Process for the preparation of prothioconazole intermediates

Abstract

The invention relates to processes for the preparation of intermediates in the synthesis of prothioconazole and novel compounds related thereto. The process of the invention provides prothioconazole from cheap starting material in a low number of steps.

Description

[0001] PROCESS FOR THE PREPARATION OF PROTHIOCONAZOLE INTERMEDIATES

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to the field of organic synthesis. More particularly, the invention relates to improved processes for the synthesis of l-(l-chlorocyclopropyl)-2-(2- chlorophenyl)ethan-l-one, a key intermediate for the synthesis of prothioconazole.

[0004] BACKGROUND OF THE INVENTION

[0005] Prothioconazole, 2-[(2RS)-2-(l-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-2H- l,2,4-triazole-3(4H)-thione, is a fungicide used to treat infected crops, first described in US 5,789,430. The structure is reproduced below:

[0006] Prothioconazole

[0007] A key intermediate in the synthesis of prothioconazole is the compound l-(l-chlorocyclopropyl)-

[0008] 2-(2-chlorophenyl)ethan-l-one (1):

[0009] Several processes have been disclosed for the preparation of prothioconazole through this intermediate (1), for example by conversion of the keto group to the corresponding oxirane derivative (2), followed by nucleophilic addition reaction of triazole and sulfurization reaction.

[0010] (2) Prothioconazole For example, CN112010813 discloses a synthetic route where 1 is used as starting material, converted into the corresponding oxirane by epoxidation reaction with alkali, sulfoxide halide and solvent under reflux, to obtain compound 2, followed by reaction with triazole in the presence of a weak base such as sodium carbonate or potassium carbonate in a polar solvent under reflux, and reaction of the resulting compound with sulfur in dimethyl sulfoxide as solvent to obtain prothioconazole.

[0011] A similar approach is disclosed in IN371149, in which epoxidation of compound 1 is carried out by reaction with trimethylsulphoxonium chloride in the presence of strong bases such as potassium hydroxide, potassium t-butoxide and sodium methoxide in various solvents such as dimethyl sulphoxide, acetonitrile, etc. Then, prothioconazole is obtained by subsequent addition of 1,2,4-triazole and reaction of the intermediate with n-butyllithium and elemental sulfur.

[0012] However, the preparation of the l-(l-chlorocyclopropyl)-2-(2-chlorophenyl)ethan-l-one intermediate (1) still presents many challenges as it can be deduced from the problems of the different strategies disclosed in the prior art.

[0013] For example, in US5146001 the preparation of intermediate 1 is performed from 2-chlorobenzyl chloride by a process using zinc powder and addition of the unstable compound 1- chlorocyclopropanecarbonyl chloride and bis(triphenylphosphine) palladium (II) chloride, which is a toxic and costly palladium complex.

[0014] IN371149 discloses the preparation of this intermediate 1 using two different synthetic routes. According to one of them, 1-chlorocyclopropanecarboxylic acid in hexane is reacted with thionyl chloride, followed by formation of 1-chloro-N-methoxy-N-methylcyclopropane carboxamide and also other derivatives and reaction with 2-chloro-benzylmagnesiumchloride. In the alternative process, y-butyrolactone in excess of thionyl chloride is treated with ZnCL to obtain 2,4-dichlorobutanoylchloride, which is further reacted with 2-chlorobenzylmagneium chloride in the presence of diethyl ether. Finally, intermediate 1 is obtained by cyclization with ethylene glycol and metallic sodium. However, this process is not suitable for commercial manufacturing due to sodium metal used in the process.

[0015] Therefore, there is still a need in the art for to develop new processes and intermediates for the synthesis of prothioconazole that overcome all or part of the problems associated with the known processes of the state of the art.

[0016] BRIEF DESCRIPTION OF THE INVENTION The invention faces the problem of providing an improved process for the preparation of 1-(1- chlorocyclopropyl)-2-(2-chlorophenyl)ethan-l-one intermediate, as well as new intermediates and processes for the synthesis of prothioconazole.

[0017] First, the inventors have developed a new method for the preparation of compounds of formula (I) which includes the above referred intermediate. This method is based on a very different approach over the previous methods in the prior art for related compounds. Additionally, this approach leads to the compounds of formula (I) in a very effective manner, with a reduced number of steps.

[0018] Thus, in a first aspect the invention is directed to a process for the preparation of a compound of Formula (I): which comprises reacting a compound of Formula (II) with a compound of Formula (III): wherein:

[0019] - R is >CR1R2or >C=CH2, where:

[0020] R1and R2form together with the C atom to which they are attached a cyclopropyl ring, or

[0021] R1is selected from H or halogen, and R2is -CH2-CH2X;

[0022] - each X is independently selected from a halogen;

[0023] - W is a metal or a metal complex, optionally comprising one or more halogen atoms; and

[0024] - Y is selected from O, or NZ where Z is H or a monovalent metal or MX, wherein M is a divalent metal and X is halogen.

[0025] In a second aspect, the present invention relates to a compound of formula (la): or a salt or solvate thereof; wherein

[0026] - R is >CR1R2or >C=CH2, where:

[0027] R1and R2form together with the C atom to which they are attached form a cyclopropyl ring, or

[0028] R1is selected from H or halogen, and R2is -CH2-CH2X;

[0029] - each X is independently selected from a halogen, and

[0030] - Z is H or a monovalent metal or MX, wherein M is a divalent metal and X is halogen.

[0031] An additional aspect of the invention is the use of a compound of formula (II) as defined above as intermediate in the preparation of a pesticide.

[0032] An additional aspect of the invention is the use of a compound of formula (II), preferably a compound of formula (Ila) as described below, as defined above as intermediate in the preparation of prothioconazole.

[0033] An additional aspect is a method for the preparation of 2,4-dichlorobutanenitrile (compound of formula (lie)) that comprises the reaction between acrylonitrile, a catalyst, such as a Cu salt or a complex thereof (e.g. CuCI)), dichloromethane, and a phase transfer catalyst under irradiation, wherein the reaction comprises one or more of the following reaction conditions: i. continuous addition of acrylonitrile; ii. performing the reaction at a temperature comprised between -20 °C and 30 °C, preferably between -10 °C and 15 °C; ill. performing the reaction in the presence of water; iv. performing the reaction in the presence of THF, acetonitrile or an alcohol; and / or v. subjecting the reaction mixture comprising acrylonitrile, a phase transfer catalyst, a catalyst, such as a Cu salt or a complex thereof (e.g. CuCI)), and dichloromethane to a preirradiation step prior to performing the reaction.

[0034] An additional aspect of the present invention is a reaction to produce the compound of formula (Ila) that comprises treating 2,4-dichlorobutanenitrile (compound of formula (lie)) with a base in an organic solvent and, optionally, in the presence of a phase transfer catalyst. DETAILED DESCRIPTION OF THE INVENTION

[0035] In the search for a more efficient process, the inventors have designed a strategy that is surprisingly more efficient than those of the prior art, and provides the intermediate 1-(1- chlorocyclopropyl)-2-(2-chlorophenyl)ethan-l-one in a reduced number of steps.

[0036] The first aspect disclosed herein is therefore a process for the preparation of a compound of Formula (I): which comprises reacting a compound of Formula (II) with a compound of Formula (III): wherein:

[0037] - R is >CR1R2or >C=CH2, where:

[0038] R1and R2form together with the C atom to which they are attached form a cyclopropyl ring, or

[0039] R1is selected from H or halogen, and R2is -CH2-CH2X;

[0040] - each X is independently selected from a halogen; and

[0041] - W is a metal or a metal complex, optionally comprising one or more halogen atoms; and

[0042] - Y is selected from O, or NZ where Z is H or a monovalent metal or MX, wherein M is a divalent metal and X is halogen.

[0043] The term "halogen" refers to bromine, chlorine, iodine or fluorine.

[0044] The term "divalent metal" refers to any metal element the valence of which is 2, for example, an alkaline earth-metal, such as magnesium; a transition metal such as zinc; or if it has several valences, one of them is 2, for example, tin, etc. The term "monovalent metal" refers to any metal element the valence of which is 1, for example, an alkali metal such as sodium, potassium or lithium.

[0045] The notation ">C" is used to designate a carbon atom that is attached to two different substituents of a given formula Markush.

[0046] Some of the compounds described herein have ketone groups with a hydrogen available in the alpha position (e.g. compounds of formula (I), (lb), (lb') or (Id)) and can therefore be in equilibrium with their corresponding enol forms. All forms, the keto and the enol forms, are covered in each case. Exemplary keto and enol isomers are depicted below:

[0047] Keto Enol

[0048] Analogously, some of the compounds described herein have enamine groups with a hydrogen available in the alpha position (e.g. compounds of formula (I), (la), (la'), (la'1) or (lc)) and can therefore be in equilibrium with their corresponding amine forms. All forms, all the enamine and all the amine forms, are covered in each case. Exemplary enamine and amine isomers are depicted below:

[0049] Enamine Amine

[0050] Preferably, X is selected from bromo or chloro, more preferably it is chloro.

[0051] In a particular embodiment, R is >CR1R2where R1and R2form together with the C atom to which they are attached a cyclopropyl ring.

[0052] In a preferred embodiment, the compound of formula (II) is a compound of Formula (Ila):

[0053] In another particular embodiment, R is >C=CH2.

[0054] In a preferred embodiment, the compound of formula (II) is 2-chloroacrylonitrile (compound (Hb)):

[0055] In a further particular embodiment, R is >CR1R2, where R1is selected from H or halogen, and R2is -CH2-CH2X. In a more particular embodiment, R1is H. In another more particular embodiment, R1is halogen, preferably chloro or bromo, more preferably chloro. In a particular embodiment, R2is -CH2-CH2X where X is halogen, preferably selected from chloro or bromo, more preferably chloro. In a preferred embodiment, the compound of formula (II) is selected from the group consisting of a compound of Formula (lie) and a compound of Formula (lid):

[0056] (He) (lid)

[0057] The compound of formula (III) is: wherein W is a metal or a metal complex, optionally comprising one or more halogen atoms, and X is selected from halogen.

[0058] In the compound of formula (III), X may be fluoro, bromo, chloro, or iodo in position ortho, meta or para of the benzyl ring. In a particular embodiment, X is bromo or chloro, preferably chloro, preferably in position ortho of the benzyl ring.

[0059] In a particular embodiment, W is MX', wherein M is a divalent metal, preferably selected from magnesium, copper, manganese, zinc, mercury and tin, preferably from magnesium.

[0060] X' may be fluoro, bromo, chloro, or iodo. In a particular embodiment, X' is bromo or chloro, preferably chloro.

[0061] Preferably, MX' is MgCl.

[0062] Grignard reagents and other organometallic species are typically notated as RW, more usually as RMX', wherein R is an aliphatic group, M is a metal and X' a halogen, for example, as RMgCI or RMgBr, but are in reality a complex mixture of species comprising, not only RW or RMX', but also dimmers, trimers thereof, ate complexes and other intermediates. Each of these intermediates may participate in the reaction in different degrees to produce the final products. Thus, the process of the invention involves the use of compounds of formula (III) as well as dimmers or trimers thereof, as well as other complex species, such as ate complexes. For simplicity, and using the common notation used for these compounds, they are referred to in the present document as compounds of formula (III). Such species (e.g. dimmers, trimmers or ate complexes) include, for example, the compounds (A), (B) and (C):

[0063] (B),

[0064] In a particular embodiment, the process of the invention comprises:

[0065] (i) reacting a compound of formula (Illa): wherein M is a divalent metal, and X and X' are independently selected from halogen, with the compound of Formula (II): wherein:

[0066] X is halogen:

[0067] R is >CR1R2or >C=CH2, where:

[0068] R1and R2form together with the C atom to which they are attached form a cyclopropyl ring, or

[0069] R1is selected from H or halogen, and R2is -CH2-CH2X, to provide an imine derivative of Formula (la): wherein each X is independently selected from a halogen:

[0070] Z is H or a monovalent metal or MX, wherein M is a divalent metal and X is halogen;

[0071] R is >CR1R2or >C=CH2, where:

[0072] R1and R2form together with the C atom to which they are attached form a cyclopropyl ring, or

[0073] R1is selected from H or halogen, and R2is -CH2-CH2X, and

[0074] (ii) optionally subjecting the compound of formula (la) to hydrolysis to provide a compound of Formula (lb): wherein X and R are as defined above.

[0075] Step (i) of this process may use a lithium salt as a promotor, such as lithium bromide and / or lithium chloride. When present, the molar ratio of the lithium salt with respect to the compound of formula (Illa) is between 0.1 to 1.5, preferably between 0.3 and 1.

[0076] In a particular embodiment, said reaction is usually maintained at a temperature comprised between 20 °C and 100 °C, for example between 30 °C and 80 °C. Alternatively, the temperature may be raised over the course of the reaction, i.e., applying a temperature gradient. For example, during the reaction the temperature can be comprised between 20 °C and 100 °C, starting from an initial temperature below 20 °C, e. g., from between -5 °C to 10 °C, for example, from about 0 °C. A temperature gradient may be preferred in order to increase the reaction rate without significantly affecting the yield. In a another particular embodiment, the reaction is maintained at a temperature comprised between 0 °C and 25 °C, for example between 0 °C and 20 °C. Alternatively, the temperature may be raised over the course of the reaction, i.e., applying a temperature gradient, to a temperature comprised between 0 °C and room temperature from a starting temperature below 20 °C, e. g., from about 0 °C.

[0077] Typical ly, the use of lithium salt as a promotor allows using additional solvent and / or employing lower temperatures. Thus, in an embodiment, a lithium salt such as lithium chloride is used in step (i), and the temperature is maintained between 20 °C and 40 °C. When a lithium salt promotor is not employed, higher temperatures are generally preferred. In such cases, the temperature in step (i) is preferably maintained between 30 °C and 80 °C. With the use of a lithium salt, such as LiCI, it is possible to obtain better yields with solvents such as diethylether and dispense with the use of MTBE. The amount of lithium salt added (e.g. LiCI) is typically between 0.1 equivalents and 2.0 equivalents, for example, between 0.2 and 1.2 equivalents. Step (i) typically proceeds in an organic solvent under inert atmosphere.

[0078] Any suitable inert organic solvent can be used. Preferred solvents used in step (i) are ethers, such as diethyl ether, dibutyl-ether, methyl tert-butyl ether (MTBE), tetrahydrofuran, 2-methyl- tetrahydrofuran, 2,5-dimethyl-tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol tert-butyl methyl ether, diethylene glycol diethyl ether and 1,4-dioxane. Alternatively, it is possible to use a co-solvent (e.g. toluene, cyclohexane) in admixture with the "inert solvent". The solvents are preferably employed in dry form. In a particular embodiment, the solvent of step (i) is selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyl-tetrahydrofuran, 2-dimethyl-tetrahydrofuran and mixtures thereof. Preferably, the solvent of step (i) is selected from the group consisting of diethyl ether and methyl tert-butyl ether.

[0079] As used herein, the term "inert atmosphere" refers to an atmosphere mainly composed of an inert gas such as nitrogen, helium, neon, argon, etc. Any suitable inert gas known in the art may be used. Gases which can preferably be used are argon and nitrogen.

[0080] In some embodiments, this process further comprises a step (ii) of subjecting the compound of formula (la) to hydrolysis to provide a compound of formula (lb).

[0081] Hydrolysis treatment may be performed in acid or basic media according to methods commonly used in the art. For example, the imine derivative of formula (la) may be subjected to acid hydrolysis using a suitable acid, for example hydrochloric acid, in a solvent. Suitable acids for use in acid hydrolysis include sulfuric acid, hydrochloric acid, phosphoric acid, ammonium chloride, hydrocyanic acid, hydrobromic acid, and other mineral acids known to those of skill in the art. In a particular embodiment, the hydrolysis of step (ii) may be performed by mixing the compound of formula (la) with an aqueous acid solution, such as hydrochloric acid between 1 and 10 N, preferably in a concentration between 4 and 8 N. The aqueous acid solution of step (ii) may be added to the reaction mixture of step (i) without isolation. Analogously, it is possible to perform the hydrolysis in the presence of a suitable base, such as aqueous ammonium hydroxide or aqueous NaCN.

[0082] In a particular embodiment, the compound of formula (la) is the compound of formula (Ic): or a salt or solvate thereof, wherein Z is H or a monovalent metal or MX, wherein M is a divalent metal and X is halogen.

[0083] In a preferred embodiment, the compound of formula (lb) is the compound l-(l-chloro- cyclopropyl)-2-(2-chloro-phenyl) ethanone of formula (Id):

[0084] In a more particular embodiment, the process of the invention comprises:

[0085] (i) reacting a compound of formula (Illa): wherein M is a divalent metal, X' is halogen and X is halogen; with a compound of formula (Ila): to provide an imine derivative of formula: wherein X is a halogen and Z is H or a monovalent metal or MX , wherein M is a divalent metal and X' is halogen; and, optionally,

[0086] (ii) subjecting the compound of formula (la') to a hydrolysis to provide a compound of formula (lb'): wherein X is halogen.

[0087] In a preferred embodiment, the compound of formula (la') is a compound of formula (Ic): wherein Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen.

[0088] In another preferred embodiment, the compound of formula (lb') is l-(l-chloro-cyclopropyl)-2- (2-chloro-phenyl) ethanone of formula (Id):

[0089] In another particular embodiment, the process of the invention comprises:

[0090] (i) reacting a compound of formula (Illa): wherein M is a divalent metal, X and X' are independently selected from a halogen, for example a compound of formula (Illa) wherein -MX' is -MgCI, with a compound of formula (II'): wherein:

[0091] R is >CR1R2or >C=CH2, wherein R1is selected from H or halogen, and R2is -CH2-CH2X, wherein X is halogen; to provide a compound of formula (la"): wherein:

[0092] X is a halogen;

[0093] R is >CR1R2or >C=CH2, wherein R1is selected from H or halogen, and R2is -CH2-CH2X, wherein X is halogen; and

[0094] Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen, (ii) transforming the compound of formula (la") into a compound of formula (la'): wherein X is a halogen and Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen; and, optionally,

[0095] (iii) subjecting the compound of formula (la') to a hydrolysis to provide a compound of formula (lb'):

[0096] In a preferred embodiment, the compound of formula (II') is the compound of formula (lib):

[0097] In another preferred embodiment, the compound of formula (la") is a compound of formula

[0098] (la'"): wherein X is a halogen and Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen.

[0099] In a further particular embodiment, the process of the invention comprises:

[0100] (i) reacting a compound of formula (Illa): wherein M is a divalent metal, X and X' are independently selected from a halogen, for example a compound of formula (Illa) wherein -MX' is -MgCI, with a compound of formula (II'): wherein:

[0101] R is >CR1R2or >C=CH2, wherein R1is selected from H or halogen, and R2is -CH2-

[0102] CH2X, wherein X is halogen; to provide a compound of formula (lalv): wherein:

[0103] R is >CR1R2or >C=CH2, where R1is selected from H or halogen, and R2is -CH2-CH2X, wherein X is halogen or R1and R2form together with the C atom to which they are attached form a cyclopropyl ring, and

[0104] Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen; and, optionally,

[0105] (ii) subjecting the compound of formula (lalv) to a hydrolysis to provide a compound of formula (lb"):

[0106] In a preferred embodiment, the compound of formula (lalv) is a compound of formula (lav): wherein X is a halogen and Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen; a compound of formula (la'): or a mixture thereof.

[0107] In another preferred embodiment, the compound of formula (lb") is a compound of formula

[0108] (lbv): a compound of formula (lb') or a mixture thereof.

[0109] The order of steps (ii) and (iii) can be reversed so that the compound of formula (la") is first hydrolyzed to the corresponding compound of formula (lb"), onto which the cyclopropyl ring is constructed to provide the corresponding compound of formula (lb').

[0110] In a particular embodiment, the process of the present invention further comprises transforming the compound l-(l-chloro-cyclopropyl)-2-(2-chloro-phenyl) ethanone of formula (Id) in the compound 2-(2-chloro-benzyl)-2-(l-chloro-cyclopropyl)-oxirane of formula (IV):

[0111] Conversion of the compound of formula (Id) into the compound of formula (IV) may be carried out by means disclosed in the prior art.

[0112] In a particular embodiment, the conversion of the compound of formula (Id) into the compound of formula (IV) is carried out by reacting said compound of formula (Id) with an electron withdrawing group, optionally in the presence of a base.

[0113] As used herein, the term "electron withdrawing group" refers to a functional group that draws electrons away from the atom to which it is bound. Suitable electron withdrawing may be selected from sulfinyl (— SOR), sulfonyl (— SO2R), sulfite (— SO3R), sulfonium salt, diazo (— N=N+), and nitro (— NO2) groups, where R represents an alkyl group, preferably methyl. In a more particular embodiment, the electron withdrawing group may be selected from the group consisting of sulfonium salts.

[0114] Preferably, the electron withdrawing group is in the form of a sulfonium salt or a sulfoxonium salt.

[0115] As used herein, the term "sulfonium salt" refers to any compound of formula (R1R2R3S)X, where R1, R2and R3are identical or different and denote alkyl, aryl, aralkyl or alkaryl radicals, and X denotes a valence anion. The anion X is generally a halogen or sulfate, preferably chlorine or methyl sulfate (MeOSC j. The sulfonium salt may be selected from the group consisting of trimethylsulfonium chloride, trimethylsulfonium bromide, trimethylsulfonium hydroxide, trimethylsulfonium hydrogen sulfate, bis trimethylsulfonium sulfate, trimethylsulfonium triflate, trimethylsulfonium mesitilate, trimethylsulfonium iodid, trimethylsulfonium and methyl sulfate. A preferred sulfonium salt is trimethylsulfonium chloride. Likewise, the term "sulfoxonium salt" refers to any compound of formula (R1R2R3SO)X, where R1, R2and R3are identical or different and denote alkyl, aryl, aralkyl or alkaryl radicals, substituted or not, and X denotes a valence anion. The anion X is generally a halogen, or sulfate, preferably chlorine. The sulfoxonium salt may be selected from the group consisting of trimethylsulfoxonium chloride, trimethylsulfoxonium chloride, trimethylsulfoxonium bromide, trimethylsulfoxonium hydroxide, trimethylsulfoxonium hydrogen sulfate, bis trimethylsulfoxonium sulfate, trimethylsulfoxonium triflate, trimethylsulfoxonium mesitilate, trimethylsulfoxonium iodid, trimethylsulfoxonium methyl sulfate. A preferred sulfoxonium salt is trimethylsulfoxonium chloride.

[0116] In an embodiment, the molar ratio of the sulfonium or sulfoxonium salt with respect to the compound of formula (Id) is from 1:3 to 3:1, preferably is about 1:1.

[0117] Examples of the base to be used may include inorganic bases such as alkali metal hydroxides or alkali metal alcoholates. Preferred possible bases are sodium hydroxide and potassium hydroxide. Optionally, the reaction can take place in the presence of a PTC (phase transfer catalyst) like TBAB (Tetrabutylammonium bromide).

[0118] In a preferred embodiment, the reaction is carried out in the presence of trimethyl sulfoxonium chloride, and sodium hydroxide or potassium hydroxide as base.

[0119] The reaction is typically performed in the presence of an organic solvent. Any customary inert organic solvent can be employed in the reaction of step (ii). Solvents which can preferably be used are polar organic solvents such as alcohols and ethers, for example methanol, ethanol, n- propanol, isopropanol, n-butanol, diethyl ether, dioxane, tetrahydrofuran; water and mixtures thereof. In a particular embodiment, the reaction is performed in the presence of an alcohol solvent, preferably selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol. In a more preferred embodiment, the solvent is n-butanol. In an embodiment, the reaction is carried out at a temperature between 25 °C and 60 °C, preferably between 30 °C and 40 °C.

[0120] In a particular embodiment, the process of the invention further comprises converting the compound of formula (Id) into prothioconazole, or a salt or solvate thereof. In another embodiment, further converting the compound of formula (Id) into prothioconazole comprises converting the compound of formula (Id), or a solvate thereof, into a compound of formula (IV) or a solvate thereof.

[0121] The compound of formula (IV) can then be converted into prothioconazole or a salt or solvate thereof by methods known in the prior art, such as from IN371149. For example, the compound of formula (IV) may be reacted with 1,2,4-triazole in an organic solvent such as N,N- dimethylformamide (DMF), with a base such as potassium tert-butoxide, to yield 2-(l-chloro- cyclopropyl)-l-(2-chloro-phenyl)-3-(l,2,4-triazole-l-yl)propan-2-ol, followed by addition of sulfur powder in an organic solvent such as DMF under heating, as disclosed in examples 10 and 11 of IN371149.

[0122] In some embodiments, the compound of formula (II) is a compound of Formula (Ila), as defined above.

[0123] According to an embodiment, the compound of Formula (Ila) may be obtained by reacting 2- chloroacrylonitrile with a Me-L derivative, wherein Me denotes a methyl group and L is an electron withdrawing group, optionally in the presence of a base.

[0124] As used herein, the term "electron withdrawing group" refers to a functional group that draws electrons away from the atom to which it is bound. Suitable electron withdrawing may be selected from sulfinyl (— SOR), sulfonyl (— SO2R), sulfite (— SO3R), sulfonium salt, diazo (— N=N+), and nitro (— NO2) groups, where R represents an alkyl group, preferably methyl. In a more particular embodiment, the electron withdrawing group may be selected from the group consisting of diazo (— N=N+) groups.

[0125] In a preferred embodiment, the Me-L derivative is diazomethane. The diazomethane compound can be obtained by methods known in the art. For example, diazomethane may be prepared by reacting urea with methylamine or a salt thereof and sodium nitrite to yield N- methylnitrosourea, which may then be hydrolyzed in aqueous basic solutions at temperatures of 0 °C to 10 °C.

[0126] The reaction of 2-chloroacrylonitrile with a Me-L derivative may proceed in a first organic solvent at temperatures of 0 °C to 10 °C, optionally with a base; followed by reflux in a second organic solvent.

[0127] A base may be used in the reaction, preferably selected from inorganic bases such as alkali metal hydroxides or alkali metal alcoholates. Preferred bases are sodium hydroxide and potassium hydroxide. The first and second organic solvents may be independently selected from ethers such as diethyl ether, dibutyl-ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2,5- dimethyl-tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol tert-butyl methyl ether, diethylene glycol diethyl ether and 1,4-dioxane, aromatic hydrocarbons such as benzene, monochlorobenzene, toluene, xylene; and mixtures thereof. The solvents are preferably employed in dry form. In a particular embodiment, the solvent of step (i) is selected from the group consisting of diethyl ether, tert-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran, 2-dimethyl-tetrahydrofuran and mixtures thereof.

[0128] Preferably, the first organic solvent is diethyl ether and the second organic solvent is 2-methyl- tetrahydrofuran.

[0129] In an alternative embodiment, the compound of Formula (Ila) is obtained by treating 2,4- dichlorobutanenitrile with a base in an organic solvent and, optionally in the presence of a phase transfer catalyst. To the best of the authors knowledge such reaction has never been described and presents numerous advantages. It is thus a further aspect of the present invention a reaction to produce the compound of formula (Ila) that comprises treating 2,4-dichlorobutanenitrile (compound of formula (lie)) with a base in an organic solvent and, optionally in the presence of a phase transfer catalyst.

[0130] Suitable bases may be selected from from inorganic bases such as alkali metal hydroxides or alkali metal alcoholates. Preferred bases are sodium hydroxide and potassium hydroxide.

[0131] The organic solvent may be selected from aromatic hydrocarbons such as benzene, monochlorobenzene, toluene, mesitylene, xylene, and mixtures thereof, or mixtures with unsaturated hydrocarbons like hexane. Preferably, the solvent is monochlorobenzene.

[0132] In some embodiments, a phase transfer catalyst may be used in the reaction. Exemplary phase transfer catalysts are ammonium or phosphonium compounds. Phase transfer catalysts can be selected from the group consisting of tetraalkyl ammonium salts, trialkyl aralkylammonium salts or tetraalkyl-phosphonium salts such as tetrabutylammonium bromide or chloride, methyl trioctylammonium bromide, methyl tributylammonium chloride, triethyl benzyl ammonium bromide or chloride, and benzyl dodecyl dimethyl ammonium chloride. In a particular embodiment, the phase transfer catalyst may be selected from the group consisting of tetraethyl ammonium bromide, tetrabutyl ammonium bromide, tetrabutyl ammonium chloride, tetraoctylammonium bromide, tetraethyl ammonium hydrogen sulfate, tetrabutyl ammonium hydrogen sulfate, dimethyl dioctadecyl ammonium bromide, dimethyl didecyl ammonium bromide, methyl tributyl ammonium chloride, methyl trioctylammonium bromide, hexadecyl trimethyl ammonium chloride, triethyl benzyl ammonium bromide or chloride, methyltributylammonium chloride and benzyl dodecyl dimethyl ammonium chloride (benzalkonium chloride). In a preferred embodiment the phase transfer catalyst is methyltributylammonium chloride.

[0133] In a particular embodiment, the molar percentage of phase transfer catalyst with respect to 2,4- dichlorobutanenitrile is between 0.01% and 50%, preferably between 0.1 and 2 mol%.

[0134] In a preferred embodiment, the reaction is carried out in the presence of sodium hydroxide as base and tetrabutylammonium bromide as phase transfer catalyst. In another preferred embodiment, the reaction is carried out in the presence of sodium hydroxide and / or potassium carbonate as base and methyl tributyl ammonium chloride as phase transfer catalyst. In another preferred embodiment, the reaction is carried out in the presence of a mixture of an inorganic carbonate and an alkaline or an alkali-earth hydroxide. For example, the reaction may take place in the presence of potassium carbonate and sodium hydroxide. It is preferred that the reaction takes place in the presence of a mixture of an inorganic carbonate and an alkaline or an alkali- earth hydroxide and a phase transfer catalyst. For example, the reaction can take place in the presence of a) sodium or potassium carbonate, b) sodium, magnesium or potassium hydroxide and c) methyl tributyl ammonium chloride as phase transfer catalyst.

[0135] In preferred embodiments, 2,4-dichlorobutanenitrile is added continuously during the reaction. Temperature may be required for the reaction to proceed in a reasonable time. Thus, in some embodiments the reaction is maintained at a temperature comprised between 20 °C and 80 °C, for example, between 20 °C and 50 °C, preferably between 35 °C and 55 °C. In another preferred embodiment, the reaction is maintained at 15 °C to 30 °C, for example at room temperature.

[0136] The inventors have found that continuous distillation of the compound obtained in the reaction, i. e., the compound of Formula (Ila), significantly increases the yield. Thus, continuous distillation of the compound of Formula (Ila) is preferred.

[0137] Preparation of 2,4-dichlorobutanenitrile

[0138] The 2,4-dichlorobutanenitrile used as starting material to obtain a compound of formula (Ila) may be obtained by methods disclosed in the prior art, such as in Mitani et al., J. Chem. Soc. Chem, 1983, 1446-1447. For example, a solution of acrylonitrile, dichloromethane, Cu source, and a phase transfer catalyst (e.g. tetrabutylammonium bromide) may be irradiated using a low- pressure Hg lamp. This process comprises a catalyst, for example, a catalyst comprising a metal, such as copper. Said copper can be in the form of a copper salt or a complex thereof, such as in the form of CuCI, CuBr, Cui, CuCL, CU2O or Cu(acetonitrile)4BF4 for example CuCI. The catalyst is typically added in amounts that range from 0.001 to 0.5 molar equivalents with respect to acrylonitrile, typically, between 0.005 and 0.15 molar equivalents. The co catalyst (e.g. phase transfer catalyst) is also typically added in catalytic amounts, for example, from 0.005 to 0.5 molar equivalents with respect to the acrylonitrile, typically, between 0.01 and 0.2 molar equivalents. Exemplary phase transfer catalysts are ammonium or phosphonium compounds. Phase transfer catalysts can be selected from the group consisting of tetraalkyl ammonium salts, trialkyl aralkylammonium salts or tetraalkyl-phosphonium salts such as tetrabutylammonium bromide or chloride, methyl trioctylammonium bromide, methyl tributylammonium chloride, triethyl benzyl ammonium bromide or chloride, and benzyl dodecyl dimethyl ammonium chloride.

[0139] Exemplary conditions for the preparation of 2,4-dichlorobutanenitrile can comprise mixing acrylonitrile with 0.005 to 0.5 molar equivalents, with respect to the acrylonitrile, of a tetraalkyl ammonium bromide or chloride (e.g. tetrabutylammonium bromide or chloride) and 0.001 to 0.5 molar equivalents, with respect to the acrylonitrile, of a metal catalyst such as CuCI, CuCL, or CuBr, optionally in the presence of an organic solvent, and irradiating the mixture. The molar proportion between the catalyst and the phase transfer catalyst can be comprised between 10:1 and 1:10 (catalyst:phase transfer catalyst), for example, between 8:1 and 1:8, or between 5:1 and 1:2. For example, the molar proportion between the catalyst and the phase transfer catalyst can be comprised between 6:1 and 1:1, or between 4:1 and 1:4, for example, between 2:1 and 1:2.

[0140] The authors have found specific conditions for the reaction that improve conversion, yield and / or prevent or minimize the production of solid impurities (fouling).

[0141] Accordingly, the authors have found that it is preferred that all or part of the acrylonitrile is added continuously during the reaction in order to reduce or even avoid the formation impurities, particularly of insoluble film impurities (fouling).

[0142] Another parameter that has proved surprisingly helpful in controlling fouling is the temperature. In a preferred embodiment the temperature at which acrylonitrile, dichloromethane, and the phase transfer catalyst are reacted is comprised between -20 °C and 30 °C, for example, between -15 °C and 20 °C, between -10 °C and 15 °C, between -5 °C and 10 °C, or between -5 °C and 5 °C. Alternatively, or in addition to the continuous addition of acrylonitrile and / or the temperature, the addition of water and / or of an organic solvent selected from THF, acetonitrile and an alcohol, preferably an alcohol, can also help reduce the amount of insoluble film impurities, i.e., fouling. The alcohols can be aliphatic (e.g. methanol, ethylene glycol). The amount of THF, acetonitrile or alcohol added can range from 0.1 V / V% to 30 V / V%, with respect to the total volume of the sum of dichloromethane and THF, acetonitrile or alcohol. For example, from 1 V / V% to 20 V / V%, or from 5 V / V% to 15 V / V%, with respect to the total volume. The amount of water added can range from 0.01 V / V% to 10 V / V%, with respect to the total volume of dichloromethane and THF, acetonitrile or alcohols (if present). For example, from 0.1 V / V% to 5 V / V%, or from 0.5 V / V% to 3 V / V%, with respect to the total volume of dichloromethane and THF, acetonitrile or alcohols.

[0143] Surprisingly, the addition of water and / or of THF, acetonitrile or an alcohol, preferably an alcohol, additionally allows for a significant reduction in the amount of phase transfer catalyst needed in the reaction. For example, below 0.5 molar equivalents, with respect to the acrylonitrile, for example, below 0.4 molar equivalents, of below 0.3 molar equivalents, below 0.2 molar equivalents, below 0.1 molar equivalents, below 0.08 molar equivalents, below 0.05 molar equivalents, with respect to the acrylonitrile; for example, between 0.001 and 0.1 molar equivalents, with respect to the acrylonitrile, of phase transfer catalyst, or between 0.001 and 0.1 molar equivalents, or between 0.005 and 0.07 molar equivalents, or between 0.008 and 0.08 molar equivalents, with respect to the acrylonitrile, of phase transfer catalyst. Advantageously, this unexpected reduction in the amount of phase transfer catalyst needed results in a significant reduction of costs.

[0144] Even further, the addition of water and / or of THF, acetonitrile or an alcohol, preferably an alcohol, provides excellent conversions and yields even at high concentrations of starting material acrylonitrile. This is critical to improve the overall efficiency. The higher the concentration, the more product output can be obtained per volume unit, allowing for a more efficient use of reactors. For example, the process comprises reacting a solution of acrylonitrile, dichloromethane, a catalyst (e.g. Cu source), and a phase transfer catalyst (e.g. tetrabutylammonium bromide) while irradiating using a low-pressure Hg lamp, wherein the concentration of the acrylonitrile is above 1.0 m / V%, or above 2.0 m / V%, above 3 m / V%, above 4 m / V%, for example, wherein the concentration of acrylonitrile is between 1.0 m / V% and 10 m / V%, for example, between 2.0 m / V% and 8.0 m / V%.

[0145] Thus, one aspect is a method for the preparation of 2,4-dichlorobutanenitrile that comprises the reaction between acrylonitrile, dichloromethane, and a phase transfer catalyst (e.g. tetrabutylammonium bromide) under irradiation (e.g. low-pressure Hg lamp) in the presence of a catalyst, such as a Cu salt or a complex thereof (e.g. CuCI), wherein the reaction comprises one or more of the following: i. continuous addition of acrylonitrile; ii. performing the reaction at a temperature comprised between -20 °C and 30 °C, preferably between -10 °C and 20 °C; ill. performing the reaction in the presence of water; iv. performing the reaction in the presence of THF, acetonitrile or an alcohol, preferably an alcohol; and / or v. subjecting the reaction mixture (comprising acrylonitrile, phase transfer catalyst, and optionally one or more of a catalyst, such as a Cu salt or a complex thereof (e.g. CuCI)), dichloromethane, and optionally water, THF, acetonitrile or an alcohol) to a preirradiation step prior to performing the reaction.

[0146] In a preferred embodiment, the reaction to obtain 2,4-dichlorobutanenitrile comprises at least two reaction conditions selected from i., ii., iii., iv. and v., as defined above. Thus, the reaction to obtain 2,4-dichlorobutanenitrile may comprise reaction conditions i. and ii., i. and iii., i. and iv., i. and v., ii. and iii., ii. and iv., ii. and v., iii. and iv., iii. and v. or iv. and v, as defined above.

[0147] In a particular embodiment, the reaction is carried out in the presence of a catalyst, preferably CuCI, more preferably in an amount between 0.005 and 0.15 molar equivalents with respect to acrylonitrile.

[0148] In a preferred embodiment, the reaction is performed in the presence of an alcohol, preferably an aliphatic alcohol, more preferably an alcohol selected from the group consisting of ethylene glycol, methanol, 2-butanol and mixtures thereof. In a more preferred embodiment, the amount of alcohol is between 5 V / V% to 15 V / V%, with respect to the total volume of dichloromethane and alcohols. In another preferred embodiment, alternatively or additionally to the presence of alcohol(s), the reaction is performed in the presence of water, preferably in an amount between 0.1 V / V% to 5 V / V% with respect to the total volume of dichloromethane, and alcohols if present. Most preferably, the reaction is carried out in the presence of water and an alcohol selected from ethylene glycol, methanol and mixtures thereof, preferably in the amounts as defined in any of the embodiments described above.

[0149] In a further preferred embodiment, the reaction is performed at a temperature between -5 °C and 5 °C, preferably at about 0 °C. In a further preferred embodiment, the reaction is performed at a temperature between 10 °C and 25 °C, preferably at about 18 °C.

[0150] Alternatively, or in addition to the hereinabove disclosed conditions, the authors have found that subjecting the reaction mixture (comprising acrylonitrile, phase transfer catalyst, one or more of a catalyst (e.g. CuCI), dichloromethane and optionally water, THF, acetonitrile or an alcohol) to a pre-irradiation step prior to performing the reaction (e.g., in a reactor such as a tubular horizontal continuous reactor) is surprisingly helpful to obtain a homogeneous solution and minimizing formation of impurities (fouling).

[0151] According to a preferred embodiment, the method to prepare 2,4-cichlorobutanenitrile comprises the addition of water, THF, acetonitrile and / or an alcohol, and less than 0.5 equivalents, with respect to the total amount of acrylonitrile, of a phase transfer catalyst.

[0152] According to a preferred embodiment, the method to prepare 2,4-cichlorobutanenitrile comprises the addition of water and an alcohol.

[0153] The procedures described herein for the preparation of 2,4-dichlorobutanenitrile result in low amounts or no fouling. n case fouling is produced, the present application also provides a cleaning process of the reaction installations that effectively removes fouling.

[0154] Thus, a further aspect of the present application is a method for producing 2,4- dichlorobutanenitrile wherein, once the reaction is complete, the process comprises a first cleaning step that comprises contacting the reaction equipment (e.g. reactors, tubes, and / or stirring equipment) with a solvent. Said solvent is preferably one selected from the group consisting of an organic solvent (e.g. DMF), preferably an alcohol (e.g. MeOH, or ethylene glycol), aqueous KSCN, aqueous ZnCL and aqueous base (e.g. aqueous NaOH). Aqueous acid (HNO3) failed to remove fouling. The process may comprise one or more of these solvents that can be used sequentially. The process optionally comprises a second cleaning step with acetone. The use of alcohols such as methanol or ehtylene glycol as cosolvent during the reaction produced minimal amounts of fouling that can be removed with veraiety of solvents or by a mechanical cleaning method. Thus, an advange of using alcohols as co-solvents of the reaction is that there is no need of using any special cleaning step of the equipment after the reaction is complete.

[0155] According to a preferred embodiment, the method to prepare 2,4-cichlorobutanenitrile comprises a cleaning step that comprises contacting the reaction equipment with a solvent selected from the group consisting of an organic solvent, aqueous KSCN, aqueous ZnCI2 and aqueous base.

[0156] According to an embodiment, the compound of formula (III) may be prepared by a process comprising contacting a compound of Formula (V): (V) wherein X and X" are each independently selected from a halogen; with a metal, preferably with a divalent metal (e.g. Mg) in the presence of an organic solvent. Conversion of a compound of formula (V) can typically be carried out by reacting it with a divalent metal selected from magnesium, copper, manganese, zinc, mercury and tin, preferably with magnesium or with a monovalent metal selected from lithium, sodium, potassium preferably with lithium.

[0157] In a particular embodiment, the molar ratio of the metal with respect to the compound of formula (V) is from 1:2 to 4:1, preferably from 0.9:1 to 3:1, preferably from 1:1 to 2:1.

[0158] In a particular embodiment, X and / or X" is selected from chloro or bromo, preferably chloro. In a preferred embodiment, the compound of formula (V) is l-chloro-2-(chloromethyl)benzene. This process may typically proceed in an organic solvent under inert atmosphere.

[0159] Any suitable inert organic solvent can be used. Preferred solvents are ethers, such as diethyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2,5- dimethyl-tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol tert-butyl methyl ether, diethylene glycol, diethyl ether, cyclopentyl methyl ether and 1,4-dioxane. The solvents are preferably employed in dry form. In a particular embodiment, the solvent is selected from the group consisting of diethyl ether, tert-butyl methyl ether, tetrahydrofuran, methyltetrahydrofuran, 2-dimethyl-tetrahydrofuran and mixtures thereof. Preferably, the solvent is selected from the group consisting of diethyl ether 2-methyl-tetrahydrofuran, and tert-butyl methyl ether. Optionally, a co-solvent may be used, for example, a saturated or unsuturated hydrocarbon like toluene, benzene xylem (xylene), mesitylene, hexane, methylcyclohexane, or cyclohexane. In a preferred embodiment, the solvent used is a mixture of a first solvent selected from the group consisting of diethyl ether, dibutyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, 2,5-dimethyl-tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol tert-butyl methyl ether, diethylene glycol, diethyl ether, cyclopentyl methyl ether and 1,4-dioxane; and a second solvent selected from the group consisting of an aromatic hydrocarbon such as toluene or benzene xylem (xylene). For example, the solvent can be a mixture of a first solvent selected from the group consisting of diethyl ether, tetrahydrofuran, and 2-methyl-tetrahydrofuran; and a second solvent selected from the group consisting of toluene and benzene xylem (xylene).

[0160] Temperature may be required for the reaction to proceed in a reasonable time. Thus, in some embodiments the reaction is maintained at a temperature comprised between 20 °C and 100 °C. In a particular embodiment, the reaction is performed at a temperature between 30 and 80 °C, preferably between 40 and 70gC, more preferably between 50-60 °C.

[0161] In a particular embodiment, the reaction is performed at a temperature between -5 °C and room temperature, preferably between 0 and 25 °C, more preferably between 0-5 °C.

[0162] In a particular embodiment, the reaction is started at lower temperature, after which a temperature gradient is applied to achieve a similar yield to that of the reaction of at low temperature but in a shorter period of time.

[0163] Compounds of formula (la)

[0164] In another aspect, the present invention relates to a compound of formula (la): or a salt or solvate thereof; wherein

[0165] R is >CR1R2or >C=CH2, where:

[0166] R1and R2form together with the C atom to which they are attached form a cyclopropyl ring, or

[0167] R1is selected from H or halogen, and R2is -CH2-CH2X;

[0168] - each X is independently selected from a halogen, and

[0169] - Z is H or a monovalent metal or MX, wherein M is a divalent metal and X is halogen.

[0170] Each X is halogen independently selected from fluoro, bromo, chloro, or iodo, preferably bromo or chloro, more preferably chloro.

[0171] In a particular embodiment R is >CR1R2where R1and R2form together with the C atom to which they are attached a cyclopropyl ring.

[0172] In another particular embodiment R is >CR1R2, where R1is selected from H or halogen, and R2is X2H2-CH2X. In a more particular embodiment, R1is H. In another more particular embodiment, R1is halogen, preferably chloro or bromo, more preferably chloro. In a particular embodiment, R2is -CH2-CH2X where X is halogen, preferably selected from chloro or bromo, more preferably chloro.

[0173] In a further particular embodiment, R is >C=CH2.

[0174] In a more preferred embodiment, the compound of formula (la) is: or a salt or solvate thereof, wherein Z is H or a monovalent metal or MX, wherein M is a divalent metal and X is halogen, preferably wherein MX is MgCl.

[0175] In an additional aspect, the invention refers to the use of a compound of formula (II) as defined above as intermediate in the preparation of a pesticide.

[0176] In a further aspect, the invention relates to the use of a compound of formula (II), preferably a compound of formula (Ila), as defined above as intermediate in the preparation of prothioconazole.

[0177] EXAMPLES

[0178] Example 1: Preparation of 1-chlorocvclopropane-l-carbonitrile (compound Ila)

[0179] Step 1: Preparation of N-methyl-nitrosourea

[0180] To a 500ml round bottom flask, water (4V), methylamine hydrochloride (l.Oeq), and urea (3.4eq) were added. The reaction mass temperature was raised to 100-105 °C and kept under stirring for lOh at said temperature. After lOh, the reaction mass was cooled down to 0-5 °C, sodium nitrite (1.0 eq.) was added and the reaction mass stirred for 30 min at 0-5 °C.

[0181] To another IL round bottom flask 330g of ice-cold water were added followed by slow addition of sulphuric acid (0.7eq.), and the solution was cooled to -5 to 0 °C. Then, the reaction mass of the previous step was added slowly to this solution at -5 to 0 °C over a period of 2-3h. After addition, the resulting reaction mass was stirred for 45-60 min. The obtained solid was filtered, washed with water and dried for 2-3h to give N-methyl nitrosourea.

[0182] Step 2: Preparation of 1-chlorocyclopropane-l-carbonitrile

[0183] To a round bottom flask water (3V), KOH (3.7eq.) and diethylether (8V) were added, and the reaction mass cooled to 0-5 °C. N-methyl nitrosourea was added portion-wise at 0-5 °C over 30- 45 min at 0-5 °C. The organic layer (diazomethane) was separated and kept at 0-5 °C. 2-Chloroacrylonitrile (l.Oeq) in diethyl ether (IV) were added to another round bottom flask and cooled to 0-5 °C. The prepared diazomethane in diethyl ether was slowly added to the reaction mass at 0-5 °C and continued to stir for 30min at 0-5 °C. After 30min, 0.01 eq of acetic acid were added to yield a colourless solution, followed by addition of KOH (O.Oleq). The reaction mass was filtered to remove KOH, and the filtrate transferred to another round bottom flask fitted with a condenser. 2-MeTHF (2V) was added, and the reaction mass temperature raised to 80-85 °C for 16h.

[0184] Compound of formula (Ila) was purified by fractional distillation. Product was collected at 35 °C under 10 mm / Hg (1HNMR as reported in the literature). iple 2: preparation of 1-chlorocvclopropane-l-carbonitrile (the compound of formula from 2,4-dichlorobutanenitrile (the compound of formula (He))

[0185] Cr

[0186] 2,4-dichlorobutanenitrile was prepared by methods known in the art, such as those disclosed in Mitani et al., J. Chem. Soc., Chem. Commun., 1983, 1446-1447. .

[0187] Alternatively, 2,4-dichlorobutanenitrile can be produced as described below in examples 7, 8 or 9.

[0188] To a clean and dry 100ml round bottom flask, 30% aq. NaOH (1.5eq) solution was added and the reaction mass temperature raised to 50-55 °C. 2,4-dichlorobutanenitrile (2g) in monochlorobenzene MCB (10V) solvent was added dropwise at 50-55 °C over a period of lh, and the reaction mass stirred at that temperature for 1 h. The pH of the reaction mass was adjusted to 7-7.5 using H3PO4, and the organic layer separated to yield the compound of formula (Ila).

[0189] Dried Mg turnings (1.25 eq.) and diethyl ether (2V) were added to a clean and dried 250mL round bottom flask connected with condenser under N2 atmosphere. The reaction mass temperature was raised to reflux and l-chloro-2-(chloromethyl)benzene (10g, l.Oeq) in diethylether (5V) was added dropwise. Exothermicity was observed. The reaction mass was stirred for lh to yield a clear solution. (2-chlorobenzyl)magnesium chloride as prepared was stored under nitrogen atmosphere and used for next step immediately.

[0190] Alternatively, (2-chlorobenzyl)magnesium chloride was obtained by the following procedures (b) or (c):

[0191] (b) Methyl-tert-butyl-ether (MTBE):

[0192] Dried Mg turnings (1.25 eq.) and either diethyl ether (2V) were added to a clean and dried 250mL round bottom flask connected with condenser under N2 atmosphere, and the reaction mass temperature raised to 50-55 °C °C. (2-chlorobenzyl)magnesium chloride prepared in diethyl ether (0.5 mL) was added to the reaction flask to initiate the reaction at 50-55 °C. l-chloro-2- (chloromethyl)benzene (10g, l.Oeq) in MTBE (5V) was added dropwise and the reaction mass stirred for lh. The prepared (2-chlorobenzyl)magnesium chloride was stored under nitrogen atmosphere and used for next step immediately.

[0193] (c) 2-methyl-tetrahydrofuran (2-MeTHF):

[0194] Dried Mg turnings (2.0eq.) and 2-MeTHF (2V) were added to a clean and dried 250mL round bottom flask connected with condenser under N2 atmosphere, and the reaction mass temperature raised to 50-55 °C. (2-chlorobenzyl)magnesium chloride prepared in diethyl ether (0.5 mL) was added to the reaction flask to initiate the reaction at 50-55 °C. l-chloro-2- (chloromethyl)benzene (10g, l.Oeq) in 2-MeTHF (5V) was added dropwise at 50-55 °C. The reaction mass was stirred for lh to yield a clear solution. The prepared (2- chlorobenzyl)magnesium chloride was stored under nitrogen atmosphere and used for next step immediately.

[0195] Example 4. Preparation of l-(l-chlorocvclopropyl)-2-(2-chlorophenyl)ethan-l-one (Compound (Id)) with LiCI

[0196] To a clean and dried 50 mL round bottom flask connected with a condenser under N2 atmosphere (2-chlorobenzyl)magnesium chloride in diethyl ether (lg in 10 mL EtjO) solvent was added. Dry LiCI (l.Oeq) was added at 25-30 °C, and the reaction mass stirred for 30min at that temperature. 1-chlorocyclopropane-l-carbonitrile (compound of formula (Ila)) (0.54 g, l.Oeq.) in diethylether (2mL, 2V)) was added dropwise over a period of 10-15min, and the reaction mass stirred for 16h. Reaction was monitored by TLC. After completion of reaction, the reaction mass was quenched with 6N HCI solution and stirred for 10-15 min. The organic layer was separated, dried over sodium sulphate, and concentrated to yield crude compound of formula (Id). The crude product was further purified by column chromatography, product eluted at 2-3% Ethyl acetate: Hexane Yield: 0.5 g (40.6%).

[0197] Alternatively, the compound of formula (Id) was also obtained by a similar procedure but using MTBE as solvent instead of diethyl ether.

[0198] To a clean and dried 50 mL round bottom flask connected with a condenser under N2 atmosphere (2-chlorobenzyl)magnesium chloride in MTBE (lg in 10 mL Et20) solvent was added. Dry LiCI (0.3 eq) was added at 25-30 °C, and the reaction mass stirred for 30min at that temperature and then the temperature was raised to 40-45 °C. 1-chlorocyclopropane-l- carbonitrile (0.54 g, l.Oeq.) in MTBE (2mL, 2V)) was added dropwise over a period of 10-15 min, and the reaction mass stirred for 16h at 40-45 °C. Reaction was monitored by GC. After completion of reaction, the reaction mass was quenched with 6N HCI solution and stirred for 10- 15 min. The organic layer was separated, dried over sodium sulphate, and concentrated to yield crude compound of formula (Id). (1HNMR as reported in the literature). To a clean and dried 50 mL round bottom flask connected with a condenser under N2 atmosphere (2-chlorobenzyl)magnesium chloride in MTBE (lg in 10 mL MTBE) solvent was added. The reaction mass temperature was raised to 60-65 °C. 1-chlorocyclopropane-l- carbonitrile (Compound of formula (Ila)) (0.54 g, l.Oeq.) in MTBE (2V) was added dropwise over a period of 10-15min, and the reaction mass stirred for 16h. Reaction was monitored by GC. After completion of reaction, the reaction mass was quenched with 6N HCI solution and stirred for 10-15 min. The organic layer was separated, dried over sodium sulphate, and concentrated to yield crude compound of formula (Id). The crude product was further purified by column chromatography, product eluted at 2-3% Ethyl acetate:Hexane. Yield: 0.4 g (32.5%).

[0199] Example 6. Preparation of 2-(2-chlorobenzyl)-2-(l-chlorocvclopropyl)oxirane (Compound of formula (IV))

[0200] To a clean and dried 50mL round bottom flask n-butanol (9V) and potassium hydroxide (l.Oeq) at 25-30 °C were charged. The reaction mass was stirred until a clear solution was obtained (5- lOmin). The compound of formula (Id) (0.1 g, l.Oeq) in n-butanol (IV) was added followed by addition of trimethyl sulfoxonium chloride (l.Oeq). The reaction mass temperature was raised to 35-40 °C and stirring continued for 3h at 35-40 °C. After that, water (10V) was added to the reaction mass and stirred for RM 3h at 35-40 °C. The organic layer was separated and concentrated completely under vacuum to obtain crude 2-(2-chlorobenzyl)-2-(l- chlorocyclopropyl)oxirane according to HPLC against standard.

[0201] Example 7: Alternative reaction conditions for the preparation of 2,4-dichlorobutanenitrile (compound of formula (He))

[0202] Acrylonitrile (200 mg, 3.769 mmol) was added into a degassed solution of a phase transfer catalyst (PTC) and a catalyst in the amounts indicated in Table 1, in dichloromethane (20 mL) at room temperature under argon atmosphere. The resulting mixture was irradiated at 254 nm (light source: 4 pieces of Osram HNS 25W G13 (G25T8 / OF)) at room temperature for 21 h in a 25 mL quartz vial (23 mm OD, 85 mm L). Conversion of the reaction was followed by1H-NMR. Red-brown insoluble film was formed on the surface of the glass exhibiting IR peak at ~2243 cm'1(associated with nitrile containing material / polymer like polyacrylonitrile). After completion the reaction mixture was diluted with dichloromethane (100 mL), washed with 10% solution of HCI (100 mL) and water (100 mL) and dried on MgSC . This solution was filtered on a short pad of silica and concentrated at reduced pressure (40 °C at 100 mbar).

[0203] In each case Table 1 provides the yield of the reaction. The yield of the reaction is calculated according to the qNMR data, using tetrachloronitrobenzene as ISTD, corrected by sampling during the reaction.

[0204] Table 1

[0205] Example 8: Scale-up preparation de 2,4-dichlorobutanenitrile (compound of formula (He))

[0206] Acrylonitrile (5750 mg, 108.4 mmol) was added into a degassed solution of tetrabutylammonium bromide (2329 mg, 7.23 mmol) and CuCI (179 mg, 1.81 mmol) in dichloromethane (230 mL) at room temperature under argon atmosphere. The resulting mixture was irradiated at 254 nm (light source: 4 pieces of Osram HNS 25W G13 (G25T8 / OF)) at room temperature for 21 h in a 350 mL quartz vial (30 mm ID, 500 mm L). Conversion of the reaction was followed by1H-NMR. Red-brown insoluble film was formed on the surface of the glass exhibiting IR peak at ~2243 cm'1(associated with nitrile containing material / polymer like polyacrylonitrile). After completion the reaction mixture was washed with 10% solution of HCI (500 mL) and water (500 mL) and dried on MgSC . This solution was filtered on a short pad of silica and concentrated at reduced pressure (40 °C at 100 mbar).

[0207] Isolated product: m: 13840 mg (90 m / m %) 2,4-dichlorobutanenitrile

[0208] Yield of the reaction: 83 % (according to the qNMR data (using tetrachloronitrobenzene as ISTD).

[0209] Example 9: Continuous addition of Acrylonitrile for the preparation of 2,4- dichlorobutanenitrile (compound of formula (He))

[0210] Acrylonitrile (50 mg, 0.942 mmol) was added into a degassed solution of tetrabutylammonium bromide (81.0 mg, 0.251 mmol) and CuCI (6.2 mg, 0.063 mmol) in dichloromethane (20 mL) at room temperature under argon atmosphere. The resulting mixture was irradiated at 254 nm (light source: 4 pieces of Osram HNS 25W G13 (G25T8 / OF)) at room temperature for 6.5 h in a 25 mL quartz vial (23 mm OD, 85 mm L). During irradiation mixture of acrylonitrile : DCM = 1:1 was added continuously by a syringe pump at 1 uL / min flow-rate (0.4 mg / min acrylonitrile) for 5.5 hours. Overall, 185 mg (3.481 mmol) of acrylonitrile were added. Conversion of the reaction was followed by1H-NMR. After 6.5 hours the reaction mixture was diluted with dichloromethane (100 mL), washed with 10% solution of HCI (100 mL) and water (100 mL) and dried on MgSO4. This solution was filtered on a short pad of silica and concentrated at reduced pressure (40 °C at 100 mbar).

[0211] Formation of red-brown insoluble film on the surface of the glass was not observed. Isolated product: m: 402 mg (87 m / m %) 2,4-dichlorobutanenitrile. Yield of the reaction: 89 % (according to the qNMR data (using tetrachloronitrobenzene as ISTD, corrected by sampling during the reaction).

[0212] Example 10: Effect of the temperature in fouling for the preparation of 2,4- dichlorobutanenitrile (compound of formula (He))

[0213] The effect of the temperature in the fouling was analyzed. The reaction was conducted by adding acrylonitrile (200 or 1000 mg) into a degassed solution of tetrabutylammonium bromide (aprox. 0.07 eq.) and CuCI (aprox. 0.02 eq.) in dichloromethane (20 mL) at room temperature under argon atmosphere. The resulting mixture was placed inside a cooling bath and irradiated at 254 nm (light source: 4 pieces of Osram HNS 25W G13 (G25T8 / OF)) at the temperature indicated in each case in Table 2 for 48 h in a 25 mL quartz vial (23 mm OD, 85 mm L). Conversion of the reaction was followed by1H-NMR. After completion, the reaction mixture was diluted with dichloromethane (100 mL), washed with 10% solution of HCI (100 mL) and water (100 mL) and dried on MgSO4. This solution was filtered on a short pad of silica and concentrated at reduced pressure (40 °C at 100 mbar).

[0214] It can be seen that fastest reaction rates combined with a reduced amount of fouling were obtained at 0 °C.

[0215] Example 11: Effect of the addition of water in fouling for the preparation of 2,4- dichlorobutanenitrile (compound of formula (He))

[0216] The effect of water addition in the fouling was analyzed. The reaction was conducted by adding acrylonitrile (1000 mg, 18.847 mmol) into a degassed solution of tetrabutylammonium bromide (405.0 mg, 1.256 mmol) and CuCI (31.1 mg, 0.315 mmol) in dichloromethane (20 mL) and the amounts of water as indicated in Table 3 below at room temperature under argon atmosphere. The resulting mixture was irradiated at 254 nm (light source: 4 pieces of Osram HNS 25W G13 (G25T8 / OF)) at room temperature for 24 h in a 25 mL quartz vial (23 mm OD, 85 mm L). Conversion of the reaction was followed by1H-NMR. After completion, the reaction mixture was diluted with dichloromethane (100 mL), washed with 10% solution of HCI (100 mL) and water (100 mL) and dried on MgSO4. This solution was filtered on a short pad of silica and concentrated at reduced pressure (40 °C at 100 mbar).

[0217] Table 3

[0218] Example 12: Effect of the addition ofTHF, acetonitrile or alcohols in fouling for the preparation of 2,4-dichlorobutanenitrile (compound of formula )

[0219] The effect of THF, acetonitrile or alcohol addition in the fouling was analyzed. The reaction was conducted by adding acrylonitrile (1000 mg, 18.847 mmol) into a degassed solution of tetrabutylammonium bromide (405.0 mg, 1.256 mmol) and CuCI (31.1 mg, 0.315 mmol) in dichloromethane (18 mL) and the additive (2 mL, 10 V / V% with respect to the total amount of dichloromethane and additive) as indicated in each case in Table 4 below at room temperature under argon atmosphere. The resulting mixture was irradiated at 254 nm (light source: 4 pieces of Osram HNS 25W G13 (G25T8 / OF)) at room temperature for 24h in a 25mL quartz vial (23 mm OD, 85 mm L). Conversion of the reaction was followed by1H-NMR.

[0220] Table 4

[0221] The addition of alcohols (ethylene glycol or methanol) proved far more effective at reducing fouling than other additives or compared to no additive added. When no additive was added fouling was up to 17 mg with 65% conversion. The addition of acetonitrile or THF still provided some fouling, but was reduced with respect to the reaction with no additive. Also, the conversion was increased. The reaction with DMF provided low conversion and significant amounts of fouling. On the other hand, the addition of ethylene glycol or methanol resulted in no fouling and conversions of 73 % and 94 %, respectively. In the case of methanol a small amount of yellow-brown oil was observed.

[0222] Example 13: Effect of the addition of alcohols and water in fouling for the preparation of 2,4- dichlorobutanenitrile (compound of formula

[0223] The effect of alcohol and water addition in the fouling was analyzed. The reaction was conducted at room temperature by adding acrylonitrile (1000 mg, 18.847 mmol) into a degassed solution of tetrabutylammonium bromide (405.0 mg, 1.256 mmol) and CuCI (31.1 mg, 0.315 mmol) in dichloromethane (18 mL), water (270 pL, 1.35 V / V%) and the additive as indicated in each case in Table 5 below (10 V / V% with respect to the total amount of dichloromethane and additive) at room temperature under argon atmosphere. The resulting mixture was irradiated at 254 nm (light source: 4 pieces of Osram HNS 25W G13 (G25T8 / OF)) at room temperature for 24 h in a 25 mL quartz vial (23 mm OD, 85 mm L). Conversion of the reaction was followed by1H-NMR.

[0224] Table s

[0225] The combined use of an alcohol and water further reduced the fouling and provided excellent conversions and yields.

[0226] Example 14: Effect of the addition of alcohol and water in reducing amount of co-catalyst and fouling for the preparation of 2,4-dichlorobutanenitrile (compound of formula (He))

[0227] A process essentially equivalent to that of Example 13 was repeated but reducing the ratio between TBAB and CuCI from 4:1 to 1:1.

[0228] Acrylonitrile (1053 mg, 19.84 mmol) was added into a degassed solution of tetrabutylammonium bromide (108.0 mg, 0.34 mmol) and CuCI (32.7 mg, 0.34 mmol) in dichloromethane (18 mL), ethylene glycol (2 mL) and distilled water (270 pL) at rt under argon atmosphere. The resulting mixture was irradiated at 254 nm (light source: 4 pieces of Osram HNS 25W G13 (G25T8 / OF)) at room temperature for 24h in a 25mL quartz vial (23 mm OD, 85 mm L). Conversion of the reaction was followed by 1H-NMR. No fouling was observed in the glass.

[0229] Conversion of the reaction: 100% (According to the NMR of the reaction mixture)

[0230] Yield of the reaction: >99 % (according to the qNMR data (using tetrachloronitrobenzene as ISTD) Fouling on the surface of the glass: Still no fouling was observed.

[0231] Example 15: cleaning of fouling

[0232] Once the process for the preparation of 2,4-dichlorobutanenitrile was finished, different methods for cleaning equipment were tested. In each case the solvent listed in Table 6 below was used.

[0233] Table 6

[0234] The best results were obtained when performing the reaction in the presence of an alcohol, for example, methanol or ethylene glycol. Good cleaning was also possible even when not using an alcohol as co-solvent. The use of a basic aqueous media (e.g. NaOH) provided in this case the best results.

[0235] Example 16. Preparation of compounds of formula lavand lbv

[0236] Step 1: Preparation of the Grignard reagent (2-chlorobenzyl)magnesium chloride (a compound of formula (III))

[0237] One hundred mL flask was charged with 1.7g of Mg, 8.5g of MeTHF + 30g of Xylene (or Toluene) and heated to 55°C. To this mixture, 10% (0.94g) of overall l-chloro-2-(chloromethyl)benzene (Total 9.4g) was added at once for initiation of the reaction. When initiation took place, the reactor was cooled to under 40 °C and the rest of the chlorobenzyl chloride was fed over approximately lh keeping the temperature at 45 °C.

[0238] Step 2: Reaction of 2,4-chloroacetonitrile (compound of formula (He)) with Grignard reagent (2- chlorobenzyl)magnesium chloride In another flask, a solution of 4g of 2,4-chloroacetonitrile in 15g of Xylene (or Toluene) was prepared. The solution was cooled to 0 °C-3 °C and a suspension of (2-chlorobenzyl)magnesium chloride was added to the solution in portions.

[0239] The reaction was sampled after being fed approximately leq of (2-chlorobenzyl)magnesium chloride and after 2eq of (2-chlorobenzyl)magnesium chloride.

[0240] Step 3: Preparation of 3,5-dichloro-l-(2-chlorophenyl)pentan-2-one (a compound of formula (lblv):

[0241] In a third vessel a cold solution of 7g 32% HCI + 15g water was prepared. The solution was stirred on ice bath. The reaction mixture from step 2 was fed onto the acid solution with stirring for few minutes and the suspension was tested for acidity, which needs to be under pH of 2.

[0242] The phases were separated, a water solution was extracted again with 40g of xylene (or Toluene) and the combined organic phases were washed with water and the pH fixed to 7, to provide 3,5- dichloro-l-(2-chlorophenyl)pentan-2-one (a compound of formula (lbv)) as major product and l-(l-chlorocyclopropyl)-2-(2-chlorophenyl)ethan-l-one (a compound of formula (lb')) in approximately 1%. reaction between a compound of formula of formula of formula (2-i ium chloride (a compound of formula (Illa)) from l-chloro-2-i compound of formula

[0243] Mg excess is recycled from cycle to cycle. The first cycle uses 1.25eq Mg to 1 eq of 161 (1-chloro- 2-(chloromethyl)benzene).

[0244] One liter reactor is charged with 14.5g of Mg (for a first cycle) 76g MeTHF + 280g Xylene (or Toluene) and heated to 55 °C. To this mixture, 10% (7.6g) of overall l-chloro-2- (chloromethyl)benzene (total 76.5g) is added at once for initiation of the reaction. When initiation takes place, the reactor is cooled to under 40 °C and the rest of l-chloro-2- (chloromethyl)benzene is fed over approximately lh keeping the temperature at 45 °C.

[0245] When reaction is finished, the solution is pumped out to a second reactor leaving the Mg in the previous reactor. The Mg is washed with another 40g portion of Xylene (Or toluene) to carry over the leftover (2-chlorobenzyl)magnesium chloride.

[0246] Step 2: Preparation of a compound of formula (Ic) by reacting 1-chlorocyclopropane-l- carbonitrile (compound (Ila)) with (2-chlorobenzyl)magnesium chloride (a compound of formula UUall

[0247] The (2-chlorobenzyl)magnesium chloride suspension of Step 1 is cooled to -5 °C and 40g of 1- chlorocyclopropane-l-carbonitrile (99.6%) is fed to the reactor over 30min keeping the temperature 0°. Two different temperature profiles were tested: a. In the first profile the reaction was stirred for 8-20h at 0 °C. b. In the second temperature profile the reactor was heated from 0 °C to 20 °C over 3-4h. The resulting compound of formula (Ic) (either in neutral form or in its corresponding Magnesium salt) was submitted in both cases to Step 3 below.

[0248] Step 3: Preparation of l-(l-chloro-cvclopropyl)-2-(2-chloro-phenyl) ethan-l-one (a compound of formula (lb')

[0249] A cold solution of 70g 32% HCI + 220g water is prepared in a separate vessel. The solution is stirred on ice bath. For each temperature profile a. and b. the reaction from Step 2 is fed onto the acid solution with stirring for few minutes and the suspension is tested for acidity until the pH is below 2.

[0250] The phases are separated, a water solution is extracted again with 40 g of xylene (or Toluene) and the combined organic phases are washed with water and the pH is fixed to 7.

[0251] The solvents are evaporated to obtain approx. 93g of 86% purity l-(l-chloro-cyclopropyl)-2-(2- chloro-phenyl) ethan-l-one. The yield of l-(l-chloro-cyclopropyl)-2-(2-chloro-phenyl) ethan-l- one for temperature profile a. (fixed temperature of 0 °C in Step 2) was ~92% and ~87-89% for the temperature profile b. (gradient from 0 °C to 20 °C in Step 2). Thus, gradient b. provided a comparable yield to profile a. but in less time. of formula of formula with or without Pre-irradiation

[0252] Acrylonitrile (400 g, l.Oeq), DCM (7200 mL, 18 V), TBAB (38.88 g, 0.016eq), CuCI (11.94 g,

[0253] 0.016eq), ethylene glycol (800 mL, 2 V), and H2O (108 mL, 0.27 V) were charged into a 10L four- mouth reactor and stirred at 16-25 °C for 0.5 h.

[0254] The reaction mixture was pre-irradiated in a first photoreactor: vertical coil reactor that with

[0255] Peristaltic pump (Cole-Parmer). 4*75 W low pressure mercury lamps. The flow quartz tube: Inner diameter = 6 mm and Outer diameter = 8 mm, including a water tank to control temperature.

[0256] Flow rates: 70 ml / min for the reaction mixture. The reaction mixture circulated for 4 hours and the reaction solution became clear, and then transferred to a second photoreactor.

[0257] The second photoreactor is an horizontal reactor equipped with a Plunger Pump (Jingjin, JJRZ-

[0258] 50010S). 4*75 W low pressure mercury lamps. 1.1 L flow reactor: Volume of the reactor: 1.1 L,

[0259] Each tube size: Inner diameter 8 mm, length 690 mm, Number of quartz tubes: 32. Flow rates:

[0260] 400 ml / min for the reaction mixture. The reaction solution circulates for 160 hours and the reaction was completed - the quartz tubes remained clear. The reaction was repeated and both solutions were combined.

[0261] The reaction mixture was concentrated to 3.0 kg (40 °C) and the remaining organic solution was washed with water (2000 mL) two times and dried over NajSC (~200 g). After filtration the organic phase was concentrated with rotavapor to 1.80 kg of solution of compound (lie) (70 %

[0262] Yield).

[0263] The same procedure as in Example 18A was repeated but without submitting the reaction mixture to a pre-irradiation. The reaction mixture (not a clear solution) was fed under the same conditions directly to the second photoreactor. After 16 h solid impurities (fouling) were blocking the walls of the tubes. As the reaction progressed, in an attempt to improve conversion, the mixture was allowed more time to react, but more solids were produced in the quartz tube and the reaction was stopped after 66h. The amount of compound of formula (lie) obtained was lower than in the case of Example 18A (with pre-irradiation) and, more importantly, the amount of solids was higher. NMR analysis in DMSO-D6 of the solids are consistent with polyacrylonitrile. from a of formula ,4-dii

[0264] Finely grounded K2CO3 (10 mol%, 5 mmol), finely grounded NaOH (1.2 equivalents, 60 mmol),

[0265] MTBAC (phase transfer catalyst*) 75% aqueous solution (3 mol%, 1.5 mmol) and DCM

[0266] (2V / M137W, 14.2 gr) are added into a 250 ml reactor equipped with a mechanical stirrer. The resulting suspension is stirred at 600 RPM and at 25 °C. Compound (lie) is then added (1 equivalent, 50 mmol) in IV of DCM (7.1gr) over 5h using a syringe pump, through a dip-pipe. The reaction is then monitored by gas chromatography. Upon completion, 5V of water (35.5 ml) and

[0267] 2V of DCM (14.2 ml) are added. Optionally, the reaction mixture is neutralized with HCI 32% to pH = 7. The phases are separated, and the aqueous phase extracted with 2V of DCM (14.2 ml).

[0268] Purification by distillation provided the compound of formula (Ila) in 82% yield (boiling point 137

[0269] C).

[0270] *Different phase transfer catalysts (PTCs) were tested with similar results, including

[0271] Dimethyldioctadecylammonium bromide, Hexadecyltrimethylammonium chloride,

[0272] Tetrabutylammonium chloride, Tetraethylammonium hydrogen sulfate,

[0273] Didecyldimethylammoium bromide, Benzalkonium chloride, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, Tetraethylammonium bromide,

[0274] Tetraoctylammonium Bromide, Methyltributylammonium chloride, wherein tributylmethylammonium chloride provided the best results. from a of formula 4-dii with or without distillation of the

[0275] Finely grounded K2CO3 (10 mol%, 5 mmol), finely grounded NaOH (1.2 equivalents, 60 mmol),

[0276] MTBAC 75% aqueous solution (3 mol%, 1.5 mmol) and dichlorobenzene (3V / M137W, 21.3 gr) are added into a 250 ml reactor equipped with a mechanical stirrer, a distillation condenser

[0277] (cooled by ethylene glycol to 0 °C), a thermometer for the reaction and for the vapors. Thus, with respect to Example 19, the solvent was changed to dichlorobenzene to allow the continuous distillation of compound (Ila). The resulting suspension is stirred at 600 RPM, 60 °C and a pressure of 20 mbar. Compound (He) is then added (1 equivalent, 50 mmol) in 20V of dichlorobenze over 5h using a syringe pump, through a dip-pipe. The distillation rate (including the product) is adjusted to 4V / h by altering the jacket temperature. The reaction is then monitored by gas chromatography. Upon completion, 5V of water (35.5 ml) and 2V of dichlorobenzene (14.2 ml) are added. Optionally, the reaction mixture is neutralized with HCI

[0278] 32% to pH = 7. The phases are separated, and the aqueous phase extracted with 2V of dichlorobenzene (14.2 ml). Purification by fractional distillation provided the compound of formula (Ila).

[0279] The same conditions were repeated but without allowing the continuous distillation of the compound of formula (Ila) (at ~ latm). The yield in this case was reduced, presumably due to the partial decomposition of the compound of formula (Ila).

Claims

CLAIMS1 . A process for preparing a compound of Formula (I):which comprises reacting a compound of Formula (II) with a compound of Formula (III):wherein:- R is >CR1R2or >C=CH2, where:R1and R2form together with the C atom to which they are attached a cyclopropyl ring, orR1is selected from H or halogen, and R2is -CH2-CH2X;- each X is independently selected from a halogen; and- W is a metal or a metal complex, optionally comprising one or more halogen atoms; and- Y is selected from O, or NZ where Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen.

2. The process according to claim 1, comprising:(i) reacting a compound of formula (Illa):wherein M is a divalent metal, and X and X' are independently selected from halogen, with the compound of Formula (II)wherein X and R are as defined in claim 1 to provide an imine derivative of Formula (la):whereinX, Z and R are as defined in claim 1; and(ii) optionally, subjecting the compound of formula (la) to hydrolysis to provide a compound of Formula (lb):wherein X and R are as defined in claim 1.

3. The process according to claim 1, wherein the compound of formula (III) is prepared by a process comprising contacting a compound of Formula V:wherein X and X" are independently selected from halogen; with a metal in the presence of an organic solvent, wherein the metal is preferably magnesium.

4. The process according to any one of the preceding claims, wherein X is in each case chloro.

5. The process according to any one of claims 1 to 4, wherein the compound of formula (II) is a compound of Formula Ila:Cl CNX (Ila)6. The process according to claim 5, wherein the compound of Formula (Ila) is obtained by reacting 2-chloroacrylonitrile with a Me-L derivative, wherein L is an electron withdrawing group selected from sulphinyl, sulphonyl, sulfite, sulfonium salt, diazo and nitro, preferably in the presence of a base.

7. The process according to claim 6, wherein the Me-L derivative is diazomethane.

8. The process according to claim 5, wherein the compound of Formula (Ila) is obtained by treating 2,4-dichlorobutanenitrile with a base in the presence of an organic solvent and a phase transfer catalyst.

9. The process according to any one of claims 1 to 4, wherein the compound of formula (II) is 2-chloroacrylonitrile:

10. The process according to any of the preceding claims, wherein the compound of formula (I) is the compound of formula (Ic):or a salt or solvate thereof, wherein Z is H or a monovalent metal or MX', wherein MX' is MgCl.11 . The process according to any one of preceding claims, wherein the compound of formula (I) is l-(l-chloro-cyclopropyl)-2-(2-chloro-phenyl) ethanone:

12. The process according to claim 11, which further comprises transforming the compound 1- (l-chloro-cyclopropyl)-2-(2-chloro-phenyl) ethanone into the compound 2-(2-chloro- benzyl)-2-(l-chloro-cyclopropyl)-oxirane:

13. The process according to claim 12, which further comprises converting the compound 2-(2- chloro-benzyl)-2-(l-chloro-cyclopropyl)-oxirane into prothioconazole, or a salt or solvate thereof.

14. A compound of formula (la):or a salt or solvate thereof; wherein- R is >CR1R2or >C=CH2, where:R1and R2form together with the C atom to which they are attached form a cyclopropyl ring, orR1is selected from H or halogen, and R2is -CH2-CH2X;- each X is independently selected from halogen, and- Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen.

15. The compound of formula (la) according to claim 14, wherein the compound of Formula (la) is a compound of formula (Ic):or a salt or solvate thereof, wherein Z is H or a monovalent metal or MX', wherein M is a divalent metal and X' is halogen, preferably wherein MX' is MgCl.

16. A method for the preparation of 2,4-dichlorobutanenitrile (compound of formula (lie)) that comprises the reaction between acrylonitrile, a catalyst, dichloromethane, and a phase transfer catalyst under irradiation, wherein the reaction comprises one or more of the following reaction conditions: i. continuous addition of acrylonitrile; ii. performing the reaction at a temperature comprised between -20 °C and 30 °C, preferably between -10 °C and 20 °C; ill. performing the reaction in the presence of water; iv. performing the reaction in the presence of THF, acetonitrile or an alcohol; and / or v. subjecting the reaction mixture comprising acrylonitrile, a catalyst, a phase transfer catalyst, and dichloromethane to a pre-irradiation step prior to performing the reaction.

17. The method of claim 16, wherein the reaction comprises the addition of water, THF, acetonitrile and / or an alcohol, and less than 0.5 equivalents, with respect to the total amount of acrylonitrile, of a phase transfer catalyst.

18. The method according to any of claims 16 or 17, wherein the reaction comprises the addition of water and an alcohol.

19. The method of any of claims 16 to 18, wherein the process further comprises a cleaning step that comprises contacting the reaction equipment with a solvent selected from the group consisting of an organic solvent, aqueous KSCN, aqueous ZnCL and aqueous base.

20. A method to produce chlorocyclopropane-l-carbonitrile (compound of formula (Ila)) that comprises treating 2,4-dichlorobutanenitrile (compound of formula (lie)) with a base in an organic solvent.

21. The method of claim 20, wherein the reaction takes place in the presence of a phase transfer catalyst.

22. The process of any of claims 20 or 21 wherein the base is a mixture of an inorganic carbonate and an alkaline or an alkali-earth hydroxide.

23. The process of any of claim 20-22, wherein 2,4-dichlorobutanenitrile is added continuously during the reaction.

Images