WO2015125155A1 - Process for the preparation of 2,6-dihalo-para-trifluoromethyl- anilines as intermediates of pyrazoles - Google Patents

Process for the preparation of 2,6-dihalo-para-trifluoromethyl- anilines as intermediates of pyrazoles Download PDF

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WO2015125155A1
WO2015125155A1 PCT/IN2015/000095 IN2015000095W WO2015125155A1 WO 2015125155 A1 WO2015125155 A1 WO 2015125155A1 IN 2015000095 W IN2015000095 W IN 2015000095W WO 2015125155 A1 WO2015125155 A1 WO 2015125155A1
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formula
compound
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Sarathy IYENGAR
Thanga Selvam KAMARAJ
Ravi Kumar YARRAPOTHU
Maheshwaran CHELLAIAH
Arumugam NAGAPPAN
Srinivasan RAGURAMAN TIRUCHY
Rahul Saxena
Rajdeep Anand
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Srf Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/10—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings

Definitions

  • the present invention provides a process for the preparation of N-substituted fluorine- 5 containing pyrazole derivatives and their intermediates.
  • the N-substituted fluorme-containing pyrazole derivatives and their intermediates such as 2, 6-dihalo-para-trifluoromethylaniline, are valuable in the field of medicine and agricultural chemicals.
  • the EP Patent No. 1,558,560 Bl discloses a process for the preparation of 2, 6-dihalo-para- trifluoromethylaniline from para-trifluoromethylaniline by reaction of para- trifluoromethylaniline with dihalogen X 2 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.
  • 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 X 2 (X being chlorine atom) at a high temperature of 110°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 the0 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.
  • the present invention provides a process for the preparation of a compound of Formula I,
  • step i) isolating compound of Formula I, wherein step i) is carried out a temperature ranging from 20°C to 80°C.
  • the present invention also provides a process for the preparation of a compound of Formula I,
  • Formula III Formula II ii) reacting a compound of Formula II with dihalogen X 2 , and in) isolating compound of Formula I, wherein step ii) is carried out a temperature ranging from 20°C to 80°C.
  • the solvent is selected from the group consisting of dioxane, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidine, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof.
  • the solvent is N-methyl pyrrolidine.
  • the solvent is selected from the group consisting of dioxane, tetrahydrofuran, dimethyl sulfoxide, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof.
  • the present invention provides a process for the preparation of a compound of Formula I,
  • step i) isolating compound of Formula I, wherein step i) is carried out a temperature ranging from 20°C to 80°C.
  • step 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 III may be prepared by any method known in the art or by the 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-trifluoromethylamline.
  • the reaction of compound of Formula III with ammonia to obtain the compound of Formula II may take place in the presence of aprotic solvent.
  • the aprotic solvent may be selected from group consisting of dioxane, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidine, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof.
  • the reaction of compound of Formula III with ammonia 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 II obtained is not isolated from the mixture.
  • the process may be continuous and unreacted compound of Formula III may be recycledfor conversion to compound of Formula II.
  • the reaction between compound of Formula II 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, dimethyl sulfoxide, N-methyl pyrrolidine, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof.
  • the reaction of compound of Formula II with dihalogen takes place at a temperature preferably for about 20°C to about 80°C for about 12 hours to 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 invention is pure to greater than 98.0%, preferably greater than 98.5 % by HPLC.
  • 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.
  • 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 absence of 4-trifluromethyl aniline. Thereafter, theammonia gas (130 g) was passed into the reaction mixture at below 60°C, the mixture was cooled to 20 to 25°C and filtered. The filtrate was distilled to obtain the title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides a process for the preparation of 2,6-dihalo-para-trifluoromethylanilines as intermediates for pyrazoles comprising the halogenation of para-trifluoromethylaniniline with dihalogen.

Description

PROCESS FOR THE PREPARATION OF 2,6-DTHAEO-PARA-TRTFT JTOROMETHYT ANTT TNES AS TNTER MEDIATES OF PYRAZOEES
Field of the Invention
The present invention provides a process for the preparation of N-substituted fluorine- 5 containing pyrazole derivatives and their intermediates.
Background of the Invention
The N-substituted fluorme-containing pyrazole derivatives and their intermediates such as 2, 6-dihalo-para-trifluoromethylaniline, are valuable in the field of medicine and agricultural chemicals. 0 The EP Patent No. 1,558,560 Bl discloses a process for the preparation of 2, 6-dihalo-para- trifluoromethylaniline from para-trifluoromethylaniline by reaction of para- trifluoromethylaniline 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. 5 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 110°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 the0 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.
Object 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. 5 Summary of the Invention
The present invention provides a process for the preparation of a compound of Formula I,
Figure imgf000003_0001
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 from 20°C to 80°C.
Figure imgf000003_0002
Formula II The present invention also provides a process for the preparation of a compound of Formula I,
Figure imgf000003_0003
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 III with ammonia to obtain a compound of Formula II,
Figure imgf000004_0001
Formula III Formula II ii) reacting compound of Formula II with dihalogen X2, and
iii) isolating compound of Formula I, wherein compound of Formula II is not isolated from the reaction mixture.
The present invention also provides a process for the preparation of a compound of Formula I,
Figure imgf000004_0002
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 III with ammonia to obtain a compound of Formula II,
Figure imgf000004_0003
Formula III Formula II ii) reacting a compound of Formula II with dihalogen X2, and in) isolating compound of Formula I, wherein step ii) is carried out a temperature ranging from 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, cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof.
In another embodiment of the invention, the solvent is N-methyl pyrrolidine.
In yet 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. Detailed Description of the Invention
The present invention provides a process for the preparation of a compound of Formula I,
Figure imgf000005_0001
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 from 20°C to 80°C.
Figure imgf000005_0002
Formula II The present invention also provides a process for the preparation of a compound of Formula
I,
Figure imgf000006_0001
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 III with ammonia to obtain a compound of Formula II,
Figure imgf000006_0002
Formula III Formula II ii) reacting compound of Formula II with dihalogen X2, and
iii) isolating compound of Formula I, wherein compound of Formula II is not isolated from the reaction mixture. The present invention also provides a process for the preparation of a compound of Formula I,
Figure imgf000006_0003
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 III with ammonia to obtain a compound of Formula II,
Figure imgf000007_0001
Formula III Formula II ii) reacting a compound of Formula II 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 III may be prepared by any method known in the art or by the 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-trifluoromethylamline.
The reaction of compound of Formula III with ammonia to obtain the compound of Formula II may take place in the presence of aprotic solvent. The aprotic solvent may be selected from group consisting of dioxane, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidine, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof. The reaction of compound of Formula III with ammonia 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 II obtained is not isolated from the mixture. The process may be continuous and unreacted compound of Formula III may be recycledfor conversion to compound of Formula II.
The reaction between compound of Formula II 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, dimethyl sulfoxide, N-methyl pyrrolidine, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof. The reaction of compound of Formula II with dihalogen takes place at a temperature preferably for about 20°C to about 80°C for about 12 hours to 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 invention is pure to greater than 98.0%, preferably greater than 98.5 % by HPLC.
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.
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.
Examples Preparation of 2, 6-Dichloro-4-(Trifluoromethyl")Aniline i) Dry Chlorine gas (1014 g) was passed through 4-chlorotoluene (500 g) which is heated to 35°C 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 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 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 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 absence of 4-trifluromethyl aniline. Thereafter, theammonia gas (130 g) was passed into the reaction mixture at below 60°C, the mixture was cooled to 20 to 25°C and filtered. The filtrate was distilled to obtain the title compound.
Yield: 75 %.
Purity: 98.59%

Claims

We claim:
1. A process for the preparation of a compound of Formula I,
Figure imgf000010_0001
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 from 20°C to 80°C.
Figure imgf000010_0002
Formula II
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 pyrrolidine, glyme, diglyme, toluene, cyclohexane, methylcyclohexane and carbon tetrachloride or mixture thereof.
3. A process for the preparation of a compound of Formula I,
Figure imgf000011_0001
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 III with ammonia to obtain a compound of Formula II,
Figure imgf000011_0002
Formula III Formula II ii) reacting compound of Formula II with dihalogen X2, and
iii) isolating compound of Formula I, wherein compound of Formula II is not isolated from the reaction mixture.
The process of claim 3, wherein step i) takes place in the presence of solvent selected from group consisting of dioxane, tetrahydrofuran, dimethyl sulfoxide, N-methyl pyrrolidine, 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 III may be recycled for conversion to compound of Formula II.
6. A process for the preparation of a compound of Formula I,
Figure imgf000012_0001
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 III with ammonia to obtain a compound of Formula II,
Figure imgf000012_0002
Formula III Formula II ii) reacting a compound of Formula II 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%.
PCT/IN2015/000095 2014-02-19 2015-02-19 Process for the preparation of 2,6-dihalo-para-trifluoromethyl- anilines as intermediates of pyrazoles WO2015125155A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109574863A (en) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 A kind of synthetic method of -4 ' of 2- amino-fluoro- benzophenone

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EP1558560B1 (en) 2002-10-25 2008-12-31 BASF Agro B.V., Arnhem (NL)-Wädenswil-Branch Process for the preparation of 2,6-dihalo-para-trifluoromethylaniline
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109574863A (en) * 2017-09-28 2019-04-05 安徽省庆云医药股份有限公司 A kind of synthetic method of -4 ' of 2- amino-fluoro- benzophenone
CN109574863B (en) * 2017-09-28 2021-09-14 安徽省庆云医药股份有限公司 Synthesis method of 2-amino-4' -fluoro-benzophenone

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