DE1250437B - Process for the preparation of 4-chloro-6alkyl-17-acyloxy-4-pregnen-3,20-dione - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

C °? J

German class: 12 ο -25/05

Number: 1250437

File number: F45936IVb / 12o

Filing date: April 30, 1965

Opened on: September 21, 1967

The invention relates to a process for the preparation of new 4-chloro-6-alkyl-17-acyloxy-4-pregnen-3,20-diones, which is characterized in that a 6-alkyl-17-acyloxy-4-pregnen-3,20-dione is used in a manner known per se reacted in an organic basic solvent with sulfuryl chloride and the 4,5-dichloropregnene derivative initially obtained, optionally after its isolation, treated with an agent which splits off hydrogen chloride.

From German Patent 1142 359, 4-chloro-is already known / 1 ¹ -3-keto steroids to produce by reacting the solution of a J ⁴ -3-keto steroid in pyridine at 10 to 25 ⁰ C and sulfuryl chloride. However, this known process does not lead to the desired result if ά ⁴ -3-ketosteroids are used as starting materials which have an alkyl or halogen substituent, for example chlorine, in the 6-position.

It has been found that when sulfuryl chloride ^{acts in organic basic solvents on / l 4} -3-keto steroids which have an alkyl substituent in the 6-position, predominantly the corresponding 4,5-dichloro-6-alkyl-3-keto steroids are obtained and not, as would have been expected from the prior art mentioned, the corresponding 4-chloro- / l ⁴ -3-ketosteroids are formed directly. In the case of substitution in the 6-position, as has been found in accordance with the process of the invention, the corresponding 4-chloro ^{-I 4} -3-ketosteroids can only be obtained after subsequent further treatment of the 4,5-dichloro derivatives initially obtained with agents which split off hydrogen chloride.

The new 4-chloro-6-alkyl-17-acyloxy-4-ρregnen-3,20-diones obtained by the process according to the invention are characterized by gestagens and anti-ovulation Effect with oral application.

As starting materials for the inventive process are, for example in question: 6a and 6ß- methyl-acetoxy-17ix / 1 ⁴ -pregnen-3,20-dione as well as their 16-methyl derivatives.

^{The 6-alkyl-17-acyloxy-J 4} -pregnen-3,20-diones required as starting materials for the process according to the invention are prepared by processes which are already known.

To carry out the method according to the invention, the steroid component is in an organic basic solvents such as pyridine, picoline, N-dimethylaniline, quinoline, collidine or lutidine, dissolved, where, if necessary, an inert solvent, for example benzene, as an additional solution partner, Toluene or xylene, can be added, then 1 to 4 equivalents of sulfuryl chloride, which may be added dropwise in an inert solvent such as benzene, process for the preparation of

4-chloro-6-alkyl-17-acyloxy-4-pregnen-

3,20-dione

Applicant:

Farbwerke Hoechst, Aktiengesellschaft

formerly Master Lucius & Brüning, Frankfurt / M.

Named as inventor:

Dr. Ulrich Stache,

Dr. Werner Haede, Hofheim (Taunus);

Dr. Werner Fritsch, Neuenhain (Taunus)

Toluene or xylene, is dissolved, with stirring to

ao reaction solution and then stirred for about 10 to 60 minutes. The reaction temperatures are advantageously between -30 and +30 ⁰ C, which also (see below) can be used at somewhat higher temperatures. It is preferred to work at 0 to 10 ^° C.

With the usual working up, the so far unknown are 4,5-dichloro-6-alkyl-17x-acyloxy-pregnene-3,20-dione in 80 to I00 ° / _o yield obtained in pure form. If the chlorine addition at temperatures between 10 and 3O ⁰ C, one obtains the 4,5-dichloro derivatives also still as the main product, but with small amounts of other consequential or decomposition products. The increasing tendency towards decomposition, which is attributed to excess unreacted sulfuryl chloride, becomes noticeable at the elevated temperatures through a likewise increasing darkening and resinification of the reaction mixture. At reaction temperatures above 3O ⁰ C, as a rule, the main product isolated is exclusively dark-colored,

resinified oils from which the 4,5-dichloro derivatives can only be obtained in low yields. Since in general the elimination of hydrogen chloride from the 4,5-dichloro-6-alkyl-l 7'-acyloxy-pregnen-3,20-diones It takes a long time to isolate the 4,5-dichloro derivatives to avoid undesirable side reactions advantageous.

Treated to convert the 4,5-dichloro-6-alkyl-17a-acyloxy-pregnane-3,20-diones obtained into the corresponding ^ chloro-o-alkyl-1Tcx-acyloxy-J ⁴ -pregnen-3,20-dione the dichlorides ^x / a for up to 48 hours, preferably 24 hours, with agents that split off hydrogen chloride, such as organic bases, for example

709 648/377

3 4

or mild inorganic basic alkali or earth stirred for 40 minutes at room temperature. After the alkali metal compounds have been worked as described under bj, 1.4 g are obtained. The reaction temperatures for splitting off hydrogen chloride 4-chloro-6 <x-methyl-17a-acetoxy-2J ⁴ -pregnen-3,20-dione are between 0 and ⁰ C and the Siedetempe- (= 61% yield) of melting point 182 ⁰ C and temperatures of the used hydrochloric basic 5 with the same data of the UV spectra and TR, as nucleating agents, optionally indiffe- specified under b _x).

rent solvents, such as ether, tetrahydrofuran, bj 500 mg 4,5-dichloro-6a-methyl-17a-acetoxy-pre-

Dioxane, alcohols, dimethylformamide or benzene, gnan-3,20-dione are in a suspension of 30 ecm

can be added. The methanol, 20 ecm of dioxane and 10 ecm of aqueous

Stand reaction mixture at room temperature. As a saturated sodium hydrogen carbonate solution for 24 hours

Organic bases are preferably triethylamine, stirred between 20 and 30 ° C. One pours on water

Trimethylamine, piperidine, pyrrolidine, N-dimethyl ether and washes the essential extracts with it

aniline, collidine, lutidine, pyridine, picoline and quino water. After distilling off the ether

line in question. The inorganic base chosen is 340 mg of 4-chloro-6oc-methyl-17 <x-acetoxy-

preferably alkaline earth and alkali carbonates, -hydrogen- 15 zl ⁴ -pregnen-3,20-dione (= 74% yield) of the same

carbonates, hydroxides and alcoholates. Melting point and with the same data of the UV and

IR spectra as indicated under bi).
example 1

a) To a solution of 5 g of oa-methyl-Ha-acetoxy- Example 2
/ l ⁴ -pregnen-3,20-dione in absolute pyridine 60ecm ° * To a solution of Ig 6A-methyl-17 <% - one acetoxytropft over 15 minutes with stirring and zl ⁴ -pregnen-3,20-dione in 10 ecm of absolute pyridine while strictly adhering to a reaction temperature is added dropwise within 5 minutes with stirring and between 0 and 5 ° C. a solution of 4.2 g of suIfuryl chloride in 5 ecm of absolute benzene while strictly adhering to a reaction temperature, and the mixture is stirred between 20 and 25 ° C a solution of 0.5 ecm SuI - another 15 minutes between 0 and 5 ° C. An * 5 furyl chloride in 1 ecm of absolute benzene is added and then the yellow-colored reaction solution is stirred for a further 30 minutes at a temperature between 11 and 11 of water, etherified several times and washed at 20 and 25 ° C. The brown organic extracts are then poured one after the other with black colored reaction solution to water, extra-2normaler aqueous hydrochloric acid, water, aqueous overall hiert several times with ether and wash the ethereal sättigter sodium bicarbonate solution and but- 3 <> extracts successively with 10 ° / ₀ hydrochloric acid, a corn with water to neutral Reaction. After 5 ° / _o aqueous solution of sodium carbonate and distilling off the organic solvent with water. After drying over anhydrous, yellow crystals remain, which are distilled off from ether and sodium sulfate, the solvent, and crystallized. 5.3 g of 4,5-dichloro are obtained, the remaining brown crystals from ether um-6a-methyl-17 <x-acetoxy-pregnane-3,20-dione (= 91% 35 crystallized. 760 mg of 4, 5-dichloro-6 "- yield). Melting range: 160 to 170 ° C; a UV-methyl-17 "-acetoxy-pregnan-3,20-dione (= 65 ° ΐημ /" Off absorption maximum in the range 220 to 270 yield), of melting point 160 to 17O ⁰ C.
unavailable. Characteristic IR bands: 1720 The UV spectrum shows only a weakly indicated up to 1740, 1250 cm " ^1st maximum in the range around 260 πΐμ. IR spectrum

bj) 500 mg 4,5-dichloro-6 <x-methyl-17a-acetoxy-pre- 40 identical to that of the reaction product after

Gnan-3,20-dione are in 4 ecm absolute tetraplay 1 a).

hydrofuran and dissolved with 4 ecm of absolute triethyl- The compound obtained is after one of the

amine added. The treatment is allowed to continue for 20 hours at room temperature.

stand temperature, with a precipitate of triethyl. .

amine hydrochloride separates. Then it is poured onto 45 B e 1 s ρ 1 e l 3

100 ecm of water, exhales several times and washes the to a solution of 2 g of 6 "-Methyl-17" -acetoxy-

combined organic extracts one after the other with Zl * -pregnen-3,20-dione in 22 ecm absolute pyridine

Aqueous 2N hydrochloric acid and aqueous saturated sodium are added dropwise over the course of 15 minutes with stirring

bicarbonate solution and water. After a reaction temperature between 0 and 5 ⁰ C a

distilling the solvent leaves a white solution of 1.7 g of sulfuryl chloride in 2 ecm absolute

yellow crystals that are recrystallized from ether. Add benzene and stir for a further 15 minutes

This gives 410 mg of 4-chloro-6 '-methyl-17a-acetoxy between 0 and 5 ⁰ C. Then, it removes the

Zl ⁴ -pregnen-3,20-dione (= 89% yield) in fine half of the reaction mixture and it works like

white crystals. Melting point: 180 to 182 ° C. given under Example 1, a). 980 mg are obtained

λη, αχ = 258 ηιμ (methanol), ε = 12,400. Characteristic 55 4,5-dich) or-6 "-methyl-17ix-acetoxy-pregnane-3,20-dione

static IR bands: 1735, 1690, 1580, 1250 cm- ¹ . (84% yield) from melting point 160 to 170 ^° C.

b ₂ ) 500 mg 4,5-dichloro-6'-methyl-17 '-acetoxy-pre- A UV absorption maximum in the range 220 to

Gnan-3,20-dione are in 3 ecm absolute pyridine 270 ΐημ is not present.

dissolved and left to stand for 24 hours at room temperature - the other, not yet worked up half of the left. After working up, as described under bj- 60 reaction mixture is brought to room temperature, is obtained by crystallization from ether, 5 ecm of absolute pyridine is added and the n-hexane is 315 mg of 4-chloro-6'-methyl-17a acetoxy mixture stand for 24 hours with exclusion of moisture at z) ' ^l -pregnen-3 ₁ 20-dione (= 68% yield) from the melting point to room temperature. Then one works the point 182 ⁰ C and with the same data of the UV and now brown-black reaction solution, as given under IR spectra, as given under b _x ). <> 5 game 1, a) specified, and receives a dark brown,

b ₃ ) 2.5 g of 4,5-dichloro-6'-methyl-17a-acetoxy-pre-oily crystals which are recrystallized from ether.

gnan-3,20-dione are in 30 ecm absolute, about 700 mg of 4-chloro-6 "-methyl-17" -acetoxy-

Potassium hydroxide dissolved pyridine and ^{I 4} -pregnen-3,20-dione (64% yield) in brown

Crystals of melting point 178-180 ⁰ C. X _max = 258 ηιμ (ε = 11100). With benzene by filtration on 20 g of neutral aluminum oxide, after the benzene has been distilled off, the reaction product is obtained in the pure form obtainable according to Example 1, b).

Claims (1)

Claim: Process for the preparation of 4-chloro-6-alkyll ^ S ^ Odi characterized in that one is known per se Way a 6-alkyl-17-acyloxy-4-pregnen-3,20-dione in an organic basic solvent with Reacts sulfuryl chloride and the 4,5-dichloro-pregnene derivative initially obtained, optionally after its isolation treated with an agent which splits off hydrogen chloride. Considered publications:
German Auslegeschrift No. 1142 359;
Journ. Chem. Soc., 1956, pp. 1184 to 1186. 709 648077 9.67 Q Bundesdruckerei Berlin