DE1017608B - Process for the preparation of 15-halogen- or 15-oxy-4-pregnen-14 alpha, 17 alpha-diol-3, 20-diones - Google Patents

Description

GERMAN

The present invention relates to a process for the preparation of new steroid compounds of the formula

OH (IV)

O = ¹

in which R ^{1 is} a ^ oxy or keto group, R ^{2 is} hydrogen, an oxy group or their esters or ethers having 1 to 10 carbon atoms and R ^{3 is} an oxy group or a halogen atom. Of course, when R ^{1 is} an oxy group, there is also a hydrogen atom on the carbon atom in position.

The starting materials for these syntheses are compounds of the following formula:

Method of manufacture
of 15-halogen- or 15-oxy-4-pregnen-14 a, 17a-diol-3,20-dione

Applicant:

Chas. Pfizer & Co., Inc.,
Brooklyn, NY (V. St. A.)

Representative: Dr. W. Beil, lawyer,
Frankfurt / M.-Höchst, Antoniterstr. 36

Claimed priority:
V. St. v. America May 26, 1954

Eugene Joseph Agnelle, Barry Malcolm Bloom
and Gerald David Laubach, Jackson Heights, NY

(V. St. Α.),
have been named as inventors

is introduced; the
speak the formula

received

Connections

R ²

I.
CH ₂

R ¹ -i

C = O
3L ... OH

C = O

CH,

Ο = '

wherein R ¹ and R ^{2 have} the same meaning as above. These compounds are obtained according to the method described in patent application P 14178 IVb / 12o by fermentation with the species Curvularia.

In the process according to the invention, the starting compounds are initially not with a strong one treated oxidizing acid in the presence of an organic solvent, e.g. B. with p-toluenesulfonic acid in Benzene, which, with removal of the OH group in the 14-position, creates a double bond in this 14-position The term strong acid includes substances which, in aqueous solution, are at least as strong as acetic acid ionize and deliver hydrogen ions. A substance is not oxidizing if none of its atoms are during the Implementation suffers a loss of value. Other suitable non-oxidizing, strong acids are e.g. B. Hydrochloric acid and oxalic acid. Instead of benzene, various other solvents such as toluene, chloroform, Carbon tetrachloride, cyclohexane and dioxane can be used.

There is already a method known, after which a 14 hydroxyl group, but in the absence of one

709 756/424

17α- and 21-position oxy group, are split off with formation of a 14 (15) double bond can. From this method it could not be deduced that in the presence of a 17a and 21 position hydroxyl group only the 14a oxy group was split off. Rather, one had to assume that among the Reaction conditions used according to the invention, in addition to the 14-position, also the 17- and 21-position Hydroxyl group was attacked. All of these products fall under those specified above general formula IV.

In order to achieve the best yields, it is important to ensure that side reactions occur at other points on the molecule, e.g. B. in the 11-position if there is an OH group, or in the 21-position if there is e.g. B. contains an ester group, be reduced to a minimum. Such considerations influence the choice of the particular Reacg jg

tion means, the temperature, p _H -value of the solvent

The compounds obtained, which are unsaturated in the 14-position, and the reaction time, the most favorable fertilizers then being treated with an oxidizing agent.
delt. Various substances can be used for this, since the 21-position oxy group is the only one in all products. Organic peracids or primary alkoxides and chromates, such as perbenzoic acid, perphthalic acid and hol group, are particularly suitable; they can easily be converted to sodium chromate by conventional methods. This results in 14a, 15a-Epoxyver- 15 selectively esterify or etherify. Generally will

dÄililKb

bonds of the following formula:

O =

OH

(III)

In these epoxy compounds, the epoxy ring is then either with 1. a hydrogen halide, eg. B. Hydrogen chloride or hydrogen bromide, in an organic solvent or 2. with water as a catalyst a non-nucleophilic strong acid, e.g. B. perchloric acid or trichloroacetic acid, contains opened. The expression non-nucleophilic acid is used in the usual sense, i.e. i.e., it is understood to be an acid, the anion of which centers do not have positive charges

attacks. In this way, compounds are obtained which contain a halogen in 40 for the preparation of compounds which contain an oxy group and a halogen atom or two which contain OH groups in these positions, and around? Oxy groups have taken the place of the epoxy ring. swept. These implementations can easily be like that
The following formulas represent such compounds.

R ² CH ₅ , so esters and ethers containing 1 to 10 carbon atoms in the substituent can be obtained without difficulty. These include esters such as formate, acetate, propionate, TrtEaethylacetat, benzoate, succinate, phthalate and cyclohexanecarboxylate, and ethers such as methyl, ethyl and benzyl ethers. In general, it is easier to prepare the higher esters and ethers directly from the 21-oxy compound of the product, rather than to esterify or etherify at the beginning, and to carry the added group through the other process steps, although this is also possible and sometimes as in Case of the lower groups, e.g. B. the acetate, is even advantageous.

All of these products are very valuable. Many have clearly pronounced physiological effects, especially adrenocortical effects. Every product has either an oxy or a keto group, in the important 11 position a 14a position Oxy group, which is also valuable. Products, their own Effectiveness is not as great as that of the most effective products that are used as intermediates for synthesis used by extremely potent compounds. Such syntheses are carried out in a known manner. For example, all compounds are suitable which have an OH group in the 14 position and an OH group in the 15 position

OH (IVa)

OH

R ²

CH,

C = O

CH,

R ¹ -

OH (IVb) cause the epoxy compound is formed and then the Epoxy ring is reopened with the reagent that delivers the desired product. In particular In cases the 11 keto group can also be used selectively with lithium aluminum hydride to the often more desirable one Lesser oxy group can be reduced.

The following examples explain the process according to the invention.

example 1
Creation of the 14 double bond

A solution of p-toluenesulfonic acid in benzene was made prepared in such a way that 400 mg of the acid monohydrate were taken up in 150 ecm of benzene and a few ecm of an azeotropic one Benzene water mixture were distilled off. The acid solution then became 4 g of 4-Pregnen-llß, 14a, 17a, 21-tetraol-3,20-dione-21-acetate (Ha-oxyhydrocortisone-21-acetate) given in 650 ecm benzene and the mixture is heated under reflux in an apparatus which contained a moisture trap. A nitrogen atmosphere was maintained throughout the reaction maintain. The resulting solution was vigorously washed with water, twice with sodium bicarbonate solution and finally shaken with water. The benzene was removed and the crystalline residue with a minor Amount of methanol triturated. The product was purified by recrystallization and was found to be 4, 14-Pregnadien-11/3, 17a, 21-triol-3, 20-dione-21-acetate.

Melting point 253 to 255 ° (with decomposition);
[α] «« »= + 116 °; E ^ "" ¹ "= 16,200;

Analysis:

Calculated for C ₂₃ H ₃₀ O ₆ C = 68.63, H = 7.51.

Found C = 68.47, H = 7.56.

The treatment described above was applied to the 4-pregnen-II / ?, 14a, 17a-triol-3, 20-dione. The reaction took place as before and gave 4, 14-pregnadiene-11 / S, 17a-diol-3, 20-dione; Melting point 172 to 174 °; [a] f " ^a " = + 90.5 °; E ₂ ^ * ¹ = 14 600.

The values given are approximate values; the sample was not analytically pure.

The same reaction was performed using 4-pregnen-14a, 17a-diol-3, 11,20-trione as a starting material carried out. The product was 4, 14-pregnadien-17a-ol-3, 11, 20-trione.

In the same way, 4, 14-pregnadiene-17a, 21-diol-3, 11, 20-trione was prepared from 4-pregnen-14a, 17a, 21-triol-3,20-dione (14a-oxycortisone). 4,14-pregnadiene-17a, 21-diol-3, 11, 20-trione-21-acetate. Melting point 200 to 201 °; [a] jf * ^a "= + 121.3 °

Analysis:

Calculated for C ₂₃₈

Found C = 68.92; H = 6.86.

₂₃ H ₂₈ O ₆ C = 68.98; H = 7.05.

In this and the following examples, starting materials were used for compounds with a 21-position hydroxyl function which have a free 21-position hydroxyl group, as well as compounds with various ester or ether groups in this 21-position. The overall response is the same in all cases, and the 21 groups remain unchanged throughout. With the use of 21-esters or ethers, the yield of 21-dehydrated product is 80% · If, instead of the ester or ether, the free 21-steroid alcohols, then one obtains a 50 ° / ₀ yield under the same conditions. Formate, acetate, propionate, trimethyl acetate, succinate, phthalate and cyclohexanecarboxylate were used as esters, and methyl, ethyl and benzyl ethers or generally those esters and ethers containing 1 to 10 carbon atoms in the substituent were used as ethers.

Manufacture of the epoxy

This experiment was repeated using perbenzoic acid instead of monoperphthalic acid. In a further experiment, aqueous potassium chromate solution was used instead of monoperphthalic acid. In each case a product consistent with that described above was obtained.

In an analogous manner, the 14a, 15a-oxido-4-pregnen-17, 21-diol-3, 11, 20-trione-21-acetate, melting point 184 to 186 °, [a] ^ »" = + 186 , 2 °; E ₂ ^ "' ¹ " ¹¹ = 16600, ίο made.

The epoxy ring opens with the formation of
Halohydrins

A solution of 500 mg 14a, 15a-Oxido-4-pregnen-11 / ?, 17a, 21-triol-3, 20-dione-21-acetate in 25 ecm chloroform was at -10 ° with 50 ecm a saturated solution treated by anhydrous hydrogen bromide in chloroform. After 1 hour the chloroform solution was with Washed water until neutral, then dried over sodium sulfate and evaporated to dryness. Of the solid residue was triturated with ether and recrystallized from an ethyl acetate-cyclohexane mixture. The product was the 15/3-bromo-4-pregnen-II / 3, 14a, 17a, 21-tetrol-3, 20-dione-21-acetate.

If this experiment was repeated using hydrogen chloride instead of hydrogen bromide, then the product was the corresponding 15 / S-chloro-4-pregnen-II / ?, 14a, 17a, 21-tetrol-3,20-dione-21-acetate, melting point 172 to 174 ° (with decomposition). This value is an approximate value; the sample was not analytically pure.

35 Opening of the epoxy ring with formation
of the 14a, 15 ^ glycols

14a, lSa-Oxido-4-pregnen-II / S, 17a, 21-triol-3, 20-dione was overnight at room temperature in contact with a water-dioxane solution, which is a catalytic amount Containing perchloric acid, left to stand. The product was 4-Pregnen-II / ?, 14α, 15β, 17a, 21-pentol-3, 20-dione won. The same result was obtained when trichloroacetic acid was used in place of perchloric acid became.

Monoperphthalic acid (7.5 ecm of a 0.25 molar ether solution) was added to a solution of 300 mg of 4, 14-pregnadiene-llß, 17a, 21-triol-3, 20-dione-21-acetate in 150 ecm of ethyl acetate. The mixture was left to stand in the dark for 24 hours. The solution was washed with dilute aqueous sodium bicarbonate and water, dried over magnesium sulfate and evaporated to dryness. A crude crystalline residue of 14,15a-oxido-4-pregnen-II; S, 17a, 21-triol-3, 20-dione-21-acetate remained. After recrystallization from methanol, crystal flakes were obtained; Melting point 229 to 230 °; [a] ^Siosan = + 143.0 °; E ₂ ^ " ¹ '""=16200; analysis:

For C ₂₃ H ₃₀ O ₇ C = 66.01; H = 7.23.

Found C = 65.68; H = 7.14.

14a, 15a-Oxido-4-pregnen-ll ^, 17a, 21-triol-3, 20-dione had a melting point of 225 to 226.5 °; [α] £ ^ίοΜ "

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of 15-halogen or 15-Oxy-4-pregnen-14a, 17a-diol-3,20-dione, thereby characterized in that a 4-pregnene-14a, 17a-diol-3, 20-dione of the general formula = 16800; ^ = 3.0; 5.85; 6.07; 6.20. O-1 = +159 Analysis: For C ₂₁ H ₂₈ O ₆ C = 67.00; H = 7.50. Found C = 66.65; H = 7.45. 70 in which R ^{1 is} a ^ oxy or keto group and R ² denotes hydrogen, an oxy group or its ethers or esters with 1 to 10 carbon atoms, dehydrated with a strong, non-oxidizing acid, the 4,14-pregnadien-17a-ol-3, 20-dione obtained with an organic peracid or converts a chromate into the corresponding 14,15-oxido-4-pregnen-17ct-ol-3, 20-dione and converts this with a hydrogen halide in an organic solvent or with water which contains a non-nucleophilic strong acid as a catalyst. 2. The method according to claim 1, characterized in that the dehydration with p-toluenesulfonic acid, the oxidation with perbenzoic acid and the opening of the epoxy ring with perchloric acid containing Water carries out. Considered publications:
Fieser & Fieser, Natural Products related to Phenanthrene, 1949, pp. 222 and 542;
Ber. der German former Ges., 71, 1938, p. 654/1927, © 709 756/424 10.57