DESC:TITLE OF THE INVENTION
Process for the preparation of Crisaborole.

FIELD OF THE INVENTION
The present invention relates to process for the preparation of (5-(4-cyanophenoxy)-l-hydroxy-l,3- dihydro-2,l-benzoxaborole having formula (I). The compound of formula (I) has adopted name “Crisaborole”.

BACK GROUND OF THE INVENTION
Crisaborole [code name: AN2728, 5-(4-cyanophenoxy)-l-hydroxy-l,3- dihydro-2,l-benzoxaborole] of formula (I) is disclosed in US 8,039,451 assigned to Anacor Pharmaceuticals Inc. 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 under the name of EUCRISATM.
The process for preparation of Crisaborole of formula (I) is disclosed in US Patent 8,039,451, CN 106928264, CN 107759625, CN 108047261 and Bioorganic & Medicinal Chemistry Letters 2009, 19 (8) Pg 2129-2132.
Based on the available literature, it would be desirable and of paramount importance to have a process for the preparation of Crisaborole of formula (I), by employing inexpensive, readily available, easy to handle reagents. It would also be desirable to have a process that can be readily scaled up.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to the process for the preparation of Crisaborole of formula (I),

which comprises:
Step 1) reducing the compound of formula (a)

X= any halogen atom
with reducing agent and solvent to obtain hydroxyl moiety of formula (b);

Step 2) protecting hydroxyl moiety of formula (b) with hydroxyl protecting agent in presence of base and solvent to obtain hydroxyl protected compound of formula (c);

PG= Hydroxyl protecting group
Step 3) cyclizing the hydroxyl protected compound of formula (c) by using alkyl metal reagent in presence of borylation reagent and solvent, followed by treatment with acid to obtain compound of formula (d);

Step 4) reacting compound of formula (d) with compound of formula (e)

in presence of catalyst, base and solvent, optionally using ligand to obtain Crisaborole of compound of formula (I).

In another aspect, the present invention relates to the process for the preparation of Crisaborole of formula (I),

which comprises:
Step 1) reducing the compound of formula (a1)

X= any halogen atom
with reducing agent and solvent to obtain hydroxyl moiety of formula (b1);

Step 2) protecting hydroxyl moiety of formula (b1) with hydroxyl protect agent in presence of base and solvent to obtain hydroxyl protected compound of formula (c1);

PG= Hydroxyl protecting group
Step 3) cyclizing the hydroxyl protected compound of formula (c1) by using alkyl metal reagent in presence of borylation reagent and solvent, followed by treatment with acid to obtain compound of formula (d1);

Step 4) reacting compound of formula (d1) with compound of formula (e1)

in presence of a base, phase transfer catalyst and solvent to obtain Crisaborole of compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to the process for the preparation of Crisaborole of formula (I) is shown in the Scheme-I mentioned below:

Scheme-I:

X= any halogen atom; PG= Hydroxyl protecting group
Step 1) reducing the compound of formula (a) with reducing agent and solvent to obtain hydroxyl moiety of formula (b)

The reducing agent used in the reaction can be selected from 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 and mixtures thereof.

Step 2) protecting hydroxyl moiety of formula (b) with hydroxyl protect agent in presence of base and solvent to obtain hydroxyl protected compound of formula (c);

The hydroxyl protecting agent used in the reaction can be selected from 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.

The base used in the reaction can be selected from organic base, inorganic base or mixtures thereof. Suitable organic bases useful for this reaction include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine and mixture thereof. Suitable inorganic bases for use in this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides and mixtures thereof. Suitable alkaline metal hydroxides for use in this reaction include, but are not limited to, sodium hydroxide, potassium hydroxide and mixtures thereof. Suitable alkaline metal bicarbonates useful in this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates useful in this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate and mixtures thereof. Suitable alkaline alkoxides useful in this reaction include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide and mixtures thereof.

The solvent used in the reaction can be selected from non-polar solvent, polar aprotic solvent, polar protic solvent or mixtures thereof. Suitable non-polar solvents useful in this reaction include, but are not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane and mixtures thereof. Suitable polar aprotic solvents useful in this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N- dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful in this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol and mixtures thereof.

Step 3) cyclizing the hydroxyl protected compound of formula (c) by using alkyl metal reagent in presence of borylation reagent and solvent, followed by treated with acid to obtain compound of formula (d).

The alkyl metal reagent used in the reaction can be selected from n-butyllithium, sec-butyllithium, tert-butyllithium or isopropylmagnesium chloride. The borylation reagent used in the reaction can be selected from trialkyl borate, pinacolborane (HBPin), catecholborane, bis(neopentyl glycolato)diboron, bis(pinacolato)diboron (B2Pin2), bis(hexylene glycolato)diboron or bis(catecholato)diboron. The acid reagent used in the reaction can be selected from organic acid or inorganic acid, optionally the acid is in aqueous or alcohol medium. Suitable organic acids useful in this step include, but are not limited to, formic acid, acetic acid, propanoic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid and mixtures thereof. Suitable inorganic acids useful in this step include, but are not limited to, hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid and combinations thereof.

The solvent used in the reaction can be selected from non-polar solvent, polar aprotic solvent, polar protic solvent or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N- dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol and mixtures thereof.

Step 4) reacting compound of formula (d) with a compound of formula (e) in presence of catalyst, base and solvent, optionally using ligand to obtain Crisaborole of compound of formula (I).

The catalyst used in the reaction can be selected from Copper-containing catalyst. Suitable Copper -containing catalysts useful for this reaction include, but are not limited to, copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper (I) bromide trisstriphenylphosphine complex, copper trifluoromethanesulfonate (I) benzene complex, Copper(I) acetate or Copper(II) acetate.

The ligand used in the reaction can be selected from Tetramethylethylenediamine (TMEDA), N,N'-dimethylethylenediamine (DIPEA), 1,2-cyclohexanediamine, 2-aminopyridine, 1,10- Phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol, picolinic acid

The base used in the reaction can be selected from organic base, inorganic base or mixtures thereof. Suitable organic bases useful for this reaction include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine and mixtures thereof. Suitable inorganic bases for use in this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides and mixtures thereof. Suitable alkaline metal hydroxides for use in this reaction include, but are not limited to, sodium hydroxide, potassium hydroxide, and mixtures thereof. Suitable alkaline metal bicarbonates useful in this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate, and mixtures thereof. Suitable alkaline metal carbonates useful in this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides useful in this reaction include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide and mixtures thereof.

The solvent used in the reaction can be selected from non-polar solvent, polar aprotic solvent, polar protic solvent or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N- dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol and mixtures thereof.

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

Scheme-II:


Step 1) reducing the compound of formula (a1) with reducing agent and solvent to obtain hydroxyl moiety of formula (b1)

The reducing agent used in the reaction can be selected from sodium borohydride, potassium borohydride, sodium cyanoborohydride and tetramethyl ammonium borohydride. The solvent used in the reaction can be selected from water, methanol, ethanol, isopropyl alcohol, n-butanol and mixtures thereof.

Step 2) protecting hydroxyl moiety of formula (b1) with hydroxyl protect agent in presence of base and solvent to obtain hydroxyl protected compound of formula (c1);

The hydroxyl protecting agent used in the reaction can be selected from 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.

The base used in the reaction can be selected from organic base, inorganic base or mixtures thereof. Suitable organic bases useful for this reaction include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine and mixture thereof. Suitable inorganic bases for use in this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides and mixtures thereof. Suitable alkaline metal hydroxides for use in this reaction include, but are not limited to, sodium hydroxide, potassium hydroxide and mixtures thereof. Suitable alkaline metal bicarbonates useful in this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate and mixtures thereof. Suitable alkaline metal carbonates useful in this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate and mixtures thereof. Suitable alkaline alkoxides useful in this reaction include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide and mixtures thereof.

The solvent used in the reaction can be selected from non-polar solvent, polar aprotic solvent, polar protic solvent or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but are not limited to 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N- dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol and mixtures thereof.

Step 3) cyclizing the hydroxyl protected compound of formula (c1) by using alkyl metal reagent in presence of borylation reagent and solvent, followed by treatment with acid to obtain compound of formula (d1).

The alkyl metal reagent used in the reaction can be selected from n-butyllithium, sec-butyllithium, tert-butyllithium or isopropylmagnesium chloride. The borylation reagent used in the reaction can be selected from a trialkyl borate, pinacolborane (HBPin), catecholborane, bis(neopentyl glycolato)diboron, bis(pinacolato)diboron (B2Pin2), bis(hexylene glycolato)diboron or bis(catecholato)diboron. The acid reagent used in the reaction can be selected from organic acid or inorganic acid, optionally the acid is in aqueous or alcohol medium. Suitable organic acids useful in this step include, but are not limited to, formic acid, acetic acid, propanoic acid, methane sulphonic acid, p-toluene sulphonic acid, trifluoroacetic acid and mixtures thereof. Suitable inorganic acids useful in this step include, but are not limited to, hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid and combinations thereof.

The solvent used in the reaction can be selected from a non-polar solvent, polar aprotic solvent, polar protic solvent or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N- dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol and mixtures thereof.

Step 4) reacting compound of formula (d1) with compound of formula (e1) in presence of base, phase transfer catalyst and solvent, to obtain Crisaborole of compound of formula (I).

The base used in the reaction can be selected from organic base, inorganic base or mixtures thereof. Suitable organic bases useful for this reaction include, but are not limited to pyridine, trimethylamine, N, N-diisopropylethylamine and mixturest thereof. Suitable inorganic bases for use in this reaction include, but are not limited to, alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, alkaline alkoxides and mixtures thereof. Suitable alkaline metal hydroxides for use in this reaction include, but are not limited to, sodium hydroxide, potassium hydroxide and mixtures thereof. Suitable alkaline metal bicarbonates useful in this reaction include, but are not limited to, sodium bicarbonate, potassium bicarbonate and mixtures thereof. Suitable alkaline metal carbonates useful in this reaction include, but are not limited to, sodium carbonate, potassium carbonate, cesium carbonate, and mixtures thereof. Suitable alkaline alkoxides useful in this reaction include, but are not limited to, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium propoxide, sodium tert-butoxide, potassium tert-butoxide and mixtures thereof.

The phase transfer catalyst (PTC) used in the reaction can be selected from tetrabutylammonium bromide, benzyl trimethylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutyl ammonium bisulphate, tetrapropylammonium bromide, tributylbenzylammonium chloride, tetraethylammonium bromide, tetraoctylammonium bromide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium acetate, ethyltriphenylphosphonium bromide, methyltributyl ammonium chloride or crown ethers.

The solvent used in the reaction can be selected from non-polar solvent, polar aprotic solvent, polar protic solvent, or mixtures thereof. Suitable non-polar solvents useful within this reaction include, but are not limited to, 1,4-dioxane, toluene, benzene, xylene, methyl t-butyl ether (MTBE), dichloromethane and mixtures thereof. Suitable polar aprotic solvents useful within this reaction include, but are not limited to, acetone, acetonitrile, methyl ethyl ketone (MEK), methyl isobutyl ketone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidinone (NMP), dimethylsulfoxide (DMSO), 1 ,2-dimethoxyethane and mixtures thereof. Suitable polar protic solvents useful within this reaction include, but are not limited to, water, methanol, ethanol, isopropyl alcohol, n-butanol and mixtures thereof.

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 2-Bromo 5-Hydroxy Benzyl alcohol
100 grams of 2-Bromo 5-Hydroxy benzaldehyde was dissolved in Methanol (1.0 Lt). Sodium borohydride (85 grams) was added lot wise at 0-10 °C. Reaction mass was stirred for 24 hours at 25-35 0C. After completion of reaction quenched with 10% ammonium chloride solution (300 mL). Extracted the aqueous layer with ethylacetate (2 X 200 mL). Solid was isolated in ethylacetate and heptane (2:5). The wet material was dried under vacuum at 50-55 °C for 6-8 hours to obtain the title compound.

Example 2:
Process for the preparation of 1,3-dihydro-2,1-benzoxaborole-1,5-diol
50 grams of 2-Bromo 5-hydroxy benzyl alcohol was suspended in dichlormethane, N, N-Diisopropylethylamine (DIPEA) (171 mL), chloro methyl methyl ether (75 mL) was added to the reaction mass at 25-35 °C. Reaction mass was stirred for 3 hours at 25-35 °C. After completion of reaction quenched with water (500 mL) and of 5% ammonium chloride solution (200 mL). Organic layer was separated and completely distilled under vaccum. To the crude material, THF (500 mL), n-BuLi (250 mL), Trisopropyl borate (80 mL) was added to the reaction mass at -55 °C to -65 °C. The reaction mass was stirred for 2 hours. After completion of reaction quenched with 5% ammonium chloride solution (250 mL). Extracted the aqueous layer with ethyl acetate and distilled under vaccum. 6N HCl (200 mL) was added to the crude material and stirred for 4-6 hours at 25-35 °C. Extracted the aqueous layer with ethyl acetate (2 X100 mL) and completely distilled under vacuum. Solid was isolated in 200 ml of dichloromethane. The wet material was dried under vacuum at 50-55 °C for 4-6 hours to obtain the title compound.

Example 3:
Process for the preparation of Crisaborole
1,3-dihydro-2,1-benzoxaborole-1,5-diol was suspended in dichloromethane at 25-35 °C. Copper (II) acetate and phenyl cyano boronic acid, triethyl amine was added to reaction mass at 25-35 °C. Reaction mass was stirred for 18-24 hours at 25-35 °C. After completion of reaction filtered the solid, diluted the filtrate with water. Extracted the aqueous layer extracted with dichlormethane. Reaction mass was distilled under vaccum and isolated the solid material in dichloromethane and hepatane (1:6). Material was dried under vacuum at 50-55 °C for 10-12 hours to obtain the title compound.

Example 4:
Process for the preparation of Crisaborole
4-Fluorobenzonitrile was suspended in DMF at 25-35 °C. Potassium carbonate and tetrabutyl ammonium iodide (TBAI) was added to the reaction mass at 25-35 °C. Reaction mass was stirred at 55-65 °C for 60-90 minutes. Slowly added the 1,3-dihydro-2,1-benzoxaborole-1,5-diol to the reaction mass at 55-65 °C. Reaction mass was stirred for 90 minutes for 4-6 hours, filtered and washed with DMF. Water was added to the filtrate at 25-35 °C and stirred for 60 minutes at 25-35 °C. Solid was filtered and washed with the water. Solid was purified by using DMSO and Water (2:6). Material was dried under vacuum at 50-55 °C for 10-12 hours to obtain the title compound. ,CLAIMS:1. A process for the preparation of Crisaborole of formula (I),

which comprises:
Step 1) reducing the compound of formula (a)

X= any halogen atom
with a reducing agent and solvent to obtain hydroxyl moiety of formula (b);

Step 2) protecting hydroxyl moiety of formula (b) with a hydroxyl protect agent in presence of base and solvent to obtain hydroxyl protected compound of formula (c);

PG= Hydroxyl protecting group
Step 3) cyclizing the hydroxyl protected compound of formula (c) by using alkyl metal reagent in presence of borylation reagent and solvent, followed by treatment with acid to obtain compound of formula (d);

Step 4) reacting compound of formula (d) with compound of formula (e)

in presence of a catalyst, base and solvent, optionally using ligand to obtain Crisaborole of compound of formula (I).

2. The process according to claim 1, reducing agent is selected from sodium borohydride, potassium borohydride, sodium cyanoborohydride or tetramethyl ammonium borohydride.

3. The process according to claim 1, hydroxyl protect agent is selected from chloromethyl methyl ether, chloro ethoxy ethyl ether, acetyl chloride, cyanuric chloride, tertiary butyl dimethyl silyl ether, trimethyl silyl chloride or triethyl silyl chloride.

4. The process according to claim 1, alkyl metal reagent is selected from n-butyllithium, sec-butyllithium, tert-butyllithium, or isopropylmagnesium chloride; borylation reagent is selected from trialkyl borate, pinacolborane , catecholborane, bis(neopentyl glycolato)diboron, bis(pinacolato)diboron (B2Pin2), bis(hexylene glycolato)diboron or bis(catecholato)diboron.

5. The process according to claim 1, catalyst is selected from copper (0), copper (I) iodide, copper (I) chloride, copper (I) oxide, copper (I) bromide trisstriphenylphosphine complex, copper trifluoromethanesulfonate (I) benzene complex, Copper(I) acetate or Copper(II) acetate; base is selected from organic base, an inorganic base or mixtures thereof; optionally ligand is selected from Tetramethylethylenediamine, N, N'-dimethylethylenediamine, 1,2-cyclohexanediamine, 2-aminopyridine, 1,10- Phenanthroline, 2-hydroxybenzaldehyde oxime, ethylene glycol or picolinic acid.

6. The process according to claim 1, solvent is selected from non-polar solvent, polar aprotic solvent, polar protic solvent or mixtures thereof.

7. A process for the preparation of Crisaborole of formula (I),

which comprises:
Step 1) reducing the compound of formula (a1)

X= any halogen atom
with a reducing agent and a solvent to obtain hydroxyl moiety of formula (b1);

Step 2) protecting hydroxyl moiety of formula (b1) with a hydroxyl protect agent in presence of a base and a solvent to obtain hydroxyl protected compound of formula (c1);

PG= Hydroxyl protecting group
Step 3) cyclizing hydroxyl protected compound of formula (c1) by using alkyl metal reagent in presence of a borylation reagent and a solvent, followed by treated with acid to obtain a compound of formula (d1);

Step 4) reacting compound of formula (d1) with a compound of formula (e1)

in presence of base, phase transfer catalyst and solvent, to obtain Crisaborole of compound of formula (I).

8. The process according to claim 7, reducing agent is selected from sodium borohydride, potassium borohydride, sodium cyanoborohydride or tetramethyl ammonium borohydride ; hydroxyl protect agent is selected from chloromethyl methyl ether, chloro ethoxy ethyl ether, acetyl chloride, cyanuric chloride, tertiary butyl dimethyl silyl ether, trimethyl silyl chloride or triethyl silyl chloride;

9. The process according to claim 7, alkyl metal reagent is selected from n-butyllithium, sec-butyllithium, tert-butyllithium, or isopropylmagnesium chloride; borylation reagent is selected from trialkyl borate, pinacolborane (HBPin), catecholborane, bis(neopentyl glycolato)diboron, bis(pinacolato)diboron (B2Pin2), bis(hexylene glycolato)diboron or bis(catecholato)diboron; base is selected from organic base, inorganic base or mixtures thereof; phase transfer catalyst is selected from the tetrabutylammonium bromide, benzyl trimethylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutyl ammonium bisulphate, tetrapropylammonium bromide, tributylbenzylammonium chloride, tetraethylammonium bromide, tetraoctylammonium bromide, tetrabutylammonium hydrogen sulfate, benzyltrimethylammonium chloride, benzyltriethylammonium chloride, tetrabutylammonium acetate, ethyltriphenylphosphonium bromide, methyltributyl ammonium chloride or crown ethers.

10. The process according to claim 7, solvent is selected from non-polar solvent, polar aprotic solvent, polar protic solvent or mixtures thereof.

Dated this 24th day of June 2019