NO840065L - PROCEDURE FOR THE PREPARATION OF 17-ESTERS OF CLOBETASOL - Google Patents

Description

The present invention relates to a method for the production of 17-esters of clobetasol. A further object is clobetasol 17-esters obtained according to the method of the present invention. It is known from US patent no. 3,721,687 that clobetasol 17-esters can be prepared from 17-esters of betamethasone via the corresponding 21-alkyl sulphonates. However, the reaction proceeds slowly and requires reaction times of 1-3 days, and the yield of product obtained is poor and impure, necessitating chromatography and repeated crystallization to obtain the pure form.

It is an aim of the present invention to provide a simple and effective method for the production of dlobetasol 17-esters, which does not involve long reaction times and which provides the product in an easily purified form and which is suitable for industrial production on a large scale.

These objects have been achieved by a process where readily available esters of 9beta,11beta-epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione with the formula I

where R is an alkyl group or aryl group of up to 6 carbon atoms and R' is hydroxy, treated with methanesulfonyl chloride to the corresponding 21-mesylate derivatives of the general formula I, where R is as defined above and R' is mesyloxy, followed by treatment with lithium chloride

which give the corresponding 21-chloro derivatives with the general formula I, where R is as stated above and R' is chlorine, which on treatment with hydrogen fluoride gives the corresponding i

terminal 17-esters of clobetasol of formula II,

where R is as indicated above.

The successful result of the reaction sequence in the present

invention is surprising as the nucleophilic substitution of a 21-mesyloxy group with chlorine in a substrate containing a 9beta,11betaepoxy group without breaking the 9beta,11betaepoxy group could not be foreseen by a person skilled in the art. The opening of 9beta,11beta steroid epoxides to the corresponding chlorohydrins by reaction with lithium chloride in acetic acid is known from US Patent No. 3,652,604. Under the reaction conditions of the invention, however, no detectable amounts of chlorohydrins are formed. In fact, the yields of 21-chloro 9beta,11beta-epoxy compounds are almost quantitative, which is remarkable in view of the low yields obtained using 9alpha-fluoro-11beta-hydroxy compounds in US Patent No. 3,721,687.

A further surprising feature of the nucleophilic substitution of 9beta,11beta-epoxides is the ease with which the reaction proceeds. In US Patent No. 3,721,687, a similar substitution of 9alpha-fluoro-11beta-hydroxy compounds is carried out under conditions requiring 3 days at reflux and using a 2000% excess of lithium chloride.

Under the conditions of the present invention, the reaction proceeds completely in 1-3 hours at temperatures from

60 to 90°C with only a small excess of lithium chloride.

! A clear advantage of the present invention is that between

the products are obtained in a sufficiently pure form by simple aqueous precipitation (or total extraction), so that purification of the intermediate product becomes unnecessary. Furthermore, the end products are obtained in such a pure form that they can be brought to pharmacopoeia standard by simple crystallization. Using the method from US Patent No. 3,721,687, the intermediate product requires purification, and the final product must be chromatographed and crystallized several times. Thus, the method according to the present invention is more suitable for industrial production on a large scale.

The first step in the present invention consists in the formation of a 21-mesylate derivative from the corresponding 21-hydroxy compound using methanesulfonyl chloride in pyridine, a known reaction. The yields in this step are almost quantitative.

The second step of the invention consists in substituting the 21-mesyloxy group with chlorine. This procedure is carried out

in a suitable dipolar apriotic solvent such as acetone, dimethylformamide, hexamethylphosphoric acid triamide or mixtures thereof. The applicant prefers to use dimethylformamide, as the substrates have good solubility in this solvent, thus enabling the reaction to be carried out in high concentrations (16-20% weight/volume), an important factor in industrial production.

In contrast, the method in US Patent No. 3,721,687 is carried out at a concentration of less than 1.5% w/v.

The preferred chloride ion source is anhydrous lithium chloride, although any compound capable of emitting chloride ions may be used. An advantage of the method according to the invention is that only a small excess of lithium chloride is used. The reaction can be carried out at temperatures between 30° and 120°C, preferably.

i i The yields obtained in this step are surprisingly high

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(92-96% of theoretical).

The final step in the invention consists in the transfer of the 9beta, 11beta-epoxy group in the corresponding fluorohydrin using hydrogen fluoride, a known reaction. Fluorination can be carried out by usual methods, e.g. aqueous hydrogen fluoride or mixtures of aqueous hydrogen fluoride with tetrahydrofuran, dimethylformamide, urea or pyridine. The applicant finds 70% aqueous hydrogen fluoride appropriate, which gives high yields.

The starting materials for the present invention, namely 9beta,llbeta-epoxy-17,2l-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione 17-esters are either known or can be easily prepared from the betamethasone intermediate 9beta,llbeta-epoxy -17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione which is commercially available, using the method of US Patent No. 3,755,302.

Without further elaboration, it is assumed that a person skilled in the art will be able, by using the preceding description, to utilize the present invention to its full extent.

The following preferred particular embodiments are therefore to be considered illustrative only and not limiting the rest of the scope in any way.

In the following examples, all temperatures are given in degrees Celsius.

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Intermediate 1

To a suspension of 1 kg of 93/113-epoxy-17,21-dihydroxy-. 160-methylpregna-1,4-diene-3,20-dione in 2 1 of dry tetrahydrofuran and 1 liter of triethylorthopropionate is added to a solution of 10 g of par.α-toluenesulfonic acid in 1 liter of dry tetrahydrofuran. The mixture quickly dissolves and after 1 hour it is neutralized with 100 g of sodium acetate and poured into 50 liters of water. The precipitated 17,21-orthoester is collected, washed with water and suspended in 10 liters of methanol. A solution of 20 ml of acetic acid and 3.2 g of sodium acetate in 4 liters of water is added and the mixture is heated under reflux for 3 hours, concentrated to a volume of 4 liters and diluted with 10 liters of water. The precipitated 90,110-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propiorate is collected, washed well with water and dried under vacuum. Dividend:

1.1 kg.

A sample crystallized from diethyl ether has the following characteristics:

m.p.: 150°C during decomposition

Additional 17-esters of 93/113-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione were prepared according to the above general method. By e.g. using triethylorthobenzoate instead of triethylorthopropionate, the corresponding 17-benzoate with the following characteristics is obtained. I.R.v 3500, 1725, 1715 , 1670, 1630, 1610 , 1590, 1280 ,

720 cm"1, mp 144-146°C.

By using trimethyl orthovalerate instead of triethyl orthopropionate, the corresponding 17-valerate is obtained with the following characteristics: I I I

I.R.^)^r 3510 , 3460 , 1740 , 1675, 1640, 1615 cm 1.'

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EXAMPLE 1

To a solution of 1 kg of 93,113_epoxy-17,2l-dihydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propionate prepared under Intermediate 1, in 5 liters of dry pyridine at 0aC was added during 10 minutes 500 ml methanesulfonyl chloride. After 30 minutes at 0-5°C, the excess reagent was destroyed with 100 g of ice and the reaction mixture completely in a well-stirred mixture of 5.2 liters of concentrated hydrochloric acid and 50 liters of water at 0°C. The precipitate of 93/113-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione.17-propionate-21-mesylate was collected, washed thoroughly with water and dried under vacuum . Yield: 1.18 kg.

A sample crystallized from diethyl ether had the following characteristics:

m.p. 139.5°C

In a similar manner, but using the 17-acetate, 17-butylate, 17-valerate or 17-benzoate of 93/113_epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione the corresponding 21-mesylate derivatives were obtained.

Physicochemical characteristics of 93/113-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione-17-benzoate 21-mesylate: m.p. 194°C. I.R.\)<KBr>: 1740 , 1710 , 1665, 1630 ,

Jr., max

1605, 1585, 720 cm.

EXAMPLE 2

To a solution of 1.012 kg (2 mol) 93/113-epoxy-17,21-di-hydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propionate ! 21-mesylate (Example 1) in 6.72 liters of dry dimethylformamide

106 g (2.5 mol) of anhydrous lithium chloride were added and the mixture was heated under nitrogen for 1.5 hours at 85-90°C. cooled and slowly poured into 6 7 liters of water at 2°C with vigorous stirring. The precipitate of 21-chloro-93,110-epoxy-17-hydroxy-160-methylpregna-1,4-diene-3,20-dione 17-propionate was collected, washed well with water and dried under vacuum. Yield: 860 g (96% of theoretical).

A sample crystallized from dichloromethylene diisopropyl ether had the following characteristics:

m.p. 110°C.

In a similar manner, but using the 17-acetate, 17-butylate, 17-valerate or 17-benzoate of 93,113_epoxy-17,21-di-hydroxy-163_m'ethylpregna-1,4-diene-3,20-dione 2 1-mesylate, prepared in Example 1, the corresponding 17-ester of 21-chloro-93,113_epoxy-17-hydroxy-163-methylpregna-1,4-diene-3,20-dione was obtained.

Physicochemical characteristics of the 17-benzoate of .2l-chloro-93,113_epoxy-17-hydroxy-163_methylpregna-1,4-diene-3,20-dione: m.p. 202°C. I.R.\><Kbr>: 1740, 1710, 1665, 1630, 1605, 1585, 715 cm .

EXAMPLE 3

To 10 liters of 70% aqueous hydrofluoric acid at -30°C was added 1 kg of 2l-chloro-9 3/113-epoxy-17-hydroxy-163-methylpregna-1,4-. diene-3,20-dione 17-propionate (Example 2). The mixture was brought to -20°C and stirred at this temperature for 2.5 hours, and then very slowly in 100 liters of deionized water while stirring. The precipitate of clobetasol 17-propionate was collected, washed thoroughly with water to neutral reaction and dried under vacuum. Dividend : 1020. g.

j The raw product, which was approx. 80%-ig was easy to purify to ^>98%|

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by crystallization from dichloromethane diisopropyl ether and/or ethanol/water. The purified product thus obtained is identical to an authentic sample.

Similarly, using the 17-acetate, 17-butylate, 17-valerate or 17-benzoate of 21-chloro-93,113-epoxy-17-hydroxy-16(3-methyl-1-pregna-1,4-diene- 3, 20-dione prepared in example 2 gave the corresponding 17-ester of clobetasol, whose physico-chemical properties are as previously indicated: Clobetasol 17-valerate: mp 147° C. I.R.\)KBr: 3330, 1745, 1 max 1730 , 1660, 1610, .1600 ;

Clobetasol 17-benzoate: m.p. 183°C. I.R.n) KBr : 3390 , 1740 ,

max 1710, 1660, 1620, 1600, 1590, 715.

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Claims (12)

1. Procedure for the production of clobetasol 17-esters, characterized in that one: a) converts 93,113-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione 17-esters into the corresponding 21-mesy1-ates by reaction with mesyl chloride; b) transfers the 21-mesylates in the corresponding 21-chloro derivatives by substitution with chloride ions; c) cleaves the epoxide ring with hydrofluoric acid to clobetasol 17-esters. 2. Method according to claim 1, characterized in that the starting product is chosen from the 17-propionate, the 17-acetate, the 17-butyrate, the 17-valerate or the 17-benzoate of 93f 113-epoxy-17,2l-dihydroxy-16'3- methylpregna-1, 4-diene-3,20-dione. 3. Method according to claim 2, characterized by. that the 17-propionate of 93 / 113-epoxy-17., 2 l-dihydroxy-163~methylpregna-1, 4-diene-3,20-dione is used as starting product. 4... Process for the production of 21-chloro-93,113-epoxy-17-hydroxy-163-methylpregna-1,4-diene-3,20-dione 17-esters, characterized in that the corresponding 17-esters of 93/ 113-epoxy-17,21-dihydroxy-163-methylpregna-1,4-diene-3,20-dione 21-mesylate is subjected to selective nucleophilic substitution of the 21-mesyl group by means of chloride ions. 5. Method according to claim 4, characterized in that the selective nucleophilic substitution of the 21-mesyloxy group by means of chloride ions is carried out in aprotic dipolar solvents, such as acetone, dimethylformamide, hexamethylphosphoramide or mixtures thereof. ! 6. Method according to claim 5, characterized in that the selective nucleophilic substitution is carried out by. temperatures from +30 to +120°C, preferably from +60 to +90°C over periods of time varying from 1 to 3 hours and in concentrations from 15 to 20% weight/volume. 7. Method according to claim 6, characterized in that anhydrous lithium chloride is used as chloride ion source and dimethylformamide as solvent. ■ 8. Process according to claims 4-7, characterized in that 93,113-epoxy-17,2l-dihydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propionate 21-mesylate is transferred into 21-chloro-93 / 113-epoxy-17-hydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propionate. 9. Process for the production of clobetasol 17-esters, characterized in that the corresponding 17-esters of 2l-chloro-93-113-epoxy-17-hydroxy-163-rnetylpregna-1,4-diene-3,20-dione are treated with hydrofluoric acid. 10. Method according to claim 9, characterized in that aqueous hydrofluoric acid is used in concentrations from 50 to 80% and at temperatures from -40° to 0°C. 11. Method according to claim 10, characterized in that aqueous hydrofluoric acid is used with a concentration of approx. 70% and the reaction is carried out in a temperature range from -30° to -10°C. 12. Method according to claims 9-11, characterized in that 21-chloro-90,113_epoxy-17-hydroxy-163-methylpregna-1,4-diene-3,20-dione 17 propionate is transferred into clobetasol propionate.