DE1070632B - Process for the preparation of 2-alkyl and 2-aralkylide derivatives of 17ec-lower-alkyl-z! 4-androstene-17 /? Ol-3-ones and 17a-lower alkyl-androstane (or testane) -17 ^ -01-3-ones - Google Patents

Description

PATENT OFFICE

KL. 12 ο 25/04

INTERNAT. KL. C 07 C

S52137IVb / 12o

NOTE DAY: 30. J A N T Y A R 1957

ANNOUNCEMENTDMC LOGIN AND ISSUE OF THE DISPLAY: DECEMBER 10, 1959

The present invention relates to a method for Production of new androgenic hormones, the 2-alkyl and 2-aralkyl derivatives of 17 α-lower alkyl testosterones and ^ a-lower alkyl dihydrotestosterones are. Likewise, the present invention relates to the production of active hormones of the androgen type, which the corresponding 3-oxy-2-alkyl and -2-aralkyl derivatives the 17 α-lower alkyl testosterone and dihydro test osterone are. The new androgens produced according to the invention differ in their properties of similar compounds which do not contain any substituents in the 2-position, in particular as a result of which that the ratio of anabolic to androgenic effect is higher than with previously known compounds, such as B. Methyltestosterone. They also have a greater anti-estrogenic effect than testosterone and dihydro testosterone, and they are much more effective at preventing breast cancer from growing in rats as dihydro testosterone.

The process according to the invention for the preparation of 2-alkyl and 2-aralkyl derivatives of 17a-low-alkyl- ^{I 4} -androsten-17ß-ol-3-ones and 17 α-low-alkylandrostane (or testane) -17 / 3-ol-3-ones is characterized in that a ^{17α-lower alkyl-I 4} -androsten-17 /? - ol-3-one or 17α-lower-alkylandrostan-17 / i-ol- »5 3-one is reacted in a known manner with ethyl formate, the oxymethylene derivative obtained is reacted in a known manner with an alkyl or aralkyl iodide and the 2-alkyl-2'-formyl or 2-aralkyl-2'-formyl derivative obtained is converted with a mild base Carbon monoxide is split off or the 2-alkyl- or 2-aralkyl derivative of a 17a-lower alkyl- / l * -androsten-17/3-ol-3-one obtained is hydrogenated in a known manner in the presence of a hydrogenation catalyst.

The compounds prepared according to the invention correspond to the following formulas: OH

Method of manufacture

of 2-alkyl and 2-aralkyl derivatives

of 17a-lower-alkyl-zl4-androsten-

17/3-ol-3-ones and 17 α-lower alkyl

androstan- (or -testan) -17 / 3-ol-3-ones

Applicant:
Syntex SA, Mexico (Mexico)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Claimed priority:
Mexico 7 February 1956

Dr. Howard J. Ringold and Dr. George Rosary,

Mexico (Mexico),
have been named as inventors

In these formulas, R stands for an alkyl group, preferably a lower alkyl group with fewer than 7 carbon atoms, such as a methyl, ethyl or propyl group, or an aralkyl group, such as the benzyl group. R 'stands for hydrogen or for an acyl group, as it usually occurs in the case of esterified steroidal alcohols; mostly those derived from hydrocarbon carboxylic acids with fewer than 12 carbon atoms, such as. B. Essigsätire ^ propionic acid, cyclopentylpropionic acid, benzoic acid, etc. X represents a saturated C ₄ , C ₈ bond or a double bond. R ² represents a lower alkyl group of fewer than 7 carbon atoms, such as the methyl, ethyl or propyl group.

The method according to the invention proceeds accordingly the following equations:

90 »6M / 431

OH

O =

Ethyl formate

OH

Clay

OH

... R2

Hydrogenation catalyst

OH

OH

Reduction of sodium borohydride

, In the above equations, R, R ² and X are as defined above.

In carrying out the first step of the above process, the starting compound, which is a 17 may be α-lower alkyl testosterone derivative, e.g. B. methyl or Ethyl testosterone or the corresponding derivatives of the allo series saturated in the 4 (5) position, such as that 17a-methyl- or ^ a-Äthylandrostan - ^ / J-ol-S-one, in an organic solvent such as anhydrous benzene, and then with ethyl formate and suspended Sodium hydride mixed. The reaction mixture is then left for a long time, about 1 day, at room temperature kept under nitrogen. Then the hydride is made by carefully adding methanol. decomposed and cold water was added to form two layers, the desired product in the aqueous Layer is located in the form of the sodium salt. The walls Layer is separated, washed and washed with a dilute mineral acid; like hydrochloric acid; acidified and extracted with an organic solvent such as methylene chloride. The organic solution becomes the desired 2-oxymethyl compound by evaporation obtained to dryness and recrystallization.

The 2-oxymethylene compound is used to carry out the second stage of the process according to the invention in suspension in an organic solvent with sodium hydride as well as with an alkyl or aralkyl iodide treated, preferably a lower alkyl iodide or benzyl iodide.

The treatment is advantageously carried out under reflux conditions and in a nitrogen or hydrogen atmosphere carried out. The reaction takes longer, about 72 hours, with successive additions of iodide every 24 hour intervals carried out. The mixture is cooled and washed with a dilute base to remove any unreacted To remove material, and the resulting 2-alkyl- or 2-aralkyl-2'-formyl derivative from the organic Layer obtained by evaporation and recrystallization.

The 2-alkyl- or 2-aralkyl-2'-formyl derivatives so prepared are treated with a mild base, preferably activated alumina (of the chromatographic type) of treated with an alkaline reaction. In this treatment, a benzene solution of the compound is replaced by a Alumina column carried out and after about 1 day the

Claims (1)

Chromatograph product from the column with an organic solution. After eluting with mixtures of medium, such as ethyl acetate, eluted. The compounds obtained after crystallization benzene and ether were first fractions of sation are the corresponding 2a, 17a-dimethyltestan-17 (3-ol-3-one and then fractions 2a-alkyl or 2-aralkyl derivatives (e.g. 2α -low-alkyl- of 2a, 17a-dimethylandrostan-17 ^ -ol-3-one, enamel derivatives such as methyl, ethyl or propyl or point 151 to 154 ° C, [a] _D = +8 . ° (CHCl ₃₎ obtained benzyl compound) of the 17 α-lower alkyl ^ l ⁴ -androsten- A solution of 1 g of 2a, 17a-Dimethyltestosteron in 17 /? - ol-3-one or the corresponding androstan-17 / J-ol- 20 ecm of methanol was mixed with 100 mg of sodium borohydride, 3-one derivatives, which had previously been dissolved in 2 ecm of water In the second stage of the process according to the invention and the mixture overnight at room temperature, a modified process for producing the ίο is left to stand. The solvent has been shown under saturated compounds according to the invention. removed under reduced pressure, then water and some Hydrogenation catalyst, 2a, 17a-dimethyl-d ⁴ -androsten-3 <z, 17jft-diol and 2α, 17α-vorzugswcise a palladium catalyst, in particular 15 dimethyl-zl * -androsten-3 / ?, 17 /? - diol. After that of a palladium-barium sulfate catalyst, hydrogenated. The last-mentioned compound possessed the usual separation. After separation of the catalyst, the two isomers, ie the testane and androstane derivative chromatographically separated. In the third above example 2 The level shown is the reduction of the corresponding 20 3-Ketones to the New 3-Alcohols According to the Invention Following the procedure of Example 1 was shown. For this purpose the 2a, 17ot-di-ethyl iodide are used instead of methyl iodide and so 2a-ethyl methyl derivatives in a lower aliphatic alcohol, 17 a-methy! testosterone and 2a-ethyl-17a-methyldihydro- like methanol, dissolved and obtained with sodium borohydride testosterone (melting point 93 to 95 ° C), mixes. After standing overnight at room temperature 25 the solvent is removed, the product obtained Example 3 is purified and a mixture of the 3 a- and 3 /? - Oxy- get connections. These compounds are in If in the process according to Example 1 of the 2-Oxy- Usually with acid anhydrides or chlorides methylene-17a-ethyltestosterone instead of 17a-methyl esterified and so 3-esters of hydrocarbon carbon- 30 homologous started, then 2a-methyl-17a-ethyl- acid of less than 12 carbon atoms, e.g. B. such, testosterone (melting point 141 to 143 ° C, [ά] _υ = + 88 °) as described above. and 2a-methyl-17a-äthylandrostan-17ß-ol-3-one (enamel The following examples explain the invention point 128 to 131 ° C, [α] χ> = + 6 °), according to procedures. 35 Example 4 example 1 According to example 1, if the corresponding 17a-methyltestosterone was transformed into this in the same way, according to the starting materials Method by Weisenborn, Remy and Jacobs, 2a-ethyl-17a-methylandrostan-17 / J-ol-3-one (F. = 87 bis J. Am. Chem. Soc, 76 (1954), p. 552, the 2-oxymethylene- * o 93 ° C) can be prepared. 17a-methyltestosterone manufactured. . . 2.3 g of 2-oxymethylene-17a-methyltestosterone and example 5 170 mg of sodium hydride were suspended in 50 ecm of benzene according to the method of Example 1, however dated, treated with 10 ecm of methyl iodide and refluxed the mixture using 17α-methyldihydrotestosterone in an atmosphere of nitrogen. +5 as the starting material was the corresponding 2-0xy-After 24 hours a further 10 ecm and then after ^; methylen-17a-methylandrostan-17j9-ol-3-one (F. = 175 to 48 hours, another 10 ecm of methyl iodide was added and 177 ° C; [<x] d = + 36 °; / U, * = 282 πιμ; log E = 3.96) reflux is maintained for a total of 72 hours. Obtained through the usual esterification of these connectors. The cooled mixture was washed with a manure the corresponding 2-acetate (F. = 144 to 1% sodium hydroxide solution to trace 50 148 ° C; ληαχ - 255 ΐημ; log E = 4.09), propionate (F. von to remove unreacted starting material = 135 to 138 ° C; Xmax = 257 πιμ; log E = 4.11) and and the organic layer under reduced pressure benzoate (F. = 188 to 190 ⁰ C; Xmax = 230 πιμ; log E evaporated to dryness. The crystallization of the Rück- = 4.15) obtained. Further treatment of the 2-oxystandes from acetone-hexane gave the 2-methyl-methylene compounds according to Example 1 and became 2'-formyl-17a-methyl-Zl ⁴ -androsten-17 /? - ol-3-one. 55 the 2a, 17a-dimethylandrostane-17 /? - ol- described above A solution of 1 g of the above compound in benzene 3-one was obtained. was used to impregnate a column of 100 g with patent claims Alkali activated clay used. After 24 hours γατεντλν ^ ρηοοηε. the column was eluted with ethyl acetate and the 1st process for the preparation of 2-alkyl and Eluate from acetone-hexane crystallizes, whereby the 60 2-aralkyl derivatives of 17ct-lower-alkyl-J ⁴ -andro-2a, 17a-dimethyltestosterone with a melting point sten-17 / J-ol-3-ones and 17 α-low- Alkyl androstane was obtained from 150 to 152 ^C C, [a] _D = + 82 ° (CHCl _3). (or testane) -17 / S-ol-3-ones, characterized in that A mixture of 1 g of 2a, 17a-dimethyltestosterone, that a 17α-lower-alkyl- Δ ⁴ -androsten-17 /? - ol- 100 ecm of methanol (or ethyl acetate) and 100 mg of 3-one or 17a-low-alkylandrostane-17 /? - ol-3-one in 5 ° / _o palladium-barium sulphate catalyst is reacted in known manner with 65 ÄJhylformiat that a hydrogen atmosphere at atmospheric pressure Oxymethylenderivat obtained in a known manner hydrogenated at 25 ° C until the equivalent of one mole of water reacts with an alkyl or aralkyl iodide and off substance had been absorbed. The catalyst was the obtained 2-alkyl-2'-formyl- or 2-aralkyl- then filtered off, the filtrate evaporated to dryness and the 2'-formyl derivative carbonized with a mild base Residue is split off in a column with activated alumina 70 monoxide or that the obtained 7 8 2-alkyl or 2-aralkyl derivative of an ITa lowering agent methyl, ethyl, propyl or benzyl Alkyl-.d * -androsten-17 /} - ol-3-one used in the presence of an iodide. Hydrogenation catalyst hydrogenated in a known manner. 3. The method according to claim 1 and 2, characterized ge-2. Method according to claim 1, characterized in that, for splitting off coal, that one is used as alkylating or aralkylyl monoxide activated alumina. 909 Ml / 431 12.5 »