WO2018150327A1

WO2018150327A1 - Crisaborole production process

Info

Publication number: WO2018150327A1
Application number: PCT/IB2018/050883
Authority: WO
Inventors: Li PEIJIE; Sun YUANCHAO; Zhang MUQUN; Du HENG; Gao SUWAN; Hu ZHENYU; Sonia Krivonos; Arkady KHASHPER; Vitaly Shteinman; Yana Sery; Revital Ben-Daniel
Original assignee: Wavelength Enterprises Ltd
Priority date: 2017-02-14
Filing date: 2018-02-13
Publication date: 2018-08-23

Abstract

The present invention relates to methods for producing crisaborole, and methods for isolating and purifying crisaborole. The present invention also relates to intermediates, which may be used in the production of crisaborole, and methods for producing such intermediates. The present invention additionally relates to pharmaceutical compositions containing crisaborole produced in accordance with the present invention.

Description

CRISABOROLE PRODUCTION PROCESS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims the benefit of U.S. Provisional Application No. 62/458,875, filed February 14, 2017, which is incorporated by reference.

FIELD OF THE INVENTION [0002] The present invention relates to novel process for production of crisaborole.

BACKGROUND OF THE INVENTION

[0003] Crisaborole (code name AN2728) is a non-steroidal boron-containing drug (a phenoxybenzoxaborole) used for the topical treatment of psoriasis and atopic dermatitis (atopic eczema). Crisaborole is a phosphodiesterase-4 inhibitor acting on the phosphodiesterase 4B gene, which is a member of the type IV, cyclic AMP (cAMP)-specific, cyclic nucleotide phosphodiesterase (PDE) family (PDE4B).

[0004] The chemical name of crisaborole is 4-[(l-hydroxy-l,3-dihydro-2, l- benzoxaborol-5-yl)oxy]benzonitrile. It has a molecular formula of C14H10BNO3 and a molecular weight of 251.045. Crisaborole is soluble in organic solvents such as ethanol, DMF and ethyl acetate. Crisaborole is sparingly soluble in water. Crisaborole has the following structural formula:

Crisaborole

[0005] Crisaborole and a pharmaceutical formulation containing it are described in US Patent 8,039,451 (hereinafter the '451 patent). Example 4 of the '451 patent describes a method for preparing a series of compounds, which include crisaborole (Compound No. 4.2.q). The method described in Example 4 of the '451 patent involves metalation of an aryl halide using tert-butyllithim or ^-butyllithim at -78 °C. However, tert-butyllithim and n- butyllithim are extremely pyrogenic and hazardous to use on large scales as they can combust spontaneously on contact with air. Using a temperature of -78 °C is also highly impractical and generally unsuitable for large scale syntheses. Accordingly, the method described in Example 4 of the '451 patent would not be commercially viable.

[0006] US patents 8,039,450, 8,461,135, 8,461, 136, 9,012,431 and 9,416,146 describe 16 strategies for the preparation of boron-containing small molecules, which are named therein strategies A-P.

[0007] Strategy A, specifically relating to the synthesis of crisaborole, is depicted in Scheme 1 below.

Scheme 1

Crisaborole [0008] Strategy A includes 5 steps as follows: In Step 1, the formyl group of Compound 1 is protected as ethylene acetal with excess ethylene glycol in the presence of 1-10% acid catalyst such as p-toluenesulfonic acid, methanesulfonic acid, hydrogen chloride, hydrogen bromide and using toluene, benzene or xylene as solvents. The reaction is carried out under azetropic condition with a Dean-Stark head at reflux and is complete within 1-24 hours.

[0009] In Step 2, Compounds 2 and 3 are coupled in the presence of 1-5 equivalents of a base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, potassium tert-butoxide in a solvent such as Ν,Ν-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide and acetonitrile to afford compound 4. The reaction is carried out at 70-150°C and is complete within 1-24 hours.

[0010] In Step 3, Compound 4 is treated with 1-50 equivalents of an acid such as hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid and acetic acid to hydrolyze the acetal. The solvent is selected from methanol, ethanol, tetrahydrofuran, 1,4-dioxane or 1,2-dimethoxy ethane and the reaction is complete within 1-24 hours.

[0011] In Step 4, Compound 5 is subjected to Miyaura coupling to introduce boron atom. A mixture of Compounds 5, 6, [l, l'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complex with dichloromethane, and potassium carbonate is stirred at a temperature of 50°C to reflux in a solvent such as 1,4-dioxane, 1,2-dimethoxy ethane, tetrahydrofuran, dimethylsulfoxide, dimethylformamide and toluene. The palladium catalyst is used at 1-5 mol %, and the base is used at 2-5 equivalents. The reaction is complete within 1-24 hours.

[0012] In Step 5, Compound 7 is treated with a reducing agent, such as sodium borohydride or lithium aluminum hydride in an inert solvent. 0.5-2 equivalents of reducing agent are used in a solvent such as methanol, ethanol, tetrahydrofuran and ether. The reaction is carried out at 0°C to room temperature, and is complete within 1 to 12 hours. The pinacol is removed by washing with aqueous boric acid during the extraction and the crude product is treated with water, or subjected to freeze drying after purification.

[0013] The disadvantages of the synthetic methods described in Strategy A are, inter alia, long reaction times, use of Class 1 solvents such as benzene and techniques such as freeze drying that are complicated when used for commercial scale production.

[0014] There are inherent problems associated with the production of crisaborole, particularly for processes that require the production and separation of impurities, which tend to produce poor yields on a commercial scale. Accordingly, there is a need for improved methods of preparing crisaborole and intermediates thereof, which facilitate the production of crisaborole, particularly on a commercial scale. The present invention provides such methods and intermediates, as will be apparent from the description of the invention provided herein.

SUMMARY OF THE INVENTION

[0015] In one embodiment, the present invention provides a process for preparing crisaborole, which process comprises the following stages:

1. Reacting the starting material of formula I, 4-(4-amino-3-(hydroxymethyl)- phenoxy)benzonitrile (AHBN), with an acid to obtain the compound of formula IA;

2. Reacting sodium nitrite (NaN0₂) with the compound of formula IA to obtain the compound of formula II, 4-(4-cyanophenoxy)-2-hydroxymethyl-benzenediazonium salt (hereinafter the diazonium salt), optionally in situ;

3. Reacting the diazonium salt with a borylation agent; and

4. Working up the reaction mixture, isolating crisaborole and optionally purifying it to afford highly pure crisaborole.

[0016] According to the present invention, there is provided the intermediate of formula I, 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN), having the following structural formula:

I

-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN)

[0017] Further provided by the present invention are ammonium salts of AHBN (compounds of the formula IA) having the following structural formula:

Specific compounds according to the present invention are: the hydrochloride salt (X^"=C1^"), the hydrobromide salt (X^"=Br^"), the hydroiodide salt (X^"=T), the sulfate salt (X^"=HS04^"), the nitrate salt (X^"=N0₃ ^"), the methanesulfonate salt (X^"= CH3SO3^"), the p- toluenesulfonate salt

and the borate salt (X^"= Η2ΒΟ3^")· Preferably, the compound is a hydrochloride salt.

[0018] In a further aspect of the present invention, there are provided the compounds of formula II, 4-(4-cyanophenoxy)-2-hydroxymethyl-benzenediazonium salts having the following structural formula:

wherein X^" is selected from the group comprising CI^", Br^", Γ, BF₄ ^", PF₆ ^" , H2BO3^", NO3^", HSO4- , CH3SO3-, CH3C6H4SO3- and CIO4-. Preferably, X^" is CI^".

[0019] The present invention provides crisaborole obtainable by the process described herein, which employs the intermediate 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN) as starting material.

[0020] In another embodiment, the present invention provides a process for preparing the intermediate of formula I, 4-(4-amino-3-(hydroxymethyl)phenoxy)-benzonitrile (AHBN), as depicted in Scheme 3, which process comprises the following stages:

1. Coupling a 2-(5-halo-2-nitrophenyl)-l,3-dioxolane (wherein halo = F, CI, Br) with p-cyanophenol in the presence of a base to afford the compound of formula III, 4-(4- nitro-3-(l,3-dioxolane-2-yl)phenoxy)benzonitrile;

2. Deprotecting the compound of formula III with an acid to afford the compound of formula IV, 4-(4-nitro-3-formylphenoxy)benzonitrile; and

3. Reducing the compound 4-(4-nitro-3-formylphenoxy)benzonitrile to afford the product 4-(4-amino-3-(hydroxymethy)phenoxy)benzonitrile (AFIBN).

[0021] In a further aspect of the present invention, there are provided the intermediate of formula III, 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)benzonitrile

4-(4-nitro-3-(1 ,3-dioxolan-2-yl)

phenoxy)benzonitrile

III

and the intermediate of formula IV, 4-(4-nitro-3-formylphenoxy)benzonitrile.

4-(4-nitro-3-formyl

phenoxy)benzonitrile

IV

[0022] The present invention provides pharmaceutical compositions comprising the crisaborole obtainable by a process depicted in Scheme 2 and at least one pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 depicts the DSC curve of the intermediate 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN) showing peak maximum at 106.27°C.

[0024] Figure 2 depicts the IR spectrum of the intermediate 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN).

[0025] Figure 3 depicts the LC-MS (Fraction 13 collected at RT 15.7 minutes with m/z=224.0708 corresponding to C14H11NO2) of the 4-(3- (hydroxymethyl)phenoxy)benzonitrile (The Des-amine) impurity.

[0026] Figure 4 depicts the proton NMR spectrum of the intermediate 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN).

[0027] Figure 5 depicts the peak list of the proton NMR spectrum of the intermediate 4- (4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN).

[0028] Figure 6 depicts the ¹³C NMR spectrum of the intermediate 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN). [0029] Figure 7 depicts the peak list of the C NMR spectrum of the intermediate 4-(4- amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN).

DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention provides compounds, which are useful intermediates for the production of crisaborole, processes for producing such intermediates, and processes for producing crisaborole therewith.

[0031] Compounds of the present invention include the intermediate of formula I, 4-(4- amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN) and its ammonium salts (compounds of the formula IA), the compounds of formula II (the diazonium salts), the intermediate of formula III, 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)-benzonitrile and the intermediate of formula IV, 4-(4-nitro-3-formylphenoxy)-benzonitrile.

[0032] In accordance with the present invention, the preparation of the intermediates (4- amino-3-(hydroxymethyl)-phenoxy)benzonitrile (AHBN) and its salts, the intermediate of formula III, 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)benzonitrile and the intermediate of formula IV, 4-(4-nitro-3-formylphenoxy)benzonitrile can be achieved in high yield and high purity. The intermediates of the present invention are particularly useful for producing crisaborole.

[0033] In one embodiment, the present invention provides a process for preparing crisaborole, which process comprises the following stages:

2. Reacting sodium nitrite (NaN0₂) with the compound of formula IA to obtain the compound of formula II, 4-(4-cyanophenoxy)-2-hydroxymethyl-benzenediazonium salt (the diazonium salt), optionally in situ;

3. Reacting the diazonium salt with a borylation agent; and

4. Working up the reaction mixture, isolating crisaborole and optionally purifying it to afford highly pure crisaborole. Scheme 2

Stage 1

4-(4-a mino-3-( yd roxymet yl) Ammon iu m sa lt of 4-(4-a min o-3-(hyd roxymethyl)- ph en oxy)benzo n itrile (A H B N ) p_h en oxy)benzo n itrile

I

Stage 2

C risa bo ro le

[0034] The process of the present invention for preparing crisaborole, starting from 4-(4- amino-3-(hydroxymethy)phenoxy)benzonitrile (AHBN) is depicted in Scheme 2 above. Although crisaborole may be obtained from 4-(4-amino-3- (hydroxymethy)phenoxy)benzonitrile (AHBN) in a one pot reaction, the process may optionally comprise isolating the diazonium salt of formula II.

[0035] According to certain embodiments of the present invention, depicted in Scheme 2a below, the starting material 4-(4-amino-3-(hydroxymethy)-phenoxy)benzonitrile of formula I is mixed with an organic solvent selected from the group comprising methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran (THF), 2- methyltetrahydrofuran (methyl-THF), 1,4-dioxane, dimethyl sulfoxide (DMSO), methyl isobutyl ketone (MIBK), acetonitrile and mixtures thereof, preferably methanol.

[0036] According to some embodiments of the present invention, the ratio between

AHBN and the solvent is at least about 0.1 g per 8 mL, preferably 1 g per 8 mL.

[0037] According to some embodiments of the present invention, the acid used for preparing the aqueous acidic solution employed in Stage 1, is selected from the group comprising hydrochloric acid (HCl), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid and acetic acid. Preferably, the acid is aqueous HCl solution.

[0038] According to some embodiments of the present invention, the quantity of aqueous HCl solution is from about 1 equivalent to about 20 equivalents, preferably 4 equivalents.

[0039] According to some embodiments of the present invention, the borylation agent, employed in Stage 3, is selected from the group comprising pinacoloborane, cathecholborane, bis(catecholo)diboron, bis(neopentyl glycolato) diboron, bis(hexylene glycolato)diboron, bis(pinacolo)diboron (B₂Pin₂), tetrahydroxybiboron, 4,4,5, 5-tetramethyl-l,3,2-dioxaborolane, 4,4,5, 5-tetramethyl-l,3,2-dioxaborolane and 4,6,6-trimethyl-l,3,2-dioxaborinane. The borylation agent can be used as is or in solution in a solvent such as methanol, THF, DMSO or 1,4-dioxane.

[0040] Preferably, the borylation agent is bis(pinacolo)diboron (B₂Pin₂) or tetrahydrobiboron.

Scheme 2a

Stage 1

4-(4-amino-3-(hydroxymethyl) Ammonium salt of 4-(4-amino-3-(hydroxymethyl)- phenoxy)benzonitrile (AHBN) phenoxy)benzonitrile

I

Stage 2 CI

NaN0₂ / Water

The diazonium salt

Stages 3 and 4 II

Crisaborole [0041] According to an aspect of the present invention, working up the reaction mixture (Stage 4 in the process for preparing crisaborole) comprises the following steps:

1. Evaporating the solvent, adding water and an organic solvent and carrying out at least one extraction and separating the phases;

2. Adding a base to the aqueous phase and carrying out a second extraction with the organic solvent;

3. Acidifying the aqueous phase, adding the organic solvent, extracting and separating the phases; and

4. Washing the organic phase, drying and evaporating the solvent to afford solid crisaborole.

[0042] The organic solvent used for the extractions in Steps 1-3 of the working up procedure is selected from the group comprising dichloromethane (DCM), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate, methyl-THF and mixtures thereof. Preferably, the organic solvent used for the extractions is MIBK.

[0043] The base added to the aqueous phase in Step 2 is selected from the group comprising sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium hydroxide and potassium hydroxide. Preferably, the base is potassium carbonate or sodium hydroxide.

[0044] The acid used to acidify the aqueous phase in Step 3 of the work up is selected from the group comprising hydrochloric acid (HQ), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p- toluenesulfonic acid, methanesulfonic acid, formic acid and acetic acid. Preferably, the acid is acetic acid.

[0045] According to another aspect of the present invention, working up the reaction mixture comprises the following steps:

I. Adding a base to the reaction mixture and filtering off the thus formed solid and obtaining a solution;

II. Adding an organic solvent to the solution, extracting and separating the phases;

III. Acidifying the aqueous phase and filtering off the thus formed solid crisaborole; and

IV. Washing and drying the crude crisaborole. [0046] The base added to the aqueous phase in Step I is selected from the group comprising sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium hydroxide and potassium hydroxide. Preferably the base is 10% solution of potassium carbonate.

[0047] The organic solvent used for the extraction in Step II is selected from the group comprising dichloromethane (DCM), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate, methyl-THF and mixtures thereof. Preferably, the organic solvent used for the extraction is MIBK.

[0048] The acid used to acidify the aqueous phase in Step III is selected from the group comprising hydrochloric acid (HQ), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid and acetic acid. Preferably, the acid is acetic acid.

[0049] The solvent used to wash the crude crisaborole in Step IV is selected form the group comprising n-pentane, n-hexane, n-heptane, toluene, methyl tert-butyl ether (MTBE), water and mixtures thereof. Preferably, the solvent is water.

[0050] In a specific embodiment of the present invention, a process for preparing crisaborole comprises the steps of mixing the starting material of formula I, 4-(4-amino-3- (hydroxymethyl)-phenoxy)benzonitrile (AHBN) with methanol and adding aqueous hydrochloric acid solution while cooling to about 0°C and stirring; adding an aqueous solution of sodium nitrite (NaNCh) while maintaining stirring and cooling; adding bis(pinacolo)diboron and methanol and mixing for about one hour; evaporating the methanol and adding MIBK to form a two-phase system, extracting and separating the phases; adding saturated solution of potassium carbonate to the aqueous phase, extracting with MIBK, and separating the phases; acidifying the aqueous phase with acetic acid, extracting with MIBK and separating the phases; washing the organic phase with water, drying and evaporating the solvent.

[0051] In another specific embodiment of the present invention, a process for preparing crisaborole comprises the steps of mixing the starting material of formula I 4-(4-amino-3- (hydroxymethyl)-phenoxy)benzonitrile (AHBN) with methanol and adding aqueous hydrochloric acid solution while cooling to about 0°C and stirring; adding an aqueous solution of sodium nitrite (NaNCh) while maintaining stirring and cooling; adding tetrahydrodiboron and methanol and mixing for about one hour; adding a basic solution and filtering off the thus formed solid; extracting the obtained aqueous solution with MIBK and discarding the organic phase; adding an acid to the aqueous phase and filtering off the thus precipitated solid; washing with water and drying.

[0052] In another embodiment, the present invention provides a process for preparing the intermediate of formula I, 4-(4-amino-3-(hydroxymethyl)phenoxy)-benzonitrile (AHBN), which process comprises the following stages:

1. Coupling a 2-(5-halo-2-nitrophenyl)-l,3-dioxolane (wherein halo = F, CI, Br) with p- to in presence of a base to afford the compound of formula III, ( 4-(4-nitro-3-(l,3- di oxol ane-2-y l)phenoxy )b enzonitril e;

2. Deprotecting the compound of formula III with an acid to afford the compound of formula IV, 4-(4-nitro-3-formylphenoxy)-benzonitrile; and

3. Reducing the compound 4-(4-nitro-3-formylphenoxy)benzonitrile to afford 4- (4-amino-3-(hydroxymethy)phenoxy)benzonitrile (AHBN).

[0053] Scheme 3 below depicts embodiments of the process of the present invention for preparing the starting material 4-(4-amino-3-(hydroxymethy)-phenoxy)benzonitrile:

Scheme 3

Stage 1

X=F, CI, Br

4-(4-nitro-3-(1 ,3-dioxolan-2-yl) 2-(5-halo-2-nitrophenyl)-1 ,3-dioxolane phenoxy)benzonitrile

III

4-(4-nitro-3-formyl

phenoxy)benzonitrile

IV

Stage 3

Reduction

4-(4-amino-3-(hydroxymethyl)

phenoxy)benzonitrile (AHBN)

I

[0054] According to some embodiments of the present invention, the base used in the coupling reaction to afford the compound 4-(4-nitro-3-(l,3-dioxolane-2- yl)phenoxy)benzonitrile (Stage 1) is selected from sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate and combinations thereof. Preferably, the base is potassium carbonate.

[0055] According to some embodiments of the present invention, the organic solvent used in Stage 1 (the coupling reaction) to afford the compound of formula III, 4-(4-nitro-3- (l,3-dioxolane-2-yl)phenoxy)benzonitrile, is selected from acetonitrile, N-methyl-2- pyrrolidone (NMP), THF, methyl-THF, 1,4-dioxane, DMSO, N,N-dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMA) and mixtures thereof. Preferably, the solvent is DMF.

[0056] According to some embodiments of the present invention, deprotecting the compound of formula III to afford the compound of formula IV (Stage 2) is carried out using an acid selected from HCl, HBr, TFA, p-toluenesulfonic acid, methanesulfonic acid and sulfuric acid. Preferably, the acid is p-toluenesulfonic acid.

[0057] According to the present invention, reducing the compound of formula IV, 4-(4- nitro-3-formylphenoxy)benzonitrile in Stage 3, to afford 4-(4-amino-3-(hydroxymethyl)- phenoxy)benzonitrile (AHBN) is carried out in one step or in two steps.

[0058] According to some embodiments of the present invention, the solvent used in the deprotection of the compound of formula III to afford the compound of formula IV (Stage 2) is selected form methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, acetone, THF, toluene, diethylene glycol, water and mixtures thereof. Preferably, the solvent is methanol.

[0059] According to an embodiment of the present invention, reduction of the compound 4-(4-nitro-3-formylphenoxy)benzonitrile in Stage 3 is carried out using sodium borohydride in an organic solvent such as ethanol followed by homogenous catalytic hydrogenation with hydrogen using metal catalyst selected from palladium, platinum, ruthenium and Raney nickel, preferably the metal catalyst is palladium on carbon in an organic solvent such as methanol.

[0060] According to another embodiment of the present invention, reduction of the compound 4-(4-nitro-3-formylphenoxy)benzonitrile in Stage 3 is carried out using the catalyst aluminum sec-butylae and/or aluminum isopropoxide in an organic solvent such as isopropanol followed by using a metal catalyst such as iron or zinc in an organic solvent such as methanol.

[0061] Preferably, zinc dust in methanol and hydrazine are used at ambient temperature, under which conditions nitrile and ether groups are tolerated.

[0062] The present invention relates to methods of purifying crisaborole, e.g., by crystallization or by using liquid chromatography comprising reducing the level of impurities such as the isolated impurity 4-(3-(hydroxymethyl)phenoxy)benzonitrile (the Des-amine) of formula V, which is a byproduct formed in the process. The Des-amine impurity has the formula C14H11NO2, a molecular weight of 225.246 and the following structural formula:

4-(3-(hydroxymethyl)phenoxy)benzonitrile (the Des-amine)

V [0063] The present invention provides crisaborole obtainable by the process described herein, employing the compound 4-(4-amino-3-(hydroxymethyl)phenoxy)-benzonitrile (AHBN) as starting material.

[0064] According to a specific embodiment of the present invention, there is provided crisaborole having purity greater than about 99.5%, preferably greater than about 99.8%, containing less than about 0.1% of the Des-amine impurity by weight, according to HPLC.

[0065] The present invention provides a method of isolating the Des-amine impurity that comprises providing a solution containing, inter alia, crisaborole, the Des-amine impurity and a solvent; precipitating the Des-amino impurity from the solution; and isolating the Des- amine impurity and/or subjecting said mixture to preparative HPLC or column chromatography. Suitable solvents include, but are not limited to, at least one of an alcohol, preferably methanol, a halogenated hydrocarbon such as dichloromethane, a ketone such as MIBK, a C5-C8 hydrocarbon such as n-hexane or n-heptane, or an ester such as ethyl acetate and mixtures thereof. Preferably, the solvent is MIBK. The method may include a step of concentrating a solution containing the Des-amine impurity.

[0066] According to some embodiments of the present invention, there is provided a process for purifying crisaborole, said process comprising the following steps:

1. Dissolving crisaborole in a solvent selected from the group comprising acetone, acetonitrile, anisole, dichloromethane, ethyl acetate, isopropyl alcohol, isopropyl acetate, MEK, MIBK, THF, methyl-THF and mixtures thereof and optionally adding activated carbon under constant mixing;

2. Optionally filtering the mixture, discarding the solid activated carbon and obtaining a filtrate;

3. Adding a solvent selected form the group comprising n-pentane, n-hexane, n- heptane, toluene, methyl tert-butyl ether (MTBE), water and mixtures thereof, optionally drop-wise while mixing;

4. Isolating the crystals by a method selected from evaporation or removal of a solvent or solvents optionally under reduced pressure, freeze drying or spray drying and filtration, preferably, isolating the crystals by filtration, washing and, optionally, drying.

[0067] In a specific embodiment of the present invention, a process for purifying crisaborole comprises the steps of dissolving crisaborole in acetone (1 g per about 4 mL), adding activated carbon and mixing for about 30 minutes at ambient temperature followed by filtering off the activated carbon and obtaining a filtrate; adding water drop-wise to the filtrate (4 mL per about 1 g) and filtering the thus formed crystals, washing and drying.

[0068] In another specific embodiment of the present invention, a process for purifying crisaborole comprises the steps of dissolving crisaborole in isopropanol (1 g per about 4 mL), adding activated carbon and mixing for about 30 minutes at ambient temperature followed by filtering off the activated carbon and obtaining a filtrate; adding water drop-wise to the filtrate (4 mL per about 1 g) and filtering the thus formed crystals, washing and drying.

[0069] In another specific embodiment of the present invention, a process for purifying crisaborole comprises the steps of dissolving crisaborole in ethyl acetate (4 mL per about 1 g) and stirring at ambient temperature to complete dissolution; adding n-heptane while mixing (10 mL per about 1 g); collecting the precipitated crystals washing with n-heptane and drying under reduced pressure.

[0070] The process of the present invention for the preparation of crisaborole provides substantially pure crisaborole having purity greater than or equal to about 99.5% and preferably greater than or equal to about 99.8% by weight, as determined by using HPLC. Furthermore, the present invention also provides crisaborole containing less than about 0.1% of the Des-amine impurity. The impurities in crisaborole may be analyzed using various methods such as liquid chromatography methods, e.g., an HPLC method.

[0071] According to the present invention, there is provided the intermediate of formula I, 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN), having the following structural formula:

I

4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN)

[0072] Further provided by the present invention are ammonium salts of AHBN (compounds of the formula IA) having the following structural formula:

IA

[0073] Further provided by the present invention are the compounds of formula II, 4-(4- cyanophenoxy)-2-hydroxymethyl-benzenediazonium salts (the diazonium salts) having the following structural formula:

II wherein X^" is selected from the group comprising CI^", Br^", Γ, BF₄ ^", PF₆ ^" , H2BO3^", NO3^", HS04^" , CH3SO3^", CH3C6H4SO3^" and CIO4-. Preferably, X^" is CI^".

[0074] In a further aspect of the present invention, there are provided the intermediate of formula III, 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)benzonitrile

4-(4-nitro-3-(1 ,3-dioxolan-2-yl)

phenoxy)benzonitrile

I I I

and the intermediate of formula IV, 4-(4-nitro-3-formylphenoxy)benzonitrile.

4-(4-nitro-3-formyl

phenoxy)benzonitrile

IV

[0075] The present invention provides pharmaceutical compositions comprising the crisaborole obtainable by a process depicted in Scheme 2 and at least one pharmaceutically acceptable excipient.

EXAMPLES

[0076] The following examples further illustrate the invention but should not be construed as in any way limiting its scope.

[0077] Example 1- Preparation of crisaborole using 4-(4-amino-3-(hydroxymethyl)- phenoxy)benzonitrile and bis(pinacolo)diboron

[0078] To a solution of 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (5.0 g, 20.8 mmol, 1.0 equiv.) in methanol (40 mL, 8 Vol.) was added hydrochloric acid, 32% (4.08 mL, 12.48 mmol, 3.4 equiv.) dissolved in water (4 mL). The reaction mixture was stirred for 5 minutes to complete dissolution and cooled to about 0°C using water/ice bath. A solution of NaNCh (1.44 g, 20.8 mmol, 1.0 equiv.) in water (9 mL, 2.1 mL of 2M solution of NaNCh) was added and the mixture was stirred for 30 minutes at about 0°C.

[0079] Bis(pinacolato)diboron (15.85 g, 62.4 mmol, 3.0 equiv.) was added to the reaction mixture followed by addition of methanol (60 mL, 12 Vol); [bis(pinacolato)diboron may be added also as MeOH solution (8-12V MeOH)]. The reaction mixture was stirred for about 1 hour.

[0080] Methanol was evaporated and MIBK (100 mL) was added to the mixture to form a two-phase solvent system and extraction was carried out. The phases were separated and saturated K2CO3 solution (100 mL) was added to the organic phase. A second extraction was carried out and the phases were separated. The aqueous phase was acidified with glacial acetic acid and extracted with MIBK. The organic phase was washed with water and dried over Na₂S04, and evaporated to afford crude solid crisaborole in 87.8% yield containing about 0.2% Des-amine. [0081] Example 2- Preparation of crisaborole using 4-(4-amino-3-(hydroxymethyl)- phenoxy)benzonitrile and tetrahydroxydiboron

[0082] To a solution of 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (5.0 g, 20.08 mmol, 1.0 equiv.) in methanol (40 mL, 8 Vol.) was added hydrochloric acid, 32% (4.08 mL, 12.48 mmol, 3.4 equiv.) dissolved in water (4 mL). The reaction mixture was stirred for 5 minutes to complete dissolution and cooled to about 0°C using water/ice bath. A solution of NaNC-2 (1.44 g, 20.8 mmol, 1.0 equiv.) in water (9 mL, 2.1 mL of 2M solution of NaNCte) was added and the mixture was stirred for 30 minutes at about 0°C.

[0083] Tetrahydroxydiboron, (4.48 g, 50 mmol, 3.0 equiv.) was added to the reaction mixture followed by addition of methanol (60 mL); [tetrahydroxydiboron may be added also as a solution in DMSO, 22 mL]. The reaction mixture was stirred for 1 hour.

[0084] A 10% solution of K2CO3 (75 mL) was added to pH=10 and the thus formed solid, containing the Des-amine impurity, was isolated by decantation. The obtained solution was extracted with MIBK (50 mL) and the organic phase was discarded. Acetic acid (6 mL) was added to the aqueous phase to pH=5 and the thus precipitated solid was filtered off, washed with water and dried to afford crude solid crisaborole, in 75% yield having 97.3% purity (according to HPLC).

[0085] Example 3- Purification of crisaborole by crystallization from acetone and water

[0086] Crisaborole (1.5 g) was dissolved in acetone (10 mL), activated carbon (0.15 g) was added and the mixture was stirred for about 30 minutes at ambient temperature. The activated carbon was discarded by filtration and water (10 mL) was added drop-wise to the filtrate. The precipitated crystals were collected by filtration, washed with water (9 mL), and dried at 45°C under reduced pressure to afford purified crisaborole (1.2 g) having purity of 99.86%) and containing about 0.03% of the Des-amine impurity (according to HPLC).

[0087] Example 4- Purification of crisaborole by crystallization from ethyl acetate and hexane

[0088] Ethyl acetate (10 mL) was added to crisaborole (2.5 g) and stirred at ambient temperature to complete dissolution, n-heptane (25 mL) was added while mixing. The precipitated crystals were collected, washed with n-heptane (20 mL), and dried under reduced pressure to afford crystalline crisaborole (1.7 g) having purity of 99.7% and containing about 0.02% of the Des-amine (according to HPLC).

[0089] Example 5- Purification of crisaborole by crystallization from isopropanol and water

[0090] Crisaborole (7.4 g) was dissolved in isopropanol (10 mL), activated carbon ( 20 g) was added and the mixture was stirred for about 30 minutes at a temperature of 25-40°C. The activated carbon was discarded by filtration and water (70 mL) was added drop-wise to the filtrate. The precipitated crystals were collected by filtration, washed with isopropanol (9 mL) and dried at 45°C under reduced pressure to afford purified crisaborole having purity of 99.6% containing about 0.09% of the Des-amine impurity (according to HPLC).

[0091] Example 6- Purification of crisaborole using column chromatography

[0092] Silica gel 40-63 microns (180 g) was slurried in dichloromethane (50 mL). The slurry was added into a 3.5 cm diameter glass column. After stabilization of the medium, a solution of crude crisaborole (7.8 g) dissolved in dichloromethane (50 mL) was added to the column under continuous flow. From time to time the column was filled with fresh solvent. The eluent included dichloromethane (500 mL), 5% ethyl acetate in dichloromethane (500 mL), 10%) of ethyl acetate in dichloromethane (1700 mL) and ethyl acetate (500 mL). Portions of 100 mL each of effluent were collected. In total, 33X100 mL solvent was collected; portions 15-17 were combined and evaporated under reduced pressure to afford crisaborole (2.5 g) having purity of 99.5%, (according to HPLC).

[0093] Example 7 - Preparation of 4-(4-amino-3-(hydroxymethyl)- phenoxy)benzonitrile

[0094] 26 g of p-Cyanophenol in 0.5L round bottom flask is dissolved in 100 mL watendioxane mixture (1 : 10) and 8 g of NaOH flakes are added. The resulting solution is stirred for 0.5 hr at room temperature and 55 g of 2-(5~bromo~2-nitrophenyl)- 1 ,3-dioxolane dissolved in 220 mL of dioxane is added dropwise. The resulted solution is heated for 3 hr at 55 °C, and then cooled to room temperature. The reaction mixture is evaporated to dryness and extracted three times with 50 mL of methylene chloride. The combined extracts are evaporated to dryness and the obtained product is treated with 100 mL 1 N HC1 at room temperature for 1 hr. The pH is adjusted to neutral with NaOH (10N), extracted three times with methylene chloride, and the combined extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The obtained product is dissolved in 200 mL tetrahydrofurane and 10 g of sodium borohydride is added. The reaction mixture is stirred overnight, filtered, and evaporated to dryness. The residue is recrystallized from acetonitrile to afford approximately 52 g of the desired product.

Claims

Leydig 738071 WO 2018/150327 PCT/IB2018/050883 22 CLAIMS

1. A process for preparing crisaborole, comprising the following stages:

2. Reacting sodium nitrite (NaNCh) with the compound of formula IA to obtain the compound of formula II, 4-(4-cyanophenoxy)-2-hydroxymethyl- benzenediazonium salt (the diazonium salt), optionally in situ;

3. Reacting the diazonium salt with a borylation agent; and

2. The process of claim 1, wherein the starting material 4-(4-amino-3- (hydroxymethy)phenoxy)benzonitrile (AHBN) is mixed with an organic solvent selected from the group comprising methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran (THF), 2-methyltetrahydrofuran (methyl-THF), 1,4-dioxane, dimethyl sulfoxide (DMSO), methyl isobutyl ketone (MIBK), acetonitrile and mixtures thereof.

3. The process of claim 2, wherein the solvent is methanol.

4. The process of claim 1, wherein the acid which is used as an aqueous acidic solution is selected from the group comprising hydrochloric acid (HQ), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid and acetic acid.

5. The process of claim 4, wherein 1 equivalent to 20 equivalents of aqueous HC1 are used in the reaction.

6. The process of claim 1, wherein the borylation agent is selected from the group comprising pinacoloborane, cathecholborane, bis(catecholo)diboron, bis(neopentyl glycolato)diboron, bis(hexylene glycolato)diboron, bis(pinacolo)diboron (B₂Pin₂), tetrahydroxybiboron, 4,4,5,5-tetramethyl-l,3,2-dioxaborolane, 4,4,5, 5-tetramethyl-l, 3,2- dioxaborolane, 4,6,6-trimethyl-l,3,2-dioxaborinane, which is used as is or in solution in a solvent selected from methanol, THF, DMSO, 1,4-dioxane and mixtures thereof. Leydig 738071

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7. The process of claim 6, wherein the borylation agent is bis(pinacolo)diboron (B₂Pin₂) or tetrahydroxybiboron.

8. The process of claim 1, wherein working up the reaction mixture comprises the following steps:

9. The process of claim 8, wherein the organic solvent used for the extractions is selected from the group comprising dichloromethane (DCM), methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), ethyl acetate, methyl-THF and mixtures thereof.

10. The process of claim 9, wherein the organic solvent used for extraction is

MIBK.

11. The process of claim 8, wherein the base added to the aqueous phase after the first extraction is selected from the group comprising sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, sodium hydroxide and potassium hydroxide.

12. The process of claim 11, wherein the base added to the aqueous phase after the first extraction is potassium carbonate or sodium hydroxide.

13. The process of claim 8, wherein the acid used to acidify the aqueous phase after the second extraction is selected from the group comprising hydrochloric acid (HC1), hydrobromic acid, trifluoroacetic acid (TFA), nitric acid, sulphuric acid, boric acid, periodic acid, phosphoric acid, p-toluenesulfonic acid, methanesulfonic acid, formic acid and acetic acid. Leydig 738071

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14. The process of claim 13, wherein the acid used to acidify the aqueous phase after the second extraction is acetic acid.

15. A process for preparing the intermediate of formula I, 4-(4-amino-3- (hydroxymethyl)phenoxy)benzonitrile (AHBN) of claim 1, comprising the following stages:

1. Coupling a 2-(5-halo-2-nitrophenyl)-l,3-dioxolane (wherein halo = F, CI, Br) with p-cyanophenol in the presence of a base to afford the compound of formula III, 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)benzonitrile;

3. Reducing the compound 4-(4-nitro-3-formylphenoxy)benzonitrile to afford 4-(4-amino-3-(hydroxymethy)phenoxy)benzonitrile (AHBN).

16. The process of claim 15, wherein the base used in the coupling reaction to afford the compound 4-(4-nitro-3-(l,3-dioxolane-2-yl)phenoxy)benzonitrile (Stage 1) is selected from the group comprising sodium carbonate, potassium carbonate, ammonium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate and combinations thereof.

17. The process of claim 15, wherein a solvent is used in Stage 1 (the coupling reaction) to afford the compound of formula III, 4-(4-nitro-3-(l,3-dioxolane-2- yl)phenoxy)benzonitrile, which is selected from the group comprising acetonitrile, N-methyl- 2-pyrrolidone (NMP), THF, methyl-THF, 1,4-dioxane, DMSO, N,N-dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMA) and mixtures thereof.

18. The process of claim 15, wherein deprotecting the compound of formula III to afford the compound of formula IV (Stage 2) is carried out using an acid selected from HC1, HBr, TFA, p-toluenesulfonic acid, methanesulfonic acid and sulfuric acid.

19. The process of claim 15, wherein a solvent is used in the deprotection of the compound of formula III to afford the compound of formula IV (Stage 2), which is selected form the group comprising methanol, ethanol, 1-propanol, 2-propanol, acetonitrile, acetone, THF, toluene, diethylene glycol, water and mixtures thereof. Leydig 738071

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20. The process of claim 15, wherein the reduction of the compound 4-(4-nitro-3- formylphenoxy)benzonitrile in Stage 3 is carried out using sodium borohydride in ethanol followed by homogenous catalytic hydrogenation with hydrogen using metal catalyst selected from palladium on carbon, platinum, ruthenium and Raney nickel.

21. A process for purifying crisaborole, said process comprising the following steps:

2. Optionally filtering the mixture, discarding the solid activated carbon and obtaining a filtrate:

3. Adding a solvent selected form the group comprising n-pentane, n-hexane, n-heptane, toluene, methyl tert-butyl ether (MTBE), water and mixtures thereof, optionally drop-wise while mixing;

4. Isolating the crystals by filtration, washing and, optionally, drying.

22. Substantially pure crisaborole having purity greater than or equal to 99.5%, or greater than or equal to 99.8%, containing less than 0.1% of the Des-amine impurity by weight, as determined by using HPLC.

23. A diazonium salt having the following structural formula:

wherein X^" is selected from the group comprising CI^", Br^", Γ, BF₄ ^", PF₆ ^" , H2BO3^", NO3-, HSO4- , CH3SO3-, CH3C6H4SO3- and CIO4-. Leydig 738071

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24. The compound of claim 23, which is 4-(4-cyanophenoxy)-2-hydroxymethyl- benzenediazonium chloride of the structural formula:

25. A compound of formula I, 4-(4-amino-3-

(hydroxymethyl)phenoxy)benzonitrile (AHBN), having the following structural formula:

I

26. Ammonium salt compounds of 4-(4-amino-3-(hydroxymethyl)- >xy)benzonitrile (AHBN) of the structural formula:

comprising the hydrochloride salt (X^"=C1^"), the hydrobromide salt (X^"=Br^"), the hydroiodide salt

the nitrate salt (X^"=N0₃ ^"), the methanesulfonate salt (X^"= CH3SO3^"), the p- toluenesulfonate salt (X^CHsCeftSCb^") and the borate salt (X^"= H2BO3 . Leydig 738071

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27. The compound of claim 26, which is the hydrochloride salt of the compound 4-(4-amino-3-(hydroxymethyl)phenoxy)benzonitrile (AHBN) of the structural formula:

28. A compound of formula III, 4-(4-nitro-3-(l,3-dioxolane-2-yl)phi benzonitrile

4-(4-nitro-3-(1 ,3-dioxolan-2-yl)

phenoxy)benzonitrile

III

29. A compound of formula IV, 4-(4-nitro-3-formylphenoxy)benzonitrile.

4-(4-nitro-3-formyl

phenoxy)benzonitrile

IV

30. Crisaborole obtainable by a process of claim 1, which employs the compound of formula l (AHBN).

31. A pharmaceutical composition comprising crisaborole obtainable by a process of claim 1 and at least one pharmaceutically acceptable excipient.