CA1122592A - Process for the preparation of oxime-3-steroid derivatives and intermediates useful in production of same - Google Patents

Abstract

The invention relates to a new process for the preparation of steroid-derived oximes, of formula: (I) in which R is methyl or ethyl and R ′ is hydrogen or acyl, starting from a compound 3,5- corresponding 4,5-seco dioxo, by direct passage of an intermediate enamine to the oxime by the action of hydroxylamine without formation of the 3-oxo derivative .DELTA.4. The invention also relates to products designed for the implementation of said method.

Description

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~ The present invention relates to a new method of preparation of oximes in 3 of steroid derivatives as well as products designed for its implementation.
~ The invention relates to a process for preparing compounds of formula I:

GOLD' ¦ ~ C- CH

~ ~ J (I) in which R represents a methyl or ethyl radical and R 'a hydrogen atom or an acyl radical containing 2 to 8 atoms of carbon, from the compounds of formula II:

ORI
C _ CH
~ ~ \ /
lll O ~ O ~ (II) By acyl radical is preferably meant the remainder of acetic, propionic, butyric, oenanthylic or capricious. .
~ es compounds of formula I are known products and which enter into the composition of drugs: they can be prepared for example according to the process indicated in the patent American 3,532,689.
~ a Applicant company has just discovered a process of preparation for obtaining the products of formula I by total synthase, surprisingly and with excellent yields.

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~ The invention relates to a process for preparing compounds of formula I:
GOLD' ~.

HON ~ ~ ~
in which R and R 'are defined as above, character-laughed in that lt is subjected to a compound of formula II:

~ C_ CH (II) ~ 0 // ~
in which R and R 'retain their previous meaning at the action of a secondary amine, then the action of an acid and finally to that of hydroxylamine or of a hydroxylamine salt, to obtain the corresponding desired compound in the form of a mixture of syn and anti isomers, which are separated, if desired, into each of the isomers.
~ The invention relates in particular to a pig of prepa-ration defined above, characterized in that R represents a radical ethyl, e ~ t also a process characterized in that Rt represents ~ ente an acyl radical and in particular an acetyl radical.
~ The invention more particularly relates to a pro-assigned as defined above, characterized in that one operates in anhydrous medium.
Can we isolate or not isolate the enamine obtained by action of the secondary amine on compound II and the invention includes both the process comprising isolating the ena-mine that the process does not involve it.

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In a preferred embodiment of the invention, uses pyrrolidine or morpholine as a secondary amine and we use ~ e acid coDme, acetic acid or phos acid-phoric.
~ A separation of the syn and anti isomers is carried out from preferably according to the usual chromatography techniques.
~ e 3-pyrrolidyl 13 ~ -ethyl 17 ~ -acetoxy 17 ~ -ethynyl gona

3,5-diene possibly isolated is a new product and is in itself one of the objects of the present invention, as a pro-new industrial product.
~ ~ es compounds of formula II used ~ as a product of on the other hand are generally known compounds, they can be pre-trimmed for example according to the process described in the French patent 1,490,590.
~ e 3,5-dioxo 4,5-seco 13 ~ -ethyl 17 ~ -acetoxy 17 ~ -ethynyl gonane used as starting material for the process of the invention is a new product, it can be prepared by the action of anhy-acetic dride on 3,5-bis ethylenedioxy 4,5-seco 13 ~ -ethyl 17 ~ -hydroxy 17a-ethynyl gonane, (product prepared according to the process indicated in Israeli patent 28020) and hydrolysis of 3,5-bis ethylenedioxy 4,5-seco 13 ~ -ethyl 17 ~ -acetoxy 17 ~ -ethynyl gonane thus formed whether or not it is isolated.
~ The invention therefore also relates to as a pro-new industrial products 3,5-bis ethylenedioxy 4,5-seco 13 ~ -ethyl 17 ~ -acetoxy 17 ~ -ethynyl gonane and 3,5-dioxo 4,5-seco 13 ~ -ethyl 17 ~ -acetoxy 17 ~ -ethynyl gonane.
`~ e method of the invention therefore allows in particular not-be directly of an enamine such as for example 3-pyrrolidyl 13 ~ -ethyl 17 ~ -acetoxy 17 ~ _ethynyl gona 3,5-diene with oxime in 3 corresponding. If it is classic to prepare the oximes in 3 from the corresponding ketones and the ketones in 3 from enamines, the direct passage of an enamine conjugated to oxime 112259 ~

correspondent ~ years intermediate formation of the 3-keto 4 derivative, had never been carried out until now.
~ Chromatographic analysis confirms that no time there is formation of the compound 3-keto ~ -4.
~ a reaction can be explained ain ~ i: there is first formation of ~ el of immonium by action of an acid on the enamine, then action of the hydroxylamine on the immonium salt to give the oxime according to the following mechanism:

~ OH ~ ~

~ e method of the invention provides excellent yields. For example, we can prepare the 3-oxime du 13 ~ -éthyl 17 ~ -acétoxy 17 ~ -éthynyl gon 4-en 3-one à par-shot of 3,5-dioxo 4,5-seco 13 ~ -ethyl 17 ~ -acetoxy 17a-ethynyl gonane with a yield greater than 83 ~ p.
~ The process of the invention is particularly interesting industrially healthy because it delivers a practical end product-ment free from all impurities.
~ es following examples illustrate the invention without any-times limit it.
Preparation of 3,5-dioxo 4,5-seco 13 ~ -ethyl 17 ~ -acéto-xy 17 ~ -eth ~ nyl gonane:
Stage A: 3,5-bis ethylenedioxy 4,5-seco 13 ~ -ethyl 17g-acetoxy 17 ~ -eth ~ nyl gonane.
58 g of 3,5-bis 3,5-sec ethylenedioxy are introduced 13 ~ -ethyl 17 ~ -hydroxy 17 ~ -ethynyl gonane (prepared according to the die described in patent i ~ raélien 28020) in 174 cm3 of toluene. Under stirring and bubbling with nitrogen, the suspen ~ ion is brought to reflux and distills 50 cm3 of toluene. We add to the solution , i ~ i -4-Y '~:

`llZZ592 obtain ~ e 116 cm3 of acetic anhydride, and bring again ~ water to reflux. After the usual treatments, the product obtained sought melting at 165-166 C
Stage B: 3.5-dioxo 4,5-seco 13 ~ -ethyl 17 ~ -acetoxy 17a-ethynyl gonane.
116 cm3 of water are added to the acetic solution obtained in the previous stage, leads to reflux. We maintain the mixture reaction at reflux for three hours and distills the toluene.
The precipitate formed is isolated, wrung, washed and dried. We thus obtains 51.35 g of the desired product melting at 123C.
Example 1 = 3-oxime of 13 ~ -ethyl 17 ~ -acetoxY 17a-ethynyl ~ ona 4-ene Sta __A: 3-pyrrol - y ~ = -hy ~ -a-é-oxy ~ --eth ~ nyl goaa ~ ~ -di ~
30 g of the product, the preparation of which is given above in 150 cm3 of methanol. Then we add 15 cm3 of pyrrolidine. Is maintained for 1 hour at 25-30 C under agitation and nitrogen atmosphere. We spin, wash and dry the pre-Cipity formed. 35 g of sought-after fondant product are thus obtained at 153 C.
a20 = -276 + 3 (c = 0.5 ~ dimethyl formamide) D
S_ad__B: 3 = oxim__ __13 ~ ethy ~ acé__x ~ = eth ~ nyl_g_na_4-èn_ I) Preparation of a suspensioll of h, ydroxylamine:
1.534 g of hydroxylamine hydrochloride are dissolved in 60 cm3 of methanol. We have ~ go to the solution thus obtained 1,931 g - anhydrous sodium acetate. A suspension of hy-droxylamine which is used as is.
II) 3-oxime of 13 ~ eth ~ l 17 ~ ac ~ tox ~ 17a-eth ~ nYl gona

4-ene.
Introduced with stirring, and with nitrogen bubbling, 6 g of the product prepared in stage A in 12 cm3 of acetic acid.
The solution obtained is kept for 30 minutes with stirring , ~. .

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and pours dan ~ the hydroxylamine suspension prepared above.
The reaction mixture is then brought to reflux with stirring.
and sparging nitrogen for 3 hours. Then we add at 20 C, 180 cm3 of water. We ice, spin, wash and paste with water. We 5.327 g of product are thus obtained which is purified by recrystall-reading in methanol ~ 4.795 g of the product are thus obtained sought melting at 223 C.
a20 = + 40 to ~ 46 (c = 0.5 ~ chloroform) Example 2: 17a-ethyn 3-oxime ~ l 17 ~ -hydroxy estr 4-ene 3-one St ~ r ~ Qlidyl-l7 ~ -ét-h ~ y ~ -r ~ y-- ~ t ~ 6) = _ iene By operating as in Example 1, stage A from 3,5-dioxo 4,5-seco 17a-ethynyl 17 ~ -hydroxy estrane, we obtain the sought-after compound melting at 186C.
Stage B: 17a-ethynyl 17 ~ 3-oxime-hydroxy estr 4-ene 3-one.
____________ _:
By operating as in Example 1, stage B from the product prepared in stage A of the present example, the product is obtained sought melting at 112-114C.

Claims (6)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the preparation of the compounds of formula I:

(I) in which R represents a methyl or ethyl radical and R 'a hydrogen atom or an acyl radical containing 2 to 8 atoms carbon, characterized in that a compound of formula II:

(II) in which R and R 'retain their previous meaning to the action of a secondary amine, then to the action of an acid and finally to that of hydroxylamine or of a hydroxylamine salt, to obtain the corresponding desired compound in the form of a mixture of syn and anti isomers, which are separated, if desired, in each of the isomers. 2. Preparation process according to claim 1, characterized in that R represents an ethyl radical. 3. Preparation process according to claim 1 or 2, characterized in that R 'represents an acyl radical or a acetyl radical. 4. Preparation process according to claim 1, characterized in that one operates in an anhydrous medium. 5. Preparation process according to claim 1, characterized in that the compound of formula II is subjected to the ac-tion of a secondary amine, isolates the compound thus obtained that we submit to the action of an acid, then to that of hydroxylamine or a hydroxylamine salt to obtain the desired compound as a mixture of syn and anti isomers which are separated, if desired, in each of the 2 isomers. 6. Preparation process according to one of the claims cations 1 and 5, characterized in that the secondary amine used is selected from the group consisting of pyrrolidine and morpholine.