WO2018115362A1 - Process for preparing 4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) - Google Patents

Abstract

The present invention relates to a new one-pot synthesis employing 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) for preparing (4-[(1-hydroxy-1,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) and pharmaceutically acceptable salts thereof in high yield and high purity. The novel process of the present invention is particularly suitable for industrial scale manufacture of crisaborole and its salts with excellent purity and good yields. The present invention also describes an intermediate, 4-(3-formyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (compound I), which is inter alia suitable for preparing (4-[(1-hydroxy-1,3-dihydro-2, 1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) and pharmaceutically acceptable salts thereof, as well as a another process suitable for industrial scale applications, employing the intermediate compound I in the preparation of crisaborole and pharmaceutically acceptable salts thereof, in high yield and high purity.

Description

PROCESS FOR PREPARING

4-[(1 -HYDROXY-1 ,3-DIHYDRO-2,1 -BENZOXABOROL-5-YL)OXY]BENZONITRILE (CRISABOROLE)

FIELD OF THE INVENTION

[0001] The present invention relates to a new one-pot synthesis employing 4-(4-bromo-3- (hydroxymethyl)phenoxy)benzonitrile (compound B) for preparing (4-[(1-hydroxy-1 ,3-dihydro-2,1- benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) and pharmaceutically acceptable salts thereof in high yield and high purity. The novel process of the present invention is particularly suitable for industrial scale manufacture of crisaborole and its salts with excellent purity and good yields.

[0002] The present invention also describes an intermediate, 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)benzonitrile (compound I), which is inter alia suitable for preparing (4-[(1-hydroxy- 1 ,3-dihydro-2, 1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) and pharmaceutically acceptable salts thereof, in good yield and high purity.

[0003] The present invention further describes another efficient and environmentally friendly process, which is also suitable for industrial scale applications, employing the intermediate compound I in the preparation of crisaborole and pharmaceutically acceptable salts thereof, in high yield and high purity.

BACKGROUND OF THE INVENTION

[0004] 4-[(1-hydroxy-1 ,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile, also known as crisaborole, depicted below, is a non-steroidal topical anti-inflammatory PDE-4 inhibitor developed by Anacor Pharmaceuticals for the treatment of mild-to-moderate atopic dermatitis and psoriasis. Crisaborole is commercialized under the trade name Eucrisa® for the treatment of mild-to-moderate atopic dermatitis in patients 2 years of age and older.

Crisaborole

[0005] Crisaborole was first disclosed in European patent EP 2 343 304 B1 in the name of Anacor Pharmaceuticals, which describes a synthetic approach to the preparation of crisaborole by reduction of the aldehyde group of the compound 4-(4-bromo-3-formylphenoxy)benzonitrile by means of sodium borohydride in methanol yielding the corresponding benzylic alcohol. This alcohol is then protected as the methoxymethyl ether by treatment with chloromethyl methyl ether and DIEA in methylene chloride. Metalation of aryl bromide (with t-butyl lithium or n-butyl lithium), followed by borylation with trimethyl borate in tetrahydrofuran and subsequent treatment with hydrochloric acid in a mixture of water and methanol gives rise to the crisaborole active substance.

[0006] The process described in the aforementioned patent involves the use of a large number of steps providing crisaborole in very low yields, as low as 33 %, and with a purity of 80 % which thus had to be purified by means of column chromatography, an unsuitable method for industrial scale applications. In addition, this method presents some disadvantages, such as the need to use protecting groups.

[0007] While the compound 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (also referred herein as "compound B") has been disclosed in the art, for example in EP 2 343 304 B1 or its U.S. family member US 7,582,621 , it has, to the best of applicant's knowledge, not yet been directly converted to crisaborole, i.e. in a one-pot synthesis that for example does not require protecting the benzylic alcohol function as described in the prior art.

[0008] As already explained, to date the prior art failed to provide efficient methods for obtaining crisaborole in high purity and with high yields. The lack of efficient manufacturing processes increases the cost of the final API crisaborole and the pharmaceutical compositions containing it, which has already resulted in expensive medications. In view of the pharmaceutical value of this compound, it is thus desirable to develop an efficient and safe process for the preparation of crisaborole in high purity and high yield, which can be easily applied at an industrial scale with low energy requirements and costs.

SUMMARY OF THE INVENTION

[0009] The present invention provides efficient and environmentally friendly processes for manufacturing 4- [(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) in high yield and high purity and applicable at industrial scale. This process also allows obtaining 4-[(1-hydroxy-1 ,3-dihydro-2,1-benzoxaborol- 5-yl)oxy]benzonitrile (crisaborole) without requiring laborious and unfeasible purification steps, yielding a high purity product which complies with pharmaceutical standards.

[0010] In a first aspect, the present invention provides a one-pot process for preparing 4-[(1-hydroxy-1 ,3- dihydro-2, 1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) or a pharmaceutically acceptable salt or co- crystal thereof starting from 4-(4-bromo-3- hydroxymethyl)phenoxy)benzonitrile (compound B):

Compound B

[001 1] Thus, the conversion of compound B to crisaborole according to the novel process provided herein proceeds in a single container / reaction vessel. In other words, the conversion of compound B is achieved without the isolation and/or purification of an intermediate product (such as the protected benzyl alcohol employed in the prior art), leading directly to crisaborole with excellent yields and high purity.

[0012] As will be appreciated by those skilled in the art, a one-pot process is advantageous because it reduces the number of steps that were hitherto required to produce the final API crisaborole (or a salt thereof) from compound B. The one-pot process of the present invention avoids unnecessary separation steps and the need for purification of the intermediate compounds, thus saving time and reducing costs, while still providing the crisaborole product in excellent yields and with high purity.

[0013] The present invention also relates to a process for preparing a pharmaceutical composition containing crisaborole or a pharmaceutically acceptable salt or co-crystal thereof comprising the one-pot process for preparing crisaborole as described herein, and further combining the obtained crisaborole or pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier or excipient.

[0014] A further aspect of the present invention provides 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenoxy)benzonitrile, compound I:

Compound I

[0015] Another aspect of the present invention relates to a process for preparing 4-(3-formyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (compound I), wherein the process comprises at least the following steps: a) contacting 4-(4-bromo-3-formylphenoxy)benzonitrile (also referred herein as "compound A") with a boron reagent in the presence of a base and a catalyst in an organic solvent to yield 4-(3-formyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy) benzonitrile (compound I).

b) optionally, isolating the 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)benzonitrile (compound I) obtained in step a) by means of conventional isolation techniques.

c) optionally, purifying the 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenoxy)benzonitrile (compound I) of step b) by means of conventional purification techniques.

[0016] A further aspect of the present invention provides a process for preparing compound I, comprising preparing compound A by contacting 2-bromo-5-hydroxybenzaldehyde with 4-fluorobenzonitrile in the presence of a base in an organic solvent, and further comprising reacting compound A with a boron reagent in the presence of a base and a catalyst in an organic solvent to obtain compound I as described above.

[0017] Yet another aspect of the present invention relates to a process for preparing crisaborole or a pharmaceutically acceptable salt thereof, which includes the above-described process for preparing compound I from compound A, and further includes converting compound I to crisaborole or a pharmaceutically acceptable salt thereof. Optionally, this process may further include the process for preparing compound A as described herein.

[0018] In some embodiments, the process for manufacturing crisaborole or a pharmaceutically acceptable salt thereof comprises at least the following steps: a) contacting the 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (compound I) with a reducing agent in the presence of an organic solvent to yield 4-(3- (hydroxymeth (compound II);

Compound I Compound II

contacting the compound obtained in step a) with an aqueous acid solution to yield crisaborole;

Compound II Crisaborole

c) isolating the crisaborole of step b) by means of conventional isolation techniques.

d) optionally, purifying the crisaborole of step b) or c) by means of conventional purification techniques; e) optionally, converting the crisaborole obtained in step b), step c) or d) into a pharmaceutically acceptable salt or co-crystal.

[0019] A further aspect of the present invention relates to the use of compound I as defined above as an intermediate for the preparation of crisaborole and pharmaceutical acceptable salt or co-crystal thereof. The process employing compound I may yield crisaborole in high purity and high yields.

[0020] Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of crisaborole or a pharmaceutically acceptable salt obtainable by a process as described above in paragraph [0017], optionally together with an appropriate amount of pharmaceutically acceptable excipients or carriers.

[0021] A further aspect of the present invention relates to the pharmaceutical composition of the present invention as described in paragraph [0020] above for use as a medicament, optionally wherein said composition is used in the treatment of mild-to-moderate atopic dermatitis.

DEFINITIONS

[0022] The term "one-pot" reaction is generally known in the art and refers to a chemical reaction wherein the starting material is converted to the end product of the reaction in a single reaction vessel or container, i.e. there is no intermediary reaction product which is isolated, removed or purified from the reaction vessel. A "one-pot" reaction in its broadest meaning still allows the formation of intermediary products which are, however, further converted to the end-product by addition of further reactants (in situ generation of the intermediate). A one-pot reaction also encompasses a reaction in a single reaction vessel where the starting product is converted to the end product through the formation of one or multiple intermediate products that are formed sequentially, even without further addition of a reagent ("multistep" reaction). Thus, a "one-pot" process is characterized by at least two reaction steps carried out without isolation and/or purification of the intermediate product or products, and suitably carried out in a single reaction vessel/container. It will be understood by one of skill in the art that a simple transfer of the whole reaction mass at an intermediate stage, but without isolating and/or purifying the intermediate product, is still a "one-pot" process according to the present invention, not the least because such a process would still achieve the technical advantage associated with a one-pot process in that the intermediate formed in situ does not need to be isolated and/or purified.

[0023] As used herein the term "organic solvent" refers to an organic molecule capable of at least partially dissolving another substance (i.e., the solute). Organic solvents may be liquids at room temperature. In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents, or by the combination of an organic solvent and water.

[0024] The term "polar solvent" as used herein means a solvent that tends to interact with other compounds or itself through acid-base interactions, hydrogen bonding, dipole-dipole interactions, or by dipole-induced dipole interactions.

[0025] The term "non-polar solvent" as used herein means a solvent that is not a polar solvent. Non-polar solvents interact with other compounds or themselves predominantly through dispersion forces. Non-polar solvents interact with polar solvents mainly through dipole-induced dipole interactions or through dispersion forces. [0026] The term "aprotic solvent" as used herein means any molecular solvent which cannot donate H+, i.e. a compound not having labile hydrogens.

[0027] The terms "conventional isolation techniques" or "purification" as used herein refers to the process of rendering a product clean of foreign elements whereby a purified product can be obtained. The term "industrial purification" refers to purifications which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, evaporation, centrifugation or crystallization. The terms "conventional isolation techniques" as used herein refers to the process of separating a desired product from other (unwanted) components of the reaction mixture. Examples for conventional isolation techniques include, but are not limited to centrifugation, decantation, filtration, solvent evaporation, and the like. [0028] The terms "conventional purification techniques" as used herein refer to the process of rendering a product (substantially) clean of unwanted elements, whereby a purified product can be obtained. Examples include, but are not limited to solvent extraction (with or without phase separation), filtration, slurrying and crystallization/precipitation from a solvent or solvent mixture. Purification by chromatographic techniques is also "conventional", it is much less preferred in the industry in view of the typically low yields and high costs associated with this technique (due to, inter alia, large volumes of solvent and need for chromatography material) which often effectively prevents upscale of the process to an industrial scale.

[0029] As used herein, the term "solvent extraction" refers to the process of separating components of a mixture by using a solvent which possesses greater affinity for one component, and may therefore separate said one component from at least a second component which is less miscible than said one component with said solvent.

[0030] The term "filtration" refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression "filtrate" refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The expression "filter cake" refers to residual solid material remaining on a feed side of a filtration element.

[0031] The term "evaporation" refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor. Various solvents may be evaporated during the synthetic route disclosed herein. As known to those of skilled in the art, each solvent may have a different evaporation time and/or temperature.

[0032] The term "phase separation" refers to a solution or mixture having at least two physically distinct regions.

[0033] As used herein, the term "slurrying" refers to any process which employs a solvent to wash, suspend or disperse a crude solid product. [0034] The term "crystallization" refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound , optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as dissolving the compound in a solvent and precipitating it by addition of an antisolvent (i.e. a solvent in which the desired compound has a lower solubility).

[0035] The term "high purity" as used herein refers to a purity of greater than 98%, or greater than 99% , or greater than 99.5%, or greater than 99.7% , or greater than 99.8%.

[0036] The term "high yield" as used herein refers to a yield of greater than 70%, or greater than 75%, or greater than 80% , or greater than 85%. DETAILED DESCRIPTION OF THE INVENTION

[0037] The present invention provides an efficient and environmentally friendly process for manufacturing 4- [(1 -hydroxy-1 ,3-dihydro-2, 1 -benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) in high yield and high purity and applicable at an industrial scale.

[0038] The process described herein allows for obtaining 4-[(1 -hydroxy-1 ,3-dihydro-2, 1 -benzoxaborol-5- yl)oxy]benzonitrile (crisaborole) through a one-pot synthesis from 4-(4-bromo-3- (hydroxymethyl)phenoxy)benzonitrile (compound B), and therefore does not require laborious and unfeasible purification steps, while still yielding a high purity product which complies with pharmaceutical standards.

[0039] According to the present invention, there is provided a process for preparing 4-[(1 -hydroxy-1 ,3- dihydro-2, 1 -benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) or a pharmaceutically acceptable salt thereof, comprising converting 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) to crisaborole in a one-pot reacti

Compound B Crisaborole

[0040] In the context of the present invention the one-pot reaction is preferably one where all reagents are added to the starting material , thereby allowing the reaction to directly proceed towards the desired end product, i.e. without requiring the addition of additional reactants after the formation of an (in s/^'fiv-formed) intermediate product.

[0041 ] In some embodiments of this aspect, the one-pot process for preparing crisaborole comprises contacting 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) with a borylation agent in the presence of a base, a palladium catalyst and a ligand in an organic solvent to yield crisaborole. [0042] In some embodiments, the reaction product crisaborole may be isolated, typically by conventional isolation techniques, and/or purified, typically by conventional purification techniques. A preferred purification technique involves solvent extraction, where the desired product is separated from impurities by phase separation, and/or recrystallization of the crude (or pre-purified) reaction product from an organic solvent (or a mixture of organic solvents, or a mixture of one or more organic solvents and water). The precipitated product may then be conveniently isolated by centrifugation, decantation or filtration.

[0043] It is readily apparent that the purification of crisaborole may be carried out while still in the reaction vessel used for the one-pot reaction, or it can be isolated and then purified in a separate (or the same, but cleaned) reaction vessel. [0044] In certain embodiments of the one-pot process described herein above, compound B may be also contacted with an additive. Preferably, the additive is ethylene glycol (OH(CH₂)20H), as the yield is increased. In other embodiments, the one-pot process may be carried out without an additive, such as ethylene glycol (cf. Example 4 below).

[0045] The process may in certain embodiments further entail the conversion of crisaborole into a pharmaceutically acceptable salt or co-crystal thereof. Pharmaceutically acceptable salts or co-crystals of crisaborole can be prepared in a manner generally known to those of skill in the art, by contacting crisaborole with a pharmaceutically acceptable acid or co-crystal former, respectively, in a suitable solvent at a temperature of typically between -10 °C and 100 °C.

[0046] It will again be apparent to those skilled in the art that the conversion into a salt or co-crystal may take place in the same reaction vessel (i.e. before isolation and/or purification), or after isolation and/or purification, in which case said conversion may take place in the same (cleaned) or in a different reaction vessel.

[0047] The palladium catalyst is preferably used in quantities ranging from about 0.001 (molar) equivalents to about 0.005 equivalents, more preferably about 0.0025 equivalents of the starting material (compound B). [0048] The ligand is preferably used in quantities ranging from about 0.002 equivalents to about 0.01 equivalents, more preferably about 0.005 equivalents of the starting material (compound B). The ligand to catalyst ratio is preferably between about 1 :1 and about 3:1 , and even more preferably about 2: 1.

[0049] The base is preferably used in quantities ranging from 2 equivalents to 4 equivalents, more preferably 3.0 equivalents while the borylation agent is preferably used in quantities ranging from about 1 equivalent to about 3 equivalents, more preferably about 1.5 equivalents of the starting material (compound B). In case an additive is employed in the process, the additive such as ethylene glycol is preferably used in quantities ranging from 2 equivalents to 4 equivalents, more preferably 3 equivalents of the starting material (compound B). [0050] Alternatively or in addition, the palladium catalyst employed in the one-pot conversion of compound B to crisaborole is in some embodiments selected from:

Pd(OAc)₂

Pd(dba)₃

[Pd(allyl)CI]₂

Pd(acac)₂

Pd 100: Pd(PPh₃)₂CI₂

Pd 106: PdCI₂(dppf) CH₂CI₂

Pd-116: (Pd[P(tBu)₃]₂)

Pd-127: (PdCI₂(dcypf)

Pd 168: Chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(ll)

P(Cy₃)-Pd-G2: Chloro(tricyclohexylphosphine)(2'-aminobiphen-2-yl)palladium(ll)

[(1 ,3,5J-Tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2'-amino-1 ,1 ^,-biphenyl)]palladium(ll) methanesulfonate

Mesyl[(tri-f-butylphosphine)-2-(2-aminobiphenyl)]palladium(ll)

XPhos-Pd-G1 : Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1 '-biphenyl)[2-(2- aminoethyl)phenyl)]palladium(ll)

SPhos-Pd-G1 : Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1 ,1 ^,-biphenyl)[2-(2- aminoethylphenyl)]palladium(ll)

tBuXPhos-Pd-G1 : [2-(Di-tert-butylphosphino)-2',4',6'-triisopropyl-1 , 1 -biphenyl][2-(2- aminoethyl)phenyl)]palladium(ll) chloride

BrettPhos-Pd-G1 : Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4', 6'-triisopropyl-1 , 1 -biphenyl][2-(2- aminoethyl)phenyl]palladium(ll)

RuPhos-Pd-G1 : Chloro-(2-Dicyclohexylphosphino-2',6'-diisopropoxy-1 , 1 -biphenyl)[2-(2- aminoethyl)phenyl]palladium(ll)

XPhos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll)

XantPhos-Pd-G2: Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll)

SPhos-Pd-G2: Chloro(2-dicyclohexylphosphino-2^,,6^,-dimethoxy-1 ,1 ^,-biphenyl)[2-(2^,-amino-1 ,1 '- biphenyl)]palladium(ll)

RuPhos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',6^,-diisopropoxy-1 ,1 ^,-biphenyl)[2-(2^,-amino-1 ,1 '- biphenyl)]palladium(ll)

Neopentyl-tBu₂P-Pd-G2: Chloro[(di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium(ll)

MorDalphos-G2: Chloro(2-(di-1-adamantylphosphino)morpholinobenzene)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll)

CyJohnPhos-G2: Chloro(2-dicyclohexylphosphino-1 , 1 '-biphenyl)[2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) CPhos-Pd-G2: Chloro[(2-dicyclohexylphosphino-2^,,6'-bis(N,N-dimethylamino)-1 ^)iphenyl)-2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll)

cataCXium A-Pd-G2: Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(ll)

(f-Bu)₂ MeP-Pd-G2: Methanesulfonato (di-tert-butyl) methylphosphino (2'-amino-1 , 1 '-biphenyl-2-yl) palladium(ll)

APhos-Pd-G2: Chloro[4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palla

Pd-G3-XPhos: 2-Dicyclohexylphosphino-2^4^6'-triisopropyl-1 ,1 '-biphenyl)[2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll)

SPhos-Pd-G3: (2-Dicyclohexylphosphino-2',6'-diiTiethoxybiphenyl) [2-(2^,-amino-1 , 1 ^,-biphenyl)]palladium(ll) methanesulfonate

RuPhos-Pd-G3: (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1 ,1 ^,-biphenyl)[2-(2^,-amino-1 ,1 '- biphenyl)]palladium(ll) methanesulfonate

fBuXPhos-Pd-G3: [(2-Di-tert-butylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)-2-(2'-amino-1 ,1 -biphenyl)] palladium(ll) methanesulfonate

BrettPhos-Pd-G3: -Di-cyclohexylphosphino-S^-dimethoxy^'^'^'- triisopropyl-1 , 1 '-biphenyl)-2-(2'-amino- 1 ,1 ' -biphenyl)]palladium(ll) methanesulfonate

fert-BuBrettPhos-Pd-G3: [(2-Di-feff-butylphosphino-3,6-dimethoxy-2 4 6^,-triisopropyl-1, -biphenyl)-2-(2^,- amino-1 , 1 '-biphenyl)]palladium(ll) methanesulfonate

XantPhos-Pd-G3: [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll) methanesulfonate

TrixiePhos-Pd-G3: Mesyl(2-(di-tert-butylphosphino)-1 ,1 '-binaphthyl)[2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) RockPhos-Pd-G3: [(2-Di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6 -triisopropyl-1 ,1 '-biphenyl)-2-(2- aminobiphenyl)]palladium(ll) methanesulfonate

Neopentyl(t-Bu)₂P-Pd-G3: [(Di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium(ll)

methanesulfonate

MorDalphos-Pd-G3: (2-(Di-1-adamantylphosphino)morpholinobenzene)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll) methanesulfonate, Mesyl(2-(di-1-adamantylphosphino)morpholinobenzene)[2-(2'- amino-1 , 1 '-biphenyl)]palladium(ll)

Josiphos SL-J009-1-Pd-G3: {(R)-1-[(Sp)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine}[2- (2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate

JackiePhos-Pd-G3: [(2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy- 2',4',6'- triisopropyl- 1 ,1 '-biphenyl )-2-(2'-amino-1 , 1 '-biphenyl)]palladium(ll) methanesulfonate

P(Cy₃)-Pd-G3: [(Tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(ll) methanesulfonate

CyJohnPhos-Pd-G3: Methanesulfonato (2-biphenyl)dicyclohexylphosphino(2'-amino-1 ,1 '-biphenyl-2- yl)palladium(li

CPhos-Pd-G3: [(2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino) -1,r-biphenyl)-2-(2'-amino-1,r- biphenyl)] palladium(ll) methanesulfonate cataCXium-A-Pd-G3: Mesylate[(di(1-adamantyl)-n-butylph^

[(Di(1-adamantyl)-butylphosphine)-2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate

(t-Bu)₂PMe-Pd-G3: Methanesulfonato (di-tert-butyl) methylphosphino (2'-amino-1 ,1 '-biphenyl-2-yl) palladium(ll)

PPh(t-Bu)₂-Pd-G3: Methanesulfonato (di-tert-butyl) phenylphosphino (2'-amino-1 , 1 '-biphenyl-2-yl) palladium(ll)

APhos-Pd-G3: Palladium G3-(4-(N,N-Dimethylamino)phenyl)di-tert-butylphosphine, [4-(Di-tert- butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(ll) methanesulfonate

Ad-BrettPhos-Pd-G3: ^-(Di-l-adamantylphosphino^'^'.e'-triisopropyl-S.e-dimethoxybiphenyll^^'-amino- 1 ,1 '-biphenyl)]palladium(ll) methanesulfonate

XPhos-Pd-G4

XantPhos-Pd-G4

SPhos-Pd-G4

RuPhos-Pd-G4

PCy₃-Pd-G4

MorDalPhos-Pd-G4

cataCXium-Pd-G4

BrettPhos-Pd-G4

rac-BINAP-Pd-G4, or combinations thereof. [0051] Preferably, the palladium catalyst is selected from Pd168, XPhos-Pd-G1 , XPhos-Pd-G2, XPhos-Pd- G3, XPhos-Pd-G4, Chloro(tricyclohexylphosphine)(2'-aminobiphen-2-yl)palladium(ll), with XPhos-Pd-G2 being particularly preferred.

[0052] Alternatively or in addition, the ligand for said one-pot reaction is in certain embodiments preferably selected from: Triphenylphosphine, Trioctylphosphine, Tricyclohexylphosphine, XPhos, RuPhos, SPhos, DavePhos, QPhos, JohnPhos, BrettPhos, AmPhos, tBuXPhos, tBuMePhos, tBuBrettPhos, tBuDavePhos, AdBrettPhos, AlPhos, PhDave-Phos, Me₄tButylXphos, MePhos, Me₃(OMe)tBuXPhos, CyJohnPhos, Ad₂PBu, tBu₃P, 'BU3P-HBF4, 1 , 1 '-Bis(di-tert-butylphosphino)ferrocene, 2'-Dicyclohexylphosphino-2,4,6- trimethoxybiphenyl, Bis(3,5-bis(trifluoromethyl)phenyl)(2',6'-bis(isopropoxy)-3,6-dimethoxybiphenyl-2- yl)phosphine, (2-Biphenyl)di-1-adamantylphosphine, or mixtures thereof. [0053] Preferably, the ligand is selected from Tricyclohexylphosphine, XPhos, SPhos, QPhos, DavePhos, JohnPhos, BrettPhos, RuPhos, with XPhos being particularly preferred.

[0054] Alternatively or in addition, the base for said one-pot reaction is in some embodiments preferably selected from triethylamine (Et₃N), diazabicycloundecene (DBU), diisopropylethylamine (DIPEA or DIEA), triethylenediamine (DABCO), 1 ,2,2,6,6-pentamethylpiperidine, 1 , 1 ,3,3-tetramethylguanidine, NH₄OAc, KOAc, LiOH, KOH, NaOH, Mg(OH)₂, CaOH₂, ROLi, RONa, or ROK, wherein R is an alkyl group ranging from 1 -5 carbon atoms, preferably wherein the base is selected from Et₃N, DIPEA, and KOAc, with KOAc being particularly preferred.

[0055] Alternatively or in addition, the borylation agent for said one-pot reaction may be as bis(pinacol)borane, pinacol borane and tetrahydroxydiboron (B₂(OH)₄). Preferably, borylation agent is B₂(OH)₄.

[0056] Alternatively or in addition, the organic solvent may in some embodiments be selected from N,N- dimethylacetamide (DMA), DMF, DMSO, acetonitrile, ethers, toluene, benzene, and alcohols. Preferably, the organic solvent is selected from MeOH, EtOH, IPA, and even more preferably the organic solvent is MeOH.

[0057] The reaction temperature for the above described one-pot process generally depends on the solvent used for the reaction and may typically range from about 40 to about 1 10 °C, or from about 50 to about 90 °C, or about 60 to 80°C. In some embodiments, the reaction is preferably carried out at reflux temperature of the solvent / solvent mixture.

[0058] In a particularly preferred embodiment of this aspect of the present invention, the palladium catalyst is Pd-G2-XPhos (0.0025 equivalents), the ligand is XPhos (0.005 equivalents), the borylation agent is B₂(OH)₄ (1.5 equivalents), the base is KOAc (3.0 equivalents), the additive is OH(CH₂)₂OH (3.0 equivalents), the solvent is MeOH (5 Vol to 15 Vol, preferably 10 Vol), and the reaction temperature is about 64-66 °C.

[0059] In certain embodiments of this aspect of the invention, the process for preparing crisaborole or a pharmaceutically acceptable salt or co-crystal thereof further includes a process for preparing the starting compound 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B). In these embodiments, the process to prepare compound B comprises contacting 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A) with a reducing agent in the presence of an organic solvent to yield 4-(4-bromo-3- (hydroxymethyl)phenoxy)benzonitrile (compound B):

Reducing agent

Organic solvent

Compound A Compound B

[0060] Compound B may either be used directly in the one-pot reaction towards crisaborole, or it may be isolated, typically by conventional isolation techniques, and/or purified, typically by conventional purification techniques, before its subsequent one-pot conversion to crisaborole. A preferred purification technique involves filtration of the precipitated product, followed by recrystallization of the crude (or pre-purified) reaction product from an organic solvent (or a mixture of organic solvents, or a mixture of one or more organic solvents and water). The precipitated product may then be conveniently isolated by centrifugation, decantation or filtration, optionally followed by drying.

[0061] It is readily apparent that the purification of compound B may be carried out while still in the reaction vessel used for the reaction, or it can be isolated and then purified in a separate (or the same, but cleaned) reaction vessel, which may in turn be used for the subsequent one-pot reaction converting compound B to crisaborole as described herein.

[0062] Suitable reducing agents in this reaction to prepare compound B are selected from sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium triethylborohydride, lithium tri- sec-butylborohydride, potassium tri-sec-butylborohydride, lithium aluminum hydride in the presence of lanthanide salts (e.g. LaCI₃, CeBr₃), lithium tri-ferf-butoxyaluminium hydride, lithium trimethoxyaluminum hydride, diisobutylaluminum hydride, zinc borohydride on Y-zeolite or combinations thereof. Preferably, the reducing agent is sodium borohydride.

[0063] Suitable quantities of the reducing agent typically range from about 0.1 equivalents to about 0.9 equivalents, more preferably about from about 0.3 equivalents to about 0.7 equivalents, or about 0.5 equivalents.

[0064] This reaction proceeds in the presence of an organic solvent as reaction medium. Examples of organic solvents that may be used for this reaction step include, but are not limited to: hydrocarbon solvents (e.g. n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, nitrobenzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ether solvents (e.g. diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, methyltetrahydrofuran, 1 ,4-dioxane, etc.), alcohol solvents (e.g., methanol, ethanol, isopropanol, 1 -propanol, 2-methyl-1-propanol, 1-butanol, 2-butanol, 1 - pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), dimethyl sulfoxide (DMSO), A/-methyl-2-pyrrolidone and acetonitrile. In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents. In some embodiments, the organic solvent may be combined with water. Preferably, the organic solvent is selected from 1 ,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, or mixtures thereof. Most preferably, the organic solvent is methanol , ethanol, 1 ,4-dioxane, methyltetrahydrofuran, toluene, acetonitrile, or mixtures thereof.

[0065] The reaction may typically be carried out at a temperature from about -10 °C to about 10 °C. Preferably, the temperature is about 0 °C. The obtained mixture can also be stirred to facilitate the formation of 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) as a precipitate. [0066] In a preferred embodiment, the reducing agent is sodium borohydride (NaBH₄), the solvent is methanol (MeOH) (2 Vol to 6 Vol, preferably 4 Vol) and the reaction temperature is 0 °C.

[0067] After precipitation, the obtained 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) may be isolated by means of conventional isolation techniques. Preferably, compound B is isolated by filtration. Optionally, compound B may be purified or dried, or both.

[0068] In some embodiments, the process for preparing crisaborole or a pharmaceutically acceptable salt or co-crystal thereof further includes, besides the one-pot process to prepare crisaborole and the process to prepare the starting material compound B from compound A, also a process for preparing compound A.

[0069] Accordingly, in these embodiments the process to prepare 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A) involves contacting 2-bromo-5-hydroxybenzaldehyde with 4-fluorobenzonitrile in the presence of a base in an organic solvent to yield compound A:

Compound A

[0070] Compound A may either be used directly in the subsequent process for preparing compound B, or it may be isolated, typically by conventional isolation techniques, and/or purified, typically by conventional purification techniques, before its subsequent conversion to compound B. A preferred purification technique involves solvent extraction with phase separation, and/or recrystallization of the crude (or pre-purified) reaction product from an organic solvent (or a mixture of organic solvents, or a mixture of one or more organic solvents and water). The precipitated product may then be conveniently isolated by centrifugation, decantation or filtration, optionally followed by drying.

[0071] The purification of compound A may be carried out while still in the reaction vessel used for the reaction, or it can be isolated and then purified in a separate (or the same, but cleaned) reaction vessel, which may in turn be used for the subsequent conversion into compound B as described herein.

[0072] The 4-fluorobenzonitrile is preferably used in quantities ranging from 3 equivalents to 7 equivalents, and even more preferably 5 equivalents.

[0073] The base used in this reaction step may be an organic or an inorganic base. Suitable bases include, but are not limited to: metal hydroxides, such as sodium hydroxide and potassium hydroxide; metal carbonates, such as sodium carbonate, cesium carbonate and potassium bicarbonate; metal phosphates, such as sodium orthophosphate, cesium orthophosphate and potassium orthophosphate, metal acetates, such as sodium acetate and potassium acetate; linear or branched alkoxides of metals (metal alkoxides), ammonium (ammonium alkoxides), boron (boron alkoxides) or silicon (silicon alkoxides), such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium isobutoxide, sodium sec-butoxide, sodium tert-butoxide, lithium methoxide, lithium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide, potassium isobutoxide, potassium sec-butoxide, and potassium tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, magnesium ethoxide, barium methoxide, barium ethoxide, aluminum methoxide, aluminum ethoxide, titanium methoxide, titanium ethoxide, zirconium methoxide, zirconium ethoxide, ammonium methoxide, ammonium ethoxide, silicon methoxide, silicon ethoxide, boron methoxide, boron ethoxide; ammonia derivatives, such as triethylamine, A/,A/-dicyclohexylmethylamine, A/,A/-dicyclohexylamine, A/,A/-diisopropylethylamine and methanolic ammonia; heterocyclic bases such as pyridine, or mixtures thereof. Among the bases listed above, ammonia derivatives, metal acetates and metal carbonates are preferred. Most preferably, the base is potassium carbonate.

[0074] The reaction may be carried out in the presence of an organic solvent as a reaction medium. Examples of organic solvents that may be used for this aspect of the invention include, but are not limited to: hydrocarbon solvents (e.g. n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also include aromatic hydrocarbon solvents (e.g., benzene, nitrobenzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, cyclopentanone, 2-pentanone etc.), ether solvents (e.g. diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, methyltetrahydrofuran, 1 ,4-dioxane, 1 ,2-dimethoxyethane), carbon disulfide, N,N- dimethylformamide (DMF), A/,A/-dimethylacetamide (DMAC or DMA), dimethyl sulfoxide (DMSO), A/-methyl-2- pyrrolidone and acetonitrile. In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents. In some embodiments, the organic solvent may be combined with water. Preferably, the organic solvent is selected from 1 ,4-dioxane, A/,A/-dimethylformamide, tetrahydrofuran, 2- methyltetrahydrofuran, toluene, toluene/water, A/,A/-dimethylacetamide, or mixtures thereof. Most preferably, the organic solvent is 1 ,4-dioxane, methyltetrahydrofuran, or dimethylformamide, or mixtures thereof. Most preferably, the organic solvent is selected from A/,A/-dimethylformamide, toluene, or mixtures thereof.

[0075] The reaction may typically be carried out at a temperature from 20 °C to reflux. Preferably, the temperature is from 40 °C to reflux. More preferably, the temperature is from 80 °C to reflux. The obtained mixture can also be stirred to facilitate the formation of 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A) as a precipitate. [0076] In a preferred embodiment, 4-fluorobenzonitrile is used (about 5 equivalents), the base is K₂C0₃ (about 3 equivalents), the solvent is a mixture of DMF (about 2.5 Vol) and toluene (about 5 Vol) and the temperature is reflux temperature.

[0077] After precipitation, the obtained compound A may be isolated by means of conventional isolation techniques. Preferably, compound A is isolated by filtration. Compound A may then also be purified, for example by recrystallization, before conversion into compound B. Alternatively, compound A obtained according to the process described above may not be isolated before it is further converted to compound B as described herein. In other words, in these embodiments, compound A is prepared in situ and then directly converted to compound B as described herein.

[0078] The full process described above is illustrated in the following reaction scheme that summarizes steps 1 to 3 of the process. Step 1 illustrates preparing 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A), step 2 illustrates preparing 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) from 4-(4- bromo-3-formylphenoxy)benzonitrile (compound A), and step 3 illustrates converting 4-(4-bromo-3- (hydroxymethyl)phenoxy)benzonitrile (compound B) to 4-[(1-hydroxy-1 ,3-dihydro-2, 1-benzoxaborol-5- yl)oxy]benzonitrile (crisaborole).

STEP 1

Compound I Crisaborole [0079] It will be understood that in embodiments where crisaborole is further converted into a pharmaceutically acceptable salt or co-crystal, the isolation may in some instances only be accomplished after said salt or co-crystal formation, i.e. crisaborole as obtained from the one-pot reaction is, if necessary, directly converted to a salt / co-crystal form which is then isolated and, optionally, purified. Alternatively, the salt / co-crystal conversion can be accomplished after isolation but before purification, or the salt / co-crystal conversion is accomplished as a last step of the reaction sequence, after purification of crisaborole.

[0080] The crisaborole prepared according to the process described herein is typically obtained in very high purity and with excellent yields. The conversion of compound B into crisaborole by the one-pot process may be achieved with yields of at least 70%, or at least 75%, or even higher. In fact, as can be seen from Example 3 below, even with two recrystallizations the yields of the reaction were as high as 80%. Similarly, the one-pot process described herein allows to produce crisaborole with very high purity of at least 97%, 98%, 99%, 99.5% or even 99.8% (as determined by HPLC) by using only conventional isolation and purification techniques that are suitable for industrial scale manufacturing (such as phase separation, solvent evaporation, slurrying and recrystallization). In Example 3 below, the purity of the final product after two recrystallizations from methanol was even >99.9% (by HPLC).

[0081] A further aspect of the present invention relates to a process for preparing a pharmaceutical composition containing crisaborole or a pharmaceutically acceptable salt thereof comprising a process for preparing crisaborole as described herein, and further combining the obtained crisaborole or pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier or excipient.

[0082] In some embodiments of this aspect, the pharmaceutical composition is formulated into a medicament suitable for administration to a patient in need thereof. Preferably, the pharmaceutical composition or medicament is adapted for use in the treatment of atopic dermatitis and/or psoriasis.

[0083] A further aspect of the present invention is a novel intermediate, 4-(3-formyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (also referred herein as "compound I"):

Compound I

[0084] Advantageously, compound I is easily obtained and isolated, in good yield and high purity. In addition, it was found that compound I is very stable, and does not exhibit any change in color over a long period of time, preferably over a month, most preferably over 3 months, when left under atmospheric conditions at room temperature. The term "room temperature" in this context means that the temperature is between 15 and 30 °C. In addition, at a temperature of 30 °C and 60 % RH (relative humidity) no water uptake was observed. Thus, compound I does not need to be stored in special packaging containers or under expensive inert gas conditions to prevent or minimize its degradation or water uptake.

[0085] A further aspect of the present invention relates to a process for preparing 4-(3-formyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (compound I), wherein the process comprises at least the following steps: a) contacting 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A) with a boron reagent in the presence of a base and a catalyst in an organic solvent to yield 4-(3-formyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenoxy) benzonitrile (compound I).

Compound A Compound I b) optionally, isolating the 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)- benzonitrile (compound I) obtained in step a) by means of conventional isolation techniques; and c) optionally purifying the 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)- benzonitrile (compound I) of step b) by means of conventional purification techniques.

[0086] The boron reagent in step a) may be selected from pinacolborane, bis(pinacolato)diboron (B₂Pin₂), 2- isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane, 2-(4-methanesulfonylphenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane, 2-(iodomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane, 2-(4-cyclohexylphenyl)-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane, 2-(3-ethynylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane, 2-methoxy- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane, 2-(bromomethyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane or 2-(4- biphenylyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane. Preferably, the boron reagent is bis(pinacolato)diboron since by-products are avoided and the purity of the compound I is higher than with any other boron reagent.

[0087] The base used in step a) can be an organic or an inorganic base. Suitable bases include, but are not limited to metal hydroxides, such as sodium hydroxide and potassium hydroxide; metal carbonates, such as sodium carbonate, cesium carbonate and potassium bicarbonate; metal phosphates, such as sodium orthophosphate, cesium orthophosphate and potassium orthophosphate, metal acetates, such as sodium acetate and potassium acetate; linear or branched alkoxides of metals (metal alkoxides) or ammonium (ammonium alkoxides), such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium isobutoxide, sodium sec-butoxide, sodium tert-butoxide, lithium methoxide, lithium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, potassium butoxide, potassium isobutoxide, potassium sec-butoxide, and potassium tert- butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, magnesium ethoxide, barium methoxide, barium ethoxide, aluminum methoxide, aluminum ethoxide, titanium methoxide, titanium ethoxide, zirconium methoxide, zirconium ethoxide, ammonium methoxide, ammonium ethoxide; ammonia derivatives, such as triethylamine, N,N-dicyclohexylmethylamine, Ν,Ν-dicyclohexylamine and N,N-diisopropylethylamine, and heterocyclic bases such as pyridine, or mixtures thereof. Among the bases listed above, ammonia derivatives, metal acetates and metal carbonates are preferred. More preferably, the base is potassium acetate, or triethylamine as the yield was found to be improved over other bases.

[0088] The catalyst in step a) is preferably an organopalladium catalyst or any combination of a palladium salt and a ligand that under the reaction conditions can generate a catalytically active palladium(O) species. Examples of organopalladium catalysts that may be used for the present aspect of the invention include, but are not limited to tetrakis(triphenylphosphine)palladium (0), palladium chloride, palladium(ll) acetate, dichloro[1 ,1 -bis(diphenylphosphino)ferrocene]palladium(ll) acetone adduct, bis(tri-tert- butylphosphine)palladium(O), dichloro[1 , 1 'bis(di-tert-butylphosphino)]ferrocenepalladium(ll), 1 ,2,3,4,5- pentaphenyl-1 '-(di-tert-butylphosphino)ferrocene, dichlorobis(tri-orthotolylphosphine)palladium(ll), [1 , 1 - Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) complex with dichloromethane and dichlorobis(di-tert- butylphenylphosphine)palladium(ll), or combinations thereof. [0089] The reaction proceeds in the presence of an organic solvent as a reaction media. Examples of organic solvents that may be used for the present aspect of the invention include, but are not limited to: hydrocarbon solvents (e.g. n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone, methyl isopropyl ketone, cyclohexanone, cyclopentanone, 2-pentanone etc.), ether solvents (e.g. diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, methyltetrahydrofuran,, 1 ,4-dioxane, 1 ,2-dimethoxyethane, etc.), carbon disulfide, nitrobenzene, Ν,Ν-dimethylformamide (DMF), N,N- dimethylacetamide, dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone, acetonitrile, silicone solvents (e.g., silicone oils, polysiloxanes, cyclosilicones). In some embodiments, the organic solvent may be formed by the combination of two or more organic solvents. Preferably, the organic solvent is selected from 1 ,4-dioxane, Ν,Ν-dimethylformamide (DMF), tetrahydrofuran, 2-methyltetrahydrofuran, ethanol, methanol, acetone, ethyl acetate, isopropyl acetate, acetonitrile, methyl ethyl ketone, and methyl isobutyl ketone, or mixtures thereof. Most preferably, the organic solvent is 1 ,4-dioxane, methyltetrahydrofuran, toluene, acetonitrile or ethanol, or mixtures thereof. [0090] In some embodiments of this aspect, the molar ratio of the 4-(4-bromo-3-formylphenoxy)benzonitrile to base may be from 1 : 1 to 1 :5. More preferably, the molar ratio of the 4-(4-bromo-3- formylphenoxy)benzonitrile to base may be from 1 :2 to 1 :4. Most preferably, the molar ratio is about 1 :2.5 giving the highest yields.

[0091] In some embodiments of this aspect, the molar ratio of the 4-(4-bromo-3-formylphenoxy)benzonitrile to catalyst may be from 1 :0.01 to 1 :0.05. More preferably, the molar ratio of the 4-(4-bromo-3- formylphenoxy)benzonitrile to catalyst may be from 1 :0.01 to 1 :0.03. Most preferably, the molar ratio is about 1 :0.02.

[0092] The reaction may typically be carried out at a temperature from 0 °C to the reflux temperature of the reaction mixture. Preferably, the temperature is from 30 °C to reflux. Most preferably, the temperature is from 50 °C to reflux. The obtained mixture can also be stirred to facilitate the formation of the novel compound I as a precipitate.

[0093] After precipitation, the obtained compound I may be isolated by means of conventional isolation techniques. Preferably, the compound I is isolated by filtration. Optionally, compound I obtained is purified or dried or both.

[0094] The starting material, compound A, may be prepared by the reaction of 2-bromo-5- hydroxybenzaldehyde and 4-fluorobenzonitrile according to the following process: a) contacting 2-bromo-5-hydroxybenzaldehyde with 4-fluorobenzonitrile in the presence of a base in an organic solvent to yield Compound A;

Compound A

b) optionally, isolating the compound A obtained in step a) by means of conventional isolation techniques; and

c) optionally, purifying compound A of step b) by means of conventional purification techniques. [0095] The base used in step a) is as defined above, see paragraph [0073].

[0096] The reaction may be carried out in the presence of an organic solvent as defined above, see paragraph [0074]. [0097] The reaction may typically be carried out at a temperature from 0 °C to reflux. Preferably, the temperature is from 40 °C to reflux. Most preferably, the temperature is from 80 °C to reflux. The obtained mixture can also be stirred to facilitate the formation of compound A as a precipitate.

[0098] Accordingly, the present invention also relates to a process that includes at least the above- described process for preparing compound A and further comprises the process for preparing compound I from compound A as described herein.

[0099] In some embodiments of this aspect, the compound A obtained according to step a) above is not isolated before it is further converted to compound I as described herein. In other words, in these embodiments, compound A is prepared in situ and then directly converted to compound I as described above.

[0100] A further aspect of the present invention relates to a process for preparing crisaborole or a pharmaceutically acceptable salt thereof, which includes the above-described process for preparing compound I from compound A, and further includes converting compound I to crisaborole or a pharmaceutically acceptable salt thereof. Optionally, this process may further include the process for preparing compound A as described herein.

[0101] In some embodiments, the process for converting compound I to crisaborole comprises at least the following steps: a) contacting the 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (compound I) with a reducing agent in the presence of an organic solvent to yield 4-(3- (hydroxymethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (compound II);

Compound I Compound II

contacting the compound obtained in step a) with an aqueous acid solution to yield crisaborole;

Compound II Crisaborole isolating the crisaborole of step b) by means of conventional isolation techniques;

optionally, purifying the crisaborole of step b) or c) by means of conventional purification techniques; and

optionally, converting the crisaborole obtained in step b), step c) or step d) into a pharmaceutically acceptable salt or co-crystal.

[0102] The reducing agent is typically added to a mixture of the compound I in an organic solvent (alternatively the reducing agent is added to the solvent and then compound I is added to the mixture), to yield 4-(3-(hydroxymethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (compound II). Preferably, the reducing agent is slowly added to the mixture of the compound I in an organic solvent to allow a good control of the reaction. The mixture can also be stirred to facilitate the formation of the compound II. Finally, the compound II is optionally isolated by means of conventional isolation techniques. Preferably, the solvent is removed by distillation. Optionally, the compound II obtained is purified by means of conventional purification techniques. [0103] Suitable reducing agents are selected from lithium aluminum hydride in the presence of lanthanide salts (e.g. LaCI₃, CeBr₃), sodium borohydride, sodium triacetoxyborohydride, zinc borohydride on Y-zeolite or combinations thereof. Preferably, the reducing agent is sodium borohydride.

[0104] The reaction of step a) proceeds in the presence of a solvent, typically an organic solvent or water, as a reaction media. Examples of organic solvents that may be used for the present aspect of the invention include, but are not limited to: hydrocarbon solvents (e.g. n-pentane, n-hexane, n-heptane, n-octane, paraffin, cyclohexane, methylcyclohexane, decahydronaphthalene, mineral oil, crude oils, etc.) which also includes aromatic hydrocarbon solvents (e.g. benzene, nitrobenzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1 ,2-dichloroethane, dichloromethane, chloroform, etc.), alcohol solvents (e.g., methanol, ethanol, isopropanol, 1 -propanol, 2-methyl-1-propanol, 1 - butanol, 2-butanol, 1 -pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), ether solvents (e.g., diethyl ether, dipropyl ether, diphenyl ether, tetrahydrofuran, methyltetrahydrofuran, 1 ,4-dioxane, 1 ,2-dimethoxyethane, etc.), N-methyl-2-pyrrolidone and acetonitrile. In some embodiments, the solvent may be formed by the combination of two or more solvents. Preferably, the solvent is selected from methanol, ethanol or water, or mixtures thereof.

[0105] In a particular embodiment of the present aspect, the molar ratio of the compound I to reducing agent may be from 1 :1.1 to 1 :5. More preferably, the molar ratio of the compound I to reducing agent may be from 1 :1.1 to 1 :4. Most preferably, the molar ratio of the compound I to reducing agent may be from 1 : 1.1 to 1 :2 since yields were found to be improved. [0106] The reaction may typically be carried out at a temperature from -10 °C to 40°C. Preferably, the temperature is from 0 °C to 20 °C. Most preferably, the temperature is from 0 °C to 10°C, thereby avoiding the formation of undesirable products. The obtained mixture can also be stirred to facilitate the formation of the compound II as a precipitate. [0107] Suitable acids that may be used for step b) include, but are not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, fumaric acid, acetic acid, trifluoroacetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid, succinic acid, malic acid, or mixtures thereof. Preferred acids are hydrochloric acid, hydrobromic acid or sulfuric acid. Most preferably, the acid is hydrochloric acid. [0108] Preferably, the crisaborole is isolated by precipitation and filtration, and/or by removing the solvent by distillation.

[0109] It will be understood that in embodiments where the crisaborole is further converted into a pharmaceutically acceptable salt, the isolation may in some instances only be accomplished after salt formation, i.e. crisaborole as obtained from step b) is directly converted to a salt form which is then isolated and, optionally, purified. Alternatively, the salt conversion can be done after isolation but before purification, or the salt conversion is accomplished as a last step of the reaction sequence, after purification of crisaborole.

[01 10] Crisaborole prepared according to the above process is typically obtained in very high purity and yields. Yields of the reaction are as good as 90%, and the purity is always very high, being as good as 99.8%.

[01 1 1] Salts or co-crystals of crisaborole, can be prepared by contacting crisaborole with a pharmaceutical acceptable acid or co-crystal former at temperatures of between -10 °C and 100 °C.

[01 12] Another aspect of the present invention relates to the use of the compound I as an intermediate for the preparation of crisaborole and pharmaceutical acceptable salts thereof, preferably in high purity and high yields. In certain embodiments, compound I is preferably obtained as described above in paragraphs [0083], [0085] and [0098].

[01 13] In a related aspect, the present invention also discloses a preparation process of crisaborole and pharmaceutical acceptable salts thereof, preferably in high purity and high yields, from the compound I as described herein. Preferably, compound I is provided as described above in paragraphs [0083], [0085] and [0098].

[01 14] A further aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of crisaborole or a pharmaceutically acceptable salt thereof, obtainable according to any one of the processes for preparing crisaborole as described herein , optionally together with an appropriate amount of one or more pharmaceutically acceptable excipients or carriers.

[01 15] Another aspect of the present invention relates to the pharmaceutical composition described above in paragraph [01 14] for use as a medicament. A related additional aspect of the present invention relates to the pharmaceutical composition described above in paragraph [01 14] for use in the treatment of mild-to- moderate atopic dermatitis.

[01 16] The present invention also discloses a method of treating mild-to-moderate atopic dermatitis in a subject in need thereof. This method encompasses the administration of the pharmaceutical composition of the present invention described above in paragraph [01 14]. [01 17] Having described the various aspects of the present invention in general terms, it will be apparent to those of skill in the art that many modifications and slight variations are possible without departing from the spirit and scope of the present invention. The present invention is now further illustrated by the following working examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. Unless indicated otherwise, all indications of percentage are by weight and temperatures are in degrees Celsius.

EXPERIMENTAL

[01 18] The compounds of the present invention were characterized by common analytical techniques such as H-NMR or ³C-NMR, IR spectrometry (Perkin Elmer FTIR Spectrum One appliance using a Perkin Elmer ATR accessory) and Differential Scanning Calorimetry (DSC) using the following methods: [01 19] DSC analyses were recorded in a Mettler Toledo DSC822e calorimeter. Experimental conditions: 40 μΙ_ aluminum crucibles; atmosphere of dry nitrogen at 50 mL/min flow rate; heating rate of 10 °C/min between 30 and 300 °C. Data collection and evaluation was done with software STARe.

EXAMPLES

Example 1 : Synthesis of 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A)

[0120] In a round bottom flask, under nitrogen atmosphere, 2-bromo-5-hydroxybenzaldehyde (100 g, 497 mmol) and 4-fluorobenzonitrile (301 .2 g, 2487 mmol) were dissolved in DMF (250 ml) and toluene (500 ml). To the resulting dark solution, potassium carbonate (206.2 g, 1492 mmol) was added and the resulting mixture was stirred for 8 hours at 1 15 °C. After the reaction was completed by TLC, the heterogeneous mixture was filtered. The solvents and 4-fluoro-benzonitrile were distilled under reduced pressure from the obtained filtrate. Ethyl acetate (800 ml), water (500 ml) and brine (40 ml) were added and the formed phases were separated at 65-70 °C. The aqueous phase was extracted with ethyl acetate (150 ml) at 65-70 °C and the combined organic phase was washed with a mixture of water (225 ml) and brine (180 ml) at 65-70 °C. The obtained organic phase was evaporated under reduced pressure to give a brown solid. The solid was purified twice by recrystallization in a hot mixture of ethyl acetate and toluene to give 4-(4-bromo-3- formylphenoxy)benzonitrile (compound A) (107.5 g).

Yield: 71 %

Purity by HPLC: >99%

¹H-NMR (200 MHz, CDCI₃, δ ppm): 10.32 (1 H, s); 7.62-7.72 (3H, m); 7.57-7.59 (1 H, dd; J= 3, J= 1 ); 7.18- 7.23 (1 H, dd, J=8 Hz, J=3 Hz), 7.01 -7.08 (2H, m)

¹³C-NMR (50 MHz, CDCI₃, δ ppm): 190.69; 160.08; 155.13; 135.59; 134.89; 134.39; 126.86; 121.81 ; 120.28; 1 18.68; 1 18.33; 107.32

DSC: Endothermic peak at 1 1 1.9 °C.

Example 2: Synthesis of 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B)

[0121] In a round bottom flask, under nitrogen atmosphere, a mixture of 4-(4-bromo-3- formylphenoxy)benzonitrile (compound A) (28.1 g, 93 mmol) and methanol (1 12 ml) was prepared and cooled to 0 °C. To the resulting suspension, a solution of sodium borohydride (1 .79 g, 46.5 mmol), water (5.9 ml) and 1 M NaOH (0.2 ml) was added dropwise for 15 minutes. The reaction mixture was stirred for 1 hour at 0 °C and 3M HCI was added until pH 4.5. Afterwards, water (1 12 ml) was added and the suspension was stirred for 1 hour at room temperature. The resulting solid was filtered and purified by recrystallization from a mixture of methanol to give 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B).

Yield: 80%

Purity by HPLC: >99.9%

¹H-NMR (200 MHz, DMSO-d₆, δ ppm): 7.81-7.86 (2H, d, J=8); 7.60-7.64 (1 H, d, J=8 Hz); 7.21-7.22 (1 H, d, J=3 Hz), 7.10-7.14 (2H, d, J=8), 6.96-7.02 (1 H, dd, J=8, J=3), 5.51-5.56 (1 H, t, J=5), 4.46-4.48 (2H, d, J=5) ¹³C-NMR (50 MHz, DMSO-d₆, δ ppm): 161.04; 154.74; 144.08; 135.07; 134.08; 120.53; 1 19.73; 1 19.02; 1 18.82; 1 16.30; 106.02; 62.83

DSC: Endothermic peak at 94.2 °C.

Example 3: Preparation of 4-[(1 -hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-5-yl)oxy]benzonitrile

(crisaborole)

[0122] 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) (10.0 g, 32.9 mmol), potassium acetate (9.7 g, 99.0 mmol), XPhos (0.078 g, 0.16 mmol), XPhos-Pd-G2 (0.068 g, 0.082 mmol) and tetrahydroxydiboron (4.4 g, 49.3 mmol) were added to an oven dried glass reactor with a positive N₂ pressure. The vessel was sealed and then evacuated and backfilled with N₂ (four times). MeOH (100 mL, degassed) was added via syringe, followed by the addition of ethylene glycol (5.5 mL, 99.0 mmol). The reaction was then heated to 64-66 °C until the starting material was consumed (as monitored by TLC). The solvent was concentrated in vacuo and the crude reaction product was dissolved in EtOAc (50 mL) and then transferred to a separatory funnel. H₂0 was added (50 mL), the layers were separated and the aqueous layer was further extracted with more EtOAc (30 mL). The combined organic layers were washed once with 1 M HCI (30 mL) and once with H₂0 (30 mL), then dried over Na₂S0₄ and concentrated in vacuo. The solid residue was purified twice by recrystallization in hot methanol, thus affording pure 4-[(1-hydroxy-1 ,3-dihydro- 2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) (6.6 g, 26.3 mmol) as a white solid.

Yield: 80% (calculated from 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile)

Purity by HPLC: > 99.9%

¹H-NMR (200 MHz, DMSO-d₆, δ ppm): 9.22 (1 H, s); 7.85-7.83 (2H, m, J= 8.9 Hz); 7.81 -7.79 (1 H, d, J= 8.1 Hz); 7.15-7.13 (3H, m); 7.10-7.08 (1 H, dd, J= 8.1 , 2.1 Hz); 4.97 (2H, s)

¹³C-NMR (50 MHz, DMSO-d₆, ppm): 160.6; 157.1 ; 156.6; 134.7; 132.6; 1 18.9; 1 18.6; 1 12.7; 105.5; 69.7.] FT-IR: 2222.9, 1600.8, 1501.2, 1467.5, 1406.0, 1390.9, 1360.6, 1244.7, 1 167.3, 1 1 16.1 , 1010.7, 937.3, 892.5

-1

cm .

Example 4: Preparation of 4-[(1 -hydroxy-1 ,3-dihydro-2,1 -benzoxaborol-5-yl)oxy]benzonitrile

(crisaborole) without the use of an additive

[0123] 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) (10.0 g, 32.9 mmol), potassium acetate (9.7 g, 99.0 mmol), XPhos (0.078 g, 0.16 mmol), XPhos-Pd-G2 (0.065 g, 0.079 mmol) and tetrahydroxydiboron (4.4 g, 49.3 mmol) were added to an oven dried glass reactor with a positive N₂ pressure. The vessel was sealed and then evacuated and backfilled with N₂ (three times). Methanol (100 mL, degassed) was added and the resulting mixture was heated at 64-66 °C until the starting material (compound B) was consumed (as monitored by TLC). The solvent was concentrated in vacuo and the crude reaction product was dissolved in ethyl acetate (50 mL) and then transferred to a separatory funnel. Water was added (50 mL), the layers were separated and the aqueous layer was further extracted with more ethyl acetate (30 mL). The combined organic layers were washed with an aqueous solution of W-acetylcysteine 5% (30 mL), then washed with water (30 mL), treated with active carbon and filtered off. The resulting residue was slurred in toluene for three hours and filtered off. The solid residue was recrystallized in methanol. Afterwards, the solid obtained was further purified by slurrying in water, filtered off and dried to provide 4-[(1-hydroxy-1 ,3- dihydro-2, 1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole) (6.0 g, 23.9 mmol) as a white solid.

Yield: 72%

Purity by HPLC: > 99.7%

DSC: Broad endothermic peak with an onset at 127.3 °C. Example 5: Synthesis of 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)benzo- nitrile (Compound I)

[0124] To a mixture of 4-(4-bromo-3-formylphenoxy)benzonitrile (17 g, 56.3 mmol), bis(pinacolato) diboron (14.3 g, 56.3 mmol, 1 equiv.), potassium acetate (13.8 g, 140.7 mmol, 2.5 equiv.) and 1 , 1 '- Bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (460 mg, 0.563 mmol, 0.01 equiv.) was added methyltetrahydrofuran (170 mL) under nitrogen atmosphere. The heterogeneous mixture was stirred at 80 °C for 2 hours and cooled to 20 °C. Water (170 mL) was added and layers were separated. To the organic layer was added carbon (255 mg, 0.015 equiv.) and the mixture was stirred at 40 °C for 30 minutes and 1 hour at 20 °C. The mixture was filtered through DIAFIOC-4 and washed with methyltetrahydrofuran (2 x 20 mL). The dark solution was evaporated under reduced pressure to give a brown-dark solid. To this brown-dark solid was added isopropanol (85 mL) and mixture was stirred at 80 °C for 1 hour and 2 hours at 20 °C. The mixture was filtered and the solid was washed with isopropanol (3 x 17 mL) to give a brown solid which was dried under vacuum at 45 °C for 2 hours. 10.6 g of 4-(3-formyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy) benzonitrile were obtained as a brown solid.

Yield: 54 % (from compound A as in Example 1 )

Purity by HPLC: 99.5 %

¹H-NMR (400 MHz, DMSO-d₆, δ ppm): 10.4 (1 H, s); 7.88-7.86 (3H, m); 7.52-7.43 (2H, m); 7.24-7.20 (2H, m); 1.37 (12H, s)

¹³C-NMR (100 MHz, DMSO-d₆, ppm): 193.4; 159.8; 157.3; 143.1 ; 137.7; 134.9; 124.2; 1 19.3; 1 18.6; 1 17.8; 160.4; 84.3; 24.6 Example 6: Synthesis of 4-((1 -hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5-yl)oxy)benzonitrile

(crisaborole)

[0125] To a mixture of 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (1 g, 2.86 mmol) and methanol (15 mL) was added at 0-5 °C sodium borohydride (390 mg, 10.46 mmol, 3.6 equiv.). The mixture was stirred 30 minutes at 0-5 °C and slowly warmed to 20 °C. To the compound obtained water (1 mL) and hydrochloride acid 1 N (2 mL) were added at 0 °C. Methanol was evaporated under reduced pressure and isopropyl acetate (5 mL) was added. The aqueous layer was extracted with isopropyl acetate (5 mL). The combined organic layers were filtered through DIAFIOC-4 and the resulting solution was concentrated under reduced pressure to give a dark oil. This oil was dissolved in acetone (1 mL) and heated to 40 °C. Water (5 mL) was added dropwise and the resulting mixture was cooled to 20 °C, stirred 1 hour a nd filtered. The solid was washed with water (3 x 2 mL). Additionally, the solid can be purified by stirring 30 minutes in heptane (5 mL) at 20 °C. The mixture was filtered and washed with heptane (3 x 1.5 mL). The solid was dried under vacuum at 20 °C for 7 hours to give 0.4 g of 4-((1-hydroxy-1 ,3- dihydrobenzo[c][1 ,2]oxaborol-5-yl)oxy)benzonitrile as an off-white solid.

Yield: 57% (from compound I of Example 5)

Purity by HPLC: 99.8%

Claims

A process for preparing 4-[(1-hydroxy-1 ,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile

(crisaborole) or a pharmaceutically acceptable salt or co-crystal thereof, comprising converting 4-(4- bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) to crisaborole in a one-pot reaction; optionally further comprising isolating crisaborole and/or purifying crisaborole; preferably by recrystallization from a solvent.

The process according to claim 1 , comprising:

contacting 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) with a borylation agent in the presence of a base, a palladium catalyst and a ligand in an organic solvent to yield 4-[(1- hydroxy-1 ,3-dihydro-2,1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole).

The process according to claim 2, wherein 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile

(compound B) is further contacted with an additive;

preferably wherein the additive is ethylene glycol (OH(CH₂)20H).

The process according to claim 2 or claim 3, wherein the borylation agent is B₂(OH)₄.

The process according to any one of claims 2 to 4, wherein the base is selected from triethylamine (Et₃N), diazabicycloundecene (DBU), diisopropylethylamine (DIPEA), triethylenediamine (DABCO), 1 ,2,2,6,6-pentamethylpiperidine, 1 , 1 ,3,3-tetramethylguanidine, NH₄OAc, KOAc, LiOH, KOH, NaOH, Mg(OH)₂, CaOH₂, ROLi, RONa, and ROK, wherein R is an alkyl group ranging from 1 -5 carbon atoms,

preferably wherein the base is selected from Et₃N, DIPEA, KOAc, and more preferably wherein the base is KOAc.

The process according to any one of claims 2 to 5, wherein the palladium catalyst is selected from:

Pd(OAc)₂,

Pd(dba)₃,

[Pd(allyl)CI]₂,

Pd(acac)₂,

Pd 100: Pd(PPh₃)₂CI₂,

Pd106: PdCI₂(dppf) CH₂CI₂,

Pd-116: (Pd[P(tBu)₃]₂),

Pd-127: (PdCI₂(dcypf),

Pd168: Chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(ll),

P(Cy₃)-Pd-G2: Chloro(tricyclohexylphosphine)(2'-aminobiphen-2-yl)palladium(ll), [(1 ,3,5J-Tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll) methanesulfonate,

Mesyl[(tri-f-butylphosphine)-2-(2-aminobiphenyl)]palladium(ll),

XPhos-Pd-G1 : Chloro(2-dicyclohexylphosphino-2',4^,,6^,-triisopropyl-1 , 1 ^,-biphenyl)[2-(2- aminoethyl)phenyl)]palladium(ll),

SPhos-Pd-G1 : Chloro(2-dicyclohexylphosphino-2^,,6'-dimethoxy-1 , 1 ^,-biphenyl)[2-(2- aminoethylphenyl)]palladium(ll),

tBuXPhos-Pd-G1 : [2-(Di-tert-butylphosphino)-2',4',6'-triisopropyl-1 , 1 -biphenyl][2-(2- aminoethyl)phenyl)]palladium(ll) chloride,

BrettPhos-Pd-G1 : Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4', 6'-triisopropyl-1 , 1 '- biphenyl][2-(2-aminoethyl)phenyl]palladium(ll),

RuPhos-Pd-G1 : Chloro^-Dicyclohexylphosphino^'.e'-diisopropoxy-l .l '-biphenyl)^^- aminoethyl)phenyl]palladium(ll),

XPhos-Pd-G2-: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll),

XantPhos-Pd-G2: Chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll),

SPhos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',6^,-dimethoxy-1 , 1 ^,-biphenyl)[2-(2^,-amino-1 , 1 '- biphenyl)]palladium(ll),

RuPhos-Pd-G2: Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1.1 '-biphenyl^-^'-amino-l .l '- biphenyl)]palladium(ll),

Neopentyl-tBu₂P-Pd-G2: Chloro[(di-tert-butylneopentylphosphine)-2-(2- aminobiphenyl)]palladium(ll),

MorDalphos-G2: Chloro(2-(di-1-adamantylphosphino)morpholinobenzene)[2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll),

CyJohnPhos-G2: Chloro(2-dicyclohexylphosphino-1 ,1 ^,-biphenyl)[2-(2^,-amino-1 , 1 '- biphenyl)]palladium(ll),

CPhos-Pd-G2: Chloro[(2-dicyclohexylphosphino-2^,,6'-bis(N,N-dimethylamino)-1 , 1 '-biphenyl)-2-(2'- amino-1 , 1 '-biphenyl)]palladium(ll),

cataCXium A-Pd-G2: Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(ll), (t-Bu)₂ MeP-Pd-G2: Methanesulfonato (di-tert-butyl) methylphosphino (2'-amino-1 , 1 '-biphenyl-2-yl) palladium(ll),

APhos-Pd-G2: Chloro[4-(di-tert-butylphosphino)-N,N-dimethylaniline-2-(2'- aminobiphenyl)]palladium(ll),

Pd-G3-XPhos: 2-Dicyclohexylphosphino-2^,,4^,,6^,-triisopropyl-1 ,1 ^,-biphenyl)[2-(2^,-amino-1 ,1 '- biphenyl)]palladium(ll),

SPhos-Pd-G3: (2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl) [2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll) methanesulfonate, RuPhos-Pd-G3: (2-Dicyclohexylphosphino-2^6'-diisopropoxy-1 , 1 ^,-biphenyl)[2-(2^,-amino-1 ,1 '- biphenyl)]palladium(ll) methanesulfonate,

tBuXPhos-Pd-G3: [(2-Di-tert-butylphosphino-2 4 6^,-triisopropyl-1, -biphenyl)-2-(2^,-amino-1, - biphenyl)] palladium(ll) methanesulfonate,

BrettPhos-Pd-G3: -Di-cyclohexylphosphino-S^-dimethoxy^'^'^'- triisopropyl-1 , 1 '-biphenyl)-2-(2 - amino-1 , 1 ' -biphenyl)]palladium(ll) methanesulfonate,

fert-BuBrettPhos-Pd-G3: -Di-ferf-butylphosphino-S.e-dimethoxy^'^'.e'-triisopropyl-l , 1 -biphenyl)- 2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate,

XantPhos-Pd-G3: [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll) methanesulfonate,

TrixiePhos-Pd-G3: Mesyl(2-(di-tert-butylphosphino)-1 , 1 '-binaphthyl)[2-(2'-amino-1 , 1 '- biphenyl)]palladium(ll),

RockPhos-Pd-G3: -Di-tert-butylphosphino-S-methoxy-e-methyl^'^'.e'-triisopropyl-l .l '-biphenyl)- 2-(2-aminobiphenyl)]palladium(ll) methanesulfonate,

Neopentyl(t-Bu)₂P-Pd-G3: [(Di-tert-butylneopentylphosphine)-2-(2-aminobiphenyl)]palladium(ll) methanesulfonate,

MorDalphos-Pd-G3: (2-(Di-1-adamantylphosphino)morpholinobenzene)[2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll) methanesulfonate, Mesyl(2-(di-1-adamantylphosphino)morpholinobenzene)[2- (2'-amino-1 ,1 '-biphenyl)]palladium(ll),

Josiphos SL-J009-1 -Pd-G3: {(R)-1-[(Sp)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-tert- butylphosphine}[2-(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate,

JackiePhos-Pd-G3: [(2-{Bis[3,5-bis(trifluoromethyl)phenyl]phosphine}-3,6-dimethoxy- 2',4',6'- triisopropyl-1 , 1 '-biphenyl )-2-(2'-amino-1 , 1 '-biphenyl)]palladium(ll) methanesulfonate,

P(Cy₃)-Pd-G3: [(Tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(ll) methanesulfonate, CyJohnPhos-Pd-G3: Methanesulfonato (2-biphenyl)dicyclohexylphosphino(2'-amino-1 , 1 '-biphenyl-2- yl)palladium(ll),

CPhos-Pd-G3: [(2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino) -1 , 1 '-biphenyl)-2-(2'-amino- 1 ,1 -biphenyl)] palladium(ll) methanesulfonate,

cataCXium-A-Pd-G3: Mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino-1 ,1 '- biphenyl)]palladium(ll), [(Di(1 -adamantyl)-butylphosphine)-2-(2'-amino-1 , 1 '-biphenyl)]palladium(ll) methanesulfonate,

(t-Bu)₂PMe-Pd-G3: Methanesulfonato (di-tert-butyl) methylphosphino (2'-amino-1 ,1 '-biphenyl-2-yl) palladium(ll),

PPh(t-Bu)₂-Pd-G3: Methanesulfonato (di-tert-butyl) phenylphosphino (2'-amino-1 , 1 '-biphenyl-2-yl) palladium(ll),

APhos-Pd-G3: Palladium G3-(4-(N,N-Dimethylamino)phenyl)di-tert-butylphosphine, [4-(Di-tert- butylphosphino)-N,N-dimethylaniline-2-(2'-aminobiphenyl)]palladium(ll) methanesulfonate, Ad-BrettPhos-Pd-G3: [2-(Di-1-adamantylphosphino)-2^4^6'-triisopropyl-3,6-dimethoxybiphenyl][^

(2'-amino-1 ,1 '-biphenyl)]palladium(ll) methanesulfonate,

XPhos-Pd-G4,

XantPhos-Pd-G4,

SPhos-Pd-G4,

RuPhos-Pd-G4,

PCy₃-Pd-G4,

MorDalPhos-Pd-G4,

cataCXium-Pd-G4,

BrettPhos-Pd-G4, and

rac-BINAP-Pd-G4,

preferably wherein the palladium source is selected from Pd168, XPhos-Pd-G1 , XPhos-Pd-G2, XPhos-Pd-G3, XPhos-Pd-G4, and Chloro(tricyclohexylphosphine)(2'-aminobiphen-2-yl)palladium(ll), and more preferably wherein the palladium source is XPhos-Pd-G2.

The process according to any one of claims 2 to 6, wherein the ligand is selected from

Triphenylphosphine, Trioctylphosphine, Tricydohexylphosphine, XPhos, RuPhos, SPhos, DavePhos, QPhos, JohnPhos, BrettPhos, AmPhos, tBuXPhos, tBuMePhos, tBuBrettPhos, tBuDavePhos, AdBrettPhos, AlPhos, PhDave-Phos, Me₄tButylXphos, MePhos, Me₃(OMe)tBuXPhos, CyJohnPhos, Ad₂PBu, *Bu₃P, 'BU3P-HBF4, 1 ,1 '-Bis(di-tert-butylphosphino)ferrocene, 2 -Dicyclohexylphosphino- 2,4,6-trimethoxybiphenyl, Bis(3,5-bis(trifluoromethyl)phenyl)(2',6'-bis(isopropoxy)-3,6- dimethoxybiphenyl-2-yl)phosphine, or (2-Biphenyl)di-1-adamantylphosphine, preferably wherein the ligand is selected from Tricydohexylphosphine, XPhos, SPhos, QPhos, DavePhos, JohnPhos, BrettPhos, RuPhos,

and even more preferably wherein the ligand is XPhos.

The process according to any one of claims 2 to 7, wherein the organic solvent is selected from dimethylacetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, ethers, toluene, benzene, and alcohols, preferably wherein the organic solvent is selected from MeOH, EtOH, and IPA, and more preferably wherein the solvent is MeOH.

The process according to any one of claims 2 to 8, wherein the reaction temperature is about 40-1 10 °C, preferably about 50-90 °C, more preferably about 60-75 °C and even more preferably about 65 °C.

The process according to any one of claims 1 to 9, wherein the process further comprises preparing 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B) by:

contacting 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A) with a reducing agent in the presence of an organic solvent to yield 4-(4-bromo-3-(hydroxymethyl)phenoxy) benzonitrile

(compound B); preferably wherein the reducing agent is NaBH₄;

optionally wherein compound B is isolated and/or purified before converting compound B to crisaborole.

The process according to claim 10, wherein the process further comprises preparing 4-(4-bromo-3- formylphenoxy)benzonitrile (compound A) by:

contacting 2-bromo-5-hydroxybenzaldehyde with 4-fluorobenzonitrile in the presence of a base in an organic solvent to yield 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A);

optionally wherein compound A is isolated and/or purified before converting compound A to compound B.

The compound 4-(3-formyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl) phenoxy)benzonitrile (compound I) having the following formula:

Compound I

A process for preparing compound I according to claim 12, comprising:

contacting 4-(4-bromo-3-formylphenoxy)benzonitrile (compound A) with a boron reagent in the presence of a base and a catalyst in an organic solvent to yield 4-(3-formyl-4-(4,4,5,5-tetramethyl-

1 ,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile (compound I), preferably wherein the boron reagent is bis(pinacolato)diboron.

Use of the compound according to claim 13 as an intermediate in the preparation of 4-[(1-hydroxy- 1 ,3-dihydro-2, 1-benzoxaborol-5-yl)oxy]benzonitrile (crisaborole), or a pharmaceutical acceptable salt or co-crystal thereof.

A process for preparing a pharmaceutical composition containing crisaborole or a pharmaceutically acceptable salt thereof, comprising the process according to any one of the preceding claims to obtain crisaborole or a pharmaceutically acceptable salt thereof, and further combining said crisaborole or a pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable carrier or excipient;

optionally wherein the pharmaceutical composition is adapted for use in the treatment of atopic dermatitis or psoriasis.