Improved process for the prepration of crystalline forms of oxaborole derivatives

Abstract

The present invention relates to an improved process for the preparation of crystalline forms of oxaborole derivatives which are used as agents in the treatment of mild-to-moderate atopic dermatitis. The present invention specifically relates to an improved process for the preparation of crystalline forms of Crisaborole (Form II). The present invention specifically relates to an improved process for the preparation of crystalline forms of Crisaborole (Form II) through crisaborole sodium salt. The present invention specifically relates to an improved process for the preparation of highly pure Crisaborole through crisaborole sodium salt.

Description

[0001] IMPROVED PROCESS FOR THE PREPRATION OF CRYSTALLINE FORMS OF OXABOROLE DERIVATIVES FIELD OF THE INVENTION

[0002] The present invention relates to an improved process for the preparation of crystalline forms of oxaborole derivatives which are used as agents in the treatment of mild-to-moderate atopic dermatitis.

[0003] The present invention specifically relates to an improved process for the preparation of crystalline forms of Crisaborole (Form II).

[0004] The present invention specifically relates to an improved process for the preparation of crystalline forms of Crisaborole (Form II) through crisaborole sodium salt.

[0005] The present invention specifically relates to an improved process for the preparation of highly pure Crisaborole through crisaborole sodium salt.

[0006] BACKGROUND OF THE INVENTION

[0007] Crisaborole is a novel boron-containing small molecule. Crisaborole topical ointment, 2%, is an investigational non-steroidal topical anti-inflammatory PDE-4 inhibitor approved by the USFDA for the treatment of mild-to-moderate atopic dermatitis. Crisaborole is chemically represented as 5-(4-cyanophenoxy)-l,3-dihydro- 1 -hydroxy-2, 1-benzoxaborole. The chemical formula is C14H10BNO3, the molecular weight is 251.045100 g / mol and the structural formula is:

[0008] Crisaborole was first disclosed in US 8,039,451 B2. This patent also discloses a process for the preparation of Crisaborole, which is shown in the scheme given below:

[0009]

[0010] Scheme-I

[0011] Further, in ‘451, Crisaborole was purified by column chromatography over silica gel to provide a solid. However, no physicochemical characteristics were provided except the proton NMR data. The example-4 process reported, purification of crude product by flash column chromatography over silica gel to provide solid with 80% purity. The 80% purity solid was further purified by washing with hexane to afford Crisaborole, which is impure Crisaborole because hexane washings cannot eliminate process impurities, such as Keto impurity, Des-bromo impurity, Hydroxy impurity, Acid impurity and other process impurities. By the purification process of example-4, API purity / pharmaceutical quality with 99.5% purity is not possible.

[0012] Bioorganic & Medicinal Chemistry Letters 19, 2129-2132, 2009 discloses a process for the preparation of Crisaborole, which is shown in the scheme given below: et to , d) HCI, THF,

[0013] Scheme-IV wherein R is cyano group. IN 201941025196 discloses a process for the preparation

[0014] MDC, ethylvinyl ether pyridinium p-toluenesulfonate

[0015] US 11,014,944 B2 discloses a process for the preparation of crisaborole as shown below:

[0016] The detailed procedure given in this patent is 10.0 gm compound of formula (III) of was added to the stirred solution of methylene chloride (50 ml) at 25° C.-300C. TBAB (0.5 gm) was added. After the addition of concentrated hydrochloric acid (30 ml), the mixture was stirred for 24 hours at 25° C.-300C. After completion of the reaction, the phases were separated. Water (30 ml) was added to the organic layer and phases were separated. The organic layer obtained was added 200 ml water followed by aqueous sodium hydroxide (4.49 ml 30%) and stirred for 15 mins. The aqueous layer was filtered and acidified with hydrochloric acid (9.22 ml 10%) at 25° C.-300C. The obtained solid was filtered and washed with water (10 ml) and dried at 50° C. under vacuum for 24 hrs to obtain Crisaborole (3.6 gm); Purity=99.5%. However, this patent does not disclose isolation of crisaborole sodium salt and its use in the preparation of crisaborole crystalline forms.

[0017] US 11,447,506 B2 discloses Crystalline Forms I, II and III of Crisaborole with XRD and the process for the preparation of these forms. The generic process given for the preparation of Crisaborole Form II is

[0018] 1) solids of crisaborole in free form are suspended in a mixed solvent of water and an alcohol to produce a suspension, and the suspension is stirred, subjected to centrifugal separation and dried, to provide the solids of the crystal form II, wherein the water to alcohol volume ratio is 1:1, wherein the alcohol is preferably methanol, and the stirring and separating steps each are conducted at room temperature; or

[0019] 2) solids of crisaborole in free form are dissolved in a positive solvent, and then a reverse solvent is added thereto; the resultant mixture crystallized while being stirred, separated and dried, to produce the solids of crystal form II, wherein the solids of crisaborole in free form are present in the positive solvent in a state that the solids are dissolved until the resultant mixture is clear or in a state that the solids are completely dissolved, and the reverse solvent is added until solids are produced; the positive solvent includes, but not limited to, alcohols, ketones, cyclic ethers, amides, and dimethyl sulfoxide, and the inverse solvent is preferably water, wherein: the alcohol solvent is isopropanol, the ketone solvent is acetone, the cyclic ether solvent is selected from tetrahydrofuran, and 1,4-dioxane, and the amide solvent is dimethylformamide; and the stirring crystallizing step and the separating step both are conducted at room temperature.

[0020] The specific process given here is that 34.5 mg of solids of crisaborole in free form were added to 1.6 mL of a mixed solvent system (methanol: water, with the volume ratio 1:1). The resultant mixture was magnetically stirred at room temperature, and then it was subjected to centrifugal separation and vacuum dried at room temperature, to produce white solid crystals. This document fails to disclose clear yield and purity of the resulting Form II.

[0021] The prior-art processes disclosed for the preparation of Crisaborole Form II does not yield the product in good purity and yield. In order to improve the yield, product purity, the inventors of the present invention tried to prepare Crisaborole sodium salt which is in turn converted into Crisaborole Form II. The process has simple operations, which can be used in bigger batch sizes, in high yields. These features make the process of the invention highly suitable for industrial scale up production. OBJECTIVE OF THE INVENTION

[0022] The main objective of the present invention is to provide an improved process for the preparation of crystalline forms of oxaborole derivatives which are used as agents in the treatment of mild-to-moderate atopic dermatitis.

[0023] In yet another objective of the present invention is to provide an improved process for the preparation of crystalline forms of Crisaborole (Form II).

[0024] Still another objective of the present invention is to provide an improved process for the preparation of crystalline forms of Crisaborole (Form II) through crisaborole sodium salt.

[0025] Yet another objective of the present invention is to provide an improved process for the preparation of highly pure Crisaborole through crisaborole sodium salt.

[0026] Yet another objective of the present invention is to provide an improved process for the preparation of pure Crisaborole Form II which is having better yields and purity.

[0027] SUMMARY OF THE INVENTION

[0028] Accordingly, the present invention provides an improved process for the preparation of crystalline forms of oxaborole derivatives which are used as agents in the treatment of mild-to-moderate atopic dermatitis.

[0029] In one aspect, the present invention provides an improved process for the preparation of crystalline forms of Crisaborole (Form II).

[0030] In another aspect, the present invention provides an improved process for the preparation of crystalline forms of Crisaborole (Form II) through crisaborole sodium salt.

[0031] In yet another aspect, the present invention provides an improved process for the preparation of highly pure Crisaborole through crisaborole sodium salt.

[0032] In yet another aspect, the present invention provides a process for the preparation of Crisaborole form (II) which comprises the steps of: i) providing a solution of Crisaborole sodium salt in an organic solvent or mixture of solvents and water, ii) acidifying the resulting mixture using an acid, iii) isolating pure crystalline form (II) of Crisaborole.

[0033] In yet another aspect, the present invention provides a process for the preparation of Crisaborole form (II) which comprises the steps of: i) providing a solution of Crisaborole sodium salt in an organic solvent and / or mixture with water, ii) adding the above solution to an organic solvent and / or mixture with water, iii) acidifying the resulting mixture using an acid, iv) isolating pure crystalline form (II) of Crisaborole.

[0034] In yet another aspect, the present invention provides a process for the preparation of Crisaborole sodium which comprises the steps of: i) providing a solution of Crisaborole in an organic solvent or mixture of solvents, ii) adding a second solvent to the mass obtained in step (i), iii) basifying using a base, iv) isolating pure Crisaborole sodium.

[0035] In yet another aspect, the present invention provides novel crystalline

[0036] Crisaborole sodium salt.

[0037] In yet another aspect, the present invention provides novel crystalline

[0038] Crisaborole sodium salt characterised by XRD peaks at 4.60, 6.49, 7.27, 9.18, 10.2, 11.7, 13.79, 18.4, 20.1, 22.9 9 ±0.2° 20.

[0039] In still another aspect, the present invention provides novel crystalline Crisaborole sodium salt, which can be used in the preparation of Crisaborole Form II in high purity and yield.

[0040] BRIEF DESCRIPTION OF DRAWINGS

[0041] Fig.l: X-ray powder diffraction pattern of crude Crisaborole crystalline form (II) before purification

[0042] Fig.2: X-ray powder diffraction pattern of crude Crisaborole crystalline form (II) after purification Fig.3: X-ray powder diffraction pattern of Crisaborole sodium salt of the present invention

[0043] Fig.4: X-ray powder diffraction pattern of pure Crisaborole crystalline form (II) of the present invention prepared as per example 3

[0044] Fig.5: X-ray powder diffraction pattern of pure Crisaborole crystalline form (II) of the present invention prepared as per example 4

[0045] Fig.6: X-ray powder diffraction pattern of pure Crisaborole crystalline form (II) of the present invention prepared as per example 5

[0046] Fig.7: X-ray powder diffraction pattern of pure Crisaborole crystalline form (II) of the present invention prepared as per example 6

[0047] Fig.8: X-ray powder diffraction pattern of pure Crisaborole crystalline form (II) of the present invention prepared as per example 7

[0048] Fig.9: X-ray powder diffraction pattern of crude Crisaborole crystalline form (II) of the present invention prepared as per example 8

[0049] Fig.10: X-ray powder diffraction pattern of crude Crisaborole crystalline form (II) of the present invention prepared as per example 9

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0052] The acid as used herein is selected from inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid; organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid, TsOH or mixture thereof.

[0053] The base as used in the present invention are not limited to sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate.

[0054] In yet another embodiment, solvents used in the present invention are selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, diethylether, pet-ether, diisopropyl ether, 1,4- dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran and dimethoxyethane; "non-polar organic solvents" such as benzene, toluene, xylene, hexane, and cyclohexane, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane; amides such as dimethyl formamide, N- methyl acetamide, N,N-dimethyl acetamide; N-methyl pyrrolidone, dimethyl sulfoxide and / or mixtures thereof, preferably the solvent is alcoholic solvent

[0055] The Crisaborole form (II) obtained by the process disclosed herein is stable, consistently reproducible and have good flow properties, and which is particularly suitable for bulk preparation and handling.

[0056] The term "stable" relates to a compound which after storage for up to 2 weeks, more suitably up to 4 weeks, still more suitably up to 12 weeks, or at least 12 weeks and especially up to 6 months, particularly at least 6 months at 25°C and 60% relative humidity, 40°C and, when protected from moisture is at least 95% chemically identical to the starting sample and retains its crystalline nature. Further, the solvent choice and the temperature at which the recrystallization take place has impact on the nature of the crystalline form when any form of Crisaborole is dissolved in solvent to Crisaborole Form II. The solvents and temperature effect on Form-I & II are tabulated below:

[0057] As can be seen from the above table, at higher temperatures either Form I or Form I and form II mixture is formed and below -20 °C pure Form II is formed. However, lower temperatures need not maintained for crystallization of Form II when Crisaborole sodium is used as starting material.

[0058] The Crisaborole form (II) obtained by the process disclosed herein is highly pure with purities ranging above 99.5% and with keto impurity less than 0.1%.

[0059] Possible impurities in Crisaborole as per the process of the present invention are as given below and the levels of each of these impurities are given after each process example:

[0060] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore, the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments. The present invention is exemplified by the following examples, which are provided for illustration only and should not be construed to limit the scope of the invention.

[0061] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[0062] EXAMPLES

[0063] Example 1:

[0064] Preparation of crude Crisaborole Form-II:

[0065] To the solution of 4-(4-bromo-3-((l -ethoxyethoxy) methyl) phenoxy) benzonitrile (100g) in tetrahydrofuran (2000 ml), Triisopropyl borate (156g) is added and cooled to -80 to -70°C. n-Butyl lithium is added to the reaction mass at -80 to -70°C and stirred for 3h. The reaction mass is quenched with water (800 ml) and adjusted pH to 0.3 with cone hydrochloric acid at 20-30°C (120 ml). The reaction mass stirred for 4h at 20-30°C and separated the organic layer. Water (1000ml) is added to the organic layer, adjusted pH to 11 with 30% aqueous sodium hydroxide and separated aqueous layer. Methylene chloride (1000ml) is added to the aqueous layer and adjusted pH to 0.3 with 6N hydrochloric acid (35ml) and extracted the product at 20-30°C. Organic layer is washed with water and concentrated to yield liquid mass (80g; HPLC purity: 85-90%) with the following impurities.

[0066] The concentrated liquid mass (80g; HPLC purity: 88.7%) is added to the precooled methanol (400 ml) at -25 to -30°C and stirred for 5h at -20 to -30°C. The solid is filtered, washed with precooled methanol (80ml; -20 to -30°C) and collected the wet crude Crisaborole form- II (52 gr) with HPLC: 96.7% (60%) with the following impurity profile. The wet crude solid is added to the precooled methanol (260ml; -20 to -30°C) and stirred for 4h at -20 to -30°C. The product is filtered, washed with precooled methanol (40ml; -20 to -30°C) and dried at 20-30°C under vacuum to yield crude Crisaborole form- II with HPLC purity 98.5% (41g) with the following impurity profile Example 2:

[0067] Preparation of Crisaborole sodium salt:

[0068] The crude Crisaborole form- II (41g) is passed through silica gel (15 micron) column chromatography, with mixture of ethyl acetate-hep tane (1:9). Pure fractions with purity greater than 99.0% (by HPLC) are combined.

[0069] To the combined pure fractions are partially concentrated. Equal volume of isopropanol is added to the concentrated solution mass and then partially concentrated. To the concentrated solution mass, 50% aqueous sodium hydroxide solution is added at 0-10°C, stirred for 4-5h at 0-15°C, filtered the solid and washed with isopropanol (20 ml). The wet Crisaborole Sodium new form (wet solid 55g) with HPLC purity 99.5% is collected and has the following impurity profile.

[0070] Example 3: Preparation of Crisaborole Form-II: Crisaborole sodium (2g) was added portion wise slowly to a solution of methanol (10ml), DM water (80ml) and Con HC1 (1.5ml) at 10-15°C for 10 min. The solution was stirred for 5h at 10-15°C. The solid was filtered, washed with water and dried at 30°C to obtain form-II (1.5 gr, HPLC purity 99.8) with the following impurity profile. Example-4: Preparation of Crisaborole Form-II:

[0071] Crisaborole sodium (2g) was added portion wise slowly to a solution of acetone (10ml), DM water (80ml) and Con HC1 (1.5ml) at 10-15°C for 10 min. The solution was stirred for 5h at 10-15°C. The solid was filtered, washed with water and dried at 30°C to obtain form-II (1.46 g).

[0072] Example-5: Preparation of Crisaborole Form-II:

[0073] Crisaborole sodium (5g) was dissolved in DM water (25ml) at 40°C. The solution was added to the mixture of methanol (25ml), water (175ml) and Cone HC1 (2.5ml) at 0- 10°C in lOmin. The resulting slurry was stirred for 4h at 0-10°C. The solid was filtered, washed with water and dried at 30°C to obtain form-II (4.38g).

[0074] Crisaborole sodium (5g) was dissolved in DM water (25ml) at 0°C. The solution was added to the mixture of acetone (50ml), water (175ml) and Cone HC1 (2.5ml) at 0- 10°C in lOmin. The resulting slurry was stirred for 4h at 0-10°C. The solid was filtered, washed with water and dried at 30°C to obtain form-II (3.46g). Preparation of Crisaborole Form-II:

[0075] Crisaborole sodium (5g) was dissolved in acetic acid (25ml) at 0°C. The solution was added to the water (200ml) at 0-10°C in lOmin. The resulting slurry was stirred for 2h at 0-10°C. The solid was filtered, washed with water and dried at 30°C to obtain form-

[0076] II (3.38g).

[0077] Example-8: Preparation of Crisaborole Form-II:

[0078] Crisaborole sodium (5g) was dissolved in formic acid (25ml) at 0°C. The solution was added to the water (200ml) at 0-10°C in lOmin. The resulting slurry was stirred for 2h at 0-10°C. The solid was filtered, washed with water and dried at 30°C to obtain form- II (4.2g).

[0079] Example-9: Preparation of Crisaborole Form-II:

[0080] Crisaborole form-II (2g) was dissolved in acetic acid (15ml) at 0°C. The solution was added to the water (80ml) at 20-30°C in lOmin. The resulting slurry was stirred for 2h at 20-30°C. The solid was filtered, washed with water and dried at 30°C to obtain form-II (3.55g).

Claims

We Claim:

1. An improved process for the preparation of Crisaborole form (II) which comprises the steps of: i) providing a solution of Crisaborole sodium salt in an organic solvent or mixture of solvents and water, ii) acidifying the resulting mixture using an acid, iii) isolating pure crystalline form (II) of Crisaborole.

2. An improved process for the preparation of Crisaborole form (II) which comprises the steps of: i) providing a solution of Crisaborole sodium salt in an organic solvent and / or mixture with water, ii) adding the above solution to an organic solvent and / or mixture with water, iii) acidifying the resulting mixture using an acid, iv) isolating pure crystalline form (II) of Crisaborole.

3. An improved process for the preparation of Crisaborole sodium which comprises the steps of: i) providing a solution of Crisaborole in an organic solvent or mixture of solvents, ii) adding a second solvent to the mass obtained in step (i), iii) basifying using a base, iv) isolating pure Crisaborole sodium.

4. The process as claimed in claims 1 and 2, wherein the acid is selected from hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, polyphosphoric acid, formic acid, acetic acid, propionic acid, citric acid and oxalic acid, TsOH.

5. The process as claimed in claims 1 and 2, wherein the solvent is selected from "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents" such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like or "ether solvents" such as di-tert-butylether, diethylether, pet-ether, diisopropyl ether, 1,4-dioxane, methyl tert-butylether, ethyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran and dimethoxyethane; "non-polar organic solvents" such as benzene, toluene, xylene, hexane, and cyclohexane, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane; amides such as dimethyl formamide, N-methyl acetamide, N,N-dimethyl acetamide; N-methyl pyrrolidone, dimethyl sulfoxide.

6. The solvent as claimed in claim 5 wherein the solvent is alcoholic solvent.

7. The process as claimed in claim 3, base is sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate.

8. The process as claimed in claims 1 and 2 wherein the reaction is carried out at temperature in the range of 0 to 30 °C.

9. Novel crystalline Crisaborole sodium salt characterised by XRD peaks at 4.60, 6.49, 7.27, 9.18, 10.2, 11.7, 13.79, 18.4, 20.1, 22.9 9 ±0.2° 20.

10. Novel crystalline Crisaborole sodium salt, which can be used in the preparation of Crisaborole Form II in high purity and yield.

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