nickel, hydrogenation of lead in a steel autoclave under stirring at 80-110aboutC and a pressure of 10-15 MPa. The reaction finished, when absorbed approximately 100-150-fold amount of hydrogen as compared with calculated. Then the reaction mixture is cooled to room temperature, the catalyst is filtered off, the solvent evaporated on a rotary evaporator. The residue is dissolved in 40 ml of pyridine, to the obtained solution was added with stirring the reagent Saretta prepared from 3.2 g of chromic anhydride and 35 ml of pyridine, the reaction mixture is left for a day at room temperature. The excess oxidizing agent is decomposed with 10 ml of alcohol, osadochnoi hydrochloric acid (1:1), three times with equal volumes of 5% aqueous solution of sodium acetate, then with water until neutral. The solvent is dried with sodium sulfate, the drying agent is filtered off, the ether removed on a rotary evaporator. The residue is crystallized from methanol. Gain of 2.45 g (69%) of target compound (II) with so pl. 144,5-147aboutC.Mass spectrum, m/z (%): 286 (100) (M); 229 (4,0); 201 (70); 161 (82); 137 (10); 91 (9,9); 77 (10).Calculated, 75,26; N 7,80.C18H22O3.Found, 75,35; N To $ 7.91.P R I m m e R 2. Methyl ether 18-methyl-6-oxa-8-isooctane (IV).< / BR>0.8 g of 18-methyl-3-methoxy-6-oxa-1,3,5(10),8,14-astreinte-17-she (III) hydronaut on the Raney Nickel followed by oxidation products of the reaction reagent Saretta as described in example 1. The target compound (IV) was isolated after crystallization from methanol, the yield of 0.39 g (48%), so pl. 138-139aboutC.An NMR spectrum13With memorial plaques 130,0 (s-1); 107,3 (C-2); 158,8 (C-3); Of 101.3 (C-4); 155,0 (C-5); A 64.6 (C-7); To 36.7 (C-8 or C-9); 37,2 (C-8 or C-9); 118,9 (C-10); 27,5 (C-11 and C-12); 50,1 (C-13); And 47.0 (C-14); 20,6 (C-15 or C-18); 20,2 (C-15 or C-18); 35,3 (C-16); 217,5 (C-17); And 8.4 (C-18a).Calculated With 75,97; N 8,05.WITH19H24ABOUT3< / BR>Found, C 75,82; N 8,14.P R I m e R 3. Methyl ester of 6-oxa-D-Homo-8-isooctane (VI).
aboutC.Range of PMR, , M. D. of 1.08 (3H, WITH18-N3); 3,76 (3H, CH3O); 4,08-4.30 m (2N, WITH7H2); 6,38 d (1H, WITH4N); 6,50 DD (1H, WITH2N); 7,02 d (1-N).Calculated With 75,97; N 8,05.WITH19H24ABOUT3< / BR>Found, 75,85; N 8,21.P R I m e R 4. Acetate 3-methyl ester 7-methyl-6-oxa-8-soustredila (VIII).< / BR>3,82 g of 17-acetoxy-7-methyl-3-methoxy-6-oxa-1,3,5(10),8,14-extrapontine in 270 ml of benzene hydronaut in the presence of 5 g of Raney Nickel under the conditions described in example 1. After the reaction the catalyst is filtered off, the solvent is removed on a rotary evaporator and the residue is crystallized from methanol. Obtain 1.78 g (46%) of the desired product with so pl. 101-104aboutAnd 113-114,5aboutC.Range of PMR, , memorial plaques to 0.92 (3H, WITH18H3); 1,45 D. (3H, J 6 Hz, WITH7-CH3); 2,02 (3H, CH3CO); 3,74 (3H, CH3O); 4.2-4.5 m (1H, WITH7N); 4,62 m (1H, WITH17N); 6,3-6,5 m (2N, WITH2N and4N); 6,95 d (1H, J 8 Hz, WITH1N).Calculated With 73,23; N 8,19.WITH21H28ABOUT4< / BR>Found, 73,44; N 8,35.P R I m e R 5. AC-1,3,5(10),8,14-extrapontine (IX) hydronaut, as described in example 4. The reaction product produce by crystallization from methanol. Yield 1.55 g (44%), so pl. 106-110aboutC.Range of PMR, , M. D. 0,86 t (3H, J 7 Hz, CH3-CH2); 2,00 (3H, CH3WITH); to 3.73 (3H, CH3O); 4,19 m (2N, WITH7H2); 4,71 m (1H, WITH17N); 6,35-6,57 m (2N, WITH2N and4H); 7.03 is d (1H, WITH1-N).Calculated With 73,71; N 8,44.WITH22H30ABOUT4< / BR>Found, 73,88; N 8,45.P R I m e R 6. Methyl ester of 16,16-dimethyl-6-oxa-D-Homo-8-isooctane (XII). 1 g 16,16-dimethyl-3-methoxy-6-oxa-D-Homo-1,3, 5(10),8,14-astreinte-17A-she (XI) hydronaut on the Raney Nickel followed by oxidation products of the reaction reagent Saretta as described in example 1. The target connection allocate crystallization from methanol, the yield of 0.87 g (39%), so pl. 150,5-152,5aboutC.< / BR>An NMR spectrum13With memorial plaques 130,0 (s-1); To 107.6 (C-2); 159,1 (C-3); Of 101.5 (C-4); 155, 1mm (C-5); 64,1 (C-7); 39,1 (C-8 and C-9)*; 119,5 (C-10); 27,8 (C-11); 31,9 (C-12); With 46.6 (C-13); 41,0 (C-14 and C-15)*; 35,0 (C-16); 50,8 (C-17); 214,0 (C-17A); 26,3 and 32.5 (methyl group at C-16); 55,3 (CH3) (* The assignment is not unique).Calculated With 76,79; N 8,59.WITH21H28ABOUT3< / BR>Found, 76,69; N 8,80.Thus, the proposed method of obtaining 6-oxa-8-isanalogous steroid is antigenome method get with outputs respectively 69% and 48% whereas by a known method outputs are 13% and 15%
The proposed method allows to synthesize compounds containing substituents near double bonds in the original 6-oxa-1,3,5(10),8,14-extrapontine (examples 4 and 6). At the same time when the synthesis of an analog of (VIII) (example 4) is known a method of the target product to allocate failed (O. Dann et al. Chem. Ber. 1971, Bd. 104, No. 10. S. 3313). The proposed method can obtain analogues of estrogen with a six-membered ring (examples 3 and 6), as well as connections with voluminous Deputy at C-13 (example 5). The WAY to OBTAIN 6-OXA-8-ISANALOGOUS STEROID ESTROGENS General formula
< / BR>where R1- CH3C2H5C3H7;
R2- H, CH3;
R3- H, CH3;
R4, R5- O;
< / BR>n = 0,1,
includes catalytic hydrogenation of 6-oxa-1,3,5(10),8,14-extrapontine, characterized in that, with a view to increasing output 8-isanalogous hydrogenation is carried out in benzene in the presence of Raney Nickel in the temperature range 80 - 110oC at a pressure of 10 to 15 MPa.
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 of steroids, chemical technology.
SUBSTANCE: invention relates to the improved method for preparing chemical compounds of steroid order, namely, to a method for preparing epibrassinolide representing (22R,23R,24R)-2α,3α,22,23-tetrahydroxy-B-homo-7-oxa-5α-ergostane-6-one and relating to biologically active substance - a phytostimulator regulating growth of plants. Method involves the successive carrying out the following stages: a) synthesis of ergosterol mesylate by treatment of ergosterol with methanesulfochloride in pyridine; b) synthesis of isoergosterol by boiling ergosterol mesylate in aqueous acetone in the presence of potassium (sodium) hydrocarbonate; c) synthesis of isoergosterone by oxidation of isoergosterol with chrome anhydride in pyridine; d) synthesis of 7,8-dihydroergosterol by reduction of isoergosterone with sodium dithionite in the presence of a solubilizing medium containing cationic, anionic or nonionic surface-active substances of the following order: CnH2n+1X wherein n = 9-18; X means -NMe3, -NEt3, -COOH, -SO3H, -OSO2M, -OP(O)(OM)2 wherein M means alkaline metal, polyethylene glycol, (C2-C6)-aliphatic alcohols or monoesters of ethylene glycol or diethylene glycol as a co-solubilizing agent, electrolyte and water taken in the molar ratio = 1:(5-6):(100-250), respectively; e) steroid rearrangement of 7,8-dihydroisoergosterol; f) formation of 24-epicastasterone by treatment of (22E,24R)-5α-ergosta-2,22-diene-6-one with methanesulfoneamide and potassium carbonate with using catalytic amounts of potassium ferricyanide (III) and osmium tetraoxide; g) dissolving 24-epicastasterone formed in chloroform followed by treatment with trifluoroperacetic acid forming in mixing trifluoroacetic anhydride and hydrogen peroxide in chlorinated organic solvent, and isolation of the end product of the formula (I) with high yield.
EFFECT: improved preparing method.
2 cl, 7 ex
FIELD: organic chemistry, steroids, medicine, pharmacy.
SUBSTANCE: invention describes novel halogen- and pseudohalogen-substituted 17-methylene-4-azasteroids of the general formula (I) wherein each R20 and R20a means independently fluorine, chlorine, bromine atom, (C1-C4)-alkyl, hydrogen atom (H), cyano-group; R4 and R10 mean hydrogen atom or methyl group; both R1 and R2 represent hydrogen atom and form an additional bond. Compounds are inhibitors of 5α-reductase and can be used in treatment of diseases caused by the enhanced blood and tissue testosterone and dihydrotestosterone level.
EFFECT: valuable medicinal and biochemical properties of compounds.
9 cl, 5 dwg, 1 tbl, 10 ex
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention describes compound of the formula (I) or its pharmaceutically acceptable salt, or an enantiomer wherein n = 0 or 1; a - b means -CF=CH or -CHFCH2; R1 represents (C1-C3)-alkyl wherein alkyl is unsubstituted; R2 represents hydrogen atom; R3 is chosen from (C1-C4)-alkyl, (CH2)n-cycloheteroalkyl and (CH2)n-aryl; or R2 and R3 form in common 6-membered saturated ring condensed with 5-membered aromatic ring system comprising 2 heteroatoms chosen from nitrogen atom (N), and pharmaceutical compositions. Compounds of the formula (I) represent modulators of androgen receptors (AR) possessing tissue-selective effect. Proposed compounds are useful as androgen receptors agonists in osseous and/or muscle tissue in antagonizing AR in male patient prostate or in female patient uterus.
EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.
36 cl, 2 tbl, 72 ex
FIELD: organic chemistry, chemical technology.
SUBSTANCE: invention describes an improved method for synthesis of 17β-substituted 4-azaandrost-1-en-3-one of the general formula (I): wherein R means -OH, (C1-C4)-alkyl, (C1-C4)-alkenyl, phenyl, benzyl and others, or their pharmaceutically acceptable salts. Method involves insertion protective groups into 3-keto-4-aza (lactam) form of compound of the general formula (II): wherein R has indicated values to form compound of the general formula (III): wherein R3 means trialkylsilyl, or in common with R4 residue -C(O)-C(O)- or -C(O)-Y-C(O)- wherein R4 means tert.-butyloxycarbonyl preferably; Y means -(CH2)n wherein n = 1-4, or ortho-phenylene. Then a synthesized compound is converted in the presence of a dehydrogenation catalyst of in the presence of benzoquinone, allylmethylcarbonate, allylethylcarbonate and/or allylpropylcarbonate, and ▵1-double bond is introduced in 1,2-position followed by removal of protective groups and, if necessary, (when R means -OH) conversion to salts. Method provides the high yield and purity degree of synthesized compounds.
EFFECT: improved method of synthesis.
21 cl, 9 ex
SUBSTANCE: description is given of thiomorpholine derivatives of steroids with general formula I . These steroids are characterised by presence of a thiomorpholine fragment, bonded to a C17 steroid skeleton through an alkylene spacer, where R4 and R4' are hydrogen and methyl, under the condition that, both R4 and R4' represent hydrogen at the same time.
EFFECT: invention can be successfully used for stimulating meiosis of human oocyte.
12 cl, 2 ex, 5 tbl, 6 dwg
SUBSTANCE: invention refers to production of new tritiated analogues of physiologically active compounds - triterpene glycosides of holothurians Cucumaria of formula: .
EFFECT: there are produced new tritiated analogues of physiologically active compounds.
2 cl, 2 ex
FIELD: medicine, pharmaceutics.
SUBSTANCE: invention refers to racemic 3,17β-dihydroxy-7α,18-dimethyl-6-oxaextra-1,3,5(10),8(9)-tetraene diacetate of formula .
EFFECT: production of the substance exhibiting osteoprotective, hypocholesteremic and antioxidant action with lowered uterotropic activity.
1 cl, 2 ex, 2 tbl, 2 dwg
SUBSTANCE: invention relates to novel 4-oxa- and 4-aza-16α, 17α-cyclohexanopregnanes (4-oxa- and 4-aza-pregna-D'-pentaranes), which can be used n medicine to treat malignant tumours, having general formula I , where X=0 or NR, R=R1=R2=R4=H where R1+R3 form a bond. Said compounds are obtained by oxidising ring A 16α, 17α-cyclohexano-progesterone with potassium permanganate and sodium periodate in the presence of sodium carbonate in 5-oxo-A-nor-3,5-secoacid followed by closure of ring A in 4-oxa-16α, 17α-cyclohexanopregn-5-en-20-one while treating with a sodium acetate dehydrating agent in Ac2O and in 4-aza-16α, 17α-cyclohexanopregn-5-en-20-one using ammonium acetate in acetic acid.
EFFECT: compounds are effective inhibitors of oestrogen-stimulated cell proliferation HeLa.
2 cl, 2 ex, 1 tbl
SUBSTANCE: disclosed is a composition for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing) containing natural brassinosteroid or analogue of brassinosteroid. Described is a method for preventing or treating Huanglongbing (HLB) disease in citrus, characterised by periodic application of brassinosteroid on plants. Described is use of brassinosteroid for making composition for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing), where said composition is periodically applied.
EFFECT: described is a method for stimulating natural protection and inducing resistance to diseases caused by Candidatus Liberibacter asiaticus in citrus plants (Huanglongbing), characterised by application of brassinosteroid compound on plant.
11 cl, 7 dwg, 3 tbl, 8 ex