SU688125A3 - Method of obtaining 1 alpha, 24(s)-dioxyholecalciferoi or 1 alpha, 24(r)-dioxyholecalciferol, or their derivatives - Google Patents

Description

Whether, if necessary, Christmas hydrolysis is carried out in the medium of alcohol or reduction using lithium aluminum hydride in an inert organic solvent.

Example 1., 24-dioxoiccalciferol.

16 mg of N, 3, 24-trioxycholesta-5, 7-diene is dissolved in 500 ml of diethyl ether, after which the prepared solution is irradiated. UV rays for 2.5 minutes at a temperature in argon atmosphere using a high-pressure mercury lamp 200 W / 654A-36. A portion of the solution is separated and the UV spectrum is determined. An increased absorption rate is detected at 262 and 263 n / 4, which is indicative of the presence of Id, 24-di6xyprecholecalciferol. After completion of the reaction, the sulfuric ether is evaporated at room temperature and reduced pressure, 50 ml of benzene is added to the residue, and then isomerization is carried out for 4 hours while boiling the benzene under reflux.

After completion of the reaction, benzene is evaporated under reduced pressure, and 16 mg of a white solid are obtained. The product was separated by preparative thin layer chromatography using a silica gel carrier which contained approximately 1.5% silver nitrate, and the development was carried out twice using a mixture of 6% methanol with chloroform. Three bands are obtained for this product by irradiation with UV rays. From the least polar band, 2f8 mg of a white solid is obtained. It is identified as Id, 24-dioxycholecalciferol, and has the following properties:

UV spectrum: D. 265 nd; , max (

Max

 ethanol

228 nl; YMR spectrum max

(C, DaO): 0.57 (BM, d, iS-CHj); 0.86 (6H, d, J 7 Hz, 26 - 27 -CHj) 0.96 (3N, d, J 5 HZ, 21-CHj); 3.19 (IH, m, 24-H); 4.15 (IH, m, .1 ft - H); 4.36. (IH, m, 3cA — H); 4.85 (IH, b, S, 19-H) 5.30 1H, b, S, 19-H); 6.05 (IH, d,

;} d 11 HZ, 6 or 7-H); 6.16 (IH, d, 11 Hz, 6 or 7 - H).

Mass spectrum. 416 (M), 398, 380, 269, 251, 134.

High-resolution mass spectrum:

Found: 416, 32768 С „Н„ Oj Calculated: 416.32927 t. Pl. from 84 to 8 C.

Example 2. lei., 24 (R) -dioxycholecalciferol.

10 mg of U, sp, 24 (H) -trioxychol 5,7-diene is dissolved in 140 ml of diethyl ether, and the resulting solution is irradiated with UV light for 2 minutes. A portion of the solution is separated and the UV spectrum is determined. Absorption at 262 and 263n / indicates the presence of the original product. After completion of the reaction, the sulfuric ether is evaporated at room temperature and under reduced pressure. 50 ml of benzene are added to the residue and isomerization is carried out for 4 h under argon at refluxing of benzene with reflux condensers.

After completion of the reaction, the reaction mixture is treated analogously to example 1, followed by isolation and purification by preparative

- | thin layer chromatography. 1.8 mg of a white solid are obtained. . The product is identified as let, 24 (R) -dioxycholecalciferol, has the following properties.

0 DF-spectrum: L ° 265

228 NMR spectrum (C): 0.59 (3N, S, 18-cN3); 0.87 (6H, d,

J 7 Hz, 26-27-CH3); 3.20 (IH, m, 29-H); 4.14 (IH, m, l6-H); 4.42 (IH, 5 m,); 4.87 (IH, b, S, 19-H); 5.32 (IH, b, S, 19-H); 6.08 (IH, d, JAB 11 Hz; 6 - or - 7 H); 6.30 (IH, d, -11 HZ, 6- or 7-H);.

Mass spectrum: 416 (M), 398, 380, 0 269, 251.

Mass spectrum with high resolution:

Found: 416.33084. C Calculated 416.32927

5 Example ZY, 24 (S) -dioxycholecalciferol

15 mg of 1, 3b, 24 (S) -trioxycholesta-5, 7-diene is dissolved in 140 ml of diethyl ether, and the resulting solution is irradiated with UV light for 2 minutes

at 5 ° C. After this, a part of the process described in Example 2 is repeated, resulting in a CR / 1 of 2.8 mg of protein 6 of a solid product. The product, identified as Id, 24 (S) -dioxychol, calciferol, has the following properties: UV spectrum 265 nm;

  228 am, NMR spectrum of p (): 0.58 (3N, S, 18-CHj); 0.87 0 (SI, d, 3 7 HZ, 26 - H, 27-CHR; 3.20 (1H, t, 24-H); 4.14 (IH, m, if-H) - 4I2 ( IH, m, 34-H); 4.87 (IH, b, S, 19-U; 5.32 (iH, b, S, 19-W f -. 6.08 (IM, d, JAO 11 HZ , 6 - or 5 7 - H); 6.30 (IH, d; 0 „11 Hz,

6 - or 7 - H). Mass spectrum: 416 (M), 398, 380, 269, 251, 134. Mass spectrum with high resolution: Found: 416.33096 CJT Nd S. Found: 60 416.32927

Example 4. U, Sp, 24-triacetoxycholest-5, 7-diene.

200 mg M, 3 | J, 3f, 24-trioxycholast-5, 7-diene are used for proA5 I reaction with 2 ml of acetic anhydride and 5 ml of pyridine at a temperature of 95 ° C for 3 hours. The reaction mixture is further placed in a mixture of ice water and extracted with 40 ml of diethyl ether. The ether phase is washed with dilute hydrochloric acid, then with alkali and again with water, after which it is dried. “The sulfuric ether is evaporated, Id, 3, 24-triacetoxycholeste 5, 7-diene is obtained as a yellowish oily product,

B) 1c, 24-diacetoxycholecalciferol-3-acetate.

50 mg of D, 24-diacetoxycholecalciferol-3 3-acetate is dissolved in 500 ml of diethyl ether. The prepared solution is subjected to UV light in an argon atmosphere for 4 min.

A portion of this solution is separated and its UV spectrum is determined.

Absorption in the range of 262 to 263 nm indicates the presence of the starting compound. After completion of the reaction, the sulfuric ether is evaporated under reduced pressure and at room temperature, 100 ml of benzene is added to the residue, and the mixture is heated under reflux for 2 hours under argon atmosphere. After completion of the reaction, most of the benzene is evaporated under reduced pressure, and 2 ml of a 5% solution of potassium hydroxide in methanol, 2 ml of methanol and 2 ml of benzene are added to the residue. The mixture was allowed to stand at room temperature for 1 day to complete the hydrolysis. The reaction product is diluted by extraction and extracted with ethyl acetate. The ethyl acetate phase is washed several times with water and dried. The ethyl acetate is evaporated under reduced pressure to give 35 mg of a slightly yellow oily product.

This product is isolated and purified by chromatography using silica gel, which contains silver nitrate.

5.7 mg of solid product are obtained. This product, obtained after isomerization, is identified as S, 24-diacetoxycholecalciferal-3-acetate,

Example 5, a) lot, 3, 24-tribenzoyl-xycholesta-5, 7-diene,

160 mg of IdL, 3j8, 24-trioxypshapesta-5,7-diene is reacted with 41 bg of benzoyl chloride and 15 ml of pyridine.

The reaction mixture is diluted by extraction and extracted with 40 ml of diethyl ether. The ether phase is washed with dilute hydrochloric acid, then alkali and finally with water, followed by drying,

The sulfuric ester is evaporated to give let, 3, 24-tribenzoyl-xycholesta-5, 7-diene; as a white amorphous product.

B) 24-dibenzoyl-oxycholecaldiferol-3-benzoate.

30 mg, 3j3, 24-tribenzoyl-xycholesta-5, 7-diene is dissolved in 500 ml of benzene and the prepared solution is irradiated with UV rays in an argon atmosphere at 2 minutes. After completion of the reaction, the isomerization reaction is carried out under an argon atmosphere and under refluxing of benzene. After completion of the reaction, most of the benzene is evaporated under reduced pressure and

0 to the residue are added 2 ml of a 5% strength solution of potassium hydroxide in methanol and 2 ml of benzene. The mixture is kept at room temperature for 28 hours in an argon atmosphere,

5 carry out the hydrolysis. The reaction product is then diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed several times with water and dried. Ethyl acetate is evaporated under reduced pressure. The residue was separated and purified to give 1.9 mg of a lot, 24-dioxycholecalciferol, the properties of which are identical to those of the product obtained in Example 4.

A product is obtained which, after carrying out the isomerization reaction. Is identified as Idv, 24-dibenzoyl cholocalciferol-3-benzoate,

0 Example 6. A) ldk-hydroxy-3, 24-dibenzoyl-xycholesta-5,7-diene,

250 mg of Id ,, 3jS, 24-trioxycholesta-5, 7-diene is mixed with 210 mg of benzoyl chloride and 5 ml of pyridine,

5 after which the mixture stands at 23 C one day. Then the mixture is treated, analogously to example 5,. 1L-ca. si-3 ft, 24-dibenzoyl-xycholesta-5,7-diene is obtained.

B) 1 (hydroxy-24-benzoyloxycholecal0 ciferol-3/3-benzoate,

20 mg of 1A-hydroxy-ZD 24-dibenzoyl-xycholesta-5, 7-diene is dissolved in 500 ml of diethyl ether. The solution is irradiated with UV rays, isomerization and hydrolysis are carried out as in Example 5B, 1.9 mg of IK, 24-dioxycholecalciferol is obtained, which is characterized by the same properties as the product obtained by

0 example 4,

The product obtained after the isomerization reaction is 11-oxy-24-benzoylcholecalciferol-3) 5-benzo 1T,

five

Example 7, 1Л. 24 (Yu-diacetoxycholecalciferol-Sp-acetate,

Claims (1)

lek., 3jJ, 24 (R) -trioxycholesta-5,7-diene, is subjected to acetylation as in Example 4B, 1L, 0 3 (R) -thioxypshapesta-5,7-diene is obtained, 2b mg of the product is treated in the same way as Example 4B, irradiated with UV rays for 2 min. Obtain 3.4 mg of the product, the properties of which correspond to the properties of I, 24 (R) -dis9 sulfuric ILLCIFEROL. The product obtained after the isomerization reaction is Ick, 24 (R) -diacetoxycholecalciferal-3 | -acetate. Example 8. S, 24 CH) -Dibenzoyl-oxycholecalciferol-3/3-benzoate. Idkf 3 | 3, 24 (R) -trioxicholesta-5, 7-diene is benzylated as in Example 5A, 1D, 3 p, 24 (R) -ribenoyloxycholesto-5, 7-diene is obtained. The product is treated in the same way as Example 5B, . except that in this case 30 mg of this product is used, and the operation of irradiation with UV rays is carried out at a temperature of 2. min. 3.4 mg of product is obtained, the properties of which correspond to the properties of S, 24 (R) -dioxycholecalciferol. Thus, the product obtained after the isomerization reaction is identified as ip, 24 (K) -dibenzoyl-psycholecalciferol-3 p-benzoate. Example 9. 1c h-hydroxy-24 (R) -be zoyloxycholecalciferol-3-benzoate. loL, ЗЙ, 24 (R) -trioxycholesta-5, 7 -diene is benzylated as described in Example 6A, 1c1h-hydroxy, 1, 24 is obtained (Rdibenzoylxycholestole-5, 7-diene. 10 mg of the product is processed as in Example 6B, 1.2 mg of product is obtained, the properties of which correspond to the properties of L, 24 (R) -diox of cholecalciferol. Thus, the product obtained after the isomerization reaction is 1 o1.-hydroxy-24 (R) -benzoxy hydroxycalciferol-3-d- benzoate Example 10. 1l, 24 (3) -diacetoxycholecalciferol-3 acetate, idv, 3, 24 (S) -trioxycholesta-5, 7 -diene, is subjected to acetyls In the same way as in Example 4A, Id 38, 24 (S) -trioxycholeste-5,7-diene is obtained. 20 mg of the product is processed in the same way as in Example 7 to obtain 3.1 mg of a product, the properties of which correspond to the properties of id, 24 (S Dioxycholecalciferol. After the isomerization reaction, a product is obtained which is 24 (S) -diacetoxycholecalciferol-3-acetate. Example 11. 1t1.-hydroxy-24 (S) -ben zoyloxychol ykicifer6l-, 3 | 3-benzoate. Id., 3, 24 (S) -trioxycholesta-5, -diene, is benzylated similarly to Example OA, as a result of go, 1c-hydroxy-3 8, 24 {3) -diibe zoyloxycholeste-5,7-diene is obtained. 15 mg of the product, orbited, similarly to Example 9, a product is obtained, the properties of which correspond to the properties of l 24 (S) -dioxycholecalciferol. The product obtained after the isomerization reaction is - hydroxy-24 (S) -benzene-psycholecalciferol-3-benzoate, Example 12. 1H-acetoxy-, 24 (S) -benzoyl-psycholecalciferol-3-benzoate, 1L-hydroxy-3 (( 5, 24 (S) -dibenzoyloxyolest-5, 7-diene, obtained by analogy with example 11, is subjected to acylation, get 1 (A.-acetoxy-3 |, 4 (S) -dibenzoyloxycholesta-5,7-diene. 15 mg the product is subjected to processing as in Example 10, it is fired with UV rays at 1 minute, 1.5 mg of the product is obtained, the properties of which correspond to the properties of 1L, 24 (S) -dioxycholecalciferol. Obtained after the isomerization was carried out, it was both M-acetic hydroxy-24 (S) -benzoyloxyolecalciferol-3 8-benzoate. Example 13. Idk, 24-dioxyolecalciferol 10 mg mixture Id., 3, 2,4-trioxycholestane 5, 7-diene with 1 (X, 3 p, 24-trioxycholesta-4, 6-diene in a molar ratio of 3: 1, dissolved in 500 mp diethyl ether, after which the solution is irradiated with VO-rays at 5 C 2 min After completion of the reaction, the diethyl ether is carefully evaporated under reduced pressure. 50 ml of benzene was added to the residue and heated under reflux for 2 hours under argon H. After completion of the reaction, the benzene is evaporated, and 10 mg of a brown oily product are obtained. Get the UV spectrum of the product. The absorption band at 265 nm, characteristic of a lot, 24-dioxycholecalciferol, is absent. Comparison of the reaction product with the sample CL, 24-deoxycholecalciferol by thin layer chromatography on silica gel indicates the absence of Id, 24-deoxycholecalciferol. Thus, in the case when the degree of purity of Idv, WZ, 24-trioxycholesta-5, 7-diene is low, during the isomerization reaction using UV irradiation 14, 3, 24-trioxycholecalciferol is not formed at all. Example 14., 24-diacetoxycholic alciferol-3-acetate. 10 mg of a mixture which contains 3, 24-triacetoxycholesta-5,7-diene and C, 3j8, 24-triacetoxy-4, b-diene in a molar ratio of 3: 1, is dissolved in 500 ml of diethyl ether and the solution is subjected UV irradiation at 5 ° C for 2 min. the color of the reaction mixture becomes yellowish brown. After completion of the reaction, diethyl ether was carefully evaporated under reduced pressure. 50 ml of benzene is added to the residue and the mixture is heated under reflux for 2 hours under argon atmosphere and the reaction HsoiviepHsaib.H is carried out. After completion of the reaction, most of the benzene is evaporated under reduced pressure. To the residue is added 1 ml of a 5% strength solution of potassium hydroxide in methanol, and the mixture is left to stand at room temperature for 24 hours under argon to conduct the hydrolysis. After completion of the reaction, the benzene is evaporated. Example 15, 60 mg of 1A, 3j3, 24 (R) -triacetoxycholesta-5,7-diene is dissolved in 500 ml of distillate ether. The resulting solution is subjected to UV irradiation in an argon atmosphere at 5 ° C for 5 minutes, after completion of the reaction, the ether is evaporated at room temperature and reduced pressure, 150 ml of benzene is added to the residue and isomerization is carried out for 2 hours, in argon atmosphere at a temperature reflux bin ash. After completion of the reaction, benzene is evaporated under reduced pressure, and 20 ml of dry diethyl ether and 50 mg of LiASHx are added to the residue. The reaction mixture was stirred for 2 hours at the temperature of refluxing of diethyl ether until it was reduced. The reaction product is diluted (with diethyl ether, saturated with water, and extracted. The ether phase is sequentially washed with water and dried over NajSO4. The diethyl ether is evaporated. Under reduced pressure, 38 mg of a light yellow oily product are formed. The product is isolated, purified using thin-layer chromatography using silica gel containing silver nitrate as a carrier. The spectra and other characteristics of this product fully correspond to Ids, 24 (R) - deoxycholecalciferol. Similarly, from let. , 24 (S) -triacetoxycholeste-5,7-diene get IdL, 24 (S) -dioxycholecuciferol. Claim 1 /, Method of preparing la, 24 (S) -dioxycholecalciferol or Idk, 24 (R) -dioxychopecalferol or their derivative (to the general formula where R, Rj, Rj are the same or different, hydrogen or a protecting group that represents an aliphatic or aromatic carboxylic acid residue, such as acetyl or benzoyl, characterized in that i., Sp, 24 (S) -trigidroxycholeste-5, 7-diene or lo, 3, 24 (R) -trigidroxycholesta-5, 7-diene or their derivatives of the general formula where R, Rj and Rj have t vyieukazannye value is subjected to ultraviolet radiation in the wavelength region of 200-600 N in an inert organic solvent with post-. following isomerizing of the obtained product, which either isolates or, if necessary, conducts an alkaline hydrolysis in an alcohol medium or a reductive decomposition with lithium aluminum hydride in an inert organic solvent 2. A method according to claim 1, characterized in that ultraviolet radiation is used in the region of 260-310 n /. Priority on the grounds 09,12,74 when R-1, Rj. Rj is hydrogen; 27,12.74 with R, R ,, Rj - acetyl, yenzoyl group. Sources of information taken into account in the examination 1. Hess A. F. Weinstock M.Z. . Bioe, ChemT 64, 181, 193, (1925),