CN115536541A - Synthesis method of common intermediate of flurradine and afurane - Google Patents
Synthesis method of common intermediate of flurradine and afurane Download PDFInfo
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- CN115536541A CN115536541A CN202211252823.4A CN202211252823A CN115536541A CN 115536541 A CN115536541 A CN 115536541A CN 202211252823 A CN202211252823 A CN 202211252823A CN 115536541 A CN115536541 A CN 115536541A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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
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 material drugs; in particular to a synthetic method of a common intermediate of fluridone and alfilamide, in particular to a synthetic method of 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide.
Background
Both fluralanide (English name: fluralaner) and Aforamide (English name: affoxolaner) are isoxazoline insecticides and acaricides, and block the transmission of chloride ions from the presynaptic membrane to the postsynaptic membrane by acting on ligand-gated chloride ion channels, especially channels gated by the neurotransmitter gamma-aminobutyric acid (GABA), resulting in increased excitement and over-death of insect neurons. The loratadine and the aforaline are broad-spectrum insecticides, have good insecticidal activity on pests such as acarina, siphonaptera, phthiraptera, hemiptera and diptera, and have higher or equivalent toxicity to common insecticides. The fraxidin and the afurar have no obvious cross resistance with the existing pesticide, and even have better insecticidal activity to partially resistant pests. The Chinese Ministry of agriculture approved the imported drug Aframomum postcoitus chewable tablet in 2018 to be used for treating flea and canine brand infection, and simultaneously preventing canine heartworm infection and/or treating gastrointestinal nematode infection. In addition, the afuram can be independently prepared (Nixin, nexGard, afuram chewable tablet) and is the first oral anthelmintic for dogs which can kill two parasites of the plena and the flea in China. The fraxidin is mainly used for treating flea and tick infections on dog body surface, and can be used for adjuvant treatment of allergic dermatitis caused by flea. The fluranide is used as a flea and tick infection resistant chewable tablet for providing 12-week long-term protection for dogs, and the product is only administered once every 12 weeks, so that more convenient and efficient guarantee is provided for pets and pet owners. Flurania was first registered in the European Union in 1 month 2014, and Merck was first commercially produced with Flurania as a veterinary drug Bravector and marketed in 4 months of the same year.
In view of the fact that the fradora and the afuram are novel deinsectization veterinary drugs and have wide market prospects at home and abroad, the synthesis research on the key segment of the common intermediate of the fradora and the afuram can further improve and guarantee the quality of the fradorana and the afuram products, and the finding of a production process suitable for production amplification is particularly important, so that the production cost of the raw material drugs can be reduced.
Intermediates common to both flurarana and afurana: 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide. The chemical structures of the flurarana, the afurana and the common intermediate 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide are as follows:
at present, the synthesis method of 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide at home and abroad mainly comprises three methods:
1. the method comprises the following steps of reacting N-phthaloyl glycine starting material with trifluoroethylamine to obtain N-phthalimido-N- (2, 2, 2-trifluoroethyl) acetamide, and reacting with hydrazine hydrate to obtain 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide, wherein the process route is as follows:
2. chloroacetic acid and dibenzyl amine are used as starting materials, N-dibenzyl glycine is obtained after the reaction of chloroacetic acid and dibenzyl amine, 2-dibenzyl amino-N- (2, 2, 2-trifluoroethyl) acetamide is obtained by the reaction of the N-dibenzyl glycine and trifluoroethylamine, and the dibenzyl is removed by a Pd/C hydrogenation method to obtain 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide, wherein the process route is as follows:
3. boc-glycine is used as a starting material and reacts with trifluoroethylamine to obtain 2-Boc-amino-N- (2, 2, 2-trifluoroethyl) acetamide, and then the Boc protecting group is removed by HCl gas to obtain 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide hydrochloride, wherein the process route is as follows:
all three methods can obtain 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide, but the last step in the method 1 uses hydrazine hydrate as a tube product, and generates a large amount of phthalic hydrazide which is a byproduct and is difficult to remove; in the last step of the method 2, a palladium-carbon hydrogenation process is used, so that not only is precious metal used, the cost is high, but also certain process safety risk exists; in the method 3, boc-glycine is used as a starting material, the material is expensive, HCl gas is used for removing Boc protecting groups, and the cost is high; the 3 methods have certain disadvantages, such as poor atom economy, high cost, poor conformity with the requirements of the existing green manufacturing process and certain limitation in the amplification process, so that a process route with high yield and low atom economy and high cost is necessary to find.
Disclosure of Invention
The invention aims to obtain qualified 2-
The amino-N- (2, 2, 2-trifluoroethyl) acetamide product is favorable for industrial scale-up production. The scheme is as follows:
the embodiment of the invention provides a synthetic method of a common intermediate of flurarana and afurana, which comprises the following steps:
(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 the 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide to the ammonia is 1:10-40.
The reaction process of the invention is as follows:
wherein, in the step (1), the trifluoroethylamine salt is selected from trifluoroethylamine hydrochloride, trifluoroethylamine sulfate, trifluoroethylamine phosphate or trifluoroethylamine p-toluenesulfonate and the like, and is preferably trifluoroethylamine hydrochloride.
Wherein, in the step (1), the solvent is one or two mixed solvents selected from water, dichloromethane, methyl tert-butyl ether, 1, 2-dichloroethane, tetrahydrofuran, ethyl acetate, n-hexane and n-heptane, etc., preferably dichloromethane.
Wherein in the step (1), the mass ratio of the solvent to the trifluoroethylamine is 3-15:1.
wherein, in the 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 the step (2), ammonia is selected from ammonia water, liquid ammonia methanol solution, liquid ammonia ethanol solution or liquid ammonia tetrahydrofuran solution, and the like, and liquid ammonia methanol solution (methanol as a solvent) is preferred.
Further, in the step (1), after the reaction is finished, adding water (the solvent is not water), 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 (preferably 55 deg.C), dissolving, cooling to 5-15 deg.C (preferably 10 deg.C), filtering, and oven drying to obtain 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide.
Further, in the step (2), after the reaction is completed, the product is obtained by reduced pressure distillation.
Specifically, the synthesis method of the common intermediate of the frataxin and the alfilamide provided by the invention comprises the following steps:
(1) Dissolving trifluoroethylamine or hydrochloride thereof in dichloromethane, adding triethylamine, dropwise adding chloroacetyl chloride at a 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 trifluoroethylamine or hydrochloride thereof to 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 after the reaction is finished, distilling the 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide under reduced pressure, wherein the molar ratio of the 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide to the liquid ammonia is 1:10-40.
The invention has the advantages of very high atom economy and innovation points that: the important intermediate 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide can be synthesized by removing only 2 molecules of HCl from three basic raw materials, namely chloroacetyl chloride, trifluoroethylamine and ammonia, so that the post-treatment cost and the environmental pollution are greatly reduced, the green synthesis process concept is met, the reaction is mild, and the industrial production amplification is facilitated.
Drawings
FIG. 1 is a GC spectrum of a crystalline product of 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide;
FIG. 2 is a GC spectrum of a reaction solution of 2-ammonia-N- (2, 2, 2-trifluoroethyl) acetamide;
FIG. 3 is a GC spectrum of the product of distillation under reduced pressure of 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings.
Example 1 synthesis of 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide:
weighing 360g of dichloromethane into a four-neck flask with 1L, adding 57g of triethylamine into the four-neck flask, adding 47.6g of 2, 2-trifluoroethylamine into a solvent, cooling to-5-0 ℃ under the protection of nitrogen, dropwise adding a mixed solution of 60.8g of chloroacetyl chloride and 60g of dichloromethane, wherein T is less than 0 ℃, dropwise adding time is 0.5-1h, transferring to room temperature (25 ℃) for reaction for 3h after dropwise adding, adding 200g of water, stirring, standing and separating liquid; the aqueous phase is extracted with 100ml of dichloromethane and the organic phases are combined. The organic phase is washed to pH 7-8 with about 200ml of saturated sodium bicarbonate and the organic phase is washed to neutrality with 100ml of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent, to obtain 81.7g of a crude white solid. 60g of n-hexane was added and the mixture was heated to 55 ℃ to dissolve. Cooling to 10 ℃, filtering, drying at 42 ℃ to obtain 68.9g of a white solid product, detecting the purity by GC (gas chromatography) to be 99.1 percent, and obtaining the yield to be 81.7 percent.
Example 2 synthesis of 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide:
in a 2L four-necked flask, 800g of ammonia water, 50g of 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide and ammonia water were added, the temperature was raised to 50 ℃ to react for 12 hours, after the reaction was completed, a large amount of water was distilled off, extraction was performed with methylene chloride, organic layers were combined, the solvent was distilled off, distillation under reduced pressure was performed, 35.3 g of the obtained fraction was collected, the purity was 99.1% by GC detection, and the yield was 79.1%.
Example 3 synthesis of 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide:
weighing 1200g of dichloromethane into a four-neck flask of 2L, adding 222g of triethylamine into the four-neck flask according to the feeding amount, adding 136g of 2, 2-trifluoroethylamine hydrochloride into a solvent, cooling to-5-0 ℃ under the protection of nitrogen, dropwise adding a mixed solution of 124.3g of chloroacetyl chloride and 125g of dichloromethane, enabling T to be less than 0 ℃, dropwise adding for 1h, after dropwise adding, transferring to room temperature (25 ℃) for reaction for 3h, adding 500g of water, stirring, standing and separating; the aqueous phase is extracted with 500ml of dichloromethane and the organic phases are combined. The organic phase is washed to pH 7-8 with about 400ml of saturated sodium bicarbonate and the organic phase is washed to neutrality with 400ml of saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent, to obtain 168.8g of a crude white solid. 130g of n-hexane was added and the mixture was heated to 55 ℃ to dissolve. Cooling to 10 ℃, filtering, drying at 42 ℃ to obtain 129.9g of white solid product, detecting the purity by GC (gas chromatography) to be 99.6 percent, and obtaining the yield to be 83.2 percent.
Example 4 synthesis of 2-amino-N- (2, 2, 2-trifluoroethyl) acetamide:
adding 600g of methanol into a 2L four-neck flask, cooling to 0 ℃, introducing approximately 300g of liquid ammonia, weighing 50g of 2-chloro-N- (2, 2, 2-trifluoroethyl) acetamide, adding the mixture into a methanol ammonia solution, reacting at 0-10 ℃ for 12h, evaporating the solvent after the reaction is finished, carrying out reduced pressure distillation, collecting 36.5 g of the obtained fraction, detecting the purity by GC (gas chromatography) to be 99.1 percent, and obtaining the yield of 82.1 percent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.
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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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115772091A (en) * | 2023-01-05 | 2023-03-10 | 济南久隆医药科技有限公司 | Synthesis method of 2-amino-N- (2, 2-trifluoroethyl) acetamide |
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| JP2009173621A (en) * | 2007-10-29 | 2009-08-06 | Nissan Chem Ind Ltd | Method for producing 2-amino-n-(2,2,2,-trifluoroethyl)acetamide compound or salt thereof |
| US20130267729A1 (en) * | 2010-09-27 | 2013-10-10 | E.I. Du Pont De Nemours And Company | Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide |
| WO2020222158A1 (en) * | 2019-04-30 | 2020-11-05 | Hikal Limited | Process for the preparation of 2-amino-n-(2,2,2-trifluoroethyl)-acetamide and salts thereof |
| CN114057594A (en) * | 2020-07-31 | 2022-02-18 | 广东东阳光药业有限公司 | Process for preparing 2-amino-N- (2,2, 2-trifluoroethyl) acetamide or its salt |
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Patent Citations (4)
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| JP2009173621A (en) * | 2007-10-29 | 2009-08-06 | Nissan Chem Ind Ltd | Method for producing 2-amino-n-(2,2,2,-trifluoroethyl)acetamide compound or salt thereof |
| US20130267729A1 (en) * | 2010-09-27 | 2013-10-10 | E.I. Du Pont De Nemours And Company | Method for preparing 2-amino-n-(2,2,2-trifluoroethyl) acetamide |
| WO2020222158A1 (en) * | 2019-04-30 | 2020-11-05 | Hikal Limited | Process for the preparation of 2-amino-n-(2,2,2-trifluoroethyl)-acetamide and salts thereof |
| CN114057594A (en) * | 2020-07-31 | 2022-02-18 | 广东东阳光药业有限公司 | Process for preparing 2-amino-N- (2,2, 2-trifluoroethyl) acetamide or its salt |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115772091A (en) * | 2023-01-05 | 2023-03-10 | 济南久隆医药科技有限公司 | Synthesis method of 2-amino-N- (2, 2-trifluoroethyl) acetamide |
| CN115772091B (en) * | 2023-01-05 | 2023-06-23 | 济南久隆医药科技有限公司 | Synthesis method of 2-amino-N- (2, 2-trifluoroethyl) acetamide |
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