NL8400910A - 17-ESTERS OF CLOBETASOL AND METHOD FOR PREPARING THE SAME - Google Patents

Description

Esters of dobetasol and method of preparation thereof.

* _ <, - ______ VO 6164

The present invention relates to a method of preparing 17-esters of Clobetasol. The invention further relates to Clobetasol 17 esters obtained by the method according to the invention.

It is known from US Pat. No. 3,721,687 that Clobetasol 17 esters can be prepared from 17 esters of beta-methasone via the corresponding 21 alkyl sulfonates. However, the reaction is slow, requires reaction times of 1-3 days, and the product is obtained in low yield and in an impure state.

10 requiring chromatography and repeated crystallization to obtain the pure feed.

The object of the present invention is to provide a simple and efficient process for the preparation of Clobetasol 17 esters, which does not involve long reaction times and provides the product in an easily purified form and which is suitable for large-scale technical application.

These purposes are achieved by a process in which readily available esters of 9beta, 11beta-epoxy-17,21-di-hydroxy-16beta-methylpregna-1,4-diene-3,20-dione of formula 1 of the formula sheet wherein R represents an alkyl group or aryl group having up to 6 carbon atoms and R 'hydroxy are treated with methanesulfonyl chloride to form the corresponding 21 mesylate derivatives of formula 1 wherein R is as defined above and R' is mesyloxy followed by treatment with lithium chloride to form the corresponding 21-chloro derivatives of the formula 1, wherein R is as defined above and R 'is chlorine, which when treated with hydrogen fluoride give the corresponding 17-esters of Clobetasol of the formula 2, wherein R is as above is defined.

The success of the reaction sequence of the invention is surprising because the nucleophilic substitution of a 21-mesyloxy group by chlorine in a substrate containing a 9beta, 11beta epoxy group, without breaking the 9beta, 1beta epoxy group, could not be to provide. The opening of 9beta, 1-beta-steroidal 8400310_ _____ ¢ - ΐ -2-epoxides to the corresponding chlorohydrins by reaction with lithium chloride in acetic acid is known from U.S. Pat. No. 3,652,604. However, under the reaction conditions of the invention no discernible amounts of chlorohydrins 5 are formed. The yields of the 21-chloro-9beta, 11-beta epoxy compounds are indeed almost quantitative, which is remarkable in view of the low yields obtained using the 9-alpha-fluoro-11 beta-hydroxy compounds according to U.S. Pat. No. 3,721 .687.

A further surprising feature of the nucleophilic substitution on the 9beta, 11beta epoxides is the ease with which the reaction proceeds.

In U.S. Pat. No. 3,721,687, a similar substitution is made with 9-alpha-fluoro-11beta-hydroxy compounds under conditions requiring reflux for 3 days and using a 2000% excess of lithium chloride.

Under the conditions of the present invention, the reaction is completed after 1-3 hours at temperatures ranging from 60-90 ° C while using only a small excess of lithium chloride.

A marked advantage of the present invention is that the intermediates are obtained in a sufficiently pure form by simple aqueous precipitation (or total extraction), rendering purification of the intermediate unnecessary. Furthermore, the end products are obtained in such a pure state that they can be brought to pharmacopoeia standards by simple crystallization. Using the process of U.S. Pat. No. 3,721,687, the intermediates require purification and the final product must be chromatographed and crystallized repeatedly. The method of the present invention is therefore more suitable for large-scale technical application.

The first stage of the present invention consists of 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 virtually quantitative.

8400910 __ * '-i -3-

The second stage according to the invention consists of replacing the 21-mesyloxy group with chlorine. This process is carried out in a suitable dipolar aprotic solvent such as acetone, dimethyl formamide, hexamethylphosphoric acid, or mixtures thereof. Dime-5-thylfon seed.de is preferably used because the substrates of this solvent dissolve well, allowing the reaction at high concentrations (16-20% w / v) can be performed, an important factor in industrial production.

In contrast, the process of U.S. Pat. No. 3,727,687 is conducted at a concentration of less than 1.5% w / v.

The preferred source of chloride ions is anhydrous lithium chloride, although any compound that can provide chloride ions can be used. An advantage of the method according to the invention is that only a slight excess of lithium chloride is used.

The reaction can be carried out at temperatures preferably between 30 and 120 ° C.

The yields obtained in this step are surprisingly high (92-96% of the theory).

The final step of the invention consists of the conversion of the 9beta, 1beta epoxy group into the corresponding fluorohydrin using hydrogen fluoride, a known reaction.

The fluorination can be performed by conventional methods, for example, with aqueous hydrogen fluoride or mixtures of anhydrous hydrogen fluoride with tetrahydrofuran, dimethylformamide, urea, or pyridine. The use of 70% aqueous hydrogen fluoride has been found to be suitable and gives high yields.

The starting materials for the present invention are n3.

Beta, 11beta-epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-dien-3, 3,20-dione 17-esters are known or can be readily prepared from the commercially available betamethasone intermediate 9betar-1beta epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione using the procedure of U.S. Patent 3,755,302.

Without further elaboration, it is believed that those skilled in the art from the foregoing description are able to practice the present invention to its fullest extent.

-84-0 -4 -9 1 0 -: - -4-

The following specific preferred embodiments are therefore for illustrative purposes only and do not limit the rest of the description in any way.

The temperatures in the examples are expressed in degrees 5 Celsius.

Preparation 1

To a suspension of 1 kg of 9B, 11 6-epoxy-17,21-dihydroxy-16B-methylpregna-1,4-diene-3,20-dione in 7 liters of dry tetrahydrofuran and 1 liter of triethyl orthopropionate is dissolved added 10 g of para-toluenesulfonic acid in 1 liter of dry tetrahydrofuran. The mixture quickly becomes a solution and after 1 hour 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 15 and 3.2 g of sodium acetate in 4 liters of water is added and the mixture is refluxed for 3 hours, concentrated to a volume of 4 liters and diluted with 10 liters of water.

The precipitated 9B, 11B-epoxy-17.21-dihydroxy-16B-methylpregna-1,4-diene-3,20-dione 17-propionate is collected, washed well with water and dried under reduced pressure. The yield is 1.1 kg.

A sample crystallized from diethyl ether had the following properties:

Melting point: 150 ° C with decomposition [α] β + 47.5® (C = 1, chloroform) 25 RBr I.R. v 3470, 1730, 1665, 1630, 1610 cm ”1.

j max [t · 2 Further 17-esters of 98,11 B-epoxy-17,21-dihydrosy-1,6 B-methyl-j-pregna-1,4-diene-3,20-dione were used according to the above general 30 method prepared. For example, by replacing triethyl orthopropionate with triethyl orthobenzoate, the corresponding 17 benzoate having the following properties was obtained.

KBr I.R. v 3500, 1725, 1715, 1670, 1630, 1610, 1590, 1280, 35 max; 720 cm 1, melting point 144-146 ° C.

§400910_i .1 * -5-

By replacing triethyl orthapropionate with trimethyl ortho valerate, the corresponding 17 valerate with the following properties was obtained:

Melting point 125-127 ° C (from diethyl ether) 5 'KBr ΙΛ. V 3510, 3460, 1740., 1675, 1640, 1613 cm "1, max

Example I

To a solution of 1 kg of 96,11δ-epoxy-17,21-dihydroxy-16 S-10-methylpregna-1,4-diene-3,20-dione 17-propionate, as obtained under preparation 1, in. 5 liters of dry pyridine were added at 0 ° C for 10 min 500 ml of methanesulfonyl chloride. After 30 min at 0-5 ° C, the excess reagent was destroyed with 100 ice and the reaction mixture was poured into a well stirred mixture of 5.2 liters of concentrated hydrochloric acid and 50 liters of water at 0 ° C. The precipitate of 9β, 11th-epoxy-17.21-hydroxy-16S-methylpregna-1,4-diene-3,20-dione 17-propionate-21-mesylate was collected, washed thoroughly with water and under reduced pressure dried. The yield was 11.8 kg.

A sample crystallized from diethyl ether had the following * 20 properties:

Melting point 139.5 ° C

Γα] ^ + 60 ° (C * 1, chloroform) KBr I.R. V 1750, 1730, 1670, 1635, ± 615 cm "1 * 25 max

Similarly, using the 17-acetate, 17-butyrate, 17-valerate, or 17-benzoate of 9β, 11δ-epoxy-17,21-diiydroxy-16B-methylpregna-1,4-d. One, 3, 20-dione, the corresponding 21-mesylate derivatives are obtained.

The chemical physical properties of 9S, 11S-epoxy-17,21-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-17-benzoate 21-mesylate were: mp 194 ° C.

KBr I.R. v 1740, 1710, 1665, 1630, 1605, 1585, "320.cm" 1.

35 max 84 0 0 910_______ 4 · -6-

Example II

To a solution of 1.012 kg (2.0MD ^ B ^ 1B-epoxy - ^ 1-dihydroxy-10B-methylprecyl-1,4,4-diene-3,20-dione 17-propionate 21-mesylate (Example I 106 g of 5 (2.5 mol) anhydrous lithium chloride were added in 6.72 liters of dry dimethylformamide, and the mixture was heated at 85-90 ° C under nitrogen for 1.5 hours, cooled and mixed slowly in 67 liters of water at 2 ° C were poured with vigorous stirring.

The precipitate of 2l-chloro-9β, 11β-epoxy-17-hydroxy-16 O-methylpregna-1,4-diene-3,20-dione 17-propionate was collected, washed well with water, and dried under reduced pressure . The yield was 860 g (96% of the theory).

A sample crystallized from dichloromethane diisopropyl ether had the following properties:

Melting point 110 ° C

15 + 79.5 ° (C, 1, chloroform) KBr I. v 3450, 1740, 1665, 1630, 1610, 1590 af1, max

Similarly, using 17-acetate, 20 17-butyrate, 17-valerate or 17-benzoate of 9B, 11B-epoxy-17> 21-dihydroxy-16B-methylpregna-1,4-diene-3.20 -dione 21-mesylate obtained in Example 1, the corresponding 17-ester of 21-chloro-9B, 11B-epoxy-17-hydraxy-1,6-beta-methylpregna-1,4-diene-3,20-dione was obtained.

The chemical physical properties of 17-benzoate of 21-chloro-25 TO-9B, 11B-epoxy-17-hydroxy-16B-methylpregna-1,4-diene-3,20-dione were: mp 202 ° C.

KBr.

j- -V {1740., 1710, 1-665., 1530., 1605, 1585 ^ 715 rmT1- ". j max

30 Example UI

1 kg of 21-chloro-9B, 11B-epoxy-17-hydroxy-16B-methyl-pregna-1,4-diene-3.20 was added to 10 liters of 70% aqueous hydrogen fluoride at -30 ° C. -dione 17-propionate (Example II). The mixture was brought to -20 ° C and stirred at this temperature for 2.5 hours, after which it was slowly poured into 100 liters of deionized water while stirring. The precipitate of Clobetasol 17-propionate 891Q91Q-7- was collected, washed thoroughly with water until neutral, and dried under reduced pressure. The yield was 1020 g.

The crude product with an analysis at about 80% is easily purified to more than 98% by crystallization from dichloro-S-methane diisopropyl ether and / or ethanol / water. The purified product obtained today is identical to an authentic sample.

Similarly, using the 17-acetate, 17-butyrate, 17-valerate, or 17-benzoate of 2l-chloro-96,11B-epoxy-17-hydroxy-16B-methylpregna-1,4-diene- 3,20-dione obtained in Example II, obtained the corresponding 17-ester of Clobetasol, the chemical-physical properties of which are as follows; KBr

Clobetasol 17 valerate: melting point 147 ° C. I.R. v: 3330, max 15 1745, 1730, 1660, 1610, 1600; KBr

Clobetasol 17-benzoate: melting point 183SC. I.R. v: 3390, c max 1740, 1710, 1660, 1620, 1600, 1590, 715.

_8 4 0 0 9 10 ____

Claims (15)

A process for the preparation of Clobetasol 17 esters, characterized in that • a) 9β, 11B-epoxy-17,2l-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17-esters are converted to the corresponding .21 mesylates by reaction with mesyl chloride; b) the 21 mesylate is converted to the corresponding 21-chloro derivative by substitution with chloride ions; c) the hydrogen fluoride epoxidation is opened to form Clobetasol 17 esters. 2. Process according to claim 1, characterized in that the starting product is selected from 17-propionate, 17-acetate, 17-butyrate, 17-valerate or 17-benzoate-of 9β, 11B-epoxy-17,21- dihydroxy-166-methylpregna-1,4-diene-3,20-dione. 3. Process according to claim 2, characterized in that the starting product is the 17-propionate of 9β, 11g-epoxy-17,21-dihydroxy-166-methylpregna-1,4-diene-3,20-dione . 4. Process for preparing 21-chloro-9g, 11B-epoxy-17-hydroxy-16B-methylpregna-1,4-diene-3,20-dione 17-esters, characterized in that the corresponding 17- esters of 9β, 11B-epoxy-17,21-dihydroxy-168-20 methylpregna-1,4-dien-3,20-dione 21-mesylate are subjected to a selective nucleophilic displacement of the 21-mesyl group by means of chloride ions. 5. Process according to claim 4, characterized in that the selective nucleophilic displacement of the 21-mesyloxy group is carried out in aprotic dipolar solvents, such as acetone, dimethylformamide, hexamethylphosphoramide or mixtures thereof, by means of chloride ions. 6. Method according to claim 5, characterized in that the selective nucleophilic displacement is carried out at temperatures ranging from +30 to + 120 ° C, preferably from +60 to + 90eC, for a time ranging from 1 to 3 hours and at concentrations ranging from 15 to 20% w / v. 7. Process according to claim 6, characterized in that the source of chloride is anhydrous lithium chloride and that the solvent is "35 dimethylformamamide. 8 4 0 0 9 1 0__ • ✓ -9- Process according to claims 4-7, characterized in that 9S, 11S-epoxy-17,21-dihydroxy-16s-methylpregna-1,4-diene-3,20-dione 17-propionate 21-mesylate is transformed into 21-chloro-9B, 116-epoxy-17-hydroxy-16β-methyl-regna-1,4-diene-3,20-dione 17-propionate. 9. Process for the preparation of Clobetasol 17 esters, characterized in that the corresponding 17 esters of 21-chloro-9B, β-epoxy-17-hydroxy-16B-methylpregna-1,4-diene-3,20 -dione to be treated with hydrogen fluoride. 10. A method according to claim 9, characterized in that aqueous hydrogen fluoride is used at concentrations ranging from 50-80% and at temperatures ranging from -40 to 0 ° C. A method according to claim 10, characterized in that the aqueous hydrogen fluoride has a concentration of about 70% and the reaction is carried out at a temperature ranging from 15 -30 to -10 ° C. Process according to claims 9-11, characterized in that 21-chloro-9B, 11β-epoxy-17-hydroxy-16β-methylpregna-1,4-diene-3,20-dione 17-propionate is transformed into Clobetasol propionate. 13. 21-Chloro-9s, 11β-epoxy-17-hydroxy-16β-methylpregna-1,4-diene-3,20-dione 17-esters obtained according to one or more of claims 1-12. 14. 21-Chloro-9B, 11B-epoxy-17-hydroxy-16β-methylpregna-1,4-diene-3.20-dione 17-propionate obtained according to one or more of claims 1-12-25 15. 21-Chloro -9B, 11B-epoxy-17-hydroxy-16B-methylpregna-1,4-diene-3.20-dione 17-acetate obtained according to one or more of claims 1-12. 16-21-Chloro-96,11B-epoxy-17-hydroxy-16β-methylpregna-1,4-diene-3.20-dione 17-butyrate obtained according to any one of claims 1-12. 17. 21-Chloro-9e, 11-epoxy-17-hydroxy-16e-methylpregna-1,4-diene-3,20-dione 17-valerate obtained according to one or more of claims 1-12. 18. 21-Chloro-9e, ilB-epoxy-17-hydroxy-16B-methylpregna-1,4-diene-3,20-dione 17-benzoate obtained according to one or more of claims 1-12. __ β4 0 0 9 t 0_________ if -to- I _____________ ".... - .. A -10- 19. Clobetaso.1 17 valerate obtained according to one. or more of claims 1-12. Clobetasol 17-benzoate obtained according to one or more of claims 1-12. . 84 0 0 9 1 0 F-R '= 0. OCOR 0 CH3 2 —ci = Ό HO ^ .OCOR 1 ~ CH3 8400910 SICOR Societa Italiana Corticosteroidi S.p.A.