DE1221632B - Process for the preparation of 2beta, 19-oxido-5alpha-steroids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

Number:
File number:
Registration date:
Display day:

C 07c

German class: 12 ο - 25/02

1 221 632
C27982IVb / 12o
20th September 1962
28. Wed 1966

The invention relates to a process for the preparation of 2 / 5,19-oxido-5a-steroids from 19-unsubstituted 2,8-hydroxy-5a-steroids. Said oxidosteroids can, for. B. for the production of pharmacologically important 19-nor-steroids (anabolic steroids, progestatives and estrogens), such as derivatives of 19-nor-testosterone, 19-nor-progesterone, / d ¹ -3-oxo-17 | S-hydroxy-19- nor-5a-androstens or estrone, can be used.

The inventive method consists in that one 19-unsubstituted in a manner known per se 2 ^ -Hydroxy-5a-steroid, which has no other free hydroxyl group, with an oxidizing acting lead acylate in a solvent inert to the oxidizing agent, expedient at elevated temperature, and, if desired, the 2 / S, 19-Oxido-5 <z-steroid obtained with oxidized with a strong oxidizing agent.

The procedural implementations are z. B. illustrated by the following partial formula scheme,

Process for the production of
2 / ?, 19-oxido-5a-steroids

Applicant:

CIBA Aktiengesellschaft, Basel (Switzerland)

Representative:

Dr.-Ing. Dr. jur. F. Redies,
Dipl.-Chem. Dr. rer. nat. B. Redies
and Dr. D. Türk, patent attorneys,
Opladen, Rennbaumstr. 27

Named as inventor:

Dr. Albert Wettstein, Riehen;

Dr. Georg Anner,

Dr. Karl Heusler,

Dr. Jaroslav Kalvoda, Basel (Switzerland)

Claimed priority:
Switzerland of September 22, 1961 (11073),
dated August 31, 1962 (10403)

where Ri 2 hydrogen atoms, 1 hydrogen atom and an etherified or esterified hydroxyl group or a ketalized oxo group and R2 is a hydrogen or halogen atom or an etherified or esterified hydroxyl group, where Ri and R ₂ together also represent the radical of a dibasic acid or a lower aliphatic or can represent araliphatic diol.

This course of the reaction was surprising, although the formation of 18, 20 or 6 ^, 19 -oxidosteroids by reacting 20- or 6ß-hydroxy steroids with lead tetraacylates was known. In the latter, the oxygen atom entering the oxido bridge is located on the stable ring B. or in a stable position on ring D. In the starting steroids to be used according to the invention the corresponding oxygen atom, however, on the labile ring A, the z. B. in the only slightly more energetic Boat shape can fold down, making the oxygen atom in question in relation to the angular 10-methyl group is at a very unfavorable distance for ether formation.

For the sake of simplicity, the 5a-hydrogen atom is no longer specifically mentioned below.

Corresponding 2 / β-hydroxy compounds are suitable as starting materials for the process of the invention the Androstan-, Pregnan-, Cholan-, Cholestan-, Stigmastan-, Spirostan- and Cardanolid-

609 607/410

row, which in the ring system, in particular in one or more of the positions 1, 3, 4, 6, 7, 8, 9, 11, 12, 14, 15, 16, 17, 20 and 21 can have further substituents, such as free or functionally modified ones Oxo groups, esterified or etherified hydroxyl groups, lower alkyl or alkenyl groups, such as methyl, ethyl, vinyl or allyl groups, and / or halogen atoms. Under functionally modified Oxo groups are ketalized or converted into enol derivatives, e.g. B. enol ethers or enol esters transferred Understood oxo groups. In addition, the starting materials can also have double bonds or Have oxido groups, e.g. B. in the 9.11 or 16.17 position.

Suitable starting materials are, for. B. such 2/9 hydroxy steroids, which in the 3- and optionally also in the 1-position are those given above for Ri and R2 Have substituents. These allow the formation after the opening of the 2 [beta], 19-oxido bridge a zl ^ -oxo grouping. Such starting compounds are z. B. derivatives of la, 2 / ?, 3a-trihydroxy steroids, such as cyclic carbonates, sulfites, Acetonides or benzal compounds, or in particular 3-esters and 3-ethers of 2 / S, 3-dihydroxyla-halogen-steroids or ketals of 3-oxo-2 ^ -hydroxy-la-halogen steroids.

Specific starting materials are z. B. the following compounds: the 2/3-hydroxy-3 / S, 17 / S-dibenzoyloxyandrostane, the Iß -hydroxy -3ß, 17β - dibenzoyloxy-17a-methyl-androstane, the cyclic 1,3-carbonate resp. -Acetonide des la, 2j3,3a-trihydroxy-17-oxo- and -17 /? - benzoyloxy-androstane, la -Chlor -2ß- hydroxy-3 | S, 17 | S-dibenzoyloxy-androstane, la-bromine -2jS-hydroxy-3 _i 8,17 _/ 8-dibenzoyloxy- or -didecanoyloxy-androstane, la-chloro-2/8-hydroxy-3 ^, 17 / S-dibenzoyloxy- and la-chloro-2 ^ - hydroxy-3 ^ -benzoyloxy-17; S-acetoxy-17a-methyl-androstane, the cyclic 1,3-carbonate or acetonide of 1α, 2 / ?, 3α-Τπ-hydroxy-20-benzoyloxy-5a-pregnans , la-chloro- 2ß- hydroxy -3ß- benzoyloxy-spirostane, 2/3-hydroxy - Π β - acetoxy- or - hexahydrobenzoyloxyandrostane or 2 _j S-hydroxy-17jS-acetoxy-17α-methyl-androstane. The starting materials mentioned are known or, if new, can be prepared in a manner known per se.

The above-mentioned la-chloro-2 / S-hydroxy-3jS-acyloxy compounds are preferably prepared by reducing the corresponding ^ ^x -3-oxosteroids by means of a complex metal hydride, acylation of the hydroxyl groups formed and subsequent addition of hypochlorous acid to the 1,2- Double bond.

For the preparation of the cyclic 1,3-carbonates or acetonides used as starting materials, the above-mentioned zl ^ / S-hydroxy compounds obtained by reduction of zl ^ -oxo-steroids are benzoylated and the resulting benzoates are benzoylated according to 'T amm and A1 brecht (HeIv . Chim. Acta, 42, p. 2177 [1960]) converted into the corresponding zI ¹ -3a-hydroxy steroids by chromatography on aluminum oxide. The epoxidation of the 1 (2) double bond and subsequent acidic hydrolysis of the crude epoxides provides the 1α, 2β, 3α-Τή- hydroxyyerbindungen, which by reaction with acetone in the presence of anhydrous copper sulfate in the desired acetonides or by means of phosgene in the known way corresponding cyclic carbonates are converted.

For the production of those unsubstituted in the 3-position 2jS, 19-oxido-5a-steroids according to the method of the invention can be obtained from the catalytic Reduction of the 2-ketones resulting 3-unsubstituted 2 /? - hydroxy compounds go out. Particularly 2 / S-hydroxy-17 / S-acetoxy or -hexahydrobenzoyloxy-androstane, the 2 / S-hydroxy-17 / S-acetoxy-17a-methyl-androstane and the 2 / J-hydroxy-spirostane. The 2 - oxo compounds for their part can be obtained from the corresponding 3-oxo steroids be prepared by known methods, e.g. B. by bromination in the 2-position, conversion of the obtained 2-bromo-3-ketone into the 2-pyridinium salt by heating with pyridine, oxidation of the latter according to K r ö h η k e to the nitrone, which can easily be hydrolyzed to the 2,3-dioxo-steroid. Treated this diketone with p-toluene sulfonic acid chloride in pyridine, the 2-oxo-3-enol tosylate is obtained, which either becomes the 3-unsubstituted 2-ketone or directly to the desired 2 /? - hydroxysteroid can be hydrogenated.

The oxidizing lead acylates used for the process according to the invention are z. B. Lead tetraacylates, the acid component of which is z. B. from a lower aliphatic, cycloaliphatic, derived from araliphatic or aromatic acid, such as vinegar, propionic, trifluoroacetic, hexahydrobenzoic, Phenylacetic or benzoic acid. Furthermore, dialkyl lead diacylates, such as diethyl lead diacetate, or anhydrides of metableic acid with the above carboxylic acids, such as diacetoxy lead oxide, are used will.

The procedural implementation is z. B. made so that the starting materials, optionally with the addition of a weak inorganic or organic base, for. B. of alkaline earth carbonates such as calcium, barium or strontium carbonate, or of tertiary amines such as pyridine, together with an excess of oxidizing lead acylate, preferably in a non-polar, inert to the oxidizing agent, for. B. to its boiling temperature, but preferably above 6O ⁰ C, and the 2 / S, 19-oxido-5a-steroid obtained as a process product is isolated by customary methods.

Particularly suitable solvents are aliphatic, cycloaliphatic and aromatic hydrocarbons, such as hexane, heptane, cyclohexane, Methylcyclohexane, dimethylcyclohexane or benzene.

The reaction time is generally dependent on the reaction temperature and is preferably 4 to 20 hours.

If desired, in the 19-unsubstituted 2 / 3,19-ethers obtained according to the process, the oxygenated angular C-10 methyl group can be further oxidized under more drastic conditions. this can e.g. B. done by the said 2 / S, 19 ethers with strong oxidizing agents, z. B. with Ruthenium tetroxide or especially with derivatives of hexavalent chromium, such as chromic acid or tertiary butyl chromate, in solvents, e.g. B. lower fatty acids such as acetic acid, propionic acid, or in chlorinated hydrocarbons, such as carbon tetrachloride, especially at elevated temperatures, z. B. between 50 and 100 ° C treated. It is obtained in this way by introducing an oxo group in the 19-position 2,19-lactones of 2 /? - hydroxy-steroid-19-acids.

The conversion of the obtained according to the process

2jö, 19-oxido-steroids in pharmacologically effective Compounds is described in patent application C 27981 IV b / 12 ο,

The following may be mentioned in particular as process products: saturated and unsaturated 2 / ?, 19-oxido-5a-steroids of the androstane and pregnane series, e.g. B. 3-Hydroxy-la-halogen- or-hydroxy-2 / 3,19-oxido-androstane and esters thereof, like 3JS, 17 $ -dihydroxy-la-chloro - 2ß, 19 - oxido - androstane, 3ß, 1 Iß - Dihydroxy- 1 α-chloro- or -bromo ^ & W-oxido-na-alkenyl-androstane. The compounds corresponding to the above compounds with a 3-oxo group instead of a 3-hydroxyl group and esters thereof, as well as the 2β, 19-oxido-androstanes unsubstituted in the 3-position, such as 2 / S, 19-oxido-17 / S-hydroxy-androstane and esters of this compound; further 2β, 19-oxido-1 a-halogenandrostane.

The inventive method also relates to the production of 3-hydroxy-la-halogen or -hydroxy-2 / 3,19-oxido-5a-pregnanes and esters thereof, z. B. those in the 20-position a free or esterified hydroxyl group or a free or have ketalized oxo groups, as well as corresponding ones in the 3 or 3 and 1 positions unsubstituted 2 / ?, 19-oxido-5a-pregnanen.

Particularly valuable process products are those of the general formulas I and II

(D

35

40

(H)

50

where Ri for 2 hydrogen atoms, 1 hydrogen atom together with a free, esterified or etherified hydroxyl group, an oxo group or a lower alkylenedioxy group, Ra for 1 hydrogen or halogen atom or a free, esterified or etherified hydroxyl group, Ri and Ra together also for the remainder of a dibasic acid or of a lower aliphatic or araliphatic diol, R3 for an oxo or lower alkylenedioxy group, a hydrogen atom or a lower aliphatic hydrocarbon radical, such as an alkyl, alkenyl or alkynyl group, together with a free, esterified or etherified hydroxyl group in the / ^ position, X for 2 hydrogen atoms or an oxo group, R4 for 2 hydrogen atoms, 1 hydrogen atom together with a free or esterified hydroxyl group or an oxo group, Rs for 1 hydrogen atom, a methyl group or a free, esterified or etherified hydroxyl group, R5 and R6 together also for the remainder of one lower aliphati or araliphatic diol, R6 and Rs for 1 hydrogen atom or a free, esterified or etherified hydroxyl group and R ₇ for 1 hydrogen atom together with a free or esterified hydroxyl group, an oxo group or a lower alkylenedioxy group.

The acyl groups contained in the above-mentioned esters are in particular those of aliphatic, cycloaliphatic, araliphatic or aromatic carboxylic acids with 1 to 15 carbon atoms, such as ant, methyl or ethyl carbon, vinegar, trifluoroacetic, propionic, butter, trimethyl acetic, Valerian, Capron, Oenanth, Decane, Hexahydrobenzoe, Cyclopentylpropion-, Phenylpropion-, Benzoic or furancarboxylic acid. Etherified hydroxyl groups are e.g. B. lower alkoxy groups or the tetrahydropyranyloxy group.

The following examples explain the process according to the invention. The temperatures are in CeI-sius degrees specified.

example 1

To a suspension, briefly heated to 80 °, of 800 mg of predried lead (IV) acetate and 250 mg of calcium carbonate in 100 ml of cyclohexane, 100 mg 2 /? - hydroxy-17 (S-hexahydrobenzoyloxy-5a-androstane is added. The reaction mixture is then added with stirring refluxed for 16 hours, then cooled, inorganic components filtered off, the filtrate washed with 15 ml of a 10% strength potassium iodide solution and with 15 ml of a 10% strength sodium thiosulphate solution, dried and evaporated in a water jet vacuum, giving 119 mg of a crystalline crude product Chromatography of the mixture of aluminum oxide (activity II) gives 70 mg of pure 2 / 3,19-oxido- IT β -hexahydrobenzoyloxy-5a-androstane, which melts at 145 ° to 147 ° after being redissolved from methanol Compound, among other things, absorption bands occur at 5.81, 8.53, 8.83, 9.80, 9.92 and 11.45 μ The NMR spectrum is consistent with the structure of the compound mentioned A small amount (about 10%) of 2-oxo-17 ^ -hexahydrobenzoyloxy-5a-androstane with a temperature of 139 to 141 ° is obtained from the mother liquors and subsequent crystallization.

The 2/3-hydroxy-17/3 used as the starting material - hexahydrobenzoyloxy - 5a - androstane can be made as follows:

3 - oxo -17/3 - hexahydrobenzoyloxy - 5a - androstane is brominated in dimethylformamide, and the corresponding 2-bromo steroid is obtained from F. 175 bis 176 °. This is heated to 100 ° in pyridine for 1 hour, and the 2-pyridinium salt (mp 300 up to 302 °), which is oxidized by p-nitroso-dimethylaniline to the corresponding nitrone (mp 198 to 199 °) will. Treatment with dilute hydrochloric acid converts this compound to 2,3-dioxo-17 /? -Hexahydrobenzoyloxy-5a-androstane (F. 218 to 219 °) hydrolyzed, which gives two tosylates. The melting at 179 to 182 ° is in ethanol at 50 ° in The presence of Raney nickel hydrogenates, and the desired 2/3-hydroxy-17 ^ -hexahydrobenzoyloxy-5a-androstane is obtained from F. 179 to 180 °.

Example 2

50 mg of the 2 / S, 19-Oxido-17 /? - hexahydrobenzoyloxy-5a-androstane obtained according to Example 1 are in 2 ml of glacial acetic acid for 30 minutes at 90 ° with a solution of 100 mg of chromium (VI) oxide in 0, Treated 1 ml of water and 0.68 ml of glacial acetic acid. The cooled reaction mixture is then diluted with water and extracted with methylene chloride. The methylene chloride solution is washed successively with water, saturated sodium bicarbonate solution and with water, dried and evaporated in a water jet vacuum. After one recrystallization of the crude product from methylene chloride-petroleum ether to obtain 31 mg of pure 2,19 - lactone of the 2SS - hydroxy - 17/3 - hexahydrobenzoyloxy-5α-androstan-19-oic acid, mp 163-164 °.

Example 3

^

1 g pre-dried lead (IV) acetate, 350 mg barium carbonate and 100 mg la-chlorine-2 /? - hydroxy-3 | S, 17 | 8-dibenzoyloxy-5a-androstane in 30 ml of benzene refluxed with stirring for 16 hours. The cooled reaction solution is then filtered, the residue washed with about 60 ml of benzene, the combined filtrates with Washed 10% potassium iodide and sodium thiosulphate solution, dried and in a water jet vacuum evaporated. The crude product obtained is exposed to 30 times the amount of neutral aluminum oxide (activity II) chromatographed, whereby 52 mg of crude la-chloro-2 / S, 19-oxido-3 ^, 17j3-dibenzoyloxy-5a-androstane (characteristic IR bands at 5.85, 6.26, 6.34, 7.65, 8.95 and 11.44 μ, among others).

The chlorohydrin used as the starting product is produced in the following way:

10.0 g Δ ¹ -3, Π -Oioxo -5a-androstane are dissolved in 100 ml of absolute tetrahydrofuran and added dropwise to the stirred suspension of 5.0 g of lithium aluminum hydride in 200 ml of tetrahydrofuran. The reaction mixture is refluxed for 1 hour, cooled, the excess hydride is decomposed by careful dropwise addition of ethyl acetate and, after adding the theoretical amount of water, filtered. Evaporation of the filtrate gives 9.5 g of Δ ^χ -2> β, 17 ^ -dihydroxy-5a-androstene. This is dissolved in 80 ml of pyridine, 14.0 ml of benzoyl chloride are added to the solution while cooling and it is left to stand at 20 ° for 16 hours. After adding 25 ml of methanol (with cooling), the reaction mixture is concentrated in vacuo, taken up in ether, the ethereal solution shaken out successively with dilute hydrochloric acid, water and sodium hydrogen carbonate solution, dried and evaporated in vacuo. This gives 10.30 g of crude zl ¹ -3 (9.17 ^ -dibenzoyloxy-5a-androstene, which is chromatographed on aluminum oxide for the purpose of purification.

The crude dibenzoate obtained above (7.0 g) is dissolved in ml of ether. Then 350 ml of water and 6.5 g of chlorinated lime are added, shaken well and then acidified by adding 4.0 ml of glacial acetic acid. The mixture is stirred thoroughly for 30 minutes, separated off and the ethereal solution is washed with sodium thiosulphate solution and with water, dried and evaporated. 3.02 g of α-chloro-2β -hydroxy-3 / 3.17 / 3-dibenzoyloxy-5a-androstane are obtained from the residue by crystallization from ether-petroleum ether.

Claims (7)

Patent claims: 1. A process for the preparation of 2 / 3,19-oxido-5a-steroids, characterized in that a 19 - unsubstituted 2ß - hydroxy - 5α - steroid which has no further free hydroxyl group is oxidized in a manner known per se acting lead acylate in a solvent inert to the oxidizing agent, expediently at elevated temperature, and, if desired, the 2jS, 19-oxido-5a-steroid obtained is oxidized with a strong oxidizing agent. 2. The method according to claim 1, characterized in that one acts as an oxidizing agent Lead acylate a lead tetraacylate, in particular lead tetraacetate, is used. 3. Process according to Claims 1 and 2, characterized in that the reaction is carried out of the starting steroid in the presence of a weak inorganic base, in particular an alkaline earth metal carbonate. 4. Process according to Claims 1 to 3, characterized in that the reaction is carried out of the starting steroid in an apolar solvent, especially in an aliphatic, cycloaliphatic or aromatic hydrocarbon,. performs. 5. Process according to claims 1 to 4, characterized in that the reaction of the starting steroid is carried out ^{at a temperature above 6O 0 C.} 6. The method according to claim 1, characterized in that the 19-unsubstituted obtained 2 / S, 19-Oxido-5a-steroid with a derivative of hexavalent chromium is oxidized. 7. The method according to claims 1 to 6, characterized in that 19-unsubstituted 2 / S-Hydroxy-5a-steroids of the androstane series are used as starting materials. Considered publications:
Chemistry and Industry, 1960, p. 1299;
HeIv. Chim. Acta, 42, 1124-1127 (1959). 609 607/410 7.66 © Bundesdruckerei Berlin