DESC:The present invention relates to an improved process for the preparation of (5-(4-cyanophenoxy)-l-hydroxy-l,3- dihydro-2,l-benzoxaborole having the structural formula-I.

(I)
The present invention also relates to novel intermediates which is useful in the preparation of Crisaborole of formula-I.

(II) (VI) (XI)

BACK GROUND OF THE INVENTION
Crisaborole is a nonsteroidal topical medication used for the treatment of mild to moderate atopic dermatitis developed by Anacor Pharma. It is chemically known as 5-(4-Cyanophenoxy)-l,3-dihydro-l-hydroxy-[2,l]-benzoxaborole. It is a phosphodiesterase 4 inhibitor indicated for topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older. Crisaborole is marketed in United states under the name of EUCRISATM.
Crisaborole and its synthetic process is first disclosed in US 8039451 B2. The process disclosed in US8039451 B2 suffers from several disadvantages which includes utilization of flash column chromatography to purify the product which is a cumbersome, expensive and time-consuming technique. Further the product is obtained in very low yield and less purity even after column purification. Hence, one or more purification steps are required to purify the obtained compound in order to comply with various regulatory requirements. These lengthy purification procedures will greatly reduce the yield of the product and there by increases the overall cost of the production. Hence, this process is not suitable to adopt it on commercial scale.
Prior art literature CN 106928264, CN 107759625, CN 108047261 and Bioorganic & Medicinal Chemistry Letters, 2009, 19 (8), 2129-2132 discloses the process for the preparation of Crisaborole.
Based on the available literature, the reported processes provide Crisaborole with low yield and less purity.
In view of all these disadvantages, there is a significant need to develop a cost effective, commercially viable process for the preparation of highly pure Crisaborole with good yield.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides an improved process for the preparation of Crisaborole of formula-I,

(I)
which comprises:

a) condensation of compound of formula-II

(II)
with compound of formula-III

(III)

in a solvent to obtain compound of formula-IV;

(IV)

b) coupling of compound of formula-IV with compound of formula-V

(V)
in presence of a base and a solvent to obtain compound of formula-VI;

(VI)
c) hydrolysis of compound of formula-VI in presence of a mild acid and water to obtain compound of formula-VII;

(VII)
d) reduction of compound of formula-VII with a reducing agent in a solvent to obtain compound of formula-VIII;

(VIII)
e) hydroxy protection of compound of formula-VIII with a hydroxy protecting group in presence of an acid catalyst and a solvent to obtain compound of formula-IX;

(IX)
f) cyclization of compound of formula-IX with borylating agent in presence of alkali metal reagent and a solvent to obtain Crisaborole of formula-I.

In other embodiment, the present invention provides an improved process for the preparation of Crisaborole of formula-I,

(I)
which comprises:

a) converting compound of formula-II

(II)
to compound of formula-X

(X)

in presence of sodium bisulfite and a solvent;

b) coupling of compound of formula-X with compound of formula-V

(V)
in presence of potassium carbonate and N, N-dimethyl formamide to obtain compound of
formula-XI;

(XI)
c) hydrolysis of compound of formula-XI in presence of hydrochloric acid and water to obtain compound of formula-VII;

(VII)
d) reduction of compound of formula-VII with sodium borohydride in methanol to obtain compound of formula-VIII;

(VIII)
e) hydroxy protection of compound of formula-VIII with ethyl vinyl ether in presence of pyridinium para toluene sulfonate and dichloromethane to obtain compound of formula-IX;

(IX)
f) cyclization of compound of formula-IX with triisopropyl borate in presence of n-butyl lithium and tetrahydrofuran to obtain Crisaborole of formula-I.

In yet another embodiment, the present invention provides the following novel intermediates useful in the preparation of Crisaborole of formula-I

(II) (VI) (XI)

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to an improved process for the preparation of Crisaborole of formula-I as shown in the Scheme-I mentioned below:

Scheme-I

In step-1, compound of formula-II is condensed with compound of formula-III in a solvent to obtain compound of formula-IV. The solvent used in the reaction can be selected from the group consisting of alcoholic solvents, ester solvents, ether solvents, keto solvents, nitrile solvents, hydrocarbon solvent or its mixture. Preferably using alcoholic solvent. This reaction is carried out at a temperature of 15-40°C, preferably at 25-30°C. The duration of the reaction may range from 1 hour to 4 hours, preferably for a period of 2 hours to 3 hours.

In step-2, compound of formula-IV coupled with compound of formula-V in presence of a base and a solvent to obtain compound of formula-VI. The base used in this reaction can be selected from the group consisting of alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides or its mixtures thereof. Preferably using potassium carbonate

The solvent used in the reaction can be selected from the group consisting of alcoholic solvents, ester solvents, ether solvents, keto solvents, nitrile solvents, hydrocarbon solvent, polar aprotic solvent, water or its mixture. Preferably using N, N-dimethylformamide. This reaction is carried out at a temperature of 90-110°C, preferably at 100-105°C. The duration of the reaction may range from 3 hour to 6 hours, preferably for a period of 4 to 5 hours.

In step-3, compound of formula-VI is converted to compound of formula-VII in presence of an acid and solvent. The acid used in this reaction can be selected from hydrochloric acid or acetic acid, preferably using hydrochloric acid. This reaction is carried out at a temperature of 15-40°C, preferably at 25-30°C. The duration of the reaction may range from 1 hour to 4 hours, preferably for a period of 2 hours to 3 hours.

In step-4, compound of formula-VII is reduced to compound of formula-VIII using a reducing agent. The reducing agent used in this reaction can be selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyanoborohydride or tetramethyl ammonium borohydride. The solvent used in the reaction can be selected from water, methanol, ethanol, isopropyl alcohol, n-butanol or its mixtures thereof. This reaction is carried out at a temperature of 15-40°C, preferably at 25-30°C. The duration of the reaction may range from 1 hour to 4 hours, preferably for a period of 2 hours to 3 hours.

In step-5, Compound of formula-VIII is protected with a hydroxy protecting agent in presence of an acid catalyst and a solvent to obtain IX. The hydroxy protecting agent used in the reaction can be selected from the group consisting of ethyl vinyl ether, chloromethyl methyl ether (MOMCl), chloro ethoxy ethyl ether, acetyl chloride, cyanuric chloride, tertiary butyl dimethyl silyl ether (TBDMSCl), trimethyl silyl chloride or triethyl silyl chloride. Preferably using ethyl vinyl ether. The acid catalyst used in this reaction is pyridinium para toluene sulfonate. This reaction is carried out at a temperature of 15-40°C, preferably at 25-30°C. The duration of the reaction may range from 1 hour to 4 hours, preferably for a period of 2 hours to 3 hours.

In step-6, compound of formula-IX is cyclized with trialkyl borate in presence of alkali metal reagent in a solvent to obtain Crisaborole of formula-I. Trialkyl borate used in this reaction is selected from the group consisting of triisopropyl borate, pinacolborane, catecholborane, bis(neopentyl glycolato) diboron, bis(pinacolato)diboron, bis(hexylene glycolato)diboron or bis(catecholato)diboron. Preferably using triisopropyl borate. The alkali metal reagent used in this reaction can be selected from the group consisting of n-butyllithium, sec-butyllithium, tert-butyllithium or isopropyl magnesium chloride.

Accordingly, the present invention relates to an improved process for the preparation of Crisaborole of formula (I) as shown in the Scheme-II mentioned below:

Scheme-II

In step-I, compound of formula-II is reacted with sodium bisulfite in a solvent to obtain compound of formula-X. It is coupled in-situ with compound of formula-V in presence of a base and a solvent to obtain compound of formula-XI followed by hydrolysis to obtain compound of formula-VII.
Addition of sodium bisulfite is carried out at a temperature of 15-40 °C, preferably at 25-30 °C. The duration of the reaction may range from 4 hour to 8 hours, preferably for a period of 5 hours to 6 hours.

The base used in this reaction can be selected from the group consisting of alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides or its mixtures thereof. Preferably using potassium carbonate

The solvent used in the reaction can be selected from the group consisting of alcoholic solvents, ester solvents, ether solvents, keto solvents, nitrile solvents, hydrocarbon solvent, polar aprotic solvent, water or its mixture. Preferably using N, N-dimethylformamide. This reaction is carried out at a temperature of 90-110 °C, preferably at 100-105 °C. The duration of the reaction may range from 3 hours to 6 hours, preferably for a period of 4 hours to 5 hours.
Hydrolysis process carried out in this reaction by using hydrochloric acid and water.

In step-II, compound of formula-VII is reduced to compound of formula-VIII using a reducing agent. The reducing agent used in this reaction can be selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyanoborohydride or tetramethyl ammonium borohydride. The solvent used in the reaction can be selected from water, methanol, ethanol, isopropyl alcohol, n-butanol or its mixtures thereof. This reaction is carried out at a temperature of 15-40 °C, preferably at 25-30 °C. The duration of the reaction may range from 1 hour to 4 hours, preferably for a period of 2 hours to 3 hours.

In step-III, Compound of formula-VIII is protected with a hydroxy protecting agent in presence of an acid catalyst and a solvent to obtain IX. The hydroxy protecting agent used in the reaction can be selected from the group consisting of ethyl vinyl ether, chloromethyl methyl ether (MOMCl), chloro ethoxy ethyl ether, acetyl chloride, cyanuric chloride, tertiary butyl dimethyl silyl ether (TBDMSCl), trimethyl silyl chloride or triethyl silyl chloride. Preferably using ethyl vinyl ether. The acid catalyst used in this reaction is pyridinium para toluene sulfonate.
This reaction is carried out at a temperature of 15-40 °C, preferably at 25-30 °C. The duration of the reaction may range from 1 hour to 4 hours, preferably for a period of 2 hours to 3 hours.

In step-IV, compound of formula-IX is cyclized with trialkyl borate in presence of alkali metal reagent in a solvent to obtain Crisaborole of formula-I. Trialkyl borate used in this reaction is selected from the group consisting of triisopropyl borate, pinacolborane, catecholborane, bis(neopentyl glycolato) diboron, bis(pinacolato)diboron, bis(hexylene glycolato)diboron or bis(catecholato)diboron. Preferably using triisopropyl borate. The alkali metal reagent used in this reaction can be selected from the group consisting of n-butyllithium, sec-butyllithium, tert-butyllithium or isopropyl magnesium chloride.

In yet another embodiment, the present invention provides the following novel intermediates useful in the preparation of Crisaborole of formula-I

(II) (VI) (XI)

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limit the scope of the present invention in any way. Several variants of these examples would be evident to person ordinarily skilled in the art.

Examples:

Example 1: Process for the preparation of Crisaborole

Stage-1: Synthesis of (E)-4-bromo-3-((phenylimino)methyl) phenol
A stirred solution of 2-Bromo 5-Hydroxy benzaldehyde (1.0 eq) and Aniline (1.0 eq) in ethanol (5 vol) was stirred for 2-3 hours at room temperature. The resultant reaction mixture was concentrated to get the title compound.
Yield: 100 %
Stage-2: Synthesis of (E)-4-(4-bromo-3-((phenylimino)methyl)phenoxy)benzonitrile
A stirred solution of (E)-4-bromo-3-((phenylimino)methyl) phenol (obtained in stage-1) (1.0 eq), 4-Fluorobenzonitrile (1.5 eq), potassium carbonate (3.0 eq) in N, N-Dimethylformamide (5 vol) was stirred for 4 hours to 5 hours at 105-110 °C. After completion of reaction, the resulting reaction mixture was cooled to room temperature. Filtered the reaction mixture and washed with N, N-Dimethylformamide (2 vol). The resulting filtrate added to water at room temperature and stirred for 30 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 80 %.

Stage-3: Synthesis of 4-(4-bromo-3-formylphenoxy) benzonitrile
6 N Hydrochloric acid (1.0 vol) was slowly added to a stirred solution of (E)-4-(4-bromo-3-((phenylimino)methyl) phenoxy) benzonitrile (obtained in stage-2) (1.0 eq) and water (5.0 vol) at 25-30 °C. The resulting reaction mixture was stirred for 4 hours to 5 hours at 25-30 °C and filtered the precipitated solid to get the title compound.
Yield: 80 %

Stage-4: Synthesis of 4-(4-bromo-3-(hydroxymethyl)phenoxy) benzonitrile
Sodium borohydride (1.1 eq) was added lot wise to a stirred solution of 4-(4-bromo-3-formyl phenoxy) benzonitrile (obtained in stage-3) (1.0 eq) and methanol (8 vol) at 0-10 °C. The resulting reaction mixture was stirred for 2 hours to 3 hours at 25-35 0C. After consumption of the starting material, reaction mixture was quenched with water (20 vol) at 10-15 oC and stirred for 1 hour at room temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 70 %.

Stage-5: Synthesis of 4-(4-bromo-3-((1-ethoxyethoxy) methyl) phenoxy) benzonitrile
Ethyl vinyl ether (2.0 eq) was slowly added to a stirred solution of 4-(4-bromo-3-(hydroxy methyl) phenoxy) benzonitrile (obtained in stage-4) (1.0 eq), Pyridinium para toluene sulfonic acid (0.2 eq) and dichloromethane (5 vol) at 25-30 °C. The resulting reaction mixture was stirred for 2 hours to 3 hours at 25-30 °C, after consumption of the starting material, the reaction mixture was neutralized with Saturated sodium bicarbonate solution (2 vol). Volatiles were evaporated under reduced pressure to get the title compound.
Yield: 80 %

Stage-6: Synthesis of 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2] oxaborol-5-yl) oxy)benzonitrile

n-Butyl lithium (1.5 eq) in Tetrahydrofuran was added to a stirred solution of 4-(4-bromo-3-((1-ethoxyethoxy) methyl) phenoxy) benzonitrile (obtained in stage-5) (1.0 eq), Triisopropyl borate (2.0 eq) and tetrahydrofuran (5 vol) at -65 °C to -75 °C. The resulting reaction mixture was stirred for 2 hours at the same temperature. After consumption of the starting material, reaction mixture allowed to room temperature. 6N HCl (1 vol) was added to the reaction mixture at 25-30 °C and stirred for 1 hour at the same temperature. Methanol (2 vol) was added to the reaction mixture and heated to reflux temperature. Water and ethyl acetate were added to the reaction mixture and both layers were separated. Aqueous layer was extracted twice with ethyl acetate. Combine the organic layers and volatiles were evaporated under reduced pressure. The obtained crude was triturated with cyclohexane (10 vol) and stirred for 1 hour at 25-30 °C. The precipitated solids were separated by filtration and dried to get the title compound.
Yield: 70 %.

Example 2: Alternative process for the preparation of Crisaborole

Stage-1: Synthesis of 4-(4-bromo-3-(hydroxymethyl)phenoxy) benzonitrile
A mixture of 2-Bromo 5-Hydroxy benzaldehyde (1.0 eq) and Aniline (1.0 eq) in N, N-Dimethyl formamide (5 vol) was stirred for 2-3 hours at 25-30°C. After consumption of starting material, 4-Fluorobenzonitrile (1.5 eq) and Potassium carbonate (3.0 eq) were added to the reaction mixture and stirred for 4-5 hours at 105-110 °C. After completion of reaction, reaction mixture was cooled to 25-30 °C. Filtered the solid and washed with N, N-Dimethylformamide (2 vol). The obtained filtrate was added to water (20.0 v) at room temperature and stirred for 2 hours at the same temperature. The precipitated solids were separated by filtration. The resulted wet material was suspended in Water (5 vol) and concentrated HCl (1 vol) was added to the reaction mixture at 10-15 oC. Stirred the reaction mixture for 3-4 hours at room temperature. The resulted solids were separated by filtration. The obtained wet material was suspended in Methanol (8 vol) and cooled to 10-15 oC. Sodium borohydride (1.1 eq) was added to the reaction mixture at 10-15 oC and stirred for 3-4 hour at room temperature. After completion of reaction, the reaction mixture was quenched with water (20 vol) at 10-15 oC and stirred for 1 hr at room temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 70 %

Stage-2: Synthesis of 4-(4-bromo-3-((1-ethoxyethoxy) methyl) phenoxy) benzonitrile
Ethyl vinyl ether (2.0 eq) was slowly added to a stirred solution of 4-(4-bromo-3-(hydroxy methyl) phenoxy) benzonitrile (obtained in stage-1) (1.0 eq), Pyridinium para toluene sulfonic acid (0.2 eq) and dichloromethane (5 vol) at 25-30 °C. The resulting reaction mixture was stirred for 2-3 hours at 25-30 °C, after consumption of the starting material, the reaction mixture was neutralized with Saturated sodium bicarbonate solution (2 vol). Volatiles were evaporated under reduced pressure to get the title compound.
Yield: 80 %

Stage-3: Synthesis of 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2] oxaborol-5-yl) oxy)benzonitrile

n-Butyl lithium (1.5 eq) in Tetrahydrofuran was added to a stirred solution of 4-(4-bromo-3-((1-ethoxyethoxy) methyl) phenoxy) benzonitrile (obtained in stage-2) (1.0 eq), Triisopropyl borate (2.0 eq) and tetrahydrofuran (5 vol) at -65 °C to -75 °C. The resulting reaction mixture was stirred for 2 hours at the same temperature. After consumption of the starting material, reaction mixture allowed to room temperature. 6N HCl (1 vol) was added to the reaction mixture at 25-30 °C and stirred for 1 hour at the same temperature. Methanol (2 vol) was added to the reaction mixture and heated to reflux temperature. Water and ethyl acetate were added to the reaction mixture and both layers were separated. Aqueous layer was extracted twice with ethyl acetate. Combine the organic layers and volatiles were evaporated under reduced pressure. The obtained crude was triturated with cyclohexane (10 vol) and stirred for 1 hour at 25-30 °C. The precipitated solids were separated by filtration and dried to get the title compound.
Yield: 70 %.

Example-3: Process for the preparation of Crisaborole
Stage-1: Synthesis of 4-(4-bromo-3-(hydroxymethyl)phenoxy) benzonitrile
Sodium bisulphate (1.0 eq) was added to a stirred solution of 2-Bromo 5-Hydroxy benzaldehyde (1.0 eq) and N, N-Dimethyl formamide (5 vol) at 25-30 °C and stirred for 5-6 hours at the same temperature. After consumption of the starting material, 4-Fluorobenzonitrile (1.5 eq) and Potassium carbonate (3.0 eq) were added to the reaction mixture. Heated the reaction mixture to 105-110 °C and stirred for 4-5 hours at the same temperature. After completion of reaction, reaction mass was cooled to room temperature. Filtered the precipitated solid and washed with N, N-Dimethylformamide (2 vol). The resulting filtrate was added to water (20.0 v) at room temperature and stirred for 30 minutes at same temperature. Filtered the precipitated solid. The resulting wet material was suspended in water (5 vol) and stirred for 10 minutes at 25-30 °C. Concentrated hydrochloric acid was added to the reaction mixture at 10-15 oC. Stirred the mass for 3-4 hours at room temperature. Filtered the precipitated and suck dry for 30 minutes. The obtained wet material was suspended in Methanol (8 vol) and cooled to 10-15 oC. Sodium borohydride (1.1 eq) was added to the reaction mixture at 10-15 oC and stirred for 3-4 hours at room temperature. After completion of reaction, the reaction mixture was quenched with Water (20 vol) at 10-15 oC and stirred for 1 hour at room temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 75%.

Stage-2: Synthesis of 4-(4-bromo-3-((1-ethoxyethoxy) methyl) phenoxy) benzonitrile
Ethyl vinyl ether (2.0 eq) was slowly added to a stirred solution of 4-(4-bromo-3-(hydroxy methyl) phenoxy) benzonitrile (obtained in stage-1) (1.0 eq), Pyridinium para toluene sulfonic acid (0.2 eq) and dichloromethane (5 vol) at 25-30 °C. The resulting reaction mixture was stirred for 2-3 hours at 25-30°C, after consumption of the starting material, the reaction mixture was neutralized with saturated sodium bicarbonate solution (2 vol). Volatiles were evaporated under reduced pressure to get the title compound.
Yield: 80 %

Stage-3: Synthesis of 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2] oxaborol-5-yl) oxy)benzonitrile

n-Butyl lithium (1.5 eq) in Tetrahydrofuran was added to a stirred solution of 4-(4-bromo-3-((1-ethoxyethoxy) methyl) phenoxy) benzonitrile (obtained in stage-2) (1.0 eq), Triisopropyl borate (2.0 eq) and tetrahydrofuran (5 vol) at -65 °C to -75 °C. The resulting reaction mixture was stirred for 2 hours at the same temperature. After consumption of the starting material, reaction mixture allowed to room temperature. 6N HCl (1 vol) was added to the reaction mixture at 25-30 °C and stirred for 1 hour at the same temperature. Methanol (2 vol) was added to the reaction mixture and heated to reflux temperature. Water and ethyl acetate were added to the reaction mixture and both layers were separated. Aqueous layer was extracted twice with ethyl acetate. Combine the organic layers and volatiles were evaporated under reduced pressure. The obtained crude was triturated with cyclohexane (10 vol) and stirred for 1 hour at 25-30 °C. The precipitated solids were separated by filtration and dried to get the title compound.
Yield: 70 %.

Advantages:
• The present invention is simple and cost effective.
• The present invention avoids the formation of impurity-A at stage-b). This avoids multiple recrystallizations.

Impurity-A
• High yields and purity.
,CLAIMS:1. A process for the preparation of Crisaborole of formula (I),

(I)
which comprises:
a) condensation of compound of formula-II

(II)
with compound of formula-III

(III)

in a solvent to obtain compound of formula-IV;

(IV)

b) coupling of compound of formula-IV with compound of formula-V

(V)
in presence of a base and a solvent to obtain compound of formula-VI;

(VI)
c) hydrolysis of compound of formula-VI in presence of an acid and water to obtain compound of formula-VII;

(VII)
d) reduction of compound of formula-VII with a reducing agent in a solvent to obtain compound of formula-VIII;

(VIII)

e) hydroxy protection of compound of formula-VIII with a hydroxy protecting group in presence of an acid catalyst and a solvent to obtain compound of formula-IX;

(IX) Pg = Hydroxy protecting group

f) cyclization of compound of formula-IX with borylating agent in presence of alkali metal reagent and a solvent to obtain Crisaborole of formula-I.

2. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of
hydrocarbon solvents, ether solvents, ester solvents, alcohol solvents, keto solvents, nitrile
solvents, chlorinated solvents, polar aprotic solvents or its mixture.

3. The process as claimed in step-b) of claim 1, wherein the base is selected from organic or inorganic
base.

4. The process as claimed in step-c) of claim 1, wherein the acid is selected from hydrochloric acid or acetic acid.

5. The process as claimed in step-d) of claim 1, wherein the reducing agent is selected from sodium borohydride, potassium borohydride, sodium cyanoborohydride or tetramethyl ammonium borohydride.

6. The process as claimed in step-e) of claim 1, wherein the hydroxyl protect agent is selected from ethyl vinyl ether, chloro methyl methyl ether, chloro ethoxy ethyl ether, acetyl chloride, cyanuric chloride, tertiary butyl dimethyl silyl ether, trimethyl silyl chloride or triethyl silyl chloride.

7. The process as claimed in step-f) of claim 1, wherein the alkyl metal reagent is selected from n-butyllithium, sec-butyl lithium, tert-butyllithium; borylation reagent is selected from trialkyl borate, pinacol borane, catecholborane, bis (neopentyl glycolato) diboron, bis(pinacolato)diboron (B2Pin2), bis (hexylene glycolato) diboron or bis(catecholato)diboron.

8. An improved process for the preparation of Crisaborole of formula (I),

(I)
which comprises:
a) converting compound of formula-II

(II)
to compound of formula-X

(X)

in presence of sodium bisulfite and a solvent;

b) coupling of compound of formula-X with compound of formula-V

(V)
in presence of potassium carbonate and N, N-dimethyl formamide to obtain compound of
formula-XI;

(XI)
c) hydrolysis of compound of formula-XI in presence of hydrochloric acid and water to obtain compound of formula-VII;

(VII)

d) reduction of compound of formula-VII with sodium borohydride in methanol to obtain compound of formula-VIII;

(VIII)

e) hydroxy protection of compound of formula-VIII with ethyl vinyl ether in presence of pyridinium para toluene sulfonate and dichloromethane to obtain compound of formula-IX;

(IX)

f) cyclization of compound of formula-IX with triisopropyl borate in presence of n-butyl lithium and tetrahydrofuran to obtain Crisaborole of formula-I.

9. A process for the preparation of compound of formula-XI

(XI)
which comprises:
a) converting compound of formula-II

(II)
to compound of formula-X

(X)

in presence of sodium bisulfite and a solvent;

b) coupling of compound of formula-X with compound of formula-V

(V)
in presence of potassium carbonate and N, N-dimethyl formamide to obtain compound of
formula-XI.

10. Novel intermediate compounds having the following structural formulae:

(II) (VI) (XI)