DESC:FIELD OF THE DISCLOSURE:

The present disclosure relates to a process for synthesizing 2-bromo-4-methyl phenol.

BACKGROUND:

2-bromo-4-methyl phenol is an intermediate used in the synthesis of various drugs/chemicals.
Synonyms:
2-Bromo-4-cresol; 2-Bromo-p-cresol; 3-Bromo-4-hydroxytoluene

Molecular Formula: C7H7BrO

CAS No: 6627-55-0

Molecular weight: 187.03

It is known that the chlorination of 4-methyl phenol give 2-chloro-4-methyl phenol. The synthesis 2-chloro-4-methyl phenol is carried out using various solvents in the presence of Lewis acid catalyst. However, the selectivity of the process is poor even if the molar ratio of chlorine to 4-methyl phenol is strictly maintained at 1:1. It has been observed that undesired 3-chloro-4-methyl phenol is also formed along with desired 2-chloro–4-methyl phenol. The selectivity for the desired 2-chloro isomer ranges between 60 % and 80 %.

High selectivity (up to 95%) of the desired 2-chloro isomer is achieved by using carbon disulfide as a solvent during the chlorination reaction without using a catalyst. However, the drawback associated with this process is that the carbon disulfide is a very hazardous chemical and generally not suitable as a industrially usable solvent as it is highly flammable and toxic.

Chlorination of 4-methyl phenol with chlorine gas without using a solvent is further disclosed in US Patent No. 2494993. The yield and purity of the product obtained by the process disclosed in US Patent No. 2494993 are low. Further, the process requires an additional stage of distillation which renders the process uneconomical.

Various catalysts such as organic compound of the elements of main groups V, VI, and VII of the Periodic Table of the elements or the use of a primary, secondary or tertiary amine (US Patent No.5149858 or US Patent No.4876396) have been reported to promote ortho-chlorination of phenols.

In view of the above, it can be concluded that the chlorination reaction of phenol has low selectivity for 2-chloro isomers. The chlorination reaction is also associated with drawbacks of low purity of the product and complex work up process.

Considering the drawbacks associated with the chlorination of phenols, it is desired to provide a substitution reaction for the chlorination reaction. One of the approaches can be selective bromination of phenols instead of chlorination based on the understanding that the two products namely 2-chloro-4-methyl phenol and 2-bromo 4-methyl phenol can be used interchangeably as an intermediate for the preparation of crop protection agents, pharmaceuticals and specialty chemicals.

Accordingly, the present disclosure provides a process for synthesizing 2-bromo-4-methyl phenol that obviates the drawbacks associated with the prior art processes.

OBJECTS:

Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:

It is an object of the present disclosure to provide a process for the synthesis of 2-bromo-4-methyl phenol.

It is an object of the present disclosure to provide a process for the synthesis of 2-bromo-4-methyl phenol which is highly selective.

It is still another object of the present disclosure to provide a high yielding process for the synthesis of 2-bromo-4-methyl phenol.

It is still another object of the present disclosure to provide a simple and safe process for the preparation of 2-bromo-4-methyl phenol.

It is an object of the present disclosure to provide a process for the synthesis of 2-bromo-4-methyl phenol which does not require complex work up and purification operations.
Other objects and advantages of the present disclosure will be more apparent from the following description, which are not intended to limit the scope of the present disclosure.
SUMMARY

The present disclosure provides a process for the synthesis of 2-bromo-4-methyl phenol; said process comprises brominating 4-methyl phenol in the absence of light in a solvent using a brominating agent at a temperature ranging from 200C to 400C.

In one embodiment the bromination is carried in the presence of at least one Lewis acid. Typically, the Lewis acid is methane sulfonic acid.
Typically, the amount of the Lewis acid used is in the range of 0.1 to 10 % by weight of 4-methyl phenol.

Typically, the brominating agent is selected from the group consisting of bromine, HBr/H2O2, HBr/NaNO2 and combinations thereof.

Typically, the amount of the brominating agent ranges from 1 to 1.5 mole per mole of 4-methyl phenol, preferably 1.0 to 1.05 mole per mole of 4-methyl phenol.

Typically, the purity of 2-bromo-4-methyl phenol is >99.5 %.

Typically, the selectivity of formation of 2-bromo-4-methyl phenol is at least 84 %.
Typically, the solvent is selected from the group consisting of carbon tetrachloride, chloroform, methane sulfonic acid, trifilic acid, chloro benzene and combinations thereof.

Typically, the amount of solvent ranging from 250 to 3000 ml per mole of 4-methyl phenol.

DETAILED DESCRIPTION:

Bromination of p-cresol to form 2 - bromo-4 – methylphenol has been disclosed in the few prior art documents.
For instance, CN102766028 discloses bromination of p-cresol using bromine in the presence of a solvent such as methylene chloride and chloroform. The bromination is particularly carried out at -5 to 100C.
Furthermore, CN101279896 discloses bromination of p-cresol using bromine in the presence of a solvent such as dichloroethane and chlororform. The 2-bromine-4-methylphenol generated by said method is avoided to come in contact with the bromine, thereby reducing the side reaction. The bromination reaction as per CN101279896 is carried out at a low temperature. Particularly, the reaction temperature is controlled at -10 to -5oC.

The processes disclosed in the prior art are carried out at a very low temperature. The present disclosure provides an alternative, simple and high yielding process for the preparation of 2-bromine-4-methylphenol which can be carried out at room temperature and which exhibit high selectivity towards the formation of 2-bromo-4-methyl phenol.
The process according to the present disclosure is particularly carried out in the absence of light i.e. the reaction is carried out in a reactor which is protected from light. Thus, the process of the present disclosure avoids the side reactions. The process of the present disclosure can also be carried out in the presence of at least one Lewis acid. The Lewis acid is methane sulfonic acid.
The amount of the Lewis acid used is in the range of 0.1 to 10 % by weight of 4-methyl phenol.

The process involves brominating 4-methyl phenol in the absence of light in a solvent using a brominating agent at a temperature ranging from 200C to 400C.

The brominating agent suitable for brominating 4-methyl phenol includes but is not limited to molecular bromine, HBr/H2O2, HBr/NaNO2, combinations thereof and the like. The amount of the brominating agent used ranges from 0.5 to 1.5 mole per mole of 4-methyl phenol. To avoid dibromination or formation of undesired isomer, the amount of brominating agent is maintained from 0.8 to 1.2 mole per mole of 4-methyl phenol, more preferably from 1.0 to 1.05 mole per mole of 4-methyl phenol.

The unreacted p-cresol plays a detrimental role in the process of purification of the final product as it cannot be separated easily. The separation of p-cresol is very difficult due to the fact that boiling points of p-cresol (201.9 oC) and 2-bromo-4-methyl phenol (213 oC) are very close. Further, they cannot be separated by fractional crystallization because of their low melting points. In accordance with the present disclosure it is observed that p-cresol can be almost completely converted into the product by using 1.0 m/m to 1.03 mole of bromine per mole of 4-methyl phenol without generating other isomers or di-bromo products. Due to complete conversion, it is possible to achieve >99.5 % purity of 2-bromo-4-methyl phenol in accordance with the present disclosure.

The solvent useful in the process of the present disclosure includes but is not limited to carbon tetrachloride, chloroform, methane sulfonic acid, trifilic acid, chloro benzene, combinations thereof and the like. The amount of solvent used in the reaction ranges from 250 to 3000 ml per mole of 4-methyl phenol.
The selectivity of formation of 2-bromo-4-methyl phenol in accordance with the present disclosure is found to be at least 84 %.

The present disclosure is further described in light of the following non-limiting examples which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure.

Example 1:
21.6 g of 4-methyl phenol was introduced into a 3” integrated reactor equipped with mechanical agitator, a thermowell and a double coiled condenser with chilled water circulation. 134 ml of anhydrous CCl4 was added and the reactor was protected from light. The temperature of the solution was brought to 30 oC. 32 g (0.20 mole) of liquid bromine dissolved in 106 ml of CCl4 was introduced in the course of approximately 6 hrs at 30oC at a uniform rate. The off gases were scrubbed in water. After the addition the reaction mixture was maintained at the same temperature for 3 hrs. The reaction mixture was analyzed by gas chromatography to monitor the progress of the reaction.
The reaction mixture was taken for work up when the content of the p-cresol in the reaction mixture was less than 0.2 % by gas chromatography. The dissolved HBr was removed by purging nitrogen through the reaction mixture. Organic layer was further washed with water and aqueous bicarbonate solution to remove traces of HBr. Carbon tetrachloride was distilled from the organic layer under reduced pressure to obtain 36.1 g of concentrated mass having 0.10 % p-cresol, 95.12 % 2-bromo-4-methyl phenol and 4.78 % unknown substances.

Example 2:
21.6 g of 4-methyl phenol was introduced into a 3” integrated reactor equipped with mechanical agitator, a thermowell and a double coiled condenser with chilled water circulation. 134 ml of anhydrous CCl4 and 0.96 g of methane sulfonic acid were added and the reactor was protected from light. The temperature of the solution was brought to 30oC. 32 g (0.20 mole) of liquid bromine dissolved in 106 ml of CCl4 was introduced in the course of approximately 6 hrs at 30 oC at a uniform rate. The off gases were scrubbed in water. After the addition the reaction mixture was maintained at the same temperature for 3 hrs. The reaction mixture was analyzed by gas chromatography to monitor the progress of the reaction.
The reaction mixture was taken for work up when the content of the p-cresol in the reaction mixture was less than 0.2 % by gas chromatography. The dissolved HBr is removed by purging nitrogen through the reaction mixture. Organic layer was further washed with water and aqueous bicarbonate solution to remove traces of HBr and carbon tetrachloride was distilled from the organic layer under reduced pressure to obtain 37 g of concentrated mass having 98 % 2-bromo-4-methyl phenol and 2 % unknown substances.

Example 3:
21.6 g of 4-methyl phenol were introduced into a 3” integrated reactor equipped with mechanical agitator, a thermowell and a double coiled condenser with chilled water circulation. 134 ml of anhydrous CCl4 and 1.92 g of methane sulfonic acid were added and the reactor was protected from light. The temperature of the solution was then brought to 32 oC. 32 g (0.20 mole) of liquid bromine dissolved in 106 ml of CCl4 was introduced in the course of approximately 6 hrs at 25oC at a uniform rate. The off gases were scrubbed in water. After the addition the reaction mixture was maintained at the same temperature for 3 hrs. The reaction mixture was analyzed by gas chromatography to monitor the progress of the reaction.
The reaction mixture was taken for work up when the content of the p-cresol in the reaction mixture was less than 0.2 % by gas chromatography. The dissolved HBr was removed by purging nitrogen through the reaction mixture. Organic layer was further washed with water and aqueous bicarbonate solution. Carbon tetrachloride was distilled from the organic layer under reduced pressure to obtain 35.13 g of concentrated mass having 0.1% p-cresol, 96 % 2-bromo-4-methyl phenol and 3.9 % unknown substances.

Example 4:
21.6 g of 4-methyl phenol was introduced into a 3” integrated reactor equipped with mechanical agitator, a thermowell and a double coiled condenser with chilled water circulation. 260 ml of anhydrous CCl4 was added and the reactor was protected from light. The temperature of the solution was then brought to 30oC. 32 g (0.20 mole) of liquid bromine dissolved in 200 ml of CCl4 was introduced in the course of approximately 0.5 hr at 30 oC at a uniform rate. The off gases were scrubbed in water. After the addition the reaction mixture was maintained at the same temperature for 5 hrs. The product mixture obtained was analyzed by gas chromatography to monitor the progress of the reaction.
The reaction mixture was taken for work up when the content of the p-cresol in the reaction mixture was less than 0.2 % by gas chromatography. The dissolved HBr was removed by purging nitrogen through the reaction mixture. Organic layer was further washed with water and aqueous bicarbonate solution. Carbon tetrachloride was distilled from the organic layer under reduced pressure to obtain 36.1 g of concentrated mass having 0.10 % p-cresol, 95.12 % 2-bromo-4-methyl phenol and 4.78 % unknown substances.

Example 5:
756 g of p-cresol (7.0 m) was introduced into a 6” integrated reactor provided along with 670 ml/m CCl4 as in example one. The reactor was protected from light and the temperature of the solution was brought to 32 oC. 1120 g (7.0 mole) of liquid bromine dissolved in 530 ml/m of CCl4 was introduced in the course of approximately 4hrs at a uniform rate at 30 oC. The off gases were scrubbed in water. After the addition the reaction mixture was maintained at 0 deg for a period of 5 hrs. The reaction progress was monitoring by gas chromatography. The reaction mixture was taken for work up when the content of the p-cresol in the reaction mixture was less than 0.2 % by gas chromatography. The reaction mixture was then worked up as above and organic layer was concentrated under reduced pressure to give 1264.5 g of concentrated mass having 0.89 % p-cresol, 95.97 % 2-bromo-4-methyl phenol and 3.14 % unknown substances.

The crude 2-bromo-4-methyl phenol was fractionally distilled under reduced pressure at 100-120 oC liquid temperatures and 20 mm Hg pressure over a 2” dia packed glass column of 4’ height to give 99.5 to 99.8 % pure 2-bromo-4-methyl phenol.

Example 6:
54 g of p-cresol was taken in a 4” integrated reactor along with 335 ml CHCl3.
The reactor was protected from light and the temperature of the solution was brought to 30oC. 82.4 g of bromine dissolved in 265 ml of CHCl3 was introduced in the course of approximately 4 hrs at 30 oC at a uniform rate. After the addition the reaction mixture was maintained at same temperature for 3 hrs and the reaction progress was monitored by gas chromatography. The reaction mixture was worked up as above and organic layer was concentrated as above to give 89.8 g crude concentrated mass having 0.1 % p-cresol, 87.34 % -2-bromo-4-methyl phenol and 11.78 % unknown substances.

Example 7:
21.6 g of p-cresol were taken in a 3” integrated reactor along with 134 ml methane sulfonic acid. The reactor was protected from light and the temperature of the solution was brought to 30oC. 32 g of bromine dissolved in 106 ml of methane sulfonic acid was introduced in the course of approximately 4 hrs at 25-30 oC at a uniform rate. After the addition the reaction mixture was maintained at same temperature for 3 hrs and the reaction progress was monitored by gas chromatography. The reaction mixture was worked up as above and organic layer was concentrated as above to give 35.2 g crude concentrated mass having 14.32 % p-cresol, 71.70 % -2-bromo-4-methyl phenol and 13.98 % unknown substances.

Example 8:
2.16 g of p-cresol dissolved in 40 ml of triflic acid was introduced in a three neck flask of 100 ml capacity equipped with magnetic stirring, a thermowell and a condenser.
The flask was protected from light and the temperature of the solution was brought to 30oC. 3.2 g (0.02 mole) of liquid bromine dissolved in 20 ml triflic acid was introduced at 25oC over 1 hr. The reaction mixture was maintained at this temperature for 6 hrs. The reaction mixture was then drowned in water and extracted with CCl4. CCl4 layer was neutralized with dilute aq. NaHCO3 and concentrated to give 9.2 g of concentrated mass. Gas chromatography showed 13.8 % p-cresol; 12.05 % 2-bromo-4-methyl phenol and 74.15 % other unknown substances.

Example 9:
108 g of p-cresol were taken in a 3” integrated reactor. The reactor was protected from light and the mixture was brought to 360C. 160.8 g of bromine was introduced in the course of approximately 8 hrs. at 32 0C at a uniform rate. The reaction mixture was further maintained for 3 hr and the reaction progress was monitored by gas chromatography. The reaction mixture was analyzed by gas chromatography which showed 17 % p-cresol, 64 % -2-bromo-4-methyl phenol and 17 % unknown substances.

The selectivity for formation of 2-bromo-4-methyl phenol for various solvents is tabulated in table 1:
Solvent employed Solvent Quantity Temperature °C Bromine used Selectivity for 2-Bromo-4-methyl phenol
Carbon tetrachloride 2300 ml/m 30 1 m/m 95 %
Carbon tetrachloride 1200 ml/m 30 1 m/m 96 %
Chloroform 1200 ml/m 30 1 m/m 87 %
Methane sulfonic acid 1200 ml/m 30 1 m/m 84 %
Triflic acid 1200 ml/m 25 1 m/m 14 %
Chloro benzene 300 ml/m 30 1 m/m 95 %
Carbon tetrachloride +
4.44M% methane sulfonic acid as catalyst 1200 ml/m 30 1m/m 98%
Carbon tetrachloride +
8.88M% methane sulfonic acid as catalyst 1200 ml/m 30 1m/m 96%
No solvent, No catalyst - 36 1m/m 77%

Technical advantages:
The process of the present disclosure has the following advantages:
- The process is carried out at room temperature;
- The process exhibits high selectivity towards the formation of 2-btomo-4methyl phenol;
- The process provides highly pure 2-btomo-4methyl phenol;
- The process provides high yield of 2-btomo-4methyl phenol;
- The purification of the product is simple and economic; and
- The process is carried out in the absence of light, thereby avoiding side reactions.

Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the invention as it existed anywhere before the priority date of this application.
While considerable emphasis has been placed herein on the preferred embodiment, it will be appreciated that many embodiments can be made and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other changes in the preferred embodiments of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation. ,CLAIMS:1. A process for the synthesis of 2-bromo-4-methyl phenol; said process comprises brominating 4-methyl phenol in the absence of light in a solvent using a brominating agent at a temperature ranging from 200C to 400C.

2. The process as claimed in claim 1, wherein the bromination is carried in the presence of at least one Lewis acid.

3. The process as claimed in claim 1, wherein the brominating agent is selected from the group consisting of bromine, HBr/H2O2, HBr/NaNO2 and combinations thereof.

4. The process as claimed in claim 1, wherein the amount of the brominating agent ranges from 1 to 1.5 mole per mole of 4-methyl phenol, preferably 1.0 to 1.05 mole per mole of 4-methyl phenol.

5. The process as claimed in claim 1, wherein said process characterized in the purity of 2-bromo-4-methyl phenol is >99.5 %.

6. The process as claimed in claim 1, wherein said process characterized in the selectivity of formation of 2-bromo-4-methyl phenol is at least 84 %.

7. The process as claimed in claim 1, wherein the solvent is selected from the group consisting of carbon tetrachloride, chloroform, methane sulfonic acid, trifilic acid, chloro benzene and combinations thereof.

8. The process as claimed in claim 1, wherein the amount of solvent ranging from 250 to 3000 ml per mole of 4-methyl phenol.

9. The process as claimed in claim 2, wherein the amount of the Lewis acid used is in the range of 0.1 to 10 % by weight of 4-methyl phenol.

10. The process as claimed in claim 2, wherein the Lewis acid is methane sulfonic acid.