DE1135900B - Process for the production of ª ‡, ª ‰ -unsaturated ketosteroids, which have a 1- or 16-position methyl group on the ª ‰ carbon atom - Google Patents

Description

GERMAN

PATENT OFFICE

Sch 28392 IVb / 12 ο

REGISTRATION DATE: AUGUST 27, 1960

NOTIFICATION OF THE REGISTRATION AND ISSUE OF THE
EDITORIAL: SEPTEMBER 6, 1962

Processes have already been described by which α, ^ - unsaturated ketosteroids, which carry a methyl group on the / S carbon atom, are obtained from the pyrazolino steroids obtainable by diazomethane addition to the carbon-carbon double bond of a, ß-unsaturated ketones can produce.

It is known from German patent specification 1 023 764 that the nitrogen of the 3-keto- A ! -Steroids derived ^ '- pyrazolines can be split off pyrolytically at a high temperature (about 220 to 250 ° C.) and expediently in a high vacuum:

HN - CH ₂

The crude products obtained by this process are oily and contain due to UV spectroscopy Examination only about 60% of the desired l-Methykdi-S-ketosteroid, and the The resulting pure yields are only around 40% of theory. Technically disadvantageous is also that this low pure yield can only be obtained by using the pyrolysis reaction with very pure starting material. Another disadvantage is that the thermal decomposition these pyrazolines are carried out on an operational scale and in a high vacuum a process that is technically difficult to control.

Efforts were therefore made to make the thermal cleavage of the pyrazolines in question safer to handle To replace working methods and has already used acidic catalysts for this purpose, such as B. perchloric acid, fluoroboric acid or boron trifluoride etherate, dissolved in organic solvents (see the German Auslegeschriften 1 096 353 and 1 107 663). Has but it has been shown that the desired elimination of nitrogen is only possible on the corresponding / U'-pyrazolines takes place at room temperature, but with the desired a ^ -unsaturated / J-methylketosteroids arise only as by-products and preferably the saturated, isomeric α, / 3-methylene-keto-steroids are formed.

Finally, it was also proposed in German Patent 1,117,113 that the catalytic nitrogen

Method of manufacture

α, / 3-unsaturated keto steroids,

the carbon atom on the / 3 position

carry a 1- or 16-position methyl group

Applicant:

Schering Aktiengesellschaft, Berlin N 65, Müllerstr. 170/172

Dr. Rudolf Wiechert, Berlin-Lichterfelde, has been named as the inventor

separation instead of acidic catalysts present in homogeneous solution at the interface an acidic adsorbent, which is only weakly eluting the pyrazoline, organic Solvent suspended is to let go.

Although this process can be carried out from an operational point of view, it is necessary because of the large quantities of adsorbents to be pretreated acidic in a separate operation (the Ratio of pyrazoline compound to adsorbent is about 1:50) and because of the high solvent requirement for eluting after nitrogen has been split off with regard to working hours and working hours

tecimik too expensive.

It has now been found that you can easily and with good yield with avoidance the technical difficulties described for the desired a, /? - unsaturated keto steroids, carry a 1- or 16-position methyl group on the ß-carbon atom, from the through Diazomethane attachment to the carbon-carbon double bond α, / S-unsaturated ketones in known Obtainable pyrazolino steroids arrives if you remove nitrogen in organic bases, such as. B. quinoline, iso-quinoline, Quinaldine, collidine, lutidine, Ν, Ν-dimethylaniline, Aniline and / or mixtures thereof and optionally in the presence of a diluent such as

z. B. tetralin, at a reaction temperature of over 140 ° C takes place. But also organic bases with a boiling point below 140 ° C, e.g. B. pyridine,

209 639/428

3 4

are applicable when recrystallized from isopropyl ether to achieve the emergency. You get

agile reaction temperature the nitrogen splitting l-methyl-zU-androsten-Hß-ol-S-on-n-acetate vom

execution under pressure. Melting point 140 ° C. The yield is 60%

For the inventive method ^ - are as the theory,

Organic bases generally prefer such 5 Example 2

Bases whose dissociation constant is less than 10 ~ 6 ^p

is, with particularly favorable embodiments _% lg (zl ² '-pyrazolino) -4', 3 ': l, 2-androstane-17 / S-ol-3-one

the use of quinoline or aniline to be in 20 ml of quinoline for 1 hour under nitrogen

Are nitrogen elimination. heated to 170 ° C and then according to Example 1

To carry out the Spal io process according to the invention, 1-methyl-zi! -Androsten-l7 / 9-ol-

The pyrazoline to be cleaved is obtained in finely divided 3-on-17-acetate, m.p. = 140 ° C.

Condition to the freshly distilled, organic.

Base registered, to avoid the formation Example i

of undesirable decomposition products, the air lg (z1 ² '-Pyrazolino) -4', 3 ^/: l 2-androstan-17jS-ol-3-one, oxygen expediently by an inert gas, 15 in 20 ml of aniline 1 hour nitrogen

preferably by nitrogen, displaced and then heated to the boil. Then according to example 1

the reaction mixture proceed for about 20 to 90 minutes, l-methyl-zU-androstene-lT ^ -ol-

to the corresponding reaction temperature of 3-on-17-acetate, m.p. = 140 ° C.

above 140 ° C, preferably to about 170 to 240 ° C,. .

heated. Example 4 is used to split off nitrogen

a base whose boiling point is below 140 ° C, lg (zl ^{2 /} -pyrazolino) -4 ', 3 ^/ : l, 2-androstan-17 ^ -ol-3-one

z. B. pyridine, the reaction is carried out in 20 ml of collidine for 1 hour under nitrogen

closed pressure vessels, heated to boiling for smaller batches. Now according to example 1

z. B. also in the bomb tube, preferably about proceeding further, l-methyl-zU-androstene-200 ° C through. After the reaction has ended, the 25 17 /? - ol-3-on-17-acetate is obtained, m.p. = 140 ° C. Reaction mixture worked up in the usual way.

The resulting raw products are, regardless of whether Example 5

one of a pure melting point or even only 1 g (/ 1 ² '-pyrazolino) -4', 3 ': l, 2-cholestan-3-one is

Technically pure starting material has started in 20 rill quinoline under nitrogen for 30 minutes usually crystalline and contain due to 30 heated to 220 to 230 ° C. After cooling down

UV spectroscopic examination to about 80% is diluted with hexane, this solution with 4nor-

the desired α, / 3-unsaturated ß-methyl-ketone painter aqueous hydrochloric acid and then with

steroids. After cleaning the raw products, washed neutral in water. The hexane solution will

Likewise customary, pure yields are dried over sodium sulfate and, after filtration

about 60% of theory achieved. 35 the desiccant removed the solvent. Of the

The starting materials can be recrystallized from methanol, and in any residue

Wise substituted, they can be free or one obtains l-methyl-zU-cholesten-S-one from the enamel

Functionally modified hydroxyl groups have a point of 77 to 78 ° C.

or free or functionally modified keto groups “·. ,,

or halogen atoms, but the preparation 40 ^

of the corresponding 11-oxygen derivatives are not Ge 1 g (zl ² '-pyrazolino) -4', 3 ': l, 2-cholestan-3-one

is to be the subject of the present invention. den in 20 ml of lutidine under nitrogen for 1 hour

As z. B. esterified hydroxyl groups come pre-heated and then heated according to Example 5

preferably in question who worked with aliphatic, ali- further. The melting point of the thus obtained

cyclic, araliphatic, aromatic or hetero- 45 l-methyl-zU-cholesten-S-one is also 77 to

cyclic carboxylic acids with 1 to 11 carbon - 78 ° C.

atoms are esterified, e.g. with acetic acid, chlorine- Example 7 acetic acid, propionic acid, butyric acid, diethyl acetic acid

acid, oenanthic acid, caproic acid, undecylic acid, 200 mg (z1 ² '-pyrazolino) -4', 3 ': 1,2a-androstane-cyclopentylpropionic acid, succinic acid, phenyl-50 17 /? - ol-3-one and 4 ml pyridine are heated in bomb acetic acid, furancarboxylic acid, phenoxyacetic acid, tube at 200 ° C for 1 hour. Then it becomes capric acid or benzoic acid. the cooled reaction mixture taken up in ether, washed 3 times with 2η hydrochloric acid and then with Example 1 water until neutral. The ethereal solution 10 g (z1 ² '-pyrazolino) -4', 3 ': 1,2-androstane-17 | Ö-ol-55 is dried over sodium sulfate, and then 3-one is added to 200 ml of quinoline. This ßend, after filtration of the desiccant, the solution is then heated to boiling under nitrogen for 30 minutes solvent in vacuo to dryness. After cooling, it is steamed with. This gives 114 mg of a mixture of ether diluted and neutralized with 4 normal aqueous chlorine of 1-methyl-zli-androsten-n / i-ol-S-one with a little hydrochloric acid and then with water wash a UV absorbance. The ethereal solution has sodium of ε 242 = 8530.

sulfate dried and after filtration from the dry The purification of this crude product is carried out according to

means the ether withdrawn. Crude Example 1 thus obtained.

l-methyl-zli-androsten-17 ^ -ol-3-one (UV: ε 242 _n · ·, ₈

= 10350), 30 ml of pyridine and 18 ml of acetone _6s example 0

anhydride heated on the steam bath for 90 minutes. 100 mg (A ² ' - pyrazolino) - 4', 3 ': 1,2 a- androstane -

This solution is then stirred into ice water, 17β-ο1-3-οη, 0.5 ml of quinoline and 1.5 ml of tetralin

the deposited precipitate is filtered off with suction, dried and heated to boiling under nitrogen for 1 hour.

After cooling, this solution is diluted with ether and with 2N hydrochloric acid and then with Washed neutral in water. The ethereal solution is dried over sodium sulfate and after Filtration of the desiccant stripped the solvent in vacuo to dryness, and that way The crude product obtained is acetylated according to Example 1. L-methyl - ^ - androsten-n / J-ol-S-one-17-acetate is obtained with a melting point of 140 ° C.

Example 9

3 g of (^ i'-pyrazolino) -4 ', 5'-16,17a-zl ⁵ -pregnen-3 ^ -ol-20-one-3-acetate are heated to 160 to 170 ° C. in 60 ml of quinoline for 30 minutes heated. After cooling, the solution is diluted with ether and washed neutral with 4N aqueous hydrochloric acid and then with water. The ethereal solution is dried over sodium sulphate and, after filtration, the drying agent is removed from the solvent in vacuo to dryness. The residue is recrystallized from ethyl acetate. 1.9 g of 16-methyl-z] 5,16-pregnadien-3; Ö-ol-20-one-3-acetate with a melting point of 171 ° C. and a UV absorbance of e 251 = 8750 are obtained.

Claims (7)

PATENT CLAIMS: * 5 1. A process for the preparation of α, ^ - unsaturated ketosteroids, which carry a 1- or 16-position methyl group on the ^ carbon atom by pyrolysis of the pyrazolino steroids obtainable by diazomethane addition to α, / S-unsaturated ketosteroids, characterized in that the elimination of nitrogen in organic bases, their mixtures and optionally in the presence of a diluent, when using high-boiling bases at a reaction temperature above about 140 ° C and when using bases boiling below 140 ° C under pressure at preferably about 200 ° C, in the presence an inert protective gas, preferably nitrogen. 2. The method according to claim 1, characterized in that those with a dissociation constant lower than 10 ~ ⁶ are used as organic ■ bases. 3. The method according to claim 1 and 2, characterized in that the high-boiling organic Bases quinoline or aniline are used. 4. The method according to claim 1 to 3, characterized in that the elimination of nitrogen preferably carried out at a temperature of 170 to 240 ° C. 5. The method according to claim 1 and 2, characterized in that as below 140 ° C boiling organic base pyridine used. 45 6. The method according to claim 1 to 5, characterized in that the starting product Pyrazolino steroids of the following general formula HN - CH ₂ worm R = O
OH H ' OH OH Alkyl or COCH ₃ or alkyl and X = H or CH3 and where the hydroxyl group is also functionally modified Form may be used. 7. The method according to claim 1 to 5, characterized in that there is used as starting materials Pyrazolines with the following general formula wherein R _{1 is} hydrogen or a free or functionally modified hydroxyl group, / H / H R ₂ <, <or = O ^X OH ^x OAc means, whereby these compounds and / or additionally a carbon-carbon double bond starting from carbon atom 5 (Δ ⁴ or / I ⁵ ) can contain and, in the case that the starting product contains a / ^ double bond, the carbon-carbon double bond may be saturated or additionally unsaturated between the carbon atoms in the 6- and 7-positions. © 209 639/428 8.62