DE1054087B - Process for the production of new 18 norsteroids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

PATENT 1 054 APPLICATION DATE:

NOTICE
THE REGISTRATION
AND ISSUE OF
DESIGN S CHRIFT:

ISSUE OF
PATENT LETTERING!

kl. 12 ο 25/02

INTERIM T. KL. C 07 C JULY 6, 1957

APRIL 2, 1959 SEPTEMBER 24, 1959

agrees Oberein with aüslegeschrift

1054 087 (C 151B9 IV W 12 o)

The invention relates to a method for production of new 18 norsteroids.

The process according to the invention leads to 2-methylene-hydrophenanthrenes of the sub-formula below of the ring C

R ²

CH,

R ¹

CH,

IO

(CH ₂ ) «Process for the production of new 18-norsteroids

Patented for:

CIBA Aktiengesellsdiaft, Basel (Sfcbweiz)

where R ^{1 is} an activating radical and R ^{2 is} a hydrogen atom, a free or functionally modified oxo or oxy group and η is the numbers 2 or 3, by oxidation into the corresponding hydrophenanthren-2-ones, these condense to form 18-norsteroids of the sub-formula claimed priority: Switzerland of July 13, 1956

(CH ₂ ) "

and optionally saturates the 13,17 double bond in the compounds obtained with hydrogen and or or leads a free or functionally modified carboxyl group in the 17- or 17a-position in the acetyl or free or esterified oxyacetyl group.

In particular, compounds of the formula are used as starting materials

R ²

R ¹

CH,

(CH ₂ ) _m

where η = 2 or 3 and R ^{1 is} an activating radical, ζ. B. a free or functionally modified carboxyl group, such as an esterified carboxyl group, a nitrile or carboxamide group, an acetyl or oxyacetyl group with a substituted, especially etherified, oxy group, R ^{2 is} a hydrogen atom or a free or functionally modified oxy or oxo group, e.g. . B.

Dr. Leopold Ruzicka, Zurich,

Dr. Rudolf Anliker, Binningen,

and Dr. Hans Heusser, Kreuzungen (Switzerland),

have been named as inventors

an esterified oxy group, R ^{3 is} a free or functionally modified oxy or oxo group, e.g. B. an esterified or etherified oxy group or a ketalized oxo group, or their derivatives unsaturated in the ring system.

The compounds unsaturated in the ring system can have one or more double bonds, preferably a double bond starting from carbon atom 8 a. The starting materials are in patent 1,049,855 described. The oxidative cleavage of the methylene double bond occurs through direct hydroxylation with osmium tetroxide or by epoxidation with peracids, hydrolysis and subsequent glycol cleavage with lead tetraacetate or periodic acid, by ozonization and splitting of the ozonides or by oxidation with Potassium permanganate.

The hydrophenanthren-2-ones are condensed to give the 13,17-unsaturated 18-norsteroids in the presence of catalysts or condensing agents in a suitable solvent, e.g. B. in the presence of strongly alkaline condensing agents such as alkali metal hydroxides or alcoholates, amides or

'909606/417

3 4

-hydrides, such as potassium hydroxide, sodium ethylate, sodium copper, aluminum, tin and the alkali metals. Man

trium amide or sodium hydride, or in the presence of this leads to the methyl ketones, which are, as above

Catalysts, such as piperidine acetate, benzoate or tri-described, can be converted into oxymethyl ketones,

ethylamine benzoate in an inert solvent, such as acid esters with the methyl metal compounds

z. B. dioxane, benzene, toluene or xylene. 5 implemented, so arise from the intermediately formed

The optionally to be undertaken saturation of the carbinols by dehydration compounds that 13 (17) double bond in the obtained 18-nor- on carbon atom 20 a methylene group on steroid can indicate chemical or biochemical. This can be penetrated by oxidizing agents Ways take place. For chemical reduction come replace an oxo group. One example is here both catalytically excited and nascent io oxidation with a compound of ovalent chromium, Hydrogen in question. So can this double bond like chromic acid, permanganate, by ozonization and for example by hydrogenation in the presence of a cleavage of the ozonides, by the action of peroxides, Palladium catalyst or metals through the action of alkali such as benzopersic acid, phthalic monoperic acid or hydrogen, especially lithium, superoxide in liquid ammonia, advantageous in the presence of osmium tetra- or a lower aliphatic amine, such as methyl oxide, and reduce the cleavage of the oxide or ethylamine during hydrolysis. rings or by direct addition of two hydroxyl

For the conversion of a free or functional groups on the double bond formed glycols, modified carboxyl group in 17- or 17a-position z. B. by means of lead tetraacetate or periodic acid.
In the conversion of nitriles with methyl metal there are various methods available in the acetyl or oxyacetyl group. So you can get the corresponding 20 compounds imino compounds that react with acid halides with diazomethane or saponify to ketones by hydrolyzing agents, functional derivatives of acids, such as halides, esters, should an oxo group be formed in ring A, such as acid amides or Nitriles, methyl metal compounds one can, for. B. let an esterified oxy group act by saponification. with the help of alkali metal bicarbonates, carbonates

The implementation of the acid halides with diazomethane 25 or hydroxides and subsequent oxidation, e.g. B. can be carried out with an excess of the latter with a compound of the ovalent chromium, such as chromium, whereby trioxide is obtained with elimination of hydrogen halide in glacial acetic acid or chromium trioxide-pyridine comdie diazoketones. If, on the other hand, the diazoplex, or with a metal alcoholate or phenolate in methane solution, is gradually added to the acid halide, the presence of ketones, such as. Acetone or cyclohexanone, the 30 released during the condensation or a ketalized oxo group is converted into a free oxo group by cleavage with hydrohalic acid with aqueous acids formed as an intermediate diazoketone, so that the corresponding halo ketone becomes
wins. Protected oxy or oxo groups, if so

To form oxyketones, the diazo ketones obtained are not already done in the course of other reactions in the crude state or after separation and 35 is set free at the end. So z. B. cleaning with hydrolyzing agents, such as ketals and acetals, both open-chain as with water or dilute acids, such as. B. sulfur cyclic, z. B. ethylene ketals, treated by treatment with acid, or with organic sulfonic acids, such as methane mineral acids or sulfonic acids at room temperature, sulfonic acid or toluenesulfonic acid. Esters of the pyruvic acid, advantageously in the presence of a ketone, such as acetone or oxyketones, can be cleaved with dilute acetic acid by reacting the diazoketones 40 or by gently warming them with low-water organic or inorganic acids. Under the same conditions, for example with acetic acid and also with propionic acid conditions, enol ethers or tetric acid, butyric acid, trimethyl acetic acid, crotonic acid and hydropyranyl ether are also cleaved. Benzyl ethers can except-oenanthic acid, palmitic acid, benzoic acid, phenyl acetic acid easily with hydrogen in the presence of a catalytic acid, ß-phenylpropionic acid, / S-cyclopentylpropionic acid, 45 sators, z. B. Palladium on carrier substances, such as animal chlorine, bromine or hydroiodic acid, phosphoric acid carbon or alkaline earth metal carbonates, are split,
or boric acid. If a double bond must be formed in 1 (2) - and / or haloketones as intermediate products, these can be introduced through the 4 (5) position. B. by halogenation of the 3-ketone and the free oxyketones or with salts of the above 50 subsequent elimination of hydrogen halides or by using acids to convert them into their esters. The oxyketones and dehydrogenation of the 3-ketone with a dehydrogenating ester can also be obtained from the methyl ketones in a di- acting selenium compound, in particular with a selenium direct or indirect route. So dioxide or selenium acid, advantageously in the presence, they are obtained by the action of a suitable oxy tertiary alcohol, such as tert. Butanol or amylene dying agents, e.g. B. lead tetraacylates, such as lead tetraacetate 55 hydrate, happen.

or aryl iodosoacylates. But one can also use the. Finally, the process-

Methyl ketones in the 21-position directly or indirectly (via products, in particular the lS-Nor ^ O-oxo ^ l-oxy-preg-

halogenate the 21-oxalyl derivatives) and convert the resulting nene into their esters in a known manner. In

Haloketones according to the above information in the oxy- these esters and / or enol esters are the acid

convert ketones or their esters. . 60 residues of any organic or inorganic residue

The methyl ketones can be obtained from the diazoketones by acids such as aliphatic, alicyclic, araliphatic, Reduction with metals, e.g. B. zinc, copper, magnesium aromatic or heterocyclic carbon, thion carbon, or their alloys, in the presence of a wide variety of thiol carbonic or sulfonic acids, preferably the ant solvents, such as alcohols, aqueous alcohols, lower acid, acetic acid, chloroacetic acid, trifluoroacetic acid, aliphatic acids, hydrohalic acids and al- 65 propionic acid, butyric acids, valeric acids, trimethyl alkalis, can be obtained. acetic acid, caproic acids, oenanthic acids, caprylic acids,

The acid halides mentioned can also be used with palmitic acids, undecylenic acid, / 3-cyclopentylpropionic

Methyl metal compounds, e.g. B. those of the magnetic acid, hexahydrobenzoic acid, benzoic acid, phenyl acetic acid

siums, cadmium and zinc, are implemented; to acid, cyclohexylacetic acid, phenylpropionic acids, furan

Mention should also be made of compounds of mercury, carboxylic acid, sulfuric acids or phosphoric acid!

The products of the process are 18-norsteroids saturated or unsaturated in the ring system with the following Formula of the ring C

in particular compounds of the formula

R ²

(CH ₂ ),

where η = 2 or 3, R ^{1 is} a free or functionally modified carboxyl group, such as an esterified carboxyl group, a nitrile or carboxylic acid amide group, an acetyl or oxyacetyl group with a free or substituted, in particular esterified, oxy group, R ^{2 is} a hydrogen atom, a free or functional modified, z. B. esterified oxy group or a free or functionally modified oxo group, R ^{3 is} a free or functionally modified oxy or oxo group, z. B. an esterified or etherified oxy group or a ketalized oxo group means. The compounds unsaturated in the ring system have the double bond in particular in the 4 (5), 5 (6) and / or 13 (17) position. The products of the process are intended to be used as medicinal products or as intermediate products for the manufacture of new steroids. 18-norprogesterone and 18-nor-13,17-dehydro-progesterone are characterized by a strong progestative effect.

The invention is described in more detail in the following examples. The temperatures are in degrees Celsius specified.

example 1

500 mg of the A ^Sa Aß- (y'-cyanopropyl) -2-methylene-7,7-ethylene-dioxy-4b /? - methyl-1,2,3,4 ^ α, 4 ^ described in patent 1,049,855 5,6,7,8,10, lOaß-dodecahydrophenanthren be (stabilized with 1 ° / ₀ ethanol) in 2 cm ³ of pyridine and 8 cm ³ of absolute chloroform solved. An ozone stream is passed through the vigorously turbinated solution at -15 to -18 °. In the precisely measured ozone flow, 21.35 mg of ozone flow per minute. After 400 seconds (= 2 equivalents of ozone) the ozonization is interrupted and the reaction vessel is flushed with nitrogen for 10 minutes. It is then diluted with 16 cm ^{3 of} a mixture, cooled to -15 °, of 4 cm ^{3 of} water, 8 cm ^{3 of} pyridine and 4 cm ^{3 of} glacial acetic acid, and about 1 g of zinc dust activated with dilute acetic acid is added with vigorous turbination. After 15 minutes the cold reaction mixture (-15 °) is filtered immediately. Extensive rinsing is carried out with benzene. The organic phase is washed in succession three times with water, twice with saturated sodium hydrogen carbonate solution and three times with water, dried and carefully evaporated in vacuo. The crystalline residue (520 mg) is chromatographed on aluminum oxide (act. III). With benzene-petroleum ether (4: 1) 53 mg of unchanged starting material with a melting point of 138 to 139 ° can be eluted, while the benzene fractions 432 mg of pure A ^8a- l /? - (/ - cyanopropyl) -4b, S-methyl-7 , 7-ethylenedioxy -1,2,3,4,4aa, 4b, 5,6,7,8,10,1Oa / I-dodecahydrophenanthren-2-one with a temperature of T37 °.

ίο [a] | ² = -47 ° (chloroform). The following bands can be observed in the IR absorption spectrum: 1712 cm- ¹ (6-ring ketone); 2240 cm " ¹ (aliphatic nitrile).

100 mg Δ ⁸ M / ^ (/ - cyanopropyl) -4b /? - methyl-7,7-ethylenedioxy-1, 2 A44aa, 4b, 5A7,840 ^ 0ajS-dodecahydropherianthren-2-one with a melting point of 135 ° are listed below Nitrogen together with 20 cm ^{3 of} 0.5 η alcoholic sodium ethylate solution left to stand for 1 hour and then refluxed for 3 hours. The cold reaction solution is poured onto ice and extracted with choroform.

The oily residue of the choroform extract (87 mg) is chromatographed on aluminum oxide (act. III). With benzene-petroleum ether 1: 4, 53 mg / l ⁵ ' ¹³ ' ¹⁷ -3,3-ethylenedioxy-18-nor-ethiadienoic acid nitrile with a melting point of 150 ° can be eluted. The pure nitrile obtained, with a melting point of 173 °, has a maximum in the UV at 227 ΐημ (log ε = 4.13). [α] ο = -97 ° (chloroform). In the IR, bands are ^{visible at 2220 cm -1} (α, / 3-unsaturated nitrile) and at 1645 cm ^-1 (13.17 double bond). Sodium tertiary amylate in benzene is also particularly suitable as a condensing agent.

Example 2

To a solution of 103 mg Δ ^8a -l /? - (y'-cyanopropyl) -2 - methylene - 7,7- ethylenedioxy -4b /? - methyl -1,2,3,4,4 aa, 4b, 5 , 6,7,8,10,10a / 3-dodecahydrophenanthrene in 1.5 cm ^{3 of} absolute benzene are given 77 mg of osmium tetroxide. The solution is left to stand for 12 hours, then diluted with 7 cm ^{3 of} ethanol, shaken for 4 hours at room temperature after adding 0.7 g of sodium in 4 cm ^{3 of} water and filtered through kieselguhr (known under the trade name Celite). The filtrate is concentrated in vacuo and extracted with chloroform. The residue of the chloroform extract (104 mg) crystallizes from methanol-water. The pure glycol melts at 194 °, [a] _D = - 44 ° (chloroform). The crude glycol (104 mg) is dissolved in a mixture of 12 cm ^{3 of} methanol and 3 cm ^{3 of} pyridine and, after adding 500 mg of periodic acid in 2 cm ^{3 of} water, left to stand for 30 minutes at room temperature. The reaction mixture is diluted with water and extracted with chloroform. The crude compound (92 mg) remaining after evaporation of the solvent melts at 129 °. By recrystallizing three times, the melting point rises to 137 °. The thus obtained Δ. ^8α -1 β- (γ'- cyanopropyl) -4b /? - methyl-7,7-ethylenedioxy-1, 2,3,4,4aa, 4b, 5,6,7,8,10,10a _/ e ~ Dodecahydrophenanthren-2-one is identical in every respect to the compound obtained by ozonization and described in Example 1. The conversion to the 18-norsteroid takes place according to Example 1.

Example 3

a) To a methylmagnesium bromide, prepared from 2.2 g of magnesium, 10 g of methyl bromide and 20 cm ³ of absolute ether are rapidly 277 of the Δ described in Example 1 ^{5il3 '17} mg -3,3-Äthy.lendioxy-18-nor- etiadienoic acid nitrile in 20cm ³ ether was added. The reaction mixture is left with exclusion of moisture for 48 hours

heated to reflux, then cooled to Q ° and decomposed dropwise with water. After adding ammonium chloride, the mixture is extracted with chloroform. The yellow oily residue (310 mg) is dissolved in 25 cm ^{3 of} dioxane and 25 cm ^{3 of} water and refluxed for 5 hours. The reaction solution is concentrated in vacuo and extracted with chloroform. For cleaning, the residue is adsorbed on aluminum oxide (act. III). With petroleum ether-benzene (1: 1) 193 mg of pure A ⁵ '· ¹³ · ¹⁷ - 3,3 - ethylenedioxy - 20 - oxo - 18 - nor - pregnadiene can be obtained. [a] _D = .- 76 ° (chloroform). F. = 135 °. In the UV the connection shows a maximum at 256 ταμ (loe = 4.2). IR bands at 1622 and 1678 cm ^-1 (a, /? - unsaturated ketone).

b) Carefully dried and pre-cooled ammonia gas is condensed in a three-necked flask. At -45 °, 250 mg of pure lithium are quickly introduced into the liquid ammonia (300 cm ^{3) with vigorous stirring.} A solution of 1 g of the above-described Zl ^{5; 13> 17} -3,3-ethylenedioxy-20-oxo-18-nor-pregnadiene in 50 cm ^{3 of} ether is then added dropwise to the dark blue lithium solution. The reaction mixture is mixed vigorously at -45 ° for 2 hours and then poured onto crushed ice. The organic components are extracted with ether. The raw product is adsorbed on aluminum oxide (act. III). The petroleum ether-benzene (1: 1) fractions yield 763 mg of ⁵ -3,3-ethylenedioxy-20-oxo-18-nor-pregnen. In the IR bands at 1715, 1223 and 1174 cm- ¹

30th

-C =

CH,

67 of zd described in Example 3, ^{5 mg; 13 '17} obtained -3,3-ethylenedioxy-20-oxo-18-nor-pregnadieris.

Example 5
100 mg / J ^8a -1/3 - ((5'-Oxoamyl) -7,7-ethylenedioxy-4b _/ 5-me-

thren-2-one with a temperature of 201 ° are dissolved in 27 cm ^{3 of} methanol and 3 cn? ³ dissolved water and, after the addition of 1.5 g of potassium carbonate, heated under reflux for 3 hours under nitrogen. The cold reaction solution is diluted with the same volume of water and extracted with ether. The residue is chromatographed on aluminum oxide. 44 mg of pure A ^s ' · ¹³ · ¹⁷ -

3,3-ethylenedioxy-20-oxo-18-nor-pregnadiene with a temperature of 144 ° to win.

Example 6

A solution of pure A ^8α -1 / 3- (o'-oxoamyl) -7,7-ethylenedioxy-4b ^ -methyl-1,2,3,4,4aa, 4b, 5,6,7,8,10 , 10a _/ 3 dodecahydrophenanthren-2-one melting at 201 ° in 10 cm ³ of isopropyl ether und.2 cm ³ of absolute benzene are boiled over 500 mg of aluminum oxide (act. I) for 2 hours Rücknuß. The cold reaction mixture is filtered through "Celite" and evaporated in vacuo. The residue is chromatographed on aluminum oxide (act. III). The petroleum ether-benzene (1: 1) fractions yield 23 mg Zl ⁵ ; ^{13 '17} -3,3-ethylenedioxy-20-oxo-18-nor-pregnadiene, mp 143 ° which is crystallized from acetone-hexane in prisms. With benzene, 17 mg of starting material are obtained.

35

Claims (3)

Claims: In the compound obtained, the ketal group in the 3-position can be split as follows: 500 mg of Zl5-3,3-ethylenedioxy-20-oxo-18-nor-pregnen are dissolved in 20 cm3 of acetone, with 0.2 cm3 of 2n- Hydrochloric acid is added and the mixture is heated on a water bath for 15 minutes. After dilution with water, the acetone is evaporated off in vacuo and extracted with ether. 415 mg of pure J4-3,20-dioxo-18-nor-pregnen (18-norprogesierone) can be crystallized in fine needles from the ether extract from methanol-water. In the UV the connection has a maximum at 240 τημ (log ε = 4.23). In the IR bands at 1672 and 1622 cm-1 (α, β-unsaturated ketone) and 1715, 1220 and 1170 cm-1 (methyl ketone). Example 4 600 mg of the ASa-iß- (δ'-oxoamyl) -2-methylene-4b / S-methyl-7,7-ethylenedioxy- described in patent 1,049,855 are ozonated as described in example 1. After chromatography on aluminum oxide (Act. III), in addition to 153 mg of starting material, 425 mg of pure ASa-i j3 - ((5'-oxoamyl) -7,7-ethylenedioxy-4b / S-methyl-1,2,3,4 , 4aa, 4b, 5,6,7,8,10,10a / 9-dodecahydrophenanthren-2-one with a melting point of 181 °, [d] r> = -71 ° (chloroform) 100 mg of the pure compound from C. 181 ° are left to stand for 1 hour under nitrogen together with 20 cm 3 of 0.5 η alcoholic sodium ethylate solution and then refluxed for 3 hours The cold reaction solution is poured onto ice and extracted with chloroform, the residue is chromatographed on aluminum oxide, with petroleum ether-benzene (4: 1) 1. Process for the production of new 18-norsteroids, characterized in that 2-methylene-hydrophenanthrene derivatives the following partial formula of the ring C where R ^{1 is} an activating radical and R ^{2 is} a hydrogen atom or a free or functionally modified hydroxyl group or oxo group and η denotes the numbers 2 or 3, the corresponding hydrophenanthren-2-ones obtained are oxidized to 18-norsteroids of the partial formula (CH ₈ ) ,, condensed and optionally the 13 (17) double bond in the compounds obtained Hydrogen saturates and / or a free or functionally modified carboxyl group in 17 or 17 a division into the acetyl or a free or esterified one Oxvacetvlgruppe transferred. 2. The method according spoke 1, characterized in that that the starting materials are compounds of the formula R ² H ₃ C CH, R ¹ CH ₂ ί
(CH ₂ ) " IO R ³ used, where η = 2 or 3 and R ^{1 is} an activating radical, for example a free or functionally modified carboxyl group, such as an esterified carboxyl group, a Nitrü- oderCarbonsäureamidgrappe, an acetyl or oxyacetyl group with a substituted, in particular etherified, oxy group, R ^{2 is} a hydrogen atom or a free or functionally modified oxy or oxo group, for example an esterified oxy group, R ^{3 is} a free or functionally modified oxy or oxo group, e.g. B. an esterified or etherified oxy- group or a ketalisieite Ctograppe, means or their derivatives unsaturated in the ring system., 3. The method according to claims 1 and 2, characterized characterized ,, that the starting materials are compounds of the formula used which, starting from carbon atom 8 a, have a double bond and in which R ^{1 is} a functionally modified carboxyl group or an acetyl group and R ^{3 is} a free or functionally modified oxy or oxo group. © 809 788/347 3.59 (909 £ 06/417 9. 59)