Process for the esterification of a carbothioic acid

1

The present invention generally relates to a process for the esterification of a carbothioic acid, particularly, but not exclusively, in the preparation of fluticasone propionate; and to the use of certain intermediates.

In one aspect, the present invention relates to an improved process for esterification of the hydroxyl group at C-17 of 6α, 9α-difluoro-11β, 17αdihydroxy-16α-methyl-3-oxoandrosta-1,4-diene- 17β Carbotioic, compound of the formula [I], which comprises treating this intermediate with a slight excess of an acyl chloride of the general formula R-COCl, where R represents -CH2CH3, -CH2CH2CH3 or -CH (CH3) 2, in the presence of an appropriate tertiary amine, in an inert solvent, at a temperature between 5 ° C and -20 ° C, to selectively obtain the 17α-acyl derivative of formula [II].

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This invention creates an esterification process that is simpler and more economically efficient than those described in the prior art because it suppresses one of the two chemical reactions described in those procedures. Another feature of the process of this invention is that it gives 17α-esters of high purity.

More particularly, this invention relates to an improved process for the preparation of 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3oxoandrosta-1,4-diene-17β-carbothioic acid, compound of formula [ III], which is an intermediate in the synthesis of fluticasone propionate, an active ingredient used as an anti-inflammatory steroid, effective for the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

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U.S. Patent 4,335,121, British Patents GB 2,088,877, GB 2,137,206, U.S. Patent 4,578,221 and J. Med. Chem., 1994, 37, 3717-3729, describe the propionylation at position 17α of the compound [I], to obtain the fluticasone propionate intermediate [III], by the two chemical steps illustrated below, via the compound an

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In the first step (a), the mixed anhydride [IV] is prepared with an excess of at least 2 moles of propionyl chloride per mole of compound [I], in the presence of triethylamine and using dichloromethane as solvent. After the completion of the propionylation reaction, the reaction mixture is treated and an ante-colored solid is obtained. In the second stage (b), the solid is dissolved in acetone and treated with diethylamine to convert the mixed anhydride into the compound [III]. Once the aminolysis reaction is complete, the reaction mixture is treated to isolate the compound [III].

International patent application WO 03/066654 claims the preparation of intermediate [III] by: (a) reacting compound [I] with at least 1.3 moles of an activated propionic acid derivative per mole of compound [I ], and removal of the sulfur-bound moiety of any compound of formula

[IV] with an organic primary or secondary amine such as diethanolamine or N-methylpiperazine.

Patent application WO 01/62722 describes the esterification in the 17α position of the hydroxy acid compound [V] with an alkanoyl halide, in the presence of a base, and particularly describes the preparation of the 17α-propionate compound of formula [VI]

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by: (a) reacting the hydroxy acid of formula

[V] with 2.3 moles of propionyl chloride per mole of compound [V], using triethylamine as the base, and (b) reacting in situ the compound obtained in (a) with diethylamine.

All acylation procedures at position 17α described in the prior art, or for carbothioic acid [I] or related carboxylic acid [V], use an excess of the acylating agent to ensure completion of acylation at position 17α, therefore requiring aminolysis, with a suitable primary or secondary amine, of any mixed anhydride formed.

We have now found that the transformation of the carbothioic acid compound [I] into the compounds of the general formula [II] can take place selectively directly, with negligible formation of the corresponding mixed anhydride, under conditions described hereinafter. Following the process of the present invention, the 6α, 9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3oxoandrosta-1,4-diene-17β-carbotioic acid, compound [I], is directly converted into compounds of general formula [II]

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by reaction with a slight excess of the corresponding acyl chloride, in an inert solvent, in the presence of an appropriate tertiary amine.

The particular advantage of the present invention over those of the prior art is that the compounds of general formula [II] are obtained directly from the compound

[I] without the need to carry out the aminolysis of the corresponding mixed anhydride. Additionally, under the aminolysis conditions described in the prior art, the chemical stability of carbotioic acid derivatives, such as compound [III], is therefore limited, therefore the simplified process of this invention, eliminating the aminolysis reaction, gives 17α-esters of greater purity.

According to the present invention, a process for preparing compounds of formula [II] is created,

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by esterification of the C-17 hydroxyl group of 6α, 9α-difluoro-11β, 17α-dihydroxy-16α-methyl-3-oxoandrosta1,4-diene-17β-carbothioic acid compound of formula [I], which process comprises Treat this compound [I] with from 1.0 mol to 1.2 moles of an acyl chloride of the general formula R-COCl, where R represents -CH2CH3, -CH2CH2CH3 or -CH (CH3) 2 per mole of compound [I ], in an inert solvent, in the presence of a tertiary amine, which is pyridine, 2-picolina, 3-picolina, 4-picolina, Nmethylimidazole or N-methylpyrrolidine, preferably pyridine, 3-picoline, 4-picoline, N-methylimidazole or Nmethylpyrrolidine.

The invention also creates a process for the preparation of therapeutically useful medicaments, which method comprises preparing a compound of formula [II] according to the method of any one of claims 1 to 11 and then preparing said medicaments therefrom.

The present invention creates an improved and simplified process for selective esterification at position 17α of compound [I], forming negligible amounts of mixed anhydrides of general formula [VII]

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in which R represents –CH2CH3, -CH2CH2CH3 or –CH (CH3) 2 without the need to carry out the aminolysis reaction of the corresponding mixed anhydrides.

The process comprises the reaction of compound [I], 6α, 9α-difluoro-11β, 17α-dihydroxy-16αmethyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid, with from 1.0 mol to 1.2 moles of an acyl chloride of the general formula R-COCl, wherein R represents -CH2CH3, -CH2CH2CH3 or -CH (CH3) 2, per mole of compound [I], in the presence of an appropriate organic tertiary amine as defined above, in an inert solvent, to give the compounds of general formula [II],

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where R represents –CH2CH3, -CH2CH2CH3 or –CH (CH3) 2.

A particularly preferred embodiment of the present invention is to create an improved process for the preparation of 6α, 9α-difluoro-11β-hydroxy-16αmethyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17βcarbotioic acid, compound of formula [ III], which comprises reacting 6α, 9α-difluoro-11β, 17α-dihydroxy16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid [I] with a slight excess of propionyl chloride, in the presence of an appropriate tertiary amine as defined above, in an inert solvent.

The compound of formula [III] is a known intermediate useful in the preparation of anti-inflammatory steroids such as fluticasone propionate of formula [A] (described in US 4 335 121), highly effective in the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD), and in the preparation of the S- (2-oxo-tetrahydrofuran-3-yl) ester of 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17αpropionyloxy-androsta-1,4-diene-17β acid -carbotioic formula

[B] related (described in application WO 97/24365), which has a useful anti-inflammatory activity and has little

or no systemic activity.

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Accordingly, the invention also creates a process for preparing fluticasone propionate, which process comprises preparing 6α, 9α-difluoro11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid according to the process of the invention and converting said compound into fluticasone propionate.

A process for the preparation of the S- (2-oxo-tetrahydrofuran-3-yl) ester of 6α, 9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17αpropionyloxy-androsta-1,4 acid is also created -diene-17β-carbothioic acid, which process comprises preparing 6α, 9α-difluoro-11βhydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene17β-carbothioic acid according to the process of the invention and converting said compound in said S-ester.

The present invention creates an advantageous process for the preparation of 6α, 9α-difluoro-11βhydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene17β-carbothioic acid, compound of formula [III], which comprises treating the compound [I] 6α, 9α-difluoro-11β, 17αdihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17βcarbotioic acid, with propionyl chloride, in the presence of an appropriate tertiary amine as defined above, in an inert solvent, at a temperature between 5 ° C and -20 ° C.

The acyl chloride of the general formula R-COCl is used in the process of the present invention in a molar ratio of 1.0 to 1.2 moles of acyl chloride per mole of the starting compound [I], preferably in an amount within this interval.

The inert solvents for the acylation process at position 17α of the present invention include acetone, tetrahydrofuran, dimethylacetamide, dichloromethane, ethyl acetate, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone and 2-butanone. Acetone is the preferred solvent. Tertiary amines suitable for carrying out propionylation in the selective 17α position include pyridine, 2-picoline, 3-picoline, 4-picoline, N-methylimidazole and N-methylpyrrolidine.

The acylation reaction in position 17α of the invention is preferably carried out at a temperature of from 5 ° C to -20 ° C.

The use of the tertiary amines defined above as suitable for the patent process has advantages over other bases previously described in the prior art such as triethylamine, tripropylamine, ethyldiisopropylamine, N, N-dimethylaniline, N, N-dimethylcyclohexylamine, inorganic carbonates such as, for example, sodium hydrogen carbonate, potassium carbonate and sodium carbonate. When these bases are used, the formation of high levels of the mixed anhydride compound is avoided

[IV] or incomplete consumption of the compound [I] or the formation of high levels of impurities, as is the case when sodium hydrogen carbonate is used.

Under the preferred conditions of the process of the present invention, esterification at position 17α reaches completion with 1.0 to 1.2 moles of propionyl chloride per mole of compound [I], in the presence of pyridine, and the levels of Mixed anhydride formed during the reaction is below 3% (in area, by HPLC). With these low levels of mixed anhydride, the aminolysis reaction is not required and the compound [III] is isolated with a high degree of purity, in the final treatment of the propionylation reaction.

Under the conditions described in the prior art, when compound [III] is prepared via mixed anhydride, partial degradation of compound [III] can occur during the aminolysis reaction. This degradation is especially problematic when prolonged reaction times take place, which is what is expected on an industrial scale. Under the conditions described in the present invention, this in situ degradation of the compound [III] is avoided.

We have found that, following the prior art, a precursor (precursor of G) is formed to an impurity (impurity G).

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GG precursor

With the process of the present invention, the dimer G, which is difficult to separate from the final product, fluticasone propionate, by recrystallization when it is at levels greater than 0.5%, is formed at levels below 0.3%. Therefore, repeated recrystallizations are avoided to obtain material of the required purity, which if carried out significantly reduces the overall yield.

Another embodiment of this invention is to create an improved process for the preparation of the compounds 6α, 9α-difluoro-11β-hydroxy-16α-methyl-17αbutyryloxy-3-oxoandrosta-1,4-diene-17β-carbothioic, compound of formula [VIII], and 6α, 9α-difluoro-11βhydroxy-16α-methyl-17α -isobutir-yloxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid, of formula [IX].

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The compounds of formula [VIII] and [IX] are prepared directly from the compound [I] by reaction with the corresponding acyl chloride, without the need for an aminolysis reaction of the corresponding mixed anhydrides.

According to a preferred aspect of the present invention, the esterification of the compound [I] to obtain the compound [VIII] is carried out with 1.0 to 1.2 moles of butyryl chloride, in acetone, in the presence of pyridine, a a temperature between 5 ° C and -20 ° C, preferably between 5 ° C and 0 ° C.

The esterification of the compound [I] to obtain the compound [IX] is preferably carried out with 1.0 to 1.2 moles of isobutyryl chloride, in acetone, in the presence of pyridine, at a temperature between 5 ° C and - 20 ° C, preferably between 5 ° C and 0 ° C.

The following examples illustrate the invention and certain preferred embodiments and are exempt from the scope of the invention.

Example 1: Preparation of 6α, 9α-difluoro-11β-hydroxy16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17βcarbotioic acid

A suspension of compound [I] (10 g, 0.024 mol) in acetone (175 ml) is cooled to -20 ° C and treated with pyridine (30 ml) and propionyl chloride (2.3 ml, 0.026 mol) while the temperature is maintained between -20 ° C and -15 ° C. The mixture is stirred at -20 ° C / -15 ° C until completion of the reaction. A second addition of propionyl chloride (0.02 ml) can be carried out if necessary to complete the reaction. The compound [III] is precipitated by the addition of water (240 ml) and concentrated hydrochloric acid (30 ml). The suspension is stirred for 2 hours at a temperature between 0 ° C and 5 ° C, filtered, and the wet cake is washed with cold water until neutral pH. The solid is dried at a temperature below 40 ° C, under vacuum, to give the title compound as a white to off-white solid (10.04 g; 88%; Purity,% HPLC area: 96.1% ).

Example 2: Preparation of 6α, 9α-difluoro-11β-hydroxy16α-methyl-17α-isobutyryloxy-3-oxoandrosta-1,4-diene-17β carbotioic acid

Isobutyryl chloride (0.28 ml, 0.0027 mol) is slowly added to a mixture of acetone (17.5 ml), compound [I] (1 g, 0.0024 mol) and pyridine (3 ml), to temperatures between 5 ° C and 0 ° C, and the mixture is stirred at that temperature range until the consumption of the compound [I]. After completion of the reaction, the title compound is precipitated by the addition of water (24 ml) and concentrated hydrochloric acid (3 ml). The suspension is stirred for 1 to 2 hours at a temperature between 0 ° C and 5 ° C, filtered, and the wet cake is washed with cold water until neutral pH. The wet solid is dried at a temperature below 40 ° C, under vacuum, to give the title compound as a white to off-white solid (1.09 g; 93%; Purity,% HPLC area: 94.8% ).

Example 3: Preparation of 6α, 9α-difluoro-11β-hydroxy16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17βcarbotioic acid

A suspension of compound [I] (1 g, 0.0024 mol) in acetone (17 ml) is cooled to a temperature between -20 ° C and -15 ° C. N-methylimidazole (2.9 ml) and propionyl chloride (0.23 ml, 0.0026 mol) are added sequentially to the solution, keeping the temperature between -20 ° C and -15 ° C. After completion of the reaction, compound [III] is precipitated by the addition of water (24 ml) and concentrated hydrochloric acid (3 ml). The suspension is stirred for 2 hours at about 0 ° C, filtered, and the wet cake is washed with cold water until neutral pH. The wet solid is dried at a temperature below 40 ° C, under vacuum, to give the title compound as a white to off-white solid (1.0 g; 88%; Purity,% HPLC area: 96.8 %).