CN115745838B - Method for synthesizing amidine compound and N-benzyl acetamidine hydrochloride - Google Patents
Method for synthesizing amidine compound and N-benzyl acetamidine hydrochloride Download PDFInfo
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- CN115745838B CN115745838B CN202211322857.6A CN202211322857A CN115745838B CN 115745838 B CN115745838 B CN 115745838B CN 202211322857 A CN202211322857 A CN 202211322857A CN 115745838 B CN115745838 B CN 115745838B
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Abstract
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of an amidine compound and N-benzyl acetamidine hydrochloride. The synthesis method of the N-benzyl acetamidine hydrochloride provided by the invention comprises the following steps: step 1: under the protection of inert atmosphere, slowly adding acetyl chloride into an organic solution containing benzylamine and sodium carbonate, and removing water-soluble components after reaction to obtain an organic solution of N-acetyl benzylamine; step 2: adding ammonium chloride hydrochloride and solid superacid into an organic solution of N-acetyl benzylamine, carrying out reflux reaction with water, and recrystallizing the reaction solution to obtain a crude product of N-benzyl acetamidine hydrochloride; step 3: purifying the crude product of the N-benzyl acetamidine hydrochloride to obtain a refined product of the N-benzyl acetamidine hydrochloride. The synthesis method provided by the invention overcomes the problems of unstable intermediates, low product content, large environmental risk and the like in the prior art, and has good industrialized prospect.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of an amidine compound and N-benzyl acetamidine hydrochloride.
Background
The amidine compound is an important intermediate in medicine and pesticide application, has wide application in the fields of medicine and chemical industry, and the synthesis method thereof is always focused in the industry.
Taking N-benzyl acetamidine hydrochloride as an example, the substance is an important medical intermediate, and the chemical structure of the substance is shown in figure 1.
The synthetic route for this intermediate has been reported in patent WO 2015/005615 Al, and is shown in FIG. 2. However, the above synthetic routes have several technical drawbacks that are difficult to overcome, including: the content of the product is low; the production process generates a large amount of hydrogen chloride gas with strong corrosiveness; the intermediate is unstable and is easy to be heated or damp and decomposed, which is not beneficial to industrial production; a large amount of three wastes are generated, and environmental pollution is easily caused.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a synthesis method of amidine compounds and N-benzyl acetamidine hydrochloride, which solves the problems of unstable intermediates, low product content, large environmental risk and the like existing in the existing method and has good industrialized prospect.
The synthetic method of the amidine compound provided by the invention is shown in the figure 3, wherein R-in the figure 3 can be benzyl, methyl, ethyl, isopropyl and the like.
The synthetic route can be widely applied to the synthesis of medicines and medicine intermediates, and has wide application prospect and huge market demand.
Further, the invention provides a synthesis method of N-benzyl acetamidine hydrochloride, and the synthesis route of the N-benzyl acetamidine hydrochloride is shown in fig. 4. Wherein the first reaction is carried out under the action of alkali, and the second reaction is carried out under the action of solid super acid.
Further, the synthesis method of the N-benzyl acetamidine hydrochloride comprises the following steps:
step 1: under the protection of inert atmosphere, slowly adding acetyl chloride into an organic solution containing benzylamine and sodium carbonate, and removing water-soluble components after reaction to obtain an organic solution of N-acetyl benzylamine;
step 2: adding ammonium chloride hydrochloride and solid superacid into an organic solution of N-acetyl benzylamine, carrying out reflux reaction with water, and recrystallizing the reaction solution to obtain a crude product of N-benzyl acetamidine hydrochloride;
step 3: purifying the crude product of the N-benzyl acetamidine hydrochloride to obtain a refined product of the N-benzyl acetamidine hydrochloride.
Further, the step 1 of the synthesis method of the N-benzyl acetamidine hydrochloride is as follows: adding benzylamine and sodium carbonate into toluene, stirring and cooling to 0-15 ℃ under the protection of inert atmosphere, slowly dropwise adding acetyl chloride, and reacting for 2-4h at room temperature after the addition; adding purified water, stirring, standing, and removing water layer; then adding a drying agent to absorb water, and filtering to obtain a toluene solution of N-acetyl benzylamine.
Further, the step 2 of the synthesis method of the N-benzyl acetamidine hydrochloride is as follows: adding ammonium chloride hydrochloride into toluene solution of N-acetyl benzylamine, adding solid superacid and DMF, heating to 115-125 ℃ and carrying out reflux reaction with water for 5-8h, and continuously separating out water phase until the reaction is finished; and filtering to recover solid super acid after the reaction is completed, concentrating the filtrate under reduced pressure to remove most of solvent, adding isopropanol, and recrystallizing to obtain a crude product of the N-benzyl acetamidine hydrochloride.
Further, the step 3 of the synthesis method of the N-benzyl acetamidine hydrochloride is as follows: adding the crude product of the N-benzyl acetamidine hydrochloride into alcohol, adding active carbon, heating and refluxing, filtering while the active carbon is hot, cooling the filtrate to 0-5 ℃, and filtering out solids to obtain the product of the N-benzyl acetamidine hydrochloride.
Further, in the above synthetic method of N-benzyl acetamidine hydrochloride, the solid super acid is fluorosulfonic acid resin.
Further, in the above synthesis method of N-benzyl acetamidine hydrochloride, the alcohol used in step 3 is isopropanol.
Advantageous effects
The synthesis route provided by the invention has mild reaction conditions, is easy to realize, has lower requirements on production conditions, saves cost, does not generate corrosive gases such as hydrogen chloride and the like, is more environment-friendly, and is also more friendly to production personnel.
Compared with the prior art, the synthesis method of the N-benzyl acetamidine hydrochloride provided by the invention has obvious progress. Specifically, acetonitrile and methanol are used for the first step in the prior art to react under the catalysis of excessive hydrogen chloride to generate methyl acetamido hydrochloride, and the reaction process is catalyzed by the hydrogen chloride which is a corrosive gas with a significant excess, so that equipment corrosion in the production process is easy to cause; in addition, the methyl acetimide intermediate produced in the production process in the existing path is unstable and is easy to decompose by heating, and meanwhile, the methyl acetimide intermediate reacts with excessive methanol to generate byproducts, the low temperature is strictly controlled in post-treatment concentration, the operation condition is harsh, and the large-scale industrial production is not facilitated. The synthesis method overcomes the technical defects, has mild reaction conditions, stable intermediate quality, less three wastes, no generation of corrosive gas, simple and convenient post-treatment, meets the current requirements of green chemistry, has obvious economic and social benefits, and has good industrial application prospect.
Drawings
FIG. 1 is a chemical structure of N-benzyl acetamidine hydrochloride.
FIG. 2 is a diagram showing the synthetic route of N-benzyl acetamidine hydrochloride in the prior art.
FIG. 3 is a synthetic route diagram of amidine compounds provided by the invention.
FIG. 4 is a synthetic route diagram of N-benzyl acetamidine hydrochloride provided by the invention.
Detailed Description
The invention is further illustrated by the following specific examples, which are intended to illustrate the problem and to explain the invention, without limiting it.
Example 1
The synthetic route of the N-benzyl acetamidine hydrochloride is shown in FIG. 4, and the synthetic procedure is as follows.
Step 1: under the protection of nitrogen, 20.0g (186.9 mmol) of benzylamine, 19.8g (186.9 mmol) of sodium carbonate and 200ml of toluene are added into a 500ml reaction bottle, stirred and cooled to 0-5 ℃, 25.7g (243.0) of acetyl chloride is added into a constant pressure dropping funnel, acetyl chloride is slowly added dropwise at the temperature of 0-15 ℃ and stirred for 2 hours at room temperature, 100.0ml of purified water is added, stirred for 30 minutes, the lower water phase is removed by standing, the organic phase is washed once again, 2.0g of anhydrous sodium sulphate is added, the mixture is dried overnight, the mother liquor is obtained by suction filtration, and the mother liquor is N-acetyl benzylamine toluene solution and is directly added into the next step.
Step 2: 15.0g (280.4 mmol) of ammonium chloride hydrochloride is added into the N-acetyl benzylamine toluene solution, 10.0g of solid super acid of fluorosulfonic acid resin and 20.0ml of DMF are added, the temperature is raised to 115 to 125 ℃ and the mixture is reacted with water for 8 hours, and the water phase is continuously separated in the process. After the reaction is completed, filtering and recovering solid superacid, concentrating the filtrate under reduced pressure to remove most of solvent, adding 100.0ml of tert-butyl methyl ether, stirring and cooling to 5-10 ℃, crystallizing for 2 hours, filtering and drying to obtain 29.5g of off-white solid N-benzyl acetamidine hydrochloride crude product, and the yield of the two steps is 85.5%.
Step 3: 29.5g of crude product is added into 100.0ml of isopropanol, 0.5g of active carbon is added, heating reflux is carried out, filtering is carried out while the active carbon is hot, solid is filtered, filtrate is cooled to 0-5 ℃, solid is filtered out, 26.4g of product N-benzyl acetamidine hydrochloride is obtained after drying, HPLC purity is 95%, and total yield is 76.5%.
Characterization data for the product N-benzathine hydrochloride is as follows: 1H NMR (d-DMSO, 500 MHz) δ:2.26 (3H, s), 4.63 (2H, m), 7.27-7.31 (5H, m), 9.36 (1H, m), 9.57 (1H, m), FAB-MS (m/z): 185.67 (M+H).
Example 2
The synthetic route of the N-benzyl acetamidine hydrochloride is shown in FIG. 4, and the synthetic procedure is as follows.
Step 1: under the protection of nitrogen, 40.0g (373.8 mmol) of benzylamine, 39.6g (373.8 mmol) of sodium carbonate and 400ml of toluene are added into a 1L reaction bottle, stirred and cooled to 0-5 ℃, 51.4g (486.0) of acetyl chloride is added into a constant pressure dropping funnel, the temperature is controlled to be 0-15 ℃, acetyl chloride is slowly dropped into the constant pressure dropping funnel, the mixture is stirred for 3 hours at room temperature after the addition, 200.0ml of purified water is added, the mixture is stirred for 30 minutes, the mixture is stood for separating the lower water phase, the organic phase is washed once again, 5.0g of anhydrous sodium sulphate is added for drying overnight, the mother liquor is obtained through suction filtration, and the mother liquor is N-acetyl benzylamine toluene solution, and is directly added into the next step;
step 2: 30.0g (560.8 mmol) of ammonium chloride hydrochloride is added into the N-acetyl benzylamine toluene solution, 20.0g of solid super acid of fluorosulfonic acid resin and 50.0ml of DMF are added, the temperature is raised to 115 to 125 ℃ and the mixture is reacted with water for 10 hours, and the water phase is continuously separated in the process. After the reaction is completed, filtering and recovering solid superacid, concentrating the filtrate under reduced pressure to remove most of solvent, adding 200.0ml of tert-butyl methyl ether, stirring and cooling to 5-10 ℃, crystallizing for 2 hours, filtering and drying to obtain 61.0g of off-white solid N-benzyl acetamidine hydrochloride crude product, and the yield of the two steps is 88.4%.
Step 3: 61.0g of crude product is added into 200.0ml of isopropanol, 1.0g of active carbon is added, heating reflux is carried out, filtering and filtering is carried out while the active carbon is hot, the solid is filtered, the filtrate is cooled to 0-5 ℃, 54g of N-benzyl acetamidine hydrochloride is filtered out, the solid is dried, and the product N-benzyl acetamidine hydrochloride with the purity of 95% and the total yield of 78.2% is obtained.
Example 3
The synthetic route of the N-benzyl acetamidine hydrochloride is shown in FIG. 4, and the synthetic procedure is as follows.
Step 1: under the protection of nitrogen, 40.0g (373.8 mmol) of benzylamine, 39.6g (373.8 mmol) of sodium carbonate and 400ml of toluene are added into a 1L reaction bottle, stirred and cooled to 0-5 ℃, 51.4g (486.0) of acetyl chloride is added into a constant pressure dropping funnel, the temperature is controlled to be 0-15 ℃, acetyl chloride is slowly dropped into the constant pressure dropping funnel, the mixture is stirred for 3 hours at room temperature after the addition, 200.0ml of purified water is added, the mixture is stirred for 30 minutes, the mixture is stood for separating the lower water phase, the organic phase is washed once again, 5.0g of anhydrous sodium sulphate is added for drying overnight, the mother liquor is obtained through suction filtration, and the mother liquor is N-acetyl benzylamine toluene solution, and is directly added into the next step;
step 2: 30.0g (560.8 mmol) of ammonium chloride hydrochloride is added into the N-acetyl benzylamine toluene solution, 20.0g of solid super acid of fluorosulfonic acid resin and 50.0ml of DMSO are added, the temperature is raised to 120 to 130 ℃ and the mixture is reacted with water for 10 hours in a reflux way, and the water phase is continuously separated in the process. Filtering to recover solid super acid after the reaction is completed, concentrating the filtrate under reduced pressure to remove most of solvent, adding 200.0ml of tert-butyl methyl ether, stirring and cooling to 5-10 ℃, crystallizing for 2 hours, filtering, and drying to obtain 58.0g of off-white solid N-benzyl acetamidine hydrochloride crude product, wherein the yield of the two steps is 84.1%.
Step 3: 58.0g of crude product is added into 200.0ml of isopropanol, 1.0g of active carbon is added, heating reflux is carried out, filtering is carried out while the active carbon is hot, solid is filtered, filtrate is cooled to 0-5 ℃, solid is filtered out, and the product N-benzyl acetamidine hydrochloride is obtained by drying, wherein the purity of HPLC is 95%, and the total yield is 74.2%.
The synthetic route of the invention has mild reaction conditions, high product yield, less three wastes and low post-treatment cost, and has a large-scale industrialized production prospect.
The above embodiments are illustrative for the purpose of illustrating the technical concept and features of the present invention so that those skilled in the art can understand the content of the present invention and implement it accordingly, and thus do not limit the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.
Claims (7)
1. A synthesis method of N-benzyl acetamidine hydrochloride is characterized by comprising the following steps: the following synthetic route is adopted:
wherein the first reaction is carried out under the action of alkali, and the second reaction is carried out under the action of solid superacid;
the method comprises the following steps:
step 1: under the protection of inert atmosphere, slowly adding acetyl chloride into an organic solution containing benzylamine and sodium carbonate, and removing water-soluble components after reaction to obtain an organic solution of N-acetyl benzylamine;
step 2: adding ammonium chloride hydrochloride and solid superacid into an organic solution of N-acetyl benzylamine, carrying out reflux reaction with water, and recrystallizing the reaction solution to obtain a crude product of the N-benzyl acetamidine hydrochloride.
2. The method for synthesizing the N-benzyl acetamidine hydrochloride according to claim 1, wherein the method comprises the following steps: further comprising the step 3: purifying the crude product of the N-benzyl acetamidine hydrochloride to obtain a refined product of the N-benzyl acetamidine hydrochloride.
3. The method for synthesizing the N-benzyl acetamidine hydrochloride according to claim 1, wherein the method comprises the following steps: the step 1 is as follows: adding benzylamine and sodium carbonate into toluene, stirring and cooling to 0-15 ℃ under the protection of inert atmosphere, slowly dripping acetyl chloride, and reacting for 2-4h at room temperature after the addition; adding purified water, stirring, standing, and removing water layer; then adding a drying agent to absorb water, and filtering to obtain a toluene solution of N-acetyl benzylamine.
4. The method for synthesizing the N-benzyl acetamidine hydrochloride according to claim 1, wherein the method comprises the following steps: the step 2 is as follows: adding ammonium chloride hydrochloride into toluene solution of N-acetyl benzylamine, adding solid superacid and DMF, heating to 115-125 ℃ and carrying out reflux reaction with water for 5-8h, and continuously separating out water phase until the reaction is finished; and filtering to recover solid super acid after the reaction is completed, concentrating the filtrate under reduced pressure to remove most of solvent, adding isopropanol, and recrystallizing to obtain a crude product of the N-benzyl acetamidine hydrochloride.
5. The method for synthesizing the N-benzyl acetamidine hydrochloride according to claim 2, wherein the method comprises the following steps: the step 3 is as follows: adding the crude product of the N-benzyl acetamidine hydrochloride into alcohol, adding active carbon, heating and refluxing, filtering while the active carbon is hot, cooling the filtrate to 0-5 ℃, and filtering out solids to obtain the product of the N-benzyl acetamidine hydrochloride.
6. The method for synthesizing N-benzyl acetamidine hydrochloride according to claim 4, wherein the method comprises the following steps: the solid super acid is fluorosulfonic acid resin.
7. The method for synthesizing N-benzyl acetamidine hydrochloride according to claim 5, wherein the method comprises the following steps: the alcohol used in step 3 is isopropanol.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105377819A (en) * | 2013-07-09 | 2016-03-02 | Cj医药健康株式会社 | Method for preparation of benzimidazole derivatives |
| CN109020837A (en) * | 2018-07-27 | 2018-12-18 | 广东省石油与精细化工研究院 | A kind of preparation method of 2- substituted-phenyl-B amidine hydrochloric acid salt |
| CN110446708A (en) * | 2017-07-21 | 2019-11-12 | 安塔比奥公司 | Chemical compound |
| CN110878032A (en) * | 2019-10-31 | 2020-03-13 | 苏州诚和医药化学有限公司 | Synthesis method of N-benzylacetamidine hydrochloride |
| CN114213337A (en) * | 2021-12-30 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of benzimidazole drug intermediate |
| CN115028587A (en) * | 2022-06-23 | 2022-09-09 | 苏州诚和医药化学有限公司 | Preparation process of benzimidazole derivative intermediate |
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- 2022-10-27 CN CN202211322857.6A patent/CN115745838B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105377819A (en) * | 2013-07-09 | 2016-03-02 | Cj医药健康株式会社 | Method for preparation of benzimidazole derivatives |
| CN110446708A (en) * | 2017-07-21 | 2019-11-12 | 安塔比奥公司 | Chemical compound |
| CN109020837A (en) * | 2018-07-27 | 2018-12-18 | 广东省石油与精细化工研究院 | A kind of preparation method of 2- substituted-phenyl-B amidine hydrochloric acid salt |
| CN110878032A (en) * | 2019-10-31 | 2020-03-13 | 苏州诚和医药化学有限公司 | Synthesis method of N-benzylacetamidine hydrochloride |
| CN114213337A (en) * | 2021-12-30 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of benzimidazole drug intermediate |
| CN115028587A (en) * | 2022-06-23 | 2022-09-09 | 苏州诚和医药化学有限公司 | Preparation process of benzimidazole derivative intermediate |
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