FIELD OF THE INVENTION
The present invention relates to a process for preparation of 3,5-difluorobenzyl derivatives from 2,4-dichloronitrobenzene.
BACKGROUND OF THE INVENTION
The 3,5-difluorobenzyl derivatives are known chemical with varied uses. In particular, it is used as an important intermediate for synthesizing agrochemical and pharmaceutical products.
The US application No. 20040024238, discloses a process for preparing the 3,5-difluorobenzyl derivatives by a chlorine-fluorine exchange in sulfolane as solvent, which is expensive and requires purification measures to be taken before use, in particular to prevent it from incorporating too much water.
Therefore, there is a need to develop a process for preparation of 3,5-difluorobenzyl derivatives from 2,4-dichloronitrobenzene to overcome the above problems
OBJECT OF THE INVENTION
The invention provides an efficient, easy and safe process for the preparation of 3,5-difluorobenzyl derivatives.
SUMMARY OF THE INVENTION
The first aspect of the present invention provides a process for the preparation of 3,5-difluorobenzyl bromide,
comprising the steps of:
a) fluorinating 2,4-dichloronitrobenzene using a fluorinating agent in presence of a phase transfer catalyst and a solvent at 100-200°C to obtain 2,4-difluoronitrobenzene;
b) reducing 2,4-difluoronitrobenzene using hydrogen in presence of a catalyst and solvent to obtain 2,4-difluoroaniline;
c) brominating 2,4-difluoroaniline using bromine in presence of acid to obtain 2-bromo-4,6-difluoroanilinium salt;
d) diazotising 2-bromo-4,6-difluoroanilinium salt and decomposing in situ to obtain 1-bromo-3,5-difluorobenzene;
e) formylating 1-bromo-3,5-difluorobenzene using a formylating agent to obtain 3,5-difluorobenzaldehyde;
f) reducing 3,5-difluorobenzaldehyde in presence of a solvent to obtain a 3,5-difluorobenzyl alcohol;
g) converting 3,5-difluorobenzyl alcohol using hydrogen bromide and sulfuric acid into 3,5-difluorobenzyl bromide;
h) isolating 3,5-difluorobenzyl bromide.
wherein optionally intermediates are isolated in present invention.
The second aspect of the present invention provides a process for the preparation of 3,5-difluorobenzyl alcohol,
comprising the steps of:
a) fluorinating 2,4-dichloronitrobenzene using a fluorinating agent in presence of a phase transfer catalyst and a solvent at 100-200°C to obtain 2,4-difluoronitrobenzene;
b) reducing 2,4-difluoronitrobenzene using hydrogen in presence of a catalyst and solvent to obtain 2,4-difluoroaniline;
c) brominating 2,4-difluoroaniline using bromine in presence of acid to obtain 2-bromo-4,6-difluoroanilinium salt;
d) diazotising 2-bromo-4,6-difluoroanilinium salt and decomposing in situ to obtain 1-bromo-3,5-difluorobenzene;
e) formylating 1-bromo-3,5-difluorobenzene using a formylating agent to obtain 3,5-difluorobenzaldehyde;
f) reducing 3,5-difluorobenzaldehyde in presence of solvent to obtain a 3,5-difluorobenzyl alcohol;
g) isolating 3,5-difluorobenzyl alcohol;
wherein optionally intermediates are isolated in present invention.
DESCRIPTION OF THE INVENTION
As used herein, the ‘3,5-difluorobenzyl derivatives’ refers to the 3,5-difluorobenzyl bromide and 3,5-difluorobenzyl alcohol.
As used herein, the “fluorinating” refers to adding a fluorine group in organic moiety. The fluorinating agent may be selected from a group consisting of potassium fluoride, sodium fluoride, cesium fluoride, tertiary butyl ammonium fluoride, tertiary methyl ammonium fluoride or like. In preferred embodiment, fluorination is carried out in anhydrous condition.
Fluorination is carried out in presence of a phase transfer catalyst. The quantity of phase transfer catalyst may be selected in the range of 1-5 wt% w.r.t 2,4-dichloronitrobenzene, and preferably 2%. The phase transfer catalyst may be selected from a group consisting of benzyltriethylammonium chloride, methyltributylammonium chloride, tetra-n-butylammonium bromide and tetramethylammonium chloride or the like.
The reduction in step b) is carried out in hydrogen in the presence of a catalyst and a solvent selected from a group consisting of water, ethanol, isopropanol, methanol and propanol or a mixture thereof.
The catalyst used in step b) is selected from a group consisting of palladium-on-carbon, platinum-on-carbon and Raney nickel or the like.
The hydrogen pressure is selected in the range of 3-15 kg/cm2 and preferably in the range of 4-6kg/cm2.
The bromination in step c) is carried out using bromine in the presence of an acid is selected from hydrogen chloride, hydrogen bromide and sulfuric acid.
The bromination in step c) is optionally carried out in the presence of solvent is selected from chloroform, dichloromethane, carbontetrachloride or a mixture thereof.
The step of diazotisation is carried out using sodium nitrite and cuprous oxide in presence of water, dichloromethane, toluene or the like. The sodium nitrite used for present invention is solid or in solution form.
The step of formylation is carried out using a formylating agent selected from a group consisting of dimethylformamide, formylmorpholine, N-formylpiperidine, ethyl formate, methyl formate or a mixture thereof. The formylation is carried out in an inert atmosphere. The nitrogen, argon or helium may be used as inert atmosphere gas.
The reduction in step f) is carried out using a reducing agent at a temperature below 20°C. The reducing agent may be selected from a group consisting of sodium borohydride, lithium aluminium hydride, di-isobutylaluminiumhydride or the like.
The reduction in step f) is carried out in the presence of solvent is selected from water, ethanol, dichloromethane, chloroform and a mixture thereof.
The reaction of step-g) is carried out using a hydrogen bromide in presence of an acid at 30°C.
The reaction of step-g) is carried out using a hydrogen bromide in alcohol in presence of an acid at 30°C. The acid is selected from a group consisting of sulphuric acid, phosphoric acid, acetic acid or the like.
As used herein, the term “isolating” refers isolating a compound from the reaction mixture by any of the process consisting of extraction, distillation, filtration, decantation, washing, dryings or combination thereof.
All the intermediates may be isolated before carrying to the next step.
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 (GAS CHROMATOGRAPHY), liquid chromatography (LC) and alike.
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
Step-1: Preparation of 2,4-difluoronitrobenzene
To a dried suspension of potassium fluoride (303.5g, 5.23mol) and N,N-dimethylformamide (1009.04g, 13.8mol), 2,4-dichloronitrobenzene (250.2g, 1.3mol) was added. The reaction mass was heated to reflux and maintained for 4 hours. After 4 hours, tetramethylammonium chloride (5.05g, 0.05mol) was added to the reaction mass. Progress of the reaction was monitored by gas chromatography. After completion of reaction, the reaction mass was cooled, filtered and distilled under vacuum to obtain 2,4-difluoronitrobenzene.
Step-2: Preparation of 2,4-difluoroaniline
Pure 2,4-difluoronitrobenzene (99.89g, 0.63mol), methanol (316.4g, 9.89mol) and 5% raney nickel (5g) were added sequentially in an autoclave. Boxed up, flushed with nitrogen and hydrogen. Pressurized the autoclave to 6 bar with hydrogen and heated to 55°-60?. Hydrogen gas was continuously added till the pressure becomes constant. Progress of reaction was monitored by gas chromatography. After completion of reaction, reaction mass was cooled to room temperature, filtered and concentrated to obtain crude 2,4-difluoroaniline.
Step-3: Process for the preparation of 2-bromo-4,6-difluoroaniline
Concentrated hydrochloric acid (159.4g, 1.39mol), water (299.5g, 16.6mol) and crude 2,4-difluoroaniline (72.23g, 0.56mol) were added sequentially in a reaction vessel. Cooled the mass to 20°C and bromine (90.12g, 0.56mol) was added dropwise to the mass. After addition, reaction temperature was maintained in the range of 25-30°C. Progress of reaction was monitored by gas chromatography. After completion of reaction, sodium sulphite was added to the mass to quench the unreacted bromine and carried as such for next reaction.
Step-4: Preparation of 3,5-difluorobromobenzene
To the above step-3 mass, isopropanol (311.8g, 5.18mol) and cuprous oxide (4.71g, 0.06mol) were added sequentially in a reaction vessel. Cooled the mass to -15°C using cooling bath. Solid sodium nitrite (39.2g, 0.57mol) was added lot wise to the reaction mass while maintaining the temperature. After addition, reaction was maintained for additional 1 hour. Heated the reaction mass upto 110°C to boil off and collect the low boilers. Obtained low boilers contains product, isopropanol and water which was further treated with water and layer were separated. Organic layer was further distilled under vacuum to obtain 3,5-difluorobromobenzene.
Step-5A: Preparation of 3,5-difluorobenzaldehyde
Activated magnesium (10g, 0.41mol) and tetrahydrofuran (20.7g, 0.7mol) were added sequentially to the reaction vessel. Mass was heated to reflux and slowly step-4 product (69.8g, 0.36mol) dissolved in tetrahydrofuran (204g, 2.83mol) was added in the reflux mass. After addition, reaction mass was cooled to 10°C and dimethylformamide (32.1g, 0.44mol) was added. Progress of reaction was monitored by gas chromatography. After completion of reaction, mass was acidified with dilute hydrochloric acid solution and extracted with dichloromethane. Organic layer was washed with water and concentrated to get crude product which was further purified by vacuum boil off to obtain pure 3,5-difluorobenzaldehyde.
Step-5B: Preparation of 3,5-difluorobenzaldehyde
Tertiary butylmagnesium bromide (0.41mol) in tetrahydrofuran (20.7g, 0.7mol) was added slowly to step-4 product (69.8g, 0.36mol) dissolved in tetrahydrofuran (204g, 2.83mol). After addition, reaction mass was cooled to 10°C and dimethylformamide (32.1g, 0.44mol) was added. Progress of reaction was monitored by gas chromatography. After completion of reaction, mass was acidified with dilute hydrochloric acid solution and extracted with dichloromethane. Organic layer was washed with water and concentrated, followed by vacuum boil off to obtain 3,5-difluorobenzaldehyde.
Step-5C: Preparation of 3,5-difluorobenzaldehyde
Dichloromethylmethylether (0.4mol) was added to a reactor containing titanium chloride (0.01mol) in tetrahydrofuran (20.7g, 0.7mol) and step-4 product (69.8g, 0.36mol) dissolved in tetrahydrofuran (204g, 2.83mol). After addition, reaction mass was heated to 70°C. The progress of reaction was monitored by gas chromatography. After completion of reaction, mass was acidified with dilute hydrochloric acid solution and extracted with dichloromethane. Organic layer was washed with water and concentrated, followed by vacuum boil off to obtain 3,5-difluorobenzaldehyde.
Step-6: Preparation of 3,5-difluorobenzyl alcohol
Water (44.6g, 2.48mol) and sodium borohydride (4.82g, 0.13mol) were sequentially added to the reaction vessel and cooled to 0-5°C. Step-5 product (29.5g, 0.21mol) dissolved in dichloromethane (62.3g, 0.73mol) was slowly added to the aqueous sodium borohydride solution. Progress of reaction was monitored by gas chromatography. After completion of reaction, layer separated and extracted the aqueous layer with dichloromethane. Combined organic layer was concentrated to obtain 3,5-difluorobenzyl alcohol.
Step-7: Preparation of 3,5-difluorobenzyl bromide
Crude step-6 product (28.4g, 0.2mol) and aqueous hydrobromic acid (68.5g, 0.4mol) were sequentially added to the reaction vessel and cooled to 15°C. Sulphuric acid (68.2g, 0.68mol) was added dropwise to the above mass. Heated to 30°C and maintained the reaction. Progress of reaction was monitored by gas chromatography. After completion of reaction, quenched the reaction mass in water. Layer separated and extracted aqueous layer with dichloromethane. Combined organic layer was washed with water, concentrated to obtain crude product. Crude product was distilled under vacuum to obtain pure 3,5-difluorobenzyl bromide.
Purity: 98%

We Claim:
1. A process for the preparation of 3,5-difluorobenzyl bromide,
comprising the steps of:
a) fluorinating 2,4-dichloronitrobenzene using a fluorinating agent in presence of a phase transfer catalyst and a solvent at 100-200°C to obtain 2,4-difluoronitrobenzene;
b) reducing 2,4-difluoronitrobenzene using hydrogen in presence of a catalyst and solvent to obtain 2,4-difluoroaniline;
c) brominating 2,4-difluoroaniline using bromine in presence of acid to obtain 2-bromo-4,6-difluoroanilinium salt;
d) diazotising 2-bromo-4,6-difluoroanilinium salt and decomposing in situ to obtain 1-bromo-3,5-difluorobenzene;
e) formylating 1-bromo-3,5-difluorobenzene using a formylating agent to obtain 3,5-difluorobenzaldehyde;
f) reducing 3,5-difluorobenzaldehyde in presence of water to obtain a 3,5-difluorobenzyl alcohol;
g) converting 3,5-difluorobenzyl alcohol using hydrogen bromide and sulfuric acid into 3,5-difluorobenzyl bromide;
h) isolating 3,5-difluorobenzyl bromide;
2. A process for the preparation of 3,5-difluorobenzyl alcohol,
comprising the steps of:
a) fluorinating 2,4-dichloronitrobenzene using a fluorinating agent in presence of a phase transfer catalyst and a solvent at 100-200°C to obtain 2,4-difluoronitrobenzene;
b) reducing 2,4-difluoronitrobenzene using hydrogen in presence of a catalyst and solvent to obtain 2,4-difluoroaniline;
c) brominating 2,4-difluoroaniline using bromine in presence of acid to obtain 2-bromo-4,6-difluoroanilinium salt;
d) diazotising 2-bromo-4,6-difluoroanilinium salt and decomposing in situ to obtain 1-bromo-3,5-difluorobenzene;
e) formylating 1-bromo-3,5-difluorobenzene using a formylating agent to obtain 3,5-difluorobenzaldehyde;
f) reducing 3,5-difluorobenzaldehyde in presence of water to obtain a 3,5-difluorobenzyl alcohol;
g) isolating 3,5-difluorobenzyl alcohol;
3. The process as claimed in claim 1 and claim 2, wherein the fluorinating agent used in step a) is selected from a group consisting of potassium fluoride, sodium fluoride, cesium fluoride, tertiary butyl ammonium fluoride and tertiary methyl ammonium fluoride or a mixture thereof.
4. The process as claimed in claim 1 and claim 2, wherein the phase transfer catalyst used in step a) is selected from a group consisting of benzyltriethylammonium chloride, methyltributylammonium chloride, tetra-n-butylammonium bromide and tetramethylammonium chloride or a mixture thereof.
5. The process as claimed in claim 1 and claim 2, wherein the catalyst used in step b) is selected from group consisting of palladium-on-carbon, platinum oxide and Raney nickel or a mixture thereof.
6. The process as claimed in claim 1 and claim 2, wherein the solvent used in step b) is selected from a group consisting of water, ethanol, isopropanol, methanol and propanol or mixture thereof.
7. The process as claimed in claim 1 and claim 2, wherein the acid used in step c) is selected from hydrogen chloride, hydrogen bromide and sulfuric acid.
8. The process as claimed in claim 1 and claim 2, wherein the diazotisation in step d) is carried out using sodium nitrite and cuprous oxide in presence of water, dichloromethane, toluene or a mixture thereof.
9. The process as claimed in claim 1 and claim 2, wherein the formylating agent used in step e) is selected from a group consisting of dimethylformamide, formylmorpholine, N-formylpiperidine, ethyl formate and methyl format or a mixture thereof.
10. The process as claimed in claim 1 and claim 2, wherein the reduction in step f) is carried out using a reducing agent is selected from a group consisting of sodium borohydride, lithium aluminium hydride and di-isobutylaluminiumhydride or a mixture thereof.