CS270300B1 - The process for the production of 20 (.beta.-X-dihydroxy-5 -sterold derivatives) - Google Patents

Abstract

The solution concerns the preparation of 2<X, 3o<-dihydroxy-5oC-ateroids from 2,3-unsaturated 5<x-etherodis; while eliminating the need to use toxic and expensive 0s04, which was previously necessary for the preparation of substances of this type. One is a substance having versatile use in the chemistry of etheroids, especially as analogues of bra88steroids, usable as plant growth regulators. The starting etheroid 2,3-olafin 1 is converted by the action of peracid into 2ος, 3<X.-epoxide II, which by the action of hydroiodic acid provides 2ω- -Iodo-3<X-hydroxyderivative III. This is acylated by reaction with peracid and replaces the iodine atom with a 2o<-hydroxyl group. Saponification provides the desired 2o<, 3<x-dlhydroxy-5oc-8teroid VI. The procedure does not require purification of intermediates and provides yields higher than or comparable to the method using 0s04.

Description

The invention relates to a process for the production of 20ζ, 3<X-dihydroxy-5<X-etherold derivatives of the general formula VI

(VI)/ where X is O or 2 H and R is H, or alkyl with 2 to 10 carbons, from 2,3-unsaturated 5<X-etheroid compounds.

These substances have many uses in steroid chemistry, as plant growth regulators (brassinoetsroids and their analogues) or as intermediates for their preparation. For example, substance XIII has significant growth activity (Kohout L., Vslgová H., Strnad M.; Kamínek M.: Coll. Czech. Chern. Commun. 52, 476 (1987)).

The 20(,3CX-diol group is a characteristic feature of brasslnosterols and is essential for their effect as growth regulators. The practically applicable introduction of this group has so far been limited to the addition of osmium tetroxide to 2^3-unsaturated 5 o<-asteroids (Kohou L. Chem. Listy 78, 1129 (1984). The starting unsaturated compounds are readily available, but the use of osmium tetroxide has fundamental disadvantages: the reagent is very expensive and extremely toxic. It is therefore unsuitable, especially for use on a technical scale. In contrast, the process according to the invention makes it possible to avoid this reagent while maintaining completely comparable yields.

The above-mentioned shortcomings are eliminated by the method of producing 2οζ, 3o<-dihydroxy-5o<etheroids according to the invention, the essence of which is that on 2,3-unsaturated 5(X-steroids of formula I

where R and X have the above meanings, is treated with a peroxyacid to form a 2of, 3<χepoxide of formula II

wherein R and X have the meanings given above;

from which cleavage of the oxirane ring with hydroiodic acid yields a dlaxial

Iodohydrin of formula III

where R and X have the above meaning, which is acylated and the resulting acyl derivative of formula IV

CS 270 300 Bl

kds acyl contains 1 to 10 carbons and where R and X have the meanings given above, is subjected to the action of a peroxyacid and the resulting compound of formula V

where acyl, R and X have the meanings given above, is hydrolyzed and the resulting product of formula VI is isolated. As peroxyacid, 3-chloroperbenzoic, perphthalic or perbenzoic acid is used.

The individual steps in this scheme are reactions known per se, but combined in such a way as to achieve the desired goal, i.e. the conversion of 2,3-olefins of formula I to 2,3-dihydroxy-5-hydroxy-sterols of formula VI; using OsO^. This is achieved by choosing highly stereoselective reactions, which makes it possible to work without purifying individual intermediates and thus eliminate losses that would inevitably occur during purification; purification is limited to the final product only. The course of the reactions can be easily monitored by thin layer chromatography. The individual reactions proceed rapidly, so that the process from the starting material of formula I to the crude final product of formula VI can be carried out within 2 to 3 days.

The first step of this sequence is the preparation of the 2,3- _olefin I from the corresponding 2,3-olefin I using a suitable peroxyacid; preferably 3-chloroperbenzoic acid. It is known that this reaction proceeds practically exclusively with the formation of the 2,3-epoxide (Furst A., Plattner PÍ. A.: Helv. Chim. Acta 32 275 (1949). Cleavage of the oxirane ring in the following step with hydroiodic acid is a rapid and stereoselective reaction yielding the diaxial iodohydrin III (Berton □. HR, King FF; 3. Chem. Soc. 1958. 4398). This substance is acylated by one of the known acylation methods, and preferably with acetic anhydride in pyridine at room temperature. The resulting acyl derivative IV is subjected to the action of a peroxyacid, e.g. 3-chloroperbenzoic acid, which is again a highly stereoselective reaction which leads to the replacement of the iodine atom by a hydroxyl group of the opposite configuration (Cambie RC et al.; Chem. Commun 1978, 919). Conversion of the acyloxy group of the resulting monoester of formula V to hydroxyl by a suitable method (preferably alkaline hydrolysis) provides the desired diol of formula VI, which is purified by a suitable method; preferably chromatography. The yields are comparable to those obtained by the catalytic saponification method.

Instead of peroxyacid, it is possible to subject the iodo derivative IV to the reaction of an organic acid salt, e.g. with manganese acetate, potassium acetate, etc., whereby the iodine atom is replaced by an acyloxy group of the opposite configuration. In this case, a ester is formed, which is saponified in the next step to the desired diol VI.

Since this is a general method for preparing various substances including substituents such as 2οζ, 3οζdihydroxy-5οζ-steroid derivatives, this method can also be used for other starting compounds of this type, substituted in other positions both in the basic skeleton and in the side chain R (R is e.g. -COOCH^, or -CH(OC0CH ₃ )CH ₃ ).

Example 1 '

5o<-Choleethane-2C<, 3 of-diol (formula X) 5pC-Cholest-2,3-ane (formula VII; 1 g) is dissolved in benzene (to 40 ml), 82% 3-chloropyrbenzoic acid (900 mg) is added and left to stand at room temperature. The course of the reaction is monitored by thin-layer chromatography. When the starting material is absent (after about 3 h), the solution is washed with aqueous NaOH solution (1%), Na ₂ ^SO ₃ and water. After drying, the solvent was evaporated in vacuo, the residue was dissolved in chloroform (30 ml) and shaken with hydroiodic acid (57%, stabilized with H ₃ P0 ₂ for 4 minutes. The solution was then washed with water, Na ₂ S0 ₃ , NaHCO- and water, dried with Na ₂ S0 ₄ and the solvent was evaporated in vacuo at a maximum temperature of t-c30 °C. The residue was immediately acetylated in pyridine (10 ml) with acetic anhydride (5 ml) at room temperature overnight. The mixture was poured onto ice, taken up in ether, washed with water, aqueous HCl (5%). NaHCO^ and water, dried with Na ₂ S0^ and evaporated under reduced pressure (t<30 °C). The residue was dissolved in CH _{2 C} C1 ₂ (50 ml) and 3-chloroperbenzoic acid (800 mg) was added. The progress of the reaction was monitored by chromatography on thin layer} requires 3 to 5 h. Then the solution is washed with water, Na ₂ S0 ₃ , NaOH (3%),- water, Na ₂ S0 ₄ is evaporated and the solvent is evaporated in vacuo. The residue is dissolved in methanol (100 ml) and a solution of KOH (2 g) in water (3.5 ml) is added. After stirring overnight, the mixture is concentrated to a small volume, water is added and the product is taken up in ether. The crude product is chromatographed on a silica gel column in benzene, then benzene-ether (1:1). Crystallization from methanol gives 5 X-cholestane-2 <X, 3 o-diol (formula XI, 626 mg,' m.p. 210-215 °C, [<X^+31°). Literature (Henbest H. 8., Smith M. □. Cham. Soc. 1957» 926) gives mp 212 - 214°C, [x]q+32°.

Example 2 oe, 3°<-dihydroxy-5<X-choletan-6-one (formula XI) <£-Choleat-2,3-en-6-one (formula VIII, 1.04 g) It is subjected to the same procedure as in Example 1 e, using perbenzoic acid instead of 3-chloroperbenzoic acid e. The crude product is chromatographed on a silica gel column, with benzene-ether (9:1) eluting a fraction (700 mg, 62%) of satisfactory purity: mp 205-207 °C, f<K] ₀ +7°. Crystallization from methanol gives the product (628 mg, -56%) mp 206-209 °C, [o(]q+7 ⁰ . Literature (Thompson M. et al.: Steroids 39, 89 (1982)) reports 206-209 °C, [o<] ₀ +7 ⁰ .

Example 3

2K,3<X-Oihydroxy-5°<-androstan-6-one (formula XII) 5<K-Androat-2,3-en-6-one (formula X, 735 mg) was subjected to the same procedure as in Example 1. The crude product was chromatographed on silica gel using a benzene-ether mixture (30, 40 and 50%, respectively). The fraction thus obtained (540 mg) was crystallized from methanol to give the pure diol (442 mg, 54%) mp 157-158 °C, [<x] _D -2O ⁰ .

Example 4

5<X-Cholaatan-2<X; 3<X-diol (formula X)

The procedure is the same as in Example 1, but the acetoxy derivative (obtained by acetylation of iodohydrin) is subjected to the action of copper acetate (396 mg) in boiling 96% acetic acid (60 ml) for 1 hour. After cooling, the inorganic material is separated by filtration, washed with acetic acid, the filtrate is poured onto ice, the precipitated substance is collected, dissolved in ether, the solution is washed with KHCO ₃ , H ₂ 0; dried over MgSO 4 and evaporated. The residue is dissolved in benzene (60 ml), 10% methanolic KOH (60 ml) is added and boiled for 3 hours. Then it is concentrated to a small volume, 60 ml of methanol is added again, concentrated, poured onto ice and filtered with suction. After recrystallization from methanol: 680 mg of 5<K-cholestane-2CK, 3<X-diol, mp 210-215°C.

Furthermore, 2 drawings (Fig. 1, Fig. 2) with chemical formulas, which are given in the description of the invention, are attached.

Claims (2)

P 8 E 0 Μ £ T OF THE INVENTION 1. Process for the production of 2o<,3<X-dihydroxy-5oC-steroid derivatives of general formula VI where X is O or X is 2H R is H; or alkyl with 2 to 5 carbons -steroid of formula I 10 characterized by being 2,3-unsatd wherein R and X have the meanings given above; is treated with peroxyacid to form 2 οζ, 3<X epoxide of formula II where R and X have the above meaning, from which cleavage of the oxirane ring with hydroiodic acid gives the diaxial iodohydrin of formula III where R and X have the above-mentioned valence; which is acylated and the resulting acyl derivative of formula IV where acyl contains 1 to 10 carbons and R and X have the meanings given above; ee is subjected to the action of peroxyacid and the resulting compound of formula V / CS 270 300 Bl wherein R and X and acyl are as defined above; The product is hydrolyzed and the resulting product of formula VI is isolated. 2. The method according to item 1, characterized in that 3-chloroperbenzoic, perphthalic or perbenzoic acid is used as the peroxy acid.