FIELD OF THE INVENTION
The present invention provides a process for the preparation of compound of Formula I.
BACKGROUND OF THE INVENTION 5
The substituted benzotrihalide of Formula I finds a wide range of purposes, mainly for organic reagents, pharmaceutical intermediates and agrochemical intermediates;
CX3XY
Formula I 10
wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NR1R2; R1 and R2, independent of each other, are selected from the group consisting of hydrogen, C1-4 alkyl and –COR; R is C1-4 alkyl.
The Chinese patent Publication No. 102951996 describes a following process for 15 the synthesis of 2-bromo-5-fluorobenzotrifluoride:
CF3FCF3FNO2CF3FNH2CF3FBr
The present inventors observed that nitration, as mentioned in above scheme, results in numerous isomeric nitro compounds, thereby resulting in need of numerous purification steps and high yield loss. While working for present 20
3
invention, the present inventors observed that the present process is economic, simple and has an advantage of high conversion, selectivity, yield and low effluent load.
OBJECTS OF THE INVENTION 5
An object of the present invention is to provide a process for the preparation of compound of Formula I:
CX3XY
Formula I
10
Another object of the present invention is to provide a process for the preparation of compound of Formula Ia:
CX3X2X1
Formula Ia
15
SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of compound of Formula I, comprising;
CX3XY
4
Formula I
wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NR1R2; R1 and R2, independent of each other, are selected from the group consisting of hydrogen, C1-4 alkyl and –COR; R is C1-4 alkyl; 5
a) halogenating a compound of Formula II in the presence of a halogenating agent to obtain a reaction mixture containing a compound of Formula I,
CX3Y
Formula II
X and Y have the same meaning as described earlier; 10
b) isolating the compound of Formula I from the reaction mixture,
wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, and alcohol solvent or mixture thereof.
In another aspect, the present invention provides a process for the preparation of 15 compound of Formula Ia, comprising;
a) halogenating a compound of Formula IIa in the presence of a halogenating agent to obtain a compound of Formula IIb, CX3NR1R2 CX3NR1R2X1 20
Formula IIa Formula IIb
5
X1, independent of each other, is selected from fluorine, chlorine, bromine and iodine; R1, R2 and X have the same meaning as described earlier
b) converting the compound of Formula IIb into a compound of Formula Ia in a reaction mixture, and
CX3X2X1 5
Formula Ia
X2 is selected from fluorine, chlorine and bromine; X1, and X have the same meaning as described earlier,
c) isolating the compound of Formula Ia from the reaction mixture,
wherein step a) takes place in the presence of solvents selected from the group 10 consisting of water, acetic acid, acetonitrile, and alcohol solvent or mixture thereof.
DESCRIPTION OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of compound of Formula I, comprising; 15
CX3XY
Formula I
wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NR1R2; R1 and R2, independent of each
6
other, are selected from the group consisting of hydrogen, C1-4 alkyl and –COR; R is C1-4 alkyl,
a) halogenating a compound of Formula II in the presence of a halogenating agent to obtain a reaction mixture containing a compound of Formula I,
CX3Y 5
Formula II
X and Y have the same meaning as described earlier;
b) isolating the compound of Formula I from the reaction mixture,
wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, alcohol solvent and 10 mixture thereof.
In another aspect, the present invention provides a process for the preparation of compound of Formula Ia, comprising;
halogenating a compound of Formula IIa in the presence of a halogenating agent to obtain a compound of Formula IIb, 15 CX3NR1R2 CX3NR1R2X1
Formula IIa Formula IIb
a)
X1, independent of each other, areis selected from the group consisting of fluorine, chlorine and bromine; R1,R2 and X have the same meaning as 20 described earlier,
7
b) converting the compound of Formula IIb into a compound of Formula Ia in a reaction mixture, and
CX3X2X1
Formula Ia
X2 is selected from fluorine, chlorine and bromine; X1, and X have the 5 same meaning as described earlier,
c) isolating the compound of Formula Ia from the reaction mixture,
wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, and alcohol solvent or mixture thereof. 10
The compound of Formula II and Formula IIa may be prepared by any method known in the art or the method disclosed in present art. The halogenating agent is selected from the group consisting of brominating agent, fluorinating agent, chlorinating agent, and iodinating agent. The brominating agent is selected from bromine or HBr/H2O2. The alcohol solvent may be selected from the group 15 consisting of methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, n-pentanol, 2-pentanol and mixture thereof. The halogenation may take place at a temperature of about 15oC to about 100oC, for example, at about 25oC to about 50oC. The halogenation of Formula II and/or Formula IIa may take about 1.0 hour to about 24 hours, for example, about 12 hours. 20
The compound of Formula I and/or Formula Ia may be isolated by filtration, layer separation, decantation, evaporation, concentration, crystallization and distillation or mixture thereof.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those 25
8
skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
5
Example 1
Preparation of N-(4-Bromo-3-Trifluoromethylphenyl)Acetamide
N-(3-Trifluoromethyl-phenyl)-acetamide (10 g), acetic acid (50 g) and hydrobromic acid (47%, 8.5 g) were taken together in a reaction vessel and temperature was maintained at 25oC. The hydrogen peroxide (50%, 3.32 g) was 10 added to the reaction mixture and temperature was maintained at 25oC. The reaction assembly inertized by nitrogen gas and mixture was further stirred for 30 minutes. The progress of the reaction was monitored by Gas Chromatography. The sodium bisulphite (30% aqueous solution) was added to the mixture and mixture was extracted twice with methylene dichloride. The organic layer was recovered 15 to obtain the title compound.
Yield (%): 90
Example 2
Preparation of 4-Bromo-3-trifluoromethyl-phenylamine 20
Charged 4-Bromo-3-(Trifluoromethyl phenyl) acetamide (100gm., 0.35 moles) and 14.7% aqueous solution of hydrochloric acid (224gm., 0.88 moles) at RT to a reaction flask. The temperature of the reaction mixture is raised to 90°C and maintained for 5-6 hrs. Monitor the reaction by HPLC. After complete conversion, the reaction mixture is cooled to 60-65°C. Charged 40% aqueous solution of 25 NaOH (142gm., 1.42moles) to neutralize the reaction mass. The organic phase was separated and title compound was isolated.
9
Yield (%): 94%
Example 3
Preparation of 2-bromo-5-iodo benzotrifluoride
Charged 35% aqueous hydrochloric acid solution (47gm., 0.44 moles), water 5 (95gm) and 5-amino-2-bromo-benzotrifluoride (20gm., 0.083moles) in the reaction flask. Cooled reaction mass to 5°C and charged chilled 15% aqueous solution of sodium nitrite (40gm., 0.09moles) in small portions maintaining 0°C. After complete addition of sodium nitrite, stirred the reaction mass at 0°C to 5°C for 1.0 hour to get diazonium salt solution. Then charged an aqueous solution of 10 potassium iodide (14gm., 0.08 moles) and further heated the reaction mixture to reflux point using a reflux condenser until no more gas is evolved then allowed to cool and stand undisturbed until the heavy organic layer has settled. The title compound was isolated.
Yield (%): 75% 15
Example 4
Preparation of 2-bromo-5-chloro benzotrifluoride
The diazonium salt solution was prepared as exemplified in example 3. The cold diazonium salt solution was poured into the well stirred and cooled mixture of 20 CuCl (8.9gm., 0.091moles) in concentrated hydrochloric acid (46gm., 0.44moles). The cold mixture is allowed to warm up to room temperature and stirring is continued for 2 to 3 hours. Further heat the reaction mixture to 60 – 70°C to complete the reaction and title compound was isolated.
Yield (%): 65% 25
10
Example 5
Preparation of 2,5-dibromo benzotrifluoride
Prepared diazonium salt solution as given in example 3, then cold diazonium salt solution is poured rapidly into the well stirred and cooled mixture of CuBr (13gm., 0.091moles) in concentrated hydro bromic acid(71gm., 0.44moles). The 5 cold mixture is allowed to warm up to room temperature and stirred for 2 to 3 hours. The reaction mixture was heated to 60 – 70°C to obtain title compound.
Yield (%): 63%
Example 6 10
Preparation of 1-Bromo-4-fluoro-2-trifluoromethyl-benzene
5-Amino-2-bromo-benzotrifluoride (48gm., 0.20 moles) was taken in autoclave reactor and reaction mass was cooled to – 10°C. The anhydrous hydrofluoric acid (104gm., 5.2moles) was added to the reaction mass and the temperature of the reaction mass was maintained at – 5°C. The sodium nitrite (15gm., 0.22moles) 15 was added to the reaction mixture in small portions. After complete addition of sodium nitrite, the reaction mass was stirred at – 5°C to 0°C for 1.0 hour. The reaction mass was heated to 125°C and the temperature was maintained for 30 minutes. The reaction mixture is poured into cooled water and the title product was isolated. 20
Yield (%): 80%

We claim:
1. A process for the preparation of compound of Formula I, comprising;
CX3XY
Formula I
wherein X is selected from the group consisting of fluorine, chlorine, bromine 5 and iodine; Y is selected from X and -NR1R2; R1 and R2, independent of each other, are selected from the group consisting of hydrogen, C1-4 alkyl and –COR; R is C1-4 alkyl,
a) halogenating a compound of Formula II in the presence of a halogenating agent to obtaina reaction mixture containing a compound of Formula I, 10
CX3Y
Formula II
wherein X is selected from the group consisting of fluorine, chlorine, bromine and iodine; Y is selected from X and -NR1R2; R1 and R2, independent of each other, are selected from the group consisting of hydrogen, C1-4 alkyl and –15 COR; R is C1-4 alkyl;
b) isolating the compound of Formula I from the reaction mixture,
wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile, and alcohol solvent, or mixture thereof. 20
2. A process for the preparation of compound of Formula Ia, comprising;
12
a) halogenating a compound of Formula IIa in the presence of a halogenating agent to obtain a compound of Formula IIb, CX3NR1R2 CX3NR1R2X1
Formula IIa Formula IIb
5
wherein X1 is selected from the group consisting of fluorine, chlorine, bromine and iodine; X is selected from the group consisting of fluorine, chlorine, bromine and iodine; R1 and R2, independent of each other, are selected from the group consisting of hydrogen, C1-4 alkyl and –COR; R is C1-4 alkyl; 10
b) converting the compound of Formula IIb into a compound of Formula Ia in a reaction mixture, and
CX3X2X1
Formula Ia
X2 is selected from fluorine, chlorine and bromine; X1, and X have the 15 same meaning as described earlier,
c) isolating the compound of Formula Ia from the reaction mixture, wherein step a) takes place in the presence of solvents selected from the group consisting of water, acetic acid, acetonitrile and alcohol solvent or mixture thereof. 20
13
3. The process of claim 1 or 2, wherein the halogenating agent is selected from the group consisting of brominating agent, fluorinating agent, chlorinating agent, and iodinating agent.
4. The process of claim 3, wherein the brominating agent is selected from bromine or HBr/H2O2. 5
5. The process of claim 1 or 2, wherein the alcohol solvent may be selected from methanol, ethanol, n-propanol, 2-propanol, n-butanol, 2-butanol, n-pentanol and 2-pentanol or mixture thereof.
6. The process of claim 1 or 2, wherein the halogenation takes place at temperature in the range of 15oC to 100oC. 10
7. The process of claim 6, wherein the halogenation takes place at temperature in the range of 25oC to 50oC.
8. The process of claim 1 or 2, wherein the compounds of Formula I and/or Formula Ia are isolated by filtration, layer separation, decantation, evaporation, concentration, crystallization and distillation or mixture 15 thereof.