DE1668665B1 - Process for the preparation of 13-alkyl-gona-1,3,5 (10) -trienes - Google Patents

Description

wherein R, R ¹ and X have the above meanings, the C / D ring bond is in the trans configuration and the hydrogen atom in the 8-position, which is in the anti-position to the hydrogen atom in the 14-position, after an known methods is reduced by catalytic hydrogenation and, if desired, the 17-hydroxy compounds obtained are oxidized in a manner known per se to the corresponding 17-keto compounds or the 17-keto compounds obtained are reduced to the corresponding 17-hydroxy compound or the 17-keto or 17-hydroxy compounds obtained are converted into their functional derivatives or these derivatives are hydrolyzed to compounds which contain free 17-keto and hydroxy groups, or the 3-ether compounds obtained are converted to the corresponding 3-hydroxy Compounds are dealkylated or the 3-hydroxy compounds obtained are esterified or alkylated.

2. The method according to claim 1, characterized in that compounds of the general formula II, in which R ^{1 is} an ethyl-isopropyl, n-propyl or n-butyl group, are used as starting compounds.

60

The present invention relates to a process for the preparation of 13-alkyl-gona-1,3,5 (10) -trienes, which are valuable intermediates for the production of 18-homo-19-nor-steroids, some of which have a significantly increased physiological effectiveness. In addition, these connections show in many Cases a greater separation of the physiological activities. This opens up the possibilities the application of a particular single hormone effect expands without an undesirable, secondary one Cause effect, which would result if a corresponding steroid - i.e. a compound with a methyl group in the 13-position - would be applied under the same conditions.

Examples of the separation of physiological activities which can be produced by the process according to the Compounds can be achieved, the ratios are anabolic / androgenic and feminization / Blood lipoid depression.

The process of the invention is used for the preparation of 13-alkyl-gona-1,3,5 (10) -trienes of the general kind Formula (I)

RO

wherein R is hydrogen or an alkyl or acyl group, R ^{1 is} an alkyl group having at least 2 carbon atoms, X is hydrogen and a free hydroxyl group or a functional derivative thereof, or X is a free or protected oxo group and the substituents on the tertiary carbon atoms in C. Ring are in the trans-anti-trans configuration, the process being characterized in that a compound of the general formula (II)

i = X

(Π)

in which R, R ¹ and X have the meaning given above, the C / D ring bond is in the trans position and the hydrogen atom in the 8 position is anti to the hydrogen atom in the 14 position according to methods known per se is reduced by catalytic hydrogenation and, if desired, the 17-hydroxy compounds obtained are oxidized in a manner known per se to the corresponding 17-keto compounds or the 17-keto compounds obtained are reduced to the corresponding 17-hydroxy compound or the obtained 17-keto or 17-hydroxy compounds are converted into their functional derivatives or these derivatives are hydrolyzed to compounds which contain free 17-keto and hydroxy groups or the 3-ether compounds obtained are dealkylated to give the corresponding 3-hydroxy compounds or the 3-hydroxy compounds obtained are esterified or alkylated.

Compounds of the general formula (I) are 18-homologated oestrones and derivatives and show a decrease in the concentration of blood lipids with little suppression of testicular development. the Homologation at the 18 position exercises a

ORIGINAL INSPECTED

3 4

deep effect by increasing the first and decreasing formula (I), where R is hydrogen, dealkylated

the second of these effects. will. The dealkylation can, for example, by

Starting materials are appropriate compounds - heating the compound with pyridine hydrochloride

fertilize with ethylenic bond in the 9 (11) position or with sodium amide and piperidine,

(referred to as 9-dehydro compound). 5 A compound in which R is an acyl group can

The term "alkyl group", as it is generally saponified by hydrolysis, and a term used in this description, includes both bonds in which R is hydrogen, and can be alkylated or acylated by standard methods, both stane-substituted and unsubstituted alkyl groups,
a. Such an alkyl group can be straight or low-chain. It is understandable that wherever difficulties arise, there may be a branch-chain group with or without a substituent in achieving saturation of the ethylenic compounds. R can, for example, be a methyl, ethyl, dung due to the incompatibility between a methoxymethyl or benzyl group _# or an acetyl special group R or X and the used or benzoyl group and R ¹ an ethyl, n-propyl, reducing agent occur, this difficulty may be due to isopropyl or n-butyl group. Preferably, the selection of a suitable starting material, containing R and R ¹ not more than 10 each or reduction thereof and furthermore substitution of the common 20 carbon atoms. Particularly suitable as a desired group R or X can be avoided. R and R ¹ are lower alkyl groups which contain up to 9-dehydro compound starting materials in 4 or 6 carbon atoms, and for smoke generally from 8-dehydro compounds through a lower acyl group with up to 4 or 6 carbon simple acid catalytic Isomerization available,
atoms. Preferably, R ^{1 is} also an alkyl group. Processes in which the starting materials have a —CH ₂ group in the position. for the process according to the invention ^ The group X means hydrogen and a free can, are both in the British patents W or functionally modified hydroxy group, or 975 593, 975 594 and 975 595 as well as the German a free or protected carbonyl group, for example patents 1,231,699, 1,235,908 and 1,213,404 as well as hydrogen, and an esterified hydroxyl group, 05 mentioned in some of the following examples, or they such as (H, O-acetyl) or (H, O-propionyl), or a can be obtained from the compounds mentioned there by ketalized carbonyl group, such as an Äthylendioxy- suitable process to group and an enol derivative of a carbonyl group. wished to introduce groups R and X like this

The catalytic hydrogenation of the starting 9-De- is familiar to the person skilled in the art. For example, a

hydro compounds was found to be sufficient stereo- 3 ° o-alkoxyphenylhex-l-en-3-one with a 2-alkylcyclo-

specifically for the production of the desired trans-antipentane-l, 3-dione with the formation of a 2 (-6-alkoxy-

trans compounds found. phenyl-S-oxohexy ^^ - alkylcyclopentane-l ^ -dions kon-

Where a starting material or reduction process condenses, which in turn is used in the presence of an acid which can cyclodehydrate a compound with a catalyst under group X, another than necessary to result in 35 formation of the corresponding 3-alkoxygona-1,3,5 (10) 8, the desired group X is given by a 14-pentaen-17-ons. This pentaene can then be selectively formed by the appropriate following process. by catalytic hydrogenation to the corresponding. Accordingly, 17-hydroxy compounds obtained Gona-1,3,5 (10) 8-tetraene can be reduced, which to fertilize, for example by Oppenauer-oxidation corresponding Gona-1,3,5 ( 10), 9 (ll) -tetraene isomeric or can be degassed by oxidation with chromic acid. This can be oxidized as a starting material for speaking 17-ketones. Obtained can be used for the process according to the invention. 17-ketones can be converted into the corresponding 17-hydroxy- In the above formula (I), the 13 /? - and 13 a-Ver compounds are not differentiated separately using, for example, bonds, ψ sodium borohydride or lithium aluminum hydride 13 /? - and 13 "-forms are present in equimolecular reduced or by heating with sulfuric acid and 45 mixed or as a racemate, if the glycolized with a suitable alcohol (for example ethylene starting compounds produced by total synthesis). Obtained 17-ketals can and a separation of the enantions not be decatalized by acid hydrolysis. In the same followed. If the starting material (for example) the 17-hydroxy compounds obtained can be a separated 13/5 enantiomer, this will be esterified with an acyl chloride, for example. 5 ° product naturally have the 13 ^ shape.

In many cases, the reduction can be carried out on a process in which the following examples explain the invention. The temperatures are in ° C, desired group X is already present. Example pressures given in mm of mercury: Infrared repellants can be compounds of the formula (II), in sorption numbers (IR) refer to the position of which X is an oxo or hydroxyl group, through 55 maxima in cm " ¹ and UV absorption data (UV) to direct catalytic hydrogenation, with the formation of the maxima in πιμ with numbers in brackets, which of the compounds of the general formula (I), with which the molecular extinction coefficients for these same group X, with the addition of hydrogen, indicate wavelengths,
in the correct stereochemical positions in each.
Case to be converted. 60 B e 1 s ρ 1 e 1 1

Similarly, where the desired end a) To manufacture the starting product was group R after the reduction process not before- to (dz) -8-dehydro-18-homo-oestrone (0.1 g) in Mehanden is to create this in the following process ethanol (10 ecm) concentrated hydrochloric acid (2 ecm) will. So a compound of the given and the mixture under reflux for 2 hours Formula (I) where R is held an alkyl (e.g. 65. The cooled product was washed with ether Methyl) group and X a carbonyl group or extracted, the extracts were washed and purified ketalized carbonyl group is dried after one. The evaporation then gave a pale pink color appropriate methods to give a compound residue (0.094 g); UV: 267 (17,000).

5 6

Recrystallization in methanol gave pale pink vapors of the solvent then gave a Stalle of (±) -9-dehydro-18-homo-oestrone, enamel green crystalline material, which is made from methanol point 248 to 251 °, which crystallizes out to a red liquid (±) -8-dehydro-18-nor-13-n-propylmelt; after recrystallization, UV absorption oestrone (0.36 g) resulted in a melting point of 210 ° to 220 ° data unchanged. _ 5 much disintegration into a red liquid; UV: 281 (11,800).

b) (±) -9-dehydro-18-homo-oestrone (0.06 g) in etha- The 8-dehydro compound (0.36 g) was found under

nol (25 ecm) was heated under reflux for 15 minutes by shaking with hydrogen reflux with methanol (18 ecm) and water (2 ecm) at 1 ¹ J ₂ atm. pressure in the presence of a 10% strength. Ether (100 ecm) and drate were added to the palladiumised charcoal catalyst (0.06 g) hygender pink solution. When the hydrogenation ceased after 4 hours, io water (50 ecm) was added and the ether solution gave up after filtering the catalyst and, separately, washed and dried. Evaporation, evaporation of the solvent as a residue gave a residue which crystallized from acetone as a colorless resin, which crystallized as crude upon scratching and (±) -9-dehydro-18-nor-13- (±) -18-homo-oestrone ; UV: 281 (2.100) n-propyl-oestrone resulted as colorless crystals (0.17 g), without a maximum at 267, which indicates the perfect melting point 220 to 225 °, which indicates a red reduction of the ethylene bond. The liquid melted; UV: 266 (14,000).
Crude product was first made from aqueous methanol; b) The 9-dehydro compound (0.17 g) in ethanol

then recrystallized from ethanol to give colorless (30 ecm) was with hydrogen at atmospheric Crystals, melting point 216-219 °, with a pressure in the presence of a 30% palladized Change of shape at 190 °. 20 charcoal catalyst (0.09 g) shaken until the

Hydrogenation was complete (8 hours). Filtering and

Example 2 Evaporation gave a colorless crystalline solid λ

body, which was crystallized from ethanol *

(±) -18-homo-oestrone (0.32 g) was obtained with sodium and (±) -18-nor-13-n-propyl-oestrone (0.083 g), borohydride (0.13 g) in ethanol (25 ecm) 20 minutes 25 melting point 206 to 212 °; UV 281 (2.050); IR: heated to reflux. The reaction mixture became 3270, 1708, 1610, 1218.
then cooled, acidified with ice cold acetic acid. .

and evaporated to dryness. The residue was B e 1 s ρ 1 e 1 4

taken up in ether (50 ecm) and water and the (±) -18-nor-13-n-propyl-oestrone (0.17 g) in ethanol

The separated ethereal layer was washed and 30 (20 ecm) and sodium borohydride (0.09 g) were under dries. Evaporation of the solvent gave reflux for 15 minutes under mild conditions raw product (0.33 g) which heats up when scratched. Acetic acid (0.3 ecm) was added to the cooled one crystallized. Recrystallize from aqueous Me solution added and the solvent under ethanol and then removed from anhydrous methanol under reduced pressure; Ether (50 ecm) and resulted in (±) -18-homo-oestradiol (0.14 g) as through-35 water (25 ecm) was added, the ether layer Clear white needles with the melting point of separated, washed and dried. The Ver-190 up to 193 °; IR: 3500 to 3100 (broad band), 1055, steam gave a resin which, after the addition of 1030 with no band, which crystallized to methylene dichloride from the ketone absorption. Recrystallize from write is. a mixture of ethyl acetate and light petroleum

. 40 gave (±) -18-nor-13-n-propyl-oestradiol (0.10 g),

Example 3 melting point 183 to 186 °; UV: 281 (2,000); IR:

a) To produce the starting material, 3425, 3270, 1615, 1582, 1040.
2-n-propylcyclopentane-1,3-dione (13 g) 1-diethylamino

6-m-hydroxyphenylhexan-3-one and 0.12% metha- Example5 \

Nolian potassium hydroxide solution (38 ecm) 12 hours 45

together under gentle reflux conditions a) To prepare the starting compound, was

heats. The separation of the product gave the Mi- (±) -13-n-butyl-8-dehydro-18-nor-oestrone-methylchael adduct 2- (6-m-Hydroxy-phenyl-3'-oxohexyl) -2-n-ether (0.2 g) in methanol (24 ecm) and more concentrated propylcyclopentane-1,3-dione as a brown resin hydrochloric acid (1.5 ecm) refluxed for 20 minutes (7.18 G). 50 hold. Some solvent was then re

The adduct (7.18 g) was removed after heating in benzene reduced pressure, water added and the (210 ecm), which p-toluenesulfonic acid (0.75 g) ent mixture extracted with ether. The evaporation of the held, cyclodehydrated to give a deep green washed and dried extract gave a Resin (6.4 g), which in benzene over a column with pink resin, which crystallizes from methanol activated clay (known under the trade name 55 and colorless crystals of (±) -13-n-butyl-Fuller's Earth) was chromatographed, whereby 9-dehydro-18-nor-oestron-methyl-ether (0.075 g) erein yellow resin resulted. Crystallization from ethanol gave, melting point 109 to 114 °; UV: 264 (17,800). and then from a mixture of benzene and light b) The 9-dehydroether described above

petroleum gave (±) -8 ₃ 14-bisdehydro-18-nor-13-n- (0.065 g) in ethanol (8 ecm) and benzene (2 ecm) became propyloestrone (0.59 g), melting point 149-155 ° 60 in an atmosphere of hydrogen with one with some premelt at 135 to 138 °; UV: 313 10% palladized charcoal catalyst (0.05 g) (27,000). shaken until the hydrogen uptake ceased.

The tetracyclic diene (0.59 g) in benzene (30 ecm) filter the catalyst and evaporate the was in hydrogen at atmospheric pressure in solvent gave a resin which was rapidly upon Presence of a palladized charcoal catalyst. Inoculation with the product of the previous additive (0.3 g) shaken until the required amount crystallized. The recrystallization of the Ma-Hydrogen for the selected semi-hydrogenation ab- terials from ethanol resulted in 13-butyl-18-nor-oestrosorbed was. Filtering the catalyst and methyl ether; Melting point 97 to 99 °.

Example 6

(±) -13-n-Butyl-18-nor-oestrone methyl ether (0.2 g) was treated with pyridine hydrochloride (3 g) in a nitrogen atmosphere Heated for 40 minutes. The cooled product was dissolved in aqueous methanol, in addition Water was added and the mixture was extracted with ether. The washed and dried ether extracts were evaporated, leaving a resin which partially crystallized. All the stuff was taken up in a mixture of equal volumes of benzene and ether (20 ecm) and with Claisen alkali extracted; the aqueous extract was acidified with hydrochloric acid and extracted with ether. Work up the ether extracts gave a crystalline residue after evaporation. Recrystallize from

a mixture of light petroleum and ethyl acetate gave (±) -13 - η - butyl -18 - nor - oestron (0.045 g), Melting point 174 to 176 °; IR: 3345, 3280 (one broad band), 1715.

Example 7

(±) -18-homo-oestrone methyl ether (0.5 g) and pyridine hydrochloride (5 g) were melted together under nitrogen for 40 minutes. The chilled

ίο Melt was taken up in methanol (10 ecm), poured into water (100 ecm) and processed with ether. They gave a solid body consisting of 95% i £ ^em aqueous ethanol crystallized crystalline (±) -18-homo-estrone (0.5 g), mp 232-233 °, resulted. (It showed a change in crystalline form between 190 and 200 °.)

209519/416

Claims (1)

Patent claims: 1. Process for the preparation of 13-alkyl-gonal, 3,5 (10) -trienes of the general formula (I), = X (I) in which R is hydrogen or an alkyl or acyl group, R ^{1 is} an alkyl group having at least 2 carbon atoms, X is hydrogen and a free hydroxy group or a functional derivative thereof, or X is a free or protected oxo group and the substituents on the tertiary carbon atoms are im Ring C are in the trans-anti-trans configuration, characterized in that a compound of the general formula (II), as