Synthesis of cyclopropylamide compounds, its intermediates and uses

Abstract

The present invention provides a process to obtain cyclopropylamide compounds that can be used in controlling parasitic infestations of animals and a crystalline form thereof. The disclosed process can be used in large scale production with sufficiently high yield and purity.

Description

[0001] TITLE

[0002] Synthesis of cyclopropylamide compounds, its intermediates and uses

[0003] TECHNICAL FIELD

[0004] The present invention relates to the synthesis of cyclopropylamide compounds that can be used in controlling parasitic infestations of animals, and the synthesis of its intermediates and crystalline forms.

[0005] BACKGROUND

[0006] Certain cyclopropylamide compounds have been described in international patent applications WO2016 / 168056, WO2016 / 168058, WO2016 / 168059 and WO2018 / 172327. These compounds are described to have insecticidal and acaricidal activity and therefore useful in controlling agricultural plant pests. Certain cyclopropylamide compounds have been also described in WO2022 / 161972, WO2022 / 162016, WO2022 / 162001 to be useful in the treatment of parasitic infestations of animals.

[0007] There is still a need to provide synthesis methods of such compounds and its intermediates that can be used in large scale production, with high yield and purity and preferably do not require toxic or unstable reagents.

[0008] SUMMARY OF INVENTION

[0009] The present invention provides a process to obtain a compound of Formula 10:

[0010]

[0011] Formula 10 wherein each of Ri and R2 is independently selected from H, CH3, Cl and F, and X is selected from N and CH,

[0012] comprising a step of reacting a compound of Formula 5A or its acid halide in a first solvent:

[0013]

[0014] Formula 5A

[0015] with a compound of Formula 9:

[0016]

[0017] The present invention further provides a cocrystal of the compound of Formula 10a:

[0018]

[0019] Formula 10a

[0020] with an acid selected from p-toluenesulfonic acid and benzenesulfonic acid.

[0021] DESCRIPTION OF DRAWINGS

[0022] Fig. 1 illustrates synthesis steps according to some of the embodiments of the invention.

[0023] DETAILED DESCRIPTION

[0024] The starting compound of the synthesis described herein is a compound of Formula

[0025]

[0026] R2 Formula 1

[0027] wherein each of Ri and R2 is independently selected from H, CH3, Cl, CN, Br, OCH3, CF3 and F, preferably from H, Cl and F. In some embodiments, R1 is H or F. In some embodiments, R2 is H or Cl.

[0028] In a preferred embodiment, R1 is H and R2 is Cl. The compound of Formula 1 is then 1-bromo-3,5-dichlorobenzene (compound 1a).

[0029] In another preferred embodiment, R1 is F and R2 is H, corresponding to 4-bromo-2-chloro-1 -fluorobenzene (compound 1b).

[0030] A bromine compound of Formula 1 has advantages over the respective benzaldehyde as a starting compound that is for example disclosed in Example 99 of WO2016 / 168059 A1. Particularly, the bromine compound is more accessible than the benzaldehyde and hence is more suited for economic reasons for large scale production.

[0031] Step (a)

[0032] In step (a), a compound of Formula 1 :

[0033]

[0034] R2 Formula 1

[0035] wherein R1 and R2 are as defined above, is reacted with a protected alkene, in the presence of at least one base and a palladium catalyst in a solvent. An example of a protected alkene is an acrolein acetal.This type of reaction is known as the Heck reaction (also called the Mizoroki-Heck reaction). It involves palladium-catalyzed C-C coupling between aryl halides and activated alkenes in presence of a base.

[0036] Preferably the alkene is acrolein and it is used in a protected form, such as acrolein acetal. Acetal form means -CH(OR3)OR4:

[0037] OR3

[0038] <

[0039]

[0040] ^ZZA'OR4

[0041] Each of Rs and R4 can independently of each other be a C1-C3 alkyl group or together form an C1-C4 alkylene group. Together with the O atoms they can form a heterocycle, e.g. a 5-8-membered ring. In case R3 and R4 form together C2H4, they constitute a dioxolane group.

[0042] Preferably, the protected alkene is 3,3-dialkoxyprop-1-ene. The dialkoxy group can for example be diethoxy or dimethoxy group. The preferred alkene is 3,3-diethoxyprop-1-ene (also known as acrolein diethyl acetal).

[0043] The stoichiometric amount of the protected alkene is preferably at least 1.0, preferably at least 1.05 equivalent (eq), more preferably at least 1.1 eq to the compound of Formula 1. If the protected alkene is used in amounts of less than 1.0 eq of compound of Formula 1, conversion and yield strongly decrease. Generally, the amount of the protected alkene is less than 5.0 eq, preferably less than 4.5 eq.

[0044] A base is defined as a compound that is able to accept protons (hydrogen ions). In the present invention it is preferred to use an inorganic base. Some organic bases were tested and resulted in less than sufficient conversion and / or slower reaction rate than inorganic bases. Some organic bases may promote the formation of increased amount of the saturated ester side products. As a base, preferably a basic salt is used. Alkali hydroxides were also tested but were considered less preferred as they showed lower conversion rates.Basic salts are typically salts of weak acids and strong bases, such as phosphate, carbonate, acetate salts of alkali metals. Particular examples include potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate. Preferably, phosphates of alkali metals are used, more preferably tripotassium phosphate K3PO4. Some other salts are less preferred, e.g. potassium carbonate may lead to generation of CO2, which may induce environmental and safety concerns.

[0045] The base is preferably used in an amount of 0.1-10 eq, preferably 1-5 eq relative to the compound of Formula 1.

[0046] In addition, other inorganic salts can also be present, particularly of alkali metals, more particularly sharing the same cation as the basic salt used. Preferably, potassium salts are used, more preferably potassium chloride. Without wishing to be bound by theory, the use of an additional salt with the same cation as the basic salt, particularly potassium salt, can prevent the reaction from slowing down.

[0047] The optional inorganic salt can be used in an amount of 0.1-10 eq, preferably 1-5 eq relative to the compound of Formula 1.

[0048] In some embodiments, a phase transfer catalyst can be used, which can be an ammonium salt, preferably a quaternary ammonium salt. Suitable ammonium salts could be selected from tetraalkyl ammonium salts such as tetraethyl ammonium chloride, tetrabutyl ammonium chloride, tetraethyl ammonium fluoride, tetrabutyl ammonium fluoride, tetraethyl ammonium bromide, tetrabutyl ammonium bromide, tetraethyl ammonium acetate, tetrabutyl ammonium acetate. Preferably, tetraalkyl ammonium salts with longer alkyls (e.g. butyl) are used, such as tetrabutyl ammonium acetate, as it was shown to lead to less formation of by-products and to higher conversion. The use of tetraethyl ammonium chloride was shown to lead to increased formation of a homocoupling biphenyl by-product. Amines are less preferred since, for example, triethylamine was observed to lead to a lower conversion (only partial conversion).The phase transfer catalyst can be used in an amount of 0.01 -10 eq, preferably 0.1-5 eq.

[0049] In other embodiments, no phase transfer catalyst is used.

[0050] Palladium catalysts for this type of reaction are known in the art. Examples of suitable palladium catalysts include tetrakis(triphenylphosphine)palladium(0), palladium^ I) chloride, palladium^ I) acetate, palladium^ I) bromide, palladium^ I)-acetylacetonate and palladium^ I) pivalate. It was found that ligand free palladium catalysts were particularly suited for the Heck reaction in the present invention. Preferred palladium catalyst is palladium^ I) acetate. Less preferred although still acceptable catalyst is Pd(CF3CO2)2.

[0051] The palladium catalyst can be used in a suitable amount, for example in an amount of 0.001-10 eq, or 0.01-5 eq, or 0.1 -2.5 eq relative to compound of Formula 1.

[0052] Any suitable solvent can be used, for example selected from the list: / V, / V-dimethylacetamide (DMA), cyclopentyl methyl ether (CPME), 2-butanol, methyl tert-butylether (MTBE), / V, / V-dimethylformamide (DMF), / V-methyl-2-pyrrolidone (NMP), dimethyl carbonate (DMC), acetonitrile (MeCN), 2-methyltetrahydrofuran (mTHF), n-propanol, ethanol, and mixtures thereof. Preferably, the solvent is an alcohol such as n-propanol, ethanol or 2-butanol, more preferably it is 2-butanol. In some embodiments, mixtures of the aforementioned solvents with 2-butanol can be used, such as CPME with 2-butanol. Best results are obtained with 2-butanol as it results in less formation of by-products.

[0053] Optionally, phosphine ligands for the palladium catalyst can be used, such as 1,2-bis(diphenylphosphino)ethane (dppe) and [2-Dicyclohexylphosphino-2',4',6'-triisopropy Ibi phenyl] known as xPhos.

[0054] The reaction can be carried out at an elevated temperature, preferably at a temperature above 60°C, more preferably above 70°C, yet more preferably above 80°C. The reaction temperature can for example be in the range 60-90°C. In otherembodiments, the reaction can be carried out at room temperature (i.e. 25°C).

[0055] After the reaction, the solvent can be removed. Also, the resulting compound can be washed using a mixture of an organic solvent and water. As an organic solvent, any suitable solvent e.g. from the above list can be used. In some embodiments, it can be preferred to use methyl tert-butylether.

[0056] Optionally, the resulting compound can be purified, however it is not necessary.

[0057] When acrolein acetal is used in step (a), the result of this step is a compound of Formula 2:

[0058] 3

[0059] OR

[0060]

[0061] Formula 2

[0062] wherein Ri, R2, R3 and R4 are defined as described above.

[0063] In a preferred embodiment, R1 is H and R2 is Cl. The compound of Formula 2 is in this case 1,3-dichloro-5-(3,3-diethoxyprop-1-en-1-yl) benzene (compound 2a).

[0064] In another preferred embodiment, R1 is F and R2 is H. The compound of Formula 2 is in this case 2-chloro-4-(3,3-diethoxyprop-1-en-1-yl)-1 -fluorobenzene (compound 2b).

[0065] It is known from Example 99 of WO2016 / 168059 A1 to obtain a compound with Formula 2 by aldol condensation of the respective benzaldehyde with acetaldehyde, followed by the protection of the aldehyde to the acetal. The disadvantage of this approach is that it requires the use of a protective group in an additional step, hence increasing the number of steps. Also, acetaldehyde is less preferred as a reagent, due to genotoxicity, its low boiling point and easy formation of condensation products, which are toxic as well. The approach disclosed in the present invention requires less steps, less toxic reagents (hence higher safety) and results in a higheryield and purity.

[0066] Step (b)

[0067] In step (b), a compound of Formula 2:

[0068]

[0069] wherein Ri, R2, R3 and R4 are as defined above, is subjected to dihalocyclopropanation with a carbene optionally in the presence of a catalyst in a suitable solvent, in order to result in a compound of Formula 3:

[0070]

[0071] wherein each of Rs and Re is a halogen, independently selected from Cl, Br and F, preferably Cl. In some embodiments, Rs and Re are the same halogen, preferably both Cl.

[0072] Carbene used in this step is a dihalocarbene, such as difluorocarbene, or dichlorocarbene. Most preferred is dichlorocarbene CCI2.

[0073] The dihalocarbene can be used as such or prepared in situ. Preferably, the dihalocarbene is prepared in situ from a trihaloalkane (e.g. CHCI3, CHBrs, preferably CHCI3) and a strong base. Strong base is defined as a base that dissociates wholly into its constituent ions in its aqueous solution. Strong bases typically have a pKaof their conjugate acid above 13. Weak bases typically have a lower pKa of their conjugate acid, e.g. below 13, for example in the range 7-11 or lower. Acid dissociation constant pKa can be looked up in handbooks or measured, e.g. by titration. Examples of strong bases are hydroxides of alkali metals and alkaline earth metals, and basic salts as defined above. Suitable strong bases in this case include KOH, NaOH, KOt-Bu, LiOt-Bu. Preferably NaOH is used. The strong base is preferably used in the form of an aqueous solution.

[0074] In some embodiments, the trihaloalkane can be used as a solvent for the reaction. Preferably, chloroform is used. In other embodiments, other solvents can be used, for example those recited above for the previous step.

[0075] The trihaloalkane is preferably used in excess relative to the compound with Formula 2, e.g. at least 10 eq, 20 eq or 30 equivalents.

[0076] The strong base is preferably used in excess relative to the compound with Formula 2, e.g. at least 10 eq, 20 eq or 30 equivalents.

[0077] When the dihalocarbene is prepared in situ, it is beneficial to add at least a part of the strong base as described above to the compound of Formula 2 before or simultaneously (at the same time) with the trihaloalkane. In this way, side reactions resulting from the compound of Formula 2 reacting with the haloform can be prevented or at least minimized. Therefore, the reaction results in less side-products and higher purity of the resulting compound of Formula 3. “At least part” can be at least 1%, or at least 5%, or at least 10%, or at least 50% of the total amount added. In some embodiments, all of the base is added before or together with the trihaloalkane.

[0078] The reaction in this step is optionally carried out in the presence of a catalyst, preferably a phase transfer catalyst. Suitable phase transfer catalysts are ammonium and phosphonium salts, such as tetrabutylammonium bromide (TBAB), tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAH), triethylbenzylammonium chloride (TEBA), benzyltrimethylammonium hydroxide(known as Triton B), triethylbenzylammonium chloride (TEBAC). The catalyst is preferably selected from the list consisting of tetrabutylammonium acetate and triethylbenzylammonium chloride.

[0079] Particularly preferred catalysts are quaternary ammonium and phosphonium chlorides. Preferred catalyst is triethylbenzylammonium chloride. Without wishing to be bound by any particular theory, chlorides used as phase transfer catalysts may contribute to a higher conversion and a higher yield in this specific reaction by being an additional source of chlorine, especially in the embodiments where the dihalocarbene is prepared in situ as described above.

[0080] In some embodiments, the reaction can be carried out in the absence of a phase transfer catalyst. If was surprisingly found by inventors that the process can still be carried out with acceptable reaction rate and yield. Elimination of the catalyst offers significant advantages for large scale implementation of the process.

[0081] The reaction can be carried out at an elevated temperature, such as above ambient until the boiling point of the solvent. For example, the temperature can be in the range 40-80°C, preferably in the range 50-60°C.

[0082] In some embodiments, the reaction can be carried out at a lower temperature, such as below 40°C, for example in the range 15-30°C and particularly at room temperature (about 20°C). Surprisingly, it was found by inventors that the process can still be carried out with acceptable reaction rate and yield at lower temperatures e.g. at room temperature. Lower reaction temperature offers significant advantages for large scale implementation of the process.

[0083] After the reaction, the solvent can be removed. Also, the resulting compound can be washed using a mixture of an organic solvent and water. As an organic solvent, any suitable solvent e.g. from the list recited for step (b). In some embodiments, it can be preferred to use methyl tert-butylether.

[0084] Optionally, the resulting compound can be purified, however it is not necessary.Halocyclopropanation of similar compounds is known in the prior art, e.g. from WO2022235863, W02020112390, WO2018071327, WO2016168059, WO2016168056, WO2016168058. However, in these publications the chloroform is first added to the compound, and then the strong base is added. As the present inventors have discovered, this leads to side reactions that could be caused by the reaction of chloroform with the compound of Formula 2. In the present invention, in contrast, a higher purity and higher yield (>85%, preferably >90%) compared to known methods from the prior art are achieved. Also, the present invention allows to carry out the reaction in some embodiments without a phase transfer catalyst and at ambient temperature, which has significant benefits for production on a large scale.

[0085] Step (c)

[0086] In step (c), a compound of Formula 3:

[0087]

[0088] Formula 3

[0089] wherein R1, R2, R3, R4, Rs and Re are as defined above, is subjected to deprotection and oxidation to result in a compound of Formula 4:

[0090]

[0091] Formula 4

[0092] wherein Ri, R2, Rs and Re are as defined above.The process comprising reacting the compound of Formula 3 with an acid in the presence of water and subsequently with an oxidating agent, wherein both steps are done as a one-pot reaction. One-pot reaction means a reaction in which all reactants are subject to consecutive chemical reactions in the same reactor. It means in this case that no intermediate purification or isolation of the (intermediate) compound is performed after the first step (deprotection) before subjecting it to the next step (oxidation).

[0093] Surprisingly, it was found possible to perform these two steps as a one-pot reaction. In contrast, in the prior art only a two steps reaction with intermediate purification is known for such compounds, particularly, in Examples 36 and 39 of WO2016168056. In this known method, the compound after the deprotection is isolated and purified on a column chromatography, which is labour intensive and not suitable for large scale production. Because in the present invention a one-pot reaction is used, this improves efficiency of the chemical reaction, saves resources and time, and results in a higher yield. It may further be more suitable for a large scale production.

[0094] The acid to be used in the deprotection step in the present invention can be any aqueous acid compatible with the oxidating agent used. Examples of suitable acids include hydrochloric acid (HCI) and acetic acid. Preferably, acetic acid is used.

[0095] The skilled person is able to determine suitable amounts of the acid to be used relative to the compound of Formula 3. In some embodiments, the acid can be used in an excess, e.g. 1.01-20 eq, or 1.1-10 eq. In some embodiments, the acid is only used in catalytic amounts.

[0096] The reaction preferably takes place in an organic solvent, or a mixture of organic solvent, or a mixture of an organic solvent with water. Examples of suitable solvents include: dimethylacetamide (DMA), cyclopentyl methyl ether (CPME), 2-butanol, methyl tert-butylether, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl carbonate (DMC), acetonitrile (MeCN), acetone, 2-methyltetrahydrofuran (Me-THF), n-propanol, ethanol, and mixtures thereof. Preferably, acetonitrile or acetone is used, more preferably acetonitrile.The reaction can be carried out at room temperature (e.g. 25°C) or an elevated temperature, such as above ambient until the boiling point of the solvent or solvent mixture. For example, the temperature can be in the range 30-80°C, preferably in the range 30-70°C.

[0097] Subsequently, without intermediate isolation or purification of the deprotected compound, an oxidising agent is added to the reaction mixture.

[0098] The oxidation reaction used in this step is preferably Pinnick oxidation, i.e. an organic reaction by which aldehydes can be oxidized into their corresponding carboxylic acids using sodium chlorite (NaCICk) under mild acidic conditions.

[0099] Besides NaCICk, also other oxidising agents can be used, e.g. sodium hypochlorite, potassium permanganate, sodium periodate. In some embodiments, it can be preferred to use sodium hypochlorite (NaCIO).

[0100] Preferably, a scavenger is used to consume the HOCI that is formed as a byproduct. Examples of HOCI scavengers are 2-methyl-2-butene, resorcinol, sulfamic acid, hydrogen peroxide. Preferably, hydrogen peroxide is used. The remaining hydrogen peroxide and oxidizing agents can be quenched using conventional reducing agents, e.g. sodium bisulfite, sodium thiosulfate.

[0101] After the reaction, the solvent can be removed by any known method e.g. evaporation or distillation under reduced pressure. Also, the resulting compound can be washed using a mixture of an organic solvent and water. As an organic solvent, any suitable solvent, e.g. from the above list for this step, can be used. In some embodiments, it can be preferred to use methyl tert-butylether.

[0102] Optionally, the resulting compound can be purified, although it is not necessary. Purification can be done e.g. by trituration with a suitable solvent. In some embodiments, the solvent used in trituration is n-heptane. Purification can also be done by recrystallization. In this case, the preferred solvent is toluene.As described above under steps (a)-(c), compounds of Formula 4 can be advantageously obtained from compounds of Formula 1. It is known from WO2016 / 168059 A1 to obtain the compound of Formula 4 from 3,5-dichlorobenzaldehyde as the starting compound. A benzaldehyde as a starting compound has the disadvantages that it requires the use of a protective group in an additional step, hence increasing the number of steps. Also, acetaldehyde is less preferred as a reagent, due to genotoxicity, its low boiling point and easy formation of condensation products, which are toxic as well. The approach disclosed in the present invention requires less steps, less toxic reagents and results in a higher yield and purity, thus more suitable for use on a large scale.

[0103] Step (d)

[0104] In step (d), a compound of Formula 4, which is obtained in the previous step as a race mate:

[0105]

[0106] ^2 Formula 4

[0107] wherein Ri, R2, Rs and Re are as defined above, is subjected to chiral separation.

[0108] Chiral separation (or chiral resolution, enantiomer resolution) of racemic compounds of Formula 4 can be done as described in patent applications W02025032210 and PCT / EP2024 / 081483, which are both incorporated herein by reference.

[0109] In general, such process can comprise the steps of:

[0110] (a) treating the racemic compound of Formula 4 with a chiral base in an organic solvent,

[0111] (b) isolating a diastereoisomeric salt formed in step (a),(c) optionally, treating the isolated diastereoisomeric salt with an acid, to obtain one of the enantiomers present in the racemic compound. Particularly, the (R,R) enantiomer is preferably obtained.

[0112] In case wherein Ri is H, R2 is Cl, Rs is Cl, and Re is Cl, the compound of Formula 4 is trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid. The preferred chiral base in this case is for example (1S,2R)-2-amino-1,2-diphenylethan-1-ol. Preferably, the organic solvent is selected from cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC), toluene, 2-methyltetrahydrofuran (2-MeTHF), or ethyl acetate. More preferably, cyclopentyl methyl ether (CPME), dimethyl carbonate (DMC) or ethyl acetate is used, since these solvents allow to achieve a high yield of the desired diastereoisomeric salt. Most preferably, ethyl acetate is used since it allows to reach both a high yield and a high optical purity of the desired diastereoisomeric salt. The chiral separation method described above results in (1 R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid or a salt thereof.

[0113] In case wherein R1 is F, R2 is H, Rs is Cl, and Re is Cl, the compound of Formula 4 is trans-2, 2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1 -carboxylic acid. The chiral base in this case is preferably selected from the list consisting of quinine, (S)-1-cyclohexylethan-1 -amine and (L)-leucinamide. Preferably, the solvent is selected from organic solvents such as ethyl acetate, acetonitrile, acetone and dimethyl carbonate. More preferably, ethyl acetate or acetonitrile is used, since these solvents were found to give the best combination of yield and optical purity. The chiral separation method described above results then in (1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1 -carboxylic acid or a salt thereof.

[0114] e

[0115] In step (e), a compound of Formula 5A or its acid halide in a first solvent:

[0116]

[0117] Formula 5A

[0118] wherein Ri and R2 are as defined above, is reacted with a compound of Formula 9:

[0119]

[0120] to obtain a compound of Formula 10:

[0121]

[0122] R2 Formula 10

[0123] wherein X is selected from N or CH.

[0124] This reaction is also known as amide coupling. There are several ways of amide coupling known, and preferred methods to be used in the present disclosure are described below.

[0125] The acid with Formula 5A can react directly with the amine of Formula 9 using a suitable amide coupling agent.

[0126] However, it is preferred to include an intermediate step of activation of the carboxyl group of the acid of Formula 5A. This allows to use more accessible reagents, which leads to economic benefits especially when producing in a large scale. Activated carboxylic acids may be an acyl halide, such as an acid chloride, an acid bromide, or an acid fluoride; a carboxylic ester, such as a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl (hydroxyiminio)cyanoacetate ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-yl ester, or a hydroxypyridyltriazol-1 -yl ester; an O-acylisourea; an acid anhydride; ora thioester.

[0127] In some embodiments, activation of the carboxyl group is done through formation of an acid halide such as acid chloride. In these embodiments, the acid with Formula 5A is reacted with a source of chlorine, e.g. oxalyl chloride (COCI2), thionyl chloride (SOCI2), or another suitable chlorinating agent. Preferably, oxalyl chloride is used. In some embodiments however thionyl chloride can be preferred. Preferably, the chlorinating agent is used in an equivalent amount or a slight excess with respect to the amine of Formula 9. For example, in an amount 1 - 1.5 eq, preferably 1-1.2, more preferably 1.005-1.1 eq.

[0128] When oxalyl chloride is used as the chlorinating agent, it is beneficial if DMF is present in catalytic amounts such as less than 0.1 eq to the amount of oxalyl chloride. If no DMF is present, the reaction may be too slow. If too much DMF is present, a lot of side reactions take place and the purity and yield become unsatisfactory.

[0129] Formation of the acid chloride can take place at ambient conditions.

[0130] No intermediate isolation or purification is necessary.

[0131] In other embodiments, activation of the carboxylic group is done through mixed carboxylic acid anhydride formation. In these embodiments, the acid of Formula 5A is converted to the corresponding anhydride. Typical reagents for this are for example acetic anhydride, pivaloyl chloride, ethyl chloroform ate, isobutyl chloroform ate.

[0132] The formation of the acid anhydride in the above two embodiments can take place at ambient conditions. No intermediate isolation or purification is necessary.

[0133] The resulting acid chloride or acid anhydride can be reacted with a compound of Formula 9 or its salt, e.g. chloride. The acid chloride of the compound of Formula 9 can be obtained by known method, e.g. reacting with an acid, preferably HCI.The amide coupling reaction preferably takes place while cooling, e.g. to a temperature below 5°C to dissipate heat and decrease side product formation.

[0134] The amide coupling is preferably performed in the presence of an organic base. Suitable bases include tertiary amines and heterocyclic amines, such as triethylamine (TEA), N,N-diisopropylethylamine (DIPEA), 4-methylmorpholine, 4-methylaminopyridine, pyridine, preferably triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) and pyridine. Most preferably pyridine is used.

[0135] The amide coupling reaction can be performed in the presence of an organic solvent. Any suitable organic solvent can be used, preferably an anhydrous aprotic solvent such as dichloromethane, 1,2-dichloroethane, dimethyl carbonate (DMC), ethyl acetate (EtOAc), isopropyl acetate, tetrahydrofuran (THF), acetonitrile (MeCN), 2-methyltetrahydrofuran (2-Me-THF), and mixtures thereof. Preferably, ethyl acetate is used since it allows higher solubility of the compounds involved in this reaction.

[0136] In a preferred embodiment, both steps (activation of the carboxyl group and amide coupling) are performed in the same organic solvent, preferably ethyl acetate due to the optimal solubility of all the involved reaction compounds in it. This avoids the necessity to isolate intermediate products before the next step, which would lead to lower yield and higher chance of impurities.

[0137] After the reaction, the solvent can be removed. Also, the resulting compound can be washed using a mixture of an organic solvent and water. As an organic solvent, any suitable solvent e.g. from the above list can be used. In some embodiments, it can be preferred to use methyl tert-butyl ether.

[0138] Next, the crude product of Formula 10 can be isolated and purified. This can be done by any conventional method known to the skilled person. Suitable methods include for example silica gel column filtration and recrystallization. For silica gel column filtration any suitable silica gel column can be used.Recrystallization as a method of purification is known to a skilled person. Recrystallization can be done in various ways, e.g. single-solvent recrystallization, multi-solvent recrystallization, hot filtration-recrystallization. In the present invention, recrystallization does not necessarily lead to the formation of crystals but to the formation of the desired compound in a solid form. The precipitate can be amorphous.

[0139] Solvents suitable for recrystallization are for example as mentioned above for the amide coupling reaction, particularly methyl tert-butyl ether, ethyl acetate, acetonitrile, methanol, isopropyl acetate, or mixtures thereof with other solvents e.g. water. Mixtures thereof with an apolar solvent can also be used, e.g. with heptane, hexane, pentane. Preferred solvent is methyl tert-butyl ether or a mixture of it with heptane. Mixture of methanol / water can also be used.

[0140] Generally, the crude product is first dissolved in the solvent or solvent mixture at an elevated temperature, e.g. 40-70°C. After that, the temperature is decreased accompanied by the precipitation of the compound of Formula 10. Optionally, trituration with a suitable solvent can be applied, to remove impurities. Preferred solvent for trituration is n-heptane. Optionally, seed crystals of the final compound are added during the cooling down to aid the precipitation.

[0141] In some embodiments, Ri is H, R2 is Cl and X is N. The compound of Formula 10 is then 2-chloro-5-((1 R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxamido)-N-(3,5-difluoropyridin-2-yl)benzamide (compound 10a).

[0142] In some embodiments, R1 is F, R2 is H and X is CH. The compound of Formula 10 is then 2-chloro-5-((1 R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide (compound 10b).

[0143] The compound of Formula 9 can be obtained from a compound of Formula 8 as described below.In this step, a compound of Formula 8:

[0144]

[0145] Formula 8

[0146] wherein X is selected from N or CH,

[0147] is subjected to NO2-reduction to result in a compound of Formula 9:

[0148]

[0149] Formula 9

[0150] The NO2-reduction is performed using a reducing agent, which is preferably selected from the list consisting of carbon-supported Pt catalysts (optionally poisoned with sulfur) with hydrogen, carbon-supported Pd catalysts (optionally poisoned with sulfur) with hydrogen, Raney-Nickel catalyst with hydrogen, Pt / C with hydrogen, Zn with NH4CI, Zn with NH4HCO2, Ni foam with hydrogen. More preferably, Raney-Nickel with hydrogen, Ni foam with hydrogen orZn with NH4CI is used.

[0151] In some embodiments, X is N. In these cases, the preferred hydrogenation agent is a Raney-Nickel catalyst and hydrogen. Raney-Nickel catalyst is a heterogeneous hydrogenation catalyst known to the skilled person.

[0152] In some embodiments, X is CH. In these cases, the preferred hydrogenation agent is Zn and NH4CI or Ni foam with hydrogen, more preferred Ni foam with hydrogen. Zn is typically used in the form of powder or dust. Ni foam is a known catalyst with a particularly large reactive surface, which is commercially available e.g. from Evonik.

[0153] The reaction can be performed in a solvent or a mixture of those. Any suitablesolvent can be used. When carbon-supported Pd (Pd / C) catalyst is used, it is preferred to use esters as a solvent, e.g. ethyl acetate, to prevent dehalogenation. For other catalysts there can be other preferred solvent mixtures, e.g. alcohols such as ethanol. The skilled person is able to determine a suitable solvent for each reducing agent. Preferred solvents include esters such as ethyl acetate, isopropyl acetate; alcohols such as methanol, ethanol, isopropyl alcohol; tetrahydrofuran (THF), 1,4-dioxane.

[0154] The compound of Formula 8 can, in its turn be prepared from a compound of Formula 6, as described below.

[0155] In this step, a compound of Formula 6 or its HCI salt:

[0156] '2

[0157]

[0158] Formula 6

[0159] wherein X is selected from N or CH, is subjected to amide coupling with a compound of Formula 7 (2-chloro-5-nitrobenzoic acid) or its acid chloride:

[0160] .OH

[0161] NO2'

[0162]

[0163] Formula 7

[0164] to result in a compound of Formula 8:

[0165] NO2

[0166]

[0167] Formula 8

[0168] In the present disclosure, the amide coupling reaction can be performed in two steps - formation of an acid chloride of the compound of Formula 7, followed by amidecoupling.

[0169] For the formation of an acid chloride of the compound of Formula 7, 2-chloro-5-ntirobenzoic acid can be reacted with a source of chlorine, e.g. oxalyl chloride (COCh), thionyl chloride (SOCI2), or another suitable chlorinating agent. Preferably, oxalyl chloride is used. Skilled person is able to determine suitable amounts of the chlorinating agent. Preferably, the chlorinating agent is used in an equivalent amount or a slight excess with respect to the amine of Formula 6. For example in an amount 1 - 1.5 eq, preferably 1-1.2, more preferably 1.005-1.1 eq.

[0170] When oxalyl chloride is used as the chlorinating agent, it is beneficial if DMF is present in catalytic amounts such as less than 0.1 eq to the amount of oxalyl chloride. If no DMF is present, the reaction may be too slow. If too much DMF (>10 eq) is present, more side reactions take place and the purity and yield become less satisfactory.

[0171] The formation of the acid chloride can take place at ambient conditions.

[0172] No intermediate isolation or purification is necessary.

[0173] The resulting acid chloride can be reacted with a compound of Formula 6 or its HCI salt. The acid chloride of the compound of Formula 6 can be obtained by known method, e.g. reacting with an acid, preferably HCI.

[0174] The amide coupling reaction preferably takes place while cooling, e.g. to a temperature below 5°C.

[0175] The amide coupling is preferably performed in the presence of a base, such as pyridine.

[0176] The amide coupling reaction can be performed in the presence of an organic solvent. Any suitable organic solvent can be used, for example, those mentioned above in earlier steps. Preferably, ethyl acetate, THF, 2-MeTHF, DMF, acetonitrile, acetone or a mixture thereof is used, more preferably, acetonitrile. Somechlorinating agents can be used as a solvent, too, e.g. thionyl chloride.

[0177] In step (f), the compound of Formula 10a:

[0178]

[0179] Formula 10a

[0180] is crystallized in the form of a cocrystal, solvate or both (cocrystal solvate).

[0181] Cocrystal in this case is defined as a crystal that comprises the molecule of Formula 10a and a coformer. Solvate in this case is defined as a crystal that comprises the molecule of Formula 10a and a solvent. Cocrystal solvate in this case corresponds to a crystal that comprises both a coformer and a solvent in addition to the molecule of Formula 10a.

[0182] It should be noted that cocrystals of the present invention can also be considered salts, because they have acidic coformers and the precise definition of a cocrystal or a salt in each particular case depends on the proximity of the hydrogen atom in the intermolecular hydrogen bond N...H...O. The proximity of the hydrogen can be calculated or determined by conventional methods. For clarity, in the rest of the present disclosure these compounds will be referred to as cocrystals.

[0183] Inventors have screened various coformers and identified that only p- toluenesulfonic acid and benzenesulfonic acid formed crystals with the compound of Formula 10a. Therefore, the coformer in the cocrystal can be selected from p- toluenesulfonic acid and benzenesulfonic acid.

[0184] The cocrystal according to the invention can be isolated as such or with a cocrystallized solvent (cocrystal solvate), particularly with ethyl acetate. An example of cocrystal solvate is hemi-ethyl acetate of the above-mentioned cocrystals.Cocrystal forming can be done by known methods. For example, the compound of Formula 10a can be mixed with either p-toluenesulfonic acid or benzenesulfonic acid or their respective monohydrates in a suitable solvent.

[0185] In some embodiments, p-toluenesulfonic acid monohydrate is used.

[0186] In other embodiments, benzenesulfonic acid monohydrate is used.

[0187] Solvents suitable for this step are the same as mentioned above for the purification by recrystallization, particularly methyl tert-butyl ether (MTBE), ethyl acetate, acetonitrile, tert-amyl methyl ether (TAME), isopropyl acetate, methanol, or mixtures thereof.

[0188] For the cocrystal with p-toluenesulfonic acid, a preferred solvent is ethyl acetate.

[0189] For the cocrystal with benzenesulfonic acid, a preferred solvent is selected from acetonitrile, ethyl acetate, toluene of mixtures thereof, more preferably ethyl acetate.

[0190] In a preferred embodiment, the solvent used for the formation of the cocrystal is the same as in the amide coupling reaction in step (e) discussed above. This avoids the necessity to isolate intermediate products before the next step, which would lead to lower yield and higher chance of impurities. Preferably, such solvent is ethyl acetate.

[0191] Crystalline forms (including cocrystals) can have many advantages over the amorphous form. One of the advantages for pharmaceutical development is higher reproducibility, which leads to the ease of manufacturing and improved pharmaceutical processing. Also, crystals are generally more stable than the amorphous form, which is typically a less thermodynamically stable form.

[0192] After precipitation of the cocrystals, these can be easily filtered out of the solution.

[0193] The compound of Formula 10a is preferably obtained as described above for thecompounds of Formula 10. It is advantageous to perform cocrystal formation as the final step after step (e) since this allows to separate the compounds of Formula 10 with high purity from the reaction mixture without additional purification steps. Therefore, the crystallization in the form of cocrystals described in this step can be used as a purification step after step (e).

[0194] Cocrystals of the compound of Formula 10a can be converted back to the compound of Formula 10a (free base form) by known methods, e.g. by allowing to react with a base, preferably with a weak base.

[0195] In a further aspect, the present invention provides a cocrystal of the compound of Formula 10a:

[0196]

[0197] Formula 10a

[0198] with an acid selected from p-toluenesulfonic acid and benzenesulfonic acid. The molar ratio of the molecule of Formula 10a to the acid coformer is preferably 1:1.

[0199] In one embodiment, the acid is p-toluenesulfonic acid and the cocrystal is referred to as tosyl ate.

[0200] Preferably, the tosylate has an X-ray powder diffraction (XRPD) pattern comprising peaks approximately at the following positions: 5.1, 10.1, 15.5 and 25.2 degrees (20), more preferably approximately at the following positions: 5.1, 7.9, 8.3, 10.1, 13.9, 15.3, 15.5, 16.3, 17.1, 18.1, 19.5, 20.1 , 23.7, 24.3, 25.2 and 25.9 degrees (20) as measured using X-Ray Cu Ka radiation.

[0201] Preferably, the tosylate has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 195.6°C measured at heating rate of 107min. The DSC is preferably performed on TA Instruments Discovery TGA, ramp 107min, 25 to 250 or300°C, 50 ml / min N2 sweep.In another embodiment, the acid is benzenesulfonic acid and the cocrystal is referred to as besylate.

[0202] Preferably, the besylate has an X-ray powder diffraction (XRPD) pattern comprising peaks approximately at the following positions: 4.7, 8.0, 8.5, 14.2, 18.1, 18.9, 20.3, 23.2, 25.1, 26.0 and 28.6 degrees (20), more preferably approximately at the following positions: 4.7, 8.0, 8.5, 10.1, 13.3, 13.6, 14.2, 15.8, 16.1, 16.6, 17.7, 18.1, 18.9, 20.3, 21.1, 21.8, 22.1 , 23.0, 23.2, 25.1 , 25.6, 26.0, 27.0 and 28.6 degrees (20) as measured using X-Ray Cu Ka radiation.

[0203] Preferably, the besylate has a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 185.5°C measured at heating rate of 107min.

[0204] The obtained cocrystals can be used in pharmaceutical compositions, particularly veterinary pharmaceutical compositions, more particularly antiparasitic veterinary pharmaceutical compositions. The pharmaceutical composition according to the present invention contain the cocrystal as described above and at least one pharmaceutical excipient.

[0205] Such composition can be used to control parasites in animals. Therefore, the present disclosure also provides method to control parasites using the pharmaceutical composition of the invention.

[0206] The pharmaceutical composition of the invention and / or embodiments thereof is suitably used in a method to treat or control an ectoparasite infestation, particularly wherein the parasitic infestation is a tick infestation or flea infestation. The pharmaceutical composition is suitably used for a tick infestation, particularly against Rhipicephalus microplus.

[0207] In a suitable use or method of the present disclosure and / or any embodiment thereof, the animal is a warm-blooded animal such as a mammal. The pharmaceutical composition can for example be used in a livestock animal, such asa ruminant, bovine animal, cattle, or in fish, against a sea lice infestation. The pharmaceutical composition can also be used in a companion animal, such as a canine animal or a feline animal, especially a dog or cat.

[0208] In a suitable use or method of the invention and / or any embodiment thereof, the animal is protected from a parasite infestation. Preferably an existing parasite infestation of the animal is treated or controlled.

[0209] In a suitable use or method of the invention and / or any embodiment thereof, the method comprises administering the pharmaceutical composition to an animal weekly, bi-weekly, monthly, every 6 weeks, every 2 months or every 3 months.

[0210] Suitably, the veterinary composition is a topical composition, an oral composition, or an injection composition.

[0211] EXAMPLES

[0212] Analytical methods

[0213] HPLC

[0214] B_BEHC18

[0215] Instrument: Agilent Technologies UHPLC / MS Series 1290

[0216] Column: Waters Column XP, 2.1 x 50 mm Xbridge BEH C18+, 2.5 p Oven 40 °C

[0217] temperature:

[0218] Eluents: A: acetonitrile

[0219] B: water with 0.1 % (vol. / vol.) ammonia

[0220] Flow: 0.8 mL / min

[0221] Gradient: From 2 to 100 % eluent A in 1.2 min, 0.5 min 100 % eluent A Run time: 2.2 min

[0222] Detection: ESI / APCI / MS, positive ions scan: 100-1000 m / z

[0223] UV at 254, 210 and 280 nm

[0224]

[0225] B_BEHC18_CPA

[0226] Instrument: Agilent Technologies UHPLC / MS Series 1290 Column: Waters Column XP, 2.1 x 50 mm Xbridge BEH C18+, 2.5 p Oven 40 °C

[0227] temperature:

[0228] Eluents: A: acetonitrile

[0229] B: water with 0.1 % (vol. / vol.) ammonia

[0230] Flow: 0.8 mL / min

[0231] Gradient: From 40 to 90 % eluent A in 2.0 min

[0232] from 90 to 100 % eluent A in 0.5 min, 0.5 min 100 % eluent A Run time: 3.6 min

[0233] Detection: ESI / APCI / MS, positive ions scan: 100-1000 m / z

[0234] UV at 254, 210 and 280 nm

[0235]

[0236] A_BEHC18

[0237] Instrument: Agilent Technologies UHPLC / MS Series 1290 Column: Waters Column XP, 2.1 x 50 mm Xbridge BEH C18, 2.5 p Oven 40 °C

[0238] temperature:

[0239] Eluents: A: acetonitrile with 0.05 % (vol. / vol.) formic acid.

[0240] B: water with 0.05 % (vol. / vol.) formic acid Flow: 0.8 mL / min

[0241] Gradient: From 2 to 100 % eluent A in 1.2 min, 0.5 min 100 % eluent A Run time: 2.2 min

[0242] Detection: ESI / MS, positive and negative ions scan: 100-1000 m / z UV at 254, 210 and 280 nm

[0243]

[0244] C10b-rac

[0245] Instrument: Agilent Technologies UHPLC / MS Series 1290 Column: LUX Amylose- 1 , 250*4.6mm, 5p von Phenomenex

[0246]

[0247] Oven 35 °C

[0248] temperature:

[0249] Eluent: / so-Hexane / Ethanol 97 / 3 (vol. / vol.) + 0.1% TFA Flow: 1.0 mL / min

[0250] Run time: 20 min

[0251] Detection: UV at 254, 220 and 280 nm

[0252]

[0253] C10a-R,R

[0254] Instrument: Agilent Technologies UHPLC / MS Series 1290 Column: Lux-Amylose 1 , 4.6 x 250 mm, 5 p von Phenomenex Oven 35 °C

[0255] temperature:

[0256] Eluent: / so-Hexane / Ethanol 97 / 3 (vol. / vol.) + 0.1 % (vol.) TFA Flow: 1.0 mL / min

[0257] Run time: 10 min

[0258] Detection: UV at 220 nm

[0259]

[0260] C10b-R,R

[0261] Instrument: Agilent Technologies UHPLC / MS Series 1290 Column: Chiralpak IG, 4.6 x 250 mm, 5 p von Chiral Technologies Oven 35 °C

[0262] temperature:

[0263] Eluent: / so-Hexane / Ethanol 90 / 10 (vol. / vol.)

[0264] Flow: 1.0 mL / min

[0265] Run time: 10 min

[0266] Detection: UV at 220 nm

[0267]

[0268] C2-10a-R,R

[0269] Instrument: Agilent Technologies UHPLC / MS Series 1290 Column: Chiralpak IC, 4.6 x 250 mm, 5 p von Phenomenex

[0270]

[0271] Oven 35 °C

[0272] temperature:

[0273] Eluent: / so-Hexane / Ethanol 75 / 25 (vol. / vol.)

[0274] Flow: 1.0 mL / min

[0275] Run time: 8 min

[0276] Detection: UV at 220 nm, 254 nm

[0277]

[0278] NMR

[0279] NMR spectra were recorded on a Bruker Avance Neo 600 MHz spectrometer, or a Bruker Avance III HD 300 MHz spectrometer and are calibrated using residual undeuterated solvent (CHCh at 7.26 ppm1H NMR, 77.16 ppm13C NMR; DMSO at 2.50 ppm1H NMR, 39.52 ppm13C NMR). Data are reported as following: chemical shift 5 in ppm (multiplicity, coupling constant Jin Hz, number of protons) for1H NMR spectra and chemical shift 5 in ppm for13C NMR spectra. Multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet, or combinations thereof.

[0280] X-ray powder diffraction (XRPD)

[0281] Instrument: Panalytical Empyrean

[0282] Parameters: X-Ray tube Cu (Ka radiation); tube voltage 45 kV; tube current 40 mA Scanning range: 2 to 4020 (degree)

[0283] Step size: 0.01 degree

[0284] Scanning speed: 1.31 degree (20) per minute

[0285] Polarized Light Microscopy (PLM)

[0286] Instrument: Nikon Eclipse Ci POL

[0287] Camera: Nikon DS-Fi3

[0288] Software: Nikon NIS ElementsExample 1

[0289] Synthesis of (E)-1,3-Dichloro-5-(3,3-diethoxyprop-1-en-1-yl) benzene:

[0290] OEt

[0291] Br Pd(OAc)2

[0292] nBu4NOAc

[0293] KCI, K3PO4,

[0294] BuOH

[0295]

[0296] 1a

[0297] A three-neck round-bottom flask (2 L) equipped with a reflux condenser with a reflux divider head, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with butan-2-ol (800 mL), tetrabutylammonium acetate (72.7 g, 217 mmol), potassium phosphate tribasic (142 g, 651 mmol), and potassium chloride (32.7 g, 434 mmol). After the addition of 3,3-diethoxyprop-1-ene (76 mL, 477 mmol) and 1-bromo-3,5-dichlorobenzene (100 g, 434 mmol) the temperature of the mixture was adjusted to 85 °C and palladium (II) diacetate (248 mg, 1.085 mmol) was added. During addition the temperature increased to 100 °C within 5 min, gradually decreased after 10 min. After stirring at 95 °C for 15 min a reaction control by LC showed complete conversion.

[0298] The reaction mixture was cooled to 58 °C and approximately 90 % of the solvent volume was distilled off under reduced pressure (about 125 mbar). After cooling to ambient temperature methyl tert-butylether (500 mL) and water (500 mL) were added. The layers were separated, and the aqueous phase was extracted with methyl tert-butylether (100 mL). The combined organic layers were washed with brine (100 mL, 18% w / w), filtered over a plug of magnesium sulfate (100 g) and concentrated under reduced pressure. The resulting brown oil was dissolved in methyl tert-butylether (100 mL) and filtered over a silica pad (100 g) which was rinsed with methyl tert-butylether (300 mL). The combined filtrates were concentrated to afford (E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en-1-yl) benzene as a yellow oil (120.7 g, 272 mmol, 63 % yield, 62 wt.%).

[0299] The product was used in Examples 3 and 4 without further purification.HPLC Method B_BEHC18: Ret. time: 1.394 min

[0300] 1H NMR (300 MHz, d6-DMSO) 6 (ppm): 7.61 (d, J = 1.8 Hz, 2H), 7.48 (s, 1 H), 6.65 (d, J = 16.2 Hz, 1 H), 6.48 (dd, J = 16.1 , 5.0 Hz, 1 H), 5.04 (d, J = 4.6 Hz, 1 H), 3.60 (dq, J= 9.5, 7.1 Hz, 2H), 3.48 (dq, J= 9.6, 7.0 Hz, 2H), 1.14 (t, J= 7.1 Hz, 6H)

[0301] Example 2

[0302] Synthesis of (E)-2-chloro-4-(3,3-diethoxyprop-1 -en-1 -yl)-1 -fluorobenzene:

[0303] OEt

[0304] OEt

[0305] Br Pd(OAc)2

[0306] nBu4NOAc

[0307] KCI, K3PO4,

[0308]

[0309] BuOH 2b

[0310] A four-neck round-bottom flask (2 L) equipped with a reflux condenser with a reflux divider head, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with butan-2-ol (800 mL), tetrabutylammonium acetate (78 g, 234 mmol), potassium phosphate tribasic (154 g, 702 mmol), and potassium chloride (35.2 g, 468 mmol). After the addition of 3,3-diethoxyprop-1-ene (82 mL, 515 mmol) and 4-bromo-2-chloro-1 -fluorobenzene (100 g, 468 mmol) the temperature of the mixture was adjusted to 85 °C and palladium (II) diacetate (536 mg, 2.34 mmol) was added. During addition the temperature increased to 100 °C within 5 min, gradually decreased after 10 min. After stirring at 95 °C for 15 min additional palladium (II) diacetate (804 mg, 3.51 mmol) was added in three portions over 1 h, then the reaction mixture was stirred for further 30 min at this temperature.

[0311] The reaction mixture was cooled to 55 °C and approximately 90 % of the solvent volume was distilled off under reduced pressure (about 110 mbar). After cooling to ambient temperature methyl tert-butylether (500 mL) and water (500 mL) were added, and the resulting mixture was stirred for 10 min. The layers were separated, and the aqueous phase was extracted with methyl tert-butylether (100 mL). Thecombined organic layers were washed with half concentrated brine (100 mL), filtered over a plug of magnesium sulfate (100 g) and concentrated under reduced pressure. The resulting brown oil was dissolved in methyl tert-butylether (200 mL) and filtered over a silica pad (100 g) which was rinsed with methyl tert-butyl ether (400 mL). The filtrate was concentrated to afford (E)-2-chloro-4-(3,3-diethoxyprop-1-en-1-yl)-1-fluorobenzene as an orange oil (119.45 g, 291 mmol, 62 % yield, 63 wt.%).

[0312] The product was used in Example 5 without further purification.

[0313] HPLC Method B_BEHC18_CPA: Ret. time: 1.430 min

[0314] 1H NMR (300 MHz, d6-DMSO) 6 (ppm) : 7.79 (dd, J = 2.1 , 7.3 Hz, 1 H), 7.58 - 7.49 (m, 1 H), 7.39 (t, J = 8.9 Hz, 1 H), 6.66 (d, J = 16.1 Hz, 1 H), 6.34 (dd, J = 5.2, 16.1 Hz, 1H), 5.04 (d, J = 4.7 Hz, 1H), 3.67 - 3.43 (m, 4H), 1.15 (t, J = 7.1 Hz, 6H)

[0315] Example 3

[0316] Synthesis of trans- ,3-dichloro-5-(2,2-dichloro-3-(diethoxy

[0317] methvDcyclopropyDbenzene:

[0318]

[0319] ci ci

[0320] 2a 3a

[0321] A jacketed reactor (5 L) equipped with a reflux condenser, a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with (E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en-1-yl) benzene (260 g, 567 mmol, 60 % content by1H NMR) dissolved in chloroform (2744 mL, 34.0 mol) and aqueous 50 wt% sodium hydroxide (59.7 mL, 1.13 mol). The temperature of the mixture was adjusted to 35 °C and benzyltriethyl ammonium chloride (1.29 g, 5.67 mmol) was added. The resulting solution was heated to 50 °C and aqueous 50 wt% sodium hydroxide (1014 mL, 19.3 mol) was added within 45 min. The reaction mixture was further stirred for 3 h at this temperature before cooling down to 33 °C to distill off the volatiles under reduced pressure (about 330 mbar).The reaction mixture was cooled to ambient temperature, diluted with water (1.3 L) and extracted with methyl tert-butyl ether (1.3 L). After phase separation the aqueous layer was extracted with methyl tert-butyl ether (300 mL). The combined organic phases were filtered over a plug of magnesium sulfate (130 g). The filtrate was concentrated under reduced pressure to a volume of about 2X (by vol.) to afford trans-1, 3-dichloro-5-(2,2-dichloro-3-(diethoxy methyl)cyclopropyl)benzene (320.7 g, 502 mmol, 88 % assay yield, 56 wt% content by UV-UPLC) as a dark brown oil. The product was used in Example 6 and 7 without further purification.

[0322] HPLC Method B_BEHC18: Ret. time: 1.432 min

[0323] 1H NMR (300 MHz, d6-DMSO) 6 (ppm): 7.57 (t, J = 1.8 Hz, 1 H), 7.49 (d, J = 1.8 Hz, 2H), 4.46 (d, J= 7.0 Hz, 1H), 3.77-3.51 (m, 4H), 3.18 (d, J= 8.7 Hz, 1H), 2.93 (dd, J = 8.7, 7.1 Hz, 1 H), 1.20 (t, J = 7.0 Hz, 3H), 1.08 (t, J = 7.0 Hz, 3H)

[0324] Example 4

[0325] is of trans- ,3-dichloro-5-(2,2-dichloro-3-(di

[0326]

[0327]

[0328] 2a 3a

[0329] A round-bottom flask (100 mL) equipped with a dropping funnel and a magnetic stirrer was charged with (E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en-1-yl) benzene (2.4 g, 8.72 mmol) dissolved in aqueous 50 wt% sodium hydroxide (918 pL, 17.4 mmol) and chloroform (42.2 mL, 523 mmol). The aqueous 50 wt% sodium hydroxide (15.6 mL, 297 mmol) was added dropwise to the solution. After stirring for 28 h at room temperature, the reaction mixture was diluted with water (50 mL) and dichloromethane (50 mL). After phase separation the aqueous layer was extracted with dichloromethane (25 mL). The combined organic phases were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure toafford trans- ,3-dichloro-5-(2,2-dichloro-3-(diethoxy methyl)cyclopropyl)benzene (3.05 g, 8.4 mmol, 97 % yield) as a yellow oil.

[0330] The product was used without further purification.

[0331] Example 5

[0332] of trans-2-chloro-4-(2,2-dichloro-3-(di

[0333]

[0334] i-1-fluorobenzene:

[0335]

[0336] A jacketed reactor (5 L) equipped with a reflux condenser, a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with (E)-2-chloro-4-(3,3-diethoxyprop-1-en-1-yl)-1 -fluorobenzene (183 g, 403 mmol, 57 % content by1H NMR) dissolved in chloroform (1951 mL, 24.2 mol) and aqueous 50 wt% sodium hydroxide (42.4 mL, 806 mmol). The temperature of the mixture was adjusted to 35 °C and benzyltriethyl ammonium chloride (918 mg, 4.03 mmol) was added. The resulting solution was heated to 50 °C and aqueous 50 wt% sodium hydroxide (721 mL, 13.7 mol) was added within 45 min. The reaction mixture was further stirred for 3 h at this temperature before cooling down to 45 °C to distill off the volatiles under reduced pressure (about 450 mbar).

[0337] The reaction mixture was cooled to ambient temperature, diluted with water (900 mL) and extracted with methyl tert-butyl ether (900 mL). After phase separation the aqueous layer was extracted with methyl tert-butyl ether (300 mL). The combined organic phases were washed with brine (300 mL) and filtered over a plug of magnesium sulfate (180 g). The filtrate was concentrated under reduced pressure to afford trans-2-chloro-4-(2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-1 -fluorobenzene (223.2 g, 372 mmol, 92 % assay yield, 57 wt% content by UV-UPLC) as a brown oil.The product was used in Example 8 without further purification.

[0338] HPLC Method B_BEHC18_CPA: Ret. time: 1.718 min

[0339] 1H NMR (300 MHz, d6-DMSO) 5 (ppm) 7.68 - 7.61 (m, 1H), 7.47 - 7.38 (m, 2H), 4.49 (d, J= 7.0 Hz, 1H), 3.81 - 3.53 (m, 4H), 3.15 (d, J= 8.7 Hz, 1H), 2.80 (dd, J = 8.7, 7.1 Hz, 1H), 1.22 (t, J= 7.1 Hz, 3H), 1.09 (t, J= 7.0 Hz, 3H)

[0340] Example 6

[0341] of trans-2, 2-dichloro-3-(3,5-di !-1-i acid:

[0342] 1. AcOH, MeCN, H2O 2. NaCIO2, H2O2, H2O

[0343]

[0344] 4a

[0345] A jacketed glass reactor (3 L) equipped with a gas washer, a reflux condenser, a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with trans-1, 3-dichloro-5-(2,2-dichloro-3-(diethoxy methyl)cyclopropyl)benzene (250 g, 314 mmol, 45 % content by1H NMR) dissolved in water (28.3 mL, 1571 mmol), acetonitrile (1250 mL) and acetic acid (90 mL, 1571 mmol). The temperature was raised to 68 °C and the reaction mixture was stirred at this temperature for 2 h.

[0346] Aftercooling to 25 °C, aqueous 12 wt% hydrogen peroxide (241 mL, 943 mmol) was added followed by the addition of a solution of sodium chlorite (71 g, 628 mmol) in water (250 mL) within 45 min, while keeping the temperature below 25 °C. The resulting mixture was stirred for 1 h. A solution of sodium bisulfite (163 g, 1.57 mol) in water (250 mL) was carefully added, while keeping the temperature below 25 °C. The resulting reaction mixture was stirred for 15 min at this temperature affording a negative peroxide test.Approximately 75% of the solvent volume of acetonitrile (750 mL) was distilled off under reduced pressure. The reaction mixture was diluted with water (1250 mL) and extracted with methyl tert-butyl ether (1250 mL). After phase separation the organic layer was washed with halfconc. brine (500 mL) and filtered over a plug of magnesium sulfate (200 g). Halfconcentrated means at a concentration that is half of the maximal possible concentration (saturated). The filtrate was concentrated under reduced pressure. n-Heptane (1250 mL) was added, and the resulting mixture was stirred overnight at ambient temperature. The resulting precipitate was filtered and washed with n-heptane. The crude product was recrystallized from toluene (200 mL), filtered, washed with n-heptane, and dried under reduced pressure at 40 °C to afford trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid (50.5 g, 165 mmol, 53 % yield) as off-white solid.

[0347] The filtrate was concentrated under reduced pressure. The resulting solid was recrystallized from toluene (60 mL), filtered, washed with n-heptane and dried under reduced pressure at 40 °C to afford trans-2, 2-dichloro-3-(3, 5-dichlorophenyl)cyclopropane-1 -carboxylic acid (11.2 g, 32.4 mmol, 10 % yield) as off-white solid.

[0348] HPLC Method A_BEHC18: Ret. time: 1.174 min, m / z 596.8

[0349] HPLC Method C10a-R,R: Ret. time: 11.552 min, 15.765 min

[0350] 1H NMR (300 MHz, d6-DMSO) 5 (ppm): 13.39 (s, 1H), 7.70 - 7.48 (m, 3H), 3.57 (d, J = 8.6 Hz, 1 H), 3.50 (d, J = 8.6 Hz, 1 H)

[0351] Example 7

[0352] Synthesis of trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid:

[0353]

[0354] 3a 4a

[0355] A three-neck round-bottom flask (250 mL) equipped with a reflux condenser, a dropping funnel, a magnetic stirrer and an internal thermometer was charged with trans- ,3-dichloro-5-(2,2-dichloro-3-(diethoxy methyl)cyclopropyl)benzene (112.5 g, 20.23 mmol, 63 % content by1H NMR) dissolved in water (1.8 mL, 101 mmol), acetone (60 mL) and acetic acid (5.8 mL, 101 mmol). The reaction mixture was heated to reflux under vigorous stirring. After stirring for 6 h at this temperature the reaction mixture was cooled to room temperature and stirred for 16 h at this temperature.

[0356] An aqueous 13 wt% sodium hypochlorite (38.4 mL, 81 mmol) was added dropwise over 10 min, while keeping the temperature below 25 °C. After 1 h stirring acetone was distilled off under reduced pressure. The reaction mixture was diluted with water (50 mL) and extracted with methyl tert-butyl ether (50 mL). After phase separation the organic layer was washed with brine (25 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford a yellow solid.

[0357] The solid was triturated with n-heptane (100 mL) at room temperature. The precipitate was filtered, washed with n-heptane, and dried under reduced pressure at 40 °C to afford trans-2, 2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylic acid (4.18 g, 13.24 mmol, 65 % yield) as off-white solid. The filtrate was concentrated under reduced pressure. The resulting yellow oil was diluted with n-heptane (50 mL), seeded, and stirred for 16 h at room temperature. The formed precipitate was filtered, washed with n-heptane, and dried under reduced pressure at 40 °C to afford a second crop of trans-2, 2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1 -carboxylic acid (0.46 g, 1.488 mmol, 7 % yield) as off-white solid.

[0358] Example 8

[0359] is of trans-2,2-dichloro-3-(3-chloro-4-

[0360]

[0361] !-1-ic acid:

[0362] 1. AcOH,

[0363] MeCN, H2O Cl Cl

[0364] 2. NaCIO2,

[0365] H2O2, H2O

[0366]

[0367] A jacketed glass reactor (3 L) equipped with a gas washer, a reflux condenser, a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with trans-2-chloro-4-(2,2-dichloro-3-(diethoxy methyl)cyclopropyl)-1 -fluorobenzene (223 g, 372 mmol, 57 % content by1H NMR) dissolved in acetonitrile (1100 mL), water (33.5 mL, 1.86 mol) and acetic acid (106 mL, 1.86 mol). The temperature was then raised to 68 °C and the reaction mixture was stirred at this temperature for 3 h.

[0368] After cooling to 25 °C, aqueous 12 wt% hydrogen peroxide (285 mL, 1116 mmol) was added followed by the addition of a solution of sodium chlorite (84 g, 774 mmol) in water (300 mL) within 35 min, while keeping the temperature below 25 °C. The resulting mixture was stirred for 1 h. A solution of sodium bisulfite (194 g, 1.86 mol) in water (300 mL) was carefully added, while keeping the temperature below 25 °C. The resulting reaction mixture was stirred for 15 min at this temperature affording a negative peroxide test.

[0369] Approximately 75% of the solvent volume of acetonitrile (800 mL) was distilled off under reduced pressure. The reaction mixture was diluted with water (1100 mL) and extracted with methyl tert-butyl ether (1100 mL). After phase separation the organic layer was washed with halfconc. brine (440 mL) and filtered over a plug of magnesium sulfate (220 g). The filtrate was concentrated under reduced pressure. n-Heptane (1100 mL) was added and the resulting mixture was stirred overnight at ambient temperature. The resulting precipitate was filtered, washed with n-heptane and was dried under reduced pressure at 40 °C to afford trans-2, 2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1 -carboxylic acid (78.34 g, 268 mmol, 72 % yield) as beige solid.HPLC Method A_BEHC18: Ret. time: 1.120 min, m / z 564.9

[0370] HPLC Method C10b-rac: Ret. time: 17.386 min, 23.827 min

[0371] 1H NMR (300 MHz, d6-DMSO) 6 (ppm): 13.38 (s, 1H), 7.71 (dd, = 7.1 , 1.9 Hz, 1H), 7.56 - 7.37 (m, 2H), 3.46 (s, 2H)

[0372] Example 9

[0373] carboxylic acid:

[0374]

[0375] A jacketed glass reactor (10 L) equipped with a reflux condenser, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with trans-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid (319.5 g, 1065 mmol) and ethyl acetate (3 L) at room temperature. The temperature was raised to 72 °C and the reaction mixture was stirred at this temperature until a clear solution was obtained. After the addition of the chiral base (1S,2R)-2-amino-1,2- diphenylethan-1-ol (159 g, 746 mmol) and ethyl acetate (550 mL) to the resulting solution, the reaction mixture was maintained for 5 min under vigorous stirring at 77°C affording a clear solution before cooling down to -2 °C over 14 h and maintaining the temperature at -2 °C for additional 3 h.

[0376] The formed precipitate was filtered off (frit pore 3), the wet cake was washed (approx. 5 times) with ethyl acetate (each 1100 mL) until an optical purity of 99 % ee was obtained.

[0377] Recovery of a first crop of the chiral base (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol The filtrate was acidified with aqueous 1N hydrochloric acid (500 mL). After theaddition of water (3 L) the mixture was stirred for 20 min followed by the separation of the phases. The aqueous phase was basified with 4N aqueous sodium hydroxide (100 mL) and extracted with ethyl acetate (3 L and 2 L were added). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a first crop of (1S,2R)-2-amino-1,2-diphenylethan-1-ol (solid, 36.95 g, 173 mmol, recovery 23 %).

[0378] Isolation of (1R, 3R)-2, 2-dichloro-3-(3, 5-dichlorophenyl)cyclopropane-1 -carboxylic acid

[0379] The beige precipitate was suspended in aqueous 1N hydrochloric acid (2600 mL) and ethyl acetate (6500 mL). After 1 h under vigorous stirring water (1300 mL) was added to afford two clear layers within 15 min. The phases were separated and the organic phase was washed with water (2 x 1000 mL), followed by brine (600 mL) and was filtered over a filter filled with a pad of sodium sulfate. The volume of the solution was reduced to about 400 mL by evaporation under reduced pressure. The precipitate formed after evaporation was filtered off (frit pore 3) to obtain (1R,3R)-2, 2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid as beige solid (104.6 g, 349 mmol, yield 33 %, >99 % ee). Further precipitation from the filtrate occurred and the formed precipitate was filtered off (frit pore 3) to obtain further (1 R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid as beige solid (15.1 g, 50.2 mmol, yield 5 %, 97 % ee).

[0380] Recovery of a second crop of the chiral base (1 S,2R)-2-amino-1 ,2-diphenylethan-1-ol

[0381] To the aqueous phases obtained above 4N aqueous sodium hydroxide (2 L) was added affording a suspension. After extraction with ethyl acetate (2 x2 L) the organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain a second crop of (1S,2R)-2-amino-1,2-diphenylethan-1-ol (81.43 g, 382 mmol, recovery 51 %).

[0382] HPLC Method C10a-R,R: Ret. Time: 15.686 min

[0383] HPLC Method A_BEHC18: Ret. Time: 1.196 min, m / z 596.8

[0384] 1H NMR (300 MHz, d6-DMSO) 5 (ppm): 13.39 (s, 1H), 7.70 - 7.48 (m, 3H), 3.57 (d,J = 8.6 Hz, 1 H), 3.50 (d, J = 8.6 Hz, 1 H)

[0385] Example 10

[0386] of (1 R,3R)-2,2-dichloro-3-(3-chloro-4-

[0387]

[0388] carboxylic acid:

[0389] EtOAc 2- HCI AcOEt

[0390]

[0391] Step 1: Formation of the diastereomeric salt

[0392] A vacuum jacketed glass reactor (2 L) equipped with a reflux condenser, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with trans-2, 2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylic acid (100 g, 353 mmol) and acetonitrile (1765 mL) at room temperature. The resulting solution was heated to 80 °C and quinine (80 g, 247 mmol) was added within 10 min. The reaction mixture was further stirred for 3 h at this temperature before cooling down to -7 °C over 14 h and maintaining the temperature at -7 °C for additional 1 h.

[0393] The precipitate formed was filtered off (frit pore 3), the wet cake was washed with acetonitrile (3 x 500 mL). The resulting solid was suspended in acetonitrile (700 mL) and was heated to reflux under vigorous stirring. The suspension was further stirred for 6 h at this temperature before cooling to 0 °C and maintaining the temperature at 0 °C for additional 2 h. After filtration (frit pore 3) the precipitate was slurry washed with acetonitrile (500 mL) and filtered. In case 99 % ee was not achieved, slurry wash was repeated until an optical purity of 99 % ee was attained.

[0394] HPLC Method A_BEHC18: Ret. Time: 1.13 min, m / z 564.9, Ret. Time: 0.69 min, m / z 325.2

[0395] 1H NMR (300 MHz, MeOD) 5 (ppm) 8.74 (d, J = 4.6 Hz, 1H), 8.02 (d, J = 9.2 Hz,1 H), 7.80 (d, J = 4.6 Hz, 1 H), 7.56 - 7.38 (m, 3H), 7.33 - 7.15 (m, 2H), 6.00 (s, 1 H), 5.81 (ddd, J= 17.3, 10.4, 7.1 Hz, 1H), 5.28-4.99 (m, 2H), 4.33-4.15 (m, 1H), 4.03 (s, 3H), 3.77 - 3.53 (m, 2H), 3.33 (dt, J = 3.2, 1.6 Hz, 3H), 2.94 - 2.67 (m, 2H), 2.35 - 2.06 (m, 3H), 2.06 - 1.86 (m, 1 H), 1.70 - 1.48 (m, 1 H)

[0396] Step 2: Release of the free acid

[0397] The resulting precipitate was suspended in aqueous 1 N hydrochloric acid (250 mL) and ethyl acetate (500 mL) and was stirred until a clear solution was obtained. The phases were separated, and the organic phase was washed with water (50 mL), dried over magnesium sulfate and filtered (frit pore 3). After concentration under reduced pressure (1 R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1 -carboxylic acid (46.6 g, 163 mmol, 46 % yield) with an optical purity of 99 % was obtained as beige solid.

[0398] HPLC Method C10b-R,R: Ret. Time: 5.13 min

[0399] HPLC Method A_BEHC18: Ret. Time: 1.13 min, m / z 564.9

[0400] 1H NMR (300 MHz, d6-DMSO) 6 (ppm): 13.38 (s, 1H), 7.71 (dd, J = 7.1, 1.9 Hz, 1H), 7.56 - 7.37 (m, 2H), 3.46 (s, 2H)

[0401] Example 11

[0402] Preparation of 2-chloro-N-(3,5-difluoropyridin-2-yl)-5-nitrobenzamide:

[0403] pyridine (COCI)2DMF cat. ACN

[0404]

[0405] 7 6a

[0406] Step 1: Formation of the acid chloride

[0407] A three-neck round-bottom flask (1 L) equipped with a gas washer, a reflux condenser, a dropping funnel, a mechanical stirrer and placed under nitrogen atmosphere was charged with acetonitrile (250 mL), DMF (4.65 mL, 60 mmol) and 2-chloro-5-nitrobenzoicacid (133 g, 660 mmol). Oxalyl chloride (55.2 mL, 630 mmol)was added within 15 mm at ambient temperature and the resulting reaction solution was stirred for 3 h at 40 °C.

[0408] Step 2: Amide coupling

[0409] A vacuum jacketed glass reactor (3 L) equipped with a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with acetonitrile (650 mL), pyridine (126 mL, 1561 mmol) and 3,5-difluoropyridine2-amine hydrochloride (100 g, 600 mmol). The temperature of the reaction mixture was adjusted to 0 °C. The solution of the acid chloride formed in step 1 was added within 45 min, while keeping the temperature below 5 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 5 °C, diluted with water (350 mL) and stirred for 30 min at this temperature. After filtration the precipitation was slurry washed water twice (each 750 mL), followed by a 1:1 mixture of acetonitrile / water (1000 mL). After drying at 40 °C 2-chloro- / V-(3,5-difluoropyridin-2-yl)-5-nitrobenzamide (181.1 g, 548 mmol, 91 % yield) was obtained as beige solid.

[0410] HPLC Method A_BEHC18: Ret. Time: 0.896 min, m / z 312.0

[0411] 1H NMR (300 MHz, d6-DMSO) 5 (ppm): 11.21 (s, 1 H), 8.49 - 8.25 (m, 3H), 8.20 -8.02 (m, 1H), 7.90 (d, J= 8.6 Hz, 1H)

[0412] 19F NMR (283 MHz, d6-DMSO) 5 (ppm): -117.68, -126.07

[0413] Example 12

[0414] Preparation of 2-chloro- / \ / -(2,4-difluorophenyl)-5-nitrobenzamide:

[0415] _ Cl F pyridine l| Y H2N. Y. (COCI)2f| JHO2N^^f DM F eat. °2N^^

[0416]

[0417] OFACN07 6b 8b

[0418] Step 1: Formation of the acid chloride

[0419] A vacuum jacketed glass reactor (1 L) equipped with a gas washer, a reflux condenser, a dropping funnel, a mechanical stirrer and placed under nitrogenatmosphere was charged with acetonitrile (400 mL), DMF (6.0 mL, 77 mmol) and 2-chloro-5-nitrobenzoic acid (172 g, 852 mmol). Oxalyl chloride (71.2 mL, 813 mmol) was added within 15 min at ambient temperature and the resulting reaction solution was stirred for 1 h at 40 °C.

[0420] Step 2: Amide coupling

[0421] A vacuum jacketed glass reactor (3 L) equipped with a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with acetonitrile (800 mL), pyridine (100 mL, 1239 mmol) and 2,4-difluoroaniline (79 mL, 775 mmol). The temperature of the reaction mixture was adjusted to 0 °C. The solution of the acid chloride formed in step 1 was added within 2 h, while keeping the temperature below 5 °C. The reaction mixture was allowed to warm to room temperature and stirred overnight.

[0422] The reaction mixture was cooled to 5 °C, diluted with water (800 mL) and stirred for 30 min at this temperature. After filtration the precipitation was slurry washed water (500 mL), followed by a 2:1 mixture of acetonitrile / water (900 mL). After drying at 40 °C 2-chloro- / V-(2,4-difluorophenyl)-5-nitrobenzamide (235.2 g, 732 mmol, 95 % yield) was obtained as beige solid.

[0423] HPLC Method A_BEHC18: Ret. Time: 1.042 min, m / z 311.0

[0424] 1H NMR (300 MHz, d6-DMSO) 6 (ppm): 10.59 (s, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.34 (dd, J = 8.7, 2.4 Hz, 1H), 7.88 (q, J = 7.4 Hz, 2H), 7.47 - 7.33 (m, 1H), 7.16 (t, J = 8.3 Hz, 1H)

[0425] 19F NMR (283 MHz, d6-DMSO) 5 (ppm) -113.08 (p, J = 8.3 Hz), -117.77 (q, J = 9.6 Hz)

[0426] Example 13

[0427] of 5-amino-2-chloro- / V-(3,5-di idin-2-

[0428] H2

[0429] Ra / Ni

[0430] H2O

[0431]

[0432] AcOEt8a 9a

[0433] A stainless steel pressure vessel (5 L) equipped with a mechanical stirrer and placed under nitrogen atmosphere was charged with ethyl acetate (1000 mL) and 50 wt% Raney Nickel in water (16.4 g, 96 mmol). Ethanol (110 mL) was used to flush remaining Raney Nickel from the wall of the vessel. A suspension of 2-chloro- / V-(2,4-difluorophenyl)-5-nitrobenzamide (100 g, 319 mmol) in ethyl acetate (1000 mL) was added into the vessel. After the addition of ethyl acetate (1000 mL) three hydrogen / vacuum purges were performed. The vessel was charged with hydrogen (1 atm; 101 kPa) and the reaction mixture was stirred at 60 °C for 21.5 h.

[0434] The resulting reaction mixture was allowed to cool to room temperature and the vessel was depressurized. After the addition of saturated sodium bicarbonate (500 mL) the reaction mixture was stirred at ambient temperature for 5 h. The reaction mixture was filtered over a plug of Celite (50 g) and rinsed with ethyl acetate (500 mL). The phases were separated, and the organic phase was washed with water (2x 500 mL), followed by brine (300 mL). The solution was concentrated under reduced pressure (to a solvent volume of approximately 750 mL) to afford a slurry. After filtration and drying under reduced pressure at 40 °C 5-amino-2-chloro- / V-(3,5-difluoropyridine-2-yl)benzamide (64.5 g, 223 mmol, 70 % yield) was obtained as a beige solid.

[0435] The filtrate was further concentrated under reduced (to a solvent volume of approximately 150 mL) to afford a slurry. After filtration and drying under reduced pressure at 40 °C a second crop of 5-amino-2-chloro- / V-(3,5-difluoropyridine-2-yl)benzamide (19.0 g, 62.3 mmol, 20 % yield) was obtained as a beige solid.

[0436] HPLC Method A_BEHC18: Ret. Time: 0.762 min, m / z 284.0

[0437] 1H NMR (300 MHz, d6-DMSO) 6 (ppm): 10.72 (s, 1H), 8.38 (d, J= 2.5 Hz, 1H), 8.18 -7.96 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.64 (dd, J = 8.6, 2.7 Hz, 1H), 5.50 (s, 2H)

[0438] Example 14of 5-amino-2-chloro- / V-(2,4-di

[0439] Zn

[0440] NH4CI

[0441] 1 ,4-dioxane

[0442] H20

[0443]

[0444] 8b 9b

[0445] A vacuum jacketed glass reactor (10 L) equipped with a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with water (900 mL), 1,4-dioxane (3750 mL), 2-chloro- / V-(2,4-difluorophenyl)-5- nitrobenzamide (150 g, 467 mmol), zinc (153 g, 2334 mmol) and ammonium chloride (125 g, 2334 mmol). The temperature of the reaction mixture was adjusted to 85 °C. Gas evolution was observed. After 1 h stirring at this temperature the reaction was cooled to 25 °C and filtered over a plug of Celite (150 g), rinsed with ethyl acetate (2x 750 mL).

[0446] Approximately 75% of the solvent volume was distilled off under reduced pressure. The resulting reaction mixture was diluted with ethyl acetate (1500 mL), water (750 mL) and aqueous 1 N hydrochloric acid (300 mL). After phase separation the organic phase was washed with water (750 mL), dried over sodium sulfate (300 g), filtered and concentrated under reduced pressure to afford a slurry.

[0447] n-Heptane (300 mL) was added, and the resulting mixture was stirred overnight. After filtration the precipitation was slurry washed n-heptane (2x 30 mL) and dried at 40 °C to afford 5-amino-2-chloro- / V-(2,4-difluorophenyl)benzamide (127.95 g, 433 mmol, 93 % yield) as a beige solid.

[0448] HPLC Method A_BEHC18: Ret. Time: 0.963 min, m / z 283.0

[0449] 1H NMR (300 MHz, d6-DMSO) 6 (ppm): 10.16 (s, 1H), 7.67 (q, J= 8.8 Hz, 1H), 7.50 - 7.24 (m, 1 H), 7.24 - 6.98 (m, 2H), 6.74 (d, J = 2.4 Hz, 1 H), 6.65 (dd, J = 8.6, 2.5 Hz, 1H), 5.48 (s, 2H)

[0450] 19F NMR (283 MHz, d6-DMSO) 5 (ppm): -113.43 - -113.66 (m), -116.71 - -116.92(m)

[0451] Example 15

[0452] of 2-chloro-5-((1 R,3R)-2,2-dichloro-3-(3,5- M-i i-A / -(3,5-difluoropyridin-2-

[0453] (COCI)2pyridine DMF cat. AcOEt

[0454]

[0455] 5a 9a 10a

[0456] Step 1: Formation of the acid chloride

[0457] A three-neck round-bottom flask (500 mL) equipped with a gas washer, a dropping funnel, a magnetic stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with ethyl acetate (220 mL), DMF (26 pL, 0.333 mmol) and (1 R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid (20.8 g, 69.3 mmol). Oxalyl chloride (6.1 mL, 69.3 mmol) was added within 10 min at ambient temperature and the resulting reaction solution was stirred for 100 min at 25 °C.

[0458] Step 2: Amide coupling

[0459] A vacuum jacketed glass reactor (1 L) equipped with a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with ethyl acetate (220 mL), pyridine (6.6 mL, 82 mmol) and 5-amino-2-chloro- / V-(3,5-difluoropyridin-2-yl)benzamide (20 g, 68 mmol). The temperature of the reaction mixture was adjusted to 0 °C. The solution of the acid chloride formed in step 1 was added within 30 min, while keeping the temperature below 5 °C. The reaction mixture was stirred for 3 h at this temperature.

[0460] After dilution with water (120 m L) at 0 °C methyl tert-butyl ether (120 mL) was added, and the reaction mixture was allowed to warm to room temperature. The reactionmixture was filtered (frit pore 3), rinsed with methyl tert-butyl ether (80 mL) and the phases were separated. The organic phase was washed with aqueous 1N hydrochloric acid (80 mL), followed by water (80 mL) and halfconc. sodium bicarbonate (80 mL). After 16 h the phases were separated, the organic phase was washed with halfconc. brine (80 mL), filtered over a plug of sodium sulfate and rinsed with methyl tert-butyl ether. After concentration under reduced pressure the crude product was obtained as light-yellow foam.

[0461] The crude product was dissolved in methyl tert-butyl ether (200 mL) during heating. After cooling to ambient temperature the resulting mixture was filtered over a pore 3 frit funnel filled with a layer of silica (200 g) which was rinsed with methyl tert-butyl ether before filtration. The first filtrate (200 mL) was discarded. Then, the funnel was rinsed with methyl tert-butyl ether (500 mL) and the filtrate (500 mL) was collected and concentrated under reduced pressure. The resulting solid was dissolved in methanol (100 mL) and evaporated under reduced pressure to afford 2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)- / \ / -(3,5-difluoropyridin-2-yl)benzamide (36.3 g, 63.5 mmol, 93 % yield) as beige solid.

[0462] HPLC Method A_BEHC18: Ret. Time: 1.259 min, m / z 565.9

[0463] HPLC Method C2-10a-R,R: Ret. Time: 4.809 min

[0464] 1H NMR (300 MHz, d6-DMSO) 5 (ppm): 10.94 (d, J= 10.0 Hz, 2H), 8.40 (d, J= 2.5 Hz, 1H), 8.10 (ddd, J = 9.7, 8.5, 2.5 Hz, 1H), 7.94 (d, J= 2.5 Hz, 1H), 7.75 (dd, J = 8.8, 2.6 Hz, 1 H), 7.63 (t, J = 1.8 Hz, 1 H), 7.59 - 7.53 (m, 3H), 3.63 (d, J = 8.5 Hz, 1H), 3.51 (d, J= 8.5 Hz, 1H)

[0465] Example 16

[0466] of 2-chloro-5-((1 R,3R)-2,2-dichloro-3-(3,5- !-1-i i-A / -(3,5-di idin-2-

[0467] ci. ci Cl, Cl (COCI)2Cl pyridine Cl N Y DMF cat.H

[0468]

[0469] F AcOEt Cl Cl5a 9a 10a

[0470] Step 1: Formation of the acid chloride

[0471] A three-neck round-bottom flask (500 mL) equipped with a gas washer, a dropping funnel, a magnetic stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with ethyl acetate (330 mL), DMF (35 pL, 0.456 mmol) and (1 R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid (30.5 g, 101 mmol). Oxalyl chloride (9 mL, 103 mmol) was added within 10 min at ambient temperature and the resulting reaction solution was stirred for 100 min at 25 °C.

[0472] Step 2: Amide coupling

[0473] A vacuum jacketed glass reactor (1 L) equipped with a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with ethyl acetate (330 mL), pyridine (9.8 mL, 122 mmol) and 5-amino-2-chloro- / V-(3,5-difluoropyridin-2-yl)benzamide (30 g, 101 mmol). The temperature of the reaction mixture was adjusted to 0 °C. The solution of the acid chloride formed in step 1 was added within 30 min, while keeping the temperature below 5 °C. The reaction mixture was stirred for 2.5 h at this temperature.

[0474] After dilution with water (180 mL) at 0 °C methyl tert-butyl ether (180 mL) was added, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was filtered (frit pore 3) and the phases were separated. The organic phase was washed with aqueous 6N hydrochloric acid (120 mL), followed by water (120 mL) and halfconc. sodium bicarbonate (120 mL). After 16 h the phases were separated, the organic phase was washed with halfconc. brine (120 mL), filtered over a plug of silica (45 g) and rinsed with methyl tert-butyl ether (100 mL). After concentration under reduced pressure the crude product was obtained as lightyellow foam.

[0475] The crude product was suspended with methyl tert-butyl ether (175 mL). The resulting mixture was stirred and heated to 40 °C to afford a clear solution. While heating to 60 °C n-heptane (115 mL) was slowly added to the solution. The reaction solution was lowered to 20 °C within 3 h resulting in a precipitation at 25 °C. Theresulting suspension was stirred at ambient temperature for 3 h before n-heptane (95 mL) was added. After filtration, the precipitation was slurry washed with n-heptane (3x 25 mL) and dried under reduced pressure at 40 °C to afford 2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)- / \ / -(3,5-difluoropyridin-2-yl)benzamide (48 g, 81 mmol, 80 % yield) as beige solid.

[0476] HPLC Method A_BEHC18: Ret. Time: 1.259 min, m / z 565.9

[0477] HPLC Method C2-10a-R,R: Ret. Time: 4.809 min

[0478] 1H NMR (300 MHz, d6-DMSO) 5 (ppm): 10.94 (d, J= 10.0 Hz, 2H), 8.40 (d, J= 2.5 Hz, 1H), 8.10 (ddd, J = 9.7, 8.5, 2.5 Hz, 1H), 7.94 (d, J= 2.5 Hz, 1H), 7.75 (dd, J = 8.8, 2.6 Hz, 1 H), 7.63 (t, J = 1.8 Hz, 1 H), 7.59 - 7.53 (m, 3H), 3.63 (d, J = 8.5 Hz, 1H), 3.51 (d, J= 8.5 Hz, 1H)

[0479] Example 17

[0480] of 2-chloro-5-((1 R3R)-2,2-dichloro-3-(3,5-di

[0481]

[0482]

[0483] I-1 -I i-A / -(3,5-di idin-2-

[0484]

[0485] toluenesulfonic acid

[0486] ci TsOH AcOEt

[0487]

[0488] Step 1: Formation of the acid chloride

[0489] A three-neck round-bottom flask (250 mL) equipped with a gas washer, a dropping funnel, a magnetic stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with ethyl acetate (90 mL), DMF (17 pL, 0.225 mmol) and (1 R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1 -carboxylic acid (14.99 g, 49.9 mmol). Oxalyl chloride (4.5 mL, 51.2 mmol) was added within 10 min atambient temperature and the resulting reaction solution was stirred for 90 min at 25 °C.

[0490] Step 2: Amide coupling

[0491] A three-neck round-bottom flask (500 mL) equipped with a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with ethyl acetate (120 mL), pyridine (4.85 mL, 59.9 mmol) and 5-amino-2-chloro- / V-(3,5-difluoropyridin-2-yl)benzamide (15.05 g, 49.9 mmol). The temperature of the reaction mixture was adjusted to 0 °C. The solution of the acid chloride formed in step 1 was added within 30 min, while keeping the temperature below 5 °C. The reaction mixture was stirred for 2 h at this temperature.

[0492] After dilution with water (100 mL) at 0 °C ethyl acetate (10 mL) was added, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was filtered (frit pore 3), rinsed with water (10 mL) and ethyl acetate (30 mL). After phases separation the organic phase was washed with aqueous 3N hydrochloric acid (50 mL), followed by water (50 mL). After 16 h the phases were separated, the organic phase was filtered over a plug of cellulose (2.5 g) and celite (3 g) and rinsed with ethyl acetate (2x 10 mL).

[0493] Step 3: Formation of the cocrystal

[0494] A solution of 4-methylbenzenesulfonic acid hydrate (10.07 g, 52.4 mmol) dissolved in ethyl acetate (72 mL) was added to the filtrate during stirring. After stirring for 64 h approximately 40 % of the solvent was removed under reduced pressure. The suspension was cooled to 0 °C for 1 h, filtered and slurry washed with ethyl acetate (6 mL). Drying of the filter cake under reduced pressure at 40 °C afforded 2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)- / \ / -(3,5-difluoropyridin-2-yl)benzamide - para-toluenesulfonic acid (1:1) cocrystal (30.7 g, 41.6 mmol, 83 % yield) as white solid.

[0495] 1H NMR (300 MHz, d6-DMSO) 5 (ppm): 10.94 (d, J = 7.4 Hz, 2H), 8.40 (d, J = 2.5 Hz, 1H), 8.16-8.02 (m, 1H), 7.94 (d, J= 2.5 Hz, 1H), 7.75 (dd, J= 8.8, 2.6 Hz, 1H), 7.66 - 7.60 (m, 1 H), 7.59 - 7.52 (m, 3H), 7.51 - 7.43 (m, 2H), 7.11 (d, J = 7.8 Hz, 2H), 3.63 (d, J= 8.5 Hz, 1H), 3.52 (d, J= 8.5 Hz, 1H), 2.29 (s, 3H).Table 1. Characteristic peak position and intensity in XRPD pattern of the obtained cocrystal

[0496] Pos. Height

[0497] No. [°20] [cts]

[0498] 1 5.0529 664.63

[0499] 2 7.8659 42.77

[0500] 3 8.3413 35.26

[0501] 4 10.1369 138.54

[0502] 5 13.9274 32.75

[0503] 6 15.2631 81.19

[0504] 7 15.5457 400.53

[0505] 8 16.3061 48.13

[0506] 9 17.0668 37.32

[0507] 10 18.1036 55.59

[0508] 11 19.4891 51

[0509] 12 20.1429 50.7

[0510] 13 23.7479 46.01

[0511] 14 24.2912 27.84

[0512] 15 25.1785 133.02

[0513] 16 25.8804 46.87

[0514]

[0515] Example 18

[0516] Preparation of 2-chloro-5-((1 R3f?)-2,2-dichloro-3-(3,5-dichlorophenyl) cyclopropane-1 -carboxamido)- / \ / -(3,5-difluoropyridin-2-yl)benzamide - benzenesulfonic acid (1:1) cocrystal:

[0517]

[0518] 10a

[0519] A solution of benzene sulfonic acid (158 mg, 0.978 mmol) dissolved in ethyl acetate (0.4 mL) was added to a solution of 2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)- / \ / -(3,5-difluoropyridin-2-yl)benzamide (500 mg, 0.849 mmol) in ethyl acetate (5 mL) during stirring. After stirring for 3 h the suspension was filtered and slurry washed with ethyl acetate (0.5 mL). Drying of the filtercake under reduced pressure at 40 °C afforded 2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)- / \ / -(3,5-difluoropyridin-2-yl)benzamide - benzenesulfonic acid (1:1) cocrystal (0.61 g, 0.843 mmol, 99 % yield) as white solid.

[0520] 1H NMR (300 MHz, de-DMSO) 5 (ppm): 10.94 (d, J = 7.2 Hz, 2H), 8.40 (d, J = 2.3 Hz, 1H), 8.16-8.02 (m, 1H), 7.94 (d, J= 2.4 Hz, 1H), 7.75 (dd, J = 8.8, 2.5 Hz, 1H), 7.65 - 7.50 (m, 6H), 7.38 - 7.24 (m, 3H), 3.63 (d, J = 8.5 Hz, 1H), 3.52 (d, J = 8.5 Hz, 1H).

[0521] Table 2. Characteristic peak position and intensity in XRPD pattern of the obtained cocrystal

[0522] Pos. Height

[0523] No. [°20] [cts]

[0524] 1 4.7033 1709.42

[0525] 2 8.021 239.46

[0526] 3 8.4538 455.45

[0527] 4 10.0828 49.96

[0528] 5 13.3085 56.59

[0529] 6 13.5879 79.58

[0530] 7 14.1929 161.69

[0531] 8 15.8372 68.41

[0532] 9 16.0807 27.84

[0533] 10 16.6316 42.58

[0534] 11 17.681 519

[0535] 12 18.0513 106.36

[0536]

[0537] 13 18.9064 122.76

[0538] 14 20.317 267.62

[0539] 15 21.1005 56.39

[0540] 16 21.8366 84.94

[0541] 17 22.0681 64.56

[0542] 18 22.9863 69.99

[0543] 19 23.2258 107.59

[0544] 20 25.1014 194.7

[0545] 21 25.5644 64.23

[0546] 22 26.0087 173.5

[0547] 23 27.0224 91.03

[0548] 24 28.5893 121.7

[0549]

[0550] Example 19

[0551] Preparation of 2-chloro-5-((1 F?,3F?)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cvclopropane-1-carboxamido)- / \ / -(2,4-difluorophenyl)benzamide:

[0552] Cl, Cl (COCI)2Cl pyridine Cl DMF cat. AcOEt "Cl

[0553]

[0554] Step 1: Formation of the acid chloride

[0555] A vacuum jacketed glass reactor (2 L) equipped with a gas washer, a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with ethyl acetate (1.1 L), DMF (136 pL, 1.751 mmol) and (1 R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1 -carboxylic acid (100 g, 350 mmol). Oxalyl chloride (31.4 mL, 359 mmol) was added within 15 min at ambient temperature and the resulting reaction solution was stirred for 2.5 h at 25 °C.Step 2: Amide coupling

[0556] A vacuum jacketed glass reactor (3 L) equipped with a dropping funnel, a mechanical stirrer, an internal thermometer and placed under nitrogen atmosphere was charged with ethyl acetate (1.1 L), pyridine (34.1 mL, 420 mmol) and 5-amino-2-chloro- / V-(2,4-difluorophenyl)benzamide (104 g, 354 mmol). The temperature of the reaction mixture was adjusted to 0 °C. The solution of the acid chloride formed in step 1 was added within 20 min, while keeping the temperature below 5 °C. The reaction mixture was stirred for 2.5 h at this temperature.

[0557] After dilution with water (400 mL) at 0 °C methyl tert-butyl ether (400 mL) was added, and the reaction mixture was allowed to warm to room temperature. The phases were separated and the organic phase was washed with aqueous 5N hydrochloric acid (3x 400 mL), followed by water (400 mL) and halfconc. sodium bicarbonate (400 mL). After 16 h the phases were separated, the organic phase was washed with halfconc. brine (400 mL), filtered over a plug of silica (100 g) and rinsed with methyl tert-butyl ether. After concentration under reduced pressure the crude product was obtained as light-yellow foam.

[0558] The crude product was suspended with methyl tert-butyl ether (2.35 L). The resulting mixture was stirred and heated to 40 °C to afford a clear solution. While heating to 70 °C n-heptane (5 L) was slowly added to the solution. After stirring for 30 min at 70 °C the temperature of the reaction solution was lowered to 45 °C within 3 h and seeded with 2-chloro-5-((1 R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)- / V-(3,5-difluoropyridin-2-yl)benzamide (500 mg). The mixture was stirred at this temperature for 2 h. Afterwards, the temperature was lowered to 0 °C within 19 h resulting in a precipitation between 50 °C and 40 °C. The resulting suspension was stirred at this temperature for 3 h before n-heptane (95 mL) was added. After filtration, the precipitation was slurry washed n-heptane (2x 500 mL), dissolved in methanol (1 L) and filtered over a plug of cellulose (10 g). The solvent of the resulting filtrate was evaporated under reduced pressure. After drying under reduced pressure at 40 °C 2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)- / \ / -(3,5-difluoropyridin-2-yl)benzamide (48 g, 81 mmol, 80 % yield) was obtained as beige solid.HPLC Method A_BEHC18: Ret. Time: 1.279 min, m / z 546.9

[0559] HPLC Method C2-10a-R,R: Ret. Time: 3.795 min

[0560] 1H NMR (300 MHz, d6-DMSO) 6 (ppm): 10.95 (s, 1H), 10.40 (s, 1H), 7.92 (d, J = 2.5 Hz, 1 H), 7.82 - 7.65 (m, 3H), 7.56 (d, J = 8.8 Hz, 1 H), 7.53 - 7.44 (m, 2H), 7.43 -7.34 (m, 1 H), 7.21 - 7.09 (m, 1 H), 3.60 (d, J = 8.5 Hz, 1 H), 3.45 (d, J = 8.5 Hz, 1 H)

[0561] Example 20

[0562] Cocrystal screening of compounds 10a and 10b

[0563] About 30 mg starting free base of compound of Formula 10a or 10b and the corresponding counterion or coformer were mixed in solvents or solvent mixtures based on the approximate solubility, with a molar charge ratio of 1:1. The solvents and mixtures used were acetonitrile (ACN), ethyl acetate (EtOAc), toluene, isopropanol (iPrOH), ethanol / water (EtOH / F , 3:1). After magnetically stirring for 4 days at room temperature (20 °C), any precipitation was isolated by centrifugation. If there was no precipitation after 5 days at room temperature, the clear solutions were transferred to stir at 5 °C. The final clear solutions were then subjected to slow evaporation at room temperature. Any isolated solid was air dried at ambient condition before analysis by XRPD and polarized light microscopy (PLM). Turbid samples were put under stirring condition for at least one more week and antisolvents such as water and heptane were added to the clear systems repeated analysis. Table 3 shows the results of the screening for compound 10a.

[0564] Table 3. Cocrystal screening for compound 10a

[0565] Exp. EtOH / H2O Counter ions ACN EtOAc Toluene IPrOH

[0566] ID (3:1)

[0567] Hazy, no

[0568] 0 - Amorphous Gel Gel Amorphous solid*

[0569] TransTransT rans- T rans- Trans-aconitic

[0570] 1 aconitic aconitic aconitic Gel aconitic acid

[0571] acid acid acid acid 2 Maleic acid Gel Gel Gel Gel Gel Fumaric

[0572] 3 Fumaric acid Fumaric acid Fumaric acid Gel Amorphous acid

[0573]

[0574] 4 Gentisic acid Gel Gel Gentisic acid Hazy, no Gelsolid*

[0575] AlphaHazy, no

[0576] 5 ketoglutaric Gel Gel Gel Gel solid*

[0577] acid

[0578] Hazy, no

[0579] 6 Citric acid Gel Gel Gel Amorphous solid*

[0580] L-tartaric Hazy, no

[0581] 7 L-tartaric acid Gel Gel Gel acid solid*

[0582] Hazy, no

[0583] 8 Benzoic acid Gel Gel Gel Gel solid*

[0584] 9 Succinic acid Amorphous Amorphous Succinic acid Gel Gel 10 Glutaric acid Gel Gel Amorphous Gel Amorphous Hazy, no

[0585] 11 Nicotinamide Gel Gel Nicotinamide Amorphous solid*

[0586] Hazy, no

[0587] 12 Malic acid Gel Gel Gel Gel solid*

[0588] Hazy, no

[0589] 13 L-Lactic acid Gel Gel Gel Gel solid*

[0590] L- Hazy, no

[0591] 14 pyroglutamic Gel Gel Gel Gel solid*

[0592] acid

[0593] L-Ascorbic Hazy, no

[0594] 15 Amorphous Gel Gel Gel acid solid*

[0595] BenzeneBesylate Besylate Besylate Hazy, no

[0596] 16 Gel sulfonic acid Type A Type A Type A solid*

[0597] Glutamic Glutamic Glutamic Glutamic Glutamic 17 Glutamic acid

[0598] acid acid acid acid acid Hazy, no

[0599] 18 TRIS Gel Gel Gel Gel solid*

[0600] 19 Meglumine Meglumine Meglumine Gel Meglumine Gel D- 20 D-Tagatose D-Tagatose Gel Gel Gel Tagatose

[0601] 21 Mucic acid Mucic acid Mucic acid Mucic acid Mucic acid Mucic acid 22 Quercetin Quercetin Quercetin Quercetin Quercetin Quercetin 23 Oxalic acid Gel Gel Gel Gel Gel 3-0-Ethyl-L- Hazy, no

[0602] 24 Gel Gel Gel Gel ascrobic acid solid*

[0603] Hazy, no

[0604] 25 Guaifenesin Gel Gel Gel Gel solid*

[0605] p-Toluene- Tosylate

[0606] 26 — — — — sulfonic acid Type A

[0607]

[0608] 27 Salicylic acid — Gel — — — Anti-solvent addition with heptane

[0609] From this screening two cocrystals of compound of Formula 10a were detected: a cocrystal with benzene sulfonic acid (also mentioned here as besylate), and with p-toluene sulfonic acid (also mentioned here as tosylate).Cocrystal screening for the compound of Formula 10b was carried out in the same manner with the same counter ions as in Table 3, however no cocrystals were detected.

Claims

CLAIMS1. Process to obtain a compound of Formula 10:Formula 10 wherein each of Ri and R2 is independently selected from H, CH3, Cl and F, and X is selected from N and CH,comprising a step of reacting a compound of Formula 5A or its acid halide in a first solvent:with a compound of Formula 9:wherein(i) R1 is H, R2 is Cl and X is N, or(ii) R1 is F, R2 is H and X is CH.

2. The process according to claim 1 , wherein the compound with the Formula 5A is first reacted with a chlorinating agent selected from oxalyl chloride, thionyl chloride.

3. The process according to any one of claims 1-2, followed by the reaction withthe compound of Formula 9 in the presence of a base selected from triethylamine (TEA), N,N-diisopropylethylamine (DIPEA) and pyridine.

4. The process according to any one of claims 1-3, wherein the compound of Formula 5A or its halide is obtained from the compound of Formula 4R2Formula 4wherein Ri, R2 are as defined in claim 1 and Rs and Re are both Cl.

5. The process according to any one of claims 1-4, wherein the compound of Formula 9 is obtained from the compound of Formula 82Formula 8wherein X is selected from N or CH.

6. The process according to any one of claims 1-5, further comprising a step of reacting the compound of Formula 10 with an acid selected from p-toluenesulfonic acid and benzenesulfonic acid or its hydrate in a second solvent to form a cocrystal.

7. The process according to claim 6, wherein p-toluenesulfonic acid monohydrate is used.

8. The process according to claim 6, wherein benzenesulfonic acid monohydrate is used.

9. The process according to any one of claims 1-8, wherein the first solvent is ethyl acetate.

10. The process according to any one of claims 6-9, wherein the second solvent is selected from the list consisting of methyl tert-butyl ether (MTBE), ethyl acetate, acetonitrile, tert-amyl methyl ether (TAME) and methanol, preferably ethyl acetate.

11. The process according to any one of claims 1-10, wherein the compound of Formula 5A is obtained from a compound of Formula 1 :R2 Formula 1wherein Ri and R2 have the same meaning as in Formula 5A, by a method comprising the steps of:i) reacting the compound of Formula 1 with an acrolein acetalOR3^XA'OR4wherein each of R3 and R s independently a C1-C3 alkyl group or together form an C1-C4 alkylene group to obtain a compound of Formula 2:ii) subjecting the compound of Formula 2 to dihalocyclopropanation to obtain a compound of Formula 3:R2 Formula 3 wherein each of Rs and Re is Cl,iii) subjecting the compound of Formula 3 to deprotection and oxidation to obtain a compound of Formula 4:R2 Formula 4iii) subjecting the racemic compound of Formula 4 to chiral separation to obtain the (R,R) enantiomer of Formula 5A.

12. A cocrystal of a compound of Formula 10a:Formula 10awith an acid selected from p-toluenesulfonic acid and benzenesulfonic acid.

13. The cocrystal according to claim 12, wherein the molar ratio of the compound of Formula 10a to the acid is 1 : 1.

14. The cocrystal according to claim 12 or 13, wherein the acid is p-toluenesulfonic acid, the cocrystal has an X-ray powder diffraction (XRPD) pattern comprising peaks approximately at the following positions: 5.1, 10.1, 15.5 and 25.2degrees (20) when measured with Cu Ka radiation and a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 195.6°C measured at a heating rate of 107min.

15. The cocrystal according to claim 12 or 13, wherein the acid is benzenesulfonic acid, the cocrystal has an X-ray powder diffraction (XRPD) pattern comprising peaks approximately at the following positions: 4.7, 8.0, 8.5, 14.2, 18.1, 18.9, 20.3, 23.2, 25.1, 26.0 and 28.6 degrees (20) when measured with Cu Ka radiation and a differential scanning calorimetry (DSC) thermogram comprising an endothermic peak at about 185.5°C measured at a heating rate of 107m in16. Pharmaceutical composition comprising the cocrystal according to any one of claims 12-15 and a pharmaceutical excipient.

17. The pharmaceutical composition according to claim 16 for use to control parasites in animals.

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