PROCESS FOR THE PREPARATION OF PYRAZOLES AND THEIR
INTERMEDIATES
Field of the Invention
The present invention provides a process for the preparation uf N-substituted fluorine-
5 containing pyrazole derivatives and their intermediates.
Background of the Invention
The N-substituted fluorine-containing pyrazole derivatives and their intermediates such as 2,
6-dihalo-para-trifluoromethylaniline,a re valuable in the field of medicine and agricultural
chemicals.
10 The EP Patent No. 1,558,560 B1 discloses a process for the preparation of 2, 6-dihalo-paratrifluoromethylaniline
from para-trifluoromethylaniline by reaction of paratrifluoromethylaniline
with dihalogen X2 at a temperature ranging from 100°C to 300°C in the
presence of chlorinated aromatic solvent. The X represents a halogen atom. The X can be
chlorine atom, bromine atom, an iodine atom or a fluorine atom.
15 The present inventors have observed that many undesired polymeric impurities such as poly
chlorinated compounds are formed while performing reaction of para-trifluoromethylaniline
with dihalogen X2(X being chlorine atom) at a high temperature of 1 10°C or above. While
performing the reaction, the present inventors observed that temperature range plays an
important role in the formation of impurities. The present inventors discovered that the
20 reaction carried out at a lower range of temperature significantly reduced the formation of
polymeric impurities, thus making the process commercially more viable and feasible.
Obiect of the Invention
It is an object of the invention to provide a process for the preparation of N-substituted
fluorine-containing pyrazole derivatives and their intermediates.
Summarv of the Invention
The present invention provides a process for the preparation of a compound of Formula I,
Formula I
wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
or a fluorine atom, the process comprising:
i) reacting compound of Formula I1 with dihalogen X2, and
ii) isolating compound of Formula I, wherein step i) is carried out a temperature ranging
from 20°C to 80°C.
Formula II
The present invention also provides a process for the preparation of a compound of Forinula
I,
Formula I
wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
or a fluorine atom, the process comprisirig:
i) reacting compound of Formula III with ammonia to obtain a compound of Formula 11,
I P O DELHH 19-02-8815 3 . G : E 7
Formula III
CF
Formula II
ii) reacting compound of Formula 11 with dihalogen X2, and
5 iii) isolating compound of Formula I, wherein compound of Formula 11 is not isolated
from the reaction mixture.
The present invention also provides a process for the preparation of a compound of Formula
I,
Formula I
wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
or a fluorine atom; the process comprising:
i) reacting compound of Formula 111 with ammonia to obtain a compound of Formula 11,
Formula El Formula 11
ii) reacting a compound of Formula II with dlhalogen Xz, and
iii) isolating'compound of Formula I, wherein step ii) is carried out a temperature ranging
fiom 20°C to 80°C.
In an embodiment of the invention, the solvent is selected from the group consisting of
dioxane, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidine, glyme, diglyme, toluene,
5 cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof.
In another embodiment of the invention, the solvent is N-methyl pyrrolidine.
In ye; another embodiment of the invention, the solvent is selected from the group consisting
of dioxane, tetrahydrofuran, dimethyl sulfoxide, glyme, diglyme, toluene, cyclohexane,
methylcyclohexane and carbon tetrachloride or mixture thereof.
10 Detailed Descrivtion of the Invention
The present invention provides a process for the preparation of a compound of Formula I,
Formula I
wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
15 or a fluorine atom, the process comprising:
i) reacting compound of Formula I1 with dihalogen X2, and
ii) isolating compound of Formula I, wherein step i) is carried out a temperature
ranging from 20°C to 80°C.
Formula II
The present invention also provides a process for the preparation of a compound of Formula
I,
Formula I
5 wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
or a fluorine atom, the process comprising:
i) reacting compound of Formula 111 with ammonia to obtain a compound of Formula 11,
Formula III Formula II
ii) reacting compound of Formula 11 with dihalogen X2,an d
iii) isolating compound of Formula I, wherein compound of Formula II is not isolated
from the reaction mixture.
15 The present invention also provides a process for the preparation of a compound of Formula
I,
Formula I
wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
or a fluorine atom; the process comprising:
i) reacting compound of Formula 111 with ammonia to obtain a compound of Formula 11,
Formula III Formula II
ii) reacting a compound of Formula 11 with dihalogen X2, and
iii) isolating compound of Formula I, wherein step ii) is carried out a temperature ranging
from 20°C to 80°C.
The compound of Formula ID may be prepared by any method known in the art or by the
10 method exemplified in the present disclosure.
The compound of Formula I prepared by virtue of the process of present invention is
preferably 2,6-dichloro-para-trifluoromethylaniline.
The reaction of compound of Formula 111 with ammonia to obtain the compound of Formula
I1 may take place in the presence of aprotic solvent. The aprotic solvent may be selected from
15 group consisting of dioxane, tetrahydrofilran, dimethyl sulfoxidc, N-methyl pyrrolidine,
glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon tetrachloride or
mixture thereof. The reaction of compound of Formula 111 with aqunonia may take place at a
temperature of about 120°C to about 180°C preferably for about 12 hours to about 20 hours.
The compound of Formula I1 obtained is not isolated from the mixture. The process may be
20 continuous and unreacted compound of Formula 111 may be recycledfor conversion to
compound of Formula 11.
The reaction between compound of Formula I1 and dihalogen to obtain the compound of
Formula I may take place in the presence of aprotic solvent. The aprotic solvent may be
selected from group consisting of dioxane, tetrahydrofuran, dirnethyl sulfoxide, N-methyl
25 pyrrolidine, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon
tetrachloride or mixture thereof. The reaction of compound of Formula I1 with dihalogen
takes place at a temperature preferably for about 20°C to about 80°C for about 12 hours to
- - - f " k j - . ~ s w 6 h ~ ~ ~ - ~ ~ - ~ ~ - & d - ~ - ~ - k ~ L - P -
about 20 hours..The compound of Formula I may be isolated from the reaction mixture by the
methods known in the art, for example, filtration, decantation, layer separation, precipitation,
distillation and evaporation or mixture thereof.
The 2,6-dichloro-para-trifluoromethylaniline prepared by virtue of the process of present
5 invention is pure to greater than 98.0%, preferably greater than 98.5 % by KPLC.
The compound of Formula I is a very useful intermediate in the synthesis of fipronil and
ethiprole. The fipronil and ethiprole compounds may be prepared by any method known in
the art using compound of Formula I, wherein compound of Formula I is prepared as per
present invention.
10 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.
Preparation of 2. 6-Dichloro-4-~Trifluoromethy1~Aniline
15 i) Dry Chlorine gas (1014 g) was passed through 4-chlorotoluene (500 g) which is
heated to 35OC initially in a glass assembly using visible lights. The reaction was
found to be complete in 8 hours to 9 hours.The reaction mass was cooled to room
temperature and dry nitrogen gas was passed through it for 1 hours to 2 hours. The
crude mixture was analysed for free chlorine, hydrochloric acid and then used in next
20 step.
ii) Anhydrous HF (200 g) was passed into 4-chlorobenzotrichloride (500 g) in an
autoclave and the mixture was heated to 50°C. The pressure was maintained at 10 bar
by releasing the excess hydrochloric acid through condenser which was cooled to -
30°C continuously. The reaction was maintained for 7 hours to 8 hours. The reaction
25 pressure was vented and the mass was heated to 80°C and dissolved hydrochloric
acidandhydro fluoric were expelled. The reaction mass was worked up to get pure 4-
chlorobenzotrifluoride.
iii) The 4-Chloro benzotrifluride (1000 g), Copper powder (35 g), Copper (II) acetate
monohydrate (275 g), lime (77 g), N- methyl pyrrolidone(2500 g) and ammonia (500
30 g) were taken in 5 litre autoclave. The autoclave was heated to 140°C and initial
pressure was maintained at 42 kg/cm2. These reaction conditions were maintained for
20 hours.After 20 hours, the pressure of the reaction was reduced to 30 kg/cm2andthe
reaction mass was cooled to room temperature. The resultant mass was filtered
followed by distillation to remove unreacted 4-chloro benzotrifluride.To the residue,
535 g of chlorine gas was passed at below 60°C and reaction was monitored for the
5 absence of 4-rifluromethyl aniline. Thereafter, theammonia gas (1 30 g) was passed
into the reaction mixture at below 60°C, the mixture was cooled to 20 to 2S°C and
filtered. The filtrate was distilled to obtain the title compound.
Yield: 75 %.
Purity: 98.59%

We claim:
1. A process for the preparation of a compound of Formula I,
5 Formula I
wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
or a fluorine atom, the process comprising:
i) reacting compound of Formula II with dihalogen X2, and
ii) isolating compound of Formula I, wherein step i) is carried out a temperature ranging
10 fi-om 20°C to 80°C.
Formula I1
2. The process of claim 1, wherein step i) takes place in the presence of solvent selected
from group consisting of dioxane, tetrahydrofuran, dimethyl sulfoxide, N-methyl
15 pyrrolidine, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon
tetrachloride or mixture thereof.
3. A process for the preparation of a compound of Formula I,
Formula I
wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
or a fluorine atom, the process comprising:
i) reacting compound of Formula 111 with ammonia to obtain a compound of Formula 11,
5
Formula III Formula II
ii) reacting compound of Formula I1 with dihalogen X2, and
10 iii) isolating compound of Formula I, wherein compound of Formula 11 is not isolated
from the reaction mixture.
4. The process of claim 3, wherein step i) takes place in the presence of solvent selected
fiom ,group consisting of dioxane, tetrahydrofuran, dimethyl sulfoxide, N-methyl
15 pyrrolid&e, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon
tetrachloride or mixture thereof.
5. The process of claim 3, wherein the process may be continuous and unreacted
compound of Formula 111 may be recycled for conversion to compound of Formula II.
20
6. A process for the preparation of a compound of Formula I,
Formula I
wherein X represents a halogen atom; X can be chlorine atom, bromine atom, an iodine atom
or a fluorine atom; the process comprising:
i) reacting compound of Formula 111 with ammonia to obtain a compound of Formula 11,
Formula III Formula I1
ii) reacting a compound of Formula LI with dihalogen X2, and
iii) isolating compound of Formula I, wherein step ii) is carried out a temperature ranging
from 20°C to 80°C.
7. The process of claims 1, 3 or 6, wherein the compound of Formula I is isolated from
the reaction mixture by filtration, decantation, layer separation, precipitation,
distillation and evaporation or mixture thereof.
8. The compound of Formula I, as prepared by process claimed in claims 1, 3 or 6,
having purity greater than 98.5%.