IT201800002347A1 - INTERMEDIATES AND PROCEDURE FOR THE PREPARATION OF A CRYSTALLINE FORM OF A TOPICAL ANTI-INFLAMMATORY DRUG - Google Patents

Description

Description of the patent for industrial invention entitled:

"INTERMEDIATES AND PROCEDURE FOR THE PREPARATION OF A CRYSTALLINE FORM OF A TOPICAL ANTI-INFLAMMATORY DRUG"

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of 5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxybenzoxyborol (Crisaborol) in crystalline form 1, which comprises the formation of Crisaborole C1-C5 alkyl ester from Crisaborol in a solvent comprising a C1-C5 alkanol, and its conversion into Crisaborol in crystalline form 1 at a high degree of purity.

STATE OF THE TECHNIQUE

5- (4-cyanophenoxy) -1,3-dihydro-1-hydroxybenzoxyborol, aka Crisaborol, is a topical non-steroidal inhibitor of phosphodiesterase 4 (PDE4), an enzyme that regulates inflammation through the breakdown of cyclic adenosine monophosphate (cAMP). PDE4 appears to be hyperactivated in atopic dermatitis and leads to an increase in the signs and symptoms of the same pathology. Inhibition of PDE4 thus blocks the release of pro-inflammatory cytokines and in clinical studies Crisaborole has shown a significant improvement in itching and clinical signs of the disease.

On December 14, 2016, the FDA approved Crisaborol as an ointment for the topical treatment of atopic dermatitis in adults and children aged two and over.

Crisaborole having formula (I)

is known from US 8,039,451, which claims the compound as such and a pharmaceutical salt thereof.

Three crystalline forms have been presented in patent application WO2017 / 093857, filed

. A crystalline form, named crystalline form 1, has been specifically claimed with an XRPD spectrum where characteristic peaks are found at about 6.0; 12.1; 14.1; and 15.4 ± 0.2 ° in 2θ, using CuKα (λ = 1.54056 Å) as the radiation source. According to WO2017 / 093857, the crystalline form 1 was used in phase 3 clinical studies and was selected for the formulation to be placed on the market. The crystalline form 2 was used in phase 1 and 2 clinical studies, while according to the inventors the crystalline form 3 is typically found after rapid evaporation of solvents such as ethyl acetate, methylethyl ketone or methyl-tert-butyl ether.

WO2017 / 093857 provides a procedure for the preparation of each of these three crystalline forms, however for the procedures for the crystalline form 1 and for the form 3 only procedures are provided where the crystallization is triggered with the same crystals of forms 1 and 3 that you intend to prepare. However, the patent application does not report any description regarding the preparation of primers for the crystalline forms 1 and 3. The authors of the present invention have slavishly repeated the procedure reported in WO2017 / 093857 for the preparation of form 1 without using the primer. and chrysaborole was obtained in crystalline form 2.

Therefore there is a need for processes for the preparation of crystalline form 1 Crisaborole which are sufficiently described to allow one skilled in the art to be able to repeat them. Furthermore, there is a need for these processes to be environmentally friendly, industrially safe and / or simple and allow the desired polymorph to be obtained in a particularly advantageous, easy, economical, high yield and purity manner and also be practicable on an industrial scale.

SUMMARY OF THE INVENTION

A process for the preparation of Crisaborole crystalline form 1 has been surprisingly found here, which allows to obtain the crystalline form 1 in an advantageous way.

Furthermore, surprisingly, this new crystallization process is also an effective method of preparing Crisaborole crystalline form 1 with a high purity, typically greater than or equal to 99.8% HPLC.

BRIEF DESCRIPTION OF ANALYTICAL FIGURES AND METHODS

The crystalline forms of Crisaborole 1 and of Crisaborole methyl ester of form α were characterized by X-ray powder diffraction (X-ray powder diffraction). The water content was determined by titration with the Karl Fischer technique.

The X-ray diffraction spectra (XRPD) were collected with the D8 Bruker diffractometer with CuKα (λ = 1.54 Å), scanning with angular range 3-40 ° in 2θ, with an angular step of 0.02 ° in 2θ and 0.5 s of acquisition for each position.

The <1> H NMR spectra were acquired using a Varian NMR Spectrometer Mercury 300 MHz instrument with VNMR 6.1B software, operating at the frequency of 300 MHz for <1> H using CDCl3 as solvent.

Figure 1 shows the XRPD spectrum of Crisaborole crystalline form 1. Figure 2 shows the XRPD spectrum of Crisaborole methyl ester crystalline form α.

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is a new process for the preparation of Crisaborole crystalline form 1, having an XRPD spectrum where the most intense peaks are found at about 6.0; 12.1; 14.1; and 15.4 ± 0.2 ° in 2θ, comprising:

i) the hydrolysis of Crisaborole C1-C5 alkyl ester of formula (II)

where R <1> is a C1-C5 alkyl.

The C1-C5 alkyl group of R <1> can be linear or branched, and more preferably it is a C1-C4 alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, preferably methyl or isopropyl.

Crisaborole C1-C5 alkyl ester of formula (II) can be, for example, Crisaborole methyl ester of crystalline form α having an XRPD spectrum as reported in Figure 2, where the characteristic peaks are found at about 14.1; 16.2; 19.8; 24.7; and 26.6 ± 0.2 ° in 2θ.

Preferably, Crisaborole methyl ester of crystalline form α has an XRPD spectrum as shown in Figure 2, where the characteristic peaks are found at about 7.4; 12.2; 13.0; 14.1; 16.2; 17.6; 18.8; 19.8; 24.7; 25.5; and 26.6 ± 0.2 ° in 2θ.

The hydrolysis of Crisaborole C1-C5 alkyl ester of formula (II) can be carried out by treating Crisaborole C1-C5 alkyl ester of formula (II) with water. For example, Crisaborole C1-C5 alkyl ester of formula (II), in particular Crisaborole methyl ester of crystalline form α, can be suspended in water preferably between about 0 ° C and 40 ° C, for example at 15/20 ° C or at room temperature, obtaining Crisaborole crystalline form 1, having an XRPD spectrum, where the most intense peaks are found at about 6.0; 12.1; 14.1; and 15.4 ± 0.2 ° in 2θ.

In particular, the inventors of the present invention have found that the hydrolysis of the Crisaborole C1-C5 alkyl ester of formula (II) can also be carried out by exposing the Crisaborole C1-C5 alkyl ester of formula (II) to air and the presence of humidity already leads to Crisaborole of crystalline form 1, having an XRPD spectrum where the most intense peaks are found at about 6.0; 12.1; 14.1; and 15.4 ± 0.2 ° in 2θ.

Alternatively, the hydrolysis can be carried out by means of a suspension of Crisaborole C1-C5 alkyl ester of formula (II) in a C5-C9 alkane or in a mixture composed of C5-C9 alkane and a C1-C6 alkyl ester of an acid carboxylic, maintaining the suspension under stirring in an atmosphere containing humidity at a temperature between about -20 ° C and the boiling temperature of the solvent or mixture of solvents, preferably at a temperature between about -20 and 60 ° C, plus preferably between about 20 ° C and 40 ° C, for example at 25 ° C or at 40 ° C.

A C5-C9 alkane, which can be linear or branched, is specifically hexane or heptane.

A carboxylic acid is preferably a C1-C6 alkyl carboxylic acid, for example acetic acid, propionic acid or butyric acid.

A C1-C6 alkyl ester of a carboxylic acid, preferably a C1-C6 alkyl carboxylic acid, where the C1-C6 alkyl group can be linear or branched, is more preferably a C1-C4 alkyl ester of a C1-C4 alkyl carboxylic acid , for example methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate, preferably ethyl acetate.

Typically the ratio of a mixture composed of a C5-C9 alkane and a C1-C6 alkyl ester of a carboxylic acid is 1: 1 (volume: volume, v: v) or higher, preferably between about 10: 1 (v: v ) and 1: 1 (v: v).

The suspension of Crisaborole C1-C5 alkyl ester of formula (II) can be kept under stirring, preferably for at least one hour, more preferably for at least 12 hours, typically for at least 24 or for at least 48 hours at a temperature ranging from about - 20 ° C and the boiling temperature of the solvent or mixture of solvents, preferably at a temperature between about 20 ° C and 40 ° C.

To increase the yield of the solid consisting of Crisaborole in crystalline form 1, the suspension of Crisaborole C1-C5 alkyl ester of formula (II) can be cooled to a temperature lower than or equal to about 20 ° C, for example lower than 0 ° C or between 0 ° C and 5 ° C. Cooling can be performed slowly, for example at a rate of between about 0.1 and 0.4 ° C per minute.

The recovery of the solid consisting of Crisaborole in crystalline form 1 can be carried out with one of the known techniques, for example by filtration or centrifugation, preferably by filtration.

Crisaborole crystalline form 1 thus obtained has a water content between 0 and about 1% w / w, preferably between about 0.01 and 0.1%, preferably around about 0.07% so that it can be defined as substantially anhydrous .

The size of the crystals of Crisaborole crystalline form 1, as obtainable in accordance with the invention, is characterized by a value of D50 between about 25 and 250 µm. If desired, this value can be reduced by micronization or fine milling.

Crisaborole C1-C5 alkyl ester of formula (II) can be obtained with a process comprising:

ii) the formation of a solution of Crisaborol in a C1-C5 alkanol or in a mixture of solvents comprising a C1-C5 alkanol; iii) cooling and / or concentration of the solution and recovery of Crisaborolo C1-C5 alkyl ester of formula (II)

where R <1> is defined as above.

Preferably, the formation of the Crisaborole C1-C5 alkyl ester of formula (II) in step ii) and iii) is carried out under anhydrous conditions. Typically, anhydrous conditions are conditions where the water content quantified by Karl Fischer measurement is equal to or less than 0.1%, preferably equal to or less than 0.05%.

Crisaborol, used as starting material according to step ii) of the above procedure, can be Crisaborol in any known solid or non-solid form, also Crisaborol in crude form, for example Crisaborol as obtainable according to US 8,039,451 or one of the forms Crystals of Crisaborole known from WO2017 / 093857 or obtained directly from a reaction crude.

A C1-C5 alkanol is typically a linear or branched C1-C5 alkanol or a mixture, for example of two or three, of said alkanols. A C1-C5 alkanol preferably is a C1-C3 alkanol, such as for example methanol, ethanol, n-propanol or isopropanol, more preferably methanol or isopropanol.

The solvent mixture comprising a C1-C5 alkanol can further contain one or more, typically one, two or three, solvents selected from an aprotic polar solvent, for example dimethylformamide or acetonitrile; an ethereal solvent, for example diethylether, methylterbutyl ether or tetrahydrofuran; a ketone, for example methyl ethyl ketone, methyl isobutyl ketone or acetone; an aprotic apolar solvent, for example hexane, heptane, toluene or xylene; an ester solvent; a chlorinated solvent, for example dichloromethane (CH2Cl2), chloroform or chlorobenzene; a C1-C6 alkyl ester of a carboxylic acid.

A preferred solvent is a C1-C6 alkyl ester of a carboxylic acid, more preferably a C1-C6 alkyl carboxylic acid, where the C1-C6 alkyl group can be linear or branched, is more preferably a C1-C4 alkyl ester of an acid C1-C4 carboxylic alkyl, for example methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate or butyl acetate, preferably ethyl acetate. A C1-C6 alkyl carboxylic acid, for example, is acetic acid, propionic acid or butyric acid. Typically the volumetric ratio between a C1-C6 alkyl ester of a carboxylic acid and a C1-C5 alkanol in a mixture thereof according to the present invention in step ii) is between 10: 1 and 1:10, preferably about 1: 1 .

If necessary, the dissolution of the Crisaborole referred to in step ii) can be carried out at room temperature or by heating up to the reflux temperature of the solvent or solvent mixture.

The cooling of the solution in step iii) can be carried out according to known processes, for example it can be carried out by bringing the temperature of the solution to room temperature or to about 0-5 ° C.

The concentration of the solution in step iii) can be carried out according to known processes, for example the reaction mixture can be concentrated to about half volume or less.

Optionally in step iii) a crystalline germ of Crisaborolo C1-C5 alkyl ester of formula (II), previously obtained, can be added.

The recovery of the solid referred to in step iii), consisting of Crisaborole C1-C5 alkyl ester of formula (II), for example Crisaborol methyl ester of crystalline form α, can be carried out with one of the known techniques, for example by filtration or centrifugation, preferably by filtration.

A further aspect of the invention is the preparation, and isolation, of a Crisaborole C1-C5 alkyl ester of formula (II), for example Crisaborol methyl ester; Crisaborol ethyl ester; Crisaborol propylester; Crisaborole isopropylester; Crisaborol butyl ester or Crisaborole methyl ester of crystalline form α, starting from Crisaborol.

For example, the preparation and isolation of a compound of formula (II) can be carried out under the conditions as described above for steps ii) and iii).

A further aspect of the present invention is directed to the Crisaborole C1-C5 alkyl ester compound of formula (II)

where R <1> is a C1-C5 alkyl.

The C1-C5 alkyl group of R <1> can be linear or branched, it is preferably a C1-C4 alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, more preferably methyl or isopropyl.

Preferred Crisaborole C1-C5 alkyl esters of formula (II) are selected from: Crisaborol methyl ester;

Crisaborol ethyl ester;

Crisaborol propylester;

Crisaborole isopropylester; And

Crisaborole butyl ester.

Particularly preferred compounds of formula (II) are

Crisaborole isopropylester e

Crisaborole methyl ester of crystalline form α having an XRPD spectrum as shown in Figure 2, where the characteristic peaks are found at about 14.1; 16.2; 19.8; 24.7; and 26.6 ± 0.2 ° in 2θ.

Preferably, Crisaborole methyl ester of crystalline form α has an XRPD spectrum as shown in Figure 2, where the characteristic peaks are found at about 7.4; 12.2; 13.0; 14.1; 16.2; 17.6; 18.8; 19.8; 24.7; 25.5; and 26.6 ± 0.2 ° in 2θ.

A further aspect of the present invention is directed to the use of Crisaborole C1-C5 alkyl ester of formula (II) as defined above in a process for preparing Crisaborol crystalline form 1, having an XRPD spectrum where the most intense peaks are found at about 6 , 0; 12.1; 14.1; and 15.4 ± 0.2 ° in 2θ.

The following examples further illustrate the invention.

EXAMPLE 1

1.0 g of Crisaborole is completely dissolved in a 1: 1 AcOEt / MeOH mixture. The solution is concentrated under reduced pressure and the residual oil is left to slowly solidify overnight. The residue is subsequently treated with a hexane / ethyl acetate mixture (9: 1, v: v) and kept under stirring for 48 hours at about 40 ° C. The suspension is then filtered and the solid washed with hexane. 0.8 g of Crisaborole in crystalline form 1 are obtained, having an XRPD spectrum where the most intense peaks are found at about at about 6.0; 12.1; 14.1; and 15.4 ± 0.2 ° in 2θ (Figure 1). The HPLC purity is approximately 99.88% w / w at 220 nm.

EXAMPLE 2

75.0 g of Crisaborole are completely dissolved at 60/65 ° C in 900 ml of MeOH. A yellow solution is obtained which is kept at 60/65 ° C for 30 minutes. It is cooled to 50/55 ° C and the mixture is kept under these conditions for 15-30 minutes, the mixture is concentrated at half volume then it is cooled to 0/5 ° C. The suspension is filtered and the solid washed with MeOH. 72.0 g of Crisaborole methyl ester of crystalline form α are obtained having an HPLC purity> 99.50% (220 nm) and where the main peaks (expressed in ° in 2θ) are found at about 7.4; 12.2; 13.0; 14.1; 16.2; 17.6; 18.8; 19.8; 24.7; 25.5; and 26.6 ± 0.2 °.

<1> H-NMR (300 MHz, CDCl3): δ 7.73 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.26 - 6.99 (m, 4H), 5.07 (s , 2H), 3.89 (s, 3H) ppm.

EXAMPLE 3

The procedure of Example 2 can also be carried out using a previously obtained crystalline form α Crisaborole methylester primer, which can be added to the mixture cooled to 50/55 ° C. The mixture is kept under these conditions for 15-30 minutes, the mixture is concentrated at half volume and then cooled to 0/5 ° C. The suspension is then filtered and the solid washed with MeOH.

EXAMPLE 4

72.0 g of Crisaborole methyl ester of crystalline form α, as obtained in Example 2 or 3, are suspended in 1500 ml of water at 15/20 ° C. The suspension is kept under stirring for 2 hours, then it is filtered and the solid is washed with water. After drying under vacuum at 50 ° C, 65.1 g of Crisaborole crystalline form 1 having an HPLC purity> 99.50% (220 nm) are obtained.

EXAMPLE 5

1.00 g of Crisaborol is solubilized under reflux in 10 mL isopropanol. The solvent is removed under reduced pressure, until 1.16 g Crisaborole isopropyl ester is obtained as a white crystalline solid.

<1> H-NMR (300 MHz, DMSO): δ 7.84 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.1 Hz, 1H), 7.16 - 7.06 (m, 4H), 5.03 (s , 2H), 4.76 - 4.68 (m, 1H), 1.26 (d, J = 6.0 Hz, 6H) ppm.

According to the procedure for obtaining Crisaborol isopropyl ester, the following compounds can be similarly prepared:

Crisaborol ethyl ester;

Crisaborol propylester; And

Crisaborole butyl ester

EXAMPLE 6

Crisaborol ethyl ester; Crisaborol propylester; Crisaborol isopropyl ester; and Crisaborol butyl ester as obtained in Example 5 can be converted into Crisaborole crystalline form 1 in accordance with the procedure of Example 4.

Claims (10)

CLAIMS 1. A process for the preparation of Crisaborole crystalline form 1, having an XRPD spectrum where the most intense peaks are found at about 6.0; 12.1; 14.1; and 15.4 ± 0.2 ° in 2θ, comprising: i) the hydrolysis of Crisaborole C1-C5 alkyl ester of formula (II) where R <1> is a C1-C5 alkyl. 2. A process according to claim 1, wherein the Crisaborole C1-C5 alkyl ester of formula (II) is Crisaborole methyl ester of crystalline form α having an XRPD spectrum as reported in Figure 2, where the characteristic peaks are found at about 14 , 1; 16.2; 19.8; 24.7; and 26.6 ± 0.2 ° in 2θ. 3. A process according to claims 1 or 2, wherein Crisaborol C1-C5 alkyl ester of formula (II) where R <1> is as defined in claim 1 or 2, it is obtained with a process comprising: ii) the formation of a solution of Crisaborol in a C1-C5 alkanol or in a mixture of solvents comprising a C1-C5 alkanol; iii) cooling and / or concentration of the solution and recovery of Crisaborolo C1-C5 alkyl ester of formula (II). 4. A process according to claim 3, wherein Crisaborol C1-C5 alkyl ester of formula (II) is Crisaborole methyl ester of crystalline form α having an XRPD spectrum, where the characteristic peaks are found at about 14.1; 16.2; 19.8; 24.7; and 26.6 ± 0.2 ° in 2θ. 5. A process according to claims 3 or 4, in which the formation of the Crisaborole C1-C5 alkyl ester of formula (II) in step ii) and iii) is carried out under anhydrous conditions. 6. A process according to claims 3-5, wherein a crystalline germ of Crisaborole C1-C5 alkyl ester of formula (II), previously obtained, is added to step iii) as defined in claim 3. 7. Crisaborole C1-C5 alkyl ester of formula (II) where R <1> is a C1-C5 alkyl. 8. Crisaborole C1-C5 alkyl ester of formula (II), as defined in claim 7, selected from: Chrysaborol methyl ester, Crisaborol ethyl ester, Crisaborol propylester, Crisaborole isopropylester e Crisaborole butyl ester. 9. Crisaborole C1-C5 alkyl ester of formula (II), as defined in claim 8, selected from Crisaborole isopropylester or Crisaborole methyl ester of crystalline form α having an XRPD spectrum, where the characteristic peaks are found at about 14.1; 16.2; 19.8; 24.7; and 26.6 ± 0.2 ° in 2θ. 10. Use of Crisaborole C1-C5 alkyl ester of formula (II) as defined in claims 7-9 in a process for preparing Crisaborole crystalline form 1, having an XRPD spectrum where the strongest peaks are found at about 6.0; 12.1; 14.1; and 15.9 ± 0.2 ° in 2θ.