DD268956A1 - PROCESS FOR THE PREPARATION OF CHOLESTEROL DERIVATIVES WITH AN OXYGEN FUNCTION AT C-25 - Google Patents

Abstract

The invention relates to a process for the preparation of cholesterol derivatives having an oxygen function at C-25 of the general formula I in which the rings A / B can have the partial structures a and b and in which R 0 is hydrogen or OR 2 R 1: hydrogen, SiR 3 R 4 R 5 (R 3, R 4 , R 5 alkyl, aryl) R 2: represent the functional groups or acyls indicated under R 1, wherein the steroid molecule may contain additional double bonds. It is characterized in that it is a Grignard reagent of the general formula VIII in the X: Cl, Br, IR8: R1, Mg X, with the solution of a steroid of the general formula II, in which the rings A / B have the partial structures a and b and in which R 6 is Br, I or OSO 2 R 7 (R 7 is alkyl, aryl, alkylaryl), can react in a solvent in the presence of a Cu (I) or Cu (II) salt or one of its complexes with lithium salts.

Description

22-Hyriroxygruppe two steps, in turn, as a by-product of the order of 10% in turn 22,23-unsaturated steroid is obtained. All of the processes mentioned above, which lead to 22,23-unsaturated steroids, have in common that the removal of this double bond in the presence of further easily hydrogenatable double bonds in the basic radical. is selectively carried out only with special reagents.

There are no known methods which allow the conversion of compounds of formulas III to VII in compounds of the general formula I in one step.

Object of the invention

The aim of the invention is to produce cholesterol derivatives with an oxygen function at C-25 of the general formula I economically favorable from readily available steroids.

Explanation of the essence of the invention

The invention has for its object to develop a technically easy to implement and economically favorable method that allows, starting from readily available steroids of general formula II, cholesterol derivatives with an oxygen function at C-25 produce.

It has been found that cholesterol derivatives having an oxygen function at C-25 of the general formula I in which the rings A / B may have the partial structures a and b and in which

R ⁰ : hydrogen or OR ²

R ¹ : hydrogen, alkyl, tetrahydropyranyl, alkoxyalkyl, SiR ³ R ⁴ R ⁶ (R ³ , R ⁴ , R ⁶ = alkyl, aryl) t> R ² : the functional groups indicated under R ¹ or acyl

represent, wherein the steroid molecule may contain additional double bonds in the 7-position and for R ° = H in the 1-position, be prepared by a Grignard reagent of the general formula VIII in the

X: Cl, Br, IR ⁸ : R ¹ , Mg X

, at low temperatures to room temperature with the solution of a steroid of the general forms! II, in which the rings A / B may have the partial structures a and b and in denan

R *: Br, I or OSO ₂ R ⁷ (R ⁷ = alkyl. Aryl, alkylaryl)

is, in tetrahydrofuran, tetrahydrofuran / Diethyl ether or other organic solvents in the presence of a Cu (I) - oaer Cu (II) salt or one of their complexes with lithium salts, such as lithium bromide or lithium chloride. lets react. Preferably, Grignard reagents of general formula VIII is used in THF with X = Br or Cl and R = Si _(CH3 J ₃ Suitable copper catalysts are Cu (I) ^-. And Cu (II) salts, and complexes thereof with Li-salts, in particular dilithium tetrachlorocuprate, Li ₂ CuCl ₄ , which are used in proportions of 1 to 10 mol%, based on the Grignard reagent The Grignard reagent is used in excess, based on the steroid of the general formula II ° C at room temperature, preferably at -1O ⁰ C to room temperature is performed. the following example illustrates the invention. without the process in any way limiting.

embodiment Sweet-tert-butyldimethylsilyloxy ^ S-trimethylsilyloxy-cholesta-I.S-diene: In a dry apparatus, under argon pressure 38 ml, one of 650 mg of Mg, 37 ml of dry THF and 3.11 g of 2-methyl-2-one is added.

trimethylsilyloxy-4-chlorobutane freshly prepared. Grignard solution and cooled to ⁰ ° C. Then, dropwise with 2 ml of fresh from 48 mg of dry lithium chloride, 77.6 mg of dry copper (II) chloride and 5.6 ml of THFzLbareiteten

Dilithiumtetrachlorocupratlösung added. After 10 minutes, a solution of 810 mg of 3β-tert. Butyl-dimethylsilyloxy-22-tosyloxy-23,24-bisnorchola-1,5-diene in 11 ml of THF, stirred for 2 hours at ^{0 0} C and then allowed to Heat room temperature. The mixture is allowed to stand overnight, filtered, with sat. NH ₄ Cl solution to about 240 ml

filled; after phase separation, secondary extraction of the aqueous phase with benzene, washing with neutral, drying with Na ₂ SO ₄ ,

Filtration and concentration on a vacuum rotary evaporator gives a slightly yellowish crystalline substance. The residue

is mixed with 15 ml of acetone and the suspension concentrated to a thick crystal pulp. It is then suctioned off cold, washed with a little cold acetone and 740 mg of Sß-tert-butyldimethylsilyloxy ^ S-trimethylsilyloxy-chole.Ma-I.S-dien (white, leaves-shaped crystals).

Mp 142 to i44 ^e C, | a) g ° (c = 1, CHCl ₃ ) + 25.5 °, NMR (100MHz, COCl ₃ ): 0.69 ppm (s, 3H-18H), 0.91 (s, 9H-tert.C ₄ H ₉ ), 1.08 (s, 3H-19-H), 1, 20 (s, 6H-26 and 27H), 4.21 (m, 1H-3a-H),

5.36 (m, 1 H-6-K), 5.58 (q, 2 H-AB-TeM 1, and 2-H).

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Claims (4)

1. A process for the preparation of cholesterol derivatives having an oxygen function at C-25 of the general formula I in which the rings A / B may have the partial structures a and b and in which R ⁰ : hydrogen or OR ² R ¹ : hydrogen, alkyl, tetrahydropyranyl, alkoxyalkyl, SiR ³ R ⁴ R ⁵ IR ³ , R ⁴ , R ⁵ = alkyl, aryl) R ² : the functional groups indicated under R ¹ or acyl in which the steroid molecule can contain additional double bonds in the 7-position and for R ⁰ = H also in the 1-position, characterized in that a Grignard reagent of the general formula VIII already containing the later 25-oxygen function, in which X: Cl, Br, I
R ⁸ : R ¹ , Mg X represent, at low temperatures to room temperature with the solution of a steroid of the general formula II, in which the rings A / B may have the partial structures a and b and in which R ^e : Br, I or OSO ₂ R ⁷ (R ⁷ = alkyl, aryl, alkylaryl) is, in tetrahydrofuran, tetrahydrofuran / diethyl ether or other organic solvents in the presence of a Cu (I) or Cu (II) salt or one of its complexes with lithium salts, such as lithium bromide or lithium chloride, react. 2. The method according to claim 1, characterized in that is preferably used as Grignard reagent, the compounds Viii with R ⁸ = SiMe ₃ and X = Br or Cl. 3. The method according to claim 1 and 2, characterized in that one carries out the reaction preferably at -10 ⁰ C to room temperature. 4. The method according to claim 1 to 3, characterized in that Cu (I) halides or Dilithiumtetrachlorocuprat (Li ₂ CuCl ₄ ) is used as the copper salt. For this 2 pages formulas Field of application of the invention The invention relates to a process for the preparation of cholesterol derivatives having an oxygen function at C-25 of the general formula I (formula scheme) in which R ° is hydrogen or OR ² , R ^{1 is} hydrogen, alkyl, tetrahydropyranyl, alkoxyalkyl or SiR ³ R ⁴ R ⁵ ( R ³ , R ⁴ , R ⁶ = alkyl, aryl), R ^{2 represents} the functional groups or acyl indicated under R ¹ and the steroid backbone additional double bonds In 7-position and for R ⁰ = H may also contain in the 1-position. The compounds of the general formula I are important intermediates for the preparation of 2S-hydroxycho-ecalciferol and its derivatives, which for some time have been of particular interest to the pharmaceutical industry. Characteristic of the known technical solution Methods are described which include the construction of steroid side chains which are similar to those of the compounds of general formula I, by adding a C ₆ unit to steroids of formulas III to VII. As further synthesized steps describe those described in general formula I. Side chains can be obtained, these methods should be mentioned in the description of the state of the art. Thus, the compounds III and IV (R * = OSOaC (H ₄ CH ₃ ) are reacted with a halogen-free lithium acetylide under relatively drastic conditions to III A or IVA, the triple bonds in an additional, not completely uniform hydrogenation step must be removed In another variant, the same substances are transfused with the lithium salt of sulfone IX to give the desired side chain structure, and the phenylsulfonyl group has to be reductively removed with sodium amalgam in a second synthesis step (Helvetica Chim 57 [1974] 764.65 [1982] 1499). another method involves the reaction of III (R ³ = I) by Wittig product III B, the 22,23-double bond must be removed by a hydrogenation step (Helvetica Chim. Acta 64 (19C1] Λ! 5). The desired cholesterol side chain with oxygen function at C-25 can also be prepared from aldehydes by Wittig. (Formulas V, Vl, VII) or ürignardreaktion (formula V) can be obtained with suitable C _{6 building} blocks (Helvetica Chim. Acta 65 [1982] 1499, 64 [1981] 915, Ger. Offen. 2,601,523.2730529). While the 22,23-double bond formed in the Wittig reactions can be removed by hydrogenation in one step, the elimination of the resulting in the Grignard reactions