PROCESS FOR THE PREPARATION OF 2-(TRIHALOMETHYL)
BENZAMIDE
FIELD OF THE INVENTION
The present invention relates to a process for preparation of 2-(trihalomethyl)
benzamide.
BACKGROUND OF THE INVENTION
The substituted benzamides, especially 2-(trihalo methyl) benzamideof Formula I,
find vast usage in pharmaceutical and agrochemical field. The Welch et. al.,Journal
of Medicinal Chemistry (1969), 12(2), 299-303 describes a general process for
preparation of α,α,α-trifluorotoluamides by reacting corresponding α,α,α-
trifluorotoluic acid chloride with concentrated ammonium hydroxide. However,
Journal of Medicinal Chemistry (1969), 12(2), 299-303 provides no specific
example for such amidation reaction wherein the yield and purity of the product is
illustrated.
CX3
NH
O
R
Formula I
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group.
Despite the teaching of the prior art, the research for new preparation processes of
halo alkyl substituted benzamides is still an active field and there still persists a need
in the art to develop industrially scalable and economic process for the preparation
of halo alkyl substituted benzamides.
2
OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a process for preparation of
2-(trihalomethyl) benzamide.
SUMMARY OF THE INVENTION
An aspect of the present invention provides a process for the preparation of 2-
(trihalomethyl) benzamide of Formula I,
CX3
NH
O
R
Formula I
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
said process comprising;
(i) reacting a compound of Formula II with a compound of Formula III in the
presence of iso-propanol to obtain a reaction mixture; and
CX3
Cl
O
R NH2
Formula II Formula III
3
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
(ii) isolating the compound of Formula I from the reaction mixture.
In an embodiment of the present invention, there is provided a process for the
preparation of 2-(trihalomethyl) benzamide of Formula I, wherein the reaction is
carried out at a temperature in the range of about -75oC to about 25oC.
In another embodiment of the present invention, there is provided a process for the
preparation of 2-(trihalomethyl) benzamide of Formula I, wherein the reaction is
carried out at a time period in the range of about 10 minutes to about 6 hours.
In yet another embodiment of the present invention, there is provided a process for
the preparation of 2-(trihalomethyl) benzamide of Formula I, wherein the compound
of Formula I is isolated by a process selected from the group consisting of filtration,
precipitation, decantation, crystallization, evaporation, layer separation and
distillation or a combination thereof.
In still another embodiment of the present invention, there is provided a process for
the preparation of 2-(trihalomethyl) benzamide of Formula I, wherein the reaction
mixture is stirred to facilitate the reaction.
Another aspect of the present invention provides a process for the preparation of 2-
(trihalomethyl) benzamide of Formula I,
CX3
NH
O
R
Formula I
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
4
said process comprising;
(i) reacting a compound of Formula II with a compound of Formula III in the
presence of cold water to obtain a reaction mixture; and
CX3
Cl
O
R NH2
Formula II Formula III
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
(ii) isolating the compound of Formula I from the reaction mixture.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparation of 2-(trihalomethyl)
benzamide of Formula I,
CX3
NH
O
R
Formula I
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
said process comprising;
5
a) reacting a compound of Formula II with a compound of Formula III in the
presence of iso-propanol to obtain a reaction mixture; and
CX3
Cl
O
R NH2
Formula II Formula III
wherein X is selected from the group consisting of fluorine, chlorine, bromine
and iodine; and R is hydrogen or substituted/un-substituted C1-C7 alkyl group,
b) isolating the compound of Formula I from the reaction mixture.
The present invention also provides a process for the preparation of 2-
(trihalomethyl) benzamide of Formula I,
CX3
NH
O
R
Formula I
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
said process comprising;
(i) reacting a compound of Formula II with a compound of Formula III in the
presence of cold water to obtain a reaction mixture; and
6
CX3
Cl
O
R NH2
Formula II Formula III
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
(ii) isolating the compound of Formula I from the reaction mixture.
The compound of Formula II is prepared by any method known in the art, for
example, as provided in Indian Patent Application no. 3476/DEL/2011. The reaction
of compound of Formula II with compound of Formula III in iso-propanol or cold
water takes place at a temperature in the range of about -75oC to about 25oC, for a
time period in the range of about 10 minutes to about 6 hours. The compound of
Formula III may be in liquid form or in gaseous form. The reaction mixture may be
stirred to facilitate the reaction. The compound of Formula I is isolated by filtration,
precipitation, decantation, crystallization, evaporation, layer separation and
distillation or a combination thereof.
The compound of Formula I, obtained by the present invention, has a purity greater
than about 98%, for example, greater than about 99% by HPLC.
The compound of Formula I, obtained by the present invention, is used for
preparation of various agrochemical and medicinal products.
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.
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EXAMPLE
Preparation of 2-(Trifluoromethyl) Benzamide
a) 2-Trifluoromethyl benzoyl chloride (50 g) and iso-propanol (400 g) were taken in a reaction vessel and ammonia gas was purged into it. The reaction was allowed to stir for 3.5 hours at a temperature in the range of -10°C to 0°C to facilitate the reaction. The ammonium chloride was precipitated out and the reaction mixture was filtered to obtain a filtrate. The filtrate was concentrated to obtain the compound of Formula I.
Yield: 90%
Purity (% by HPLC): 99%
a) 2-Trifluoromethyl benzoyl chloride (20 g), cold water (20 g) and ammonium hydroxide (aqueous ammonia) (19.6 g) were taken in a reaction vessel and the temperature was maintained at 10oC. The reaction was allowed to stir for 3.5 hours to facilitate the reaction. The reaction mixture was then filtered and washed with water. The filtrate was concentrated to obtain the compound of Formula I.
Yield: 90.6 %
Purity (% by HPLC): > 99% 8

We claim:
1. A process for the preparation of 2-(trihalomethyl) benzamide of Formula I,
CX3
NH
O
R
Formula I
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
said process comprising:
a) reacting a compound of Formula II with a compound of Formula III in the
presence of iso-propanol to obtain a reaction mixture; and
CX3
Cl
O
R NH2
Formula II Formula III
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
b) isolating the compound of Formula I from the reaction mixture.
2. The process as claimed in claim 1, wherein the reaction is carried out at a
temperature in the range of about -75oC to about 25oC.
3. The process as claimed in claim 1, wherein the reaction is carried out at a time
period in the range of about 10 minutes to about 6 hours.
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4. The process as claimed in claim 1, wherein the compound of Formula I is isolated
by a process selected from the group consisting of filtration, precipitation,
decantation, crystallization, evaporation, layer separation and distillation or a
combination thereof.
5. The process as claimed in claim 1, wherein the reaction mixture is stirred to
facilitate the reaction.
6. A process for the preparation of 2-(trihalomethyl) benzamide of Formula I,
CX3
NH
O
R
Formula I
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
said process comprising:
(i) reacting a compound of Formula II with a compound of Formula III in the
presence of cold water to obtain a reaction mixture; and
CX3
Cl
O
R NH2
Formula II Formula III
wherein X is selected from the group consisting of fluorine, chlorine,
bromine and iodine; and R is hydrogen or substituted/unsubstituted C1-C7
alkyl group,
ii) isolating the compound of Formula I from the reaction mixture.