FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Benzoxaboroles.
BACKGROUND OF THE INVENTION
Crisaborole (Eucrisa1^, chemically known as 5-(4-Cyanophenoxy)-l,3-dihydro-l-hydroxy-[2,l]-benzoxaborole a compound of formula 1 is a phosphodiesterase 4 inhibitor indicated for topical treatment of mild to moderate atopic dermatitis in patients two years of age and older.
US 8,039,451 B2 (US'451) discloses the Crisaborole and its pharmaceutically acceptable salts thereof. US '451 discloses the following scheme for the preparation of Crisaborole:
wherein Pg selected from methoxymethyl, ethoxyethyl, tetrahydropyran-2-yl, trimethyl silyl, tert-butyldimethylsilyl, tributylsilyl, combinations thereof; X represents bromo or iodo; Z is selected from H, alkyl, and aryl; Y is selected from H, lower alkyl, and arylalkyl; R ' R4 are Hydrogen.
US 8,039,450 B2 (US'450) discloses the preparation of Crisaborole by following below
process:
A.

B. Process for the preparation of Crisaborole as follows:
The present inventors have found that the prior art process involves low yields due to formation of impurities by the use of lithium reagents in halogen metal exchange reaction and by the use of trialkylborate reagents in borolation reaction.
Further the prior art process yields are low due to the formation of by-products using acetyl protecting group.
The present inventors have now found a process for the preparation of Crisaborole, which is suitable industrially and eliminates by-product formation and reduces formation of impurities in turn obtain Crisaborole having high yield and purity.
OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a process for the preparation of Crisaborole, which is commercially and industrially feasible.
Another objective of the present invention is to provide a process for the preparation of Crisaborole having high yields and purities.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Crisaborole compound of formula I,
which comprises:
a. protecting the compound of formula II,

. vviih a protecting agent in presence of a base to obtain a compound of formula III:
wherein X is halogen selected from -F, ~C\, -Br. -1
b. reacting the compound of formula III with a boronating agent in presence of transition
metal catalyst and base, optionally in presence of a ligand to obtain the compound of
formula IV;
c. converting the compound of formula IV to yield compound of formula I. wherein the protecting agent is a protecting group (Pg) selected from -Si(R)3 -COR' -CH2OR»; R is alkyl, aryl; R- is C2.5 alky], aryl; R» is alkyl, aryl, tetrahydropyran-2- yl tetrahydrofuran-2-yl; boronating agent is selected from substituted diborates.
In other embodiment of the present invention relates to a process for the preparation of Cnsaborole compound of formula I,
which comprises:
a. condensation of compound of formula VII,
wherein X is halogen selected from -F, -CI, -Br, -I with compound of formula VIII in presence of a base,
wherein X is halogen selected from -F, -Cl3 -Br -I to obtain a compound of formula IX;

wherein X is halogen selected from -F, -CI, -Br. -1
b. treating the compound of formula ,X with reducing agent to yield a compound of formula II; i\jr
wherein X is halogen selected from -F, -CI, -Br, -I
c protecting the compound of formula I, with a'protecting agent in the presence of a base to obtain compound of formula III;
d. reactmg the compound of formula III with a boronating agent in the presence of a trans.tion meta, catalyst and base, optionally in presence of Hgand to obtain the compound of formula IV;
e. converting the compound of formula IV to yield compound of formula I wherein the protecting agent is a protecting group (Pg) selected from selected from -Si(R)3 COR'. -CH2OR»; R ,s a,kyl, ary,; R- is C,5 a,kyl, ary,; R- ls alkyl, ary|, tetrahyd JJl yl. tetrahydrofuran-2-yl; boronating agent is selected from substituted dlborates.
in another embod.ment of the present invention relates ,o a process for the preparat.on of Cnsaborole, which is substantially free of the following impurities:

DETAILED DESCRIPTION OF THE INVENTION
In one aspect the present invention relates to a process for the preparation of Crisaborole compound of formula 1, which comprises: condensation of compound of formula VII, with formula VIII in the presence of base and a solvent wherein base is selected from the group comprising of alkali metal hydroxides, alkali metal carbonates, alkaline metal hydrogen carbonates and alkaline metal alcoholates to obtain compound of formula IX; treating the compound of formula IX with reducing agent selected from the group comprising of borane complexes, borohydrides to yield a compound of formula II; protecting the compound of formula II, with a protecting group Pg selected from -Si(R)3, -COR', -OR" in the presence of a base wherein base is selected from the comprising of inorganic base or organic base to obtain compound of formula III; reacting the compound of formula' III with substituted diborates selected from the group comprising of bis pinacalato diboran, bis(neopentyl glycolato)diboron, bis (catecholato) diboran, in the presence of transition metal catalyst, base selected from the group comprising of inorganic or organic base and optionally in the presence of ligand to obtain the compound of formula IV; converting the compound of formula IV to compound of formula I with suitable agent selected from acetic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, p-toluenesulfonic acid, tetra-n-butylammonium fluoride in the presence of polar aprotic solvents.
In other aspect of the present invention the protecting group -Si(R)3 wherein R is alkyl, aryl. -Si(R)3 specifically is selected from group comprising of tert-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-Butyldiphenylsilyl.
In other aspect of the present invention the protecting group -COR' wherein R' is C2-5 alkyl, aryl. R' is specifically selected from the group comprising of t-butyl, trityl, benzyl, naphthyl.
In other aspect of the present invention the protecting group -CH2OR", wherein R" is alkyl,
aryl. R" is specifically selected from the group comprising of methyl, ethyl, t-butyl, trityl,
benzyl, naphthyl. ^———-

In other aspect of the present invention transition meta, catalyst is se.ected fr0m the group
-Wising of palladium(H) acela(e; pa|iadium(u) acetoace(onaie
etrak,s(tnPheny,p„0Sphine)pa„adium, dich,orobis(tnpheny,PhosPhine)Pa„adium r, y. b1s(d,Phe„ylphosphino)ferrocen]dichloroPal,adium(Ii) and its solvates such 'as methylenedichloride, chloroform or combinations thereof.
In other aspect of the present invention ligand is selected from the group comprising of 1 I,
Ferrocenediyl-bis(diPhenylphosphine),Tris(diben2y,ideneacetone)diPaMadium(0),Tri-n-butyl Phosphate, triphenylphosphine, tri(o-to,y,)PhosPhine, tricyc,ohexy,phosPhine 2-
D>cyc3 (1.93 mL, 17.3 mmol) was injected in one portion and the cooling bath was removed. The mixture was warmed gradually with stirring for 30 min and then stirred with a water bath for 2 h. After addition of 6N HC1 (6 mL), the mixture was stirred overnight at room temperature and about 50% hydrolysis has happened as shown by TLC analysis. The solution was rotary evaporated and the residue was dissolved in MeOH (50 mL) and 6N HC1 (4 mL). The solution was refluxed for I h and the hydrolysis was completed as indicated by TLC analysis. Rotary evaporation gave a residue which was dissolved in EtOAc, washed with water, dried and then evaporated. The crude product was purified by flash column chromatography over silica gel

lo provide a solid with 80% purity. The solid was further purified by washing with hexane afford 7.2 mmol of Crisaborole.
Example 1.
Preparation of 4-(4-Bromo-3-formylphenoxy)benzonitrilc.
Charged 5-Hydroxy-2-bromo benzaldehyde (100 g), 4-fluorobenzonitrile (108 g), potassiu: carbonate (206 g) and dimethylsulfoxide at 25 - 30°C and heated to 60 - 70°C. The reaclic mass was maintained for 14 - 16 hours and cooled to 15 - 20°C. Added water and filtered Methanol was added to the solid obtained and stirred for 2 hours at 45-50°C . Cooled to : 10°C and filtered the solid to yield 97.5 g of 4-(4-Bromo-3-formylphenoxy)benzonitrile.
Preparation of 4-(4-Bromo-3-(hydroxymethyl)phcnoxy)benzonitrile.
Charged 4-(4-Bromo-3-formylphenoxy)benzonitrile(100 g), methanol and toluene at 25 30°C and cooled to 0-5°C. To the reaction mass added sodium borohydride (6.15 g) at 2'. 30°C and maintained for 2-3 hours. Added water and toluene, stirred, separated the laye and distilled off the solvent. The crude product thus obtained was treated with hexane an filetered to yield 92.5 g of 4-(4-Bromo-3-(hydroxymethyl)phenoxy)benzonitrile.
Preparation of 4-(4-bromo-3-(((tert-butyldimethylsiIyl)oxy)methyI) phenoxy benzonitrilc.
Charged 4-(4-Bromo-3-(hydroxymethyl)phenoxy)benzonitrile (100 g
dimethylaminopyridine, imidazole (90 g) and dimethylformamide at 25 - 30°C. Cooled tr reaction mass to 0-5°Cand added tert-Butyldimethylsilyl chloride (55 g). Stirred the reactic mixture at 25-30°C for 2-3 hrs. Added water, filtered, dried to yield 97.5 g of 4-(4-bromo-! (((tert-butyldimethylsilyl)oxy)methyl) phenoxy) benzonitrile.
Preparation of Crisaborole
Charged 4-(4-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl) phenoxy) benzonitrile (100 g potassium acetate (100 g), bis pinacalato diboron (75 g), dioxane at 25 - 30°C To the reactio mass PdCI2dppf was added . The reaction mass was stirred at 100-110°C for 5-hours.Cooled the reaction mass and added water, ethylacetate. Separated the layers an distilled off the solvent. To the residue added cone HC1, water and stirred for 2-3 hours. Tr reaction mass was extracted with toluene and distilled off toluene.Added-m$thaneTand~stirre Li^^Dl--0^1^n^inulc^Finer^Jthfe~sb1tar<3ned to obtain crisaborole methanolate (GC: 900

ppm). The obtained solvate was dissolved in acetic acid at 60 - 65°C. Added water and cooled to 10-15 °C. Filtered the solid and dried to yield 43.5 g Crisaborole (HPLC purity >