HU195670B - Process for production of steroide /2,3-d/ inaxasoles - Google Patents

Abstract

The present invention relates to a process for the preparation of an endocrinologic steroid [2,3-d] isoxazole of the general formula (I), wherein R is C1-C4 alkyl, alkenyl or alkynyl - a compound of formula (11). in which R is a reaction of the above - and a hydroxylamine or acid addition salt thereof, such that the reaction is carried out in a solvent medium containing pyridine in the presence of a strong acid, and the reaction mixture is treated with strong acid in the presence of water and the product is isolated. -1-

Description

The present invention relates to a new process for the preparation of the steroid f, 2,3-d | to produce isoxazoles.

In formula (I), E is C 1-4 alkyl, alkenyl or alkynyl.

Λ Compounds have a wide range of therapeutic applications and have mainly therapeutically useful endocrinological properties. Their preparation is described in U.S. Patent Nos. 3,135, 743, and 4,055,562, and in U.S. Pat. Med. Chem. 6.1-9 (1963).

U.S. Patent 4,055,562, e.g. discloses the preparation of compounds of formula (I) wherein R is ctin.l or 1-propynyl. According to the process described in the patent, these compounds are prepared by the addition of 17-oxo-androstane-ene [2,3-d] isoxazole with cinyl or 1-propynylniagnesium imnhalide / CH-C-MgX; CH ₃ -C C-MgX / ethinyl or 1-propynyl lithium / HC = CLi; CH ₃ -C - = C-Li / in an inert solvent under anhydrous conditions.

The reaction with ethynyl magnesium halide is carried out at room temperature. The yield of the reaction is low, e.g. 17a-Ethinyl-17β-hydroxy-androst-4-ene [2,3-d] isoxazole is obtained with a yield of 41.4%. Add to this 17-oxo-androst-4-ene [2,3-dj isoxazole is obtained from the corresponding 170-hydroxyisoxazole in 33% yield (J.Med.Chern. 6, 8 (1963)], then 17-allyl-17β-hydroxyandrost4-ene [2,3-d | isoxazole can be prepared from only 17 β-hydroxyandrost-4-ene [2,3-d] isoxazole with a total kit of 5.5%.

The yield of ctinyl lithium ctinylation is significantly better (73.4%), but the combined yield of the two steps is still low (24.5%). The disadvantages of this embodiment are the use at a reaction temperature of -70 ° C, the use of a difficult-to-handle delicate reagent / ethynyl lithium prepared from butyllithium and the complexity of purification of the final product.

No. 3,135,743. U.S. Pat. 6, 1-9 (1963), the steroid isoxazoles of formula (1) are prepared by reacting a compound of formula (11), wherein R is as defined above, with 2- (hydroxymethylene) -3. oxo-steroids are reacted with at least one molar equivalent of hydroxylamine, or an acid addition salt thereof, at a temperature between 50 ° C and 150 ° C in an inert solvent. The 2- (hydroxymethylene) -3-oxo-steroids of formula (11) can be prepared from the corresponding 3-oxo-steroids by condensation with ethyl formate in an anhydrous medium such as a strong base. in the presence of an alkali metal alcohol, amide or hydride.

According to the teachings above, the reaction of hydroxylamine or its acid addition salt with 2- (hydroxymethylene) -3-oxo-steroids can lead to the formation of two isomeric isoxazoles, namely the steroid [2,3-d] isoxazoles and the steroid [3,2-c] isoxazolocliosis.

The desired steroid [2,3-d] isoxal is formed when the condensation is carried out in the presence of a weak acid with a hydroxylamine or a weak acid addition salt in lower alcohols or lower aliphatic carboxylic acids or in a mixture of these strong acids. excluded. Condensation in the presence of strong acids under

powerful steroids in the 17-position tcrcicr hydroxy of steroids of the formula! dehydration, followed by a profound rearrangement of the steroid skeleton. Thus, when the reactant is hydroxylamine hydrochloride, a weak acid salt of a strong base, e.g. potassium or soda ash acetate should be added to the system for approx. in an equivalent amount to neutralize the hydrochloric acid, thereby converting the hydroxylamine salt to a weak acid

If, on the other hand, 2- (hydroxyethylene) -3-oxo-steroids with hydroxylamine. or an acid addition salt thereof with a base, e.g. in the presence of pyridine, in particular the unwanted isomers, i. the steroid [3,2-c] isoxazoles are formed with the steroid [2,3 dj isoxazoles.

The isomeric isoxazole mixing compound cannot be obtained by dirckt methods such as. crystallization or chromatography. They can be separated only by chemical methods, e.g. under strongly basic conditions, whereby the steroid [2,3-d] isoxazole is converted to 2a-cyano-3-oxo-steroid, so it is lost as isoxazole. The steroid [3.2-c] isoxazoles remain unchanged under the above conditions.

Surprisingly, it has been found that when the 2- (hydroxymethylene) -3-oxo-steroids of formula (11) are hydroxylamine. or the acid addition salt thereof in a pyridine-containing medium in the presence of a strong acid, then treating the reaction mixture with an aqueous solution of a strong acid, avoiding the above-mentioned side reaction and practically quantitatively producing steroid (2,3-d) isoxazoles.

The invention thus relates to a steroid of the general formula 1/1/ [2,3 d] isoxazoles wherein R 1 is C 1 -C 4 alkyl, alkenyl, or alkynyl, a compound of Formula 11 wherein R is as defined above, by reacting a 5-hydroxylamine or an acid addition salt thereof with The reaction is carried out in the presence of a solvent medium containing pyridine and a strong acid. The reaction mixture is treated with a strong acid in the presence of water and the product is isolated.

At least one molar equivalent of hydroxylamine or its acid addition salt is used for the condensation. Preferably the acid addition salt of hydroxylamine is hydroxyl antinyl chloride.

Solvents include water, pyridine, lower aliphatic alcohols, e.g. methanol, ethanol; lower aliphatic carboxylic acid esters e.g. formic acid methyl ester, formic acid ethyl ester, halogenated organic solvents, e.g. dichloromethane, chloroform, aliphatic and aromatic hydrocarbons, e.g. hexane, benzene, low-carbon aliphatic ethers e.g. isopropyl ether or a mixture of the above solvents and may be employed in a homogeneous or heterogeneous system. ·

The reaction temperature may range from -10 ° C to 60 ° C, preferably from 20 ° C to 50 ° C.

As strong acids, mineral acids such as. hydrochloric acid, sulfuric acid, or 0.9 pK. organic acid with a pK value of less than pK, e.g. trichloroacetic acid, trifluoroacetic acid, etc. alkai- * may be reduced. The strong acid is preferably hydrochloric acid. * The product is isolated by filtration or extraction and is conventionally prepared e.g. by chromatography, crystallization, etc. purified. I

The process of the invention is an embodiment; Thus, in j mode, we use / 11 / general. Y i

195,670 - where R is the pyridine solution of the 2-hydroxymethylene / -3-oxo-steroids already given is preferably reacted with an aqueous solution of hydroxylamine hydrochloride at room temperature followed by the addition of aqueous hydrochloric acid and chloroform to the heterogeneous reaction mixture. After stirring at 20-50 ° C for 30-60 minutes, the steroid β-2,3-d] isoxazoles are isolated from the chloroform solution.

A further great advantage of the process according to the invention is that it allows the preparation of steroid [2,3-d] isoxazoles of formula (I)

3-oxo-steroids, wherein R is as defined above, without isolating the 2-hydroxymethylene / 3-oxo-steroid of formula (11), by a substantially higher total cationization than known processes,

The advantages of the process of the invention over the process described in U.S. Patent No. 3,135,743i, as compared to the example of 17α-ethynyl-17β-hydroxyandrost-4-ene [2,3-d] isoxazole, are shown below. :

According to the procedure described in US patent, a solution of the pyridine of 17α-octinyl t-stosterone of formula (III) in the presence of sodium sodium ethylate is reacted with ethyl formate for 42 hours at room temperature. The reaction mixture is then poured into ice water and the aqueous alkaline solution is acidified with glacial acetic acid. The excellent sticky sticky product is separated and dissolved in ether. Extract from the ethereal solution with an aqueous solution of 17? -Ethynyl-2- (2-hydroxymethylene) testosterone potassium hydroxide, then cool the aqueous potassium hydroxide solution to 5 ° C and neutralize with hydrochloric acid. The solid precipitated product was filtered off and dried in vacuo at 60 ° C with phosphorus pentoxide. The crude 17β-ethynyl-2-hydroxymethylene / testostron is obtained in 87.2% yield.

The above product is reacted in a solution of acetic acid with hydroxylamine acetate which is formed in situ from hydroxylamine hydrochloride and anhydrous sodium acetate. The reaction mixture was heated on a steam bath for 1.5 hours and then the acetic acid was removed in vacuo. The distillation residue is taken up in ether. The ethereal solution is washed neutral with water and, after drying, evaporated to dryness in vacuo. The residue is triturated with ether, filtered and washed with hexane. Thus, crude 17α-ethyl-17β-hydroxyandrost-4-ene [2,3-diisoxazole is obtained in 54.8% yield. After recrystallization from acetone (the yield of which is not related), the physical constants of the product are given.

Thus, by the above procedure, crude 17α-ethynyl-17 (3-hydroxyandrost-4-ene [2,3-dj isoxazole) can be prepared with a maximum total yield of 47.2% relative to 17α-ethynyl testosterone.

In a preferred embodiment of the process of the present invention, 17α-ethynyl testosterone of formula III is condensed in pyridine in the presence of sodium inethylate with stirring with ethyl formate for 4 hours, followed by cooling with a solution of hydroxylaniline hydrochloride in aqueous hydrochloric acid. to the reaction mixture. After stirring for 5-15 minutes at 20-30 ° C, the mixture is treated with aqueous hydrochloric acid while the internal temperature rises to 48-52 ° C. After the addition of hydrochloric acid, chloroform was added to the reaction mixture, the mixture was stirred for 30 minutes at 48-50 ° C, then the chloroform phase was separated at room temperature, filtered through silica gel and washed in vacuo. The residue was recrystallized from methanol to give 75-80% yield of 17α-ethyl-17β-hydroxyandrosl-4-cn [2,3- (1) -isoxazole relative to 17α-ethinyltestosterone.

The process according to the invention has a total yield of about 28-33%. better than the procedure described above. It also has the advantage of being simpler, industrially easy to carry out, eliminating the need for isolation of 2-hydroxymethylene-3-oxo-steroids, requiring fewer operations, and implemented in a single device.

The invention is further illustrated by the following non-limiting Examples.

Example 1

17α-Crynyl-17β-hydroxy-aldrosr-4-yl [22β-z] isoxazole

17.61 g of 17α-ethynyl-2-hydroxy-methylene-testosterone are dissolved in 54.4 ml of 80% (v / v) aqueous pyridine at room temperature, and a solution of 3.06 g of hydroxyl-atnine hydrochloride in 6 ml of water is added. The reaction mixture was stirred at room temperature for an additional 10 minutes and then poured into 500 ml of 1.5 N hydrochloric acid with stirring. Stirring was continued at room temperature for a further 90 minutes, and the resulting white solid was filtered, washed neutral, and dried at 60 ° C under vacuum.

Yield: 13.11 g, 97.2% of the title compound.

Mp 224-226 ° C / methanol;

Elemental analysis calculated for C _{2 2} IL 7NCK: calculated ^c ': C 78 30: H 8.07: N4.15: 0 0.48 *

Example 2

17α-Methyl-17β-hydroxytindrost-4-ene 2,3-disoxazole

6.6 g of 2- (hydroxymethylene) -1,7α-ethyltestosterone are suspended in 32.6 ml of 80% aqueous pyridine, and 1.53 g of hydroxylamine hydrochloride in 3 ml of water are added to the suspension. After stirring at room temperature for 5 minutes, 62.4 mL of 6N hydrochloric acid was added with 66 mL of chloroform at a temperature between 47-50 ° C. The heterogeneous reaction mixture was stirred at this temperature for a further 30 minutes and then cooled to room temperature. The organic layer was separated and the aqueous layer was extracted with chloroform (2 x 15 mL) and the combined organic layers washed with water until neutral. After drying over anhydrous magnesium sulfate and filtration, the solvent was removed in vacuo from the filtrate.

Yield: 6.4 g (98%) of the title compound.

176-179 ° C (ethyl acetate)

Elemental Analysis calculated for C ₂₁ H ₂₄ NO ₂ ,% C 77.02; H, 8.93 *; N4,28; O, 9.77; Found: C, 77.10; H 8.81: N4.30: 0 9.68.

Example 3

17α-Ethynyl-17β-hydroxy-andros-4-ethyl [2,3-isoxazole

To a suspension of 125 g of 17α-ethynyl testosterone in 500 ml of pyridine was added 44.30 g of solid sodium methylate under a nitrogen atmosphere. To the suspension was added dropwise 192.5 ml of ethyl phonate over 1 hour with stirring, and the reaction mixture was stirred for an additional 4 hours. After cooling, a solution of 30.58 g of hydroxylamine hydrochloride in 164 ml of 5N aqueous hydrochloric acid was added at 20-30 ° C. Let C be between. The reaction mixture was stirred for a further 5 to 15 minutes on these aliquots and then 1250 in. 6N aqueous hydrochloric acid was added.

^U -3miközben 48-52 ° C, the temperature rises. To the reaction mixture was added chloroform (1250 mL) and the mixture was stirred vigorously at 48-50 ° C for an additional 30 minutes and then cooled to room temperature. The chloroform phase is separated off and the aqueous phase is extracted twice with 600 ml of chloroform. The combined chloroform phases were washed neutral with water, dried over anhydrous sodium sulfate, filtered and the resulting solution was filtered through silica gel and evaporated to dryness in vacuo. The crude product was purified by charcoal in methanol, crystallized to give 105.82 g of the title compound. The yield was 78.4% of 17α-ethynyl testosterone and the physical constants of the product were the same as in Example 1.

¹⁵

Example 4

17a-methyl-17 ' -hydroxy-androst-4-ene, 2,3-d} isoxazole

6.6 g of 17? -Methyl-2-hydroxyethylene / testosterone are suspended in 24 ml of 90% aqueous pyridine, and a solution of 4.52 g of hydroxylamine trichloroacetate in 6 ml of water is added. The reaction mixture was stirred at room temperature for 5 min, then a solution of trichloroacetic acid (72.2 g) in water (62 ml) and chloroform (68 ml) was added.

The reaction mixture was heated at 48 to 50 for 50 minutes with vigorous stirring. After reflux, the chloroform phase is separated off, the aqueous phase is washed twice with 30 ml of chloroform each; This solution is 5% chloroform solution. ^; The oxide is then filtered. it is then washed with neutral water, dried over anhydrous magnesium sulfate and, after filtration, evaporated in vacuo.

Yield: 5.7 g (87.4%) of the title compound having the same physical constants as in Example 2.

Example 5

17-tin-vinyl-17H-hydroxy-androst-4-ene [2,3-d] isoxazole

17a-dimethylaminocarbonyl-2- / hydroxymethyl-methylene / -tesztoszteronbó! starting analogously to Example 2 and the product

Crystallization from 195,670 ethyl acetate gave 85.2% of the title compound.

140-145 ° C

Calcd for C ₂₂ H ₂₉ NO ₂ : Calcd: C, 77.84; H, 8.61; O, 9.43; Found: C, 77.90; H, 8.55; 0 9.25.

Example 6

17α-Ethyl-7β-ΙιίάΓθχΐ-αηΰΓθίζί-4-εη [2,3-ά] isoxazole

Starting from 2- (b-hydroxymethylene) -7α-ethyl testosterone, analogous to Example 2 and crystallizing the product from ethyl acetate gave 82% of the title compound.

Mp 146-148 ° C

Analysis calculated for C ₂ i li, NO ₂ requires: Calculated%: 0 77.3 * 7 *; H9.15; N4.10; 0 9.37; Found: 0, 77.41; H, 9.11; N4.18; 0 9.40.

Claims (4)

Claims 1. Procedure is. For the preparation of steroid [2,3-dj isoxazoles of the general formula (1) - in which Rmax represents a C4-alkyl, alkenyl or alkynyl group, optionally prepared in situ (11) - in which R has the meaning given above - and bidroxil amine or by reacting an acid addition salt thereof, characterized in that the reaction medium containing oldószercs pyrindine, is carried out in the presence of a strong acid, and then from the tip ^ύ action treated with a strong acid in the presence of water, and the product is isolated. Process according to Claim 1, characterized in that the starting compound is the compound of formula 11 prepared in situ. 35 Process according to claim 1 or 2, characterized in that the strong acid is hydrochloric acid, sulfuric acid or a similarly strong inorganic acid. 4. The process according to claim 1 or 2, wherein the strong acid is a selective acid having a pK of less than 0.9.