DEU0002373MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration day: August 29, 1953 BekaiHitgeamaclit on October 18, 1956

GERMAN PATENT OFFICE

The invention relates to a process for the preparation of 2o-keto-2i-formyl steroids and their Alkali metal enolates, which are in their enol form by the formula

Ο —Μ

st - e - CH = CH

can be reproduced; In this formula, M denotes hydrogen or an alkali metal, St denotes a cyclopentanopolyhydrophenanthrene nucleus which is bonded with carbon atom 17 to the abovementioned side chain. The new compounds prepared by the process according to the invention may or may not contain the angular methyl groups on carbon atoms 10 or 13, and the steroid nucleus may have an a- or ^ -hydroxyl group, groups which can be hydrolyzed or converted into these 'groups, such as Acyloxy groups or ether groups, or ketonic oxygen or groups hydrolyzable or convertible thereto, such as a dialkyl ketal, a glycol ketal, eihe.enol acylate, an enol ether or an enamine group, on one of the carbon atoms 3 or 11 or on both. In addition, the steroid nucleus can contain a hydrogen atom, a hydroxyl group, an oxido group, a halogen atom, e.g. B. chlorine, bromine or iodine, or a double bond or any other non-reacting-

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de group on the carbon atom τη or in any other position of the steroid nucleus.

According to the method of the present invention, a compound having the formula

St-C- CH,

(Π)

in the St the meaning given for the formula (I)

ίο has, in the presence of an alkali metal base with a Alkyl esters of formic acid converted into an alkali metal enolate of a 2O-keto-2i-formyl steroid (I).

By acidifying a solution of an alkali metal enolate of a 20-keto-2i-formyl steroid of the present invention [(I); M = alkali metal] becomes the corresponding free 20-keto-2i-formyl steroid [(I); M - hydrogen] get: '. . . ■ ', _: . The compounds which can be prepared by the process of the invention are useful intermediates for the preparation of known and new compounds, many of which are physiologically active. For example, the treatment of Ii-keto-21-formylprogesterone or one of its alkali metal enolates with about two molar equivalents of bromine in methanol, preferably in the presence of e.g. potassium acetate, II-keto-21,2i-dibromo-2i-formylprogesterone, which after treatment with sodium methylate in methanol the 4, i7 (2o) -Pregnadiene-3, 11-. methyl dione-21-carboxylate results. After the 3-position keto group of the latter compounds by conversion into a ketal group, z. B. in the 3-ethylene glycol ketal, which is prepared by reacting 4, i7 (2o) -pregnadiene-3, ii-dione-21-carboxylic acid methyl ester with ethylene glycol in the presence of an acid catalyst; this compound is converted into 4, i7 (2o) -Pregnadien-ii / ?, 2irdiol-3-one by treatment with lithiumamminium hydride in ether and subsequent mild hydrolysis with acid. This latter compound or one of its 21-acyloxy esters can be prepared using osmium tetroxide and hydrogen peroxide or an equivalent oxidizing agent by known methods (Prins and Reichstein, HeIv. Chim. Acta, Vol. 25, 1942, p. 300; Ruzicka and Mueller, there, Vol. 22, 1939, p. 755) into the physiologically active 4-pregnen-11/5, 17a, 2i-triol-3, 20-dione (Kendall's compound F).

The 21-formyl steroids which can be prepared by the process according to the invention can also be used in many known and new Ätiocholansäuren by treatment with hydrogen peroxide in methanol or another suitable solvent. For example, by reacting 21-formylpregnan-3a-ol-ii, 20-dione with one molar equivalent or an excess of 3% hydrogen peroxide at room temperature, e.g. B. the well-known 3a-oxy-ii-ketoätiocholansäure (Gallagher and Belleau, Journ. Amer. Chem. Soc, Vol. 74, 1952, p. 2819). These etiocholanic acids give successively Reaction with thionyl chloride or oxalyl chloride, diazomethane and finally acetic acid 2O-keto-2i-acetoxysteroids, some of which, like corticosterone acetate, are physiologically active.

The preferred steroids among, the, new, after ..the- ■.-.- · ■ 'connection' that can be produced according to the invention Can fertilize represented by the following formula become:;> '■ "., / -.,

- Μ

CH = CH

C-O

(HI)

in which R is hydrogen, an α or /? - hydroxyl group /: or ketonic oxygenates: (= O) and M "Hydrogen" or an alkali metal, 'preferably sodium or potassium, means. Since the ring A des previously described steroid contains a 4-position unsaturated 3-ketone moiety, the typical for the physiologically active bark hormones, these compounds can be easily found on the above described. Ways to convert them into physiologically active steroids. ,

When carrying out the method according to the invention becomes a 20-ketosteroid which can be represented by the formula (II) in an alkanol or a solvent that is not reactive under the reaction conditions, such as benzene, Toluene, ether, a hydrocarbon, mixtures of one or more of these solvents with one Alkanol, dissolved and mixed with the selected alkyl formate in the presence of an alkali metal base. Alkyl formates, the alkyl group of which contains 1 to 8 carbon atoms inclusive, in particular methyl formate and ethyl formate are preferred when carrying out the process according to the invention. Alkali metal alkoxides, especially sodium methoxide, sodium ethoxide and potassium tertiary butylate are the preferred bases; but you can also use the alkali metals, z. B. sodium, potassium, lithium or their amides and hydrides, use.

The selected alkyl ester of formic acid is mixed with the steroid in one of the solvents described above, and the mixture is at a temperature between about 0 ° and the boiling point of the reaction mixture, preferably between about room temperature, ie 20 to 30 ^0, and about 6o °, is maintained until the reaction is substantially complete, which up to about 3 days is usually in about ¹ J ₂ hours the case. If the keto group on carbon atom 20 is the only keto group in the steroid molecule with the exception of a keto group on carbon atom 11 or another hindered position, the reaction is sometimes advantageously carried out at temperatures substantially above room temperature, for example between about

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40 ° and the boiling point of the reaction mixture,

..·, accomplished. ; ,. , '·':. ·; ,,

When carrying out the method according to the invention with a 3, 20-diketosteroid which is unsaturated in the 4-position it was found that the reaction product, instead of a mixture of on the carbon atoms 2 and 1.2 formylated products in the presence of a keto group in the 11- or 21-position, essentially a formylated at carbon atom 21

tes steroid is ..; ,,

. Optimal yields of a 21-formylmonoketo-

.,. steroid the .; Formula (I) are usually ·. obtained if in each case about one molar equivalent of alkyl formate and alkali metal base per mole of starting steroid or in each case a substantial, molar excess is used in carrying out the process according to the invention, while optimal yields of a 21-formyl steroid of the formula (III) are usually obtained, when about one mole equivalent of alkali metal base and about one mole equivalent or more of alkyl formate are used per mole of steroid.
. ■■ The reaction product, an alkali metal enolate of a 2O-Ketp-2i-formylsteroids, usually drops during the reaction from the reaction mixture if a substantially non-ionic reaction solvent is used, while the reaction product usually remains in the solution, if substantial amounts of z . B. methanol or ethanol can be used as a solvent.

The isolation of the alkali metal enolate of 20rKeto-2i-formylsteroid obtained by the reaction is usually achieved by e.g. B. ether, pentane, hexane or methylene chloride is added to the reaction mixture and so the alkali metal enolate is fully constantly fails, the precipitation with z. B. Ether washes and dries; essentially pure is obtained in this way Alkali metal enolate.

The alkali metal enolates are usually high-melting, sometimes colored solids that pass through Dissolve in water, acidic, filter, dissolve in Benzene and the subsequent addition of a molar equivalent, e.g. B. a methanolic alkali metal alcoholate or the like, whereby the purified alkali metal enolate is precipitated, can be purified.

The acid production of, for example, a methanolic, ethanolic or aqueous solution of a alkali metal enolate prepared by the process according to the invention [(I); M = alkali metal], e.g. B. with Hydrogen chloride, hydrochloric acid, sulfuric acid or acetic acid, gives a free 2i-formyl-20-ketosteroid [(I); M = hydrogen]. Filtering off and drying the precipitate, if water is used as the solvent for the alkali metal enolate, is used, or the addition of a large volume of water, filtering off, and drying when using z. B. methanol or ethanol as a solvent gives essentially pure free Enol.

The compounds prepared by the process according to the invention, ie the 2O-keto-2i-formyl steroids represented by the formula (I), can be isolated and purified in the manner described above or in further syntheses without isolation or purification, e.g. in the production of Äthiocholansäuren, which in turn can be converted into physiologically active steroids by known processes, or for. Preparation of the above-described in iy (2o) -position unsaturated 21-acids or esters thereof can be used. ■
The following examples explain the process according to the invention. ■ '... ■; ■.,'. ' example 1

äi-formylpregnan-sci-ol-ii, 20-dione and its ,, Sodium enolate

A mixture of 7.6 cm ^{3 of} a 3.4 n-methanolic sodium methyl ^{acetate solution, 45 cm 3 of} anhydrous benzene and 5 cm ^{3 of} absolute ethanol was distilled until 25 cm ^{3 of} distillate had been collected, after which 6.5 cm ^{3 of} ethyl formate were dem added cooled distillation residue and stirred the whole for 15 minutes. Then the stirred solution quickly became a solution of 8.3 g (0.025 mol) of pregnan-3a-ol-11, 20-dione (Von Euw, Lardon and Reichstein, HeIv. Chim. Acta, Vol. 27, 1944, p. 821) in 100 cm ^{3 of} anhydrous benzene was added. The reaction mixture was heated to 50 to 60 ° for 2 hours; During this time there was considerable precipitation of the product. The cooled reaction mixture was ^{mixed with 250 cm 3 of} anhydrous ether and the whole was kept at room temperature for 16 hours. The precipitate was then filtered off from the reaction mixture, washed with water, dried in vacuo and gave 6.1 g of an ivory-colored sodium enolate of 2i-formylpregnan-3ct-ol-11, 20-dione. The sodium enolate was readily soluble in water and gave an orange color with aqueous ferric chloride. The acidification of an aqueous solution of the above-described sodium enolate caused the precipitation of 2i-formylpregnan-3ct-ol-11, 20-dione as a white powder which, after drying, ^{melted at 94 to 102 0} , as analyzed below, with alcoholic ferric chloride orange-red coloration.

Analysis for C ₂₂ H ₃₂ O ₄ :
calculated: C = 73.30, H = 8.95;
found: C = 73.03, H = 8.99.

The compound obtained can be converted into 3cc-oxyii-ketoätiocholansäure and their 3a-acylate are converted.

Example 2

2i-formylallopregnan-3 /? - ol-ii, 20-dione and its Potash Enolate

Following the procedure of Example 1, the sodium enolate des 2i-formylallopregnan-3/3-ol-ii, 20-dione by implementing Allöpregnan ^ ß-ol · !!, 20-dione (Stork et al., Journ. Amer. Chem. Soc, Vol. 73, 1951, p. 3546) with ethyl formate and potassium tertiary butoxide manufactured. The acidification of an aqueous solution of potassium enolate with hydrochloric acid results in a precipitation of ^ i-formylallopregnan ^ ß-ol-11, 20-dione, which by reaction with hydrogen peroxide gives 3/3-Oxy-iT-ketoätioallocholanäure, after recrystallization from acetone and water

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melts at 272 to 274 ° (Mason et al., Journ. Biol. Chem., Vol. 120, 1939, p. 719):

The implementation of 2i-formylallopregnan-3 / J, ττβ-

diol-20-one with hydrogen peroxide leads to 3 / ?, 11/3-dioxy-ätioallocholansäure, the 3 / ?, iiß-Dioxyätioallocholansäuremethylester in the esterification with diazomethane results after recrystallization

from acetone and ether melts at 237 to 238.5 ° (Von Euw and Reichstein, HeIv. Chim. Acta, Vol. 30, 1947, p. 205).

Example 3

2T-formylpregnane-3a. iict-diol-ii, 20-dione and
its sodium enolate

Following the procedure described in Example 1, 3.48 g (0.010 mol) of pregnan-3a, ^ a-diol ^ n, 20-dione (Sarett, Journ. Amer. Chem. Soc, Vol. 70, 1948, p. 1454 ) reacted in 50 cm ^{3 of} benzene and 5 cm ^{3 of} ethanol with 2.6 cm ^{3 of} ethyl formate and 3.04 cm ^{3 of} 3.4 n-methanolic sodium methylate in a solution of 20 cm ^{3 of} benzene and 2 cm ^{3 of} absolute ethanol, from the 10 cm ³ had been distilled off. The pale yellow sodium enolate of 21-formylpregnan-3a, i7a-diol-ii, 20-dione which precipitated was filtered off from the reaction mixture and, after drying, weighed 2.59 g. The sodium enolate was obtained with ferric chloride in water

, -. · A dark purple color. The acidification of an aqueous solution of the sodium enolate caused the precipitation of pregnan-3 a, 17a-diol-n, 20-dione, which after drying ^{melted at 135 to 145 0} and had the following composition. An-al-

■? ■■ Alcoholic solution of this latter compound showed a deep red color with ferric chloride.
Analysis for C ₂₂ H ₃₂ O ₆ :

calculated: C = 70.18. H = 8.57;
- Found: C = 69.39, H = 8.30.

■. ', Λ? α -Allopregnan-3a, I7a-diol-n, 20-dione can be converted into 3 a, i7a-dioxyrii-ketoätioallocholansäure by the action of hydrogen peroxide.

Recrystallization of the latter compound from acetone and water gives crystalline 3 a, I7a-Dioxy-

■ ?: - ii-ketoätioallocholanic acid, which is at 282 to, 284 °

melts. _. . _n

Example, 4. .

2i-formyl-5, i6-pregnadien-3a-ol-2ö-one-3-acetate and its sodium enolate

. · ■ :. A suspension of 1.08 g of sodium methylate in 25 cm ^{3 of} benzene and 4 cm ^{3 of} ethyl formate was stirred at room temperature for 30 minutes, then a solution of 3.54 g (0.01 mol) of 5, i6-pregnadien-3-ol- 20-on-3-acetate in 75 cm ^{3 of} anhydrous benzene quickly poured in. The stirred solution was kept at room temperature for 6.5 hours; during this time some gelatinous solid fell

out; then 156 cm ^{3 of} anhydrous ether were added and stirring continued for an additional hour. The precipitate was then filtered off, washed with ether and, after drying, had a weight of 4.05 g. The sodium enolate gave an orange-red color with aqueous ferric chloride. Coloring. The acidification of an aqueous solution of the sodium enolate gave a pale yellow precipitate of the 2i-formyl-5, 16-pregnadien-3-ol-2O-one-3-acetate, which after drying took on a light red color. The infrared absorption spectrum of the material showed a stronger maximum at 1618 " ¹ cm, which is typical for an enol compound.

Example 5

ii-Keto-21-formylprogesterone and its
Sodium enolate

According to the method described in Example ι were using 3.28 g (0.01 mol) of 11-ketoprogesterone, 2 cm ^{3 of} ethyl formate in a by distillation of a mixture of 3.4 cm ^{3 of} 3.4 n-methanolic sodium methylate, 20 cm ^{3 of} benzene and 0.7 cm ^{3 of} anhydrous ethanol until 8 cm ^{3 of} distillate are obtained, the reaction mixture obtained, 2.55 g of the sodium enolate of ii-keto-21-formylprogesterone produced as a yellow powder. An aqueous solution of the sodium enolate gave a pink color with ferric chloride. The acidification of an aqueous solution of the sodium enolate produced a precipitation of II-keto-21-formylprogesterone, which melted at 85 to 90 °. The infrared absorption spectrum of this compound corresponded to this structure. The compound obtained can be converted into 3, ii-diketo-4-etiocholenic acid,

Example 6

iia-Oxy-21-formylprogesterone and its
Sodium enolate

According to the method described in the preceding examples, the sodium enolate of 11 a-oxy-21 - formylprogesterone from Iia-oxyprogesterone (Peterson and Murray, Journ. Amer. Chem. Soc, Vol. 74, 1948, p. 1871) by using these the latter compound is reacted with methyl formate in the presence of sodium ethylate; the sour position an aqueous solution of the sodium enolate gives 11α-oxy-21-formylprogesteron.

According to the method of Examples 1 to 6, further 2i-formyl-pregnan-20-ones and their Alkaline metal enolates are produced.

The potassium enolates of any of the compounds of Examples 1 to 6 are prepared by adding a potassium base, preferably tertiary potassium butoxide, used in place of the sodium methylate or ethylate in the reaction. Be accordingly other alkali metal enolates of the foregoing and other compounds prepared by the selected alkali metal base, preferably an alkali metal alcoholate used in the above reaction. -

Claims (2)

PATENT CLAIMS:, i. Process for the preparation of 20-keto-2iformyl steroids the Pregnan series or their 'alkali metal enolates, characterized in that one a pregnan of the formula -St-C-CH ₃ in the St a cyclopentanone bonded with carbon atom 17 to the indicated side chain 658 / 4S0 U 2373 IV bl 12 ο Polyhydrophenanthrene nucleus means, in a known manner, in the presence of an alkali metal base, preferably an alkali metal alcoholate, with an alkyl formate, preferably at one temperature between about o ° and the boiling point of the reaction mixture, reacted and optionally a Acidified solution of the alkali metal enolate obtained. 2. The method according to claim i, characterized in that that methyl formate or ethyl formate is used as the alkyl formate. Considered publications: German Patent Specifications No. 834 989, 836 800; French patents nos. 891 441, 869 653.