DESC:Field of the invention

This disclosure relates to a process for the preparation of 1H-pyrrolo[2,3-b]pyridin-5-ol, particularly to an improved process for the preparation of 1H-pyrrolo[2,3-b]pyridin-5-ol which is useful in the preparation of a key intermediate of Venetoclax, namely 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid ester of formula (A).

Background of the invention

Compound 1H-pyrrolo[2,3-b]pyridin-5-ol is useful in the preparation of 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid ester of formula (A), which is a key intermediate of Venetoclax.


Venetoclax blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of CLL cells. Venetoclax is used as a second line treatment for chronic lymphocytic leukemia in those with a specific chromosomal abnormality.

Various processes are known in the art for the preparation of Formula I. Synthesis of Venetoclax using key intermediate (A), is disclosed in US 8,546,399. The process involves 1-protection of 5-bromo-1H-pyrrolo[2,3-b]pyridine using triisopropylchlorosilane in tetrahydrofuran. 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine formed is treated with 2.5 M butyl lithium in tetrahydrofuran and trimethyl borate to form 5H-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol. Reactions using butyl lithium are highly sensitive to handle and requires atmost care at higher scale production. The reaction requires lots of safety precautions for handling.

Further, WO2008064265 discloses reaction of 5-bromo-7-azaindole with sodium methoxide and Copper (I) bromide at room temperature in N, N-Dimethylformamide and methanol. The reaction occurs at 120°C under nitrogen for 3 hours. 5-Methoxy-lH-pyrrolo[2,3-b]pyridine was isolated as white solid (81, 0.4 g, 50%) which was hydrolyzed using boron tribromide at room temperature for 3 hours. 1-H-Pyrrolo[2,3-b]pyridin-5-ol is isolated as white off-white solid. However the yield obtained is very low i.e. around 40-50%.

Furthermore, Chemistry - A European Journal, 2016, vol. 22, No. 40, p. 14397-14400 describes synthesis of 1-(benzenesulfonyl)-3-trimethylsilyl-pyrrolo[2,3-b]pyridin-5-ol from 1-(benzenesulfonyl)-3-trimethylsilyl-pyrrolo[2,3-b]pyridin-5-ol by Br–Mg exchange followed by a borylation with methoxyboronic acid pinacol ester and followed subsequent oxidation. The reaction provides good yields, however the methoxyboronic acid pinacol ester is not easily available. Also an additional stage of ester cleavage for preparation of boronic acid is also required.

In addition, though the Grignard exchange is known for several substrates in the literature, it presents a challenge when it comes to taking the reaction to complete conversion. The reaction conditions required for complete conversion can be varied and several combinations of solvents, stoichiometry, temperature and rate and time of addition of reagents are possible, arriving at an optimized solution remains a challenge.

Accordingly, there is a need for an improved process for the preparation of pyrrolo[2,3-b]pyridin-5-ol that overcomes the above mentioned drawbacks of the prior art.

Summary of the invention
In one aspect, the present invention provides an improved process for the preparation of 1H-pyrrolo[2, 3-b]pyridin-5-ol of formula (I). The process comprises the steps of reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) with a N-protecting compound and a predefined ethereal or hydrocarbon solvent to form 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II). Next step involves reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) with a predefined molarity of Turbo Grignard reagent in a predefined hydrocarbon solvent to form a Grignard mixture. The aforesaid Grignard mixture is treated with a predefined trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) and pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) is oxidized with a predefined oxidizing agent to form pyrrolo[2,3-b]pyridin-5-ol of formula (I).

In an embodiment, a process for the preparation of 1H-pyrrolo[2,3-b]pyridin-5-ol of formula (I) is disclosed wherein 1H-pyrrolo[2,3-b]pyridin-5-ol of formula (I) is prepared from 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) comprising the steps of: reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) with the predefined molarity of Turbo Grignard reagent in a predefined hydrocarbon solvent to form a Grignard mixture. Next step involves treating said Grignard mixture with the predefined trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III); and oxidizing pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) with the predefined oxidizing agent to form pyrrolo[2,3-b]pyridin-5-ol of formula (I).

In an embodiment, the N-protecting compound is selected from Triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropyl-silyl chloride and tert-butyldiphenylsilyl chloride.
The solvent is selected from ethereal and hydrocarbon solvent and mixture thereof. The ethereal solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, 1,4-dioxan, and dimethoxyethane. The hydrocarbon solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane and cycloheptane. The Trialkyl borate is selected from trimethyl borate, triethyl borate, triisopropyl borate and tributyl borate. The protecting silyl group is selected from Triethylsilane (TES), tert-butyldimethylsilane (TBS), triisopropyl-silane (TIPS) and tert-butyldiphenylsilane (TBDPS). The step of treating the Grignard mixture with trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) is carried out at a temperature ranging from 30-70°C, preferably at a temperature ranging from 40-60°C, more preferably at a temperature ranging from 50-55°C. The oxidizing agent is hydrogen peroxide, preferably 50% hydrogen peroxide.

In another aspect, the present invention provides an improved process for the preparation of 1H-pyrrolo[2, 3-b]pyridin-5-ol of formula (I) and intermediates thereof. The process comprises further condensing of pyrrolo[2,3-b]pyridin-5-ol of formula (I) with 2,4-difluoro benzoic acid ester to form 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid ester of formula (A), an intermediate of Venetoclax. The condensation reaction is carried out at a temperature ranging from 70-100°C, preferably at a temperature ranging from 90-95°C. Said reaction is carried out in an ethereal solvent selected from diglyme and 1,4-dioxane.

wherein ‘R1’ is C1-C4 alkyl

In yet another aspect, the present invention provides a process for the preparation of 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) comprising reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) with a predefined N-protecting compound and a predefined ethereal or hydrocarbon solvent to obtain 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II).

Detailed description of the invention

The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.

All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.

Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.

References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.

In a preferred embodiment, an improved process for the preparation of 1H-pyrrolo[2,3-b]pyridin-5-ol of formula (I) is disclosed. The process comprising the steps of:
i. reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) with a N-protecting compound and a predefined ethereal or hydrocarbon solvent to form 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) ;

wherein ‘X’ is selected from chloro, bromo iodo;
ii. reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) with a predefined molarity of Turbo Grignard reagent in a predefined hydrocarbon solvent to form a Grignard mixture;
iii. treating the Grignard mixture formed in step (ii) with a predefined trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III); and

wherein ‘X’ is a halogen selected from chloro, bromo, iodo and ‘P’ is a protecting silyl group;
iv. oxidizing pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) with a predefined oxidizing agent to form pyrrolo[2,3-b]pyridin-5-ol of formula (I).

.

In this embodiment, the N-protecting compound of step (i) is selected from Triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropyl-silyl chloride and tert-butyldiphenylsilyl chloride. Preferably 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) is reacted with triisopropyl-silyl chloride in presence of lithium hexamethyldisilamide (Li-HMDS). The step (i) reaction is carried out in ethereal solvent such as tetrahydrofuran. The step (i) reaction is carried out at room temperature. The Turbo Grignard reagent is an Isopropyl magnesium chloride lithium chloride complex. Trialkyl borate is selected from trimethyl borate, triethyl borate, triisopropyl borate and tributyl borate. It is to be noted that trialkyl borate may vary in alternative embodiments. The protecting silyl group is selected from Triethylsilane (TES), tert-butyldimethylsilane (TBS), triisopropyl-silane (TIPS) and tert-butyldiphenylsilane (TBDPS). The reaction of step (i) is carried out in a solvent selected from ethereal solvent, hydrocarbon solvent and mixture thereof. The ethereal solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, 1,4-dioxan, dimethoxyethane. The hydrocarbon solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane and cycloheptane. It is to be noted that the step (i) solvent may vary in alternative embodiments.

In this embodiment of the present invention, the reaction is preferably carried out at reflux. The reaction of step (iii) i.e treating the Grignard mixture formed in step (ii) with trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) proceeds at 30-70°C, preferably at 40-60°C, particularly at 50-55°C. The oxidation proceeds in presence of suitable oxidizing agent, such as hydrogen peroxide. Preferably the oxidation is carried out using 50% hydrogen peroxide. The hyrocarbon solvent selected from benzene, toluene, hexane, heptane, cyclohexane and cycloheptane, preferably toluene.

In another embodiment, the present invention discloses an improved process for the preparation of 1H-pyrrolo[2,3-b]pyridin-5-ol of formula (I). The process comprising the steps of:
a) reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) with a predefined molarity of Turbo Grignard reagent in a predefined hydrocarbon solvent to form a Grignard mixture;
b) treating the Grignard mixture formed in step (a) with a predefined trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III); and

wherein ‘X’ is a halogen selected from chloro, bromo, iodo and ‘P’ is a protecting silyl group;
c) oxidizing pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) with a predefined oxidizing agent to form pyrrolo[2,3-b]pyridin-5-ol of formula (I).

.
In this embodiment, the Turbo Grignard reagent is an Isopropyl magnesium chloride lithium chloride complex. Trialkyl borate is selected from trimethyl borate, triethyl borate, triisopropyl borate and tributyl borate. It is to be noted that trialkyl borate may vary in alternative embodiments. The protecting silyl group is selected from Triethylsilane (TES), tert-butyldimethylsilane (TBS), triisopropyl-silane (TIPS) and tert-butyldiphenylsilane (TBDPS). The reaction of step (a) is carried out in a solvent selected from ethereal solvent, hydrocarbon solvent and mixture thereof. The ethereal solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, 1,4-dioxan, dimethoxyethane. The hydrocarbon solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane and cycloheptane. It is to be noted that the step (a) solvent may vary in alternative embodiments.

In this embodiment of the present invention, the reaction is preferably carried out at reflux. The reaction of step (b) i.e treating the Grignard mixture formed in step (a) with trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) proceeds at 30-70°C, preferably at 40-60°C, particularly at 50-55°C. The oxidation proceeds in presence of suitable oxidizing agent, such as hydrogen peroxide. Preferably the oxidation is carried out using 50% hydrogen peroxide. The hyrocarbon solvent selected from benzene, toluene, hexane, heptane, cyclohexane and cycloheptane, preferably toluene.

In another embodiment, the present invention relates to a process for the preparation of pyrrolo[2,3-b]pyridin-5-ol of formula (I) and intermediates thereof. The process comprising the steps of:
i) reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) with a N-protecting compound and a predefined ethereal or hydrocarbon solvent to form 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) ;

wherein ‘X’ is selected from chloro, bromo iodo;
ii) reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) with a predefined molarity of Turbo Grignard reagent in a predefined hydrocarbon solvent to form a Grignard mixture;
iii) treating the Grignard mixture formed in step (ii) with a predefined trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III);

wherein ‘X’ is a halogen selected from chloro, bromo, iodo and ‘P’ is a protecting silyl group.
iv) oxidizing pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) with a predefined oxidizing agent to form pyrrolo[2,3-b]pyridin-5-ol of formula (I); and

v) condensing Pyrrolo[2,3-b]pyridin-5-ol of formula (I) with 2,4-difluoro benzoic acid ester to form an intermediate of Venetoclax, namely 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid ester of formula (A).

wherein ‘R1’ is C1-C4 alkyl;

In this embodiment, the N-protecting compound of step (i) is selected from Triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropyl-silyl chloride and tert-butyldiphenylsilyl chloride. Preferably 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) is reacted with triisopropyl-silyl chloride in presence of lithium hexamethyldisilamide (Li-HMDS). The step (i) reaction is carried out in ethereal solvent such as tetrahydrofuran. The step (i) reaction is carried out at room temperature.

In this embodiment, The Turbo Grignard reagent is an Isopropyl magnesium chloride lithium chloride complex. Trialkyl borate is selected from trimethyl borate, triethyl borate, triisopropyl borate and tributyl borate. It is to be noted that trialkyl borate may vary in alternative embodiments. The protecting silyl group is selected from Triethylsilane (TES), tert-butyldimethylsilane (TBS), triisopropyl-silane (TIPS) and tert-butyldiphenylsilane (TBDPS). The reaction of step (ii) is carried out in a solvent selected from ethereal solvent, hydrocarbon solvent and mixture thereof. The ethereal solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, 1,4-dioxan, dimethoxyethane. The hydrocarbon solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane and cycloheptane. It is to be noted that the step (i) solvent may vary in alternative embodiments.

In this embodiment, the reaction is preferably carried out at reflux. The reaction of step (iii) i.e treating the Grignard mixture formed in step (ii) with trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) proceeds at 30-70°C, preferably at 40-60°C, particularly at 50-55°C. The step (iv) oxidation is carried out in presence of a suitable oxidizing agent, such as hydrogen peroxide. Preferably the oxidation is carried out using 50% hydrogen peroxide. The hyrocarbon solvent selected from benzene, toluene, xylene, hexane, heptane, cyclohexane and cycloheptane, preferably toluene. In step (v), the Pyrrolo[2,3-b]pyridin-5-ol of formula (I) prepared by the process of the present invention is condensed with 2,4-difluoro benzoic acid ester. R1 is C1-C4 alkyl. The step (v) reaction is carried out in presence of tripotassium phosphate and in an ethereal solvent selected from diglyme and 1,4-dioxane. The step (v) reaction is carried out at 70-100°C, preferably at 90-95°C.

In another embodiment, the present invention discloses a process for the preparation of 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II). 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) is prepared by reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) with a compound selected from Triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropyl-silyl chloride and tert-butyldiphenylsilyl chloride.

Preferably 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) is reacted with triisopropyl-silyl chloride in presence of lithium hexamethyldisilamide (Li-HMDS). The reaction is carried out in ethereal solvent such as tetrahydrofuran. The reaction is carried out at room temperature.

In accordance with an embodiment of the present invention, in the process for the preparation of 1H-pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) as an intermediate, the reaction essentially involves Grignard exchange with Turbo Grignard reagent (Isopropyl magnesium chloride lithium chloride complex). The halide of the substrate is transferred to the Grignard reagent and is converted to its magnesium chloride (Arylmagnesium chloride). Isopropyl halide and arylmagnesium chloride are formed as a result of this exchange. Arylmagnesium chloride is then converted to corresponding boronic acid of formula (III).

In another embodiment, a process for the preparation of an intermediate of Venetoclax, namely 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid ester of formula (A) is disclosed. The process comprising condensing pyrrolo[2,3-b]pyridin-5-ol of formula (I) with a predefined acid ester in presence of tripotassium phosphate and a predefined ethereal solvent to obtain 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid ester of formula (A), a key intermediate of Venetoclax.

In this embodiment, Pyrrolo[2,3-b]pyridin-5-ol of formula (I) prepared by the process of the present invention is condensed with 2,4-difluoro benzoic acid ester. R1 is C1-C4 alkyl. The reaction is carried out in presence of tripotassium phosphate and in an ethereal solvent selected from diglyme and 1,4-dioxane. The reaction is carried out at 70-100°C, preferably at 90-95°C. Advantageously, the process is conducted under mild conditions to obtain a pure form of pyrrolo[2,3-b]pyridin-5-ol of formula (I). The pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) and pyrrolo[2,3-b]pyridin-5-ol of formula (I) has a purity above 98%.

In an embodiment, the N-protecting compound is selected from Triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropyl-silyl chloride and tert-butyldiphenylsilyl chloride.

In an embodiment, the ethereal solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme , 4-dioxan, dimethoxyethane.

In an embodiment, the hydrocarbon solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane and cycloheptane.

In an embodiment, the Trialkyl borate is selected from trimethyl borate, triethyl borate, triisopropyl borate and tributyl borate.

In an embodiment, the protecting silyl group is selected from Triethylsilane (TES), tert-butyldimethylsilane (TBS), triisopropyl-silane (TIPS) and tert-butyldiphenylsilane (TBDPS).

In an embodiment, the step of treating the Grignard mixture with trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) is carried out at a temperature ranging from 30-70°C, preferably at 40-60°C, particularly at 50-55°C.

In an embodiment, the condensation reaction is carried out at a temperature ranging from 70-100°C, preferably at 90-95°C.

The reaction scheme for the preparation of a compound of Formula 1 is represented below:

The reaction scheme for the preparation of an intermediate 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid ester of formula (A), is represented below:

EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.

Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

Example 1
Preparation of (5-bromopyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane (Formula II)
In an inert atmosphere 5-bromo-1H-pyrrolo[2,3-b]pyridine (180 gms) was charged in tetrahydrofuran (900 ml). The reaction mixture was stirred to get clear solution. 1M solution of Li-HMDS in tetrahydrofuran (1035 ml) was added to the reaction mixture gradually over the period of 2-3 hours and during addition temperature was maintained to 30-35°C. The mixture was stirred for 30 minutes at 30°C. Triisopropylsilyl chloride (218.4 gm) was charged to the reaction mass at 30-35°C and stirred for 30 minutes. The mass was cooled to 10-15°C and saturated ammonium chloride solution (1 L) was added gradually in 1 hour and stirred for 0.5 hour. Tetrahydrofuran layer was separated and aqueous layer was extracted with methyl tert-butyl ether (200 ml). MTBE layer was separated and both the organic layers were combined and distilled under vacuum. Chloroform (1L) and water (500 ml) was charged in the residue and stirred for 30 minutes. Chloroform layer was separated and washed with 20% brine solution (200 ml). The separated chloroform layer was distilled under vacuum . IPA (600 ml) was added to the residue and heated to 60-70°C and maintained for 1 hour. The mass was gradually cooled to RT and then to 10-15°C. The mass was filtered, suck dried and washed with IPA (100 ml). The wet solid was dried under vacuum at 30-35°C to yield (5-bromopyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane (290 gm, 89.92%).
HPLC purity: 99%.

Example 2
Preparation of (1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-yl)boronic acid (Formula III)
Under moisture free conditions toluene (75 ml) and tetrahydrofuran (225 ml) was charged to (5-bromopyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane (25 gm) and warmed to 50-55°C. 1M solution Turbogrignard reagent in THF (220 ml, 3.1 mole) was added gradually over the 45-60 minutes and the mixture was maintained for 4 hours at 50°C. The mass was gradually cooled to 25-30°C and finally cooled to -70°C by using dry ice. Trimethyl borate (11 ml) was added to the mass at -70 to -65°C. The mass was stirred and maintained at -70 to -65°C for 15-20 minutes. Reaction mass was quenched with saturated ammonium chloride solution (125 ml) and THF layer was separated. Aqueous layer was washed with THF (100 ml). The combined THF layers were concentrated under vacuum below 50°C. MDC (100 ml) and water (100 ml) was charged to the residue and stirred for 15 minutes. MDC layer was washed with brine solution (100 ml) and combined MDC layer was concentrated under under vacuum below 50°C. The crude mass was crystallized with acetonitrile (125 ml) to get pure (1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-yl)boronic acid solid (16 gm, 71%) as a white solid.
HPLC purity: 96%
Example 3
Preparation of 1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-ol (Formula I)
(1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-yl)boronic acid (15 gm) was added to Toluene (25 ml). 50% hydrogen peroxide (3.5 ml) was added to the mixture. The mass was maintained for 2 hours. 10% Sodium bicarbonate solution (50 ml) was added to the mixture and stirred for 30 minutes. The layers were separated and aqueous layer was extracted Toluene (100 ml). The combined Toluene layer was washed with water (100 ml) followed by washing with 20% brine solution (100 ml). The toluene layer was filtered and concentrated on rota-vapor at 50°C to get 1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-ol (13.2 gm, 96% yield).
HPLC purity: >97%
Example 4
Preparation of methyl 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoate (Formula A)
1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-ol (0.5 gm) was charged in 1,4-doxane (25 ml). tripotassium phosphate (1.1 gm) and methyl-2,4-difluorobenzoate (0.295 gm) was added and the mixture was heated to 90-95°C and maintained for 30-35 hours. The mass was cooled to RT and water (10 ml) was added and stirred for 10 minutes. MDC (10 ml) was added and stirred for 15 minutes. The organic layer was separated and aqueous layer was extracted with MDC (10 ml). Combined MDC layer was washed with water (10 ml) and 20% brine (10 ml). The organic layer was separated and concentrated on rotavapor. To this residue methanol (5 ml) and Concentrated HCl (1 ml) was charged. Resulting mixture was heated for 4 hours at reflux and concentrated to yield (0.8 gm) methyl 4-fluoro-2-(1-triisopropylsilylpyrrolo[2,3-b]pyridin-5-yl)oxy-benzoate. The residue was purified using 5V methanol to get pure white solid.
HPLC purity: >99%.

The process of the present invention advantageously provides complete conversion of 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) by optimizing reaction conditions such as choosing correct solvent and reagents and efficient temperature range. The process of the present invention provides pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) and pyrrolo[2,3-b]pyridin-5-ol of formula (I) with higher yield and better purity.

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. An improved process for the preparation of 1H-pyrrolo[2,3-b]pyridin-5-ol of formula (I) comprising the steps of:
i. reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) with a N-protecting compound and a predefined ethereal or hydrocarbon solvent to form 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) ;

wherein ‘X’ is selected from chloro, bromo iodo;
ii. reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) with a predefined molarity of Turbo Grignard reagent in a predefined hydrocarbon solvent to form a Grignard mixture;
iii. treating the Grignard mixture formed in step (ii) with a predefined trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III); and

wherein ‘X’ is a halogen selected from chloro, bromo, iodo and ‘P’ is a protecting silyl group
iv. oxidizing pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) with a predefined oxidizing agent to form pyrrolo[2,3-b]pyridin-5-ol of formula (I).

2. The process for the preparation of 1H-pyrrolo[2,3-b]pyridin-5-ol of formula (I) as claimed in Claim 1, wherein 1H-pyrrolo[2,3-b]pyridin-5-ol of formula (I) is prepared from 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) comprising the steps of:
a) reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) with the predefined molarity of Turbo Grignard reagent in a predefined hydrocarbon solvent to form a Grignard mixture;
b) treating the Grignard mixture formed in step (i) with the predefined trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III); and

wherein ‘X’ is a halogen selected from chloro, bromo, iodo and ‘P’ is a protecting silyl group; and
c) oxidizing pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) with the predefined oxidizing agent to form pyrrolo[2,3-b]pyridin-5-ol of formula (I).

.
3. The process as claimed in Claim1, wherein pyrrolo[2,3-b]pyridin-5-ol of formula (I) is condensed with 2,4-difluoro benzoic acid ester to form 4-fluoro-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzoic acid ester of formula (A), an intermediate of Venetoclax.

wherein ‘R1’ is C1-C4 alkyl
4. The process as claimed in Claim 3, wherein the condensation reaction is carried out at a temperature ranging from 70-100°C.
5. The process as claimed in Claim 3, wherein the condensation reaction is carried out at a temperature ranging from 90-95°C.
6. The process as claimed in Claim 3, wherein the reaction is carried out in an ethereal solvent selected from diglyme and 1,4-dioxane.
7. A process for the preparation of pyrrolo[2,3-b]pyridin-5-ol of formula (I) and intermediates thereof, wherein said process comprising the steps as claimed in any of the preceding Claims 1-3.
8. The process as claimed in Claim 1, wherein a process for the preparation of 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II) comprising reacting 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (IV) with a predefined N-protecting compound and a predefined ethereal or hydrocarbon solvent to obtain 5-halo-1H-pyrrolo[2,3-b]pyridine of formula (II).

9. The process as claimed in Claim 1, wherein the N-protecting compound is selected from Triethylsilyl chloride, tert-butyldimethylsilyl chloride, triisopropyl-silyl chloride and tert-butyldiphenylsilyl chloride.
10. The process as claimed in Claim 1, wherein the ethereal solvent is selected from tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, 1,4-dioxan, and dimethoxyethane.
11. The process as claimed in Claim 1, wherein the hydrocarbon solvent is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane and cycloheptane.
12. The process as claimed in Claim 1, wherein the Trialkyl borate is selected from trimethyl borate, triethyl borate, triisopropyl borate and tributyl borate.
13. The process as claimed in Claim 1, wherein the step of treating the Grignard mixture with trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) is carried out at a temperature ranging from 30-70°C.
14. The process as claimed in Claim 1, wherein the step of treating the Grignard mixture with trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) is carried out at a temperature ranging from 40-60°C.
15. The process as claimed in Claim 1, wherein the step of treating the Grignard mixture with trialkyl borate to form pyrrolo[2,3-b]pyridin-5-ylboronic acid of formula (III) is carried out at a temperature ranging from 50-55°C.
16. The process as claimed in Claim 1, wherein the oxidizing agent is hydrogen peroxide.
17. The process as claimed in Claim 16, wherein the oxidizing agent is 50% hydrogen peroxide.