DEG0012098MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Date of registration: June 29, 1953 Notified on September 20, 1956

GERMAN PATENT OFFICE

PATENT APPLICATION

CLASS 12o GROUP 25o5 INTERNAT. CLASS C 07c

G 12098 IVb / 12 ο

Thomas Walker, South Harrow, Middlesex (Great Britain)

has been named as the inventor

Glaxo Laboratories Limited, Greenford, Middlesex (Great Britain)

Representative: Dr. F. Zumstein, patent attorney, Munich 2

Process for the preparation of allopregnan-3 ß, 17a-diol-ll _r 20-dione The priority of the applications in Great Britain from September 4, 1952 and June 22, 1953

is used

The invention relates to a process for the production of allapregnan-3 / ?, 17 earth! K> l-ii, 20-dione by reacting an allapregnan-3 ß, 20-diol-ii-one- diacylates of the general formula

CH _q

CR ²

in which R ₁ and R _{2 are} esterified hydroxyl groups, and zwa, r R _{1 is} preferably an acyloxy group, e.g. B. an acetoxy group, propionyloxy group or benzoyloxy group, and R _{2 possibly an acyloxy group, which is derived from an aliphatic acid with 2 to} 5 carbon atoms, mean with an organic peracid in an inert organic solvent and subsequent alkaline hydrolysis. According to the invention; Compounds that can be produced by processes are intermediates for the synthesis of cortisone.

Chem he da and coworkers (Journ. Amer. Chem. Scc., Vol. 73, 1951, p. 4052) and Rosenkranz and; Staff (Journ. Amer. Chem. Soc, Vol. 73, 1951, p. 4055) have methods for the preparation of allopregnan-3 / ?, 17CrCUoI-II, 20-diion

609 619/401

G 12098 IVb / 12 ο

from AU op regnan - 3 β - oil - 11, 20 - dione. As can be seen from the cited references in their publications, both working groups have published them in the Journ. Amer. Chem. Soc, Vol. 71, 1949, p. 3262 and Journ. biol. Chem., Vol. 179, 1949, p. 507, for the introduction of a hydroxyl group in the 170-stel development of compounds of the normal series, transferred to compounds of the alloric series. In the enol acylation of AMopregnan-3/5-ol-ii, 20-dione with acetic anhydride and ^ p-toluenesulfonic acid by refluxing, they obtained the 11, 20-dienoleaetate (cf. Journ. Amer. Chem. Soc., Vol . 73, 1951,

P. 4055, right column, lines through 13), like this a course analogous to the reaction known in the normal series was also to be expected.

It. However, it has been found that the conversion of the 11, .20-Dienolaoetats in the epoxy in the AlIoreibe runs differently than in the normal series. While in the normal series the epoxy formation occurs selectively at the double bond in 17 (20) -S division, the oxidation of the 11, 20-dienol ester of the Alloreihei with peracids Mixture of two Mpnoxidoverbinduxigen, and one Obtained DiO'xidoverbindungen. These three connections which are present in approximately the same amounts correspond to the following formulas:

CH,

COAc

CH,

AcO

The subsequent alkaline treatment of this mixture then in turn provides a mixture consisting of allopregnan, -3 /?, 9 α-diol -11, 20-dione, AUopregnan-3 ß, i ^ et-diol-ii, 20-dione and allopregnan -3 / ?, ga, 17a-triol-i, 20-dione. Among the, by the. The reaction conditions described by the authors mentioned, the yield of AHopregnan- 3β , 17a-diol-ii, 20-dione is only about 25 to 30% (cf. Bartoin, Evans, Hamlet, Jo <nes and Walker, Journ. Chem, Soc, London , 1954, p. 747).

According to the invention, therefore, a compound of the general formula given at the outset is Subjected to reaction with an organic peracid in an inert organic solvent. Such compounds result exclusively in 17a, 20-MonO'xidoverbindungen and in the subsequent alkaline hydrolysis, the desired allopregnan-3 / ?, 17a-diol-i 1, 20-dione-in excellent yield. The preparation of the starting compounds for the inventive Processes which have the formula given at the beginning are described in patent application G 12097 IVb / 120.

Peracids suitable for carrying out the process according to the invention are peracetic acid, Performic acid, perbenzoic acid and preferably Monoperphthalic acid.

Suitable inert solvents for the process according to the invention are chloroform, ether, Acetic acid, Dio'xan or benzene, which can be used alone or in a mixture.

Preferably 1 to 10 moles of peracid are used each Moles of the starting teroi ds are used and it has been found that, for example, good results are obtained with Using 2 moles of monoperphthalic acid in the form of a 2.8 η solution can be obtained.

The reaction is expedient at temperatures carried out between -20 and + 60 °. '

The 17, 20-epoxides obtained are then subjected to alkaline hydrolysis, advantageously with alcoholic alkali, e.g. B. using sodium hydroxide in ethanol, converted into the AUopregnan-3 ß, ■ 17 ά-diöl-11, 20-dione, 1 °°

The following examples illustrate the process according to the invention.

Example ι

Production of 17, 20-oxidoallopregnan, ^ / ?, 20-di-

ol-i-on-diacetate

A solution of 1.3 g of crystalline 17 (20) -AHopregnen-3 / ?, 20-diol-ii-one-diacetate (F. = 154 to 156 °) in S ecm ether was 4.5 ecm of a 2, 8 see η-ether, added monoperphthalic acid solution (molar ratio 1: 2). After standing overnight, ether was further added and the solution was washed three times with ice-cold 5% sodium hydroxide solution and three times with water. After drying, over magnesium sulfate, dissolving and ¹¹ S evaporation of the ether, 1.3 g of a solid material was obtained, from which, after recrystallization from petroleum ether (boiling range 80 to 100 °), the 17.2O-oxido & llopregnan-3/3, 20-diol-ii-one diacetate was obtained in prismatic needles; Yield 1.05 g (78%> of theory) F. = 161 to 165 ⁰ [a] _D = + 15.8 ° (chloroform). The above-described properties, which were determined on the purest sample of the new compound which was to be obtained, may vary depending on the purity of the product.

61 · 9 / 4ιΟ1

G 12098 IVb / 12 ο

You can also use a solution of 5 g of the above. Treat enolaoetats in 20 ecm ether and 20 ecm chloroform at room temperature with peracetic acid solution (1.1 Mod) (cf. Findley and coworkers, Journ. Amer. Chem. Sog., Vol. 67, 1945, p. 412). After standing for 2 hours more ether was added: and the; Solution washed with sodium hydroxide solution and water. After drying over magnesium sulfate, the solvent was im. Removed vacuum and, the residue from petroleum ether (boiling range 80 to 100 °) ¹ recrystallized, and one received S g (96% of theory) 17,2O-oxidoallop'regnan-3 ^, 20-ddol-n-ondiacetate from F. = 158 to 160 °, which was identical to the compound described above.

Heirstelflung of Allopregnan-3 / ?, I7a-diol-11, 20-dione

A solution of 0.2 g of crystalline 17, 20-oxido-

ao allopregnan-3/5, 20-diol-11-one diacetate in 10 ecm ethanol was mixed with 10 ecm o, 6N sodium hydroxide solution. After standing for 2 hours at room temperature, the crystals were filtered off, washed with water ¹ and dried in vacuo over phosphorus pentoxide. Allopregnan-3 / ?, i7a-diol-ii, 20-dione with a melting point of 267 and 286 ° were obtained in a yield of 0.11 g (68.2% of theory).

Example 2

This example is intended to describe the conversion of anopregnan-3 /? - ol-ii, 20-dioni-acetate into allopregnan-3 / ?, lya-diol-ii, 20-dione, carried out without separating off the intermediate products.

A solution of 10 g Allopregnan-3 / J-ol-11, 20-dio ⁱ n-acetate in 95 cc of carbon tetrachloride has been at room temperature with a solution of 0.2 cc of 50 ^ / cent aqueous perchloric acid in 5 cc of acetic anhydride, After standing for 1 hour at room temperature, the solution was washed with ice-cold 5% aqueous sodium hydroxide and water and dried over anhydrous magnesium sulfate. The residue remaining after evaporation of the solvent in vacuo was taken up in 20 ecm of chloroform and; mixed with SS ecm of a 2N-ethereal monophthalic acid solution. After standing for 3 hours at room temperature, the solvent was evaporated and the remaining greasy substance treated with vigorous stirring and heating with 80 ecm of a hot 0.8 N potassium hydroxide solution in methanol. The solution became clear and a crystalline substance began to separate out almost immediately Cooling to room temperature and adding water, the solid substance was filtered off, washed with water and dried over phosphorus pentoxide at room temperature in vacuo to give pure AUopregnan-3 / ?, i7a-diol-ii, 20-dione in a yield of .8, 4 g (92% of theory).

This compound has two melting points, namely at 267 to 271 ° and at 286 to 289 ⁰ ; [α] ο = + 6s ° (C = 0.5%>dioxane); v _max (in Nujol) = 3400 and 3330 cm " ¹ (hydroxyl groups); and 1702 cm" ¹ (keto groups).

Claims (3)

PATENT CLAIMS: i. Process for the preparation of allopregnan-3 / ?, i7a-ddoL-ii, 20-dione, characterized in that an allopregnen-3 ß, 20-diol-11-one diacylate of the general formula CH ₃ in which R ₁ and R ₂ denote esterified hydroxyl groups and can be identical or different from one another, where R _{1 is} preferably an acetoxy, propionyloxy or benzoyloxy group and R _{2 is} preferably an acyloxy group derived from an aliphatic acid having 2 to 5 carbon atoms, for example an acetO'xy group means, in a known manner, with an organic! Reacts peracid in an inert organic solvent and the 17, 20-epoxide thus obtained of the general formula in which R ₁ and R _{2 have} the abovementioned meaning, which, if desired, can be separated off, then hydrolyzed under alkaline conditions in a known manner. 2. The method of claim 1, characterized, g - kennzeiebnet in that 1 to 10 Moli the organic peracid per ¹ Moil applying the starting steroid. 3. The method according to claim 1 and 2, characterized characterized because, ß the epoxidation, at a temperature in the range of -20 to + 6o °. © 609 619/401 9.56