Fluralaena impurity and synthesis method thereof

Abstract

The invention relates to a fluralaena impurity and a synthesis method thereof, and the inventor finds a new impurity compound dechlorinated fluralaena through careful exploration of the synthesis process and confirms the existence of the impurity during the research of the synthesis process of fluralaena; the method for preparing the impurity is further researched and explored by the inventor, and the method is simple in step, mild in reaction condition and high in product purity. The impurity can be used as a reference substance to be used for process research and quality control of the fluralan, so that the product quality of the fluralan is further improved, and the impurity has great significance on the process research of the fluralan; the impurity compound dechlorinated fluralaena obtained by the invention can also be used as an intermediate for synthesizing other insecticides.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of pharmaceutical compounds, and specifically refers to a fluralaner impurity and a method for synthesizing the same. Background Art

[0002] Fluralaner is an oral systemic insecticide and acaricide. Fluralaner, CAS: 864731-61-3, trade name: Bravecto Chemical name: 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide. It is a white to off-white crystalline or powder, with the molecular formula C 22 H 17 Cl2F6N3O3 and a molecular weight of 556.29.

[0003] Fluralaner was developed by Nissan Chemical Industries, Ltd. in Japan. The successful research and development of fluralaner has created a new research direction for GABA-gated chloride channel disruptors, attracting the attention and favor of animal medicine and pesticide science workers. In May 2014, the US Food and Drug Administration (FDA) approved it for the treatment of fleas in dogs under the trade name Bravecto. The European Union approved the drug in February 2014. Australia has approved it for sale as a flea and tick control drug.

[0004] The quality control of drugs and medication safety have always been very important aspects in drug research and development, and the impurity research of drug substances and intermediates is directly related to the quality control and medication safety of drugs. By controlling the impurity content in the drug production process, the quality and safety of the product can be ensured. When the inventor was conducting research on the synthesis process of fluralaner, through a detailed exploration of the synthesis process, a compound with the following structure was found:

[0005]

[0006] And the existence of this impurity was confirmed. This compound is a process impurity of fluralaner, and there is currently no literature reporting the existence and preparation method of this compound. Summary of the Invention

[0007] The first technical problem to be solved by the present invention is, in view of the current situation of the prior art, to provide a new compound as a process impurity of fluralaner, which is used for the process research and quality control of fluralaner to improve the product quality of fluralaner.

[0008] The second technical problem to be solved by the present invention is, in view of the current situation of the prior art, to provide a method for synthesizing a fluralaner impurity.

[0009] The technical solution adopted by the present invention to solve at least one of the above technical problems is as follows:

[0010] A fluralaner impurity, the structural formula of which is:

[0011]

[0012] The ESI-MS spectral parameters of the fluralaner impurity are as follows:

[0013] In the ESI-MS positive ion mass spectrum, the stronger ion peak at m / z 522.10 corresponds to the [M+H]+ ion of the sample, and the molecular weight of the sample is 521.10 (35Cl).

[0014] A synthesis method of a fluralaner impurity, comprising the following steps:

[0015] (1) In an organic solvent, compound Ⅳ and 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride are subjected to a condensation reaction under the action of a condensing agent to obtain compound Ⅲ;

[0016]

[0017] (2) Compound Ⅲ and 1-(3-chlorophenyl)-2,2,2-trifluoroethan-1-one are subjected to an addition reaction and an elimination reaction under the action of a catalyst to obtain compound Ⅱ;

[0018]

[0019] (3) Compound Ⅱ is subjected to an addition reaction and a cyclization reaction with hydroxylamine under the action of a catalyst to obtain compound Ⅰ,

[0020]

[0021]

[0022] Compound Ⅰ is the target product.

[0023] Preferably, in step (1), the condensing agent is selected from N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the molar dosage ratio of the condensing agent to compound Ⅳ is (1-2):1.

[0024] Preferably, in step (1), the organic solvent is a non-polar organic solvent, selected from tetrahydrofuran, acetonitrile, ethers, hydrocarbons and organic hydrocarbons.

[0025] Preferably, in step (1), the molar dosage ratio of compound Ⅲ to compound Ⅳ is 1:1 to 1:2.

[0026] Preferably, the catalyst described in step (2) is selected from triethylenediamine, DBU, and tertiary amine organic basic solvents, and the molar ratio of the catalyst to compound II is (1.5 - 2.5):1.

[0027] Preferably, the reaction solvent used in step (2) is a hydrocarbon and an organic hydrocarbon non-polar organic solvent, selected from toluene and 1,2-dichloroethane.

[0028] Preferably, the catalyst in step (3) is a phase transfer catalyst, selected from tetrabutylammonium bromide and benzyltriethylammonium chloride; the molar ratio of the catalyst to compound II is (0.3 - 1.0):1.

[0029] Preferably, compound III reacts with 1-(3-chlorophenyl)-2,2,2-trifluoroethan-1-one to obtain an acetophenone amide intermediate, and compound II is further reacted with hydroxylamine in one pot without separation to obtain the target product dechlorofluralaner.

[0030] Compared with the prior art, the advantages of the present invention are as follows: When the inventors were studying the synthesis process of fluralaner, they discovered a new impurity compound, dechlorofluralaner, through a detailed exploration of the synthesis process and confirmed its existence; through further research by the inventors, a method for preparing this impurity was developed. This method has simple steps, mild reaction conditions, and high product purity. This impurity can be used as a reference substance for the process research and quality control of fluralaner, thereby improving the product quality of fluralaner, which is of great significance for the process research of fluralaner; the obtained impurity compound dechlorofluralaner of the present invention can also be used as an intermediate to synthesize other pesticides. Description of the Drawings

[0031] Figure 1 It is the mass spectrum of compound III obtained in Example 1 of the present invention;

[0032] Figure 2 It is the mass spectrum of compound I obtained in Example 1 of the present invention. Detailed Embodiments

[0033] The present invention will be further described in detail below with reference to the embodiments in the drawings.

[0034] The structural formula of the fluralaner impurity in the embodiment of the present invention is:

[0035]

[0036] The ESI-MS spectrum parameters of this fluralaner impurity are:

[0037] The ESI-MS diagram is as Figure 2。The stronger ion peak at m / z 522.10 in the ESI-MS positive ion mass spectrum corresponds to the [M+H]+ ion of the sample, from which it can be known that the molecular weight of the sample is 521.10 ( + Cl). Therefore, it can be determined that the molecular weight of the sample is consistent with that of dechlorofluralaner. The structure of the target compound is correct. 35 ).

[0038] Example 1:

[0039] The synthetic method of the fluralaner impurity in this example comprises the following steps:

[0040] (1) Preparation of p-acetylbenzamide intermediate (Compound III):

[0041] Add 35.8 g of 2-methyl-4-acetylbenzoic acid, 300 mL of tetrahydrofuran, 2 g of 4-dimethylaminopyridine, and 40 g of diisopropylethylamine to a 500 mL reaction flask, and stir at room temperature for 2 h. Under nitrogen protection, cool down to 0 - 5 °C, and add 22.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in portions. Keep the temperature at 30 - 35 °C for 20 h. Add 300 mL of water dropwise, and adjust the pH to 6 - 7 with about 50 mL of concentrated hydrochloric acid. After dropping, keep the temperature at 0 °C for about 1 h. Solids precipitate out. Filter and dry to obtain about 58.3 g of pale yellow solid, with a yield of about 92% (Compound III).

[0042] The ESI-MS spectrum is as Figure 1 . The stronger ion peak at m / z 317.1 in the ESI-MS positive ion mass spectrum corresponds to the [M+H]+ ion of the sample, from which it can be known that the molecular weight of the sample is 316.1. Therefore, it can be determined that the molecular weight of the sample is consistent with that of the p-acetylbenzamide intermediate (Compound III). The structure of the target compound is correct.

[0043] (2) Preparation of dechlorofluralaner (Compound I):

[0044] Add 31.7 g of Compound III to a 500 mL reaction flask, add 300 mL of 1,2-dichloroethane, and add 25.1 g of 1-(3-chlorophenyl)-2,2,2-trifluoroethan-1-one under stirring. Continuously introduce nitrogen, add 30.0 g of DBU in portions, first heat up to 60 °C and react for 8 h, then heat up to reflux and react for 3 h. Cool down to room temperature to obtain a 1,2-dichloroethane solution of Compound II, which is directly used for the next step.

[0045] Cool down to -10~-5°C, add 10 g of benzyltriethylammonium chloride, and dropwise add 2.0 equivalents of 30% hydroxylamine hydrochloride; adjust the pH to greater than 12 with 30% sodium hydroxide, and keep the temperature at 0°C for about 2 h. Adjust the pH to 6-7 with 2% hydrochloric acid, and let it stand for layering at 20-30°C. Concentrate the organic layer to dryness under reduced pressure, add 100 mL of 50% isopropanol for crystallization. Filter and dry to obtain about 42.1 g of pale yellow solid, with an overall yield of about 83% (Compound I).

[0046] The ESI-MS spectrum is as Figure 2 . In the ESI-MS cation mass spectrum, the stronger ion peak at m / z 522.1 corresponds to the [M+H]+ ion of the sample. From this, it can be known that the molecular weight of the sample is 521.1 (35Cl). Therefore, it can be determined that the molecular weight of the sample is consistent with that of deschlorofluralaner. The structure of the target compound is correct.

[0047] Example 2:

[0048] The synthesis method of the fluralaner impurity in this example includes the following steps:

[0049] (1) Preparation of the p-acetylbenzamide intermediate:

[0050] Add 35.8 g of 2-methyl-4-acetylbenzoic acid, 200 mL of acetonitrile, and 48.8 g of N,N'-carbonyldiimidazole to a 500 mL reaction flask; stir at room temperature for 2 h, and cool down to -5~0°C. Add 23.2 g of Compound V in batches below 0°C; keep the temperature at 30~35°C for 20 h. Cool down to -10~-5°C, and dropwise add 200 mL of water; after dropping, keep the temperature at 0°C for about 1 h. Solids precipitate out. Filter and dry to obtain about 57.2 g of pale yellow solid, with a yield of about 91% (Compound III). The ESI-MS spectrum is as Figure 1 . In the ESI-MS cation mass spectrum, the stronger ion peak at m / z 317.11 corresponds to the [M+H] + ion of the sample. From this, it can be known that the molecular weight of the sample is 316.10 ( 35 Cl). Therefore, it can be determined that the molecular weight of the sample is consistent with that of deschlorofluralaner. The structure of the target compound is correct.

[0051] (2) Preparation of deschlorofluralaner (Compound I):

[0052] Add 31.7 g of Compound III and 150 mL of toluene to a 500 mL reaction flask, and add 25.1 g of Compound VI with stirring. Add 20.0 g of triethylenediamine in batches, first heat up to 60°C and react for 8 h, then heat up to reflux and react for 3 h. Cool down to room temperature to obtain a toluene solution of Compound II, which is directly used for the next step.

[0053] Cool the temperature to -10~-5°C, add 10 g of tetrabutylammonium bromide, and dropwise add 2.5 equivalents of 30% hydroxylamine hydrochloride; adjust the pH to greater than 12 with 30% sodium hydroxide, and keep the temperature at 0°C for about 2 h. Add 150 mL of ethyl acetate, then adjust the pH to 6-7 with 2% hydrochloric acid, and let it stand for liquid separation at 20-30°C. Concentrate the organic layer under reduced pressure to dryness, add 100 mL of 50% isopropanol for crystallization. Filter and dry to obtain about 40.5 g of a pale yellow solid, with an overall yield of about 80% (Compound I).

Claims

1. A fluralaner impurity, characterized in that: The structural formula is 2. The fluralaner impurity according to claim 1, wherein: The strong ion peak at m / z 522.10 in the ESI-MS positive ion mass spectrum of the fluralaner impurity corresponds to the [M+H] ion of the sample, and the molecular weight of the sample is 521.10 ( + Cl). 35 ​ 3. A method for synthesizing a fluralaner impurity, characterized in that It includes the following steps: (1) In an organic solvent, compound Ⅳ and 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride are subjected to a condensation reaction under the action of a condensing agent to obtain compound Ⅲ; (2) Compound Ⅲ and 1-(3-chlorophenyl)-2,2,2-trifluoroethan-1-one undergo an addition reaction and an elimination reaction under the action of a catalyst to obtain compound Ⅱ; (3) Compound Ⅱ undergoes an addition reaction and a cyclization reaction with hydroxylamine under the action of a catalyst to obtain compound Ⅰ, Compound Ⅰ is the target product.

4. The synthesis method of the fluralaner impurity according to claim 3, characterized in that: The condensing agent described in step (1) is selected from N,N'-carbonyldiimidazole, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the molar dosage ratio of the condensing agent to compound Ⅳ is (1-2):

1.

5. The synthetic method of the fluralaner impurity according to claim 3, characterized in that: The organic solvent described in step (1) is a non-polar organic solvent, selected from tetrahydrofuran, acetonitrile, ethers, hydrocarbons and organic hydrocarbons.

6. The synthetic method of the fluralaner impurity according to claim 3, characterized in that: The molar dosage ratio of compound Ⅲ to compound Ⅳ in step (1) is 1:1 to 1:

2.

7. The synthetic method of the fluralaner impurity according to claim 3, wherein: The catalyst described in step (2) is selected from 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, tertiary amine organic basic solvents, and the molar dosage ratio of the catalyst to compound Ⅱ is (1.5-2.5):

1.

8. The synthetic method of the fluralaner impurity according to claim 3, characterized in that: The reaction solvent used in step (2) is a non-polar organic solvent of hydrocarbons and organic hydrocarbons, selected from toluene, 1,2-dichloroethane.

9. The synthetic method of the fluralaner impurity according to claim 3, characterized in that: The catalyst described in step (3) is a phase transfer catalyst, selected from tetrabutylammonium bromide, benzyltriethylammonium chloride; the molar dosage ratio of the catalyst to compound Ⅱ is (0.3-1.0):

1.

10. The synthetic method of the fluralaner impurity according to claim 3, characterized in that: Compound Ⅲ reacts with 1-(3-chlorophenyl)-2,2,2-trifluoroethan-1-one to obtain a p-acetylbenzamide intermediate, and compound Ⅱ is not separated and further reacts with hydroxylamine in one pot to obtain the target product dechlorofluralaner.

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