CN115536541A - Synthetic method of common intermediate of Freilaner and Afraner - Google Patents

Abstract

The invention discloses a synthetic method of a common intermediate of fluridone and alfilamide, belonging to the technical field of chemical synthesis. According to the invention, chloracetyl chloride and triethylamine are used as initial raw materials, 2-chloro-N- (2, 2-trifluoroethyl) acetamide is subjected to acylation reaction, then the 2-chloro-N- (2, 2-trifluoroethyl) acetamide is directly reacted with ammonia to obtain a crude product of 2-amino-N- (2, 2-trifluoroethyl) acetamide, and the crude product is subjected to reduced pressure distillation reaction to obtain a high-purity important intermediate 2-amino-N- (2, 2-trifluoroethyl) acetamide pure product.

Description

Synthetic method of common intermediate of Freilaner and Afraner

technical field

The invention belongs to the technical field of chemical synthesis, and also belongs to the technical field of synthesis of veterinary drugs and pharmaceutical raw materials; in particular, it relates to a method for synthesizing a common intermediate of Freilaner and Afraner, specifically 2-amino-N-(2, 2,2-trifluoroethyl) acetamide synthesis method.

Background technique

Both Fluralaner (English name: Fluralaner) and Afoxolaner (English name: Afoxolaner) are isoxazoline insecticides and acaricides, which act on ligand-gated chloride ion channels, especially It inhibits the channel gated by the neurotransmitter γ-aminobutyric acid (GABA), blocks the transmission of chloride ions from the presynaptic membrane to the postsynaptic membrane, and leads to increased neuronal activity in insects, excessive excitation and death. Frellana and Afulaner are broad-spectrum insecticides with good insecticidal activity against pests such as ticks, fleas, lice, hemiptera and diptera, and their toxicity is high At or equivalent to commonly used insecticides. Frellana and Afulaner not only have no significant cross-resistance with existing insecticides, but even have good insecticidal activity against partially resistant pests. In 2018, the Ministry of Agriculture of the People's Republic of China approved the imported drug Avola Namilbe Chewable Tablets for the treatment of canine flea and card infection, as well as the prevention of canine heartworm infection and/or the treatment of gastrointestinal nematode infection. In addition, Aflana can also be made into medicine alone (NexGard, NexGard, Aflana chewable tablets), which is the first oral anthelmintic for dogs in China that kills both parasites and fleas. Frelaner is mainly used to treat flea and tick infestation on the surface of dogs, and can also assist in the treatment of allergic dermatitis caused by fleas. As a chewable tablet against flea and tick infection that provides long-term protection for dogs for 12 weeks, Frellanat only needs to be administered once every 12 weeks, providing pets and pet owners with more convenient and efficient protection. Frellana was registered in the European Union for the first time in January 2014, and Merck was the first to commercialize Frellana as a veterinary drug Bravecto and it went on the market in April of the same year.

In view of the fact that Frellana and Afurana are new types of anthelmintic veterinary drugs and have broad domestic and foreign market prospects, the research on the synthesis of the key fragments of the common intermediates of Frellana and Afurana can further improve and guarantee It is particularly important to find a production process suitable for production scale-up for the quality of Freilaner and Afraner products, which will help reduce the production cost of APIs.

The common intermediate of Freilaner and Afraner: 2-Amino-N-(2,2,2-trifluoroethyl)acetamide. The chemical structures of Frellaner, Afuraner and the common intermediate 2-amino-N-(2,2,2-trifluoroethyl)acetamide are as follows:

At present, there are three main methods for synthesizing 2-amino-N-(2,2,2-trifluoroethyl)acetamide at home and abroad:

1. With N-phthaloylglycine starting material, react with trifluoroethylamine to obtain N-phthalimido-N-(2,2,2-trifluoroethyl)acetamide, and then Reaction with hydrazine hydrate to obtain 2-amino-N-(2,2,2-trifluoroethyl)acetamide, the process route is as follows:

2. Using chloroacetic acid and dibenzylamine as starting materials, after the reaction between the two, N-dibenzylglycine is obtained, and then reacted with trifluoroethylamine to obtain 2-dibenzylamino-N-(2,2,2- Trifluoroethyl) acetamide, then use the method of Pd/C hydrogenation to remove dibenzyl to obtain 2-amino-N-(2,2,2-trifluoroethyl) acetamide, the operational route is as follows:

3. Using Boc-glycine as the starting material, react with trifluoroethylamine to obtain 2-Boc-amino-N-(2,2,2-trifluoroethyl)acetamide, and then use HCl gas to remove the Boc protecting group Obtain 2-amino-N-(2,2,2-trifluoroethyl)acetamide hydrochloride, the operational route is as follows:

These three methods can obtain 2-amino-N-(2,2,2-trifluoroethyl)acetamide, but the last step in method 1 uses the pipe product hydrazine hydrate, and will produce a large amount of side effects that are difficult to remove Product phthalic hydrazide by-product; used palladium carbon hydrogenation process in the last step in method 2, not only used precious metal, cost is higher, also has certain process safety risk in addition; In method 3, Boc-glycine As the starting material, the material is more expensive, HCl gas is used to remove the Boc protecting group, and the cost is high; these three methods have certain disadvantages, the atom economy is poor, and the cost is high, and they are not in line with the existing green The manufacturing process requirements and the amplification process have certain limitations, so it is necessary to find a process route with high yield, high atom economy and low cost.

Contents of the invention

The purpose of the present invention is exactly to obtain qualified 2-

Amino-N-(2,2,2-trifluoroethyl)acetamide product is beneficial to industrial scale-up production. The scheme is as follows:

The embodiment of the present invention provides a method for synthesizing the common intermediate of Frellana and Afraner, the method comprising the following steps:

(1) Dissolve trifluoroethylamine or its salt in a solvent, add alkali, drop chloroacetyl chloride at -20°C to 30°C, and obtain 2-chloro-N-(2,2,2 - trifluoroethyl) acetamide, the molar ratio of trifluoroethylamine or its salt to chloroacetyl chloride is 1:0.8-2.0, the molar ratio of base to trifluoroethylamine or its salt is 1:1-10.

(2) 2-Chloro-N-(2,2,2-trifluoroethyl)acetamide reacts with ammonia at 0°C to 60°C to obtain 2-amino-N-(2,2,2-trifluoroethyl) Base) acetamide, the molar ratio of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide to ammonia is 1:10-40.

The reaction process of the present invention is as follows:

Wherein, in step (1), the trifluoroethylamine salt is selected from trifluoroethylamine hydrochloride, trifluoroethylamine sulfate, trifluoroethylamine phosphate or trifluoroethylamine p-toluenesulfonate, etc., preferably For trifluoroethylamine hydrochloride.

Wherein, in step (1), the solvent is selected from one of water, dichloromethane, methyl tert-butyl ether, 1,2-dichloroethane, tetrahydrofuran, ethyl acetate, n-hexane and n-heptane, etc. Or two mixed solvents, preferably dichloromethane.

Wherein, in step (1), the mass ratio of solvent to trifluoroethylamine is 3-15:1.

Wherein, in step (1), the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine or diisopropylethylamine, etc., preferably triethylamine.

Wherein, in step (2), ammonia is selected from ammonia water, liquid ammonia, liquid ammonia methanol solution, liquid ammonia ethanol solution or liquid ammonia tetrahydrofuran solution, etc., preferably liquid ammonia methanol solution (methanol is used as a solvent).

Further, in step (1), after the reaction is completed, add water (the solvent is not water), let it stand, and take the organic phase; the organic phase is washed with saturated sodium bicarbonate to a pH of 7-8, and then washed with saturated sodium chloride to Neutral, and finally dried with anhydrous sodium sulfate; filtered, concentrated to remove the solvent to obtain the crude product, the crude product was added to n-hexane and heated to 52-60°C (preferably 55°C) to dissolve, and cooled to 5-15°C (preferably 10 ℃), filtered and dried to obtain 2-chloro-N-(2,2,2-trifluoroethyl)acetamide.

Further, in step (2), the product is obtained by distillation under reduced pressure after the reaction is completed.

Specifically, the synthetic method of the common intermediate of Frellana and Afraner provided by the invention comprises the following steps:

(1) Dissolve trifluoroethylamine or its hydrochloride in dichloromethane, add triethylamine, add chloroacetyl chloride dropwise at -20°C to 30°C, add water after the reaction is completed, let stand, and take the organic phase The organic phase is washed with saturated sodium bicarbonate to pH 7-8, then washed with saturated sodium chloride to neutrality, and finally dried with anhydrous sodium sulfate; filtered, concentrated to remove the solvent to obtain a crude product, the crude product is added in n-hexane and heated to Dissolve at 52-60°C, lower the temperature to 5-15°C, filter and dry to obtain 2-chloro-N-(2,2,2-trifluoroethyl)acetamide; trifluoroethylamine or its hydrochloride and The molar ratio of chloroacetyl chloride is 1:0.8-2.0, and the molar ratio of triethylamine to trifluoroethylamine or its hydrochloride is 1:1-10.

(2) 2-Chloro-N-(2,2,2-trifluoroethyl)acetamide reacts with liquid ammonia methanol solution at 0°C to 60°C. After the reaction is completed, 2-amino-N-( 2,2,2-trifluoroethyl)acetamide, the molar ratio of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide to liquid ammonia is 1:10-40.

The advantage of the present invention is that the atom economy is very high, and the innovation point is that the important intermediate 2-amino-N-(2, 2,2-trifluoroethyl)acetamide greatly reduces post-processing cost and environmental pollution, conforms to the concept of green synthesis process, and has relatively mild reaction, which is beneficial to industrial production scale-up.

Description of drawings

Fig. 1 is the crystallization product GC spectrogram of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide;

Fig. 2 is the reaction solution GC spectrogram of 2-amino-N-(2,2,2-trifluoroethyl)acetamide;

Fig. 3 is the GC spectrogram of the vacuum distillation product of 2-amino-N-(2,2,2-trifluoroethyl)acetamide.

detailed description

In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with the accompanying drawings.

Example 1 Synthesis of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide:

In a 1L four-necked flask, weigh 360g of dichloromethane and add it to the four-necked flask, weigh 57g of triethylamine according to the feeding amount, add 47.6g of 2,2,2-trifluoroethylamine and add it to the solvent, under nitrogen protection, Cool down to -5°C-0°C, add dropwise a mixture of 60.8g chloroacetyl chloride and 60g methylene chloride, T<0°C, dropwise for 0.5-1h, after the dropwise addition, transfer to room temperature (25°C) for reaction 3h, add 200g of water, stir and stand still for liquid separation; the aqueous phase is extracted with 100ml of dichloromethane, and the organic phases are combined. The organic phase was washed with about 200 ml of saturated sodium bicarbonate to a pH of 7-8, and then the organic phase was washed with 100 ml of saturated sodium chloride until neutral. The organic phase was dried by adding anhydrous sodium sulfate, and the solvent was concentrated by filtration to obtain 81.7 g of a white solid crude product. Add 60g of n-hexane and heat up to 55°C to dissolve. The temperature was lowered to 10°C, filtered, and dried at 42°C to obtain 68.9 g of a white solid product with a purity of 99.1% and a yield of 81.7% as determined by GC.

Example 2 Synthesis of 2-amino-N-(2,2,2-trifluoroethyl)acetamide:

In a 2L four-necked flask, add 800g of ammonia water, add 50g of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide into the ammonia water, then raise the temperature to 50°C for 12 hours, after the reaction is completed, distill A large amount of water was removed, and extracted with dichloromethane. After the organic layers were combined, the solvent was evaporated, and then vacuum distillation was carried out to collect 35.3 g of fractions. The purity of GC was 99.1%, and the yield was 79.1%.

Example 3 Synthesis of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide:

In a 2L four-necked flask, weigh 1200g of dichloromethane and add it to the four-necked flask, weigh 222g of triethylamine according to the feeding amount, add 136g of 2,2,2-trifluoroethylamine hydrochloride into the solvent, and protect it under nitrogen Cool down to -5°C-0°C, add dropwise a mixture of 124.3g chloroacetyl chloride and 125g methylene chloride, T<0°C, dropwise for 1h, after the dropwise addition, transfer to room temperature (25°C) for reaction 3h, add 500g of water, stir and stand still for liquid separation; the aqueous phase is extracted with 500ml of dichloromethane, and the organic phases are combined. The organic phase was washed with about 400ml of saturated sodium bicarbonate to pH 7-8, and the organic phase was washed with 400ml of saturated sodium chloride until neutral. The organic phase was dried by adding anhydrous sodium sulfate, and the solvent was concentrated by filtration to obtain 168.8 g of a white solid crude product. Add 130g of n-hexane and heat up to 55°C to dissolve. The temperature was lowered to 10°C for filtration, and then dried at 42°C to obtain 129.9 g of a white solid product with a purity of 99.6% and a yield of 83.2% as determined by GC.

Example 4 Synthesis of 2-amino-N-(2,2,2-trifluoroethyl)acetamide:

In a 2L four-neck flask, add 600g of methanol, cool down to 0°C, pass through about 300g of liquid ammonia, weigh 50g of 2-chloro-N-(2,2,2-trifluoroethyl)acetamide and add methanol ammonia solution, and then reacted at 0-10°C for 12 hours. After the reaction was completed, the solvent was evaporated and vacuum distillation was carried out to collect 36.5 g of the obtained fraction. The purity of GC was 99.1%, and the yield was 82.1%.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection of the present invention. within range.

Claims (8)

1. A method for synthesizing a common intermediate of frataxin and afurat, the method comprising the steps of:

(1) Dissolving trifluoroethylamine or a salt thereof in a solvent, adding alkali, dropwise adding chloroacetyl chloride at a temperature of between 20 ℃ below zero and 30 ℃, and carrying out acylation reaction to obtain 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide, wherein the molar ratio of the trifluoroethylamine or the salt thereof to chloroacetyl chloride is 1:0.8-2.0, the molar ratio of the base to the trifluoroethylamine or the salt thereof is 1:1-10;

(2) Reacting 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide with ammonia at 0 ℃ to 60 ℃ to obtain 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide, wherein the molar ratio of 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide to ammonia is 1:10-40.

2. The method for synthesizing a common intermediate of frataxin and afurana according to claim 1, wherein in step (1), the trifluoroethylamine salt is selected from trifluoroethylamine hydrochloride, trifluoroethylamine sulfate, trifluoroethylamine phosphate or trifluoroethylamine p-toluenesulfonate.

3. The method for synthesizing the common intermediate of frataxin and afurane according to claim 1, wherein in the step (1), the solvent is one or two of water, dichloromethane, methyl tert-butyl ether, 1, 2-dichloroethane, tetrahydrofuran, ethyl acetate, n-hexane and n-heptane.

4. The process for the synthesis of a common intermediate of frataxin and afurana according to claim 1, wherein in step (1), the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine or diisopropylethylamine.

5. The method for synthesizing a common intermediate of frataxin and afurade according to claim 1, wherein in step (2), the ammonia is selected from ammonia water, liquid ammonia methanol solution, liquid ammonia ethanol solution or liquid ammonia tetrahydrofuran solution.

6. The method for synthesizing the common intermediate of the flurararina and the afurascen according to claim 1, wherein in the step (1), water is added after the reaction is completed, and the mixture is allowed to stand to obtain an organic phase; washing the organic phase with saturated sodium bicarbonate until the pH value is 7-8, then washing with saturated sodium chloride until the organic phase is neutral, and finally drying with anhydrous sodium sulfate; filtering, concentrating to remove solvent to obtain crude product, adding the crude product into N-hexane, heating to 52-60 deg.C for dissolving, cooling to 5-15 deg.C, filtering, and oven drying to obtain 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide.

7. The process for the synthesis of a common intermediate of frataxin and afurana according to claim 1, wherein in step (2), the product is obtained by distillation under reduced pressure after the reaction is completed.

8. The process for the synthesis of a common intermediate of flurararina and afurana according to claim 1, comprising the following steps:

(1) Dissolving trifluoroethylamine or hydrochloride thereof in dichloromethane, adding triethylamine, dropwise adding chloroacetyl chloride at the temperature of between 20 ℃ below zero and 30 ℃, adding water after the reaction is finished, standing, and taking an organic phase; washing the organic phase with saturated sodium bicarbonate until the pH value is 7-8, then washing with saturated sodium chloride until the organic phase is neutral, and finally drying with anhydrous sodium sulfate; filtering, concentrating to remove solvent to obtain crude product, adding the crude product into N-hexane, heating to 52-60 deg.C for dissolving, cooling to 5-15 deg.C, filtering, and oven drying to obtain 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide; the mol ratio of the trifluoroethylamine or the hydrochloride thereof to the chloroacetyl chloride is 1:0.8-2.0, the molar ratio of triethylamine to trifluoroethylamine or hydrochloride thereof is 1:1-10;

(2) Reacting 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide with liquid ammonia methanol solution at 0-60 ℃, and distilling the 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide under reduced pressure after the reaction is finished, wherein the molar ratio of the 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide to the liquid ammonia is 1:10-40.

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