DE1231699B - Process for the preparation of 13-alkyl-1, 3, 5 (10), 8 (9) - [or 9 (11)] - gonatetraenen - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

German class: 12 ο -25/07

Number: 1231699

File number: S 70442IV b / 12 ο

Filing date: September 20, 1960

Opened on: January 5, 1967

This invention relates to processes for the preparation of 13-alkyl-1,3,5 (10), 8 (9) - [or 9 (II)] - gonatetraenen, that contain a carbon skeleton related to that of steroids.

In recent years there have been many attempts to produce steroids synthetically. Here stood the partial synthesis from naturally occurring steroids, which are easily used as starting materials are available, and the manufacture of analogs and derivatives by altering the steroid structures found in nature in the foreground.

There are also some total syntheses in the steroid series have become known. Typical for these syntheses is the large number of individual steps that are necessary, mainly because of the stereochemical ones that are present not simple circumstances.

There has now been a new way of total synthesis of steroid hormones or related ones Found compounds which has the advantage that the compounds required to form the ring system essential carbon atoms in an early stage of a highly stereospecific synthesis are formed. Thus a 13-position angular methyl group was generated at such an early stage that the production of an unfavorable ratio of stereoisomers, which occurs in general, is avoided, when attempts are made to introduce this methyl group at a later stage. With this Furthermore, analog and homologous hormones which are not or can easily be produced in a new way at best, they are not accessible from natural steroids without serious difficulty. So became Provided access to steroids of various types that have an oxygen substituent in the 11 position. The new route also makes the production of homologous steroids possible Process for the preparation of 13-alkyl-I, 3,5 (10), 8 (9) - [or 9 (II)] - gonatetraenen

Applicant:

Dr. Herchel Smith, Wayne, Pa. (V. St. A.)

Representative:

Dr. M. Owl

and Dipl.-Chem. Dr. rer. nat. W. J. Berg,

Patent Attorneys, Munich 2, Hilblestr. 20th

Named as inventor:

Dr. Herchel Smith, Buxton, Derbyshire;

Dr. Gordon Alan Hughes,

Manchester, Lancashire (UK)

Claimed priority:
Great Britain September 25, 1959, February 19, 1960

have corner groups larger than methyl in the 13-position.

Ultimately, the path creates new total syntheses of estrone and estradiol, two valuable therapeutic ones Substances. These can easily be carried out by the new synthesis with good overall yield and by an effectively smaller number of steps than an overall synthesis has hitherto required can be achieved. The new way is shown in the following equation for the total synthesis of oestrone, in which the numbers refer to the structural formulas shown.

II

III CH ₃ O LJ CH2CH2CH2OH

CH ₃ O LJ CH ₂ CH ₂ CH ₂ Br

CH ₃ O LJICH ₂ CH ₂ CH ₂ C = CH

609 750/439

CH ₃ O \ ß CH ₂ CH ₂ CH ₂ C = CCH ₂ N (C ₂ Hs) ₂

N (C ₂ Hs) ₂

CH ₃ O

CH ₃ O

VII

H ₃ C

VIII

CH ₃ O

CH ₃ O

I-X

CH ₃ O

CH ₃ O

XXV

XXVI XXXVII XXXVIII

XXXIX

XII

H\

CH ₃ O

XIII

CH ₃ O

XIV

CH ₃ O

• XIX

OH

CH ₃ O

CH ₃ O

H\

CH ₃ O

HO

HO

OH

XXIX

XXX

XV

OH

XVI

The known compound 3-m-methoxyphenylpropan-I-ol (I) is converted to the corresponding bromide (II), which with sodium acetylide in liquid ammonia or other suitable solvents is condensed. The acetylene obtained (III), whose acetylenic hydrogen atom is reactive, is subjected to the Mannich reaction, where formaldehyde (or a formaldehyde polymer) and diethylamine is used to to give the acetylenic amine (IV).

The next stage is the hydration of the acetylenic bond under suitable conditions, for example with aqueous mercury (II) sulphate and sulfuric acid to get the 3-ketoamine (V) to surrender. This 3-ketoamine, which diethylamine easily excretes, even with distillation, its excretion product, the vinyl ketone (VI) or a mixture of both, is treated with 2-methylcyclohexane-1,3-dione (VII) condensed under reflux in benzene containing pyridine. The product of this Michael condensation is the dicyclic triketone (VIII), which is the whole carbon skeleton of a Contains 19-nor-D-homo-steroids.

Reflux treatment of this triketone in xylene, in the presence of triethylammonium benzoate as Catalyst, brings about an internal aldol condensation and dehydration, which the tricyclic diketone (IX), which has unsaturation in the newly formed ring, which corresponds to ring C in the 8 (14) position of the terminal steroid.

This tricyclic diketone is a mixture of enantiomers, which has an asymmetric center at Ci3 currently has. Only the 13 ß connection is shown, although it should be understood that the mixture contains an equal amount of 13-a-compound such as the following compounds; Resolution to form a 13 / S enantiomer can be achieved at any suitable stage.

The catalytic hydrogenation of the tricyclic diketion mixture saturates ring C and gives a oily mixture of reduced tricyclic diketones (X), in which two further asymmetric centers as Cs and Cu appear. The cyclodehydration this mixture according to the invention with methanolic hydrochloric acid follows at room temperature, forming ring B and yielding the tetracyclic ketone (XI). This ketone, which is obtained with 51% yield from diketone (IX) is (±) -D-homo-9 (II) -dehydro-oestrone methyl ether, in the correct stereochemical structure for Cg and Cu.

Further processing results in the reduction of ketones (XI) and (XIX) with potassium and ammonium chloride in liquid ammonia (±) -D-homoestradiol methyl ether (XII), which is a fourth asymmetric Center at C9, with the introduced hydrogen again being stereochemically correct for the D-homo-oestrone series, and contains a fifth center as Ci7a.

Oxidation with bromic acid in acetone turns the diol ether (XII) into (±) -D-homo-estrone methyl ether (XIII) converted. Ultimately, when the ketonic ether (XIII) is present with benzaldehyde a base is condensed, a benzilidene derivative (XIV) is obtained which is identical to that Substance corresponding to oestrone (XV) according to Johnson et al, J. Amer. Chem. Soc, 1952, 74, p. 2832, by ozonolysis to homomarrianol acid methyl ether, was converted by pyrolysis of the lead salt of this acid and demethylation. oestrone can easily reduced to estradiol (XVI).

It has also been found that similar sequences of reactions can be carried out in which instead of 2-methylcyclohexane-1,3-dione (VII) the corresponding cyclopentane derivative (XXV) is used to form the dicyclic triketone Michael adduct (XXVI), which is the entire carbon skeleton contains a 19-nor steroid; this leads to the tricyclic diketone (XXXVII) and then directly via the ketones (XXXVIII) and (XXXIX) to (±) -estradiol-3-methyl ether (XXIX) and (±) -esstrone methyl ether (XXX), thus avoiding the need to contract ring D. (±) -estrone methyl ether can be converted to (±) -estrone (XV) by demethylation.

For the production of the starting products as well as for the further processing of the method according to In the context of the present invention, protection is not sought after the compounds that can be produced.

The process according to the invention for the preparation of 13-alkyl-1,3,5 (10), 8 (9) - [or 9 (II)] - gonatetraenen of the general formulas:

R R

R R

furthermore the ring D can be substituted, as well as their D-homoanalogues. It is characterized by that you have a corresponding compound of the general formula

R R

35

40

45

55

60

wherein each group R is hydrogen or an alkyl group with fewer than 5 carbon atoms, R ^{1 is} an alkyl group, Y is a keto group, (Η, ΟΗ) or a functional derivative of these groups and E is a group which activates an aromatic ring in electrophilic aromatic substitution and directed predominantly in the o- or p-position, where R, Ri, E and Y have the meaning given above, or their D-homoanalogues are cyclohydrated in an acidic medium and optionally a group E or Y hydrolyzed during the reaction per se known way. So z. B. a 3-position hydroxy group can be reacylated or a 17-position keto group can be recatalized.

Of particular value as general intermediates for the synthesis of the steroids which have an oxygen substituent in the 11-position are the above J ⁹ · ¹ ! Compounds.

The group R ¹ is preferably a saturated alkyl group, especially one which has fewer than 10 or, more generally, fewer than 20 carbon atoms; it can be, for example, a methyl, ethyl or isopropyl group. An alkyl group of less than 6 carbon atoms is accordingly very suitable. The alkyl group is preferably a hydrocarbon group, but can also be a group substituted by other suitable groups.

The compounds are preferably those in which the hydrogen in the 14 position has the stereochemical configuration trans to the group R ¹ and thus corresponds to the configuration of the naturally occurring steroids.

The group R ¹ preferably has the / i-stereochemical configuration as it has the 13-methyl group in natural estrone and estradiol (so-called / i-configuration). If R is ¹ / i-constantly and _as d 14 constant hydrogen atom in α-position is present, the invention can be prepared according to the compounds of C-atoms 13 and 14, the stereochemical configuration of the natural estrones and estradiols have.

For example, one or both R groups in a group CR2 can be a methyl or ethyl group be. Preferably each R group is hydrogen.

The group E is suitably hydroxy, acyloxy (e.g. acetoxy), alkoxy (e.g. Methoxy), amino, monoalkylamino or dialkylamino (for example diethylamino) Group.

The group Y, which represents a keto group or (Η, ΟΗ), can in the form of its functional Derivatives that can be converted into one of these groups. So Y can be a ketal group, for example the ethylenedioxy group, or an (H, O-acyl) group, for example the (H, O-acetyl) group be.

In general, the cyclodehydration according to the invention takes place in an acidic medium easy. It can usually be effected with methanolic HCl at room temperature. she can also be effected by heating with aqueous sulfuric acid.

The following examples explain the invention Procedure. The temperatures are given in degrees Celsius. The UV absorption data denote the position of the maxima in πΐμ, the values in brackets denote the molecular extinction coefficients at these wavelengths.

example 1

15th

1.5 g of 5- (2'-m-methoxyphenylethyl) -9-methyltrans-decalin-1,6-dione (X) were dissolved in 16 cm ^{3 of} methanol which contained 4 cm ^{3 of} concentrated hydrochloric acid. The solution was kept at room temperature for 3 hours and then at 0 ° for 1 hour. The crystalline precipitate was filtered off and recrystallized from ethyl acetate. It gave 0.96 g of (±) -D-homo-9 (II) -dehydro-estrone methyl ether (XI) with a melting point of 172 to 175 °.

Analysis found: 80.8% C, 8.1% H; the gross formula C20H24C2 requires 81.0% C and 8.2% H; Ultraviolet Absorption: 262 (18,700).

Example 2

30th

Ig 5 - (2 '- m - methoxyphenylethyl) - 9 - methyltrans-decalin-1,6-dione (X) was refluxed in 25 cm ^{3 of} ethanol with 0.2 cm ^{3 of} 20% strength sulfuric acid for 2 hours. After cooling, a crystalline solid of 273 mg separated out and was filtered off; after recrystallization from an ethanol-ethyl acetate mixture, it was found to be (±) -D-homo-9 (II) -dehydrooestrone methyl ether, which was identical to that of Example 1.

The mother liquors collected from several such experiments became after standing for several days a crystalline substance excreted. This was recrystallized from ethanol to give a Product which melted within the range of 115 to 140 ° and has ultraviolet absorption properties that could be expected from a mixture of (±) -D-homo-8- and -9 (1I) -dehydroestrone methyl ether (XIX and XI) with an ultraviolet absorption of 270 (17,100).

Example 3

0.5 g of 5 - (2 '- m - methoxyphenylethyl) - 9 - methyltrans-decalin-l, 6-dione (X) was refluxed in 25 cm ^{3 of} ethanol with 10 cm ^{3 of} 20% strength sulfuric acid for 2 hours; water was added to the cooled solution and the mixture extracted from ether. Evaporation of the washed and washed and dried ether extracts left 332 mg of crystalline residue melting in the range of 115 to 149 °, with ultraviolet absorption properties equal to those of the mixed dehydro compounds of Example 2.

Example 4

0.77 g of 4 - (2 '- m - methoxyphenylethyl) - 8 - methyltranshexahydro-indan-1,5-dione in 25 cm ^{3 of} methanol

65 and 4 cm ^{3 of} concentrated hydrochloric acid were left to stand at 0 ° overnight. A colorless crystalline solid was deposited, the mixture was ^{treated with 50 cm 3 of} water and extracted with a mixture of ether and benzene. The washed and dried extracts were evaporated, leaving 0.65 g of a resin which crystallized. Recrystallization au _a a mixture of ethyl acetate and ethanol to give (±) -8 (II) -dehydro-estrone-methyl ether having a melting point of 144 ° to 148 °; Ultraviolet Absorption: 264 (18,700).

Example 5

0.5 g of 5- (2'-m-methoxyphenylethyl) -9-methyltrans-decalin-l, 6-dione (X) in 8 cm ^{3 of} methanol, which

2 cm ^{3 of} 1N hydrochloric acid

Maintained at room temperature for 3 hours, then cooled to 0 ° for 1 hour. The filtered precipitate was crystallized from ethanol-ethyl acetate and yielded 0.32 g of (±) -D-homo-9 (II) -dehydro-estrone methyl ether (XI, 68%), melting point 172 to 175 °.

Example 6

4 - (2 '- m - methoxyphenylethyl) - 8 - methyl - 5 - oxotrans-hexahydroindan -1 - oil (0.25 g) in methanol (2.5 cm ³ ) was treated with concentrated hydrochloric acid (1.5 cm ³ ) treated at 0 °. The solution was then allowed to warm to room temperature. After 30 minutes, the precipitate formed was filtered off as (±) -8 (II) -dehydroestradiol-3-methyl ether (0.065 g), melting point 114 ° to 128 °; UV absorption: 264 (18,500), along with a shoulder at 272, indicating the presence of a small amount of the corresponding 8-dehydro compound.

Claims (2)

Patent claims: 1. Process for the preparation of 13-alkyl-0,5 (10), 8 (9) - [or 9 (II)] - gonatetraenen of the general formula R R in which each group R is hydrogen or an alkyl group with fewer than 5 carbon atoms, R ^{1 is} an alkyl group, Y is a keto group, (H, OH) or a functional derivative of these groups and E is a group which activates an aromatic ring in electrophilic aromatic substitution and predominantly directed in the o- or p-position, whereby the ring D can also be substituted, as well as their D-homoanalogues, thereby marked 609 750/439 11 draws that one has a corresponding connection the general formula in which R, Ri, E and Y have the abovementioned meaning, or their D-homoanalogues in one acidic medium cyclodehydrated and optionally one hydrolyzed during the reaction Group E or Y restores in a manner known per se. 2. The method according to claim 1, characterized in that in the starting material R ^{1 is} an ethyl group and the C / D ring bond preferably has the trans configuration. R R 609 750/439 12.65 ® Bundesdruckerei Berlin