PROCESS FOR THE PREPARATION OF HALO DERIVATIVES OF BENZODIOXOLE
Field of the invention
The present invention relates to the process for preparing methyl-2,2-difluorobenzo-1,3-dioxole carboxylate of Formula I.
Background of the invention
Difluorobenzodioxolecarboxylic acids and their derivatives such as esters play an important role as precursors for the preparation of medicaments and crop protection agents.
Formula I
wherein R is C1-C6 alkyl
The ester derivative of difluorobenzodioxolecarboxylic acid is prepared in prior art by traditional esterification methods of difluorobenzodioxolecarboxylic acids.
The CN Patent Application No. 105153106 describes a process for the preparation of methyl-2,2-difluorobenzo-1,3-dioxole-5-carboxylate by performing
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esterification of 2,2-difluorobenzo-1,3-benzodioxole carboxylic acid with
methanol to obtain corresponding ester. The process involves isolation of 2,2-
difluorobenzo-1,3-benzodioxole carboxylic acid prior to esterification.
Thus, there is a need in the art to provide simple, cost-effective and industrially
scalable process for the preparation of compound of Formula I from halogen
substituted 2,2-difluoro-1,3-benzodioxole in one pot.
Summary of the Invention
The present invention provides a process for the preparation of compounds of
Formula I, comprising;
a) contacting a compound of Formula II with magnesium to obtain a first
reaction mixture,
b) contacting the first reaction mixture of step a) with a source of carbon-dioxide
to obtain a second reaction mixture,
O
O
F
F
X
Formula II
wherein X represents a chlorine, bromine or iodine
c) contacting the second reaction mixture with methylating agent to obtain a
compound of Formula I, and
d) isolating the compound of Formula I from step c).
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Formula I
wherein R is C1-C6 alkyl
Detailed Description of the Invention
In an aspect, the present invention provides a process for the preparation of
compounds of Formula I, comprising;
a) contacting a compound of Formula II with magnesium to obtain a first
reaction mixture,
b) contacting the first reaction mixture of step a) with a source of carbondioxide
to obtain a second reaction mixture,
O
O
F
F
X
Formula II
wherein X represents a chlorine, bromine or iodine
c) contacting the second reaction mixture with methylating agent to obtain a
compound of Formula I, and
d) isolating the compound of Formula I from step c).
Formula I
wherein R is C1-C6 alkyl
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The compound of Formula II may be prepared by any method known in the art.
The step a) of the present invention may take place in the temperature range of 10oC to 80oC, for example, in the range of 20oC to 60oC. The step b) of the present invention may take place in the temperature range of -10oC to 30oC, for example, in the range of 0oC to 20oC. The step c) of the present invention may take place in the temperature range of 10oC to 80oC, for example, in the range of 20oC to 60oC.
The source of carbon-dioxide used in step b) is selected from the group consisting of solid carbon-dioxide (dry ice), carbon-dioxide gas and inorganic carbonate salt with acid. The inorganic carbonate salt is selected from the group consisting of sodium carbonate, potassium carbonate and alike. The acid is selected from the group consisting of sulphuric acid, hydrochloric acid, hydrobromic acid and alike.
The step c) of present invention may take place in the presence of alkali carbonate. The alkali carbonate may be selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate and francium carbonate or mixture thereof.
The methylating agent is selected from the group consisting of chloromethyl formate, dimethyl carbonate and dimethyl sulphate or mixture thereof.
The compound of formula I is isolated by any method known in the art such as filtration, evaporation of solvent, distillation, azeotropic distillation, acid-base treatment, layer separation, extraction or combination thereof.
.
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.
Example:
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Process preparation of methyl-2,2-difluoro-1,3-benzodioxole-5-carboxylate:
Step 1: The magnesium turnings (11.13g, 0.46 mol) and tetrahydrofuran (600g, 8.32 mol) under nitrogen atmosphere were taken in a reaction vessel at room temperature. Initially 30 grams of 5-bromo-2,2-difluoro-1,3-benzodioxole (30g, 0.12 mol) was added to the reaction mixture, which initiated the formation of Grignard reagent. The temperature was raised from 28o to 34oC. In this stage the reaction mixture temperature was maintained at 25ºC by using ice water bath and remaining portions of 5-bromo-2,2-difluoro-1,3-benzodioxole (70g, 0.29 mol) were added drop wise in such a way that the temperature is maintained at 25 ºC. After complete addition of 5-bromo-2,2-difluoro-1,3-benzodioxole, the reaction mass was refluxed for 1 hour at 40ºC. After 1 hour the reaction mass was allowed to cool down 0ºC. Carbon-dioxide (93g, 2.1 mol) gas was purged in to reaction mass at 0º C for 40 minutes and the reaction mass temperature was maintained between 0ºC to 10ºC by using ice and salt mixture. The progress of the reaction was monitored by HPLC analysis.
Step 1a: The temperature of reaction mass raised to 30 ºC. To this potassium carbonate (232g 1.67 mol) and water (60g, 3.37 mol) were added. The reaction mixture was allowed to stir for one hour and dimethyl sulphate (106.4g, 0.843 mol) was added drop wise into the reaction mass at 30ºC. After complete addition, the reaction mass was stirred at 30ºC for 3 hours. Then the reaction mass was cooled down to room temperature and filtered. The inorganic cake was washed twice with excess of tetrahydrofuran (300g 4.16mol). The filtrate was evaporated and distilled under vacuum to obtain colourless liquid as product.
Yield: 70%
Purity by HPLC: 98.9%

WE CLAIM:
1. A process for the preparation of compound of Formula I,
Formula I
wherein R is C1-C6 alkyl
comprising;
a) contacting a compound of Formula II,
O
O
F
F
X
Formula II
wherein X represents a chlorine, bromine or iodine
with magnesium to obtain a first reaction mixture;
b) contacting the first reaction mixture of step a) with a source of carbon-dioxide
to obtain a second reaction mixture;
c) contacting the second reaction mixture with a methylating agent to obtain a
compound of Formula I, and
d) isolating the compound of Formula I from step c).
2. The process as claimed in claim 1, wherein the process is carried out at a
temperature in the range of -10oC to 80oC.
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3. The process as claimed in claim 1, wherein in step b), the source of carbon-dioxide is selected from the group consisting of solid carbon-dioxide, carbon-dioxide gas and inorganic carbonate salt with acid.
4. The process as claimed in claim 3, wherein the inorganic carbonate salt is selected from the group consisting of sodium carbonate, potassium carbonate; and the acid is selected from the group consisting of sulphuric acid, hydrochloric acid and hydrobromic acid.
5. The process as claimed in claim 1, wherein in the step c) the methylating agent is selected from the group consisting of chloromethyl formate, dimethyl carbonate and dimethyl sulphate or mixture thereof.
6. The process as claimed in claim 1, wherein the step c) is carried out in the presence of alkali carbonate is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate and francium carbonate or mixture thereof.
7. The process as claimed in claim 1, wherein in the step d) the compound of formula I is isolated by the method comprises filtration, evaporation, distillation, azeotropic distillation, acid-base treatment, layer separation, extraction or combination thereof.