PROCESS FOR THE PREPARATION OF SUBSTITUTED BENZOATES
Field of the invention
The present invention provides a process for the preparation of 2-fluoro-3-nitrobenzoates of
Formula I.
Background of the invention
The 2-fluoro-3-nitrobenzoates represented by Formula I are key intermediate for
agrochemicals and pharmaceuticals. Particularly, methyl 2-fluoro-3-nitrobenzoate is an
important intermediate for the synthesis of an anti-cancer drug dabrafenib.
F
COOR
NO2
Formula I
wherein R is selected from C1-C6 alkyl, substituted C1-C6 alkyl group with
optionally substituted C1-C4 alkoxy or C1-C4 haloalkoxy group, C1-C6 halo
alkyl, C3-C10 cycloalkyl, aryl, benzyl.
The U.S. patents no. 8,569,378 and 8,853,440 provide a process for the preparation of methyl
2-fluoro-3-nitrobenzoate from methyl 2-chloro-3-nitrobenzoate by using cesium fluoride. The
disclosed process requires the use of cesium fluoride, which is very expensive and is not
environmental-friendly.
The present invention provides a process of preparation of 2-fluoro-3-nitrobenzoates of
Formula I which is simple, economically viable, industrially doable and environmentallyfriendly.
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Summary of the invention
The present invention provides a process for the preparation of a compound of Formula I,
comprising;
a) contacting a compound of Formula II with potassium fluoride to obtain a
reaction mixture,
b) contacting the reaction mixture with a compound of Formula III to obtain a
compound of formula I, and
c) isolating the compound of Formula I from step b).
F
COOR
NO2
Cl
COCl
NO2
Formula I Formula II
wherein R is selected from C1-C6 alkyl, substituted C1-C6 alkyl group with
optionally substituted C1-C4 alkoxy or C1-C4 haloalkoxy group, C1-C6 halo
alkyl, C3-C10 cycloalkyl, aryl and benzyl.
R-OH
Formula III
wherein R is defined as above
Detailed description of the invention
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The present invention provides a process for the preparation of a compound of Formula I,
comprising;
a) contacting a compound of Formula II with potassium fluoride to obtain a
reaction mixture,
b) contacting the reaction mixture with a compound of Formula III to obtain a
compound of formula I, and
c) isolating the compound of Formula I from step b).
F
COOR
NO2
Cl
COCl
NO2
Formula I Formula II
wherein R is selected from C1-C6 alkyl, substituted C1-C6 alkyl group with
optionally substituted C1-C4 alkoxy or C1-C4 haloalkoxy group, C1-C6 halo
alkyl, C3-C10 cycloalkyl, aryl and benzyl.
R-OH
Formula III
wherein R is defined as above
The step a) may be carried out at a temperature in the range of 50oC to 140oC.
The step a) may be carried out in the presence of solvents selected from dimethyl formamide,
dimethyl sulfoxide, sulfolane, acetonitrile, methyl pyrrolidine, benzonitrile and dimethyl
acetamide or a mixture thereof.
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The compound of Formula II may be obtained commercially or may be prepared by any of the methods known in the art, for example, as in the PCT publication no. WO 2010013567.
The isolation of the compound of Formula I is carried out by filtration, decantation, crystallization, re-crystallization or mixture thereof.
The compound of Formula I, obtained by the process of the present invention has a purity greater than 95% by gas chromatography, preferably greater than 98%.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
The following examples are given by way of illustration and therefore should not be construed to limit the scope of the present invention.
Examples
Example 1: Preparation of methyl 2-fluoro-3-nitrobenzoate
2-chloro-3-nitrobenzoyl chloride (2209.9g) was dissolved in dimethyl formamide (13.2 litres) and this mixture was added to dry potassium fluoride (1687.6g) in a round bottom flask. The reaction mass was heated to 145°C and was stirred for 2 hours while maintaining the temperature between 110°C to 140°C. The reaction mass was then cooled to 50°C. The methanol (1litre) was added to the reaction mass and was stirred for 15 minutes and the temperature was brought down to the room temperature. The reaction mass was filtered. The unreacted potassium fluoride and formed potassium chloride mixture was washed with dichloromethane (2 litres) and the filtrate was evaporated under vacuum at 60°C to get crude. Deionized water (4 litres) was added to the crude and stirred for 10 minutes. The solid was filtered and washed with deionized water (1 litre) and dried. The dry solid was dissolved in
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ethyl acetate (10 litres) and washed with 2×3 litres 0.5% aq. NaOH. The organic layer was washed with 2×4 litres saturated NaCl solution and was dried with dry sodium sulphate. The solvent was evaporated to get the title compound which was recrystallized from isopropyl alcohol.
Yield (%): 65
Purity (%): 99.5

We claim:
1. A process for the preparation of a compound of Formula I, comprising;
a) contacting a compound of Formula II with potassium fluoride to obtain a
reaction mixture,
b) contacting the reaction mixture with a compound of Formula III to obtain a
compound of formula I, and
c) isolating the compound of Formula I from step b).
F
COOR
NO2
Cl
COCl
NO2
Formula I Formula II
wherein R is selected from C1-C6 alkyl, substituted C1-C6 alkyl group with
optionally substituted C1-C4 alkoxy or C1-C4 haloalkoxy group, C1-C6 halo
alkyl, C3-C10 cycloalkyl, aryl and benzyl.
R-OH
Formula III
wherein R is defined as above
2. The process as claimed in claim 1, wherein the step a) is carried out at a temperature in
the range of 50oC to 140oC.
3. The process as claimed in claim 1, wherein the step a) is carried out in the presence of
solvents selected from the group consisting of dimethyl formamide, dimethyl
sulfoxide, sulfolane, acetonitrile, methyl pyrrolidine, benzonitrile and dimethyl
acetamide or a mixture thereof.
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4. The process as claimed in claim 1, wherein the isolation of the compound of Formula I is carried out by filtration, decantation, crystallization, re-crystallization or mixture thereof.