WO2019097306A2

WO2019097306A2 - Synthesis of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-ethylsulfanyl-1h-pyrazole-3-carbonitrile and related compounds

Info

Publication number: WO2019097306A2
Application number: PCT/IB2018/001622
Authority: WO
Inventors: Eran FOGLER; Yehudah Rachamim WISEMAN; Sanaa MUSA; Natalia STRIZHIVER; Michael Grabarnick; Michael MOGILNITSKY
Original assignee: Adama Makhteshim Ltd
Current assignee: Adama Makhteshim Ltd
Priority date: 2017-11-15
Filing date: 2018-11-13
Publication date: 2019-05-23
Anticipated expiration: 2020-05-15
Also published as: CN111386256A; BR112020009705A2; WO2019097306A3; JP2021502991A

Abstract

The present disclosure relates to a process for the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-4-ethylsulfanyl-1H-pyrazole-3-carbonitrile and related compounds.

Description

SYNTHESIS OF 5-AMINO-l-(2,6-DICHLORO-4-TRIFLUOROMETHYL- PHENYL)-4-ETHYLSULFANYL-lH-PYRAZOLE-3-CARBONITRILE AND RELATED COMPOUNDS

This application claims priority of U.S. Provisional Application No. 62/586,342, filed November 15, 2017, the entire content of which is hereby incorporated by reference herein.

Throughout this application various publications are referenced. The disclosures of these documents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

TECHNICAL FIELD

The present disclosure relates to a process for the preparation of 5-amino-l-(2,6-dichloro- 4-trifluoromethyl-phenyl)-4-ethylsulfanyl-lH-pyrazole-3-carbonitrile and related compounds.

BACKGROUND OF THE INVENTION

Ethiprole, 5-amino-l-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-(ethylsulfinyl)-li/- pyrazole-3-carbonitrile (CAS Registry No. 181587-01-9), is represented by the following structural formula:

Ethiprole belongs to the phenylpyrazole chemical family. It acts as a blocker of the GABA-regulated chloride channel, and is used for controlling insects.

5-Amino-l-(2,6~dichloro-4-trifluoromethyl-phenyl)-4-ethylsulfanyl-lH-pyrazole-3- carbonitrile of the structure

is an important intermediate in the preparation of ethiprole, and it may be obtained by the thiolation of the corresponding phenylpyrazole.

" Synthetic Communications", 2012, 42, 3472-3481 discloses a thiolation process of phenylpyrazole with disulfide using FeBr₃/I₂ complex as the catalyst in MeCN at 80 °C. This reaction exhibits some disadvantages. This catalytic reaction is performed in air atmosphere, thus requires oxygen; due to the reaction temperature, the disulfides require aromatic functional groups having a high boiling point; and a very long reaction time. These requirements render the reaction unsuitable for industrial processes. First, the extremely long reaction time makes the reaction less favorable. Second, industrial reactions are usually performed in inert conditions that will require the addition of oxygen to the reaction which is highly explosive.

Indian application No. 331/MUM/2014 filed January 30, 2014, discloses a process for synthesizing alkyl thiopyrazole. The reaction comprises reacting an alkyl sulfenyl halide, an aminopyrazole, an amine salt and a solvent selected from ethylene chloride and methylene chloride, in an inert atmosphere in the temperature range of (-20) to 50 °C. The solvents disclosed in Indian application No. 331 /MUM/2014 are volatile and highly polluting and are consider carcinogenic and very problematic to use, the amine salt that is formed by complexing an amine with a strong acid is highly corrosive, and the reaction time is long.

Based on the disadvantages in the above processes, it would be highly desirable to have an improved process for the production of 5-amino-l-(2,6-dichloro-4-trifluoromethyl- phenyl)-4-ethylsulfanyl-lH-pyrazole-3-carbonitrile which is suitable for industrial use, simple, low-cost, highly efficient, short reaction time and environmentally friendly, thereby overcoming the deficiencies of the prior art.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing a compound of formula (I)

[I], the process comprises reacting a compound of formula (II)

with disulfide having the structure of Ri-S-S-Ri and an halogenating agent selected from sulfuryl chloride, Cl₂, Br_2, l_2,iV-chlorosuccinimide, 7V-bromosuccinimide and N- iodosuccinimide in the presence of nitrile solvent, wherein

Ri is selected from Ci-C₆ alkyl, Ci-C₆ haloalkyl, cycloalkyl, heterocyclyl, aryl and benzyl;

R₂ is selected from cyano, nitro, halogen, C₁-C4 alkyl, C1-C4 haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C₁-C₄ alkyl sulphinyl which is unsubstituted or substituted by one or more halogen atoms, and Ci-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

The present invention also provides a process for preparing a compound of formula (I)

comprising reacting a compound of formula (II)

with a mixture of disulfide having the structure of Ri-S-S-Rj and an halogenating agent selected from sulfuryl chloride, Cl₂, Br_2, l_2,-V-chlorosuccinimide, /V-bromosuccinimide and /V-iodosuccinimide in the presence of nitrile solvent, wherein

R₂ is selected from cyano, nitro, halogen, Ci-C₄ alkyl, C₁-C₄ haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C₁-C₄ alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C₁-C₄ alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

The present invention also provides a compound of formula (III)

[III] wherein,

R is selected from cyano, nitro, halogen, Ci~C₄ alkyl, C₁-C₄ haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C1-C₄ alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms;

R₄ is optionally substituted Ci-CV, alkyl or optionally substituted phenyl, and n is an integer from 1-5.

The present invention further provides a process for preparing ethiprole having the structure

which comprises converting the compound of formula (II) into a compound of formula (I), wherein the compound of formula (I) is prepared according to any embodiment of the present invention.

The present invention further provides a process for preparing iiproni) having the structure

The present invention further provides a process for preparing a compound having the formula (IV)

comprising the oxidation of the compound having the formula (I) with an oxidizing agent, wherein the oxidation is carried out without isolating the compound of formula (I) prior to the oxidation step, and wherein:

Ri is selected from Ci-C₆ alkyl, Ci-C₆ haloalkyl, cycloalkyl, heterocyclyl, aryl and benzyl; R₂ is selected from cyano, nitro, halogen, C₁-C₄ alkyl, C₁-C4 haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C1-C4 alkyl, C₁-C4 haloalkyl, CjATt alkoxy, C_J-C₄ haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C₁-C₄ alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C4 alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Prior to setting forth the present subject matter in detail, it may be helpful to provide definitions of certain terms to be used herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this subject matter pertains. The following definitions are provided for clarity.

The term“a” or“an” as used herein includes the singular and the plural, unless specifically stated otherwise. Therefore, the terms“a,”“an,” or“at least one” can be used interchangeably in this application.

As used herein, the term“about” when used in connection with a numerical value includes ±10% from the indicated value. In addition, all ranges directed to the same component or property herein are inclusive of the endpoints, are independently combinable, and include all intermediate points and ranges. It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention.

Throughout the application, descriptions of various embodiments use the term

“comprising”; however, it will be understood by one of skill in the art, that in some specific instances, an embodiment can alternatively be described using the language “consisting essentially of’ or“consisting of’. In each such instance, the terms “comprising,”“consisting essentially of,” and“consisting of’ are intended to have the same meaning as each such term would have when used as the transition phrase of a patent claim.

In the context of the present invention, the terms used generically are defined as follows:

The term "halogen" denotes in each case fluorine, bromine, chlorine or iodine.

The term "C₁-C₄ alkyl" denotes an optionally substituted linear or branched alkyl radical comprising from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, l-methylethyl (isopropyl), butyl, 1 -methyl-propyl (sec-butyl), 2-methylpropyl (isobutyl) or 1,1- dimethylethyl (tert-butyl).

The term "Ci-C₆ alkyl" denotes an optionally substituted linear or branched alkyl radical comprising from 1 to 6 carbon atoms. Examples are the radicals specified for Ci -₄-alkyl, phenyl and hexyl.

The term "C₁-C₄ haloalkyl" denotes an optionally substituted straight-chain or branched alkyl groups having from 1 to 4 carbon atoms, where some or all of the hydrogen atoms of these groups have been replaced by halogen atoms. Examples thereof are

chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl,

difluoromethyl, trifluoromethyl, chlorofluoromethyl, di-chlorofluoromethyl,

chlorodifluoromethyl, 1-chloroethyl, l-bromoethyl, l-fluoroethyl, 2-fluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2- dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 3,3,3-trifluoroprop-l-yl, l,l,l-trifluoroprop-2-yl, 3,3,3-trichloroprop-l-yl, heptafluoro-iso-propyl, 1 -chlorobutyl, 2-chlorobutyl, 3-chlorobutyl, 4-chlorobutyl, l-fluorobutyl, 2-fluoro-butyl, 3-fluorobutyl, 4-fluorobutyl and the like.

The term "C₁-C₆ haloalkyl" denotes an optionally substituted straight-chain or branched alkyl groups having from 1 to 6 carbon atoms, where some or all of the hydrogen atoms of these groups have been replaced by halogen atoms.

The term "C₁-C₄ alkoxy" denotes an optionally substituted straight-chain or branched saturated alkyl groups comprising from 1 to 4 carbon atoms, which are bound via an oxygen atom to the remainder of the molecule. Examples of Ci-₄-alkoxy are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, l-methylpropoxy (sec- butoxy), 2-methylpropoxy (isobutoxy) and l,l-dimethylethoxy (tert-butoxy).

The term "Ci-C₄ haloalkoxy" denotes an optionally substituted straight-chain or branched saturated haloalkyl groups comprising from 1 to 4 carbon atoms, which are bound via an oxygen atom to the remainder of the molecule. Examples thereof are chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, l-chloroethoxy,l-bromoethoxy, 1 -fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,

2.2.2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2- dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, l,l,2,2-tetrafluoroethoxy, 1 -chloro- 1,2,2- trifluoroethoxy, pentafluoro-ethoxy, 3,3,3-trifluoroprop-l-oxy, l,l,l-trifluoroprop-2-oxy,

3.3.3-trichloroprop-l-oxy, l-chlorobutoxy, 2-chlorobutoxy, 3-chlorobutoxy, 4- chlorobutoxy, 1 -fluorobutoxy, 2-fluorobutoxy, 3-fluorobutoxy, 4-fluorobutoxy and the like.

The term "cycloalkyl" denotes optionally substituted mono- or bicyclic saturated or unsaturated non-aromatic hydrocarbon radicals having 3 to 14 carbon atoms.

The term "heterocyclyl" denotes optionally substituted saturated, partially saturated or fully unsaturated cyclic radical, which contains 3 to 6 ring atoms, of which 1 to 4 are from the group consisting of oxygen, nitrogen and sulfur. Examples thereof comprise piperidinyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl and oxetanyl.

The term "aryl" denotes optionally substituted carbocyclic aromatic radicals having from 6 to 14 carbon atoms. Examples thereof comprise phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl and phenanthrenyl.

The term“Ci-C₆ alkylthio” denotes an optionally substituted straight-chain or branched saturated alkyl radicals having 1 to 6 carbon atoms which are bound via a sulfur atom to the remainder of the molecule. Examples for Ci-C₆ alkylthio include methylthio, ethylthio, propylthio, l-methylethylthio, butylthio, l-methylpropylthio, 2- methylpropylthio and l,l-dimethylethylthio.

The term "aryloxy" refers to an -O-aryl group.

The term "acyloxy" refers to an -O-acyl group.

The term "alkylamino" refers to a -NH-alkyl group.

The term "alkylamido” refers to a -NHC(0)-alkyl, or -C(0)NH-alkyl.

The term "arylamino" refers to a -NH-aryl group.

The term "arylthio" refers to a -S-aryl group.

The term "alkylsulfonyl" refers to -S0₂-alkyl group.

The term "alkylsulfmyl" refers to -SO-alkyl group.

The term "arylsulfonyl" refers to -S0₂-aryl group.

The term "arylsulfmyl" refers to -SO-aryl group.

The term "optionally substituted" means that a group may or may not be further substituted by one or more groups such as Ci-₆ alkyl, C_l-6 alkenyl, Ci_-6 alkynyl, aryl, halogen, hydroxyl, thio, amino, cyano, oxo, nitro, acyl, amido,Ci-₆ alkoxy, Ci.

₆ alkenyloxy, aryloxy, acyloxy, Ci_-6 alkylamino, arylamino, Ci_-6 alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, alkylsulfmyl, arylsulfmyl, Ci_₈ alkylamido, and carboxyl.

The present invention provides a process for preparing a compound of formula (1)

[I]. the process includes comprising reacting a compound of formula (II)

with disulfide having the structure of Ri-S-S-Ri and an halogenating agent selected from sulfuryl chloride, Cl₂, Br_2, 1_2,iV-chlorosuccinimide, /V-bromosuccinimide and N- iodosuccinimide, in the presence of nitrile solvent, wherein

R_] is selected from Ci-C₆ alkyl, Ci-C₆haloalkyl, cycloalkyl, heterocyclyl, aryl and benzyl;

R₂ is selected from cyano, nitro, halogen, Ci-C₄ alkyl, Ci-C₄ haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C₁-C4 alkyl, Ci-C₄ haloalkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkoxy, nitro, cyano, Ci-C₄ alkylthio, Ci-C₄ alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and Ci-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

In some embodiments, the Br₂ or Cl₂ or I₂ are optionally generated in situ during or prior to the reaction of compound (II) to compound (I).

In some embodiments, the disulfide having the structure of Ri-S-S-Ri is optionally generated from the oxidation of the corresponding thiol groups. Processes for preparing disulfides are described for example in SYNTHESIS 2008, No. 16, pp 2491-2509, the contents of which is hereby incorporated by reference.

In some embodiments, the disulfide having the structure of Ri-S-S-Ri is optionally generated in situ during or prior to the reaction of compound (II) to compound (I).

The presence of the nitrile solvent provides the formation of a highly reactive intermediate which enables an extremely fast reaction.

The presence of the nitrile solvent expedites the process of the formation of compound (I) from compound (II).

The conversion of compound (II) to compound (I) in the presence of the nitrile solvent is at least 95%.

The yield of the reaction of compound (II) to obtain compound (I) in the presence of the nitrile solvent is at least 70%, 80% or 90%. In some embodiments, the yield of the reaction of compound (II) to obtain compound (I) in the presence of the nitrile solvent is at least 90%.

Nitrile solvent may include but is not limited to acetonitrile, butyronitrile,

isobutyronitrile, benzonitrile, propionitrile, isovaleronitrile, valeronitrile, 2- methylbutyronitrile, hexanenitrile, isohexanenitrile or any combination thereof. In some embodiments, the nitrile solvent is acetonitrile.

In some embodiments the process further comprises non-nitrile solvents. Non-nitrile solvents may include but are not limited to monochlorobenzene, toluene, xylenes, methylcyclohexane, dichloromethane, chloroform, ethylene chlorides and

trifluorotoluene.

In some embodiments, the reaction of compound (II) to obtain compound (I) is carried out in the presence of at least one solvent.

In some embodiments, the reaction is carried out in a nitrile solvent.

In some embodiments, the reaction is carried out in at least two nitrile solvents.

In some embodiments, the reaction is carried out in a mixture of nitrile solvent and at least one non-nitrile solvent.

In some embodiments, the reaction of compound (II) to obtain compound (I) is carried out in the presence of at least 10 %, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of a nitrile solvent of the total amount of solvent.

The reaction of compound (II) to obtain compound (I) in the presence of the nitrile solvent takes place highly rapidly. As the amount of nitrile solvent increases, the reaction to obtain compound (I) is faster.

The reaction of compound (II) to obtain compound (I) in the presence of the nitrile solvent occurs within less than about 60, 50, 40, 30, 20, 10, 5 or 1 minutes. In some embodiments, the reaction occurs within less than about 5 minutes. In some

embodiments, the reaction occurs within less than about 1 minute. In some embodiments, the reaction occurs within less than about 0.5 minute.

In some embodiments, the halogenating agent is sulfuryl chloride.

In some embodiment, the reaction is carried out in an inert atmosphere.

In some embodiments, the reaction is carried out under N₂ atmosphere.

In some embodiments, the reaction is carried out without external addition of 0₂.

In some embodiments, the disulfide is diethyl disulfide. In some embodiments, the disulfide is bis(trifluoromethyl) disulfide.

In some embodiments, the compound of formula (I) is

In some embodiments, the compound of formula (I) is

The process for obtaining the compound of formula (I) may be carried out either in situ, wherein the compound (II) is mixed with disulfide, and the halogenating agent-is added; or continuously, wherein the disulfide is reacted with the halogenating agent and the resulting mixture is reacted with compound (II).

In some embodiments, the disulfide R₁-S-S-R₁ is reacted with the halogenating agent and the compound of formula (II).

In some embodiments, the disulfide R₁-S-S-R₁ is reacted with the halogenating agent prior to the reaction with compound (II). In some embodiments, the compound of formula (II) is mixed with the disulfide, and the obtained mixture is reacted with the halogenation agent.

In some embodiments, the compound of formula (II) is mixed with the disulfide, prior to the reaction with the halogenation agent.

In some embodiments, the molar ratio between the disulfide and compound (II) is from about 1 :3 to about 3:1. In some embodiments, the molar ratio between the disulfide and compound (II) is about 1 :2.

In some embodiments, the molar ratio between the disulfide and the halogenating agent is from about 1 :10 to about 10:1. In some embodiments, the molar ratio between the disulfide and the halogenating agent is about 1:1. In some embodiments, the molar ratio between the disulfide and the halogenating agent is about 1 :2.

In some embodiments, the reaction temperature is from about (-50) °C to about 50 °C. In some embodiments, the reaction temperature is from about (-30) °C to about 10 °C. In some embodiments, the reaction temperature is 0 °C.

the process comprising reacting a compound of formula (II)

with a mixture of disulfide having the structure of R₁-S-S-R₁ and an halogenating agent selected from sulfuryl chloride, Cl₂, Br₂ I_2,/V-chlorosuccinimide, iV-bromosuccinimide and iV-iodosuccinimide, in the presence of nitrile solvent wherein,

Ri is selected from Ci-C₆ alkyl, Ci-C₆haloalkyl, cycloalkyl, heterocyclyl, aryl and benzyl;

R₂ is selected from cyano, nitro, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C₁-C4 haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C1-C4 alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and Cj-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

In some embodiments, the disulfide having the structure of R₁-S-S-R₁ is optionally generated from the oxidation of the corresponding thiol groups. Processes for preparing disulfides are described for example in SYNTHESIS 2008, No. 16, pp 2491-2509, the contents of which is hereby incorporated by reference. In some embodiments, the disulfide having the structure of R₁-S-S-R₁ is optionally generated in situ during or prior to the reaction of compound (II) to compound (I).

The yield of the reaction of compound (II) to obtain compound (I) in the presence of the nitrile solvent is at least 90%.

Nitrile solvent may include but is not limited to acetonitrile, butyronitrile,

trifluorotoluene.

In some embodiments, the reaction is carried out in a nitrile solvent.

In some embodiments, the reaction is carried out in a mixture of nitrile solvent and at least one non-nitrile solvent. In some embodiments, the reaction of compound (II) to obtain compound (I) is carried out in the presence of at least 10 %, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of a nitrile solvent of the total amount of solvent.

embodiments, the reaction occurs within less than about 1 (one) minute. In some embodiments, the reaction occurs within less than about 0.5 minute.

In some embodiments, the halogenating agent is sulfuryl chloride.

In some embodiment, the reaction is carried out in an inert atmosphere.

In some embodiments, the reaction is carried out under N₂ atmosphere.

In some embodiments, the disulfide is diethyl disulfide.

In some embodiments, the disulfide is bis(trifluoromethyl) disulfide.

In some embodiments, the compound of formula (I) is

In some embodiments, the compound of formula (I) is

The process for obtaining the compound of formula (I) may be carried out either in situ, wherein the compound (II) is mixed with disulfide, and the halogenating agent is added; or continuously, wherein the disulfide is reacted with the halogenating agent and the resulting mixture is reacted with compound (II).

In some embodiments, the disulfide Ri-S-S-Ri is reacted with the halogenating agent and the compound of formula (II).

In some embodiments, the disulfide Ri-S-S-Ri is reacted with the halogenating agent prior to the reaction with compound (II).

In some embodiments, the compound of formula (II) is mixed with the disulfide, and the obtained mixture is reacted with the halogenation agent. In some embodiments, the compound of formula (II) is mixed with the disulfide, prior to the reaction with the halogenation agent.

In some embodiments, the molar ratio between the disulfide and compound (II) is from about 1 :3 to about 3 :1. In some embodiments, the molar ratio between the disulfide and compound (II) is about 1:2.

In some embodiments, the molar ratio between the disulfide and the halogenating agent is from about 1 : 10 to about 10:1. In some embodiments, the molar ratio between the disulfide and the halogenating agent is about 1 :1. In some embodiments, the molar ratio between the disulfide and the halogenating agent is about 1 :2.

the process comprises reacting a compound of formula (II)

with disulfide having the structure of R₁-S-S-R₁ and an halogenating agent selected from sulfuryl chloride, Cl₂, Br_2, I_2,-/V-chlorosuccinimide, /V-bromosuccinimide and N- iodosuccinimide in a nitrile solvent, wherein

R.₂ is selected from cyano, nitro, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C₁-C4 alkyl, C₁-C₄ haloalkyl, C₁-C4 alkoxy, C1-C₄ haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C₁-C4 alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

In some embodiments, the disulfide having the structure of R₁-S-S-R1 is optionally generated from the oxidation of the corresponding thiol groups. Processes for preparing disulfides are described for example in SYNTHESIS 2008, No. 16, pp 2491-2509, the contents of which is hereby incorporated by reference.

In some embodiments, the disulfide having the structure of R₁-S-S-R₁ is optionally generated in situ during or prior to the reaction of compound (II) to compound (I). The presence of the nitrile solvent provides the formation of a highly reactive intermediate which enables an extremely fast reaction.

Nitrile solvent may include but is not limited to acetonitrile, butyronitrile,

trifluorotoluene.

In some embodiments, the reaction is carried out in a nitrile solvent.

In some embodiments, the reaction of compound (II) to obtain compound (I) is carried out in the presence of at least 10 %, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of a nitrile solvent of the total amount of solvent. The reaction of compound (II) to obtain compound (I) in the presence of the nitrile solvent takes place highly rapidly. As the amount of nitrile solvent increases, the reaction to obtain compound (I) is faster.

In some embodiments, the halogenating agent is sulfuryl chloride.

In some embodiment, the reaction is carried out in an inert atmosphere.

In some embodiments, the reaction is carried out under N₂ atmosphere.

In some embodiments, the disulfide is diethyl disulfide.

In some embodiments, the disulfide is bis(trifluoromethyl) disulfide.

In some embodiments, the compound of formula (I) is

In some embodiments, the compound of formula (I) is

In some embodiments, the disulfide R₁-S-S-R₁ is reacted with the halogenating agent prior to the reaction with compound (II).

In some embodiments, the compound of formula (II) is mixed with the disulfide, and the obtained mixture is reacted with the halogenation agent.

In some embodiments, the molar ratio between the disulfide and the halogenating agent is from about 1 :10 to about 10:1. In some embodiments, the molar ratio between the disulfide and the halogenating agent is about 1 :1. In some embodiments, the molar ratio between the disulfide and the halogenating agent is about 1 :2. In some embodiments, the reaction temperature is from about (-50) °C to about 50 °C. In some embodiments, the reaction temperature is from about (-30) °C to about 10 °C. In some embodiments, the reaction temperature is 0 °C.

[I], comprising reacting a compound of formula (II)

with a mixture of disulfide having the structure of Ri-S-S-Ri and an halogenating agent selected from sulfuryl chloride, Cl₂, Br₂ I_2,/V-chlorosuccinimide, iV-bromosuccinimide and 7V-iodosuccinimide in a nitrile solvent, wherein

Ri is selected from Ci-C₆ alkyl, C_]-C₆ haloalkyl, cycloalkyl, heterocyclyl, aryl and benzyl;

R₂ is selected from cyano, nitro, halogen, C₁-C₄ alkyl, C₁-C4 haloalkyl, and cycloalkyl; R₃ is selected from halogen, hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, Ci-C₄ alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

Ih some embodiments, the disulfide having the structure of R₁-S-S-R₁ is optionally generated from the oxidation of the corresponding thiol groups. Processes for preparing disulfides are described for example in SYNTHESIS 2008, No. 16, pp 2491-2509, the contents of which is hereby incorporated by reference.

In some embodiments, the disulfide having the structure of R₁-S-S-R₁ is optionally generated in situ during or prior to the reaction of compound (II) to compound (I).

The presence of the nitrile solvent provides the formation of a highly reactive

intermediate which enables an extremely fast reaction.

Nitrile solvent may include but is not limited to acetonitrile, butyronitrile,

isobutyronitrile, benzonitrile, propionitrile, isovaleronitrile, valeronitrile, 2- methylbutyronitrile, hexanenitrile, isohexanenitrile or any combination thereof. In some embodiments, the nitrile solvent is acetonitrile. In some embodiments the process further comprises non-nitrile solvents. Non-nitrile solvents may include but are not limited to monochlorobenzene, toluene, xylenes, methylcyclohexane, dichloromethane, chloroform, ethylene chlorides and

trifluorotoluene.

In some embodiments, the reaction is carried out in a nitrile solvent.

In some embodiments, the halogenating agent is sulfuryl chloride.

In some embodiment, the reaction is carried out in an inert atmosphere.

In some embodiments, the reaction is carried out under N₂ atmosphere.

In some embodiments, the reaction is carried out without external addition of 0₂. In some embodiments, the disulfide is diethyl disulfide.

In some embodiments, the disulfide is bis(trifluoromethyl) disulfide. In some embodiments, the compound of formula (I) is

In some embodiments, the compound of formula (I) is

In some embodiments, the disulfide R₁-S-S-R₁ is reacted with the halogenating agent and the compound of formula (II). In some embodiments, the disulfide R₁-S-S-R₁ is reacted with the halogenating agent prior to the reaction with compound (II).

In some embodiments, the molar ratio between the disulfide and compound (II) is from about 1 :3 to about 3 : 1. In some embodiments, the molar ratio between the disulfide and compound (II) is about 1 :2.

In some embodiments, the molar ratio between the disulfide and the halogenating agent is from about 1 : 10 to about 10: 1. In some embodiments, the molar ratio between the disulfide and the halogenating agent is about 1 :1. In some embodiments, the molar ratio between the disulfide and the halogenating agent is about 1 :2.

The present invention also provides a compound of formula (III)

[III] wherein,

R₂ is selected from cyano, nitro, halogen, Ci-C₄ alkyl, C1-C4 haloalkyl, and cycloalkyl;

R₃ is independently selected from halogen, hydrogen, C₁-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C₁-C₄ haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C₁-C4 alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; n is an integer from 1-5; and

R₄ is optionally substituted Ci-C₆ alkyl or optionally substituted phenyl.

In some embodiments, the compound of formula (III) is

The present invention also provides a process for preparing ethiprole having the structure

which comprises converting the compound of formula (II) to the compound of formula (I) prepared according to any embodiment of the present invention.

The present invention also provides a process for preparing fipronil, having the structure

which comprises converting the compound of formula (II) to the compound of formula (I) prepared according to any embodiment of the present invention. A process for preparing fipronil or ethiprole by converting the compound of formula (I) using oxidizing agent such as hydrogen peroxide is described in US 20140155620 A1 and US 5,814,652, the contents of which are hereby incorporated by reference.

The present invention also provides a process for preparing a compound of the formula (IV)

comprising the oxidation of the compound having the formula (I)

[I], with an oxidizing agent, wherein the oxidation is carried out in a telescoping synthesis, without isolating the compound of formula (I) prior to the oxidation step, and wherein

Ri is selected from Ci-C₆ alkyl, Ci-C₆haloalkyl, cycloalkyl, heterocyclyl, aryl and benzyl; R₂ is selected from cyano, nitro, halogen, C₁-C4 alkyl, C1-C4 haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C₁-C₄ alkyl, C -C₄ haloalkyl, C -C₄ alkoxy, C -C₄ haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C₁-C4 alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

comprising the oxidation of the compound having the formula (I)

[I], with an oxidizing agent, wherein the oxidation is carried out without isolating the compound of formula (I) prior to the oxidation step, and wherein

Ri is selected from Cj-C₆ alkyl, Ci-C₆ haloalkyl, cycloalkyl, heterocyclyl, aryl and benzyl;

R₂ is selected from cyano, nitro, halogen, C1-C4 alkyl, C₁-C4 haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C₁-C₄ alkyl, C1-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, nitro, cyano, Ci-C₄ alkylthio, C₁-C4 alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C4 alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

In some embodiments, the oxidation is carried out without precipitation the compound of formula (I) prior to the oxidation step.

In some embodiments, the oxidation is carried out without crystallization of the compound of formula (I) prior to the oxidation step.

In some embodiments, the oxidation is carried out directly in the same solvent in which the compound of formula (I) is dissolved.

In some embodiments, the oxidation is carried out in the same solvent in which the compound of formula (I) is dissolved.

In some embodiments, the oxidation is carried out in a mixture of the solvent in which the compound of formula (I) is dissolved, and at least one additional solvent.

In some embodiments, the oxidation is carried out in a different solvent from the solvent in which the compound of formula (I) is dissolved.

In some embodiments, the process for preparing compound (I) and the oxidation step for preparing compound (IV) are carried out in a telescoping synthesis. The present invention also provides a process for preparing a compound of the formula (IV)

comprising the steps:

(a) Reacting compound having the formula (II) with a sulfide source to obtain a compound having the formula (I)

(b) oxidation of the compound having the formula (I)

R₂ is selected from cyano, nitro, halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and cycloalkyl;

R₃ is selected from halogen, hydrogen, C₁-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C₁-C4 haloalkoxy, nitro, cyano, C₁-C₄ alkylthio, C₁-C4 alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C₁-C₄ alkylsulphonyl which is unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

In some embodiments, the oxidation is carried out without precipitation of the compound of formula (I) prior to the oxidation step.

In some embodiments, the oxidation is carried out directly in the same solvent in which the compound of formula (I) is dissolved. In some embodiments, the oxidation is carried out in the same solvent in which the compound of formula (I) is dissolved.

In some embodiments, the process for preparing compound (I) and the oxidation step for preparing compound (IV) are carried out in a telescoping synthesis.

It is understood that where a parameter range is provided, all integers within that range, and tenths thereof, are also provided by the invention.

Each embodiment disclosed herein is contemplated as being applicable to each of the other disclosed embodiments. Thus, all combinations of the various elements described herein are within the scope of the invention.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.

The invention is illustrated by the following examples without limiting it thereby.

EXAMPLES

Example 1 :

A 1L stirred reactor was charged with a solution of the compound (II) (35g) in acetonitrile (220 ml) and the solution was cooled to -5°C. Solutions of sulfuryl chloride (8g) in ACN (48 ml), and diethyl disulfide (l4.6g) in ACN (48ml) were added (in parallel) using syringe pump to a cold 0°C FR (flow reactor). The output of the FR was added directly to the above 1L reactor. After the addition of the solution from the FR, the reaction mixture was stirred at the same temperature for additional 10 min.

Workup: To the reaction mixture was added 140 ml of ~5% sodium bicarbonate solution. After complete precipitation of the solid (if necessary, additional amount of sodium bicarbonate solution or water is added for complete precipitation), the water was filtered off and the solid was washed with hexane and dried in oven to give the pure product (Yield 91%).

Example 2:

A reactor was charged with a solution of compound (II) (3.95g) and diethyl disulfide (l .48g) in a acetonitrile, and the solution was cooled to 0 °C. Solution of sulfuryl chloride (0.83g) in ACN (lOml), was added to this solution using syringe pump, and the reaction mixture was stirred at the same temperature for additional 10 min.

Workup: To the reaction mixture was added l5ml of ~5% sodium bicarbonate solution. After complete precipitation of the solid (if necessary, additional amount of sodium bicarbonate solution or water is added for complete precipitation), the water was filtered off and the solid was washed with hexane and dried in oven to give the pure product (Yield 90.5%).

Claims

Claims:

1. A process for preparing a compound of formula (I),

comprising reacting a compound of formula (II)

with a disulfide having the formula Ri-S-S-Ri and a halogenating agent selected from a group consisting of sulfuryl chloride, Cl₂, Br_2, I_2, iV-chlorosuccinimide, N- bromosuccinimide and A-iodosuccinimide, in the presence of a nitrile solvent, wherein:

Ri is selected from Ci-C₆ alkyl, C -C₆ haloalkyl, cycloalkyl, heterocyclyl, aryl and benzyl;

R₃ is selected from halogen, hydrogen, Ci-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, nitro, cyano, Ci-C₄ alkylthio, Ci-C₄ alkylsulphinyl which is unsubstituted or substituted by one or more halogen atoms, and C1-C4 alkylsulphonyl which is

unsubstituted or substituted by one or more halogen atoms; and n is an integer from 1-5.

2. The process of claim 1, wherein the nitrile solvent is selected from a group consisting of acetonitrile, butyronitrile, isobutyronitrile, benzonitrile, propionitrile, isovaleronitrile, valeronitrile, 2-methylbutyronitrile, hexanenitrile and isohexanenitrile and combination thereof.

3. The process of claim 2, wherein the solvent is acetonitrile.

4. The process of any one of claims 1-3, wherein the process further comprises at least one non-nitrile solvent.

5. The process of claim 4 wherein the non-nitrile solvent is selected from the group consisting of monochlorobenzene, toluene, xylenes, methylcyclohexane, dichloromethane, chloroform, ethylene chloride and trifluorotoluene.

6. The process of claim 1, wherein the halogenating agent is sulfuryl chloride.

7. The process of claim 1, wherein Ri is ethyl group and R₂ is cyano group.

8. The process of claim 1, wherein Ri is trifluoromethyl and R₂ is cyano group.

9. The process of claim 1, wherein the disulfide having the formula Ri-S-S-Ri is generated from the oxidation of the corresponding thiol.

10. The process of claim 1, wherein the compound of formula (I) is

11. The process of claim 1, wherein the compound of formula (I) is

12. The process of any one of claims 1-11 wherein the molar ratio between the disulfide and the compound of formula (II) is from about 1 :3 to about 3:1.

13. The process of any one of claims 1-11 wherein the molar ratio between the disulfide and the halogenating agent is from about 1 : 10 to about 10:1.

14. The process of claim 1, wherein:

(i) the disulfide is reacted with the halogenating agent and the resulting mixture is reacted with the compound of formula (II); or

(ii) the compound of formula (II) is mixed with the disulfide, and the resulting mixture is reacted with the halogenation agent.

15. The process of any one of claims 1-14, wherein the reaction temperature is from about (-50) °C to about 50 °C.

16. The process of claim 15, wherein the reaction temperature is from 0 °C to 10 °C.

17. The process of claim 16, wherein the reaction temperature is 0 °C.

18. A method for obtaining a compound of formula (I), comprising reacting a compound of formula (II) according to the process of any one of claims 1-17.

19. A process for preparing a compound having the formula:

comprising reacting a compound of formula (I) prepared according to any one of claims 1 - 18 with an oxidizing agent.

20. A process for preparing a compound having the formula:

comprising reacting a compound of formula (I) prepared according to any one of claims 1- 18 with an oxidizing agent.

21. A process for preparing a compound having the formula (IV)

comprising the oxidation of the compound having the formula (I)

[I],

with an oxidizing agent, wherein the oxidation is carried out without isolating the compound of formula (I) prior to the oxidation step, and

wherein R₁-R₃ and n are as defined in any one of the preceding claims.

22. The process of claim 21, wherein the oxidation is carried out without precipitation the compound of formula (I) prior to the oxidation step.

23. The process of claim 21, wherein the oxidation is carried out without crystallization of the compound of formula (I) prior to the oxidation step.

24. The process of any one of claims 21-23, wherein the oxidation is carried out directly in the same solvent in which the compound of formula (I) is dissolved.

25. The process of any one of claims 21-23, wherein additional solvent is added to the solvent in which the compound of formula (I) is dissolved prior to the oxidation step.

26. The process of any one of claims 21-23, wherein additional solvent is added to the solvent in which the compound of formula (I) is dissolved, and the original solvent is removed prior to the oxidation step.

27. The process of any one of claims 21-26, wherein the compound of formula (IV) is ethiprole.

28. The process of any one of claims 21-26, wherein the compound of formula (IV) is fipronil.

29. A compound of formula

wherein Ri - R₃ and n are as defined in any one of the preceding claims; and

R₄is optionally substituted Ci-C₆ alkyl or optionally substituted phenyl.

30. The compound of claim 29, having the following formula: