DESC:FIELD OF THE INVENTION

The invention relates to a commercially viable and efficient process for the preparation of 4-Fluoro-2-methyl benzonitrile (1) starting from 2-bromo-5-fluoro toluene (2) by employing a solvent such as N-Methyl-2-pyrrolidone (NMP) as reaction medium for reducing impurity formation during cyanation reaction; thereby leading to substantial yield improvement of 4-Fluoro-2-methyl benzonitrile (1) and subsequently of Trelagliptin (I). Also, the process relates to a selective method for preparation of 2-bromo-5-fluoro toluene (2) by bromination of 3-fluoro toluene (3) with bromine in acetic acid, in presence of catalytic quantities of iron powder and iodine.

BACKGROUND OF THE INVENTION

Trelagliptin of formula (I) in the form of its succinate salt, with proprietary name “Zafatek” is approved for the treatment of type 2 diabetes. The active pharmaceutical ingredient (API), chemically known as 2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxopyrimidin-1-yl]methyl]-4-fluorobenzonitrile is a dipeptidyl peptidase IV (DPP-IV) inhibitor.

Trelagliptin (I)

4-Fluoro-2-methylbenzonitrile of Formula (1) is a key starting material for the synthesis of trelagliptin.

4 -Fluoro-2-methylbenzonitrile (1)

CN102964196 discloses a method for synthesis of 4-fluoro-2-methylbenzonitrile wherein 4-fluoro-2-methylbenzyl alcohol is treated with an oxidant and ammonium hydroxide in the presence of a copper salt catalyst, a co-catalyst, and optionally a ligand. The reaction is carried out at 20-30°C, in presence of 2,2,6,6-tetramethylpiperidine oxide (TEMPO) as the co-catalyst and in presence of either oxygen, air or hydrogen peroxide as the oxidant. A copper salt like cuprous iodide or cuprous chloride and 2,2'-bipyridine or pyridine was employed as the ligand.
CN102964196 discloses that the corresponding benzyl alcohol is oxidized to aldehyde using the reagent TEMPO, followed by amination and oxidation of amide using air or peroxide. However, while the air oxidation is a slow process, use of peroxides imparts the possibility of explosion in large scale operations.

WO2016024224 discloses a process comprising reaction of 4-fluoro-2-methylbenzaldehyde with hydroxylamine hydrochloride to give 4-fluoro-2-methylbenzaldoxime, which after treatment with reagents selected from phosphorous pentoxide, concentrated sulphuric acid and sodium bisulphate monohydrate, using toluene as solvent provides 4-fluoro-2-methylbenzonitrile (1).
WO2016024224 discloses that the benzaldehyde intermediate is converted to an oxime which is treated with bisulfate to give the corresponding nitrile. The formation of the nitrile functional group with the disclosed reagents is quite slow and generates lots of impurities during the reaction.

US 7,795,428 and US 8,288,539 disclose a process for preparation of 4-fluoro-2-methylbenzonitrile (1), involving reaction of 2-bromo-5-fluorotoluene with copper cyanide using a large excess of N,N-dimethylformamide (DMF), about 30 times volume of the substrate, as a solvent. The reaction mixture is refluxed for 24 hours and after completion, the reaction mass is diluted with water and extracted with hexane. Drying, concentration of the hexane layer provides 4-fluoro-2-methylbenzonitrile in a moderate yield of 60%.
The process disclosed in US 7,795,428 has severe limitations such as a lengthy time cycle of more than 24 hours, and a moderate yield of 60%. The inventors, while trying to attempt the said reaction, also observed lot of exothermicity and charring of the reaction mass, which hampered the isolation of desired benzonitrile compound (1) and drastically reduced the yield.
Further, the use of DMF in quite a large excess (about 30 times), coupled with use of low boiling, highly flammable solvent such as hexane and most importantly, moderate yield, made the reaction industrially unviable. Since DMF is a high boiling solvent and used in large excess, it is very difficult to remove traces of DMF from the final product, which hampers the purity of final active pharmaceutical ingredient (API).

CN112573990B discloses preparation of 4-bromo-3-fluorotoluene, by treating 3-fluorotoluene with liquid bromine in dichloroethane, in presence of iron powder as catalyst to give a mixture of 2,4-dibromo-5-fluorotoluene (85%) and 2,6-dibromo-3-fluorotoluene (14%), which on reduction with palladium on carbon provided a mixture of 3-fluorotoluene (25.2%), 2-bromo-5-fluorotoluene (18.4), 4-bromo-3-fluorotoluene (41.4%), 2,4-dibromo-5-fluorotoluene (10.2%) and 2,6-dibromo-3-fluorotoluene (3.6%). The crude mixture was fractionally distilled to get 4-bromo-3-fluorotoluene. Further, the reaction of 3-fluorotoluene with liquid bromine gave a mixture of 2,4-dibromo-5-fluorotoluene and 2,6-dibromo-3-fluorotoluene. There is no disclosure of any selective method for preparation of 2-bromo-5-fluoro toluene from 3-fluoro toluene. Also, the process leads to generation of excess byproduct and preparation of 4-bromo-3-fluorotoluene, and not 2-bromo-5-fluoro toluene.

The present inventors, while working on the various prior art processes and synthetic strategies for preparation of 4-fluoro-2-methylbenzonitrile (1), observed that the said processes were not commercially viable and industrially applicable. The prior art reactions were quite lengthy and cumbersome, involving various intermittent unit steps, tedious purification procedures and thus were not suitable for commercial scale manufacture of the key intermediate (1).

The increasing demand for Trelagliptin necessitates the need for development of an economical method for manufacture of the molecule on an industrial scale. Consequently, while working on robust, commercial process for Trelagliptin, it was imperative for the present inventors to find suitable reaction conditions, appropriate solvents and product isolation methods which can be used on industrial scale, which would provide an economical, yet industrially viable process for the key intermediate 4-fluoro-2-methylbenzonitrile (1); overcoming the limitations of prior art methods.

OBJECT OF THE INVENTION

An objective of the present invention is to provide a robust and economical process for the preparation of 4-fluoro-2-methylbenzonitrile (1).

Another objective of the instant invention is to provide a process for the preparation of 4-fluoro-2-methylbenzonitrile (1) which utilizes N-Methyl-2-pyrrolidone (NMP) as a solvent to reduce the impurity level and obtain the nitrile compound (1) with desired yield and purity, complying with regulatory specifications.

Yet another objective of the instant invention is to provide a process for the preparation of 2-bromo-5-fluoro toluene (2) comprising bromination of 3-fluoro toluene (3) with bromine in acetic acid in presence of iron and iodine.

SUMMARY OF THE INVENTION

An aspect of the invention relates to process for the preparation of 4-fluoro-2-methylbenzonitrile (1).

Yet another aspect of the invention relates to a process for the preparation of 4-fluoro-2-methylbenzonitrile (1) comprising reaction of 2-bromo-5-fluoro toluene (2) with copper cyanide in N-Methyl-2-pyrrolidone (NMP) as solvent, followed by concentration of the reaction mixture, treatment of the distillate with water and filtration to provide 4-fluoro-2-methylbenzonitrile, having desired purity.

Yet another aspect of the instant invention is to provide a process for the preparation of 2-bromo-5-fluoro toluene (2) comprising bromination of 3-fluoro toluene (3) with bromine in acetic acid, in presence of iron and iodine.

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

DETAILED DESCRIPTION OF THE INVENTION

The present inventors, while working on development of an industrially applicable, cost-efficient process for trelagliptin, carried out extensive experimentation for designing and developing a robust process for the key intermediate, 4-fluoro-2-methylbenzonitrile (1). It was surprisingly found that the reaction of 2-bromo-5-fluoro toluene with copper cyanide was quite facile when N-Methyl-2-pyrrolidone (NMP) was used as a solvent. It was observed that the reaction was faster, impurity formation was significantly reduced and moreover, the isolation of final product, 4-fluoro-2-methylbenzonitrile (1) was easier. Consequently, the yield and purity of the nitrile compound (1) were significantly higher as compared to methods reported in prior art.

Inventors of instant invention also worked on various reported methods for preparation of 4-fluoro-2-methylbenzonitrile (1) and carried out experimentation based on disclosures in WO2005095381 A1/ WO2008033851 A2 using DMF as solvent. It was observed that after completion of reaction, addition of water to reaction mass led to a thick emulsion causing difficulties in product isolation. The product was obtained in a yield of only 60% and observed purity was also quite low, around 93-94% (GC). (Please refer to comparative examples, Table 1 on page 13, 14)

It may be noted that the said prior art references are silent about the purity of desired nitrile compound (1).

Similarly, the instant inventors attempted to carry out the cyanation reaction using other solvents such as dimethylacetamide, toluene, acetonitrile etc.; results of which are reported in Table 1 on page 14.
It was observed that in case of solvents like dimethylacetamide, isolation of product was not feasible, whereas more than 50% of the starting material remained unreacted after eight hours of reaction using toluene or acetonitrile as solvents.

In an embodiment of the present invention, the reaction of 2-bromo-5-fluoro toluene (2) with copper cyanide in NMP was carried out in the temperature range of 120°C to 160°C and completion of the reaction was monitored by gas chromatography (GC). After completion of reaction, the reaction mass was distilled to collect the product-enriched fraction in the distillate. The distillate was then treated with water to separate out the final compound (1), which was filtered and dried. The desired compound (1) was obtained in good yield and was also found to have purity as high as = 99% (by GC).

The use of a polar aprotic solvent like NMP was found to be advantageous for the cyanation reaction both in terms of yield and purity. The purity was above 99% with desired impurity profile and the yield was about 15-20% higher than prior art.

Further advantages of instant invention are listed below.
1) As compared to the prior art processes disclosing use of around 28 to 30 volumes of solvent DMF per gram of substrate 2-Bromo-5-fluoro toluene (2) for the cyanation reaction, the present invention utilized very low quantities of solvent NMP.
2) The instant process is carried out using only 1.0 to 2.5 volumes of solvent NMP per gram of the substrate (2).
3) The drastic reduction in the volume of the solvent significantly increases the batch size, reduces the energy requirements and time for isolation of the product, thus improving the commercial viability of the process.
4) The product isolation procedures in reactions using DMF as solvent were associated with emulsion formation, causing difficulties in isolation of the nitrile compound (1), which consequently lowered purity and yield of the product. These major disadvantages of prior art process are avoided by using NMP.
5) In contrast with the reported reactions using DMF, isolation procedure in present process ensures removal of even traces of the high boiling solvent and around 80% recovery of solvent NMP. Thus, in addition to the cost and environment-related benefits, the final compound Trelagliptin (I) is free of residual solvent impurities and also has desired purity.

Scheme-1: Synthesis of 4-Fluoro-2-Methyl benzonitrile (1)

The present invention provides a selective process for preparation of 2-bromo-5-fluoro toluene (2) by bromination of 3-fluoro toluene (3) using bromine in acetic acid, in presence of iron powder and iodine.

In an embodiment, bromination of 3-fluoro toluene (3) to provide 2-Bromo-5-fluoro toluene (2) was carried out using bromine in acetic acid, in presence of iron powder and iodine; wherein both iron and iodine were used in catalytic quantities. The reaction was carried out in the temperature range of -15°C to 35°C. Completion of the reaction was monitored by GC.

The amount of acetic acid utilized was between 0.35 volume and 4.0 volume per gram of 3-fluoro toluene (3).

Bromine used in the reaction was in the range of 1.0 to 2.0 moles per mole of 3-fluoro toluene (3).
After completion of reaction, distillation of the reaction mass, optionally under vacuum, selectively provided 2-Bromo-5-fluoro toluene (2), wherein the other isomers such as 3-Bromo-5-fluoro toluene, 4-Bromo-5-fluoro toluene and 6-Bromo-5-fluoro toluene were less than 5% (by GC).

In yet another embodiment, 2-bromo-5-fluoro toluene (2) was reacted with copper cyanide using NMP as solvent, optionally in presence of an additive such as potassium iodide (KI), to give the key intermediate for trelagliptin, 4-fluoro-2-methylbenzonitrile (1).

In yet another embodiment, 2-Bromo-5-fluoro toluene (2) was treated with copper cyanide using 1.0 to 2.5 volumes of solvent NMP, per gram of the substrate of formula (2), wherein the progress and completion of the reaction were monitored by GC.

In yet another embodiment, the said reaction of 2-bromo-5-fluoro toluene (2) with copper cyanide in NMP was carried out in the temperature range of 120°C to 160°C.
After completion, the reaction mass was distilled under reduced pressure to furnish crude 4-fluoro-2-methylbenzonitrile (1). Further addition of solvent NMP to the reaction mixture followed by distillation provided second crop of the desired compound (1).
The distillates were combined followed by treatment with water, and the resultant product was separated by filtration to provide 4-Fluoro 2-methyl benzonitrile (1), which was then dried under reduced pressure.

4-Fluoro 2-methyl benzonitrile (1) obtained using the embodied process was found to have the desired purity and was used directly for preparation of Trelagliptin, without any further purification.

The advantages of the instant invention over the prior art processes are listed below.
1. Significant reduction in reaction time due to faster and facile reaction. The prior art processes require almost 24 hours for completion whereas the instant reaction is completed in around 8 hours.
2. Control on use of solvent, as compared to prior art processes wherein large excess of DMF is used in the reaction. Higher volumes of DMF were found to give higher range of unidentifiable impurities.
3. Easier isolation of the final compound which involves distillation, collecting the product-enriched fraction and mixing it with water to separate out the product. On the other hand, isolation of the product (1) in prior art processes involved extraction of the reaction mixture with industrially hazardous, low-boiling, flammable solvent like hexane followed by concentration of the organic layer. The reported yield of product (1) using DMF as solvent by prior art processes was around 60%.
4. Substantial yield improvement is observed for the isolated compound (1) having purity greater than 99%. The compound is obtained with a yield of around 75% which is at least 15% higher than prior art methods.
5. The convenient process and reduced cost for the key intermediate, 4-fluoro-2-methylbenzonitrile (1) has a significant positive impact on the production cost of Trelagliptin.
6. Selective and a cost effective process for preparation of 2-bromo-5-fluoro toluene (2) from 3-fluoro toluene (3), without significant formation of undesired regioisomers or mixtures thereof.

All the above listed factors have significant importance in case of industrial scale production of Trelagliptin, wherein higher yield, reduced cycle-time, reduction in number of unit operations and processes for the intermediates cause substantial reduction in overall project cost.

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-Bromo-5-Fluoro toluene (2)
Iron powder (0.22 g) and iodine (0.22 g) were added to a stirred mixture of 3-Fluoro toluene (22.1g) in acetic acid (8.8 ml). The mixture was cooled to -10°C to 0°C, and bromine (41.6 g) in acetic acid (25 ml) was gradually added to it. The reaction mixture was stirred at 25°C to 30°C, till completion of the reaction, as monitored by GC. The resultant reaction mass was distilled to provide 2-Bromo-5-fluoro toluene.
Yield: 26.5 g (70%)
Purity: >95% (GC)

Example 2: Preparation of 4-Fluoro-2-methyl benzonitrile (1)
2-Bromo-5-fluoro toluene (18.9 g) was added to a mixture of N-Methyl-2-pyrrolidone (28 ml) and copper cyanide (10.75 g) and heated at 120°C to 160°C, till completion of the reaction, as monitored by GC.
After completion, the reaction mixture was distilled under reduced pressure to obtain 4-Fluoro-2-methylbenzonitrile which was then stirred with water to separate out the product, which was filtered and dried to provide 4-Fluoro-2-methylbenzonitrile. The product was then used as such for the preparation of trelagliptin.
Yield: 10.14 g (75%)
Purity: >99% (GC)

Example 3: Preparation of 4-Fluoro-2-methyl benzonitrile (1)
2-Bromo-5-fluoro toluene (18.9 g) was added to a mixture of N-Methyl-2-pyrrolidone (28 ml), copper cyanide (10.75 g) and potassium iodide (0.189g) heated at 120°C to 160°C, till completion of the reaction, as monitored by GC.
The reaction mixture was distilled under reduced pressure to obtain 4-Fluoro-2-methylbenzonitrile which was then stirred with water to separate out the product which was filtered to provide 4-Fluoro-2-methylbenzonitrile and dried. The product was then used as such for the preparation of trelagliptin.
Yield: 10.14 g (75%)
Purity: >99% (GC)

Comparative examples:
Details of experiments for preparation of 4-fluoro-2-methylbenzonitrile (1) carried out using different solvents such as N, N-Dimethyl acetamide, toluene, acetonitrile are presented in Table 1. The table also includes experimental details wherein DMF is used as a solvent, as disclosed in prior art references, WO2005095381A1/ WO2008033851A2. Results obtained by using solvent NMP are also incorporated in the table for comparison.

A brief process for preparation of 4-Fluoro 2-methyl benzonitrile (1) based on the method disclosed in WO2005095381A1/ WO2008033851A2 is given below.

A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and copper cyanide (2 g, 22 mmol) in DMF (100 ml) was refluxed for 24 hours. The reaction mixture was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent was removed to give product 4-Fluoro-2-methylbenzonitrile (yield 60%).
Table 1: Comparative examples for preparation of 4-Fluoro-2-methyl- benzonitrile (Compound 1)

Solvent
(Volumes per gram) Temp. (°C) Additive Reaction Time (hrs) Yield (%) Purity
(GC) Comments
N-Methyl-2-pyrrolidone (2vol) 120-160 -------- 8.0 75 99.69 High purity; No purification.
N-Methyl-2-pyrrolidone (2vol) 120-160 KI 8.0 75 99.27 High purity; No purification.
N,N-dimethyl formamide (28.5 V) WO2005095381A1/ WO2008033851A2 153 -------- 24 60 93.91 Emulsion after reaction; Product could not be isolated.
N,N-Dimethyl acetamide (5.0 vol.) 165 -------- 8.0 ------- ------- Product could not be isolated.
N,N-Dimethyl acetamide (5.0 vol.) 165 KI 8.0 ------- ------- Product isolation was not feasible.
Toluene (5.0 vol.) 110 -------- 8.0 ------- ------- More than 50% starting material unreacted.
Toluene (5.0 vol.) 110 KI 8.0 ------- ------- More than 50% starting material unreacted.
Acetonitrile
(5.0 vol) 82 -------- 8.0 ------- ------- More than 50% starting material unreacted.
Acetonitrile
(5.0 vol) 82 KI 8.0 ------- ------- More than 50% starting material unreacted.

,CLAIMS:1. A process for the preparation of 4-fluoro-2-methylbenzonitrile (1) comprising reaction of 2-bromo-5-fluoro toluene (2) with copper cyanide using N-methyl-2-pyrrolidone (NMP) as solvent, followed by isolation of 4-fluoro-2-methylbenzonitrile (1).
2. The process as claimed in claim 1, wherein isolation of 4-fluoro-2-methylbenzonitrile (1) comprises concentration of the reaction mixture, treating the distillate with water and filtration of the resulting solid.
3. The process as claimed in claim 1 wherein the solvent N-methyl-2-pyrrolidone (NMP) is used in the range of 1.0 to 2.5 volumes per gram of 2-bromo-5-fluoro toluene (2).
4. The process as claimed in claim 1 wherein, the reaction is carried out in the temperature range of 120°C to 160°C.
5. A process for preparation of 2-bromo-5-fluoro toluene comprising bromination of 3-fluoro toluene (3) using bromine in acetic acid, in the presence of iron and iodine.
6. The process as claimed in claim 5 wherein, the amount of acetic acid is between 0.35 volume and 4.0 volume per gram of 3-fluoro toluene.
7. The process as claimed in claim 6 wherein, bromine used in the reaction is in the range of 1.0 to 2.0 moles per mole of 3-fluoro toluene (3).