CN107337618B - Production method for simultaneously improving purity and yield of metformin hydrochloride - Google Patents
Production method for simultaneously improving purity and yield of metformin hydrochloride Download PDFInfo
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- CN107337618B CN107337618B CN201710507365.7A CN201710507365A CN107337618B CN 107337618 B CN107337618 B CN 107337618B CN 201710507365 A CN201710507365 A CN 201710507365A CN 107337618 B CN107337618 B CN 107337618B
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- C07—ORGANIC CHEMISTRY
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- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
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Abstract
The invention discloses a production method for simultaneously improving the purity and yield of metformin hydrochloride, which comprises the following steps: the method comprises the following steps: preparing dimethylamine hydrochloride and preparing metformin hydrochloride; the preparation step of the metformin hydrochloride comprises the following steps: adding raw materials and a solvent, heating, cooling for the second time, centrifuging, washing, crystallizing and drying; the cooling is carried out, materials in the addition kettle are pressed into a crystallization kettle by using compressed air, a hot water circulating pump is started, water is heated to 40-65 ℃ by using a steam-water mixer, the crystallization kettle is cooled, the stirring speed is adjusted to be 60-100 rpm, the temperature of the crystallization kettle is reduced to 60-75 ℃ within 3-6 hours, and the temperature is kept for 1-1.5 hours; the preparation of the metformin hydrochloride uses two components of dimethylformamide and ethylene glycol mono-n-propyl ether as solvents, and utilizes the synergistic effect of two solvents with different properties to prepare the metformin hydrochloride, wherein the product yield is more than 95 percent, and the purity is more than 99.90 percent.
Description
The invention is application No. 201510197624.1, filing date: 24 days 4 and 2015, the invention name is as follows: a method for preparing high-purity high-yield metformin hydrochloride by using a two-component solvent, which is applied in divisional cases.
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a production method for preparing high-purity high-yield metformin hydrochloride by using a two-component solvent.
Background
Metformin hydrochloride has very strong physiological activity like other guanidine substances, can reduce fasting and postprandial hyperglycemia of type II diabetes patients, and glycosylated hemoglobin (HbAlc) can be reduced by 1-2%, has unique treatment effect on type 2 diabetes, can obviously improve the glucose tolerance and hyperinsulinemia of patients, reduce the level of free fatty acid and triglyceride in plasma, has small side effect and high safety, and is the most common hypoglycemic agent in clinic at present.
The existing preparation of metformin hydrochloride mainly comprises the following steps: dimethylamine reacts with hydrochloric acid to generate dimethylamine hydrochloride, and then the dimethylamine hydrochloride and dicyandiamide are added to generate metformin hydrochloride. The synthesis conditions of dimethylamine hydrochloride and dicyandiamide are different from those of refining operation, and the obtained product has different purity, melting range, solubility and clarity, raw material conversion rate, product benefit and the like.
The existing production process for producing dimethylamine hydrochloride by reacting dimethylamine with hydrochloric acid is mostly as follows: dripping hydrochloric acid into 40% dimethylamine water solution, concentrating, crystallizing and drying; some need to add EDTA to dimethylamine hydrochloride concentrate to remove impurities; part of manufacturers concentrate dimethylamine hydrochloride to almost anhydrous state, and then add solvent and dicyandiamide to carry out addition reaction, so that the final metformin hydrochloride has low purity (about 95 percent of content).
In the industry, two main methods for preparing metformin hydrochloride by adding dimethylamine hydrochloride and dicyandiamide are adopted: the first is a wet process, namely, dimethylamine hydrochloride reacts with dicyandiamide in the presence of an organic solvent; the first method is a dry method, namely dimethylamine hydrochloride and dicyandiamide react in a molten state, and the advantages and the disadvantages of the dimethylamine hydrochloride and the dicyandiamide are analyzed as follows:
(I) Wet Process
The advantages are that: (1) The organic solvent can well dissolve the organic compound, and when the organic solvent is used as a reaction medium, the reaction can be promoted to occur in a homogeneous phase; (2) the uniform mixing of materials and the stable heat exchange can be ensured, the reaction rate is accelerated, and the reaction rate is improved to a certain extent; (3) the reaction is relatively complete, and the process is convenient to control;
the disadvantages are as follows: (1) The organic solvents used in the prior art are cyclohexanol, tertiary amyl alcohol, benzene and the like, and the toxicity and the difficulty in recovery of the organic solvents are factors harmful to the environment; (2) the reaction temperature is higher, generally 130-160 ℃, and the energy consumption is larger; (3) the reaction time is long, and a plurality of side reactions are easy to occur; (4) the obtained metformin hydrochloride crude product has more impurities and higher impurity content, and requires a large amount of low-boiling-point solvents such as ethanol or methanol for refining, so that the product cost is higher.
(II) Dry Process
The advantages are that: (1) The melt synthesis method is a novel synthesis method, and is a method for heating and melting solid substances to perform chemical reaction in a synthesis environment without solvent. Compared with the solvent method, the method does not need to use toxic and harmful solvents, does not need to consider the problems of solvent recovery, waste treatment and the like, and can eliminate the emission of pollutants from the source; (2) simple technological process, less required equipment, higher yield and low cost.
The disadvantages are as follows: (1) The stirring resistance is large, and because no solvent exists, the reactant is sticky in a molten state, the fluidity is poor, and the stirring resistance is large; (2) the reaction temperature is difficult to control, and in the melting reaction, because no solvent is added, the heat loss is slow after the reactants are heated to be molten, and the reaction temperature is difficult to control. In case the temperature is not controlled, a plurality of side reactions such as polymerization, oxidation and the like can occur when the temperature exceeds the required temperature, and the quality and the yield of the product are greatly influenced; (3) the product is difficult to refine, because the early stage and the final stage of the reaction are heterogeneous reactions, the homogeneous reaction is only carried out in the middle stage of the reaction, the uniform mixing degree and the reaction uniformity of the materials are influenced by different degrees, more unreacted raw materials are needed, and the qualified product can be obtained by secondary crystallization.
The prior art for producing metformin hydrochloride has the following defects:
(1) the solvent is toxic, and generates polluted gas to cause environmental pollution;
(2) the reaction temperature is high, so that the energy consumption is high and the safety is poor;
(3) the reaction time is long, and the productivity of a single device is poor;
(4) side reactions are easy to occur;
(5) the product purity is low;
(6) the reaction yield is low.
Disclosure of Invention
Aiming at the defects, the invention provides an industrial production method for preparing high-purity high-yield metformin hydrochloride by using a two-component solvent, and the following aims are achieved:
(1) the purity of the product reaches 99.90 percent;
(2) the product yield reaches 95 percent;
(3) the reaction temperature is reduced from 130-160 ℃ in the prior art to 118-125 ℃, and is about 20 ℃ lower than the boiling point of the solvent, so that the production safety is improved;
(4) the production period is shortened, and the reaction time is shortened by 2 hours compared with the prior art;
(5) no pollution to the environment;
(6) the production capacity of single equipment is improved, and the feed amount of a single equipment is improved by 20%;
(7) energy is saved, production cost is reduced, and cost per ton of finished products is reduced by more than 300 yuan.
Aiming at the defects in the current metformin hydrochloride production, the invention adopts the following technical scheme:
a method for preparing high-purity high-yield metformin hydrochloride by using a two-component solvent comprises the following steps: preparing dimethylamine hydrochloride and preparing metformin hydrochloride;
the dimethylamine hydrochloride preparation step comprises the following steps: adding partial hydrochloric acid and dimethylamine gas, feeding the materials into a blow-down pipe, adding dimethylamine and hydrochloric acid for the second time, and reacting;
the preparation step of the metformin hydrochloride comprises the following steps: adding raw materials and solvent, heating, cooling for the second time, centrifuging, washing, crystallizing, and drying.
The following is a further optimization of the above technical solution:
the dimethylamine hydrochloride preparation step comprises the following steps of: the weight ratio of 31% industrial hydrochloric acid is 1: 2.75-2.98.
And the step of adding part of hydrochloric acid and dimethylamine gas comprises the step of putting 60% of hydrochloric acid in total into a salt-forming reaction kettle for reaction.
And the step of feeding the materials into the emptying pipe, starting a circulating pump, and opening a valve leading to the high end of the emptying pipe to enable the materials to be sprayed into the emptying pipe from three spraying ports uniformly distributed on the circumference of the pipe wall.
And in the reaction step, sampling and detecting, and if the pH value is 2.2-3.6, continuing to react for 15-30 minutes.
In the step of adding raw materials and a solvent in the preparation of the metformin hydrochloride, the charging proportion of dimethylamine hydrochloride is as follows: dicyandiamide dimethylformamide: ethylene glycol mono-n-propyl ether =1: 1.06-1.11: 0.8-1.65: 0.2-1.2.
The second cooling step in the preparation of the metformin hydrochloride comprises the following steps: reducing the temperature of the crystallization kettle to 30-50 ℃ within 3.5-5 hours, and keeping for 1-1.5 hours; adjusting the stirring speed to 30-50 rpm, then reducing the temperature of the crystallization kettle to 0-10 ℃ within 2-4 hours, and keeping the temperature for 1-2.5 hours.
In the step of crystallization in the preparation of metformin hydrochloride, the stirring speed is adjusted to be 60-100 rpm, circulating water is introduced into a jacket of a crystallization kettle, the temperature of the finished crystallization kettle is reduced to 30-50 ℃ within 2-3 hours, and the temperature is kept for 1-1.5 hours; and adjusting the stirring speed to 30-50 rpm again, reducing the temperature of the finished product crystallization kettle to 0-15 ℃ within 2-4 hours, and keeping the temperature for 1-1.5 hours.
In the drying step in the preparation of the metformin hydrochloride, the metformin hydrochloride is dried for 2-2.5 hours at the temperature of 60-90 ℃ and under the vacuum degree of 0.06-0.08 MPa, so that a finished product is prepared.
The metformin hydrochloride prepared by the method has the product yield of more than 95 percent and the purity of more than 99.90 percent.
Compared with the prior art, the invention has the following beneficial effects:
1. the product purity is high and reaches 99.90 percent. Due to the unique chemical structure and physical and chemical properties of the metformin and the difference of polarity, solubility and the like of a solvent used in cooling crystallization, the control difficulty of the supersaturation point interval is higher. Different solvents have different supersaturation points, the crystallization process is different, the supersaturation point of a single solvent is not easy to select, the supersaturation degree is not enough, the crystallization is difficult, and the crystal growth is not improved. Crystallizing in the presence of a composite solvent, adjusting the over-saturation range, and controlling the process conditions to facilitate the control of the crystallization process. The crystallization process time is shortened, and the crystal form, the particle size distribution, the hardness and the like of the obtained crystal are superior to those of the crystal formed by using a single solvent. Effectively controlling the stirring speed, the cooling speed, the temperature retention time and other crystallization conditions and the subsequent refining process, and ensuring the purity of the finished product and the distribution of crystal particles.
2. The product yield is high, reaches 95 percent, and the reaction is more complete. The invention uses two components of dimethylformamide and ethylene glycol mono-n-propyl ether as solvents to carry out addition reaction of dicyandiamide and dimethylamine hydrochloride, and replaces the existing method that single components such as isoamyl alcohol, benzene and dimethylacetamide are used for carrying out reaction; the raw materials have low solubility at low temperature and high solubility at high temperature by using a single solvent, and as the metformin hydrochloride product has low solubility in the solvent, once the operation is not proper or the process index is not well controlled during synthesis, the unreacted raw materials dicyandiamide, dimethylamine hydrochloride and the product can be quickly separated out from the solvent and the reaction is incomplete. The subsequent refining difficulty is high, the product purity is low, and even the product can reach the medical standard by secondary refining, so that the product yield is low and the benefit is poor. By adopting the preparation method, the yield of the finished product is improved to more than 95 percent from 90 percent of the prior art.
3. The production capacity of single equipment is improved, and the feed amount of the single equipment is improved by 20 percent. The problem of poor solubility of a single component to one of the reaction raw materials is solved, and the two components of dimethylformamide and ethylene glycol mono-n-propyl ether are used as solvents, so that the feed amount of dicyandiamide and dimethylamine hydrochloride is increased by 20% under the synergistic effect of the two solvents. In the prior art, a single component is used as a solvent, or the dicyandiamide dissolving capacity is strong, or the dimethylamine hydrochloride has high solubility in the solvent, and the dissolving conditions of the final product metformin hydrochloride are also different.
4. The reaction temperature is reduced by about 20 ℃, and the safety is improved. The reaction temperature is reduced to 118-125 ℃ from 130-160 ℃ in the prior art. The reaction temperature is about 20 ℃ lower than the boiling point of the solvent, the material flushing cannot occur in the reaction, and the production safety is improved.
5. The production period is shortened. The reaction time is shortened by 2 hours compared with the prior art. Dimethylamine gas is used for replacing 40 percent dimethylamine solution and 31 percent hydrochloric acid to carry out salt forming reaction, the concentration of reaction materials in a reaction system is correspondingly increased, the concentration evaporation water amount of each ton of dimethylamine hydrochloride is reduced by nearly 1000Kg, and the production period is shortened.
6. Energy is saved, and the production cost of each ton of dimethylamine hydrochloride is reduced by more than 300 yuan. When a pump is used for material circulation, a cooler is arranged on an outlet pipeline of the pump for cooling reaction liquid, and the cooling effect of the cooling water of the jacket of the salifying synthesis kettle is added, so that the reaction temperature can be ensured to meet the process requirement, the cooling of a reaction system by frozen salt water is not needed, and the energy is saved; the dimethylamine hydrochloride solution is concentrated in vacuum, so that the evaporation temperature is reduced, the decomposition of dimethylamine hydrochloride and other side reactions are reduced, the purity and yield of dimethylamine hydrochloride are improved, and the comprehensive cost is reduced by about 3 percent compared with the prior art; the energy is saved, dimethylamine gas is used for replacing 40% dimethylamine solution and 31% hydrochloric acid to carry out salt forming reaction, the concentration of reaction materials in a reaction system is correspondingly increased, the concentration evaporation water amount of each ton of dimethylamine hydrochloride is reduced by nearly 1000Kg, and the cost is reduced by more than 300 yuan.
7. No pollution to environment. Dimethylamine gas is added from the bottom of a reaction kettle, hydrochloric acid with the total amount of about 60 percent is added into the reaction kettle, the rest hydrochloric acid is added from a head tank after the reaction reaches a certain degree, a pump is used for circulating all the time in the reaction process, and three spray nozzles which are uniformly distributed on the circumference of the pipe wall are designed on the upper part of a blow-down pipe and are in countercurrent contact with the rising unreacted dimethylamine; the tail gas discharged from emptying enters a hydrochloric acid absorption tank to absorb dimethylamine gas in the hydrochloric acid absorption tank, and no dimethylamine gas is discharged into the atmosphere, so that the environment is not polluted.
8. More accurately controlling the end point of the salt-forming reaction. And controlling the pH value at the end point of the salt forming reaction to be 2.2-3.6, sampling 15 minutes after the pH value is qualified through sampling detection, and stopping introducing the dimethylamine if the pH value meets the requirement again, and continuously circulating the pump for 2 hours to terminate the reaction for subsequent concentration.
The specific implementation mode is as follows:
the following description of the preferred embodiments of the present invention is provided for the purpose of illustration and description, and is in no way intended to limit the invention.
Example 1
A method for preparing high-purity high-yield metformin hydrochloride by using a two-component solvent comprises the following steps:
preparation of (mono) dimethylamine hydrochloride
1. Addition of part of hydrochloric acid and dimethylamine gas
920Kg of hydrochloric acid with the concentration of 31% is metered and injected into an elevated tank, 560Kg of hydrochloric acid in the elevated tank is metered and injected into a salt forming reaction kettle, stirring is started, frozen saline water is injected into a jacket of the reaction kettle, the frozen saline water is injected into a shell pass of a cooler when the temperature of the kettle is reduced to 10 ℃, dimethylamine gas is injected into the salt forming reaction kettle, the feeding speed of the dimethylamine gas is adjusted, the adding amount of the dimethylamine gas is about 200Kg, and the temperature of the kettle is kept to 20 ℃.
2. Material entering emptying pipe
Starting a circulating pump, and opening a valve leading to the high end of the blow-down pipe to enable the materials to be sprayed into the blow-down pipe from three spraying ports uniformly distributed on the circumference of the pipe wall; and observing the bubbling condition of the tail gas entering the hydrochloric acid absorption tank.
3. Adding dimethylamine and hydrochloric acid for the second time
Adding dimethylamine gas from a dimethylamine steel cylinder, sampling from a pump circulation port, detecting the pH value to be 4-5, and then beginning to dropwise add the residual 360Kg of hydrochloric acid from the head tank, wherein the dimethylamine feeding valve is not closed, and the residual hydrochloric acid is dropwise added for 1-1.5 hours.
4. Reaction of
And after the dripping of the hydrochloric acid is finished, sampling and detecting from a sampling position of a pump circulation port, and if the pH value is 2.2-3.6, continuing to react for 15-30 minutes, thus stopping adding the dimethylamine. The total amount of dimethylamine gas added at this time should be about 330 Kg.
5. Crystallization of
And pumping the liquid in the salifying reaction kettle into a concentration kettle by using vacuum, starting stirring, and introducing steam into a jacket of the concentration kettle.
Starting a hydraulic jet pump, and controlling the vacuum degree of the concentration kettle to be 0.048 MPa.
When crystal precipitation in the concentration kettle is observed, the jacket of the concentration kettle is closed and a steam valve is arranged, and the stirring speed is adjusted to 400 rpm.
When the bottom of the concentration kettle is observed to generate annular crystal bands, the vacuum degree of the concentration kettle is increased to 0.066 MPa.
When the annular crystal at the bottom of the concentration kettle is suddenly increased, a steam valve of a jacket of the concentration kettle is closed, and the vacuum degree of the concentration kettle is increased to 0.08 MPa.
6. Centrifugation
Cooling water is introduced into a jacket of the concentration kettle to reduce the temperature, when the temperature of the kettle is reduced to 28 ℃, the vacuum is closed, and the stirring is continued for 20 minutes. And (5) putting the materials in the concentration kettle into a centrifugal machine, and drying by spin.
7. Drying by baking
And (3) putting the solid material into a double-cone dryer for drying, controlling the vacuum degree to be 0.064MPa, introducing the jacket steam pressure of the double-cone dryer to be 0.25MPa, and drying for 2.5 hours.
583.2Kg of dimethylamine hydrochloride is obtained, and the yield is 97.7%.
Preparation of metformin (di) hydrochloride
1. Adding raw materials and solvent
Starting a vacuum pump, pumping 600Kg of dimethylformamide and 110Kg of ethylene glycol mono-n-propyl ether solvent into an addition kettle, and sequentially adding the following raw materials under the stirring condition: 350Kg dimethylamine hydrochloride and 380Kg dicyandiamide.
2. Heating and raising temperature
Introducing steam into the jacket of the addition kettle, heating, adjusting the stirring speed to 80 rpm, heating the kettle to 110 ℃ for 40 minutes, keeping the temperature for 20 minutes, continuously heating, heating to 119 ℃ for 20 minutes, and carrying out heat preservation reaction for 2 hours.
3. Temperature reduction
Pressing the materials in the addition kettle into a crystallization kettle by using compressed air, starting a hot water circulating pump, heating water to 40 ℃ by using a steam-water mixer, starting to cool the crystallization kettle, adjusting the stirring speed to 60rpm, cooling the crystallization kettle to 60 ℃ within 4 hours, and keeping the temperature for 1 hour.
4. Second cooling
Hot water is put out of the jacket of the crystallization kettle, circulating water is started to be introduced into the jacket of the crystallization kettle, the temperature of the crystallization kettle is reduced to 30 ℃ within 3 hours, and the temperature is kept for 1.5 hours. Adjusting the stirring speed to 40 r/m, discharging circulating water from the jacket of the crystallization kettle, starting to introduce frozen brine into the jacket of the crystallization kettle, reducing the temperature of the crystallization kettle to 8 ℃ within 2.5 hours, and keeping for 2 hours.
5. Centrifugation
And opening a discharging valve of the crystallization kettle, and putting the material from the crystallization kettle into a centrifugal machine for spin-drying. The solid material is ready to be put into a washing kettle.
6. Washing machine
2200Kg of ethanol with concentration of 80% (mass percentage concentration) is pumped into a washing kettle by vacuum, stirring is started, centrifugal solid materials are added, and the mixture is heated to 60 ℃ and kept for 60 minutes.
7. Crystallization of
And (3) pressing the materials in the washing kettle into a finished product crystallization kettle after passing through a precision filter by using compressed air. Adjusting the stirring speed to 60 r/m, starting to introduce circulating water into the jacket of the crystallization kettle, reducing the temperature of the finished crystallization kettle to 35 ℃ within 3 hours, and keeping the temperature for 1 hour. And adjusting the stirring speed to 40 rpm again, discharging the finished product crystallization kettle jacket circulating water, starting introducing frozen brine into the finished product crystallization kettle jacket, reducing the temperature of the finished product crystallization kettle to 5 ℃ within 2 hours, and keeping the temperature for 1 hour.
8. Drying
The material is put into a centrifuge for spin-drying, the solid in the centrifuge is put into a vacuum drier for drying for 2 hours under the condition that the temperature is 80 ℃ and the vacuum degree is 0.08MPa, and 678.1Kg of finished product is obtained, and the yield is 95.4 percent (not counting the product in the mother liquor).
The filtrate is continuously recycled, and part of solvent is added after 4 times of recycling.
Through detection: the technical performance indexes of the prepared product are as follows:
TABLE 1 technical Performance index of the product
Example 2
Tests were conducted using the procedure of example 1, using the following process parameters:
preparation of (mono) dimethylamine hydrochloride
1. Addition of part of hydrochloric acid and dimethylamine gas
Metering 31% hydrochloric acid, pumping the hydrochloric acid into an overhead tank, putting the hydrochloric acid with the total amount of about 60% into a salt forming reaction kettle, starting stirring, introducing frozen salt water into a reaction kettle jacket, introducing the frozen salt water into a cooler shell side when the temperature of the kettle is reduced to 10-20 ℃, starting introducing dimethylamine gas into the salt forming reaction kettle, wherein the addition amount of the dimethylamine gas is about two thirds of the total amount, and adjusting the feeding speed of the dimethylamine gas to keep the temperature of the kettle to 15-25 ℃.
Dimethylamine: 31% industrial hydrochloric acid (weight ratio) =1: 2.75-2.98.
2. Material entering emptying pipe
Starting a circulating pump, and opening a valve leading to the high end of the blow-down pipe to enable the materials to be sprayed into the blow-down pipe from three spraying ports uniformly distributed on the circumference of the pipe wall; and observing the bubbling condition of the tail gas entering the hydrochloric acid absorption tank.
3. Adding dimethylamine and hydrochloric acid for the second time
Adding metered dimethylamine gas, sampling from a pump circulation port to detect that the pH value is 4-5, then dropwise adding the residual hydrochloric acid with the total amount of about 40% (during the period, the dimethylamine is continuously introduced into the salt forming reaction kettle) from the head tank, and the residual hydrochloric acid is dropwise added for 1-1.5 hours.
4. Reaction of
After the hydrochloric acid is dripped, all the metered dimethylamine gas is added, sampling and detecting from a sampling position of a pump circulation port, and if the pH value is 2.2-3.6, continuing to react for 15-30 minutes (if the pH value is lower than 2, properly supplementing 2-3 Kg of the dimethylamine gas).
5. Crystallization of
And pumping the liquid in the salifying reaction kettle into a concentration kettle by using vacuum, starting stirring, and introducing steam into a jacket of the concentration kettle.
And starting a hydraulic jet pump, and controlling the vacuum degree of the concentration kettle to be 0.04-0.056 MPa.
When crystal precipitation is observed in the concentration kettle, closing a steam valve of a jacket of the concentration kettle, and adjusting the stirring speed to 40-60 rpm.
When the annular crystal band is observed to be generated at the bottom of the concentration kettle, the vacuum degree of the concentration kettle is increased to 0.06-0.07 MPa.
When the annular crystal at the bottom of the concentration kettle is suddenly increased, a steam valve of a jacket of the concentration kettle is closed, and the vacuum degree of the concentration kettle is improved to be more than 0.076 MPa.
6. Centrifugation
And (3) introducing cooling water into a jacket of the concentration kettle for cooling, closing the vacuum when the temperature of the kettle is reduced to below 30 ℃, and continuously stirring for 20-30 minutes.
Putting the materials into a centrifuge, drying, and recycling mother liquor (or preparing hydrochloric acid with the concentration of 31 percent, or concentrating the hydrochloric acid to a certain amount for centralized treatment and utilization);
and (3) putting the solid material into a double-cone dryer for drying, controlling the vacuum degree to be 0.06-0.07 MPa, introducing the jacket of the double-cone dryer into the double-cone dryer, wherein the steam pressure is lower than 0.3MPa, and the drying time is 2-2.5 hours.
Dimethylamine hydrochloride is obtained with a yield of 97.7-97.9%.
Preparation of metformin (di) hydrochloride
1. Adding raw materials and solvent
Starting a vacuum pump, metering dimethylformamide and ethylene glycol mono-n-propyl ether, pumping into an addition kettle, and sequentially adding metered dimethylamine hydrochloride and dicyandiamide under the stirring condition.
Feeding proportion (weight ratio) of dimethylamine hydrochloride: dicyandiamide dimethylformamide: ethylene glycol mono-n-propyl ether =1: 1.06-1.11: 0.8-1.65: 0.2-1.2.
2. Heating and raising temperature
And introducing steam into the jacket of the addition kettle, heating, and adjusting the stirring speed to 80-130 rpm. And (3) heating the kettle to 110-115 ℃ in 30-50 minutes, keeping the temperature for 10-30 minutes, continuously heating for 15-30 minutes to 118-125 ℃, and carrying out heat preservation reaction for 1.5-2.5 hours.
3. Temperature reduction
Pressing the materials in the addition kettle into a crystallization kettle by using compressed air, starting a hot water circulating pump, heating water to 40-65 ℃ by using a steam-water mixer, starting to cool the crystallization kettle, adjusting the stirring speed to 60-100 rpm, cooling the crystallization kettle to 60-75 ℃ within 3-6 hours, and keeping the temperature for 1-1.5 hours.
4. Second cooling
And (3) putting hot water out of the jacket of the crystallization kettle, starting to introduce circulating water into the jacket of the crystallization kettle, reducing the temperature of the crystallization kettle to 30-50 ℃ within 3.5-5 hours, and keeping the temperature for 1-1.5 hours. Adjusting the stirring speed to 30-50 rpm, discharging circulating water from a jacket of the crystallization kettle, starting introducing frozen brine into the jacket of the crystallization kettle, reducing the temperature of the crystallization kettle to 0-10 ℃ within 2-4 hours, and keeping the temperature for 1-2.5 hours.
5. Centrifugation
And opening a discharging valve of the crystallization kettle, putting the material from the crystallization kettle into a centrifugal machine for spin-drying, putting the solid material into a washing kettle, and using the centrifugal mother liquor for the next addition reaction.
6. Washing machine
And (3) pumping 75-90% (mass ratio) ethanol into the washing kettle in vacuum, wherein the use amount of the 75-90% (mass ratio) ethanol is 6-10 times of the feeding amount of dimethylamine hydrochloride. Starting stirring, adding all solid materials obtained by centrifugation, heating to 60-70 ℃, and keeping for 40-80 minutes.
7. Crystallization of
And (3) pressing the materials in the washing kettle into a finished product crystallization kettle after passing through a precision filter by using compressed air. Adjusting the stirring speed to 60-100 rpm, starting to introduce circulating water into the jacket of the crystallization kettle, reducing the temperature of the finished crystallization kettle to 30-50 ℃ within 2-3 hours, and keeping the temperature for 1-1.5 hours.
And adjusting the stirring speed to 30-50 rpm again, discharging the finished product crystallization kettle jacket circulating water, starting introducing frozen brine into the finished product crystallization kettle jacket, reducing the temperature of the finished product crystallization kettle to 0-15 ℃ within 2-4 hours, and keeping the temperature for 1-1.5 hours.
8. Drying
Putting the materials into a centrifuge, spin-drying, continuously recycling the filtrate, and performing after-treatment to a certain degree; and putting the solid in the centrifuge into a vacuum drier, and drying for 2-2.5 hours at the temperature of 60-90 ℃ and under the vacuum degree of 0.06-0.08 MPa to obtain a finished product.
The filtrate is continuously recycled, and part of solvent is added after 4 times of recycling.
The product yield is more than 95 percent, the purity is more than 99.90 percent, and each technical index is excellent.
Through tests, the embodiment 1 is the preferable embodiment, and the yield, the purity and various technical performance indexes are all the best.
By adopting the technical scheme of the invention, the method has the following advantages:
1. dimethylamine hydrochloride is prepared by taking dimethylamine gas and 31% hydrochloric acid as raw materials for reaction, arranging a cooler to cool down together with a reaction kettle jacket, and adopting a pumping circulation mode to spray and absorb dimethylamine tail gas and hydrochloric acid to absorb dimethylamine tail gas, so that the utilization rate of the raw materials is ensured to the maximum extent, the loss of the raw materials is reduced, and the product yield is improved.
The solution containing dimethylamine hydrochloride is concentrated by vacuum evaporation, other side reactions do not occur in the dimethylamine hydrochloride, the cooling speed and the stirring speed are controlled, the uniformity of crystallized particles is good, and the mother liquor after crystallization is synthesized.
2. The preparation of the metformin hydrochloride uses two components of dimethylformamide and ethylene glycol mono-n-propyl ether as solvents, utilizes the synergistic effect of two solvents with different properties, increases the single batch feeding amount, reduces the reaction temperature, shortens the reaction time, ensures that the dicyandiamide and dimethylamine hydrochloride have uniform addition reaction, and improves the operation safety.
3. Dicyandiamide and dimethylamine hydrochloride carry out addition reaction under the condition of using a two-component solvent, the viscosity of the solvent is hardly influenced by temperature and is lower, a finished product is easy to separate out from the solvent, and the solvent is easy to wash out from the finished product in refining, so that the finished product can reach the medicinal quality standard.
4. After the addition reaction is finished, in order to ensure that crystals are separated out and crystal forms and particle sizes are ensured, the stirring speed, the cooling speed and the temperature retention time are determined to simultaneously achieve the optimized operation, and the pure metformin hydrochloride crystal with certain particle size distribution is prepared. The particle size and distribution of the metformin hydrochloride crystal product mainly depend on the crystal nucleus generation rate, the crystal growth rate and the average residence time of the crystals in the crystallizer. Under the conditions of proper stirring speed, cooling speed and temperature retention time, the supersaturation degree of the metformin hydrochloride is usually controlled in a metastable zone, and at the moment, the concentration crystallization kettle has higher production capacity, can obtain crystal products with certain sizes and has high product purity.
In the above embodiments, the best mode of the present invention has been described, and it is apparent that many changes can be made under the inventive concept of the present invention. It should be noted here that any changes made under the inventive concept of the present invention shall fall within the protective scope of the present invention.
Claims (1)
1. A production method for simultaneously improving the purity and yield of metformin hydrochloride is characterized in that: the method comprises the following steps: preparing dimethylamine hydrochloride and preparing metformin hydrochloride;
the preparation method of the metformin hydrochloride comprises the following steps:
(1) adding raw materials and solvent
Starting a vacuum pump, pumping 600Kg of dimethylformamide and 110Kg of ethylene glycol mono-n-propyl ether solvent into an addition kettle, and sequentially adding the following raw materials under the stirring condition: 350Kg dimethylamine hydrochloride and 380Kg dicyandiamide;
(2) heating and raising temperature
Introducing steam into a jacket of the addition kettle, heating, adjusting the stirring speed to 80 rpm, heating the kettle to 110 ℃ within 40 minutes, keeping for 20 minutes, continuously heating, heating to 119 ℃ within 20 minutes, and carrying out heat preservation reaction for 2 hours;
(3) temperature reduction
Pressing the materials in the addition kettle into a crystallization kettle by using compressed air, starting a hot water circulating pump, heating water to 40 ℃ by using a steam-water mixer, starting to cool the crystallization kettle, adjusting the stirring speed to 60rpm, cooling the crystallization kettle to 60 ℃ within 4 hours, and keeping for 1 hour;
(4) second cooling
Putting hot water out of a jacket of the crystallization kettle, starting to introduce circulating water into the jacket of the crystallization kettle, reducing the temperature of the crystallization kettle to 30 ℃ within 3 hours, keeping for 1.5 hours, adjusting the stirring speed to 40 rpm, putting circulating water out of the jacket of the crystallization kettle, starting to introduce frozen brine into the jacket of the crystallization kettle, reducing the temperature of the crystallization kettle to 8 ℃ within 2.5 hours, and keeping for 2 hours;
(5) centrifugation
Opening a discharging valve of the crystallization kettle, putting the material from the crystallization kettle into a centrifugal machine for spin-drying, and preparing to put the solid material into a washing kettle;
(6) washing machine
2200Kg of ethanol with the mass concentration of 80 percent is pumped into a washing kettle by vacuum, stirring is started, centrifugal solid materials are added, the temperature is raised to 60 ℃ and is kept for 60 minutes;
(7) crystallization of
Pressing the materials in the washing kettle into a finished product crystallization kettle after passing through a precision filter by using compressed air;
adjusting the stirring speed to 60rpm, starting to introduce circulating water into a jacket of the crystallization kettle, reducing the temperature of the finished crystallization kettle to 35 ℃ within 3 hours, and keeping the temperature for 1 hour; adjusting the stirring speed to 40 r/min again, discharging the finished product crystallization kettle jacket circulating water, starting to introduce frozen brine into the finished product crystallization kettle jacket, reducing the temperature of the finished product crystallization kettle to 5 ℃ within 2 hours, and keeping for 1 hour;
(8) drying
The materials are put into a centrifuge for spin-drying, the solid in the centrifuge is put into a vacuum drier for drying for 2 hours under the condition that the temperature is 80 ℃ and the vacuum degree is 0.08MPa, and 678.1Kg of finished products are obtained.
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| CN110194727A (en) * | 2018-12-05 | 2019-09-03 | 武汉武药制药有限公司 | A kind of refining methd of Metformin hydrochloride |
| CN110256300B (en) * | 2019-06-26 | 2022-04-05 | 武汉大学 | Metformin hydrochloride compound and metformin hydrochloride tablet composition |
| CN112717866A (en) * | 2020-12-10 | 2021-04-30 | 安徽广信农化股份有限公司 | Synthesis process of dimethylamine hydrochloride |
| CN113735741A (en) * | 2021-09-13 | 2021-12-03 | 天方药业有限公司 | Synthetic preparation method of metformin hydrochloride |
| CN114522439A (en) * | 2022-04-24 | 2022-05-24 | 天津长芦汉沽盐场有限责任公司 | Temperature-controlled crystallization process of bromine flame retardant |
| CN115108945B (en) * | 2022-07-14 | 2024-05-17 | 山东省分析测试中心 | Preparation method of metformin hydrochloride crystal and monodisperse rod-shaped crystal with uniform granularity obtained by adopting method |
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| CN101450920B (en) * | 2007-11-30 | 2011-08-10 | 山东方兴科技开发有限公司 | Method for producing metformin hydrochloride large particle crystal |
| CN101450918B (en) * | 2007-11-30 | 2011-08-10 | 山东方兴科技开发有限公司 | Metformin hydrochloride purification method |
| US20110021634A1 (en) * | 2009-06-18 | 2011-01-27 | Patel Pranav Dushyant | Processes for preparing metformin hydrochloride |
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