DD286361A5 - PROCESS FOR PREPARING 3 BETA-SUBSTITUTED (20S) -20-HYDROXYMETHYL-1,5-PREGNADIENES AND THEIR DERIVATIVES - Google Patents

Abstract

The target compounds of general formula I serve as starting material for important active ingredients such as vitamin D derivatives, ecdysone analogs and brassinolides. The essence of the invention is that the readily available 1,5-pregnadienes with 22-acid function of the general formula 2 with chloroformic acid esters with the addition of a basic reagent, preferably a tertiary amine, and subsequent action of complex borohydrides, preferably sodium borohydride, to new Formula I to be implemented. The Alylfunktion in the ring A is retained and in the presence of a 7-Ketogruppierung this is not or only insignificantly attacked under suitable reaction conditions. By acylation or etherification of the 3b-hydroxy and the 20-hydroxymethyl group, corresponding derivatives can be obtained.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of 3β-substituted (2US) -20-hydroxymethyl-1,5-pregnadienes and their derivatives of general formula 1 in which the substituents

R '= H, acyl, slightly .paltbure ketal or acetal group, -SiRl (R ⁶ »alkyl)

R »= R '= H or - 0

R ⁴ = H or radicals such as R ¹ , aryl or alkylsulfonyl

mean.

The compounds are of particular interest to the pharmaceutical industry because of the side chain structure and variation in rings A and B which make important drugs such as vitamin D derivatives, ecdysone analogs and brassinolides accessible.

Characteristics of the known »1 state of the art

The compounds of general formula 1 are new and have not been described in the chemical literature and in patents.

Object of the invention

The aim of the invention is the elaboration of an economically favorable synthesis of new 1,5-pregnadienes of general formula 1 starting from readily available 3β-substituted (20S) -20-carboxy-1,5-pregnadienes.

Explanation of the essence of the invention

The invention is based on the object of providing a technically simple process for the preparation of 3β-substituted (20S) -20-hydroxymethyl-1,5-pregnadienes and derivatives thereof which may contain a 7-keto group, starting from 3β-substituted (20S) -20-carboxy-1,5-pregnadienes.

According to the invention, 3β-substituted (20S) -20-hydroxymethyl-1,5-pregnadienes and their derivatives of general formula 1, in which R '= H, acyl, easily cleavable ketal or acetal groups, -SiRj (R ⁵ = alkyl) ; R ² = R ³ = H or = 0; R ⁴ = H or radicals such as R ¹ or aryl or alkylsulfonyl prepared by (20S) -20-carboxy-1,5-pregnadiene of the general formula 2 (formula scheme) in which R ¹ = H or acyl, readily cleavable ketal or acetal groups or trialkylsilyl; R * = R ¹ = H or = 0, with chloroformates with the addition of a basic reagent, preferably a tertiary amine, and subsequent action of complex borohydrides, preferably sodium borohydride, are reacted.

It was surprisingly found that the alkyl function was not attacked in the ring A, d. H. both free 3-hydroxy groups and 3-derivatives such as ethers and esters may be present. Also, a 7-keto grouping is attacked under suitable reaction conditions using a minimum amount of sodium borohydride or not to an insignificant extent. As a result, according to the invention, the synthesis of the novel 3β-substituted (20S) -20-hydroxymethyl-1,5-pregnadienes is possible. The 3β- and 20-hydroxymethyl groups may, if desired, be acylated and etherified in a conventional manner to give corresponding derivatives.

The synthesis is carried out in a water-miscible inert solvent such as. Tetrahydrofuran by reacting the (20S) -20-carboxy-1,5-pregnadienes with chloroformates, e.g. Ethyl chloroformate with the addition of a basic reagent, preferably a tertiary amine such. As triethylamine or pyridine with subsequent action of complex borohydrides such. For example, sodium borohydride. The work-up is carried out in a suitable manner by addition of water and extraction. The desired compounds are obtained in good yields and in pure form.

embodiments

Example 1

(20S) -20-hydroxymethyl-1,5-pregnadiene-3.beta.-ol

2g (20S) -20-carboxy-1,5-pregnadiene-3β-ol are added in 80 ml of tetrahydrofuran (anhydrous) and cooled to ⁰ ° C with stirring. Subsequently, 0.67 ml of ethyl chloroformate and 0.98 ml of triethylamine are added at 0 ° C. The mixture is allowed to react at ⁰ ° C. for 20 minutes. Thereafter, at 0.degree. C., a solution of 2 g of sodium borohydride in 11.4 ml is added in portions

Water added. The mixture is allowed to react for 2 hours at 0 to +5 ⁰ C. The workup is carried out by adding 100 ml of water

and 2 ml of acetone, extraction with 50 ml of chloroform and two times subsequent extraction with chloroform, the aqueous phase being acidified with dilute hydrochloric acid prior to post-extraction (»pH 2). The combined chloroform phases are with

Washed water until neutral and dried over sodium sulfate. Evaporation of the solvent on a rotary evaporator

1.73g crystalline end product.

Mp .: 177 ⁰ C to 182 ⁰ C

Ia) J ⁰ = ± 0 ° C (ethanol) Recrystallization from methanol gives an analytically pure product.

Mp: 183 ⁰ C to 187 ⁰ C

Example 2

(20S) -20-hydroxymethyl-3.beta.-acetoxy-1,5-pregnadien

2g (20S) -20-carboxy-3β-ac-toxy-1,5-pregnadiene are dissolved in 26 ml of tetrahydrofuran (anhydrous). The temperature is adjusted to ⁰ ° C. and, with stirring, 0.5 ml of ethyl chloroformate and 0.85 ml of triethylamine are added. The mixture is stirred for 20 minutes (O ⁰ C). Then added dropwise at ^{0 0} C to -5 ⁰ C, a solution of 2g sodium borohydride in 20 ml of water within 5 minutes.

The mixture is left for 2 hours at O ⁰ C to +5 ⁰ C to react further. The workup is done by adding 80m. Water, after 16 minutes, the pH with 6N hydrochloric acid to 2 to 2.5

set.

The mixture is concentrated in vacuo until no odor of tetrahydrofuran is more perceptible in the aqueous oily residue. It is then extracted with 70 ml and 4x with 20 ml of chloroform. The combined chloroform phase,) are mixed with water

washed neutral, dried over sodium sulfate and concentrated on a rotary evaporator to the oil. The oil is used several times

Acetone added and concentrated in each case to dryness. The oil is crystallized by addition of 2 ml of acetone and subcooling while rubbing. In portions Adding water: and mutual cooling or mixing to fill up to a volume of about 20ml. After all Lubrication residues are eliminated, is filled with water to about 50ml and vacuumed. The fine precipitate is

repeatedly washed thoroughly with water and pulled dry.

Yield: 2g

Mp: 6O ⁰ C to 70 ⁰ C.

Recrystallization from methanol yields an analytically pure product

M.p .: 104 ^° C. to 107 ^° C.

Ia] J ^0. -9 ⁰ C (c = 1,2; CHCl ₃ )

Example 3

(20S) -20-hydroxymethyl-3.beta.-acetoxy-1,5-pregnadien-7-one

2 g of (20S) -20-carboxy-3β-acetoxy-1,5-pregnadien-7-one are dissolved in 80 ml of tetrahydrofuran (anhydrous) and stirred up

O ⁰ C cooled. Subsequently, 0.5 ml of ethyl chloroformate and 0.72 ml of triethylamine are added at ⁰ ° C. One lets

Stir for 20 minutes (O ⁰ C). Then added dropwise at U ⁰ C, a solution of 0.88 g of sodium borohydride in 4 ml of water and allowed to react for 2 hours at 0 ° C to +5 ⁰ C.

The work-up is carried out by adding 100 ml of water, a little acetone and about 8 ml of hydrochloric acid. The pH should be about 2

be. Then you extract with 70ml and 4x with 20ml chloroform. The combined chloroform phases are with

Washed water until neutral, dried over sodium sulfate and concentrated on a rotary evaporator to the oil. The oil contains as by-product allyl alcohol UO-hydroxymethyl-S, S-acetoxy-S, S-precynadiene (-ol). The cleaning takes place

column chromatography on silica gel (elution with hexane / ethyl acetate 4: 1).

Yield: 1.18g

Mp .: 139.5 ⁰ C to 142.5 ⁰ C.

MS ⁰ -55 ⁰ C (CHCI _3, C = 1)

Example 4 (20S) -20-Acetoxymethyl-3β-acetoxy-1,5-pregnadiene

A. From (20S) -20-hydroxymethyl-1,5-pregnadiene-3β-ol

2g (20S) -20-hydroxymethyl-1,5-pregnadiene-3β-ol are dissolved in 40 mM pyridine and 20 ml acetic anhydride. It is allowed to stand at room temperature overnight. The mixture is stirred into 200 ml of ice water and stirred for 15 minutes at ^{0 0} C on. The precipitated crystals are filtered off, washed with water gewasqhon and sucked dry on the frit. Yield: 2.28g

B. From (20S) -20-hydroxymethyl-3β-acetoxy-1,5-pregnadiene

2,4g (20S) -20-hydroxymethyl-3β-acetoxy-1,5-pregnadiene are dissolved in 24 ml pyridine and 12 ml acetic anhydride. Next v / ieunter A.

Yield: 2.4g

Recrystallization from methanol yields an analytically pure product.

Mp .: 128.5 ⁰ C to 132.5 ⁰ C.

[a] ° °: -8 ° C (c = 1, CHCI ₃ )

Example 5

(20S) -20-ethoxycarbonyloxymethyl-3.beta.-ethoxy-carbonyloxy-1,5-pregnadien

2 g of (20S) -20-hydroxymethyl-1,5-pregnadiene-3β-ol are suspended in 40 ml of Muthylenchlorid and the suspension to - 1O ⁰ C cooled. Add 20 ml of pyridine. 10ml of ethyl chloroformate are then slowly added dropwise at -10 ^0C.

The initially precipitated solid gradually returns to solution. The mixture is stirred at 0 ° C. for a further 2 hours. After that will be

40ml of water added. 60 ml of methylene chloride are added and extracted. The aqueous phase is still 2x with

Methylene chloride nachextraiert. The combined methylene chloride phases are washed with water, then 3x with dilute hydrochloric acid

washed (the aqueous phase of hydrochloric acid wash must last acidic), then washed with the organic phase

Water neutral. It is dried over sodium sulfate and concentrated on a rotary evaporator. This gives a reddish brown

crystalline crude product.

Recrystallization from 20 ml of methanol and 16 ml of ethyl acetate gives a weakly colored product

Yield: 2.6g

Recrystallization again from the same volume of the same solvent mixture gives a colorless,

analytically pure product.

Mp: 140 ⁰ C to 144 ⁰ C

Ia] S ⁰ : +9 ⁰ C (CHCl ₃ , c = 1)

Examples

(2CS) -20-tert-butyldimethylsilyloxymethyl-3β-tert-butyldimethylsilyloxy-1,5-pregnadiene 2g (20S) -20-hydroxymethylM.5-pregnadiene-3β-ol are submerged in 14.5 ml of distilled anhydrous dimethylformamide

Stirring suspended. Thereafter, 3.08 g of imidazole are added, resulting in a clear solution. Then done quickly Add 3.08 g of tert-butyldimethylsilyl chloride. It creates a suspension. It is rinsed with about 2 ml of dimethylformamide

and allowed to stand overnight at room temperature. After dropwise addition of water, the product is filtered off with suction, the product is washed with methanol and dried on the frit.

Yield: 2.12 g

Mp .: 112 ⁰ C to 114.5 ⁰ C

Recrystallization from acetone yields an analytically pure product.

Mp: 118.5 ^o C to 120.5 ° C

[a) J °: +16 ⁰ C (CHCl ₃ , c = 1)

Example 7

(20S) -20-hydroxymethyl-3.beta.-t-butyldimothylsilyloxy-1,5-pregnadien

1.4 g (20S) -20-carboxy-3.beta.-t-butyldimethylsilyloxy-1,5-pregnadiene were dissolved in 28 ml of anhydrous tetrahydrofuran and under argon cooled to -5 ⁰ C. Then, with stirring, 0.37 ml of ethyl chloroformate and 0.59 ml

Triethylamine too. The mixture is allowed to react for 15 minutes at ^{0 0} C and then added dropwise within 5 minutes at -5 ⁰ C to ^{0 0} C a Solution of 1.24g of sodium borohydride in 13ml of water too. After 3 hours Nachroagieren the implementation is complete. The work-up is carried out by pouring into 180 ml of saturated ammonium chloride solution, the pH of the mixture is 6.9. It is extracted with a total of 200 ml of chloroform in several portions, washed with the combined chloroform phases Ammonium chloride solution and then neutral with water, dried over sodium sulfate and concentrated on a rotary evaporator. The crystalline residue is added twice more with acetone and once with η-hexane and in each case the solvent

deducted. The yellowish crystalline residue is dried at room temperature under oil pump vacuum to constant weight. Recrystallization from Acoton gives colorless crystals.

Yield: 1.1g

Mp .: 136 ^° C. to 141 ^° C.

Ia] J ^0: +22 ⁰ C (CHCIj ₁ C = I) Example 8

(20S) -20-p-toluenesulfonyloxymethyl-3β-tert-butyldimethylsilyloxy-1,5-pregnadiene2g (20S) -20-hydroxymethyl-3β-tert-butyldimethylsilyloxy-1,5-pregnadiene are dissolved in 20 ml of pyridine and dissolved in 20 ml of pyridine. Cooled to 5 ° C.

Subsequently, 4 g of p-toluenesulfonyl chloride are added with stirring, which dissolves after a short time. At temperatures around O ⁰ C is

the reaction is complete after approx. 2 hours.

The work-up takes place after 3 hours by adding pieces of ice with stirring and cooling. The resulting Crystal suspension is added in glacial acetic acid; the final volume should be 350 to 400 ml. After 30 minutes, it is filtered off with suction, washed thoroughly with water and dried on the frit.

Yield: 2.48 g

The crude product is purified by filtration of its benzene solution over silica gel (Merck, 0.063-0.2 mm, 23 g). This one dissolves in

20ml benzene and eluted with benzene, the product being in the fraction 30 to 230 ml. This faction will be on

Rotary evaporator concentrated to dryness, treated twice with hexane and the solvent removed again.

Yield: 2.15 g

It is then crystallized by dissolving in 20 ml of hexane in the heat, allowed to cool to room temperature and about 5.5 ml

einengj. After standing for 2 hours at + 1O ⁰ C is filtered off with suction (cooling in acetone / dry ice bath to -3O ⁰ C), washed twice with 3ml of cold hexane and pulled dry.

Yield: 2.05g

M.p .: 117 ^° C. to 119 ^° C.

[atf ⁰ : +17 ⁰ C (CHCI ₃ , C = U ^

Example 9

(20S) -20-p-Toluensulfonyloxymethyl-3.beta.-acetoxv-1,5-pregn3dien

2 g of (20S) -20-hydroxymethyl-3β-acetoxy-1,5-pregnadiene are dissolved in 10 ml of pyridine with stirring and cooled to ⁰ ° C.

Then, 2.1 g of p-Toiuensulfcnylchlorid are added with stirring, which dissolves after a short time. One lets in overnight Room temperature stand. The workup is carried out by adding pieces of ice while stirring and cooling. The crystal suspension is 10 minutes

stirred, then poured onto 200 ml of ice-cream and stirred for a further 30 minutes.

It is then filtered off, washed thoroughly with water and pulled dry on the frit. You get an orange red Crude.

Yield: 2.44g

Recrystallization from methanol / ethyl acetate 1: 1 gives an analytically pure product.

Mp .: 162.5 ° C 165.5 ⁰ C

[a] g °: +9 ⁰ C (CHCl ₃ , c = 1)

Example 10

(20S) -20-hydroxymethyl-3.beta.-ethoxycarbonyloxy-1,5-pregnadien

2g (20S) -20-carboxy-1,5-pregnadiene-3β-ol are dissolved in 70 ml of anhydrous tetrahydrofuran.

In a 350 ml sulfonation bath with stirrer, thermometer and dropping funnel, 2.4 ml of pyridine (anhydrous) with 120 ml Tetrahydrofuran (anhydrous) mixed and cooled to -20 ° C. A solution of 2.8 ml of ethyl chloroformate is added dropwise

in 20 ml of tetrahydrofuran at -2O ⁰ C to -15 ⁰ C to the pyridine solution. To the resulting suspension is added dropwise at -25 ⁰ C to -20 ° C, the solution of (20S) -20-carboxy-1,5-pregnadiene-3ß-ol in tetrahydrofuran. It is stirred for 5 hours, while the

Temperature after 1 hour to ^{0 0} C and then rise to room temperature, and allowed to stand overnight at Raumumperatur. The mixture is cooled to -5 ⁰ C, and a solution of 2 g of sodium borohydride are added with stirring in 12ml water

dropwise at -5 ⁰ C to ⁰ ° C to.

It is allowed to react for 15 minutes (O ⁰ C), 1 ml of acetone and then 200 ml of water. The mixture is acidified with dilute hydrochloric acid (about 6 n). Extract with 150 ml of chloroform and then 2 more times

with 50 ml of chloroform after each. The combined chloroform phases are washed once more with dilute hydrochloric acid (about 2n) and then with water until neutral. The chloroform extract is dried with sodium sulfate and rotary evaporator

concentrated to dull brown oil.

The oil is dissolved in 21 ml of methanol under reflux, it destroys a clear yellow solution. After cooling to -20 ° C takes place Crystallization. The crystals are filtered off, washed with 5 ml of cold methanol and pulled dry on the frit.

Yield: 1.77 g

Mp: 102 ^o C to 104.5 ° C

Recrystallization from methanol yields an analytically pure product.

Fp.:106,5°Cbis108,5°C

IaIi ⁰ : +13 ⁰ C (CHCl ₃ ; c = 1)

-ε-

28636 \

Claims (4)

1. A process for the preparation of the 3β-substituted (20S) -20-hydroxymethyl-1,5-pregnadienes and their derivatives of general formula 1 in which the substituents R ¹ = H, acyl, readily cleavable ketal or acetal group, -SSRU (R ⁵ = alkyl) 2 3 R ⁴ = H or radicals such as R ¹ , aryl or alkylsulfonyl represent, characterized in that 3ß-substituted (20S) -20 * carboxy-1,5-pregnadienes of the general formula 2 in which the substituents R ¹ = H, acyl, easily cleavable ketal or acetal group, -S 1 R 3 (R ⁶ = alkyl) R ² = R ³ = H or = 0, with chloroformates with the addition of a basic reagent, in a water-miscible inert solvent and subsequent action of complex borohydrides, wherein the alkyl function is retained in the ring A and in the presence of a 7-Ketogruppierung this is not or only insignificantly attacked. 2. A process for the preparation of 3ß-substituted (20S) -20-hydroxymethyl-1,5-pregnadienen and derivatives thereof according to claim 1, characterized in that a tertiary amine is preferably used as the basic reagent. 3. A process for the preparation of 3ß-substituted (20S) -20-hydroxymethyl-1,3-pregnadienes and derivatives thereof according to claim 1 to 2, characterized in that is preferably used as the complex borohydride sodium borohydride. 4. A process for the preparation of 3ß-substituted (20S) -20-hydroxymethyl-1,5-pregnadienes and derivatives thereof according to claim 1 to 3, characterized in that is used as the water-miscible inert solvent, preferably tetrahydrofuran ₍ is used.