DD251141A1 - PROCESS FOR PREPARING DERIVATIVES OF 3-BETA-ACYLOXY-22,25-DIHYDROXY-DELTA HIGH 1-CHOLESTEROL - Google Patents

Abstract

The invention aims to provide derivatives of the 3b-acyloxy-22,25-dihydroxy-D-1-cholesterol of the general formula I in which R1 represents hydrogen or Si R2R3R4 (R2, R3, R4alkyl, aryl) R6: alkylcarbonyl or arylcarbonyl, in an economically favorable manner manufacture. The title compounds are intermediates for key drugs such as ecdysone and 25-hydroxy-cholecalciferol derivatives. The essence of the invention is based on that a Grignard reagent of the general formula V with XCl, Br, J and R5Si R2R3R4 or Li or Mg Y (YCl, Br, J) is reacted under such mild conditions with steroidaldehydes of the general formula II, that 3-acyloxy group is retained.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for preparing derivatives of the 3β-acyloxy-22,25-dihydroxy-A ¹ -cholesterol of the general formula I in which R ^{1 is} hydrogen or SiR ² R ³ R ⁴ (R ² , R ³ , R ⁴ = Alkyl, aryl) and R _{6 represents} alkylcarbonyl or arylcarbonyl.

Compounds of general formula I are important intermediates for the preparation of ecdysone and 25-hydroxycholecalciferol derivatives.

Characteristic of the known technical solution

Compounds of general formula I are new. The literature (J. Med. Chem. 28 [1985] 194) discloses the reaction of the aldehyde III, in which the 3/3-acetoxy group is not allylated and thus less reactive, with S-methyl-S-trimethylsilyloxy-butylmagnesium chloride , Since the 3/3-acetoxy reacts, the reaction product is triol IV.

Object of the invention

The aim of the invention is to produce derivatives of 3 _/ 8-acyloxy-22,25-dihydroxy-A ¹ -cholesterol economically favorable to obtain the 3/3-acyloxy function from readily available Steroidaldehyden.

Explanation of the essence of the invention

The invention has for its object to develop a technically easy to implement and economically favorable process, prepared by means of which derivatives of 3ß-acyloxy-22,25-dihydroxy-A ¹ -cholesterol of general formula I from readily available Steroidaldehyden of the general formula II can be.

It has been found that derivatives of the 3/3-acyloxy-22,25-dihydroxy-A ¹ -cholesterol of the general formula I in which R ^{6 is} alkylcarbonyl or arylcarbonyl and R ^{1 is} hydrogen or SiR ² R ³ R ⁴ (R ² , R ³ , R ⁴ = alkyl, aryl) can be prepared by reacting a Grignard reagent of the general formula V in which X is chlorine, bromine or iodine and R ⁵ MgY (Y = chlorine, bromine or iodine), lithium or SiR ² R ³ R ⁴ , in aprotic solvents at temperatures from -3O ⁰ C to room temperature with a steroid aldehyde of the general formula II in which R ^{6 has} the abovementioned meaning, react and the excess of Grignard reagent after the reaction under neutralization destroyed.

Preferred aprotic solvents are THF or mixtures of THF and diethyl ether. Preferably, Grignard reagents of general formula V where X = Cl and R ⁵ are MgY (Y = chlorine, bromine or iodine) or R ⁶ = Si (CH ₃ I used = ₃ in THF and temperatures of -20 to 0 ⁰ C. The Grignard Reagent is used in excess, based on the steroid of general formula II The reaction to the compound of general formula I is completed after a surprisingly short time (10 minutes), the isolation of the product succeeds in good yields.

The following example illustrates the invention without limiting the process in any way.

embodiment

3/3-acetoxy-25-trimethylsilyloxy-1,5-cholestadiene-22-ol

With exclusion of moisture and low pressure of argon, 500 mg (20S) -3j8-acetoxy-1,5-pregnadiene-20-carbaldehyde are dissolved in 14 ml of THF and cooled to -5 ° C. 12.8 ml of a Grignard solution prepared from 255 mg of magnesium turnings, 16 ml of THF and 1.33 g of S-methyl-S-trimethylsilyloxy-butyl chloride are added dropwise to the stirred solution in 5 minutes. The reaction mixture is mixed with 50 ml of saturated ammonium chloride solution, the phases are separated, the aqueous phase is extracted with a total of 150 ml of benzene, washed with ammonium chloride solution and water, dried over sodium sulfate, filtered, evaporated on a vacuum rotary evaporator and largely separated from volatile aliphatic residues at the oil pump , The crystalline residue is recrystallized from hexane. This gives 556 mg of 3 / S-acetoxy-25-trimethylsilyloxy-1,5-cholestadien-22-ol; F .: 139 to 142 ° C; [a] § ° (c = 1, CHCL ₃ ) + 12 °;

NMR (CDCl ₃ , 10OMhz): 0.12 (9H, s, Si (CH ₃ ) ₃ ), 0.71 (3H, s, 18-H), 0.92 (3H, d, J = 6.5Hz , 21-H), 1.10 (3H, s, 19-H), 1.24 (6H, s, 26- and 27-H), 2.06 (3H, s, CH ₃ CO), 3, 63 (1H, m, 22H), 5.25 (1H, m, 3aH), 5.43 (1H, m, 6H), 5.66 (2H, q, AB). Part, 1- and 2-H).

-Ι Ή

Claims (4)

1. A process for the preparation of derivatives of 3/3-acyloxy-22,25-dihydroxy-Ä ¹ -cholesterol of general formula I, in which R ¹ : hydrogen or SiR ² R ³ R ⁴ (R ² , R ³ , R ⁴ = alkyl, aryl) R ⁶ : alkylcarbonyl or arylcarbonyl represent, characterized in that a Grignard reagent of the general formula V, in X: Cl, Br, J R ⁵ : Mg Y (Y = Cl, Br, J), Li or Si R ² R ³ R ⁴ mean in aprotic organic solvents at temperatures of -30 ° C to room temperature with a steroid aldehyde of general formula II, in the R ^6, the above Has meaning, can react and destroy the excess of Grignard compound after the reaction under neutralization. 2. The method according to claim 1, characterized in that is preferably used as the aprotic solvent THF or mixtures of THF and diethyl ether. 3. The method according to claim 1 and 2, characterized in that is preferably used as Grignard reagent, the compound V with X = Cl and R ⁵ = Mg Y (Y = Cl, Br, J) or Si (CH ₃ ) ₃ . 4. Process according to claims 1 to 3, characterized in that one carries out the reaction preferably at -20 ° C to O ⁰ C.