ITMI20060474A1 - PROFESS AND INTERMEDIATE FOR THE PREPARATION OF 11-METHYLEN-18-METHYLESTR-4-EN-3,17-DION - Google Patents

Description

Patent application for Industrial Invention entitled:

"Process and intermediates for the preparation of 11-methylene-18-methylextr-4-en-3,17-dione"

FIELD OF THE INVENTION

The present invention relates to the field of processes for the synthesis of steroids, and in particular to a process for the preparation on an industrial scale of 11-methylene-18-methylextr-4-en-3,17-dione, a precursor of steroids to progestin activity, in particular of desogestrel.

The invention also refers to the new intermediates that are formed in this process.

STATE OF THE ART

The steroid of the formula below, whose chemical name is 11-methylen-18-methylextr-4-en-3, 17-dione,

is a known product in the literature, described for the first time in US patent No. 3,927,046.

US patent No. 3,927,046 also describes the synthesis of this product, which uses as starting product 11 α-hydroxy- 18-methylestra-4-en-3,17-dione, obtainable from 3,17-diket-18- methyl-estra-4-ene by hydroxylation in position 11a with Aspergillus Ochraceus.

The 11a-hydroxy-18-methyl-extra-4-en-3,17-dione compound thus obtained is then reacted with ethylene glycol, thus protecting the two ketone groups as acetals.

The main problem connected to this reaction is that it gives rise to a complex mixture of products due both to the migration of the double bond from positions 4 (5) to positions 5 (10) and 5 (6) and to the configurational instability induced by hydroxyl in 11 a, as also noted by Schwarz S. et al. in Tetrahedron 50 (36), 10709-10720, 1994. This complex mixture of products, composed of double bond isomers and structural stereoisomers of the skeleton, is separable with refined chromatographic methods, only at the cost of a long and expensive laboratory work . Furthermore, once an acceptable separation of the mixture into the various components has been obtained, an unsatisfactory reaction yield is nevertheless found, burdened by product fractions not suitable for the continuation of the synthesis to arrive at the desired final product.

This makes this synthesis absolutely not applicable to the preparation of quantities of product, such as to be able to develop the synthesis at an industrial level.

Still according to what described in US patent No. 3,927,046, the compound 11 α-hydroxy-18-methylextr-5-en-3, 17-dione 3, 17-diethylenchetal is oxidized to 18-methylestr-5-en-3.11, 17-thione 3,17-diethylenchetal with CrO3-sulfuric acid mycelia (or Jones reagent).

Also in this case, we find in the use of a chromium VI reagent, a recognized carcinogen, a further reason why this synthesis is not applicable to large-scale production.

The methylene function in position 11 is introduced on the 18-methylextr-5-en-3,11,17-thione 3,17-diethylenchetal via the triphenylphosphonium bromide ylide (Wittig reaction), and the synthesis continues with hydrolysis acidity of the two acetals finally obtaining the product 11-methylene-18-methylextr-4-en-3,17-dione.

As far as the Applicant is aware, to date no processes have been developed for the synthesis on an industrial scale of 11-methylene-18-methylextr-4-en-3,17-dione, which allow to overcome the drawbacks highlighted above. for the processes of the known art.

SUMMARY OF THE INVENTION

The Applicant has now developed a new process that allows the preparation on an industrial scale of the product 11-methylen-18-methylestr-4-en-3,1 7-dione, overcoming the disadvantages highlighted above and related to its use. of toxic and carcinogenic reagents, such as Chromium VI, and the need to perform complex chromatographic purifications to separate the product mixture obtained from the above described reaction of the intermediate 11 a-hydroxy-18-methyl-estro-4-en-3, 17-dione with ethylene glycol, in order to achieve the double protection of the carbonyl groups in positions 3 and 17.

Therefore, the object of the present invention is a process for the preparation of 11-methylene-18-methylextr-4-en-3,17-dione, comprising the following steps:

a) selective protection of the carbonyl group in position 3 of 11ahydroxy-18-methyl-estro-4-en-3,17-dione by reaction with methylhydroxylamine hydrochloride to obtain 11α-hydroxy- 18-methyl-ester-4-en- 3,17-dione 3-methyloxime in the form of a sin + anti mixture:

b) protection as ethylenchetal of the carbonyl group in position 17 of 11a-hydroxy-18-methyl-ester-4-en-3,17-dione 3-methyl oxime coming from step a) by reaction with ethylene glycol in a solvent in the presence of an acid catalyst and a dehydrating agent, or alternatively to the dehydrating agent, by azeotropic distillation of the solvent, to obtain 17-ethylenedioxy-11α-hydroxy-18-methyl-extra-4-en-3-one 3-methyloxime in sin + anti blend form:

c) oxidation of the hydroxy group in 11α position of 17-ethylenedioxy-11α-hydroxy-18-methyl-estro-4-en-3-one 3-methyloxime from

step b) to the corresponding carbonyl, to obtain 17-ethylenedioxy-18-methyl-ester-4-en-3,11-dione 3-methyloxime in the form of a sin + anti mixture:

d) alkylation of the carbonyl in position 11 of 17-ethylenedioxy-18-methylestra-4-en-3,11-dione 3-methyloxime coming from step c) with a suitable alkylating agent, to obtain 17-ethylenedioxy-11β-hydroxy- 11a, 18-dimethyl-ester-4-en-3-one 3-methyloxime in the form of a sin + anti mixture:

e) dehydration of 17-ethylenedioxy-1 1 β-hydroxy-11α, 18-dimethyl-ester-4-en-3-one 3-methyloxime from step d) to obtain 11-methylen-18-methyl-ester-4 -en-3,17-dione 3-methyloxime in the form of a sin + anti mixture:

f) removal of the protective group in position 3 from the 11-methylene-18-methyl-ester-4-en-3,17-dione 3-methyloxime coming from step e) to obtain the desired final product 11-methylene-18-methylestr -4-en-3,17-dione:

The reaction intermediates in the aforementioned process, which are formed in steps a) to e) in the form of sin and anti mixtures, i.e. 11a-hydroxy-18-methyl-extra-4-en-3,17-dione 3-methyloxime , 17-ethylenedioxy-11α-hydroxy-18-methyl-ester-4-en-3-one 3-methyloxime, 17-ethylenedioxy-18-methyl-ester-4-en-3, 11-dione 3-methyloxime, 17 -ethylenedioxy-11 β-hydroxy11α, 18-dimethyl-ester-4-en-3-one 3-methyloxime, and 11-methylene-18-methyl-estro-4-en-3,17-dione 3-methyloxime, they are new products.

The new intermediates of formula (I) in the form of sin anti mixtures

where R1 is selected from O and an ethylenedioxy group, and R2 is selected from O, methylene, αΟΗ (βΗ) and αCΗ3 (βΟΗ), provided that:

i) when R1 is O, R2 is methylene or αΟΗ (βΗ); And

ii) when R1 is ethylenedioxy, R2 is chosen from O, αΟΗ (βΗ) and αCΗ3 (βΟΗ). constitute a further object of the invention.

A further object of the invention is also the use of 11-methylene-18-methylextr-4-en-3,17-dione obtained with the aforementioned process for the preparation of steroids with progestin activity.

Features and advantages of the present process will be detailed in the following description.

DETAILED DESCRIPTION OF THE INVENTION

At stage a) of the present process the protection of the carbonyl in position 3 as a nitrogenous removable derivative does not cause the migration of the double bond which maintains the original position 4,5 in the first ring of the steroid, while at stage b) the protection of the carbonyl in position 17 as ethylenchetal no longer has any influence on the position of the double bond in the first ring of the steroid since the carbonyl in position 3 is protected as methyl oxime which does not react with ethylene glycol.

The methylhydroxylamine used as reactive in step a) in salified form with hydrochloric acid, can be used as such or as aqueous solution; in this stage the reaction solvent can be selected for example from the group consisting of heptane, ethyl ether, methanol, ethanol, isopropanol, methylene chloride, toluene, pyridine, triethylamine, water, and their mixtures.

The reaction temperature in step a) can be for example between 0 ° C and the boiling point of the reaction mixture itself.

In the case of a two-phase reaction mixture, the use of a phase transfer agent such as for example tetrabutylammonium bromide is preferable.

Preferably, the reaction in step a) is carried out in a mixture of methanol and pyridine, using an aqueous solution of methylhydroxylamine hydrochloride, at a temperature between 0 and 20 ° C.

The reaction solvent in step b) can be selected for example from the group consisting of ethylene glycol, isopropyl ether, dimethoxyethane, methyltertbutyl ether, heptane, ethyl ether, methylene chloride, toluene, acetonitrile, and their mixtures; while the reaction temperature is for example comprised between 5 ° C and the boiling point of the reaction mixture itself.

Always in step b) the acid catalyst is preferably selected from the group consisting of paratoluenesulfonic acid (PTS), pyridinium hydrochloride (C5H5NHCI), pyridinium tosylate (PPTS), hydrochloric acid, sulfuric acid, acid alumina, and trifluor of boron etherate (BF3 .Et2O); while the dehydrating agent is preferably selected from triethylorthoformate, trimethylorthoformate, and molecular sieves.

According to a particularly preferred embodiment of the invention, the reaction is carried out in ethylene glycol with PTS and triethylorthoformate at a temperature between 40 and 80 ° C.

The oxidation reaction in step c) can be obtained for example by using dimethylsulfoxide (DMSO) coupled to an electrophilic reactive activating in the presence of a solvent selected from the group consisting of toluene, methylene chloride, triethylamine, and their mixtures. The activating electrophilic reactive is preferably selected from the pyridine - SO3 complex, trifluoroacetic anhydride, oxalyl chloride, and phosphorus pentoxide.

The reaction temperature is for example between -60 ° C and 40 ° C. Preferably, the oxidation reaction in step c) is carried out in a dimethylsulfoxide: triethylamine mixture with the pyridine -SO3 complex at a temperature between 0 and 20 ° C.

At stage d) the reaction with formic acid is useful both for the dehydration of the hydroxyl in position 11 and to remove the protective group in position 17.

The reaction solvent is selected for example from the group consisting of ethyl ether, tetrahydrofuran, heptane, hexane, dimethoxyethane, and their mixtures; while the reaction temperature is for example comprised between 5 ° C and the boiling point of the reaction mixture itself.

A suitable alkylating agent in step d) can be selected, for example, from methylmagnesiumbromide, methylmagnesiumchloride and methyllithium.

Preferably, the alkylation reaction in step d) is carried out in a mixture of ethyl ether tetrahydrofuran (THF) with methylmagnesiumbromide at a temperature between 0 ° C and 40 ° C. According to a preferred embodiment of the present process, the reaction in step e) is carried out using formic acid as a solvent with the addition of hydrochloric acid as catalyst at a temperature between 40 and 80 ° C.

More preferably, the reaction in step e) is carried out at a temperature comprised between 45 and 55 ° C.

At stage f) the regeneration of the carbonyl in position 3 is obtained with the use of an acid resin in a heterogeneous phase.

The reaction can be carried out, for example, in an acetone: water mixture with paraformaldehyde and with an acid resin at a temperature between 20 and 60 ° C.

Preferably, the reaction is carried out at a temperature between 30 and 50 ° C and the resin used is the acid resin Amberlyst <®> 15 or equivalent, i.e. an acid resin with a macroreticular styrenedivinylbenzene matrix with a particle size between 10 and 60 mesh usable for acid catalysis in heterogeneous phase.

The present process, as described above, allows to obtain the desired product 11-methylene-18-methylextr-4-en-3,17-dione with good yields and high purity. Furthermore, the process according to the invention, in addition to avoiding the use of carcinogenic reagents by providing, on the contrary, the use of only reagents and solvents of common industrial use, easily available on the market and characterized by low toxicity, has as a further advantage the absence of preparative chromatography, ie with a crude product / silica gel ratio of at least 1/5.

In addition to the new intermediates of formula (I) described above, the purpose of the invention is the use of 11-methylene-18-methylextr-4-en-3,17-dione obtained with the aforementioned process for the preparation of steroids for progestin activity, in particular of (17a), 13-ethyl-11-methylene-18,19-dinorpregna-4-en-20-in-17β-ol (desogestrel) and of (17α), 13-ethyl-17- hydroxy-11-methylene-18.19-dinorpregna-4-en-20-in-3-one (3-ketodesogestrel).

The following examples are given for illustrative and not limitative purposes of the present invention.

EXAMPLE 1

Preparation of 11α-hydroxy-18-methyl-ester-4-en-3.17-dione 3-methyloxime

1.4 kg of 11 α-hydroxy-18-methylestra-4-en-3,17-dione, 7.5 kg of methanol and 4.4 kg of pyridine were loaded into a suitable reactor, keeping under stirring and at the temperature of 20 ° C.

After bringing the temperature to 5 ° C, 1.6 kg of 35% aqueous solution of methylhydroxylamine hydrochloride were added, keeping the temperature during the addition at values below 10 ° C. At the end of the addition, the reaction mixture is kept under stirring at 0-5 ° C until the end of the reaction, verified by HP-TLC.

At the end of the reaction, the suspension is poured into 105 l of water previously cooled to 0-5 ° C, kept under stirring for 90 minutes, then filtered by washing the product collected on the filter with water. In this way, 1.76 kg of 11α-hydroxy-18-methyl-ester-4-en-3,17-dione 3-metiloxime (sin anti mixture) were obtained which were used, wet with solvent, for the subsequent reaction without further purification or drying.

On the product thus obtained, purified by chromatography for analytical purposes, spectroscopic <1> H-NMR and mass analyzes were performed, obtaining the following results:

Mass for electronic impact: [M <+>] = 331; [M <+>] - H2O = 313; [M <+>] -CH3O = 300; [M <+>] - H2O - CH3O = 282

<1> H-NMR (300 MHz, CDCl3): δ (ppm) 0.84 (t, J = 8 Hz, 3H, 18-methyl); 0.92-2.68 (∑m, 21H); 3.76 (m, 1H, H11); 3.84 (s, 3H, NOCH3); 5.90 and 6.48 (s, ∑ = 1H, H4).

EXAMPLE 2

Preparation of 17-ethylenedioxy-11α-hydroxy-18-methyl-ester-4-en-3-one 3-methyl oxime

1.76 kg of 11α-hydroxy-18-methyl-ester-4-en-3,17-dione 3-methyloxime (sin anti mixture) were loaded into a suitable reactor under stirring and at a temperature of 20 ° C. obtained as described above in Example 1, 18.5 kg of methylene chloride and 14 kg of water.

The biphasic solution is kept under stirring for about 30 minutes before separating the phases, recovering the organic phase from which the methylene chloride is distilled off at 60 ° C and reduced pressure, until about 1.7 kg of a solid product is obtained. . This product is taken up with 4 kg of ethylene glycol and 3 kg of triethyl orthoformate, heated to 40 ° C under stirring, and added with 150 g of p-toluenesulfonic acid.

The solution thus obtained is kept under stirring at about 50 ° C for about 7 hours, during which a further 300 g of p-toluenesulfonic acid are added in two portions.

At the end of the reaction, monitored by TLC, the reaction mixture was poured into 22 l of a 5% aqueous solution of NaHCO3, then cooling the resulting solution to 0-5 ° C and stirring for 60 minutes before filtering the solid on a buckner. .

The wet product recovered by filtration was taken up with 23 kg of methylene chloride, stirring until complete dissolution. This organic solution is then washed with 14 kg of aqueous solution of NaCl at 10%, the phases were separated and the methylene solution, filtered after treatment with decolorizing carbon and dicalite, was subjected to distillation at 60 ° C and reduced pressure for remove the solvent.

There are thus obtained 1.69 kg of 17-ethylenedioxy-11α-hydroxy-18-methylestra-4-en-3-one 3 methyl oxime (sin anti mixture) which are used for the subsequent reaction without further purification.

On the product thus obtained, purified by chromatography for analytical purposes, spectroscopic <1> H-NMR and mass analyzes were performed, obtaining the following results:

Mass for electronic impact: [M <+>] = 375; [M <+>] - H2O = 357; [M <+>] - CH3O = 344; [M <+>] - CH3O -H2O = 326

<1> H-NMR (300 MHz, CDCl3): δ (ppm) 1.00 (t, J = 6Hz, 3H, 18-methyl); 1.16-2.66 (∑m, 21H); 3.60 (m, 1H, H); 3.76-3.92 (m, 7H, -OCH2CH2O- e = NOCH3); 5.84 and 6.42 (s, ∑ = 1H, H4).

EXAMPLE 3

Preparation of 17-ethylenedioxy-18-methyl-extra-4-en-3.11-dione 3-methyloxime

In a suitable reactor, 1.55 Kg of 17-ethylenedioxy-1 1α-hydroxy-18-methyl-extrac-4-en-3-one 3 methyl oxime (sin anti mixture) were charged at a temperature of 20 ° C. as described above in Example 2, 6 Kg of dimethyl sulfoxide and 6.8 Kg of triethylamine; it was stirred until complete dissolution.

Maintaining a temperature of 15-20 ° C, the resulting solution was added with 620 g of PySO3 complex, kept under stirring for 30 minutes, cooled to 0-5 ° C and added in portions with an additional 2.9 kg of Py complex. SO3.

The solution thus obtained is kept under stirring until the end of the reaction, monitored by TLC.

At the end of the reaction, the mixture was poured into 62 l of water previously cooled to 0-5 ° C, and kept under stirring for about 60 minutes before filtering the solid on a buckner.

The wet product recovered by filtration was washed with water, then with a 5% sodium hypochlorite solution in water, and finally again with water.

The wet product thus washed was taken up with 50 kg of methylene chloride, then stirred until complete dissolution.

This organic solution was then washed with water, then with a 5% sodium hypochlorite solution in water and finally again with water until a clear organic phase was obtained, then subjected to distillation at 60 ° C and reduced pressure to eliminate the solvent.

There were thus obtained 1.23 kg of crude 17-ethylenedioxy-18-methyl-estro-4-en-3,11-dione 3-methyloxime (mix sin anti), which were used for the subsequent reaction without further purification.

On the product thus obtained, purified by chromatography for analytical purposes, spectroscopic <1> H-NMR and mass analyzes were performed, obtaining the following results:

Mass for electronic impact: [M <+>] = 373; [M <+>] - H2O = 355; [M <+>] -C2H4 = 345; [M <+>] - H2O - C2H5 = 326

<1> H-NMR (300 MHz, CDCl3): δ (ppm) 0.98 (t, J = 8 Hz, 3H, 18-methyl); 0.8-2.56 (∑m, 20H); 3.72-3.88 (m, 7H, -OCH2CH2O- e = NOCH3); 5.82 and 6.44 (∑ = 1H, s, H4).

EXAMPLE 4

Preparation of 17-ethylenedioxy-11β-hydroxy-11α, 18-dimethyl-ester-4-en-3-one 3-methyl oxime

In a suitable reactor, 1.23 kg of 17-ethylenedioxy-18-methyl-estro-4-en-3,11-dione 3-methyloxime (mix sin anti) obtained as described in Example 3, dissolved in 12.7 Kg of tetrahydrofuran, and 6.5 Kg of ethyl ether; the mixture was then heated to reflux.

While maintaining the reflux, 11.2 Kg of a 1.35 M solution of Methylmagnesium bromide in toluene-THF (7/3) were added. The mixture was kept under stirring and refluxed until the end of the reaction, monitored by TLC. It was cooled to 20 ° C and the organic solution was poured into 95 kg of pre-cooled water at 0-5 ° C.

2.46 kg of ammonium chloride in portions were added to the mixture, stirring, from the end of the addition, for 45 minutes.

The phases were separated, the aqueous phase re-extracted with toluene and the organic phases joined by washing them with water.

The solvent was distilled off at 60 ° C and reduced pressure from the organic solution containing the product.

Approximately 1.3 kg of 17-ethylenedioxy-11-hydroxy-11a, 18-dimethyl-ester-4-en-3-one crude 3-methyloxime (sin anti mixture) are thus obtained which are used for the subsequent reaction without further purification. On the product thus obtained, purified by chromatography for analytical purposes, spectroscopic <1> H-NMR and mass analyzes were performed, obtaining the following results:

Mass for electronic impact: [M <+>] = 389 nd; [M <+>] - H2O = 371; [M <+>] - H2O -HOCH2CH2OH = 309

<1> H-NMR (300 MHz, CDCl3): δ (ppm) 0.92-1.04 (m, 2H); 1.06 (t, J = 8Hz, 3H, 18-methyl); 1.20-1.40 (∑m, 3H); 1.38 (s, 3H, 11-CH3); 1.44-1.88 (∑m, 8H); 2.0-2.24 (∑m, 4H); 2.30-2.56 (∑m, 4H); 3.76-3.90 (m, 4H, OCH2CH2O); 3.82 (s, 3H, CH3ON =); 5.82 and 6.42 (∑s = 1H, H4) EXAMPLE 5

Preparation of 11-methylene-18-methyl-extrac-4-en-3.17-dione 3-methyloxime

In a suitable reactor, at a temperature of 20 ° C, 1.3 kg of 17-ethylenedioxy-11β-hydroxy1α, 18-dimethyl-ester-4-en-3-one 3-methyloxime (sin anti mixture) were charged as described above in Example 4, dissolved in 60 kg of formic acid. 0.5 kg of 37% hydrochloric acid are added to the solution, then the temperature is brought to 50 ° C and maintained at this value until the end of the reaction, monitored by TLC, adding 0.75 kg of 37% hydrochloric acid in portions. %.

At least 2/3 of the formic acid in the reaction mixture is distilled off at 50 ° C and reduced pressure, then it is cooled to 20 ° C and 24 kg of water and 45 kg of methylene chloride are added.

The phases are separated, and the methylene phase washed first with a 5% aqueous solution of NaHCO3 then with water up to neutral pH. The solvent is distilled off at 60 ° C and under reduced pressure from the organic solution containing the product.

Approximately 1 kg of crude 11-methylene-18-methyl-ester-4-en-3,17-dione 3-methyl oxime (sin anti mixture) was obtained, which was used for the next reaction without further purification.

On the product thus obtained, purified by chromatography for analytical purposes, spectroscopic <1> H-NMR and mass analyzes were performed, obtaining the following results:

Mass for electronic impact: [M <+>] = 327; [M <+>] - OCH3 = 296

<1> H-NMR (300 MHz, CDCl3): δ (ppm) 0.74 (t, J = 8Hz, 3H, 18-methyl); 1.00-2.96 (∑m, 20H); 3.84 (s, 3H, CH3ON); 4.82 (s, 1H, 11-CH2); 4.94 (s, 1H, 11-2); 5.93 and 6.52 (∑s = 1H, H4).

EXAMPLE 6

Preparation of 11-methylene-18-methylextr-4-en-3.17-dione

In a suitable reactor, at a temperature of 20 ° C, 1 kg of crude 11-methylene-18-methyl-ester-4-en-3,17-dione 3-methyl oxime (sin anti mixture) obtained as described above were charged. in Example 5, dissolved in 28 kg of acetone; 3.6 kg of water, 1.8 kg of Amberlyst <®> 15 resin and 2.7 kg of paraformaldehyde were added to the solution. The reaction mixture was heated to 40 ° C and kept at this temperature under stirring until the end of the reaction, monitoring by TLC.

At the end of the reaction, it was cooled to 20 ° C, then 0.4 kg of dicalite were added, and it was filtered on a buckner washing with acetone. Then the acetone was distilled away from the mixture, and the remaining part was taken up with 22 kg of toluene; the aqueous phase was separated, and the toluene phase was washed first with a 5% aqueous solution of NaHCO3 then with water up to neutral pH.

The solvent was distilled off at 60 ° C and reduced pressure from the organic solution containing the product.

The semisolid residue obtained is eluted through 5 kg of silica gel using initially pure toluene as solvent and then the mixture toluene: ethyl acetate 95: 5 to recover the product.

The solvent is distilled off at 50 ° C and reduced pressure from the organic solution containing the product.

The residue thus obtained is recrystallized from the methylene chloride: isopropyl ether mixture (1: 5 w / w), finally obtaining, after drying at 45 ° C and reduced pressure, 490 g of 11-methylene-18-methyl-4-en- 3,17-dione. On the product thus obtained, purified by chromatography for analytical purposes, spectroscopic <1> H-NMR and mass analyzes were carried out, obtaining data corresponding to the analytical data reported in the literature.

Claims (26)

CLAIMS 1. A process for the preparation of 11-methylene-18-methylextr-4-en-3,17-dione, comprising the following steps: a) selective protection of the carbonyl group in position 3 of 11α-hydroxy-18-methyl-estro-4-en-3,17-dione by reaction with methylhydroxylamine hydrochloride to obtain 11α-hydroxy-18-methyl-estr-4-en-3 , 17-dione 3-methyloxime in the form of a sin + anti mixture: b) protection as ethylenchetal of the carbonyl group in position 17 of 11α-hydroxy-18-methyl-ester-4-en-3,17-dione 3-methyl oxime coming from step a) by reaction with ethylene glycol in a solvent in the presence of an acid catalyst and a dehydrating agent, or alternatively to the dehydrating agent, by azeotropic distillation of the solvent, to obtain 17-ethylenedioxy-11α-hydroxy- 18-methyl-extra-4-en-3-one 3-methyloxime in sin + anti blend form: c) oxidation of the hydroxy group in 11 a position of 17-ethylenedioxy-11a-hydroxy-18-methyl-estro-4-en-3-one 3-methyloxime from step b) to the corresponding carbonyl, to obtain 17-ethylenedioxy-18-methyl-ester-4-en-3,11-dione 3-methyloxime in the form of a sin + anti mixture: d) alkylation of the carbonyl in position 11 of 17-ethylenedioxy-18-methylestra-4-en-3,1 1-dione 3-methyloxime from step c) with a suitable alkylating agent, to obtain 17-ethylenedioxy-11β-hydroxy -11a, 18-dimethyl-ester-4-en-3-one 3-methyloxime in the form of a sin + anti mixture: e) dehydration of 17-ethylenedioxy-11β-hydroxy-11α, 18-dimethyl-ester-4-en-3-one 3-methyloxime from step d) to obtain 11-methylene-18-methyl-estr-4-en -3.17-dione 3-methyloxime in the form of a sin + anti mixture: f) removal of the protective group in position 3 from the 11-methylene-18-methyl-ester-4-en-3,17-dione 3-methyloxime coming from step e) to obtain the desired final product 11-methylene-18-methylestr -4-en-3,17-dione: The process according to claim 1, wherein the reaction solvent in step a) is selected from the group consisting of heptane, ethyl ether, methanol, ethanol, isopropanol, methylene chloride, toluene, pyridine, triethylamine, water, and mixtures thereof . The process according to claim 1, wherein the reaction temperature in step a) is between 0 ° C and the boiling point of the reaction mixture. The process according to claim 1, wherein a phase transfer agent is further added to step a), in case the reaction mixture is a two-phase mixture. 5. The process according to claim 1, wherein the reaction in step a) is carried out in a mixture of methanol and pyridine, using methylhydroxylamine hydrochloride in the form of an aqueous solution, at a temperature between 0 and 20 ° C. The process according to claim 1, wherein the reaction solvent in step b) is selected from the group consisting of ethylene glycol, isopropyl ether, dimethoxyethane, methyl tertbutyl ether, heptane, ethyl ether, methylene chloride, toluene, acetonitrile, and mixtures thereof . 7. The process according to claim 1, in which the reaction temperature in step b) is comprised between 5 ° C and the boiling point of the reaction mixture itself. The process according to claim 1, wherein said acid catalyst in step b) is selected from the group consisting of paratoluenesulfonic acid (PTS), pyridinium hydrochloride (C5H5NHCl), pyridinium tosylate (PPTS), hydrochloric acid, sulfuric acid, alumina acid, and etherate boron trifluoro (BF3.Et2O). 9. The process according to claim 1, wherein said dehydrating agent in step b) is selected from triethylorthoformate, trimethylorthoformate, and molecular sieves. 10. The process according to claim 1, wherein the reaction in step b) is carried out in ethylene glycol with PTS and triethylorthoformate at a temperature of between 40 and 80 ° C. 11. The process according to claim 1, wherein said oxidation at step c) is carried out using dimethylsulfoxide (DMSO) coupled to an activating electrophilic reactive in the presence of a solvent selected from the group consisting of toluene, methylene chloride, triethylamine, and their mixtures . 12. The process according to claim 11, wherein said activating electrophilic reactive is selected from the pyridine-SO3 complex, trifluoroacetic anhydride, oxalyl chloride, and phosphorus pentoxide. 13. The process according to claim 1, wherein the temperature at step c) is comprised between -60 ° C and 40 ° C. 14. The process according to claim 1, wherein the oxidation reaction in step c) is carried out in the dimethylsulfoxide: triethylamine mixture with the pyridine - SO3 complex at a temperature between 0 ° C and 20 ° C. The process according to claim 1, wherein the solvent in step d) is selected from the group consisting of ethyl ether, tetrahydrofuran, heptane, hexane, dimethoxyethane, and mixtures thereof. 16. The process according to claim 1, in which the reaction temperature in step d) is comprised between 5 ° C and the boiling point of the reaction mixture itself. 17. The process according to claim 1, wherein said alkylating agent at step d) is selected from methylmagnesiumbromide, methylmagnesiumchloride and methyl lithium. 18. The process according to claim 1, wherein the alkylation reaction in step d) is carried out in the mixture ethyl ether: tetrahydrofuran (THF) with methylmagnesiumbromide at a temperature between 0 ° C and 40 ° C. 19. the process according to claim 1, wherein the reaction in step e) is carried out using formic acid as a solvent with the addition of hydrochloric acid as catalyst at a temperature between 40 and 80 ° C. 20. The process according to claim 19, wherein the reaction in step e) is carried out at a temperature comprised between 45 and 55 ° C. 21. The process according to claim 1, wherein said removal of the protecting group of the carbonyl in position 3 at stage f) is obtained with the use of an acid resin in a heterogeneous phase. The process according to claim 21, wherein said removal of the protecting group is carried out in the acetone: water mixture with paraformaldehyde and with an acid resin at a temperature between 20 ° C and 60 ° C. 23. The process according to claim 22, wherein said temperature is between 30 ° C and 50 ° C and said acid resin is an acid resin with styrene-divinylbenzene macroreticular matrix with particle size between 10 and 60 mesh suitable for acid catalysis in heterogeneous phase. 24. Intermediates of formula (I) in the form of sin anti mixtures where R1 is selected from O and an ethylenedioxy group, and R2 is selected from O, methylene, αΟΗ (βΗ) and αΟΗ3 (βΟΗ), provided that: i) when Ri is O, R2 is methylene or αΟΗ (βΗ); And ii) when R1 is ethylenedioxy, R2 is chosen from O, αΟΗ (βΗ) and αCΗ3 (βΟΗ). 25. Use of 11-methylene-18-methylextr-4-en-3,17-dione obtained with the process as defined in claims 1-23, for the preparation of steroids with progestin activity. Use according to claim 25, wherein said steroids with progestogenic activity are selected from desogestrel and 3-ketodesogestrel.