DESC:Field of the Invention
The present invention relates to an improved process for preparation of phenylboronic acid and its ester derivatives, and particularly to an improved process for preparation of carboxyphenyl boronic acid and its ester derivatives.

Background and prior art
Carboxyphenyl boronic acid and ester derivatives of general formula (I) are important building moiety of starting materials of various active pharmaceutical ingredients.

Various references report processes for preparation of carboxyphenyl boronic acid and ester derivatives.
Inorganic Chemistry, 48(11), 4616-4618; 2009 discloses Grignard of 4-bromo toluene using magnesium turning in methyl borate in THF to yield 4-methylphenyl boronic acid. Further oxidation of 4-methylphenyl boronic acid using KMnO4 in presence of phase transfer catalyst Tetrabutyl ammonium bromide yields 4-boronobenzoic acid.

SCHEME 1
The KMnO4 used for the oxidation readily reacts with any traces of organic material or any other reducing substance in water. Further, it forms sludge in reaction mass due to which isolation of the product becomes difficult thereby increasing the load on Effluent Treatment Plant (ETP). Therefore, it is difficult to obtain the production pure form.

Thus, there is a need for preparation of phenylboronic acid or ester derivatives and carboxyphenyl boronic acid and ester derivatives which yields higher yield and better purity.

Summary of the invention
In a general aspect, the present invention provides a process for preparation of phenyl boronic acid or its ester derivative of Formula (I).

where R1 is H or 1-4C alkyl, R2 and R3 are independently H, CH3, iso-propyl or R2 and R3 together forms Formula (B) .
The process comprises reacting a solution of iodobenzoic acid or its ester of Formula (II) with isopropyl magnesium halide of Formula (A) forming in situ Grignard species of Formula (C)
where R1 is H or 1-4C alkyl and X is Cl or Br; and adding a boric acid ester derivative of Formula (III) to said in situ Grignard species (C) obtaining phenyl boronic acid and ester derivatives of Formula (I),
said compound of Formula (III):

where R2 and R3 are independently H, CH3, iso-propyl, or R2 and R3 together forms Formula (B) and R4 is H, CH3, iso-propyl.

The solution of iodobenzoic acid or its ester of Formula (II) is prepared by dissolving in a solvent selected from a hydrocarbon solvent, preferably an aliphatic hydrocarbon solvent selected from heptane, cyclohexane, octane or iso-octane or an aromatic hydrocarbon solvent such as benzene, xylene and toluene; or ethereal solvent such as tetrahydrofuran (THF), diethyl ether and 2-methyl THF. The solvent preferably is tetrahydrofuran.
In an aspect, a process for preparing 4-boronobenzoic acid of Formula (IA) is provided.
The process comprises reacting a solution of 4-iodobenzoic acid of Formula (IIA) prepared in tetrahydrofuran (THF) with isopropyl magnesium halide (A) forming in situ Grignard species of Formula (C1)
where X can be Cl or Br; and
adding tri-isopropyl borate of Formula (IIIA) to the in situ Grignard species of Formula (C1) obtaining compound (IA).

In an aspect, a process for preparing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid of Formula (IC) is provided.
The process comprises reacting a solution of 4-iodobenzoic acid of Formula (IIA) prepared in tetrahydrofuran (THF) with isopropyl magnesium halide (A) forming in situ Grignard species of Formula (C1)
where X can be Cl or Br; and
adding 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Formula (IIIB) to the in situ Grignard species of Formula (C1) obtaining compound (IC).

In an aspect, a process for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid of Formula (IB) is provided.

The process comprises reacting a solution 3-iodobenzoic acid of Formula (IIB) prepared in tetrahydrofuran (THF) with isopropyl magnesium halide (A) forming in situ Grignard species of Formula (C2)
where X can be Cl or Br; and
adding 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Formula (IIIB) to the in situ Grignard species of Formula (C2) obtaining compound (IB).

In another aspect, a process for preparing is 3-boronobenzoic acid of Formula (ID) is provided.

The process comprises reacting a solution of tert-butyl-3-iodobenzoate of Formula (IID) prepared in tetrahydrofuran (THF) with isopropyl magnesium halide of Formula (A) forming in situ Grignard species of Formula (C3)
where X can be Cl, or Br ; and
adding trimethyl borate of Formula (IIIC) to the in situ Grignard species of Formula (C3) obtaining compound (ID).
The solution of 3-iodobenzoic acid of Formula (IID) can be prepared by dissolving compound (IID) in tetrahydrofuran (THF). The solution can be cooled to -25°C to -35°C before the addition of isopropyl magnesium halide (A).

The solution can be cooled to -20°C to -40°C and preferably at -25°C to -35°C before the addition of isopropyl magnesium halide (A).

In an embodiment, a process of preparing [4-(2-pyridylcarbamoyl)phenyl]boronic acid of Formula (IV) from compound (IA) is provided.

The process comprises reacting a solution of 4-boronobenzoic acid of Formula (IA) with 2-aminopyridine in the presence of a coupling agent and a condensing agent. The solution can be prepared by dissolving (IA) in a solvent selected from dichloromethane (DCM), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), toluene, dimethyl formamide (DMF). The reaction can be carried out at 20-40°C.

In another embodiment, a process of preparing N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide of Formula (V) from compound (IB) is provided.

The process comprises reacting a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid of Formula (IB) with 2-aminopyridine in the presence of a coupling agent and a condensing agent. The solution can be prepared by dissolving (IB) in a solvent selected from dichloromethane (DCM), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), toluene, dimethyl formamide (DMF). The reaction can be carried out at 20-40°C.

In yet another embodiment, a process of preparing [3-(2-pyridylcarbamoyl)phenyl]boronic acid of Formula (VI) from compound (ID) is provided.

The process comprises reacting a solution of Formula (ID) with 2-aminopyridine in the presence of a coupling agent and a condensing agent. The solution can be prepared by dissolving (IB) in a solvent selected from dichloromethane (DCM), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), toluene, dimethyl formamide (DMF). The reaction can be carried out at 20-40°C.

The coupling agent can be selected from N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), ethylene dichloride hydrochloride (EDC.HCl) and N,N'-diisopropylcarbodiimide. The condensing agent can be selected from (1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), hydroxybenzotriazole (HoBt).

Detailed description of the invention
The present invention relates to an improved process for preparation of phenyl boronic acid and ester derivatives of Formula (I).

where R1 is H or 1-4C alkyl, R2 and R3 are independently H, CH3, iso-propyl or R2 and R3 together forms Formula (B) .
In an embodiment, the process for preparing compound of Formula (I) is provided. The process comprises reacting a solution of iodobenzoic acid or its ester of Formula (II) with isopropyl magnesium halide of Formula (A) forming an in situ Grignard species of Formula (C)

where R1 is H or 1-4C alkyl and X can be Cl or Br.

The use of isopropyl magnesium halide proceeds with the trans Grignard reaction (in situ) and hence it is a easy process as compared to the prior art processes where Grignard species is formed in situ.
A boric acid ester derivative of Formula (III) is added to in situ Grignard species of Formula (C) obtaining compound (I). The boric acid derivative of Formula (III) can be:
where R2 and R3 are independently H, CH3, iso-propyl or R2 and R3 together forms Formula (B) and R4 is H, CH3, iso-propyl.

Boric acid ester derivative of Formula (III) added in the process reacts with said Grignard species of Formula (C) formed in situ resulting in phenyl boronic acid or ester derivative of Formula (I). It would be apparent that the desired phenyl boronic acid compounds or its ester derivatives can be prepared by substituting R1 group of Formula (II) and/or R2, R3, and/ or R4 groups of Formula (III) as described.
Scheme 1 illustrates the embodiment of the process of preparing Formula (I).
Scheme 1:

where X, R1, R2, R3, and R4 are as described.
The solution of iodobenzoic acid or its ester of Formula (II) is prepared by dissolving compound (II) in a solvent and preferably a hydrocarbon solvent selected from an aliphatic hydrocarbon such as heptane, cyclohexane, octane or iso-octane and an aromatic hydrocarbon solvent such as benzene, xylene and toluene; or ethereal solvent such as tetrahydrofuran (THF), diethyl ether and 2-methyl THF. The reaction can be carried out at -20°C to -40°C, preferably at -25°C to -35°C. The reaction is preferably carried out in a solvent selected from tetrahydrofuran. The solution can more preferably be cooled to about -20°C to about -30°C before the addition of isopropyl magnesium halide.
The temperature difference during the Grignard reaction is of importance as it -60°C to -70°C in the prior art process, which is difficult to achieve at plant scale. The preferred temperature for present invention is -25°C to -35°C.

In an aspect, the compound of Formula (II) can be selected from 4-iodobenzoic acid of Formula (IIA), 3-iodobenzoic acid of Formula (IIB) and 2-iodobenzoic acid of Formula (IIC), tert-butyl-3-iodobenzoate of Formula (IID).
, , ,
The Grignard species obtained in situ is reacted with boric acid ester derivative of Formula (III), wherein compound (III) can be selected from tri-isopropyl borate of Formula (IIIA), 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Formula (IIIB), trimethyl borate of Formula (IIIC).
, ,
The step of adding boric acid derivative of Formula (III) can to said in situ Grignard species (C) preferably proceeds at -25°C to -35°C. The reaction is preferably carried out in a solvent selected from tetrahydrofuran.
The process further comprises the step of quenching the solution with an acid and water; warming the solution to room temperature; separating and recovering the compound of Formula (I). Apparently, pH of the reaction mixture can be adjusted using hydrochloric acid, acetic acid, ammonium chloride and ammonium acetate, preferably hydrochloric acid.
In an embodiment, the desired phenyl boronic acid compound or derivate prepared by the process of the present invention is 4-boronobenzoic acid of Formula (IA):

The process of preparing compound (IA) is provided. The process comprises reacting a solution of 4-iodobenzoic acid of Formula (IIA)
with isopropyl magnesium halide of Formula (A) forming in situ Grignard species of Formula (C1) where X can be Cl, or Br. Tri-isopropyl borate of Formula (IIIA) is then added to the in situ Grignard species of Formula (C1) obtaining compound (IA). The solution of 4-iodobenzoic acid of Formula (IIA) can be prepared by dissolving compound (IIA) in tetrahydrofuran (THF). The solution can be cooled to -25°C to -35°C before the addition of isopropyl magnesium halide (A).
Scheme 2 below shows the process of preparing 4-boronobenzoic acid of Formula (IA) according to the embodiment of the present invention.
Scheme 2:

where X is as described.
In another embodiment, the desired phenyl boronic acid compound or derivate prepared by the process of the present invention is 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid of Formula (IB):

The process for preparing compound (IB) is provided. The process comprises reacting a solution of 3-iodobenzoic acid of Formula (IIB) with isopropyl magnesium halide of Formula (A) forming in situ Grignard species of Formula (C2) where X can be Cl, or Br. 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Formula (IIIB) is then added to the in situ Grignard species of Formula (C2) obtaining compound (IB). The solution of 3-iodobenzoic acid of Formula (IIB) can be prepared by dissolving compound (IIB) in tetrahydrofuran (THF). The solution can be cooled to about -25°C to about -35°C before the addition of isopropyl magnesium halide (A).
Scheme 3 below shows the process of preparing 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid of Formula (IB) according to the embodiment of the present invention.
Scheme 3:

where X is as described.

In yet another embodiment, the desired phenyl boronic acid compound or derivate prepared by the process of the present invention is 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid of Formula (IC).
The process of preparing the compound (IC) is provided. The process comprises reacting dissolving solution of 4-iodobenzoic acid of Formula (IIA) with isopropyl magnesium halide of Formula (A) forming in situ Grignard species of Formula (C1)
wherein X can be Cl, or Br. 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Formula (IIIB) can be added to the in situ Grignard species of Formula (C1) obtaining compound (IC). The solution of 4-iodobenzoic acid of Formula (IIA) can be prepared by dissolving compound (IIA) in tetrahydrofuran (THF). The solution can be cooled to about -25°C to about -35°C before the addition of isopropyl magnesium halide (A).
Scheme 4 below shows the process of preparing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid of Formula (IC) according to the embodiment of the present invention.
Scheme 4:

where X is as described.

In yet another embodiment, the desired phenyl boronic acid compound or derivate prepared by the process of the present invention is 3-boronobenzoic acid of Formula (ID):

The process of preparing compound (ID) is provided. The process comprises reacting a solution of tert-butyl-3-iodobenzoate of Formula (IID) with isopropyl magnesium halide of Formula (A) forming in situ Grignard species of Formula (C3) where X can be Cl, or Br. Trimethyl borate of Formula (IIIC) is then added to the in situ Grignard species of Formula (C3) obtaining compound (ID). The solution of 3-iodobenzoic acid of Formula (IID) can be prepared by dissolving compound (IID) in tetrahydrofuran (THF). The solution can be cooled to -25°C to -35°C before the addition of isopropyl magnesium halide (A).
Scheme 5 below shows the process of preparing 3-boronobenzoic acid of Formula (ID) according to the embodiment of the present invention.
Scheme 5:

where X is as described.
The present invention also provides a process of preparing derivatives of phenyl boronic compound.
In an embodiment, the phenyl boronic acid derivate prepare by the process of the present invention is 4-boronobenzoic acid derivative i.e. [4-(2-pyridylcarbamoyl)phenyl]boronic acid of Formula (IV).

The process according to the embodiment comprises reacting a solution of 4-boronobenzoic acid of Formula (IA) with 2-aminopyridine in the presence of a coupling agent and a condensing agent. The solution of 4-boronobenzoic acid of Formula (IA) can be prepared by dissolving in a solvent selected from dichloromethane (DCM), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), toluene, dimethyl formamide (DMF). The reaction can be carried out at 20°C to 40°C, preferably at 20°C to 30°C.

In another embodiment, the present invention provides a process of preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid derivative i.e. N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide of Formula (V).

The process comprises reacting a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid of Formula (IB) with 2-aminopyridine in the presence of adding a coupling agent and a condensing agent. The solution of 4-boronobenzoic acid of Formula (IA) can be prepared by dissolving in a solvent selected from dichloromethane (DCM), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), toluene, dimethyl formamide (DMF). The reaction can be carried out at 20°C to 40°C, preferably at 20°C to 30°C.

In yet another embodiment, a process of preparing [3-(2-pyridylcarbamoyl)phenyl]boronic acid of Formula (VI) from compound (ID) is provided.

The process comprises reacting a solution of Formula (ID) with 2-aminopyridine in the presence of a coupling agent and a condensing agent. The solution can be prepared by dissolving (IB) in a solvent selected from dichloromethane (DCM), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), toluene, dimethyl formamide (DMF). The reaction can be carried out at 20-40°C, preferably at 20°C to 30°C.

The coupling agent can be selected from N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), ethylene dichloride hydrochloride (EDC.HCl) and N,N'-Diisopropylcarbodiimide. The condensing agent can be selected from (1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), hydroxybenzotriazole (HoBt).

In context of the present invention, the process of the present invention is an eco-friendly, industrially practical, and economical process. The process of the present invention results in high yield of the end product of the present invention with maximum HPLC purity. The process of the present invention obviates the use of KMnO4 for oxidation, therefore, less by-products are formed making the process much eco-friendly. Further, the process of the present invention can be performed in lesser number of steps with higher yield of the product and hence is economical and efficient.

EXAMPLES
Example and implementation is provided herein below for illustration of the invention. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Example 1
Preparation of 4-carboxyphenyl boronic acid (4-boronobenzoic acid) - Compound of Formula (IA)

Tetrahydrofuran (1750 ml) was charged to 4-iodobenzoic acid (250g) (IIA) and the mixture was cooled to -25°C to -35°C. Isopropyl magnesium chloride (2M solution in tetrahydrofuran) was charged slowly to the mixture at -25°C to -35°C within about 1.5 hours. The mixture was maintained for 1 hour at -25°C to -35°C. Tri-isopropyl borate (473 g) (IIIA) was charged to the above mixture within 30 minutes. The mixture was maintained for 1 hour at -25°C to -35°C. pH of the solution was adjusted to 2 using HCl. The mixture was warmed to room temperature. The layers were separated and THF layer was distilled under vacuum. The solid obtained was stripped out with toluene. Toluene was charged in the solid obtained. The mixture was heated to 50-55°C for 1 hour. Water (190 ml) was charged and maintained for 30 to 45 minutes. The mixture was cooled to room temperature. The solid was filtered and washed with water (250 ml) at room temperature. The solid obtained was suck dried well.
Purification: The solid obtained was charged to THF (750 ml) and the mixture was heated to 50-55°C. The solution obtained was filtered and activated charcoal (25 g) was charged to the filtrate. The mixture was stirred at room temperature for 30 minutes. The mixture was filtered through hyflo bed and washed with THF. Part of the THF was distilled out to obtain slurry. MDC (350 ml) was charged to the slurry obtained and stirred for 1 hour. The solid obtained was washed with MDC (250 ml) and suck dried well. The solid obtained was further dried at 50 to 55°C under vacuum in oven to obtain pure 4-boronobenzoic acid (100 g).
Yield: 60%; Purity: 97.9%

Example 2
Preparation of [4-(2-pyridylcarbamoyl)phenyl]boronic acid – Compound of Formula (IV)

THF (920 ml) was charged to 4-boronobenzoic acid (2 gm) (IA) obtained from Example 1 under inert atmosphere at 25°C. EDC.HCl (2.05 gm) and HoBt was charged to the solution at 25°C. 2-aminopyridine (1.2 gm) was charged in the mixture under stirring at room temperature. The mixture was stirred till the reaction completion which is monitored by in-process TLC check. The mixture was quenched by DM water (10 ml) and stirring continued. DM water (50 ml) was added with stirring and stirring continued for 0.5 hours. The solid obtained was filtered and suck dried and washed by water (10 ml). Dry Wt: 1.89 gm
Yield: 64.8%; Purity: 99.67%

Example 3
Preparation of 4-carboxyphenyl boronic acid (4-boronobenzoic acid) - Compound of Formula (IA)

4-iodobenzoic acid (IIA) (100 gm) was charged to toluene (500 ml) and the reaction mixture was stirred at room temperature. The temperature was raised to 105 to 115°C and 300-400 ml toluene was distilled out at atmospheric pressure. The mass was gradually cooled to 25 to 35°C. THF (1000 ml) was charged and mass was cooled to -25°C to -35°C. Isopropyl magnesium chloride (700 ml) was charged slowly and the mass was stirred. Trimethyl borate (105 g) was charged and the mass was stirred at -25°C to -35°C for 1-1.5 hours. The mass was quenched with aqueous Hydrochloric acid below 10°C. The pH of the reaction mass was adjusted to 1-2. The temperature was raised to 25 to 35°C and stirred for 1-1.5 hours. The mass was settled and the layers were separated. MTBE (200 ml) was charged to the aqueous layer and stirred at 25 to 30°C. The organic layers were combined and distilled under vacuum. The mass was cooled and distilled water was charged to the mixture. The pH of the mass was adjusted to 1-2 using concentrated hydrochloric acid. The mass was filtered, washed with water and suck dried at 25 to 35°C. To the wet cake, water (500 ml) was charged and the temperature was raised to 65 to 70°C. The reaction suspension was stirred, filtered hot and washed with water (100 ml). The wet cake was suck dried and further dried at 55 to 60°C under vacuum. 4-carboxyphenyl boronic acid was obtained as white colored solid (58 gm).
Yield - 86.68%; HPLC purity: 96.7%

Example 4
Preparation of [4-(2-pyridylcarbamoyl)phenyl]boronic acid - Compound of Formula (IV)

DMF (300 ml) was charged to the 4-carboxyphenyl boronic acid (IA) (100 gm) obtained in example 3 and mass was stirred at 25-35°C for 10 minutes. HOBt (122 g) was charged to the reaction mass and stirred for 10 minutes at 25-35°C. 2-aminopyridine (283 gm) was charged to the reaction mass at 25-35°C and the mass was stirred for 10 minutes. The temperature of the reaction mass was raised to 60 to 70°C. The solution of DCC (prepared separately by adding DCC (186 gm) in DMF (200 ml) was charged slowly within to the above reaction mass at 60 to 70°C. The mass was stirred for 1.5-2 hours and the mass was gradually cooled to 25 to 35°C. The mass was filtered and washed with DMF (2x100 ml) at 25-35°C. The filtrate was distilled under reduced pressure at 60 to 70°C to remove the 5V-6V solvent. Water (1000 ml) was charged and mass was stirred for 15 minutes. The pH of the solution was adjusted to 5-6 using concentrated HCl and the mass was stirred for 15 minutes. The pH of the mass was adjusted 5-6 using concentrated HCl and stirred for 1.5-2 hours at 25 to 35°C. The mass was filtered and washed with water (100 ml) and suck dried well. The wet solid was charged to water (1000 ml) and the solution was stirred for 10 minutes. The mass was cooled to 0-10°C and the pH was adjusted to 11-12 using 10% aqueous NaOH. The mass was stirred for 1 hour, filtered and washed with water (50 ml). The pH of the filtrate was adjusted to 5-6 using concentrated Hydrochloric acid and mass was stirred at 25-35°C for 1 hour. The solution was filtered, washed with water (2x50 ml) and suck dried well. Methanol (600 ml) was charged to wet solid and mixture was stirred for 10 minutes at 25 to 35°C. The temperature was raised to 55-60°C and stirred for 30 minutes. The mass was gradually cooled and stirred for 60 minutes at 25 to 35°C. The mass was filtered, washed with methanol (100 ml) and suck dried well. The [4-(2-pyridylcarbamoyl) phenyl] boronic acid obtained was further dried under vacuum at 50-60°C (dry weight 110 g).
Yield: 75.42%; HPLC purity: 99.97%

Example 5
Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid – Compound of Formula (IB)

THF (500 ml) was charged to 3-iodobenzoic acid (100 g) (IIB) and the mixture was cooled to -35°C. Isopropyl magnesium chloride (500 ml) was slowly and gradually charged to the mixture over 1.5 hours at -25°C to -35°C. The mixture was stirred for 1 hour at -25°C to -35°C. 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (127.5 g) (IIIB) was charged gradually in about 20-30 minutes. The pH of the mixture was adjusted to 3 by slowly adding the mixture of HCL and water (1:1) at -25°C to -35°C. The mixture obtained was warmed slowly to room temperature. The layers were separated and THF layer was distilled out under vacuum till semi-solid is obtained. MDC (2.25 L) was charged and mixed well. The mixture was filtered through hyflo bed. Charcoal was charged to the filtrate and stirred for 30 minutes. The solution was filtered and the toluene layer was distilled completely under vacuum to obtain sticky solid. Toluene (200 ml) was charged to the solid obtained and the solution was heated to 100°C to obtain the clear solution. The solution was stirred for 30 minutes at 100°C. The solution was cooled to room temperature to obtain suspension containing the product. 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (IB) obtained was filtered and washed with chilled toluene (100 ml). The solid was suck dried and further dried under vacuum at 50 to 55°C for 8 hours. (Dry wt. 60 g).
Yield: 80.2%; Purity: 98.87%

Example 6
Preparation of N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide – Compound of Formula (V)

3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (20 gm) (IB) obtained from Example 5 was charged to THF (200 ml). HOBt (16.4 gm) and EDC.HCl (23.2 gm) was charged to the above mixture with stirring at 28°C. 2-aminopyridine (9.1 g) was charged to the reaction mass obtained and reaction was maintained with stirring till completion of the reaction. The solvent was concentrated under reduced pressure. MDC (140 ml) was charged to the residue obtained. The organic layer was washed by 10% NaHCO3 solution (40 ml). The layers were separated and the organic layer was dried over sodium sulfate. The dried layer was concentrated under reduced pressure. The residue obtained was purified using mixture of heptane:ethyl acetate. N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (14 g) of Formula (V) was isolated.
Yield: 50.50%; Purity: 99.57%

Example 7
Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid – Compound of Formula (IC)

THF (1400 ml) was charged to 4-iodobenzoic acid (200 g) (IIA) and the mixture was cooled to -50°C. Isopropyl magnesium chloride (1L) was slowly and gradually charged to the mixture over 1-2 hours at -25°C to -35°C. The mixture was stirred for 0.5 hour at -25°C to -35°C. 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (191 g) (IIIB) was charged gradually in about 1 hour. The reaction mixture was quenched by gradual addition of mixture of HCl and water (1:4.5) (1350 ml) at -25°C to -35°C. The mixture obtained was warmed slowly to room temperature. The layers were separated and THF layer was dried over sodium sulfate and sodium chloride at room temperature. THF was evaporated and residue obtained was stripped using toluene (200 ml). Toluene (500 ml) was added to the residue obtained. The solution obtained was heated to 60°C to make clear solution. The solution was cooled gradually to room temperature and then to 10 to 15°C. The precipitate obtained was filtered and washed using chilled toluene (100 ml). The solid obtained was dried under vacuum at RT for 7-8 hours. (Dry wt. 117 g).
Yield: 58.5; Purity: 99.47%

Example 8
Preparation of (3-tert-butoxycarbonyl)phenyl)boronic acid

Toluene (500 ml) was charged to tert-butyl-3-iodobenzoate (50 g) (IID) under inert atmosphere. The reaction mixture was heated to 100-110°C and toluene (150 ml) was distilled out from reaction mass. The reaction mass was cooled to -25°C to -35°C. Isopropyl magnesium chloride (125 ml) was added to the reaction mass dropwise. After completion of Grignard reaction, reaction mass was cooled to -20°C to -25°C and trimethyl borate (50.80 g) was charged. The mass was maintained at 0°C to 10°C till completion of the reaction. Water (250 ml) was added to the reaction mixture and stirred for half an hour. Toluene (150) was added to the mass and stirred for half an hour at room temperature.
Yield: 83.8%; Purity: 99.86%

Example 9
Preparation of 3-boronobenzoic acid i.e. (3-carboxyphenyl boronic acid) (ID)

To (3-tert-butoxycarbonyl)phenyl)boronic acid (95 gms) obtained in above example 8, concentrated HCl (285 ml) was charged in inert atmosphere with continuous stirring. The mixture was heated to 50 to 60°C and temperature was further raised to 80 to 85°C. The mixture was maintained for 1-2 hours and cooled to 70°C. The mixture was filtered at 70°C and suck dried. The product was washed with (2x200 ml) water and the product was suck dried. The product was dried under vacuum at 60 to 65°C.
Yield: 64.6 gm, 90.98%; Purity: 90.7%

Example 10
Preparation of [3-(2-pyridylcarbamoyl)phenyl]boronic acid (VI)

3-boronobenzoic acid i.e. (3-carboxyphenyl boronic acid) (ID) (30 gms) obtained in example 9 was charged to dimethyl formamide (100 ml) at 25 to 30°C. HoBt (36.6 gms) was charged to the reaction mixture at 25 to 30°C and stirred for 10-15 minutes. 2-aminopyridine (85 gms) was charged to the reaction mass and stirred continuously for 10 minutes. The mixture was heated at 65 to 70°C. A solution of DCC was prepared by charging DCC (55.8 gm) to DMF (60 ml). The DCC solution was slowly added to the reaction mass and stirred for 2-3 hours. Heating was stopped and the mass was cooled to 30°C and maintained for 15 minutes. The mass was filtered and the residue was washed with DMF (60 ml). The filtrate was distilled to remain 2V of the solvent and cooled to room temperature. DM water (300 ml) was charged to reaction mass and pH was adjusted to 5-6 by concentrated HCl and stirred for 1 hour. The mass was filtered and suck dried. Water (300 ml) was charged to the wet solid and cooled to 5 to 10°C and pH of the mixture was adjusted to 11 to 12 using sodium hydroxide. The mass was filtered and the residue was washed with DM water (300 ml). The pH of the clear filtrate was adjusted to 5 to 6 using concentrated HCl at 5-10°C. Stirring was continued at RT for 1 hour and the product was filtered and suck dried. The residue was washed with DM water (30 ml). The wet solid was dissolved in methanol (180 ml) at 25 to 30°C. The temperature was raised to 55 to 60°C and stirred for 1 hour. The mass was cooled to RT and filtered and suck dried. The residue was dried under vacuum at 50 to 55°C.
Yield: Dry weight 27 gm (61%); HPLC Purity: 99.96%

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
,CLAIMS:
1. A process of preparing phenyl boronic acid or its ester derivative of Formula (I)
where R1 is H or 1-4C alkyl, R2 and R3 are independently H, CH3, iso-propyl or
R2 and R3 together forms Formula (B)
comprising:
(a) reacting a solution of iodobenzoic acid or its ester of Formula (II)
with isopropyl magnesium halide of Formula (A) forming in situ Grignard species of Formula (C)
where R1 is H or 1-4C alkyl and X is Cl or Br; and

(b) adding a boric acid ester derivative of Formula (III) to said in situ Grignard species (C) obtaining phenyl boronic acid or ester derivatives of Formula (I),
said compound of Formula (III):

where R2 and R3 are independently H, CH3, iso-propyl, or R2 and R3 together forms Formula (B) and R4 is H, CH3, iso-propyl.

2. The process as claimed in claim 1, wherein the solution of iodobenzoic acid or its ester of Formula (II) is prepared by dissolving iodobenzoic acid or its ester in a hydrocarbon solvent selected from an aliphatic hydrocarbon solvent such as heptane, cyclohexane, octane or iso-octane or an aromatic hydrocarbon solvent such as benzene, xylene and toluene; or ethereal solvent such as tetrahydrofuran (THF), diethyl ether and 2-methyl THF.

3. The process as claimed in claim 2, wherein the solvent is tetrahydrofuran.

4. The process as claimed in claim 1, wherein the solution is cooled to -20°C to -40°C before the addition of isopropyl magnesium halide (A).

5. The process as claimed in claim 1, wherein the solution is cooled to -25°C to -35°C before the addition of isopropyl magnesium halide (A).

6. The process as claimed in claims 1 to 5, wherein comprises a process of preparing 4-boronobenzoic acid of Formula (IA):

said process comprising:
reacting a solution of 4-iodobenzoic acid of Formula (IIA) prepared in tetrahydrofuran (THF) with isopropyl magnesium halide (A) forming in situ Grignard species of Formula (C1)
where X can be Cl or Br; and
adding tri-isopropyl borate of Formula (IIIA) to the in situ Grignard species of Formula (C1) obtaining compound (IA).

7. The process as claimed in claims 1 to 5, wherein comprises a process for preparing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoic acid of Formula (IC)

said process comprising:
reacting a solution of 4-iodobenzoic acid of Formula (IIA) prepared in tetrahydrofuran (THF) with isopropyl magnesium halide (A) forming in situ Grignard species of Formula (C1)
where X can be Cl or Br; and
adding 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Formula (IIIB) to the in situ Grignard species of Formula (C1) obtaining compound (IC).

8. The process as claimed in claims 1 to 5, wherein comprises a process for preparing 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid of Formula (IB):

said process comprising:
reacting a solution of 3-iodobenzoic acid of Formula (IIB) prepared in tetrahydrofuran (THF) with isopropyl magnesium halide (A) forming in situ Grignard species of Formula (C2)
where X can be Cl or Br; and
adding 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of Formula (IIIB) to the in situ Grignard species of Formula (C2) obtaining compound (IB).

9. The process as claimed in claims 1 to 5, wherein comprises a process for preparing 3-boronobenzoic acid of Formula (ID):

said process comprising:
reacting a solution of tert-butyl-3-iodobenzoate of Formula (IID) prepared in tetrahydrofuran (THF) with isopropyl magnesium halide of Formula (A) forming in situ Grignard species of Formula (C3)
where X can be Cl, or Br; and
adding trimethyl borate of Formula (IIIC) to the in situ Grignard species of Formula (C3) obtaining compound (ID).

10. The process as claimed in claims 7 to 9, wherein the solution is cooled to -25°C to -35°C before the addition of isopropyl magnesium halide (A).

11. The process as claimed in claims 1 to 5 and 6, wherein comprises a process of preparing [4-(2-pyridylcarbamoyl)phenyl]boronic acid of Formula (IV)

said process comprising
reacting a solution of 4-boronobenzoic acid of Formula (IA) with 2-aminopyridine in the presence of a coupling agent and a condensing agent.

12. The process as claimed in claims 1 to 5 and 8, wherein comprises a process of preparing N-(2-pyridyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide of Formula (V)

said process comprising:
reacting a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid of Formula (IB) with 2-aminopyridine in the presence of a coupling agent and a condensing agent.

13. The process as claimed in claims 1 to 5 and 9, wherein comprises a process of preparing 3-(2-pyridylcarbamoyl)phenyl]boronic acid of Formula (VI)

said process comprising:
reacting a solution of 3-boronobenzoic acid of Formula (ID) with 2-aminopyridine in the presence of a coupling agent and a condensing agent.

14. The process as claimed in claim 11, 12 and 13, is carried out at 20°C to 40°C.

15. The process as claimed in claim 11, 12 and 13, wherein the coupling agent is selected from N,N'-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC), ethylene dichloride hydrochloride (EDC.HCl) and N,N'-Diisopropylcarbodiimide.

16. The process as claimed in claim 11, 12 and 13, wherein the condensing agent is selected from (1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), hydroxybenzotriazole (HoBt).

17. The process as claimed in claim 11, 12 and 13, wherein the solution of 4-boronobenzoic acid of Formula (IA) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid of Formula (IB) is prepared by dissolving in a solvent selected from dichloromethane (DCM), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), toluene, dimethyl formamide (DMF).