SE187962C1 - - Google Patents

Description

CLASS INTERNATIONAL SWEDISH C 07 c12 o: 25 PATENT AND REGISTRATION AGENCY Ans. 10 106/1954 on 8/11 1954 OLIN MA'THIESON CHEMICAL CORP., NEW YORK, NY, USA SAN TO PRODUCE FOR MEDICAL USE STEROOD RELEASES BELONGING TO THE PREGANAN OR PREGNANCY SERIES TJINFINNER: J Fried USA) The present invention relates to the synthetic preparation of valuable steroid compounds.

The object of the invention is to provide an advantageous process for the preparation of 9-α-fluorine, 11-8-hydroxisteroids of the pregnancies (including the pregnancies), in particular 9afluorohydrocortisone and acetic acid esters thereof, and a process for the preparation of 9α-fluorine, ketosteroids of the pregnane (including pregnen) series, in particular 9a-fluotcortisone and attic acid esters thereof, and to produce certain compounds which are immutable in the manufacture of physiologically active steroids and (in some cases) also useful due to their own physiological action.

The compounds of the invention consist of steroids belonging to the pregnane or pregnancies series having a 9α-fluorine substituent and an 11-keto or 11β-hydroxy substituent.

The process of the invention consists essentially in reacting a 9 / 3,11 / 3-oxide steroid from the pregnane or pregnancies with fluorate to give a 9a-fluorine, 11,8-hydroxisteroid, belonging to the pregnane or pregnancies, and in the resulting 11,8-hydroxysteroid may then be chromed with chromic acid to its 11-keto derivative.

Among the compounds prepared in accordance with the present invention, Aro is such as the general formula: CH 2 -YC = -O wherein the 4,5-position Or is double-bonded or saturated, in which formula R represents -H, R 'represents -OH or R and R 'together are O or a group which can be transferred thereto by hydrolysis, R "represents H, R" represents (15) -OH, or R "and R" together = O, Y represents -H, -OH or -O- (acyl), and Z represents either -Ii or (a) -OH. (Among the groups which can be transferred to a keto group may be mentioned acetal, in particular cyclic acetal groups).

Dupl. at 12 9: 25/06 The 9β, 11β-oxide steroids from the pregnancy series which can be used in the process according to the invention are prepared from the corresponding 9α-bromine, 118-hydroxide derivatives by all bromine hydrogen being cleaved from the latter. Among the 9α-bromo, 11β-hydroxisteroids of the pregnancy series, which can be used in the preparation of the starting material in the preparation according to the invention are marked: 9α-bromo-.614-pregnene-11β, 17α, 21-trio1-3,20-dione (Oven cand. such as 9α-bromo-17α-hydroxycorticosterone, α-bromo-2 --- - hydrocortisone or 9α-bromo-F), 9α-bromocorticosterone and its esters (especially the carboxylic acid esters, such as the lower alkanoic acid esters (eg acetate) ], these 9α-bromo-21-oxisteroids being prepared, for example, by the method set forth in J. Am. Chem. Soc., 75, 2273 (1953), 9a-bromo-11/3-hydroxyprogesterone and 9abromo-11 / 3-17a-dihydroxyprogesterone, these 9a-bromo-21-substituted steroids being prepared by the method described below. The obtained 9/3,11β-oxidosteroids, namely 916, 119oxido-Z14-pregnene-17α-21-diol1,20-dione (also known as 9/3,11β-oxido-17α, 21-dihydroxyprogesterone), 9 , 11β-oxido-L14pregnen-21-o1-3,20-dione (also called 913, 1113-coddo-21-hydroxyprogesterone), esters thereof, 9β, 1119-oxidoprogesterone and 9/3, 11/3-oxido-17a -hydroxyprogesterone is then treated with fluoroacetic acid, in non-alcoholic solvent, preferably at about 0 ° C, to give the corresponding 9α-fluorine, 11β-hydroxide derivatives namely: 9α-fluorocorticortisone, 9α-fluorocorticosterone, esters thereof, 9a -fluoro-11β-hydroxyprogesterone CELY C = O H0 - / \ / Z ./ \ BrKOAc 0 = \ / \ / I Y.-0AG; Z = OH II Y --- 0Ac; Z = 1-1 III Y — Z = H IV Y = H; Z = OH and 9α-fluoro-110,17α-dihydride progesterone. These 9α-fluoro, 11β-hydroxisteroids may optionally be converted to the corresponding keto compound by conventional oxidation procedures, e.g. with the aid of chromic acid in glacial acetic acid.

The steroids from the pregnancy series with a 9α-fluorine substituent and 11-keto or 119-hydroxy substituent (and the esters of these with a 21-hydroxy group) show, contrary to what can be predicted, corticoid activity in liver glycogen tests.

This activity is the activity of the corresponding steroids, where an additional halogen radical is replaced with the 9α-fluorine group and Or aven stk.- re The activity of the corresponding steroids, which joke aro are substituted in (The compounds of the invention with a 21-hydroxy group can be obtained directly in the form of or rapidly transferred to its fatty acid esters, in particular lower alkanoic acid esters).

For the sake of simpler first invention, in the following reference, the following reaction formulas should be given: CHO (C = 0 \ 0 = \ / \ / \ / VY = 0Ac; Z = OH VI Y = 0Ac; Z = H VII Y = Z = H VIII Y = 1-1; IX Y = Z OH HF HO— / N 0 = \ / \ / \ / XY = 0Ac; Z = OH XI Y = Z = OH XII Y = 0Ac; XIII Y --- = OH ; Z = H XIV Y = Z = H XV Y = H; Z = OH O = \ \ / XVI Y ---- 0Ac; Z XVII Y = Z = OH XVIII Y = 0Ac; Z = H XIX Y = OH ; XX Y = Z = H XXI Y = H; Z = OH CH2Y C = 0 lz CH, YC = 0 CrO, The following examples are intended to ash-grade degrees and all solutions refer to aqueous solutions, the invention and all temperatures are given in C another sages.

- - Example 1.

Preparation of 9α-fluorocortisone acetate (XVI). 9α-Fluorohydrocortisone acetate (X) from L14-pregnene-9 / 3,11 / 3-oxido-17α, 21-diol1,20-dione-21-acetate (V).

Anhydrous fluorine was added to a solution of Al-pregnene-913,11 / 3-oxido-17a, 21-diol-3,20-dione21-acetate in 300 ml of chloroform (stored in a polyethylene vessel equipped with riled copper inlet tubes) . During the addition, the solution is kept in an ice bath and stirred by magnetic stirring until the solution assumes a marked red color. The inlet tube was replaced (Wafter with a (polyethylene) plug) and the reaction was allowed to proceed with stirring for 4 1/2 hours at 0 DEG C. Concentrated sodium bicarbonate solution in water was then added until the mixture became slightly alkaline, and the two layers were separated. The yellow yellow chloroform solution is washed with water and evaporated to dryness. Over sodium sulfate to dryness in vacuo, the residue (about 17.0 g) is then taken up in 125 ml of hot ethyl acetate, the resulting suspension is filtered and the precipitate (pa. filter) is treated and the filtrate is treated. , as described below.

The ethyl acetate filtrate, on cooling, gives a crystalline precipitate consisting of long needles mixed with small heavy prisms. This material (about 6.2 g) is narrower at 228-230 ° and is essentially pure 9α-fluorohydrocortisone acetate. For analysis, this is recrystallized from ethyl acetate and then slapped at about 233-234 °. (Incidentally, samples are obtained which soften at about 205-208 °, solidify anyo and possibly melt at about 226-228 ° probably due to polymorphism). It has the following properties: [α] g + 123 ° (c, 0.64 in CHCl 3); 2.2Ik 238 (e = 16,800) 1 "° '2.86 p, 3.01, u, 5.62 p, 5.78, u, 5.83 z, 6.0pc; composition (calculated for C23113106F (422 ): C, 65, 39; H, 7.39; F, 4.52; Found (approximate): C, 65.32; H, 7.26; F, 4.50).

Fractionation of the ethyl acetate mother liquor gives an additional amount of 9α-fluorohydrocortisone acetate, thereby increasing the yield to a total of 50%. 9a-Fluorohydrocortisone acetate Or about eleven times more active On cortisone acetate in hepatic glycogen levels and about 1-2 times as active as desmdcorticosterone acetate in causing sodium retention in the rat (in causing sodium retention in the rat).

The ethyl acetate-soluble material on the filtrate (about 1.35 g) is recrystallized from acetone. The pure Direningen has the following properties: about 259-262 °, during browning; [α] + 262 ° (c, 0.53 in 95% ethanol); A itax 239 mu (s = 18,000); PTtai: 2.94 p, 3.03 p, 5.7 p, 5.82, a, 6.07, a; 6.11 p composition (calculation for C 23 HO 6 (402): C, 68.63; H, 7.51; found (approximate); C, 68.45; H, 7.17). 9a-fluorohydrocortisone (XI) from 9a-fluorohydrocortisone acetate (X).

To a solution of 103.8 mg of 9α-fluorohydrocortisone acetate in 10 ml of absolute methanol was added under a nitrogen atmosphere a solution of 11.4 mg of sodium in 1.9 ml of anhydrous methanol. The mixture is allowed to stand at room temperature for 30 minutes. and surdores genorri addition of a few drops of concentrated attic acid. Water was then added and after the methanol was removed in vacuo, the 9α-fluorocorticone was extracted with ethyl acetate. The extract is washed with sodium bicarbonate solution and water and dried over sodium sulfate. After evaporation of the solvent, a crystalline residue is obtained (about 92 mg). After recrystallization from 95% alcohol, Aiken has the following properties: about 260-262 ° (probing); [α] + 139 ° (c, 0.55 in 95% alcohol); qul, 239 mu (s = 17,600); Num 3.01 p, 5.84 p, 6.07, a, 6,, u; composition (calculated for CJ290F (380.4): C, 66.30; 1-1, 7.68; found (approximate): C, 66.49; H, 8.22). 9a-fluorohydrocortisone has the closest co-. ma biological activity as its acetate. 9a-fluorocortisone acetate (XVI) from 9a-fluorocortisone acetate (X).

To a solution of 31.2 mg of 9α-fluorohydrocortisone acetate in 3 ml of concentrated attic acid was added a solution of 10 mg of chromic acid in 2 ml of attic acid. Half an hour later, 1 ml of methanol was added, and the resulting mixture was concentrated in vacuo. The residue is partitioned between chloroform and water, and the resulting chloroform extract is washed with water, sodium bicarbonate solution and again with water. After drying over sodium sulphate and evaporation of the solvent in vacuo, the residue (about 25 mg) is recrystallized from 95% alcohol. The pure 9a-fluorocortisone acetate has the following properties: c: a 254- °, [a] g + ° (c, 0.45 in CHCl 2); Alk 234 mg (s = 17,000); A, No. 21 2.86, a, 5.72, a, 5.78, a, ax5.83 a, 6.0, u; composition (calculated for C231-12906F: C, 65, 70; H, 6.95; found (approximate): c, 65.62; H, 7.19). 9a-fluorocortisone acetate Or c: a tic times as active as cortisone acetate with & rattle liver glycogen. 9a-fluorocortisone (XVII) from 9a-fluorocortisone acetate (XVI). mg of 9a-fluorocortisone acetate is deacetylated as described in Example 1, paragraph b). About 18.4 mg of the product are obtained, which after crystallization from 95% alcohol gives about 14 mg of 9a-fluorocortisone with the following properties: about 261-262 '; [α] 2 3 - 1 4 4 ° (c, 0.41 in CHCl 3); A Ilk. 234 mit (8 = 16,000); niNue 2.88 p, 5.87, u, 6.08, a; composition (calculated for G 11-1270F; C, 66, 65; H, 7, 19; Found: C, 66.50; H, 6.98).

Example 2. 9α-Fluorocorticosterone acetate (XII) from 44-pregnene-9β, 11β-oxide-21-o1-3,20-dione-21-acetate (VI).

Anhydrous fluorine was added to an ice-cold solution of 100 mg of Z14-pregnene9p, 1113-oxide-21-o1-3,20-dione21-acetate in 10 ml of chloroform. After half an hour at 0 °, more chloroform was added, and the solution was extracted with sodium bicarbonate solution and finally Lorkas Over sodium sulfate. The ether residue (about 125 mg) is taken up in hot ethyl acetate and purified as described in Example 1 (a). The pure 9a-fluorocorticosterone acetate has the following properties: Signal point c: a 212-214 ° C, [a] y + 184 ° (c, 0.11 in CHCl 3); the activity is four times as great as for the cortisone acetate in liver glycogen tests, and more than ten times greater than for deoxycorticosterone acetate in terms of being able to retain sodium.

The procedure is the same as in Example 1, paragraph b), whereby 9a-fluorocorticosterone acetate can be hydrolyzed to 9a-fluorocorticosterone (XIII). Proceed in the same manner as in Example 1, paragraph c), 9a-fluorocorticosterone acetate can be oxidized to 9a-fluoro-11-dehydrocorticosterone acetate (XVIII). Proceeding in the same manner as in Example 1 (b), 9α-fluoro-11-dehydrocorticosterone acetate can be hydrolyzed to 9α-fluoro-11-dehydrocorticosterone (XIX).

Example 3. 9α-fluoro-11β-hydroxyprogesterone (XIV) from 9/3,11β-oxidoprogesterone (VIII). 63.2 mg of 9,11β-mddoprogesterone in 6.3 ml of chloroform are reacted with gaseous fluorine at 0 ° C for 1 hour. The reaction mixture is worked up as described in Example 1 (a), and the resulting residue (about 61 mg) is crystallized from acetone-hexane. Pure 9α-fluoro-11β-hydroxyprogesterone is obtained after a further recrystallization from absolute alcohol and has the following properties: about 216-217 ° C; [α] + 191 ° (c, 0.74 in chloroform); the activity is the same as for cortisone acetate in liver glycogen tests, and twice the activity for deoxycorticosterone acetate is able to retain sodium.

Oxidation of 9α-fluoro-11,13-hydroxyprogesterone with chromic acid in the same manner as in Example 1, paragraph c) gives 9α-fluoro-11-ketoprogesterone (XX).

Example 4. 9α-Fluoro-11β-, 17α-dihydroxyprogesterone (XV) from 614-pregnene-9β, 11β-oxido-17α-o1-3,20-dione (VIII). 42 mg of 44-pregnene-9fl, 11fl-oxido-17α-o1-3,20-dione are dissolved in 3 ml of chloroform and reacted with gaseous fluorine at 0 ° C for 1 hour. The reaction mixture is worked up as described in Example 1, paragraph a), and the residue obtained (about 36 mg) after crystallization from acetone-chloroform-hexane gives pure 9α-fluoro-11/3, 17α-dihydroxyprogesterone having the following properties: Melting point c : 274-27 ° C; [α] D 4-136 ° (c, 0.3 in dioxane); activity one third of the activity of the cortisone acetate in liver glycogen tests. 9α-fluoro-11 / 3,17a-dihydroxyprogesterone can be oxidized to 9α-fluoro-11-keto-17α-hydroxyprogesterone (XXI) by the method of Example 1, paragraph c).

Claims (3)

Patent claim: A method of preparing for medical use steroid compounds belonging to the pregnane or pregnancies series, characterized in that a 9β, 11/3-oxidosteroid is reacted from the pregnane or pregnancies series with fluorvate to obtain a 9α-fluoro-1116-hydroxy steroid belonging to the pregnane or pregnancies series and that the resulting 11phydride steroid may then be oxidized with chromic acid to its 11-keto derivative. 2. Claimed according to claim 1, characterized in that the reaction with fluorvate is carried out in the presence of an alcohol-free lifting agent. 3. A kit according to claim 1 or 2, characterized in that L14-pregnane-913, 11/3-wddo-17a, 21-diol-3,20-dione or its attic acid ester, Z14-pregnene-9 / 3,1119-oxido-21-o1-3,20-dione or its acetic acid ester, 916, 11/3-coddoprogesterone or L14-pregnene-9 / 3,11 / 3-coddo-17a-o1-3,20-dione . Request publications: American chemical society. Easton. Journal 75. (1953), pp: 2273, 76 (1954), pp. 1455-56.