FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of 2,3-dihalo-6-trifluoromethylbenzene derivatives of Formula I using a flow reactor,

Formula I
wherein X1 and X2 are independently selected from fluoro or chloro; Z represents COOH, CONH2, CN, CHO, CH=NOH or COOR’, wherein R’ is C1-C4 alkyl.

BACKGROUND OF THE INVENTION
2,3-Dihalo-6-trifluoromethylbenzene derivatives are very useful intermediate for pharmaceuticals or agrochemicals.
US Patent No. 6,054,605 describes a process for preparation of 2,3-dihalo-6-trifluoromethylbenzene derivatives by ortho lithiation of the trifluoromethylbenzene derivatives in presence of metallating agent under cryogenic conditions. The cryogenic conditions are difficult to maintain during commercial scale and it is always desirable to perform these reactions under easily conceivable conditions.
Thus with this state of the art in mind, there is need to provide improved process over the existing one. The present invention provides a commercially viable process for preparation of 2,3-dihalo-6-trifluoromethylbenzene derivatives.

OBJECT OF THE INVENTION
The main object of present invention is to provide an industrially viable process for the preparation of 2,3-dihalo-6-trifluoromethylbenzene derivatives.

SUMMARY OF THE INVENTION
The present invention provides an improved process for preparation of 2,3-dihalo-6-trifluoromethylbenzene derivatives of Formula I,

Formula I
wherein X1 and X2 are independently selected from fluoro or chloro; Z represents COOH, CONH2, CN, CHO, CH=NOH or COOR’, wherein R’ is alkyl group,
comprising the step of:
a) concurrently adding a compound of Formula II, metallating agent and an electrophilic agent to a reactor; and

Formula II
wherein X1 and X2, Z are defined above,
b) isolating the compound of Formula I.
DETAILED DESCRIPTION OF DRAWINGS
Figure 1 describes pinched coil flow reactor.
Figure 2 represents an image of pinched coil flow reactor
The flow reactor consists of an outer cylinder equipped with tube like coiled reactor, which is pinched at regular interval. The reactor is further equipped with two coils coil-1; coil-2 and two static mixing and feeding chambers F-1 and F-2. The coil-1 has inlets P-1 and P-2 for compound of formula II and metalling agent respectively. The coil-2 has inlet for the metalliated intermediates, P-3 for electrophilic agent and an outlet for removing the product.

DETAILED DESCRIPTION OF THE INVENTION
As used herein, “alkyl” refers to C1-C5 alkyl. Examples of alkyl include methyl, ethyl, propyl, iso-propyl, butyl, t-butyl or the like. The alkyl may be substituted by halogen at one or more positions to form halogenated alkyl group.
As used herein, “metallating agent” refers to any of alkyl lithium compounds. Examples of alkyl lithium compounds includes n-butyl lithium, Sec-butyl lithium, tert-butyl lithium, methyl lithium and lithium diisopropylamide or the like. The metallating agent may optionally need base such as N,N,N',N'- tetramethyl ethylenediamine (TMEDA) and N.N.N',N',N'- pentamethyl diethylenetriamine (PMDTA), or the like.
As used herein, “an electrophilic agent” refers to organic compound capable of generating electrophile. Suitable electrophilic agent include carbon dioxide, ethyl formate, methyl formate, propyl formate, isopropyl formate, butyl formate, t-butyl formate, phenyl formate, benzyl formate ethyl acetate and dimethylformamide, or the like.
As used herein, “solvent” refers to a polar aprotic or nonpolar organic solvents. Examples of polar aprotic solvent includes diethylether, diisopropyl ether, methyl t-butylether, tetrahydrofuran and dioxane, or the like. Examples of nonpolar organic solvent includes hexane, pentane, toluene and xylene, or the like.
As used herein, “reactor” refers to a flow reactor. Preferably, the flow reactor is a pinched coil flow reactor. Flow reactor consists of two coils with three inlet with two static mixture. Coils were made up of Stainless Steel -316 tube (Outside diameter 6 mm and Inside diameter 4 mm) with different volume.
High-pressure HPLC dosing pump with different material of construction, pressure rating and flow rate were used for dosing the feeds.
In an embodiment of the present invention, the process is carried out at a temperature of -10 to -20°C.
In another embodiment of the present invention, the flow rate of feed-F1 and F2 is 2.5 ml/minute to 11 ml/minute and feed-F3 is 5 ml/minute to 22 ml/minute.
In another embodiment of the present invention, the process provides for ortho-lithiation of trifluoromethyl benzene using a metallation agent, wherein the process is carried out in a pinch coiled flow reactor.
In another embodiment of the present invention, the solvent used is recovered, recycled and reused.
The compound of Formula I is isolated by using techniques known in the art for example distillation, evaporation, column chromatography and layer separation or combination thereof.
The compound of Formula I so obtained by the present invention has a purity greater than 95 %, more preferably greater than 98 %, most preferably greater than 99.6 % by gas chromatography.
The compound of Formula I so obtained by the present invention has a product composition in reaction mass greater than 90%, more preferably greater than 95 %, most preferably greater than 95 % by gas chromatography.
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: Process for preparation of 2,3-dichloro-6-trifluoromethyl benzaldehyde.
Reaction details: Solvent feed (2.5 ml/minute) started in the pre fixed continuous flow reactor attached three dosing pump, feed reservoir, pressure gauge, thermostat and backpressure regulator. The feed solution, F-1 (60 ml by mixing of 10.56 gm, 3,4-dichlorotrifluoromethylbenzene in Tetrahydrofuran), F-2 (60 ml by mixing 45 ml, 1.5 M n-butyl lithium solution in Tetrahydrofuran) and F-3 (70 ml by mixing of 9.49 gm, ethyl format in Tetrahydrofuran) were prepared and charged in their respective reservoirs under nitrogen atmosphere. Maintained the -10.8°C temperature in pinched coil flow reactor. Tetrahydrofuran feed is discontinued and F-1 feed (2.5 ml/minute) of 3,4-dichlorotrifluoromethylbenzene solution and F-2 feed (2.5 ml/minute) of n-butyl lithium started from P-1 point and P-2 point of Coil-1. F-3 feed (2.5 ml/minute) of ethyl format was started 1-minute after, starting of feed F-1 and F-2. In Coil-1 and Coil-2, 2.6 minutes and 1.86 minutes residence time was maintained to form lithiated salt and desired product respectively. Reaction sample was done after reaction attained the steady state. The eluted reaction mass from flow reactor was collected and quenched with aqueous hydrochloric acid (10%). After completion of the reaction, desired product (80-85%) composition obtained in reaction mass. Product was isolated using methyl tertiarybutylether extraction from reaction mass. Pure product was obtained by fractional distillation of organic mass. Yield: 70%; Purity: 99 %
Example-2:
Reaction details: Solvent feed started in the pre fixed continuous flow reactor attached three dosing pump, feed reservoir, pressure gauge, and thermostat and backpressure regulator. The feed solution, F-1 (120 ml by mixing of 21 gm, 3,4-dichlorotrifluoromethylbenzene in Tetrahydrofuran), F-2 (120 ml by mixing 90 ml, 1.5 M n-butyl lithium solution in Tetrahydrofuran) and F-3 (140 ml by mixing of 19 gm, ethyl format in Tetrahydrofuran) were prepared and charged in their respective reservoirs under nitrogen atmosphere. Maintained the -11°C temperature in pinched coil flow reactor. Tetrahydrofuran feed was discontinued and F-1 feed (9 ml/minute) of 3,4-dichlorotrifluoromethylbenzene solution and F-2 feed (9 ml/minute) of n-butyl lithium started from P-1 point and P-2 point of Coil-1. F-3 feed (18ml/minute) of ethyl format was started 1-minute after, starting of feed F-1 and F-2. In Coil-1 and Coil-2, 1.6 minutes and 1.4 minutes residence time was maintained to form lithiated salt and desired product respectively. Reaction sample was done after reaction attained the steady state and analysed by GC-A%. The eluted reaction mass from flow reactor was collected and quenched in aqueous hydrochloric acid (10%). Analysis: 3,4-dichlorotrifluoromethylbenzene–13.58%; 2,3-dichloro-6-trifluoromethyl benzaldehyde–70%;
Example-3:
Reaction details: As per example-1, reaction done in batch mode using round bottom flask with same reactant, solvent, reagents and mole ratios at -10°C reaction temperature. Reaction mass was analysed by GC-A% and reaction composition shows: 3,4-dichlorotrifluoromethylbenzene–4.31%; 2,3-dichloro-6-trifluoromethyl benzaldehyde–24.63%; Isomer–1.90%; Dimeric impurities-54.43%; Total unknown–14.73%.

CLAIMS:WE CLAIM:
1. A process for preparation of 2,3-dihalo-6-trifluoromethylbenzene derivatives of formula I,

Formula I
wherein X1 and X2 are independently selected from fluoro or chloro; Z represents COOH, CONH2, CN, CHO, CH=NOH or COOR’, wherein R’ is alkyl group,
comprising the step of:
a) concurrently contacting a compound of Formula II, metallating agent and an electrophilic agent in a flow reactor; and

Formula II
wherein X1 and X2, Z are defined above,
b) isolating the compound of Formula I.
2. The process as claimed in claim 1, wherein the metallating agent is selected from a group consisting of n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium and lithium diisopropylamide.
3. The process as claimed in claim 1, wherein the reaction is carried out in presence of a base selected from N,N,N',N'- tetramethyl ethylenediamine and N,N,N',N',N'- pentamethyl diethylenetriamine.
4. The process as claimed in claim 1, wherein the electrophilic agent is selected from a group consisting of carbon dioxide, ethyl formate, methyl formate, propyl formate, isopropyl formate, butyl formate, t-butyl formate, phenyl formate, benzyl formate ethyl acetate and dimethylformamide.
5. The process as claimed in claim 1, wherein the reaction is carried out in presence of a solvent selected from an aprotic or nonpolar organic solvent.
6. The process as claimed in claim 5, wherein the aprotic solvent is selected from diethylether, diisopropyl ether, methyl t-butylether, tetrahydrofuran, dioxane and nonpolar organic solvent is selected from hexane, pentane, toluene and xylene.
7. The process as claimed in claim 1, wherein the process is carried out at a temperature of -10 to -20°C.
8. The process as claimed in claim 1, wherein the process is carried out in a pinched coil flow reactor as depicted in “Figure 1” comprises of an outer cylinder equipped with a tube, which is pinched at regular interval.
9. The process as claimed in claim 1, wherein the compound of formula I is obtained with a purity greater than 95 %.

10. The process as claimed in claim 1, wherein the compound of formula I is obtained with a purity greater than 98 %.
Dated this 18th December 2019.