NO115262B - - Google Patents

Description

Method for the partial removal of oxo groups.

One of the most common methods of reductive

removal of oxo groups is the procedure according to Wolff-Kishner, which was later modified and improved by Huang-Minlon. In the last reaction, the carbonyl compound is boiled in di- or triethylene glycol together with 10 per cent alkali hydroxide and an excess of hydrazine hydrate approx. y2 hour at reflux cooler. The solvent mixture is then distilled until the residue has a boiling temperature of approx. 200°, and then boiled for a few hours with a reflux cooler.

Also the indicated improved execution.

form of the reaction leads to poor results in the production of monooxo compounds of α-dioxo compounds from the steroid series or their enols, in particular 1M2-diketones or Δ9'1:|-11-oxy-12-ketones. Thus, not only is the oxo group in the 12-position removed, but also the 11-oxo group is reduced to the 11-oxy group or eliminated completely.

It was now done by surprise

observation that in the reaction of 11,12-dioxo compounds from the steroid series, their enols or enolates with hydrazine or their derivatives, the one oxo group can be partially removed already at significantly lower temperatures. It is therefore not necessary for it to be heated to a temperature at which all lower-boiling parts distil. Thereby, it is possible to carry out the partial removal of the one oxo group under significantly milder conditions and obtain the monooxo compounds in good yield. The new method is characterized by heating the aforementioned starting materials with hydrazine or its derivatives in close

weather of a basic alkali compound to a temperature at which nitrogen evolution occurs at not more than 160°.

As starting materials, α-dioxo compounds of the steroid series are used, which contain two neighboring oxo groups in the 11- and 12-position, respectively the corresponding enols, such as α9'11-11-oxy-12-ketones or their enolates, e.g. metal enolates, enolacylate or enolet. The steroids can e.g. be derived from estran-, androstane-, testane-, etiocholan-, pregnan-, spirostane-, furostane-, bufostane-, cholan-, cholestane-, nor. and the bisnor cholestane or ergostane series, respectively their stereoisomers, and besides the two neighboring oxo groups contain further substituents in the usual positions.

The following partial formula of the steroid nucleus

are common to these starting materials

The reaction according to the method takes place with hydrazine or its derivatives such as hydrazine hydrate or semicarbazide or their salts, e.g. acetates, chlorides or sulfates, together with basic alkali metal compounds, above all alkali. metal hydroxides or alcoholates, such as sodium or potassium hydroxide, methylate or ethylate. The reaction is preferably carried out in organic solvents, esp. lig in mono- or polyoxy compounds, e.g. glycol, di- or polyethylene glycol, propylene glycol, butanol or benzyl alcohol, further also in hydrocarbons, such as xylol or tetralin. It is expedient to heat at a temperature at which nitrogen is already strongly developed, such as at 120-150°, and for as long as the calculated amount of nitrogen has formed for the removal of an oxo group.

The invention is described in the following examples. Between weight part and volume part there is the same relationship as between grams and ems. The temperatures are indicated in degrees Celsius.

Example 1:

40.4 parts by weight of 3α-oxy-11,12-diketocholanic acid, which is partly present in enol form, are added to 20 parts by volume of 10-n. caustic soda, 200 parts by volume ethylene glycol and 20 parts by volume hydrazine hydrate. It is heated for 2 hours with stirring to 135-145°, as 2,200 parts by volume of nitrogen are split off. After cooling, it is introduced with 250 parts by volume of water for the diluted reaction solution. ning in 300 volume parts 2-n. hydrochloric acid. The precipitated and separated reaction product from the mother liquor is dissolved in 500 parts by volume of 5-n. caustic soda, stirs the solution with diatomaceous earth or filter asbestos, filters it and allows it to flow into 200 parts by volume of acetic acid in 300 parts by volume of water. 37.2 parts by weight of 3α-oxy-ll-keto-cholanic acid with m.p. = 215-218°.

Example 2:

44.6 parts by weight of A9'13-3 a, 11-dioxy-12-keto-cholenic acid-3-acetate are heated together with 30 parts by volume of 10-n. caustic soda, 200 parts by volume of ethylene glycol and 20 parts by volume of hydrazine hydrate with stirring for 2-3 hours at 130°, as 2200 parts by volume of nitrogen are split off. The cooled reaction solution is diluted with 250 parts by volume of water and allowed to flow into 300 parts by volume of 2-n. hydrochloric acid. The precipitated reaction product is sucked off, washed and dried. 39 parts by weight of 3α-oxy-ll-keto-cholanic acid with m.p. = 212-215°.

The starting material is obtained by dissolving

3 a-oxy-11,12-diketo-cholanic acid in the 3-5 times larger amount of glacial acetic acid on a boiling water bath and cooling, m.p. = 156-158°

[a]D + 85° (in dioxane).

Example 3:

50.2 parts by weight of A9-ii-3 a,ll-diacetoxy-12-keto-cholenic acid methyl ester are heated together with 50 parts by volume of 10-n. caustic soda, 20 parts by volume of hydrazine hydrate and 200 parts by volume of ethylene glycol with stirring at 125-130° until 2200 parts by volume of nitrogen are split off. It is then cooled, diluted with 200 parts by volume of water and allowed to flow into 300 parts by volume of 2-n. hydrochloric acid. The precipitated reaction product is sucked off, washed with water and dried. 38 parts by weight of 3α-oxy-ll-keto-cholanic acid with m.p. = 214-218°.

Example 4:

56.7 parts by weight of A23-3 α-acetoxy-11,12-diketo-24,24-diphenylcholine, which is partly present in enol form, is heated together with 50 parts by volume of 10-n. caustic soda, 200 parts by volume of diethylene glycol and 20 parts by volume of hydrazine hydrate with stirring to 124-125° until 2200 parts by volume of nitrogen are split off. The reaction mixture is then divided into water, and the precipitated reaction product is extracted with ether, the ether solution is washed with water, dried and evaporated. The residue (51 parts by weight) is dissolved in 100 parts by volume of pyridine and 50 parts by volume of acetic anhydride are added. After standing overnight, the solution is concentrated in vacuo, the acetylation product is taken up in ether, washed successively with dilute hydrochloric acid, sodium bicarbonate and water. After drying, concentrate to a small volume, add 250 parts by volume of ethanol, evaporate 70 parts by volume of ethanol and allow to cool. It crystallizes 48.2 parts by weight of A 23-3 α-acetoxy-11-keto-24,24-diphenyl-choline, m.p. = 168 — 169°, [a]D + 77° (in dioxane).

The A23-3a-acetoxy-11,12-diketo-24,24-di-phenyl-choline used as starting material can be prepared as follows: 160 parts by weight of bismuth trioxide, 160 parts by volume of glacial acetic acid and 1500 parts by volume of chlorobenzene are heated while stirring to boiling , and within 1 hour 300 parts by volume of liquid are distilled off until the distillation temperature exceeds 120°. 71.6 parts by weight of A'23-3a-acetoxy-12flj-oxy-11-keto-24,24-diphenyl-choline dissolved in 50 parts by volume of chlorobenzene and 300 parts by volume of glacial acetic acid are then added. While stirring, 300 parts by volume of solvent are once again distilled off over the course of 1-1 y. 2 hours, until the distillation temperature exceeds 120°, whereby the color of the reaction mixture changes from white to grey. The clear filtrate is then cooled, filtered, evaporated and the remainder crystallized from isopropyl ether. 48.5 parts by weight of A23-3ct-acetoxy-11,12-diketo-24,24-diphenyl-choline with m.p. = 142-144°

[a?<j>f = + 100° (c = 1 in dioxane).

After evaporation and acetylation of the residue with boiling acetic anhydride, the mother liquors give 19.4 parts by weight of A23-3a-acetoxy-11,12-diketo-24,24-diphenyl-cholen-11-enol-acetate with m.p. = 165—167°, [a] f = + 125° (c = 1 in dioxane).

Example 5: 44.4 parts by weight of 3[3-oxy-11,12-diketo-iso-allospirostane, which is partly present as enol, is heated together with 20 parts by volume of 10-n. caustic soda, 200 parts by volume of ethylene glycol and 20 parts by volume of hydrazine hydrate while stirring to 130-135° until 2200 parts by volume of nitrogen have been split off. The cooled solution is diluted with water and the precipitated reaction product is extracted with an ether-chloroform mixture

(4 : 1). The extract is then washed with water, then dried and evaporated. From the ether or ether-pentane solution of the residue crystallizes 29.7 parts by weight of 3(3-oxy-11-keto-iso-allo-spirostane with m.p. = 216—227°. On recrystallization the melting point rises to 229— 232°, [a]n —29° (in chloroform).

Claims (2)

1. Process for the partial removal of oxo groups from 11,12-dioxo compounds from the steroid series, characterized by heating these, their enols or enolates with hydrazine or its derivatives in the presence of a basic alkali compound to a temperature at which nitrogen evolution occurs, up to a maximum of 160°. 2. Method according to claims 1-2, characterized by working at a temperature of 120-150°.