The way isomerization aquilina

 

(57) Abstract:

The invention relates to a method of isomerization Aquilina or its derivative in the Delta (8,9)-degidro estrone [Delta (8,9)DHE, R1- H, alkyl, acyl or silyl (alkyl)3; R2- H1and R3- OH, O-alkyl or O-silyl (alkyl)3or R2and R3together = O, or R2and R3together acetaline or cycloacetal group, which is characterized by the fact that equilin or its derivative is treated with a lithium salt of Ethylenediamine or Amida lithium in dimethyl sulfoxide. The method allows to obtain pure Delta (8,9)DHE in the presence of acidic conditions. The output of Delta (8,9)DHE-95%. 4 C.p. f-crystals.

The invention relates to a method of isomerization Aquilina (equilin) or its derivatives, and more specifically to isomerization Aquilina 3-hydroxy-östra-1,3,5(10), 8(9)-Tetra-ene-17-one [Delta (8, 9)-degidro estrone; Delta (8,9)DHE; Delta 8 estrone; 8,9 degidro estrone; CAS number 61612-83-7].

Sulfate Delta (8, 9) derived Aquilina [Delta (8, 9) DHES], present in small quantities approximately 3-4% in natural conjugated compositions of estrogen, such as a commercially available product Premarinused in substitution garmt to make a significant contribution to the effect of conjugated estrogens. It was further suggested that the Delta (8, 9) DHES, which has a relatively low affinity for the estrogen receptor has a high functional activity, which may play a role in the well-known properties of lowering LDL cholesterol and in action conjugated estrogens, in particular Premarinon the cardiovascular system. Data show that Delta (8, 9) DHES is approximately 18% of circulating estrogen Premarin. It is therefore important to get an easy way to get Delta (8, 9) DHE, which can easily be converted into sulfate Delta (8, 9) DHES methods known to experts in this field.

In addition to time-consuming total synthesis, J. C. Jacquesy and co-authors, Chem. Abstr. 76 (1972), 154000f disclosed isomerization Aquilina in smirkily environments. The transformation in the Delta (8, 9) DHE was achieved by using hydrogen fluoride or hydrogen fluoride/fluoride antimony at -30oC. it is Obvious that such a dangerous reaction conditions are totally inappropriate and unacceptable for large-scale production of Delta (8, 9) DHE. Furthermore, in U.S. patent 5,395,831, which applies the method Jacquesy, it was revealed that the hydrofluoric method does not provide obtaining Chistoprudny, through isomerization Aquilina or not, which are commercially acceptable, were not disclosed.

The present invention first provides an easy and inexpensive way to get Delta (8, 9) DHE, through isomerization Aquilina or its derivative at a specified derivative, characterized in that equilin or its derivative is treated with a lithium salt of Ethylenediamine or Amida lithium in dimethyl sulfoxide.

The General formula Aquilina and specified derivative shown in formula 1:

< / BR>
in which R1represents hydrogen, alkyl, acyl or silyl(alkyl)3; R2is hydrogen and R3represents hydroxyl, O-acyl, O-alkyl or O-silyl(alkyl)3or R3is hydrogen and R2is hydroxyl, O-acyl, O-alkyl or 0 - silyl(alkyl)3; or R2and R3together represent oxygen; or R2and R3together represent acatalog or cycloacetal group.1may also be substituted by alkyl, such as, for example, methoxyethoxymethyl.

According to the method of isomerization of the present invention can be obtained from derivatives of the General formula II:

< / BR>
in which R1, R2and R3is I the lithium salt of Ethylenediamine, because this method yields a very pure Delta (8, 9) DHE. These lithium salts can be obtained by treating ethylene diamine lithium or alkyllithium, preferably by methyllithium. Can be added (co)solvents such as tetrahydrofuran, dimethylsulfoxide, etc., when add () solvents, typically results in a mixture of Delta (8, 9) DHE and aquiline or its derivatives. Amide lithium in dimethyl sulfoxide (DMSO) also gives a mixture of Delta (8, 9) DHE and aquiline or its derivatives, which can be converted as such in their sulfates for use in the preparation of pharmaceutical compositions containing conjugated estrogens.

The term alkyl, as used in the definition of formula 1, means a branched or unbranched alkyl group having preferably 1-6 carbon atoms such as hexyl, isobutyl, tertiary butila, propylene, isopropyl, ethyl and preferably the stands. The term acyl means an acyl group derived from alkalicarbonate acid, and the alkyl part has the values given above, or derived from formic acid. Acetals are derived from alcohols having preferably 1-6 carbon atoms.

If in the compound of the formula I R1is silyl(alkyl)3derivatives will also be either hydrolyzed during the reaction, leading to compounds according to formula II, in which R1is hydrogen. Similarly, if R1or R3is O-acyl or silyl(alkyl)3can be selected compounds in which R2or R3is a hydroxyl group.

Preferably, the isomerization is carried out at a temperature between approximately 0 and 90oC and more preferably at approximately 30oC if equilin or its derivative is treated with a lithium salt of ethylene diamine, or approximately 65oC if equilin or its derivative is treated with Amida lithium in dimethyl sulfoxide.

Conditions isomerizate Aquilina in acidic conditions, for example acetic acid, hydrochloric acid, triptoreline acid, efratom boron TRIFLUORIDE or a combination of solvents, such as methanol, ethanol, tetrahydrofuran or toluene. However, when one of these conditions has not been obtained acceptable results, since the reaction did not pass or did intractable mixture of compounds.

Isomerization catalytic conditions (for example, palladium/carbon/benzyl alcohol) also did not lead to acceptable results. The same thing happened in most cases, when isomerization under alkaline conditions. Conventional methods, such as isomerization with butyllithium/tertbutoxide potassium, amidon sodium, tertbutoxide potassium or sodium hydride in the usual solvents, amidon lithium in dimethylformamide, sodium or potassium in Ethylenediamine and lithium in a variety of amines have had, such as diisobutylamine, pentylamine, dimethylethylenediamine, piperazine and piperidine were actually completely unsuccessful. In the best conditions were obtained only from 2 to 8 % of the desired material in demanding a mixture of different isomers, unknown reaction products and starting material. Unexpectedly, it was found that only Ezra gave a mixture of approximately 55% of Delta (8,9) DHE and 45% of the source material (equilin), which can be used as such, is successful. I believe that these unique conditions provide a rare, if not unique, opportunity to get directly commercially available by way of Delta (8,9) DHE from Aquilina.

The following examples are illustrative for the invention and in no way should be interpreted as limiting the scope of invention.

Example 1

Lithium (13 g) was added in portions to 920 ml of Ethylenediamine in a nitrogen atmosphere at 95oC and the mixture was stirred for 30 minutes at 100oC. the Reaction mixture was cooled to 23oC, after which was added 100 g Aquilina at a temperature of 30oC. the Mixture was stirred for a further 2 hours at 30oC. the Suspension was poured into 2.5 liters of ice water and at a temperature of 25oC was added acetic acid to pH 7. The aqueous layer was extracted three times with 2.5 liters of ethyl acetate. The organic layer was washed with water, was added 5 g of active carbon (Noritand the suspension was stirred at 21oC for 30 minutes. The suspension was filtered over dicalite (dicalite and the filtrate evaporated under vacuum to a volume of approximately 500 ml of the Suspension was stirred for 1 hour at 0oC, after which Lucite 81 g of Delta(8,9)-degidro estrone, having a purity of approximately 95 %.

The content of Delta (8, 9) DHE and Aquilina was determined using proton1H-NMR spectroscopy, with characteristic peaks: 0.90 M. D. (0.90 ppm) (C18) for Delta (8,9) DHE and 5.53 M. D. (5.53 ppm) (C7) and 0.79 m D. (0.79 ppm) (C18) for Aquilina.

Example 2

Amide lithium (5 g) was added to a mixture of 5 g Aquilina in 150 ml of DMSO. The mixture was heated to 65oC and was stirred for 70 minutes. The reaction mixture was poured into 500 ml of water and acidified to pH 6.5 using 4N hydrochloric acid. The crystals were filtered off, washed with water and dried under vacuum at 40oC, to obtain 5 g of a mixture of 4:5 Aquilina and Delta(8,9)-degidro estrone.

Example 3

6% solution of complex motility-lithium bromide in diethyl ether (23.5 ml) was added over approximately 15 minutes to 46 ml of Ethylenediamine in nitrogen atmosphere at a temperature of approximately 25oC. the Temperature of the mixture was raised to 55oC and drove diethyl ether. Subsequently, the reaction mixture was stirred for 1 hour at 55oC. the Mixture was cooled to 20oC and was added 2.5 g Aquilina. The mixture was stirred for a further 90 minutes at 30oC.

The suspension was poured into ice water and the mixture was extracted with ethyl is Starichenko the Delta-8-estrone.

Example 4

Lithium (1.1 g) was added in portions to 80 ml of Ethylenediamine in a nitrogen atmosphere at 100oC and the mixture was stirred for 30 minutes at 100oC. the Reaction mixture was cooled to 23oC, and then were added 4 g 17-dihydroequilin at a temperature of 30oC. the Mixture was stirred for another 4 hours at 30oC. the Suspension was poured into 250 ml of ice water was added acetic acid to pH 7 at a temperature of 25oC. the Suspension was cooled to 5oC and the crystals were filtered off. The crystals are suspended in 150 ml of water was added 100 ml of ethyl acetate. The layers were separated and the solution in ethyl acetate is evaporated under vacuum to a volume of 20 ml, the Suspension was stirred at -15oC for 1 hour, after which the crystals were filtered off, washed with ethyl acetate and dried under vacuum at 40oC obtaining 2.5 g of 8,9-dihydro-17-estradiol, having a purity >95%.

Example 5

The solution metallice-lithium bromide (20 ml, 2.1 M) in diethyl ether was added over 10 minutes to 40 ml of Ethylenediamine in a nitrogen atmosphere at 36oC. the Temperature of the mixture was raised to 55oC and drove diethyl ether. The mixture was stirred for 1 hour at 55oC. the Reaction mixture was cooled to 3oC, then SUP>C, after which was added 200 ml of ice water. To the mixture was added acetic acid to pH 8. The suspension was stirred for 1 hour at 15oC, after which the crystals were filtered off, washed with water and dried in vacuum at 45oC, to obtain 2.0 g of 8,9-degidro-estrone-3-methyl ether having a purity of approximately 80%.

Example 6

According to the method described in example 5-dihydro-aquilin 3,17-diacetate were treated with methyllithium/Ethylenediamine at 30oC, quantitative getting 8,9-degidro-17-estradiol, having a purity of approximately 90%.

Example 7

According to the method described in example 4, equilin-17-tetramethylene acetal was treated with lithium/Ethylenediamine at 20oC, obtaining a 8.9-degidro-estrone-17-tetramethylene acetal with the release of 90% with a purity of approximately 90%.

Example 8

According to the method described in example 4 17-dihydroequilin - 3,17-di(trimethylsilyloxy ether) was treated with lithium/Ethylenediamine, with quantitative getting 8,9-degidro-17-estradiol, having a purity of approximately 90%.

1. The way isomerization Aquilina or its derivative having a General formula I

< / BR>
in which R1is particularly a hydroxyl, O-acyl, O-alkyl or O-silyl(alkyl)3,

or R3is hydrogen and R2is hydroxyl, O-acyl, O-alkyl, or O-silyl(alkyl)3;

or R2and R3together represent oxygen;

or R2and R3together represent acatalog or cycloacetal group

in the Delta(8, 9)-degidro estrone or its derivative, characterized in that equilin or its derivative is treated with a lithium salt of Ethylenediamine or Amida lithium in dimethyl sulfoxide.

2. The method according to p. 1, in which R1is acyl and R2and R3together represent O.

3. The method according to p. 1 or 2, in which equilin or its derivative is treated with a lithium salt of ethylene diamine.

4. The method according to PP. 1 to 3, in which the reaction temperature is between approximately 0 and 90oC.

5. The method according to p. 4, in which the reaction temperature is equal to approximately 30oC if equilin or its derivative is treated with a lithium salt of ethylene diamine, or approximately 65oC if equilin or its derivative is treated with Amida lithium in dimethyl sulfoxide.

 

Same patents:

Androstane // 2160740
The invention relates to new androstenone steroids of formula I

< / BR>
where P1OKSO,-(-)hydroxy,-(-)-C1-4-alkoxy or-(-)benzyloxy; P2- C1-4-alkyl, hydroxy-C1-4-alkyl; P3missing or C1-4-alkyl; P4is hydrogen, oxo or hydroxy; P5- one or two hydrogen atoms, methyl or methylene; P6- hydrogen, which are ligand Poluchenie products, communicating with neuroepithelial receptor

Steroid compound // 2160279
The invention relates to extrenely steroids that are associated with neuroepithelial cells in the vomeronasal organ of the human body

The invention relates to 17-deformation-estratriene, to a method for their production and to their use for pharmaceutical products (medicines)

acyl(hydr)oxosteroid with antitumor activity" target="_blank">

The invention relates to the chemistry of steroids and related specifically to 3-OR-di-(2-chloroethyl)aminecontaining 11-acyl(HYDR)oxosteroid with antitumor activity General formula (I), where R = COCH2C6H4N(CH2CH2Cl)2; R1=-OCOCH3+-CCH;-OCOC2H5+-H; R2= H, OCOH, COCH3

-benzaldoxime-Östra-4,9-diene, the method of production thereof, and pharmaceutical composition" target="_blank">

The invention relates to new derivatives of 11-benzaldoxime-östra 4-9-diene, the way they are received and containing these compounds medicines

The invention relates to a new 11-(substituted phenyl)-östra-4,9-diene derivative of the formula I, where a is the residue of a 5 - or 6-membered ring containing two heteroatoms, which are not related to each other and are independently selected from O and S, and the specified ring may be substituted by one or more halogen atoms, or a residue of a 5 - or 6-membered ring, in which there is no double-bond containing one heteroatom selected from O and S, when the heteroatom is connected with a phenyl group at the position indicated by the asterisk, and the ring may be substituted by one or more halogen atoms; R1is hydrogen; R2is hydrogen, (C1-8)-alkyl, halogen or CF3; X is O or NOH, the dotted line represents a possible link

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, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the general formula (2) and a method for its preparing wherein R1 represents hydrogen atom or salt-forming metal; R2 represent a direct or branched (C1-C7)-halogenalkyl group; m represents a whole number from 2 to 14; n represents a whole number from 2 to 7; A represents a group taken among the following formulae: (3) , (4) ,

(5) ,

(6) ,

(17) , (18) , (19) , (20) , (23) , (25) and (26) wherein R3 in formula (6) represents a direct or branched group (C1-C5)-alkyl group; R8 in formulae (18) and (20) represents a direct or branched (C1-C5)-alkyl group, a direct or branched (C2-C5)-alkenyl group or a direct or branched (C2-C5)-alkynyl group; in formula (23) each R21, R22, R23 and R24 represents independently hydrogen atom, a direct or branched (C1-C5)-alkyl group, a direct or branched (C1-C7)-halogenalkyl group, halogen atom or acyl group; in formulae (25) and (26) X represents halogen atom; or enantiomers of compound, or hydrates, or pharmaceutically acceptable salts of compound, or its enantiomers. Also, invention relates to a pharmaceutical composition containing indicated compound as an active component and to a therapeutic agent used against breast cancer based on thereof.

EFFECT: valuable medicinal properties of compounds.

10 cl, 2 tbl, 39 ex

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, steroids, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 7-substituted steroid compounds of the general formula (I):

wherein R1 means hydrogen atom (H) or -COR2 group wherein R2 means (C1-C6)-alkyl, (C1-C6)-alkoxy-group; Z1 means -CH2- or wherein R3 is in α-configuration; R3 means H or -COR2; Z2 means -CH-, or Z1 and Z2 mean in common a double bond; Q means ,,,,,,; Y means -CN, -CH2-CH=CH2 or -CHR4C(O)Ar, -CHR4C(O)-(C1-C6)-alkyl, -CHR4C(O)XAr or -CHR4C(O)X-(C1-C6)-alkyl wherein R4 means -O-(C1-C6)-alkyl or aryl X means oxygen (O) or sulfur (S) atom that are intermediate compounds used in synthesis of eplerenon.

EFFECT: improved method of synthesis.

7 cl, 1 tbl, 2 dwg, 20 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, steroids, medicine.

SUBSTANCE: invention relates to steroid compounds of the general formula (I) given in the invention description wherein R1 means oxygen atom (O); R2 and R3 mean independently hydrogen atom (H), CH3, C2H5, and at least radical among R2 and R3 means CH3 and C2H5; R4 means H. Compounds are useful in treatment associated with androgens, such as androgen deficiency and contraception in males and females.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, steroids, medicine, pharmacy.

SUBSTANCE: invention relates to compositions containing 16α-bromo-3β-hydroxy-5α-androstane-17-one semihydrate and one or more excipients wherein the composition contains less 3% of water. Compositions are useful in preparing improved pharmaceutical compositions. Invention describes methods for discontinuous dosing steroid compounds, such as analogs of 16α-bromo-3β-hydroxy-5α-androstane-17-one and compositions useful in such dosing regimens. Also, invention describes compositions and methods for inhibition of pathogenic viral replication, improving symptoms associated with disorders in immune response and modulation of immune response in a patient by using indicated compounds and their analogs. Also, invention describes methods for their preparing and using these immunomodulatory compositions.

EFFECT: improved preparing method, valuable medicinal properties of compounds and pharmaceutical compositions.

63 cl, 3 tbl, 13 sch, 13 dwg, 37 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, pharmaceuticals.

SUBSTANCE: invention relates to improved method for production of 4,17(20)-E-pregnadiene-3,16-dione (E-guggulsterone) of formula III and 4,17(20)-Z-pregnadiene-3,16-dione (Z-guggulsterone) of formula IV including oxidation of compound of formula II , wherein C-OH or =O; ----- is optional double bond with pyridinium chlorochromate, pyridinium dichromate etc to produce 4,17(20)-E-pregnadiene-3,16-dione of formula III followed by conversion thereof by photochemical, thermochemical reaction or reaction in presence of acidic catalyst. Compounds of formulae III and IV effectively decrease increased low density lipoprotein levels and high cholesterol levels.

EFFECT: improved method for production of 4,17(20)-Z-pregnadiene-3,16-dione.

8 cl, 46 ex, 9 dwg

Up!