Description:FIELD OF THE INVENTION
The present invention relates to the process for preparing aromatic ethers. Aromatic ethers are important intermediates for synthesizing the agrochemical and pharmaceutical products.
BACKGROUND OF THE INVENTION
Aromatic ethers are used as an important intermediate for synthesizing the agrochemical and pharmaceutical products.
The EP. Pat. No. 1,502,908 provides a process for the preparation of aromatic ethers such as 2, 2-difluoro-1, 3-benzodioxole by providing a mixture of 1,3-benzodioxol and 2,4-dichloro-benzotrifluoride in a reactor equipped with a UV lamp, followed by heating to reflux temperature. The UV lamp was turned on followed by chlorine addition. The mixture of crude 2, 2-dichloro-1, 3-benzodioxole and solvent so obtained with a purity of 99% is cooled to 0-4°C and fluorinated using HF to obtain 2, 2-difluoro-1, 3-benzodioxole crude mixture. The HCl was vented out followed by removal of excess HF by heating crude mixture to 50?. The remaining HF was removed using distillation to obtain pure 2, 2-difluoro-1, 3-benzodioxole with a purity of 99.9% and yield of 85% w.r.to 1,3-benzodioxol.
The 2,4-dichlorobenzotrifluoride used in the process as solvent has boiling point of 117oC, which is very close to the boiling point of 2,2-difluoro-1,3-benzodioxole (130oC). Thus, there arises a difficulty in the separation of product from solvent.
To overcome above challenge, IN433819 which is also a patent of applicant of the present invention provided a process for synthesis of 2, 2-difluoro-1,3- benzodioxole in which chlorine was added to a mixture of 1,3-bendodioxole in benzotrifluoride and AIBN at 85-95°C. Then the reaction mass was cooled to room temperature and the nitrogen gas was passed to remove unreacted dissolved chlorine and hydrogen chloride. The crude 2,2-dichloro-1,3-bendodioxole in benzotrifluoride was fluorinated using HF at 0°C followed by HCl and HF removal and distillation to obtain 2, 2-difluoro-1, 3-benzodioxole with 94% purity.
In a comparative example, it also shown that when solution of AIBN (azobisisobutyronitrile) in 1,3-bendodioxole and chlorine are simultaneously introduced in the reactor followed by distillation. The 2,2-dichloro-1,3-bendodioxole is obtained with a very low yield and purity i.e., 66% and 74% respectively.
SRF’s Indian Patent 311998 also discloses production of 2,2-difluoro-1,3-bendodioxole by reacting 1,3-bendodioxole with chlorine in the presence of pentafluorobenzene and a radical initiator (such as azobisisobutyronitrile).
Thus, a particular mode of addition greatly effects the yield and purity in the synthesis of aromatic ethers.
The inventors of the present invention have found an improved process for the preparation of aromatic ethers that overcome the drawbacks of the existing processes.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an industrially advantageous, efficient, and safe alternate process for the preparation of aromatic ethers.

SUMMARY OF THE INVENTION
The present invention relates to a process for preparation of an aromatic ether of formula I, comprising the steps of:

Formula I
wherein R1 represents a Halogen, R2 represents a hydrogen atom or R1 and R2 together are an oxygen atom, and R3 represents Hydrogen or Halogen.
a) providing a solvent and a compound of formula II in a reactor and heating to 70-85?;
b) simultaneously adding chlorine and solution of radical initiator with a compound of formula II to step a) reactor at 70-85? to obtain a reaction mixture comprising the compound of formula III;

Formula II Formula III
wherein R1 and R2 are as defined above
c) fluorinating the compound of formula III to obtain the compound of formula I; and
d) isolating the compound of formula I,
wherein 0-100% of compound of formula II out of total quantity is provided in step a) reactor and rest of compound of formula II was supplied by making its solution with radical initiator.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, fluorination refers to reacting a compound of formula III with a fluorinating agent selected from a group consisting of hydrogen fluoride, amine-HF adduct and potassium fluoride.
As used herein, a radical initiator refers to benzoyl peroxide, diacetyl peroxide, succinyl or azobisisobutyronitrile (AIBN). Radical initiators are used in amounts of from 0 to 10 wt %.
As used herein, the solvent used in the present invention is selected from a group consisting of benzotrifluoride, mono and polyfluorinated benzenes.
In an embodiment, 0-100% of compound of formula II out of total quantity is provided in step a) reactor and rest of compound of formula II was supplied by making its solution with radical initiator.
In another embodiment, all of compound of formula II was supplied by making its solution with radical initiator.
In another embodiment, all of compound of formula II was supplied as such in step a) reactor along with solvent without making its solution with radical initiator.
As used herein, the term “isolating” refers to the method used to isolate the compound from the reaction mixture. The isolation is carried out using any of the process consisting of extraction, distillation, filtration, decantation, washing, dryings, or combination thereof.
In a preferred embodiment, the isolation is carried out using distillation.
As used herein, the term “inert gas” refers to nitrogen, helium or argon.
In another embodiment of the present invention, 2,2-dichloro-1,3-benzodioxole is not isolated and its reaction mixture with solvent is carried forward to the next step.
In another embodiment of the present invention, the undesired gases like HF and HCl are vented out either by heating or by purging an inert gas and additionally by washing the reaction mixture with an aqueous solution of sodium bicarbonate.
In an embodiment the present invention relates to a process for preparation of aromatic ether of formula I, comprising the steps of:

Formula I
wherein R1 represents a Halogen, R2 represents a hydrogen atom or R1 and R2 together are an oxygen atom, and R3 represents Hydrogen or Halogen.
a) providing a solvent in a reactor and heating to 70-85?;
b) simultaneously adding chlorine; and solution of radical initiator with a compound of formula II to step a) reactor at 70-85? to obtain a reaction mixture comprising the compound of formula III;

Formula II Formula III
wherein R1 and R2 are as defined above
c) fluorinating the compound of formula III to obtain the compound of formula I; and
d) isolating the compound of formula I.
In another embodiment, the present invention relates to a process for preparation of aromatic ether of formula I, comprising the steps of:

Formula I
wherein R1 represents a Halogen, R2 represents a hydrogen atom or R1 and R2 together are an oxygen atom, and R3 represents Hydrogen or Halogen.
a) providing benzotrifluoride solvent in a reactor and heating to 70-85?;
b) simultaneously adding chlorine and solution of AIBN with a compound of formula II to step a) reactor at 70-85? to obtain a reaction mixture comprising the compound of formula III;

Formula II Formula III
wherein R1 and R2 are as defined above
c) removing HCl from the reaction mixture of step b);
d) cooling the reaction mixture of step c) and adding to HF cooled at 0-10? to obtain the compound of formula I in crude form; and
e) removing excess of HF from step d) reaction mixture; and
f) isolating the pure compound of formula I.
In another embodiment, the present invention relates to a process for preparation of 2,2-difluoro-1,3-benzodioxole, comprising the steps of:
a) providing benzotrifluoride solvent in a reactor and heating to 70-85?;
b) simultaneously adding chlorine and solution of AIBN with 1,3-benzodioxole to step a) reactor at 70-85? to obtain a reaction mixture comprising 2,2-dichloro-1,3-benzodioxole;
c) fluorinating 2,2-dichloro-1,3-benzodioxole to obtain 2,2-difluoro-1,3-benzodioxole; and
d) isolating 2,2-difluoro-1,3-benzodioxole.
In another embodiment, the present invention relates to a process for preparation of 2,2-difluoro-1,3-benzodioxole, comprising the steps of:
a) providing benzotrifluoride solvent in a reactor and heating to 70-85?;
b) simultaneously adding chlorine and solution of AIBN with 1,3-benzodioxole to step a) reactor at 70-85? to obtain a reaction mixture comprising the 2,2-dichloro-1,3-benzodioxole;
c) removing HCl from the reaction mixture of step b);
d) cooling the reaction mixture of step c) and adding to HF cooled at 0-10? to obtain the 2,2-difluoro-1,3-benzodioxole in crude form; and
e) removing HCl and excess of HF from step d) reaction mixture; and
f) isolating the pure 2,2-difluoro-1,3-benzodioxole.
The completion of the reaction may be monitored by any one of chromatographic techniques such as thin layer chromatography (TLC), high pressure liquid chromatography (HPLC), ultra-pressure liquid chromatography (UPLC), Gas chromatography (GC), liquid chromatography (LC) and alike.
The reagents and raw materials used in the present invention may be prepared or obtained commercially.
Unless stated to the contrary, any of the words “comprising”, “comprises” and includes mean “including without limitation” and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it.
Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.
The following example is given by way of illustration and therefore should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of 2,2-difluoro-1,3-bendodioxole
Step 1: Benzotrifluoride (BTF) (4.9 moles, 2 eq) was charged in 2 liter four neck RBF. Reaction mass was heated to 85?. Then Chlorine purging (5.16 moles, 2.1 eq) was started with simultaneous addition of AIBN (0.012 moles, 0.0049 eq) dissolved in 1,3-Benzodioxole (2.46 moles, 1eq) at 85-95°C for 3 hours and the mass was cooked at the same temperature for 2 hours for reaction completion. Then the reaction mass was cooled to room temperature and the nitrogen gas was passed to remove unreacted dissolved chlorine and HCl. The crude step 1 solution in Benzotrifluoride was taken as such to next step. (Selectivity: 97%)
Step 2: Anhydrous HF (12.95 moles, 3.5 eq) was charged into pre-cooled autoclave (at 0?) and to this crude Step 1 (3.69 moles, 1 eq) mixture in Benzotrifluoride (7.1 moles, 1.95 eq) was added continuously to the reactor at 0°C for 2-3hours. After completion of the addition, the reaction mass was cooked at 0°C for one hour to achieve complete conversion. The excess HF was vented off by heating the mass up to 70°C and the adhered HF was removed by washing with NaHCO3 (0.54 moles, 0.15 eq) solution. Then the reaction mass was distilled through distillation column under vacuum to get the product.
Yield: 76% (step 1 and step 2 combined), Purity: 99.9%
Example 2: Preparation of 2,2-difluoro-1,3-bendodioxole
Step 1: BTF (2.45 moles, 1 eq) and 1,3-benzodioxole (2.46 moles, 1eq) were charged in 2 liter four neck RBF. Reaction mass was heated to 85?. Then Chlorine purging (5.16 moles, 2.1 eq) was started with simultaneous addition of AIBN (0.012 moles, 0.0049 eq) dissolved in BTF (2.45 moles, 1eq) at 85-95°C for 3 hours and the mass was cooked at the same temperature for 2 hours for reaction completion. Then the reaction mass was cooled to room temperature and the nitrogen gas was passed to remove unreacted dissolved chlorine and HCl. The crude step 1 solution in BTF was taken as such to next step.
Step 2: Anhydrous HF (12.95 moles, 3.5 eq) was charged into pre-cooled autoclave (0?) and to this step 1 (3.69 moles, 1 eq) solution of BTF (7.1 moles, 1.95 eq) was added continuously to the reactor at 0°C for 2-3hours. After completion of the addition, the reaction mass was cooked at 0°C for one hour to achieve complete conversion. The excess HF was vented off by heating the mass up to 70°C and the adhered HF was removed by washing with NaHCO3 (0.54 moles, 0.15 eq) solution. Then the reaction mass was distilled through distillation column under vacuum to get the product.
Yield: 75.5% (step 1 and step 2 combined), Purity: 99.8%
Comparative Example: Preparation of 2,2-dichloro-1,3-bendodioxole
In a stirred apparatus with a chlorine inlet, metering, intensive condenser and gas outlet, solution of AIBN (0.05%) in 1,3-bendodioxole (1.0 mole) and chlorine (2.05 moles) are simultaneously introduced in the reactor. After termination of the dosage was blown at 130°C with nitrogen. The titled compound was distilled out.
Yield: 66%: Purity: 74%

, C , C , Claims:WE CLAIM:
1. A process for preparation of an aromatic ether of formula I, comprising the steps of:

Formula I
wherein R1 represents a Halogen, R2 represents a hydrogen atom or R1 and R2 together are an oxygen atom, and R3 represents Hydrogen or Halogen.
a) providing a solvent and a compound of formula II in a reactor and heating to 70-85?;
b) simultaneously adding chlorine and solution of radical initiator with a compound of formula II to step a) reactor at 70-85? to obtain a reaction mixture comprising the compound of formula III;

Formula II Formula III
wherein R1 and R2 are as defined above
c) fluorinating the compound of formula III to obtain the compound of formula I; and
d) isolating the compound of formula I,
wherein 0-100% of compound of formula II out of total quantity is provided in step a) reactor and rest of compound of formula II was supplied by making its solution with radical initiator.
2. The process as claimed in claim 1, wherein the solvent used in the present invention is selected from a group consisting of benzotrifluoride, mono and polyfluorinated benzenes.
3. The process as claimed in claim 1, wherein all of compound of formula II was supplied by making its solution with radical initiator.
4. The process as claimed in claim 1, wherein all of compound of formula II was supplied as such in step a) reactor along with solvent without making its solution with radical initiator.
5. The process as claimed in claim 1 for preparation of aromatic ether of formula I, comprising the steps of:

Formula I
wherein R1 represents a Halogen, R2 represents a hydrogen atom or R1 and R2 together are an oxygen atom, and R3 represents Hydrogen or Halogen.
a) providing a solvent in a reactor and heating to 70-85?;
b) simultaneously adding chlorine; and solution of radical initiator with a compound of formula II to step a) reactor at 70-85? to obtain a reaction mixture comprising the compound of formula III;

Formula II Formula III
wherein R1 and R2 are as defined above
c) fluorinating the compound of formula III to obtain the compound of formula I; and
d) isolating the compound of formula I.
6. The process as claimed in claim 1 for preparation of aromatic ether of formula I, comprising the steps of:

Formula I
wherein R1 represents a Halogen, R2 represents a hydrogen atom or R1 and R2 together are an oxygen atom, and R3 represents Hydrogen or Halogen.
a) providing benzotrifluoride solvent in a reactor and heating to 70-85?;
b) simultaneously adding chlorine and solution of AIBN with a compound of formula II to step a) reactor at 70-85? to obtain a reaction mixture comprising the compound of formula III;

Formula II Formula III
wherein R1 and R2 are as defined above
c) removing HCl from the reaction mixture of step b);
d) cooling the reaction mixture of step c) and adding to HF cooled at 0-10? to obtain the compound of formula I in crude form; and
e) removing HCl and excess of HF from step d) reaction mixture; and
f) isolating the pure compound of formula I.
7. The process as claimed in claim 1 for preparation of 2,2-difluoro-1,3-benzodioxole, comprising the steps of:
a) providing benzotrifluoride solvent in a reactor and heating to 70-85?;
b) simultaneously adding chlorine and solution of AIBN with 1,3-benzodioxole to step a) reactor at 70-85? to obtain a reaction mixture comprising 2,2-dichloro-1,3-benzodioxole;
c) fluorinating 2,2-dichloro-1,3-benzodioxole to obtain 2,2-difluoro-1,3-benzodioxole; and
d) isolating 2,2-difluoro-1,3-benzodioxole.
8. The process as claimed in claim 1 for preparation of 2,2-difluoro-1,3-benzodioxole, comprising the steps of:
a) providing benzotrifluoride solvent in a reactor and heating to 70-85?;
b) simultaneously adding chlorine and solution of AIBN with 1,3-benzodioxole to step a) reactor at 70-85? to obtain a reaction mixture comprising the 2,2-dichloro-1,3-benzodioxole;
c) removing HCl from the reaction mixture of step b);
d) cooling the reaction mixture of step c) and adding to HF cooled at 0-10? to obtain the 2,2-difluoro-1,3-benzodioxole in crude form; and
e) removing HCl and excess of HF from step d) reaction mixture; and
f) isolating the pure 2,2-difluoro-1,3-benzodioxole.
9. The process as claimed in claim 1, wherein the radical initiator is selected from a group consisting of benzoyl peroxide, diacetyl peroxide, succinyl or azobisisobutyronitrile (AIBN).

Dated this 22nd day of December 2023