Preparation method of piracetam raw material

Abstract

The application relates to the technical field of drug chemical synthesis, and discloses a preparation method of piracetam raw material, which comprises the following steps: S1, alpha-pyrrolidone is added into a solvent and a sodium methoxide methanol solution, and is dried to obtain alpha-pyrrolidone sodium salt; S2, the alpha-pyrrolidone sodium salt is esterified to obtain alpha-pyrrolidone methyl acetate; S3, the alpha-pyrrolidone methyl acetate is ammoniated to obtain crude piracetam; and S4, after the crude piracetam is purified, piracetam is obtained; the solvent is one of toluene, acetonitrile and dimethyl sulfoxide. Through the technical scheme, the problems of complex synthesis process, low safety and high raw material cost of piracetam in the prior art are solved, and the yield and purity of piracetam are improved.

Description

A method for preparing piracetam raw material Technical Field

[0001] This invention relates to the field of pharmaceutical chemical synthesis technology, specifically to a method for preparing piracetam raw material. Background Technology

[0002] Piracetam, a derivative of gamma-aminobutyric acid (GABA), is a novel memory-enhancing drug. It improves brain metabolism and, from a medicinal chemistry perspective, belongs to the cyclic derivatives of GABA. This drug can counteract brain damage caused by chemical or physical factors, improving memory and thus enhancing learning ability. Clinically, it is mainly used to treat memory loss and brain dysfunction caused by acute and chronic cerebrovascular diseases, external brain injuries, and toxic brain diseases. It is commonly used to treat traumatic brain injury and acute and chronic cerebrovascular diseases. It has a certain therapeutic effect on memory loss and brain dysfunction caused by various reasons. If a patient's memory loss is due to traumatic brain injury, medication can achieve a therapeutic effect. Piracetam tablets were originally developed by UCB pharm GmbH in Belgium in 1963 and marketed in the 1970s under the brand name Nootropil for the treatment of memory and balance problems, generating a strong market response. In my country, the Northeast Pharmaceutical Factory was the first to successfully produce and market a generic version in 1980. However, there are few manufacturers of piracetam raw materials on the market, and the production process is complex, time-consuming, and energy-intensive, so the price remains high.

[0003] CN94100107.5 discloses a method for synthesizing α-pyrrolidone acetamide. This method uses α-pyrrolidone as a starting material and reacts with alkali metal-sodium at high temperature for up to 50 hours to prepare crude piracetam. Piracetam is then obtained by recrystallization from isopropanol. However, alkali metals are chemically very reactive, difficult to store, and can react with water to produce sodium hydroxide and release a large amount of hydrogen gas, posing a great safety hazard. The overall yield of this method is only 36%.

[0004] CN99112714.5 discloses a novel method for synthesizing piracetam. This method involves mixing ethyl 4-chlorobutyrate, glycine hydrochloride, a base, and an alcoholic organic solvent, then heating under reflux for 30 hours to obtain a crude product, which is then recrystallized to obtain the piracetam raw material. However, this method has high raw material costs and requires 30 hours of reflux during the reaction, which is time-consuming and energy-intensive, significantly increasing the overall cost.

[0005] CN201210252587.6 discloses a novel method for synthesizing piracetam, which involves mixing ethyl 4-chlorobutyrate, glycine hydrochloride, an alkali, and an alcoholic organic solvent, heating under reflux for 20-30 hours, hot filtering, distilling off the solvent under reduced pressure, and recrystallizing the residue to obtain the piracetam product. Although this method involves only one chemical reaction, the reaction takes 30 hours, which is time-consuming and energy-intensive. Furthermore, the purchase cost of 4-chlorobutyryl chloride is high, and it is highly corrosive, causing significant damage to the equipment.

[0006] CN201410680378.0 discloses a novel method for synthesizing the nootropic drug piracetam. This method uses α-pyrrolidone as a raw material, preparing a sodium salt using sodium methoxide in methanol, then reacting it with methyl chloroacetate to prepare the intermediate methyl pyrrolidone acetate. This intermediate requires purification by vacuum distillation, followed by reaction with ammonia to obtain crude piracetam, which is then recrystallized from isopropanol to obtain piracetam. However, methyl pyrrolidone acetate has a high boiling point of 260℃. Vacuum distillation consumes a significant amount of energy, resulting in waste and is also time-consuming.

[0007] CN201711413080.3 discloses a new method for synthesizing piracetam. The specific steps of this method are as follows: bromoacetic acid, ethanol, and benzene are passed through ammonia gas, concentrated sulfuric acid is added, and the alcohol and water are separated by reflux in a boiling water bath to obtain crude piracetam. The crude product is then recrystallized in toluene in the presence of potassium hydroxide. This method uses highly toxic substances, benzene, and highly corrosive concentrated sulfuric acid, which poses a significant danger to humans and the environment, and is therefore unsuitable for large-scale production.

[0008] CN201910366788.0 discloses a synthetic process for piracetam. This method involves mixing glycine hydrochloride, a phase transfer catalyst, and an alkali, then adding a 4-chlorobutyryl chloride solution dropwise at a controlled temperature. The pH is adjusted, the mixture is filtered, and crude piracetam is obtained. This crude product is then recrystallized from isopropanol to obtain piracetam. However, 4-chlorobutyryl chloride is expensive to purchase and highly corrosive, causing significant wear and tear on equipment.

[0009] Therefore, there is an urgent need to develop a simple, safe, and low-cost piracetam production process. Summary of the Invention

[0010] This invention proposes a method for preparing piracetam raw material, which solves the problems of complex synthesis process, low safety and high raw material cost of piracetam in related technologies, and improves the yield and purity of piracetam.

[0011] The technical solution of the present invention is as follows:

[0012] A method for preparing piracetam raw material includes the following steps:

[0013] S1. Add α-pyrrolidone to a solvent and sodium methoxide solution, and dry to obtain sodium α-pyrrolidone salt;

[0014] S2. Esterify sodium α-pyrrolidone to obtain methyl α-pyrrolidone acetate;

[0015] S3. Ammoniate methyl α-pyrrolidone acetate to obtain crude piracetam;

[0016] S4. After purification of crude piracetam, piracetam was obtained.

[0017] The solvent in S1 is one of toluene, acetonitrile, and dimethyl sulfoxide.

[0018] As a further technical solution, the solvent is one of acetonitrile and dimethyl sulfoxide.

[0019] As a further technical solution, the solvent is dimethyl sulfoxide.

[0020] As a further technical solution, the sodium methoxide solution is a sodium methoxide methanol solution.

[0021] As a further technical solution, the reaction temperature in S1 is 90-110℃ and the reaction time is 1-3h.

[0022] As a further technical solution, the esterification in S2 is carried out by adding sodium α-pyrrolidone and a catalyst to a solvent, mixing them evenly, and then adding methyl chloroacetate to react and obtain α-pyrrolidone; the solvent in S2 is one of toluene, acetonitrile, and dimethyl sulfoxide.

[0023] As a further technical solution, the esterification in S2 is carried out by adding sodium α-pyrrolidone and a catalyst to a solvent, stirring, adding methyl chloroacetate, reacting, filtering, concentrating under reduced pressure, and distilling off the solvent to obtain methyl α-pyrrolidone acetate.

[0024] As a further technical solution, the amount of catalyst added is 1%-10% of the molar amount of α-pyrrolidone.

[0025] As a further technical solution, the reaction temperature in S2 is 15-35℃ and the reaction time is 1-10h.

[0026] As a further technical solution, the catalyst includes one or more of benzyltriethylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium chloride.

[0027] As a further technical solution, the ammoniation in S3 is carried out by introducing ammonia gas, and the amount of ammonia gas is 2-5 times the molar amount of α-pyrrolidone.

[0028] As a further technical solution, the ammoniation temperature in S3 is 0-50℃, and the ammoniation time is 2-9.5h.

[0029] As a further technical solution, the amination in S3 is carried out by adding methyl α-pyrrolidone acetate to an organic solvent, mixing it evenly, passing ammonia gas through it for reaction, filtering, adding it to an organic solvent, filtering, washing, and obtaining crude piracetam.

[0030] As a further technical solution, the purification in S4 is to mix crude piracetam, organic solvent and activated carbon, reflux, recrystallize, filter and dry to obtain piracetam.

[0031] As a further technical solution, the reflux time is 0.5-3 hours.

[0032] As a further technical solution, the organic solvent includes one of methanol, ethanol, isopropanol, and tert-butanol.

[0033] As a further technical solution, the ratio of the amount of organic solvent added in S4 to the mass of crude piracetam is 2-4:1.

[0034] The working principle and beneficial effects of this invention are as follows:

[0035] 1. In this invention, when preparing α-pyrrolidone sodium salt, piracetam is prepared by adding toluene, acetonitrile, or dimethyl sulfoxide solvent in combination with sodium methoxide methanol solution, which improves the yield of crude piracetam. Furthermore, the yield of crude piracetam is higher when the solvent is acetonitrile or dimethyl sulfoxide than when it is toluene.

[0036] 2. This invention optimizes the synthesis process of piracetam, reducing the temperature of the esterification reaction. The esterification of sodium α-pyrrolidone can be completed at 15-35℃ to prepare methyl α-pyrrolidone acetate. Furthermore, qualified products can be obtained without vacuum distillation after the esterification reaction.

[0037] 3. The reaction conditions in the preparation process of this invention are mild, the production operation is simple, and the solvents used in each step can be recovered and reused, which saves costs and reduces the pressure on the environment. In addition, the raw materials and solvents used in the synthesis are cheap and readily available, making it suitable for large-scale industrial production. Detailed Implementation

[0038] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0039] The purity of the products in the following examples and comparative examples was determined according to the following method:

[0040] High performance liquid chromatography: An Agilent Zorbax SB-C18 column (4.6 mm × 250 mm, 5 μm) was used; the mobile phase was 0.1% dipotassium hydrogen phosphate solution (adjusted to pH 6.0 with phosphoric acid) - acetonitrile (95:5); the flow rate was 1.0 mL per minute, the detection wavelength was 205 nm, the injection volume was 20 μL, and the purity was determined.

[0041] Example 1

[0042] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) were sequentially pumped into a 1L four-necked reaction flask, stirred and heated to 110℃ and kept at that temperature for 1h.

[0043] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 25℃ for 2.5h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0044] S3. The methyl α-pyrrolidone acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5°C, 50 g of ammonia gas was introduced, and the mixture was stirred at 10°C for 9.5 h to induce crystallization. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. The mixture was stirred at 10°C for 10 min, and then filtered, washed, and dried to obtain 104 g of crude piracetam. The yield of the crude piracetam was 62.87%, and the purity was 99.03%.

[0045] S4. Add 100g of crude piracetam to a 1L reaction flask, add 200mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 2h to decolorize, control the temperature at 5±5℃, stir slowly, and crystallize for 3h. After crystallization, centrifuge, wash and dry to obtain 91g of piracetam; the yield of the obtained piracetam is 91%, and the purity is 99.99%.

[0046] Example 2

[0047] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) were sequentially pumped into a 1L four-necked reaction flask, stirred and heated to 105℃ and kept at that temperature for 2h.

[0048] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 35℃ for 1h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0049] S3. The methyl α-pyrrolidone acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5°C, 80 g of ammonia gas was introduced, and the mixture was stirred at 10°C for 6 h to crystallize. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. After stirring at 10°C for 10 min, the mixture was filtered, washed, and dried to obtain 106 g of crude piracetam. The yield of the crude piracetam was 63.47%, and the purity was 99.07%.

[0050] S4. Add 100g of crude piracetam to a 1L reaction flask, add 300mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 2h for decolorization, control the temperature at 5±5℃, stir slowly, and crystallize for 5h. After crystallization, centrifuge, wash and dry to obtain 88g of piracetam; the yield of the obtained piracetam is 88%, and the purity is 99.99%.

[0051] Example 3

[0052] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) were sequentially pumped into a 1L four-necked reaction flask, stirred and heated to 100℃ and kept at that temperature for 2h.

[0053] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 20℃ for 3h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0054] S3. The methyl α-pyrrolidone acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5°C, 75 g of ammonia gas was introduced, and the mixture was stirred at 10°C for 8 h to crystallize. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. After stirring at 10°C for 10 min, the mixture was filtered, washed, and dried to obtain 104 g of crude piracetam. The yield of the crude piracetam was 62.28%, and the purity was 99.13%.

[0055] S4. Add 100g of crude piracetam to a 1L reaction flask, add 250mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 2h for decolorization, control the temperature at 5±5℃, stir slowly, and crystallize for 5h. After crystallization, centrifuge, wash and dry to obtain 89g of piracetam; the yield of the obtained piracetam is 89%, and the purity is 100.00%.

[0056] Example 4

[0057] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) were sequentially pumped into a 1L four-necked reaction flask, stirred and heated to 90℃ and kept at that temperature for 3h.

[0058] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 20℃ for 4h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0059] S3. The α-pyrrolidone methyl acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5°C, 100 g of ammonia gas was introduced, and the mixture was stirred at 10°C for 2 h to crystallize. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. After stirring at 10°C for 10 min, the mixture was filtered, washed, and dried to obtain 101 g of crude piracetam. The yield of the crude piracetam was 60.48%, and the purity was 99.06%.

[0060] S4. Add 100g of crude piracetam to a 1L reaction flask, add 400mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 2h for decolorization, control the temperature at 5±5℃, stir slowly, and crystallize for 5h. After crystallization, centrifuge, wash and dry to obtain 87g of piracetam; the yield of the obtained piracetam is 87%, and the purity is 99.99%.

[0061] Example 5

[0062] Compared to Example 1, Example 5 differs in that all toluene is replaced with an equal amount of acetonitrile. The resulting crude piracetam product was 106 g, with a yield of 63.47% and a purity of 99.16%; the resulting piracetam product was 87 g, with a yield of 91% and a purity of 99.99%.

[0063] Example 6

[0064] Compared to Example 1, Example 6 differs in that all toluene is replaced with an equal amount of dimethyl sulfoxide. The resulting crude piracetam product was 110 g, with a yield of 65.87% and a purity of 99.19%; the resulting piracetam product was 91 g, with a yield of 91% and a purity of 100.00%.

[0065] Example 7

[0066] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) were sequentially pumped into a 1L four-necked reaction flask, stirred and heated to 110℃ and kept at that temperature for 1h.

[0067] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 15℃ for 10h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0068] S3. The methyl α-pyrrolidone acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5°C, 50 g of ammonia gas was introduced, and the mixture was stirred at 50°C for 9.5 h to induce crystallization. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. The mixture was stirred at 10°C for 10 min, and then filtered, washed, and dried to obtain 102 g of crude piracetam. The yield of the crude piracetam was 61.08%, and the purity was 99.22%.

[0069] S4. Add 100g of crude piracetam to a 1L reaction flask, add 200mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 0.5h for decolorization, control the temperature at 5±5℃, stir slowly, and crystallize for 3h. After crystallization, centrifuge, wash and dry to obtain 90.8g of piracetam; the yield of the obtained piracetam is 90.8%, and the purity is 100.00%.

[0070] Example 8

[0071] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) were sequentially pumped into a 1L four-necked reaction flask, stirred and heated to 110℃ and kept at that temperature for 1h.

[0072] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 25℃ for 2.5h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0073] S3. The methyl α-pyrrolidone acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5°C, 50 g of ammonia gas was introduced, and the mixture was stirred at 0°C for 9.5 h to induce crystallization. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. The mixture was stirred at 10°C for 10 min, and then filtered, washed, and dried to obtain 106 g of crude piracetam. The yield of the crude piracetam was 63.47%, and the purity was 99.18%.

[0074] S4. Add 100g of crude piracetam to a 1L reaction flask, add 200mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 3h to decolorize, control the temperature at 5±5℃, stir slowly, and crystallize for 3h. After crystallization, centrifuge, wash and dry to obtain 91.3g of piracetam; the yield of the obtained piracetam is 91.3% and the purity is 100.00%.

[0075] Comparative Example 1

[0076] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) are sequentially pumped into a 1L four-necked reaction flask, stirring is started, and the temperature is raised to 60℃ and kept at that temperature for 1h.

[0077] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 25℃ for 2.5h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0078] S3. The methyl α-pyrrolidone acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5 °C, 50 g of ammonia gas was introduced, and the mixture was stirred to crystallize for 9.5 h. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. The mixture was stirred at 10 °C for 10 min, and then filtered, washed, and dried to obtain 21 g of crude piracetam. The yield of the crude piracetam was 12.57%, and the purity was 98.29%.

[0079] S4. Add 20g of crude piracetam to a 1L reaction flask, add 40mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 2h for decolorization, control the temperature at 5±5℃, stir slowly, and crystallize for 3h. After crystallization, centrifuge, wash and dry to obtain 17g of piracetam; the yield of the obtained piracetam is 85% and the purity is 99.97%.

[0080] Comparative Example 2

[0081] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) were sequentially pumped into a 1L four-necked reaction flask, stirred and heated to 110℃ and kept at that temperature for 1h.

[0082] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 25℃ for 2.5h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0083] S3. The methyl α-pyrrolidone acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5°C, 50 g of ammonia gas was introduced, the temperature was raised to 60°C, and the mixture was stirred to crystallize for 9.5 h. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. After stirring at 10°C for 10 min, the mixture was filtered, washed, and dried to obtain 58 g of crude piracetam. The yield of the crude piracetam was 34.73%, and the purity was 98.46%.

[0084] S4. Add 50g of crude piracetam to a 1L reaction flask, add 100mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 2h to decolorize, control the temperature at 5±5℃, stir slowly, and crystallize for 3h. After crystallization, centrifuge, wash and dry to obtain 44g of piracetam; the yield of the obtained piracetam is 88%, and the purity is 99.98%.

[0085] Comparative Example 3

[0086] Compared with Example 1, Comparative Example 3 differs in that, in step S3, after ammonia gas is introduced, the stirring and crystallization time is 14 hours, while the rest is the same as in Example 1; the obtained crude piracetam product is 102 g, the yield of crude piracetam product is 61.08%, and the purity is 98.48%; the obtained piracetam product is 91 g, the yield of piracetam product is 91%, and the purity is 99.99%.

[0087] Comparative Example 4

[0088] S1. 100g α-pyrrolidone, 500mL toluene and 221g sodium methoxide methanol solution (28.4% w / w) were sequentially pumped into a 1L four-necked reaction flask, stirred and heated to 110℃ and kept at that temperature for 1h.

[0089] S2. Cool to 40℃, add to 500mL toluene and stir for 10min. Continue cooling to 30℃, add 10.67g benzyltriethylammonium chloride, stir evenly, then add dropwise a mixture of 140g methyl chloroacetate and 100mL toluene. React at 50℃ for 2.5h. After the reaction is complete, filter and concentrate to obtain α-pyrrolidone methyl acetate.

[0090] S3. The methyl α-pyrrolidone acetate obtained above was added to 300 mL of isopropanol. After the oily substance was completely dissolved, the temperature was lowered to 5 °C, 50 g of ammonia gas was introduced, and the mixture was stirred to crystallize for 9.5 h. After the reaction was completed, the mixture was filtered, and the resulting solid was added to 200 mL of methanol. The mixture was stirred at 10 °C for 10 min, and then filtered, washed, and dried to obtain 102.5 g of crude piracetam. The yield of the crude piracetam was 61.38%, and the purity was 98.33%.

[0091] S4. Add 90g of crude piracetam to a 1L reaction flask, add 180mL of methanol, heat until the reaction system refluxes, add 5g of activated carbon and maintain reflux for 2h for decolorization, control the temperature at 5±5℃, stir slowly, and crystallize for 3h. After crystallization, centrifuge, wash and dry to obtain 82g of piracetam; the yield of the obtained piracetam is 91%, and the purity is 99.98%.

[0092] By comparing the examples and comparative examples, it can be seen that, compared with Example 1, Example 5 replaced all toluene with an equal amount of acetonitrile, and Example 6 replaced all toluene with an equal amount of dimethyl sulfoxide. As a result, the yield of crude piracetam in Examples 5 and 6 was higher than that in Example 1, and the yield of crude piracetam in Example 6 was higher than that in Example 5. This indicates that using dimethyl sulfoxide as a solvent can better improve the yield of crude piracetam.

[0093] Compared with Example 1, the difference of Comparative Example 1 is that in step S1 of Comparative Example 1, the temperature was raised to 60°C. Due to the low temperature, the preparation of α-pyrrolidone sodium salt was incomplete under normal pressure, resulting in a yield of only 12.57% of crude piracetam.

[0094] Compared with Example 1, the difference of Comparative Example 2 is that the reaction temperature during crystallization in step S3 of Comparative Example 2 is 60°C. Due to the excessively high temperature, the solubility of isopropanol in ammonia is greatly reduced, resulting in a large amount of ammonia volatilizing and being unable to participate in the reaction. Therefore, under the same amount of ammonia, the crude product yield is only 34.73%.

[0095] Compared with Example 1, the difference of Comparative Example 3 is that the crystallization time in step S3 of Comparative Example 3 is 14 hours. As a result, the yield of crude piracetam is 61.08%, which is not much different from the yield of crude piracetam in Example 1 and does not show a significant improvement. Therefore, from the perspective of energy saving and cost reduction, increasing the crystallization time not only does not improve the yield of crude piracetam, but also increases the cost.

[0096] Compared with Example 1, the difference of Comparative Example 4 is that in step S2 of Comparative Example 4, the reaction was carried out at 50°C for 2.5 hours. As a result, the yield of crude piracetam was 61.38%, which was not much different from the yield of crude piracetam in Example 1 and did not significantly improve. Therefore, from the perspective of energy saving and cost reduction, the reaction temperature of 50°C not only did not improve the yield of crude piracetam, but also increased the cost.

[0097] Test case

[0098] Chemical analysis was performed on the product synthesized in Example 1, and the following physical property values ​​were obtained. The chemical analysis results of the following physical property values ​​confirm that the synthesized product is piracetam.

[0099] Melting point: 151℃—152℃

[0100] ESI-MS m / z: 143.0811

[0101] Table 1. 1H-NMR (500MHz, MeOD) Analysis Results

[0102]

[0103]

[0104] Table 2 13C-NMR Analysis Results

[0105] Atomic number, chemical shift (ppm): 20 -61.91 -118.24 -136.82 -143.8 surface

[0106] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing piracetam raw material, characterized in that, Includes the following steps: S1. Add α-pyrrolidone to a solvent and sodium methoxide solution, and react to obtain sodium α-pyrrolidone salt; S2. Esterification of sodium α-pyrrolidone to obtain methyl α-pyrrolidone acetate; S3. Aminolation of methyl α-pyrrolidone acetate to obtain crude piracetam; S4. Purification of crude piracetam to obtain piracetam; The solvent in S1 is dimethyl sulfoxide; The reaction temperature in S2 is 15-35℃, and the reaction time is 1-10h; The aminolation temperature in S3 is 0-10℃, and the aminolation time is 2-9.5h.

2. The method for preparing piracetam raw material according to claim 1, characterized in that, The reaction temperature in S1 is 90-110℃, and the reaction time is 1-3h.

3. The method for preparing piracetam raw material according to claim 1, characterized in that, In S2, esterification is carried out by adding sodium α-pyrrolidone and a catalyst to a solvent, mixing them evenly, and then adding methyl chloroacetate to react and obtain α-pyrrolidone; the solvent in S2 is one of toluene, acetonitrile, and dimethyl sulfoxide.

4. The method for preparing a piracetam raw material according to claim 3, characterized in that, The amount of catalyst added is 1%-10% of the molar amount of α-pyrrolidone.

5. The method for preparing a piracetam raw material according to claim 3, characterized in that, The catalyst includes one or more of benzyltriethylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium bromide, and tetrabutylammonium chloride.

6. The method for preparing a piracetam raw material according to claim 1, characterized in that, In S3, ammoniation is performed by introducing ammonia gas, and the amount of ammonia gas is 2-5 times the molar amount of α-pyrrolidone.

7. The method for preparing a piracetam raw material according to claim 1, characterized in that, The purification process in S4 involves adding crude piracetam to an organic solvent and refluxing it with activated carbon, recrystallizing, filtering, and drying to obtain piracetam.

8. The method for preparing a piracetam raw material according to claim 7, characterized in that, The organic solvent includes one of methanol, ethanol, isopropanol, and tert-butanol.

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