DE1073495B - Process for the production of new, biologically active ester compounds - Google Patents

Description

The invention relates to a process for the production of new, biologically active 19-norsteroid compounds, which are referred to below as estran compounds in the 3-position carry no oxygen-containing substituents and those in the 17-position have an unsaturated, lower aliphatic ^ Contain hydrocarbon group in addition to a free or functionally converted hydroxyl group.

In particular, it relates to a process for the production of new steroid compounds from the group of oestrans, £ / ^4- oestrene, zl ⁵ < ¹⁰ ) -oestrene and ^ 3,5_Oestradiens. These compounds are α in 17-position by the groups (R) and / 5 (OR ₁₎ substituted wherein R represents an unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and R ₁ is a hydrogen atom or an acyl group having from 1 to 1 O carbon atoms . These new compounds have anabolic, androgenic and progestative properties.

These new compounds also have very powerful inhibitory effects against sex hormones (gonad-inhibiting effects).

The process according to the invention is characterized in that a 17-oxosteroid, which belongs to the group of z) ³ ' ^5- estradiene, / i ⁴ -oestrene, / i ⁵ ( ¹⁰ ) -oestrogen and oestrans, which in 3- Position does not carry any oxygen-containing substituents, is converted into the corresponding 17-hydroxy compound by an addition reaction, which is also substituted in the 17-position by an alkynyl or alkenyl group. The 17-alkenyl compound can optionally be prepared by partial reduction of the corresponding 17-alkynyl compound, whereupon the 17-hydroxy compound thus prepared, which is substituted in the 17-position by an alkynyl or alkenyl group, is esterified on the 17-hydroxyl group .

The compounds which are used as starting materials in the present process can be prepared by reacting Δ ¹ ' ³ · ⁵ -Z - Alhaxy- 17-hydroxy-oestratriene with an alkali metal in the presence of liquid ammonia or in the presence of an aliphatic primary amine and then Oxidation of the resulting _4 ⁴ -17-hydroxyoestrene, zl ³ ( ¹⁰ ) -17-hydroxy-oestrene and Δ ³ · ⁵ -ί7-Ή.γ- hydroxy-oestradiens to the corresponding 17-oxo compounds are prepared.

The 17-oxo-oestrane can be obtained by reducing the the above-mentioned unsaturated 17-hydroxy-oestrane compounds with hydrogen and subsequent oxidation the resulting saturated 17-hydroxyoestrane compound to the corresponding 17-oxo compound getting produced.

The 17-alkynyl or alkenyl compounds are produced by adding a metal derivative. Process for the production of new,
more biologically effective
Estran compounds

Applicant:
NV Organon, Oss (Netherlands)

Representative: Dr.-Ing. F. Wuesthoff, Dipl.-Ing. G. Pulse

and Dipl.-Chem. Dr. rer. nat. E. Frhr. v. Bad luck man,

Patent Attorneys, Munich 9, Schweigerstr. 2

Claimed priority:
Netherlands 10 April 1957

Dr. Stefan Antoni Szpüfogel, Oss (Netherlands),
has been named as the inventor

an unsaturated hydrocarbon with a triple or double bond to the starting 17-oxo compound. The metal derivative can be a magnesium halide of the unsaturated hydrocarbons.

The preparation of the 17-alkynyl compounds can also be carried out as an addition reaction between the 17-oxosteroid compound and a triunsaturated hydrocarbon in the presence of an alkali metal or an alkali compound such as an alkali amide, alkali alcoholate and the like, or by adding a metal compound of a triunsaturated hydrocarbon to form the starting 17-oxo compound. the Metal compound can be an alkali or alkaline earth compound, such as a lithium, sodium or calcium compound, be.

An alkyne or alkene is used as the unsaturated hydrocarbon with a triple or double bond with 2 to 6 carbon atoms, e.g. B. acetylene, propyne, butyne, ethylene, propene, butene, hexene or hexyne.

The desired 17-hydroxy-17-alkynyl or -alkenyl compound can be obtained from the reaction mixture after hydrolysis by methods known per se, such as by crystallization or by the chromatographic route.

It is also possible to obtain the 17-hydroxy-17-alkenyl compound by reducing the corresponding 17-alkynyl to establish connection. The reduction is usually carried out using hydrogen in the presence of a Catalyst, such as nickel, palladium-calcium sulfate,

909 710/552

Palladium barium sulfate and the like. After this 1 mol of hydrogen per 1 mol of the starting substance has been absorbed, the resulting 17-hydroxy-17-alkenyl compound from the reaction mixture can be isolated in a known manner.

The 17-hydroxy compounds formed, which are in the 17-position by an alkynyl or alkenyl group Are substituted, can optionally on the 17-hydroxy group with an aliphatic, aromatic or araliphatic carboxylic acid such as acetic acid. Propionic acid, butyric acid, valeric acid, Caproic acid, isocaproic acid, succinic acid, tartaric acid, cyclopentyl acetic acid, / I-cyclopentyl propionic acid, Cyclohexylacetic acid, cyclohexy! Butyric acid, phenylacetic acid, / 5-phenylpropionic acid, benzoic acid, Glycine or phenylanaline can be esterified.

example 1

To 145 ml of dry methylamine, which has been cooled to -20 ° C., 1.5 g of lithium cut into small pieces are added. A solution of 3 g of oestradiol-3-methyl ether in 145 ml of absolute ether is added dropwise to this solution, which is blue after 10 to 20 minutes. The reaction mixture is then stirred for 40 hours at -10 ° C., after which 50 ml of absolute ethanol are added. The methylamine is then distilled off at low pressure. 50 ml of ether and 50 ml of water are added to the remaining solution. The aqueous layer is separated and extracted with ether. The ethereal layer is washed with a 2N hydrochloric acid solution, then with a saturated sodium bicarbonate solution and then with water. The ethereal solution is dried and evaporated to dryness. The resulting crude reaction product is dissolved in a mixture of benzene and petroleum ether (1: 5) and chromatographed over aluminum oxide. ^{The ^ I 4} -17 /? - Hydroxy-oestren obtained after the chromatographic purification has a melting point of 80 to 90 ° C and 95 to 100 ° C after repeated recrystallization from petroleum ether.

A solution of 13.2 g of chromium trioxide in a mixture of 20 ml of water and 20 ml of acetic acid is added with stirring to a solution of 20 g of # -17 / J-Hydroxy-oestren in 400 ml of benzene. The reaction mixture is then stirred vigorously at room temperature for 16 hours and then the Separated benzene layer. The remaining aqueous layer is drawn out a few times with benzene; the collected benzene extracts are then combined with the separated benzene layer. The collected Benzene extracts are washed successively with dilute sulfuric acid and with water and then evaporated to dryness. The residue is recrystallized from acetone and the # -17-oxoesterene obtained with a melting point of 114 to 116 ° C.

The infrared spectrum of this compound shows absorption bands at 5.75, 5.99, 12.38 and 14.82 µ (dissolved in carbon disulfide).

Example 2

Made into a solution of potassium tert-butoxide by adding 8.3 g of potassium to 125 ml of absolute tert. Butanol, 50 ml of dioxane are added. This solution is cooled to 0 ° C., whereupon a solution is formed under a nitrogen atmosphere and with stirring of 5 g of <dM7-Oxo-oestren in 125 ml of dioxane was added will. The stream of nitrogen is then replaced by a stream of acetylene. After the acetylene Was passed 2 hours at 0 ° C through the solution, the reaction mixture in 1750 ml of water, the S contains 10 ml of concentrated sulfuric acid, poured. The resulting solution is extracted with ether. The separated ether layer is then successively with a sodium carbonate solution, dilute sulfuric acid and washed with water. The essential

ίο layer is then dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from acetone, giving the ^ ⁴ -17 /? - hydroxy-17a ~ äthinyl-oestren with a melting point of 157 to 161 ° C. The infrared spectrum of this compound shows absorption bands at 2.82, 3.07, 6.02, 12.39 and 14.87 μ (dissolved in carbon disulfide).

The ^ * - 17/3-Hydroxy-17a-äthinyl-oestren is also obtained by reacting acetylene-magnesium bromide (produced by passing acetylene through a solution of methylmagnesium bromide) with Δ ¹ - 17-oxo-estren.

In an analogous manner, the # -17 /? - Hydroxy-17a-hexynyl-ester is used made by using the

as acetylene magnesium bromide by hexynyl magnesium bromide replaced.

Example 3

100 g of a Pd-BaSO ₄ catalyst (5%) are added to a solution of 0.8 g of 4 ⁴ -17 /? - hydroxy-17a-ethinyl esters in 60 ml of ethanol. This solution is shaken under a hydrogen atmosphere until 0.003 mol of hydrogen are absorbed. The catalyst is then filtered off and the filtrate is evaporated to dryness in vacuo. The residue is recrystallized from acetonitrile, with the, 4 ⁴ -17 /? - Hydroxy-17a-vinyl-oestren with a melting point of 78 to 79 ° C is obtained. The infrared spectrum of this compound shows absorption bands at 2.82 μ (OH group), 6.12 μ, 10.9 μ (vinyl group) and 6.02, 12.38 and 14.82 μ (^ bond).

Example 4

A solution of 1 g of zl * -17 / MIydroxy-17a-äthinyloestren (prepared according to Example 2), 5 ml of pyridine and 4 ml of acetic anhydride are heated to 100 ° C for 1 hour. The solution is then evaporated to dryness in vacuo, whereupon the residue is taken up in a mixture of acetone and petroleum ether. The / d ⁴ -17 /? -Acetoxy-17a-äthinyl-oestren with a melting point of 158 ° to 161 ° C. (from acetone) is obtained by crystallization.

The reduction carried out analogously to the procedure given in Example 3 leads to / l ⁴ -17 /? - acetoxy-17a-vinyl-oestren.

If you replace the acetic anhydride with succinic anhydride or / J-phenylpropionic anhydride replaced, the corresponding esters of these compounds are obtained.

Example 5

A solution of 28 g of pentenyl bromide in 85 ml of ether is added to a mixture of 3.5 g of magnesium and 200 ml of ether. This mixture is stirred for 30 minutes, whereupon a solution of 4 g / ^{l 4-1} 7-oxoesterene in 150 ml of ether is added.

Thereafter, the reaction mixture is under for 2 hours

Heated to reflux. Then 50 ml of water containing 20 ml of concentrated hydrochloric acid are added to the mixture and vigorously stirred. Then the ethereal layer is separated, dried over sodium sulfate and finally evaporated to dryness. Recrystallization of the residue from a mixture of ethyl acetate and petroleum ether gives the <d ⁴ -17 /? - hydroxy-17-pentenyl-ester. The infrared spectrum of this compound shows absorption bands at 2.82, 6.02, 12.39 and 14.80 µ. ίο

A solution of 1 g of this compound in 4 g of propionic anhydride and 4 g of pyridine is heated to 100 ° C. for 1 hour under a nitrogen atmosphere and then poured into ice water. The resulting precipitate is filtered off and recrystallized from petroleum ether, giving the zf ⁴ -17 /? - Fropionoxy-17orpentenyloestrene.

If the propionic anhydride is replaced by caproic anhydride, succinic anhydride, cyclopentylpropionic anhydride or yS-phenylpropionic anhydride, the corresponding J ⁴ -17 ^ -acycloxy-17a-pentenyl-oestrene esters are obtained.

The 17-esters, which are derived from acetic acid, trimethyl acetic acid and phenylacetic acid, can be prepared in an analogous manner from the ^ ⁴ -17 _{/ 3-hydroxy-17a-hexynyl-19-oestren.}

Example 6

A mixture of 2.72 ml is added to a mixture of 22.4 ml of absolute ether and 1.84 g of magnesium Allyl bromide and 2.72 ml of absolute ether under a nitrogen atmosphere.

A solution of 2 g / f ⁴ -17-oxoesterene in 30 ml of absolute ether is then added to the reaction mixture, whereupon the whole is stirred for 4 hours. The reaction mixture is then poured into acidified ice water. The aqueous mixture is extracted with ether, the ether layer is separated off, washed with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from a mixture of ether and petroleum ether and leads to / l ⁴ -17 /? - hydroxy-17a-allyloestren with a melting point of 79.5 to 80 ° C; [a,] _? = + 39 ° (in chloroform). The infrared spectrum shows bands at 2.82, 6.02, 6.11, 10.89, 12.38 and 14.80 µ.

When this compound is esterified by the process described in Example 4, the corresponding 17-esters, which differ from acetic acid, butyric acid, y-cyclohexylbutyric acid and ^ -phenylpropionic acid derive.

Example 7

To a solution of 1.85 g of estradiol 3-methyl ether 50 ml of liquid ammonia and 1.3 g of lithium cut into small pieces are added to 85 ml of ether. The mixture is stirred at the boiling point of ammonia for 15 minutes, followed by dropwise absolute ethanol is added until the blue color of the reaction mixture has just disappeared. Then 1.3 g of lithium are added again and then, after stirring for 15 minutes, 25 ml of absolute Ethanol. After the ammonia evaporates, the remaining ethereal solution is mixed with water washed, dried over sodium sulfate and then evaporated to dryness. The residue is then dissolved in benzene-petroleum ether (1: 1) and passed through a column filled with 100 g of aluminum oxide chromatographed.

From the benzene-petroleum ether eluates the zi ^s ' ⁵ -17 / 5-Hydroxy-oestradien with a melting point of 112 to 113 ° C is obtained. The infrared spectrum of this compound shows characteristic bands at 11.88, 12.38 and 16.69 μ. The UV spectrum has a maximum at 228 and 235 ηιμ.

1 g of zf ³ ' ⁵ -17 /? - Hydroxy-oestradien is dissolved in 22 ml of glacial acetic acid. A solution of 800 mg of chromium trioxide in 2 ml of water and 8 ml of glacial acetic acid is added at room temperature. The reaction mixture is left to stand for 5 hours at room temperature, after which it is diluted with 400 ml of water and extracted with chloroform. The chloroform extracts are washed successively with a dilute sulfuric acid solution, a sodium carbonate solution and water and then dried over sodium sulfate. The solution is evaporated to dryness. Crystallization from acetone-petroleum ether gives the / f *> ⁵ -17-oxo-oestradien, which has bands at 5.75, 11.88, 13.38 and 12.69 μ in the infrared spectrum. The UV spectrum shows maxima at 221 and 235 πιμ.

Example 8

A stream of acetylene is passed for 4 hours with stirring through a mixture of 6 g of ^{I 3} ' ⁵ -17-oxo-oestradien, 300 g of liquid ammonia and 2 g of sodium amide. The mixture is then treated with 5 g of ammonium chloride, whereupon it is left to stand at 25 ° C. for 2 hours. The reaction mixture is then poured into water, the aqueous mixture is extracted with ether, the ether layer is separated off, washed with water and then dried over sodium sulfate.

The essential solution is then evaporated to dryness. The residue is recrystallized from a mixture of acetone and petroleum ether, giving the zJ ^s ' ⁵ -17 /? - hydroxy- * 17a-ethinyl-oestradien. The infrared spectrum shows bands at 2.82, 3.06, 11.86, 12.39 and 12.69 µ. The UV spectrum has maxima at 228 and 235 πιμ.

According to the process described in Example 3, this compound is converted into the zf ^s ' ⁵ -17 /? - hydroxy-17a-phenyl-oestradiene by reduction.

When replacing the acetylene by propyne according to the method described in this example to A ^{s' 5} -17 jS-hydroxy-17 a-methyläthinyloestradien leads.

Example 9

Analogously to the manner described in Example 5, 6-chlorohexene-1 is converted into hexenyl magnesium bromide. To a solution of 4.0 g of this compound in 200 ml of ether, a solution of 4.5 g / f ^s ' ⁵ -17-Oxo-oestradien in 150 ml of absolute ether is added. This mixture is treated further as described in Example 5, so that the z ( ³ ' ⁵ -17 _/ 5-hydroxy-17a-hexenyl-oestradiene is obtained.

This compound is converted into its 17-ester according to the procedure described in Example 4, which differ from valeric acid, isocaproic acid, cyclohexylacetic acid and derive benzoic acid.

Example 10

120 mg of zf ⁴ -17 /? - I € ydroxy-oestren, prepared according to Example 1, are dissolved in 10 ml of glacial acetic acid and, after the addition of 10 mg of a platinum catalyst, shaken in a hydrogen atmosphere. After 45 minutes, the reaction mixture does not take up any more hydrogen. The catalyst is then filtered off and

the filtrate evaporated to dryness. The residue is recrystallized from acetone — ether the 17 / i-hydroxy-oestrane with a melting point ΛΌη 110 to 113 ° C obtained.

Oxidation of this compound according to the procedure described in Example 1 gives the 17-oxoestrane with a melting point of 120 to 122 ° C. The infrared spectrum shows a band at 5.76 μ.

Example 11

50 ml of dioxane are added to a solution of potassium tert-butoxide, prepared by adding 8.3 g of potassium to 125 ml of absolute tert. Butanol, given. At 0 ° C and a nitrogen atmosphere, this solution becomes a Added a solution of 5 g of 17-oxo-oestran in 150 ml of dioxane. A stream of acetylene is then passed through the solution passed for 2 hours at 0 ° C, whereupon the mixture is poured into 21 water, the 10 ml contains concentrated sulfuric acid. The aqueous mixture is then, as described in Example 2, treated, whereby the 17 /? - Hydroxy-17cräthinyloestran is obtained. In the infrared spectrum, bands at 2.81 and 3.07 μ could be detected.

Example 12

To 145 ml of dry methylamine, which has been cooled to -20 ° C., 1.5 g of lithium cut into small pieces are added. A solution of 3.0 g of oestradiol 3-methyl ether in 145 ml of absolute ether is added dropwise to this solution. The reaction mixture is then stirred at -10 ° C. for 40 hours, after which 50 ml of absolute ethanol are added. Then the methylamine is distilled off at low pressure. The remaining solution is mixed with 50 ml of ether and 50 ml of water. The aqueous layer is separated and extracted several times with ether. The combined ether extracts are added to the ether layer, whereupon this ethereal solution is washed out with a 2N hydrochloric acid solution, then with a saturated sodium carbonate solution and then with water. The ethereal solution is dried over sodium sulfate and finally evaporated to dryness. The resulting crude reaction product is dissolved in a mixture of benzene and petroleum ether (1: 5) and chromatographed over a column filled with 70 g of aluminum oxide. From the first fractions of the benzene-petroleum ether eluates, the / l ⁵ t ¹⁰ > -17 / 3-hydroxy-oesterene with a melting point of 92 to 95 ° C. is obtained.

1.0 g ^ l ^s ( ¹⁰ ) -17 ^ -hydroxy-oestren is dissolved in 100 ml acetone, whereupon 1.15 ml of an 8 n-chromium trioxide solution are added to this solution at 10 ° C. with vigorous stirring. The reaction mixture is shaken for 5 minutes and then poured into water. The aqueous mixture is extracted with chloroform, the chloroform layer is separated off, washed with a dilute sodium bicarbonate solution, then with dilute sodium bicarbonate solution and finally with water until neutral, dried and finally evaporated to dryness. The residue is filtered over 5 times the amount of aluminum oxide. Through crystallization from petroleum ether, 0.7 gz! ^{5 '10} ) -17-oxo-esters with a melting point of 115 to 122 ° C.

Example 13

12.5 g of potassium are added to a solution of 5.5 ml of absolute isopropanol and 12 ml of absolute benzene given under nitrogen atmosphere. After 15 minutes the reaction mixture is cooled to 12 ° C, whereupon a stream of purified acetylene through for 3 hours

ίο the solution is sent.

A solution of 1.9 g of ⁵ ( ¹⁰ ) -17-oxoesterene in 8 ml of benzene and 5 ml of ether is then added. Acetylene is passed through this solution for 4 hours, after which the whole is stirred for 14 hours at room temperature. A mixture of 12 ml of water and 1.5 ml of concentrated sulfuric acid is then added to the solution and the whole is stirred for 10 minutes. The reaction mixture is then diluted with 100 ml of water and washed with ether. The ethereal layer is separated, washed with water, dried over potassium sulfate and evaporated to dryness. The residue is recrystallized from a mixture of ether and petroleum ether to give ⁵ z J ⁽¹⁰⁾ -17 /? - hydroxy-17a-ethynyl-estrene from melting

point 112 to 113 ° C and [a] _D = + 116 ° (in chloroform) is obtained. The infrared spectrum shows bands at 2.81 and 3.07 μ.

The reduction of this compound by the method described in Example 3 leads to ^ J ⁵ I ¹⁰ I- ^ / I-hydroxy- ^ a-vinyl-oestren.

The above compounds are esterified by the method described in Example 4 in their 17-ester converted, which is derived from acetic acid, caproic acid, oenanthic acid, succinic acid, cyclopentylpropionic acid and /? - Derive phenylpropionic acid.

Example 14

A solution of 1 g ^ l ⁵ ( ¹⁰ ) -17-Oxo-oestren in 50 ml of absolute ether is slowly added to a solution of 6 g of allyl magnesium bromide in 50 ml of ether. The mixture is refluxed for 2 hours, then cooled and then treated with a 10% solution of tartaric acid in water. The ethereal layer is separated, washed with water, dried over sodium sulfate and then evaporated to dryness. The residue is recrystallized from a mixture of acetone and petroleum ether, giving the zl ⁵ ( ¹⁰ > -17 / 9-hydroxy-17cc-allyl-oestrene. The infrared spectrum shows bands at 2.80, 6.11 and 10.87 μ.

Claims (1)

Claim: Process for the preparation of new, biologically active estran compounds, characterized in that a 17-oxo-zi ³ ' ⁵ -oestradien, -zl ⁴ -oestren, -zf ⁵ ( ¹⁰ ) -oestren or -oestrane which is in the 3-position carries no oxygen-containing substituents, converted by known methods into the corresponding 17-hydroxy-17-alkynyl (or alkenyl) compound, it being possible for the 17-alkenyl compound to be prepared by partial reduction of the corresponding 17-alkynyl compound, and optionally the 17 hydroxy group esterified in a known manner. © 909 710/552 T. 60