Novel synthesis method of nootropic piracetam

Abstract

The invention belongs to the field of chemical synthesis and relates to a synthesis method of piracetam. The method comprises the following steps: by taking alpha-pyrrolidone as raw material, slowly dropwise adding a methanol solution (28.4% w / w) of sodium methoxide at reduced pressure; distilling the methanol solvent at reduced pressure and normal pressure; after methanol is evaporated completely, slowly dropwise adding a methylbenzene solution of methyl chloroacetate, controlling the reaction temperature to be 20 to 110 DEG C and reacting for 5.0 hours under heat-preserved condition; cooling to room temperature; carrying out suction filtering; distilling the filtrate at reduced pressure; collecting fractions with the temperature of 100 to 105 DEG C; mixing the fractions with ammonia gas / a methanol solution; reacting at the temperature of 50 to 70 DEG C for 3-18 hours; thermally filtering to obtain a primary crude product; concentrating the filtrate at reduced pressure to obtain a secondary crude product; mixing the crude products; recrystallizing by using an alcohol solvent; filtering and drying to obtain white crystals to obtain piracetam, wherein the mole ratio of alpha-pyrrolidone to methyl chloroacetate is 1:(1.0-2.0). The method is mild in reaction condition, simple and convenient in production and operation; synthesis raw materials and solvents are cheap and easily available, and therefore the method is suitable for large-scale industrial production; after the recrystallization, the yield is as high as 82.4% (metered based on the alpha-pyrrolidone), and the purity is higher than 99.9%.

Description

Technical field:

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthetic method of piracetam. Background technique:

[0002] Piracetam (Piracetam, trade name Naofukang) was first developed and synthesized by UCB Research Institute in Belgium in 1963, and was first imitated and produced by Northeast Pharmaceutical General Factory in 1980. Studies have shown that piracetam has the functions of activating, protecting and repairing nerve cells. It is the only drug that acts on the central nervous system and is called "nootropic" (nootropics). It is currently widely used clinically to treat the sequelae of encephalopathy. Drugs and nootropic drugs can significantly improve memory for memory loss caused by various reasons, mild and moderate brain dysfunction, senile dementia, and children's mental retardation.

[0003]

[0004] Chemical name: 2-(2-oxopyrrolidone)acetamide

[0005] Molecular formula: C 6 h 10 N 2 o...

Examples

Embodiment 1

[0036] The method for synthesizing piracetam, it may further comprise the steps:

[0037] Preparation of α-pyrrolidone sodium salt: Equip a 1000mL three-necked bottle with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving bottle. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added into the three-necked flask. When the temperature of the reaction system reached 70° C., a methanol solution of sodium methoxide (28.4% (w / w)); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition was completed, the temperature was raised, and the distillation was carried out at atmospheric pressure until the distillate was completely distilled off, and the reaction was completed.

[0038] Preparation of α-pyrrolidone me...

Embodiment 2

[0042] Preparation of α-pyrrolidone sodium salt: Equip a 1000mL three-necked bottle with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving bottle. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added into the three-necked flask. When the temperature of the reaction system reached 100° C., a methanol solution of sodium methoxide (28.4% (w / w)); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition, toluene was added, the temperature was raised, and distillation was carried out at atmospheric pressure until the distillate was completely distilled off, and the reaction was completed.

[0043] Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condens...

Embodiment 3

[0047] Preparation of α-pyrrolidone sodium salt: Equip a 1000mL three-necked bottle with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 1000mL receiving bottle. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added into the three-necked flask. When the temperature of the reaction system reached 70° C., a methanol solution of sodium methoxide (28.4% (w / w)); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition was completed, the temperature was raised, and the distillation was carried out at atmospheric pressure until the distillate was completely distilled off, and the reaction was completed.

[0048] Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condense...

Technical field:

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthetic method of piracetam. Background technique:

[0002] Piracetam (Piracetam, trade name Naofukang) was first developed and synthesized by UCB Research Institute in Belgium in 1963, and was first imitated and produced by Northeast Pharmaceutical General Factory in 1980. Studies have shown that piracetam has the functions of activating, protecting and repairing nerve cells. It is the only drug that acts on the central nervous system and is called "nootropic" (nootropics). It is currently widely used clinically to treat the sequelae of encephalopathy. Drugs and nootropic drugs can significantly improve memory for memory loss caused by various reasons, mild and moderate brain dysfunction, senile dementia, and children's mental retardation.

[0003]

[0004] Chemical name: 2-(2-oxopyrrolidone)acetamide

[0005] Molecular formula: C 6 h 10 N 2 o...

Examples

Embodiment 1

[0036] The method for synthesizing piracetam, it may further comprise the steps:

[0037] Preparation of α-pyrrolidone sodium salt: Equip a 1000mL three-necked bottle with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving bottle. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added into the three-necked flask. When the temperature of the reaction system reached 70° C., a methanol solution of sodium methoxide (28.4% (w / w)); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition was completed, the temperature was raised, and the distillation was carried out at atmospheric pressure until the distillate was completely distilled off, and the reaction was completed.

[0038] Preparation of α-pyrrolidone me...

Embodiment 2

[0042] Preparation of α-pyrrolidone sodium salt: Equip a 1000mL three-necked bottle with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 500mL receiving bottle. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added into the three-necked flask. When the temperature of the reaction system reached 100° C., a methanol solution of sodium methoxide (28.4% (w / w)); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition, toluene was added, the temperature was raised, and distillation was carried out at atmospheric pressure until the distillate was completely distilled off, and the reaction was completed.

[0043] Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condens...

Embodiment 3

[0047] Preparation of α-pyrrolidone sodium salt: Equip a 1000mL three-necked bottle with mechanical stirring, a constant pressure dropping funnel and a thorn-shaped fractionating column. The upper end of the fractionation column is connected with a thermometer, a condenser and a 1000mL receiving bottle. Under mechanical stirring, 46 mL (0.60 mol) of α-pyrrolidone and 250 mL of toluene were sequentially added into the three-necked flask. When the temperature of the reaction system reached 70° C., a methanol solution of sodium methoxide (28.4% (w / w)); 114.0 g; 0.60 mol) was added dropwise under reduced pressure, and the distillate was collected. After the dropwise addition was completed, the temperature was raised, and the distillation was carried out at atmospheric pressure until the distillate was completely distilled off, and the reaction was completed.

[0048] Preparation of α-pyrrolidone methyl acetate: remove the fractionation device, connect a thermometer and a condense...

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