USEFUL FOR THE SYNTHESIS OF 9BET A, 10 ALF A- STEROID S

The present invention relates to a process for the preparation of des-A-steroids, intermediates useful for the synthesis of 9p,10a-steroids, which consists of a small number of chemical steps that can be performed on an industrial scale.

State of the art

The class of steroidal compounds with (9β,10α) configurations represents an important group of molecules with known pharmacological activity.

Said derivatives are usually prepared from steroids with a 9α,10β configuration containing two unsaturations at the Δ5,6 and Δ7,8 positions, by a process comprising treatment with ultraviolet radiation. Said steroids can be of natural origin, like ergosterol, or steroids wherein the second unsaturation is inserted chemically by an allylic bromination reaction and subsequent elimination in a basic medium, as described in WO2008/089093 for pregnenolone.

Photochemical treatment promotes the electrocyclic reaction that leads to opening of the B ring of the steroid, forming a secosteroid triene intermediate which, under the same irradiation conditions, can close again, leading to the formation of the steroid with a 9β,10α configuration.

As it involves a process of balance between a number of species, the irradiation reaction does not quantitatively produce the desired steroid with the 9β,10α configuration, but provides a mixture containing the starting steroid, the secosteroid intermediate and its configurational isomers in terms of double bonds, as described in EP0152138. The product must therefore be isolated by laborious purification operations, leading to a considerable reduction in the process yield.

Another method of preparing steroids with a 9β,10α configuration, reported in US3956316, is to demolish a natural steroid, so as to obtain a des-A steroid characterised by a 5-οχο-Δ9,10 α,β unsaturated ketone system. The double bond then undergoes selective hydrogenation, leading to the formation of a des-A steroid with the 9β,10β configuration. Said system is reacted with suitable reagents to lead to the formation of the A ring, selectively obtaining a novel 9β,10α steroid.

Another synthesis route for preparing des-A -steroids, described by Daniewski A.R. et al. in Liebigs Annalen Der Chemie (1989), 11, 1061-1064, is based on a process involving the intermediate (S)-7a-methyl-2,3,7,7a-tetrahydro-lH-indene-l,5(6H)-dione, commonly known as (S)-Hajos-Parrish-ketone. Although said synthesis begins with simple, inexpensive raw materials, it involves numerous chemical steps.

Of the des-A steroids useful for the synthesis of 9β,10α steroids, especially for the synthesis of 9β,10 -progestogen derivatives, the intermediate with structure (la) is particularly advantageous:

This type of compound has a number of characteristics:

1) 9β,10β configuration, useful for subsequent construction of the 9β,10α steroid

2) a keto group at the 17 position, useful for subsequent functionalisation of the 17 position if required

3) the protected keto group at the 5 position.

Compound (la) can be prepared by combining the procedures reported in the literature by Malek, J. Organic Reactions, 1985, 34, Micheli, R.A. et al. The Journal of Organic Chemistry, 1969, 34, 5, 1457-1458 and Krubiner A.M. et al, The Journal of Organic Chemistry, 1968, 33, 9 starting from compound (II) according to Scheme 1 :

Scheme 1

Starting from compound (II), four synthesis steps are therefore required, in the following order: reduction of the 17-keto group of compound (II) to the 17-hydroxy of compound (III); hydrogenation of the double bond of compound (III) to form compound (IV) with (9β,10β) configuration; protection of the ketone at the 5 position of compound (IV) by formation of acetal (V); oxidation from the 17-hydroxy of compound (V) to the 17-keto of compound (la). The total process yield according to scheme 1 is 31% in moles of (la) vs. moles of (II), but according to the process described by Micheli et al, it can be improved by introducing a protection as acetate of the hydroxyl group at the 17 position of compound (III), which is then removed by basic hydrolysis; the obvious drawback of this process is that two more chemical steps are added.

In addition, the hydrogenation reaction reported by Micheli is necessarily conducted with alumina-supported rhodium; however, although said catalyst promotes the formation of compound (IV) with the desired isomer (9β,10β), it is very expensive.

Description

The present invention relates to a process for the synthesis of intermediates of general formula (I)

which are useful for the preparation of 9β, l Oa-steroids wherein X and Z, are independently an oxygen atom or a sulphur atom; R ¹ and R\ are independently a straight or branched or cyclic (C1-C0) alkyl group or a mono-, di- or tri-substituted (C6-C12) aromatic group or a C7-C13 alkyl aromatic group; or R ¹ and R together form a (CQ'Q - A _n -CQ ³ Q ⁴ ) alkylene group, wherein Q ¹ , Q ² , Q ³ and Q ⁴ are independently H or a straight or branched C1-C4 alkyl group; wherein A is a CH > or ('((Ή · group and n- 0, 1 , 2

or

R ¹ and R together form a (C5-C10) aliphatic or aromatic cyclic group.

During the preparation process of compound (I), compound (II) undergoes a chemical transformation whereby two reactions take place simultaneously in the same reaction medium, namely protection of the carbonyl at the 5 position by formation of the acetal or thioacetal, selectively relative to the carbonyl in 17, and selective hydrogenation of the Δ9,10 double bond, as shown in Scheme 2:

(II) (I)

Scheme 2

The stereocentres to the C9 and C ₁₀ atoms, both with the β configurations, are thus obtained, leading, through successive reactions, to selective formation of 9p,10a-steroidal derivatives.

A simultaneous protection and hydrogenation reaction effected under conditions similar to those of the present invention had already been described by Shi in Synthetic Communications (2006), Volume 36 (2), 237-248, starting with a compound of structure (i), devoid of methyl at the 10 position, to form a des-A steroid analogue of structure (ii)

Scheme 3

with the carbonyl at the 5 position protected as 1 ,2-dioxoiane and with configuration a at the 9 position.

It has surprisingly been found that if the reaction similar to Shi's is performed with substrate (I) according to the present invention which, unlike compound (i), has the methyl group in the 10 position, a derivat ive with the β configuration at the 9 posit ion, i.e. opposite to that of compound (ii), is obtained.

The simultaneous hydrogenation and protection reaction from, compound (II) to compound (I) of the invention is conducted by reacting the intermediate with an alcohol or thioaicohoi, in the presence of a catalyst, molecular hydrogen in the form of a gas, or molecular hydrogen produced in situ in the reaction medium. The reaction is optionally performed in the presence of an acid and/or a solvent.

The alcohol or thioaicohoi can be selected from the following categories:

a) a compound of general formula HX-CQ'Q ² -A _n -CQ ³ Q ⁴ -ZH, wherein X and Z are independently an oxygen or sulphur atom; Q ¹ , Q ³ and Q ⁴ , are independently H or a straight or branched 'l -C t alkyl group; wherein A is a ( Ή.· or C(CHh }> group and n is 0, 1 or 2

or b) a compound of general formula R-XH, wherein X is an oxygen or sulphur atom and R is a straight or branched or cyclic (Ci-Ce) alkyl group, or a mono-, di- or tri- su bst ituted (C6-C12) aromatic group or a --C 1 ilkyi aromatic group

or

c) a 1 ,2-dihydroxy substituted, 1 ,2-dith.iol substituted, 1 ,2-h.ydroxyth.iol substituted (C5-C10) aliphatic or aromatic cyclic hydrocarbon.

A compound of the dio! category is preferably used in the present invention. Ethylene glycol of formula HOCH2CH2OH is preferably used.

The catalyst is a substance selected from:

i. Transition metals in elemental form, including palladium, platinum, rhodium, ruthenium and nickel. Said metals can optionally be supported on inert material, including carbon, alumina, silica and barium sulphate, in percentages ranging from 1 % to 20% of the catalyst. Said catalysts can be used mixed with water, in percentages ranging from 5% to 75% of the catalyst;

ii. Oxides and hydroxides of transition metals, in all their states of oxidation, including palladium hydroxide and platinum oxide. Said catalysts can be supported on inert material, including carbon, alumina, silica and barium sulphate, and optionally used in aqueous mixture

iii. Salts and coordination complexes of transition metals, in all their states of oxidation, including ruthenium chloride and palladium tetrakis (triphenylphosphine).

A transition metal in elemental form, is preferably used. 5% Palladium, on carbon, is preferably used.

The palladium-on-carbon catalyst is used in a ratio ranging from 0. 1 % to 50% by weight of compound (II), preferably 0.5%o to 20%>, and more preferably 1 %> to 15%o.

In the present invention, the reduction reaction of the double bond of compound

(II) takes place in. the presence of molecular hydrogen, used in the form of a gas or produced in situ in the reaction medium. Gaseous hydrogen is preferably used, at a pressure ranging from 0. 1 to 10 atmospheres; a hydrogen pressure from 0.7 to 5 atmospheres is preferably used.

The acid optionally used in the process of the invention is selected from:

1) Strong and weak, mo no pro tic and polyprotic mineral acids with formula HY, wherein Y is a halide selected from F, CI, Br and I, or formula H _w BO _m wherein B is S, N, P, CI, Br or I; w is greater than or equal to 1 and m is greater than 1 , including hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid and perchloric acid, and salts of formula Me _p Pl _w BO _m wherein Me is an alkali or alkaline-earth metal cation and B is S, N, P, CI. Br or I; p and w, are independently greater than or equal to 1 and m is greater than 1 , for example sodium hydrogen sulphate; or a combination thereof.

2) Organic carboxyiic acids of general formula R ^" ( ^' ()() ( 1, wherein R' is an aliphatic or aromatic hydrocarbon chain or a haioalkyl chain, such as acetic acid, para- toluenesulphonic acid, trifluoroacetic acid or trichloroacetic acid; or a combination thereof.

A mineral acid, preferably hydrochloric acid, is preferably used.

In a preferred embodiment, acid is added to the reaction mixture so that the pi i reaches a value ranging from about 4.5 to about 5.5.

The reaction is optionally effected in the presence of a suitable solvent, selected from ethers, water, nitriles, aliphatic, acyclic and cyclic hydrocarbons, halogenated hydrocarbon, esters, or mixtures of two or more of said solvents.

Tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, water, dichioromethane, acetonitrile, hexane, heptane or cyclohexane, ethyl acetate or a mixture thereof can preferably be used. Tetrahydrofuran is more preferably used.

The reaction is conducted at a temperature ranging from about -20°C to about

+50°C. A temperature ranging from about +10 to about +30°C is preferably used.

In a preferred embodiment of the invention for the preparation of compound (la), the acid medium is neutralised by adding a basic compound at the end of the reaction.

After the work-up, compound (la) can be isolated with a good degree of purity by crystallisation in a suitable solvent, selected from ethers, aliphatic hydrocarbons, halogenated hydrocarbons, esters, ketones, nitriles, water, or mixtures thereof; the crystallisation solvent is preferably an ether.

The process of the invention provides compounds of formula (I) with the desired stereoisomery by conducting the carbonyl protection reaction at the 5 position of the intermediate of formula (II) and reducing the double bond at the Δ9, 10 position in a single synthesis step according to Scheme 2.

Moreover, unlike the known process reported in Scheme 1 , said process avoids prior reduction of the ketone group at the 17 position to a hydroxyl group, and therefore its subsequent reconversion by oxidation to a ketone, which said operations are conducted to allow the ketone group at the 5 position to be protected selectively relative to the carbonyl in 17.

The process of the invention reduces the synthesis operations, and therefore the time and costs of their conduct.

In a particular aspect, the yield from compound (II) to derivative (la), according to Scheme 4,

Scheme 4

rises from 31%, when the process according to scheme 1 of the literature is used, to 47% according to the present invention, leading to a consequent global, increase in the yield of the preparation process of steroids with a 9β,10α configuration.

Moreover, simple palladium-based catalysts, which are well known to cost less than other metals, such as the rhodium-on-aiumina reported in the literature by M ichel i et al, can also be used in the process of the invention.

In particular, the pal ladiiim-on-carbon catalyst is preferably used in a ratio ranging from 1% to 15% by weight of substrate (II); this quantity, which is much lower than the 50% by weight reported by Micheli et aL, not only increases the benefits in terms of costs, but also makes it easier to remove the catalyst when the reaction is complete.

Example

5,5-Ethylenedioxy-9p, 1 Οβ-des- A-androstan- 17-one

22.3 g (0.096 mol) of (II) is solubilised in a mixture of 223 mL tetrahydrofuran and 44.6 mL ethylene glycol. Aqueous hydrochloric acid, concentrated so that the pH falls into the 4.5-5.5 range, and 1.7 g of palladium on carbon (5% Pd), are then added; the resulting mixture is kept under stirring at room temperature in a hydrogen atmosphere until compound (II) disappears. An aqueous solution of sodium bicarbonate is then added, and the mixture is filtered. The filtrate is concentrated by low-pressure evaporation, providing an aqueous residue which is partitioned between 200 mL of ethyl acetate and 60 mL of water. The aqueous phase is separated and extracted twice with ethyl acetate. The combined organic phases are concentrated by low-pressure evaporation to obtain a residue from which product (la) is isolated by crystallisation from isopropyl ether as a white solid (12.56 g, 0.045 mol), in a 47% yield.

Ή-NMR (600 MHz, chloroform-;/) δ ppm 3.90 - 4.00 (m, 4 H), 2.45 (dd, J=19.4, 9.0 Hz, 1 H), 2.08 (dt, J=19.2, 8.8 Hz, 1 H), 2.01 (dq, J=12.4, 6.4 Hz, 1 H), 1.83 - 1.96 (m, 3 H), 1.75 - 1.82 (m, 2 H), 1.72 (dt, J=14.5, 4.2 Hz, 1 H), 1.58 - 1.67 (m, 3 H), 1.53 (dt, J=13.3, 3.3 Hz, 1 H), 1.42 - 1.51 (m, 2 H), 1.34 (td, J=13.7, 3.6 Hz, 1 H), 0.91 (s, 3 H), 0.85 (d, J=6.6 Hz, 3 H).

MS: [M+H] ⁺ = 279; [M+Na] ⁺ = 301; [2M+Na] ⁺ = 579

The configuration of the stereocentres of compound (la) was tested by single- crystal X-ray diffraction, and the following data were obtained:

Spatial group: P2i2i2r, cell dimensions a = 5.9068(3) A, <x= 90°, b = 8.3528(3) A, β= 90°, c = 30.2714(14) A, γ = 90°; volume 1493.54(12) A ³ .