DE1618806C - Process for the preparation of 3,20-Dioxo-17 alpha-hydroxy-19-nor-9 beta, 10 alpha-delta to the power of 4-pregnen - Google Patents

Description

For the partial synthesis of cortisone hormones, the breakdown of a lateral chain of oinos steroid was necessary 24 or 27 carbon atom? !! a difficult task at the time.

In the case of the total synthesis of steroids, the opposite problem is present for the Zeil. With these transfer procedures If you first build up the tetracyclic skeleton, you generally go as far as a cyclopentanopolyhydrophenanthrene with a hydroxyl or ketone function in the 17-position (compare e.g. LVcIIu ζ and coworkers, C. R. Acad, des Sciences, Vol. 250, pp. 1084, 1293 and 1510 [1960]), and es The problem then arises of the structure of »a lateral chain with 2 carbon atoms on ring D. in the 17-position and the introduction of a hydroxyl group in the same position,

CN CN

OH -

The methods used up to now to solve this problem are either via a cyanohydrin in 17-position or via a 17-Älhinylderivat.

The first-mentioned working method is cumbersome and tedious, as it is after the formation of the cyanohydrins an elimination of water from the same to form 17-cyano-16,17-dehydroderivat, a Grignard reaction with the nitrile to give the corresponding methyl ketone, and then the introduction of the hydroxyl group in the 17-position, which brings with it three more stubbornness: the formation of the 16,17-epoxy, the conversion of this into bromohydrin and the reduction of bromine. There are six in total Levels, which can be shown schematically as follows:

CH ₁

CO
OH

CH ₃
CO

OH

The procedure which resulted in the ethynylation, whereby the bromine appears in the 21-position

falling back isn't much faster. The 17 / f-hydroxy- with simultaneous displacement of the double bond

17a-ethinyl steroid first becomes the corresponding 20-21 in the 17,20 position. By acetoxylation and

Vinyl derivative reduced, then the hydroxyl 30 hydroxylating oxidation is then obtained

in the bromohydrin ether under the conditions 17a-hydroxy-20-oxo-21-acetoxylated derivative,
transferred, which at the same time an allyl rearrangement

This procedure, which accordingly comprises five stages according to the following scheme

OH

OH

- C == CH -

- CH = CH, OAc CH ₂ - OAc

has a serious disadvantage, namely the difficulty of the bromination step. This reaction is sometimes difficult to carry out with good yields and can be completely with certain steroids fail.

On the other hand, it is known that (cf. in particular F. Sondheimer and R. Mechoulam, JA.CS, 79, p. 5029 [1957]) various ylides of phosphorus can be condensed with keto steroids, but the products obtained have, for example, in the case of 3 / I-hydroxy-17-methylene / I ⁵ -androsten, no practical value for the solution of the questionable, borrowed problem.

Other authors are in their attempts to use phosphonoethyl acetate with the 17-position keto group reacting with steroids completely failed (see in particular A. K. B o s e and coworkers (Tetrahedron Letters No. 15, pp. 959 to 963 [1963]).

The invention relates to a process for the preparation of S ^ O-dioxo-na-hydroxy - ^ - nor-9 / J, 10a-zl ⁴ -pregnen, which is characterized in that 3-pyrrolidyl-17-oxo-9 / S, 10a- / J ^{3i5 -estradiene is} condensed with a carbanion of an ethylidene phosphorane, the product obtained is hydrolyzed and oxidized by hydroxylation in a manner known per se.

The condensation of Äthylidenphosphorane with

17-ketosteroids leads to 17-ethylidene derivatives, the can easily be converted into 17a-hydroxy-20-oxosteroids according to the following scheme:

CH,

CH

CH ₃

- / - OH

The hydroxylative oxidation of the 17-ethylidene steroid is in a known manner by the action of osmium tetroxide in a tertiary Alcohol, such as tert-butyl alcohol or tert-amyl alcohol, in the presence of a peroxide des Oxide of a tertiary amine, such as that of trimethylamine, triethylamine, picoline and the like, easy to carry out.

example

10

Production of ^ Dioxonahydroxy ^ no

9 / i, 10a / l ⁴ -prcgnen, starting from 3-pyrrolidyl

17-oxo-9 //, 10 "" / J ^a ' ⁵ -estradien.

Level a

3-Oxo-19-nor-9 / i, 10 "- / | ⁴ - ^{l7 (20)} -pregnadien
Preparation of the starting material and the reagent

a) 4.8 g of a 55% suspension of sodium hydride in mineral oil are added to 40 ecm anhydrous Dimethyl sulfoxide and stirred for 45 minutes under nitrogen atmosphere at a temperature of 80 ° to 85 ° C.

It is then cooled to room temperature, 39 g of triphenylethylphosphonium bromide are added in suspension in 80 ecm of anhydrous dimethyl sulfoxide and stirred for a quarter of an hour.

b) The preparation of 3-pyrrolidyl -17-oxo-9 β, 1 Ou- Δ ³ · ⁵ -estradiene is described for explanation: To a solution of 0.6 g 3-oxo-9 | 3,10a-17 / <-hydroxy- / l ⁴ -estrene in 120 ecm acetone, the solution of 218 mg chromic anhydride in 0.2 ecm sulfuric acid and 12 ecm water is added.

The mixture is stirred for 4 hours at room temperature and then precipitated with water and with Extracted methylene chloride. The organic extracts are washed with an aqueous sodium bicarbonate solution dried over sodium sulfate and then distilled. The crude diketone is isolated in practically quantitative yield.

Pasting in 1.8 ecm of isopropyl ether gives 540 mg of 3,17-dioxo-9 /!), 10a / l ⁴ -estrene with a temperature of 135 ° C. '

Priority 2 ecm pyrrolidone to 1.005 g 3,17-dioxo-9SS, 10a-/ l -estrene ⁴ and heated for 10 minutes 85 to 90 ⁰ C. To the hot solution is 30 to ECM Me, THANOL. The 3-pyrrolidyl-17-oxo-9 //, 10a- / l ³ · ⁵ -estradiene crystallizes out in the medium. It is separated by simple suction and 1.07 g of the product with a F. = 160 ^° C.

condensation

3.1 g of 3-pyrrolidyl-17-oxo-9 / ί, 10 <ί-.I ^{3i5 -estradiene are added to the suspension prepared according to the above procedure and the mixture is} stirred for 23 hours under a nitrogen atmosphere at a temperature of 50 to 55 ° C.

35

40 It is cooled, taken up in water and benzene, the benzene phase is washed with water and then extracted with 1N hydrochloric acid,

The acidic solution is left to stand for one hour and then made alkaline with 1N NaOH. The precipitate obtained is extracted with methylene chloride, washed, dried and evaporated the organic phase.

The product obtained is chromatographed on magnesium silicate and eluted with methylene chloride containing 0.5% acetone. It is recrystallized from isopropyl ether and 1.344 g of 3-oxo-19-nor-9p, 10a - / 'l ⁴ ' ^{17 (Z0)} -pregnadiene are obtained

from F. - 9O ⁰ C.

The product has not yet been described in the literature.

Level B.

3,20-Dioxo-17 "-hydroxy-19-nor-9 / J, 10u / J ⁴ -pregnen

One gives 1.344 g of 3-oxo-19-nor-9 / J, 10a-.l ⁴ x ^{17 '201} -Pregnadien in 80 cc of tert-butanol, treated with 2 cc of a solution of 0.17 g of osmium tetroxide in 6 cc Pyridine and stir for 40 minutes at room temperature.

1.44 g of triethylamino oxide peroxide are then added to the reaction mixture in part over the course of 40 minutes. stir for a quarter of an hour, pour into water to which sodium sulfite has been added, extracted with Methylene chloride, washed with water, dried and evaporated to dryness.

The product is purified by recrystallization from acetone and then from ethanol and 0.660 g of 3,20-dioxo-17a-hydroxy-19-nor-9j3,10a- / l ⁴ -pregnen with a temperature of ^ 255 ° C. is obtained.

The product has not yet been described in the literature.

Claims (1)

Claim: Process for the preparation of 3,20-dioxo-1 Ta - hydroxy-19 - nor - 9 β, 10 a - / t ⁴ - pregnen, characterized in that 3-pyrrolidyl-17-oxo-9 / U0u-J ^{3> 5} -estradiene is condensed with a carbanion of an ethylidene phosphorane, the product obtained is hydrolyzed and oxidized by hydroxylation in a manner known per se.