WO2012022880A2

WO2012022880A2 - Method for synthesizing steroids

Info

Publication number: WO2012022880A2
Application number: PCT/FR2011/051780
Authority: WO
Inventors: Michel Miesch; Blandine Ressault; Philippe Geoffroy
Original assignee: Universite De Strasbourg; Centre National De La Recherche Scientifique - Cnrs
Priority date: 2010-07-29
Filing date: 2011-07-22
Publication date: 2012-02-23
Also published as: WO2012022880A3

Abstract

The present invention relates to a method for synthesizing steroids, as well as to intermediate products and steroids produced by said method. In particular, the method of the present invention enables glycolsylated or non-glycosylated pregnanes to be manufactured at a yield never before attained in the prior art. The method of the invention is a method for synthesizing a 12-beta compound having the following formula (XIII): formula (XIII) from the compound having the following formula (XI), where: R^4p is (i), a function (I), said function being protected, or (ii) a function (II); R⁷is a substituent chosen from the group including H; a C1-C6 alkyl; an aryl selected from the group including benzyl, p-methoxybenzyl, and benzoyl; acetyl and a carbohydrate; R⁴ is a function of formula (III) or formula (IV), the substituent in position 3 being in the alpha or beta position, and the substituent in position 17 being in the beta position; and said method includes a step of breaking the 12-13 bond of the C ring in an aprotic medium by UV photochemical irradiation followed by a step of closing the C ring.

Description

PROCESS FOR THE SYNTHESIS OF STEROIDS

DESCRIPTION Technical field

The present invention relates to a process for the synthesis of steroids as well as to intermediates and steroids obtained by this method.

In the description below, references in brackets ([]) refer to the list of references at the end of the text.

State of the art

Steroids are a group of lipids derived from triterpenoids, that is to say lipids with 30 carbon atoms, mainly squalene. They are characterized by a hydrophobic cyclopentanophenanthrene (sterane) nucleus partially or totally hydrogenated. By extension, steroids also include lipids whose cyclopentanophenanthrene ring has been modified by cleavage of a linkage and the addition or deletion of a carbon. These chemical molecules are complex and their synthesis is also complex. These molecules, however, have a very important medical interest.

The treatment of obesity is one of the biggest goals to meet the public health of the XXI ^century. According to WHO, more than one billion adults are said to be overweight worldwide, and of these, 300 million are reported to be obese. These numbers have been growing steadily for over 25 years. Obesity is responsible for 5 to 10% of all health costs in European countries.

In this context, the inventors are particularly interested in the synthesis of a derivative of the glycosylated steroid named P57 and which has anti-appetizing properties. This derivative is the aglycone of P57.

The extraction of this active principle from a plant called Hoodia gordonii is carried out with a very low yield, between 0.003% and 0.01% by weight, and since this plant is protected, it is almost impossible to access this molecule easily. Van Heerden et al., In the document WO 199846243, Steroidal glycosides, methods for their production and preparation, pharmaceutical compositions containing them, and their use as appetite suppressants [1], describe a process for the synthesis of this active ingredient which unfortunately leads to a synthesis yield not exceeding 0.1 mol%. It has since developed alternative methods but whose yield remains below 0.09 mol%. Therefore, this method is unusable. Thus, access to this product is very limited or impossible.

MacLean documents, David B .; Luo, Lu-Guang From Brain Research (2004), 1020 (1-2), 1 -1 1 [2], Dall'Acqua, Stefano; Innocenti, Gabbriella, Steroidal glycosides from Hoodia gordonii, From Steroids (2007), 72 (6-7), 559-568 [3], Pawar, Rahul S .; Shukla, Yatin J .; Khan, Shabana I .; Avula, Bharathi; Khan, Ikhlas A., New oxypregnane glycosides from herbal suppressant appetite supplement Hoodia gordonii, From Steroids (2007), 72 (6-7), 524-534 [4], Van Heerden, Fanie R .; Marthinus Horak, R .; Maharaj, Vinesh J .; Vleggaar, Robert; Senabe, Jeremiah V .; Gunning, Philip J., An appetite suppressant from Hoodia species, From Phytochemistry (Elsevier) (2007), 68 (20), 2545-2553 [5], Shukla, Yatin J .; Pawar, Rahul S .; Ding, Yuanqing; Li, Xing-Cong; Ferreira, Daneel; Khan, Ikhlas A., Pregnane glycosides from Hoodia gordonii, From Phytochemistry (Elsevier) (2009), 70 (5), 675-683 [6], Rubin ID, Cawthorne MA, Bindra JS Extracts, compounds & pharmaceutical compositions having anti- diabetic activity and their use, EP 1 166 792 [7], Horak RM, Maharaj V, Hakkinen J.

Steroidal glycosides or plant extracts for treatment of gastric acid secretion damage, GB 2 396 815 [8], Raskin I, O'Neal JM, III Pregnane-based appetite suppressing compositions obtained from Asclepias plant, WO2005099737 [9], and MacLean DB , Luo LG. in Increased ATP content / production in the hypothalamus may be a signal for energy-sensing of satiety: studies of the anorectic mechanism of a plant steroidal glycoside. Brain Res. 2004; 1020: 1 -1 1 [10] describe means of synthesis and utilities of this active ingredient and derivatives thereof, and therefore examples of the prospects that would present a synthesis route really improved over those known from the prior art.

In general, we encounter the same performance problems for access to steroids, whether they come from plants or animals or that they are totally synthetic.

Because of these difficulties of synthesis, the cost of these products is very important, sometimes prohibitive for some laboratories and research organizations, in particular of public research. In addition, the products obtained are not of sufficient purity for in vivo experiments, in particular because of the difficulties of synthesis and the chemicals used, generating the presence of toxic residues. Thus, the medical research on these products and their uses is really slowed down by the absence of an effective and "clean" protocol for the synthesis of these products.

In addition, Welzel has published a number of articles on this type of steroids implementing a Norrish Prins reaction describing the formation of a mixture of 12-alpha, 12-beta steroids and other secondary product, compound 12- Alpha being obtained mainly dissuading the skilled person to draw inspiration from this literature insofar as the latter aims to synthesize 12-beta steroids with the best possible yield.

There is therefore a real need for alternative methods of steroid synthesis and this need has existed for more than 15 years without anyone having found a satisfactory solution. There is, in addition, a real need to reduce the manufacturing costs of these products and to obtain products in a quantity and quality sufficient to be tested in vivo to facilitate medical research. Presentation of the invention

The present invention is specifically intended to meet all of these needs and disadvantages of the prior art by providing a process for synthesizing a 12-beta compound of formula (XIII) below:

OH

A 12 OH

(XIII)

or a spiro derivative thereof of formula (XI I Ibis) following:

(Xlllbis)

in which :

R ⁷ represents a substituent selected from the group consisting of H; a _C 1 _{-C 6} alkyl; aryl selected from the group consisting of benzyl, p-methoxybenzyl and benzoyl; an acetyl and a carbohydrate;

• R ⁴ represents a function - c = o or - CH - ^ OR ⁶

CH, CH.

wherein R is selected from the group consisting of acetyl, benzoyl, carbohydrate, o-aminobenzoyl, nicotinoyl, 2-methylbutyryl, isovaleryl, cinnamoyl, coumaroyl, o-hydroxybenzoyl, anthraniloyl;

The compound (XIII) comprising or not a double bond at the 5-6 and / or the 14-15 position, an OH function being present in the 14-beta position when there is no double bond in the 14-position; 15, preferably having a double bond in position 5-6, no double bond in position 4-5 and an OH function in position 14-beta;

The compound (XII Ibis) comprising or not a double bond in position 5-6, preferably comprising a double bond in position 5-6,

The substituents in positions 3 and 17 being in the 3-alpha or 3-beta and 17-beta position; and

from the compound of formula (XI) below:

(XI)

in which :

R ^4p represents (i) a function, said function

being protected by a protecting group selected from the group consisting of dioxalane, thioacetal, glycol;

or (ii) a function - CH - _^ OR ⁶

I

CH ₃

where R ⁶ is as defined above;

• R ⁷ is as defined above; and

The compound (XI) comprising or not a double bond in the 5-6 position, preferably having a double bond at the 5-6 position;

The substituents in the 3 and 17-beta positions being independently of each other in the alpha or beta position; and said method comprising a step of cleaving the 12-13 ring of the C ring in an aprotic medium by UV photochemical irradiation followed by a cycle C cyclization step. According to the invention, the cutting step allows the formation of an unsaturated seco aldehyde. According to the invention, in the step of cleaving the bond 12-13 of the ring C of the compound (XI) in an aprotic medium, the irradiation may be carried out, for example, at a wavelength greater than 200 nm and less than 400 nm. The irradiation can be carried out by means of any suitable apparatus known to those skilled in the art to irradiate at these wavelengths, for example, by means of a high-pressure mercury vapor lamp such as the Philips HPK lamp 125 ( trademark).

The reaction can take place in a reactor and the irradiation can be carried out in the reactor or from outside it. When it is carried out from the outside, the reactor is preferably chosen to pass the UV used. It is preferably a quartz reactor.

According to the invention, preferably, the irradiation is carried out for a time sufficient for the chemical transformation of the compound (XI) into compound (XII). This duration therefore depends in particular on the amount of compound (XI) to be transformed. It also depends on the homogenization conditions. The duration can be generally between 1 to 60 min, generally between 20 and 30 min.

According to the invention, preferably, the irradiation is carried out at a temperature of 10 ° C to 40 ° C, preferably 15 to 30 ° C.

Preferably, the irradiation is carried out in an aprotic organic solvent, preferably compatible with photochemistry. It may be for example a solvent selected from the group comprising dichloromethane, tetrahydrofuran, dioxane or a mixture thereof. Other solvents that can be used to carry out the present invention are also described, for example, in the documents Welzel P, Janssen B and Duddeck H. 14b-Hydroxy steroids. II. Prins reaction of lumihecogenin acetate. Liebigs Ann. Chem .; nineteen eighty one ; 546-64 [1 1]; Welzel P,

Stein H. 14b -Hydroxy steroids. III. Synthesis of digoxigenin from deoxycholic acid. Tetrahedron Lett .; nineteen eighty one ; 22: 3385-8 [12]; Milkova T, Stein H, Ponty A, Boettger D, Welzel P. 14b-Hydroxy steroids. VI. Synthesis of digitoxigenin. Tetrahedron Lett .; 1982; 23: 413-14 [13]; Welzel P, Moschner R, Ponty A, Pommerenk U, Sengewein H. 14b -Hydroxysteroids. V. Synthesis of digipurpurogenin I and II derivatives. Liebigs Ann. Chem .; 1982; 564-78 [14]; Welzel P, Stein H, Milkova T. 14b -Hydroxy steroids. VII. Synthesis of digoxigenin and digitoxigenin from deoxycholic acid. Liebigs Ann. Chem .; 1982; 19-34 [15]; LaCour TG, Guo C, Bhandaru S, Fuchs PL, Boyd MR. Interphylal Product Splicing: The First Total Syntheses of Cephalostatin 1, the North Hemisphere of Ritterazine G, and the Highly Active Hybrid Analog, Ritterostatin GN1 NJ Am. Chem. Soc; 1998; 120: 692-707 [16].

According to the invention, the compound (XI) can be present in the solvent at any concentration useful for carrying out the process of the invention, including on an industrial scale. According to the invention, it is preferably present in the organic solvent at a concentration of between 1 mM and 20 mM, for example between 5 and 10 mM.

Preferably, the solution of the compound (XI) in the organic solvent is degassed before the irradiation step to remove the oxygen. The degassing may be carried out by any means known to those skilled in the art, for example under a neutral gas, for example under argon.

The irradiation step may be followed by evaporation of the solvent used. This evaporation can be carried out by any means known to those skilled in the art, for example under reduced pressure, for example at a pressure of 1000 to 5000 Pa, for example at room temperature, for example at a temperature between 20 and 30 ° C. .

According to the invention, the step of cleaving the C-ring bond 12-13 in an aprotic medium is preferably carried out by means of a Norrish reaction, for example as described in one of the documents Welzel P et al. [1 1, 12, 14 and 15] and Milkova T et al. [13]. For example, it is carried out under the conditions indicated above. This Norrish Prins reaction is an extremely dependent substrate, making its outcome unpredictable to those skilled in the art from a given molecule. According to the invention, the cyclization step may be carried out by any appropriate means known to those skilled in the art. Preferably, it follows directly the step of cutting the bond 12-13, the compound resulting from the cutting step being unstable.

Preferably, this cyclization step is carried out in the presence of an oxygenated organic solvent and an acidic solution.

According to the invention, the oxygenated organic solvent may for example be chosen from the group comprising tetrahydrofuran (THF), dioxane and ether. Equivalent solvents or mixtures of these solvents or the like can also be used.

According to the invention, the acid solution may be, for example, an acid mixture (s) / water. It may be for example a solution of AcOH / H ₂ O / CF ₃ COOH (TFA), for example in proportions, expressed in volume, 1 to 3 / 0.5 to 1, 5/0, 3 to 0.9.

This reaction is preferably carried out with stirring, for example mechanical, preferably for a time sufficient to complete it. This time depends in particular on the amount of compound to be cyclized. It can be for example between 30 minutes and 3 hours, for example between 1 hour and 2 hours.

This cyclization can be carried out for example at a temperature of 15 to 30 ° C, generally at room temperature, for example 20 to 30 ° C.

According to the invention, the cyclization step is preferably carried out by means of a Prins reaction, for example as described in the documents Welzel P et al [11, 12, 14 and 15] and Milkova T, Stein H, Ponty A, Boettger D, Welzel P. 14b-Hydroxy steroids. VI. Synthesis of digitoxigenin. Tetrahedron Lett .; 1982; 23: 413-14 [13] and LaCour TG et al. [16]. For example, it is carried out under the conditions indicated above.

The separation of the compound (XIII) obtained can be carried out for example by simple decantation or any means known to those skilled in the art for this type of compound, for example by means of a simple separating funnel. The compound (XIII) can then be isolated, washed and dried in a conventional manner known to those skilled in the art for this type of compounds. The isolation of the compound (XIII) can be achieved, for example, by means of ether or any suitable equivalent solvent. The washing can be carried out, for example, by means of a saturated aqueous solution of NaHCO 3 and / or NaCl and / or of any solution known to those skilled in the art for this washing. Compound (XIII) may be dried, for example, by means of sodium or magnesium sulphate or any equivalent product. It can then be concentrated according to conventional techniques known to those skilled in the art, for example under reduced pressure, for example from 1000 to 5000 Pa, for example at a temperature slightly above ambient, for example from 30 to 40 ° C. vs. The compound (XIII) can be purified, for example, by chromatography on silica gel, for example using an elution solvent which is a cyclohexane or petroleum ether / ethyl acetate mixture.

High resolution mass spectrometric analyzes also made it possible to demonstrate spiro derivatives of the compound (XIII) produced by the process of the invention as defined above. These spiro derivatives would come from a deprotection of carbon 20 by acid hydrolysis of the dioxolane group, forming a dienol which in the presence of water leads to the formation of spiro derivatives. These spiro derivatives may be represented by the following general formula (XII Ibis):

(Xlllbis)

in which :

R ⁷ represents a substituent selected from the group consisting of H; a _C 1 _{-C 6} alkyl; aryl selected from the group consisting of benzyl, p-methoxybenzyl and benzoyl, acetyl and carbohydrate;

• the compound (Xlllbis) with or without a double bond in the 5-6 position, preferably a double bond in the 5-6 position.

Examples of spiro derivatives are presented in the "Examples" section presented below.

The inventors are indeed the first to have obtained under these conditions and from the compound (XI) a synthesis yield of the compound (XIII) greater than 20%, or even 31% or more, where the processes of the art previous record shows only a 2% yield.

According to the invention, preferably, the cyclization step directly follows the step of cutting the bond 12-13, the compound resulting from the cutting step being unstable. According to the invention, these two reactions can be carried out for example as described in one of the documents Welzel P et al [11, 12, 14 and 15] and Milkova T, Stein H, Ponty A, Boettger D, Welzel P 14-hydroxy steroids. VI. Synthesis of digitoxigenin. Tetrahedron Lett .; 1982; 23: 413-14 [13] and LaCour TG et al. [16].

The present invention also relates to a process for synthesizing a 12-beta steroid of formula (XV) below: .R

A B

(XV)

in which :

• R ⁷ is as defined previously;

R ² represents a substituent selected from the group comprising a ketone function; an OH; an OR ⁵ where R ⁵ is selected from the group consisting of _C 1 _{-C 6} alkyl, aryl selected from the group consisting of benzyl, p-methoxybenzyl, benzoyl; a tigloyle; an angeloy; acetyl; o-aminobenzoyl; nicotinoyl; 2-methylbutyryl; isovaleryl; a cinnamoyl; coumaroyle; o-hydroxybenzoyl; anthraniloyl;

• R ⁴ is as defined above;

The compound (XV) comprising or not a double bond in position 5-6 and / or in 14-15, an OH function being present in the 14-beta position when there is no double bond in position 14- 15, preferably having a double bond in the 5-6 position, no double bond in the 4-5 position and an OH function in the 14-beta position;

from a compound of formula (I) below:

In which

• R ⁴ and R ⁷ being as defined above and R2 being as defined above;

· The junction of the carbon rings A and B being cis or trans; preferably being in the cis position, and

said method comprising the steps of the method of the invention defined above, namely the cleavage of the C-ring bond 12-13 of the compound (XI) defined above in aprotic medium by UV photochemical irradiation followed by the cycle C cyclization step to obtain the compound (XIII) defined above. According to the invention, the compound (XV) can be chosen, for example from the group comprising pregnans and glycosylated pregnans. More broadly, it may be steroids corresponding to the formula of the compound (XV). These may be for example the compounds described in the document Deepak, D., Srivastav, S., Khare, A., Pregnane Glycosides from Fortschritte der Chemie Organizer Naturstoffe / Progress in the Chemistry of Organic Natural Products Vol. 71, 1997, pp 170-325, ISBN: 978-3-21 1-82850-2 (Springer Verlag) [17]. It may be for example also compounds described in documents Abdel-Sattar, E .; Shehab, NG; Ichino, C .; Kiyohara, H .; Ishiyama, A .; Otoguro, K .; Omura, S .; Yamada, H. Phytomedicine 2009, 16, 659-664 [18]; Abdel-Sattar, E .; Harraz, FM; Al-Ansari, SMA; El-Mekkawy, S .; Ichino, C; Kiyohara, H .; Ishiyama, A .; Otoguro, K .; Omura, S .; Yamada, H. Phytochemistry 2008, 69, 2180-2186 [19]; Abdel-Sattar, E .; Ahmed, AA; Hegazy, M.-EF; Farag, MA; Al-Yahya, MA-A. Phytochemistry 2007, 68, 1459-1463 [20]; Al-Yahya, MA-A .; Abdel-Sattar, E .; Guittet, EJ Nat. Prod. 2000, 63, 1451 -1453 [21]; Rizwani, GH; Usmanghani, K .; Ahmad, M .; Ahmed, VU Pharmazie 1995, 50, 426-8 [22]; Usmanghani, K .; Rizwani, GHJ Nat. Prod. 1988, 51, 1092-7 [23]; Tschesche, R .; Grimmer, G. Chem. Ber. 1955, 88, 1569-76 [24]; Tschesche, R .; Bruegmann, G .; Marquardt, HW; Machleidt, H. Justus Liebigs Ann. Chem. 1961, 648, 185-95 [25]; Tschesche, R .; Brugmann, G .; Snatzke, G. Tetrahedron Lett. 1964, 473-80 [26]; and Satoh, D .; Morita, J. Chem. Pharm. Bull. 1968, 16, 178-80 [27]. It may be, for example, hoodigogenin, digipurpurogenin I, digipurpurogenin II, caratuberside C, russeliosides (20R or 20S).

The operating conditions may be, for example, those described herein.

The inventors are indeed the first to have obtained under these conditions, and quite unexpectedly, from the compound (I) above, synthetic yields of (XV) greater than 2%, and even greater than 5%, where the methods of the prior art only show yields of less than 0.1%, as in Van Heerden et al. [1], generally between 0.003 and 0.01% as shown in particular by Dall'Acqua et al. [3], Pawar, Rahul S. et al. [4], Van Heerden et al. [5] and Shukla, Yatin J. et al. [6],

According to the invention, the process may further comprise a step of synthesizing the compound of formula (XI) from the following compound of formula (X): OH

B

RV ^'"" 4S

(X)

• R ^4p and R ⁷ being as defined previously; and

· The compound (X) with or without a double bond at the 5-6 position; preferably having a double bond in position 5-6;

The substituents at the 3, 12 and 17 positions being independently of each other in the alpha or beta position; and

said step consisting of Dess Martin oxidation.

The Dess-Martin reaction was used because all the other oxidation reactions, well known to those skilled in the art, were not working, such as, for example, the oxidation reaction using pyridinium dichromate. , or then worked poorly giving low yield.

This is a step of oxidation of the alcohol function at position 12 of the compound (X).

According to the invention, for the implementation of this step, a solution of the compound (X) may be prepared in an aprotic organic solvent, for example dichloromethane or chloroform.

This solution can then be treated with Dess Martin reagent, also called Dess Martin periodinane. This reagent is commercially available, for example from Alfa Aesar (Johnson Matthey company), under the reference L15779 (commercial reference).

The treatment may consist of a simple mixture of the solution of the compound (X) and the Dess Martin reagent. It is preferably carried out with stirring, for example mechanical, for example for 15 minutes at 2 o'clock. It can be carried out for example at a temperature of 20 to 30 ° C.

The compound (XI) obtained can then be washed, isolated and dried in a conventional manner known to those skilled in the art for this type of compounds, for example in a separating funnel. The washing may be carried out for example by means of a saturated aqueous solution of NaHCO 3 and / or NaCl and / or any solution known to those skilled in the art for washing this type of compound. The compound (XI) can be isolated by extraction using an aprotic organic solvent, for example dichloromethane or chloroform. It may then be dried, for example by means of sodium or magnesium sulphate or any equivalent product. It can also be concentrated, for example under reduced pressure, for example 1000 to 5000 Pa, for example at a temperature of 30 ° C to 40 ° C. The compound (XI) can be purified for example by chromatography on silica gel, for example using an elution solvent which is a cyclohexane or petroleum ether / ethyl acetate mixture.

The implementation of this oxidation step can be carried out for example as described in the document Dess, DB, Martin, JC Readily accessible 12-1-5 oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones J. Org . Chem. 1983, 48, 4155-4156 [28].

According to the invention, the process for synthesizing the compound (XV) may comprise, in addition, a step of synthesizing the compound of formula (X) from the following compound of formula (IX):

(IX)

R ^4p being as defined above; and

the compound (IX) having or not a double bond in the 5-6 position, preferably having a double bond in the 5-6 position;

the substituents in the 3 and 12 positions being independently of each other in alpha or beta position and the 17-position substituent in the 17-beta position; and

said step consisting of a selective protection in basic medium of the alcohol function in position 3 of the compound of formula (IX).

According to the invention, this selective protection can be achieved by any appropriate means known to those skilled in the art and allowing this regioselective protection. For example, one of the methods described in Weber, H., Khorona, H.G. J. Mol. Biol. 1972, 72, 219 [29]; Zhdanov, R.I., Zhenodavora, 1975, Synthesis, 222 [30]; Stork, G., Takahashi, T., Kawamoto, I., Suzuki, T. 1978, J. Am. Chem. Soc. 1978, 100, 8272 [31] and Ho, G., Steglich, W., Vorbruggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569 [32] can be used for this protection.

According to the invention, the selective protection reaction can be carried out in an aprotic organic solvent, for example dichloromethane or pyridine.

According to the invention, the selective protection can be carried out in the presence of an acylating agent, for example acetic anhydride or acetyl chloride, an amine base, for example pyridine, and a catalyst. for example dimethylaminopyridine (DMAP). According to the invention, when acetic anhydride is used, it is preferably used in a stoichiometric amount not exceeding 1, 2 times the compound (IX).

According to the invention, the selective protection reaction may be carried out with stirring, for example mechanical, for example for 1 to 5 hours, for example 2 to 4 hours.

According to the invention, this selective protection reaction can be carried out for example at a temperature of 15 to 30 ° C, for example 20 to 25 ° C.

The compound (X) obtained can then be isolated by extraction using an aprotic organic solvent, for example dichloromethane or chloroform. It may then be dried, for example by means of sodium or magnesium sulphate or any equivalent product. It can also be concentrated, for example under reduced pressure, for example 1000 to 5000 Pa, for example at a temperature of 30 ° C to 40 ° C. The compound (X) can be purified for example by chromatography on silica gel, for example using an elution solvent which is a cyclohexane or petroleum ether / ethyl acetate mixture. According to the invention, the process for synthesizing compound (XV) may further comprise a step of synthesizing the compound of formula (IX) from the following compound of formula (VIII):

B

R'O '

(VIII)

R ^4p and R ⁷ being as defined above; and • the compound (VIII) with or without a double bond in the 5-6 position, preferably having a double bond in the 5-6 position;

The substituents at the 3 and 12 positions being independently of each other in the alpha or beta position and the substituent in the 17-position being in the 17-beta position; and

said step consisting of a hydrolysis in basic medium of the acetate function at position 12 of the compound of formula (VIII).

According to the invention, the hydrolysis can be carried out for example by any of the methods described in Plattner, J., J., Gless, R.D., Rapoport, H. J. Am. Chem. Soc. 1972, 94, 8613 [33].

Preferably, it is carried out in the presence of an inorganic base. It may be for example a base selected from KOH, NaOH, K 2 CO 3, preferably KOH. It may also be carried out using a reducing agent, for example lithium aluminum hydride in an oxygenated solvent such as tetrahydrofuran (THF).

According to the invention, the hydrolysis is preferably carried out in an alcoholic medium. It may be for example a C1-C6 alcohol, for example an alcohol selected from the group comprising methanol, ethanol, propanol, butanol, pentanol, hexanol.

This reaction is preferably carried out by refluxing the solution of the organic solvent and the compound (VIII) for a time sufficient to complete the hydrolysis. This time depends in particular on the amount of compound to be hydrolysed. It may be for example between 30 minutes to 6 hours, for example between 3 and 5 hours. The reflux temperature depends in particular on the alcohol used, generally from 65 to 184 ° C. with the abovementioned alcohols.

Then, preferably after cooling, the compound (XI) can be extracted. For this, one can add water to the reaction medium and extract the compound (XI) by means of an organic aprotic extraction solvent such as those mentioned above, for example dichloromethane. Drying and concentration of the compound (XI) can to be carried out under reduced pressure, for example under the conditions indicated above to extract the other compounds.

According to the invention, the compound (XI) must not be placed in an acid medium, even if it is weak.

According to the invention, the process for synthesizing compound (XV) may further comprise a step of synthesizing the compound of formula (VIII) from the following compound of formula (VII):

A 5 B

4 6

(VII)

R ^4p being as defined above and R2 being as defined above;

The substituent in the 3 and 12 positions being in the alpha or beta position and the substituent in position 17 being in the 17-beta position; and

said step consisting of a reduction of dienol acetate.

According to the invention, this reduction of the dienol acetate is preferably carried out in the presence of a large stoichiometric excess of reducing agent, preferably a very large excess, for example between 10 and 25 equivalents (in mmol). The reducing agent may for example be NaBH or Ca (BH) ₂ or an equivalent reducing agent known to those skilled in the art.

According to the invention, this reduction is preferably carried out in an alcoholic medium, for example with a C1-C6 alcohol, for example an alcohol selected from the group comprising methanol, ethanol, methanol and the like. propanol, butanol, pentanol, hexanol or a mixture of two or more thereof. According to the invention, preferably, the alcohol is MeOH.

According to the invention, the reduction is preferably carried out in an alcohol / polar aprotic solvent mixture. The alcohol can be as defined above. The polar aprotic solvent may be selected from the group consisting of acetonitrile (CH ₃ CN), dimethyl sulfoxide (DMSO, (CH ₃ ) ₂ SO), tetrahydrofuran (THF, C ₄ H ₈ O), N, N '. Dimethylformamide (DMF), preferably THF. According to the invention, the mixture is preferably an alcohol / polar aprotic solvent mixture in proportions of 0.5 to 1.5 / 1.5 to 0.5.

According to the invention, the implementation may consist of a simple mixture of the compound (VII) in the alcoholic medium or alcohol mixture / aprotic polar solvent, in the presence of the reducing agent. It can be carried out with stirring, for example mechanical. It can be carried out for example at a temperature of 20 to 30 ° C.

According to the invention, it is preferable to follow the evolution of the reduction reaction by thin layer chromatographic analysis, in order to avoid the formation of the diol which is more difficult to eliminate when silica chromatography is used to isolate the compound (VIII) synthesized.

The reaction can be stopped by addition of an acid, preferably mineral, for example HCl, for example 5 to 15% or any other equivalent acid, until a neutral pH is obtained.

The compound (VIII) is in the organic phase of the reaction medium and can be recovered for example by extraction using an organic solvent, for example tetrahydrofuran or an equivalent solvent. The compound (VIII) can then be dried, for example as indicated above, and concentrated, for example at reduced pressure for example under the conditions indicated above to extract the other compounds. The compound (VIII) can be purified for example by chromatography on silica gel, for example using a solvent elution which may be a mixture of petroleum ether / ethyl acetate, for example in proportions 70/30 expressed by volume.

For the implementation of this step of reduction of dienol acetate, the process described in Takahashi, K., Usami, K., Takahashi, T., Okada, T., Morisaki M. Chem. Pharm. Bull. 1987, 35, 3467-69 [34] may for example be used.

According to the invention, the process for synthesizing compound (XV) may further comprise a step of synthesizing the compound of formula (VII) from the following compound of formula (VI):

(VI)

R ⁴ being a CH ₃ CO- group, R2 being as defined above and R ⁷ being as defined above; and

• the compound (VI) with or without a double bond in positions 3-4 and 5-6, preferably having a double bond in the 5-6 position;

The substituents in the 3 and 12 positions being independently of each other in the alpha or beta position and the substituent at position 17 being in the 17-beta position,

said step consisting in protecting the ketone function at position 20 of the compound of formula (VI). According to the invention, the protection of the ketone function can be carried out by any method known to those skilled in the art, for example in using the method described in Crimmins, MT, DeLoach, JAJ Am. Chem. Soc. 1986, 108, 800 [35] or in Tsunoda, D., Suzuki, M., Noyori, R. Tetrahedron Lett. 1980, 21, 1357 [36].

According to the invention, the protection of the ketone function is preferably carried out in the presence of an acid catalyst. According to the invention, preferably, the catalyst is pyridinium p-toluene sulfonate (PPTS).

Preferably, the para-toluenesulphonic acid (APTS) is not used because it leads to the formation of a di-protected diketone at the 3 and 20 positions.

The reaction medium for carrying out this step may be prepared for example by bringing the compound (VI) in solution in an organic solvent, for example an aromatic solvent, for example a non-functionalized aromatic hydrocarbon, for example toluene, and by adding a diol, for example ethylene glycol, and an acid catalyst, for example pyridinium para-toluene sulfonate (PPTS).

For the protection reaction, the medium may for example be refluxed, for example on a Dean Stark (trademark) apparatus. The reaction time, for example during reflux heating, depends in particular on the amount of compound to be protected and the operating conditions. This time can be for example from 1 to 5 hours, at a temperature of 80 ° C to 130 ° C. Then, the solvent, for example toluene, can be evaporated under reduced pressure, for example at a pressure of 1000 to 5000 Pa. The solvent evaporation temperature depends in particular on the solvent, it can be for example 40 to 60 ° C, especially for toluene.

The compound (VII) obtained can then be washed, isolated and dried in a conventional manner known to those skilled in the art for this type of compounds, for example by means of a separating funnel. The washing may be carried out for example by means of a saturated aqueous solution of NaHCO 3 and / or NaCl and / or any solution known to those skilled in the art for washing this type of compound. The compound (VII) can be isolated by extraction using an aprotic organic solvent such as those mentioned above, for example dichloromethane. It can then be dried, for example by means of sodium sulphate or any equivalent product. It can finally be concentrated, for example under reduced pressure, for example 1000 to 5000 Pa, for example at a temperature of 30 ° C to 40 ° C.

According to the invention, the process for synthesizing the compound (XV) may further comprise a step of synthesizing the compound of formula (VI) from the following compound of formula (V):

(V)

R ⁴ being as defined above and R2 being as defined above;

The substituents in the 12-position being in the 12-alpha or 12-beta position and the 17-position substituent in the 17-beta position,

said step consisting of an enolization of the enone function.

This step consists in introducing into the compound of formula (V) a double bond in ring B at position 5-6.

According to the invention, this enolization can be carried out for example with a solution of the compound (V) in an anhydride, for example acetic anhydride.

According to the invention, an acid halide, for example an acid chloride, for example acetyl chloride, may be added to this solution. According to the invention, the enolization is preferably carried out at a temperature allowing reflux, for example, with acetic anhydride and acetyl chloride, by heating at a temperature of 30 to 70 ° C, for example 40 to 60 ° C.

According to the invention, the reflux can be maintained for a time sufficient to enolise the compound (V), which depends in particular on the reagents used and the amount of compound (V) to be reacted, generally from 30 minutes to 2 hours.

Preferably, the enolization reaction is preferably carried out in the absence of water under vacuum.

Alternatively or in addition to the aforementioned operating conditions, this enolization step can be carried out for example according to a protocol known to those skilled in the art, for example as described in the document Wendler, N.L., Reichstein, T., Helv . Chim. Acta 1948, 31, 1713 [37].

The compound (VI) can be recovered preferably after cooling, for example at a temperature of 20 to 30 ° C, preferably of 5 to 20 ° C, and concentrated for example under reduced pressure, for example from 1 to 100 Pa ( 10 ^"2 mbar at 1 mbar), preferably at a temperature of 5 to 20 ° C. Higher temperatures can lead in some cases to decomposition of the product Excess reagents and byproducts are volatile and can advantageously be removed Preferably, the recovery of the compound (VI) is carried out in the absence of water, in order to avoid a backtracking of the chemical reaction leading to the formation of the compound (V).

The compound (VI) obtained can be purified, for example by chromatography, for example at medium pressure, for example between 200,000 and 1,600,000 Pa (between 2 and 16 bar), for example on silica gel. According to the invention, the process for synthesizing compound (XV) may further comprise a step of synthesizing the compound of formula (V) from the following compound of formula (IV):

VS

AT

(IV)

R ⁴ being as defined above and R2 being as defined above;

• X is a halogen;

The substituent in the 12-position being in the 12-alpha or 12-beta position and the 17-position substituent in the 17-beta position,

said step consisting of dehydrohalogenation of an alpha-haloketone.

This step consists of forming an enone in ring A as shown by the formula of compound (V).

According to the invention, in the compound (IV), the halogen "X" may be chosen for example from the group comprising fluorine, chlorine, bromine and iodine.

According to the invention, the dehydrohalogenation is preferably carried out in an aprotic polar solvent, for example as those mentioned above, for example DMF, in the presence of a lithium salt, for example LiCl or a non-nucleophilic base, for example an aminated base, for example collidine, especially 2,4,6-collidine. Preferably, it is carried out with DMF and LiCl.

According to the invention, the dehydrohalogenation is preferably carried out at a temperature allowing reflux, for example at a temperature of 120 to 170 ° C, for example 120 to 160 ° C, preferably 120 to 150 ° C, preferably 140 to 150 ° C when DMF and LiCl are used. This temperature depends in particular on the solvent chosen.

According to the invention, the heating allowing this reflux is maintained for a duration depending in particular on the amount of compound to be dehydrohalogenated. Generally, the duration is 1 to 2 hours.

According to the invention, for example when X is bromine, this dehydrohalogenation step is a dehydrobromination step.

Alternatively or in addition to the aforementioned operating conditions, this dehydrohalogenation step can be carried out for example according to one of the protocols described in the document Diassi, P.A., Fried, J., Palmere, R.M., Sabo, E.F. Am. Chem. Soc. 1961, 83, 4249-4256 [38].

The compound (V) is in the organic phase of the reaction medium and can be recovered for example by extraction using an organic solvent, for example ethyl acetate, ether or an equivalent solvent. The compound can be washed with water. The compound (V) may then be dried, for example as indicated above, for example on sodium sulphate, and concentrated, for example at reduced pressure for example under the conditions indicated above to extract the other compounds. The compound (V) may be purified by chromatography on silica gel, the eluting solvent may for example be a petroleum ether / ethyl acetate mixture, for example in proportions 80/20 expressed by volume.

The method of the invention allows this step to obtain yields greater than 65% for the compound (V).

According to the invention, the process for synthesizing compound (XV) may further comprise a step of synthesizing the compound of formula (IV) from the following compound of formula (III): vs

AT

R ⁴ being as defined above and R2 being as defined above;

said step consisting of regioselective alpha-halogenation at the 4-position of the compound of formula (III). This step consists of the formation of a haloketone as indicated in the formula of compound (IV) above.

According to the invention, the junction of rings A and B is cis and the halogenation is regioselective in position 4, it is not in position 2. This regioselectivity could be explained by the preferential formation of the enol in position 3 -4, compared to that of the enol in position 2-3 following a weaker interaction between the axial methyl in position 10 and the axial hydrogen in position 6.

According to the invention, this reaction can be carried out, for example, from an acid solution of the compound (III), for example acetic acid.

According to the invention, to this acid solution may be added an acid solution of halogen, for example as defined above. The solution may be, for example, a solution of acetic acid at a concentration of 0.20 to 0.30 mol / l. The addition is preferably carried out with stirring, for example mechanical. The medium can be stirred, for example, for 30 minutes to 2 hours, generally 30 to 90 minutes. This time depends in particular on the amount of compound to be halogenated. The reaction may be carried out for example at a temperature of 5 to 25 ° C, preferably 15 to 25 ° C.

According to the invention, preferably, the amount of halogen is equal to or less than the stoichiometric amount useful for brominating the compound (III) in order to favor or even reserve the bromination in position 4. Preferably, this amount is less than or equal to to 1 equivalent. According to the invention, when the chosen halogen is bromine, this step is an alpha-bromination.

The solvent can then be evaporated, for example by means of a rotary evaporator, for example a water bath, for example at a temperature of 30 to 50 ° C.

Alternatively or in addition to the aforementioned operating conditions, this alpha-halogenation step can be carried out for example according to one of the protocols described in the document Diassi, P. A. et al [38].

The compound (IV) obtained can then be recovered in a suitable organic solvent known to those skilled in the art for this type of compound, for example dichloromethane, and then washed and dried, for example as indicated above for the other compounds.

According to the invention, the process for synthesizing compound (XV) may further comprise a step of synthesizing the compound of formula (III) from the following compound of formula (II):

(he) R2 being as defined above and R ⁴ being as defined above;

said step consisting of an oxidation of the -OH group at the 3-position of the compound of formula (II).

This step makes it possible to form a carbonyl in position 3 of the compound of formula (II).

According to the invention, the oxidation can be carried out, for example, in an organic solvent, for example acetone, or an equivalent solvent, in the presence of an oxidizing agent, for example a chromium salt or equivalent, for example in the presence of Jones reagent. Jones's reagent is well known to those skilled in the art. It can be prepared for example by dissolving CrO 3 in concentrated sulfuric acid and expanding with water. When Jones' reagent is used, the organic solvent is acetone.

A solution of the compound (II) can be prepared in the organic solvent and then the oxidant can be added. The whole is preferably stirred, for example mechanical. Water may then be added to effect the treatment of the reaction crude by extraction with ether and neutralization with NaHCO ₃ .

According to the invention, the duration of the reaction depends in particular on the reagents in the presence and on the amount of compound of formula (II) to be oxidized. Generally, the duration of this reaction may be between 30 minutes to 2 hours.

According to the invention, the reaction temperature may be for example 5 to 40 ° C, for example 20 to 25 ° C.

According to the invention, water is then added to obtain the compound of formula (III) by hydrolysis. The reaction medium comprises an aqueous phase and an organic phase. The aqueous phase can be extracted for example by means of an extraction solvent of the aqueous phase, for example by means of ether, and the organic phase comprising the compound (III) washed, dried and concentrated, for example as indicated above.

Alternatively or in addition to the aforementioned operating conditions, this oxidation step can be carried out for example according to one of the protocols described in the document Bowden, K., Heilbron, I.M., Jones, E.H.R., Weedon, B.C.L. J. Chem. Soc. 1946, 39-45 [39].

According to the invention, the process for synthesizing the compound (XV) may further comprise a step of synthesizing the compound of formula (II) from the compound of formula (I) as defined above, said step consisting of a Regioselective deprotection of the -OAc group in position 3 of the compound of formula (I).

This deprotection step consists of a saponification or hydrolysis reaction leading to removing the protection of the alcohol function in the 3-position of the compound of formula (I).

According to the invention, it may be carried out, for example, in an alcohol medium, for example such as those mentioned above, for example chosen from methanol, ethanol, propanol and butanol in basic medium, for example potassium carbonate or sodium carbonate. sodium.

According to the invention, this step is preferably carried out with stirring, for example mechanical.

According to the invention, it can be carried out at a temperature of 5 to 40 ° C, for example 20 to 25 ° C.

According to the invention, the duration of the reaction depends in particular on the reagents in the presence and on the amount of compound of formula (I) to be deprotected. Generally, the duration of this reaction may be between 30 minutes to 2 hours. According to the invention, water is then added to obtain the compound of formula (II) by hydrolysis.

The reaction medium comprises an aqueous phase and an organic phase. The aqueous phase can be extracted for example by means of ether and the organic phase comprising the compound (II) washed, dried and concentrated, for example as indicated above. The compound can be purified for example by chromatography, for example on silica gel.

Alternatively or in addition to the aforementioned operating conditions, this deprotection step can be carried out for example according to one of the protocols described in the document Plattner, J, J. et al [33].

According to the invention, the process for synthesizing the compound (XV) may further comprise a step of forming a tigloyl derivative in the 12-beta position from the compound of the following formula (XIII):

(XIII)

R ⁴ and R ⁷ being as defined in claim 1, the tigloyl derivative being a 12-beta compound of formula (XIV) different from the 12-beta compound (XIII) in that the OH at position 12 is replaced by a tigloyl.

According to the invention, the formation of this tigloyl derivative leads to a compound (XIV) which differs from the compound (XIII) in that the OH in the 12-position is replaced by a tiglic.

According to the invention, the formation of this tigloyl derivative can be carried out, for example, from a solution of the compound (XIII) in an aprotic organic solvent, for example dichloromethane or one of those mentioned above. To this solution may be added a tigloyl halide solution, for example tigloyl chloride, and an amine base, for example pyridine. A catalyst may also be added, for example 4-dimethylaminopyridine (DMAP).

According to the invention, the tigloyl halide can be prepared by any method known to those skilled in the art, preferably by the method described in Torres-Valencia, JM, Cerda-Garcia-Rojas, CM, Nathan, PJ . Tetrahedron Asymmetry 1998, 9, 757-764 [40].

According to the invention, the reaction medium thus formed can be heated under reflux for a period of 5 to 10 hours, and then cooled to ambient temperature, namely 20 ° C. to 30 ° C., to be stirred, for example mechanically, for a period of 5 to 10 hours. duration of 15 to 30 hours.

According to the invention, this stirring step can also be carried out for 5 to 10 hours at a temperature of 40 to 60 ° C, for example 45 to 55 ° C, and then for 10 to 20 hours at a temperature of 20 ° C at 30 ° C.

According to the invention, water can then be added to hydrolyze the excess acid chloride.

According to the invention, the reaction medium at the end of the tigloyie derivative formation step comprises an aqueous phase and an organic phase. The aqueous phase can be extracted, for example by means of ether, and the organic phase comprising the compound (XIV) washed, dried and concentrated, for example as indicated above. The extraction solvent can be, for example, an aprotic organic solvent, for example dichloromethane. The washing of the organic phase can also be carried out for example by means of a solution of 5 to 15% hydrochloric acid and then a solution of sodium hydrogencarbonate. The drying can also be carried out for example by means of sodium or magnesium sulphate.

The compound (XIV) can be purified for example by chromatography, for example on silica gel. The elution can be carried out for example by means of cyclohexane and / or ethyl acetate. Alternatively or in addition to the aforementioned operating conditions, this deprotection step can be carried out for example according to one of the protocols described in the document Plattner, J, J. et al [33].

According to the invention, the process for synthesizing the compound (XV) may also comprise a step of regioselective saponification at the 3-position of the 12-beta compound of formula (XIV) with formation of the 12-beta compound of formula (XV) defined above. This reaction consists in hydrolyzing the acetate function of the compound (XIV) in position 3.

For this, according to the invention, the compound (XIV) may for example be dissolved in alcohol, for example an alcohol as defined above, for example methanol. This alcoholic solution can be treated with a base, for example potassium carbonate, sodium carbonate.

According to the invention, this treatment can be carried out with stirring, for example mechanical, for example at a temperature of 15 ° C to 25 ° C, for example for a period of 1 to 3 hours, preferably less than 2 hours.

After this treatment, water can be added to stop the reaction.

According to the invention, the reaction medium at the end of this hydrolysis step also comprises an aqueous phase and an organic phase. The aqueous phase can be extracted, for example by means of dichloromethane, and the organic phase comprising the compound (XV) washed, dried and concentrated, for example as indicated above. The drying can also be carried out for example by means of sodium or magnesium sulphate. The compound (XV) obtained can be purified, for example by chromatography, for example on silica gel. The elution can be carried out for example by means of cyclohexane and / or ethyl acetate.

According to the invention, whatever the method used, the 12-beta compound of formula (XV) is as defined above, it may for example be selected from the group consisting of pregnans and glycosylated pregnans. The synthesis yields of this compound (XV) by the process of the invention are much higher than those of the processes of the prior art, at least 10 or even 100 times higher than those of the prior art on the numerous experiments. performed.

The present invention also relates to the intermediates of formula (XI), (X), (IX), (VIII), (VII), (VI) and to the spiro 12-alpha derivatives of the compound of formula (XI I Ibis) obtained by carrying out the process of the present invention. These reaction intermediates may be used, for example, as starting material for the synthesis of compound (XV). The synthesis of these reaction intermediates is described above, and, below, in the section relating to the exemplary implementation protocols of the present invention. The industrial applications of these compounds are those described herein and in particular in the document Van Heerden et al. [1].

The present invention therefore provides a steroid synthesis method to reduce the manufacturing costs of these products and to obtain products in an amount and quality sufficient to be tested in vivo to facilitate medical research.

The process of the invention gives access to products of very high purity, greater than 90% by analysis by gas chromatography and mass spectrometry (GC / MS), facilitating research in vivo, which had never been possible until now for the aforementioned molecules, or else at too high costs.

In addition, the present invention provides access to steric analogs that were almost impossible to obtain by the prior art methods, giving access to new synthetic molecules, including reaction intermediates, opening the way to the research on new therapeutic molecules potentially more effective and less toxic than those known to those skilled in the art. Other features and advantages will become apparent to those skilled in the art on reading the examples below, given by way of illustration and not limitation.

EXAMPLES

In the examples below, the melting points were measured using a Stuart Scientific SMP 3 (trademark) apparatus. Thin layer chromatography (TLC) was performed on Merck 60254 silica gel plates (commercial reference) and the spots were visualized under a UV lamp (254 or 365 nm) and / or sprayed with a vanillin solution (25). g) in EtOH / H ₂ SO ₄ (98/2; 1 L) or with a solution of phosphomolybdic acid (25 g of phosphomolybdic acid, 10 g of cerium sulphate, 60 mL H ₂ SO ₄ , 940 mL H ₂ O) followed by hot plate heating. For column chromatography Merck Si 60 40-60 silica gel was used. Infrared spectra were recorded on a Bruker ATR (trademark) spectrometer. 1 H NMR spectra were recorded at 300 MHz (Bruker AT-300) 13 C NMR spectra at 75 MHz (Bruker AC-300) using the non-deuterated residual solvent signal as an internal reference. The significant 1 H NMR values were tabulated in the following order: chemical shift (alpha) expressed in ppm, multiplicity (s, singlet state, d, doublet, t, triplet, q, quartet, m, multiplet), constants of coupling in hertz, number of protons. The microanalyses (Elementar Vario device (trade mark) were realized by the Joint Microanalysis Service of the Institute of Chemistry, Strasbourg.High resolution mass spectrometry (HRMS) was carried out on Agilent 6520 Accurrate Mass Q-TOF (Trademark).

Example 1: Synthesis of (EH (3S, 10R, 12R, 13S, 14S, 17S) -17-acetyl-3,14-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10, 11,12,13,14,15,16,17- tetradecahydro-1H-cyclopentaralphenantren-12-yl) 2-methylbut-2-enoate (Hoodigogenin A) a) Regioselective deprotection of the 3oOAc group: saponification or hydrolysis reaction

A solution of compound 1 (commercial: Steraloids-USA ref P-6470-000) (3.37 g, 8.05 mmol, 1 eq) was prepared in MeOH (80 ml), and K ₂ CO ₃ ( 1.00 g, 7.24 mmol, 0.9 eq) was added.

The mixture is stirred magnetically for 1 hour at a temperature of 25 ° C and then 50 ml of water is added to the reaction mixture.

The aqueous phase was extracted with ether (Et ₂ O 3x60mL). The ethereal phases were combined in a separating funnel washed once with 50 ml of a saturated sodium chloride solution (NaCl), dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (35.degree. 20 mbar). A white residue was obtained. This residue was purified by medium pressure chromatography (pump ProMinent Type BT4A (trademark)) on silica gel (30 g S1O2, EP / AcOEt 70/30 v / v), to isolate 2.48 g of compound 1A (5.59mmol), in solid form. The product was obtained with a yield of 83%.

(3R, 5R, 10S, 12S, 13S, 17S) -17-acetyl-3-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-12-yl acetate

Compound 1A: compound II of the claims

M = 376.53 g / mol Characteristics of the compound 1A:

Reaction type: saponification reaction

300 MHz NMR spectrum, CDC

5.12 (t, 1H, 12β-Η, J = 2.7 Hz); 3.63 (1H, tt, J 10.9-6.6, 3β-Η); 2.95 (1H, t, J 9.3, 17a-H); 2.20 - 2.05 (4H, m, with s at 2.14, 21 -H); 2.01 (3H, s, OAc); 1.95-0.85 (23H, m, with s at 0.89, Me); 0.6 (3H, s, Me).

13C NMR spectrum: 75 MHz, CDCl3

208.9 (C = O, 20-C); 170.5 (C, OAc); 74.5 (CH, 3-C); 71.6 (CH, 12-C); 55.6 (CH); 49.6 (CH); 46.7 (C); 41.9 (CH); 36.2 (CH ₂ ); 35.6 (CH); 35.0 (CH ₂ ); 34.5 (CH); 34.1 (C); 31, 1 (CH ₃ ); 30.4 (CH ₂ ); 27.0 (CH ₂ ); 26.0 (CH ₂ ); 25.6 (CH ₂ ); 23.7 (CH ₂ ); 23.0 (CH ₃ ); 22.3 (CH ₂ ); 21, 4 (CH ₃ ); 13.8 (CH ₃ ).

IR spectrum: ν (OH) = 3472 cm ^-1

v (C = O) = 1714-1696 cm ^-1

Mass for C? ₃ H ₃ _R ₄ O calculated% C,% H: C, 73.37; H, 9.64; M: 17.00 found% C,% H: C: 73.98-73.62; H: 9.892-9.991

HR-MS: 377.27 (MH +)

OD = + 154

R 201, 5- 203.8 ° C

Rf (EP / AcOEt, 60/40): 0.17

b) Oxidation of the 3-OH group

A solution was prepared from 1 g of compound 1A

(2.66 mmol, 1 eq.) In 60 ml of acetone at 0 ° C. and 2.7 ml of Jones reagent were added thereto.

To obtain the Jones reagent, 26.72 g of CrO ₃ are dissolved in 23 mL of concentrated H ₂ SO ₄ and then diluted with water to a volume of 100 mL. An orange solution was obtained and left for 1 hour with magnetic stirring at an ambient temperature of 25 ° C. Then 50 ml of water were added to this solution.

The aqueous phase was extracted 3 times with 50 ml of ether (Et ₂ O). The organic phases were combined in a separatory funnel, washed once with 50 ml of a saturated sodium bicarbonate solution (NaHCO 3), then 1 time with 50 ml of a saturated sodium chloride solution (NaCl), dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (35 ° C, 20 mbar).

0.99 g of compound 2 (2.66 mmol, quant.) Were obtained in solid form. This compound was used without purification in the next step below.

(5R, 10S, 12S, 13S, 17S) -17-acetyl-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-12-yl acetate

Compound 2: compound III of the claims

M = 374.23 g / mol

Characteristics of Compound 2:

Reaction type: oxidation reaction

300 MHz NMR spectrum, CDC

5.16 (1H, t, J 2.7, 12β-Η); 2.93 (1H, t, J 9, 17a-H); 2.63 (1H, dd, J 13.5-15.3); 2.30-1.05 (25H, m, with s at 2.1 L, 21H and s at 2.00, OAc); 0.98 (3H, s, Me); 0.70 (3H, s, Me). NMR spectrum C: 75 MHz, CDCl ₃

212.6 (C = O, 3-C); 208.6 (C = O, 20-C); 170.3 (C, OAc); 74.3 (CH, 12-C); 55.5 (CH); 49.5 (CH); 46.7 (C); 43.8 (CH); 42.1 (CH ₂ ); 36.8 (CH ₂ ); 36.5 (CH ₂ ); 35.3 (CH); 34.7 (CH); 34.3 (C); 31, 1 (CH ₃ ); 26.3 (CH ₂ ); 25.9

(CH ₂ ); 25.7 (CH ₂ ); 23.6 (CH ₂ ); 22.3 (CH ₂ ); 22.3 (CH ₃ ); 21, 3 (CH ₃ ); 13.9 (CH ₃ ).

IR spectrum: ν (C = O): 1714- 1699 cm ^-1

Mass for C _? H ₄ O ₄ calculated% C,% H: C: 73.76% H: 9.15%

O: 17.09%

found% C,% H: C: 73.59-73.67; H: 8.948-8.952

HR-MS: 375.25 (MH ⁺ )

OD = + 147

R 124- 125.7 ° C

Rf (EP / AcOEt, 70/30): 0.24

c) Regioselective α-bromination at position 4 of compound 2

A solution was prepared from 2.14 g of compound 2 (5.71 mmol, 1 eq) in 60 ml of acetic acid (AcOH). To this solution, 0.29 ml of a Br ₂ solution (5.65 mmol, 0.99 eq) in 25 ml of acetic acid was added dropwise over 45 minutes.

After the end of the addition, the medium is stirred for 30 min at 25 ° C. The solvent was evaporated under reduced pressure (40 ° C, 2000 Pa, 20 mbar).

The residue was dissolved in 50 ml of dichloromethane (CH ₂ Cl ₂ ) and then washed 3 times with 30 ml of water.

The aqueous phases were combined and extracted twice with 50 ml of dichloromethane. The organic phases were combined in a separatory funnel, washed 3 times with 30 ml of saturated sodium bicarbonate solution (NaHCO ₃ ), dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (2000 Pa). 20 mbar) at a temperature of 35 ° C. 2.59 g of compound 3 (5.71 mmol, quant.) Were obtained in solid form. This solid was used without purification in the next step below.

(4R, 5S, 10R, 12S, 13S, 14S, 17S) -17-acetyl-4-bromo-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-12-yl acetate

Compound 3: compound IV of the claims

M = 453.21 g / mol Characteristics of compound 3:

Reaction type: α-bromination reaction of a carbonyl derivative

300 MHz NMR spectrum, CDCH

5.16 (1H, t, J 2.4, 12β-Η); 4.92 (1H, d, J, 1, 7, 4a-H); 2.92 (1H, t, J 9.3, 17a-H); 2.47 (1H, dt, J 3.9-14.4); 2.35-0.60 (29H, m, with s at 2.1 L, 21 -H, s at 2.00, OAc, s at 0.88, Me and s at 0.71, Me).

NMR ^{spectrum at} C: 75 MHz, CDCH

208.5 (C = O); 201, 8 (C = O); 170.2 (OAc); 74.1 (CH, 12-C); 59.5 (CH); 55.4 (CH); 53.9 (CH); 49.4 (CH); 46.6 (C); 37.6 (C); 36.3 (CH ₂ ); 36.2 (CH ₂ ); 35.8 (CH); 35.4 (CH); 31, 1 (CH); 26.0 (CH ₂ ); 25.4 (CH ₂ ); 24.7 (CH ₂ ); 23.6 (CH ₂ ); 2.9 (CH ₃ ); 22.4 (CH ₂ ); 21, 3 (CH ₃ ); 13.9 (CH ₃ ).

IR spectrum: ν (ester): 1726 cm ^-1

v (ketone): 1698 cm ^-1

Mass for C ₃ H ₃₃ O ₄ Br calculated% C,% H: C: 60.93% H: 7.34%

Br: 17.62% 0: 14.1 1%

d) Dehydrohalogenation of α-bromoketone (dehydrobromation): formation of an enone on cycle A

A solution was prepared from 2.6 g of compound 3

(5.73 mmol, 1 eq.) And 65 ml of distilled DMF. To this solution was added 1.20 g of lithium chloride (28.24 mmol, 4.9 eq.).

After 1 hour of refluxing at 153 ° C., the medium was concentrated under reduced pressure (1000 Pa, 10 mbar) at a temperature of 55 ° C.

The residue obtained was dissolved in 50 ml of AcOEt then washed 3 times with 30 ml of water.

The aqueous phases were combined and extracted 3 times with 30 ml of AcOEt. The organic phases were combined in a separatory funnel, washed once with 30 ml of a saturated sodium chloride solution (NaCl), dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (2000 Pa, 20 mbar) at a temperature of 35 ° C.

The residue was purified by chromatography pulsed under medium pressure (pump: ProMinent Type BT4A (trademark)) on silica gel (60 g of silica, EP / AcOEt 80/20 v / v), making it possible to obtain 1.43 g of compound 4 (3.84 mmol), in solid form. The product was obtained with a yield of 67%.

(10R, 12S, 13S, 17S) -17-acetyl-10,13-dimethyl-3-oxo-2,3,6,7,8,9,10,1 1,12,13,14,15,16 , 17-tetradecahydro-1H-cyclopenta [a] phenanthrene-12-yl acetate Compound 4: Compound V of the claims

M = 372.33 g / mol

Characteristics of compound 4:

Reaction type: deshydrobromination reaction (HBr removal) 300 MHz NMR spectrum, CDCH

5.71 (1H, s, 4-H); 5.15 (1H, t, J 2.7, 12β-Η); 2.91 (1H, t, J 9, 17a-H); 2.40- 0.60 (29H, m, with s at 2.16, 21 -H, s at 2.00, OAc, s at 1, 14, Me and s at 0.72, Me).

NMR ^{spectrum at} C: 75 MHz, CDCH

208.5 (C = O, 20-C); 199.1 (C = O, 3-C); 170.2 (C = C, 5-C); 170.0 (OAc); 124.1 (CH, 4-C); 74.3 (CH, 12-C); 55.3 (CH, 17-C); 48.7 (CH), 47.9 (CH); 46.4 (C); 38.0 (C); 35.7 (CH); 35.6 (CH ₂ ); 33.8 (CH ₂ ); 32.6 (CH ₂ ); 31.6 (CH ₂ ); 31, 1 (CH ₃ ); 25.6 (CH ₂ ); 23.6 (CH ₂ ); 22.2 (CH ₂ ); 21, 2 (CH ₃ ); 17.1 (CH ₃ ); 13.7 (CH ₃ ).

IR spectrum: ν (C = O): 1729-1700-1665 cm ^-1

v (C = C): 1618 cm ^-1

MS: 373.24 (MH ⁺ )

OD = + 217

F: 147-151 ° C Rf (EP / AcOEt, 60/40): 0.40 visible in UV

e) Enolization of enone function: introduction of a double bond in cycle B, formation of dienol acetate

A solution was prepared from 2.80 g of compound 4 (7.50 mmol) and 18 ml of acetic anhydride (AC ₂ O). 30 ml of acetyl chloride (AcCl) was added to this solution.

This solution was refluxed for 1 hour at 52 ° C. After returning to a temperature of 25 ° C. (room temperature), the medium was concentrated under reduced pressure (10 ^-2 mbar) without heating, at 25 ° C. (room temperature).

The residue was purified by medium pressure chromatography (pump ProMinent Type BT4A (trademark)) on silica gel (100 g, SiO ₂ , EP / AcOEt 90/10 v / v), making it possible to obtain 2, 69 g of compound 5 (6.49 mmol), in solid form. The product was obtained with a yield of 85%.

(10R, 12S, 13S, 17S) -17-acetyl-10,13-dimethyl-2,7,8,9,10,1 1,12,13,14,15,16,17-dodecahydro-1H- cyclopenta [a] phenanthrene-3,12-diyl diacetate

Compound 5: compound VI of the claims

M = 414.53 g / mol Characteristics of Compound 5:

Reaction type: dienol formation

300 MHz NMR spectrum, CDCH

5.69 (1H, d, J 1, 8, 4-H); 5.39 (1H, d, J 3.6, 6-H); 5.18 (1H, t, J 3, 12β-Η); 2.94 (1H, t, J 8.7, 17a-H);

2.50-1.45 (20H, m, with s at 2.13, 21 -H, s at 2.11, OAc and s at 2.03, OAc); 1.45- 0.80 (7H, m, with s at 0.98, Me); 0.74 (3H, s, Me).

NMR ^{spectrum at} C: 75 MHz, CDCH

208.7 (C = O, 20-C); 170.4 (OAc); 169.4 (OAc); 147.1 (C = C); 139.2 (C = C); 132.4 (CH, C = CH); 16.8 (CH, C = CH); 74.3 (CH, 12-C); 55.4 (CH); 49.5 (CH); 46.5 (C); 42.4 (CH); 34.4 (CH ₂ ); 33.7 (C); 31.5 (CH); 31.4 (CH ₂ ); 31, 1 (CH ₃ ); 25.7 (CH ₂ ); 24.6 (CH ₂ ); 23.6 (CH ₂ ); 22.9 (CH ₂ ); 21, 3 (CH ₃ ); 21, 1 (CH ₃ ); 186 (CH ₃ ); 13.8 (CH ₃ ).

IR spectrum: ν (C = O): 1745-1726-1,700cm ^-1

v (alcene conj.): 1667 cm ^-1

HR-MS: 415.25 (MH ⁺ )

OD = + 2

134.7 to 137.5 ° C

Rf (EP / AcOEt, 70/30): 0.36 visible in UV

f) Protection of the ketone function in position 20: formation of a dioxolane

A solution was prepared from 635 mg of compound 5 (1.55 mmol, 1 eq) and 25 ml of toluene. To this solution was added 1.1L of ethylene glycol (20.03mmol, 13.2 eq), as well as pyridinium para-toluenesulfonate (10mg, 0.04mmol).

The medium was heated to reflux on a Dean Stark (trademark) device for 3h30. Toluene was evaporated under reduced pressure (2000 Pa, 20mbar) at a temperature of 50 ° C. The residue obtained was dissolved in 20 ml of dichloromethane and then washed twice with 20 ml of water.

The aqueous phases were combined and extracted twice with 20 ml of dichloromethane. The organic phases were combined in a separatory funnel, washed once with 20 ml of saturated sodium bicarbonate solution (NaHCO 3), dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (2000 Pa). , 20mbar) at a temperature of 35 ° C.

The residue was purified by medium pressure chromatography (pump ProMinent Type BT4A (trademark)) on silica gel (30 g SiO ₂ , EP / AcOEt 90/10 v / v), making it possible to obtain 702 mg of compound 6 (1, 53mmol, quantitative yield, in solid form.

(10R, 12S, 13S, 14R, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) -2,7,8,9,10,1,1,12 , 13,14,15,16,17-dodecahydro-1H-cyclopenta [a] phenanthrene-3,12-diyl diacetate

Compound 6: Compound VII Claims

M = 458.59 g / mol

Characteristics of compound 6:

Reaction type: protection reaction

300 MHz NMR spectrum, CDC

5.69 (1H, s, 6-H); 5.40 (1H, d, J 3, 4-H); 5.4 (1H, t, J 2.4, 12β-Η); 4.00 - 3.80 (4H, m, OCH ₂ ); 2.50-1.90 (10H, m, with s at 2.13, OAc and s at 2.04, OAc); 1.90-1.40 (1 OH, m); 1.40-0.90 (5H, m, with s to 1, 22, 21 -H); 0.99 (3H, s, Me); 0.88 (3H, s, Me).

13C NMR spectrum: 75 MHz, CDCl3

170.6 (OAc); 169.4 (OAc); 147.0 (C = C); 139.3 (C = C); 123.7 (C = CH);

1 16.7 (C = CH); 1 1 1, 4 (C, 20-C); 75.3 (CH, 12-C); 64.9 (CH2, acetal);

63.3 (CH2, acetal); 49.7 (CH); 49.2 (CH); 44.3 (C, 13-C); 42.5 (CH);

34.4 (CH2); 33.7 (10-C); 31.4 (CH2); 31.0 (CH); 25.4 (CH2); 24.7 (CH2); 24.0 (CH); 23.1 (CH2); 22.3 (CH2); 21, 4 (CH3); 21, 1 (CH3); 18.6 (CH3);

13.5 (CH3).

IR spectrum: v (C = O): 1733- 1680 cm ^-1

HR-MS: 459.27 (MH ⁺ )

Rf (EP / AcOEt, 70/30): 0.45 (visible in UV)

g) Reduction of dienol acetate (formation of deconjugated alcohol):

A solution was prepared from 2.01 g of NaBH ₄ (53 mmol) in 15 mL of methanol (MeOH) and 15 mL of tetrahydrofuran (THF). A solution of 1.38 g of compound 6 (3 mmol) in 5 mL of THF was added dropwise over 10 min.

The whole was stirred with a magnetic stirring bar for 1 h 30 at a temperature of 25 ° C (room temperature), then 2 mL of a 10% hydrochloric acid solution was added until a reaction was obtained. neutral pH.

The aqueous phase was extracted 3 times with 15 ml of dichloromethane (CH 2 Cl 2). The organic phases are combined in an Erlenmeyer flask then dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (35 ° C., 20 mbar).

The residue was purified by silica gel chromatography (30 g SiO ₂ , EP / AcOEt 70/30 v / v) to give 0.75 g (1.77 mmol). of compound 7 in solid form. The product was obtained with a yield of 59%.

(3S, 10R, 12S, 13S, 17S) -3-hydroxy-10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) -2,3,4,7,8, 9,10,1 1, 12,13,14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthrene-12-yl acetate

Compound 7: compound VIII of the claims

M = 418.57 g / mol

Characteristics of compound 7:

300 MHz NMR spectrum, CDC

5.35 (1H, s, 6-H-6); 5.12 (1H, s, 12-h); 4.00-3.75 (4H, m, acetal); 3.55- 3.40 (1H, m, 3a-H); 2.40-1.90 (4H, m); 2.04 (3H, s, OAc); 1.90-0.70 (15H, m); 1, 20 (3H, s, H-21); 0.98 (3H, s, Me); 0.84 (3H, s, Me).

NMR ^{spectrum at} C: 75MHz, CDCl3

170.6 (OAc); 140.7 (C = C, C-5); 121.5 (C = CH, C-6); 1 1 1, 4 (C, C-20); 75.4 (CH, C-3); 71, 6 (CH, C-12); 64.9 (CH ₂ , acetal); 63.3 (CH ₂ , acetal); 49.7 (CH); 48.9 (CH); 44.6 (CH); 44.2 (C); 42.2 (CH ₂ ); 37.2 (CH ₂ ); 31.5 (C); 31.5 (CH ₂ ); 31, 1 (CH); 25.3 (CH ₂ ); 24.1 (CH + CH ₃ ); 23.2 (CH ₂ ); 22.3 (CH ₂ ); 21, 4 (CH ₃ ); 19.2 (CH ₃ ); 13.4 (CH ₃ ).

IR: ν (OH): 3480 cm ^-1

v (OAc): 1702 cm ^-1

OD: +58

R 165.7-167.2 ° C Rf (EP / AcOEt, 60/40): 0.28

g-bis) Another experiment in the reduction of dienol acetate (formation of deconjugated alcohol):

A solution was prepared from 860 mg of NaBH ₄ (22.7 mmol) in 6 mL of methanol (MeOH) and 6 mL of tetrahydrofuran (THF). A solution of 540 mg of compound 6 (1.18 mmol) in 5 mL of THF was added dropwise over 10 min.

The whole was stirred with a magnetic stirring bar for 1 h 30 at a temperature of 25 ° C. (room temperature), then 1 ml of a 10% hydrochloric acid solution was added until a solution was obtained. neutral pH.

15ml of CH2Cl2 was added and the phases were separated.

The residue was purified by chromatography pulsed on silica gel (30 g SiO ₂ , EP / AcOEt 70/30 v / v), to obtain 0.333 g (0.80 mmol) of compound 7 in solid form. The product was obtained with a yield of 70%.

The characteristics of the product obtained are the same as those presented in the table above in section g). h) Hydrolysis of the acetate function in position 12:

A solution was prepared from 0.65 g of compound 7 (1.55 mmol) in 50 mL of methanol (MeOH). 2 g of KOH (35.64 mmol) was added to this solution.

This solution was refluxed for 4 hours at a temperature of 65 ° C. After returning to a temperature of 25 ° C

(room temperature), 20 mL of water was added. The aqueous phase was extracted 3 times with 20 ml of dichloromethane (CH 2 Cl 2). The organic phases were collected in an Erlenmeyer flask, dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (35 ° C., 20 mbar).

0.60 g of compound 8 (1.55 mmol, 100%) were obtained in solid form. This solid was used without purification in the next step below.

(3S, 10R, 12S, 13S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) -2,3,4,7,8,9,10, 1 1, 12,13,14,15,16,17-tetradecahydro-1H-cyclopena [a] phenanthrene-3,12-diol

Compound 8: compound IX of the claims

M = 376.53 g / mol

Characteristics of compound 8:

1 H NMR Spectrometer: 300 MHz, C6D6

5.35 (1H, m, 6-H); 4.01 (1H, t, J 3, 12β-Η); 3.60-3.30 (5H, m, acetal and 3a-H); 2.45-2.15 (3H, m); 2.00-0.80 (17H, m); 1, 21 (3H, s, 21-H); 0.92 (3H, s, Me); 0.87 (3H, Me).

13C NMR Spectrum: 75 MHz, C6D6

140.6 (C = C, 5-C); 121.6 (C = CH, 6-C); 12.2 (C, 20-C); 72.7 (CH, 12- C); 71.7 (CH 3 -C); 64.0 (CH2, acetal); 63.7 (CH2, acetal); 49.7 (CH); 48.0 (CH); 45.8 (C); 44.2 (CH); 42.3 (CH2); 37.0 (CH2); 36.1 (C); 31, 6 (CH); 31.3 (CH2); 31.2 (CH2); 27.6 (CH2); 23.8 (CH3); 23.1 (CH2); 22.9 (CH2); 19.2 (CH3); 13.9 (CH3).

IR spectrum: v (OH): 3460 cm ^-1

v (acetal): 1733 cm ^-1

OD: -25

R 133.0-135.2 ° C

Rf (EP / AcOEt, 60/40): 0.17

h-bis) Another experiment with hydrolysis of the acetate function at position 12:

A solution was prepared from 330 mg of compound 7 (1.15 mmol) in 15 mL of methanol (MeOH). 83 mg of KOH (1.48 mmol) was added to this solution.

This solution was refluxed for 1 h at a temperature of 65 ° C. After returning to a temperature of 25 ° C, 20 mL of water was added.

The aqueous phase was extracted 3 times with 20 ml of dichloromethane (CH 2 Cl 2). The organic phases were collected in an Erlenmeyer flask, dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (35 ° C., 20 mbar).

266 mg of compound 8 (0.71 mmol, 85%) were obtained in solid form. This solid was used without purification in the next step below.

The characteristics of the product obtained are the same as those presented in the table above in section h). i) Protection of the alcohol function in position 3 (selective protection)

A solution was prepared from 564 mg of compound 8 (1.51 mmol, 1 equivalent) in 25 mL of dichloromethane. To this solution was added 0.17 ml of distilled Ac2O (1.81 mmol, 1.2 equivalents), 0.24 ml. distilled pyridine (3.02 mmol, 2 equivalents), and 4-dimethylaminopyridine (DMAP) (10 mg, 0.08 mmol)

The medium was left for 2 hrs with magnetic stirring at a temperature of 25 ° C., then 20 ml of water were added to this reaction medium. The mixture thus obtained was poured into a separatory funnel and the organic and aqueous phases were recovered. The aqueous phase was extracted 3 times with 20 mL of dichloromethane.

The organic phases were combined in a separatory funnel, washed once with 20 ml of 10% HCl, once with 20 ml of saturated sodium bicarbonate solution (NaHCO 3) and dried over sodium sulphate (Na ₂ SO _4). ) and finally concentrated under reduced pressure (2000 Pa, 20 mbar) under a temperature of 35 ° C.

The residue was purified by medium pressure chromatography (pump ProMinent Type BT4A (trademark)) on silica gel (30 g of SiO ₂ , EP / AcOEt 70/30 v / v), making it possible to obtain 505 mg of compound 9 (1.21 mmol), in solid form. The product was obtained with a yield of 80%.

(3S, 10R, 12S, 13S, 17S) 12-hydroxy-10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) -2,3,4,7,8,9 , 10,1 1, 12,13,14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate

Compound 9: compound X of the claims

M = 418.58 g / mol Characteristics of compound 9:

[Type of reaction: reqioselective protection of the 33-hydroxy group 1H NMR Spectrum: 300 MHz, C ₆ D ₆

5.40-5.33 (1H, m, 6-H); 4.81 (1H, tt, 4.8-1, 3, 3a-H); 4.01 (1H, t, J 2.4, 12β-Η); 3.48 (4H, s, OCH ₂ ); 2.60 - 2.30 (3H, m); 2.00-0.80 (28H, m, with s at 1.75, OAc, s at 1, 22, 21 -H, s at 0.89, Me and s at 0.86, Me).

NMR spectrum 13C: 75 MHz, C _fi D _fi

169.3 (OAc); 139.5 (C, 5-C); 122.5 (CH, 6-C); 1, 1, 9 (C, 20-C); 73.6 (C, 12-C); 72.2 (CH, 3-C); 64.0 (CH ₂ , acetal); 63.2 (CH ₂ , acetal); 49.6 (CH); 47.8 (CH); 45.8 (C, 13-C); 43.9 (CH); 38.3 (CH ₂ ); 36.7 (CH ₂ ); 36.1 (C, 10-C); 31.5 (CH ₂ ); 31.2 (CH); 27.8 (CH ₂ ); 23.6 (CH ₃ ); 23.1 (CH ₂ ); 22.7 (CH ₂ ); 20.7 (CH ₃ ); 18.8 (CH ₃ ); 13.8 (CH ₃ ).

IR spectrum: ν (OH): 3417 cm ^-1

v (C = O): 1733 cm ^-1

OD = -31

R_158,8-160,6 ° C

Rf (EP / AcOEt, 70/30): 0.23

j) Oxidation of the hydroxyl function at position 12:

A solution was prepared from 143 mg of compound 9 (0.34 mmol, 1 equivalent) in 3 ml of distilled dichloromethane previously cooled to 0 ° C. This solution was treated with 174mg Dess Martin reagent (0.41 mmol, 1.2 equivalents).

After stirring for 1 hour at a temperature of 25 ° C., the medium was treated with 8 ml of a saturated aqueous solution of sodium thiosulfate (Na ₂ S ₂ O ₃ ).

In an alternative protocol, the mixture was stirred for 5 minutes and then 8 ml of saturated NaHCO ₃ solution was added. The reaction mixture was then stirred for 5 minutes.

The reaction mixture is placed in a separatory funnel and the organic and aqueous phases are separated. The aqueous phase was extracted 3 times with 10 ml of dichloromethane. Organic phases were combined and dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (2000 Pa, 20 mbar) under a temperature of 35 ° C.

The residue was purified by chromatography (possibly under medium pressure (pump: ProMinent Type BT4A (trademark))) on silica gel (5g S1O2, EP (or preferably cyclohexane) / AcOEt 70/30 v / v) allowing to obtain 140 mg of compound 10 (0.335 mmol), in solid form. The product was obtained with a 99% yield

(3S, 10R, 13S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) -12-oxo-2,3,4,7,8,9, 10.1 1, 12,13,14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate

Compound 10: compound XI of the claims

M = 416.55 g / mol

Characteristics of compound 10:

Reaction type: oxidation reaction

1 H NMR Spectrum: 300 MHz, CDCH

5.40 (1H, m, 6-H); 4.58 (1H, tt, J 4.6-1.4, 3a-H); 4.05- 3.65 (4H, m, OCH ₂ ); 2.80 - 2.55 (2H, m); 2.45-1.95 (7H, m, with s at 2.03, OAc); 1, 95-1, 10 (21H, m, with s to 1, 25, 21 -H, s at 1, 15, Me and s at 1, 12, Me).

13C NMR spectrum: 75 MHz, CDCH

214.0 (C = O, 12-C); 170.4 (OAc); 139.4 (C, 5-C); 122.3 (CH, 6-C); 1 1 1, 2 (C, 20-C); 73.5 (CH, 3-C); 65.5 (CH ₂ , acetal); 62.9 (CH ₂ , acetal); 58.3 (CH); 56.6 (C, 13-C); 53.6 (CH); 49.1 (CH); 37.9 (CH ₂ ); 37.7 (CH ₂ ); 37.5 (C, 10-C); 36.7 (CH ₂ ); 31, 4 (CH); 31.3 (CH ₂ ); 27.5 (CH ₂ ); 4.4 (CH ₃ ); 24.0 (CH ₂ ); 22.0 (CH ₂ ); 21, 4 (CH ₃ ); 18.9 (CH ₃ ); 12.9 (CH ₃ ).

OD = + 12

IR spectrum: ν (C = O): 1722-1700 cm ^-1

Rf (EP (or cyclohexane VAcOEt, 70/30): 0.36 k) Cleavage step 12-13 (formation of unsaturated seco aldehyde): Norrish reaction (photochemistry)

A solution was prepared from 250 mg of compound 10 (0.60 mmol, 1 equivalent) in 250 ml of dichloromethane distilled and degassed beforehand for 15 minutes under Argon. This solution was irradiated for 30 minutes with an HPK 125 (trademark) lamp (HPK = "high-pressure mercury vapor lamps") in a quartz reactor.

The solvent was evaporated under reduced pressure at a temperature of 25 ° C and a pressure of 1500 Pa (15 mbar).

250 mg of compound 11 were thus obtained in the form of a yellow oil which is used without urification for the next step.

4α-methyl-6- (2-methyl-3- (2-methyl-1,3-dioxolan-2-yl) cyclopent-1-enyl) -5- (2-oxoethyl) -1,2,3,4 , 4a, 5,6,7-octahydronaphthalen-2-yl acetate

Compound 11: Compound of formula (XII)

M = 416.55 g / mol The inventors have verified that it is indeed the compound 11 which has been obtained by comparing it with an analogous compound of the isolated and characterized compound 11 carrying in position an acetate group. Compound 11 is not very stable and the next step, namely the Prins reaction, is carried out directly on the crude reaction product of this compound. k-bis) Another experiment related to the 12-13 bond cleavage step (formation of unsaturated seco aldehyde): Norrish reaction (photochemistry)

A solution was prepared from 895 mg of compound 10

(2.15 mmol, 1 equivalent) in 280 ml of dichloromethane distilled and degassed beforehand for 15 minutes under Argon. This solution was irradiated for 15 minutes with an HPK 125 (trademark) lamp (HPK = high-pressure mercury vapor lamp) in a quartz reactor. The solvent was evaporated under reduced pressure at a temperature of 25 ° C and a pressure of 2000 Pa (20 mbar). 931 mg of compound 11 (SECO ALDEHYDE) were thus obtained in the form of a yellow oil which is used without purification for the next step. I) Cyclization by the Prins reaction (formation of diol 12,14)

A solution was prepared from 250 mg of compound 11 (0.6 mmol maximum) in 1.2 ml of tetrahydrofuran (THF). This solution was treated with 6 mL of a solution of AcOH / H ₂ O / CF ₃ COOH (2.5 / 1 / 0.6).

After 1 h 30 magnetic stirring at 25 ° C, the medium was diluted in 20 mL of Et ₂ O and 10 mL of water.

The reaction mixture is placed in a separatory funnel and the organic and aqueous phases are separated. The aqueous phase was extracted 3 times with 10 ml of ether. The organic phases were combined in a separatory funnel, washed 4 times with 10 ml of a saturated solution of NaHCO 3, 1 time with 10 ml of a saturated solution of NaCl, dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (2000 Pa, 20 mbar) under a temperature of 35 ° C.

The residue was purified by medium pressure chromatography (pump ProMinent Type BT4A (trademark)) on silica gel (10 g of SiO ₂ , EP / AcOEt 80/20 then 50/50 v / v), allowing obtain 50mg of 12A1 compound (0.013mmol), in solid form. The product was obtained with a yield of 21%.

(3S, 10R, 12R, 13S, 14S, 17S) -17-acetyl-12,14-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10,1,1,12,13 , 14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate

Compound 12A1: compound XIII of the claims

M = 392.54 g / mol

Characteristics of the compound 12A1:

Reaction type: Norrish reaction (photochemistry) then Prins

1 H NMR Spectrum: 300 MHz, CDCH

5.42 (1H, m, 6-H); 4.65-4.50 (1H, m, 3a-H); 4.37 (1H, s, OH); 3.61 (1H, t, J 6.3, 17a-H); 3.35 (1H, dd, J 4,2-1,17,12a-H); 2.40-2.15 (6H, m, with s at 2.27, 21-H); 2.10- 0.80 (25H, m, with s at 2.03, OAc, s at 1, 01, 18-H and s at 0.92 (19-H).

13C NMR spectrum: 75 MHz, CDCH

218.0 (C = O, 20-C); 170.6 (OAc); 137.8 (C, 5-C); 123.1 (CH, 6-C); 85.5 (C, 14-C); 73.6 (CH, 12-C); 73.4 (CH, 3-C); 56.9 (CH, 17-C); 55.0 (C, 13-C); 43.3 (CH, 9-C); 37.8 (CH ₂ , 1 -C); 37.0 (CH ₂ , 4-C); 36.8 (C, 10- VS); 35.6 (CH ₃ , 21 -C); 34.5 (CH ₂ , 15-C); 33.1 (CH, 8-C); 29.9 (CH ₂ , 1 1 - C); 27.6 (CH ₂ , 2-C); 27.3 (CH ₂ , 7-C); 24.4 (CH ₂ , 16-C); 21.4 (CH ₃ OAc); 19.3 (CH ₃ , 19-C); 8.3 (CH ₃ , 18-C).

OD = + 15

Rf (EP / AcOEt, 50/50): 0.24 l-bis) Another experiment relating to cyclization by the Prins reaction (formation of diol 12,14)

A solution was prepared from 931 mg of compound 9 (2.15 mmol maximum) in 4.0 ml of tetrahydrofuran (THF). This solution was treated with 20.0 ml of a solution of AcOH / H ₂ O / CF ₃ COOH (2/1 / 0.6). After 1 h 30 of magnetic stirring at 25 ° C., the medium was diluted in 30 ml of CH ₂ Cl ₂ and washed twice with 30 ml of water, and 3 times with 30 ml of a saturated solution of NaHCO ₃ , and then dried. on sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (2000 Pa, 20 mbar) under a temperature of 35 ° C.

The residue was purified by medium pressure chromatography (pump ProMinent Type BT4A (trademark)) on silica gel (30 g of SiO 2, EP / AcOEt 80/20 then 60/40), making it possible to obtain 210 mg of compound 12A1 with a yield of 25% (140-142 ° C), 153mg of compound 12B1 with a yield of 19% (192-194 ° C), and 1 18mg of compound 12C with a yield of 15% (1 16-1 17 ° C).

Additional analyzes made it possible to identify in Experiments I and Ia also the following compounds 12B1 and 12C:

Compound 12B1 which results from the deprotection of dioxolane

Compound 12B1: (3S, 10R, 13S, 17S) -17-acetyl-10,13-dimethyl-12-oxo-2,3,4,7,8,9,10,1 1,12,13,14, 15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthren-3-yl acetate

Characteristics of the compound 12B1:

Reaction type: reaction of Norrish (photochinnie) then Prins

300 MHz NMR spectrum, CDCH

5.42-5.40 (m, 1H, H-6); 4.59 (tt, 1H, J = 4.6-1.1, 4Hz, H-3a); 3.34 (t, 1H, J = 9.6 Hz, H-17a); 2.62 (t, 1H, J = 13.2 Hz, H-1 1); 2.50-2.00 (m, 4H); 2.26 (s, 3H, CH ₃ , H-21); 2.03 (s, 3H, CH ₃ , Ac); 2.00-0.80 (m, 12H); 1, 12 (s, 3H, CH ₃ ); 0.98 (s, 3H, CH ₃ )

NMR ^{spectrum at} C: 75 MHz, CDCH

213.0 (C = O); 209.4 (C = O); 170.2 (C = O, OAc); 139.2 (C = C, C-5); 121, 9

(C = CH, C-6); 73.1 (CH, C-3); 57.6 (C, C-13); 57.4 (CH); 54.0 (CH); 52.7

(CH); 52.7 (CH); 37.6 (CH ₂ ); 37.4 (CH ₂ ); 37.2 (C, C-10); 36.4 (CH ₂ );

31, 1 (2CH + CH ₂ ); 27.3 (CH ₂ ); 24.0 (CH ₂ ); 22.4 (CH ₂ ); 21, 2 (CH ₃ ); 18.7

(CH ₃ ); 13.2 (CH ₃ )

OD = + 55 (c 0.009, CHCl ₃ )

IR spectrum: 1729.1703 cm ^-1

Rf (EP (or cyclohexane VAcOEt, 60/40): 0.56

- Compound 12C which is the following spiro derivative

Compound 12C: Compound of Formula (XMIbis) Claims

(1S, 2'S, 7'S, 9a'R) -3-acetyl-2'-hydroxy-2,9a'-dimethyl-1 ', 2', 3a ', 4', 6 ', 7', 8 ', 9 ', 9a', 9b'-decahydrospiro [cyclopent [2] ene-1,3'-cyclopenta [a] naphthalene] -7'-yl acetate

Characteristics of 12C compound:

Reaction type: Norrish reaction (photochemistry) then Prins

300 MHz NMR spectrum, CDCH

5.36 (d, 1H, J = 4.8 Hz, H-6); 4.58 (tt, 1H, J = 4.8-1.1, 4Hz, H-3a); 4.14 (dt, 1H, J = 8.2-9.7 Hz, Η-12β); 2.80-0.80 (m, 17H); 2.22 (s, 3H, CH ₃ , H-21); 2.02 (s, 3H, CH ₃ , Ac); 1, 96 (t, 3H, J = 2.1 Hz, CH ₃ , H-18); 1, 04 (s, 3H, CH ₃ , H-19)

NMR ^{spectrum at} C: 75 MHz, CDCH

198.7 (C = O, C-20); 170.5 (C = O, OAc); 153.7 (C = C); 140.5 (C = C); 137.9 (C = C); 122.6 (C = CH); 76.5 (CH, C-12); 73.7 (CH, C-3); 65.7 (C, C-14); 48.3 (CH); 39.9 (CH); 37.9 (CH ₂ ); 37.7 (CH ₂ ); 37.2 (C, C-10); 32.4 (CH ₂ ); 30.5 (CH); 30.3 (CH ₂ ); 27.4 (CH2); 25.9 (CH 2); 21, 8 (CH2); 21, 4 (CH ₃ ); 18.0 (CH ₃ ); 12.1 (CH ₃ ).

OD = -12 (c 0.006, CHCl ₃ )

IR spectrum: 3430, 1729, 1666, 1608-cm- ¹

Rf (EP / AcOEt, 60/40): 0.21 m) Protection of the hydroxyl function in position 12: regioselective protection reaction, formation of the tigloyl derivative

A solution was prepared from 40 mg of 12A1 (0.10 mmol, 1 equivalent) in 5 ml of distilled dichloromethane. This solution was treated with 0.12 ml of a solution of distilled tigloyl chloride (1. 09 mmol, 11 equivalents), with 0.14 ml of distilled pyridine (1.74 mmol, 17 equivalents), and DMAP in catalytic amount. .

The medium was refluxed for 7 h and then stirred magnetically for 15 h at a temperature of 25 ° C.

10 ml of water were added to the reaction mixture which was then placed in a separatory funnel and the organic and aqueous phases were separated. The aqueous phase was extracted twice with 10 ml of dichloromethane. The organic phases were combined in a separatory funnel, washed 1 time with 10 ml of a 10% solution of HCl, 1 time with 10 ml of a saturated solution of sodium bicarbonate, dried over sodium sulphate (Na ₂ SO ₄ ). and finally concentrated under reduced pressure (20 mbar) under a temperature of 35 ° C.

The residue was purified by chromatography (possibly under medium pressure (pump: ProMinent Type BT4A (trademark))) on silica gel (5 g of S1O2, EP (or cyclohexane) / AcOEt 95/5 v / v), allowing to obtain 38 mg of compound 13 (0.08 mmol), in solid form. The product was obtained with a yield of 80%.

(E) -) - ((3S, 10R, 12R, 13S, 14S, 17S) -3-acetoxy-17-acetyl-14-hydroxy-10,13-dimethyl-2,3,4,7,8,9 , 10.1 1, 12,13,14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenenanthren-12-yl) 2-methylbut-2-enoate Compound 13: compound XIV of the claims

M = 472.63 g / mol

Characteristics of compound 13:

Reaction type: regioselective protection reaction

1 H NMR Spectrum: 300 MHz, CDCH

6.93 (1H, dq, J 1.5-7.2, tig-H); 5.44 (1H, m, 6-H); 4.65 (1H, dd, J 4.5-1, 7, 12a-H); 4.65-4.55 (1H, m, 3a-H); 4.29 (1H, s, OH); 3.15 (1H, m, 17a-H); 2.50 - 2.05 (6H, m, with s at 2.21, 21 -H); 2.05-0.90 (28H, m, with s at 2.03, OAc, s at 1.89, tig-Me, dd at 1.84, J 0.9-6.3, s-1, 07, 18-H and s at 1, 0219-H).

13C NMR spectrum: 75 MHz, CDCH

217.0 (C = O, 20-C); 170.5 (OAc); 167.7 (COO, tig-C); 137.8 (CH, tic-C); 123.0 (CH, 6-C); 85.7 (C, 14-C); 75.9 (CH, 3-C); 73.9 (CH, 12-C); 57.2 (CH, 17-C); 53.7 (C, 13-C); 42.9 (CH, 9-C); 37.8 (CH ₂ , 1 -C); 36.9 (CH ₂ , 4-C); 36.9 (C, 10-C); 35.6 (CH ₃ , 21 -C); 34.4 (CH ₂ , 15-C); 33.2 (CH, 8-C); 27.6 (CH ₂ , 2-C); 27.3 (CH ₂ , 7-C); 26.0 (CH ₂ , 1 1 -C); 24.4 (CH ₂ , 16-C); 21.4 (CH ₃ OAc); 19.3 (CH ₃ , 19-C); 14.5 (CH ₃ , t-C); 12.2 (CH ₃ , tig-C); 9.9 (CH ₃ , 18-C).

OD = + 5 (C 0.01 CHCl ₃ )

Rf (EP (or cyclohexane VAcOEt 70/30): 0.35 n) Regioselective saponification at position 3 of compound 13 (formation of Hoodigogenin A)

A solution was prepared from 42 mg of compound 13 (0.09 mmol, 1 equivalent) in 5 ml of methanol. This solution was treated with 33 mg of potassium carbonate (K ₂ CO ₃ ), (0.24 mmol). After stirring for 2 h under a temperature of 25 ° C., 10 ml of water were added to the reaction mixture, which was then placed in a separating funnel and the organic and aqueous phases were separated. The aqueous phase was extracted 3 times with 10 ml of dichloromethane. The organic phases were combined, dried over sodium sulfate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (2000 Pa, 20 mbar) at a temperature of 35 ° C.

The residue was purified by chromatography (possibly under medium pressure (pump: ProMinent Type BT4A (trademark))) on silica gel (5g S1O2, EP (or cyclohexane) / AcOEt 60/40 v / v), allowing isolate 26mg of compound 14.

This compound is 12-α-trioloyl, 1α-dihydroxypregn-5-en-20-one (Hoodigogenin A) (0.06 mmol), in solid form. The product was obtained with a yield of 69%. The overall yield of synthesis of this compound 14 is 3.1%, which represents a yield 31 times greater than the yields of steroid synthesis with the methods of the prior art.

(E) - ((3S, 10R, 12R, 13S, 14S, 17S) -17-acetyl-3,14-dihydroxy-10,13-dimethyl-2,3,4,7,8,9, 10, 1 1, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta [a] phenenanthren-12-yl) 2-methylbut-2-enoate

Compound 14: compound XV of the claims

Reference: Hoodigogenin A

M = 430.59 g / mol

Characteristics of compound 14 Reaction type: regioselective saponification reaction

1 H NMR spectrum: 400 MHz, CDCl 3

6.91 (1H, dq, J 1, 6-7.2, tig-H); 5.40 (1H, m, 6-H); 4.63 (1H, dd, J 4.4-12.0, 12a-H); 4.26 (1H, s, OH); 3.51 (1H, tt, J 4.6-1.1, 2, 3a-H); 3.12 (1H, m, 17a-H); 2.40-2.15 (6H, m, with s at 2.10, 21 -H); 2.10-0.90 (26H, m, with s to 1.88, tig-Me, dd at 1.83, J 0.8-6.8, tig-Me, s at 1, 06, 18- H and s at 0.99, 19-H).

13C NMR spectrum: 400 MHz, CDCHC

217.1 (C = O, 20-C); 167.7 (COO, tig-C); 139.0 (C, 5-C); 137.8 (C, t-C); 128.7 (CH, tig-C); 122.0 (CH, 6-C); 85.7 (C, 14-C); 75.9 (CH, 3-C); 71.5 (CH, 12-C); 57.2 (CH, 17-C); 53.8 (C, 136C); 43.1 (CH, 9-C); 42.0 (CH 2, 4-C); 37.2 (CH 2, 1 -C); 36.9 (C, 10-C); 35.8 (CH, 8-C); 34.5 (CH 2, 15-C); 33.2 (CH3, 21 -C); 31.4 (CH2, 2-C); 27.4 (CH 2, 7-C); 26.1 (CH 2, 1 1 -C); 24.4 (CH 2, 16-C); 19.4 (CH3, 19-C); 14.5 (CH3, tig-C); 12.2 (CH3, tig-C); 9.9 (CH3, 18-C).

IR spectrum: ν (OH): 3535, 3471 cm ^-1

v (C = O): 1698, 1682 cm ^-1

v (C = C): 1651 cm ^-1

OD = + 1, 13 (c 0.006 CHCl 3)

Rf (EP / AcOEt, 60/40): 0.21

Complementary experiments have made it possible under the conditions of this example and with more starting materials to obtain several tens of mg of product 14.

Example 2 Synthesis of Cis (Z) of (E) - ((3R, 5R, 10S, 12R, 13S, 14S, 17S) -17-acetyl-3,14-dihydroxy-10,13-dimethylhexadecahydro-1H- Cyclopentaralphenanthrene-12-yl) 2-methylbut-2-enoate

It is the analog 3alpha-OH cis-A-B cycles of the compound 14 obtained in Example 1.

Analogue P57: 3α-ΟΗ, AB cis Compound 3B:

Operating mode:

A solution was prepared from 400 mg of compound 1 (0.96 mmol, 1 equivalent) (commercial: Steraloids-USA ref P-6470-000) and 20 ml of toluene. To this solution was added 0.85 ml of ethylene glycol (15.48 mmol, 16 equivalents), as well as para toluene sulfonic acid (10 mg, 0.06 mmol).

The medium was refluxed on a Dean Stark (trademark) apparatus for 2:10. The toluene was evaporated under reduced pressure (20mbar) at a temperature of 50 ° C.

The residue obtained was dissolved in 20 ml of dichloromethane and then washed twice with 20 ml of water.

The aqueous phases were combined and extracted twice with 20 ml of dichloromethane. The organic phases were combined in a separatory funnel, washed once with 20 ml of saturated sodium bicarbonate solution (NaHCO 3), dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (20mbar) under a temperature of 35 ° C.

The residue was purified by medium pressure chromatography (pump ProMinent Type BT4A) on silica gel (10 g S1O2, EP / AcOEt 80/20 v / v), making it possible to obtain 360 mg of compound 3B (0.78 mmol, 81 g). %) in the form of an oil.

ACCF

Compound 3B

(3R, 10S, 12S, 13S, 17S) -O, 13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene-3, 12 Diethyl diacetate

M = 462.62 g / mol

Characteristics of compound 3B:

Rf (tol / AcOEt, 80/20): 0.47

Compound 3C:

Operating mode:

Same procedure as that described in Example 1 - starting with compound 3B.

Compound 3C was obtained in 81% yield.

Compound 3C

(3R, 5R, 10S, 12S, 13S, 14S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene- 3, 12-diol

M = 378.55 g / mol

Characteristics of compound 3C:

3D compound:

Operating mode:

Same procedure as that described in Example 1-i) from compound 3C

The 3D compound was obtained with a yield of 56%.

3D compound

(3R, 5R, 10S, 12S, 13S, 14S, 17S) -12-hydroxy-10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [ a] phenanthren-3-yl acetate

M = 420.20 g / mol

Characteristics of the 3D compound:

Compound 3E:

Operating mode Same procedure as that described in Example 1-j) from the 3D compound.

Compound 3E was obtained in 96% yield.

Compound 3E

(3R, 5R, 10S, 13S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) -12-oxohexadecahydro-1H-cyclopenta [a] phenanthren -3-yl acetate

M = 418.57 g / mol

Characteristics of compound 3E:

1H NMR: 300 MHz, C _fi D _{fi fi}

4.76 (1H, tt, J 4.6-1 1, 2, 3β-Η); 3.70-3.45 (4H, m, acetal); 3.10 (1H, t, J 9.9, 17-H); 2.18 (1H, t, J 12.3, 11 -H); 2.05-1.75 (2H, m); 1.98 (1H, dd, J 4.5-12.3, 11 -H); 1.77 (3H, s, OAc); 1.70-0.50 (14H, m); 1.60 (3H, s, 21-H); 1, 12 (3H, s, Me); 0.65 (3H, s, Me).

13C NMR: 75 MHz, C _fi D _fi

1, 4 (C = O, 12-C); 169.3 (OAc); 1, 1, 3 (C, 20-C); 73.3 (CH, 3-C); 65.4 (CH ₂ , acetal); 62.7 (CH ₂ , acetal); 57.4 (CH); 56.8 (C); 49.7 (CH); 43.1 (CH); 41.0 (CH); 37.2 (CH); 34.8 (CH); 34.8 (CH ₂ ); 34.6 (C); 32.0 (CH); 26.8 (CH ₂ ); 26.2 (CH ₂ ); 25.7 (CH ₂ ); 24.5 (CH ₃ ); 23.5 (CH ₂ ); 22.2 (CH ₃ ); 21, 8 (CH ₂ ); 20.6 (CH ₃ ); 13.0 (CH ₃ ).

IR: ν (C = O): 1733-1704 cm ^-1

R 189.2- 192.8 ° C

Rf (EP / AcOEt, 70/30): 0.40

Compound 3F

Operating mode Same procedure as that described in Example 1-kl) from compound 3E.

Compound 3F was obtained with a yield of 22%.

Compound 3F

(35R, 10S, 12R, 13S, 1 AS, 17S) -17-acetyl-12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenenanthren-3-yl acetate

M = 392.53 g / mol

Characteristics of compound 3F:

3G compound:

Operating mode:

Same procedure as that described in Example 1 -m) from compound 3F. The 3G compound was obtained with a yield of 60%.

3G compound

(E) - ((3R, 5R, 10S, 12R, 13S, 14S, 17S) -3-acetoxy-17-acetyl-14-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenenanthren- 12-yl) 2-methylbut-2-enoate

M = 474.63 g / mol

Features of the 3G compound:

1 H NMR: 300 MHz, CDCH

6.98 (1H, q, J 5.7, H _tig ); 4.75-4.60 (1H, m, 3β-Η); 4.61 (1H, dd, J 4,2-1,17,12a-H); 3.10 (1H, dd, J 4.8-8.7, 17-H); 2.20-0.85 (32H, m); 2.18 (3H, s, 21H); 2.03 (3H, s, OAc); 1, 02 (3H, s, Me); 0.93 (3H, s, Me).

13C NMR: 75 MHz, CDCH

217.0 (C = O, 20-C); 170.6 (OAc); 139.7 (C = CH, C _tig ); 120.7 (C = C, C _tig ); 85.5 (C, 14-C); 76.2 (CH, 12-C); 74.0 (CH, 3-C); 57.1 (CH); 54.0 (C); 41.5 (CH); 39.5 (CH); 34.8 (C); 34.8 (CH ₂ ); 34.0 (CH ₂ ); 33.1 (CH ₃ ); 32.7 (CH ₃ ); 32.2 (CH ₂ ); 26.8 (CH ₂ ); 26.7 (CH ₂ ); 25.4 (CH ₂ ); 24.7 (CH ₂ ); 23.1 (CH ₃ ); 21, 8 (CH ₂ ); 21, 4 (CH ₃ ); 14.5 (CH ₃ ); 10.0 (CH ₃ ).

Rf (EP / AcOEt, 60/40): 0.60

Compound 15:

Operating mode:

Same procedure as that described in Example 1-n) from the compound 3G.

Compound 15, which is the cis analogue of the compound, is obtained.

14, with an overall synthetic yield of 2.9% which represents a 29 times higher yield of steroid synthesis with the methods of the prior art.

Compound 15

(E) - ((3R, 10S, 12R, 13S, 14S, 17S) -17-acetyl-3,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthren-12-yl) 2 -methylbut-2-enoate

M = 432.59 g / mol

Characteristics of the compound 15:

Example 3: Towards the synthesis of the analogue 3 beta-OH cis AB ring of 12A1: product 16

Analogue P57 3B-OH, AB cis

Compound 4B

Same product as compound II of the claims.

Compound 4C

Operating mode:

A solution was prepared from 1.78 g of compound 4B (4.73 mmol) in 20 ml of THF. 0.87 g of benzoic acid (7.10 mmol), 1.90 g of triphenyl phosphine (7.10 mmol) and 1.30 ml of DEAD (7.10 mmol) were added.

The solution is placed under magnetic stirring for 17 hours at

25 ° C (room temperature).

20 ml of ethyl acetate (AcOEt) are added and the organic phase is washed twice with 20 ml of a saturated solution of sodium bicarbonate (NaHCO 3). The aqueous phases are collected in a separating funnel and extracted twice with 20 ml of AcOEt. The organic phases are combined in a separatory funnel and washed once with 20 ml of a saturated solution of sodium chloride (NaCl), dried over sodium sulphate (Na 2 SO 4) and finally concentrated under reduced pressure (35 ° C., 20 mbar). ).

The residue was purified by medium pressure chromatography (pump ProMinent Type BT4A) on silica gel (150 g SiO 2, EP / AcOEt, 90/10, v / v), making it possible to obtain 2.27 g of compound 4C (4 , 73mmol, 100%) in solid form.

Compound 4C

(3S, 5S, 12S, 13S, 17S) -12-acetoxy-17-acetyl-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-3-ylbenzoate

M = 480.64 g / mol

Characteristics of the compound 4C:

Compound 4P

Operating mode:

Same procedure as described in the example from compound 4C.

The compound 4D was obtained with a yield of 76%.

4D compound

(3S, 5S, 12S, 13S, 17S) -12-acetoxy-10,13-dimethyl-17- (2-methyl-1,3-dioxol-n-2-yl) hexadec hyd 1H-cyclopenta [a] phenanthrene-3-yl benzoate

M = 524.69 g / mol

Characteristics of the compound 4P:

1H NMR: 300 MHz, C _fi D _{fi fi}

8.23 (2H, dq, J 6.8-1.8, H _Ar ); 7.20-6.95 (3H, m, H _Ar ); 5.42 (1H, brs, 3a-H); 5.37 (1H, t, J 2.7, 12β-Η); 3.65-3.40 (4H, m, acetal); 2.52 (1H, t, J 10.2, 17a-H); 2.00-0.70 (20H, m); 1.84 (3H, s, OAc); 1, 29 (3H, s, 21 - H); 0.91 (3H, s, Me); 0.84 (3H, s, Me).

13C NMR: 75 MHz, C _fi D _fi

169.0 (OBz); 132.3 (CH, C _Ar ); 131.5 (C, C _Ar ); 129.5 (2CH, C _Ar ); 128.2 (2CH, C _Ar ); 1 1 1, 1 (C, C-20); 75.0 (CH, C-12); 70.8 (CH, C-3); 64.6 (CH ₂ , acetal); 62.9 (CH ₂ , acetal); 50.0 (CH); 49.4 (CH); 44.6 (C); 37.7 (CH); 34.9 (CH); 34.3 (C); 33.9 (CH); 30.8 (CH ₂ ); 30.6 (CH ₂ ); 26.3 (CH ₂ ); 25.8 (CH ₂ ); 25.7 (CH ₂ ); 24.0 (CH ₃ ); 23.6 (CH ₂ ); 23.5 (CH ₃ ); 23.1 (CH ₂ ); 22.6 (CH ₂ ); 20.6 (CH ₃ ); 13.6 (CH ₃ );

IR: ν (C = O): 1731-1,701 cm ^-1

Rf (Toluene / AcOEt, 80/20): 0.51

M.p. 169-171 ° C

OD = +1 13 (c 0.01 1, CHCl ₃ )

Compound 4E

Operating mode:

Same procedure as that described in Example 1 -h) from the compound 4D. Compound 4E was obtained with a yield of 25%.

Compound 4E

(3S, 5S, 2S, 13S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene- 3,12-diol

M = 378.55 g / mol

Characteristics of compound 4E:

1H NMR: 300 MHz, C _fi D _{fi fi}

3.94 (1H, d, J 3.0, 12β-Η); 3.84 (1H, s, 3a-H); 3.50-3.40 (4H, m, acetal); 2.42 (1H, t, J 9.9, 17a-H); 2.00-0.60 (22H, m); 1, 20 (3H, s, 21-H); 0.96 (3H, s, Me); 0.87 (3H, s, Me).

13C NMR: 75 MHz, C _fi D _fi

1 1 1, 1 (C, C-20); 72.8 (CH, C-3); 66.8 (CH, C-12); 64.2 (CH ₂ , acetal); 63.7 (CH ₂ , acetal); 50.4 (CH); 48.7 (CH); 36.9 (CH); 35.6 (CH); 35.0 (C); 33.9 (CH ₂ ); 33.7 (CH); 30.4 (CH ₂ ); 28.4 (CH ₂ ); 28.2 (CH ₂ ); 27.1 (CH ₂ ); 26.4 (CH ₂ ); 23.9 (2CH ₃ ); 23.5 (CH ₂ ); 23.3 (CH ₂ ); 14.4 (CH ₃ );

IR: ν (OH): 3455-3368 cm ^-1

Rf (EP / AcOEt, 60/40): 0.14

M.p. 156-157 ° C

OD = +37 (c 0.014, CHCIs)

Compound 4F

Operating mode:

Same procedure as that described in Example 1-i) from compound 4E.

Compound 4F was obtained with a yield of 69%.

Compound 4F

(3S, 5S, 12S, 13S, 17S) -12-hydroxy-10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate

M = 420.58 g / mol

Characteristics of the compound 4F:

4G compound

Operating mode:

Same procedure as that described in Example 1-j) from compound 4F.

Compound 4G was obtained with a yield of 97%.

4G compound

(3S, 5S, 1S, 3S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) -12-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate

M = 418.57 g / mol

Features of 4G compound:

1H NMR: 300 MHz, C _fi D _{fi fi}

5.07 (1H, t, J 2.7, 12a-H); 3.65- 3.45 (4H, m, acetal); 3.15 (1H, t, J 9.9, 17a-H); 2.23 (1H, t, J 12.6, 11 -H); 2.05-1.85 (3H, m); 2.80-0.60 (16H, m); 1.73 (3H, s, OAc); 1.61 (3H, s, 21-H); 1, 15 (3H, s, Me); 0.78 (3H, s, Me).

13C NMR: 75 MHz, C _fi D _fi

21 1, 2 (C = O, C-12); 170.5 (OAc); 1 1 1, 3 (C, C-20); 69.8 (CH, C-3); 65.4 (CH ₂ , acetal); 62.8 (CH ₂ , acetal); 57.7 (CH); 56.5 (C); 49.8 (CH); 42.6 (CH); 37.5 (CH ₂ ); 36.9 (CH); 35.2 (C); 34.7 (CH); 30.6 (CH ₂ ); 30.2 (CH ₂ ); 26.3 (CH ₂ ); 25.6 (CH ₂ ); 24.6 (CH ₃ ); 24.5 (CH ₂ ); 23.6 (CH ₂ ); 22.8 (CH ₃ ); 21, 9 (CH ₂ ); 20.6 (CH ₃ ); 13.0 (CH ₃ ).

Rf (EP / AcOEt, 60/40): 0.66

M.p. 142-144 ° C

OD = -3 (c 0.003, CHCl ₃ )

Compound 16A

Operating mode Same procedure as that described in Example 1-kl) from compound 4G.

Compound 16A, which is the cis analog of 12A1 compound in 15% yield, 16C spiro derivative isolated in 25% yield and 16B diketone isolated in 5% yield.

The overall yield of 16A compound synthesis is 1.6%, which represents a yield 16 times greater than the yields of steroid synthesis with the methods of the prior art.

(3S, 5R, 10S, 12R, 13S, 14S, 17S) -17-acetyl-12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenenanthren-3-yl acetate

Compound 16A

M = 392.53g / mol

Characteristics of compound 16A:

1 H NMR: 300 MHz, CDCH

5.05 (1H, s, 3β-Η); 3.55 (1H, t, J 6.3, 17a-H); 3.29 (1H, dd, J 3.9-1.1, 7, 12a-H); 2.25 (3H, s, 21H); 2.20-0.80 (21H, m); 2.04 (3H, s, OAc); 0.96 (3H, s, Me); 0.88 (3H, s, Me).

13C NMR: 300 MHz, CDCH

218.1 (C = O, C-20); 170.8 (OAc); 85.4 (C, C-14); 74.0 (CH, C-12); 70.5 (CH, C-3); 56.8 (CH, C-17); 55.3 (C); 39.4 (CH); 36.9 (CH); 35.0 (C); 34.1 (CH ₂ ); 33.1 (CH); 32.3 (CH ₃ ); 30.5 (CH ₂ ); 29.8 (CH ₂ ); 26.2 (CH ₂ ); 25.0 (CH ₂ ); 24.7 (CH ₂ ); 23.7 (CH ₃ ); 21, 6 (CH ₃ ); 21.5 (CH ₂ ); 8.4 (CH ₃ ).

IR: ν (OH): 3426 cm ^-1

Complementary NMR analyzes; HRMS and infrared allowed to identify also the following two compounds:

- The compound diketone 16B

(3S, 5R, 10S, 13S, 14S, 17S) -17-acetyl-10,13-dimethyl-12-oxohexadecahydro-1H-cyclopenta [a] phenenanthren-3-yl acetate

Compound 16B

Characteristics of the compound 16B:

- The spiro derivative 16C

(2'S, 3a'R, 5a'R, 7'S, 9a'S) -3-acetyl-2'-hydroxy-2,9a'-dimethyl-1 ', 2', 3a ', 4', 5a ', 6', 7 ', 8', 9 ', 9a', 9b'-dodecahydrospio [cyclopent [2] ene-1,3'-cyclopenta [a] naphthalene] -7'-acetate

16C compound

Characteristics of the compound 16C:

EXAMPLE 4 Synthesis of the 33-OH Anal, Trans AB Runs of Compound 14: Compound 17

Analogue P57 3B-OH, AB trans (method 1)

Compound 5A

Operating mode:

A solution was prepared from 5.02 g of purified hecogenin acetate (10.61 mmol) in 80 ml of acetic anhydride (AC 2 O). 0.60 g of NH ₄ Cl (11.1 mmol) and 1 ml of pyridine (12.36 mmol) are added.

The reaction medium is refluxed (136 ° C.) for 15 hours. The orange solution obtained is cooled to 0 ° C. and then treated dropwise over 15 min with a solution of 2.00 g of CrO 3 (20.00 mmol) in 12 ml of water and 6 ml of AcOH.

After stirring for 1 h 30 at 25 ° C. (room temperature), 100 ml of water are added and the aqueous phase is extracted 3 times with 100 ml of Et ₂ O. The organic phases are combined in a separating funnel and washed 1 100mL of saturated sodium bicarbonate solution (NaHCO 3), 1 time with 100mL of saturated sodium chloride solution (NaCl), dried over sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure (35mL). ° C, 20 mbar).

The green residue obtained is dissolved in 50 ml of acetic acid (AcOH) and brought to reflux (11 ° C.) for 1 hour. The medium obtained is concentrated under reduced pressure (35 ° C., 20 mbar) and then solubilized in

50 ml of dichloromethane (CH ₂ Cl 2) and washed twice with 50 ml of water, once with 50 ml of a saturated solution of NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated under reduced pressure (35 ° C., 20 mbar).

The residue was purified by chromatography on silica gel (150 g SiO ₂ , EP / AcOEt, 80/20, v / v), making it possible to obtain 2.66 g of compound 5A.

(7.14 mmol, 67%) in solid form.

Compound 5A

(3S, 5S, 10S, 13S) -17-acetyl-10,13-dimethyl-12-oxo 2,3,4,5,6,7,8,9,10,11,12,13,14, 15-tetradecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate

M = 372.50 g / mol

Characteristics of compound 5A:

Compound 5B

Operating mode A solution was prepared from 2.78 g of compound 5A (7.47 mmol) in 70 ml of ethanol. 0.33 g of 10% Pd / C are added and the medium is conditioned under H ₂ (vacuum / H ₂ ).

The medium is left under H ₂ at 25 ° C. (room temperature) with vigorous stirring until absorption of 176 ml of H ₂ (7.47 mmol).

After degassing with argon, the catalyst is filtered through Celite, washed with 50 ml of ethanol, 50 ml of ethyl acetate, 50 ml of dichloromethane and then concentrated under reduced pressure (35 ° C., 20 mbar).

The white solid obtained is purified by chromatography on silica gel (100 g SiO ₂ , EP / AcOEt, 80/20, v / v) to obtain 2.26 g of compound 5B (6.02 mmol, 81%) under solid form.

Compound 5B

(3S, 5S, 10S, 13S) -17-Acetyl-10,13-dimethyl-12-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-3-yl

acetate

M = 374.51 g / mol Characteristics of compound 5B:

Compound 5C

Operating mode:

Identical to that described in Example 1-k-1) from 5B Compound 5C was obtained in 20% yield.

Compound 5C

(3S, 5S, 10S, 12R, 13S, 14S) -17-Acetyl-12,14-dihydroxy-10,13-di-methyl-hexadecahydro-1H-cyclopenta [a] phenanthrene-3-ylacetate

M = 392.53 g / mol

Characteristics of the compound 5C:

300 MHz NMR, CDC

4.65 (1H, tt, J11, 5-4.9, 3a-H); 3.53 (1H, t, J 6.6, 17-aH); 3.26 (1H, dd, J 4.2-1, 7, 12a-H); 2.23 (3H, s, OAc); 2.10-0.60 (21H, m); 1.99 (3H, s, OAc); 0.87 (3H, s, Me); 0.80 (3H, s, Me).

Compound 5D

Operating mode:

Same as the one described in example 1 -m from 5C

Compound 5D was obtained with a yield of 51%.

Compound 5D

(E) - ((3S, 5S, 10S, 12, 13S, 14S) -3-acetoxy-17-acetyl-14-hydroxy-10,13-dimethylhexadecahydro1H-cyclopenta [a] phenanthrene-12-yl) 2- methylbut-2-enoate

M = 474.63 g / mol

Characteristics of the 5D compound:

300 MHz NMR, CDCH

6.92 (1H, quad, J 7.2, H _tig ); 4.67 (1H, tt, J11, 4-8.8, 3a-H); 4.56 (1H, dd, J11, 7-4.2, 12a-H); 3.09 (1H, t, J 4.5, 17a-H); 2.30-0.60 (20H, m); 2.17

Compound 17

Operating mode:

Same as described in Example 1 -n from 5D

Compound 17, which is the trans analogue of the compound, is obtained.

14, with an overall synthetic yield of 5% which represents a yield 50 times higher than the yields of steroid synthesis with the methods of the prior art.

Compound 17

(E) - ((3S, 5S, 10S, 12R, 13S, 14S) -17-acetyl-3,14-dihydroxy-

10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-12-yl) 2-methylbut-2-enoate

M = 432.59 g / mol Characteristics of the compound 17:

Analogue P57 3B-OH, AB trans (method 2)

Compound 5E

Operating mode:

Same procedure as described in the example from compound 7.

Compound 5E was obtained in 80% yield.

Compound 5E

(3S, 5S, 10S, 12S, 13S, 17S) -3-hydroxy-10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene-12-yl acetate

M = 420.58 g / mol

Characteristics of compound 5E:

Compound 5F

Operating mode:

Procedure identical to that described in Example 1 -h from compound 5E.

Compound 5F was obtained with a yield of 100%.

Compound 5F

(35,55,105,125,13S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene-3,12- diol

M = 378.55 g / mol

Characteristics of the compound 5F:

1H NMR: 300 MHz, C _fi D _{fi fi}

3.69 (1H, t, J 2.7, 12a-H); 3.50-3.30 (5H, m, acetal + 3a-H); 2.39 (1H, t, J 9.9, 17a-H); 2.00-0.50 (22H, m); 1, 20 (3H, s, 21-H); 0.87 (3H, s, Me); 0.69 (3H, s, Me).

13C NMR: 300 MHz, C _fi D _{fi fi}

1, 1, 9 (C, 20-C); 72.3 (CH, 3-C); 70.6 (CH, 12-C); 63.8 (CH ₂ , acetal);

63.3 (CH ₂ , acetal); 49.9 (CH); 48.2 (CH); 47.7 (CH); 46.2 (C); 44.7 (CH);

38.4 (CH ₂ ); 36.8 (CH ₂ ); 35.0 (CH + C); 31.7 (CH ₂ ); 31.6 (CH ₂ ); 28.9 (CH ₂ ); 28.0 (CH ₂ ); 23.5 (CH ₃ ); 23.1 (CH ₂ ); 22.8 (CH ₂ ); 14.0 (CH ₃ ); 1 1, 9 (CH ₃ ).

IR: ν (OH): 3445-3389 cm ^-1

Rf (EP / AcOEt, 60/40): 0.08

Compound 5G

Operating mode:

Procedure identical to that described in Example 1 from compound 5F.

Compound 5G was obtained in 100% yield.

Compound 5G

(3S, 5S, 10S, 12S, 13S, 17S) -12-hydroxy-10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [ a] phenanthrene-3-yl acetate

M = 420.58 g / mol

Characteristics of the 5G compound:

Method n ° 3 which makes it possible to further improve the overall yield

Synthesis of compound 5I

From a solution of 1.73 g (4.15 mmol) of 3β, 5α, 12β-diacetoxy pregnanolone in 30 ml of CH ₂ CL ₂ was added: 2.10 ml (37.6 mmol) of ethylene glycol, 5.20 ml (31.3 mmol) of triethylorthoformate and pTsOH in catalytic amounts. The reaction medium was refluxed for 24 hours (40 ° C.). After cooling to room temperature (25 ° C), 20 ml of water was added.

The phases were separated and the aqueous phase was extracted twice with 20 ml of CH ₂ Cl ₂ .

The organic phases were combined and washed with 20 ml of saturated NaHCO 3 solution, dried over sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure (35 ° C, 20 mbar).

The product obtained was purified by chromatography on silica gel (30 g SiO ₂ , EP / AcOEt 70/30), making it possible to isolate 1.72 g of compound 51. The white solid product was obtained in a yield of 90% .

(3S, 5S, 10S, 12R, 13S, 14S, 17S

) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene-3,12-diyl diacetate

Compound 51

Characteristic of compound 51

NMR Ή: 300 MHz, (C _fi D _f )

4.90 (dd, 1H, J = 4.9-1.1, 2Hz, H-12a); 4.80 (tt, 1H, J = 5.07-1.1, 7Hz, H-3a); 3.70-3.35 (m, 4H, dioxolane); 2.00-0.50 (m, 21H); 1.95 (s, 3H, CH ₃ , Ac); 1.76 (s, 3H, CH ₃ , Ac); 1.34 (s, 3H, CH ₃ , H-21); 0.92 (s, 3H, CH ₃ ); 0.57 (s, 3H, CH ₃ ).

NMR ^at C: 75 MHz, C _fi D _fi

169.3 (2C = O, 20Ac); 1, 1, 5 (C, C-20); 79.1 (CH); 73.1 (CH); 64.0 (CH ₂ , dioxolane); 63.6 (CH ₂ , dioxolane); 58.0 (CH); 55.0 (CH); 52.2 (CH); 46.1

Synthesis of 5J

From a solution of 1.96 g (3.66 mmol) of compound 51, in 70 ml of MeOH was added 4.50 g (80.20 mmol) of KOH.

The reaction medium was heated at reflux (65 ° C.) for 16 hours. After cooling to room temperature 25 ° C. 50 ml of water were added.

The aqueous phase was extracted 3 times with 100 ml of CH ₂ CL ₂ . The organic phases were combined and dried over sodium sulphate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure (35 ° C., 20 mbar) to obtain 1.14 g of compound 5J, with a yield of 83%. This white solid compound was used without purification in the next step.

(3S, 5S, 10S, 12R, 13S, 14S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene- 3, 12-diol

Compound 5J Characteristic of the compound 5J

300 MHz NMR, (C _fi D _fi )

Synthesis of 5K compound

From a solution of 612 mg (1.63 mmol) of the compound 5J in 20 ml of CH ₂ CL ₂ was added: 0.19 ml (1.96 mmol) of Ac ₂ O, 0.26 ml ( 3.26 mmol) of pyridine and DMAP in catalytic amounts.

The reaction medium was stirred for 19 hours at room temperature (25 ° C.).

20 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 20 ml of CH ₂ Cl ₂ .

The organic phases were combined and washed with 20 ml of 10% HCl solution, dried over sodium sulphate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure (35 ° C, 20 mbar).

The product obtained was purified by chromatography on silica gel (30 g SiO ₂ , EP / AcOEt 80/20), to isolate 483 mg of 5K compound the product was obtained in a yield of 70%.

(3S, 5S, 10S, 12R, 13S, 14S, 17S) -12-hydroxy-10,13-dimethyl-17- (2-methyl-1,3-dioxolan-2-yl) hexadecahydro-1 - / - cyclopenta [a] phenanthren-3-yl acetate

5K compound

Characteristic of 5K compound

Compound 5H

Operating mode:

Same procedure as that described in Example 1 -j from the compound 5K.

Compound 5H was obtained with a yield of 80%.

Compound 5H

(3S, 5S, 10S, 13S, 17S) -10,13-dimethyl-17- (2-methyl-1,3-dioxol-2-yl) -12-oxohexadecahydro-1H- cyclo penta [a] phenanthrene-3-yl acetate

M = 418.57 g / mol

Characteristics of compound 5H:

NMR 'Η: 300 MHz, C _fi D _{fi fi}

4.76 (1H, tt, J11, 5- 5.0, 3a-H); 3.70- 3.45 (4H, m, acetal); 3.12 (1H, t, J 9.9, 17a-H); 2.24 (1H, t, J 12.9, 11 -H); 2.07 (1H, dd, J 5.1 - 12.6, 11 -H); 2.00-0.40 (18H, m); 1.76 (3H, s, OAc); 1.61 (3H, s, 21-H); 1, 15 (3H, s, Me); 0.52 (3H, s, Me).

NMR ^at C: 75 MHz, C _fi D _fi

1, 6 (C = O, 12-C); 169.3 (OAc); 1, 1, 3 (C, 20-C); 72.8 (CH, 3-C); 65.4

(CH ₂ , acetal); 62.8 (CH ₂ , acetal); 57.7 (CH); 56.6 (C); 56.1 (CH); 49.7

(CH); 43.9 (CH); 37.7 (CH ₂ ); 35.9 (CH ₂ ); 35.7 (C); 34.4 (CH); 33.9 (CH ₂ );

30.9 (CH ₂ ); 28.1 (CH ₂ ); 27.3 (CH ₂ ); 24.6 (CH ₃ ); 23.7 (CH ₂ ); 21, 8 (CH ₂ );

20.7 (CH ₃ ); 13.0 (CH ₃ ); 1 1, 3 (CH ₃ ).

IR: ν (C = O): 1728- 1693 cm ^-1

Rf (EP / AcOEt, 60/40): 0.50

M.p. 136-138 ° C

OD = +67 (c 0.006, CHCl ₃ )

Compound 5C

Operating mode:

Identical to that described in Example 1-kl from 5H The isolated 5C compound is obtained with a yield of 31%, the 17C isolated spiro derivative with a yield of 19% and the 17B diketone isolated with a yield of 10%. The trans analogue of the compound 12A1 is obtained with an overall synthesis yield of 13% from the compound 3, 13 -bis (acetoxy), 5Ha pregna-20-one or 5% from the hecogenin acetate which represents a yield of at least 50 times, or even 130 times higher yields of steroid synthesis with the methods of the prior art.

Compound 5C

(3S, 5S, 10S, 12R, 13S, 14S, 17S) - 17-acetyl-12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate

M = 392.53 g / mol

Characteristics of the compound 5C:

- Diketone compound 17B

(3S, 5S, 10S, 13S, 14S, 17S) -17-acetym-10,13-dimethyl-12-oxohexadecahydro-1H-cyclopenta [a] phenenanthren-3-yl acetate

compound 17B

Characteristics of 17B

- Spiro compound 17C

(2'S, 3a'R, 5a'S, 7'S, 9a'S) -3-acetyl-2'-hydroxy-2,9a'-dimethyl-1 ', 2', 3a ', 4', 5a ', 6', 7 ' , 8 ', 9', 9a ', 9b'-dodecahydrosprio [cyclopent [2] ene-1,3'-cyclopenta [a] naphthalene] -7'-acetate

compound 17C

Characteristics of 17C compound

Example 5: relates to the synthesis of 3 analogues

Compound 18: AB cis, 3β-ΟΒζ, 12α-ΟΗ, double bond 14-15, 20-OAc Compound 19: AB cis, 3β-ΟΒζ, 12α-ΟΗ, 14β-ΟΗ, 20-OAc

Compound 20: cis AB, 3β-ΟΒζ, 12β-ΟΗ, 14β-ΟΗ, 20-OAc Analogue P57: OAc in 20, cis AB cycles

Compound 7A: (Deoxycholic acid, commercial product reference B20061 from Alfa Aesar)

Compound 7B

Operating mode:

A solution was prepared from 20.70 g of deoxycholic acid (52.7 mmol) in 200 ml of methanol. This solution was cooled to 0 ° C. and then treated with 10 ml (140 mmol) of acetyl chloride (AcCl).

After stirring for 2 h at 25 ° C. (room temperature), the mixture is cooled to 0 ° C. and 200 ml of water are added.

The aqueous phase is extracted 3 times with 200 ml of dichloromethane (CH 2 Cl 2). The organic phases are combined in an Erlenmeyer flask, dried over sodium sulphate (Na ₂ SO ₄ ) and concentrated under reduced pressure (20 mbar) under a temperature of 35 ° C.

The white residue obtained is purified by chromatography on silica gel (300 g SiO ₂ , EP / AcOEt 60/40 v / v), making it possible to obtain 20.22 g of compound 7B (49.7 mmol), in solid form. The product was obtained with a yield of 94%.

methyl 4 - ((3R, 5R, 10S, 12S, 13R, 17R) -3,12-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-17-yl) pentanoate Characteristics of compound 7B:

Compound 7C

Operating mode

A solution was prepared with 10.19 g of compound 7B

(25.05 mmol) in 1 L MeOH. This solution was degassed for 15 minutes with Argon and then irradiated for 24 hours with an HPK 125 lamp.

The solvents were evaporated under reduced pressure (20 mbar) at a temperature of 35 ° C.

The white residue obtained is purified by chromatography on silica gel (300 g SiO ₂ , EP / AcOE, 80/20 to 40/60) to obtain 2.99 g of compound 7C (9.00 mmol), in solid form. . The product was obtained with a yield of 36%.

Compound 7C

(3R, 5R, 10S, 12S, 13S, 17R) -10,13-dimethyl-17- (prop-1-en-2-yl) hexadecahydro-1H-cyclopenta [a] phenanthrene-3, 12-diol

M = 332.52 g / mol

Characteristics of compound 7C:

Compound 7D

Operating mode:

A solution was prepared from 2.28 g of compound 7C (6.88 mmol) in 40 ml of distilled THF. To this solution was added 3.81 g of triphenyl phosphine (PPh ₃ , 14.15 mmol), 1.70 g of acid benzoic acid (13.92 mmol) and 2.5 ml of a solution of DEAD (13.70 mmol) in 20 ml of distilled THF.

The yellow solution is stirred at 25 ° C. (room temperature) for 20 hours and then the solvent is evaporated under reduced pressure (20 mbar) under a temperature of 35 ° C.

The residue obtained is purified by medium pressure chromatography (pump ProMinent Type BT4A) on silica gel (200 g SiO ₂ , EP / AcOEt, 90/10) making it possible to obtain 1.10 g of compound 7D (2.54 mmol), in solid form. The product was obtained with a yield of 37%.

M = 436.63 g / mol

Characteristics of compound 7D:

Compound 7E

Operating mode:

A solution was prepared from 968 mg of compound 7D (2.23 mmol) in 56 ml of MeOH and 60 ml of CH ₂ Cl ₂ . This solution is cooled to -70 ° C and a stream of ozone is passed in the medium until appearance of a blue color (about 2 min). Then the ozone stream is replaced by a stream of argon until the blue color disappears.

1 ml of Me ₂ S (13.68 mmol) is added. The medium is allowed to return to RT with stirring and the solvents are evaporated under reduced pressure (20 mbar) under a temperature of 35 ° C.

The residue obtained is purified by medium pressure chromatography (pump ProMinent Type BT4A) on silica gel (30 g SiO ₂ , EP / AcOEt, 90/10) to obtain 898 g of compound 7E (2.06 mmol), in the form of solid. The product was obtained with a yield of 92%.

Compound 7E

(3S, 5S, 2S, 13S, 17S) -17-Acetyl-12-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-3-ylbenzoate

M = 438.60 g / mol

Characteristics of compound 7E:

Compound 7F

Operating mode Same procedure as that described in Example 1 - starting with compound 7E.

Compound 7F was obtained with a yield of 70%.

Compound 7F

(3S, 5S, 3S, 17S) -17-Acetyl-10,13-dimethyl-12-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-3-ylbenzoate

M = 436.58 g / mol

Characteristics of compound 7F:

Rf (EP / AcOEt, 70/30): 0.33

7G compound

Operating mode:

A solution was prepared from 1.23 g of compound 7F (2.83 mmol) in 20 ml of dichloromethane (CH 2 Cl 2) and then 8.0 ml of ethylene glycol (140.0 mmol) and 1.8 ml of BF ₃ . And ₂ O (14.33 mmol) are added.

The solution was stirred for 3h at 25 ° C (room temperature).

20 ml of water are added and the phases are separated in a separating funnel. The organic phase is washed once with 20 ml of saturated sodium bicarbonate solution (NaHCO 3), dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (35 ° C., 20 mbar).

The residue obtained is purified by medium pressure chromatography (pump ProMinent Type BT4A) on silica gel (50 g S1O2, EP / AcOEt, 90/10) to obtain 1.1 g of compound 7G (2.33 mmol). , in solid form. The product was obtained with a yield of 82%.

7G compound

(3S, 5R, 10S, 13S, 17S) - 17-Acetyl-10,13-dimethylhexadecahydrospiro [cyclopenta [a] phenanth

12.2 '- [1, 3] dioxolane] -3-yl benzoate

M = 480.64 g / mol Features of 7G compound:

7H compound

Operating mode:

A solution was prepared from 1.06 g of compound 7G (2.22 mmol) in 30 ml of a THF / MeOH mixture (2/1) and then 1.21 g of cerium chloride (CeCl ₃ , 7H _2). 0, 3.24 mmol) and 0.13 g of NaBH ₄ (3.37 mmol) are added.

The solution is stirred magnetically for 2h at 25 ° C (room temperature).

5 ml of a 10% hydrochloric acid solution is added until neutral pH. The aqueous phase is extracted 3 times with 20 ml of dichloromethane (CH ₂ Cl ₂ ). The oragnic phases are collected in an Erlenmeyer flask, dried over sodium sulphate (Na ₂ SO ₄ ) and concentrated under reduced pressure (35 ° C., 20 mbar). 1.05 g of compound 7H (2.17 mmol, 98%) were obtained in solid form. This compound was used without purification in the next step below.

M = 482.65 g / mol

Characteristics of compound 7H:

Mass for C ₃ H ₄₂ O ₅ calculated% C,% H: C, 74.65; H, 8.77; O, 16.57 found% C,% H: C: 73.73-73.64; H: 8.786-8703

MS: 483.31 (MH ⁺ )

R 96-99 ° C

Rf (EP / AcOEt, 70/30): 0.35

Compound 71

Operating mode:

A solution was prepared from 1.03 g of compound 7H (2.14 mmol) in 40 ml of acetone and 300 mg of para toluene sulfonic acid (1.74 mmol) were added. After 8 hours of refluxing, the solution is cooled to 25 ° C. (room temperature).

30 ml of water are added and the aqueous phase is extracted 3 times with 20 ml of ether (Et ₂ O). The organic phases are combined in an Erlenmeyer flask, washed once with saturated sodium bicarbonate solution (NaHCO 3), once with a saturated solution of sodium chloride (NaCl), dried over sodium sulphate (Na ₂ SO ₄ ) and finally concentrated under reduced pressure (35 ° C, 20 mbar).

The residue obtained is purified by medium pressure chromatography (pump ProMinent Type BT4A) on silica gel (40 g S102, EP / AcOEt, 90/10) making it possible to obtain 0.65 g of compound 71 (1.49 mmol), under solid form. The product is obtained with a yield of 70%.

Compound 71: (3S, 5R, 10S, 13S, 17S) -17 ((S) -1-hydroxyethyl) -10,13-dimethyl-12-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-3-ylbenzoate

M = 438.60 g / mol

Characteristics of compound 71:

Compound 7J

Operating mode:

Same as that described in Example 1-i) from 71. Compound 7J was obtained in 80% yield.

Compound 7J

(3S, 5R, 1S, 13S, 17S) -17- ((S) -1-Acetoxyethyl) -10,13-dimethyl-12-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-3-ylbenzoate

M = 480.64 g / mol

Characteristics of compound 7J:

Compound 18

Operating mode:

Same as that described in Example 1-k-1) from 7J. Compound 18 is obtained in solid form, which is a cis analogue of compound 12A1, with an overall yield of synthesis of 1.7%, which represents a yield of at least 17 times, or even 100 times greater than the synthesis yields. steroids with the methods of the prior art.

Compound 18

(3S, 5S, 5S, 13S 17S) -1 - ((S) -1-acetoxyethyl) -12-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9, 10.1 1, 12,13,16,17- tetradecahydro-1 / - / - cyclopenta [a] phenanthrene-3-yl

benzoate

M = 480.64 g / mol

Characteristics of compound 18:

Compound 19

Operating mode:

Same as that described in Example 1-k-1) from 7J. Compound 19 is obtained in solid form, which is a cis analogue of compound 12A1, with a total synthesis yield of 0.6%, which represents a yield of at least 6 times, or even 100 times greater than the synthesis yields. steroids with the methods of the prior art.

Compound 19

(3S, 5R, 10S, 12S, 13S, 14S, 17S) - ((S) - 1-acetoxyethyl) - 12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-3 -yl benzoate

M = 498.65 g / mol

Characteristics of compound 19:

Compound 20

Operating mode:

Same as that described in Example 1-k-1) from 7J. Compound 20 is obtained in solid form, which is a cis analogue of compound 12A1, with an overall synthesis yield of 0.5%, which represents a yield of at least 5 times, or even 100 times greater than the synthesis yields. of steroids with the methods of the prior art

Compound 20

(3S, 5S, 12R, 13S, 14S, 17S) - ((S) -1-acetoxyethyl) -12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-3-yl benzoate

M = 498.65 g / mol

Characteristics of the compound 20:

Example 6: relates to the synthesis of 2 analogues:

Compound 21: 5-6 double bond, 3β-ΟΑο, 12α-ΟΗ, 14-15 double bond, 20-OAc

Compound 22: 5-6, 3β-ΟΑο, 12α-ΟΗ, 14β-ΟΗ, 20-OAc double bond

Compound 8A

Operating mode:

The procedure is identical to that described in Example 1-g-h) from a compound falling within the definition of compound VI of the claims.

Compound 8A was obtained in 100% yield.

Compound 8A

(3S, 12S, 13S, 17S) -1 - ((S) -1-hydroxyethyl) -10,13-dimethyl-2,3,4,7,8,9,10,1 1,12,13, 14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthrene-3,12-diol

M = 334.49 g / mol

Characteristics of compound 8A:

Compound 8B

Operating mode:

The procedure is identical to that described in the example

1 -i) from 8A.

Compound 8B was obtained with a yield of 63%.

(1S) -1 - ((3S, 10R, 12S, 13S, 17S) -3-acetoxy-12-hydroxy-10,13-dimethyl-2, 3,4,7,8, 9,10,1 1, 12,13,14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 418.57 g / mol

Characteristics of compound 8B:

Compound 8C

Operating mode:

The procedure is identical to that described in Example 1 -b from 8B.

Compound 8C was obtained with a yield of 81%.

ompos 8

(1 S) -1 - ((3S, OR, 13S, 17S) -3-acetoxy-10,13-dimethyl-12-oxo 2,3,4,7,8,9,10,11,12, 13,14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 416.55 g / mol

Characteristics of compound 8C:

300 MHz NMR. CDC

5.40 (1H, m, 6-H); 4.73 (1H, dq, J 6.0- 10.2, 20-H); 4.64-4.53 (1H, tt, J1 1, 4-4.9, 3a-H);

2.62 (1H, t, J 12.9, 11 -H); 2.53-2.15 (5H, m); 2.10-0.90 (12H, m); 2.03

Compound 21

Operating mode:

The procedure is identical to that described in Example 1-k-1) from 8C.

Compound 21 is obtained in a yield of 17%. Compound 21 is obtained in solid form, which is an analogue of the compound of formula (XIII) of the claims, with a total synthesis yield of 4.0%, which represents a yield of at least 40 times, or even 100 times higher yields of steroid synthesis with the methods of the prior art

Compound 21

(1 S) -1 - ((3S, 0R, 12S, 13R, 17S) -3-acetoxy-12-hydroxy-10,13-dimethyl-2,3,4,7,8,9, 10,1 , 12,13,16,17-dodecahydro-1H-cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 416.55 g / mol

Characteristics of compound 21:

Compound 22

Operating mode The procedure is identical to that described in Example 1-kl from 8C.

Compound 22 is obtained with a yield of 12%

Compound 22 is obtained in solid form, which is an analogue of the compound of formula (XIII) of the claims, with an overall yield of synthesis of 2.9%, which represents a yield of at least 29 times, or even 100 times higher than steroid synthesis yields with prior art methods.

Compound 22

(1S) -1 - ((3S, 10R, 12R, 13S, 14S, 17S) -3-acetoxy-12,14-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10 , 1 1, 12,13, 14,15,16,17- tetradecahydro-1 / - cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 434.57 g / mol

Characteristics of compound 22:

Example 7 relates to the synthesis of 4 analogues:

Compound 23: AB trans, 3 -OAc, 12a-OH, 14-15 double bond, 20-OAc Compound 24: AB trans, 3β-OAc, 12a-OH, 8-14 double bond, 20-OAc

Compound 25: AB trans, 3β-OAc, 12α-ΟΗ, 14β-ΟΗ, 20-OAc

Compound 26: AB trans, 3β-OAc, 12β-ΟΗ, 14β-ΟΗ, 20-OAc

Compound 9C Procedure:

Procedure identical to that described in Example 5 (compound 7G) from 5B

Compound 9C was obtained in 100% yield.

9C compound

(3S, 5S, 10S, 13S) -17-acetyl-10,13-dimethylhexadecahydrospiro [cyclopenta [a] phenanthrene-12,2 '- [1,3] dioxolane] -3-yl acetate

M = 418.57 g / mol Characteristics of compound 9C:

9D compound

Operating mode:

Same procedure as that described in Example 5

(compound 7H) from 9C.

Compound 9D was obtained with a yield of 87%.

9D compound

(3S, 5S, 10S, 13S) -17- (1-hydroxyethyl) -10,13-dimethylhexadecahydrospiro [cyclopenta [a] phenanthrene-12,2 '- [1,3] dioxolane] -3-yl acetate M = 420.58 g / mol

Features of 9D compound:

9E compound

Operating mode:

Procedure identical to that described in Example 5 (compound 71) from 9D

Compound 9E was obtained with a yield of 69%.

9E compound

(3S, 5S, 10S, 13S) -17- (1-Hydroxyethyl) -10,13-dimethyl-12-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate

M = 376.53 g / mol

Characteristics of compound 9E:

9F compound

Operating mode Procedure identical to that described in Example 5 (compound 7J) from 9E

Compound 9F was obtained with a yield of 83%.

9F compound

1 - ((3S, 5S, 10S, 13S) -3-acetoxy-10,13-dimethyl-

12-oxohexadecahydro-1H-cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 418.57 g / mol

Features of 9F compound:

9G compound

Operating mode:

Same procedure as that described in Example 1 -k) from 9F.

Compound 9G was obtained in 100% yield.

9G compound

1 - (3 - ((4aS, 6S, 8aS) -6-acetoxy-8a-methyl-1- (2-oxoethyl) decahydronaphthalen-2-yl) -2-methylcyclopent-2-enyl) ethyl acetate

M = 418.57 g / mol

Characteristics of compound 9G:

MS: 419.28 (MH ⁺ )

Rf (EP / AcOEt, 70/30): 0.31

Compound 23

Operating mode:

Same procedure as described in Example 1 -1 from 9G.

Compound 23 is obtained with a yield of 26%.

Compound 23 is obtained in solid form, which is an analogue of the compound of formula (XIII) of the claims with a total synthesis yield of 7%, which represents a yield of at least 70 times, or even 100 times greater than the yields. of steroid synthesis with the methods of the prior art

Compound 23

1 - ((3,5S, 10S, 12S, 13R) -3-acetoxy-12-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9, 10, 1 1, 12, 13, 16, 17-tetradecahydro-1H-cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 418.57 g / mol

Characteristics of compound 23:

300 MHz NMR, CDC

5.24 (1H, s, 15-H); 4.95 (1H, dd, J 6.0- 10.8, 20-H); 4.66 (1H, tt, J11, 2-4.9, 3a-H); 3.69 (1H, s, 12β-Η); 2.73 (1H, qd, J 2.4-10.8, 17a-H); 2.26 (1H, m); 2.10-0.70 (20H, m); 2.02 (3H, s, OAc); 1, 22 (3H, d, J 6.1, 21 -H);

Compound 24

Operating mode:

Same procedure as that described in Example 1 -1) from 9G.

Compound 24 is obtained in a yield of 11%. Compound 24 is obtained in solid form, which is an analogue of the compound of formula (XIII) of the claims with a total synthesis yield of 3%, which represents a yield of 1%. at least 30 times, or even 100 times, higher than the steroid synthesis yields with the methods of the prior art.

Compound 24

1 - ((3S, 5S, 10S, 12S, 13R) -3-acetoxy-12-hydroxy-10,13-dimethyl-2,3,4,5,6,7,9,10,11,12, 13, 15, 16, 17-tetradecahydro-1H-cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 418.57 g / mol

Characteristics of compound 24:

Compound 25

Operating mode:

Same procedure as that described in Example 1 -1) from 9G. Compound 25 is obtained with a yield of 9%

Compound 25 is obtained in solid form, which is an analogue of the compound of formula (XIII) of the claims with an overall yield of synthesis of 2.4%, which represents a yield of at least 24 times, or even 100 times greater the steroid synthesis yields with the methods of the prior art.

Compound 25

1 - ((3,5S, 10S, 12S, 13S, 14S) -3-acetoxy-12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 436.58 g / mol

Characteristics of compound 25:

Compound 26

Operating mode:

Same procedure as that described in Example 1 -1) from 9G.

Compound 26 is obtained in a yield of 15%. Compound 26 is obtained in solid form, which is an analogue of the compound of formula (XIII) of the claims, with an overall yield of 4%, which represents a yield of at least 40 times, or even 100 times, greater than the yields of steroid synthesis with the methods of the prior art

Compound 26

1 - ((3S, 5S, 10S, 12R, 13S, 14S) -3-acetoxy-12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthrene-17-yl) ethyl acetate

M = 436.58 g / mol

Characteristics of Compound 26:

300 MHz NMR, CDC

Example 8 (method 2 for the synthesis of compound 16 A)

Synthesis of compound 10A

From a solution of 892 mg (2.02 mmol) of compound 7F in 40 ml of MeOH, 1.05 g (18.71 mmol) of KOH was added.

The reaction medium was refluxed for 2 hours (65 ° C.). After cooling to room temperature (25 ° C), 30 ml of water was added.

The aqueous phase was extracted 3 times with 50 ml of CH ₂ Cl ₂ . The organic phases were combined and dried over sodium sulfate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure (35 ° C, 20 mbar). To obtain 743 mg of compound 10A

The white solid product thus obtained with a yield of 100% was used without purification in the next step

3S, 5R, 10S, 13S, 17S) -17-acetyl-3-hydroxy-10,13-dimethyltetradecahydro-1H-cyclopenta [a] phenanthren-12 (2H) -one

Compound 10A

Characteristics of the compound 10A:

Synthesis of compound 10B

From a solution of 690 mg (1.90 mmol) of compound 10A, in 60 ml of CH ₂ Cl ₂ was added: 0.55 ml (4.99 mmol) of Ac ₂ O, 0.92 ml (1 1, 89 mmol) pyridine and DMAP in catalytic amounts.

The reaction medium was refluxed for 6 hours at room temperature (25 ° C.). After cooling to room temperature (25 ° C), 30 ml of water was added. The phases were separated and the aqueous phase was extracted 3 times with 30 ml of CH ₂ Cl ₂ .

The organic phases were combined and washed with 20 ml of a 10% solution of HCl and with 20 ml of a saturated solution of NaHCO 3, dried over sodium sulphate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure ( 35 ° C, 20 mbar).

The product obtained was purified by chromatography on silica gel (30 g SiO ₂ , EP / AcOEt 70/30), to isolate 427 mg of compound 10B, the product was obtained in a yield of 60%.

(3S, 5R, 10S, 13S, 17S) -17-acetyl-10,13-dimethyl-12-oxohexadecahydro-1H-cyclopenta [a] phenanthren-3-yl acetate

Compound 10B

Characteristics of the compound 10B:

Synthesis of compound 16A

Procedure identical to that described in Example 1-k-1 from compound 10B

Compound 16A is obtained with a yield of 10%

(3S, 5R, 10S, 12R, 13S, 1 AS, 17S) -17-acetyl-12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenenanthren-3-yl acetate

Compound 16A

Characteristics of compound 16A:

OD = +24 (c 0.022, CHCIs)

Example 9 Synthetic Method of Compounds 11A, 11B and 11C

Compound 11A

Operating mode:

The procedure is identical to that described in Example 1-k-1) from pregnan-12-one, 3,20-bis (acetyloxy) -, (3, 5, 20R).

The compound 11A was obtained in a yield of 28%.

Compound 11 A

(1 S) -1 - ((3S, 5R, 10S, 12S, 13R, 17S) -3-acetoxy-12-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8, 9, 10.1 1, 12, 13, 16, 17-tetradecahydro-1H-cyclopenta [a] phenenanthren-17-yl) ethyl

acetate

Characteristics of the compound 1 1 A:

(CH ₃ ); 17.3 (CH ₃ ).

IR: 3573, 1731, 1707 cm ^-1

HRMS (ESI) m / z: C₁ HH ^ NaO *ΓΜ + Na ⁺ 1 calculated 441, 261 1. find

441, 2623.

Compound 11 B Procedure:

Compound 11 B was obtained in 15% yield.

Compound 11 B

(1 S) -1 - ((3S, 5R, 10S, 12S, 13R, 17S) -3-acetoxy-12-hydroxy-10, 13-dimethyl-2,3,4,5,6,7,9, 10.1 1, 12,13,15, 16,17-tetradecahydro-1H-cyclopenta [a] phenanthren-17-yl) ethyl

acetate

Characteristics of the compound 1 1 B:

(C, C-10); 30.8 (CH); 30.2 (CH ₂ ); 30.1 (CH ₂ ); 26.5 (CH ₂ ); 26.1 (CH ₂ ); 26.0 (CH ₂ ); 25.3 (CH ₂ ); 24.3 (CH ₂ ); 24.2 (CH ₂ ); 21.5 (CH ₃ ); 19.7 (CH ₃ ); 19.4 (CH ₃ ).

Compound 11 C Procedure:

The compound 1 1 C was obtained with a yield of 15%.

Compound 11C

(1 S) -1-

((3S, 5R, 10S, 12R, 13S, 14S, 17S) -3-acetoxy-12,14-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta [a] phenanthren-17 yl) ethyl

acetate

Characteristics of the compound 1 1 C:

Example 10 Synthesis of 12A1 (Method 2) Compound 12A2

Operating mode:

From a suspension of 5 g of S102 in 5 ml of CH2Cl2 was added: a saturated solution of oxalic acid in water (10 drops).

The reaction medium was stirred for 10 minutes at room temperature.

A solution of 485 mg of compound 8 in 5 ml of CH 2 Cl 2 was added to the reaction medium.

The reaction medium was stirred for 1 hour at room temperature

(25 ° C.), then filtered and washed 3 times with 15 ml CH 2 Cl 2 and 3 times with 15 ml of AcOEt.

The solvents were evaporated under reduced pressure, making it possible to isolate 491 mg of compound 12A2 under undiluted oil.

Compound 12A2: 1 - ((3S, 10R, 12S, 13S, 17S) -3,12-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10,1 1,12,13 , 14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthren-17-yl) ethanone

Characteristics of the compound 12A2:

Compound 12B2 Procedure:

From a solution of 485 mg of compound 12A2 (1.46 mmol) in 25 ml of CH ₂ Cl ₂ was added 0.15 ml of Ac ₂ O (1.75 mmol), 0.21 ml of pyridine (2 92 mmol) and DMAP in catalytic amounts. The reaction medium was stirred for 4.5 hours at room temperature (25 ° C.).

20ml of water were added and the phases were separated.

The aqueous phase was extracted with twice 40 ml of CH ₂ Cl ₂ . The organic phases were combined and washed with 40 ml of a 10% solution of HCl and with 40 ml of a saturated solution of NaHCO ₃ , dried over sodium sulphate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure ( 35 ° C, 20 mbar).

The product obtained was purified by chromatography on silica gel (30 g SiO ₂ , EP / AcOEt 70/30), making it possible to isolate 151 mg of compound 12B2 in solid and white form with a yield of 28% and 151 mg of compound 12A2 with a yield of 31%.

Compound 12B2: (3S, 10R, 12S, 13S, 17S) -17-acetyl-12-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,1 1,12,13, 14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthren-3-yl acetal

Characteristics of the compound 12B2:

Compound 12B1 (Example 1: 1-bis)

Operating mode:

From a solution of 230 mg of 12B2 compound (0.61 mmol) in 10 ml of acetone was added 0.60 ml of Jones reagent. The reaction medium was stirred for 30 minutes at room temperature (25 ° C.).

15ml of water were added and the aqueous phase was extracted with 3 times 15ml of Et2O.

The organic phases were combined and washed with 15 ml of a solution of NaHCO 3, 20 ml of NaCl dried over sodium sulphate (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure (35 ° C., 20 mbar).

The product obtained was purified by chromatography on silica gel (10 g SiO ₂ , EP / AcOEt 80/20), making it possible to isolate 120 mg of compound 12B1 in solid and white form in a yield of 53%.

Compound 12B1: (3S, 10R, 13S, 17S) -17-acetyl-10,13-dimethyl-12-2,3,4,7,8,9,10,1 1,12,13,14,15, 16,17-tetradecahydro-1H-cyclopenta [a] phenanthren-3-yl acetate

Characteristics of the compound 12B1:

1 H NMR Spectrum: 300 MHz, CDCH

5.42-5.40 (m, 1H, H-6); 4.59 (tt, 1H, J = 4.6-1.1, 4Hz, H-3a); 3.34 (t, 1H, J = 9.6 Hz, H-17a); 2.62 (t, 1H, J = 13.2 Hz, H-1 1); 2.50-2.00 (m, 4H); 2.26 (s, 3H, CH3, H-21); 2.03 (s, 3H, CH3, Ac); 2.00-0.80 (m, 12H); 1, 12 (s, 3H, CH ₃ ); 0.98 (s, 3H, CH ₃ )

13C NMR spectrum: 75 MHz, CDCH 213.0 (C = O); 209.4 (C = O); 170.2 (C = O, OAc); 139.2 (C = C, C-5); 121, 9

(C = CH, C-6); 73.1 (CH, C-3); 57.6 (C, C-13); 57.4 (CH); 54.0 (CH); 52.7

(CH); 52.7 (CH); 37.6 (CH2); 37.4 (CH ₂ ); 37.2 (C, C-10); 36.4 (CH ₂ );

31, 1 (2CH + CH ₂ ); 27.3 (CH2); 24.0 (CH ₂ ); 22.4 (CH ₂ ); 21, 2 (CH ₃ ); 18.7

(CH ₃ ); 13.2 (CH ₃ )

OD = + 55 (c 0.009, CHCIs)

IR spectrum: 1729.1703 cm ^-1

Compound 12A1 Procedure:

The procedure is identical to that described in Example 1-k-1) from the compound 12B1.

Compound 12A1 is obtained with a yield of 13%.

(3S, 10R, 12R, 13S, 14S, 17S) -17-acetyl-12,14-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10,1,1,12,13 , 14,15,16,17-tetradecahydro-1H-cyclopenta [a] phenanthrene-3-yl acetate Compound 12A1: compound of formula (XIII) of the claims

The characteristics of the product obtained are the same as those presented in the table in section I). List of references

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Claims

1. Process for synthesizing a 12-beta compound of formula (XIII) below:

(XIII)

or a spiro derivative thereof of formula (XI I Ibis) following:

(Xlllbis)

in which :

• R ⁴ represents a function - c = o or - CH - ^ OR ⁶

II CH ₃ CH ₃ wherein R ⁶ is selected from the group consisting of acetyl, benzoyl, carbohydrate, o-aminobenzoyl, nicotinoyl, 2-methylbutyryl, isovaleryl, cinnamoyl, coumaroyl, o-hydroxybenzoyl, anthraniloyl ;

The compound (XIII) comprising or not a double bond in the 5-6 and / or 14-15 position, an OH function being present in the 14-beta position when there is no double bond in the 14-position; 15, preferably having a double bond in position 5-6, no double bond in position 4-5 and an OH function in position 14-beta;

from the compound of formula (XI) below:

(XI)

in which :

R ^4p represents (i) a function, said function

or (ii) a function - CH - _^ OR ⁶

I

CH ₃

where R ⁶ is as defined above;

• R ⁷ is as defined above; and

The substituents in the 3 and 17-beta positions being independently of each other in the alpha or beta position; and said method comprising a step of cleaving the 12-13 ring of the C ring in an aprotic medium by UV photochemical irradiation followed by a cycle C cyclization step.

2. The method of claim 1, wherein the irradiation is performed at a wavelength greater than 200 nm and less than 400 nm.

3. Process according to claim 1 or 2, in which the cydization step is carried out in the presence of an oxygenated organic solvent and an acidic solution.

4. Process for synthesizing a 12-beta steroid of formula (XV) below:

VS

A OH

R ⁷

(XV)

in which :

R ⁷ is as defined in claim 1;

R ⁴ is as defined in claim 1;

The substituents in positions 3 and 17 being in the 3-alpha or 3-beta and 17-beta position; and The compound (XV) comprising or not a double bond at position 5-6 and / or at 14-15, an OH function being present in position 14-beta when there is no double bond in position 14- 15, preferably having a double bond in the 5-6 position, no double bond in the 4-5 position and an OH function in the 14-beta position;

from a compound of formula (I) below:

(I)

In which

R ⁴ and R ⁷ being as defined in claim 1 and R 2 being as defined above;

The junction of the carbon rings A and B being cis or trans; preferably being in the cis position, and

said method comprising carrying out the method defined in claim 1.

The process according to claim 1, said process further comprising a step of synthesizing the compound of formula (XI) from the following compound of formula (X):

(X)

• R ^4p and R ⁷ being as defined in claim 1; and

• the compound (X) with or without a double bond in position 5-6; preferably having a double bond in position 5-6;

The substituents at the 3, 12 and 17-beta positions being independently of one another in the alpha or beta position; and said step of Dess Martin oxidation.

6. The method of claim 5, said method further comprising a step of synthesizing the compound of formula (X) from the compound of formula (IX) below:

(IX)

R ^4p being as defined in claim 1; and

• the compound (IX) with or without a double bond in the 5-6 position, preferably having a double bond in the 5-6 position;

The substituents at the 3 and 12 positions being independently of each other in the alpha or beta position and the substituent in the 17-position being in the 17-beta position; and said step consisting of a selective protection in basic medium of the alcohol function in position 3 of the compound of formula (IX).

The process according to claim 6, wherein the selective protection is carried out in the presence of acetic anhydride, an amine base and a catalyst.

8. The method of claim 7, said method further comprising a step of synthesizing the compound of formula (IX) from the compound of formula (VIII) below:

(VIII)

• R ^4p and R ⁷ being as defined in claim 1; and

• the compound (VIII) with or without a double bond in the 5-6 position, preferably having a double bond in the 5-6 position;

9. The method of claim 8, wherein the hydrolysis is carried out in the presence of a base selected from KOH, K2CO3 in an alcoholic medium.

10. The method of claim 8, said method further comprising a step of synthesizing the compound of formula (VIII) from the following compound of formula (VII):

(VII)

R ^4p being as defined in claim 1 and R2 being as defined in claim 4;

said step consisting of a reduction of dienol acetate.

1 1. A process according to claim 10, wherein the reduction of the dienol is carried out in a large stoichiometric excess of reducing agent in an alcoholic medium.

The process according to claim 10, said process further comprising a step of synthesizing the compound of formula (VII) from the following compound of formula VI):

(VI) Wherein R ⁴ is -C (= O) CH ₃ , wherein R2 is as defined in claim 4 and R ⁷ is as defined in claim 1; and

said step consisting in protecting the ketone function at position 20 of the compound of formula (VI).

13. The method of claim 12, wherein the protection of the ketone function is carried out in the presence of an acid catalyst.

The process of claim 13, wherein the acidic catalyst is pyridinium p-toluene sulfonate.

15. The method of claim 12, said method further comprising a step of synthesizing the compound of formula (VI) from the following compound of formula (V):

R ² c

A S

(V)

R ⁴ being as defined in claim 1 and R2 being as defined in claim 4: The substituents in the 12-position being in the 12-alpha or 12-beta position and the 17-position substituent in the 17-beta position,

said step consisting of an enolization of the enone function.

The process of claim 15, wherein the enolization is conducted at a refluxing temperature.

17. The method of claim 15 or 16, wherein the treatment of the enolization reaction is carried out in the absence of water under vacuum.

18. The method of claim 15, said method further comprising a step of synthesizing the compound of formula (V) from the following compound of formula (IV):

VS

AT

(IV)

R ⁴ being as defined in claim 1 and R2 being as defined in claim 4;

• X is a halogen;

said step consisting of dehydrohalogenation of an alpha-haloketone.

19. The process according to claim 18, wherein the dehydrohalogenation is carried out in an aprotic polar solvent in the presence of a lithium salt or an amine base.

20. The process according to claim 18 or 19, wherein the dehydrohalogenation is carried out at a temperature of 120 to 150 ° C.

21. The process of claim 18 or 19 or 20 wherein the dehydrohalogenation is dehydrobromination.

22. The method of claim 18, said method further comprising a step of synthesizing the compound of formula (IV) from the following compound of formula III):

R being as defined in claim 1 and R2 being as defined in claim 4;

said step consisting of regioselective alpha-halogenation at the 4-position of the compound of formula (III).

23. The method of claim 22 wherein the alphahalogenation is alpha-bromination.

24. The method of claim 22 or 23, wherein the alpha-halogenation is carried out at a temperature of 15 ° C to 25 ° C.

25. The process of claim 22 or 23 or 24, said process further comprising a step of synthesizing the compound of formula (III) from the following formula (II):

(he)

R2 being as defined in claim 4 and R ⁴ being as defined in claim 1;

26. The method of claim 25, said method further comprising a step of synthesizing the compound of formula (II) from the compound of formula (I) as defined in claim 4, said step consisting of a regioselective deprotection of the group -OAc in position 3 of the compound of formula (I).

27. The method of claim 4, further comprising a step of forming a tigloyl derivative in position 12 from the 12-beta compound of formula (XIII) below:

(XIII)

R ⁴ and R ⁷ being as defined in claim 1, the tigloyie derivative being a 12-beta compound of formula (XIV) other than compound 12-beta (XIII) in that the OH at position 12 is replaced by a tigloyie.

28. The process according to claim 27, further comprising a step of regioselective saponification at position 3 of the 12-beta compound of formula (XIV) with formation of the 12-beta compound of formula (XV) 0 defined in claim 4.

29. The method of claim 4 or 28, wherein the 12-beta compound of formula (XV) is selected from the group consisting of glycosylated pregnans and pregnanes.

5

30. Intermediate product of formula (XI) obtained according to the process of claim 5.

31. Intermediate product of formula (X) obtained according to the process of claim 6.

32. Intermediate product of formula (IX) obtained according to the process of claim 8. 5

33. Intermediate product of formula (VIII) obtained according to the process of claim 10.

34. Intermediate product of formula (VII) obtained according to the process of claim 12.

35. Intermediate product of formula (VI) obtained according to the method of claim 15.

36. Intermediate product 12-alpha which is a spiro derivative of the compound of formula (XIIIa) obtained according to the method of claim 1.