CN115974751A - Piracetam preparation method and system - Google Patents
Piracetam preparation method and system Download PDFInfo
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- CN115974751A CN115974751A CN202211593079.4A CN202211593079A CN115974751A CN 115974751 A CN115974751 A CN 115974751A CN 202211593079 A CN202211593079 A CN 202211593079A CN 115974751 A CN115974751 A CN 115974751A
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Abstract
The invention belongs to the technical field of compounds, and discloses a method and a system for preparing piracetam, wherein the method comprises the following steps: dissolving alpha-pyrrolidone in an organic solvent, stirring, adding sodium methoxide in batches, and performing reflux reaction to obtain alpha-pyrrolidone sodium; after the reaction is completed, dropwise adding methyl chloroacetate/toluene mixed solution, performing solid-liquid separation after the reaction is completed, and distilling the filtrate to obtain a light yellow oily alpha-pyrrolidone methyl acetate; adding methyl alpha-pyrrolidone acetate and ammonia water into methanol, reacting completely at high temperature and high pressure, filtering, and drying a filter cake to obtain piracetam; the raw materials are cheap and easy to obtain, so that the whole process is optimized and is suitable for industrial popularization and use; the method is a two-step method, and has high yield and low cost; the reaction condition is mild and is harmless to the environment. The system for producing piracetam is completely attached to the piracetam preparation method, is convenient to operate, has strong practicability, and is suitable for production and use.
Description
Technical Field
The invention relates to a method and a system for preparing piracetam, and belongs to the technical field of compound synthesis.
Background
Piracetam, also known as piracetam, is a central stimulant and is clinically used for treating dysmnesia and thinking disorder, in particular hypofunction of memory and thinking caused by cerebral arteriosclerosis and cerebrovascular accident.
The existing synthesis process mainly comprises the following steps:
(1) Pyrrolidone process
Taking sodium hydride as an acid-binding agent, and reacting pyrrolidone and chloroacetamide in 1, 4-dioxane to prepare piracetam; the problems with this route are: sodium hydride is dangerous, 1, 4-dioxane has strong harm to the environment, and chloroacetamide raw materials are not easy to obtain.
(2) Glycine process
Glycine is subjected to trimethyl silicification, condensation with r-chlorobutyryl chloride, chlorination, ammoniation and cyclization to convert into piracetam, or glycine derivatives are used as raw materials. The problems with this route are: by using the protection and deprotection strategies, expensive TMSCL is needed, the stability of the corresponding glycine trimethyl silicone grease is poor, the route is long, and the method is not suitable for industrial production.
(3) Succinic anhydride process
Succinic acid is used as a raw material, succinic anhydride is generated by heating and dehydration, the succinic anhydride reacts with glycine to obtain an ammonolysis product, and the ammonolysis product is reduced and ammonolyzed by sodium tetrafluoroborate to prepare piracetam. The main problems with this route are: sodium tetrafluoroborate is used as a reducing agent, so the price is high, and the method is not suitable for industrial production.
(4) One-step synthesis method
The one-step synthesis method is to prepare the piracetam by taking 4-chloro-n-butyl acetate as a raw material, taking absolute ethyl alcohol as a solvent and glycinamide hydrochloride through one-step reaction after heating reflux in the presence of sodium bicarbonate. The problems with this route are: the raw material glycylamine hydrochloride used in the one-step synthesis method is easy to absorb moisture and agglomerate to influence the reaction speed, and the reaction is not easy to control, so that the method is not suitable for industrial production.
Therefore, the synthesis in the prior art has many problems, mainly the raw materials are not available, the price is high, and the synthesis is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a piracetam preparation method and a system, and in order to achieve the aim, the invention is realized by adopting the following technical scheme:
the invention discloses a preparation method of piracetam,
(1) Dissolving alpha-pyrrolidone in an organic solvent, stirring, adding sodium methoxide in batches, and performing reflux reaction to obtain alpha-pyrrolidone sodium; after the reaction is completed, dropwise adding methyl chloroacetate/toluene mixed solution, performing solid-liquid separation after the reaction is completed, and distilling the filtrate to obtain a light yellow oily alpha-pyrrolidone methyl acetate;
(2) Adding methyl alpha-pyrrolidone acetate and ammonia water into methanol, reacting completely at high temperature and high pressure, filtering, and drying a filter cake to obtain piracetam;
the synthetic route is as follows
Further, in step 1, the organic solvent is toluene.
Further, in step 1, the ratio of methyl chloroacetate/toluene mixture was 1.
Further, in step 2, the organic solvent is one of methanol, acetonitrile, tetrahydrofuran and dichloromethane.
Further, in the step 2, the temperature is about 110 ℃, and the reaction time is 8-12h.
Further, in step 2, the subsequent purification method of piracetam comprises the following steps: isopropanol is used as a solvent, activated carbon is added, then heating, dissolving, refluxing and decoloring are carried out, the activated carbon is filtered, stirring is carried out, temperature is reduced, crystallization is carried out, and the separated crystal is dried to obtain the purified piracetam.
Compared with the prior art, the invention has the following beneficial effects: 1. the raw materials are cheap and easy to obtain, so that the whole process is optimized, the method is suitable for industrial popularization and use, the post-treatment is simple, the organic solvent can be recycled, the production of three wastes is reduced, and the production cost can be reduced; 2. the synthesis is a two-step method, the yield is high, and the cost is low; 3. the reaction condition is mild, the method is harmless to the environment, the operation is simple, the safety is high, and the large-scale production is easy; the colleagues avoid using toxic and harmful raw materials, and the safety of the industry is improved. 4. The crystal form production is controlled by selecting medium and proportion, the finished product has high refining yield, the melting point meets the EP8 standard, and the crystal form is represented as III by the crystal form; the granularity of the product is 700-800 um and can reach more than 95 percent, and the crystal form and the granularity are controllable.
The invention also discloses a system for producing piracetam, which comprises a reflux reaction kettle, a first centrifuge, a high-temperature high-pressure reaction kettle, a second centrifuge, an airflow dryer, a cyclone separator and a screening machine;
a liquid outlet of the reflux reaction kettle is connected with a first centrifugal machine, a liquid outlet of the first centrifugal machine is connected with a distillation tower, a discharge port of the distillation tower is connected with a high-temperature high-pressure reaction kettle, a liquid outlet of the high-temperature high-pressure reaction kettle is connected with a second centrifugal machine, and a discharge port of the second centrifugal machine is connected with an airflow dryer; and a discharge port of the airflow dryer is connected with a cyclone separator, and a discharge port of the cyclone separator is connected with a sieving machine.
Further, a discharge port of the second centrifuge is connected with an activated carbon adsorption machine, and a discharge port of the activated carbon adsorption machine is connected with a crystallization kettle; and a discharge port of the crystallization kettle is connected with an air flow dryer. Adsorbing with activated carbon adsorbent, decolorizing and removing impurities. Then recrystallizing by a crystallization kettle and purifying.
Further, a liquid outlet of the second centrifugal machine is connected with a mother liquor tank 11; the mother liquor tank is connected with the high-temperature high-pressure reaction kettle through a mother liquor pump. And the mother liquor is poured back to the high-temperature high-pressure reaction kettle again by the arrangement of the mother liquor tank, and the materials are recycled.
Furthermore, the reflux reaction kettle is also connected with a batching tank. The methyl chloroacetate/toluene mixed solution is placed in a batching tank.
Furthermore, a discharge port of the screening machine is connected with the material barrel. The material is convenient to receive.
Compared with the prior art, the invention has the following beneficial effects: the system is completely attached to the piracetam preparation method, and the piracetam preparation method is convenient to operate, high in practicability and suitable for production and use.
Drawings
FIG. 1 is a liquid chromatogram of example 1 of the present invention;
FIG. 2 is a liquid chromatogram of example 2 of the present invention;
FIG. 3 is a liquid chromatogram of example 3 of the present invention;
FIG. 4 is a system block diagram of the present invention.
In the figure: reflux reaction kettle 1, first centrifuge 2, high temperature high pressure reaction kettle 3, second centrifuge 4, active carbon adsorption machine 5, crystallization kettle 6, air flow dryer 7, cyclone separator 8, sieving machine 9, distillation tower 10, mother liquor tank 11, proportioning tank 12, material barrel 13.
Detailed Description
The invention is further described below. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
Adding 1.7g of alpha-pyrrolidone and 15ml of toluene into a reaction bottle, stirring to dissolve the mixture clearly, adding 1.19g of sodium methoxide in batches, and performing reflux reaction for 4 hours to obtain alpha-pyrrolidone sodium; and (3) detecting by TLC to complete the reaction, dropwise adding methyl chloroacetate/toluene mixed solution (2.39 g/5 ml), detecting by TLC to complete the reaction, carrying out solid-liquid separation after reacting for 6h, and distilling the filtrate to obtain a light yellow oily matter alpha-pyrrolidone methyl acetate 2.57g with the yield of 81.6%.
2.57g of alpha-pyrrolidone methyl acetate, 5.1g of ammonia water and 50ml of methanol are added into a high-pressure reaction tank, the temperature is raised to 110 ℃, the high temperature and the high pressure are carried out for 10 hours, the filtration is carried out after the reaction is completed, and the crude product of piracetam is obtained after the filter cake is dried. 20ml of isopropanol is used as a solvent, activated carbon is added, heating, dissolving, refluxing and decoloring are carried out, the activated carbon is filtered, stirring is carried out, temperature crystallization is carried out, separated crystals are dried, and a piracetam final product 2.02g is obtained, wherein the yield is 71.2%. The purity was 99.12% as a result of liquid phase analysis of piracetam (after purification) as shown in fig. 1.
Example 2
Synthetic route
1) Adding 3.4 Kg of alpha-pyrrolidone into a reaction kettle, stirring 30L of alpha-pyrrolidone in toluene to dissolve, adding 2.38Kg of sodium methoxide in batches, and performing reflux reaction for 4 hours to obtain alpha-pyrrolidone sodium; and (3) detecting by TLC to complete the reaction, dropwise adding methyl chloroacetate/toluene mixed solution (4.78 Kg/10L), detecting by TLC to complete the reaction, carrying out solid-liquid separation after reacting for 6h, and distilling the filtrate to obtain a light yellow oily substance, namely 4.73Kg of alpha-pyrrolidone methyl acetate, wherein the yield is 75.4%.
2) Adding 1.57 Kg of alpha-pyrrolidone methyl acetate, 2.8Kg of ammonia water and 30L of methanol into a high-pressure reaction kettle, heating to 110 ℃, reacting at high temperature and high pressure for 10 hours, filtering after complete reaction, and drying a filter cake to obtain a crude product of piracetam. 10L of isopropanol is used as a solvent, activated carbon is added, the mixture is heated, dissolved, refluxed and decolored, the activated carbon is filtered, the mixture is stirred and cooled to crystallize, and the separated crystals are dried to obtain 0.95Kg of piracetam final product with the yield of 66.8 percent. The purity was 99.12% as a result of liquid phase analysis of piracetam (after purification) as shown in fig. 2.
Example 3
Synthetic route
1) Adding 3.1Kg of alpha-pyrrolidone into a reaction kettle, stirring 30L of alpha-pyrrolidone in toluene to dissolve, adding 2.46Kg of sodium methoxide in batches, and performing reflux reaction for 6 hours to obtain alpha-pyrrolidone sodium; and (3) detecting by TLC to complete the reaction, dropwise adding methyl chloroacetate/toluene mixed solution (5.12 Kg/10L), detecting by TLC to complete the reaction, carrying out solid-liquid separation after 5h of reaction, and distilling the filtrate to obtain 4.76Kg of light yellow oily alpha-pyrrolidone methyl acetate with the yield of 76.1%.
2) Adding 1.51 Kg of alpha-pyrrolidone methyl acetate, 2.9Kg of ammonia water and 30L of methanol into a high-pressure reaction kettle, heating to 110 ℃, reacting at high temperature and high pressure for 8 hours, filtering after complete reaction, and drying a filter cake to obtain a crude product of piracetam. 10L of isopropanol is used as a solvent, activated carbon is added, the mixture is heated, dissolved, refluxed and decolored, the activated carbon is filtered, the mixture is stirred and cooled to crystallize, and the separated crystal is dried to obtain 0.93Kg of piracetam final product with the yield of 66.4 percent. The purity was 99.05% as a result of liquid phase analysis of piracetam (after purification) as shown in fig. 3.
Example 4
1) Adding 3.6 Kg of alpha-pyrrolidone into a reaction kettle, stirring 30L of alpha-pyrrolidone in toluene to dissolve, adding 2.25Kg of sodium methoxide in batches, and performing reflux reaction for 5 hours to obtain alpha-pyrrolidone sodium; and (3) detecting by TLC to complete the reaction, dropwise adding methyl chloroacetate/toluene mixed solution (5.08 Kg/10L), detecting by TLC to complete the reaction, carrying out solid-liquid separation after reacting for 8h, and distilling the filtrate to obtain 4.69Kg of alpha-pyrrolidone methyl acetate as a light yellow oily substance with the yield of 74.9%.
2) Adding 1.63 Kg of alpha-pyrrolidone methyl acetate, 2.7Kg of ammonia water and 30L of methanol into a high-pressure reaction kettle, heating to 110 ℃, reacting at high temperature and high pressure for 12 hours, filtering after complete reaction, and drying a filter cake to obtain a crude product of piracetam. 10L of isopropanol is used as a solvent, activated carbon is added, heating, dissolving, refluxing and decoloring are carried out, the activated carbon is filtered, stirring is carried out, temperature crystallization is carried out, separated crystals are dried, and a piracetam final product of 0.96Kg is obtained, wherein the yield is 67.1%.
Example 5
As shown in fig. 4, the system for producing piracetam comprises a reflux reaction kettle 1, a first centrifuge 2, a high-temperature high-pressure reaction kettle 3, a second centrifuge 4, an activated carbon adsorption machine 5, a crystallization kettle 6, an air flow dryer 7, a cyclone separator 8 and a screening machine 9;
a liquid outlet of the reflux reaction kettle is connected with a first centrifugal machine, a liquid outlet of the first centrifugal machine is connected with a distillation tower 10, a discharge port of the distillation tower is connected with a high-temperature high-pressure reaction kettle, a liquid outlet of the high-temperature high-pressure reaction kettle is connected with a second centrifugal machine, a discharge port of the second centrifugal machine is connected with an activated carbon adsorption machine, and a liquid outlet of the second centrifugal machine is connected with a mother liquor tank 11; the mother liquor tank is connected with the high-temperature high-pressure reaction kettle through a mother liquor pump; a discharge port of the activated carbon adsorption machine is connected with a crystallization kettle; a discharge port of the crystallization kettle is connected with an airflow dryer, a discharge port of the airflow dryer is connected with a cyclone separator, and a discharge port of the cyclone separator is connected with a sieving machine; the discharge port of the screening machine is connected with a material barrel 13. The reflux reaction kettle is also connected with a dosing tank 12.
The system of this example was used for the production of piracetam of example 2; the method specifically comprises the following steps: putting materials of alpha-pyrrolidone, toluene and sodium methoxide into a reflux reaction kettle for reflux reaction, after the reaction is finished, dropwise adding methyl chloroacetate/toluene mixed solution, wherein the methyl chloroacetate/toluene mixed solution is arranged in a batching tank and is connected with the reflux reaction kettle through a peristaltic pump; after the reaction is finished, performing solid-liquid separation by a first centrifuge, and distilling the liquid by a distillation tower to obtain a product, namely a light yellow oily alpha-pyrrolidone methyl acetate. Putting the product, ammonia water and methanol into a high-temperature high-pressure reaction kettle, after the reaction is completed, filtering in a centrifuge, allowing the filtrate to enter a mother liquor tank, and continuously returning to the high-temperature high-pressure reaction kettle; the solid was dried to give crude piracetam. In the system, the crude piracetam product directly enters an activated carbon adsorption machine for activated carbon adsorption treatment without being dried, and then enters a crystallization kettle for recrystallization to obtain purified piracetam.
The above is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, it is possible to make several improvements and modifications without departing from the technical principle of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention.
Claims (10)
1. A preparation method of piracetam is characterized by comprising the following steps:
(1) Dissolving alpha-pyrrolidone in an organic solvent, stirring, adding sodium methoxide in batches, and performing reflux reaction to obtain alpha-pyrrolidone sodium; after the reaction is completed, methyl chloroacetate/toluene mixed solution is dripped, solid-liquid separation is carried out after the reaction is completed, and filtrate is distilled to obtain a light yellow oily alpha-pyrrolidone methyl acetate;
(2) Adding methyl alpha-pyrrolidone acetate and ammonia water into methanol, reacting completely at high temperature and high pressure, filtering, and drying a filter cake to obtain piracetam;
the synthetic route is as follows
2. A process for preparing piracetam in accordance with claim 1, wherein: in step 1, the organic solvent is toluene.
3. A process for the preparation of piracetam in accordance with claim 1, wherein: in step 1, the ratio of methyl chloroacetate/toluene mixed solution is 1.
4. A process for the preparation of piracetam in accordance with claim 1, wherein: in the step 2, the organic solvent is one of methanol, acetonitrile, tetrahydrofuran and dichloromethane.
5. A process for the preparation of piracetam in accordance with claim 1, wherein: in the step 2, the temperature is about 110 ℃, and the reaction time is 8-12h.
6. A process for the preparation of piracetam in accordance with claim 1, wherein: in step 2, the subsequent purification method of piracetam comprises the following steps: adding activated carbon into isopropanol serving as a solvent, heating, dissolving, refluxing and decoloring, filtering the activated carbon, stirring, cooling, crystallizing, and drying separated crystals to obtain the purified piracetam.
7. A system for preparing piracetam, which is characterized in that: the system comprises a reflux reaction kettle, a first centrifugal machine, a high-temperature high-pressure reaction kettle, a second centrifugal machine, an airflow dryer, a cyclone separator and a sieving machine; a liquid outlet of the reflux reaction kettle is connected with a first centrifugal machine, a liquid outlet of the first centrifugal machine is connected with a distillation tower, a discharge port of the distillation tower is connected with a high-temperature high-pressure reaction kettle, a liquid outlet of the high-temperature high-pressure reaction kettle is connected with a second centrifugal machine, and a discharge port of the second centrifugal machine is connected with an airflow dryer; the discharge port of the airflow dryer is connected with the cyclone separator, and the discharge port of the cyclone separator is connected with the sieving machine.
8. A system for the preparation of piracetam in accordance with claim 7, wherein: the discharge port of the second centrifuge is connected with an activated carbon adsorption machine, and the discharge port of the activated carbon adsorption machine is connected with a crystallization kettle; and a discharge port of the crystallization kettle is connected with an air flow dryer.
9. A system for the preparation of piracetam in accordance with claim 7, wherein: a liquid outlet of the second centrifugal machine is connected with a mother liquid tank; the mother liquor tank is connected with the high-temperature high-pressure reaction kettle through a mother liquor pump.
10. A system for the preparation of piracetam in accordance with claim 7, wherein: the reflux reaction kettle is also connected with a batching tank.
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| CN202211593079.4A CN115974751A (en) | 2022-12-13 | 2022-12-13 | Piracetam preparation method and system |
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| CN202211593079.4A CN115974751A (en) | 2022-12-13 | 2022-12-13 | Piracetam preparation method and system |
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