Methods of obtaining a mixture of sulfated estrogens

 

(57) Abstract:

The invention relates to a method of obtaining a mixture of sulfated estrogen containing Delta (8,9)-dehydration formula I [Delta(8,9)-DGA] or its derivatives, where R1- H, R2- N and R3- O-acyl or R3- N and R2- O-acyl, or R2and R3together - O and in formula III, R1- silyl (alkyl)3or tetrahydropyranyl, R2and R3together, O or R2and R3together - acetal. The method includes (partial) isomerization of compounds of formula III by treatment lithium salt of Ethylenediamine or Amida lithium in dimethyl sulfoxide. The method is economical and simple in execution. 4 C. and 5 C.p. f-crystals.

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The invention relates to a method of obtaining a mixture of sulfated estrogens, more precisely to the sulfation mixture containing 3-hydroxy-östra-1; 3; 5(10), 8(9)-Tetra-ene-17-one [Delta(8,9)-dehydration; Delta(8,9)-DGA; Delta-8-estrone; 8,9-dehydration; CAS 616 12-83-7].

Sodium sulfate Delta(8,9) derivative of estrone [Delta(8,9)DGAS] in small quantities (approximately 3-4%) is present in natural compositions of conjugate (conjugate) estrogen, for example, a commercially available product Premarin

In the publication SCRIP 2049 (1995) R. 15 it has been suggested that the minimum number of Delta(8,9)-GGAS can make a significant contribution to the effects of conjugated estrogens. Additionally, it has been suggested that Delta(8,9)-DGAS, which has a relatively low affinity for the estrogen receptor, has a high functional activity, which may play a role in the described properties, the decrease in the content of LDL-cholesterol, the effect of conjugated estrogens on cardiovascular activity, particularly drug Premarin. Data show that Delta(8,9)-DGAS provides approximately 18% of circulating estrogen drug Premarin. Therefore, it is very important to develop an easy way to obtain sulfated mixtures of Delta(8,9)-DGA.

In addition to the cumbersome General synthesis publications - J. S. Jacquesy et al (Chem. Abstr. 76 (1972), 154000f) described isomerization Aquilina in an environment with excessive acidity. Chemical transformation in the Delta(8,9)-DGA was about the but such dangerous conditions of the reaction are totally inappropriate and unacceptable to obtain the Delta(8,9)-DGA in large quantities. Furthermore, in U.S. patent 5395831, which is designed Jacquesy way, it is shown that this method using hydrogen fluoride does not provide the net Delta(8,9)-DGA, but leads also to receive 10% junk Delta(9,11)-isomer. Thus, ways of getting through isomerization Aquilina or without it, which would be commercially acceptable, described were not.

Synthesis of sulfated esters of steroids described in the literature. In accordance with the conclusion made by the authors - Jenkins and Sandberg (Methods in Enzymology, 15, 351-358, 1969), one of the ways includes sulfation of mono - and dihydroxy-18 and C-19 steroid compounds using complexes of pyridine with sulfuric acid. This method, however, has been applied to the individual, i.e. not containing other steroid compounds. The method in accordance with this invention has the advantage that in a single reaction mixture sulfated estrogens can be obtained in a specific ratio. Unexpectedly, it was found that although the estrogen present in the NAT is e during crystallization and solubility, the ratio of sulfated products in the reaction mixture reflects the number of input components. Therefore, one reaction vessel is sufficient to obtain a mixture of sulfated estrogens. In addition, this reaction when it is convenient, can be directly connected to the isomerization reaction, by means of which receive the Delta(8,9)-DGA, i.e. isomerization Aquilina or its derivative at a specified derivative. In this reaction equilin or its derivative is treated with a lithium salt of Ethylenediamine or Amida lithium in dimethyl sulfoxide.

Thus, this invention provides the first simple and inexpensive method of obtaining a mixture of sulfated steroids containing Delta(8,9)-DGA, through the sulfation mixture of estrogen containing Delta(8,9)-DHA or its derivatives, which can be obtained by isomerization Aquilina or its derivative.

Accordingly, a mixture of estrogen-containing compound corresponding to the General formula I

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where R1represents H,

R2represents N and R3- O-acyl; or

R3represents N and R2- O-acyl; or

R2and R3together represent the with compounds of General formula II

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where R1, R2and R3have the above specified values, and the dotted line in position 7-8 represents an optional double bond.

In the preferred embodiment of the invention R2and R3in the formula I and/or II are Acting More preferably, the Delta-8,9-estrone sulfation mixed with aquilinum.

In accordance with another embodiment of the invention compounds of General formula II represent one or more precursors of the components that are present in natural mixtures of conjugated estrogens in small quantities, such as complex sulfated esters of 17-alpha-dihydroequilin, 17-beta-dihydroequilin, 17-alpha-estradiol, and 17-beta-estradiol.

The ratio of compounds in the reaction mixture is not the determining factor, but for economic reasons, the preferred ratio is the ratio, which is represented in the physical mixtures.

Compounds of General formula I can be obtained by isomerization Aquilina and listed derivatives, which are represented by formula III

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where R1- silyl(alkyl)3or tetrahydropyranyl, R2and R3together represent Sobol, which is used in the definitions of formulas, means a branched or unbranched alkyl group containing preferably 1 to 7 carbon atoms, such as hexyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl or methyl. Preferably, silyl(alkyl)3represents Si(Me)2tert-butyl. The term acyl means an acyl group derived from alkalicarbonate acid, and alkyl fragment adopts the above values, or a group derived from formic acid. Acetals derived from alcohols, preferably containing 1-6 carbon atoms.

The term tetrahydropyranyl also equivalents multimodal acetals or multimodal polythiourethane, which means groups such as, for example, ethoxyethyl, methoxyethyl (MOM), methylmetacrylate, methoxyethoxymethyl (MEM), tetrahydrofuranyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl or ethers, such as methyl or tert-butyl, as described in the publication Greene Th., Wuts P., Protective Groups in Organic Synthesis, chapter 2, p.14-87.

The isomerization may be carried out using lithium salts of ethylene diamine. This method yields a very pure Delta(8,9)-DGA. These lithium salts can be rastvoriteli, like tetrahydrofuran, dimethylsulfoxide, etc., Usually a mixture of derivatives of Delta(8,9)-DGA and Aquilina get when you add a joint solvents. Amide lithium in dimethyl sulfoxide (DMSO) also ensures mixtures of Delta(8,9)-DGA and aquiline or its derivatives, which can be converted in accordance with this invention in their sodium sulphate for use in the manufacture of pharmaceutical compositions containing conjugated estrogens.

Preferably the C3 position of the ether of tetrahydropyranyl, as this ether can be easily obtained on the aromatic group which is stable under the conditions of isomerization and after isomerization can be easily removed with getting hydroxyl group for sulfation.

If R1in formula III represents silyl (alkyl)3the isomerization is preferably carried out at a temperature in the range from about 0 to 90oC, more preferably at about 30oIf equilin or its derivative is treated with a lithium salt of ethylene diamine, or approximately 65oIf equilin or its derivative is treated with Amida lithium in dimethyl sulfoxide. On the other hand, if R is a lithium salt of ethylene diamine at a temperature in the range of from about - 78oWith up to 50oWith, preferably in the range from about 0oC to - 20oWith out using THF as co-solvent.

If the isomerization reaction is carried out only partially, there is a mixture of compounds of General formula III, and Delta-8,9 - derivatives, which can be subjected to additional processing to obtain mixtures of sulfated conjugated estrogens. Optional can be added derivatives of General formula II and all connections can be simultaneously sulfotyrosine in one reaction. Preferably compounds that are subject to isomerization and sulfation in accordance with this invention, are compounds in which R2and R3in formulas together represent O.

If in the compound of formula III R1represents silyl (alkyl)3or tetrahydropyranyl, derivatives can be samaritani and sequentially hydrolyzed to obtain compounds of the formula I, or a mixture of compounds of the formula I or III, where R1represents H, by processing a mild acid, such as dilute (0.2 n hydrochloric acid, 50% acetic acid, sorest the social environment, such as trimethylsilyl iodide/trimethylsilyl bromide in methylene chloride; methyl iodide in acetone, N2OH, NAHCO3; p-toluensulfonate, pyridinium, tert-butanol; tetrabutylammonium in methylene chloride; gN3in acetone, as described in the publication Greene Th., Wuts P., Protective Groups in Organic Synthesis, chapter 2, p. 14-87.

Thus obtained mixture derived estrogen may be sulfotyrosine in accordance with this invention in a mixture with one or more manuallyassigned compounds selected from the group comprising: a 17-alpha-dihydroequilin, 17-beta-dihydroequilin, 17-alpha-estradiol, and 17-beta-estradiol.

The following examples are illustrative for the invention and should not be construed as limiting the scope of the invention.

Example 1. Lithium (13 g) is added in several portions to 920 ml of Ethylenediamine in a nitrogen atmosphere at 95oC and the mixture is stirred for 30 min at 100oC. the Reaction mixture is cooled at 23oWith, after which 100 g Aquilina added at a temperature of 30oC. the Mixture is stirred for further 2 h at 30oC., the Suspension is poured into 2.5 l of ice water and at a temperature of 25oTo add acetic acid until then, until the pH reaches 7. In the aqueous carbon (NoritR) and the suspension stirred at 21oC for 30 minutes the Suspension is filtered through dicalite (dicalite and the filtrate evaporated in vacuo to a volume of about 50 ml. of the Suspension is stirred for 1 h at 0oS, after which the crystalline product is filtered off, washed with ethyl acetate and dried in vacuum at 40oWith, the result is 81 g of Delta(8,9)-dehydration with a purity of approximately 95%.

The content of Delta(8,9)-DGA and Aquilina determine using 1H-NMR spectroscopy, the characteristic peaks which are 0.90 M. D. (C18) for Delta(8,9)-DGA and of 5.53 M. D. (C7) and 0.79 m D. (C18) for Aquilina.

Example 2. Amide lithium (5 g) are added to a mixture of 5 g Aquilina in 150 ml of DMSO. The mixture is heated to 65oC and stirred at this temperature for 70 minutes, the Reaction mixture was poured into 500 ml of water and acidified to pH 6.5 using 4 n hydrochloric acid. The crystals are filtered, washed with water and dried in vacuum at 40oWith, the result is 5 g of a mixture of Aquilina and Delta(8,9)-dehydration with a ratio of 4:5, respectively.

Example 3. 6% solution of complex motility-nitebreed in diethyl ether (23,5 ml) is added over about 15 min to 46 ml of Ethylenediamine in ILOAT. After that, the mixture is stirred for 1 h at 55oC. the Mixture is cooled to 20oWith and add 2.5 g Aquilina. The mixture is stirred for a further 90 min at 30oC.

The suspension is poured into ice water and the mixture extracted with ethyl acetate. After evaporation of an ethyl acetate excreta up to a volume of 20 ml and cooling to 0oTo give 2 g of crystalline Delta-8-estrone.

Example 4. Lithium (1.1 g) is added in several portions to 80 ml of Ethylenediamine in a nitrogen atmosphere at 100oC and the mixture is stirred for 30 min at 100oC. the Reaction mixture was cooled to 23oWith, and then at a temperature of 30oTo add 4 g 17-dihydroequilin. The mixture is additionally stirred for 4 h at 30oC., the Suspension is poured into 250 ml of ice water and at a temperature of 25oTo add acetic acid to bring the pH to 7. The suspension is cooled to 5oAnd the crystals filtered off. The crystals are suspended in 150 ml of water and add 100 ml of ethyl acetate. Faction share and an ethyl acetate solution is evaporated under vacuum to a volume of 20 ml, the Suspension is stirred at -15oC for 1 h, after which the crystals are filtered, washed with ethyl acetate and dried in vacuum at 40oIn the semi M) in diethyl ether is added dropwise within 10 min to 40 ml of Ethylenediamine in a nitrogen atmosphere at 36oC. the Temperature of the mixture was adjusted to 55oWith and diethyl ether is distilled off. The mixture is stirred for 1 h at 55oC. the Reaction mixture is cooled to 3oWith, and then at a temperature of 10oWith type 2 g equilin-3-methyl ether. The mixture is stirred for 2 h at 12oWith, then add 200 ml of ice water. To the mixture add acetic acid to bring the pH to 8. The suspension is stirred for 1 h at 15oS, after which the crystals are filtered, washed with water and dried in vacuum at 45oWith, the result of 2.0 g of 8,9-dehydration-3-methyl ester with a purity of approximately 80%.

Example 6. In accordance with the procedure described in example 5 17-dihydroequilin-3,17-diacetate process motility/Ethylenediamine at 30oWith the result from the quantitative yield of 8.9-degidro-17-estradiol with a purity of approximately 90%.

Example 7. In accordance with the procedure described in example 4, equilin-17-neopentecostal treated with lithium/Ethylenediamine at 20oWith, the result 8,9-dehydration-17-neopentecostal (yield 90%) with a purity of approximately 90%.

Example 8. In accordance with the procedure described in example 4 17-dihydroequilin 8,9-degidro-17-estradiol with a purity of approximately 90%.

Example 9. To a suspension Aquilina (5 g) in 80 ml of methylene chloride add a 13.3 ml of 3,4-dihydro-2H-Piran and 36 mg of p-toluenesulfonic acid at 0oC. the Mixture is stirred for 90 min at 0oWith, then add 1.3 ml of triethylamine. The reaction mixture is washed with water, dried with sodium sulfate and evaporated to dryness. Untreated equilin-3-tetrahydropyranyloxy ester (6.5 g) is used for isomerization.

Example 10. The solution motility-literotica (8.1 ml, 2.1 M) in diethyl ether is added dropwise within 10 minutes to 16.2 ml of Ethylenediamine in a nitrogen atmosphere at 36oC. the Temperature of the mixture was raised to 55oWith and diethyl ether is distilled off. The mixture is additionally stirred for 1 h at 55o, Then cooled to 3oC. After adding to 34.4 ml of tetrahydrofuran, the mixture is cooled to -10oWith and at a temperature of -5oTo add equilin-3-tetrahydropyran-niloy ether (1,15 g). The mixture is additionally stirred for 3 h at -10oWith, then add 45 ml of ice water. Then the tetrahydrofuran is distilled off under vacuum and the remaining suspension is stirred for 1 h at 15oC. the Crystals are filtered, washed with water and dried under vacuum at 45oWith, the result is the Delta(8,9)-dehydrohydrocortisone ether in a mixture of acetic acid/acetone/ water (4:2:1, 35,7 ml) is heated to the boiling point of the mixture and stirred at the boiling temperature under reflux for 90 minutes After cooling to 20oTo add to 36.5 ml of water and the crystalline product is filtered, washed with water and dried under vacuum, the result is 0,46 g Delta(8,9)-dehydration.

Example 12. Sulfuric acid (8.2 ml) and acetic anhydride (14,5 ml) are added to a pyridine (80 ml) at a temperature <30C in nitrogen atmosphere. The mixture is stirred for 1 hour at 50oWith, then add trometamol (2-amino-2-hydroxymethyl-1,3-propandiol) (0.6 g) and the mixture is stirred to obtain a clear solution. Add Delta(8,9)-dehydration (4 g) and 17-dihydroequilin monoacetate (20.2 g) followed by addition of pyridine (21 ml) and the mixture stirred for 3 h at 50oC. After completion of the reaction the mixture is cooled to 5oWith and triturated with diethyl ether (300 ml), which leads to the formation of the oil and the top layer. The upper layer is decanted and the residue is dissolved in methanol (375 ml). Add a solution of sodium hydroxide (12.8 g) in methanol (0.3 l) and the mixture is stirred for 2.5 h at boiling temperature. After completion of the reaction the mixture is cooled to 20oAnd add a mixture or sodium chloride and water. After evaporation of the organic layer to dryness the residue is dissolved in 100% ethanol (0,29 l) at 60oC and the mixture is stirred in the presence of activated charcoal (0.6 g) for 30 min at 60oC. the Suspension is filtered and the filtrate is partially concentrated in vacuo. The solution is cooled to 10oWith, grind into powder with diethyl ether (0,27 l). The precipitate is filtered, washed with diethyl ether and dried in vacuum as a result, 15.5 g of a mixture of matriculate Delta(8,9)-dehydration and matriculate 17-dihydroequilin in the ratio of 1:5. Analysis by gas chromatography (GC) shows a complete selection of all loaded steroids.

Example 13. In accordance with the procedure described in example 12, a mixture of Delta(8,9)-dehydration (12.5 g) and Aquilina (12.5 g) sulfation a mixture of sulfuric acid/acetic anhydride/pyridine. The mixture of raw pyridinemethanol omelet and make the appropriate mixture of matriculation treatment with sodium hydroxide in methanol as described in example 12, the result of 27.5 g of a mixture of Delta(8,9)-dehydration of matriculate and Aquilina of matriculate in the ratio of 1:1, GC analysis shows complete selection of all loaded steroids.

Example 14. In sooted,8 g), 17-dihydroequilin of monoacetate (3.5 g), 17-estradiol of monoacetate (9.5 g) and 17-estradiol of monoacetate (1.2 g) sulfation a mixture of sulfuric acid/acetic anhydride/pyridine. The mixture of raw pyridinemethanol treated with sodium hydroxide in methanol and treated as described in example 12, the result 44.4 g of a mixture of Delta(8,9)-dehydration of matriculate; 17-dihydroequilin of matriculate, 17-dihydroequilin of matriculate, 17-estradiol of matriculate and 17-estradiol of matriculate in the ratio 6: 8: 1:31:3. GC analysis shows complete selection of all loaded steroids.

1. The method of obtaining a mixture of sulfated estrogens, including sulfation connection - derived Delta-8,9-estrone General formula I

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where R1- N.;

R2- N and R3- O-acyl, or

R3- N and R2- O-acyl, or

R2and R3together,

in a mixture with one or more compounds selected from the group of compounds of General formula II

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where R1, R2and R3take the above specified values;

the dotted line in position 7-8 represents an optional double bond.

2. The method according to p. 1, in which R2and R3the GRF is with aquilinum.

4. The method according to p. 1, in which the Delta-8,9-estrone sulfation in a mixture of at least one of the compounds selected from the group comprising monoacrylate 17-alpha-dihydroequilin, 17-beta-dihydroequilin, 17-alpha-estradiol, and 17-beta-estradiol.

5. The method according to p. 4, characterized in that the mixture sulfation in the ratio, which is present in natural compositions of conjugated estrogens.

6. The method of obtaining a mixture of sulfated estrogens, characterized in that before the conversion of the mixture into the corresponding sulphates on PP. 1-5 receive at least a compound corresponding to the formula I, where R1-N, from compounds of the formula III, where R1-silyl(alkyl)3or tetrahydropyranyl.

7. The method of obtaining a mixture of sulfated estrogens, which includes stages: A. partial isomerization of the compounds of General formula III

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where R1- silyl(alkyl)3or tetrahydropyranyl;

R2and R3together represent O, or R2and R3together, acetal,

using the lithium salt of Ethylenediamine or with lithium amide in dimethyl sulfoxide in the compounds of General formula I

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where R1, R2and R3when the substituent R1becomes hydrogen and the substituents R2and R3together be About; C. the sulfation of the compounds obtained in stage b, optionally in a mixture with one or more manuallyassigned compounds from the group including 17-alpha-dihydroequilin, 17-beta-dihydroequilin, 17-alpha-estradiol, and 17-beta-estradiol.

8. The method of obtaining a mixture of sulfated estrogens, which includes stages: A. isomerization of compounds of General formula III

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where R1- silyl(alkyl)3or tetrahydropyranyl;

R2and R3together - Oh, or R2and R3together, acetal or cyclic acetal,

using the lithium salt of Ethylenediamine or with lithium amide in dimethyl sulfoxide in the compounds of General formula I

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where R1, R2and R3take the values defined above,

b. conversion of the compounds obtained in stage a, by which the substituent R1becomes hydrogen and the substituents R2and R3together be About; C. the sulfation of compound obtained in stage b, in a mixture with one or more manuallyassigned compounds from the group including 17-alpha-dihydroequilin, 17-beta-dihydroequilin, stavley an O.

 

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SUBSTANCE: 17β-oxoestratrienes of the general formula III and 17β-oxyestratrienes of the general formula II are used as intermediary products in obtaining 17α-alkyl-17β-oxyestra-1,3,5(10)-trienes of the general formula I with antiestrogenic effect, where Hal, R3, SK, R17', R17" represent elements listed in the invention claims.

EFFECT: improved method of obtaining the product.

19 cl, 4 ex

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