Method for preparing 6β-formyl-b-norcholestane-3β,5β-diol

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

 

The invention relates to the field of steroid chemistry, namely to a new method of obtaining 6β-formyl-In-nicholaston-3β,5β-diol of the formula (I) by narrowing six-membered B-ring of cholesterol.

6β-Formyl-In-nicholaston-3β,5β-diol (I) is an important intermediate compound (synthon in the synthesis of diverse structure-norcholesterol. The restoration of the formyl group LiAlH4leads to the corresponding carbinol then get a 3.6-diesters. An even greater number of derivatives is obtained from 6-acid, in which the acetyl derivative of the aldehyde (I) is easily converted in the oxidation. In recent years a number of norcholesterol, including In-norcholesterol, conducted an intensive search for substances with gipoholesterinemicheskoy action (Mmama, .Takahashi, S.Eguchi et al., Chem. Pharm. Bull. (1989), 37 (7), pp.1930-1931). In addition, the chemical structure of 6β-formyl-In-nicholaston-3β,5β-diol (I) due to the presence of Oh-group in the 5-th position can reduce the side chain of nicholaston known way remote oxidation (R. Breslow, ACE. Chem. Res. (1980), 13, R), which opens up opportunities for new physiologically active compounds in the series of analogues of sex hormones - In-norandrosterone and the pregnancy hormones - In-norpregnane (Lfisher, Mfisher, Steroids. M., "World", str)./p>

Known methods of narrowing six-membered B-ring of sterols, leading to the In-northernnew or In-Norstein, are multi-stage and rigidity conditions require the use of aggressive chemicals and high temperatures. For example, the synthesis of In-norcholesterol includes phase epoxidation, oxidative cleavage of the epoxide with chromic anhydride in the presence of acid, oxidation of the resulting 5,6-SECO-ketoacids by the Bayer-Wiliger in the lactone and the pyrolysis of the lactone at a temperature of 140° (J.Joska, J.Fajkos, F.Sorm, Collect. Czech. Chem. Commun., 28, 1963, p.821; J.Fried, J.Edwards, Organic Reaction in Steroid Chemistry, N.-Y., v.2, 1972, p.430).

The improvement of this method, described in L.S.Stevovic, V.D.Pavlovic et al, J.Serb. Chem. Soc., 63 (12), 1998, pp.955-959, is only the combination of the first two stages - epoxidation and epoxide cleavage - in one, but does not eliminate the use of aggressive reagents - this is the first combined phase synthesis used the following system: first, H2WO4+H2O2and then CrO3+H2SO4.

The only currently known way to obtain 6β-formyl-In-nicholaston-3β,5β-diol (I), but only in the form of its 3-acetate: 3-acetyl-6β-formyl-In-nicholaston-3β,5β-diol (II), described in .Tanabe, R.Hayashi, R.Takasaki, Chem. Pharm. Bull., 9, 1961, pp.1-6. This method, like the above-mentioned known methods reduce the deposits In six-membered-ring sterols, is multiphase. The method consists of three stages, including ozonolysis acetate cholesterol, recovery of the resulting product with zinc in acetic acid to sexualdesire and cyclization of the latter in the target product (II) by treatment with a reagent of Girard or Al2About3. The narrow part of this scheme of synthesis is phase ozonolysis, which, despite various modifications of its holding, the highly unstable output.

Thus, the main disadvantages of this method of obtaining formyl derivative In-norcholesterol are multi-stage and the volatility of the yield of the target product.

The present invention is to develop a fundamentally different chemical entity by one-stage method of producing aldehyde of the formula (I) by narrowing six-membered B-ring of cholesterol, which will be much easier known, and provide a high yield of the target product.

The solution of this problem is achieved by the proposed method of obtaining 6β-formyl-In-nicholaston-3β,5β-diol of the formula (I) by oxidizing narrowing of the six-membered B-ring of cholesterol, which consists in the fact that cholesterol is subjected to photo-oxidation by atmospheric oxygen under irradiation of visible light in the presence of porphyrin photosensitizer immobilized on niskama the molecular fraction of a copolymer of tetrafluoroethylene and PERFLUORO-3,6-dioxa-5-methyl-6-sulfonylmethane-1 (MT-SC), when the mass ratio of porphyrin photosensitizer: cholesterol 1:12-15.

As a porphyrin photosensitizer can be used 5,10,15,20-tetraphenylporphyrin.

During the development of the proposed method were carried out experimental studies of the influence of the structure of porphyrin photosensitizer, the properties of the polymer used for immobilization of porphyrin, the wavelength of the irradiating light and other process parameters on the course of the reaction of photo-oxidation of cholesterol.

Porphyrins as photosensitizers in various reactions of photo-oxidation widely studied (see, for example, review: F.Wilkinson, J.G.Brummer. Rate constants for the decay and reactions of the lowest electronically excited singlet state of molecular oxygen in solution, Journal of Physical and Chemical Reference Data, 1981, 10, N4, pp.809-999).

In this invention, we have tested the following porphyrins: the unsubstituted tetraphenylporphyrin (5,10,15,20-tetraphenylporphyrin) (DFT), 5-(p-AMINOPHENYL)-10,15,20-triphenylporphyrin (DFT-S)5-glycylamino-10,15,20-triphenylporphyrin (Ptfp), 5-capreolinae-10,15,20-triphenylporphyrin (Cacfp) and 5-undecanedioic-10,15,20-triphenylporphyrin (NTFP).

It turned out that the influence of the structure of the porphyrin photosensitizer at exit 6β-formyl-In-nicholaston-3β,5β-diol (I) is insignificant, therefore, in the reaction of photo-oxidation of cholesterol you can use any of perechisleny the x above porphyrins. It is advisable to carry out the oxidation of cholesterol with the cheapest of them is unsubstituted DFT.

Processes photosensibilisation oxidation of cholesterol studied since the early 60-ies. When the photo-oxidation of cholesterol in the presence of porphyrins, added in pure form in the reaction mixture, the reaction products were usually three types of connections: gidroperekisi, alcohols and ketones formed without compromising In-ring cholesterol (F.H.Doleiden, S.R.Fanrenholtz, A.A.Lamola and A.M.Trozzolo. Reactivity of Cholesterol and Some Fatty Acids toward Singlet Oxygen. // Photochemistry and Photobiology, 1974, Vol.20, pp.519-521).

During the development of the proposed method we have found that carrying out the reaction of photo-oxidation of cholesterol in the presence of porphyrins immobilized on a copolymer of tetrafluoroethylene and PERFLUORO-3,6-dioxa-5-methyl-6-sulfonylmethane-1 (MT-SC, production ONPO "Plastpolymer", Saint-Petersburg), leads to a narrowing of the In-ring cholesterol education 6β-formyl-In-nicholaston-3β,5β-diol (I). The highest yield (I) was observed upon immobilization of porphyrins on low molecular weight fraction of the copolymer MT-SK obtained by extraction of this copolymer with a mixture of chloroform and isopropyl alcohol in a volume ratio of 1:1.

The choice of wavelength of the light used for irradiation in the reaction of photo-oxidation of cholesterol, due to the light-sensitive properties as porphyry is new, and cholesterol. Porphyrins exhibit a maximum absorption in the visible region, which makes possible their use as photosensitizers during the photo-oxidation of cholesterol - light with shorter wavelength leads to photodegradation of cholesterol and its oxidation products, are even more sensitive to irradiation by ultraviolet light.

As a result of experiments, it was found that the effect of temperature on the course of the process, as is the case for most photochemical reactions, slightly.

Experimentally found optimal conditions for the oxidation of cholesterol made it possible to offer the inventive method of obtaining 6β-formyl-In-nicholaston-3β,5β-diol (I). The reaction of the photo-oxidation of cholesterol in the presence of immobilized porphyrin sensitizers is accompanied by a narrowing of the six-membered B-ring of cholesterol (having a double bond) to the five-membered with the simultaneous occurrence of the Oh-group at the 5th position and SNO-group in the 6th position In-ring formed In-norcholesterol.

The proposed method is as follows.

Prepare immobilized porphyrin photosensitizer: copolymer MT-SK dissolved in a mixture of chloroform and isopropyl alcohol (1:1, by vol.), when this is dissolved only low molecular weight fraction of the copolymer, to the obtained solution on billaut solution of the porphyrin in the same solvent mixture and mix. Dissolve cholesterol in the same solvent mixture (chloroform-isopropanol, 1:1) and mixed with the prepared solution immobilized porphyrin photosensitizer. The mass ratio of porphyrin photosensitizer: cholesterol should be 1:12-15, the concentration of the copolymer MT-SC in the reaction mixture of 0.4 - 0.6%. The reaction mixture is stirred at a temperature of 10-25°when saturated with oxygen and irradiation with visible light, which can be used, for example, a xenon lamp or a mercury lamp, high pressure with appropriate filters. After 3-4 hours the reaction solution is evaporated, the residue dissolved in a mixture of chloroform and ether 1:1) for separation of the target product and unreacted cholesterol from the photosensitizer by filtration, the resulting solution was again evaporated. 6β-Formyl-In-nicholaston-3β,5β-diol (I) was isolated by chromatography on silica gel in the system hexane-ethyl acetate 9:1.

Structure 6β-formyl-In-nicholaston-3β,5β-diol (I) is proved by data of the IR and PMR spectra and confirmed by the results of elemental analysis. For additional evidence of the structure obtained In-norcholesterol (I) it was obtained previously described (method-prototype) connection - 3-acetyl-6β-formyl-In-nicholaston-3β,5β-diol (II). The IR spectrum of the obtained 3-is cetyl-6β -formyl-In-nicholaston-3β,5β-diol (II) corresponds to the literary. We have also removed the PMR and mass spectra and performed elemental analysis, the obtained data also confirm the structure of compound (II). The literature describes another 6-substituted-nicholaston-3β,5β-diol: 3-acetyl-6β-carboxyl-In-nicholaston-3β,5β-diol (III), obtained in .Tanabe, R.Hayashi, R.Takasaki, Chem. Pharm. Bull., 9, 1961, pp.12-19-oxidation of 3-acetyl-6β-formyl-In-nicholaston-3β,5β-diol (II) with chromic anhydride. It should be noted that the above acid (III) is a crystalline substance with a high melting point (about 200°C), which makes it very convenient for research: this connection is described most fully of all known 6-substituted-norcholesterol. In the oxidation with chromic anhydride obtained 3-acetyl-6β-formyl-In-nicholaston-3β,5β-diol (II) was obtained in the same acid: 3-acetyl-6β-carboxyl-In-nicholaston-3β,5β-diol (III), as described in the aforementioned work, as evidenced by the coincidence of measured us and literary constants: TPL, [α]D and the data of IR spectra. We have also cleared the PMR spectrum, also corresponding to the specified structure of the acid (III).

Example 1.

6β-Formyl-In-nicholaston-3β,5β-diol (I).

To a solution of 100 mg of cholesterol in 15 ml of a mixture of chlorofo the mA and isopropyl alcohol (1:1, about.) (HL-SP) add 10 ml of a solution of 5,10,15,20-tetraphenylporphyrin (DFT), immobilized on a low molecular weight fraction of the copolymer of tetrafluoroethylene and PERFLUORO-3,6-dioxa-5-methyl-6-sulfonylmethane-1 (MT-SC), for which the solution of 7.1 mg DFT in 2 ml of a mixture of CHL-SP added to 125 mg of copolymer MT-SC in 8 ml of a mixture of HL-SP and mix. The mass ratio of the DFT: cholesterol is 1:14, the concentration of copolymer in the reaction mixture to 0.5%. The resulting reaction mixture was stirred at saturation with oxygen of air and light in a visible light of a xenon lamp at room temperature. After 3.5 h the reaction solution is evaporated, the residue dissolved in a mixture of chloroform and ether 1:1 for separating the reaction products from the photosensitizer by filtration and the resulting solution was again evaporated. The target product is separated from the source of cholesterol by chromatography on silica gel in the system hexane-ethyl acetate 9:1 and obtain 38 mg cholesterol, 41 mg 6β-formyl-In-nicholaston-3β,5β-diol (I) in the form of an oil (yield 61% with respect to conversion). Rfof 0.43 (hexane-ethyl acetate 9:1). The infrared spectrum, cm-1: 3400-3420 (HE), 2730, 1725 (SNO). PMR-spectrum (CDCl3that δ, ppm): 0,69 (3H, 18-Me), 0,836 and 0,838 D. (3H, J 6.6 Hz, 26 - and 27-IU), 0,887 (3H, J 6.5 Hz, 21-Me), of 0.90 (3H, 19-Me), 3,52 (1H, HE), 4,12 m (1H, J 4.0 Hz, 3-H), 9,67 d (1H, J 3.0 Hz, Cho).

Found, %: C 77,12; H 11,21.

With27H46About3

Calculated, %:77,46; H 11,46.

Example 2.

3-Acetyl-6β-formyl-In-nicholaston-3β,5β-diol (II).

40 mg 6β-formyl-In-nicholaston-3β,5β-diol (I) is dissolved in 0.1 ml of a mixture of acetic anhydride and pyridine 1:1 and leave at room temperature for 16 hours Evaporated to dryness with periodic addition of benzene. The residue is dissolved in benzene, filtered through silica gel and obtain 41 mg of the acetate (II). Rfof 0.57 (hexane-ethyl acetate 9:1).

The infrared spectrum, cm-1: 3410 (OH), 2715, 1705 (SNO), 1740 (SLA).

PMR-spectrum (C6D6): 0,80 (3H, 18-Me), 1,065 (3H, 19-Me). 1,083 and 1,086 D. (3H, 26 - 27-Me), at 1,138 (3H, 21-Me), 1,695 (3H, SLA), 2,11 m (1H, J 3.1 and 9.4 Hz, 7-H), 2,36 etc. (1H, J 2×11,4 and 9.4 Hz, 8-H), 2,48 USS (1H, HE), 5,15 t (1H, J 3.1 Hz, 3-H), 9,95 d (1H, J 3.1 Hz, SNO).

Mass spectrum, m/z (%): 400 (8, M CH3COOH), 382 (18, 400-N2O), 354 (100, 382-CO), 241 (17,354-C8H17).

Found, %: C 76,01; N. Of 10.72.

C29H48About4

Calculated, %: 75,68; N 10,86.

Example 3.

3-Acetyl-6β-carboxyl-In-nicholaston-3β,5β-diol (III).

To a solution of 150 mg of 3-acetyl-6β-formyl-In-nicholaston-3β,5β-diol (II) in 3.5 ml of 90%acetic acid (CA) at 0°add a solution of 50 mg CrO31.5 ml of the criminal code. The mixture is stirred for 1.5 h at 25°then decompose the excess CrO3isopropanol, diluted with water and extracted with ethyl acetate. The extract was washed with saturated NaCl solution and evaporated to dryness. The rest of rest the accelerate in chloroform, filtered through silica gel and produce 140 mg of the acid (III).

Rfof 0.15 (ethyl acetate-hexane 1:4)

TPL 194-197°, [α]D+34,9° (0,93, CHCl3).

The infrared spectrum, cm-1: 3500, 3175 (CO2H, OH), 1730 (SLA), 1690 (CO2N).

(Lit. data: TPL 199-200°, [α]D+31,3°; IR spectrum: 3615, 3150, 1736, 1693 cm-1).

PMR-spectrum (CDCl3that δ, ppm): 0,70 with (18-Me), of 0.91 (3H, J 6.5 Hz, 21-Me), of 0.97 (3H, 19-Me), 0,86 and 0,864 d 3H (J 6.6 Hz, 26 - and 27-IU)of 2.06 (3H, SLA), 5,07 USS (1H, 3-H).

Thus, a new method is proposed narrowing of the six-membered B-ring of cholesterol, leading to the formation of 6β-formyl-In-nicholaston-3β,5β-diol (I). The main advantage of the inventive method is its single-stage process. The method is technologically simple, does not require strict conditions for its implementation and provides a high yield of the target product. Received claimed process connection - 6β-formyl-In-nicholaston-3β,5β-diol (I) has a structure capable of further chemical modification that allows you to use it as an object of research devoted to the search for new derivatives of hormonal substances.

1. A method of obtaining a 6β-formyl-In-nicholaston-3β,5β-diol of the formula I:

by oxidative narrowing of the six-membered B-ring of cholesterol, characterized in that the cholesterol is subjected to photo-oxidation by atmospheric oxygen under irradiation of visible light in the presence of porphyrin photosensitizer, immobilized on a low molecular weight fraction of the copolymer of tetrafluoroethylene and PERFLUORO-3,6-dioxa-5-methyl-6-sulfonylmethane-1, when the mass ratio of porphyrin photosensitizer: cholesterol, equal =1:12-15.

2. The method according to claim 1, characterized in that as a porphyrin photosensitizer using 5,10,15,20-tetraphenylporphyrin.



 

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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

FIELD: medicine.

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

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