DE2059050B - Process for the preparation of 16 beta methyl 9alpha fluor 11 beta, 17 alpha 21 tnhydroxy 1,4 pregnadiene 3,20 dione and its 21 acylates - Google Patents

Description

HO

'5

20th

in which R is hydrogen or the remainder of a carbon or Dicarboxylic acid means, characterized in that one according to methods known per se

a) 160-methyl-17a-hydroxy-1,4,9 (11) - pregnatrien-3,20-dione (II) with a brominating agent, in particular with N-bromosuccinimide or N-bromoacetamide in the presence of aqueous perchloric acid and an inert solvent, implements,

b) the 16 / S-methyl-9 «-bromo-l 1 β, Πα-dihydroxy -1,4- pregnadiene-3,20-dione (III) obtained is reacted with an organic or inorganic base in an inert solvent,

c) the 16 / i-methyl-9 (II) -epoxy-17a-hydroxy obtained -1,4 - pregnadiene - 3,20 - dione (IV) with hydrofluoric acid in an inert solvent implements,

d) the 16 /? - methyl-9a-fluorine-l 1,0,17. «- dihydroxy-1,4-pregnadiene-3,20-dione (V) with metallic iodine in an inert medium in the presence of an alkaline earth metal oxide and

e) the 21,21-diiodo-! 6 /? - methyl-9a-fluorine obtained

11 ß, 1 Ta - dihydroxy -1,4 - pregnadiene - 3,20 - dione (VJ) is reacted with an alkali or alkaline earth metal salt of a carboxylic acid in an inert solvent and any 2,1-acylates obtained are hydrolyzed.

and from the journ. Org. Chem, 31, 26, 1966 (R a u sscr et al), known. In all known processes, the fluorine is introduced into the C9- already at the C21-hydroxylated compound, since the hydroxylation of the 2l-position in the 9 <x-fluoro-11 / J-hydroxy-stcroids causes great difficulties, which one has already tried to overcome by that in similar cases, 21-hydroxylation carried out microbiologically, a process that is very complex and only low Yields.

The present invention is based on the object with the many reaction steps of the known Process for the manufacture of betamethasone to overcome technical difficulties associated and in a simpler and faster way betamethasone and its 21-acylates with higher partial and To produce final yields.

To achieve this object, the process of the present invention is used to produce 16 / i-methyl-9a-fluoro-n / i, 17a, 21-trihydroxy "1,4-pregnadiene-3,20-dione and its 21-acylates of the general formula

As the lo / J methylcorticosteroids today both The most effective corticosteroids pharmacologically as clinically is their manufacture, especially the fluorinated, of paramount importance.

The most important compounds in this group are 16 / i-methyl-9a-fluoro-np ', 17rt, 21 -trihydroxy-1,4-pregnadiene-3,20-dione and their 21-acylates.

Betamethasone was first used by Taub et al in Journ. At the. Chem. Soc, 80, 4435, 1958 and 82, 4012, 1962, and then by 01 i ν et ο et al in Journ. At the. Chem. Soc, 80, 6688, 1958. A method for producing betamethasone is also disclosed in Portuguese patent specification 36478, U.S. Patents 3,053,865,3104,246 and 3,164,618 HO

in which R is hydrogen or the residue of a carboxylic or dicarboxylic acid, in such a way that according to methods known per se

a) 16 / i-methyl- Πα-hydroxy-1,4,9 (1 l) -pregnatriene-3,20-dione (ll) with a brominating agent, in particular with N-bromosuccinimide or N-bromoacetamide in the presence of aqueous perchloric acid and an inert solvent, reacts,

b) the loess-methyl-methyl-a-bromine-II / i.na-dJhydroxy-1,4-pregnadiene-3,20-dione (III) obtained reacts with an organic or inorganic base in an inert solvent,

c) the obtained 16 / J-methyl-9 (ll) -epoxy-17a-hydroxy-1,4-pregnadiene-3,20-dione (IV) reacts with hydrofluoric acid in an inert solvent,

d) the obtained 16 / <- methyl-9o-fluoro-1 l / j ', 17a-dihyhydroxy-1,4-pregnadiene-3,20-dione (V) with metallic iodine in an inert medium in the presence of an alkaline earth metal oxide and

e) the 21,21-diiodo-16 / j-methyl-9 «-fluoro-1 obtained l / ^ na-dihydroxy- 1,4-pregnadiene-3,20-dione (VI) with an alkali or alkaline earth metal of a carboxylic acid in an inert solvent and hydrolyzed any 21-acylates obtained.

Appropriately, to carry out the method of the invention in the individual method steps the following inert solvents are used:

of the applied lo-

a) dioxane or tetrahydrofuran,

b) methanol, ethanol, dichloromethane, chloroform or a mixture of these,

c) dichloromethane, chloroform, tetrahydrofuran, dimethyl or diethyl formamide or else Water in the form of an aqueous solution of hydrofluoric acid with a concentration which is not less than 60%,

d) methanol or a methanolic solution of calcium chloride,

e) acetone, aqueous acetone, dimethylformamide, diethylformamide, acetonitrile or a mixture this.

With regard to the temperature, it is appropriate to use the following Temperatures to be observed in the individual process steps:

a) -15 to +35 ⁰ C,

b) 0 to + 25 ° C,

c) -70 to 0 ⁰ C,. ^

d) +24 to + 28 ° C,

e) boiling point temperature
solvent.

The following time periods are expediently possible for the individual process steps:

a) I to 6 hours,

b) 1 to 4 hours,

c) 1 to 5 hours,

d) 1 to 2 hours,

e) 2 to 4 hours.

The inorganic or organic base used for process step c) can be potassium or Sodium bicarbonate or hydroxide or sodium methylate being; calcium oxide is recommended as the alkaline earth metal oxide for process step d); Examples of alkali salts of a carboxylic acid for process step) are a potassium salt Monocarboxylic acid with 2 to 28 carbon atoms or a potassium or sodium salt of a dicarboxylic acid having 2 to 28 carbon atoms, e.g. B. a potassium salt of succinic acid. Examples of monocarboxylic acids are acetic, valeric, isovaleric or palmitic acid.

The advantage of the method of the present invention is that

a) the preparation of the 9 (11) -epoxy derivatives in the absence the hydroxyl group on C21- takes place, whereby almost quantitative yields are achieved (92.6% according to Example 2), because the steroids which are not hydroxylated at C21 are more stable than the 21-hydroxy derivatives in the alkaline one essential for the preparation of these epoxides Medium are;

b) the 21-hydroxylation of the 16-alkyl-9n-fluoroII / * -hydroxysteroid derivatives with a very high yield for the first time by chemical means.

A characteristic of the present invention is that the 21-hydroxylation of 16/9-methyl-9a-fluoro-U / i, 17 «-dihydroxy-1,4-pregnadiene-3,20-dione in a fast quantitative yield takes place.

Surprisingly, as has been found, the direct diiodination of 16fl-methyl- 9a - fluoro - 1 Ιβ, Πα - dihydroxy - 1,4 - pregnadiene-3,20-dione to form a new compound, namely the 21-diiodine derivative, possible.

It is also surprising that the 21-diiodine compound with a sodium or potassium salt Carboxy acid leads to a 21-monoacylated product, although both iodine atoms are removed at 21-; even more surprising is the fact that the implementation takes place even if the 21-hemiacylates are made from dicarboxylic acids.

A previously unattained yield is achieved if 21-diiodination and a subsequent one are used De-iodination with salts of a carboxy acid carries out, leading to the introduction of the 21 -monohydroxy group in the form of acylates, which are not yet in the series of the lo / J-alkyl-Qa-fluoro-11-hydroxy steroids has been carried out.

The yields obtained in the various processes in the hydroxylation of the C21 and Fluorination can be achieved with the C9- are as follows:

Present invention 63.3%

T a u b et al 42.6%

USA patent 3,104,246 47.2%

U.S. Patent 3,164,618 9.18%

Rausseretal 40.3%

The starting material for the process of the present invention is 16 / S-methyl-17-hydroxy-1,4, 9 (ll) -pregnatriene-3,20-dione of the following general Formula:

CH ₃

C = T = o OH

CH ₃

Il

first published by Amiard et al (I.e.) in the U.S. Patent 3,164,618.

This starting material is hydroxylated in a manner known per se in the 11 / i position and at the same time brominated in the C9 position, for example by "hydroxy bromination" with N-bromo-succinimide or N-bromoacetamide, in the presence of aqueous perchloric acid or in an inert solvent, such as dioxane, tetrahydrofuran, at a temperature of -15 to + 3S ⁰ C, the new compound 16β - methyl- 9a- bromo -1 l / U7a - dihydroxy -1,4 - pregnadiene-3 , 20-dione of the general formula

HO

accrues.

. Hydrogen bromide is then split off from compound III in a manner known per se in an alkaline medium, e.g. B. with an aqueous or methanolic solution of potassium or sodium hydroxide or by means of sodium methoxide in an inert solvent, and preferably in an inert atmosphere such as nitrogen, the new compound 16β-methyl -9,11-epoxy-11 /! F, 17a -dihydroxyl, 4-pregnadiene-3,20-dione of the general formula

CH ₃

Compound 16β - methyl - 9 "- fluoro - 11 / ?, 17" - dihydroxy-21-diiodo-21,4-pregnadiene-3,20-dione of the formula

is obtained in an almost quantitative yield. The main reason for the high yield is the omission of the substitution in the case of 21-, as a result of which the molecule becomes more stable in the alkaline medium when the elimination of hydrogen bromide takes place. In the following process step the compound IV is fluorinated according to known methods, e.g. B. by intimate contact with a solution of anhydrous hydrofluoric acid in dichloromethane, chloroform, tetrahydrofuran, dimethylformamide or diethylformamide or with an aqueous solution of hydrofluoric acid with a concentration of not less than 60% at a temperature of -70 to O ⁰ C, the Compound 16 / J - methyl - 9a - fluoro -11 / 3.17a - dihydroxy -1,4 - pregnadiene-3.20-dione of the formula

HO

which is formed in British Patent 913,943 (P. 10) is described as a degradation product of betamethasone; its synthesis and its physical Properties are not known.

Then a methanolic suspension of the compound V at C21- by means of a solution of elemental iodine in methanol in the presence of calcium chloride and calcium oxide diiodinated and so the new HO

CH ₃

formed in almost quantitative yield. The implementation runs smoothly with no side reactions if you have the The reaction conditions described in detail in the examples are followed.

The acylation of the compound VI by means of potassium or sodium salts of carboxylic acids per se known process occurs without difficulty, the 21-Acy la te of betamethasone, such as the 21-acetate, from which, as is known, betamethasone is obtained by a simple hydrolysis can be.

The following examples are the conditions of use and the isolation of the products which can be prepared according to the invention are described.

Examples

1. There were 69.9 g of 16ß-methyl-17a-hydroxy-1,4, 9 (1 l) -pregnatricn-3,20-dione (melting point 168 to

170 ° C, egg * 435 at 239 to 240ΐημ) added to 812 cm ^{3 of} tetrahydrofuran and 433.8 cm ^{3 of} dilute perchloric acid (27.6 cm ^{3 of} 70% perchloric acid diluted with water to 1000 cm ³ ). The reaction mixture was cooled to +15 C and ^D 36,99g N-bromoacetamide was added and the reaction mixture stirred for 4 hours at a temperature of 25 to 30 ⁰ C. The reaction mixture was then rapidly decolorized by adding a few drops of an aqueous solution of sodium bisulfite. The desired 160-methyl-9u-bromyl / <, 17o-dihydroxy-1,4-pregnadiene-3,20-dione was precipitated by adding the reaction mixture to 41% ice water. The crude product was then washed with water and dried at 4O ⁰ C; 85.8 g of a product were obtained, which corresponded to a yield of 96%; the product had a melting point of 157 to 158 ° C, a specific rotation f. «] ο +120 (c = 1 in dioxane), EJ *„ 295 at 243 ηΐμ. After recrystallization from ethyl acetate, the melting point rose to 178 to 180 ° C, and the EU value was 308 at 243 πΐμ in methanol. The product was soluble in dioxane, somewhat soluble in ethyl acetate, and insoluble in ether and water; the main maxima of the infrared absorption curve were 2.9, 5.84, 6.02, 6.16, 9.6, 9.98, 11.3 μ.

Analysis: C ₂₂ H ₂₉ O ₄ Br = 437.4.

Calculated ... Br 18.26%;
found Br 18.37%.

2. 85.3 g of the crude product obtained according to the preceding example were suspended in 1.0111 methanol and 674.3 cm ^{3 of} chloroform and then, dropwise, 200.28 cm ^{3 of} a normal solution of sodium hydroxide for 25 minutes with stirring and a nitrogen atmosphere at a Temperature from 0 to +3 ⁰ C added. After stirring for 3 hours, the reaction mixture was neutralized with 50% aqueous acetic acid and concentrated under vacuum until a crystalline slurry was obtained. The product was then ^{precipitated by adding 1390 cm 3 of} ice water and 64.4 g of the desired new product 16 / J-methyl-9,11-epoxy -17α-hydroxy -1,4-pregnadiene-3,20-dione were obtained, which had a melting point of 186 to 191 ° C, a specific rotation [α] ₀ + 50 (c = 1 in dioxane) and an EJl 400 at 249 to 250 ηΐμ in methanol. The stoichiometric yield was 92.6%. The product was soluble in dioxane, chloroform, slightly soluble in acetone and insoluble in ethyl and isopropyl ethers and water. The major peaks of the infrared absorption curve were at 2.96. 5.84, 6.02, 6.16, 6.2 (shoulder), 8.3, 9.47, 10.03, 11.2, 11.57 μ.

Analysis: C ₂₂ H ₄₈ O ₄ = 356.44.

Calculated ... C 74.13, H 7.92%;
found .... C 73.92, H 7.88%.

3. There are 52 of such product specified above in small quantities g cm ³ (60%) and cooled to -2O ⁰ C hydrofluoric acid added with dimethylformamide for 20 minutes 365th The reaction mixture was 3 ¹ Z stirred for ₂ hours at -16 to -18 ° C and poured into a mixture of 4.8 kg of ice, 960 cm of water and 921 cm ³ concentrated ammonia. The product was filtered, washed several times with water until it no longer contained any inorganic salts, then dried and 56.5 g of the desired new product 16 /? - Methyl - 9a - fluoro - ΙΙβ, Πα - dihydroxy -1,4 - pregnadiene-3,20-dione obtained in an impure state. The product thus obtained was pulverized and recrystallized from chloroform, and the pure product was obtained in the form of chloroform solvate. The chloroform resulting from the crystallization was ^{removed by heating to 105 °} C. and 44.3 g of the product were obtained, which corresponded to a yield of 82.4%. The end product had a melting point of 230 to 234 ^° C., a specific rotation of [a] _c +100 ± 10 (c = 1 in dioxane), an EJ * "404 at 239 m | i. The product was moderately soluble in methanol, slightly soluble in dichloromethane and chloroform and insoluble in ethyl and isopropyl ethers and in water. The major infrared absorption maxima in mineral oil gauze were at 2.98, 5.82, 6.01, 6.16, 6.21, 10.13, 10.43 and 11.1 µ. This curve deviates significantly from that of the solvate.

Analysis: C ₂₂ H ₂₉ O ₄ F = 376.45. ^

Calculated ... C 70.18, H 7.76, F 5.05%;
found .... C 70.2, H 7.81, F 4.91%.

4. The same procedure was followed, but instead of a 60% solution of hydrofluoric acid 80% aqueous hydrofluoric acid is used in dimethylformamide. The final yield amounted to 43.4 g; the product was identical to that of example 3.

5. 14 g of the product obtained according to Example 4 were added to a mixture of 56 cm ^{3 of} absolute methanol and 14 cm ^{3 of} a methanolic solution of anhydrous calcium chloride at a temperature of +25 to +27 ° C. After stirring for 5 minutes 7 g of calcium oxide were added and stirring was continued for 25 minutes. A solution was then added under a nitrogen atmosphere and in the dark and at a temperature of 25 to 27 ° C., containing 18.8 g of resublimed iodine in 42 cm ^{3 of} a 10% methanolic solution solution of anhydrous calcium chloride and 28 cm ¹ absolute methanol contained. the rate of addition performed according to the decolorization of the solution added. the mixture was stirred an additional 15 minutes, cooled to -10 to -12 ⁰ C and stirring V continued for ₂ hour at this temperature The product was then ^{precipitated by adding 1500 cm J} water and ice containing 15 cm ³ acetic acid, stirring was carried out for 1 hour, and the precipitate was filtered off , washed and dried under vacuum. The desired new 21 - diiodine - 16 /: '- methyl - 9a - fluorII / i, 17ii-dihydroxy-1,4-pregnadiene-3,20-dione fell in an amount of 20.6 g with a moisture content of 4, 9%, which corresponded to a yield of 100%. After washing with methanol, the product had a melting point of 164 to 166 ^° C. with decomposition. The infrared absorption curve in mineral oil showed major maxima at 2.9, 5.85, 6.01, 6.18, 6.22, 8.26, 9.37, 9.5, 11.1 and 11.22 µ.

Analysis: C ₂₂ H ₂₇ O ₄ J ₂ F = 628.3.

Calculated ... C 42.05, H 4.33, J 40.42%;
found .... C 41.9, H 4.5, J 40.8%.

6. 9.2 g of the product obtained as above were added to a mixture of 91.08 cm ^{3 of} acetone, 0.92 cm ^{3 of} water, 0.92 cm ^{3 of} acetic acid and 9.2 g of anhydrous potassium acetate, and the whole thing was added under reflux 1 Cooked for hour and 30 minutes in the dark and under a nitrogen atmosphere. It was ^{cooled to 55 °} C. and, after stirring for 5 minutes, by adding 730 cm ^{3 of} water and ice, 6.7 g of the desired betamethasone acetate were precipitated, which corresponded to a yield of 86.6%. Recrystallization from acetone gave the pure product with a melting point of 218 to 220 ° C, a specific rotation of [«]„ +125 (c = 1 in dioxane) and an EJ * 366 at 238 ηΐμ.

7. 67.0 g of the product prepared as above were ^{added to 250 cm 3 of} methanol, whereupon 45 cm ^{1 of} methanolic sodium methoxide 2N was added; after 10 minutes a further amount of 18 cm ^{3 of} sodium methoxide 2N was added, and after 20 minutes neutralization with 50% aqueous acetic acid took place. After precipitation with water, 57.1 g of betamethasone were obtained, which corresponded to a yield of 96.4%. After recrystallization from ethyl acetate the melting point amounted to 232-234 ⁰ C; recrystallization from acetone gave a melting point of 245 ° C. The product obtained in this way is identical to the product described in the literature.

8. By exchanging the potassium acetate of the

209 541/542

game 6 through potassium valerate, isovalerate, and palmitate in a mol / mol equivalent amount and when the reaction conditions described are repeated became the corresponding 21-valerate, 21-isovalerate and 21-palmitate of betamethasone. 9. When example 6 is repeated, but using the monopotassium salt of the amber

stinic acid and by adjusting the pH of the reaction mixture to 6 with triethylamine 21-hemisuccinate of betamethasone obtained after isolating and neutralizing the free Carboxyl group with sodium hydroxide the 21-hemisuccinate of betamethasone in the form of the sodium salt revealed.

Claims (1)

Claim: Process for the preparation of 16 / J-methyl-9a-fluorine-II / 3,17a-21 -trihydroxy-1,4-pregnadiene-3,20-dione and its 21-acylates of the general formula ₂₁ CH ₂ -OR