Patent Description:
Desogestrel and Etonogestrel are synthetic steroids with strong progestational activity. They are used in third-generation contraceptive formulations.

Desogestrel is currently used as a synthetic progestin in numerous oral contraceptive formulations, whereas Etonogestrel is being used as synthetic progestin in the vaginal ring delivery system NuvaRing® and in the implant Implanon®.

Several synthetic methods have been described in the literature for the synthesis of these progestin compounds.

Desogestrel and Etonogestrel were described for the first time in the German patent <CIT> (also published as <CIT>) which discloses the synthesis of Desogestrel. The synthesis of Desogestrel disclosed in <CIT>, as well as in <NPL>, employs the compound of formula (IV) as a key intermediate. This compound is obtained by olefination of the ketone in position <NUM> of compound (II), where the ketone groups at positions <NUM> and <NUM> are protected as ketals, followed by cleavage of the protecting groups in compound (III).

<CIT> discloses the synthesis of desogestrel from 11α-hydroxy-<NUM>-methyl-estra-<NUM>-en-<NUM>,<NUM>-dione, which is obtained by microbiological hydroxylation in position 11α. Before creating the exo-methylene functionality in position <NUM>, the ketone group at position <NUM> is protected.

Desogestrel and etonogestrel can also be synthesised according to the method described in <CIT>. <NUM>-oxo functionality is obtained by epoxide rearrangement and Birch reduction to afford the compound of formula (I). Olefination at position <NUM> of intermediate (II) affords the compound of formula (III), which is used as key intermediate for the preparation of both desogestrel and etonogestrel.

In order to generate the methylene group at position <NUM>, addition of methyl lithium to the <NUM>-keto group was performed over an intermediate compound substituted at position <NUM> with a hydroxyl protected group in the synthesis of etonogestrel disclosed by <NPL>.

In <NPL>et al described the synthesis of desogestrel from 13β-ethyl-<NUM>-hydroxy-gon-<NUM>-ene-<NUM>,<NUM>-dione. Again, olefination of the ketone at position <NUM> is performed after protection of the ketone groups at positions <NUM> and <NUM> as diethylene ketal.

In <CIT>, selective protection of the <NUM>-ketone of <NUM>-ethyl-<NUM>,<NUM>,<NUM>-trione (I) as dithioketal followed by protection of the <NUM>-carbonyl group in (III) as ketal afforded intermediates (V) and (XIII). Olefination at position <NUM> of said protected intermediates, deprotection of the dioxolane, ethynylation at position <NUM> and thioketal deprotection afforded etonogestrel.

A similar strategy, selective protection of the ketone at position <NUM> as dithioketal, followed by protection of the <NUM>-keto group with ethylene glycol, was also used in <CIT>. The <NUM>-methylene derivative (VII) was obtained through Wittig reaction or Peterson olefination. Subsequent alkynylation and deprotection gave rise to etonogestrel.

<CIT> describes the synthesis of compound <NUM>, a key intermediate to desogestrel and etonogestrel. Oxidation of alcohol <NUM> under Swern conditions yielded ketone <NUM>, which was treated under Peterson olefination conditions. Birch reduction of triene <NUM> gave rise to diene <NUM>, which was hydrolyzed to furnish <NUM>-methylene diketone derivative <NUM>. Again, protection of the <NUM> ketone was performed prior to olefination at position <NUM>.

This same key intermediate to desogestrel and etonogestrel was also prepared in <CIT>. In this case, instead of protecting the <NUM>-keto group before carrying out the olefination of the ketone at position <NUM>, it was reduced to the corresponding hydroxyl compound (V) and then reoxidized to the ketone after the <NUM>-methylene group was introduced.

A totally different synthesis of desogestrel was disclosed by <NPL>, , where the steroid backbone was constructed. This strategy does not seem industrially applicable; at least <NUM> synthetic steps are required to obtain 17α-hydroxy-<NUM>-methylene-<NUM>-methylestr-<NUM>-en-<NUM>-one.

In summary, the methods disclosed in the prior art for the preparation of etonogestrel and desogestrel are too long and/or not industrially applicable. In general, most of the syntheses disclosed comprise olefination of the keto group at position <NUM>. However, in all these methods additional steps of protection/deprotection or reduction/oxidation of the <NUM>-keto group are required, which increases the number of steps of the synthesis.

It is therefore necessary to develop a new process for obtaining key intermediates in the synthesis of steroids such as desogestrel or etonogestrel which overcome all or part of the problems associated with the known processes belonging to the state of the art.

The invention faces the problem of providing intermediates for use in a process for the preparation of <NUM>-methylene-<NUM>-keto compounds and derivatives thereof. In particular, the inventors have surprisingly found that <NUM>,<NUM>-di-keto steroids can be selectively olefinated through reaction with a compound of formula (III) as defined herein. This olefination reaction is commercially important since the resulting <NUM>-methylene-<NUM>-keto steroids are intermediates in the preparation of therapeutically valuable compounds, such as e.g. Etonogestrel and Desogestrel. The processes disclosed in the present specification are embodiments of the present invention, only in as far as the claimed <NUM>-hydroxy, <NUM>-silylmethyl-intermediates of formula (Ic) and/or of formula (IVc) appear therein.

In addition, the process developed by the inventors allows preparing <NUM>-methylene steroids in an efficient manner, using easily available starting materials and applying reaction conditions suitable for large scale production.

Described herein is a process for the preparation of a compound of formula (I), or a solvate thereof
<CHM>
wherein.

which comprises reacting a compound of formula (II) or a solvate thereof
<CHM>
wherein X, R<NUM>, R<NUM>, R<NUM>, R<NUM>, and - - - can take the meanings defined above; with a compound of formula (III)
<CHM>
wherein Z can take the meanings defined above and M is selected from Li, MgBr, MgCl and Mgl.

The invention is directed to an intermediate compound of formula (Ic), or a solvate thereof
<CHM>
wherein.

In a further aspect, the invention is directed to an intermediate compound of formula (IVc), or a solvate thereof
<CHM>
wherein.

The term "alkyl" refers to a linear or branched alkane derivative containing from <NUM> to <NUM> ("C<NUM>-C<NUM> alkyl"), preferably from <NUM> to <NUM> ("C<NUM>-C<NUM> alkyl"), carbon atoms and which is bound to the rest of the molecule through a single bond. Illustrative examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl.

The term "aryl" refers to an aromatic group having between <NUM> and <NUM>, preferably <NUM> or <NUM> carbon atoms, comprising <NUM> or <NUM> aromatic nuclei bound through a carbon-carbon bond or fused to one another. Illustrative examples of aryl groups include phenyl, naphthyl, diphenyl, indenyl, phenanthryl, etc..

The term "halogen" refers to bromine, chlorine, iodine or fluorine.

The term "cycloalkyl" refers to a radical derived from cycloalkane containing from <NUM> to <NUM> ("C<NUM>-C<NUM> cycloalkyl"), preferably from <NUM> to <NUM> ("C<NUM>-C<NUM> cycloalkyl") carbon atoms. Illustrative examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc..

"Heterocyclyl" refers to a stable cyclic radical of <NUM> to <NUM> members, preferably a cycle of <NUM> or <NUM> members consisting of carbon atoms and from <NUM> to <NUM>, preferably from <NUM> to <NUM>, heteroatoms selected from nitrogen, oxygen and sulfur, and which may be completely or partially saturated or be aromatic ("heteroaryl"). In the present invention, the heterocyclyl can be a mono-, bi- or tricyclic system which may include fused ring systems. Illustrative examples of heterocyclyl groups include, for example, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran, benzimidazole, benzothiazole, furan, pyrrole, pyridine, pyrimidine, thiazole, thiophene, imidazole, indole, etc..

The term "ketone protecting group", as used herein, refers to a group blocking the ketone function for subsequent reactions that can be removed under controlled conditions. The use of ketone-protecting groups is well known in the art for protecting groups against undesirable reaction during a synthetic procedure and such protecting groups are known (e.g. <NPL>). Virtually any ketone protecting group can be used to put the invention into practice. Illustrative, non-limiting examples of ketone protecting groups include:.

The term "solvate" according to this invention is to be understood as meaning any form of the compound which has another molecule (most likely a polar solvent) attached to it via non-covalent bonding. Examples of solvate include hydrates and alcoholates, e.g. methanolates.

The term "organic solvent" includes for example cyclic and acyclic ethers (e.g. Et<NUM>O, iPr<NUM>O, MeOtBu, <NUM>,<NUM>-dioxane, tetrahydrofuran, methyltetrahydrofuran), hydrocarbon solvents (e.g. pentane, hexane, heptane), halogenated solvents (e.g. dichloromethane, chloroform), aromatic solvents (e.g. toluene), esters (e.g. EtOAc), nitriles (e.g. acetonitrile), amides (e.g. DMF), alcohols (e.g. methanol, ethanol, propanol), sulfoxides (DMSO) and mixtures thereof.

Described herein is a process for the preparation of a compound of formula (I), or a solvate thereof
<CHM>.

In a particular execution of the process described above, R<NUM>, R<NUM> and R<NUM> are H.

In another execution of the process described above, R<NUM> is C<NUM>-C<NUM> alkyl, preferably ethyl.

In another execution of the process described above, R<NUM>, R<NUM> and R<NUM> are H and R<NUM> is ethyl. Preferably, the compound of formula (I) or (II) is a compound of formula (Ia) or (IIa), or a solvate thereof.

In a particular execution of the process described above, X is H. In another embodiment, X forms together with the carbon atom to which it is bonded a ketone protecting group.

In a particular execution of the process described above, the ketone protecting group is selected from cyclic or acyclic ketals, cyclic or acyclic dithioketals, cyclic or acyclic hemithioketals, enol ethers, enamines, oximes and hydrazones. Preferably, the ketone protecting group is selected from cyclic ketals, cyclic dithioketals, cyclic hemithioketals, enol ethers and enamines. In an embodiment, X forms together with the carbon atom to which it is bonded a group selected from:.

wherein each R‴ is independently selected from C<NUM>-C<NUM> alkyl and benzyl, or the two R‴ groups together with the nitrogen atom to which they are attached form a <NUM>- or <NUM>-membered heterocyclic ring.

In a particular embodiment, X forms together with the carbon atom to which it is bonded a group selected from:.

In an execution of the process described above, X forms together with the carbon atom to which it is bonded a group selected from <NUM>,<NUM>-dioxolane, <NUM>,<NUM>-dithiolane, methyl enol ether, ethyl enol ether and pyrrolidine enamine.

In a further execution of the process described above, X forms together with the carbon atom to which it is bonded a <NUM>,<NUM>-dioxolane group and there is a double bond between C<NUM> and C<NUM>. In an execution of the process described above, X forms together with the carbon atom to which it is bonded a <NUM>,<NUM>-dithiolane group and there is a double bond between C<NUM> and C<NUM>. In an execution of the process described above, X forms together with the carbon atom to which it is bonded a methyl enol ether and there is a double bond between C<NUM> and C<NUM> and between C<NUM> and C<NUM>. In an execution of the process described above, X forms together with the carbon atom to which it is bonded an ethyl enol ether and there is a double bond between C<NUM> and C<NUM> and between C<NUM> and C<NUM>. In an execution of the process described above, X forms together with the carbon atom to which it is bonded a pyrrolidine enamine and there is a double bond between C<NUM> and C<NUM> and between C<NUM> and C<NUM>.

In a particular execution of the process described above, Y forms together with the carbon atom to which it is bonded a C=CH<NUM> group. In another embodiment, Y forms together with the carbon atom to which it is bonded a C(OH)CH<NUM>Z group.

In an execution of the process described above, Z is H.

According to the invention, Z is SiR'<NUM> wherein each R' is independently selected from C<NUM>-C<NUM> alkyl and C<NUM>-C<NUM> aryl (Peterson olefination reaction, meaning that the process results in the claimed intermediate of formula (Ic)).

Preferably, each R' is independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl and phenyl. In an embodiment, Z is selected from Me<NUM>Si-, Et<NUM>Si-, iPr<NUM>Si-, nPr<NUM>Si- , nHex<NUM>Si-, tBu<NUM>Si-, Ph<NUM>Si-, MeEt<NUM>Si-, tBuMe<NUM>Si-, tBuPh<NUM>Si-, MePh<NUM>Si-, EtMe<NUM>Si- and PhMe<NUM>Si-. More preferably, Z is Me<NUM>Si-.

In an execution of the above process, M is selected from Li and MgCl. Preferably, M is Li. In a particular embodiment, the compound of formula (III) is Me<NUM>Si-CH<NUM>-Li.

Reaction of the compound of formula (II) with the compound of formula (III) is preferably performed in the presence of an organic solvent, preferably, an anhydrous organic solvent, such as for example a cyclic or acyclic ether (e.g. Et<NUM>O, iPr<NUM>O, tBuOMe, <NUM>,<NUM>-dioxane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbonated solvent (e.g. pentane, hexane, heptane), a halogenated solvent (e.g. dichloromethane, chloroform), an aromatic solvent (e.g. toluene) or mixtures thereof. Preferably the organic solvent is a cyclic or acyclic ether, such as Et<NUM>O, iPr<NUM>O, tBuOMe, <NUM>,<NUM>-dioxane, tetrahydrofuran, methyltetrahydrofuran or mixtures thereof. In a particular embodiment, the organic solvent is tetrahydrofuran. In the present document, the term anhydrous solvent refers to a solvent containing less than <NUM> ppm of water.

In a particular execution of the above process, this reaction is performed at a temperature between - <NUM> and the reflux temperature of the solvent used. In an execution of the above process, it is performed at a temperature of between -<NUM> and <NUM>, preferably between -<NUM> and <NUM>.

In a particular execution of the above process, the compound of formula (III) is present in an amount of from <NUM> to <NUM> molar equivalents with respect to the compound of formula (II), preferably from <NUM> to <NUM> molar equivalents.

The process defined above allows selective addition of the compound of formula (III) to the keto group at position <NUM> of the compound of formula (II). Preferably, the reaction of the compound of formula (II) or a solvate thereof with the compound of formula (III) gives rise to the compound of formula (I) or a solvate thereof with a selectivity higher than <NUM>%, preferably higher than <NUM>%, preferably higher than <NUM>%, more preferably higher than <NUM>%, even more preferably higher than <NUM>% (molar), with respect to the total addition products.

After reaction of the compound of formula (II), or a solvate thereof, with the compound of formula (III), a compound of formula (I) wherein Y, together with the carbon atom to which it is bonded, forms a C(OH)CH<NUM>Z group is obtained. Said compound can be isolated and used in a subsequent step of the synthesis (e.g. ethynylation, Peterson elimination, dehydration) or it can be directly treated with an acid or a base in a one-pot process to afford a compound of formula (I) wherein Y, together with the carbon atom to which it is bonded, represents C=CH<NUM>. Therefore, in a particular embodiment, the process of the invention comprises:.

The compound of formula (I), or a solvate thereof, can be further ethynylated to obtain a compound of formula (IV), or a solvate thereof,
<CHM>
wherein.

The ethynylation reaction can be performed either before or after generating the C=CH<NUM> group at position <NUM> of the steroid. Hence, in a particular execution of the above ethynylation process, the process comprises:.

In another execution of the above ethynylation process, the process of the invention comprises:.

The ethynylation reaction can be performed under reaction conditions disclosed in the prior art for the alkynylation of steroids. In a particular execution of the above ethynylation process, the ethynylation reaction is carried out by treating the compound of formula (I), or a solvate thereof, with a compound of formula (V)
<CHM>
wherein.

In a particular execution of the above ethynylation process, each R" is independently selected from C<NUM>-C<NUM> alkyl, phenyl and Cl. In a further embodiment, each R" is independently selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-hexyl, Ph and Cl. Preferably, -SiR"<NUM> is selected from Et<NUM>Si-, Me<NUM>Si-, iPr<NUM>Si-, "Pr<NUM>Si-, nHex<NUM>Si-, tBu<NUM>Si-, Ph<NUM>Si-, Cl<NUM>Si-, MeEt<NUM>Si-, tBuMe<NUM>Si-, tBuPh<NUM>Si-, CliPr<NUM>Si-, ClMe<NUM>Si-, MePh<NUM>Si-, EtMe<NUM>Si-, EtCl<NUM>Si-, MeCl<NUM>Si-, PhMe<NUM>Si- and PhMeCISi-. More preferably, -SiR"<NUM> is selected from Me<NUM>Si-, Et<NUM>Si-, iPr<NUM>Si-, PhMe<NUM>Si-, tBuMe<NUM>Si- and tBuPh<NUM>Si-. Still more preferably, -SiR"<NUM> is Me<NUM>Si-.

In an execution of the above ethynylation process, R<NUM> is H.

In a preferred execution of the above ethynylation process, R<NUM> is a SiR"<NUM> group. Preferably, R<NUM> is a SiR"<NUM> group wherein each R" is independently selected from C<NUM>-C<NUM> alkyl, such as SiMe<NUM>.

In an execution of the above ethynylation process, M' is Li. Preferably, M' is Li and R<NUM> is a SiR"<NUM> group.

In another execution of the above ethynylation process, M' is selected from MgBr, MgCl and Mgl. Preferably, M' is selected from MgBr, MgCl and Mgl and R<NUM> is H.

The ethynylation reaction is preferably performed in the presence of an organic solvent, preferably, an anhydrous organic solvent, such as for example a cyclic or acyclic ether (e.g. Et<NUM>O, iPr<NUM>O, <NUM>,<NUM>-dioxane, tetrahydrofuran, methyltetrahydrofuran), a hydrocarbon solvent (e.g. pentane, hexane, heptane), a halogenated solvent (e.g. dichloromethane, chloroform), an aromatic solvent (e.g. toluene) or mixtures thereof. Preferably the organic solvent is a cyclic or acyclic ether, such as Et<NUM>O, iPr<NUM>O, <NUM>,<NUM>-dioxane, tetrahydrofuran, methyltetrahydrofuran; a hydrocarbon solvent, such as pentane, hexane, heptane; or mixtures thereof.

In a particular execution of the above ethynylation process, this reaction is performed at a temperature between - <NUM> and the reflux temperature of the solvent used. In an embodiment, it is performed at a temperature of between -<NUM> and <NUM>, preferably between -<NUM> and <NUM>.

In a particular execution of the above ethynylation process, the compound of formula (V) is present in an amount of from <NUM> to <NUM> molar equivalents with respect to the compound of formula (I), preferably from <NUM> to <NUM> molar equivalents.

When X in the compound of formula (I), or a solvate thereof, forms together with the carbon atom to which it is bonded a ketone protecting group, depending on the ethynylation reaction conditions, the ketone protecting group and/or the acid or based used to generate the C=CH<NUM> group at position <NUM>, then a compound of formula (IV), or a solvate thereof, wherein X forms, together with the carbon atom to which it is bonded, a ketone protecting group or a ketone group can be obtained.

In an execution of the above ethynylation process, a compound of formula (IV), or a solvate thereof, wherein X forms, together with the carbon atom to which it is bonded, a ketone protecting group is maintained after the ethynylation reaction.

In a particular execution of the above ethynylation process, a compound of formula (IV), or a solvate thereof, wherein X forms, together with the carbon atom to which it is bonded, a ketone group is obtained after treating the compound of formula (IV), or a solvate thereof, with an acid or a base to generate the C=CH<NUM> group.

When R<NUM> is a SiR"<NUM> group, desilylation can be performed to obtain a compound of formula (IV), or a solvate thereof, wherein R<NUM> is H.

This desylilation reaction can be carried out by methods known in the prior art (e.g. <NPL>). In particular, the desilylation is carried out using fluorine salts or bases in the presence of water, an organic solvent or mixtures thereof. Fluorine salts such as pyridinium fluoride, potassium fluoride or ammonium fluoride; or inorganic bases, such as sodium hydroxide, lithium hydroxide, potassium hydroxide or potassium carbonate can be used. In particular the desilylation reaction is carried out in the presence of an inorganic base and an organic solvent.

In particular the desilylation reaction is performed at a temperature between -<NUM> and +<NUM>. In another embodiment, it is performed at a temperature between -<NUM> and +<NUM>, preferably between <NUM> and <NUM>.

Desilylation reaction can be performed either before or after the generation of the C=CH<NUM> group at position <NUM> and either before or after cleavage of the ketone protecting group.

Described herein is a process wherein a compound of formula (I), or a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH<NUM>Z group, is treated with an acid or a base to obtain a compound of formula (I), or a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C=CH<NUM>.

According to the invention, where Z is a SiR'<NUM> group, treatment with an acid or a base gives rise to a compound wherein Y together with the carbon atom to which it is bonded represents C=CH<NUM> (Peterson elimination reaction).

When Z is H, treatment with an acid gives rise to a compound wherein Y together with the carbon atom to which it is bonded represents C=CH<NUM> (dehydration reaction).

Suitable acids include organic acids, inorganic acids, Lewis acids and mixtures thereof. Examples of suitable acids include acetic acid, trifluoroacetic acid, chloroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, formic acid, propionic acid, butyric acid, malic acid, citric acid, benzoic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, perchloric acid, chloric acid, sulfuric acid, nitric acid, phosphoric acid, ZnCl<NUM>, AlCl<NUM> and BF<NUM>. In a particular execution of the above process for the generation of the C=CH<NUM> group at position <NUM>, the acid is selected from acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, hydrobromic acid, perchloric acid, sulfuric acid and mixtures thereof.

Suitable bases include e.g. alkali metal hydrides, alkali metal alkoxides, alkali metal hydroxides, such as sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, sodium hydroxide and potassium hydroxide.

In a particular execution of the above process for the generation of the C=CH<NUM> group at position <NUM>, a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH<NUM>Z group, is treated with an acid or a base before the ethynylation reaction to afford a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C=CH<NUM>.

In another execution of the above process for the generation of the C=CH<NUM> group at position <NUM>, treatment with an acid or a base is performed after the ethynylation reaction so that a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH<NUM>Z group, is converted into a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C=CH<NUM>. In this case, depending on the acid or base employed, the reaction conditions and/or the ketone protecting group, a compound of formula (IV), or a solvate thereof, wherein X forms, together with the carbon atom to which it is bonded, a ketone protecting group or a ketone group can be obtained.

In a preferred execution of the above process for the generation of the C=CH<NUM> group at position <NUM>, the acid or based used to generate the C=CH<NUM> group at position <NUM> also allows cleavage of the ketone protecting group at position <NUM> so that it is obtained a compound of formula (IV) wherein Y, together with the carbon atom to which it is bonded, represents C=CH<NUM> and X, together with the carbon atom to which it is bonded, represents a ketone group.

In order to obtain a compound of formula (IV) wherein X is hydrogen or forms, together with the carbon atom to which it is bonded, a ketone group, a deprotection step of the ketone protecting group may be needed. Cleavage of the ketone protecting group can be carried out by any conventional means known in the art (e.g. <NPL>).

For example, when the ketone protecting group is a ketal, a thioketal or an enol ether, it can be cleaved to regenerate de <NUM>-keto group in acid media.

When the ketone protecting group is an enamine, it can be cleaved by hydrolysis in acid or basic media according to well established procedures of the state of the art.

When the ketone protecting group is a dithioketal, it can be cleaved by oxidation or in the presence of a Lewis acid. In addition, when the ketone protecting group is a dithioketal it can be removed under reducing conditions to obtain a compound wherein X is H.

In a particular execution of the above process for the cleavage of the ketone protecting group group at position <NUM>, the ketone protecting group is cleaved under the reactions conditions employed to generate the CH=CH<NUM> group at position <NUM>, so that both processes occur in a single step.

In view of the information provided herein, the skilled person will appreciate that different sequences of steps can be used and that further synthetic steps might be needed to put the described processes into practice.

For example, to obtain a compound of formula (IV) wherein R<NUM> is H and X is hydrogen or forms, together with the carbon atom to which it is bonded, a ketone group, it might be necessary to carry out one or both of the following steps:.

These steps can be carried out in any order. That is, if both steps are carried out, step (i) can be carried out either before or after step (ii).

In order to convert a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH<NUM>Z, into a compound of formula (IV), or a solvate thereof, wherein R<NUM> is H, X forms together with the carbon atom to which it is bonded a ketone group and Y together with the carbon atom to which it is bonded represents CH=CH<NUM>, any of the following sequences of steps can be followed:.

In order to convert a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH<NUM>Z, into a compound of formula (IV), or a solvate thereof, wherein R<NUM> is H, X is hydrogen and Y together with the carbon atom to which it is bonded represents CH=CH<NUM>, any of the following sequences of steps can be followed:.

Compounds of formula (I) obtained by the process of the invention are useful intermediates in the preparation of several pharmaceutically active agents, such as e.g. Etonogestrel and Desogestrel.

Also described herein is a process for the preparation of Etonogestrel, or Desogestrel, or a solvate thereof, which comprises reacting a compound of formula (II), or a solvate thereof, as defined herein with a compound of formula (III) as defined herein.

In a particular execution of the above process for the preparation of Etonogestrel and Desogestrel, Etonogestrel can be obtained by a process which comprises:.

In another execution of the above process for the preparation of Etonogestrel and Desogestrel, Etonogestrel can be obtained by a process which comprises:.

In another execution of the above process for the preparation of Etonogestrel and Desogestrel, Desogestrel can be obtained by a process which comprises:.

In a further execution of the above process for the preparation of Etonogestrel and Desogestrel, Desogestrel can be obtained by a process comprising:.

The invention is directed to a compound of formula (Ic), or a solvate thereof,
<CHM>
wherein X, Z, R<NUM>, R<NUM>, R<NUM>, R<NUM> and - - - are as defined herein.

Preferred embodiments for X, Z, R<NUM>, R<NUM>, R<NUM>, R<NUM> and - - - are as defined above.

In the compound of formula (Ic) Z is SiR'<NUM> wherein each R' is independently selected from C<NUM>-C<NUM> alkyl and C<NUM>-C<NUM> aryl. Preferred embodiments for R' are as defined above.

In a particular embodiment, the compound of formula (Ic) is a compound of formula (la-<NUM>), or a compound of formula (Ib-<NUM>), or a solvate thereof.

In a preferred embodiment, the compound of formula (Ic) is selected from:
<CHM>
<CHM>
or a solvate thereof.

In another aspect, the invention is directed to a compound of formula (IVc), or a solvate thereof,
<CHM>
wherein X, Z, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM> and - - - are as defined herein.

Preferred embodiments for X, Z, R<NUM>, R<NUM>, R<NUM>, R<NUM>, R<NUM> and - - - are as defined above.

In a particularly preferred embodiment, in the compound of formula (IVc) R<NUM> is SiR"<NUM>, wherein each R" is independently selected from C<NUM>-C<NUM> alkyl, C<NUM>-C<NUM> aryl and halogen. Preferred embodiments for R" are as defined above.

In a particular embodiment, the compound of formula (IVc) is a compound of formula (IVa-<NUM>), or a compound of formula (IVb-<NUM>), or a solvate thereof.

In a preferred embodiment, the compound of formula (IVc) is selected from:
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
<CHM>
or a solvate thereof.

The following examples illustrate the invention and should not be considered as limitative of the invention. Of the following examples, examples <NUM>-<NUM>, <NUM>, <NUM> and <NUM> relate to process steps which directly involve the intermediate compounds of formula (Ic) or formula (IVc) of the invention and are thus examples according to the present invention. Examples <NUM>-<NUM> and <NUM> build up to the preparation of such compounds and examples <NUM>, <NUM>, <NUM> and <NUM> relate to downstream process steps, neither of which directly involve the silylated compounds of formula (Ic) or formula (IVc) and thus which form part of the present invention only in as far as they form part of a total process scheme which involves the silylated compounds of formula (Ic) or formula (IVc). Examples <NUM> and <NUM> are not examples of the present invention and are present purely for the purposes of comparison.

Oxalyl chloride was added to <NUM> of DCM at -<NUM>. The solution was cooled down at -<NUM> and then DMSO (<NUM>) diluted in <NUM> of DCM was dropwise added keeping the temperature below -<NUM>. After addition was complete, the reaction mixture was stirred <NUM> at -<NUM>. Then, <NUM> of compound <NUM> dissolved in <NUM> of DCM were then added keeping the temperature below -<NUM>. The reaction mixture was kept at -<NUM> for <NUM>, then DIPEA (<NUM>) was quickly added and the cold bath removed allowing to warm up to room temperature (<NUM>,<NUM>). <NUM> of <NUM>% solution of acetic acid were added and the aqueous phase was separated. The organic phase was washed with <NUM> of a solution of NaHCO<NUM> <NUM>%, separated and concentrated under vacuum to a volume of <NUM>. <NUM> of IPA were added and reduced the volume to <NUM>. The operation was repeated two more times to reach a final volume of <NUM>. The resulting suspension was stirred in an ice bath for <NUM> and then filtered, the solid was washed with <NUM> of cold IPA and dried under vacuum at <NUM>. <NUM> of compound <NUM> were obtained as white solid (yield = <NUM>%).

<NUM> of compound <NUM> were dissolved in <NUM> of DMSO and then <NUM> of TEA were added. The solution was heated at <NUM>, and a solution of SO<NUM>Py (<NUM>) in <NUM> of DMSO were added. The reaction mixture was stirred at <NUM> for <NUM>, and then poured over a solution of <NUM> of glacial acetic acid in <NUM> of water forming a precipitate. The suspension was cooled in an ice bath for <NUM>, and filtered. The solid was suspended in <NUM> of IPA and heated to complete dissolution and then cooled down at <NUM>. The resulting solid was filtered and dried under vacuum at <NUM> to yield <NUM> of compound <NUM> (<NUM>%).

<NUM> of compound <NUM> were dissolved in <NUM> of THF, then <NUM> of TEOF and <NUM> of pTsOH were added. The reaction mixture was stirred at <NUM> for <NUM>. Then <NUM> of TEA were added, and <NUM> of solution of NaHCO<NUM> <NUM>%. The aqueous phase was extracted with <NUM> EtOAc. The combined organic phases were concentrated until a wet solid was obtained, <NUM> of ethanol were added and concentrated to a volume of <NUM>, cooled in an ice bath and filtered. The solid was washed with <NUM> of cold ethanol and dried under vacuum at <NUM>, to yield <NUM> of compound <NUM> (<NUM>%).

<NUM> of compound <NUM> were dissolved in <NUM> of THF and cooled down at -<NUM>. Then <NUM> of trimethylsilyl methyl lithium were slowly added, keeping the temperature below -<NUM>, and the mixture stirred for <NUM> further after addition was complete. Then <NUM> of solution of NaHCO<NUM> <NUM>% were added, separated and the aqueous phase was extracted with <NUM> EtOAc. The combined organic phases were concentrated to <NUM>, <NUM> of ethanol were added and the solvent was evaporated to a final volume of <NUM>. The operation was repeated two more times, then the suspension was cooled in an ice bath for <NUM>. The solid was filtered, washed with <NUM> of cold ethanol and dried under vacuum at <NUM>, to yield <NUM> of compound <NUM> (<NUM>% yield).

<NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>); <NUM> (t, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (d, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM>(m, <NUM>); <NUM> (s, <NUM>) <NUM> (d, <NUM>).

<NUM>C NMR (<NUM>, CDCl<NUM>): δ <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>.

To a solution of hexillithium (<NUM>) in heptane (<NUM>) cooled at <NUM>, a solution of trimethylsilyl acetylene (<NUM>) in <NUM> of a mixture of THF/heptanes <NUM>/<NUM> was slowly added. The reaction mixture was stirred at <NUM> for <NUM>, then a solution of compound <NUM> (<NUM>) in <NUM> of THF was added and the mixture stirred for <NUM> further. Water (<NUM>) was added to quench the excess of lithium reagent and the organic phase concentrated under vacuum. The residue (containing <NUM>% of compound <NUM> and <NUM>% of compound <NUM>, maximum level of conversion obtained) was purified on silica gel with EtOAc/heptanes <NUM>/<NUM>, affording pure compound <NUM> as an oil.

<NUM>H NMR (<NUM>, CDCl<NUM>): δ <NUM> (s, <NUM>); <NUM> (s, <NUM>) <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM> (d, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM> (d, <NUM>); <NUM>-<NUM> (m, <NUM>); <NUM>-<NUM>(m, <NUM>); <NUM> (s, <NUM>) <NUM> (d, <NUM>).

<NUM>C (<NUM>, CDCl<NUM>): δ <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>.

<NUM> of compound <NUM> were dissolved in <NUM> of THF, cooled down at <NUM> and <NUM> of LaCl<NUM>*2LiCl were added, followed by slow addition of ethynylmagnesium chloride (<NUM>) keeping the temperature below <NUM>. After <NUM>, <NUM> of TEA and <NUM> of solution of NaHCO<NUM> <NUM>% were added. The aqueous phase was extracted with EtOAc <NUM> X <NUM>, and the combined organic phases were washed with brine. The solvent was evaporated under reduced pressure to a volume of <NUM> and <NUM> of methanol were added. It was concentrated to <NUM> and repeated twice. The final methanol solution was treated with <NUM> of HCl, stirred at <NUM> for <NUM>, and <NUM> of solution of NaHCO<NUM> <NUM>% were added. Addition of <NUM> of water promoted the precipitation of a solid. It was filtered, washed with <NUM> of water and dried under vacuum at <NUM>, yielding <NUM> of crude Etonogestrel as brown solid (hplc purity <NUM>%).

To a solution of hexillithium (<NUM>) in heptane (<NUM>) cooled at -<NUM>, a solution of trimethylsilyl acetylene (<NUM>) in <NUM> of a mixture of THF/heptanes <NUM>/<NUM> was slowly added. The reaction mixture was stirred at -<NUM> for <NUM>, then a solution of compound <NUM> (<NUM>) in <NUM> of THF/heptanes <NUM>:<NUM> was added and the mixture stirred for <NUM> further. Water (<NUM>) was added to quench the excess of lithium reagent and the organic phase concentrated under vacuum. The residue (containing <NUM>% of compound <NUM> and <NUM>% of compound <NUM>) was dissolved in <NUM> of methanol, <NUM> of HCl were added and stirred <NUM> at <NUM>, followed by addition of <NUM> of NaOH <NUM>% and stirring for <NUM> further. The solvent was evaporated under reduced pressure, the residue dissolved in <NUM> of DCM. It was washed first with a solution of glacial acetic acid <NUM>% and then with a solution of NaHCO<NUM> <NUM>%. The crude obtained was dissolved in <NUM> of acetone, concentrated to a volume of <NUM> and <NUM> mol of IPA were added with further reduction of the volume of <NUM>%. The operation was repeated twice. The suspension was cooled in an ice bath and the solid filtered, washed with <NUM> of cold IPA and dried at <NUM> under vacuum, to yield <NUM> of Etonogestrel.

The residue obtained following Example <NUM> was dissolved in <NUM> of methanol and <NUM> of solution of HCl were added. The reaction mixture was stirred at <NUM> for <NUM>, the solvent was then evaporated, <NUM> of water were added and the mixture extracted with <NUM> of EtOAc. The crude product was purified on silica gel with EtOAc/heptanes <NUM>/<NUM>, affording pure compound <NUM> as a white solid.

The residue obtained following Example <NUM> was dissolved in <NUM> of methanol and <NUM> of solution of NaOH <NUM>% were added. The reaction mixture was stirred at <NUM> for <NUM>, the solvent was then evaporated, <NUM> of water were added and the mixture extracted with <NUM> of EtOAc. The crude product was purified on silica gel with EtOAc/heptanes <NUM>/<NUM>, affording pure compound <NUM> as an orange oil.

<NUM> of compound <NUM> was dissolved in <NUM> of acetone and then distilled up to a volume of <NUM>. <NUM> of IPA were added and concentrated up to a volume of <NUM>. The operation was repeated three times. The solution was then cooled at <NUM>, filtered and washed with <NUM> of IPA. The solid was dried under vacuum to afford pure etonogestrel.

Compound <NUM> (<NUM>) was dissolved in DCM (<NUM>), then <NUM> of <NUM>,<NUM>-ethanedithiol and <NUM> of pTsOH were added. The reaction mixture was refluxed for <NUM>, <NUM> of DCM were distilling every hour (and adding fresh solvent). <NUM> of solution of NaHCO3 <NUM>% were added and the aqueous phase extracted with <NUM> of DCM. The combined organic phases were concentrated under vacuum to a final volume of <NUM>. <NUM> of methanol were added and concentrated under reduced pressure to a final volume of <NUM>. The obtained suspension was cooled in an ice bath for <NUM>. The resulting solid was filtered, washed with <NUM> of cold methanol and dried under vacuum at <NUM>, to yield <NUM> of compound <NUM>.

Compound <NUM> (<NUM>) was dissolved in THF (<NUM>) and cooled at <NUM>. Then <NUM> of trimethylsilyl mehtyl lithium were slowly added, keeping the temperature below <NUM> and the mixture was stirred for <NUM> further after addition was complete. Then, <NUM> of solution of NaH<NUM>Cl <NUM>% were added, separated and the aqueous phase was extracted with <NUM> of EtOAc. The combined organic phases were concentrated to a volume of <NUM> and the suspension was cooled with an ice bath for <NUM>. The resulting solid was filtered, washed with <NUM> of cold EtOAc and dried under vacuum at <NUM>, to yield <NUM> of compound <NUM> (<NUM>%).

<NUM> of compound <NUM> were dissolved in <NUM> of methanol and <NUM> of HCl were added, the reaction mixture was stirred at <NUM> for <NUM>. After adjusting the pH to <NUM> and adding TEA, the suspension was cooled in an ice bath. The resulting precipitate was filtered, washed with <NUM> of methanol and dried under vacuum at <NUM>, affording <NUM> of compound <NUM> (<NUM>%).

<NUM> of compound <NUM> were dissolved in <NUM> of THF, cooled down at <NUM> and <NUM> of LaCl<NUM>*2LiCl were added, followed by slow addition of ethynylmagnesium chloride (<NUM>) keeping the temperature below <NUM>. After the addition was completed, the reaction mixture was heated for <NUM> at <NUM>. Then cooled down at <NUM> and <NUM> of a solution <NUM>% HCl were added. The aqueous phase was extracted with <NUM> of EtOAc, and the combined organic phases were washed with brine. The solvent was evaporated under reduced pressure to a volume of <NUM> and <NUM> of heptane were added. It was concentrated to <NUM> and repeated twice. The obtained suspension was cooled in an ice bath for <NUM>. The solid was filtered, washed with <NUM> of cold heptane and dried under vacuum at <NUM>, to yield <NUM> of compound <NUM> (<NUM>%).

Thioacetal was removed using periodic acid, as described in example 8A in <CIT>, or using SIBX as described in example 8C in <CIT>.

Compound <NUM> (<NUM>) was dissolved in THF (<NUM>) and cooled at <NUM>. Then, <NUM> of trimethylsilyl methyl lithium were slowly added, keeping the temperature below <NUM> and the mixture stirred for <NUM> further after addition was complete. Then, <NUM> of solution of NaH<NUM>Cl <NUM>% were added, separated and the aqueous phase was extracted with <NUM> EtOAc. The combined organic phases were concentrated to a volume of <NUM>, and the suspension was cooled with an ice bath for <NUM>. The resulting solid was filtered, dissolved in <NUM> of methanol, and <NUM> of HCl were added. The reaction mixture was stirred at <NUM> for <NUM>. After adjusting the pH to <NUM> and adding TEA, the suspension was cooled in an ice bath. The precipitate was filtered, washed with <NUM> of methanol and dried under vacuum at <NUM>, affording <NUM> of compound <NUM> (<NUM>%).

To a solution of hexillithium (<NUM> <NUM> in hexane) in hexane (<NUM>) cooled at - <NUM>, a solution of trimethylsilyl acetylene (<NUM>) in <NUM> of a mixture of THF/hexane <NUM>/<NUM> was slowly added. The reaction mixture was stirred at -<NUM> for <NUM>, then a solution of compound <NUM> (<NUM>) in <NUM> of hexane was added and the mixture stirred for <NUM> at <NUM>/<NUM>. Aqueous NaCl solution (<NUM>) was added and the phases were separated. The organic phase was mixed with <NUM> of methanol, followed by addition of <NUM> of aqueous NaOH <NUM>% and stirred for <NUM> further. <NUM> of an aqueous solution of <NUM>% Acetic acid was added. The phases were separated and the organic phase was washed with water (<NUM>). The solvent was evaporated under reduced pressure and the residue dissolved in <NUM> of MeOH. The solvent was evaporated under reduced pressure and the residue dissolved in <NUM> of Hexane. The crude obtained was dissolved in <NUM> of hexane by heating at <NUM>. The solution was cooled slowly in an ice bath and the resulting solid filtered, washed with <NUM> of cold hexane and dried at <NUM> under vacuum, to yield <NUM> of Desogestrel (<NUM>%).

<NUM> of compound <NUM> were dissolved in <NUM> of THF. Then <NUM> of methyl magnesium chloride (<NUM>%) were slowly added, heating the mixture at reflux for <NUM>. The reaction was quenched with TEA. Then a solution of NaHCO<NUM> <NUM>% was added and the aqueous phase was extracted with EtOAc. The crude product was purified on silica gel, affording compound <NUM> (<NUM>%) and the compound of di-methylation <NUM> (<NUM>%).

<NUM>C NMR (<NUM>, CDCl<NUM>): δ <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>; <NUM>.

Claim 1:
A compound of formula (Ic), or a solvate thereof
<CHM>
wherein
X represents H or it forms together with the carbon atom to which it is bonded a ketone protecting group;
Z is SiR'<NUM> wherein each R' is independently selected from C<NUM>-C<NUM> alkyl and C<NUM>-C<NUM> aryl;
R<NUM> is selected from H, C<NUM>-C<NUM> alkyl and halogen;
R<NUM> is selected from H, C<NUM>-C<NUM> alkyl and halogen, or is absent when there is a double bond between C<NUM> and C<NUM>;
R<NUM> is selected from H and C<NUM>-C<NUM> alkyl;
R<NUM> is selected from H, C<NUM>-C<NUM> alkyl and halogen; and
- - - is a single or double bond.