NOVEL PROCESS FOR THE PREPARATION OF 2-CHLORO-4-FLUOROTOLUENE

FIELD OF THE INVENTION

The present invention relates to a novel process for the preparation of 2-chloro-4-fluorotoluene of formula I.

BACKGROUND: 2-chloro-4-fluorotoluene of formula I is a key intermediate for the synthesis of several pharmaceutical, agrochemical, and other important fine chemical products.

For example, saflufenacil, a herbicide, can be prepared using 2-chloro-4-fluorotoluene of formula I. 2-chloro-4-fluorotoluene of formula I is a crucial intermediate in the synthesis of ceritinib, an antineoplastic drug.

2-chloro-4-fluorotoluene of formula I is also useful for the various drugs which are currently at various stages of development.

Several synthetic methods have been reported in literature to prepare 2-chloro-4-fluorotoluene of formula I.

US4912268 discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using ammonium bifluoride in anhydrous hydrogen fluoride, dodecane and a gas mixture of nitric oxide, nitrogen, and oxygen at 80°C to 96°C resulting diazonium salt of 2-chloro-4-aminotoluene of formula II which further decomposes to form 2-chloro-4-fluorotoluene of formula I. The process of US’268 employs f!uoropolymer-lined steel tubular reactor fitted with internal tetrafluoroethylene polymer baffles, thermocouple, bottom-inlet gas sparger and an external pump-fed recirculation loop.

CN108569948B discloses a process for the preparation of 2-chl oro-4-fluorotoluene of formula I, which consists of reacting 2-chl oro-4-anunotoluene of formula III using anhydrous hydrogen fluoride, sodium nitrite at temperature -5°C to 15°C to obtain the diazonium salt, wherein the ratio of diazonium salt to hydrogen fluoride is 1 : 8 to 1:18, followed by thermal decomposition of the diazonium salt in a steps; in first step when the temperature is within the range of 0°C to 20°C, then the temperature is increased by 0.5°C to 1°C per hour, when the temperature is within the range of 20°C to 80°C, then the temperature is increased by 1°C to 2°C per hour, and the temperature is increased to 80°C and kept for 2 hours at 80°C.

CN110759806A discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using anhydrous hydrogen fluoride, sodium nitrite at 0°C followed by pyrolysis in two stages; the first stage is to raise the temperature to 30°C wherein the heating time needs to be controlled between 1.5 hour at a constant rate; and the second stage is to raise temperature from 30°C to 50°C, and the heating time is controlled between 2.5 hour at a constant rate. After pyrolysis, the reaction mixture is kept for 19 hours.

IN201811046158 discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I, which consists of reacting 2-chloro-4-aminotoluene of formula III using aqueous hydrochloric acid, aqueous sodium tetrafluoroborate or aqueous potassium hexafluorophosphate or aqueous fluoroboric acid, and aqueous sodium nitrite at -5°C to 0°C to obtain diazonium salt of 2-chloro- 4-aminotoluene of formula II. The resulting diazonium salt is heated slowly at 110°C to obtain 2- chloro-4-fluorotoluene of formula I.

Thus these are numerous processes available in the literature for the preparation of 2-chloro-4- fluorotoluene of formula I.

However, these processes are associated with certain drawbacks.

The process of US4912268 employs dodecane and nitric oxide gas for the preparation of 2-chloro- 4-fluorotoluene of formula I making the process operation tedious and expensive. Further, the use of specific reactor such as fluoropolymer-lined steel tubular reactor makes the process expensive and industrially not feasible.

The processes of CN108569948B and CN110759806A employ anhydrous hydrogen fluoride which is highly corrosive and requires expensive assets.

Considering the challenges faced, there is a need to develop an alternative process for the manufacture of 2-chloro-4-fluorotoluene of formula I.

The inventors of the present invention provide a novel process for preparing 2-chloro-4- fluorotoluene of formula I, which is simple, requires non-expensive assets and is industrially amenable.

OBJECTS OF THE INVENTION

Some of the objects of the present invention are described herein below:

It is an object of the present invention to ameliorate one or more problems of the prior art or to at least provide a useful alternative.

An object of the present invention is to provide a process for the preparation of 2-chloro-4- fluorotoluene of formula I from 2-chloro-4-aminotoluene of formula III, which employs inexpensive/economic reagents suitable for large scale batch production which avoids the corrosion of the reactor.

Another object of the present invention is to provide a process for the preparation of 2-chloro-4- fluorotoluene of formula I which is simple and requires non-expensive assets.

Yet another object of the present invention is to provide a process for the preparation of 2-chloro- 4-fluorotoluene of formula I at a controlled temperature.

Other objects and advantages of the present invention will be more apparent from the following description which is not intended to limit the scope of the present invention. SUMMARY OF THE INVENTION

The present invention relates to a novel, efficient and industrially advantageous process for the preparation of 2-chloro-4-fluorotoluene of formula I.

A first aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) diazotizing 2-chloro-4-aminotoluene of formula IP using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II; and b) heating the reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II to obtain 2-chloro-4-fluorotoluene of formula I.

Scheme - 1

A second aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) diazotizing 2-chloro-4-aminotoluene of formula IP using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II; b) isolating diazonium salt of 2-chloro-4-aminotoluene of formula II from the reaction mixture; and c) heating isolated diazonium salt of 2-chloro-4-aminotoluene of formula II to obtain 2- chloro-4-fluorotoluene of formula I.

A third aspect of the present invention provides a process for the preparation of 2-chloro-4- fluorotoluene of formula I comprising the steps of: a) mixing 2-chloro-4-aminotoluene of formula III with a fluorinating reagent in the presence of at least one base to obtain a mixture; b) adding a diazotizing reagent to the mixture obtained in step a) at a temperature in the range of 20°C to 140°C to obtain 2-chloro-4-fluorotoluene of formula I.

Scheme - II

DETAILED DESCRIPTION OF THE INVENTION

The present invention discloses a process for the preparation of 2-chloro-4-fluorotoluene of formula I. In accordance with the first aspect of the present invention there is provided a process for the preparation of 2-chloro-4-fluorotoluene of formula I. The process is described herein after:

In step (a) 2-chloro-4-aminotoluene of formula IP is diazotized using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II, and

In step (b), the reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2-chloro-4-fluorotoluene of formula I.

The diazotizing reagent suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.

The fluorinating reagent suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.

The base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole, and Ci to C4 alkyl imidazole.

The molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent used in the step (a) is in the range of 1 : 1 to 1 :2.

The molar ratio of 2-chloro-4-aminotoluene of formula III to the fluorinating reagent used in the step (a) is in the range of 1 :2 to 1 :20.

The molar ratio of 2-chloro-4-aminotoluene of formula III to the base used in the step (a) is in the range of 1:0.8 to 1:10.0.

Specifically, the molar ratio of 2-chloro-4-aminotoluene of formula III to the base used in the step (a) is in the range of 1 : 1 to 1:5.

The diazotization reaction of the step (a) is carried out at a temperature in the range of -10°C to 40°C.

In an exemplary embodiment of the first aspect of the invention, 2-chloro-4-aminotoluene of formula III is first mixed with a fluorinating reagent in the presence of at least one base to obtain a mixture. The mixture thus obtained is mixed lot wise or slowly with the diazotizing reagent at a temperature in the range of -10°C to 40°C.

After completion of the diazotization reaction, the reaction mixture comprising diazonium salt is heated to obtain 2-chloro-4-fluorotoluene of formula I.

In one embodiment of the first aspect, step (b) is carried out by heating the diazonium salt of 2- chloro-4-aminotoluene of formula II in two steps:

1) heating diazonium salt at a rate of 0.5°C to 5.0°C per hour to achieve the temperature in the range of 0°C to 60°C; and

2) heating diazonium salt further at a rate of 1.0°C to 5.0°C per hour to achieve the temperature in the range of 60°C to 140°C.

In the second embodiment of the first aspect, step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II at a rate of 5°C to 10.5°C or more per hour to achieve the temperature in the range of 60°C to 140°C.

After completion of heating, the resulting mixture is cooled. The aqueous and organic layers are separated. The resulting organic layer is washed with an aqueous solution of inorganic base and subjected to distillation to obtain 2-chloro-4-fluorotoluene of formula I.

The excess fluorinating agent may be isolated and recovered.

The inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

In accordance with the second aspect of the present invention there is provided a process for the preparation of 2-chloro-4-fluorotoluene of formula I. The process is described herein after:

In step (a) 2-chloro-4-aminotoluene of formula IP is diazotized using a diazotizing reagent and a fluorinating reagent in the presence of at least one base to obtain a reaction mixture comprising diazonium salt of 2-chloro-4-aminotoluene of formula II.

In step (b) diazonium salt of 2-chloro-4-aminotoluene of formula II is isolated from the reaction mixture. In step (c) isolated diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2- chloro-4-fluorotoluene of formula I.

The diazotizing reagents suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.

The fluorinating reagents suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid.

The base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C4 alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole, and Ci to C4 alkyl imidazole.

The molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent is in the range of 1:1 to 1:2.

The molar ratio of 2-chloro-4-aminotoluene of formula IP to the fluorinating reagent is in the range of 1:2 to 1:20.

The molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1 : 0.8 to 1 : 100

Specifically, the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1:1 to 1:5.

The diazotization reaction is carried out at a temperature in the range of -10°C to 40°C.

In an exemplary embodiment of the second aspect, 2-chloro-4-aminotoluene of formula III is first mixed with a fluorinating reagent in the presence of at least one base to obtain a mixture. The mixture thus obtained is mixed lot wise or slowly with the diazotizing reagent at a temperature in the range of -10°C to 40°C.

After completion of the diazotization reaction, diazonium salt of 2-chloro-4-aminotoluene of formula II is isolated by filtration.

In the subsequent step, the isolated diazonium salt of 2-chloro-4-aminotoluene of formula II is heated to obtain 2-chloro-4-fluorotoluene of formula I. In one embodiment of the second aspect, the step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II in two steps:

1) heating diazonium salt at a rate of 0.5°C to 5.0°C per hour to achieve the temperature in the range of 0°C to 60°C; and

2) heating diazonium salt further at a rate of 1.0°C to 5.0°C per hour to achieve the temperature in the range of 60°C to 140°C.

In the second embodiment of the second aspect, the step (b) is carried out by heating the diazonium salt of 2-chloro-4-aminotoluene of formula II at a rate of 5°C to 10°C or more per hour to achieve the temperature in the range of 60°C to 140°C.

After completion of heating, the resulting mixture is cooled to 20°C to 35°C. The aqueous and organic layers are separated. The resulting organic layer is washed with an aqueous solution of inorganic base and subjected to distillation to obtain 2-chloro-4-fluorotoluene of formula I.

The excess fluorinating agent may be isolated and recovered.

The inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

In accordance with the third aspect of the present invention there is provided a process for the preparation of 2-chloro-4-fluorotoluene of formula I. The process is described herein after:

In step (a) 2-chloro-4-aminotoluene of formula IP is mixed with a fluorinating reagent in the presence of at least one base to obtain a mixture.

In step (b) a diazotizing reagent is added to the mixture of the step (a) at a temperature in the range of 20°C to 140°C to obtain 2-chloro-4-fluorotoluene of formula I.

The diazotizing reagents suitable for the reaction used in the step (a) is selected from the group consisting of sodium nitrite, potassium nitrite, tert-butyl nitrite and isoamyl nitrite.

The fluorinating reagents suitable for the reaction used in the step (a) is selected from the group consisting of anhydrous hydrogen fluoride and tetrafluoroboric acid. The base suitable for the reaction used in the step (a) is selected from the group consisting of pyridine, Ci to C ₄ alkyl pyridine, triethylamine, diisopropylamine, piperidine, /V-methylpiperidine, piperazine, pyrrolidine, imidazole, benzimidazole and Ci to C ₄ alkyl imidazole.

The molar ratio of 2-chloro-4-aminotoluene of formula III to the diazotizing reagent is in the range of 1:1 to 1:2.

The molar ratio of 2-chloro-4-aminotoluene of formula IP to the fluorinating reagent is in the range of 1:2 to 1:20.

The molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1 : 0.8 to 1 : 100

Specifically, the molar ratio of 2-chloro-4-aminotoluene of formula III to the base is in the range of 1:1 to 1:5.

After completion of reaction, the resulting mixture is cool to 20°C to 35°C. The aqueous and organic layers are separated. The resulting organic layer is washed with an aqueous solution of inorganic base and subjected to distillation for obtaining 2-chloro-4-fluorotoluene of formula I.

The excess fluorinating agent may be isolated and recovered.

The inorganic base suitable for washing the organic layer is selected from a group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.

Various features and embodiments of the present invention are illustrated in the following representative examples, which are intended to be illustrative and non-limiting.

EXAMPLES:

Example 1: Preparation of 2-chloro-4-fluorotoluene of formula I

To a stirred solution of anhydrous hydrogen fluoride (70. Og) and pyridine (30. Og), 2-chloro-4- aminotoluene (50.0g) of formula III was added drop wise at -5°C to 15°C. The resulting mixture was then stirred for 3 hours at the same temperature. Sodium nitrite (32. Og) was then added to the resulting mixture lot wise at -5°C to 35°C and stirred for 1 hour to obtain a mixture having diazonium salt of 2-chloro-4-aminotoluene of formula II. The resulting mixture was then heated slowly to achieve the temperature of 90°C. The resulting mixture was cooled to 30°C to 35°C. The layers were then separated and pH of the organic layer was adjusted to neutral pH followed by distillation to obtain 2-chloro-4-fluorotoluene of formula I. Yield: 79.89%, Purity: 98.30%.

Observations: No Corrosion of the Hastelloy C276 reactor observed. Further no tar material was observed.

Example 2: Preparation of 2-chloro-4-fluorotoluene of formula I

To a stirred solution of anhydrous hydrogen fluoride (70. Og) and pyridine (30. Og), 2-chloro-4- aminotoluene (50.0g) of formula III was added drop wise at -5°C to 15°C. The resulting mixture was then stirred for 3 hours at the same temperature. Sodium nitrite (32. Og) was then added to the resulting mixture lot wise at -5°C to 35°C and stirred for 1 hour to obtain a mixture having diazonium salt of 2-chloro-4-aminotoluene of formula II.

The resulting mixture was then heated slowly at a rate of more than 6°C per hour to achieve the temperature of 80°C followed by stirring at 70°C to 80°C to obtain 2-chloro-4-fluorotoluene of formula I. Yield: 72%. Purity: 98.79%.

Observations: No Corrosion of the Hastelloy C276 reactor observed. Further no tar material was observed.

Example 3: Preparation of 2-chloro-4-fluorotoluene of formula I

To a stirred solution of anhydrous hydrogen fluoride (70. Og) and pyridine (30. Og), 2-chloro-4- aminotoluene (50.0g) of formula III was added drop wise at -5°C to 15°C. The resulting mixture was then stirred for 3 hours at the same temperature. Sodium nitrite (32. Og) was then added to the resulting mixture lot wise at -5°C to 35°C and stirred for 1 hour to obtain a mixture having diazonium salt of 2-chloro-4-aminotoluene of formula II.

The resulting mixture was then heated slowly to achieve the temperature of 70°C to 80°C. The resulting mixture was cooled to 30°C to 35°C. The layers were then separated and pH of the organic layer was adjusted to neutral pH followed by distillation to obtain 2-chloro-4-fluorotoluene of formula I. Yield: 64.0% Purity: 98.65%. Observations: No Corrosion of the Hastelloy C276 reactor observed. Further no tar material was observed.

Comparative Example 1: Preparation of 2-chloro-4-fluorotoluene of formula I

To a stirred solution of anhydrous hydrogen fluoride (70. Og), and pyridine (lg), 2-chloro-4- aminotoluene (50.0g) of formula III was added drop wise at -5°C to 15°C. The resulting mixture was then stirred for 3 hours at the same temperature. Sodium nitrite (26. Og) was then added to the resulting mixture lot wise at -5°C to 35°C and stirred for 1 hour to obtain a mixture having diazonium salt of 2-chloro-4-aminotoluene of formula II.

The resulting mixture was then heated slowly to achieve the temperature of 60°C. The resulting mixture was cooled to 30°C to 35°C. The layers were then separated and pH of the organic layer was adjusted to neutral pH followed by distillation to obtain 2-chloro-4-fluorotoluene of formula I. Yield: 57.8%, Purity: 83.84%.

Observations: Heavy Corrosion of the Hastelloy C276 reactor observed when lg (2% w/w) pyridine is used. Further heavy tar material inside the reactor was observed.

The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.

The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

While considerable emphasis has been placed herein on the particular features of this invention, it will be appreciated that various modifications can be made, and that many changes can be made in the preferred embodiments without departing from the principles of the invention. These and other modifications in the nature of the invention or the preferred embodiments will be apparent to those skilled in the art from the invention herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.