DD230866A1 - PROCESS FOR THE PREPARATION OF 17 ALPHA-METHYL-17 BETA HYDROXYSTEROIDS - Google Patents

Abstract

A simple process for the preparation of 17-methyltestosterone derivatives of general formula 2 by reaction of methylmagnesium halides with the readily available 17b-carbonitrile-17a-hydroxyandrostanderivaten of general part formula 1 and subsequent acid hydrolysis for the removal of protective groups is described. 17a-Methyltestosteronderivate represent important androgen / anabolically active steroid compounds or are important starting materials for the synthesis of highly effective derivatives with improved spectrum of activity. figure

Description

For this 4-page formulas

Field of application of the invention

The invention relates to a process for the preparation of 17a-methyl-17ß-hydrosteroids by alkylation of the corresponding ^ ß-carbonitrile ^ a-hydroxysteroidderder the Androstanreihe. 17a-methyl-17ß-hydroxysteroids of Androstanreihe, wiez. B. α-methyltestosterone, 11β-hydroxy-α-methyltestosterone, 4-chloro-17a-methyl-11β-hydroxy-1,4-androstadiene represent important androgen / anabolic steroid derivatives or are important starting materials for synthesis highly effective Compounds with improved androgenic / anabolic spectrum of activity.

Characteristic of the known technical solutions -

Several methods have been reported for the synthesis of 17a-methyl-17β-hydroxysteroids. LRuzicka et al. Helv. Chim. Acta 18,994 (1935) and A. D. Chinewa et al. J. ailg. Chem. (Russ.) 9.1965 (1935) have converted androstenolone by Grignardierung with Methylmagnesiumhalogeniden in the 17a-alkyl-i7ß-hydroxy derivative, which by subsequent bromination, chromic acid oxidation and debromination or by Oppenaueroxidation with a yield of 35 to 40% in 17a-methyltestosterone was converted (formula scheme 1).

The use of androstenedione as a starting material for 17a-methyltestosterone derivatives requires the introduction of a protective grouping for the 3-keto group of the androstenedione according to the hitherto generally known methods of Grignardization in the 17-position.

Selective protection of the α, β-unsaturated C-3 carbonyl group has been reported by

- M.E. Mr. u. a. J. Am. Chem. Soc. 77,448 (1955) as well as R. Hüttenrauch and A. Schubert, Archiv der Pharmazie, 299,1011 to 1020 (1966) represented the corresponding enamines.

- A. Serini et al. Chem. Ber. 71, 1766 (1938), androstenedione is converted into the enol ether derivatives by reaction with ethyl orthoformate.

J.H.Dauben et al. J. Am. Chem. Soc. 78,3752 (1956) represented the 3,3-ethylidenedioxy derivatives by Umketalisierung with acetone ketal or Butanonketal.

The subsequent Grignardierung with methyl magnesium halide yields according to the cited authors different yields of methyl testosterone (formula scheme 2, in which R = H, OH).

According to a method of R. Philippson De-OS 2 505884 of 1975, the selective alkylation of the C-17 carbonyl group of androstenedione after intermediate protection of the C-3 carbonyl group by conversion into the 3-enolates by means of potassium tbutylat be possible, however No yield data are given for this process (equation 3). After the technical introduction of the microbiali sterol degradation to 17-ketosteroids, in particular to androstenedione and androstadiene, methods for the economical conversion of androstenedione into active substances of the androstane or pregnane series are of particular importance.

Thus, the method described by R. Philippson would have to be regarded as a particularly simple method of synthesis for the preparation of 17a-methyltestosterone. The application of the conditions described by R. Philippson for the preparation of methyltestosterone derivatives revealed that methyltestosterone is formed under the conditions of the reaction with methylmagnesium halides, but the yields are less than 20% of methyltestosterone. So this method is for a techn. Application not economically cheap. Of the process variants already mentioned via the selective introduction of protective groups for the α, β-unsaturated carbonyl group of androstenedione, the 3,3-ethylenedioxy variant is obviously the most economical variant because of the most favorable yields. However, because of the insufficient selectivity in the preparation of the 3,3-ethylenedioxy derivative of androstene-3,17-dione in the high yields of 93% mentioned above, special expenses are also required here. To avoid formation of the 3,3-17,17-bisethylene ketal derivatives which occur as by-products by applying the well-known catalization methods, the selective reaction of the androstenedione with acetone or butanone ketals described by JH Dauben is in the ratio steroid / ketalizing agent = 1:20 required. Despite the most favorable yields, this variant is not particularly favorable for industrial use because of the low throughput per reaction volume and the additional presentation of the Ketalisierungsmittei and required after carried out purification of the Ketalisierungsmittel used. It is further known that 17β-carbonitrile-17α-hydroxy steroid derivatives can be prepared according to DD-WP 147,669.

Object of the invention

The aim of the invention is to develop a new process according to which α-methyltestosterone derivatives are economically accessible in a process which is easy to carry out industrially.

Explanation of the essence of the invention

The invention has for its object to provide a method by which the high technical complexity for the synthesis of 17a-methyltestosterone reduced and a simple and economical presentation is guaranteed. It has been found that 17β-cyano-17α-hydroxysteroids of the general partial formula 1 (formula scheme 4), in which for the rings A, B or A, B and C may be the partial formulas a to g given in the formula scheme 4, with methylmagnesium halides reacted at reaction temperatures of -20 ⁰ C to the boiling point of the ethereal or other solvents used against Grignard reagents and reaction times of 5 minutes to 4 hours, then decomposed the Grignadierungsgemische and by acid hydrolysis of the protective groups in 17a-Methyltestosteronderivate the general part 2 (formula scheme 4) in which the rings A, B or A, B and C are the partial formulas h to I listed in formula scheme 4.

This result for the synthesis of Methyltestosteronderivaten was surprising, since from the literature after P. de Ruggierie u. a. [J. Amer. Chem. Soc. 81, 5725 (1959)] it was known that cyanohydrins give the starting ketones under the conditions of the Grignard reaction. However, neither in the work of P. "de Ruggierie nor in the further literature has been described the possibility of synthesis of the methyltestosterone derivatives via the steroid cyanohydrins.

The direct use of α-carbonitrile-α-hydroxy-androstenderivate for the synthesis of Methyltestosteronderivaten is particularly beneficial in the recovery of the microbial sterol degradation resulting androstenedione / androstadienedione mixtures, since their separation on the sparingly soluble 17ß-carbonitrile-17a-hydroxy derivative of the Androstendions is technically easy to carry out and the introduction of a protective moiety in the 3-position does not require selective ketalization and thus leads to an overall yield on an industrial scale of about 90%.

Exemplary embodiments Example 1

methyltestosterone

20 g of β-carbonitrile-α-hydroxy-S-ethylenedioxy-S-androstene are dissolved in tetrahydrofuran and admixed with methylmagnesium bromide (60 g) at room temperature with stirring. The reaction mixture was then heated for 2 hours to 5O ⁰ C, then cooled, decomposed with NH ₄ Cl solution, the THF solution separated, concentrated as far as possible and the resulting solid residue (18.10 g s 93.8% d.Th.) taken up in methanol and with addition of 20 ml 1 η HCI 2h. kept at 50 ° C. The reaction mixture is then neutralized with NaOH, concentrated as much as possible, added to water and extracted with chloroform. The chloroform extracts are concentrated, the residue is repeatedly dried in vacuo with acetone in vacuo and then made to crystallize with acetone. , ·. ,

Yield: 67.6% of theory ---- ^;

Mp 164bis168 ° C

+78 ⁰ Co = ΐ, CH ₅ OH)

Example 2

11β-hydroxymethyltestosterone

Androsten-17-carbonitrile 11ß17a-dihydroxy-3,3-ethylenedioxy-5 is dissolved in tetrahydrofuran and treated at -15 ⁰ C with methylmagnesium iodide. The reaction mixture is allowed to warm to 35 ⁰ C, allowed 3h. react at this reaction temperature and operates as described in Example 1:

Yield: 71% of theory

Mp 206bis209 ° C

Example 3

11β-hydroxymethyltestosterone

17-carbonitrile-17a-hydroxy-11 .beta.-trimethyl! Silyloxy-3-ethoxy-3,5-androstadien is dissolved in tetrahydrofuran, treated at 40 ° C with methylmagnesium bromide and held for 10 minutes at 55 ⁰ C reaction temperature. The reaction mixture is cooled, treated with dilute hydrochloric acid and then stirred for 30 minutes to 55 ° C. It is then cooled, extracted with chloroform, the extracts washed with water until acid free, dried over Na ₂ SO ₄ and then concentrated to dryness in vacuo. The residue obtained is taken up in acetone and crystallized.

Yield: 73.4%

Mp 205bis208 ° C

Example 4

IS-nor ^ a-methyltestosterone

^ -Carbonitril- ^ a-hydroxy-S ^ -dimethoxy-odO) estrene is dissolved in tetrahydrofuran / benzene at room temperature with CH ₃ MgJ in tetrahydrofuran / benzene and heated for 1 h. At 70 ° C. The mixture is cooled, treated with 2 ml of 2 H ₂ H ₂ SO ₄ and stirred for 1 h. At 35 ° C, then extracted with CHCl ₃ and the CHCI ₃ extracts concentrated. The residue obtained is crystallized from ethanol / water

 Yield: 69% of theory.

Mp: 155 ° Cbis158 ° C

Example 5

4,5-dihydro-17a-methyltestosterone .beta.-carbonitrile-.alpha.-hydroxy-S-ethylenedioxy-.alpha.-androstane is reacted analogously to Example 4 to give 4,5-dihydro-17a-methyltestosterone.

Yield: 62% of theory

Example 6

A ^{9 (11)} -I7a-Methyltestosterone 17β-Carbonitrile-17α-hydroxy-3,3-ethylenedioxy-5,9 (11) -androstadiene is reacted analogously to Example 1 to give A ^{9 (11} l -17a-methyltestosterone.

Yield: 58% of theory

Mp 159bis163 ° C

Example 7

A ^9l1i) -17a-Methyltestosterone 17β-Carbonitrile-17α-hydroxy-3-ethoxy-3,5,9 (11) -androstatriene is reacted in the mixture of tetrahydrofuran / benzene with Example 4 analogously.

Yield: 63% of theory.

Mp 159bis164 ° C

Claims (2)

- £. - T <iT invention claim 1. A process for the preparation of 17a-methyl-17ß-hydroxysteroiden the Androstanreihe, characterized in that 17 (3-cyano-17a-hydroxy-steroids of the general part form 1 (formula scheme 4) in derfür the rings A, B and A, B and C may be the partial formulas a to g listed in formula scheme 4, reacted with methylmagnesium halides, subsequently decomposing the Grignardierungsgemische, and acidic hydrolysis of the protective groups in 17a-Methyltestosteronderivate the general part 2 formula (formula scheme 4), in which for the rings A, B and A, B and C are the partial formulas h to I listed in formula scheme 4, are transferred. 2. A process for the preparation of 17a-methyl-17ß-hydroxysteroiden the Androstanreihe according to item 1 ^, characterized in that the reaction with magnesium halides at reaction temperatures of -20 ⁰ C to the boiling point of the ethereal used. or other solvents inert to Grignard reagents and carried out in reaction times of 5 minutes to 4 hours.