DEU0002457MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: October 26, 1953. Advertised on November 8, 1956

GERMAN PATENT OFFICE

PATENT APPLICATION UNG

CLASS 12ο GROUP 25 05
INTERNAT. CLASS C 07c

U2457lVb / 12o

Barney John Magerlein
and Robert Harold Levin, Kalämazoo, Mich. (V. St. A.)

have been named as inventors

The Upjohn Company, Kalämazoo, Mich. (V. St. A.)

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

Process for the preparation of Pregnan-11 β, 17a-diol-3,20-dione

The priority of registration in the V. St. v. America of October 27, 1952 is in claim

The invention relates to a process for the preparation of the new Pregnan-iiß, 17α-diol-3, 20-dione

CH ₃ C =

and is represented by the following equation:

CH "

⁰ p

CH ₅

(I)

CH,

OH

RCH

⁰ S CH,

(II)

CH,

-0- (CH _a ) _n

■!

O - CHR OH

6B9 7OS / 4O7

U 2457 IVb / 12 ο

.CH,

(CH ₂ ) _n

HO,

(CH ₃ ) ^ - O

RCH

CH,

C = O

(III)

in which R is hydrogen or low molecular weight alkyl groups, such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl or hexyl group, and η = τ or 2.

According to the process of the invention, pregnan-i7a-ol-3, ii, 20-trione (I) is treated in a known manner with an alkanediol, preferably an alkan-i, 2-diol or alkane, 3-diol, such as ethylene glycol, propane -i, 2-diol, propane, 3-diol, butane-i, 2-diol, butane-2, 3-diol, pentane, 2-diol, 3-methylpentane-i, 2-diol or hexane-i, 3 -diol heated in the presence of an acid catalyst, the corresponding cyclic 3,20-diketal of pregnane-17CI-0I-3,, 11, 20-trione (II) is formed. By reducing this diketal (II) with a reducing agent, e.g. B. a metal hydride or hydrogen in the presence of a catalyst, in a known manner, the cyclic 3, 20-diketal of pregnane-iiß, I7a-diol-3, 20-dione (III) is obtained in the hydrolysis carried out in a known manner with an acid gives Pregnan- ΐτβ, i7ct-diol-3, 20-dione (IV).

It was already known to have a 20-position keto group in the presence of a 16 (i7) -position Ketalize oxido group. It was also known to have a 3-position keto group in the presence of a

, .ii-keto group to selectively ketalize the

40. · ..fr-standing keto group to be reduced subsequently ,, and to restore the 3-position keto group by hydrolysis of the ketal group.

However, one could not infer from this procedure that a Pregnan-3, 11, 20-trione in the presence of a 17 α-position oxy group in 3- and 20 position would ketalize. The literature shows that in cortisone acetate, one Contains hydroxyl group in the 17-position, the 20-position Keto group, cannot be ketalized. During the ketalization of cortisone acetate, the 3-phase Keto group ketalized, but the 20-position keto group remains unchanged. Since dehydrocorticosterone acetate, which does not have a 17-position hydroxyl group, easily ketalized in the 3- and 20-positions can be, according to the invention, despite the presence of a 17-position hydroxyl group, must be smoothly in 3- and 20-position ketalization can be described as surprising.

The new compound obtainable by the process according to the invention is important as a stable, solid intermediate product for the production of physiologically active substances, such as the acetate of Kendall's compound F (4-Pregnen-iia, 17a, 21-triol-HO
CH ₃

(IV)

CH ₃

c-OH

3, 2O-dione-2T-acetate) and the new compound 4-pregnen-iiß, i7a-diol-3, 20-dione. For this purpose halogen-. _; If you ne pregnane-ii / 5, i7a-diol-3,20-dione, whereby 4-halopregnane-ir / ?, i7a-diol-3, 20-dione is formed, which by treatment with semicarbazide and then with pyruvic acid in 4- Pregnen-n / ?, I7a-diol-3, 20-dione passes and treatment with lead tetraacetate gives the acetate of Kendall's compound F 8g. The 4-pregnen-ii / ?, i7ce-diol-3, 20-dione has a marked inhibitory effect on the secretion of the adrenocorticotropic hormone (ACTH) and is therefore valuable for the treatment of diseases in which an excessive secretion of ACTH g ₀ and adrenal cortical hormones occurs, such as B. the hyperplasia of the adrenal glands and basophillism of the brain appendage (Cushing's disease).

To carry out the process, Pregnani7a-ol-3, 11, 20-trione is added with at least the theoretically required amount of the alkanediol, e.g. B. an alkane-i, 2-diol or alkane-i, 3-diol, mixed in any order in an organic solvent which is inert under the reaction conditions. The reaction temperature is between about 20 and 200 °, preferably between about 20 and 150 ^0th As a rule, it is advantageous to use an excess of the alkanediol of preferably about 5 to 50 moles per mole of the steroid. The reaction time is not critical and can vary between about 1 hour and 48 hours. It depends on the temperature, the ketal-forming agent and the catalyst.

You can work in any organic solvent that does not use the reagents and products reacts like benzene, toluene, xylene, methylene chloride, petroleum ether or ether. The preferred solvents however, they are those that distill together with water and so the water after its formation in remove the reaction. For this reason, the reaction is usually carried out under reflux, with 115 the temperature, of course, depends on the solvent and the specific reaction conditions, e.g. B. from Pressure, depends.

The ketalizing agents used are alkanediols, preferably alkane-i, 2-diols and alkanes, 3-diols, such as ethylene glycol, propane-i, 2-diol, propane-i, 3-diol, butane-i, 2-diol, butane-2, 3-diol, pentane, 2-diol, 3-methylpentane-i, 2-diol, hexane-i, 3-diol, heptane-i, 2-diol or octane-i, 2-diol .. You can use any use suitable acid catalyst, preferably a mineral acid or an organic sulfonic acid.

6; 0β 7O6 / TO7

U 2457 IVb / 12 ο

Examples of catalysts are m- and p-toluenesulfonic acid, Naphthalenesulfonic acid, benzenesulfonic acid, o-chlorobenzenesulfonic acid, hydrochloric acid and sulfuric acid / wherein Benzenesulfonic acids, e.g. B. p-toluenesulfonic acid, to be favoured.

The so obtained cyclic 3, 20-diketal of Pregnan-170-01-3, 11, 20-trione, which is dissolved in a solvent which is inert under the reaction conditions, is by adding a reducing agent such as Li-Al hydride, Li-B hydride, Na-B hydride, hydrogen in Presence of catalysts such as platinum or Raney nickel, among others, with Li-Al hydride being preferred, for cyclic 3, 20-diketal des Pregnan-iya, ii /? - diol-3, 20-dions reduced.

It is advantageous to use solvents such as ether, benzene, tetrahydrofuran or petroleum ether. According to the preferred embodiment is Li-Al hydride with a suitable organic solvent, such as Ether, mixed; the steroid is dissolved in benzene and the two mixtures are combined.

The temperature of the mixture is usually kept between about ο and 100 °, preferably between about room temperature and the boiling point of the mixture. The reaction takes about 30 minutes to 8 hours or more. If Li-Al hydride is used as the reducing agent, the reaction is advantageously carried out first at a temperature of about ο to 50 ⁰ , preferably at about room temperature; while higher temperatures are used towards the end of the reaction, the reflux temperature generally forming the upper temperature limit. The reactants are mixed and stirred, preferably for about 30 minutes to 1 hour at room temperature, and then heated for 30 minutes. 35 'or longer at reflux atmospheric pressure, the reaction time depending in part on the ratio of reactants and the temperature used.

The amount of reducing agent can vary within wide limits, and one is usually used substantial excess of up to 50 moles to 1 mole of steroid.

The pregnane-ii / S, i7a-diol-3, 11, 2O-trione-3, 20-diketal is isolated by customary methods. Thus, if reducing agents such as Li-Al hydride or Na-B hydride, are used, the reaction mixture is hydrolyzed after the reduction is complete and the Pregnan-ii / ?, i7ct-diol-3, 11, 20-trion-3, 20-diketal obtained by extracting with a solvent.

To Pregnan-ii / 3, i7a-diol-3, 20-dione from the cyclic 3, 20-diketal of pregnane-ii / 3, I7a-diol-3, To prepare 20-dione, the diketal is usually dissolved in a solvent which, under the reaction conditions does not react, and then mixes with a hydrolyzing agent. In general using aqueous acidic hydrolyzing agents, such as dilute mineral acids, organic acids, such as p-Toluenesulfonic acid, in the presence of water, phosphoric acid inter alia, with dilute mineral acids such as hydrochloric acid and sulfuric acid being preferred. Particular organic acids and other acids are also sometimes used. You can use solvents, such as acetone, methanol, dioxane, or ethanol, with acetone being preferred. Sometimes is as in Example 2, it is desirable to use the pregnan-i7a-ol-3,11, 2o-trione-3, 20-diketal mixture of the reduction stage without previous isolation of the pregnane-11 / ?, i7ct-diol-3, 2o-dione-3, 20-diketals to use. In this case, the mixture to be hydrolyzed can contain considerable amounts of unreacted Li-Al hydride and solvents such as ether or benzene.

The hydrolyzing agent is usually used in excess of what is theoretically required Amount, whereby one can use a 1 to 10 fold excess or more, while a 5 to 10 fold excess Excess is usually preferred. Usually the reaction mixture is left for about 24 hours stirred at room temperature. The reaction time depends on the ketal used and the reaction temperature and concentration of the hydrolyzing agent ι hour or longer. When using higher Concentrations of the hydrolyzing agent and higher temperatures shorten the reaction time, using temperatures from 0 ° to the boiling point of the mixture.

When the hydrolysis is practically complete, the product is isolated by customary methods. Is the If, for example, an organic and an aqueous layer is mixed, the organic layer becomes separated, the aqueous layer extracted with ether and the ether solution combined, washed with water, about z. B. Sodium sulfate dried and nitrated; the Solvents are distilled off. The residue can then from the usual organic solvents be recrystallized. One can also isolate the product by removing the solvent removed by distillation or the reaction mixture diluted with water until crystallization takes place.

The following examples explain the implementation of the process according to the invention.

example 1

a) A solution of 25 g of pregnan-170.-ol-3, 11, 20-trione, 25 cm ^{3 of} distilled ethylene glycol, ι g of p-toluenesulfonic acid monohydrate and 500 cm ^{3 of} benzene are placed in a flask equipped with a water trap The reflux condenser is provided no. The mixture is refluxed with stirring for 10 hours. The water formed distills off with the benzene and is collected in the water catcher. The reaction mixture is cooled, washed with dilute sodium bicarbonate solution and with water and ^{then dried 1: L} 5 and evaporated to dryness in vacuo. The white crystalline residue is several times from ethyl acetate-Hexankohlenwasserstoffen (known under the trade designation "Skellysolve B") recrystallized to yield 29.52 g (94.6 ° / ₀₎ pregnane J 170-01-3 ^20, 11-trione 20, -3, 20-ethylene glycol diketal vom ^; Melting point 185 to 186 °.

C ₂₅ H ₃₈ O ₆

Analysis for C ₂₅ H ₃₈ O ₆ :

Calculated C 69.09, H 8.81;

Found C 69.01, H 9.02.

609 706/407

U 2457 IVb / 12 ο

The infrared analysis confirms that for Pregnani7a-ol-3, ii, 2O-trione-3, 20-ethylene glycol diketal assumed structure.

b) 29.5 g of pregnan-i7a-ol-3, 11, 2O-trione-3, 20-ethylene glycol diketal in 100 cm ^{3 of} ether are added to a solution of 5 g of Li-Al hydride in 600 cm ^{3 of absolute ether} and 100 cm ^{3 of} benzene dissolved. The mixture is stirred for 1 hour at room temperature, then refluxed for a further hour and, after cooling, ^{hydrolyzed with 50 cm 8 of} water. The organic layer is decanted off, the remaining paste is suspended in water and extracted several times with methylene dichloride. The combined ether and methylene dichloride solutions are evaporated, and crystalline pregnan- ΐΊ-β, i7a-diol-3, 2O-dione-3, 20-ethylene glycol diketal is obtained in quantitative yield. The infrared analysis confirms the structure for Pregnanii / S, i7 <x-diol-3, 2O-dione-3, 20-ethylene glycol diketal.

c) 29.5 g of Pregnan -11 / ?, 17a - diol - 3, 20 - dione-3, 20-ethylene glycol diketal are dissolved in 600 cm ^{3 of} acetone and a solution of 4 cm ^{3 of} sulfuric acid in 100 cm ^{3 of} water is added. The mixture is left to stand for 16 hours at room temperature, the acid is neutralized with sodium bicarbonate and the acetone is evaporated off in vacuo. The remaining aqueous suspension is filtered and the crystalline precipitate is washed with water and dried. The yield of crude. product is 19.5 g (82.7 ⁰ J ₀ ). ' After recrystallization from 200 cm ^{3 of} ethyl acetate, 14.04 g (46.7 ° / ₀ ) of pregnane-11 / ?, i7a-diol-3,20-dione with a melting point of 213 to 221 ° are obtained.

Example 2

a) A solution of 700 mg of pregnan-17 α-ol-3, 11, 20-trione, 5 cm ^{3 of} freshly distilled ethylene glycol, 50 mg of o-chlorobenzenesulfonic acid and 150 cm ^{3 of} benzene is heated for 10 hours in a flask with a reflux condenser and water trap . The water formed is distilled off with the benzene and is collected in the water catcher. The reaction mixture is cooled, ^{washed with 50 cm 3 of} dilute sodium bicarbonate solution and with water, then dried and evaporated to dryness in vacuo. The white crystalline residue turns out several times

4-5 ethyl acetate ^ Skellysolve B «recrystallized and gives about 600 mg pregnan-i7a-ol-3, 11, 20-trion-3, 20-ethylene glycol diketal.

b) ι g of pregnan-i7a-ol-3, 11, 2O-trione-3, 20-ethylene glycol diketal, dissolved in 20 cm ^{3 of} dry benzene, is mixed with a solution of 1 g of Li-Al hydride in 75 cm ^{3 of} absolute ether offset. The mixture is stirred for 1 hour at room temperature and heated under reflux for 1 hour. Without isolating the intermediate product Pregnan-II / 3, i7a-diol-3, 20-dione-3, 20-ethylene glycol diketal, the Li-Al complex of the diketal is rrydrolysed and pregnan-n /? -, i7a-diol- 3, 20-dione by ^{slowly adding 100 cm 3 of} dilute hydrochloric acid (50%) and stirring the acidic mixture for 16 hours at room temperature. The organic layer is separated and the

acidic solution extracted several times with 25 cm ^{3 ether each time.} The combined washings and organic layer are washed with sodium bicarbonate and water and dried over sodium sulfate. It is recrystallized from ethyl acetate and pregnane-H (S, i7a-diol-3, 20-dione with a melting point of 208 bis is obtained

Analysis for C ₂₀ H ₃₂ O ₄ :

Calculated C 72.38, H 9.26;

Found C 72.51, H 9.09.

Example 3

a) A solution of 0.5 g of Pregnan-170-0.! - 3, 11, 20-trione, 5 cm ^{3 of} propylene glycol, 50 mg of o-chlorobenzenesulfonic acid in 100 cm ^{3 of} toluene is refluxed for 10 hours, the resulting Water is distilled off with the toluene. The cooled solution is neutralized with sodium bicarbonate, washed with water and evaporated to dryness in vacuo. The crystalline Pregnan -17 α -öl- 3, 11, 2O-trione-3, 20-propylene glycol diketal is recrystallized from ethyl acetate.

b) 1 g of pregnan-i7a-ol-3, 11, 20-trione-3, 20-propylene glycol diketal, dissolved in 20 cm ^{3 of} benzene, is added to a solution of 1 g of Li-Al hydride in 75 cm ^{3 of ether.} The solution is stirred for 1 hour at room temperature, then refluxed for a further hour and, after cooling, hydrolyzed with water. The organic layer is separated off, washed with water, dried and evaporated to dryness, giving pregnane-ii / 3, i7a-diol-3, 2O-dione-3, 20-propylene glycol diketal.

c) Following the procedure of Example ic), Pregnan-11/3, i7a-diol-3, 2O-dione-3, 20-propylene glycol diketal is hydrolyzed in acetone with dilute sulfuric acid and gives Pregnan -ixß, 17a-diol-3, 20-dione.

The latter can also be achieved by reducing the Pregnani7a-ol-3, ii, 2O-trione-3, 20-propylene glycol diketal with Li-Al hydride and hydrolysis of the Li-Al complex with hydrochloric acid according to the procedure of Example 2b) will.

Claims (1)

PATENT CLAIM: Process _ for the production of Pregnan-11 / ?, i7a-diol-3, 20-dione, characterized in that pregnan-i7a-ol-3, 11,20-trione is reacted in a known manner with an alkanediol which obtained cyclic 3, 20-diketal of pregnane-17CI-0I-3, 11, 20-trione in a known manner with a reducing agent, in particular lithium aluminum hydride, treated and the obtained cyclic 3, 20-diketal of pregnane-ii / 3, I7a-diol-3, 20-dione is acid hydrolyzed in a known manner. Considered publications: Journ. Amer. Chem. Soc, Vol. 70, 1948, pp. 882ff .; Vol. 71, 1949, p. 756; Vol. 72, 1950, pp. 367, 5793; Vol. 73, 1951, pp. 3818, 4961; Vol. 74, 1952, p. 3630.