NO137994B - PROCEDURES FOR PROCESSING A BAR-OBJECT OBJECTIVE TO PROTECT ITS OUTER SURFACE - Google Patents

Description

Process for the production of 6-halogenated A 1,4-3-ketosteroids.

The present invention relates to a new

process for the preparation of 6a-chloro- and 6a-bromo derivatives of 9a-fluoro-AM<->preg-nadien-3-ones.

The compounds produced by

the method according to the invention, can

used as therapeutic agents or as

intermediates in the preparation of compounds with beneficial therapeutics

properties. Thus, e.g. the hydrogen halide is split off from the 6-halogen-substituted steroids so that one obtains

unsaturated derivatives.

There are known methods for the preparation of 6-halogen derivatives of A<4->3-

ketosteroids. A suitable method for forming the 6-halogen derivatives is to first prepare an enol ester or enol ether of the A<4->3-ketosteroid and then halogenate this enol derivative. The 6-position in the steroid molecule is activated in the 3,5-dien-3-ol ester or

-the ether, and halogen presumably increase the selectivity of the end position (the carbon atom in the 6-position) in the conjugated system. Structural formulas for these compounds are indicated below by I (the 3-keto derivative of an A4 steroid), II (the enol ester or ether) and III (the 6-halogen derivative) of the steroid compound:

In these formulas, R denotes an esterified or etherified hydroxyl group, while X denotes chlorine or bromine.

Attempts to apply the above-described method to the production of 6-halogen derivatives of A1><4->pregnadien-3-ones

generally gives unfortunate results on

due to the propensity of the α-pregnadien-3-ones to undergo rearrangements in the molecule

under the reaction conditions used.

Thus, e.g. presence of the outermost conjugated double bond in A<1->style-

ling result in migration of the methyl group in the 19-position with consequent aromatization of the ring, as shown with the formulas below:

This "dienone-phenol rearrangement" results in products with altered biological activity. Moreover, the 6-position in the steroid ring is no longer activated by the presence of the conjugated double bond, so that selective halogenation is obtained in this position.

Due to the propensity for rearrangements of which the above formulas are typical examples, no simple direct method has been developed to date for the selective halogenation of the A^-pregnadien-3-ones in the 6-position with good overall yields and without the occurrence of side reactions with other groups that may be present in the molecule.

With the help of the present invention, a simplified method for the production of the 6-chloro and 6-bromo derivatives of 9a-fluoro A^-pregnadien-3-ones corresponding to the general formula is now obtained

in which X denotes chlorine or bromine, R denotes hydrogen or a methyl group and R' denotes a hydroxyl group or a keto group, while R" denotes hydrogen or an acyl group. The method is distinguished by reacting a compound corresponding to the general formula

in which Ac denotes an acyl group, while R, R' and R" have the meaning given above, with an N-chloro- or N-bromo-carboxylic acid imide.

Preferred starting materials are 9α-fluoro-16α-methyl-A,'<3-5->pregnatriene-3, ll|3,17α,21-tetrol-20-one-3-benzoate-21-acetate and 9α-fluoro- 16a-methyl-A<1->3-<5->pregnatriene-3,17a,21-triol-11|3,20-dione-3,17a,21-triacetate.

They used 3-enol esters of ga-fluoro-A^-pregnadien-S-ones as starting materials, e.g. The 9a-fluoro-A<1-3-3->pregnatrien-3-ol-3-acylates can be prepared by reacting the 9a-fluorosteroid with suitable acylating agents under controlled working conditions. This achieves a good conversion and high total yields of the desired 3-enol esters without side reactions or unwanted rearrangements occurring in the steroid molecule.

The aliphatic esters of the 3-enol form of the 9a-fluoro-A1'4-pregnadien-3-ones are conveniently obtained by heating the steroid with an anhydride of an aliphatic acid and an organic sulphonic acid at temperatures in the range of approx. 90—100° C for several hours. The acid anhydride used corresponds to the ester derivative to be prepared. It is preferred to use anhydrides of lower aliphatic acids. Acetic anhydride is particularly preferred, because it is readily available and cheap. Propionic anhydride can also be used. Typical examples of sulfonic acid suitable for use with the anhydrides of aliphatic acids are benzenesulfonic acid, p-toluenesulfonic acid and methanesulfonic acid.

The aromatic esters of the 3-enol form of the 9a-fluoro-A<1>'<4->pregnadien-3-ones are conveniently prepared by heating the steroid with a chloride of an aryl acid such as e.g. benzoyl chloride, p-nitrobenzoyl chloride or p-chlorobenzoyl chloride, in the presence of an organic base. Typical examples of such bases are pyridine, the N-alkylmorpholines, N-alkylpiperidines, lutidines, collidines and trialkylamines. The temperature is kept at approx. 50 °C for at least y2 hours.

It is an advantage of the method according to the invention that the speed of the halogenation reaction using the 3-enol ester derivatives is significantly increased. In many cases, it is because of this precaution that acceptable yields can be achieved. On the basis of theoretical considerations, it is believed that the thus formed 3-enol esters of 9-fluoro-A<13-5->pregnatrienes cause activation of the 6-position in the steroid ring, whereby selective halogenation in this position is facilitated.

Typical examples of halogenating agents used in the method according to the invention are N-chloro-succinimide, N-chloro-phthalimide, N-chloro-parabanic acid, N-chloro-cyanuric acid, N-chloro-hydantoin or N-chloro-barbituric acid and the corresponding bromine compounds. Instead of these, one can also use the corresponding derivatives of primary or secondary carboxylic acid amides such as acetamide-propionic acid amide or diacetamide or carboxylic acid anilides, for example halogenated or nitrated acetanilide or benzanilide in the core.

Use of the N-chloro-succinimide, respectively the N-bromo-succinimide is particularly preferred. In most cases, the reaction components are used in practically stoichiometric quantities or with a small excess of the N-chloro or bromosuccinimide. It is a particular advantage of the method according to the invention that it is unnecessary to use more than approx. 10 percent excess of the halogenating agent to obtain satisfactory yields of the 6-chloro or bromo derivative. Due to the reactivity of the 9α-fluoro-Al>3'5-pregnatrien-3-enol ester in the 6-position, halogenation preferably takes place in this position without appreciable loss of halogenating agent due to undesired side reactions.

In a preferred embodiment of the invention, the 9a-fluoro-A1>3'5-pregnatriene-3-enol ester is reacted with N-chlorosuccinimide in an inert solvent or diluent such as e.g. glacial acetic acid. The reaction is preferably carried out under slightly acidic conditions. The optimum acidity for the reaction can be maintained by adding a small amount of anhydrous hydrogen chloride to the reaction mixture. This anhydrous hydrogen chloride is conveniently added to an inert liquid which is a good solvent for the same and which keeps the reaction mixture in a liquid state at the temperature used. An approx. A 5% solution of anhydrous hydrogen chloride in a solvent such as acetic anhydride or tetrahydrofuran has been found to be satisfactory. The reaction temperature is appropriately kept in the range from approx. -20° C to + 10° C. An ice bath can be used which keeps the temperature at 0-5° C. The reaction is generally complete after approx. 1 hour, but the use of a longer reaction time does not lead to unfavorable results.

The compounds obtained by the method according to the invention can be isolated and purified using usual methods. In general, the 6-chloro derivative is not recovered as the 6-chloro derivative of the 9a-fluoro-A1'<33->pregnatrien-3-enol ester, but as the 6-chloro-9a-fluoroA1'4-pregnadien-3-one, then The 3-enol ester of the 9a-fluoro-A,'<3>'<;>'-pregnatriene under the prevailing reaction conditions can easily undergo solvolysis to the 3-hydroxyl group with subsequent rearrangement to the keto form, i.e. 9a-fluoro-A<1>><4->pregnadien-3-one.

The 9a-fluoro-A<1>>4-pregnadien-3-ones

which is used as starting material, can contain any desired substituents, in particular keto, hydroxyl, acetoxy, alkoxy or aryloxy groups or halogen atoms in other positions of the steroid ring. It is an advantage of the method according to the invention that 11-hydroxy groups or 11-keto groups are not affected under the reaction conditions used. It is known that the lip-hydroxyl group does not usually undergo acylation, but only under conditions which are so severe that they cause destruction of the molecule, particularly in the 17-side chain. Chlorination of steroids containing an 11-keto group can be expected to occur in places other than at the 11-keto group due to the known fact that 11-keto groups are generally inert. The presence of a 9a-fluoro-substituent seems to promote the formation of the 3-enol ester and consequently the formation of 6-chloro derivatives thereof.

Reactive hydroxyl groups, e.g. a 21-hydroxyl group in the side chain is preferably transferred to the corresponding ester or ether before the compounds are used as starting materials in the method according to the invention. The 21-hydroxy group can be transferred to a 21-hydroxy ester by means of suitable esterification agents such as e.g. carboxylic acid or sulphonic acid chlorides. Chlorides of propionic acid can thus be used. benzoic acid, methanesulfonic acid and toluenesulfonic acid. The 21-hydroxyl group can be transferred to a 21-hydroxyether using common etherification agents.

In the following, some embodiments of the invention are described as examples.

Example 1.

A. 9a-fluoro-16a-methyl-A1S:"'-pregna-trien-3, 17a, 21-triol-ll, 20-dione-3, 17a, 21- triacetate.

A solution of 4.0 g (9.28 m-mol) of 9α-fluoro-16α-methyl-α<1-4->pregnadiene-17α,21-diol-3,11,20-trione-21-acetate and 1.0 g of p-toluenesulfonic acid monohydrate in 200 ml of acetic anhydride was heated to 95° C. for 5 hours. The reaction mixture was then evaporated to a small volume under reduced pressure and the residue was decomposed with aqueous sodium bicarbonate solution. The mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to give an oily substance. Separation of the product's components was carried out by adsorption on 30 g of acid-washed aluminum oxide. Elution with ethyl ether gave 0.88 g of 9a-fluoro-16a-methyl-A<1>A<5->pregnatriene-3,17a,21-triol-11,20-dione-3,17a,21-triacetate with melting point 189—

192°C.

;_MeOH 300 mix; E% 105.

Analysis: calculated for C28H3308F.

B. 6a- chloro- 9a- fluoro- 16a- methyl- A1J-pregnadiene- 17a, 21- diol- 3, 11, 20- trione-17a- 21- diacetate.

A solution of 50 mg of 9a-fluoro-16a-methyl-Al-3-5-pregnatriene-3,17a,21-triol-11,20-dione,3,17a,21-triacetate and 14 mg of N-chloro-succinimide (10 per cent excess) in 3 ml of glacial acetic acid and 2 ml of 5 per cent aqueous hydrogen

chloride in acetic anhydride was added to

ice bath for 3 hours. The reaction mixture was then poured into water and the mixture extracted

hardened with chloroform. The extract was washed with water, 5% sodium bisulphite solution

ning, 5% sodium bicarbonate solution and finally with water. The extract was then

dried over anhydrous sodium sulfate and evaporated to give a crystalline residue. After the recrystallization, the product had 6α-chloro-9α-fluoro-16α-methyl-α1-4-pregnadiene-17α,21-diol-3,11,20-trione-17α,21-diacetate, melting point 199-200°C.

ÅMeOH 236 mp; E% 332; [a]2D2+ 45°

(CHCL,). Analysis calculated for C2(!H.10O7FCl:

C 61.35%, H 5.94%, Cl 6.97% Found:

C 61.44 per cent, H 6.64 per cent, Cl 6.45 per cent.

Example 2.

A. 9a- Fluoro- 16a- methyl- A' Jr'- pregnatriene-3, llfi, 17n, 21- tetrol- 20- one- 3- benzoate- 21-

acetate.

A solution of 2.0 g of 9a-fluoro-16a-methyl-A<1-4->pregnadiene-lip,17a,21-triol-3,20-dione-21-acetate in 8 ml of pyridine and 4 ml of benzoyl chloride was heated to 50° C in 3

hours. It was then cooled, kept in a 5% aqueous sodium bicarbonate solution

ning and extracted with chloroform. The ex-in the funnel was washed first with water, then

with 5 per cent hydrochloric acid, again with water, then with 5 per cent sodium bicarbonate solution and finally with water. It was then dried over anhydrous sodium sulfate and concentrated

pet, whereby an oily residue was obtained

dum. This crude product was adsorbed in 60 g of acid-washed aluminum oxide, after which it was eluted with ethyl ether. 1.66 g of the crystalline enol benzoate was obtained. After recrystallization from a mixture of acetone and petroleum ether, the 9a-fluoro-16a-methyl-AlA5-pregnatriene-3,lip,17a,2l-tetrol-20-one-3-benzoate-21-acetate had a melting point of 161-167° C.

;- SH 224 E% 374; 283 square meters; E% 96;

3oTm'(x; E%123.

B. ea- chlorSa- fluor- iea- methyl- AU- preg-nadien- llf,. 17a, 21- triol- 3, 20- dione- ace-

taken.

A suspension of 100 mg of 9a-fluoro-16a-methyl-A<1>'<3>'<5->pregnatriene-3,lip,17a,2l-tetrol-20-one-3-benzoate-21-acetate in 2 ml of glacial acetic acid was cooled to approx. 15° C and above

added 28 mg of N-chlorosuccinimide as well as a 5

pst.'s solution of dry hydrogen chloride in 2 ml of dry tetrahydropyran. It is hereby-

kept solution was stored at 0-5°C

for 2y2 hours and then distributed between chloro-

form and a 5% aqueous sodium bicarbonate solution. The chloroform layer was de-

separated and washed with several portions of water,

then with a 5 percent sodium bisulphite top-

solution and finally with water. It was there-

on dried over magnesium sulfate and in-

evaporated, whereby a colorless oil was obtained which crystallized after trituration with ether. Upon recrystallization from a mix-

addition of acetone and ethyl ether gave

stables of 6a-chloro-9a-fluoro-16a-methyl-A'-4-pregnadiene-lip,17a,21-triol-3,20-dione-,21-acetate with melting point 186—196° C. In chsOh 240 mii; E% 320.

nine 8, KS.

Claims (4)

1. Process for the preparation of steroids of the general formula in which X denotes chlorine or bromine, R denotes hydrogen or a methyl group and R' denotes a hydroxyl group or a keto group, while R" denotes hydrogen or an acyl group, characterized by reacting a compound corresponding to the general formula in which Ac denotes a acyl group, while R, R' and R" have the meaning given above, with an N-chloro- or N-bromocarboxylic acid imide. 2. Method according to claim 1, characterized in that 9a-fluoro-16a-methyl-A1A3-pregnatriene-3,lip,17a,2l-tetrol-20-one-3-benzoate-21-acetate is used as starting material. 3. Method according to claim 1, characterized in that 9a-fluoro-sjå- is used as starting material rne thyl-AW-pregnatriene-S.na^l-triol-11,20-dione-3,17a,21-triacetate. 4. Process according to any of the preceding claims, characterized in that N-chlorosuccinimide is used as carboxylic acid imide.