RU2281289C1 - METHOD FOR PREPARING 6β-FORMYL-B-NORCHOLESTANE-3β,5β-DIOL - Google Patents

Abstract

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

Description

The invention relates to the field of chemistry of steroids, and in particular to a new method for producing 6β-formyl-B-norcholestan-3β, 5β-diol of formula (I) by narrowing the six-membered B-ring of cholesterol.

6β-Formyl-B-norcholestan-3β, 5β-diol (I) is an important intermediate compound (synthon) in the synthesis of diverse in structure B-norcholestanes. The reduction of the formyl group of LiAlH ₄ leads to the corresponding carbinol, followed by the preparation of 3,6-diesters. An even greater number of derivatives are obtained from 6-acid, into which the acetyl derivative of the aldehyde (I) is easily converted by oxidation. In recent years, among a number of norcholestanes, including B-norcholestanes, an intensive search for substances with hypocholesterolemic action has been carried out (M. Mamiya, K. Takahashi, S. Eguchi et al., Chem. Pharm. Bull. (1989), 37 (7 ), pp.1930-1931). In addition, the chemical structure of 6β-formyl-B-norcholestan-3β, 5β-diol (I), due to the presence of an OH group at the 5th position, allows the side chain of B-norcholestan to be reduced by a known method of remote oxidation (R. Breslow, Ac. Chem Res. (1980), 13, p. 170), which opens up wide possibilities for obtaining new physiologically active compounds in the series of analogues of sex hormones - B-norandrostan and pregnancy hormones - B-norpregnan (L. Fizer, M. Fizer, Steroids . M., "World", p. 602).

Known methods for narrowing the six-membered B-ring of sterols, leading to the production of B-norsterans or B-norsterins, are multi-stage and stringent conditions - require the use of aggressive reagents and high temperatures. For example, synthesis of B-norcholesterol includes the stages of epoxidation, oxidative cleavage of the epoxide with chromic anhydride in the presence of acid, oxidation of the formed 5,6-seco-keto acid according to Bayer-Wiliger to lactone, and pyrolysis of the lactone at a temperature of 140 ° C (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).

An improvement of this method described in LSStevovic, VDPavlovic et al, J. Serb. Chem. Soc., 63 (12), 1998, pp.955-959, consists only in combining the first two stages — epoxidation and epoxide cleavage — into one, but does not eliminate the use of aggressive reagents — the following systems are used in this first combined synthesis step: first H ₂ WO ₄ + H ₂ O ₂ and then CrO ₃ + H ₂ SO ₄ .

The only currently known method for producing 6β-formyl-B-norcholestan-3β, 5β-diol (I), but only in the form of its 3-acetate: 3-acetyl-6β-formyl-B-norcholestan-3β, 5β-diol (II), described by K. Tanabe, R. Hayashi, R. Takasaki, Chem. Pharm. Bull., 9, 1961, pp. 1-6. This method, as well as the aforementioned known methods of narrowing the six-membered B-ring of sterols, is multi-stage. The method consists of three stages, including ozonolysis of cholesterol acetate, recovery of the obtained product with zinc in acetic acid to secoaaldehyde and cyclization of the latter into the target product (II) by treatment with Girard or Al ₂ O ₃ reagent. The narrow link in this synthesis scheme is the ozonolysis stage, which, in spite of various modifications of its conduct, differs in an extremely unstable yield.

Thus, the main disadvantages of the known method for producing the formyl derivative of B-norcholestanediol are its multi-stage and output instability of the target product.

The objective of the present invention is to develop a fundamentally different in chemical essence one-step method for producing an aldehyde of the formula (I) by narrowing the six-membered B-ring of cholesterol, which will be much simpler than the known one and ensure a high yield of the target product.

The solution of this problem is achieved by the proposed method for producing 6β-formyl-B-norcholestan-3β, 5β-diol of formula (I) by oxidatively narrowing the six-membered B-ring of cholesterol, which consists in the fact that cholesterol is subjected to photooxidation with atmospheric oxygen when exposed to visible light in the presence of porphyrin a photosensitizer immobilized on a low molecular weight fraction of a copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-5-methyl-6-sulfonyl fluoridooctene-1 (MF-4SK), with a weight ratio of porphyrin photosensitizer: cholesterol equal to 1: 12-15.

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

When developing the proposed method, experimental studies were conducted on the effect of the structure of the porphyrin photosensitizer, the properties of the polymer used to immobilize porphyrin, the wavelength of the irradiating light, and other process parameters on the course of the cholesterol photooxidation reaction.

Porphyrins as photosensitizers in various photooxidation reactions are widely studied (see, e.g., review: F. Wilkinson, JGBrummer. 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 tested the following porphyrins: unsubstituted tetraphenylporphyrin (5,10,15,20-tetraphenylporphyrin) (TFP), 5- (p-aminophenyl) -10,15,20-triphenylporphyrin (TFP-Am), 5-glycylaminophenyl -10,15,20-triphenylporphyrin (GlTPP), 5-capronoylaminophenyl-10,15,20-triphenylporphyrin (CaTPP) and 5-undecanoylaminophenyl-10,15,20-triphenylporphyrin (UnTPP).

It turned out that the effect of the structure of the porphyrin photosensitizer on the yield of 6β-formyl-B-norcholestan-3β, 5β-diol (I) is insignificant, therefore, any of the above porphyrins can be used in the cholesterol photooxidation reaction. It is advisable to carry out the oxidation of cholesterol with the cheapest of them - with unsubstituted TFP.

The processes of photosensitized oxidation of cholesterol have been studied since the beginning of the 60s. In the photooxidation of cholesterol in the presence of pure porphyrins added to the reaction mixture, the reaction products usually were three types of compounds: hydroperoxides, alcohols and ketones formed without narrowing the cholesterol B-ring (FHDoleiden, SRFanrenholtz, AALamola and AMTrozzolo. Reactivity of Cholesterol and Some Fatty Acids toward Singlet Oxygen. // Photochemistry and Photobiology, 1974, Vol.20, pp.519-521).

When developing the proposed method, we found that the photooxidation reaction of cholesterol in the presence of porphyrins immobilized on a copolymer of tetrafluoroethylene and perfluoro-3,6-dioxo-5-methyl-6-sulfonyl fluoridooctene-1 (MF-4SK, manufactured by ONPO Plastpolymer, St. Petersburg), leads to a narrowing of the B-ring of cholesterol with the formation of 6β-formyl-B-norcholestan-3β, 5β-diol (I). The highest yield (I) was observed upon the immobilization of porphyrins on the low molecular weight fraction of the MF-4SK copolymer obtained by extraction of this copolymer with a mixture of chloroform and isopropyl alcohol at a volume ratio of 1: 1.

The choice of the wavelength of light used for irradiation in the photooxidation reaction of cholesterol is due to the photosensitive properties of both porphyrins and cholesterol. Porphyrins exhibit maximum absorption in the visible region, which makes it possible to use them as photosensitizers in the photooxidation of cholesterol - light with a shorter wavelength leads to photodegradation of cholesterol and its oxidation products, which are even more sensitive to irradiation with UV light.

As a result of the experiments, it was found that the influence of temperature on the course of the process, as is observed for most photochemical reactions, is insignificant.

The experimentally found optimal conditions for the process of cholesterol photooxidation made it possible to propose the inventive method for producing 6β-formyl-B-norcholestan-3β, 5β-diol (I). The photooxidation reaction 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 five-membered with the simultaneous appearance of the OH group at the 5th position and the CHO group at the 6th position of the B-ring of the formed B-norcholestane.

The proposed method is as follows.

An immobilized porphyrin photosensitizer is prepared: the MF-4SK copolymer is dissolved in a mixture of chloroform and isopropyl alcohol (1: 1, vol.), While only a low molecular weight fraction of the copolymer is dissolved, a solution of porphyrin in the same solvent mixture is added and mixed. Cholesterol is dissolved in the same solvent mixture (chloroform-isopropanol, 1: 1) and mixed with the prepared solution of the immobilized porphyrin photosensitizer. The mass ratio of the porphyrin photosensitizer: cholesterol should be 1: 12-15, the concentration of the copolymer MF-4SK in the reaction mixture - 0.4-0.6%. The reaction mixture is stirred at a temperature of 10-25 ° C with oxygen saturation and irradiation with visible light, for which you can use, for example, a xenon lamp or a high-pressure mercury lamp with appropriate filters. After 3-4 hours, the reaction solution was evaporated, the residue was dissolved in a 1: 1 mixture of chloroform and ether to separate the target product and unreacted cholesterol from the photosensitizer by filtration, and the resulting solution was evaporated again. 6β-Formyl-B-norcholestan-3β, 5β-diol (I) is isolated by silica gel chromatography in a 9: 1 hexane-ethyl acetate system.

The structure of 6β-formyl-B-norcholestan-3β, 5β-diol (I) was proved by the data of IR and PMR spectra and confirmed by the results of elemental analysis. For additional proof of the structure of the obtained B-norcholestan (I), the compound described above (in the prototype method), 3-acetyl-6β-formyl-B-norcholestan-3β, 5β-diol (II), was obtained from it. The IR spectrum of the 3-acetyl-6β-formyl-B-norcholestan-3β, 5β-diol (II) obtained by us corresponds to the literature. We also recorded PMR and mass spectra and performed elemental analysis; the obtained data also confirm the structure of compound (II). Another 6-substituted B-norcholestan-3β, 5β-diol: 3-acetyl-6β-carboxyl-B-norcholestan-3β, 5β-diol (III) obtained by K. Tanabe, R. Hayashi, is described in the literature. R. Takasaki, Chem. Pharm. Bull., 9, 1961, pp. 12-19 by oxidation of 3-acetyl-6β-formyl-B-norcholestan-3β, 5β-diol (II) with chromic anhydride. It should be noted that this acid (III) is a crystalline substance with a high melting point (about 200 ° C), which makes it a convenient object for research: this compound is described most fully of all the known 6-substituted B-norcholestanes. When chromic anhydride oxidized 3-acetyl-6β-formyl-B-norcholestan-3β, 5β-diol (II), we obtained the same acid: 3-acetyl-6β-carboxyl-B-norcholestan-3β, 5β-diol ( III), as described in the indicated work, as evidenced by the coincidence of the measured and literary constants: mp, [α] D and the data of the IR spectra. We also recorded the PMR spectrum, which also corresponds to the indicated structure of the obtained acid (III).

Example 1

6β-Formyl-B-norcholestan-3β, 5β-diol (I).

To a solution of 100 mg of cholesterol in 15 ml of a mixture of chloroform and isopropyl alcohol (1: 1, vol.) (CL-SP) add 10 ml of a solution of 5,10,15,20-tetraphenylporphyrin (TFP) immobilized on a low molecular weight fraction of tetrafluoroethylene copolymer and perfluoro-3,6-dioxo-5-methyl-6-sulfonyl fluoridooctene-1 (MF-4SK), for which a solution of 7.1 mg TFP in 2 ml of a mixture of CL-SP is added to 125 mg of a copolymer of MF-4SK in 8 ml of a mixture HL-SP and mix. The mass ratio of TPP: cholesterol is 1:14, the concentration of the copolymer in the reaction mixture is 0.5%. The resulting reaction mixture was stirred while saturated with oxygen and illuminated with visible light from a xenon lamp at room temperature. After 3.5 hours, the reaction solution was evaporated, the residue was dissolved in a 1: 1 mixture of chloroform and ether to separate the reaction products from the photosensitizer by filtration, and the resulting solution was evaporated again. The target product is separated from the original cholesterol by chromatography on silica gel in a hexane-ethyl acetate 9: 1 system and 38 mg of cholesterol and 41 mg of 6β-formyl-B-norcholestan-3β, 5β-diol (I) are obtained in the form of an oil (61% yield, taking into account conversions). R _f 0.43 (hexane-ethyl acetate 9: 1). IR spectrum, cm ^-1 : 3400-3420 (OH), 2730, 1725 (CHO). 1 H-NMR spectrum (CDCl ₃ , δ, ppm): 0.69 s (3H, 18-Me), 0.836 and 0.838 d (3H each, J 6.6 Hz, 26- and 27-Me), 0.887 (3H, J 6.5 Hz, 21-Me), 0.90 s (3H, 19-Me), 3.52 s (1H, OH), 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.

C ₂₇ H ₄₆ O ₃

Calculated,%: 77.46; H 11.46.

Example 2

3-Acetyl-6β-formyl-B-norcholestan-3β, 5β-diol (II).

40 mg of 6β-formyl-B-norcholestan-3β, 5β-diol (I) is dissolved in 0.1 ml of a 1: 1 mixture of acetic anhydride and pyridine and left at room temperature for 16 hours. It is evaporated to dryness with periodic addition of benzene. The residue was dissolved in benzene, filtered through silica gel to give 41 mg of acetate (II). R _f 0.57 (hexane-ethyl acetate 9: 1).

IR spectrum, cm ^-1 : 3410 (OH), 2715, 1705 (CHO), 1740 (OAc).

1 H-NMR spectrum (C ₆ D ₆ ): 0.80 s (3H, 18-Me), 1.065 s (3H, 19-Me). 1.083 and 1.086 d (3H each, 26-27-Me), 1.138 (3H, 21-Me), 1.695 s (3H, OAc), 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 br.s. (1H, OH), 5.15 t (1H, J 3.1 Hz, 3-H), 9.95 d (1H, J 3.1 Hz, CHO).

Mass spectrum, m / z (%): 400 (8, M CH ₃ COOH), 382 (18, 400-Н ₂ О), 354 (100, 382-СО), 241 (17,354-C ₈ H ₁₇ ) .

Found,%: C 76.01; H, 10.72.

C ₂₉ H ₄₈ O ₄

Calculated,%: 75.68; H, 10.86.

Example 3

3-Acetyl-6β-carboxyl-B-norcholestan-3β, 5β-diol (III).

To a solution of 150 mg of 3-acetyl-6β-formyl-B-norcholestan-3β, 5β-diol (II) in 3.5 ml of 90% acetic acid (UK) at 0 ° C, a solution of 50 mg of CrO ₃ in 1 5 ml of the Criminal Code. The mixture was stirred for 1.5 hours at 25 ° C., then the excess CrO _{3 was} decomposed with isopropanol, diluted with water and extracted with ethyl acetate. The extract was washed with saturated NaCl and evaporated to dryness. The residue was dissolved in chloroform, filtered through silica gel and 140 mg of acid (III) was isolated.

R _f 0.15 (ethyl acetate-hexane 1: 4)

Mp 194-197 ° C, [α] _D + 34.9 ° (c 0.93, CHCl ₃ ).

IR spectrum, cm ^-1 : 3500, 3175 (CO ₂ H, OH), 1730 (OAc), 1690 (CO ₂ H).

(Lit. data: mp 199-200 °, [α] _D + 31.3 °; IR spectrum: 3615, 3150, 1736, 1693 cm ^-1 ).

1 H-NMR spectrum (CDCl ₃ , δ, ppm): 0.70 s (18-Me), 0.91 d (3H, J 6.5 Hz, 21-Me), 0.97 s (3H, 19-Me), 0.86 and 0.864 d in 3H (J 6.6 Hz, 26- and 27-Me), 2.06 s (3H, OAc), 5.07 br.s (1H, 3-H )

Thus, a new method has been proposed for narrowing the six-membered B-ring of cholesterol, leading to the formation of 6β-formyl-B-norcholestan-3β, 5β-diol (I). The main advantage of the claimed method is its one-stage. The method is technologically simple, does not require harsh conditions for its implementation and provides a high yield of the target product. The compound obtained by the claimed method, 6β-formyl-B-norcholestan-3β, 5β-diol (I), has a structure capable of further chemical modification, which allows it to be used as an object of research devoted to the search for new derivatives of hormonal substances.

Claims (2)

1. The method of obtaining 6β-formyl-B-norcholestan-3β, 5β-diol of the formula I:

by oxidatively narrowing the six-membered B-ring of cholesterol, characterized in that the cholesterol is subjected to photooxidation with atmospheric oxygen when exposed to visible light in the presence of a porphyrin photosensitizer immobilized on a low molecular weight fraction of a tetrafluoroethylene copolymer and perfluoro-3,6-dioxo-5-methyl-6-sulfon copolymer 1, with a porphyrin photosensitizer: cholesterol weight ratio equal to = 1: 12-15. 2. The method according to claim 1, characterized in that 5,10,15,20-tetraphenylporphyrin is used as the porphyrin photosensitizer.