HU224068B1 - Preparation of intermediates useful for the synthesis of hydrocortisone - Google Patents

Abstract

The present invention relates to the preparation of compounds of formula (I): wherein K is an oxo protecting group of formula (a) or (b), wherein n is 2 or 3, preferably 2, L is oxo and the dashed line at the 11-position represents a bond. and X is hydrogen or L is hydroxyl at position? and the dotted line at position 11 is non-significant and X is chlorine, bromine or iodine, preferably bromine, such as halogen-hydrogen of formula II. wherein X is chlorine, bromine or iodine under conversion in the presence of alcohol, then treated with acid, and the 3-oxo group of the resulting compound is selectively protected with HO- (CH2) n-SH or -HS- (CH2) n-SH - in the formulas n is 2 or 3 by treatment with a compound of formula IV wherein K is the protecting group (a) or (b) of the 3-oxo group, wherein n is as defined above, or a compound of formula (II) above, is treated with a 3-oxo protecting group selected from the group consisting of aphizines, and the resulting compound, if desired ( (IV) by rearrangement in the presence of alcohol and acid treatment. They can be used as starting materials for the hydrocortisone production of the compounds of formula (I) and allow for large industrial synthesis.

Description

The present invention relates to the preparation of compounds of formula (I)

K is an oxo protecting group of formula (a) or (b) wherein n is 2 or 3, preferably 2,

L is oxo and then the dashed line a

represents a valence bond and X represents a hydrogen atom, or

L represents a hydroxy group at the β-position and the dashed line at the 11-position does not represent a valence bond and X represents a chlorine, bromine or iodine atom, preferably a bromine atom such that a halohydrin of formula II wherein X represents chlorine -, bromine or iodine - are rearranged in the presence of alcohol, treated with acid, then the 3-oxo group of the resulting compound is selectively protected

By treatment with a compound of the formula HO- (CH ₂ ) _n -SH or HS- (CH ₂ ) _n -SH, where n is 2 or 3, to give a compound of formula IV, wherein K is

A protecting group of a 3-oxo group of formula (a) or (b), wherein n is as defined above, or a compound of formula (II) above, is selectively treated with a 3-oxo protecting group of the above and optionally ( It is converted to the compound of formula IV by rearrangement in the presence of alcohol and by acid treatment.

The compounds of formula (I) can be used as starting materials in the preparation of hydrocortisone and allow large-scale industrial synthesis.

HU 224,068 Β1

(a) (b)

The length of the description is 6 pages (including 2 pages)

HU 224,068 Β1

The present invention relates to a process for the preparation of novel selectively protected intermediates which are useful in the industrial synthesis of hydrocortisone.

There are many processes known in the art for the production of hydrocortisone and other related steroids, which differ from one another to a greater extent, but have little industrial application. However, in view of the large-scale, large-scale use of hydrocortisone, there is a constant need for more industrially advantageous processes, resulting in milder reaction conditions and / or safer reactions, with fewer by-products and thus more economical.

EP-A-30368 discloses the rearrangement of 3,17-dione-11-hydroxy compounds as starting materials for the preparation of steroids, such as hydrocortisones, to 3,11,17-trione compounds, e.g. however, high temperatures of about 200 ° C to about 300 ° C do not make it suitable for large scale industrial applications. Furthermore, no selective protection of the 3,11,17-trione compound is mentioned here or elsewhere in the literature.

It has been found that, for example, if a specially protected intermediate is used in the preparation of hydrocortisone (H), the preparation can be carried out under reaction conditions which allow large-scale production and satisfy the above-mentioned needs.

Accordingly, it is an object of the present invention to provide said protected intermediate.

The present invention therefore relates to a process for the preparation of compounds of formula I wherein K is an oxo protecting group of formula (a) or (b) wherein n is 2 or 3, preferably 2,

L is oxo and then the dashed line a

Represents a valence bond at the 11-position and X represents hydrogen or

L represents a hydroxy group at the β-position and the dashed line at the 11-position does not represent a valence bond and X represents a chlorine, bromine or iodine atom, preferably a bromine atom such that a halohydrin of formula II wherein X represents chlorine , bromine or iodine, is rearranged in the presence of alcohol, treated with acid, then the 3-oxo group of the compound of formula (III) is selectively protected

By treatment with a compound of the formula HO- (CH ₂ ) _n -SH or HS- (CH ₂ ) _n -SH, where n is 2 or 3, to give a compound of formula (IV): wherein K is The protecting group of a 3-oxo group of formula (a) or (b), wherein n is as defined above, or a compound of formula (II) above is selectively treated with a protecting group of the above 3-oxo and the resulting compound of formula (V) Compounds of formula (X) wherein X and K are as defined above, if desired, are converted to compounds of formula (IV) by rearrangement in the presence of alcohol and acid treatment.

Particularly preferred is the process of the invention wherein X in the compound of formula II is bromine.

The rearrangement reaction of the halohydride compound is preferably carried out in the presence of a higher alcohol or polyhydric alcohol such as glycerol or a diol such as propylene glycol or preferably ethylene glycol by heating at a temperature below 100 ° C. It may be advantageous to carry out the reaction in the presence of a co-solvent, preferably a solvent having a boiling point below 100 ° C and the reaction being carried out under reflux. Preferably, the co-solvent is used under inert conditions such as ethyl acetate.

The acid treatment is carried out with an aqueous acid such as aqueous hydrochloric acid, hydrobromic acid or sulfuric acid.

The protection of the 3-oxo group is accomplished by reacting the compound with, for example, a dithiol in an acidic medium, preferably ethanedithiol in the presence of a catalytic amount of concentrated hydrochloric acid or hydrobromic acid, and a Lewis acid such as zinc chloride, titanium tetrachloride or in the presence of boron trifluoride, preferably in the form of its ether.

An especially preferred embodiment is the blocking of the 3-oxo group, followed by rearrangement of the halide hydride compound and the operations of the so-called "single" method, i.e. the isolation of the intermediate compound of formula (V).

The rearrangement reaction of the halide hydride compound is facilitated by blocking the oxo groups at the 3- or 3- and 17-positions and thus very mild reaction conditions can be employed.

By way of information, it is to be noted that the blocking is likely to result in the labylation of the carbon-halo at the 9-position resulting in the facilitation of the rearrangement reaction.

The Lewis acids used in the process of the invention may be, for example, zinc chloride, aluminum chloride, diethylaluminum chloride or, preferably, titanium tetrachloride.

The operations are preferably carried out in the presence of a cyclic ether such as tetrahydrofuran or dioxane.

For example, the process according to the invention has the following advantages:

- rearrangement from 11-OH to 11-keto compound via the halohydrine intermediate can be carried out under very mild reaction conditions, which are far milder than those described, for example, in European Patent 30368 (here at 200 ° C to 300 ° C). they carry out the reaction)

blocking at the 3-position is particularly selective, in contrast to known blocking methods with enol ethers and ketals, which generally lead to a mixed blocking of the 3- and 3,17-positions;

HU 224,068 Β1

The 3-position blocking according to the invention is furthermore very stable under the reaction conditions used, whether acidic or basic and can be eliminated during synthesis, especially with iodine in basic medium or with catalytic amount of iodine under mild oxidation conditions.

Using the novel intermediate of the present invention, the hydrocortisone can be prepared without undergoing an 11-hydroxylation step, particularly when androstenedione is used as the starting material. As a result, the overall yield of hydrocortisone is better, less by-product, and more economical to synthesize.

Compounds of formula (II) are described, for example, in U.S. Patent No. 3,072,684.

The following non-limiting examples illustrate the process of the invention in more detail.

Example 1

Androst-4-ene-3,11,17-trione

9a-Bromo-1β-hydroxyandrost-4-ene-3,17-dione (1.05 g), ethyl acetate (7.5 ml) and ethylene glycol (2.5 ml) were stirred at ambient temperature in a gas atmosphere, heated and refluxed for 10 hours. . After cooling, 10 ml of 2M hydrochloric acid and 10 ml of water were added, the mixture was stirred for 20 hours, and then ethyl acetate was removed under reduced pressure. The mixture was then salted with sodium chloride, cooled to 0 °, the crystals separated, washed with water and dried. The crystals are then dissolved in methylene chloride, ethylene acetate is added, the methylene chloride is evaporated, the solution is cooled, and the crystals are separated and dried. 0.52 g of the expected product is obtained, m.p. 221 DEG C. The aqueous phase is extracted with methylene chloride. The crude product is chromatographed on silica gel, eluting with methylene chloride / ethyl acetate = 95/5, to give 0.097 g of the desired product. which is crystallized from ethyl acetate, m.p. 220 ° C.

Example 2

3,3- (1,2-ethanedioxy diiol) -androst-4-ene-11,17-dione

100 ml of methanol, 5 g of the product obtained in the previous example are mixed with 1.8 ml of ethanedithiol and 2.5 ml of boron trifluoride etherate at ambient temperature under stirring for 1 hour 30 minutes, and the methanol is evaporated. dissolved in methylene chloride, washed with saturated sodium bicarbonate solution, then water, dried and evaporated to dryness. The product was recrystallized from hexane to give 5.99 g of the desired product, m.p. 160 ° C. NMR (CDCl ₃ 90 MHz ppm)

18-CH ₃ : 0.85; 19-CH ₃ : 1.27; thioketal: 3.17-3.47;

H4: 5.6

IR spectrum (CHCl ₃ ) presence at? 4? absorption 1645 cm ^-1 (C = C)

1709 cm ^-1 (C = 0 at position 11), 1740 (C = 0 at position 17)

Example 3

3,3- (1,2-Ethane-diyldithio) -androst-4-ene-11,17-dione 9a-Bromo-1β-hydroxy-androst-4-ene-3,17-dione and 40 ml ethyl acetate was stirred under inert gas and 0.9 mL of 2 M ethanedithiol was added at ambient temperature. Hydrochloric acid (0.09 ml) was added slowly to the mixture and stirred for 6 hours, then ethylene glycol (9.3 ml) was added and the whole was heated and stirred at reflux for 20 hours. Then cooled to 20 ° C, 40 ml of 2 M hydrochloric acid and 40 ml of water The mixture is agitated for 16 hours and the ethyl acetate under reduced pressure ⁽² Pa -26Ί0) max. 35 °. The resulting slurry was then cooled to 0-5 ° C, stirred for 1 hour, and the crystals were separated, washed with water, dried and chromatographed on silica gel with hexane / dioxane = 9/1. 3.2 g of the expected product are obtained.

NMR (CDCl ₃ 300 MHz ppm)

18-CH ₃ : 0.84 (s>; 19-CH ₃ : 1.26 (s); thioketal: 3.15-3.4;

H4: 5.57; frame: 1.1-2.61 (m)

IR _(CHCl3);

1741-1709 cm ^-1 (ketones); 1641 cm ^-1 (C = C)

Example 4

Cyclic 3 - [(1,2-Ethanediyl) mercaptol] androst-4-ene-3,11,17-trione

1) 2 g of 9a-bromo-11β-hydroxyandrost-4-ene-3,17dione and 20 ml of methanol are stirred under an inert gas atmosphere, then 0.5 ml of ethanediol is added at ambient temperature followed by 1 ml of boron trifluoride. etherate. The resulting material was stirred for 30 minutes at room temperature, then cooled to 4 ° C, and the resulting crystalline material was filtered and dried. 2.2 g of the expected product are obtained.

NMR (CDCl ₃ 300 MH ₃ ppm)

13-CH ₃ : 1.12 (s>; 11β-OH: 1.55 (d); 10-CH ₃ :

1.62 (s); CH ₂ group of thioketal: 3.17-3.40; 11-H

4.66; 4-H: 5.52

2) 132 ml of n-butanol are added to 15.76 g of the product obtained in the preceding point, then 0.670 g of molecular sieve and 0.41 ml of tetrafluoroboric acid are added and the resulting suspension is heated at 115 ° C for 2 hours with stirring. At this time, the medium becomes soluble, the molecular sieve is filtered off, the filtrate is washed with ethyl acetate, and the solvent is evaporated. To the residue was added methanol (22 ml) and the mixture was stirred for 16 hours. The product was filtered off and dried. 11.42 g of the expected product are obtained.

IR _(CHCl3);

OH: 3612 cm ^-1 ; carbonyl: 1736 cm ^-1 ; double bond:

1650 cm ¹

Claims (11)

PATENT CLAIMS A process for the preparation of compounds of the formula I in the formula K is an oxo protecting group of formula (a) or (b) wherein n is 2 or 3, preferably 2, HU 224,068 Β1 L is an oxo group and then the dashed line at the 11-position represents a valence bond and X represents a hydrogen atom or L represents a hydroxyl group at the β-position and the dashed line at the 11-position does not represent a valence bond and X represents a chlorine, bromine or iodine atom, preferably a bromine atom, characterized in that a halohydrin of formula II is a chlorine, bromine or iodine atom, is rearranged in the presence of alcohol to form a compound of formula (III) and then selectively protected at its 3-oxo group with HO- (CH ₂ ) _n -SH or HS- (CH ₂ ) _n - By treatment with a compound of formula SH, wherein n is 2 or 3, to give a compound of formula IV, wherein K is a protecting group of a 3-oxo group of formula (a) or (b); or a compound of formula (II) as above is selectively treated with a protecting agent of the 3-oxo group as above and the resulting compound of formula (V) is obtained. was: - wherein X and R are as defined above - if desired, (IV) a compound of formula rearrangement by treatment with an acid and alcohol. 2. A process according to claim 1, wherein the halohydrine of formula II, wherein X is as defined in claim 1, is rearranged in the presence of an alcohol, followed by treatment with an acid of formula III. wherein the 3-oxo groups are obtained HO- (CH) _n -SH or HS- (CH ₂ ) _n -SH, wherein n is as defined in claim 1, is selectively protected with a thiol or dithiol of formula 1 to give a compound of formula (IV) is according to claim 1. 3. The process of claim 1, wherein a compound of formula II according to claim 1 is selectively protected on the 3-oxo group as described therein, wherein the resulting compound of formula V wherein X and K are and rearranging it in the presence of an alcohol according to claim 1 and converting it to a compound of formula IV by acid treatment. 4. A process according to any one of claims 1 to 3, characterized in that a compound of formula II is used wherein X is bromo. 5. A process according to any one of claims 1 to 4, wherein the halohydrogen rearrangement is carried out in the presence of a long chain alcohol or a polyhydric alcohol. The process according to claim 5, wherein the halogenohydrogen rearrangement is carried out in the presence of excess ethylene glycol. 7. The process according to any one of claims 1 to 3, characterized in that the rearrangement is carried out in the presence of a co-solvent having a boiling point below 100 ° C at the reflux temperature of this solvent. 8. A process according to claim 7, wherein the co-solvent is ethyl acetate. 9. The process according to any one of claims 1 to 3, wherein the selective blocking of the 3-oxo group is carried out with ethanedithiol in the presence of a catalytic amount of hydrochloric acid or hydrobromic acid or boron fluoride etherate. 10. Process according to any one of claims 1 to 3, characterized in that the blocking of the 3-oxo group followed by rearrangement of the halogenohydrine compound is carried out without isolation of the intermediate (V). 11. Process according to any one of claims 1 to 3, characterized in that the Lewis acid is titanium tetrachloride. HU 224 068 Β1 Int Cl ⁷ : C07 J 1/00 (V) HU 224 068 Β1 Int Cl ⁷ : C 07 J 1/00 / ^s \ <CH ₂ > _n (a) (CH ₂ ) '(b)