DD288608A5 - PROCESS FOR PREPARING 3 BETA-ADAMANTOYLOXY-25-HYDROXY-CHOLESTA-1,5-DIEN-7-ON - Google Patents

Abstract

The invention relates to a novel process for the preparation of the compound according to the invention which serves as a valuable intermediate in the synthesis of steroidal agents with calcium metabolism-regulating properties, in particular for the synthesis of 1a, 25-dihydroxycholecalciferol, or finds its application itself. The starting material used is both * and *. * is reacted in a boiling organic solvent with an organic base and adamantoyl chloride to 3-adamantoate and then allyloxidiert in 7-position. * is converted to the 3-adamantoate in an organic solvent with an organic base and adamantoyl chloride. {* * * Acylation adamantoyl chloride; Base, organic; Organic solvents; Chromium-VI-oxide; dimethylpyrazole; Oxidation}

Description

Field of application of the invention

The invention relates to a process for the preparation of Sß-Adamantoyloxy ^ ö-hydroxy-cholesta-I.S-dien ^ -one, a hitherto unknown compound. The compound of the invention serves as a valuable intermediate for the synthesis of steroid drugs with calcium metabolism-regulating properties, in particular for the synthesis of 1 a, 25-Dihydroxycholecalciferol, or finds itself as the active ingredient application.

Characteristic of the known state of the art The compound prepared according to the invention is new; Ways of making them are therefore unknown. But it is known that

starting from steroid cardenolides, the discussing 3β-adamantoyloxy compounds of digitoxigenin,

Oleandrigonins and Gitoxigenins as well as the 3ß-16ß bisadamantoat of Giloxigenins can produce. The presentation takes place

by heating a benzene cardenolide solution with an excess of adamantoyl chloride in the presence of pyridine for several hours. (H.Just, G.Baumgarten, R. Reissbrodt in Pharmacy 28 (5), 336, 1973).

Other adamantane compounds of steroids are described in the literature. (Eli LiIIi &CO; by Richard T. Rapala, BE-PS 666469 Jan. 6.1966 in CA 65.1966, P 5507a; Glaxo Laboratories Ltd .; by Gardon H. Phillips and Alan F. English, Ger.Offen.2232827inCA78,1973, P97893q; Glaxo Laboratories Ltd .; by Gordon H. Phillips, Alan F. English and Gillan H. Strigley in CA81, 1974, 120869j; Glaxo Graup Ltd. Japan, Kokai 7494.658 in CA 84.1976.165123q). Object of the invention

The aim of the invention is to develop a simple way to synthesize a 3β-substituted new adamantoyl derivative starting from readily available unsaturated and hydroxylated cholestane bonds.

Explanation of the essence of the invention The invention is based on the object in order to obtain from the relatively. 3 unobvious, 25-dihydroxy-cholesta-1,5-diene or

3β, 25-dihydroxy-cholesta-1,5-dien-7-one to give 3β-adamantoyloxy-2 '> hydroxy-cholesta-1,5-dien-7-one.

According to the invention, 3β-adamantoyloxy-25-hydroxy-1-estonia-1-diene-7-ol is prepared by reacting 3β, 25-dihydroxy-

cnOlesta-1,5-diene in an organic solvent at room temperature with an organic base and adamantoyl chloride and then allowed to react at 60 to 120 ⁰ C with stirring for 8 to 12 hours. After / udständiger implementation of the

Precipitated in ice water, filtered off with suction and recrystallized from an organic solvent. Subsequently, will

the isolated 3β-At'amantoyloxy-25-hydroxy-cholesta-1,5-diene according to a known process with chromium VI oxide /

Dimethylpyrazole in chloroform / methylene chloride in the 7-position, whereby the 3β-adamantoyloxy-25-hydroxy-cholesta-1,5-

dien-7-one can be isolated in high purity.

According to the invention, 3β-adamantoyloxy-25-hydroxy-cholesta-1,5-dien-7-one is also prepared by replacing instead of

3β, 25-dihydroxy-cholesta-1,5-disn under analogous conditions 3β, 25-dihydroxy-cholesta-1,5-dien-7-one in an organic

Reacting solvent with the addition of an organic base. As organic solvents are preferably chloroform, benzene, toluene, xylenes, pyridine-collidine or mixtures

used of it.

As organic bases, triethylamine, pyridine, dimethylamine pyridine, collidine, diazabicycloactan are preferably used Use. Ausführungsbelsplele example 1

ß-adamantoyloxy-26-hydroxy-cholesta-1,5-dien-7-one from 3 ß ^ S-Dlhydroxy-cholesta-i, 6-diene

a) 3β-adamantoyloxy-25-hydroxy-cholesta-1,5-diene from 3β, 25-dihydroxy-cholesta-1,6-diene

500mg of 3β, 25-dihydroxy-cholosta-1, G-diene (1.25 mmol) in 40 ml of pyridine are placed in a 100 ml four-necked or sulphonated flask equipped with stirrer, thermometer and reflux condenser. At room temperature, 150 mg of dimethylaminopyridine (1.24 mmol) and 1.0 g of adamantoyl chloride (5 mmol) are added. The mixture is then heated slowly while stirring until the solvent begins to boil (115 ^° C.). The course of the reaction is monitored by thin-layer chromatography. After several hours of heating, the reaction is complete and the reaction solution is added to 700 g of ice / 500 ml of water, whereby the product precipitates. It is then filtered off with suction, washed with water until pyridine-free and dried in vacuo. The crude sweetness-adamantoyloxy-S-hydroxy-cholesta-IS-diene is recrystallized from acetone. Mp: 169 to 172 "C NMR (δ, ppm, CDCl ₃ )

0.704 (3 H, s, 18 -CH ₃ ); 0.936 (3H, d, 21-CH ₃₎ (J = 6Hz); 1.11 (3H, s, 19-CH _3); 1.216 (6H, s, _26,27-CH3); 1.74 (6H, s, 3X-CH ₂ - (Ad]); 5.23 (1 H, t, 3a-H), 5.41 (1H, d, 2-H) (J = 10Hz); 5.43 (1H, s, 6-H); 5.35 (1H, d, 1-H) (J = 10Hz)

b) Sweet-adamantoyloxy-S-hydroxy-cholesta-1S-diene from the β-adamantoyloxy-S-hydroxy-cholesta-i.i-diene

In a 250 ml sulfonating flask equipped with stirrer, thermometer and reflux condenser, 3.6 g of chromium oxide (36 mmol) in 100 ml of methylene chloride dried over phosphorus pentoxide are initially charged at room temperature and admixed with 2.8 g of dimethylpyrazole (29 mmol) with stirring. After 15 min, the dark brown complex formed is cooled to -4O ⁰ C. 700 mg (1.25 mmol) of 3β-adamantoyloxy-25-hydroxy-cholesta-1,5-diene in .5 ml of methylene chloride are added dropwise to the complex solution over the course of 15 minutes. Thereafter, it is heated to 4O ⁰ C for 6 hours. After complete reaction (the course of the reaction is monitored by thin-layer chromatography), 18 ml of half-concentrated hydrochloric acid and then 20 ml of sodium bisulfate solution are added, with stirring and ice-cooling, during which the solution turns green. The separated organic phase is washed neutral 6 times with 50 ml of 10% hydrochloric acid and then with water. After drying over sodium sulfate and concentration, the pale green residue is chromatographed over a short column of silica gel (elution with hexane / ethyl acetate 75:25). This gives 373MG (0.65 mmol; Si.eyoJsp-Adamantoyloxy ^ S-hydroxy-cholesta-i.ö-dien ^ -one mp .: 228-229 ⁰ C.

1%

UV: η max 233 nm (ε = 6503) ε '= 113

1 cm

1%

Wdhg: λmax232nm (e = 6750) e '= 117

1 cm

NMR (δ, ppm, CDCl ₃ )

0.709 (3H, s, 18-CH _3); 0.93 (3H, d, 21-CH ₃₎ (J = 6Hz), 1.21 (6H, s, _26,27-CH3); 1.296 (3H , s, 19 -CH ₃ ); 1.718 (6H, s, 3x.CHj- (ad)); 1.91 (6H, s, 3X-CH ₂ - (Ad)); 2.61 (3H, m, -Cfi (Ad)); 5.3 (1H, t, 3a-H); 5.55 (1H, d, 2-H) (J = 10Hz); 5.793 (1H, g, 6-H); 5.84 (1H, d, 1-H) (J = 10Hz)

Example 2 SO-adamantoyloxy ^ B-hydroxy-cholesta-I.B-diene ^ -one from 3β, 25-dihydroxy-cholesta-1,5-dien-7-one In a sulphonation flask with stirrer, thermometer and reflux condenser, 300 mg (0.725 mmol) of 3β, 25-dihydroxy-cholesterol are added.

Dissolved 1,5-dien-7-one in 25ml pyridine and treated with 250mg dimethylaminopyridine (2.0mmol) and 1.0g adamantoyl chloride (5.0mmol). With stirring, slowly heated to 105 to 115 ⁰ C and allowed to react for about 10 hours at this temperature. The

Reaction is monitored by thin-layer chromatography. After complete reaction, the pale yellow solution in Ice water precipitated and sucked off analogously to Example 1, washed, dried and recrystallized. Man isolated Sweet-Adamantoyloxy ^ ö-hydroxy-cholesta-I.S-dien ^ -one.

Mp .: 227 to 23O ⁰ C

Claims (4)

1. A process for the preparation of 3ß-Adamantoyloxy ^ S-hydroxy-cholesta -ie-dien-y-one, characterized in that a solution of 3ß, 25-dihydroxy-cholesta-1,5-diene in an organic solvent at Room temperature with an organic base and adamantoyl chloride and allowed to react for 8 to 12 hours at 60 to 12O ⁰ C and the precipitated in water 3 ß-adamantoyloxy-25-hydroxy-cholesta-i, 5-diene in a conventional manner in 7- Staggered to 3 ß-adamantoyloxy ^ B-hydroxy-cholesta-i ^ -dien-y-on oxidized. 2. The method according to claim 1, characterized in that preferably chloroform, benzene, toluene, xylenes, pyridine, collidines or mixtures thereof are used as the organic solvent. 3. Process according to Claims 1 and 2, characterized in that they are preferably used as organic bases triethylamine, pyridine, dimethylaminopyridine, collidines, diazabicyclooctam or mixtures thereof. 4. Process according to claims 1 to 3, characterized in that a solution of 3ß, 25-dihydroxy-cholesta-1,5-dien-7-one in an organic solvent with an organic base and adamantoyl chloride at 60 to 120 ⁰ C. 8 to 12 hours is reacted.