FR2835839A1 - Production of 7 beta-hydroxy-dehydroepiandrosterone, comprises, e.g. selective oximation and reduction process involving 3-O-acetyl-7-oxo-dehydroepiandrosterone - Google Patents

Abstract

Production of 7beta-hydroxy-dehydroepiandrosterone (I), comprises: (1) protection of the 17-keto group of 3-O-acetyl-7-oxo-dehydroepiandrosterone (II) using an optionally O-protected hydrazine; (2) reduction of the 7-keto group of the obtained 17-oxime (IV) using alkali metal borohydride; (3) deprotecting the oxime; and (4) deprotecting the obtained 3-O-acetyl compound (V) by transesterification. Production of 7beta-hydroxy-dehydroepiandrosterone of formula (I) comprises: (1) regioselective protection of the 17-keto group of 3-O-acetyl-7-oxo-dehydroepiandrosterone of formula (II) using a hydrazine compound of formula NH2OR (III) in non-complexed form; (2) chemoselective and diastereoselective reduction of the 7-keto group of the obtained 3-O-acetyl-7-oxo-dehydroepiandrosterone 17-oxime of formula (IV) using alkali metal borohydride as reducing agent; (3) deprotecting the oxime; and (4) deprotecting the obtained 3-O-acetyl-7beta-hydroxy-dehydroepiandrosterone of formula (V) by transesterification. R = H, 1-3C alkyl, butyl, tert. butyl (optionally substituted benzyl (specifically 2-chlorobenzyl)), CH2SPh, SiMe3 or SiMe2tBu.

Description

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La 7béta-hydroxy-déhydroépiandrostérone (7ss-OH-DHEA) est un dérivé bien connu dans la littérature scientifique ; on peut notamment citer les documents suivants : - Collection Czechoslov. Chem. Commun. 1974,38, 982-992 ; - J. Chem. Soc. Perkin 1 1975,2040-2043 ; - Tetrahedron Lett. 1975,42, 3623-3626 ; - J. Chem. Soc. Perkin 1 1980,2535-2540 ; - Phytochemistry 1999,52, 1279-1282 ; - J. Am. Chem. Soc. 1959, 81, 6295-6297. The invention relates to a new process for the preparation of 7-beta-hydroxydéhydroépiandrosterone of formula (1):

7beta-hydroxy-dehydroepiandrosterone (7ss-OH-DHEA) is a derivative well known in the scientific literature; the following documents can be cited: - Czechoslov Collection. Chem. Common. 1974, 38, 982-992; - J. Chem. Soc. Perkin 1 1975.2040-2043; - Tetrahedron Lett. 1975, 42, 3623-3626; - J. Chem. Soc. Perkin 1 1980, 2535-2540; - Phytochemistry 1999,52, 1279-1282; - J. Am. Chem. Soc. 1959, 81, 6295-6297.

des champignons microscopiques qui pourraient présenter des propriétés phytopathogènes : Rhizopus nigricans, Syncephelastrum racemosum, Cunninghamella Elegans, Cephalosporium aphidicola. Each of the aforementioned documents reports a process for the synthesis of 7ss-OH-DHEA in one step from dehydroepiandrosterone (DHEA), 3p-OAcetyl dehydroepiandrosterone (3ss-OAc-DHEA), or from 3a, 5-cycloandrostane. These processes allow the single-step preparation of 7ss-hydroxy-DHEA, but they use

microscopic fungi which could have phytopathogenic properties: Rhizopus nigricans, Syncephelastrum racemosum, Cunninghamella Elegans, Cephalosporium aphidicola.

3ss-OAc-7ss-OH-DHEA has also been described in documents WO98 / 50409 and US 6, 111, 118 as a by-product of oxidation reactions of 3 (3-OAc-DHEA.

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Mention may also be made of the following documents which refer to the synthesis of 7OH-DHEA, but in the form of a mixture of 7-alpha and 7-beta isomers, which have optionally been separated: - The document WO94 / 08588 describes a 3-step chemical synthesis process using 3ss-OAc-DHEA with separation of the diastereoisomers by crystallization.

The document Journal of Steroid Biochemistry 1978,9, 331-336 describes a process of chemical synthesis in 4 stages starting from 3ss-OAc-17 -ethylene-dioxy-androsten-
17-one with separation of the diastereoisomers by chromatography.

- Documents US5,585, 371 and WO / 9403176 describe a chemical synthesis process in 3 stages starting from 3ss-OAc-DHEA leading to mixtures of isomers 7 (a, p) -OH.

- The Czechoslov Collection documents. Chem. Common. 1961, 26, 2452-2456 and
Journal of Labeled Compounds and Radiopharmaceuticals 1976, 14, 3-9 describe methods for the synthesis of 7ss-3ss-diacetoxy-DHEA in 1 step from 3ss-
OAc-DHEA, with separation of the diastereoisomers by chromatography and crystallization.

- The document Steroidologia 1971,2, 321-331 describes a process for the synthesis of a mixture of 7 (a, p) -OH-3p-OAc-DHEA with separation of the diastereoisomers by chromatography.

Mention may also be made of the following documents which describe processes by chemical route, for the preparation of 7ss-OH-DHEA or of a chemical precursor of 7ss-OH-DHEA: - The document Steroids 1996, 61, 453-460 describes the synthesis of 7p-OH-3j3-AcO-
DHEA in 5 steps from DHEA (protection in position 17 in the form of acetal, esterification in position 3, allylic oxidation, diastereoselective reduction with sodium borohydride (NaBH4), deprotection in position 17).

- The Collect document. Czech. Chem. Common. 1997,62, 109-123 describes the synthesis of 7ss-OH-3ss-OH-DHEA in 6 steps from 3ss, 17ss-diacetoxy-DHEA: (allylic oxidation, diastereoselective reduction with NaBH4 in the presence of CeCI3 in a mixture methanol-THF, protection in position 7, saponification in position
17, oxidation in position 17, deprotection in positions 7 and 3).

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- Document WO 95/10527 describes the synthesis of 7ss-OH-3ss-AcO-DHEA in 2 steps starting from 3p-AcO-7-oxo-DHEA-17-ethylene-acetal by diastereoselective reduction of the ketone in position 7 with NaBH4 and deprotection of the acetal in position 17. This process uses 3j3-AcO-7-oxo-DHEA-17-ethylene-acetal as starting material which is a very expensive commercial product (sold in particular by Steraloids).

The object of the present invention is to propose a process allowing the preparation of 7ss-OH-DHEA in a simple, inexpensive, rapid manner, with industrially acceptable yields and having a diastereoselectivity requiring no equilibration or elimination of the minority diastereoisomer (7a-OH).

In addition, the process according to the invention also has the advantage of comprising a regioselective protection reaction making it possible to obtain 3-0-acetyl-7oxo-DHEA-17-oxime from 3-0-acetyl-7oxo -DHEA under satisfactory conditions with minimum formation of 3-0-acetyl-7oxo-DHEA bis 7,17-oxime. The reduction reaction is not only chemoselective (selective reduction of the ketone function in position 7) but also diastereoselective (obtaining selection of the distereoisomer 7p).

 Finally, the total number of steps of the process according to the invention is only 4.

 The present invention relates to a new process for the synthesis of 7ss-OH-DHEA from 3-0-acetyl-7oxo-DHEA.

 Figure 1 illustrates the 4-step synthesis process of 7ss-OH-DHEA according to the invention.

This process essentially consists in carrying out the regioselective protection of the ketone in position 17 of the 3-0-acetyl-7-oxo-dehydroepiandrosterone of formula (2) in the form of an oxime using a reagent in non-complexed form, then in reduce the ketone in position 7 of the 3-0-acetyl-7-oxo-DHEA-17-oxime of formula (3) chemoselectively and diastereoselectively by using an alkali metal borohydride as a reducing agent, then deprotect the oxime of 3-0-acetyl-7-oxo-DHEA-17-oxime of formula (4), a final deprotection reaction by trans-esterification of 3-
0-acetyl 7ss-hydroxy DHEA of formula (5) leading to the 7p-hydroxy DHEA of formula (1).

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à partir de la 3-0-acétyl-7 -oxo-déhydroépiandrostérone, caractérisé en ce qu'il comprend essentiellement les étapes suivantes : (i) réaction de protection régiosélective de la cétone en position 17 de la 3-0- acétyl-7-céto-déhydroépiandrostérone par un réactif de formule NH20R sous forme non complexée, avec R choisi parmi un hydrogène ; un alkyl choisi parmi un groupement méthyle, éthyle, propyle, isopropyle, butyle, tertiobutyle ; un benzyle substitué ou non, avantageusement l'ortho-chloro-benzyl ; le phénylthiométhyl (CH2-S-Ph) ; un trialkyl silyl choisi parmi SiMe3, SiMe2tBu, de préférence le réactif sous forme non complexée est)'hydroxytamine (NHOH) ; (ii) réduction chémosélective et diastéréosélective de la cétone en position 7 de la
3-0-acétyl-7-oxo-DHEA-17-oxime en utilisant un borohydrure d'un métal alcalin comme agent réducteur ; (iii) réaction de déprotection de l'oxime ; (iv) réaction de déprotection par trans-estérification de la 3-O-acétyl-7ss-hydroxy
DHEA. Thus, the subject of the invention relates to a process for the preparation of 7p-OH-DHEA of formula (1) below:

from 3-0-acetyl-7-oxo-dehydroepiandrosterone, characterized in that it essentially comprises the following stages: (i) regioselective protection reaction of the ketone in position 17 of 3-0-acetyl-7 -keto-dehydroepiandrosterone with a reagent of formula NH20R in uncomplexed form, with R chosen from hydrogen; an alkyl chosen from a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl group; a substituted or unsubstituted benzyl, advantageously ortho-chloro-benzyl; phenylthiomethyl (CH2-S-Ph); a trialkyl silyl chosen from SiMe3, SiMe2tBu, preferably the reagent in uncomplexed form is) 'hydroxytamine (NHOH); (ii) chemoselective and diastereoselective reduction of the ketone in position 7 of the
3-0-acetyl-7-oxo-DHEA-17-oxime using an alkali metal borohydride as the reducing agent; (iii) oxime deprotection reaction; (iv) deprotection reaction by trans-esterification of 3-O-acetyl-7ss-hydroxy
DHEA.

 According to the invention, the regioselective protection reaction of the ketone in position 17 of the 3-0-acetyl-7-keto-DHEA according to step (i) is carried out with a reagent of formula NH20R in uncomplexed form.

 The same protective reaction implemented with a reagent in complex form with an organic or inorganic acid of formula NH3 + OR, X- for which X = Br, HS04, CI, N03, ClO4, P04, oxalate, picrate, always leads more or less partial double protection of the ketone functions in positions 7 and 17 of the starting product.

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Thus, step (i) carried out using a mixture consisting of pyridine and NH2OH. HCl in equimolar amount gives a mixture in a 2: 1 ratio of 17-oxime / (7, 17) -bisoxime. By lowering the reaction temperature the reaction to 0 "C,) the selectivity remains as bad as ever.

In addition, the same step (i) carried out in the presence of NH2OH. HCI in the absence of base, does not give the desired product of formula (3). In addition, if heated, there is a decomposition of the reaction medium.

On the other hand, the use of a reagent of formula NH20R in uncomplexed form according to step (i) of the present invention makes it possible to carry out the reaction for protecting the ketone in position 17 of 3-0-acetyl-7 - keto-dehydroepiandrosterone in excellent regioselectivity conditions.

 The reagent NH20R is generally present in complexed form with an organic or inorganic acid (NH20R. HX); in this case, it must first be neutralized by a base, making it possible to trap HX without HX being able to be subsequently released into the reaction medium.

 The bases which are used according to the invention are well known to those skilled in the art: these are in particular the following bases: LiOH, KOH, NaOH, CsOH, NazCOg, NaHC03, NLizCOs, LiHC03, KzCOs, KHC03, CS2C03, CsHC03, advantageously NaOH.

 So, for example, when NH2OH. HCI is used as a reagent, it can first be neutralized with a sodium hydroxide solution (NaOH) in a minimum of water at room temperature for 30 minutes. Under these conditions HCI is trapped in the form of an inert salt (NaCl), of water and the hydroxylamine in nonchlohydrated form (NH2OH) is generated. This solution is then added to the reaction medium containing the derivative of formula (2) in solution.

 On the other hand, when the reactant NH20R in form complexed with an organic or inorganic acid (NH20R. HX) is neutralized with a base which does not meet the definition given above, step (i) according to the present invention cannot be carried out in desired regioselectivity conditions.

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Therefore, bases such as pyridine, primary, secondary or tertiary amines (for example, triethylamine, 1,4 diazabicyclo [2, 2, 2] octane) cannot be used according to the present invention because although 'they trap HX, they do not destroy HX and they are capable of giving HX back into the reaction medium.

40 C, avantageusement à 20 C, pendant une durée comprise entre 1 et 24h, de préférence entre 3 et 20h, avantageusement pendant 15h ; d) évaporer les solvants organiques miscible à l'eau ; e) extraire la phase aqueuse par un solvant organique, avantageusement choisi parmi le diéthyléther, l'acétate d'éthyle, le chloroforme, le dichlorométhane, de préférence l'acétate d'éthyle, puis laver les phases organiques avec une solution aqueuse saturée en chlorure de sodium (Na CI) ; f) sécher les phases organiques et les évaporer à sec sous vide ; g) éventuellement purifier le résidu suivant des méthodes usuelles. Preferably, the reaction for protecting the ketone in position 17 of the 3-0-acetyl-7-keto-dehydroepiandrosterone following step (i) essentially consists in: a) dissolving the 3-0-acetyl-7-oxo DHEA in a solvent or a mixture of solvents, preferably chosen from water, methanol, ethanol, tert-butanol, pyridine,
N, N-dimethylformamide, preferably methanol; b) adding between 1 and 1.5 equivalents, preferably 1.12 equivalents of reagent of formula NH20R in the form not complexed with an organic or inorganic acid, preferably NH20H; c) stir at a temperature between 0 C and 100 C, preferably between 0 C and

40 C, advantageously at 20 C, for a period of between 1 and 24 hours, preferably between 3 and 20 hours, advantageously for 15 hours; d) evaporating the water-miscible organic solvents; e) extracting the aqueous phase with an organic solvent, advantageously chosen from diethyl ether, ethyl acetate, chloroform, dichloromethane, preferably ethyl acetate, then washing the organic phases with a saturated aqueous solution in sodium chloride (Na CI); f) drying the organic phases and evaporating them to dryness under vacuum; g) optionally purifying the residue according to usual methods.

According to the invention, a preferred embodiment of the chemoselective and diastereoselective reduction reaction according to step (ii) is carried out using as an reducing agent an alkali metal borohydride chosen from sodium borohydride (NaBH4), borohydride lithium (LiBH4), potassium borohydride (KBH4), advantageously NaBH4, optionally in the presence of cerium trichloride (CeCI3) according to a method described in the document Steroids 1996, 61, 453-460.

This preferred method of execution essentially consists of:

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 a) prepare a solution of 3-0-acetyl 7-oxo DHEA 17-oxime in a polar solvent or a mixture of polar solvents chosen from methanol, ethanol, tert-butanol, water, preferably methanol and place the reaction medium in an ice bath; b) add between 1 and 10 equivalents, preferably between 1 and 5 equivalents, advantageously 1.5 equivalents of alkali metal borohydride chosen from NaBH4, LiBH4, KBH, advantageously NaBH, at a temperature of between −10 ° C. and 10 ° C., preferably at 0 C; c) agitating the reaction medium between 0 ° C. and 60 ° C., preferably 25 ° C., for a period of between 1 and 1 ohm, preferably for 2 hours; d) destroying the excess of alkali metal borohydride by adding acetone; e) evaporating the solvents; f) dilute with water and extract the aqueous phase with an organic solvent, advantageously chosen from diethyl ether, ethyl acetate, chloroform, dichloromethane, preferably ethyl acetate, then wash the phases organic with a saturated aqueous solution of sodium chloride (NaCl); g) dry the organic phase and then evaporate to dryness; h) optionally purifying the residue, for example by chromatography.

According to the invention, step (ii) can also comprise an additional step between step a) and step b) which consists in adding between 1 and 10 equivalents of cerium chloride, preferably between 1 and 5 equivalents, advantageously 1.1 equivalents, preferably in hydrated form.

 The deprotection of the oxime in position 17 of the 3-0-acetyl-7ss-hydroxy-DHEA 17-oxime according to step (iii) can be carried out according to methods conventionally used in organic synthesis and well known to man of the trade such as those described in the document Protective Groups in Organic Synthesis, TW Greene, PG

 Mr. Wuts (Wiley Interscience).

 According to the invention, a preferred form of the oxime deprotection reaction according to step (iii) uses sodium dithionite.

 This preferred method of execution essentially consists of:

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 a) dissolving 3-0-acetyl-7 (3-OH-DHEA in a mixture of solvent consisting of water and an alcoholic solvent, said alcoholic solvent is chosen from ethanol, methanol or tert-butanol, preferably methanol; b) add between 1 and 10 equivalents, preferably between 3 and 10 equivalents, advantageously 5 equivalents of sodium dithionite; c) agitating the reaction medium for a period of between 1 and 48 hours, preferably between 1 hour and 24 hours, advantageously for 20 hours; d) evaporate the reaction solvent and dilute with water, then extract the mixture with an organic solvent preferably chosen from dichloromethane, ethyl acetate, chloroform or diethyl ether, advantageously ethyl acetate; e) dry the organic phase and then evaporate to dryness; f) optionally purifying the residue, for example by chromatography.

According to the invention, a preferred form of the deprotection reaction according to step (iv) is a transesterification reaction using an alkali metal alcoholate in the corresponding alcohol.

choisi de préférence parmi l'éthanolate, le tert-butanolate ou le méthanolate, avantageusement le méthanolate, le métal alcalin étant choisi de préférence parmi le lithium, le sodium ou le potassium, avantageusement le sodium ; c) agiter le milieu réactionnel pendant une durée comprise entre 0,5 et 12h, de préférence entre 1 h et 5h, avantageusement pendant 2h ; d) évaporer le solvant réactionnel et diluer avec de l'eau, puis extraire le mélange avec un solvant organique choisi de préférence parmi le dichlorométhane, l'acétate d'éthyle, le chloroforme ou le diéthyléther, et avantageusement l'acétate d'éthyle ; e) sécher la phase organique et puis l'évaporer à sec ; f) éventuellement purifier le résidu, par exemple par trituration dans l'acétone, ou par chromatographie. The trans-esterification reaction which is preferably used in the process of the invention essentially consists in: a) dissolving 3-0-acetyl-7 (3-OH-DHEA in an alcoholic solvent chosen from ethanol, methanol or tert-butanol, preferably methanol; b) add between 1 and 5 equivalents, preferably between 1 and 3 equivalents, advantageously 1.1 equivalents of an alkali metal alcoholate, the alcoholate being

preferably chosen from ethanolate, tert-butanolate or methanolate, advantageously methanolate, the alkali metal being preferably chosen from lithium, sodium or potassium, advantageously sodium; c) stirring the reaction medium for a period of between 0.5 and 12 hours, preferably between 1 hour and 5 hours, advantageously for 2 hours; d) evaporate the reaction solvent and dilute with water, then extract the mixture with an organic solvent preferably chosen from dichloromethane, ethyl acetate, chloroform or diethyl ether, and advantageously ethyl acetate ; e) dry the organic phase and then evaporate to dryness; f) optionally purifying the residue, for example by trituration in acetone, or by chromatography.

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 The invention is illustrated in more detail in the following examples which describe the different steps of the process according to the invention.

Dans un réacteur, solubiliser 5g de 3-0-acétyl-7-oxo-DHEA (commercialisé par la Société Quim Dis) dans 125ml de méthanol. Pendant ce temps, dans un autre récipient solubiliser 0,65g de soude en pastilles (1,12 équivalents) dans 10ml d'eau. A cette solution de soude, ajouter 1, 13g d'hydroxylamine chlorhydrate à 98% (1,12 équivalents). Laisser neutraliser 30 minutes. Additionner ensuite ce milieu neutralisé sur la solution de 3-0-acétyl-7-oxo-DHEA, et laisser réagir 15h à température ambiante. Synthesis of 3-0-acetyl-7-oxo-DHEA-17-oxime of formula (3)

In a reactor, dissolve 5 g of 3-0-acetyl-7-oxo-DHEA (sold by the company Quim Dis) in 125 ml of methanol. Meanwhile, in another container dissolve 0.65g of sodium hydroxide pellets (1.12 equivalents) in 10ml of water. To this sodium hydroxide solution add 1.13 g of 98% hydroxylamine hydrochloride (1.12 equivalents). Leave to neutralize for 30 minutes. Then add this neutralized medium to the 3-0-acetyl-7-oxo-DHEA solution, and allow to react for 15 hours at room temperature.

Concentration of the medium on a rotary evaporator. Dilution with water and extraction with ethyl acetate (AcOEt).

Mass recovered: 5.2 g. Crude yield = 100% 1 H NMR and mass spectrometry show that the expected product is present at 93% and contaminated with the starting product (2%) and with bis-oxime (4%).

Dans un réacteur, solubiliser 5, 2g de 3-0-acétyl-7-oxo-DHEA-17-oxime dans 100ml de méthanol. Ajouter 5,92 de CeCI3. 7H20 (1, 1 équivalents). Refroidir le milieu aux environs de 0 C, puis additionner lentement 0, 82g de NaBH4 en granules (1,5 équivalents). Au Synthesis of 3-0-acetyl-7-beta-hydroxy-DHEA-17-oxime of formula (4)

In a reactor, dissolve 5.2 g of 3-0-acetyl-7-oxo-DHEA-17-oxime in 100 ml of methanol. Add 5.92 of CeCI3. 7.20 AM (1.1 equivalents). Cool the medium to around 0 C, then slowly add 0.82 g of NaBH4 in granules (1.5 equivalents). At

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 after 2 hours, add acetone to destroy the residual NaBH4, 30 minutes with stirring. Concentrate the medium almost dry, then take it up in 100ml of water. Then extract with ethyl acetate. The organic phases are evaporated in vacuo.

Mass recovered: 5.2. Gross yield = 100%.

 1 H NMR and mass spectrometry conform.

Dans un réacteur, solubiliser 5,2g de 3-0-acétyl-7-béta-hydroxy-DHEA dans 100ml d'éthanol, et 50ml d'eau. Ajouter 12,52g de sodium dithionite (5 équivalents) et mettre en chauffe à 70 C pendant 20h. Concentration du milieu sous vide. La phase aqueuse résiduelle est diluée avec de l'eau, et est extraite par AcOEt. Les phases organiques sont rassemblées, séchées sur sulfate de sodium et concentrées à sec sous vide. Synthesis of 3-0-acetyl-7-beta-hydroxy-DHEA of formula (5)

In a reactor, dissolve 5.2 g of 3-0-acetyl-7-beta-hydroxy-DHEA in 100 ml of ethanol, and 50 ml of water. Add 12.52g of sodium dithionite (5 equivalents) and heat at 70 ° C for 20h. Concentration of the medium under vacuum. The residual aqueous phase is diluted with water, and is extracted with AcOEt. The organic phases are combined, dried over sodium sulfate and concentrated to dryness under vacuum.

Obtaining 4.5g of a white solid. Gross yield = 90%.

The product is purified by chromatography on silica gel (EtOAc), to obtain a yield of 75%.

 1 H NMR and mass spectrometry conform.

Synthesis of 7-beta-hydroxy-DHEA of formula (1)

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 In a reactor, dissolve 3.7 g of 3-0-acetyl-7-beta-hydroxy-DHEA in 100 ml of methanol. Add 2.77 ml of 30% sodium methanolate in methanol (1.1 equivalents), and allow to react for 2 hours at room temperature. Then neutralize to pH = 6 by adding 10% HCI. Concentration of the medium under vacuum without going dry. Dilution with 100ml of water.

Then extract with 4x 80ml of AcOEt. The organic phases are combined, dried over sodium sulfate and concentrated to dryness under vacuum.

Obtaining 3.25 g of a white solid. Gross yield = 95%.

Resumption of this solid in 10 ml of cold acetone. Agitation for 1 hour then filtered.

Recovery of 2.45 g of a white solid. Yield = 74%.

 1 H NMR and mass spectrometry conform.

Overall reaction yield = 55% for 4 stages.

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Figure 1

Process for the 4-step synthesis of 7ss-OH-DHEA (i) Regioselective protection of the ketone in position 17 in the form of oxime (ii) Regioselective and diastereoselective reduction of the ketone in position 17 (iii) Deprotection of the oxime (iv) Trans-esterification reaction

Claims (16)

DHEA.  (ii) chemoselective and diastereoselective reduction of the ketone in position 7 of the 3-0-acetyl-7-oxo-DHEA-17-oxime using an alkali metal borohydride as reducing agent; (iii) oxime deprotection reaction; (iv) deprotection reaction by trans-esterification of 3-0-acetyl-7j3-hydroxy

 from 3-0-acetyl-7-oxo-dehydroepiandrosterone, characterized in that it essentially comprises the following stages: (i) regioselective protection reaction of the ketone in position 17 of 3-0-acetyl-7 -keto-dehydroepiandrosterone with a reagent of formula NH20R in uncomplexed form, with R chosen from hydrogen; an alkyl chosen from a methyl, ethyl, propyl, isopropyl, butyl or tert-butyl group; substituted or unsubstituted benzyl, advantageously ortho-chloro-benzyl; phenylthiomethyl (CH2-S-Ph); a trialkyl silyl chosen from SiMe3, SiMe2tBu;

 CLAIM 1. Process for the preparation of 7ss-OH-DHEA of formula (1) below: 2. Preparation process according to the preceding claim, characterized in that step (i) essentially consists of the following steps: a) dissolving 3-0-acetyl-7-oxo DHEA in a solvent or a mixture of solvents; b) adding between 1 and 1.5 equivalents of reagent of formula NH20R in uncomplexed form; c) stir at a temperature between OOC and 100 C, for a time between 1 and 24 hours; <Desc / Clms Page number 14>  d) evaporating the water-miscible organic solvents; e) extract the aqueous phase with an organic solvent, then wash the organic phases with a saturated aqueous solution of sodium chloride (NaCl); D dry the organic phases and evaporate them to dryness under vacuum; g) optionally purifying the residue according to usual methods. 3. Preparation process according to claim 2, characterized in that: - in step a) the solvent is chosen from water, methanol, ethanol, terl-butanol, pyridine and / or N , N-dimethylformamide, advantageously methanol; - in step b) 1.12 equivalents of reagent of formula NH20R are added in uncomplexed form; - in step c) the mixture is stirred at a temperature between OOC and 40 C, advantageously at 20 C, for a period between 3 and 15 h, advantageously for 10 h; and / or - in step e) the organic solvent is chosen from diethyl ether, ethyl acetate, chloroform, dichloromethane. 4. Preparation process according to any one of the preceding claims, characterized in that the reagent of formula NH20R in non-complexed form is hydroxylamine. 5. Preparation process according to claim 1, characterized in that step (ii) consists essentially of the following steps: a) preparing a solution of 3-0-acetyl 7-oxo DHEA 17-oxime in a polar solvent or a mixture of polar solvents and place the reaction medium in an ice bath; b) adding between 1 and 10 equivalents of alkali metal borohydride; c) stir the reaction medium between 0 C and 60 C, for a period of between 1 and 10 h; d) destroying the excess of alkali metal borohydride by adding acetone; e) evaporating the solvents; f) dilute with water and extract the aqueous phase with an organic solvent then wash the organic phases with a saturated aqueous solution of sodium chloride (NaCl); <Desc / CRUD Page number 15>  g) dry the organic phase and then evaporate to dryness; h) optionally purifying the residue, for example by chromatography. 6. Preparation process according to the preceding claim, characterized in that: - in step a) the polar solvent chosen from methanol, ethanol, tert-butanol, water, preferably methanol; in step b) between 1 and 5 equivalents, preferably 1.5 equivalents of alkali metal borohydride, are preferably added; - in step c) the solution is stirred at a temperature between 10 and 60 C, advantageously at 25 C for a period of 2 hours; and / or - in step f) the organic sotvant is chosen from diethyl ether, ethyl acetate, chloroform, dichloromethane, preferably ethyl acetate. 7. Preparation process according to one of claims 5 to 6, characterized in that: - in step b) the alkali metal borohydride is chosen from NaBH4, LiBH4'KBH4, advantageously NaBH4. 8. Preparation process according to any one of claims 5 to 7, characterized in that step (ii) comprises an additional step between step a) and step b) which consists in adding between 1 and 10 cerium chloride equivalents, preferably in hydrated form.  9. Preparation process according to the preceding claim, characterized in that preferably between 1 and 5 equivalents are added, advantageously 1.1 equivalents of cerium chloride.  10. Preparation process according to claim 1, characterized in that the deprotection of the oxime according to step (iii) is a transesterification reaction carried out with sodium dithionite.  11. Preparation process according to any one of claims 1 and 10, characterized in that step (iii) essentially consists of the following steps: a) dissolving 3-0-acetyl-7p-OH-DHEA in a mixture of solvent consisting of water and an alcoholic solvent; <Desc / Clms Page number 16>  b) add between 1 and 10 equivalents of sodium dithionite; c) stir the reaction medium for a period of between 1 and 48 hours; d) evaporate the reaction solvent and dilute with water, then extract the mixture with an organic solvent; e) drying the organic phase east and then evaporating to dryness; f) optionally purifying the residue, for example by chromatography. 12. Preparation process according to the preceding claim, characterized in that: - in step a) the alcoholic solvent is chosen from ethanol, methanol or tertbutanol, preferably methanol; - in step b) between 3 and 10 equivalents, advantageously 5 equivalents of sodium dithionite, are added; - in step c) the reaction medium is stirred for a period of between 1 h and 24 h, advantageously for 20 h; and / or - in step d) the organic solvent is chosen from dichloromethane, ethyl acetate, chloroform or diethyl ether, advantageously ethyl acetate.  13. Preparation process according to claim 1, characterized in that the deprotection reaction according to step (iv) is a transesterification reaction using an alkali metal alcoholate in the corresponding alcohol.  14. Preparation process according to claim 1, characterized in that the deprotection reaction according to step (iv) consists essentially of the following steps: a) dissolving 3-0-acetyl-7p-OH-DHEA in a solvent alcoholic; b) adding between 1 and 5 equivalents of an alkali metal alcoholate; c) stir the reaction medium for a period of between 0.5 and 12 hours; d) evaporate the reaction solvent and dilute with water, then extract the mixture with an organic solvent; e) dry the organic phase and then evaporate to dryness; f) optionally purifying the residue, for example by trituration in acetone, or by chromatography.  15. Preparation process according to the preceding claim, characterized in that: <Desc / Clms Page number 17>  in step a) the alcoholic solvent is chosen from ethanol, methanol or tert-butanol, preferably methanol; - in step b) between 1 and 3 equivalents are added, advantageously 1 equivalent of an alkali metal alcoholate; - in step c) the reaction medium is stirred for a period of between 1 h and 5 h, advantageously for 2 h; and / or - in step d) the organic solvent is chosen from dichloromethane, ethyl acetate, chloroform or diethyl ether, and advantageously ethyl acetate. 16. Preparation process according to any one of claims 14 to 15, characterized in that in step b) the alcoholate is chosen from ethanolate, tert-butanolate or methanolate, advantageously methanolate, alkali metal being chosen from lithium, sodium or potassium, advantageously sodium.