DE758807C - Process for the preparation of new oxyketones or their esters - Google Patents

Description

ISSUED SEPTEMBER 4, 1952

REICH PATENT OFFICE

PATENT LETTERING

CLASS 12O GROUP 2504

G 90949 IVc / 120

ο Patented in the German Reich from August 6, 1935

Patent issued June 5, 1952

is used

Positional isomers of the saturated oxyketones or unsaturated androstane series, whose hydroxyl and keto groups compared to Mutual connections of the Andrösteroni series are swapped, are still; not known.

It has been found that such new oxyketones or their esters can be obtained can, if one diesters of diols of the saturated or unsaturated type Andro'Standiole- (3, 17) partially saponified, the resulting free carbinol group (in 3-position), possibly - with temporary protection of existing double bonds, for Keto group oxidized, d. H. treated with oxygen donating agents, and the obtained Ketoester cleans and saponifies if necessary. One can also use the free diols go out, these partially esterify and the resultant monovertisted in 17-position It is advisable to oxidize diols in the manner described above after prior purification.

The same oxyketone can also be obtained if the free diols are used, if appropriate under temporary protection of existing double bonds, partially oxidized directly and separating the compounds oxidized in the 3-position from the reaction product.

Finally, it is also possible to use these · new Obtain oxyketones when taking diketones

of the type that subjects androstand.ione- (3, 17) to a partial reduction and separates the 3-keto-17-oxyverbin fertilizer η from the reduction products, 5 CH ₃ CH ₃

'H ₂ ! R.

-LO-Ac. The different methods are through
explains the following formulas; Ac is an acyl radical and R is hydrogen
or a monovalent hydrocarbon radical: 65

C Xl.j CIx ₃

'H ₂₁ ' R

OH

TT

Ac-O ''

H ₈ . HHH ₂

H "H H.

H H,

(I)

H ₂ H ₂

partial saponification

CH ₃ CH ₃ H .. R

Η— ^:

H.

HHH ₂

HH ₂ H H.

0-Ac HHH ₉

H H,

(H)

H H "

HO

JXn XXo

partial esterification: ng

CH ₃ CH ₃
H ₂ R

oxidation

(III)

HO

H, H "

CH ₃ CH ₃ H ₂ R

HHH ₂

H H "

H"

(V)

Esterification O = ¹

H ₂

HHH.
TT TT

Ho

0-Ac

(IV)

Hg H ₂

CFL CH,

H,

- = O

HHH ₂

H ₂

HH ₂

(VI)

Saponification

55 partial oxidation

H"

CH ₃ CH ₃ 'H ₂ ; R.

hTH- ° ^h

HHH ₂

HH ₂ (VII)

partial reduction

HH ₂

H ₂

Suitable oxidizing agents for converting III into IV or V into VII can be, for. B. like chromium compounds, such as chromic acid in glacial acetic acid, copper oxide and the like., Can be used. In the oxidation of unsaturated diols or their esters to oxyketones or their esters to oxyketones or their esters, the carbon bond is advantageous before the action of the

ίο oxidizing agent z. B. by attachment Protected by halogen or hydrogen halide and after oxidation has taken place ■ halogen, ζ. B. by treating with zinc in glacial acetic acid or benzene, with catalytically activated Hydrogen or with alkali iodides and the hydrogen halide with alkali Means, e.g. B. tertiary bases, removed again. The transfer of the free diode in 3-Keto-17-oxy compounds by oxidation the 3-carbonyl group is particularly advantageous when the ring carbon atom is in 17-pitch with a hydrocarbon residue connected is.

Suitable acellating agents for converting II into III and. from VII to IV are z. B. acids, their halides or anhydrides, such as benzoic acid, acetic acid, formic acid, Benzoyl chloride, acetyl chloride, acetic anhydride and the like, optionally in the presence of acid-binding agents Means such as B. tertiary bases or alkalis. Especially when using acid halides or anhydrides - one for the partial esterification of II advantageous only that for the esterification of a hydroxyl group sufficient amount of acylating agent. At. interrupts the partial reduction of VI the hydrogenation after taking up that amount of hydrogen which is sufficient to reduce a carboxyl group.

It is easy to get the resulting oxyketones either by direct crystallization or to be deposited in pure form by preparing suitable, poorly soluble derivatives. Such derivatives are obtained z. B. by reaction with the usual ketone reagents, such as semicarbazide thiosemicarbazide hydroxylamine, aminoguanidine, phenylhvdrazine and its substitute productet, neutral

S-oxy-iy-keto or 3-oxy-i7-oxy compounds ι tap
comb unit Seed. ;
blow- ;
weight with i 3-keto-17-oxy compounds ι tap
comb unit Seeds
blow
weight with 600 γ
70 γ 200 y: 20 mg 15 7 50 γ: 36 mg trans-androstanol- (3) -
on- (i7)
cis-androstanol- (3) -
on- (i7)
(Androsterone) Androstanol (17) -
on- (3)
(Dihydrotestosterone)

or basic acylhydrazides etc. For purification and separation often turns out also acylation, ζ. Β. with acetic anhydride, benzoyl chloride, dimtrobenzoyl chloride and the like, as beneficial. The above can be achieved by the action of hydrolytic agents Split compounds into their components. To separate the 3-keto connections from 3-oxy compounds possibly formed as by-products also prove to be Saponins such as B. Digitonin, as appropriate, especially if the steric position of the hydroxyl group in the 3-position coincides with that of cholesterol.

Diols of the saturated or unsaturated androstediol type (3, 17) are to be understood as meaning not only the stereoisomeric androstediols concerned themselves, but also their 17-alkyl-substituted compounds; likewise extends the. Term of the 3 ,, 17-Androstandione also on the isomeric 3, 17-Ätiocholandione. The following diols are suitable, for. B. as starting materials for this process: the Androstandiole- (3, 17), the A ^ ⁵ - or. ^ ⁵ - ⁶ -Anidrostendiole- (3, 17), the 17-methyl or 17-Äthylandrostandiiole-; (3. 17) the 17-methyl- or 17-Äthyland'rostendiioile- (3, 17), whereby both the 3- and the 17-carbonil groups can be in the cis or epi and also in the trans position. Suitable starting materials of the dione series are also, inter alia, d'as androstandione- (3, 17), the Δ * · ⁵ -androstenedione ^ (3, 17) and the etiocholandione- (3, 17).

The new oxyketones and their esters are characterized by their high effectiveness Capon comb and at the seminal vesicle.

From the below. The table shows that these products (column on the right) are important are more effective than the comparable 3-oxy-17 "keto or 3,17-dioxy compounds the androstane or androstene series (column on the left). The weight of the seminal vesicles in the rat test when the specified daily dose was injected for 10 days as well the Hahnenkamm units were also named after Tschopp (HeIv. Chim. Acta, vol. 17, 1934, P. 1395) determines:

3-oxy-17 "keto or 3-oxy-17-oxy compounds ι tap
comb unit Seminal
blow-
weight with 3-keto-17-oxy compounds ι tap
comb unit Seeds
blow
weight with 140 y
400 y
25} '
450 y 20Oy: 14mg
20Oy: 24 mg
50 y: 38 mg
200 γ : 35 mg 9V
11 y
97 50 y: 80 mg
5oy: 50mg trans-androstenol- (3) -
on- (i7) (dehydro-
androsterone)
17-methyl-trans
androstandiol- (3.17)
17-methyl-cis-
androstandiol- (3.17)
17-methyl
androstenediol- (3.17) Androstenol- (i7) -
on- (3)
(Testosterone)
17-methyl
androstanol- (i7) -
on- (3)
17-methyl
androstenol- (i7) -;
on- (3);

B e i s ρ i e 1 ι

3.76 g of trans-AndiOStanediol- (3, i7) -diacetate of melting point 127 to 128 are left to stand in 1000 ecm n / 100 methyl alcoholic potassium hydroxide solution for 48 hours at room temperature. The i7-acetoxyandrciStanol- (3) formed by partial saponification is precipitated with water after the solution has been concentrated, filtered off with suction, washed with water and in vacuo over phosphorus pentoxide. dried. • It can be used for the preparation of androstanol- (i7) -one- (3) without further purification. For this purpose, the product obtained is dissolved in 50 ecm glacial acetic acid and a solution of 0.8 g of chromium trioxide in 25 ecm o, o ^a / o acetic acid is added with cooling. After standing for 14 hours at room temperature, a little methanol is added to reduce the slight excess of chromic acid. The solution is diluted with water and the precipitated product is taken up in ether. The ether solution is washed with dilute soda solution and water and evaporated. The acetate, the androstanol- (i7) -one- (3), is isolated from the residue, most expediently via the sparingly soluble semicarbazone which can be purified by recrystallization from absolute alcohol. By heating ice for one hour with a mixture of 70% sulfuric acid and alcohol 1: 2, the semicarbazone is saponified directly to androstanol- (17) -one- (3). It can be purified by recrystallization from hexane or dilute alcohol. It forms farblo.se crystals of mp. 182 ^0th Yield 32% of theory.

Example 2

3'74 g / f ^{5 'B} -Androstandiol- (3, i7) diacetate (mp. 165 to i66 °), the two hydroxyl

Groups presumably tram configuration are left to stand for 40 hours at room temperature with 1000 ecm of methyl alcohol to which 0.45 g of potassium hydroxide has been added beforehand. After the solution has been neutralized, it is strongly concentrated in vacuo, the crude I -'- ^li -i7-acetoxyandrostenol- (3) formed by partial saponification is precipitated with water, taken up in ether and the ether is then evaporated off. The thus obtained crude Monoester is purified to remove sparingly soluble components by: recrystallization from hexane ·, taking the purified ester of melting point 146 to 148 ⁰ in 50 cc of glacial acetic acid and, while cooling dropwise so long ßrom-glacial acetic acid solution, as. discoloration occurs immediately. Finally, also in the cold 1.0 g of chromium trioxide dissolved in 30 cc of 90 ⁰ / cent acetic acid added and allowed to stand for the whole overnight at room temperature. It is then poured into 1 l of water, the product which has precipitated is filtered off with suction and washed with plenty of water. The brominated ketone obtained in this way is taken up in 50 ecm of glacial acetic acid to remove bromine, 20 g of zinc dust are added and heated with vigorous shaking for 12 minutes in a boiling water bath. Then it is suctioned off through a glass filter, washed with a little hot glacial acetic acid, the solution is precipitated with water and extracted with ether. The ether solution washed with dilute soda solution and Wasiser gives a residue on evaporation, from which z. B. via the sparingly soluble semicarbazone the Λ * ■ ^5- androstenol- ( ιJ) -one- (3) acetate can be isolated, which melts after recrystallization from hexane at 141 °. Yield 41% of theory. It can by hydrolysis into free oxyketone, the J ⁴ - ³ -Androstenol- be converted 155 ° (i7) -one (3) of mp.. When using other esters, e.g. B. the benzoates,

the corresponding ketoester is obtained analogously, for example the <d ⁴ ' ⁵ -androstenol- (17) -one- (3) -benzoate with a melting point of 194 ° to 195 °, which can optionally be saponified.
5

Example 3

1.87 g / l ⁵ . ⁶ -3-trans-17-cis-androstenediol diacetate with a melting point of 168 ° are dissolved in 370 ecm of methanol, and a solution of 0.28 g of potassium hydroxide in a little methanol is added. Man: can 36 hours at 15 ⁰ are then exactly neutralized with dilute hydrochloric acid and the solution concentrated in vacuo .to ¹ 50ecm a. After diluting with water, the reaction product is taken up in ether. The ethereal solution is dried and evaporated. The residue is fractionally recrystallized from hexane, one. the 17-monoacetate of Δ ⁵ · ^6-3 -tranis-17-cis-androstenediol is obtained. This is dissolved in 30 ecm of glacial acetic acid and the calculated amount (1 mol) of bromine in glacial acetic acid is added. The bromine is immediately decolorized.

A solution of 1 mole of chromic acid is added in 90 ⁰ / cent acetic acid and left overnight are -at room temperature. The reaction product is then precipitated with water and filtered off. It is de-brominated by shaking it for 48 hours with zinc dust in an alcoholic solution and finally purified by recrystallization from hexane. The resulting acetate of zl * ■ ⁵ -Andn> sten-cis-ol- (i7) -one- (3) with a melting point of 115 ° is obtained. by saponification with 2% methyl alcoholic potassium hydroxide solution, the Δ ^ι ^ -androstencis-ol- (17) -one- (3) of melting point 220 to 221 ¹⁰ . Yield 58% of theory.

Δ ⁵ · ⁶ "3-trans -17 - cis - androstenediol diacetate is obtained by acetylating A ⁵ · ^6-3 - trans-17-cis - androsendiol - 3 - acetate, which in turn is involved in the hydrogenation of Δ ⁵ · ⁶ -trans-deihydroandroisterone acetate is formed in addition to the 3-trans-17-trans-diol-3-acetate.

Example 4

2.1 g androstandiol- (3, 17), mp 223 ° are in * 100 ecm 90% acetic acid Warmed on the water bath for 8 hours and then left to stand overnight at room temperature. You fall with water that Reaction product from, it is nuffed off and dried in vacuo over phosphorus pentoxide.

Systematic treatment with gasoline (b.p. 70 to 80 °) makes one difficult soluble and a more easily soluble part. The part that is difficult to dissolve represents unchanged Diol. From the more easily soluble part is obtained by recrystallization from dilute alcohol that at 192 ° corr.

androstandiol- (3, 17) melting 17-monoacetate. Yield 82 ¹ Vo of theory. This ester is oxidized in the manner described in Example 1 and obtained by optionally saponifying the Androstanol- (i7) -one (3), mp. 182 ^0th

Example 5 Example 6

2.9 gzl ⁵ ' ⁶ -Androstenediol- (3.17) of melting point 178 to 179' ⁰ are reacted in pyridine with 0.8 g of acetyl chloride. The reaction mixture is poured into water, and the precipitating crude product is added. Neutralization of the pyridine by acid taken up in ether and then, the: washed ether solution ¹ evaporated. It provides by fractional Umkristallisatio'n from hexane the pure A ⁵ · ⁶ - i7 AcetO'xyandrostenol- (3), mp 146 to 148 ^0th. The monoester obtained in this way, after bromination by oxidation with chromic acid in glacial acetic acid and subsequent removal with zinc dust and acetic acid, is converted into the keto ester, the <d * ' ⁵ -androstenol- (i 7) -one- (3), exactly as in Example 2. acetate of m.p. 141 ⁰ above. Yield 16% of theory. The latter may, if appropriate, by saponification in the melt at 155 ⁰ Δ ¹ x ⁵ - Androstenol- (i7) -one be converted (3).

In an analogous manner, by partial Benzoyl'ierung instead acetylation of the Δ ⁵ x ⁶ -Androstendiol- (3.17) via the 17-monobenzoate of zl ^{5 '6} -Androstendiol- (17 3) of mp. 222-223 ^0, the _/ d * '. ⁵ -Androstenol- (i7) -one (3) benzoate, mp 198-200' ⁰ and from the latter optionally, saponification of the same / l ⁴ ', ⁵ -Androstenol- (i7) - one (3) as obtained above, mp. 155 ^0th

3.06 g of i7-methylandrostandiol- (3, 17) of m.p. 185 ⁰ are dissolved in 50 ecm of glacial acetic acid and a solution of 0.8 g of chromium trioxide in 50 ecm of ice-cream acid is added dropwise at room temperature. The chromic acid is used up fairly quickly. The mixture is left to stand for 3 hours at room temperature, then poured into water, the reaction product is taken up in ether, the ether solution is washed with dilute sodium hydroxide solution and water and dried over anhydrous sodium sulfate. The resulting i7-methylandrostanol- (i7) -onr (3) crystallizes out of the strongly concentrated ether solution. Yield 88% of theory. It is purified by recrystallization from "diluted alcohol and then melts at 192 ^0th The product obtainable in a conventional manner semicarbazone melts after recrystallization from absolute alcohol at 235 ° with decomposition.

In a similar manner -one (3) 126 receives the i7 Äthylandrostariol- (i7), mp. 127 to ^0. i7 Äthylandrostandiol- (17 3); mp. 205 ° and the Androstanol- (i7) -5 on- (3) of melting point 1S2 ⁰ from the 3-trans- or -ei s-17-t ranis-Λη d rostan diols.

Example 7

3.04 g / J of ⁵ - ^fl -i7-MethylandrO'Stendiol- (3, 17) of melting point 202 to 204 ° are dissolved in 50 ecm of glacial acetic acid and mixed with a solution of 1.6 g of bromine in 10 ecm of glacial acetic acid. A solution of 0.8 g of chromium trioxide in 50 ecm of glacial acetic acid is then added dropwise. After standing for several hours at room temperature, it is poured into water, the dibromide which has precipitated is filtered off with suction, washed and reacted in glacial acetic acid solution with 3 g of zinc dust. The nitrated solution is poured into water and the precipitating / i ⁴ - ^r> -i7-methylandrostenol- (i7) -one- (3) is taken up in ether. The washed and dried ether solution is evaporated and the residue recrystallized from dilute alcohol to constant melting point 161-162 ^0th Yield 81% of theory.

Instead of glacial acetic acid, e.g. B. also benzene as a solvent be used.

Similarly, 182 may be, starting from 4 ^{5 'B} -Androstendiol- (3, 17), mp 183 to ^0, the _i ⁴ -. ⁵ -Andn> stenol- (i7) -one (3), mp. 155 ° win.

Example 8

2.88 g Androstandion- (3:17), mp. 134 ⁰ are dissolved in 30 cc of methyl alcohol and gradually into this solution at the boiling point was added the required amount of sodium. When the reduction is complete, it is precipitated by pouring into water, filtered off with suction, washed with plenty of water and the reaction product dried over phosphorus pentoxide. It represents a mixture of isomeric. Androstanolone. With the help of digitonin and the semicarbazones, the androstanol- (i7) -one- (3) can be separated from it and advantageously purified by chromatography and by recrystallization from hexane or dilute alcohol. Yield 6% of theory.

Example 9

2.86 g, d ⁴ '^r> -androstenedione- (3, 17) with a melting point of 173 ° to 174 ° are dissolved in alcohol and hydrogenated with a nickel catalyst. After the calculated amount of hydrogen for a molecule, the hydrogenation is stopped, the catalyst was filtered off from the reaction \ solution and poured latter in 400 cc of water. Alan dries out. Washes the ethereal solution with water and evaporates it in a vacuum. A few cubic centimeters of vinegar are used for esterification for a short time. Acid anhydride is heated, the latter is evaporated and the residue is advantageously chromatographed and fractionally recrystallized from dilute acetone. This gives the J ⁱ · ■ '-andrcistenol - (17) - on - (3) - acetate with a melting point of 141 °. Yield 2.5% of theory. This occurs with saponification. corresponding free oxyketone, the J ⁴ - ⁵ -AndrO'Stenol- (i7) -one (3), mp 155 °..

Claims (7)

Patent claims: i. Process for the preparation of new oxyketones of the saturated or unsaturated androstane series or their esters, characterized in that a) diesters of diols of the type of saturated or unsaturated androstane diols (3, 17) are partially saponified, the resulting free carbinol group in the 3-position , optionally with temporary protection of existing double bonds, oxidized to the keto group, ie treated with oxygen-releasing agents, and the keto esters obtained are optionally purified and saponified; b) diols of the saturated or unsaturated androstenediol (3, 17) type, partially esterified, optionally separating diols which are monoesterified in the 17-position and oxidizing them in the manner described under a); cj diols of the saturated or unsaturated androstandiol type (3, 17), optionally with temporary protection of existing double bonds, partially oxidized directly and the compounds oxidized in the 3-position are separated off from the reaction product; d) Subjecting diketones of the androstandione (3 ' ^l 7) type to a partial reduction and separating the 3-keto-17-oxy compounds from the reduction product. 2. The method according to claim 1, characterized in that for the purpose of production of the saturated or unsaturated oxyketones substituted in the 17-position by hydrocarbon radicals Androstane series. of diols correspondingly substituted in the 17-position or their Esters run out. 3. The method according to claim 1, characterized in that the partial ■ Saponification of the diester with the help of alkaline agents in alcohols runs in mild conditions. 4. The method according to claim 1, characterized characterized in that, for partial esterification, the diols with that for esterification serving acid warmed. 5. The method according to claim 1, characterized in that one to the partial Esterification of the diol with just one equivalent of an acylating agent, if necessary in the presence of acid-binding agents. 6. Process according to claims 1 to 5, characterized in that one reacting the oxyketones obtained with acylating agents and, if appropriate, converting the compounds obtained back into splits its components. 7. Process according to claims 1 to 6, characterized in that one the oxyketones obtained or their esters are reacted with ketone reagents for purification and separation and the obtained eu Splits compounds back into their components. 1 5387 8.52