DESC:FIELD OF THE INVENTION

The invention relates to a commercially viable and efficient process for the preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-methyl]-4-fluoro benzonitrile of formula (1) by reaction of 6-chloro-3-methyl uracil (2) with 2-bromomethyl-4-fluorobenzonitrile (3) in presence of a phase transfer catalyst such as tetrabutyl ammonium bromide to control formation of impurities and obtain compound (1) possessing desired purity and yield.

BACKGROUND OF THE INVENTION

Trelagliptin, which is approved as its succinate salt under the trade name “ZAFATEK”, is chemically known as 2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo pyrimidin-1-yl]-methyl]-4-fluorobenzonitrile. It is a dipeptidyl peptidase IV (DPP-IV) inhibitor, indicated for the treatment of type 2 diabetes.

Trelagliptin

The compound, 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl]-4-fluorobenzonitrile (1), is one of the important intermediates in the synthesis of trelagliptin.

2-[(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile (1)

Following synthetic methods are disclosed in the prior art for preparation of compound (1).
WO 2005095381 discloses a method for synthesis of (1), comprising reaction of 6-chloro-3-methyl uracil (2) with 2-bromomethyl-4-fluorobenzonitrile (3) at 60°C, in presence of potassium carbonate using dimethyl sulfoxide (DMSO) as a solvent. After completion of reaction, column chromatographic purification of the obtained residue provides the desired compound in 60% yield.

CN 104402832 discloses a process for synthesis of (1), involving reaction of 2-bromomethyl-4-fluorobenzonitrile (3) with 6-chloro-3-methyl uracil (2), in presence of a catalyst selected from diethyl phosphite, dimethyl phosphite and diphenyl phosphite. The synthetic sequence involves reaction of uracil derivative (2) with the bromomethyl intermediate (3), in N,N-dimethylacetamide (DMAc) as a solvent at 40-800C, in presence of diethyl phosphite, followed by addition of water. After completion of the reaction, gradient crystallization provides the desired benzonitrile-uracil intermediate (1).
WO 2015092805 discloses a method for synthesis of (1) wherein 6-chloro-3-methyl uracil (2) is treated with 2-(chloromethyl)-fluorobenzonitrile, optionally in presence of a catalyst such as sodium or potassium iodide or bromide. It is further mentioned that the reaction involving 2-(bromomethyl)-4-fluorobenzonitrile can also be carried out in the absence of a catalyst. The specification does not provide any information about the yield, purity of the product when the alkylation reaction is carried out either in presence or absence of the catalyst.

The inventors, while working on developing an economical and cost effective process for compound of formula (1), observed that the prior art methods for preparation of compound (1) had following limitations and shortcomings:

1. The reported processes involved lengthy and solvent-intensive column chromatographic separation methods and provided the desired compound (1) in a moderate yield of 60 %, which was not viable on a commercial scale.

2. Some of the processes involved additional purification steps such as gradient crystallization of the final compound which increased the cost on a commercial scale. Apart from excessive use of solvents, the methods exhibited poor reproducibility leading to significant batch to batch variation in the yield and purity of the obtained product.

The increasing demands for Trelagliptin succinate, coupled with the short comings and complexities involved in prior art methods for obtaining better yields and purity profile, necessitated the development of a new, economical method for synthesis of the compound (1), a key intermediate for Trelagliptin.
Consequently, while working on a robust, commercial process for Trelagliptin, it was imperative for the present inventors to develop a convenient and cost-effective synthetic process for the key intermediate (1), namely, 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl] -4-fluoro benzonitrile; overcoming the drawbacks of previously reported processes.

OBJECT OF THE INVENTION

An objective of the present invention is to provide a robust, cost-effective process for preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) methyl]-4-fluorobenzonitrile of Formula (1).

Another objective of the instant invention is to provide a process for 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile (1) comprising use of a phase transfer catalyst for the N-alkylation reaction of uracil derivative (2) and nitrile intermediate (3) to furnish the key intermediate (1) possessing desired purity and impurity profile, in good yield.

SUMMARY OF THE INVENTION

An aspect of the invention relates to a process for the preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile (1) comprising reaction of 6-chloro-3-methyl uracil (2) with 2-bromomethyl-4-fluorobenzonitrile (3) in presence of a phase transfer catalyst, a base and an organic solvent to give compound (1), having desired purity.

An aspect of the invention relates to a process for the preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluoro benzonitrile (1) comprising reaction of 6-chloro-3-methyl uracil (2) with 2-bromomethyl-4-fluorobenzonitrile (3) in presence of tetrabutyl ammonium bromide, a base and an organic solvent, to give intermediate (1), having desired purity.

The objectives of the present invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

While working on development of a commercially viable, cost-effective process for Trelagliptin, the present inventors carried out rigorous and meticulous experimentation for synthesis of the key intermediate, 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile (1).

The inventors serendipitously found that when a phase transfer catalyst (PTC) was employed, N-alkylation reaction of 6-chloro-3-methyl uracil (2) with 2-bromomethyl-4-fluorobenzonitrile (3) was found to proceed faster, along with a significant reduction in formation of impurities. Consequently, it was easier to isolate the N-alkylated intermediate (1) having desired impurity profile without resorting to elaborate purification procedures which also involved significant material loss. This resulted in higher yield and considerable reduction in the project cost as compared to the prior art methods.

The present inventors found that in the absence of PTC, conversion of starting material such as compound (3) in the N-alkylation reaction was very slow and the reaction proceeded with substantial impurity formation. The stubborn, difficult to remove impurities that were formed during reaction necessitated lengthy purification procedures and when such impurities were not eliminated completely, traces of same posed problems in further reactions.
In the alkylation experiments using organic bases such as N,N-diisopropylethylamine, without PTC, after six hours of reaction, impurity formation was as high as 9.10A% (HPLC) whereas one of the starting materials, the nitrile compound (3) was present in the reaction mixture to the extent of 2.64A% (HPLC). HPLC analysis of similar experiment using PTC like tetrabutyl ammonium bromide showed that in 3.5 hours the nitrile compound (3) was reduced to 0.04A% while impurity peak was only 0.17A%.

The same effect of PTC was significantly pronounced in case of inorganic bases like potassium carbonate. The reaction carried out without PTC did not go to completion even after eight hours, showing 60A% of starting material (3) and only 10A% of the product peak in HPLC analysis.

Some of the advantages of instant invention over the prior art processes are listed below.

1. Facile reaction leading to significant yield improvement of 15 to 20%.
2. Control on impurity formation,
3. Easy isolation of the key intermediate (1) with desired purity, without further
elaborate purification procedures,
4. Substantial reduction in overall project cost for Trelagliptin.

Reactions in the instant invention are summarized in the below scheme-1.

Scheme-1: Synthesis of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile (1)

In an embodiment, bromination of 4-fluoro-2-methylbenzonitile (4) was carried out with N-bromosuccinimide, in presence of 2,2’-azobisisobutyronitrile (AIBN), using a solvent selected from halogenated hydrocarbons such as dichloromethane, ethylene dichloride etc.

The reaction was carried out in the temperature range of 35°C to 45°C and completion of the reaction was monitored by HPLC.

After completion of the bromination reaction, diethyl phosphite and diisopropylethylamine were added to the reaction mass and stirring was continued at room temperature till complete conversion of the intermittent dibromo derivative into desired monobromo compound (3).

After completion, an aqueous solution of potassium carbonate was added to the reaction mass. The organic phase was separated and concentrated to provide 2-bromomethyl-4-fluorobenzonitrile (3).

In another embodiment, 2-bromomethyl-4-fluorobenzonitrile (3) so obtained was treated with 6-chloro-3-methyl uracil (2) in presence of a phase transfer catalyst (PTC), a base and an organic solvent.

The phase transfer catalyst was selected from tetra butyl ammonium chloride (TBAC), tetra butyl ammonium bromide (TBAB), benzyltriethyl ammonium chloride, methyl tributyl ammonium chloride, methyltrioctylammonium chloride and mixtures thereof.

The solvent was selected from a group of organic solvents such as tetrahydrofuran, dichloromethane, dimethylformamide, dichloroethane, toluene etc. and mixtures thereof.

The base was selected from organic bases like trimethylamine (TEA), 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA) and mixtures thereof or inorganic bases such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate and mixtures thereof.

The reaction was carried out in the temperature range of 15°C to 70°C wherein completion of the reaction was monitored by HPLC.

After completion of reaction, water was gradually added to the stirred reaction mass, the separated product was filtered and treated with water and isopropyl alcohol (IPA) to give 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile (1), having purity greater than 99% (HPLC).

The intermediate (1) thus obtained, was found to have impurity profile and purity conforming to regulatory limits and was significantly superior to the one obtained by prior art methods in terms of quantitative analysis. The said intermediate (1) was used directly for the preparation of Trelagliptin.

The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES

Example 1: Preparation of 2-Bromomethyl-4-fluorobenzonitrile (3)
N-bromosuccinimide (395.0 g) and 2,2’-azobisisobutyronitrile (AIBN, 24.3g) were added to a stirred mixture of 4-fluoro-2-methylbenzonitrile (4; 200.7g) in dichloromethane (1000 ml). The mixture was stirred at 35°C to 45°C, till completion of the reaction, as monitored by HPLC. After completion of reaction, diethyl phosphite (102.2g) and diisopropylethylamine (38.2g) were added to the reaction mixture and stirring was continued at 20°C to 30°C, till completion of the reaction, as monitored by HPLC. 20% aqueous solution of potassium carbonate was added to the reaction mass with stirring. The organic phase was separated and concentrated to provide 2-bromomethyl-4-fluorobenzonitrile (3).
Yield: 316.2 g (quantitative)
Purity: 95.4% (HPLC)

Example 2: Preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro- pyrimidin-1(2H)-yl) methyl]-4-fluorobenzonitrile (1)
Tetrabutyl ammonium bromide (22.3g) was added to the stirred mixture of 2-bromomethyl-4-fluorobenzonitrile (316.1g), 6-chloro-3-methyl uracil (240.0g), and N,N-diisopropylethylamine (238.5g) in tetrahydrofuran (1010 ml) at 40°C to 50°C. Stirring was continued at 40°C to 50°C, till completion of the reaction, as monitored by HPLC. The mixture was cooled, water was added to the reaction mass and the separated product was filtered.
The wet cake obtained after filtration was treated with water & isopropyl alcohol to give 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-methyl]-4-fluorobenzonitrile (1) which was dried and used in subsequent steps in synthesis of trelagliptin.
Yield: 410.3 g (94.5%)
Purity: 99.3% (HPLC)

Example 3: Preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin -1(2H)-yl) methyl]-4-fluorobenzonitrile (1)
Tetrabutyl ammonium bromide (14g) was added to the stirred mixture of 2-bromomethyl-4-fluorobenzonitrile (200g), 6-chloro-3-methyl uracil (153g), and triethylamine (104g) in tetrahydrofuran (640 ml) at 60°C to 70°C. Stirring was continued at 63°C to 68°C, till completion of the reaction, as monitored by HPLC.
The reaction mixture was cooled, water was added to it with stirring, followed by filtration.
The filtered solid was treated with water & isopropyl alcohol to give 2-[(6-chloro- 3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile (1) which was dried and subsequently used in the preparation of trelagliptin.
Yield: 246g (89.65 %)
Purity: 99.57% (HPLC)
Example 4: Preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin-1(2H)-yl) methyl]-4-fluorobenzonitrile (1)
Tetrabutyl ammonium bromide (0.7g) was added to a mixture of 2-bromomethyl-4-fluorobenzonitrile (10g), 6-chloro-3-methyl uracil (7.65g), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (7.82g) in tetrahydrofuran (32 ml), stirred at 60°C to 70°C. Stirring was continued at 60°C to 70°C, till completion of the reaction, as monitored by HPLC. The reaction mixture was cooled, and water was added to it, followed by filtration of the resulting solid.
The solid was treated with water & isopropyl alcohol to give 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluorobenzonitrile (1) which was dried and subsequently used in the preparation of trelagliptin.
Yield: 11.20g (81.60%)
Purity: 99.02% (HPLC)

Example 5: Preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin -1(2H)-yl) methyl]-4-fluorobenzonitrile (1)
Tetrabutyl ammonium bromide (2.5g) was added to a stirred mixture of 2-bromomethyl-4-fluorobenzonitrile (50g), 6-chloro-3-methyl uracil (38.25g), and N,N-diisopropylethylamine (33.25g) in tetrahydrofuran (160ml). The reaction mixture was stirred at 60°C to 68°C till completion of the reaction, as monitored by HPLC. The reaction mixture was cooled; water was added with stirring and the mass was filtered to separate the product.
The obtained product was treated with water and isopropyl alcohol to give 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluoro-benzo nitrile (1) which was dried and subsequently used in the preparation of trelagliptin.
Yield: 66g (96.2%)
Purity: 99.22% (HPLC).

Example 6: Preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin -1(2H)-yl) methyl]-4-fluorobenzonitrile (1)
Tetrabutyl ammonium bromide (0.7g) was added to the mixture of 2-bromomethyl-4-fluorobenzonitrile (10g), 6-chloro-3-methyl uracil (7.65g), and potassium carbonate (8.07g) in THF (32 ml), stirred at 40°C to 50°C. Stirring was continued at 40°C to 50°C, till completion of the reaction, as monitored by HPLC. The reaction mixture was cooled, water was added with stirring and the mass was filtered.
The solid obtained after filtration was treated with water & isopropyl alcohol to give 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluoro- benzonitrile (1), which was subsequently used in the preparation of trelagliptin.
Yield: 12.0g (87.6 %)
Purity: 99.76% (HPLC)

Example 7: Preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin -1(2H)-yl) methyl]-4-fluorobenzonitrile (1) without using phase transfer catalyst
A mixture of 2-bromomethyl-4-fluorobenzonitrile (10g), 6-chloro-3-methyl uracil (7.65g), and potassium carbonate (8.07g) in THF (32 ml) was stirred at 40°C to 50°C. The reaction was monitored by HPLC.
The HPLC analysis of reaction sample after 8 hours revealed more than 60 area % of the peak for unreacted starting material, 2-bromomethyl-4-fluorobenzonitrile whereas the product peak was around 10 area %.

Example 8: Preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin -1(2H)-yl) methyl]-4-fluorobenzonitrile (1)
Tetrabutyl ammonium bromide (7.0 g) was added to a stirred mixture of 2-bromomethyl-4-fluorobenzonitrile (100.2 g), 6-chloro-3-methyl uracil (76.5g), and N,N-diisopropylethylamine (66.5g) in tetrahydrofuran (320ml). The reaction mixture was stirred at 60°C to 70°C till completion of the reaction, as monitored by HPLC.

The HPLC analysis of intermittent reaction sample taken after 3.5 hours was as follows. 2-bromomethyl-4-fluorobenzonitrile (starting material) - 0.04A%, impurity 0.17A% and the product (compound 1) - 95.62A%

After completion, the reaction mixture was cooled; water was added with stirring and the mass was filtered to separate the product.
The obtained product was treated with water and isopropyl alcohol to give 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluoro-benzo nitrile (1) which was dried and subsequently used in the preparation of trelagliptin.
Yield: 130.3g (94.8%)
Purity: 99.5% (HPLC).

Example 9: Preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin -1(2H)-yl) methyl]-4-fluorobenzonitrile (1)
A mixture of 2-bromomethyl-4-fluorobenzonitrile (50.1 g), 6-chloro-3-methyl uracil (38.3g), and N,N-diisopropylethylamine (33.3g) in tetrahydrofuran (160ml) was stirred at 60°C to 70°C till completion of the reaction, as monitored by HPLC. The reaction mixture was cooled; water was added with stirring and the mass was filtered to separate the product.
The HPLC analysis of intermittent reaction sample taken after 6.0 hours was as follows. 2-bromomethyl-4-fluorobenzonitrile (starting material) - 2.64A%, impurity 9.10A% and the product (compound 1) - 82.94A%
The obtained product was treated with water and isopropyl alcohol to give 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl]-4-fluoro-benzo nitrile (1) which was dried and subsequently used in the preparation of trelagliptin.
Yield: 59.5g (86.9%)
Purity: 99.5% (HPLC).
,CLAIMS:WE CLAIM:
1. A process for the preparation of 2-[(6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2h)-yl)methyl]-4-fluorobenzonitrile (1), comprising reaction of 2-bromomethyl-4-fluorobenzonitrile (3) with 6-chloro-3-methyl uracil (2) in presence of a phase transfer catalyst, a base and an organic solvent.

2. The process as claimed in claim 1 wherein the phase transfer catalyst is selected from tetra butyl ammonium chloride (TBAC), tetra butyl ammonium bromide (TBAB), benzyltriethyl ammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride.

3. The process as claimed in claim 1 wherein the base is selected from triethylamine (TEA), 1, 8-Diazabicyclo(5.4.0)undec-7-ene (DBU), N,N-diisopropylethylamine (DIPEA), sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate.

4. The process as claimed in claim 1 wherein the organic solvent is selected from tetrahydrofuran, dimethylformamide, dichloromethane, dichloroethane, toluene.

5. The process as claimed in claim 1 wherein, 2-Bromomethyl-4-fluorobenzonitrile of formula (3) is prepared by bromination of 4-fluoro-2-methylbenzonitile (4) with 2,2’-N-bromosuccinimide in presence of azobisisobutyronitrile (AIBN) in a halogenated solvent at 35-45°C, followed by treatment with diethyl phosphite and diisopropylethylamine to provide 2-bromomethyl-4-fluorobenzonitrile (3).
6. The process as claimed in claim 5 wherein the halogenated solvent is selected from dichloromethane and ethylene dichloride.