DESC:Field of the Invention
The present invention relates to an intermediate of Tazemetostat, and more particularly to a process for preparation of alkyl 3-amino-5-bromo-2-methyl-benzoate.

Background and prior art
Alkyl 3-amino-5-bromo-2-methyl-benzoate of formula I, is a key intermediate used in the preparation of Tazemetostat.

wherein, R is optionally substituted lower alkyl, particularly C1-C4 alkyl.

Tazemetostat is a histone methyl transferase inhibitor with potential antineoplastic activity. It is orphan drug used for the treatment of patients with soft tissue sarcoma. It is specifically used for the treatment of soft tissue sarcoma and malignant rheumatoid tumors. Alkyl 3-amino-5-bromo-2-methyl-benzoate (I) is a key intermediate used in the synthesis of Tazemetostat.
There are known methods for the synthesis of methyl 3-amino-5-bromo-2-methyl-benzoate. Said methods involve reduction of methyl-5-bromo-2-methyl-3-nitrobenzoate in ethanol using iron powder in presence of ammonium chloride, and herein the amino compound was extracted with ethyl acetate. Other similar methods include reduction of methyl-5-bromo-2-methyl-3-nitrobenzoate using iron powder and the yield reported is in the range of 80-90%. However the problem associated with use of iron powder in the process is formation of insoluble iron oxide sludge. Thus the processes disclosed above are not eco-friendly and ends up with more solid waste and disposing of the iron oxide sludge raises the environmental problems. Also the recovery of catalyst is not possible and hence cost of the process remains high.

Further, conventionally known processes also include de-bromination of alkyl 3-niro-5-bromo-2-methyl-benzoate, which results in yield loss and impurity formation. Accordingly, there is a need for a process for preparation of alkyl 3-amino-5-bromo-2-methyl-benzoate which is eco-friendly, cost-effective and that selectively reduces nitro group and minimizes de-halogenation side reaction, thereby giving desired yield and purity.

Summary of the invention
In one aspect the present invention provides a process for preparation of a compound of formula I. The process comprises the step of hydrogenating a compound of formula II in presence of a predefined metal catalyst and wherein ‘R’ is optionally substituted lower alkyl, particularly C1-C4 alkyl, preferably ‘R’ is a methyl group. The compound of formula I is alkyl-3-amino-5-bromo-2-methyl-benzoate, preferably methyl-3-amino-5-bromo-2-methyl-benzoate. The metal catalyst is selected from ruthenium, rhodium, palladium, platinum and nickel, wherein the metal catalyst is a bimetallic catalyst. The bimetallic catalyst is a platinum catalyst alloyed with copper and supported on carbon composed of 1% to 2% platinum and 0.1% to 0.2% copper supported on carbon. The catalyst is in a range of 1% to 2% platinum and 0.1% to 0.2% copper supported on 97.8% - 98.9% carbon. The catalyst is used on wet basis, wherein the wet basis is in a range of 10% to 70% wet basis. The hydrogenation reaction is carried out under hydrogen pressure of 3-15 kg/Cm2, preferably under hydrogen pressure of 5-12 kg/Cm2. The hydrogenation reaction is carried out at 30°C to 100°C, preferably at 40°C to 60°C, more preferably at 45°C to 55°C. The hydrogenation reaction is carried out in a solvent selected from alcoholic solvent and hydrocarbon solvent. The alcoholic solvent is selected from methanol, ethanol, isopropanol and the hydrocarbon solvent is selected from, benzene, dioxane, toluene, xylene and heptane.

In an embodiment, the compound of formula I is alkyl-3-amino-5-bromo-2-methyl-benzoate, preferably methyl-3-amino-5-bromo-2-methyl-benzoate.

In an embodiment, the present invention relates to a process for preparation of alkyl-3-amino-5-bromo-2-methyl-benzoate that comprises hydrogenating alkyl-3-nitro-5-bromo-2-methyl-benzoate of formula II in presence of a predefined metal catalyst to obtain alkyl-3-amino-5-bromo-2-methyl-benzoate of formula I, wherein ‘R’ is optionally substituted lower alkyl, particularly C1-C4 alkyl.

In an embodiment, the present invention relates to a process for preparation of methyl-3-amino-5-bromo-2-methyl-benzoate that comprises hydrogenating methyl-3-nitro-5-bromo-2-methyl-benzoate in presence of a predefined metal catalyst.

In yet another aspect, the present invention provides a process for preparation of a compound of formula II. The process comprises methylating a compound of formula III with thionyl chloride in a predefined solvent to form a compound of formula IV; and brominating the compound of formula IV using a predefined brominating agent to form the compound of formula II. The methylation is carried out at 10°C to 40°C, preferably at 20°C to 40°C, more preferably at 25°C to 30°C. Methylation reaction is carried out in methanol. The bromination reaction is carried out at 20°C to 45°C, preferably at 30°C to 40°C, more preferably at 36°C to 38°C.The bromination reaction is carried in presence of brominating agent selected from dibromodimethyl hydantoin and N-bromosuccinamide.

In an aspect, a compound of formula I is prepared by the process of hydrogenating a compound of formula II in presence of a predefined metal catalyst, and wherein ‘R’ is optionally substituted lower alkyl, particularly C1-C4 alkyl, preferably ‘R’ is a methyl group. The compound of formula I is alkyl-3-amino-5-bromo-2-methyl-benzoate, preferably methyl-3-amino-5-bromo-2-methyl-benzoate.

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.

In general aspect, the present invention provides a process for the preparation of a compound of formula I.

In an embodiment, the present invention relates to a process for the preparation of a compound of formula I. The process comprising the steps of:
a) hydrogenating a compound of formula II in presence of a predefined metal catalyst,
wherein ‘R’ is optionally substituted lower alkyl, particularly C1-C4 alkyl.

In this embodiment, ‘R’ is selected from the alkyl groups selected from methyl, ethyl, propyl or butyl. The metal catalyst is selected from bimetallic catalyst, ruthenium, rhodium, palladium, platinum, copper and nickel, preferably platinum and copper. The metal catalyst used in the reaction is supported on activated carbon, silica, alumina, zirconium oxide and titanium oxide. The metal catalyst is a bimetallic catalyst. The bimetallic catalyst is composed of platinum catalyst alloyed with copper and supported on 98.9% carbon. The platinum and copper alloy in a typical composition loaded on carbon. The catalyst is composed of 1% to 2 % platinum and 0.1% to 0.2% copper loaded on carbon. The catalyst is used on wet basis, preferably 10% to 70% wet basis, more preferably 50% wet basis. The composition of the alloy plays an important role in the reaction and it broadly depends on substrate.

In this embodiment, the hydrogenation reaction is carried out at 30°C to 100°C, preferably at 40°C to 60°C, more preferably at 45°C to 55°C. Said hydrogenation reaction is carried out in a solvent selected from alcoholic solvent and hydrocarbon solvent. The alcoholic solvent is selected from methanol, ethanol, isopropanol and the hydrocarbon solvent is selected from, benzene, dioxane, toluene, xylene and heptane. The hydrogenation reaction is carried out under hydrogen pressure 3-15 kg/Cm2, preferably at 5-12 kg/Cm2.

In an embodiment, the compound of formula I is alkyl-3-amino-5-bromo-2-methyl-benzoate , preferably methyl-3-amino-5-bromo-2-methyl-benzoate.

In an embodiment, the present invention relates to a process for preparation of alkyl-3-amino-5-bromo-2-methyl-benzoate of formula I comprising the step of hydrogenating alkyl-3-nitro-5-bromo-2-methyl-benzoate of formula II in presence of a predefined metal catalyst to obtain alkyl-3-amino-5-bromo-2-methyl-benzoate of formula I.

wherein R is optionally substituted lower alkyl, particularly C1-C4 alkyl.

In this embodiment, the metal catalyst is selected from bimetallic catalyst, ruthenium, rhodium, palladium, platinum, copper and nickel, preferably platinum and copper. The metal catalyst used in the reaction is supported on activated carbon, silica, alumina, zirconium oxide and titanium oxide. The metal catalyst is a bimetallic catalyst. The bimetallic catalyst is composed of platinum catalyst alloyed with copper and supported on 98.9% carbon. The platinum and copper alloy in a typical composition loaded on carbon. The catalyst is composed of 1% to 2 % platinum and 0.1% to 0.2% copper loaded on carbon. The catalyst is used on wet basis, preferably 10% to 70% wet basis, more preferably 50% wet basis. The composition of the alloy plays an important role in the reaction and it broadly depends on substrate.

In this embodiment, the hydrogenation reaction is carried out at 30°C to 100°C, preferably at 40°C to 60°C, more preferably at 45°C to 55°C. Said hydrogenation reaction is carried out in a solvent selected from alcoholic solvent and hydrocarbon solvent. The alcoholic solvent is selected from methanol, ethanol, isopropanol and the hydrocarbon solvent is selected from, benzene, dioxane, toluene, xylene and heptane. The hydrogenation reaction is carried out under hydrogen pressure 3-15 kg/Cm2, preferably at 5-12 kg/Cm2.

In a preferred embodiment, a process for the preparation of methyl-3-amino-5-bromo-2-methyl-benzoate is disclosed. The process comprising a step of:
a) hydrogenating methyl-3-nitro-5-bromo-2-methyl-benzoate in presence of a predefined metal catalyst to obtain methyl-3-amino-5-bromo-2-methyl-benzoate.

In this preferred embodiment, the metal catalyst is selected from ruthenium, rhodium, palladium, platinum and nickel, preferably platinum. The metal catalyst used in the reaction is supported on activated carbon, silica, alumina, zirconium oxide and titanium oxide. The reaction is carried out in presence of platinum catalyst in methanol. The platinum metal catalyst is a bimetallic catalyst. The bimetallic catalyst is composed of platinum catalyst alloyed with copper and supported on 98.9% carbon. The platinum and copper alloy in a typical composition loaded on carbon. The catalyst is composed of 1% to 2% platinum and 0.1% to 0.2% copper loaded on carbon. The catalyst is used on wet basis, preferably 10% to 70% wet basis, more preferably 50% wet basis. The composition of the alloy plays an important role in the reaction and it broadly depends on substrate. The hydrogenation reaction is carried out at 30-100°C, preferably at 40-60, more preferably at 45°C to 55°C. The hydrogenation reaction is carried out in a solvent selected from alcoholic solvent and hydrocarbon solvent. The alcoholic solvent is selected from methanol, ethanol, isopropanol and the hydrocarbon solvent is selected from, benzene, dioxane, toluene, xylene and heptane. The hydrogenation reaction is carried out under hydrogen pressure 3-15 kg/Cm2, preferably at 5-12 kg/Cm2.

In an embodiment, the metal catalyst used is bimetallic catalyst. The bimetallic catalyst is composed of platinum catalyst alloyed with copper and supported on Carbon. The Pt and Cu alloy in a typical composition loaded on carbon. The catalyst is composed of 1% to 2% Pt and 0.1% to 0.2% copper loaded on 97.8% - 98.9% carbon. The catalyst is used on wet basis, preferably 10-70% wet basis. The composition of the alloy plays an important role in the reaction and it broadly depends on substrate.

In an embodiment, the bimetallic catalyst is composed of 1% to 2% platinum and 0.1% to 0.2 % copper supported on 97.8% - 98.9% carbon. The bimetallic catalyst is used as 10% to 70% wet basis, preferably used as 50% wet basis.

In an embodiment, the preferred composition of the modified bimetallic catalyst is 1% platinum, 0.1% copper and 98.9% carbon on 50% wet basis.

In an embodiment, the hydrogenation reaction is carried out at 30°C to 100°C, preferably at 40°C to 60°C, more preferably at 45°C to 55°C.

In an embodiment hydrogenation reaction is carried out in a solvent selected from alcoholic solvent and hydrocarbon solvent.

In an embodiment, the alcoholic solvent is selected from methanol, ethanol, isopropanol and the hydrocarbon solvent is selected from, benzene, dioxane, toluene, xylene and heptane.

In an embodiment, the hydrogenation reaction is carried out under hydrogen pressure 3-15 kg/Cm2, preferably at 5-12 kg/Cm2.
In an embodiment, a compound of formula I is prepared by the process of hydrogenating a compound of formula II in presence of a predefined metal catalyst, and wherein ‘R’ is optionally substituted lower alkyl, particularly C1-C4 alkyl, preferably ‘R’ is a methyl group. The compound of formula I is alkyl-3-amino-5-bromo-2-methyl-benzoate, preferably methyl-3-amino-5-bromo-2-methyl-benzoate.

In another embodiment, a process for the preparation of a compound of formula II is disclosed. The process comprising the steps of:
a) methylating a compound of formula III with thionyl chloride in a predefined solvent to form a compound of formula IV; and

b) brominating the compound of formula IV using a predefined brominating agent to form a compound of formula II.

In this preferred embodiment, the compound of formula II is methyl-3-nitro-5-bromo-2-methyl-benzoate. The compound of formula III is 2-methyl-3-nitrobenzoic acid. The compound of formula IV is methyl 2-methyl-3-nitro-benzoate. The compound of formula II is methyl-3-nitro-5-bromo-2-methyl-benzoate. Step a) is carried out at 10°C to 40°C, preferably at 20°C to 40°C, more preferably at 25°C to 30°C. The step a) reaction is carried out in an alcoholic solvent methanol. Step b) is carried out at 20°C to 45°C, preferably at 30°C to 40°C, more preferably at 36°C to 38°C, Step b) is carried out using the brominating agent dibromodimethyl hydantoin, N-bromosuccinamide in sulfuric acid, in a solvent selected from toluene, chlorinated solvent such as methylene dichloride.

In an embodiment, the compound of formula II is methyl-3-nitro-5-bromo-2-methyl-benzoate.

The reaction scheme for a process for preparation of compound of formula II is represented as follows:

In an embodiment, methylation is carried out at 10°C to 40°C, preferably at 20°C to 40°C, more preferably at 25°C to 30°C.
In an embodiment, methylation reaction is carried out in an alcoholic solvent methanol.
In an embodiment, bromination is carried out at 20°C to 45°C, preferably at 30°C to 40°C, more preferably at 36°C to 38°C.
In an embodiment, bromination is carried out using the brominating agent selected from dibromodimethyl hydantoin, N-bromosuccinamide in sulfuric acid, in a solvent selected from toluene, chlorinated solvent such as methylene dichloride.
The following examples illustrate the invention, but are not limiting thereof.
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 methyl- 2-methyl-3-nitro-benzoate (Formula IV)
2-methyl-3-nitro benzoic acid (200 g) was charged to methanol (1860 ml ) at 25-30°C and stirred. Dimethyl formamide (10 ml) was added to the mixture at 25-30°C. Thionyl chloride (143 gm) was added slowly at 25-30°C in one hour. The mixture was stirred for 30 minutes at 25-30°C. The mass was slowly heated to 68-70°C and maintained for 6 hours. The solvents were distilled off under pressure at 25-30°C. MDC (1000 ml) was charged and the mass was stirred till clear solution is obtained.Water (1000 ml) was added and stirred for 30 minutes and the layers were separated. MDC layer was added to 10% sodium bicarbonate (1000 ml) and stirred for 30 minutes. The layers were separated and aqueous layer was extracted with MDC (400 ml). The collective organic layer was dried over sodium sulfate and is taken for further reaction.

Example 2
Methyl -5-bromo-2-methyl-3-nitro-benzoate (Formula II)
Concentrated sulfuric acid (240 ml) was added to the MDC layer obtained in example 1 and mixture was stirred for 30 minutes. The mixture was heated to 36-38°C and n-bromosuccinamide (220 g) was added lot wise with 30 minutes intervals. The temperature was maintained below 40°C for 24 hours. The reaction mass was cooled to 25-30°C. Water (1200 ml) was cooled to 5-10°C and the reaction mass obtained was charged dropwise. MDC layer was separated and extracted with water (500 ml). MDC layer was washed with 1% sodium bisulfite solution (800 ml) and stirred for 1 hour. Separated MDC layer was washed with 10% sodium bicarbonate solution (400 ml x 2) with stirring for 1 hour every time. MDC layer was washed with 10% brine solution (530 ml). The MDC layer was dried over sodium sulfate and concentrated under reduced pressure at 25-30°C. Methanol (600 ml) was charged in the mass and heated to 35-40°C and water (400 ml) was added. The mass was cooled to 20°C and maintained for 2 hours. The solid obtained was filtered and suck dried. The solid was washed with n-heptane and stirred for 1 hour to obtain Methyl 5-bromo-2-methyl-3-nitro-benzoate (180 g). HPLC purity: 99.6%

Example 3
Methyl-3-amino-5-bromo-2-methyl-benzoate
Methyl 5-bromo-2-methyl-3-nitro-benzoate (50 g) obtained in example 2 was charged in methanol (200 ml). Catalyst with the composition 1% pt with 0.1% copper on carbon (2 g) was charged in reaction mixture at room temperature. Nitrogen pressure 2 kg/Cm2 was applied and autoclave was flushed 2-3 times with nitrogen. Autoclave was flushed by hydrogen gas 2-3 times at room temperature and 8 kg/Cm2 pressure of hydrogen was applied at room temperature. Exotherm was observed and temperature was maintained at 48-52°C till completion of reaction. The reaction mass was cooled and filtered and catalyst was recovered. The reaction mass was filtered on hyflow bed and washed with methanol (50 ml). Methanol was distilled out under vacuum to get residue. Toluene (150 ml) and active charcoal (5 gm) was charged to the residue at room temperature. Reaction mass was stirred and temperature was raised to 45-50°C and maintained for 1 hour. The mass was filtered through hyflow bed and washed with toluene (50 ml). Filtrate was collected and toluene was distilled under vacuum to get solid residue. The mass was cooled and n-heptane (100 ml) was charged and mass was stirred for 1 hour. The solid was filtered and wet cake was washed with n-heptane (50 ml). HPLC purity: 99.9%

Example 4
Methyl-3-amino-5-bromo-2-methyl-benzoate
Methyl 5-bromo-2-methyl-3-nitro-benzoate (100 g) was charged in methanol (300 ml). Catalyst with the composition 1% pt with 0.1% copper on carbon (2 g) was charged in reaction mixture at room temperature. Nitrogen pressure 2 kg/Cm2 was applied and autoclave was flushed 2-3 times with nitrogen. Autoclave was flushed gas 2-3 times with hydrogen at room temperature and 6 kg/Cm2 pressure of hydrogen was applied at room temperature. Exotherm was observed and temperature was maintained at 48-55°C till completion of reaction. The reaction mass was cooled and filtered and catalyst was recovered. The reaction mass was filtered on hyflow bed and washed with methanol (50 ml). The methanol filtrate was charcolized with activated charcoal (5gm x 2) at room temperature. The methanol filtrate was added in water (1000 ml) and stirred for 3 hours at room temperature. The slurry was filtered and washed with water (200 ml). The compound was suck dried well and charged to n-heptane (200 ml). The solution was stirred for 1 hour at room temperature. The slurry was filtered and wet cake was washed with n-heptane (100 ml). The compound was dried to obtain methyl-3-amino-5-bromo-2-methyl-benzoate (70 g). HPLC purity: 99.95%
In accordance with an embodiment of the present invention, the process of the present invention is an eco-friendly and a cost effective process. The process of the present invention eliminates the need of disposal of solid waste and iron oxide sludge. The process of the present invention aids recovery of catalyst which can be reused in the reduction reaction. The process of the present invention minimizes and/or avoids de-bromination of methyl 3-niro-5-bromo-2-methyl-benzoate. The process of the present invention results in high yield of the end product of the present invention with maximum 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. A process for the preparation of a compound of formula I
,
wherein ‘R’ is optionally substituted lower alkyl, particularly C1-C4 alkyl, comprising the step of hydrogenating a compound of formula II in presence of a predefined metal catalyst.

2. The process as claimed in claim 1, wherein ‘R’ is a methyl group.
3. The process as claimed in claim 1, wherein the metal catalyst is selected from ruthenium, rhodium, palladium, platinum and nickel.
4. The process as claimed in claim 3, wherein the metal catalyst is a bimetallic catalyst.
5. The process as claimed in claim 4, wherein the bimetallic catalyst is a platinum catalyst alloyed with copper and supported on carbon.
6. The process as claimed in claim 5 wherein the bimetallic catalyst is composed of 1% to 2% platinum and 0.1% to 0.2% copper supported on carbon.
7. The process as claimed in claim 1, wherein the catalyst is in a range of 1% to 2% platinum and 0.1% to 0.2% copper supported on 97.8% - 98.9% carbon.
8. The process as claimed in any of the preceding claim, wherein the catalyst is used on wet basis, wherein the wet basis is in a range of 10% to 70% wet basis.
9. The process as claimed in claim 1, wherein the hydrogenation reaction is carried out under hydrogen pressure of 3-15 kg/Cm2.
10. The process as claimed in claim 9, wherein the hydrogenation reaction is carried out under hydrogen pressure of 5-12 kg/Cm2.
11. The process as claimed in claim 1, wherein the hydrogenation reaction is carried out at 30°C to 100°C.
12. The process as claimed in claim 11, wherein the hydrogenation reaction is carried out at 40°C to 60°C.
13. The process as claimed in claim 11 and 12, wherein the hydrogenation reaction is carried out at 45°C to 55°C.

14. The process as claimed in claim 1, wherein the hydrogenation reaction is carried out in a solvent selected from alcoholic solvent and hydrocarbon solvent.
15. The process as claimed in claim 14, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol and the hydrocarbon solvent is selected from, benzene, dioxane, toluene, xylene and heptane.
16. The process as claimed in claim 1, wherein the compound of formula I is methyl-3-amino-5-bromo-2-methyl-benzoate.

17. A process for the preparation of compound of formula II as claimed in claim 1 comprising the steps of:
a) methylating a compound of formula III with thionyl chloride in a predefined solvent to form a compound of formula IV; and

b) brominating the compound of formula IV using a predefined brominating agent .

18. The process as claimed in claim 17, wherein the compound of formula II is methyl-3-nitro-5-bromo-2-methyl-benzoate.

19. The process as claimed in claim 17, wherein the step a) methylation is carried out at 10°C to 40°C.
20. The process as claimed in claim 17, wherein the step a) methylation is carried out at 20°C to 40°C.
21. The process as claimed in claim 17, wherein the step a) methylation is carried out at 25°C to 30°C.
22. The process as claimed in claim 17, wherein the step a) methylation reaction is carried out in methanol.
23. The process as claimed in claim 17, wherein the step b) bromination reaction is carried out at 20°C to 45°C.
24. The process as claimed in claim 17 and claim 23, wherein the step b) bromination reaction is carried out at 30°C to 40°C.
25. The process as claimed in claim 17 and 23-24, wherein the step b) bromination reaction is carried out at particularly at 36°C to 38°C.
26. The process as claimed in claim 17, wherein the step b) bromination reaction is carried in presence of brominating agent selected from dibromodimethyl hydantoin and N-bromosuccinamide.
27. A compound of formula I is prepared by the process as claimed in any of the preceding claims 1 to 26.