US3056779A

US3056779A - Process for the oxidation of 20-hydroxy-pregnanes

Info

Publication number: US3056779A
Application number: US89638A
Authority: US
Inventors: Wettstein Albert; Anner Georg; Heusler Karl; Wieland Peter
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1960-02-18
Filing date: 1961-02-16
Publication date: 1962-10-02
Anticipated expiration: 1979-10-02

Description

United States Patent Ofiice 3,056,779 Patented Get. 2, 1962 3,056,779 PROCESS FOR THE OXIDATION OF ZO-HYDROXY-PREGNANES Albert Wettstein, Riehen, and Georg Antler, Karl Heusler, and Peter Wieland, Basel, Switzerland, assignors to Ciha Corporation, a corporation of Delaware No Drawing. Filed Feb. 16, 1961, Ser. No. 89,638 Claims priority, application Switzerland Feb. 18, 1960 2 Claims. (Cl. 260239.57)

The present invention relates to a process for the oxidation of 20-hydroxy pregnanes, more especially a process for the oxidation of 18:11-lactones of 11,8:20-dihydroxypregnane-lS-acids which may contain a ketalized oxo group in the 3-position.

20-hydroxy-pregnanes are, as a rule, readily oxidizable to 20'ketones with various oxidizing agents in acid or also in weakly alkaline solution, particularly with compounds of hexavalent chromium in glacial acetic acid or with a pyridine chromate complex. It has been observed, however, that in 18:11-lactones of 11,8:20-dihydroxy-pregnane-lS-acids the ZO-hydroxy group can only be oxidized with difiiculty by pyridine chromate both in an anhydrous and in an aqueous solution, since it is evident that the hydroxyl group and the lactone group influence each other, slowing down oxidation and even partially preventing it. In attempts to oxidize 18:11-1actones of 115:20- dihydroxy-pregnane-lS-acids in several cases of oxidation with pyridine chromic acid, even with a long reaction time and at a temperature up to 40 C., oxidation to the 20- ketone was always incomplete. In some cases oxidation did not take place at .all.

It has now been found that 18:11-lactones of saturated or unsaturated 11B:20-dihydroxy-pregnane-18-acids can be oxidized easily and in excellent yield to form the corresponding ZO-ketones when oxidation is carried out with a compound of hexavalent chromium in acidic solution.

It has been surprisingly found that oxidation can even be carried out in the presence of a ketal group in acidic solution without the ketal group being split. This is surprising considering the known susceptibility of ketals to acids. It is especially important to retain a ketal group, when, starting from a resulting 20-ketone, other reactions must also be carried out in which free keto groups, for example in the 3-position, interfere, for example, in the reaction for the introduction of a 21-oxygen function and the like.

The oxidation according to the present process takes an especially rapid course and gives a good yield when the reaction is performed in acetone solution with chromic acid-sulfuric acid at a low temperature, that is to say advantageously between 20 and +10 C. The excess mineral acid is preferably neutralized before working up by the addition of sodium or potassium acetate. The oxidation of the ketal-lactones may also be carried out in glacial acetic acid with chromium trioxide when a larger quantity of sodium acetate or potassium acetate is added.

The 20-hydroxy-lactones used as starting material can be prepared, for example, according to a known process from ll-oxygenated 18:20-oxido-pregnaues by acylolytic cleavage to 18:20-di-acyloxy'pregnanes, hydrolysis and oxidation to 18:20-lactones of ll-oxo-ZU-hydroxy-pregnane-l8-acids. The latter yield on reduction with sodium borohydride with translactonization the 18:11-lactones of 115220 dihydroxy pregnane 18 acids. The 18:20-lactones of ZO-hydroxy-ll-oxo-pregnane-lS-acids are also obtainable by another process which is described in US. patent application Ser. No. 74,486, filed Decemher 8, 1960, by Charles Meystre et al., in US. patent application Ser. No. 74,487, filed December 8, 1960, by Charles Meystre et a1. and in US. patent application Ser.

No. 74,470, filed December 8, 1960 by Oskar Jeger et al. The latter process consists in reacting lead tetraacetate with IS-unsubstituted 20-hydroxy-pregnanes in the presence of iodine, oxidizing the resulting products with chromium trioxide in the presence of silver chromate and, if desired, liberating an esterified Ila-hydroxyl group by hydrolysis or introducing a free hydroxyl group by microbiological oxidation and oxidizing any free lloc-hYdIOXYl group present to the oxo group.

The starting materials may contain further substituents in the ring system, particularly in one or more of the positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 16, 17 or 21, such as esterified hydroxyl groups, or free or ketalized oxo groups, alkyl, such as methyl groups or halogen atoms. They may also contain double bonds, for example starting from carbon atom 5. Especially important starting materials are the 18:20-lactones of 9a-halogen- 11,8:20/3-dihydroxy-pregnane-l8-acids the preparation of which consists in reacting an 18:20-lactone of a 9:11;?- oxido-ZO-hydroxy-pregnane-1S-acid with a hydrohalic acid, or reacting an 18:20-lactone of A -20-hydroxypregnene-18-acid with a hypohalous acid. The soobtained compounds yield the 18:11-lactones of 11:20- dihydroxy-9e-halogen-pregnane-18-acids after oxidation of the ll-hydroxyl group to an oxo group and reduction with sodium borohydride with translactonisation.

The 18:11-lactones of 1lfl-hydroxy-20-oxo-pregnane- 18-acids obtained as endproducts are important intermediates for the preparation of 18-0xygenated corticoids of the type of aldosterone or 9a-halogen-aldosterone.

The following examples illustrate the invention:

Example 1 225 mg. of sodium dichromate and 900 mg. of crystalline sodium acetate are dissolved in 4.5 ml. of glacial acetic acid and 0.45 ml. of Water. To this solution there are added 160 mg. of the 18:11-1actone of A -3-ethylenedioxy- 11 3:ZOB-dihydroxy-pregnene-18-acid and the whole is stirred for 4 days at 20-25 C. The dark solution is then poured into 100 ml. of ice-water and extracted several times with methylene chloride. The extracts are washed with sodium bicarbonate solution and with water, dried and evaporated. There are obtained 122 mg. of a crystalline residue which contains, in addition to a little starting material and a little of the 18:1l-1actone of M8 :20-dioxo- 1lp-hydroxy-pregnene-lS-acid, as main product the 18:11- lactone of A -3-ethylenedioxy-1 1fl-hydroxy-20-oxo preg nene-l S-acid. After chromatography on 12 grams of silica gel there are obtained mg. of the latter compound melting at 239.5240.5 C. from the fractions eluted from a mixture of benzene and ethyl acetate (9: 1).

Example 2 1.0 gram of the 18:11-lactone of A -3-ethylenedioxy- 11,8:ZOB-dihydroxy-pregnene-l8-acid is dissolved in 25 ml. of acetone. The solution is cooled to -10 C. and there is added with vigorous stirring 1.25 ml. of a solution of 13.3 grams of chromium trioxide and 11.5 ml. of concentrated sulfuric acid diluted with Water to make up 50.0 ml. After 10 minutes the reaction mixture is poured into ml. of an aqueoue sodium acetate solution of 10% strength, the crystalline precipitate is filtered off and washed well with Water. After drying, there are obtained 904 mg. of the pure 18:11-lactone of A -3-ethylenedioxy- 11,B-hydroxy-ZO-oxoapregnene 18 acid melting at 232- 236 C.

Example 3 In an analogous manner to that described in Example 2 there are obtained from 273 mg. of the 18:11-1actone of A -3-ethylenedioxy-9e-bromo-1lBzZOfi dihydroxy pregnene-18-acid 231 mg. of the pure 18:11-1actone of A -3- 6 ethylenedioxy-9a-bromo-1lfi-hydroxy-ZO oxo pregnene- 18-acid.

The bromlactone used as starting material is prepared as follows:

240 mg. of the 18:20-lactone of A -3-oxo11a:20;3-dihydroxy-pregnene-18-acid are dissolved in 3 ml. of methylene chloride and after adding 1.0 ml. of pyridine and 300 mg. of para-toluene-sulfonic acid chloride the whole is allowed to stand for 3 days at room temperature. The reaction mixture is then diluted with methylene chloride, washed with dilute sulfuric acid and with water. By crystallization of the residue of the methylene chloride solution from a mixture of methylene chloride and ether there are obtained 255 mg. of the 18:20-lactone of A -3-oxo-11atosyloxy 205 hydroxy vpregnene 18 acid melting at 142144 C. (with decomposition); optical rotation [a] =+48 (in chloroform); absorption maximum in ultraviolet spectrum at 229 mn (e=24,800); infrared bands at 5.69 1. ('y-lactone); 5.96 and 6.17 (A -3-ketone); 6.24 844 and 854 (tosylate).

170 mg. of the 18:20-lactone of A -3-oxo-1lu-tosyloxy- 20fi-hydroxy-pregnene-l8-acid are stirred in ml. of a solution of lithium chloride in dimethylformamide of strength for 4 hours at 100 C. under nitrogen.

The reaction mixture is poured into 50 ml. of water, the solid precipitate is suctioned OH and washed well with water. There are obtained 120 mg. of the 18:20-lactone of A -3oxo-ZOfl-hydroxypregnadiene 18 acid which after crystallization from a mixture of methylene chloride and ether and sublimation at 180 C. under 0.05 mm. pressure of mercury melts at 205210 C.; optical rotation [M -+16 (in chloroform); ultraviolet spectrum maximum at 239 m 16,850); infrared bands at 5.68 (5-ring lactone); 5.98 and 6.17; (A -3-ketone); further bands at 7.42 8.15 8.68 9.10p. and 9.85

500 mg. of the 18:20-lactone of n -3-oxo-20fl-hydroxy-pregnadiene-1S-acid are dissolved in 10 ml. of pure dioxane, and the solution is treated with 300 mg. of N- bromosuccinimide and 1 ml. of perchloric acid of 10% strength after the addition of 2 ml. of water. The reaction mixture is stirred for minutes at room temperature, the excess hypobromous acid is destroyed by the addition of sodium sulfite solution and the mixture poured into 75 ml. of ice-water. The resulting precipitate is taken up in methylene chloride, the solution dried and evaporated. The residue consists of the crude 18:1l-lactone of A -3- oxo-9a-bromo-1 15:20fi-dihydroxy-pregnene-18-acid which is purified by chromatography on silica gel.

By ketalization of the 18:11-lactone of A -3-oxo-9otbromo-l1,8:B-dihydroxy-pregnene-18-acid with ethylene glycol and para-toluene-sulfonic acid in benzene there is obtained the 18:1l-lactone of A -3-ethylenedioxy-9ubromo-l1B:20B-dihydroxy-pregnene-l8 acid used above as starting material.

Example 4 970 mg. of the 18: ll-lactone of A -3ethylenedioxy-9afluoro-l1,8:20fl-dihydroxy-pregnene-18-acid are dissolved in ml. of acetone. The solution is cooled to 5 C. and there are then added with stirring 1.15 ml. of a chromic acid-sulfuric acid solution described in Example 2 and the whole is stirred for 20 minutes at a temperature of 5 to 0 C. 100 ml. of a sodium acetate solution of 10% strength are added and the solution is extracted several times with methylene chloride. The crude product obtained from the methylene chloride extracts is purified by chromatography on silica gel. From the fractions eluted with a mixture of benzene and ethyl acetate there is obtained by crystallization from a mixture of ether and methylene chloride the pure 18:1l-lactone of A -3-ethylenedioxy-9a-fluoro-l1fl-hydr0xy-20-oxo pregnene 18- acid.

The fluorolactone used as starting material is prepared as follows:

250 mg. of the 18:20-lactone of A -3-ethylenedioxy- 9:11,8-oxido-20,8-hydroxy-pregnene-18-acid are dissolved in 1.5 ml. of methylene chloride and slowly added to a mixture cooled to --60 C. of 10.3 ml. of tetrahydrofuran, 3.6 ml. of methylene chloride and 5.0 ml. of anhydrous hydrofluoric acid. When the addition is complete, the whole is allowed to stand for 15 minutes at --60 C., then for 3 hours at 0 C. and then poured into a cold solution of sodium bicarbonate. The mixture is then extracted with methylene chloride, the extracts are washed with water, dried and evaporated. The residue (240 mg.) is filtered through 12 grams of silica gel. The 18:11-l-act0ne of A -3-oxo-9u-fiuoro-1lflz20fi-dihydroxypregnene-18-acid is eluted with a mixture of benzene and ethyl acetate, and with ethyl acetate.

105 mg. of this compound are dissolved in 2 ml. of glacial acetic acid and after the addition of 200 mg. of chromium trioxide in 0.5 ml. of water the whole is allowed to stand for 5 hours at 25 C. Working up in the ordinary manner yields a crude product which, when crystallized from methylene chloride and ether, yields the pure 18:1l-lactone of A -3:2O-dioxo-9v-fluoro-1lp-hydroxy-pregnene-l 8-acid.

285 mg. of the 18:11-lactone of A -3-oxo-9ot-fluoro- 11B:20fl-dihydroxy-pregnene-l8-acid are dissolved in ml. of benzene and, after the addition of a solution of 20 mg. of pana-toluene-sulfonic acid in 10 ml. of ethylene glycol, boiled for 6 hours under reflux using a waterseparator. The mixture is cooled, 20 ml. of saturated sodium bicarbonate solution are added with stirring, and the solution diluted with 50 ml. of benzene. The organic solution is separated, washed with water, dried and evaporated in a water-jet vacuum. There are obtained 290 mg. of crude 18:11-lactone of A -3-ethylenedioxy-9ufiuoro-l1B:ZOfl-dihydroxy-pregnene-l8-acid which is oxidized directly as described above.

When instead of anhydrous hydrofluoric acid a solution of hydrogen chloride in methanol is used for the cleavage, the 18:11-lactone of A -3-oxo-9a-chloro-1lfi:20fi-dihydroxy-pregnene-18-acid is obtained which, as described above for the 9-fiuoro-compound, is converted into the 18 1 l-lactone of A -3ethylenedioxy-9a-chlor0-l lfB-hydroxy-20-oXo-pregnene- 1 S-acid.

What is claimed is:

1. Process for the manufacture of a member selected from the group consisting of 3-ketals of '18:11-lactones of 11hydroxy-3,20-dioxo-pregnane-18=acids and the corresponding compounds having a double bond in the S-position, which comprises oxidizing a member selected from the group consisting of 3-ketals of 18:11-lactones of 11, 20-dihydroxy-3oxo-pregnane-18-acids and the corresponding compounds having a double bond in the 5- position with a compound of hexavalent chromium in acid solution;

2. Process as claimed in claim 1, wherein the oxidation is carried out with chromium trioxide and sulfuric acid in acetone.

2,959,586 Kerwin et al. Nov. 8, 1960

Claims

1. PROCESS FOR THE MANUFACTURE OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF 3-KETALS OF 18:11-LACTONES OF 11-HYDROXY-3,20-DIOXO-PREGNANE-18-ACIDS AND THE CORRESPONDING COMPOUNDS HAVING A DOUBLE BOND IN THE 5-POSITION, WHICH COMPRISES OXIDIZING A MEMBER SELECTED FROM THE GROUP CONSISTING OF 3-KETALS OF 18:11-LACTONES OF 11, 20-DIHYDROXY-3-OXO-PREGNANE-18-ACIDS AND THE CORRESPONDING COMPOUNDS HAVING A DOUBLE BOND IN THE 5POSITION WITH A COMPOUND OF HEXAVALENT CHROMIUM IN ACID SOLUTION.