阅读说明：本技术 一种丙戊酸钠的生产工艺 (Production process of sodium valproate ) 是由 林凡友 聂昌盛 林业翔 王丽娟 于 2019-08-23 设计创作，主要内容包括：本发明公开一种丙戊酸钠的生产工艺,其生产工艺为：投料配比：正溴丙烷2100kg、四丁基溴化铵、18.6kg、乙酰乙酸甲酯420kg和碳酸钾1080kg；烷基化得二丙物；脱酰得脱酰物；碱解得粗丙戊酸；成盐,调毕,浓缩,干燥,混合,包装,检验合格后入库。本发明工艺简单易操作,成本低廉,大大降低了企业的生产成本。(The invention discloses a production process of sodium valproate, which comprises the following steps: feeding and proportioning: 2100kg of n-propyl bromide, 18.6kg of tetrabutylammonium bromide, 420kg of methyl acetoacetate and 1080kg of potassium carbonate; alkylating to obtain a dipropyl substance; deacylating to obtain deacylated product; alkali hydrolysis to obtain crude valproic acid; salifying, mixing, concentrating, drying, mixing, packaging, and warehousing after passing inspection. The method has the advantages of simple process, easy operation and low cost, and greatly reduces the production cost of enterprises.)

1. a production process of sodium valproate is characterized by comprising the following steps:

1. feeding and proportioning:

2100kg of n-propyl bromide, 18.6kg of tetrabutylammonium bromide, 420kg of methyl acetoacetate and 1080kg of potassium carbonate;

2. The production process comprises the following steps:

2.1 alkylation

Adding potassium carbonate, n-bromopropane and tetra-n-butylammonium bromide into a kettle, sealing, stirring, steaming, fully refluxing, dropwise adding methyl acetoacetate, refluxing at normal pressure for 2 hours after finishing dripping, then refluxing under pressure for 6 hours (0.04-0.06MPa), discharging part of n-bromopropane after pressurizing for 4 hours, raising the temperature to 104-106 ℃, emptying after refluxing under pressure, cooling to 70 ℃, adding 1800L of water, raising the temperature to 60 ℃, standing for 20 minutes, removing a water layer, washing with 25% sodium chloride solution twice, and putting an oil layer into a distillation kettle;

keeping total reflux for 15 minutes, collecting front fraction after total reflux, suspending heating when the temperature of a tower kettle rises to 140 ℃, collecting the smaller and smaller fraction, slowly opening vacuum to reach more than-0.095 Mpa, restarting heating to continue collecting the front fraction, switching to collect middle fraction when the temperature of the tower top rises obviously, switching to collect rear fraction when the difference between the top temperature, the middle temperature and the bottom temperature of a rectifying tower is very small, and steaming until the front fraction is not discharged basically to obtain the dipropyl substance;

2.2 deacylation:

Refined dipropyl compound, methanol, sodium methoxide = 65: 15: 16

firstly, adding methanol and sodium methoxide into a kettle, steaming until full reflux is achieved, dropwise adding the refined dipropyl product obtained in the previous step, distilling the distillate under normal pressure after refluxing for 2 hours, cooling to 70 ℃ after the fractionation is achieved, and washing with water twice to obtain a deacylated product;

2.3 alkaline hydrolysis:

deacylated product sodium hydroxide: water =3.5: 1: 2.25

adding a sodium hydroxide solution and the deacylated product into a tank, slowly heating and refluxing for 2 hours, adding 150L of water, distilling until the internal temperature reaches 110 ℃, cooling to the temperature below 80 ℃, adjusting the pH value to 9-10 by using concentrated hydrochloric acid, extracting for 2 times by using toluene, adjusting the pH value to 2 by using hydrochloric acid, and washing twice by using drinking water in layers to obtain crude valproic acid;

putting the crude valproic acid into a distillation kettle, opening vacuum to reach more than-0.096 Mpa, keeping total reflux for 15 minutes, collecting front fraction after total reflux, switching to middle distillation when the temperature of the top of the tower reaches 120 ℃, switching to rear fraction for collection when the difference between the top temperature, the middle temperature and the bottom temperature of a rectifying tower is very small, and distilling until the crude valproic acid is not substantially produced to obtain refined valproic acid;

2.4 salt formation: adding the valproic acid into a refining reaction kettle, adjusting the pH value to 10.0-10.2 by using 20% sodium hydroxide solution, concentrating, drying, mixing, packaging, and warehousing after the inspection is qualified.

Technical Field

the invention belongs to the technical field of medicines, and particularly relates to a production process of sodium valproate.

background

sodium valproate is a nitrogen-free broad-spectrum antiepileptic drug, and has different degrees of antagonistic action on convulsion caused by various methods. It is effective on various epilepsy such as small seizures, myoclonic epilepsy, local seizures, grand mal epilepsy and mixed epilepsy. Oral administration is rapid and complete, and is mainly distributed in extracellular fluid, where most of the blood binds to plasma proteins. It is mainly used for various epileptics with ineffective antiepileptic drugs, especially for small seizures. The sodium valproate production process in the prior art is complex, the production cost is high, and the development of enterprises is restricted.

disclosure of Invention

The invention aims to solve the technical problem of complex production process in the prior art, and provides a production process of sodium valproate to overcome the defects in the prior art.

The invention is realized by the following technical scheme:

the invention relates to a production process of sodium valproate, which comprises the following steps:

1. Feeding and proportioning:

2100kg of n-propyl bromide, 18.6kg of tetrabutylammonium bromide, 420kg of methyl acetoacetate and 1080kg of potassium carbonate;

2. The production process comprises the following steps:

2.1 alkylation

adding potassium carbonate, n-bromopropane and tetra-n-butylammonium bromide into a kettle, sealing, stirring, steaming, fully refluxing, dropwise adding methyl acetoacetate, refluxing at normal pressure for 2 hours after finishing dripping, then refluxing under pressure for 6 hours (0.04-0.06MPa), discharging part of n-bromopropane after pressurizing for 4 hours, raising the temperature to 104-106 ℃, emptying after refluxing under pressure, cooling to 70 ℃, adding 1800L of water, raising the temperature to 60 ℃, standing for 20 minutes, removing a water layer, washing with 25% sodium chloride solution twice, and putting an oil layer into a distillation kettle;

keeping total reflux for 15 minutes, collecting front fraction after total reflux, suspending heating when the temperature of a tower kettle rises to 140 ℃, collecting the smaller and smaller fraction, slowly opening vacuum to reach more than-0.095 Mpa, restarting heating to continue collecting the front fraction, switching to collect middle fraction when the temperature of the tower top rises obviously, switching to collect rear fraction when the difference between the top temperature, the middle temperature and the bottom temperature of a rectifying tower is very small, and steaming until the front fraction is not discharged basically to obtain the dipropyl substance;

2.2 deacylation:

refined dipropyl compound, methanol, sodium methoxide = 65: 15: 16

firstly, adding methanol and sodium methoxide into a kettle, steaming until full reflux is achieved, dropwise adding the refined dipropyl product obtained in the previous step, distilling the distillate under normal pressure after refluxing for 2 hours, cooling to 70 ℃ after the fractionation is achieved, and washing with water twice to obtain a deacylated product;

2.3 alkaline hydrolysis:

Deacylated product sodium hydroxide: water =3.5: 1: 2.25

Adding a sodium hydroxide solution and the deacylated product into a tank, slowly heating and refluxing for 2 hours, adding 150L of water, distilling until the internal temperature reaches 110 ℃, cooling to the temperature below 80 ℃, adjusting the pH value to 9-10 by using concentrated hydrochloric acid, extracting for 2 times by using toluene, adjusting the pH value to 2 by using hydrochloric acid, and washing twice by using drinking water in layers to obtain crude valproic acid;

putting the crude valproic acid into a distillation kettle, opening vacuum to reach more than-0.096 Mpa, keeping total reflux for 15 minutes, collecting front fraction after total reflux, switching to middle distillation when the temperature of the top of the tower reaches 120 ℃, switching to rear fraction for collection when the difference between the top temperature, the middle temperature and the bottom temperature of a rectifying tower is very small, and distilling until the crude valproic acid is not substantially produced to obtain refined valproic acid;

2.4 salt formation: adding the valproic acid into a refining reaction kettle, adjusting the pH value to 10.0-10.2 by using 20% sodium hydroxide solution, concentrating, drying, mixing, packaging, and warehousing after the inspection is qualified.

The method has the advantages of simple process, easy operation and low cost, and greatly reduces the production cost of enterprises.

Detailed Description

the invention relates to a production process of sodium valproate, which comprises the following steps:

1. feeding and proportioning:

2100kg of n-propyl bromide, 18.6kg of tetrabutylammonium bromide, 420kg of methyl acetoacetate and 1080kg of potassium carbonate;

2. the production process comprises the following steps:

2.1 alkylation

adding potassium carbonate, n-bromopropane and tetra-n-butylammonium bromide into a kettle, sealing, stirring, steaming, fully refluxing, dropwise adding methyl acetoacetate, refluxing at normal pressure for 2 hours after finishing dripping, then refluxing under pressure for 6 hours (0.04-0.06MPa), discharging part of n-bromopropane after pressurizing for 4 hours, raising the temperature to 104-106 ℃, emptying after refluxing under pressure, cooling to 70 ℃, adding 1800L of water, raising the temperature to 60 ℃, standing for 20 minutes, removing a water layer, washing with 25% sodium chloride solution twice, and putting an oil layer into a distillation kettle;

keeping total reflux for 15 minutes, collecting front fraction after total reflux, suspending heating when the temperature of a tower kettle rises to 140 ℃, collecting the smaller and smaller fraction, slowly opening vacuum to reach more than-0.095 Mpa, restarting heating to continue collecting the front fraction, switching to collect middle fraction when the temperature of the tower top rises obviously, switching to collect rear fraction when the difference between the top temperature, the middle temperature and the bottom temperature of a rectifying tower is very small, and steaming until the front fraction is not discharged basically to obtain the dipropyl substance;

2.2 deacylation:

refined dipropyl compound, methanol, sodium methoxide = 65: 15: 16

firstly, adding methanol and sodium methoxide into a kettle, steaming until full reflux is achieved, dropwise adding the refined dipropyl product obtained in the previous step, distilling the distillate under normal pressure after refluxing for 2 hours, cooling to 70 ℃ after the fractionation is achieved, and washing with water twice to obtain a deacylated product;

2.3 alkaline hydrolysis:

Deacylated product sodium hydroxide: water =3.5: 1: 2.25

Adding a sodium hydroxide solution and the deacylated product into a tank, slowly heating and refluxing for 2 hours, adding 150L of water, distilling until the internal temperature reaches 110 ℃, cooling to the temperature below 80 ℃, adjusting the pH value to 9-10 by using concentrated hydrochloric acid, extracting for 2 times by using toluene, adjusting the pH value to 2 by using hydrochloric acid, and washing twice by using drinking water in layers to obtain crude valproic acid;

putting the crude valproic acid into a distillation kettle, opening vacuum to reach more than-0.096 Mpa, keeping total reflux for 15 minutes, collecting front fraction after total reflux, switching to middle distillation when the temperature of the top of the tower reaches 120 ℃, switching to rear fraction for collection when the difference between the top temperature, the middle temperature and the bottom temperature of a rectifying tower is very small, and distilling until the crude valproic acid is not substantially produced to obtain refined valproic acid;

2.4 salt formation: adding the valproic acid into a refining reaction kettle, adjusting the pH value to 10.0-10.2 by using 20% sodium hydroxide solution, concentrating, drying, mixing, packaging, and warehousing after the inspection is qualified.

the method has the advantages of simple process, easy operation and low cost, and greatly reduces the production cost of enterprises.

although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that many modifications and improvements can be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of this invention as claimed.