US3705893A - Process for the 9(11)-enolisation of a steroid 1,4-diene-3,11-dione - Google Patents

Abstract

A PROCESS FOR THE SELECTIVE 3- OR 9(11)-ENOLISATION OF A STEROID 1,4-DIENE-3,11-DIONE WHEREIN THE 1,4-DIENE-3,11DIONE IS TREATED UNDER SUBSTANTIALLY OXYGEN-FREE AND ANHYDROUS CONDITIONS IN A NON-HYDROXYLIC SOLVENT WITH AN ALKALI METAL BASE, OTHER THAN A LITHIUM BASE, WHICH IS SOLUBLE IN THE SOLVENT. WHERE THE 9(11)-ENOLATE IS DESIRED, THE DIONE IN NON-ENOLIZED FORM IS ALLOWED TO REACT WITH THE 3-ENOLATE INITIALLY FORMED, AND WHEN THE 3-ENOLATE IS REQUIRED THE REACTION IS EITHER CARRIED OUT BELOW -50* C., OR THE REACTION IS CARRIED OUT IN SUCH A MANNER THAT CONTACT BETWEEN THE 3-ENOLATE AND UNREACTED DIONE IS REDUCED OR AVOIDED. THE RESULTING 3- OR 9(11)-ENOLATES CAN BE CONVERTED TO THE CORRESPONDING ESTERS, AND EITHER THE ENOLATES OR THE CORRESPONDING ESTERS CAN BE HALOGENATED WHEREBY A HALOGEN IS INTRODUCED AT THE 6- OR 9POSITION RESPECTIVELY.

Description

United States Patent O M 3,705,893 PROCESS FOR THE 9(11)-ENOLISATION OF A STEROID 1,4-DlENE-3,11-DIONE Derek Harold Richard Barton, London, England, as-

iignor to Research Institute for Medicine and Chemistry N Drawing. Filed Nov. 23, 1970, Ser. No. 92,216 Claims priority, application Great Britain, Nov. 24, 1969, 57,425/ 69 Int. Cl. C07c 173/06 US. Cl. 260-23955 D Claims ABSTRACT OF THE DISCLOSURE A process for the selective 3- or 9(ll)enolisation of a steroid 1,4-diene-3,11-dione wherein the 1,4-diene-3,11- dione is treated under substantially oxygen-free and an hydrous conditions in a non-hydroxylic solvent with an alkali metal base, other than a lithium base, which is soluble in the solvent. Where the 9(ll)enolate is desired, the dione in non-enolized form is allowed to react with the 3-enolate initially formed, and when the 3-enolate is required the reaction is either carried out below -50* C., or the reaction is carried out in such a manner that contact between the 3-enolate and unreacted dione is reduced or avoided. The resulting 3- or 9(ll)enolates can be converted to the corresponding esters, and either the enolates or the corresponding esters can be halogenated whereby a halogen is introduced at the 6- or 9- position respectively.

This invention relates to the preparation of steroid enolates and of esters derived therefrom.

Steroid 1,4diene-3,11-diones are frequently encountered among the physiologically active steroids, especially the corticosteroids, and it is oten found that the derivatives carrying substituents at the 6- or 9-position possess enhanced activity. Thus, for example, 9e-fiuoro-16/3-methylprednisone (betamethasone) possesses greater anti-inflamrnatory activity than 16 8-methyl prednisone and 6- methyl prednisone also exhibits greater activity than prednisone. In synthesising these compounds, the 6- or 9- substituent is usually introduced at a relative early stage, before the 1,4-diene-3,l1-dione system is formed but considerable difiiculty has been experienced in substituting at the sterically hindered 9-position.

We have now found that a 6- or a 9'-substituent can be introduced into an existing steroid l,4-diene-3,ll-dione by selectively forming the 3- or the 9(ll)enolate, converting this into an enol ester and reacting the latter with an electrophilic reagent to introduce the residue of an electrophile, for example, a halogen atom. In some instances the enolate itself can be reacted directly to introduce a substituent in the 6- or ll-position without intermedial-y formation of an enol ester and the key step in our new method is, in fact, the selective enolisation predominantly either at the 3- or the 9(ll)position. The new method provides a particularly effective method of introducing substituents at the hindered 9-position.

Attempts to prepare enol esters from steroid 1,4-diene- 3,11-diones by treatment with a strong base to the enolate, followed by quenching of the enolate anion with an acylating reagent have previously yielded mixtures of the 3- and the 9(ll)derivatives, with consequent difficulties of separation. Our researches have now succeeded in elucidating the mechanism of the enolisation reaction and have enabled us to formulate the conditions whereby either the 3-enolate or the 9(ll)enolate is formed predominantly.

While we do not wish to be bound by theoretical considerations, it is believed that on reaction of the 1,4-

3,705,893 Patented Dec. 12, 1972 diene-3,l1-dione with a strong base, a proton is transferred from the 6-carbon atom to the base, yielding initially the 3-enolate, the removal of a proton from the 9- carbon atom to form the 9(ll)enolate being strongly sterically hindered. The 3-lithium-enolates are stable, and do not enter into the subsequent reactions described below but other 3-alkali metal-enolates, in the presence of steroid l,4-diene-3,11-dione, tend to rearrange to yield the 9(ll)enolate which appears to be more stable. The rearrangement appears to be bimolecular, one molecule of 3-enolate reacting with one molecule of -3,l1-dione to yield one molecule of regenerated -3,1l-di0ne and one molecule of 9(ll)enolate. Thus unreacted -3,11-di0ne need only be present in a catalytic quantity since it is constantly regenerated. However, the bimolecular rearrangement is considerably slower than the enolisation and if an excess of base is added, the -3 enolate will be formed quantitatively before rearrangement can take place to a significant extent. Furthermore, at very low temperatures, for example, below 50 C., the bimolecular rearrangement is so slow as to be negligible and at such temperatures substantially only 3-enolate is apparently present (as demonstrated by forming an enol ester). It can thus be seen that if the reaction conditions are selected so that the initially formed 3-enolate cannot come in contact with the unreacted dione, or can only contact the dione under conditions in which rearrangement will not occur, the 3-enolate is obtained as reaction product, whereas if the reaction conditions are selected so that the initially formed 3-enolate can contact unreacted dione under conditions in which rearrangement can occur, the 9(ll)enolate is obtained.

If one equivalent of the dione is slowly added to a solution containing slightly more than one equivalent of the base, free dione is never present to a significant extent and only the 3-enolate is formed. On the other hand, if very slightly less than one equivalent of base is slowly added to a solution of one equivalent of dione, so that some unreacted dione is always present, predominantly 9(ll)enolate is formed, provided, of course, that sllfficient time is allowed for the bimolecular rearrangement to take place at the selected reaction temperature which, clearly, is desirably not unduly low.

As indicated above, if the reaction of base and dione is effected at a very low temperature, for example about 70 C. to C., predominantly the 3-enolate will be obtained. Our new method is to be contrasted with previously attempted enolisations of l,4-diene-3,11-diones by the straight-forward addition of an excess of a base to the dione in a single batch whereby the rapid enolisation removed all the free dione before rearrangement was complete and a substantial quantity of 3-enolate always remained at the time of ester formation.

According to the present invention therefore we provide a process for the selective 3- or 9( l1)-enolisation of a steriod 1,4-diene-3,11-dione in which the 1,4-dione-3,l1- dione is treated under substantially oxygen-free and anhydrous conditions in a non-hydroxylic solvent with an alkali metal base other than a lithium base soluble in the solvent to form the 3-enolate; when the 9(ll)enolate is required, the dione in non-enolised form being allowed or caused either subsequently or simultaneously to react with the 3-enolate initially formed; when the 3-enolate is required the reaction being carried out at a temperature below 50 C. or the reaction being carried out in a manner whereby contact between the 3-enolate and unreacted dione is reduced or avoided.

An alkali metal base, that is a sodium, potassium, rubidium or caesium base, acting as a strong nucleophile under anhydrous non-hydroxylic conditions is required to abstract the desired proton from the 6- and 9-position.

Alkali metal hydrides; amides; alkylamides, e.g. sodium or potassium diisopropylamide; triarylmethyls and acetylides or other non-hydroxylic alkali metal derivatives which do not react with ketones may be used as base. Particularly preferred bases are the alkali metal bistertiary silylamides particularly alkali metal bistrialkylsilylamides such as bistrimethylsilylamides.

The reaction conditions, as stated above, should be oxygen-free and anhydrous; and atmosphere of a dry inert gas such as nitrogen or, preferably, argon is desirable. The non-hydroxylic solvent used should be dry and further should dissolve at least part of the reactant steroid dione and base.

Ethers are useful in this respect and it is particularly advantageous to use cyclic ethers such as tetrahydrofuran, which may conveniently be used with aromatic hydrocarbons such as benzene or toluene.

The reaction temperature, where low temperatures are not required to avoid bimolecular rearrangement, is preferably from -50 C. to 100 C., advantageously ambient temperature e.g. to 25 C.

Where 9(11)-enolate is required, it may be convenient to effect the reaction under conditions leading to formatron of a 3-enolate for example a sodium 3-enolate, and to add to the initial reaction products a quantity of the dione sufiicient to efiect the bimolecular rearrangement to the 9(11)-enolate.

The enolates formed are advantageously, as indicated above, converted directly into enol esters. Thus, for example, the reaction with the alkali metal base may be conveniently quenched and the corresponding ester pro,- duced, by treating the reaction mixture in situ with an acylating agent, e.g. a reactive ester, for example, the acid halide, or more particularly, the anhydride, of an organic acid such as an aliphatic, araliphatic or aromatic carboxylic or sulphonic acid. It is particularly preferred to use the anhydride of an aromatic carboxylic acid and, for example, quenching the reaction with benzoic anhydried yields the desired 3- or 9(l1)-enol benzoate, in virtually quantitative yield. Acetic anhydride similarly yields the corresponding acetates. This quenching procedure is particularly useful in worikng up reactions carried out at very low temperatures, the rapid acylation eifectively preventing any loss of the 3-enol.

Any steroid l,4-diene-3,ll-dioue can be enolised by the process according to the present invention, especially corticosteroids of the prednisone type and suitably substituted progesterone and androstane derivatives. Particularly desirable enolates are formed from prednisone BMD ,(17,20:20,21-bismethylenedioxyprednisone) and its 160: and l6fi-meth'yl analogues, n -ll-ketoprogesterone ethylene ketal and androstane-l,4-diene-3,l1,17-trione-l7- monoethylene ketal.

The 9(l1)-enol esters described above are novel compounds and comprise a feature of the invention. The benzoate esters are preferred and among the compounds especially useful are included the 9(1l)-enol benzoates of corticosteroids of the prednisone type, particularly 17,20:20,21 bismethylenedioxyprednisone 9(ll)-enol benzoate.

The 3- and 9(ll)-enol esters or the parent 3- and 9(l1)- enolates are, as indicated previously, particularly useful as starting compounds for electrophilic substitution reactions at 6- or 9-positions. Thus, for example, reaction with sources of positive halogen such as molecular chlorine or bromine, introduces a halogen atom at the 6- or 9'position. It is particularly useful to introduce fluorine, especially at the 9a-position, by reacting an enolate or enol ester with an electrophilic fluorinating agent, such as perchloryl fluoride, or a hypofiuorite reagent such as trifluoromethyl hypofiuorite. The method according to the invention thus allows 9cz-fill0l0 prednisone or a 16mmethyl or l6fl-methyl derivative to be prepared directly from prednisone or its l-methyl derivatives.

By the term steroid as used herein we mean substances which possess the cyclopentanoperhydrophenanthrene structure and which may carry various substituents. Apart from the 3- and ll-oxo groups and the double bonds in the 1,2- and 4,5-positions, the steroid may carry substituents at the 10- and l3-positions, e.g. alkyl groups such as the methyl groups usually present in the andro stanes and pregnanes; at the 16::- or ISfl-position, for example, alkyl, e.g. methyl, or alkylene, e.g. methylene, groups, or halogen atoms and at the 17-position, for example, a hydroxy or acyloxy group which may be present together with or as an alternative to an aliphatic group such as an acyl group e.g. the acetyl or fi-hydroxyacetyl group. Where an enolisable oxo group is present such as in the 20-0xo pregnanes of the corticoid type, this should be protected prior to the reaction, for example, by formation of a ketal, or orthoester derivative. In particular, the l7m-hydroxy-20-oxo 21 hydroxy-pregnane structure which occurs in the corticosteroids of the prednisone and betarnethasone type, may be protected by formation of bis-methylenedioxide derivatives.

Where the steroid 1,4-diene-3,ll-dione used as starting material contains groups which may be hydrolysed under the basic conditions present in the reaction according to the invention, it is necessary to ensure a sufficient excess of base to complete the enolisation, the hydrolysed group, if desired, being subsequently restored to its original form. For example, acyloxy groups such as esterified hydroxy groups, may be hydrolysed under the reaction conditions and should then, if desired, be re-esterified.

The following examples are given by way of illustration:

(A) PREPARATION OF 3-ENOLATES CHARAG T ERISED AS THEIR 3-BENZOATES Example 1: Reaction at low temperature Prednisone BMD l7,20:20,2l-bismethylenedioxyprednisone) 200 mg., 0.5 mmole) was dissolved in freshly purified THF (tetrahydrofuran) (6 ml.) and sealed in a septum bottle under argon. The steroid solution was then cooled to -78 C. Sodium bistrimethylsilylamide (549.5 mg., 3.0. mmoles) in THF (5 ml.) at 78 C. was added to the steroid solution and the reaction allowed to proceed for 3 hours. Benzoic anhydride (crystallised from hexane2benzene; 452 mg., 2.0. mmoles) was added to the reaction mixture which was then allowed to warm up to room temperature. The mixture was then washed with water, dried and evaporated to dryness in vacuo and the residue taken up in chloroform. The crude mixture was purified by preparative thin layer chromatography on eluting with chloroform:ether (60:40 VOL/vol.) to yield the 3-enol benzoate (203 mg., 0.4 mmole; 80%; M.P. 226- 228 C.; [a] ='-182).

Example 2: Slow addition of steroid to base Prednisone BMD (200 mg., 0.5 mmole) in dry TI-IF (10 ml.) was added dropwise over 30 minutes with vigorous stirring to sodium bistrimethylsilylamide (120.3 mg., 0.55 mmole) in THF (5 ml.) under argon, the mixture remaining at room temperature throughout the addition. The mixture was then stirred a further 2 minutes and benzoic anhydride (452 mg., 2.0 mmoles) added. The mixture was then worked up as before to yield the 3-enol benzoate (207 mg., 0.405 mmole; 82%). Use of triphenylmethylsodium (3 mol. equiv.) or sodium acetyl ide (5 mol. equiv.) yields the identical S-enol benzoate. Following this method, the 3-enol benzoates of 16amethyl prednisone BMD, l6;3-methylprednisone BMD, A I1-keto-progesterone-20-ethylene ketal and androstanel,4-diene-3,ll,l7-trione 17-monoethylene ketal may be prepared.

(B) PREPARATION OF 9(11)-E'NOLATES CHAR- ACTERISED AS THEIR 9(11) -BENZOATES Example 3: Slow addition of base to steroid Sodium bistrimethylsilylamide (165 mg., 0.9 mmole) in THF (5 ml.) was added dropwise at room temperature over 30 minutes to A -prednisone BMD (200 mg., 0.5 mmole) in THF (6 ml.) under argon. The reaction mixture was stirred a further 2 minutes and then benzoic anhydride (452 mg., 2.0 mmoles) added. The reaction mixture as then worked up as before to yield the 9(11)- enol benzoate (203 mg., 0.4 mmole; 80%; M.P. 290 293 C., [a] =+33.4). Following this method, the 9(l1)-enol benzoates of l6u-methyl prednisone BMD, IGB-methyl prednisone BMD, A -1l-keto-progesterone-ZO- ethylene ketal and androstrane-1,4-diene-3,l1,17-monoethylene ketal may be prepared. Use of triphenylmethylsodium (2 mol. equiv.) or sodium acetylide (2 mol. equiv. dispersed in xylene/tetrahydrofuran) yields the identical 9(11)-eno1 benzoate.

Example 4: Addition of unreacted steroid to a solution of the 3-enolate The reaction of Example 1 was repeated allowing a reaction time of 4 /2 hours. The solution of 3-enolate was allowed to warm up to room temperature and more prednisone BMD (300 mg., 0.75 mmole) in THF (9 ml.) was added. The reaction mixture was stirred at room temperature for a further 6 minutes and then benzoic anhydride (452 mg., 2.0. mmoles) was added. The reaction mixture was worked up as before to yield the 9(11)-enol benzoate (192 mg., 0.38 mmole; 76%; identical with the product of Example 3 (t.l.c.)).

Example 5: Reaction of prednisone BMD 9(11)-enol benzoate with trifluoromethyl hypofluorite (CF OF) Prednisone BMD 9(11)-eno1 benzoate (500 mg.) was dissolved in a mixture of Freon (100 ml.) and methylene chloride (50 ml.) and reacted with CF OF in the presence of CaO (200 mg.) under nitrogen at about 78 C. The crude product (572 mg.) was chromatographed over alumina (grade 3, 40 g.). Elution with benzene, followed by ether/benzene mixtures up to 10% ether, produced small amounts of several non polar products (total weight 103 mg.) which were not studied further. Elution with 20% ether/benzene yielded a series of fractions containing two main components (A and B) resolved on t.l.c., of which the more polar (A) was the more abundant. Earlier fractions containing a greater abundance of (B) (total weight 127 mg.) were combined and absorbed onto a 20 x 20 x 0.1 cm. silica G thick layer chromatography plate. After elution thrice with 1% MeOH/CH Cl three zones were scraped from the plate and absorbed product was re-extracted using several aliquots of 10% MeOH/CH Cl The next few fractions (97 mg.) were treated in a similar way. Comparison of the I. R. spectra and t.l.cs of the various zones indicated that A and B could be distinguished by their characteristic carbonyl absorptions. Combination of the appropriate fractions followed by crystallization from CH Cl /MeOH gave pure A (32 mg), M.P. 276-84 C. whose I.R., was superimposable on that of 9a-fluoro predm'sone BMD and which did not depress a mixed melting point with an authentic sample. Combination of other fractions and crystallization from CH CI /MeOH gave B (20 mg.). Recrystallization from the same solvent gave heavy prisms (14 mg.), IR.

1750 (s.), 1670 (vs.), 1635 (m.), 1610 (w.), 1270 (vs.), 1210 (vs.) cm.-l. The analytical specimen had M.P. 130- 32" C., [01] +447 (c.=1.l).

Hydrolysis of B with methanolic sodium hydroxide yielded compound A suggesting that B is 9oz-fill0l0-lloztrifiuoromethoxy-l lfi-benzoyl-prednisolone BMD.

6 Example 6: 6,8-fluoro-prednisone BMD (9) Prednisone BMD 3-enol benzoate (250 mg.) was dissolved in a mixture of Freon (40 ml.) and methylene chloride (20 ml.) in the presence of calcium oxide 1740 (s.), 1260 (s.) (benzoate), 1705 (s.) (ketone) cm.- Crystallization from methylene chloride/ ether gave (9) (30 mg. 1st crop), LR.

CHC I "max.

1705 (s.) cm." (ketone), 1670 (vs.), 1625 (m.) dienone) cmr A second crop of mg. was also obtained.

What is claimed is:

1. A process for the selective 9(11)-enolisation of a 1,4- diene-3,l1-dione steroid of the androstane or pregnane series in which the 1,4-diene-3,l1-dione is treated under substantially oxygen-free and anhydrous conditions in a non-hydroxylic solvent with an alkali metal base other than a lithium base soluble in the solvent, to form the 3- enolate; the dione in non-enolised form being allowed or caused either subsequently or simultaneously to react with the 3-enolate initially formed.

2. A process as claimed in claim 1 in which the base is a bistrimethylsilylamide.

3. A process as claimed in claim 1 in which the temperature is from 50 C. to 100 C.

4. A process as claimed in claim 1 in which very slightly less than one equivalent of base is slowly added to a solution of one equivalent of dione whereby some unreacted dione is always present and predominantly 9(l1)-enolate is formed.

5. A process as claimed in claim 1 in which, where the 9(11)-enolate is required, the reaction is effected by adding to a 3-enolate a quantity of the dione sufiicient to effect the bimolecular rearrangement to the 9(l1)-enolate.

6. A process as claimed in claim 1 in which the enolate formed is converted directly into its enol ester by treatment of the reaction mixture in situ with an acylating agent selected from the group consisting of an aliphatic carboxylic acid halide, an araliphatic carboxylic acid halide,an aromatic carboxylic acid halide, an aliphatic carboxylic acid anhydride, an araliphatic carboxylic acid anhydride, an aromatic carboxylic acid anhydride, an aliphatic sulphonyl halide, an araliphatic sulphonyl halide, an aromatic sulphonyl halide, an aliphatic sulphonic acid anhydride, an araliphatic sulphonic acid anhydride and an aromatic sulphonic acid anhydride.

7. A process as claimed in claim 6 in which the acylating agent is benzoic or acetic anhydride.

8. A process as claimed in claim 1 in which the 1,4- diene-3,11-dione starting material carries other enolisable keto groups in a protected form.

9. A process as claimed in claim 1 in which the 9(1l)- enolate initially prepared, or an ester thereof, is subsequently reacted with a halogenating reagent selected from the group consisting of bromine, chlorine, perchloryl fluoride and a hydrofiuorite reagent.

10. A process for electrophilic halogenation at the 9- position of a steroid in which the 9(l1)-enolate or -enol ester of a 1,4-diene-3,11-dione steroid of the androstane or pregnane series is reacted with a halogenating reagent selected from the group consisting of bromine, chlorine, perchloryl fluoride and a hypofiuorite reagent whereby the corresponding 9a-halogenosteroid l,4-diene-3,11-dione is formed.

11. A process as claimed in claim 6 in which the halogenating reagent is trifluoromethyl hypofluorite.

12. A process as claimed in claim 1 wherein the 1,4- diene-3,ll-dione starting material is substituted at the 10- and l3-positions by hydrogen or an alkyl group, and at the 16aor 16,8-position by hydrogen or an alkyl group.

13. A 9(1l)-cno1 benzoate or acetate of a l.4-diene-3,1 I- dione steroid of the androstane or pregnane series sub stituted at the 10- and l3-positions by an alkyl group and at the 1611- or l6 8-position by hydrogen or an alkyl group.

14. A compound of claim 24 selected from the group consisting of the 9(11)-enol benzoate or acetate of 17, 20:20,2l-bismethylenedioxy-prednis0ne and its lfia-rnethyl and l6fl-rnethyl analogues, of ll-keto-progesterone-ZO- No references cited.

ELBERT L. ROBERTS, Primary Examiner Y Us. c1. X.R. 260239.55 c, 397.45