IL29578A - Process for the introduction of hydrocarbon substituents at the 10-position of 19-nor steroid derivatives and novel compounds thus obtained - Google Patents

Description

PROCESS FOR THE INTRODUCTION OF HYDROCARBON SUBSTITUENTS AT THE OF STEROID DERIVATIVES AND NOVEL COMPOUNDS THUS OBTAINED TIP 10 1168 Process for the introduction of hydrocarbon substituents at the of steroid derivatives Company named The present invention relates to the introduction of hydrocarbon substituents at the of steroid The interest presented by this introduction on the is it is the key to access to the derivatives of the androstane the pregnane starting from the corresponding proceeding particularly from the total synthesis of steroids for example Velluz et and it opens at the same time the way to the preparation of new structures distinguished by the presence of a substituent other than methyl at the or at the There exist already methods for preparing androstane or pregnane derivatives having substituents other than the methyl radical at the Thus for exam et This compound is converted into a The splitting of the group from the leads to oxidation of the group the corresponding The thus obtained is subjected to a reaction There results which is treated with an then The 3 thus formed is subjected to an alkali then to a catalytic hydrogenation which leads to 3 This last is then subjected to an oxidation according to next to the action of and finally to the action of to form the desired Although leading to the desired this synthesis is long and By the process of the present one can introduce at the of steroids carrying at the a lower alkyl radical having The process of the invention rests on two successive essential the epoxidation of steroids by the action of peracids with preponderant formation of the corresponding bitertiary epoxides at The result could not foreseen with certainty because a priori it was not obvious that there would be formed in a preponderant manner the than the 9 the opening of the oxide bridge of the bitertiary epoxides at of steroids with simultaneous introduction of hydrocarbon substituente at the by means of carriers of the desired It is note worthy that the presence of the 9 double bond brings about for the a very easy opening of the oxide in no way leading to high yields in while it for the an exclusive introduction at 10 of the hydrocarbon substituent which is altogether In is known in the case of a the addition is diaxial with formation of a the hydrocarbon substituent being placed at the The invention has as object a process for preparing the bitertiary epoxides at of characterized essentially in that one subjects o the action of obtains a mixture of and which one if need into the desired and a lower alkyl radical having 1 to 6 carbon the said steroids able to carry on the carbon at the groups such as cyclic or where R represents a hydrogen atom or a lower alkyl and on the carbon at the position groups such as cyclic or alkoxy acyloxy the acetyl where R represents a hydrogen atom or a lower alkyl the group where represents a saturated or unsaturated hydrocarbon substituted or The methods of carrying out the process of preparin the bitertiary epoxides at of steroids are by the following the peracids used to effect the epoxidation are acids such as perphthalic benzoic performic peracetic the epoxidation is effected in an organic solvent such as an aromatic solvent like a chlorinated solvent like dichlorethane methylene an ether such as The invention has in a process for opening the oxide bridge the bitertiary epoxides at of steroids by the action of um lower lower alkenyl agnesianr carriers of a or and simultaneous introduction of said hydrocarbon radical on the This object of the is essentially characterized inithat one causes an reagent lower alkyl or lower alkenyl group carrying a or unsaturated substituted or not substituted to react with a The derivatives resulting from the process of the invention can be in a known into compounds presenting a The process of opening the oxide bridge of the bitertiary epoxides of object of the is applied more particularly to the steroids which carry at the a lower radical having 1 to 6 carbon the said steroids able to carry on the carbon at the groups such as cyclic or where R represents a hydrogen atom or a lower alkyl and on the carbon at the groups as cyclic or the acetyl where a hydrogen atom or a lower alkyl radical the group where represents a saturated or unsaturated hydrocarbon substituted or not um The reaction of compound with the epoxide leads principally to derivative and is the configuration of the epoxide which determines the respective orientation of the two substituents at and at it is the bond which sensitizes the to nucleophilic whether the configuration of the epoxide be or Thus it is that the provides principally the while the provides principally the o The possibility of access both to the derivatives and to their isomers The methods of carrying out the process of opening the oxide bridge of the hitertiary epoxides at steroids are characterized by the following points the reaction between the epoxide and the compound is effected in an organic such as an ether like ethyl or isopropyl a cyclic ether like aromatic solvent like benzene or the of the starting derivative presents the and the reaction with the compound leads principally to the corresponding the the starting o steroid derivative presents a the reaction um with the compound principally to the corresponding um the compound1 is used in the form of a halide the term representin halogen atom of atomic weight equal to or greater than As has been indicated the carbon derivatives resulting the object of the can be in a known into compounds presenting a sequence To create such a e for a obtained by the process of the and of which the functions present are for in the form of to the action of an acid and obtains by splitting off the ketal or ketals present and of a molecule of watert the desired steroid al an oximido such as the In this one can prepare starting from dehydrotestosterone In an analogous when the hydrocarbon substituent at the is an propyl or one obtains the corresponding derivatives of testosterone one can starting from ene diene ί in an analogous but starting from one obtains In it is obvious to one skilled in the when the derivative carries a hydroxy1 function at the it will be 4 if one wishes create the o oxidize the said to subject compound thus formed to the action of acid The following examples make the invention better presen no limiting Example Preparation of and of of dic trogen thus formed by pours the filtrate into aqueous solution of sodium separates off the organic phase b 1 decanting and extracts the aqueous phase with methylene One adds the methylene chloride extracts to the main organic phase washes the solution thus obtained with dries it and concentrates it to The residue is on silica the fixing and the elution being effected by means of a mixture of benzene and ethyl acetate containing tri One thus isolates two main fractions and of which the more important is constituted by the This fraction is recrystallized in ethanol one obtains of A new crystallization in ethanol leaves the melting point l C2 4 7 39 7 Spectrum λ ε 770 λ ma 267 ε 800 λ ε λ 260 e The is constituted by the epoxide One the product obtained Spectrum λ at e inflexion at about e 840 λ at 273 980 λ at 280 ε 830 inflexion at about 297 160 As far as is the two epoxides are not described in literature Example Preparation of diene starting from Opening of the epoxide Into 55 of solution of methyl magnesium bromide in tetrahydrofuran one introduces lunder an atmosphere of nitrogen at One agitates the reaction mixture for three hours at ambient temperature pours into an aqueous solution of ammonium chloride containing ice and separates off the organic phase by One extracts the aqueous phase with methylene chloride combines the methylene chloride washes the organic solution thus obtained i with an aqueous solution of sodium evaporates to dryness and the residue in isopropyl One of crude ethereal propanol then in a mixture of ethyl acetate and ieopropyl ether and one obtains a product 9 Spectrum free OH 3 600 associated OH at 3 hyl at at 68 Hz at about 5 Ketal at 239 at Hz As far as is this compound is not described in the literature Hydrolysis of the ketal Into 5 of methanol and 1 of aqueous 5N hydrochloric one under an atmosphere of crude and takes to reflux for 15 One dilutes with filters in vacuo the precipitate thus washes it with dries it and obtains 34 of isolvated then A sample of this product is crystallized isopropyl riim at e 16 700 This product is identical ith a sample of The residue is hydrol in hydrochloric methanol in the way indicated then the product obtained is purified by chromatography on silica0 One obtains of of the same quality as the product previously Example Preparation of from dio ox lox Opening of the epoxide Into 5 of ethereal solution of ethyl magnesium bromide one introduces 60 of tetrahydrofuran and eliminates the ether by One cools to adds an atmosphere of of agitates for two hours at ambient pours the reaction mixture an aqueous solution of ammonium chloride containing One extracts with methylene washes organic extracts with salt and evaporates to The residue is crystallized by adding isopropyl which gives of ethereal are retained liquors one recrystallizes the above crystals in ethyl acetate then in a mixture of ethyl acetate and isopropyl which provides of A sample of this product recrystallized in the ethyl ether mixture Heads to the pure Spectrum free OH at 3 600 associated OH at 3 at methyl of the ethyl group triplet at 33 47 methylene of the ethyl group at about Hz at about 226 at Hz about Hz As far as is this compound is not described in literature Hydrolysis of the ketal Into 10 of methanol admixed 2 of hydrochloric acid one introduces of takes to reflux for 15 dilutes with filters in the precipitate thus dries it and obtains of monohydrated about then A sample of this product is recrystallized in aqueous about then This product is solvated with 500 product ndried at Spectrum free OH at 3600 Spectrum λ at ε 50 The etheral mother B are concentrated to The residue is hydrolyzed in hydrochloric methanol according to the method of operation previously then the product obtained is purified by chromatography on silica One obtains of of the same quality as the product already As far as is not described in the Example Preparation of Opening of epoxide One introduces of 181 o 20 into a solution consisting of of methyl magnesium bromide in tetrahydrofuran and of anhydrous The reaction mixture under an of nitrogen is agitated for one hour at ambient then one heats at reflux for 45 After one pours into an aqueous solution of ammonium chloride and One extracts with methylene washes the extracts with salt and with pure dries and evaporates to dryness in The relsidue is dissolved in 7 of one leaves the in an at overnight and collects about The mother liquor of crystallization is chromatographed on silica by elutio chloroform containing As far as is these two compounds not described in the The derivative can be converted as indicated in example II into ihydrox is purified by recrystallization in a ol mixture One obtains about of then which appears in the form of colourless soluble in the cold in benzene and chloroform and in the hot in the soluble in ether and insoluble in H Hz OH at at 250 Hz at about Hz 1 at about 225 Hz ketal at Hz As far as is this is not described in Hydrolysis One introduces of into a mixture of 9 of ethanol and of aqueous 5N hydrochloric placed under of heats at reflux for One then concentrates to small pours into water and leaves overnight at One filters in vacuo the precipitate thus formed and recrystallizes it in ethyl One obtains of As far aa is this product is not described in the literature This compound can serve as primary material for obtaining after protection of the ketone by oxidation at the position and introduc ion of the lateral chain by moans of a The thus is identical with a the same compound prepared by another Example Stage A One dissolves of in French Patent then pours the mixture into aqueous solution o sodium extracts with methylene washes the organic solution with dries and distils to One obtains of a mixture of and the As as two products are not described Stage Reduction of the ketone at One puts 1 of the mixture obtained above in suspension in 10 of then adds at of sodium One agitates for minutes under dilutes with water admixed with of acetic extracts with methylene washes the organic solution with an solution of sodium then with dries and distils to One obtains of a mixture of 17 and which one uses as it is for the next stage of the c As far as is two compounds are no described in Stage The product obtained in stage B is dissolved in 6 of one adds of a solution of methyl magnesium bromide in One agitates hours at temperature then pours into ah aqueous solution of ammonium One extracts with methylene chloride and isolates of crude identical with the product described in example It can be used for the preparation of example Example Stage ho e of the isomer The isopropyl ether mother liquors obtained above are concentrated to one chromatographs the residue on alumina in solution in benzene containing ethyl The product thus obtained is in petroleum ether One obtains 15 of The product obtained is soluble in ether and isopropyl it is insoluble in petroleum ether As far this compound not described in es One puts in suspension of in 8 of then one adds at of sodium One agitates 5 minutes under dilutes with of water and breaks up the excess sodium hydride by adding of acetic One for one filters washes the precipitate with water and dries in One obtains spectrum Absence of one presence of at 1620 presence of free OH The produet is soluble methanol and it is insoluble in far as is this compound is not described Stage One introduces oi into a mixture of of pyridine and of acetic anhydride and agitates for three hours at ambient temperature under One filters vacuo washes the precipitate with water and dries it in The product thus obtained is crystallized in one ice filters in vacuo and washes the precipitate with ice One obtains of The product is soluble in chloroform and it is insoluble in iwa far as this compound is not described in literature Into of a solution of methyl magnesium bromide in one introduces of te then One agitates for an hour and a half under nitrogen at ambient then takes reflux one pours into an aqueous solution of ammonium chloride and separates off the organic phase by One the aqueous phase with methylene washes the organic solution with an aqueous solution of sodium dries and evaporates to One 58 of crude 17 one uses as it is for the Stage To the preduct obtained above one adds of methanol and of hydrochloric acid and takes to reflux for 15 minutes under an atmosphere of One dilutes with extracts the resin thus obtained with methylene washes themmethylene chloride solution with then with an aqueous solution of N sodium One evaporates to dryness the methylene chloride recrystallizes the residue in an ethyl ether mixture and obtains 115 of identical with the product obtained in example Example Stage One dissolves of 17 in 37 cc of methylene adds 750 of calcined then cools to while agitating under One adds a concentrated solution of perphthalic acid in ether then agitates maintaining the temperature at about One filters in vacuo and washes the precipitate with methylene One washes the filtrate with a saturated aqueous solution of sodium then with salt One adds to the solution 2 drops of pyridine and dries it magnesium One a after evaporation to which one chromatographs on silica By elution with a mlxutre of 1 18Θ of after crystallization in isopropyl melts at The product is soluble in it is insoluble in As far as is this is not described in the of crude which one purifies by pasting in filtering and washing with cooled One obtains of product melting at soluble in methylene chloride and insoluble in As far as is this compound is described in the The starting produc can be obtained in the following introduces 1 of described in French Patent into 10 of One adds of acetic under agitation and under and maintains at for 2 One ice then pours the solution into of a One at rest for filters in washes and dries in one obtains of 9 9 11 Qne takes to reflux for 6 a mixture of pyridine One pours the mixture into an aqueous solution of sodium extracts the solution with methylene washes with dries and evaporates to One obtains of amorphous propyl Ultr spectrum λ at 242 ε spectrum presence of of the acetate at 1725 bands at As far as this compound is not described in the Operating in an analogous way to example one obtains of starting from 600 of As far as lis this compound is not described in the literatur Stage Operating in an analogous to example starting from the product obtained in stage B above one obtains 2Θ2 The product is identical with the prepared by another Example St pe Epoxida on Into of methylene one introduces agitates for incur nitrogen filters off the One washes the filtrate with a saturated aqueous solution of sodium then water till neutrality of the washings One drives off the solvent and obtains a crude which one chroraatographa on silicai gel in chloroform containing and obtains first product which one dissolves in 200 of boiling isopropyi filters then the filtrate to starts the crystallization then for One filters in vacuo and 1 of 18 Analysis 3 spectrum As far as is this compound is not described in the and then product which one dissolves in 80 of boiling isopropyl one filters and concentrates the filtrate to about One ice for minutes and filters in One obtains 673 of 16 The product is soluble in chloroform and Found spectrum λ at 229 378 Inflexion at about 267 As far as is this compound is not described in literature The starting can be obtained in the following Stage 1 One introduces of in French Patent into 226 of and of water and adds at and while agitating of sodium maintains for under nitrogen at then allows to return to ambient One dilutes with of water and adds 3 of acetic One extracts with methylene washes the methylene i extracts with wit an a ueous The product thus obtained is pasted in the ethyl mixture then crystallized in ethyl acetate in the The mother liquors deriving from the pasting and the re crystallization in ethyl acetate are distilled to One treats the with 80 of pyridine and 0 of acetic anhydride and leaves overnight under One decomposes the excess reagent by adding extracts with methylene washes the organic phase with with N hydrophloric an aqueous of sodium bicarbonate finally with one dries and distils to dryness pastes the residue 60 of isopropyl ether at boiling pools and isolates a crude which one recrystallizes by dissolving in of isopropyl ether the concentrates to and obtains of 1 1 As fax as is compound is not described in the Stage 2 One takes to reflux fori 1 hour under 12 of 25 of methanol and 29 of a solution of potassium One with water and the chloroform by bubbling of One overnight then pin vacuo and washes with The product thus obtained is recrystallized in then in eth l One obtains of drox 2 As far as is this compound described in the Stage Into 5 of a solution of methyl magnesium in one introduces of One agitates at under nitrogen for 18 One adds saturated aqueous solution of ammonium extracts with methylene washes the organic solution with dries it sodium sulphate and evaporates it to dryness in One chromatographs on silica gel in the mixture and obtains 93 of The product is soluble in acetone and C As far as is this compound described in the Stage l One puts in suspension 60 of 33 17 in 2 of One brings the 1 temperature to about 0 C under agitation and drop by One agitates 3Q minutes at about adds extracts with methylene dries the organic solution on sodium sulphate and evaporates to dryness in One obtains of The product is soluble in ethanol and As far as is this compound is not described in the literature One dissolves 16 of 3 in 1 of anhydrous then adds of concentrated hydrochloric acid and of distilled One takes to boiling point for 10 takes up in water and methylene The methylene chloride evaporated to provides 11 of 3 The product is soluble in This product is identical with a sample of 3 prepared by another Example Operating in a manner analogous to the method described in example one starting from 161oC magnesium identical with a sample of the same compound prepared by another Operating in a manner analogous to the method described in example II one starting from by means of magnesium identical with a sample of the same compound prepared by another route Example Operating in a manner analogous to the method described in example then in example one starting from 3 Belgian Patent identical with a sample of this compound prepared by another Example Operating a manner analogous to the method described in example then in example one starting from 3 in Patent which the ketone functions at 3 and 20 protected in the form of ethyleneketal identical with a sample of this compound prepared by Example Operating in a manner analogous to method described in example I in example one starting from Patent of which the ketone functions at 3 and 20 have been protected in the form of identical with a sample of this compound prepared by another route insufficientOCRQuality

Claims (1)

1. WHAT IS CLAIMED Process for preparing alkyl or alkenyl characterized in that one subjects a 13 Δ steroid to the action of a obtains a mixture of the an compounds of the corresponding 13 9 which one if need into a and a causes the mixture of the two epoxides or one or other of these of of which the possibly present ketone functions are to react with an carrying the desired hydrocarbon and isolates the desired alkyl or alkenyl Process for preparing or lower alkenyl characterized in that one subjects a of which the possibly present ketone functions are to the action of an carrying the desired hydrocarbon and isolates the desired alkyl or lower alkenyl Process according to Claims 2 characterized in that the lower alkyl radical at the contains 1 to 6 carbon Process according to 1 characterized in that the steroid carries on the carbon at the a substituent chosen from the group consisting of a keto group a cyclic or and the acyloxy and where R represents a hydrogen atom or a lower alkyl and on the carbon at the a substituent chose from the group consisting of the keto cyclic or groups where R represents a hydrogen or a lower alkyl radical and represents a hydrocarbon saturated or substituted or Process according to Claimfl 1 characterized in that the peracid used for the expoxidation is chosen from the group consisting of perphthalic perbenzois perbenzoic acid and peracetic Process according to Claims 1 in that the is effected in an organic solvent chosen from the group consisting of an aromatic a chlorinated solvent and an 2 Process according to Claims 1 or characterized in that the subjected to the action of an carries on the carbon at the a substituent chosen from the group consisting of the cyclic or acyloxy and where R represents a hydrogen atom or a lower alkyl and on the carbon at the a substituent chosen from the group consisting of the cyclic or and where R represents a hydrogen atom or a lower alkyl radical and substituted or Process according to Claims 1 or characterized in that the reaction between theepoxide and the reagent is effected in an organic solvent chosen from the consisting of an ether and an aromatic Process according to claims 1 or characterized in that the of the steroid derivative presents the and the reaction with the magnesium reagent leads principally to the corresponding 10i Process according to claims 1 or characterized in that the of the derivative presents a and with the reagent leads principally to the corresponding Process according to claims 1 or characterized in that the gnesium reagent used in the form of a the term designating a halogen atom of atomic weight equal or greater than The in the hydrocarbon substituent at the is a lower or a lower alkenyl and carrying at the afsubstituent selected from the group consisting of cyclic or and and at the a acyloxy 7 insufficientOCRQuality