PROCESS FOR THE PREPARATION OF CORTEXOLONE 17alpha-PROPIONATE AND NEW HYDRATED CRYSTALLINE FORM THEREOF

Abstract

The present invention is directed to a process for the preparation of cortexolone 17α-propionate, comprising a hydrolysis reaction of an ortho-ester of formula (III)

##STR00001## in which R is a hydrogen atom or a methyl group, in the presence of a dilute solution of acetic acid.

The present invention is also directed to a hydrated crystalline form of cortexolone 17α-propionate obtained by such process.

Claims

1) A process for the preparation of cortexolone 17α-propionate of formula (I) ##STR00011## comprising the following steps: a) ortho-esterification of cortexolone of formula (II) ##STR00012## in the presence of a reagent selected from triethyl orthopropionate and trimethyl orthopropionate, to provide the corresponding ortho-ester of formula (III) ##STR00013## wherein R is a hydrogen atom or a methyl group, b) hydrolysis of the ortho-ester of formula (III) in the presence of a dilute solution of acetic acid to give the desired cortexolone 17α-propionate of formula (I).

2) The process according to claim 1, characterized in that the molar quantity of acetic acid added in step b) is between 0.004 equivalents and 0.007 equivalents, with respect to the quantity of ortho-ester of formula (III), more preferably is of about 0.00625 equivalents, with respect to the quantity of ortho-ester of formula (III).

3) The process according to claim 1, characterized in that the molar concentration of acetic acid in the reaction mixture of step b) is between 0.7.Math.10.sup.−3 M and 1.3.Math.10.sup.−3 M, preferably is of about 1.2.Math.10.sup.−3 M.

4) The process according to claim 1, characterized by further comprising the crystallization of cortexolone 17α-propionate of formula (I) in at least two organic solvents in admixture with water.

5) The process according to claim 4, characterized in that said at least two organic solvents are selected among mixtures of acetonitrile, hexane, heptane, cyclohexane, isopropyl ether and ethyl acetate.

6) The process according to claim 4, characterized in that said at least two organic solvents are acetonitrile and hexane.

7) The process according to claim 4, characterized in that said at least two organic solvents are isopropyl ether and ethyl acetate.

8) Hydrated crystalline form of cortexolone 17α-propionate of formula (I) characterized by the following XRPD peaks at about 4.80; 11.36; 11.70; 12.29; 12.95; 14.44; 14.84; 15.93; 16.09; 16.31; 17.20; 19.56; 20.58; 22.82 f 0.2° 20 or according to FIG. 1.

9) Hydrated crystalline form according to claim 8, characterized by the IR spectrum according to FIG. 2.

10) Hydrated crystalline form according to claim 8, characterized by the DSC thermogram according to FIG. 3.

11) Hydrated crystalline form of cortexolone 17α-propionate of formula (I) obtained by the process according to claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1: XRPD of the hydrated crystalline form of cortexolone 17α-propionate obtained with the process of the present invention.

[0019] FIG. 2: IR of the hydrated crystalline form of cortexolone 17α-propionate obtained with the process of the present invention.

[0020] FIG. 3: DSC of the hydrated crystalline form of cortexolone 17α-propionate obtained with the process of the present invention.

[0021] An object of the present invention is therefore a process for the preparation of cortexolone 17α-propionate of formula (I) comprising the following steps:

[0022] a) ortho-esterification of cortexolone of formula (II)

##STR00005##

[0023] in the presence of a reagent selected from triethyl orthopropionate and trimethyl orthopropionate to provide the corresponding ortho-ester of formula (III)

##STR00006##

[0024] wherein R is a hydrogen atom or a methyl group

[0025] b) hydrolysis of the ortho-ester of formula (III) in the presence of a dilute solution of acetic acid to provide to desired cortexolone 17α-propionate of formula (I) having a reduced content of impurities.

[0026] According to the present invention, cortexolone of formula (II) used in step a) is commercially available or is synthesized according to procedures well known to the skilled person, such as for example in Journal of the American Chemical Society (1950), 72, 5145-7, Journal of Organic Chemistry (1985), 50(1), 81-4.

[0027] Preferably, cortexolone of formula (II) is prepared by hydrolysis in basic medium of a cortexolone 21-monoester of formula (IV),

[0028] according to the method disclosed for example in the Russian patent 02156256 and in Journal of the American Chemical Society (Steroids. XCIII.1 Introduction of the cortical hormone side-chain, Howard J. Ringold, 1958, 80, 1 p. 250).

##STR00007##

[0029] wherein R is an acyl group C.sub.2-C.sub.6,

[0030] According to a particularly preferred embodiment of the present invention, cortexolone 21-monoester of formula (IV) is cortexolone 21-acetate, in which R is an acetyl group.

[0031] Such particularly preferred embodiment of the process of the present invention is represented in the scheme 2 below:

##STR00008##

[0032] The conditions for performing the hydrolysis in basic medium of cortexolone 21-monoester of formula (IV) are well known to the skilled person.

[0033] For instance, cortexolone 21-monoester of formula (IV) is dissolved in an organic solvent selected from methanol, dichloromethane and mixtures thereof. Preferably, said compound of formula (IV) is dissolved in a mixture of methanol and dichloromethane.

[0034] The resultant solution is cooled at a temperature of about −5° C. and an inorganic base is added. Examples of inorganic bases according to the present invention are sodium hydroxide, potassium hydroxide and lithium hydroxide.

[0035] One hour after addition of the base, the reaction is complete and cortexolone of formula (II) is obtained, which is then used for the reaction of ortho-esterification of step a).

[0036] According to the present invention, the cortexolone that undergoes the ortho-esterification reaction (step a) is dissolved in an organic solvent. Said organic solvent is selected from dichloromethane, dimethylformamide and mixtures thereof, preferably dichloromethane. Dissolution is conveniently carried out at room temperature.

[0037] Said ortho-esterification reaction is carried out in the presence of an ortho-ester and of a buffer consisting of an acid and a base.

[0038] Said orthoester is selected from triethyl orthopropionate, trimethyl orthopropionate, preferably triethyl orthopropionate.

[0039] Said acid is preferably p-toluensulfonic acid.

[0040] Said base is an organic base selected from pyridine, triethylamine, lutidine, preferably pyridine. Once the reaction is completed, as it is well known to the skilled person, the reaction mixture can be subjected to purification, such as chromatographic column, crystallization in order to isolate the compound of formula (III) or it can be used as such in the next step.

[0041] According to a preferred embodiment of the invention, the ortho-ester of formula (III) is not isolated and is used as such in the following step b).

[0042] The process of the present invention provides that, to the solution containing the ortho-ester of formula (III) dissolved in an organic solvent, such as methanol, ethanol, alone or mixed with water, an amount of acetic acid is added such as to create a dilute solution of acetic acid.

[0043] The acetic acid used in the process of the present invention is glacial acetic acid or 80% acetic acid. Preferably, 80% acetic acid is used.

[0044] Preferably the molar quantity of acetic acid introduced into the reaction mixture is between 0.004 equivalents and 0.007 equivalents, with respect to the quantity of ortho-ester of formula (III).

[0045] More preferably, the molar quantity of acetic acid introduced into the reaction mixture is of about 0.00625 equivalents, with respect to the quantity of ortho-ester of formula (III).

[0046] The molar concentration of acetic acid in the reaction mixture is thus preferably between 0.7.Math.10.sup.−3 M and 1.3.Math.10.sup.−3 M, more preferably is of about 1.2.Math.10.sup.−3 M.

[0047] The reaction takes place at a temperature between room temperature and the reflux temperature of the reaction mixture consisting of an alcoholic solvent, such as methanol, ethanol, and water, preferably the temperature is between 65° C. and 75° C., preferably 70° C., for about 1 hour and a half.

[0048] Thanks to the process of the present invention and in particular to the use of an extremely low amount of acetic acid, the Applicant was able to prepare cortexolone 17α-propionate, reducing the formation of 21-monoester in the product below 3%. The developed process is also easily achievable on an industrial level and does not require pH control.

[0049] As it is well known to those skilled in the art, the resultant cortexolone 17α-propionate can be subjected to various purification processes, such as column chromatography and crystallization. According to a preferred embodiment of the present invention, cortexolone 17α-propionate is subjected to crystallization in at least two organic solvents mixed with water.

[0050] Said at least two organic solvents are selected from acetonitrile, hexane, heptane, cyclohexane, isopropyl ether and ethyl acetate.

[0051] More preferably, said at least two organic solvents are acetonitrile and hexane.

[0052] In alternative, said at least two organic solvents are isopropyl ether and ethyl acetate.

[0053] The Applicant has now surprisingly found that from these mixtures, a new hydrated crystalline form of cortexolone 17α-propionate is obtained, thus providing an alternative solution to those already known in the art.

[0054] A further object of the present invention is therefore a hydrated crystalline form of cortexolone 17α-propionate characterized by the following XRPD peaks at about 4.80; 11.36; 11.70; 12.29; 12.95; 14.44; 14.84; 15.93; 16.09; 16.31; 17.20; 19.56; 20.58; 22.82±0.2° 2θ or as reported in FIG. 1.

[0055] According to a preferred embodiment, said hydrated crystalline form has an IR spectrum as reported in FIG. 2.

[0056] According to a preferred embodiment, said hydrated crystalline form has a DSC thermogram as reported in FIG. 3.

[0057] As said above, the hydrated crystalline form of the present invention is novel with respect to the hydrated crystalline forms disclosed for example in WO 2009/019138, EP 2 503 005 and in Steroids, 2017, 128, 95-104.

[0058] Table 1 below reports the characterizing peaks 29 of these hydrated crystalline forms of cortexolone 17α-propionate with the corresponding intensities of each peak.

TABLE-US-00001 TABLE 1 Hydrated form Steroids EP2503005 WO2009/019138 according to example 4 2θ Int. 2θ Int. 2θ Int. 2θ Int. 4.74 16% 4.64 38% 4.80 22% 6.43 23% 6.18 38% 10.29 13% 11.07 20% 11.17 12% 11.32 24% 11.36 28% 11.42 17% 11.57 14% 11.76 24% 11.70 17% 12.19 34% 12.14 27% 12.29 35% 12.64 72% 12.85 73% 12.85 73% 12.95 100%  13.82 62% 14.11 83% 14.38 29% 14.28 60% 14.44 20% 14.73 53% 14.71 49% 14.99 51% 14.84 38% 15.79 100%  15.8 100%  15.93 68% 16.07 85% 16.09 51% 16.17 100%  16.31 47% 17.06 44% 17.35 48% 17.20 28% 17.50 39% 17.94 20% 18.82 29% 19.38 70% 19.28 64% 19.56 40% 19.64 70% 20.07 44% 20.29 36% 20.52 50% 20.58 21% 20.96 35% 21.07 41% 21.17 25% 22.35 72% 22.76 38% 22.85 35% 22.82 23% 23.52 76% 23.90 25% 23.92 42% 25.00 36% Int.: Peak intensity

[0059] The hydrated crystalline form obtained by the process of the present invention is therefore novel since some of the characteristic peaks and the intensity maximum differ from those present in the art. The corresponding XRPD spectra are consequently not superimposable between them.

[0060] Said hydrated crystalline form can be particularly interesting from an industrial point of view in the preparation of pharmaceutical compositions containing cortexolone 17α-propionate, in particular of topical creams, which is the main use of this product, thus offering an alternative solution to those already present in the state of the art.

[0061] A further object of the present invention is thus the hydrated crystalline form of cortexolone 17α-propionate obtained by the process of the present invention.

EXPERIMENTAL PART

Example 1

Hydrolysis Cortexolone-21-acetate

[0062] ##STR00009##

[0063] Cortexolone-21-acetate (10 g) is charged in a reactor together with 60 ml of dichloromethane and 120 ml of methanol. Subsequently 1.25 ml of 30% NaOH are added at −5° C.

[0064] The reaction is stopped by adding 1 ml of 80% acetic acid.

[0065] The solvent is removed by distillation and the product of formula (II) is isolated by precipitation by adding 60 ml of water on the reaction mass, obtaining, after drying, about 9.5 g of Cortexolone (II).

Example 2

Synthesis Cortexolone-17-propionate

[0066] ##STR00010##

[0067] A solution consisting of 2.5 ml of methylene chloride, 0.126 ml of pyridine and 268 mg of p-toluenesulfonic acid is prepared in a reaction flask which is added to the reaction mixture consisting of Cortexolone (10 g), 100 ml of methylene chloride and 11.6 ml of triethyl orthopropionate.

[0068] At the end of the reaction, 80 ml of water are added. After extraction, the organic phase solvent is removed by distillation.

[0069] The reaction mass is taken up with 80 ml of ethanol, 40 ml of water, 0.010 ml of 80% acetic acid and is brought to reflux (≈73° C.).

[0070] At the end of the reaction, the organic solvents are removed by distillation.

[0071] The residue obtained is taken up by adding 50 ml of ethyl acetate.

[0072] The two phases that are obtained are separated and the wet organic phase is then distilled under vacuum to a wet oily residue.

Example 3 (Preparation Crystalline Form)

[0073] The residue obtained in example 2 is taken up with 10 ml of ethyl acetate and heated to 50°-60° C. 80 ml of isopropyl ether are added to the solution and cooled to a temperature below 40° C. Cortexolone-17α-propionate precipitating from this solvent mixture is isolated by filtration with a yield of 75% by weight. KF: 4.03%

Example 4 (Preparation Crystalline Form)

[0074] The residue obtained in example 2 is taken up with 40 ml of acetonitrile and heated to 30°—35° C. To the solution 200 ml of hexane and 200 ml of water are added and it is cooled to a temperature below 0° C. Cortexolone-17α-propionate precipitating from this solvent mixture is isolated by filtration with a yield of 99% by weight. KF: 1.52%

[0075] The XRPD diffraction spectrum was performed using a Bruker D8 diffractometer equipped with a scintillation detector. The analysis was performed using a CuKα tube as an X-ray source. The data were collected in the angular range 5°-35° (2θ), step 0.03° and at a scanning speed of 4 s/step.

[0076] The IR spectrum was recorded using an iS10 Nicolet instrument, the spectrum was recorded from 4000 to 400 cm.sup.−1.

[0077] DSC analyzes were recorded from 30° C. to 180° C., with an increase of 10° C./min, using a Mettler Toledo instrument.