Synthesis of afoxolaner, fluralaner and lotilaner

Abstract

The invention relates to a process for the synthesis of Fluralaner, Afoxolaner and / or Lotilaner in an efficient and cost-effective way.

Description

Synthesis of Afoxolaner, Fluralaner and Lotilaner

[0001] Priority is claimed of European patent application no. 24 192 627.8 that was filed on August 2, 2024 and of Slovenian patent application no. P-2024 00130 that was filed on October 8, 2024.

[0002] The invention relates to an improved process for the synthesis of Afoxolaner, Fluralaner and Lotilaner in an efficient and cost-effective way.

[0003] Afoxolaner has the chemical name 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluorome- thyl)-4H-l,2-oxazol-3-yl]-N-[2-oxo-2-(2, 2, 2-trifluoroethylamino)ethyl]naphthalene-l -carboxamide or 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2- ((2,2,2-trifluoroethyl)amino)ethyl)-l -naphthamide and the following structure:

[0004] Fluralaner has the chemical name 4-[(5RS)-5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoro- methyl)-l,2-oxazol-3-yl]-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-o-toluamide or 4-(5-(3,5-di- chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoro- ethyl)amino)ethyl)benzamide and the following structure:

[0005] Lotilaner has the chemical name (S)-5-[5-(3,4,5-Trichlorophenyl)-5-trifluoromethyl-4,5-dihy- droisoxazol-3-yl] -3 -methylthiophene-2 -carboxylic acid [(2,2,2-trifluoroethyl carbamoyl) methyl] amide and the following structure:

[0006] Afoxolaner, Fluralaner and Lotilaner act as "ectoparasiticide" . They kill fleas, ticks and mites that have ingested the dog’s or cat’s blood by acting on their nervous system. They block the normal movement of charged chloride particles (ions) in and out of nerve cells, especially those associated with gamma-aminobutyric acid (GABA) and glutamate, two substances that convey messages between nerves (neurotransmitters). This results in uncontrolled activity of the nervous system and the paralysis and death of the parasites.

[0007] As the isoxazoline compounds Afoxolaner, Fluralaner and Lotilaner have been originally investigated for their use in the agricultural area, it is necessary to identify specific formulations that allow their veterinary use, i.e. safe administration to control parasites in animal effectively.

[0008] A convenient way of administering an ectoparasiticide to an animal is the topical localized administration, e.g. as spot-on formulation or pour-on formulation, and in the form of chewable tablets.

[0009] Various approaches for preparing Afoxolaner, Fluralaner and Lotilaner from various starting materials and involving various intermediates are known from the prior art.

[0010] WO 2012 / 047543 discloses a process for the synthesis of Afoxolaner intermediate 4-acetyl-N- (2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)-l-naphthamide from 4-acetyl-l -naphthoyl acid and 2- amino-N-(2,2,2-trifluoroethyl)acetamide. The coupling reagent is N,N'-carbonyldiimidazole. Compounds and the coupling reagent are contacted in the presence of a base and a polar aprotic water miscible solvent (acetonitrile, tetrahydrofuran or dioxane). 4-Acetyl-l -naphthoyl acid is first contacted with the coupling reagent.

[0011] WO 2022 / 020585 discloses in synthetic examples 3c, 4c and 6a a process for the synthesis of Lotilaner from 3-methyl-5-r(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yllthio- phene-2 -carboxylic acid and 2-amino-trifluoroethyl-acetamide. In Example 3c, a solution of 3-methyl- 5-[(5S)-5-(3, 4, 5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2 -carboxylic acid (101.5 g, 221.3 mmol) in dichloromethane (DCM) (1000 mL) was heated to 40°C. Thionyl chloride (50 g, 1.9 eq) was added dropwise and the reaction mixture was stirred at reflux for 2 to 4 hours. The reaction mixture was concentrated to 100 to 200 mL and DCM (500 mL) was added. Two more cycles of concentration followed by DCM addition were performed. In a separate vessel, a suspension of 2-amino- trifluoroetliyl-acetamide HC1 (50.26 g, 1.2 eq) in DCM (500 mL) was cooled to 0°C to 5°C, triethylamine (70.15 g, 3.1 eq) was added, and the reaction mixture was stirred at 0°C to 5°C for 30 minutes.The acid chloride solution in DCM was then transferred to the reaction mixture containing 2-amino- trifluoroethyl-acetamide maintaining the internal temperature below 5°C. The reaction mixture was stirred at 0°C to 5°C for 2 to 4 hours. 1 N HC1 (500 mb) was added dropwise and the reaction mixture was stirred at 15 to 25°C for 30 minutes. The stirring was stopped and after 30 minutes the phases were separated. The organic layer was extracted with saturated sodium bicarbonate solution (IN, 1000 mL), the layers separated and the organic layer extracted with water (1000 mL). The layers were separated and the organic layer was concentrated under vacuum to 200 to 300 mL. Twice ethyl acetate (500 mL) was added and the batch was concentrated to 200 mL. The reaction mixture was heated to 55°C and n- heptane (700 mL) was added dropwise at 55°C. After 1 hour, n-Heptane (1000 mL) was added dropwise and the mixture was stirred at 55°C for three hours. The batch was gradually cooled to 35°C over three hours, then to 20°C over three hours. The batch was filtered and the cake was washed with n-heptane (200 mL). 113 g of the title compound was obtained after drying at 50°C under vacuum for 12 hours.

[0012] WO 2005 / 085216 discloses in synthetic example 214 a process for the synthesis of Fluralaner according to the following scheme:

[0013] In a solution of 1.00 g of N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol- 3-yl]-2-methylbenzoyl]glycine (2) in 30 ml of dichloromethane, 0.65 g of l-[3-(diethylamino)propyl]- 3 -ethylcarbodiimide hydrochloride (EDCxHCl) was added, and stirred at room temperature for 15 minutes, then 0.40 g of 2,2,2-trifluoroethylamine and 0.40 g of 4-(N,N-dimethylamino)pyridine (DMAP) were added and stirred at the same temperature for further 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was purified with silica gel column chromatography that was eluted with ethyl acetate-hexane (1:3), and then crystallized from hexane to obtain 0.48 g of the aimed product as white crystal. Thus, the yields reported are low, only about 41 %.

[0014] WO 2010 / 005048 discloses a first process for the synthesis of Fluralaner according to the following scheme:

[0015] At the end of the reaction, there is no isolation of the product, only the HPLC method assignation of the reaction mixture is used.

[0016] Further, WO 2010 / 005048 discloses a process for the synthesis of Fluralaner which is one step synthesis from bromo intermediate to Fluralaner according to the following scheme:

[0017] Furthermore, WO 2010 / 005048 discloses a process for the synthesis of Fluralaner according to the following scheme:

[0018] In WO 2021 / 122356 it is assumed that the order of addition of specific reagents to the reaction mixture surprisingly reduces the formation of side products, especially of the dimeric impurity, and thereby essentially contributes to the preparation of Fluralaner in high yields and with high purity. The order of addition of reagents therefore provides the advantage that the formation of side product can be avoided or minimized and that purification procedures, especially complex, material-intensive, laborious and time-consuming purification procedures, such as column chromatography, may be avoided.

[0001] The known processes for the synthesis of Afoxolaner, Fluralaner and Lotilaner are not satisfactory in every respect.

[0020] It is an object of the invention to provide processes for the synthesis of Afoxolaner, Fluralaner and Lotilaner that have advantages compared to the prior art. The processes should provide high yields and better quality, yield and / or purity of the product in a cost-effective manner.

[0021] This object has been achieved by the subject-matter of the patent claims.

[0022] The process of the present invention considerably improves the known approaches for preparing Afoxolaner, Fluralaner and Lotilaner . It has been surprisingly found that a slight modification of the process known from the prior art provides for improved yield and quality of Afoxolaner, Fluralaner and Lotilaner.

[0023] Without wishing to be bound to any theory, it has been found that not only the order of addition of specific reagents effects the yield, but also the time frame when they are added to the mixture. It is assumed that delayed addition of specific reagents to the reaction mixture significantly improves yield and provides the desired product with high purity.

[0024] Additionally, it has been found that the content of hydrazine as an impurity in 2-amino-N-(2,2,2- trifluoroethyljacetamide hydrochloride effects the quality and purity of the desired product.

[0025] A first aspect of the invention relates to a process for preparing Fluralaner, an Fluralaner intermediate, Afoxolaner, an Afoxolaner intermediate, Lotilaner, or a Lotilaner intermediate, said process comprising the steps of(a) providing a composition comprising- a solvent;- a compound according to general formula (I):Q-COOH(I), wherein Q represents a residue selected from residues (Q- 1) through (Q-9):(Q-9)- a catalyst; preferably either (i) a base or (ii) a N-hydroxyl compound; and- either (i) 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.); or (ii) a carboxylic acid activating agent, preferable a carbodiimide;(b) adding to the composition provided in step (a) either (i) a carboxylic acid activating agent, preferably a carbodiimide, or (ii) 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.);(c) allowing the composition obtained in step (b) to react thereby synthesizing Afoxolaner, Fluralaner, Lotilaner or an intermediate thereof according to general formula (II)wherein Q represents a residue selected from residues (Q-l) through (Q-9) as above; and(d) optionally, recovering the Afoxolaner, Fluralaner, Lotilaner or intermediate thereof according to general formula (II) from the composition obtained in step (c).

[0026] Steps (a), (b) and (c) are mandatory, whereas step (d) is optional.

[0027] The improved process according to the invention can be used for the synthesis of Fluralaner, an Fluralaner intermediate, Afoxolaner, an Afoxolaner intermediate, Lotilaner, or a Lotilaner intermediate.

[0028] The process according to the invention encompasses variants (i) and (ii).

[0029] According to variant (i), the composition provided in step (a) comprises 2-amino-N-(2,2,2-tri- fluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.), and step (b) involves adding to the composition provided in step (a) a carboxylic acid activating agent, preferably a carbodiimide.

[0030] According to variant (ii), the composition provided in step (a) comprises a carboxylic acid activating agent, preferable a carbodiimide, and step (b) involves adding to the composition provided in step (a) 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.)

[0031] Both variants aim at coupling the carboxylic acid functional group of the compound according to general formula (I) Q-COOH to the amine functional group of 2-amino-N-(2,2,2-trifluoroethyl)acet- amide, which has the following structure:

[0032] Thus, the desired coupling product obtained in step (c) is an amide according to general formula (II)(II), wherein Q represents a residue selected from residues (Q-l) through (Q-9) as defined above.

[0033] The skilled person recognizes that when Q represents residue (Q-3), the amide according to general formula (II) is Afoxolaner, whereas when Q represents residue (Q-l) or residue (Q-2), the amide according to general formula (II) is an Afoxolaner intermediate.

[0034] The skilled person likewise recognizes that when Q represents residue (Q-6), the amide according to general formula (II) is Fluralaner, whereas when Q represents residue (Q-4) or residue (Q-5), the amide according to general formula (II) is a Fluralaner intermediate.

[0035] The skilled person also recognizes that when Q represents residue (Q-9), the amide according to general formula (II) is Lotilaner, whereas when Q represents residue (Q-7) or residue (Q-8), the amide according to general formula (II) is a Lotilaner intermediate.

[0036] Accordingly, final products (Afoxolaner, Fluralaner or Lotilaner) or intermediates thereof according to general formula (II) can be obtained in the reaction of step (c).

[0037] The 2-amino-N-(2,2,2-trifluoroethyl)acetamide may be employed in form of the free base or as a salt thereof. Suitable salts of 2-amino-N-(2,2,2-trifluoroethyl)acetamide include but are not limited to the hydrochloride and hydrobromide.

[0038] In contrast to synthetic example 214 of WO 2005 / 085216 and WO 2021 / 122356, the compound according to general formula (I) reacts with the carboxylic acid activating agent in presence of thecatalyst and the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.).

[0039] The composition provided in step (a) is preferably stirred for at least 5 minutes, preferably for at least 10 minutes, more preferably for at least 15 minutes before addition of- either in (variant (i)) a carboxylic acid activating agent, preferably l-ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl),- or in (variant (ii)) 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) in step (b).

[0040] When the carboxylic acid activating agent is the last reagent that is added to the composition (variant (i)), the reagents comprised in the composition provided in step (a) are preferably- the compound according to general formula (I),- the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.),- the base as a catalyst, and- the solvent.

[0041] When the carboxylic acid activating agent is not the last reagent that is added to the composition (variant (ii)), the missing reagents are preferably added to the composition provided in step (a) after the composition is stirred for at least 15 minutes, preferably for at least 30 minutes, more preferably for at least 60 minutes. In this regard, the reagents comprised in the composition provided in step (a) are preferably- the compound of formula (I),- the carboxylic acid activating agent,- the N-hydroxyl compound as a catalyst, and- the solvent.

[0042] Preferably, all the above reagents are added to the solvent within a relatively short period of time, preferably in less than 15 minutes, more preferably at most 10 minutes, still more preferably at most 5 minutes.

[0043] Preferably, the composition provided in step (a) is stirred for- at least 5 minutes, preferably for at least 10 minutes, more preferably for at least 15 minutes before addition of a carboxylic acid activating agent in variant (i), preferably a carbodiimide, or- at least 15 minutes, preferably for at least 30 minutes, more preferably for at least 60 minutes before addition of 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) in variant (ii) in step (b).

[0044] According to variant (i) of the process according to the invention, the composition provided in step (a) preferably comprises- the solvent,- the compound according to general formula (I),- the base, and- the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.); but not yet the carboxylic acid activating agent, preferably a carbodiimide. According to the invention, the carboxylic acid activating agent, preferably a carbodiimide, is subsequently added in step (b) to the composition provided in step (a). Results are presented below; see Examples, Table 1.

[0045] According to the invention, in variant (i) preferably the entire amount of 2-amino-N-(2,2,2- trifhioroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) that is employed in the process is contained in the composition provided in step (a), whereas preferably the entire amount of the carboxylic acid activating agent that is employed in the process is added in step (b).

[0046] According to the invention, in variant (i) in step (a)- the solvent,- the compound according to general formula (I),- the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc ), and- the catalyst are admixed with one another before the carboxylic acid activating agent is added thereto in subsequent step (b).

[0047] According to the invention, in variant (i) the order of admixing the solvent, the compound according to general formula (I), 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc ), and the catalyst with one another in step (a) is not particularly limited.

[0048] Preferred orders of admixing(A) the solvent,(B) the compound according to general formula (I),(C) the 2,2,2- trifluoroethylamine (or a salt thereof, for example hydrochloride, etc.), and(D) the catalyst with one another are selected from the group consisting of (A)(B)(C)(D), (A)(B)(D)(C), (A)(C)(B)(D),(A)(C)(D)(B), (A)(D)(B)(C), (A)(D)(C)(B), (B)(A)(C)(D), (B)(A)(D)(C), (B)(C)(A)(D), (B)(C)(D)(A),(B)(D)(A)(C), (B)(D)(C)(A), (C)(A)(B)(D), (C)(A)(D)(B), (C)(B)(A)(D), (C)(B)(D)(A), (C)(D)(A)(B),(C)(D)(B)(A), (D)(A)(B)(C), (D)(A)(C)(B), (D)(B)(A)(C), (D)(B)(C)(A), (D)(C)(A)(B), and(D)(C)(B)(A).

[0049] It is also contemplated that two or more of (A) the solvent, (B) the compound according to general formula (I), (C) the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.), and (D) the catalyst are admixed with one another simultaneously, and / or that anyof (A) the solvent, (B) the compound (C) the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.), and (D) the catalyst is divided into two or more portions which are admixed with the other reagents or portions thereof in any order.

[0050] When the carboxylic acid activating agent is the last reagent that is added to the composition (variant (i)), it is preferably added to the composition provided in step (a) after the composition has been stirred for at least 5 minutes, preferably for at least 10 minutes, more preferably for at least 15 minutes.

[0051] According to variant (ii) of the process according to the invention, the composition provided in step (a) comprises- the solvent,- the compound according to general formula (I),- the catalyst, preferably a N-hydroxyl compound, and- the carboxylic acid activating agent, preferably a carbodiimide; but not yet the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.). According to this variant (ii) of the process according to the invention, the 2-amino-N-(2,2,2- trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) is subsequently added in step (b) to the composition provided in step (a).

[0052] According to variant (ii) of the process according to the invention, in step (a)- the solvent,- the compound according to general formula (I),- the carboxylic acid activating agent, and- the catalyst are admixed with one another before the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) is added thereto in subsequent step (b).

[0053] According to variant (ii) of the process according to the invention, preferably the entire amount of the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) that is employed in the process is added in step (b), whereas preferably the entire amount of the carboxylic acid activating agent that is employed in the process is contained in the composition provided in step (a).

[0054] According to variant (ii) of the process according to the invention, the order of admixing the solvent, the compound according to general formula (I), the carboxylic acid activating agent, and the catalyst with one another in step (a) is not particularly limited. However, preferably the solvent, the compound according to general formula (I) and the carboxylic acid activating agent are not admixed with one another in the absence of the catalyst.

[0055] Preferred orders of admixing(A) the solvent,(B) the compound according to general formula (I),(C) the carboxylic acid activating agent, and(D) the catalyst with one another are selected from the group consisting of (A)(B)(C)(D), (A)(B)(D)(C), (A)(C)(B)(D),(A)(C)(D)(B), (A)(D)(B)(C), (A)(D)(C)(B), (B)(A)(C)(D), (B)(A)(D)(C), (B)(C)(A)(D), (B)(C)(D)(A),(B)(D)(A)(C), (B)(D)(C)(A), (C)(A)(B)(D), (C)(A)(D)(B), (C)(B)(A)(D), (C)(B)(D)(A), (C)(D)(A)(B),(C)(D)(B)(A), (D)(A)(B)(C), (D)(A)(C)(B), (D)(B)(A)(C), (D)(B)(C)(A), (D)(C)(A)(B), and(D)(C)(B)(A); more preferably from (A)(B)(D)(C), (A)(C)(D)(B), (A)(D)(B)(C), (A)(D)(C)(B),(B)(A)(D)(C), (B)(C)(D)(A), (B)(D)(A)(C), (B)(D)(C)(A), (C)(A)(D)(B), (C)(B)(D)(A), (C)(D)(A)(B),(C)(D)(B)(A), (D)(A)(B)(C), (D)(A)(C)(B), (D)(B)(A)(C), (D)(B)(C)(A), (D)(C)(A)(B), and(D)(C)(B)(A).

[0056] It is also contemplated that two or more of (A) the solvent, (B) the compound according to general formula (I), (C) the carboxylic acid activating agent, and (D) the catalyst are admixed with one another simultaneously, and / or that any of (A) the solvent, (B) the compound according to general formula (I), (C) the carboxylic acid activating agent, and (D) the catalyst is divided into two or more portions which are admixed with the other reagents or portions thereof in any order.

[0057] When the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) (variant ii) is the last reagent that is added to the composition, it is preferably added to the composition provided in step (a) after the composition is stirred for at least 15 minutes, preferably for at least 30 minutes, more preferably for at least 60 minutes.

[0058] The solvent used in the reaction of the present invention can be an aprotic solvent, especially a polar aprotic solvent. The solvent can be in particular selected from the group consisting of acetonitrile (ACN), acetone, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), ethyl acetate (EA), dichloromethane (DCM), and mixtures thereof. In particular, the solvent can essentially consist of or comprise dichloromethane. The solvent can for example comprise at least 50 wt.-%, preferably at least 95 wt.-% of dichloromethane, based on the total weight of the solvent.

[0059] The concentration of the compound according to general formula (I) in the composition is not particularly limited and can be for example within the range of from 1 to 1000 mmol / 1, more preferably from 2 to 500 mmol / 1, still more preferably from 5 to 200 mmol / 1, and most preferably about 100 mmol / 1.

[0060] The concentration of the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) in the composition is not particularly limited and can be for example within the range of from 0,5 to 1000 mmol / 1, more preferably from 1 to 500 mmol / 1, still more preferably from 2,5 to 200 mmol / 1, and most preferably about 50 to 100 mmol / 1.

[0061] The 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) is commercially available. Preferably the content of hydrazine within the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) is up to 0.2 wt.-%, more preferably up to 0.1 wt.-%, most preferably up to 0.05 wt.-%, relative to the total weight of 2-amino-N- (2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) and hydrazine.

[0062] It has been found that hydrazine contained as impurity in 2-amino-N-(2,2,2-trifluoroethyl)acet- amide (or a salt thereof, for example hydrochloride, etc.) has an impact on formation of side products (impurities) during the reaction in step (c). When the reaction was finished, product was extracted from organic phase. It has been found that the separation of the phases was significantly more difficult or even impossible to achieve when the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) contained hydrazine impurities. The content of side products (impurities) in the product was particularly high when the 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) had a high content of hydrazine impurity. Results are presented below, see Examples, Table 2 and 3. The impurities were isolated and identified.

[0063] Highly purified 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) was obtained from supplier, whereas hydrazine was additionally removed, as confirmed by analytical measurements. Also, 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (also referred to as "compound 3") was split into 2-amino-N-(2,2,2-trifluoroethyl)acetamide (also referred to as "compound 4") and hydrazine was removed during isolation.

[0064] Experimental results show different amounts of side products (impurities) as a function of different content of hydrazine in 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) as employed. Different grades of 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) were used:- standard (from supplier; contains 0.2-0.5 % hydrazine),- 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) with added hydrazine,- 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) with hydrazine content below detection limit, and- 2-amino-N-(2,2,2-trifluoroethyl)acetamide (compound 4) obtained by split reaction from 2-amino- N-(2,2,2-trifluoroethyl)acetamide hydrochloride (compound 3).

[0065] Suitable carboxylic acid activating agents are known to the skilled person. According to the invention, the carboxylic acid activating agents transiently react with the carboxyl group of the compound according to general formula (I). This reaction typically involves transient formation of reactive intermediates that subsequently react with the amino group of 2-amino-N-(2,2,2-trifluoroethyl)acetam- ide (or a salt thereof, for example hydrochloride, etc.), or that subsequently react with other reactants to form other reactive intermediates that in turn subsequently react with the amino group of 2-amino-N- (2,2,2-trifhioroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.). Typical reactiveintermediates include but are not limited to carboxylic halides (chlorides, fluorides), carboxylicazides, symmetrical or mixed anhydrides or reaction products with carbodiimides.

[0066] Preferably, the carboxylic acid activating agent is selected from:- carbodiimides; preferably selected from N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HC1, also referred to as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCxHCl, EDACxHCl, WSCxHCl), dicyclohexylcarbodiimide (DCC), N-cyclohexyl-N’-( -[N-methylmorpho- lino]ethyl)carbodiimide (CMC) and diisopropylcarbodiimide (DIC);- phosphonium-type reagents; preferably selected from benzotriazol-l-yloxy-tris(dimethylamino)- phosphonium hexafluorophosphate (BOP), benzotriazol-l-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP® ), bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP® ), 7- aza-benzotriazol-l-yloxy-tnpyrrolidmophosphonium hexafluorophosphate (PyAOP), ethyl cyano- (hydroxyimino)acetato-02)-tn-(l-pyrrolidinyl)-phosphonium hexafluorophosphate (PyOxim), and 3- (diethoxy-phosphoryloxy)-l,2,3-benzo[d] triazin-4(3H)-one (DEPBT);- aminium / uronium-imonium-type reagents; preferably selected from 2-(lH-benzotriazol-l-yl)- N,N,N’,N’-tetramethylaminium tetrafluoroborate / hexafluorophosphate (TBTU / HBTU), 2-(6- chloro-lH-benzotriazol-l-yl)-N,N,N’,N’-tetramethylaminium hexafluorophosphate (HCTU), N- [(5- chloro- lH-benzotnazol-l-yl)-dimethylamino-morpholino] -uromum hexafluorophosphate N-ox- ide (HDMC), 2-(7-aza-lH-benzotriazol-l-yl)-N,N,N’,N’-tetramethylaminium tetrafluoroborate / - hexafluorophosphate (TATU / HATU), l-[l-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethyla- mino-morpholino] -uronium hexafluorophosphate (COMU), 2-(l-oxy-pyridin-2-yl)-l,l,3,3-tetrame- thylisothiouronium tetrafluoroborate (TOTT), and tetramethylfluoroformamidinium hexafluoro phosphate (TFFH); and- further coupling reagents; preferably selected from N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquino- line (EEDQ), 2-propanephosphonic acid anhydride (T3P), 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium salts) (DMTMM), bis-trichloromethylcarbonate, also referred to as triphosgene (BTC), and I,G-carbonyldiimidazole (CDI).

[0067] The above carboxylic acid activating agents are all commercially available.

[0068] The concentration of the carboxylic acid activating agent in the composition is not particularly limited and can be for example within the range of from 10 to 640 mmol / 1, more preferably from 20 to 320 mmol / 1, still more preferably from 40 to 160 mmol / 1, and most preferably about 85 mmol / 1.

[0069] Suitable catalysts for the amide formation between the compound according to general formula (I) and 2-amino-N-(2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) by means of a carboxylic acid activating agent are known to the skilled person. The catalyst generally lowers the activation enthalpy of the reaction but is not consumed in the course of the reaction.

[0070] In a preferred embodiment, the catalyst is a base, preferably 4-dimethylaminopyridine (DMAP) In another preferred embodiment, the catalyst is a N-hydroxyl compound, preferably N-hydroxy succinimide (NHS). It is also possible that the catalyst comprises both, a base and a N-hydroxyl compound.

[0071] When the catalyst is a base, the base is preferably an organic base, more preferably selected from aliphatic amines, alicyclic amines and aromatic amines. The amines may be primary amines, secondary amines or tertiary amines. Preferably, the base is selected from the group consisting of 4-dimethylaminopyridine (DIMAP), triethanolamine, N,N-diisopropyl ethylamine (DIPEA), N-methyl-mor- pholine (NMM), 2-dimethylaminopyridine, 2,4,6-trimethylpyridine, piperidine and 4-(2-piperidi- noethyl)pyridine. Preferably, the base is 4-dimethylaminopyridine (DMAP).

[0072] The above bases are all commercially available.

[0073] The concentration of the base in the composition is not particularly limited and can be for example within the range of from 10 to 1000 mmol / 1, more preferably from 25 to 400 mmol / 1 , still more preferably from 50 to 200 mmol / 1 , and most preferably about 110 mmol / L

[0074] When the catalyst is a N-hydroxyl compound, the N-hydroxyl compound is preferably selected from the group consisting of N-hydroxysuccinimide, N-hydroxy-benzotriazoles, N-hydroxy-benzotria- zines, and 2 -hydroxy imines (oximes). Preferably, the N-hydroxyl compound is selected from N-hydroxysuccinimide, also referred to as l-hydroxypyrrohdine-2, 5-dione (NHS, HOSu); 1-hydroxyben- zotriazole (HOBt), optionally immobilized on a solid carrier such as HOBt-6-sulfonamidomethyl resin HC1; 1 -hydroxy-7 -aza- IH-benzotriazole (HOAt); hydroxy-3, 4-dihydro-4-oxo-l, 2, 3 -benzotriazine (HOOBt, HODhbt); and ethyl 2-cyana-2-(hydroximino)acetate (Oxyma Pure®). Preferably, the N-hydroxyl compound is N-hydroxysuccinimide.

[0075] The above N-hydroxyl compounds are all commercially available.

[0076] The concentration of the N-hydroxyl compound, preferably N-hydroxysuccinimide, in the com position is not particularly limited and can be for example within the range of from 10 to 640 mmol / 1, more preferably from 20 to 320 mmol / 1, still more preferably from 40 to 160 mmol / 1, and most preferably about 80 mmol / 1.

[0077] The relative molar ratio of the compound according to general formula (I) and the 2-amino-N- (2,2,2-trifluoroethyl)acetamide (or a salt thereof, for example hydrochloride, etc.) is not particularly limited. Preferably, the relative molar ratio is within the range of from 1 : 1 to 1 : 3, more preferably from 1 : 1.05 to 1 : 2.5, still more preferably from 1 : 1.2 to 1 : 2, and most preferably about 1 : 1.3

[0078] The relative molar ratio of the compound according to general formula (I) and the carboxylic acid activating agent is not particularly limited. Preferably, the relative molar ratio is within the range of from 1 : 0.5 to 1 : 5, more preferably from 1 : 0.8 to 1 : 1.5, still more preferably from 1 : 1.1 to 1 : 1.4, and most preferably about 1 : 1.2.

[0079] The temperature of the reaction in step (c) of the process according to the invention is not particularly limited. Preferably, step (c) is carried out at a temperature of above 5 °C, more preferably in the range of from 10 to 40 °C, still more preferably from 15 to 40 °C, yet more preferably from 19 to 40 °C.

[0080] Preferably, the process according to the invention provides an overall yield of Afoxolaner, Flu- ralaner, Lotilaner, or intermediate thereof according to general formula (II) of at least 45 %, more preferably at least 50 %, still more preferably at least 55 %, yet more preferably at least 60 %, even more preferably at least 65 %, more preferably at least 70 %, more preferably at least 75 %, still more preferably at least 80 %, yet more preferably at least 85 %, even more preferably at least 90 %, and most preferably about 94.3 % for Fluralaner and about 97.1 % for Afoxolaner intermediate.

[0081] In preferred embodiments of the process according to the invention,- the catalyst is 4-(N,N-dimethylamino)pyridine (DMAP) or N-hydroxy succinimide (NHS);- the solvent is dichloromethane; and- the carboxylic acid activating agent is 1- [3 -(diethylamino)propyl] -3 -ethylcarbodiimide hydrochloride (EDCxHCl).

[0082] Furthermore, carrying out the reaction of the present invention can advantageously contribute to minimizing impurities, such as in particular impurities A, B and C:

[0083] Impurity A is 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2- methylbenzoic N'-(3-(dimethylamino)propyl)-N-ethylcarbamimidic anhydride and has the following structure:

[0084] The content of impurity A in the final product is preferably below 0.2 area % determined by HPLC, preferably below 0.15 area % determined by HPLC.

[0085] Impurity B is 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3- (dimethylamino)propyl)-N-(ethylcarbamoyl)-2 -methylbenzamide and has the following structure:

[0086] The content of impurity B in the final product is preferably below 0.2 area % determined by HPLC, preferably below 0.15 area % determined by HPLC.

[0087] Impurity C is 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((3- (dimethylamino)propyl)carbamoyl)-N-ethyl-2-methylbenzamide and has the following structure:

[0088] The content of impurity C in the final product is preferably below 0.2 area % determined by HPLC, preferably below 0.15 area % determined by HPLC.

[0089] Furthermore, carrying out the reaction of the present invention can advantageously contribute to minimizing impurities when the content of hydrazine in 2,2,2-trifluoroethylamine (or a salt thereof, for example hydrochloride, etc.) is reduced. In the synthesis of Fluralaner, the content of impurity D and impurity E can be reduced. In the synthesis of Afoxolaner, the content of impurity F can be reduced:

[0090] Impurity D is 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2- methylbenzohydrazide an has the following structure:

[0091] Impurity E is 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N,-(4- (5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoyl)-2-methylben- zohydrazide and has the following structure:

[0092] Impurity F is 4-acetyl-N'-(4-acetyl-l-naphthoyl)-l-naphthohydrazide and has the following structure:

[0093] After step (c), the compound according to general formula (II), preferably Fluralaner or Aflox- olaner intermediate, of high purity can be recovered in optional step (d), preferably by isolating the compound according to general formula (II), preferably Fluralaner and Afoxolaner intermediate, (directly) from the composition. Preferably, during the isolation, firstly excess of carboxylic acid activating agents is decomposed, which is preferably done via quenching the reaction with acidic water solution (preferably 5 % HC1 aq.). Secondly, extraction to organic phase is achieved with agitating the two-phase mixture, subsequent separation of phases, and washing the water phase again with organic solvent in which the reaction was performed. The joined organic phases are preferably evaporated under reduced vacuum and preferably a white (a white to yellowish) product is gained.

[0094] The following examples further illustrate the invention but are not to be constmed as limiting its scope:

[0095] Purity assays:

[0096] The chemical purity of Fluralaner is assessed by high pressure liquid chromatography (HPLC) with stationary phase C18 and column dimensions 150 x 4.6 mm i.d., 3 pm particles; mobile phase: A: 0.01M phosphate buffer solution pH 2; B: acetonitrile; Gradient: 0 -15% B, 5’ - 22’=65% B, 25'- 57’=85% B, 59' - 65'=15% B.

[0097] The chemical purity of Afoxolaner is assessed by high pressure liquid chromatography (HPLC) with stationary phase C18 and column dimensions 150 x 4.6 mm i d., 3 pm particles; mobile phase: A: 0.1% H3PO4; B: acetonitrile; Gradient: 0'=15% B, 16’=45% B, 25'=55% B, 32' - 44'=90% B, 45’- 53’=15% B.

[0098] Inventive Example 1 - Synthesis of Fluralaner according to the invention (the composition provided in step (a) is preferably stirred for at least 5 minutes before addition of 1-ethy 1-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl)):

[0099] At room temperature (20 - 25 °C) 10.00 g 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2 -methylbenzoic acid (also referred to as "compound / ") were charged into 150 mL of dichloromethane, 5.99 g 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and 5.84 g DMAP were added into a flask and agitated for 5 minutes. Then 5.50 g l-ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl) was added to obtain light yellow solution and stirred for 5 hours at room temperature.

[0100] Then 140 mL of 5 % aqueous solution of hydrochloric acid were added, agitated (about 400 rpm) for about 5 minutes and the two phases were separated. Water phase and organic phase was separated. White and thick organic phase was stored over night at room temperature. To the organic phase 140 ml of 5 % aqueous solution of hydrochloric acid was added and agitated at 800 rpm and heated to reach 40°C. Mixture was distilled, white suspension was cooled to room temperature and stirred for about 60 min at room temperature. The product was sucked off well and washed with 50 ml H2O. The product was dried and after drying 11.83 g of white product was obtained.

[0101] Total yield for both steps was 88.6 %, HPLC purity of Fluralaner peak at the end of reaction is 97.5 area % HPLC purity of isolated and dried crude Fluralaner is 94.3 area %.

[0102] Comparative Example 2 - Synthesis of Fluralaner as from state of the art (l-Ethyl-3-(3 -dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl) is added together with the compound according to general formula (I) and solvent. 2-Amino-N-(2,2.2-trifluoroethyl)acetamide and DMAP (4-dime- thylaminopyridine) are added subsequently):

[0103] At room temperature (20 - 25°C) 2.00 g 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-di- hydroisoxazol-3-yl)-2 -methylbenzoic acid (compound l) and 1.28 g l-ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl) were charged into 60 mL of dichloromethane. Flask was agitated for 5 minutes at room temperature. Then 1.75 g 2- ammo-N-(2,2,2-trifluoroethyl)acetamide and 0.88 g DMAP (4-dimethylaminopyridine) were added and the mixture was agitated at room temperature until reaction was finished according to HPLC analysis.

[0104] HPLC purity of Fluralaner peak at the end of reaction is 75.1 area %.

[0105] Comparative Example 3 - Synthesis of Fluralaner as from state of the art (all components are added at the same time to the reaction mixture):

[0106] At room temperature (20 - 25 °C) 2.00 g 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-di- hydroisoxazol-3-yl)-2-methylbenzoic acid (compound 1), 1.28 g l-ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl), 1.75 g 2- amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride and 0.88 g DMAP (4-dimethylaminopyridine) were charged into 60 mL of dichloromethane and the mixture was agitated until reaction was finished according to HPLC analysis.

[0107] HPLC purity of Fluralaner peak at the end of reaction is 79.1 area %.

[0108] The experimental results of Examples 1 - 3 are compiled in Table 1 here below:

[0109] Table 1: HPLC yield of Fluralaner and impurities in the reaction mixture after 24 hours or 5 hours (Example 1), when different order of addition of specific reagents is applied.

[0110] Example 4 - Synthesis of Fluralaner with standard 2-amino-N-(2.2,2-trifluoroethyl)acetamide hydrochloride (compound 3) containing 0.2 - 0.5 % hydrazine w / w:

[0111] At room temperature (19 - 25 °C) 10.00 g 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2 -methylbenzoic acid (compound 1) was charged into 100 m of dichloromethane, 6,00 g 2- amino-N-(2,2,2-trifhioroethyl)acetamide hydrochloride (compound 3) (with 0.5 % hydrazine w / w) and 5.80 g DMAP were added into a flask. Flask was flushed with 30 ml of dichloromethane and agitated for 5 minutes. Then 5.50 g l-ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl) was added to obtain light yellow solution. Flask was flushed with 20 ml of dichloromethane and stirred for 5 hours at room temperature until reaction was finished according to HPLC analysis.

[0112] 140 mL of 5 % aqueous solution of hydrochloric acid and 50 mL of dichloromethane was added and agitated. Water phase and organic phase were not clearly separated.

[0113] 0.5 ml Ethyl acetate (EA) was added to speed up dissolution and mixture was agitated overnight. Water and organic phase were hardly separated, the white milky layer appeared. To organic phase without milky layer 140 ml of 5 % aqueous solution of hydrochloric acid. Then dichloromethane was distillated out during the heating to 40 °C. After all methylene chloride was distilled out, mixture was cooled to room temperature and stirred for about 1 hour, washed with 50 ml H2O and sucked off well. The product was dried and after drying 4.99 g of white product was obtained.

[0114] Total yield for both steps was 33.7 %, HPLC purity of Fluralaner peak in the end of reaction is 91.9 area % HPLC purity of isolated and dried crude Fluralaner is 89.7 area %.

[0115] Example 5 - Compound 4 obtained from compound 3 with the separation process where hydrazine was removed with split reaction:

[0116] At room temperature (20 - 25 °C) 8.76 g 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-di- hydroisoxazol-3-yl)-2 -methylbenzoic acid (compound 1) was charged into 131 mL of dichloromethane, 4.25 g 2-amino-N-(2,2,2-trifluoroethyl)acetamide (compound 4, comprising less than 0.10 % w / w), and 5.12 g DMAP were added into a flask. Flask was agitated for 5 minutes. Then 4.82 g l-ethyl-3-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl) was added and stirred for 4 hours at room temperature. Water phase and organic phase were clearly separated. Organic phase is opalescent, water phase is clear with white flakes.

[0117] Then 123 mL of 5 % aqueous solution of hydrochloric acid were added and the mixture was heated to 40°C.

[0118] Water and organic phase were separated with distillation. Mixture was cooled to room temperature and stirred for about 1 hour. To organic phase was added 140 ml of 5 % aqueous solution of hydrochloric acid. Then dichloromethane was distillated and the flask with mixture was heated to reach40°C. Mixture was distillated, cooled to room temperature, washed with 43 ml H2O and sucked off well The product was dried and after drying 10.66 g of white product was obtained.

[0119] Total yield for both steps was 75.2 %, HPLC purity of Fluralaner peak in the end of reaction is 92.5 area % HPLC purity of isolated and dried crude Fluralaner is 93.9 area %.

[0120] Example 6 - Compound 3 with added hydrazine:

[0121] At room temperature (20-25°C) 5.00 g 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihy- droisoxazol-3-yl)-2 -methylbenzoic acid (compound 1) was charged into 75 mL of dichloromethane, 2.99 g 2- amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride (compound 3, comprising 0.53 % w / w) and 2.92 g DMAP were added into a flask. Flask was flushed and agitated for at least 5 minutes. Then 2.75 g 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl) and 1,16 ml hydrazine hydrate were added to obtain light yellow solution and stirred for 5 hours at 35 °C.

[0122] 70 mL of 5 % aqueous solution of hydrochloric acid were added and agitated for about 5 minutes. Yellow suspension was obtained. Water and organic phase were separated overnight.

[0123] HPLC purity of Fluralaner peak in the end of reaction is 54.7 area % and 24.9 area % of new peak which was later isolated and identified as impurity D (4-(5-(3,5-dichlorophenyl)-5-(trifluorome- thyl)-4,5-dihydroisoxazol-3-yl)-2 -methylbenzohydrazide). Final product was not isolated due low reaction purity of main product Fluralaner.

[0124] The experimental results of Examples 4-6 are compiled in Table 2 here below:

[0125] Table 2: Yield of Fluralaner and impurities in the reaction mixture, when compound 3 or 4 with different content of hydrazine is used.

[0126] Example 8 - Synthesis of a Afoxolaner intermediate (4-acetyl-N-(2-oxo-2-((2.2,2-trifluoro- ethyl)amino)ethyl)-l -naphthamide (compound 5):

[0127] At room temperature (20-25 °C) 3.40 g 2-amino-N-(2,2,2-trifluoroethyl)acetamide (Compound 4 obtained from compound 3 with split reaction, content of hydrazine below 0.10 % w / w) was charged into 25 mL of dichloromethane. Gradually added 23 ml 4-acetyl-l -naphthoyl chloride solution in dichloromethane (ratio 94.8 g chloride in 500 mL dichloromethane) and cool the mixture (10-20°C). Adding 7.5 ml triethylamine (TEA) in drops in period of 1 hour to obtain brown suspension. Mixture was stirred at room temperature overnight.

[0128] Then 67 mL of dichloromethane, 117 mL of H2O and 73 mL of acetonitrile (ACN) was added. Additional 20 ml of acetonitrile (ACN) is added. Mixture is agitated for about 10 minutes. Water phase and organic phase were separated. Organic phase was brown and water phase was colorless. Organic phase is evaporated by rotavapor. Precipitate is further dried in vacuum dryer overnight at 40°C and 30 mbar. After drying 6.05 g of brown product was obtained.

[0129] Example 9 - Synthesis of a Afoxolaner intermediate (4-acetyl-N-(2-oxo-2-((2.2.2-trifluoro- ethyl)amino)ethyl)-l -naphthamide (compound 5) with Compound 3 from supplier, where the hydrazine was additionally removed (content of hydrazine was below the detection limit):

[0130] At room temperature (20-25°C) 4.14 g 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride was charged into 25 mL of dichloromethane. Gradually added 25 ml 4-acetyl-l -naphthoyl chloride solution (ratio 94,8 g chloride in 500 mL dichloromethane) and cool the mixture. Adding 7.5 ml tri- ethylamine (TEA) in drops in period of 1 hour to obtain brown suspension. Mixture was stirred at room temperature overnight.

[0131] Then 67 mL of dichloromethane (DCM), 117 mL of H2O and 73 mL of acetonitrile (ACN) was added. Additional 20 ml of acetonitrile (ACN) is added. Mixture is agitated for about 10 minutes. Water phase and organic phase were separated. Organic phase was brown and water phase was colorless. Organic phase was evaporated by rotavapor. Precipitate was further dried in vacuum dryer overnight at 40°C and 30 mbar. After drying 6.00 g of brown product was obtained.

[0132] The experimental results of Examples 8 and 9 are compiled in Table 3 here below

[0133] Table 3: Yield of Afoxolaner intermediate and impurities after the reaction, when compound 3 or 4 with different content of hydrazine is used.

Claims

Patent claims:

1. A process for preparing Fluralaner, an Fluralaner intermediate, Afoxolaner, an Afoxolaner intermediate, Lotilaner, or a Lotilaner intermediate, said process comprising the steps of:(a) providing a composition comprising- a solvent;- compound according to general formula (I):Q-COOH(I), wherein Q represents a residue selected from residues Q-l through Q-9:(Q-9)- a catalyst; preferably either (i) a base or (ii) a N-hydroxyl compound and- either (i) 2-amino-N-(2,2,2-trifluoroethyl)acetamide or a salt thereof, preferably the hydrochloride salt; or (ii) a carboxylic acid activating agent, preferable a carbodiimide;(b) adding to the composition provided in step (a) either (i) a carboxylic acid activating agent, preferably a carbodiimide, or (ii) 2-amino-N-(2,2,2-trifluoroethyl)acetamide ora salt thereof, preferably the hydrochloride salt;(c) allowing the composition obtained in step (b) to react thereby synthesizing Afoxolaner, Flu- ralaner, Lotilaner or an intermediate thereof according to general formula (II):(II), wherein Q represents a residue selected from residues (Q-l) through (Q-9) as above; and(d) optionally, recovering the Afoxolaner, Fluralaner, Lotilaner or intermediate thereof according to general formula (II) from the composition obtained in step (c).

2. The process according to claim 1, wherein (i) the composition provided in step (a) comprises 2- amino-N-(2,2,2-trifluoroethyl)acetamide or a salt thereof, and wherein in step (b) the carboxylic acid activating agent is added; preferably wherein the entire amount of 2-amino-N-(2,2,2-trifluo- roethyl)acetamide or a salt thereof that is employed in the process is contained in the composition provided in step (a), and wherein the entire amount of the carboxylic acid activating agent that is employed in the process is added in step (b).

3. The process according to claim 1 or 2, wherein the composition provided in step (a) comprises the solvent, the compound according to general formula (I), the catalyst, and the 2-amino-N- (2,2,2-trifluoroethyl)acetamide or a salt thereof, but not yet the carboxylic acid activating agent; and wherein the carboxylic acid activating agent is subsequently added in step (b) to the composition provided in step (a).

4. The process according to any of the preceding claims, wherein the composition provided in step (a) is stirred for at least 5 minutes, preferably for at least 10 minutes, more preferably for at least 15 minutes before addition of (i) a carboxylic acid activating agent, preferably 2,2,2-trifluoro- ethylamine or a salt thereof, preferably the hydrochloride salt, most preferably 1 -ethyl-3 -(3 - dimethylaminopropyl) carbodiimide hydrochloride (EDCxHCl).

5. The process according to claim 1, wherein (ii) the composition provided in step (a) comprises carboxylic acid activating agent, and wherein in step (b) 2-amino-N-(2,2,2-trifluoroethyl)acetam- ide or a salt thereof is added; preferably wherein the entire amount of 2-amino-N-(2,2,2-trifluo- roethyl)acetamide or a salt thereof that is employed in the process is contained in the composition provided in step (b), and wherein the entire amount of the carboxylic acid activating agent that is employed in the process is added in step (a).

6. The process according to any of the preceding claims, wherein the composition provided in step (a) comprises the solvent, the compound according to general formula (I), the catalyst, and the carboxylic acid activating agent, but not yet the 2-amino-N-(2,2,2-trifluoroethyl)acetamide or a salt thereof; and wherein the 2-amino-N-(2,2,2-trifluoroethyl)acetamide or a salt thereof is subsequently added in step (b) to the composition provided in step (a).

7. The process according to any of the preceding claims, wherein the composition provided in step (a) is stirred for at least 5 minutes, preferably for at least 10 minutes, more preferably for at least 15 minutes before addition of (ii) 2-amino-N-(2,2,2-trifluoroethyl)acetamide or a salt thereof, preferably the hydrochloride salt.

8. The process according to any of the preceding claims, wherein the 2-amino-N-(2,2,2-trifluoro- ethyl)acetamide or a salt thereof, preferably the hydrochloride salt, has a hydrazine content of up to 0.2 wt.-%, more preferably up to 0.1 wt.-%, most preferably up to 0.05 wt.-%.

9. The process according to any of the preceding claims, wherein the catalyst is or comprises a base; preferably wherein the base is selected from the group consisting of 4-dimethylaminopyridine, triethanolamine, N,N-diisopropylethylamine, N-methyl-morpholine, 2-dimethylaminopyridine, 2,4,6-trimethylpyridine, piperidine and 4-(2-piperidinoethyl)pyridine; preferably 4-dimethylaminopyridine.

10. The process according to any of the preceding claims, wherein the catalyst is or comprises a N- hydroxyl compound; preferably wherein the N-hydroxyl compound is selected from the group consisting of N-hydroxysuccinimide, N-hydroxy-benzotriazoles, N-hydroxy-benzotriazines, and 2 -hydroxy imines; preferably N-hydroxysuccinimide.

11. The process according to any of the preceding claims, wherein the solvent is selected from the group consisting of acetonitrile, acetone, N,N-dimethylformamide, tetrahydrofiiran, ethyl acetate, dichloromethane, and mixtures thereof; preferably dichloromethane.

12. The process according to any of the preceding claims, wherein the carboxylic acid activating agent is selected from the group consisting of carbodiimides, phosphonium-type reagents, and aminium / uronium-imonium-type reagents; preferably wherein the carboxylic acid activating agent is a carbodiimide selected from 1 -ethyl-3 -(3 -dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide , N -cyclohexyl-N ’ -(- [N -methylmorpholino] ethyl)-carbodi- imide, and diisopropylcarbodiimide; preferably l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

13. The process according to any of the preceding claims, wherein- the relative molar ratio of the compound according to general formula (I) and the 2-amino-N- (2,2,2-trifluoroethyl)acetamide or a salt thereof is within the range of from 1 : 1 to 1: 3; and / or- the relative molar ratio of the compound according to general formula (I) and carboxylic acid activating agent is within the range of from 1:0.5 to 1:5; and / or- step (c) is carried out at a temperature within the range of from 10 to 40°C.

14. The process according to any of the preceding claims, wherein- the catalyst is 4-(N,N-dimethylamino)pyridine (DMAP) or N-hydroxy succinimide (NHS);- the solvent is dichloromethane; and- the carboxylic acid activating agent is l-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCxHCl).

15. The process according to any of the preceding claims- which provides an overall yield of Fluralaner and / or Lotilaner of at least 45%, more preferably at least 50%, still more preferably at least 55%, yet more preferably at least 60%, even more preferably at least 65%, more preferably at least 70%, more preferably at least 75 %, still more preferably at least 80 %, yet more preferably at least 85 %, even more preferably at least 90 %, and most preferably about 94.3 %; and / or- which provides an overall yield of Afoxolaner intermediate of at least 45%, more preferably at least 50%, still more preferably at least 55%, yet more preferably at least 60%, even more preferably at least 65%, more preferably at least 70%, more preferably at least 75 %, still more preferably at least 80 %, yet more preferably at least 85 %, even more preferably at least 90 %, and most preferably about 97.1 %.

Images