CN107337618A - It is a kind of while improve Metformin hydrochloride purity and the production method of yield - Google Patents
It is a kind of while improve Metformin hydrochloride purity and the production method of yield Download PDFInfo
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- CN107337618A CN107337618A CN201710507365.7A CN201710507365A CN107337618A CN 107337618 A CN107337618 A CN 107337618A CN 201710507365 A CN201710507365 A CN 201710507365A CN 107337618 A CN107337618 A CN 107337618A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C277/08—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 of substituted guanidines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- C07C277/06—Purification or separation of guanidine
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Abstract
The invention discloses a kind of while improve Metformin hydrochloride purity and the production method of yield, including：Including：Prepared by dimethylamine hydrochloride and prepared by Metformin hydrochloride；The Metformin hydrochloride preparation process, including：Add raw material and solvent, heat temperature raising, cooling, second of cooling, centrifugation, washing, crystallization, dry；The cooling, material in addition kettle is pressed into crystallization kettle with compressed air, start hot water circulating pump, 40 65 DEG C are heated water to using steam heater to start to cool to crystallization kettle, adjust 60~100 revs/min of speed of agitator, crystallization kettle temperature is down to 60~75 DEG C in 3~6 hours, kept for 1~1.5 hour；Prepared by Metformin hydrochloride, the use of dimethylformamide and ethylene glycol propyl ether two-component is solvent, and using the synergy of two kinds of heterogeneity solvents, obtained Metformin hydrochloride, product yield is more than 95%, and purity is more than 99.90%.
Description
The present invention is application number 201510197624.1, the applying date：On April 24th, 2015, denomination of invention：" a kind of double groups
The divisional application of the method that part solvent prepares high-purity high-yield Metformin hydrochloride ".
Technical field
The invention belongs to technical field of organic synthesis, concretely relates to a kind of using two-component solvent preparation high-purity
The production method of Metformin hydrochloride in high yield.
Background technology
Metformin hydrochloride has very strong physiologically active as other guanidine materials, can reduce type II diabetes trouble
Person's empty stomach and postprandial hyperglycemia, glycosylated hemoglobin（HbAlc）1%~2% can be declined, the treatment for having uniqueness to diabetes B is made
With it can be obviously improved the resistance to sugar amount and hyperinsulinemia of patient, reduce blood plasma free fatty acid and triglyceride levels, secondary
Act on it is small, it is safe, be clinically the most frequently used antidiabetic drug at present.The medical instrument has a variety of mechanism of action, including delays grape
Sugar increases the utilization of periphery glucose, and suppress liver, kidney mistake by the intake of intestines and stomach by improving the sensitiveness of insulin
The gluconeogenesis of degree.This product does not reduce the blood sugar level of non-diabetic patients, and body weight generally mitigates during patient medication, blood plasma courage
Sterol, triglycerides and pre-β lipoprotein are horizontal to be reduced, and periphery glucose metabolism is improved.Confirmed through clinical test, can be effective
Reduce blood glucose and prevention coronary heart disease.The combination of insulin and target organ acceptor can be increased and strengthen the effect after acceptor simultaneously, increased
Add the sensitiveness of insulin.
It is prepared by existing Metformin hydrochloride：Dimethylamine and hydrochloric acid reaction generation dimethylamine hydrochloride, then two
Methylamine hydrochloride and dicyandiamide addition generation Metformin hydrochloride.Dimethylamine hydrochloride and dicyandiamide synthesis condition and purification operations
Difference, obtained product purity, it is molten away from, dissolving clarity, feed stock conversion, product benefit etc. differ widely.
Existing dimethylamine generates dimethylamine hydrochloride production technology with hydrochloric acid reaction：It is water-soluble to 40% dimethylamine
Hydrochloric acid is added dropwise in liquid, by concentrating, crystallizing, drying；Some needs to dimethylamine hydrochloride concentrate add such as EDTA with except
Decontamination；Solvent is added when dimethylamine hydrochloride is concentrated into almost no moisture by part producer and dicyandiamide progress addition is anti-
Should, cause final Metformin hydrochloride purity low（Content 95% or so）.
Dimethylamine hydrochloride mainly has two kinds with the method that dicyandiamide addition prepares Metformin hydrochloride in industry：It is first, wet
Method, i.e., in the presence of an organic, dimethylamine hydrochloride are reacted with dicyandiamide；When dry method, i.e. dimethylamine hydrochloride with
Dicyandiamide reacts in the molten state, and the strengths and weaknesses analysis of the two are as follows：
（One）Wet processing
Advantage：（1 ）The organic solvent of selection, can when it is as the medium reacted because organic compound can be dissolved well
Reaction is promoted to occur in homogeneous；（2）It can guarantee that material is well mixed and heat exchange is stable, accelerate reaction rate, and one
Determine to improve reaction rate in degree；（3）Reaction is more complete, and process is easy to control；
Shortcoming：（1 ）The organic solvent used at present in technique has cyclohexanol, tert-pentyl alcohol, benzene class etc., its toxicity and is difficult to reclaim
Environmentally harmful factor is made again；（2）Reaction temperature is higher, generally 130~160 DEG C, and power consumption is larger；（3）Reaction
Time is grown, and multiple side reactions easily occur；（4）Amount of impurities, impurity content are more in obtained Metformin hydrochloride crude product, refine
Need to consume the low boiling point solvents such as substantial amounts of ethanol or methanol and cause product cost higher.
（Two）Dry process
Advantage：（1 ）Flux synthesis procedure is a kind of new synthetic method, and it is under solvent-free existing synthetic environment, by solid-state
The method that material heating melting is chemically reacted.This method neither needs to use poisonous and hazardous solvent, again compared with solvent method
The problems such as without considering solvent recovery, waste processing, the discharge of pollutant thing can be eliminated from source；（2）Technical process is simple, institute
Need that equipment is few, yield is higher, cost is low.
Shortcoming：（1 ）It is big to stir resistance, due to no solvent, reactant is in the molten state into thick, and mobility is not
Good, the resistance of stirring is larger；（2）Reaction temperature is difficult to control, in frit reaction, due to the addition of no solvent, reactant
It is heated to after dissolving, heat scatters and disappears slower, it is difficult to controlling reaction temperature.Just in case temperature control does not live, and will be sent out more than required temperature
Multiple side reactions such as raw polymerization, oxidation, product quality and yield are influenceed very big；（3）Product purification is difficult, before reaction
Phase, latter stage are heterogeneous reaction, and only the phase is homogeneous reaction in the reaction, material mixing uniformity, reaction homogeneity all by
Influenceed to different degrees of, unreacting material is more, it is necessary to which secondary crystallization can just obtain qualified products.
Following defect be present in prior art production Metformin hydrochloride：
（1）Toxic solvent, dusty gas is produced, causes environmental pollution；
（2）Reaction temperature is high, causes high energy consumption and security poor；
（3）Reaction time is grown, and single device production capacity is poor；
（4）Side reaction easily occurs；
（5）Product purity is low；
（6）Reaction yield is low.
The content of the invention
Present invention deficiency for more than, there is provided a kind of two-component solvent prepares the work of high-purity high-yield Metformin hydrochloride
Industry production method, realize following goal of the invention：
（1）Product purity reaches 99.90%；
（2）Product yield reaches 95%；
（3）Reaction temperature is reduced, reaction temperature is reduced to 118~125 DEG C by 130~160 DEG C of existing process, reaction temperature ratio
Low 20 DEG C or so of solvent boiling point, improves production security；
（4）Shorten the production cycle, the reaction time shortens 2 hours than existing process；
（5）It is environmentally safe；
（6）Single device production capacity is improved, separate unit inventory improves 20%；
（7）The energy is saved, reduces production cost, finished product per ton reduces cost more than 300 yuan.
For deficiency present in the production of current Metformin hydrochloride, the present invention adopts the following technical scheme that：
A kind of method that two-component solvent prepares high-purity high-yield Metformin hydrochloride, including：Dimethylamine hydrochloride prepare and
It is prepared by Metformin hydrochloride；
The dimethylamine hydrochloride preparation process, including：The addition of part hydrochloric acid and dimethylamine gas, material enter blow-down pipe,
Second of addition dimethylamine and hydrochloric acid, reaction；
The Metformin hydrochloride preparation process, including：Add raw material and solvent, heat temperature raising, cooling, second of cooling, from
The heart, washing, crystallization, drying.
It is the further optimization to above-mentioned technical proposal below：
The dimethylamine hydrochloride preparation process, raw material dimethylamine：The weight ratio of 31% technical hydrochloric acid is 1：2.75~2.98.
The addition step of the part hydrochloric acid and dimethylamine gas, the hydrochloric acid of total amount 60% is first put into salt-forming reaction kettle and entered
Row reaction.
The material enters blow-down pipe step, open the circulation pump, and open lead to the high-end valve of blow-down pipe make material from
Equally distributed three mouth sprays spray into blow-down pipe on tube wall circumference.
The reactions steps, sampling detection, if pH value is 2.2~3.6, continue reaction 15~30 minutes.
The Metformin hydrochloride adds raw material and solvent step, ingredient proportion dimethylamine hydrochloride in preparing：Dicyandiamide:
Dimethylformamide：Ethylene glycol propyl ether=1:1.06~1.11:0.8~1.65:0.2~1.2.
Second of cooling step in prepared by the Metformin hydrochloride：Crystallization kettle temperature is down to 30 in 3.5~5 hours~
50 DEG C, kept for 1~1.5 hour；30~50 revs/min of speed of agitator is adjusted, crystallization kettle temperature is then down to 0 in 2~4 hours
~10 DEG C, kept for 1~2.5 hour.
Crystallisation step in prepared by the Metformin hydrochloride, 60~100 revs/min of speed of agitator is adjusted, is started to crystallization kettle
Chuck is passed through recirculated water, and finished product crystallization kettle temperature is down into 30~50 DEG C in 2~3 hours, is kept for 1~1.5 hour；Adjust again
Speed of agitator is that finished product crystallization kettle temperature is down into 0~15 DEG C in 30~50 revs/min, 2~4 hours, is kept for 1~1.5 hour.
Drying steps in prepared by the Metformin hydrochloride, are that 60~90 DEG C of vacuums are 0.06~0.08MPa in temperature
Under the conditions of dry 2~2.5 hours, finished product.
Using Metformin hydrochloride made from methods described, product yield is more than 95%, and purity is more than 99.90%.
The present invention compared with prior art, has the advantages that：
1st, product purity is high, reaches 99.90%.Due to melbine unique chemical constitution and physicochemical properties, plus cooling
The difference of the polarity of used solvent, dissolubility etc. during crystallization, its supersaturation point range restraint difficulty are larger.Different solvents
Supersaturation point is different, and Crystallization Process varies, and puts bad choosing using single solvent supersaturation, degree of supersaturation is inadequate, it is difficult to analyse
Crystalline substance, let alone growing the grain.Crystallized in the presence of double solvents, adjust supersaturated section, by controlling process conditions, crystallization mistake
Journey is easy to control.The Crystallization Procedure time shortens, and obtained crystalline solid its crystalline form, size distribution, hardness etc. are superior to using single
Solvent.Effectively crystallization condition and the follow-up process for refining such as control mixing speed, cooling rate, temperature residence time, it is ensured that into
Product purity and crystal grain distribution.
2nd, product yield is high, and yield reaches 95%, and reaction is more complete.The present invention uses dimethylformamide and ethylene glycol list
Positive propyl ether two-component is that solvent carries out dicyandiamide and dimethylamine hydrochloride addition reaction, and replacement uses one-component such as isoamyl at present
Alcohol, benzene class, dimethyl acetamide single solvent are reacted；Using single solvent, solubility is small during raw material low temperature, and temperature is higher
When solubility it is big, because the dissolving of product Metformin hydrochloride in a solvent is smaller, once misoperation or technique refer to during synthesis
Mark control is bad, and unreacted raw material dicyandiamide, dimethylamine hydrochloride and product can separate out rapidly from solvent, and reaction is endless
Entirely.Subsequently refined difficulty is big, and product purity is low, or even needs secondary refining product to can be only achieved medical standard, causes product to be received
Rate is low, of poor benefits.Using preparation method of the present invention, product yield brings up to more than 95% by the 90% of existing process.
3rd, single device production capacity is improved, separate unit inventory improves 20%.It is anti-to one of which to solve one-component
The problem of answering dissolution of raw material degree difference, is solvent using dimethylformamide and ethylene glycol propyl ether two-component, and two kinds of solvents are assisted
Same-action makes dicyandiamide add 20% with dimethylamine hydrochloride inventory.One-component is used in existing process as solvent, or
It is stronger to dissolve dicyandiamide ability, or solubility is big in a solvent for dimethylamine hydrochloride, to the molten of final products Metformin hydrochloride
Solution situation also differs widely.
4th, reaction temperature reduces by 20 DEG C or so, improves security.Reaction temperature is dropped by 130~160 DEG C of existing process
For 118~125 DEG C.20 DEG C lower than solvent boiling point or so of reaction temperature, is not in slug in reaction, and production security improves.
5th, the production cycle is shortened.Reaction time shortens 2 hours than existing process.Substituted using dimethylamine gas and use 40%
Dimethylamine solution and 31% hydrochloric acid carry out salt-forming reaction, accordingly add the concentration of reaction mass in reaction system, dimethylamine per ton
Hydrochloride concentration and evaporation discharge reduction shortens the production cycle close to 1000Kg.
6th, the energy is saved, dimethylamine hydrochloride production cost per ton reduces by more than 300 yuan.When carrying out Matter Transfer with pump,
Cooler is provided with pump discharge pipeline to cool to reaction solution, can be with plus the cooling effect into salt synthesis reactor chuck cooling water
Ensure that reaction temperature meets technological requirement, it is not necessary to which chilled brine cools to reaction system, has saved the energy；Dimethylamine hydrochloride
Solution reduces evaporating temperature, reduces the generation of decomposition and the other side reactions of dimethylamine hydrochloride using being concentrated in vacuo, and two
Methylamine hydrochloride purity and yield improve, and integrated cost reduces by 3% or so than existing process；The energy has been saved, has used dimethylamine
Gas instead carries out salt-forming reaction using 40% dimethylamine solution and 31% hydrochloric acid, accordingly adds reaction mass in reaction system
Concentration, dimethylamine hydrochloride concentration and evaporation discharge reduction per ton decline more than 300 yuan close to 1000Kg, cost.
7th, it is environmentally safe.Dimethylamine gas is added from reactor bottom, and the hydrochloric acid of total amount about 60% is first added in kettle,
Remaining hydrochloric acid is added from head tank after reaction to a certain extent, plays circulation in course of reaction always with pump, blow-down pipe top is set
In respect of equally distributed three mouth sprays on tube wall circumference and the unreacted dimethylamine counter current contacting risen；Discharged from emptying
Tail gas enter absorption by Hydrochloric Acid tank and absorb dimethylamine therein into gas, no dimethylamine gas is discharged into air, environmentally safe.
8th, salt-forming reaction terminal is more accurately controlled.It is 2.2~3.6 by the control of salt-forming reaction endpoint pH, sampling detection pH
It is worth the qualified pH value that samples again for 15 minutes afterwards to meet the requirements, then stops dimethylamine and be passed through, pump continues cycling through can terminate instead for 2 hours
Subsequent concentration should be carried out.
Embodiment：
The preferred embodiments of the present invention are illustrated below, it will be appreciated that preferred embodiment described herein is only used for
The bright and explanation present invention, is not intended to limit the present invention.
Embodiment 1
A kind of method that two-component solvent prepares high-purity high-yield Metformin hydrochloride, comprises the following steps：
（One）It is prepared by dimethylamine hydrochloride
1st, the addition of part hydrochloric acid and dimethylamine gas
It is that head tank is squeezed into the metering of 31% hydrochloric acid by 920kg concentration, then the hydrochloric acid of the 560Kg in head tank is first measured and is put into
Salt-forming reaction kettle, stirring is opened, chilled brine is passed through to reacting kettle jacketing, treats that kettle temperature is down to 10 DEG C, be passed through to cooler shell side
Chilled brine, start to be passed through dimethylamine gas to salt-forming reaction kettle, adjust dimethylamine gas charging rate, dimethylamine gas adds
Measure as 200Kg or so, keep kettle temperature to 20 DEG C.
2nd, material enters blow-down pipe
Open the circulation pump, and opening leads to the high-end valve of blow-down pipe and material is sprayed for equally distributed three from tube wall circumference
Mouth penetrating blow-down pipe；Observe the bubbling situation that tail gas enters absorption by Hydrochloric Acid tank.
3rd, second of addition dimethylamine and hydrochloric acid
Dimethylamine gas is added from dimethylamine steel cylinder, after sampling detection pH value is 4~5 at pump circulation mouth sampling, is started from height
Remaining 360Kg hydrochloric acid is added dropwise in position groove, and during which dimethylamine charging valve door is not closed, and remaining hydrochloric acid time for adding is 1~1.5
Hour.
4th, react
Hydrochloric acid is added dropwise, and detection is sampled at pump circulation mouth sampling, continues 15~30 points of reaction if pH value is 2.2~3.6
Clock stops dimethylamine and added.Now add dimethylamine gas total amount and should be 330Kg or so.
5th, crystallize
The liquid in salt-forming reaction kettle is pumped into concentration kettle with vacuum, stirring is started, steam is passed through to concentration kettle chuck.
Hydraulic jet pump is opened, it is 0.048MPa to control concentration kettle vacuum.
When observe in concentration kettle have crystallization separate out when, turn down concentration kettle chuck and enter steam valve, speed of agitator is adjusted
For 400rpm.
When observing that the generation of ring-type zone of a crystal is arranged at concentration kettle bottom, concentration kettle vacuum is brought up into 0.066MPa.
When observing that concentration kettle bottom annular crystal increases suddenly, close concentration kettle chuck and enter steam valve, will be dense
Contracting kettle vacuum brings up to 0.08MPa.
6th, centrifuge
Cooling water temperature is passed through to concentration kettle chuck, when kettle temperature is down to 28 DEG C, vacuum is closed, continues stirring 20 minutes.Will be dense
Material is put into centrifuge in contracting kettle, dries.
7th, dry
Solid material is put into the drying of double-cone type drier, controls vacuum 0.064MPa, is passed through double-cone type drier jacket steam pressure
Power 0.25MPa, drying time 2.5 hours.
Obtain dimethylamine hydrochloride 583.2Kg, yield 97.7%.
（Two）It is prepared by Metformin hydrochloride
1st, raw material and solvent are added
Vavuum pump is opened, 600Kg dimethylformamides and 110Kg ethylene glycol propyl ethers solvent are pumped into addition kettle, stirring
Under the conditions of sequentially add raw material：350Kg dimethylamine hydrochlorides and 380Kg dicyandiamides.
2nd, heat temperature raising
Steam is passed through to addition kettle chuck, is heated, adjusts 80 revs/min of speed of agitator, kettle temperature 110 DEG C was risen in 40 minutes, kept
20 minutes, continue to heat up, temperature is risen to 119 DEG C at 20 minutes, insulation reaction 2 hours.
3rd, cool
Material in addition kettle is pressed into crystallization kettle with compressed air, starts hot water circulating pump, is heated water using steam heater
Start to cool to crystallization kettle to 40 DEG C, crystallization kettle temperature is down to 60 DEG C in 60 revs/min, 4 hours of speed of agitator of regulation, keeps 1
Hour.
4th, second of cooling
The kettle chuck hot water that decrystallizes is put, starts to be passed through recirculated water to crystallization kettle chuck, crystallization kettle temperature is down to 30 in 3 hours
DEG C, kept for 1.5 hours.40 revs/min of speed of agitator is adjusted, the kettle chuck recirculated water that decrystallizes is put, starts to be passed through to crystallization kettle chuck
Chilled brine, crystallization kettle temperature is down to 8 DEG C in 2.5 hours, kept for 2 hours.
5th, centrifuge
Crystallization kettle baiting valve is opened, material is put into centrifuge from crystallization kettle dries.Prepare solid material being put into washing kettle.
6th, wash
With vacuum by concentration be 80%（Mass percent concentration）Ethanol 2200Kg be pumped into washing kettle, open stirring, add centrifugation
Solid material, 60 DEG C are heated to, are kept for 60 minutes.
7th, crystallize
Material in washing kettle is pressed into finished product crystallization kettle after accurate filter with compressed air.60 turns of speed of agitator of regulation/
Point, start to be passed through recirculated water to crystallization kettle chuck, finished product crystallization kettle temperature is down to 35 DEG C in 3 hours, kept for 1 hour.Again
It is 40 revs/min to adjust speed of agitator, puts finished product crystallization kettle chuck recirculated water, starts to be passed through freezing to finished product crystallization kettle chuck
Salt solution, finished product crystallization kettle temperature is down to 5 DEG C in 2 hours, kept for 1 hour.
8th, dry
Material is put into centrifuge, dried, solid is put into vacuum desiccator in centrifuge, is that 80 DEG C of vacuums are in temperature
Dried 2 hours under the conditions of 0.08MPa, obtain finished product 678.1Kg, yield 95.4%（The product in mother liquor is not calculated）.
Filtrate continues cycling through use, and partial solvent is added after recycling 4 times.
After testing：The technical performance index of obtained product such as following table：
The technical performance index of the product of table 1
Embodiment 2
Through experiment, the step of using embodiment 1, using following technological parameter：
（One）It is prepared by dimethylamine hydrochloride
1st, the addition of part hydrochloric acid and dimethylamine gas
Head tank is squeezed into the metering of 31% hydrochloric acid, the hydrochloric acid of total amount about 60% is first put into salt-forming reaction kettle, stirring is opened, to reaction
Kettle chuck is passed through chilled brine, treats that kettle temperature is down to 10~20 DEG C, is passed through chilled brine to cooler shell side, starts to salt-forming reaction
Kettle is passed through dimethylamine gas, and dimethylamine gas addition is 2/3rds or so of total amount, adjusts dimethylamine gas charging rate
Kettle temperature is kept to 15~25 DEG C.
Dimethylamine：31% technical hydrochloric acid（Weight ratio）=1 ：2.75~2.98.
2nd, material enters blow-down pipe
Open the circulation pump, and opening leads to the high-end valve of blow-down pipe and material is sprayed for equally distributed three from tube wall circumference
Mouth penetrating blow-down pipe；Observe the bubbling situation that tail gas enters absorption by Hydrochloric Acid tank.
3rd, second of addition dimethylamine and hydrochloric acid
The dimethylamine gas of metered amount is added, after sampling detection pH value is 4~5 at pump circulation mouth sampling, is added dropwise from head tank
The hydrochloric acid of remaining about total amount 40%（Period dimethylamine continues to be passed through salt-forming reaction kettle）, remaining hydrochloric acid time for adding be 1~
1.5 hour.
4th, react
Hydrochloric acid is added dropwise, add the dimethylamine gas all measured after, detection is sampled at pump circulation mouth sampling, if pH value is
2.2~3.6, then continue reaction 15~30 minutes（2~3Kg dimethylamine gas is suitably added if pH value is less than 2）.
5th, crystallize
The liquid in salt-forming reaction kettle is pumped into concentration kettle with vacuum, stirring is started, steam is passed through to concentration kettle chuck.
Hydraulic jet pump is opened, it is 0.04~0.056MPa to control concentration kettle vacuum.
When observe in concentration kettle have crystallization separate out when, turn down concentration kettle chuck and enter steam valve, speed of agitator is adjusted
For 40~60rpm.
When observing that the generation of ring-type zone of a crystal is arranged at concentration kettle bottom, concentration kettle vacuum is brought up to 0.06~
0.07MPa。
When observing that concentration kettle bottom annular crystal increases suddenly, close concentration kettle chuck and enter steam valve, will be dense
Contracting kettle vacuum brings up to more than 0.076MPa.
6th, centrifuge
Cooling water temperature is passed through to concentration kettle chuck, when kettle temperature is down to below 30 DEG C, vacuum is closed, continues 20~30 points of stirring
Clock.
Material is put into centrifuge, dried, Recycling Mother Solution uses（Or it is 31% hydrochloric acid for configuration concentration, or focus on
Focus on, utilize after a certain amount of）；
Solid material is put into the drying of double-cone type drier, controls 0.06~0.07MPa of vacuum, is passed through the steaming of double-cone type drier chuck
Steam pressure is less than 0.3MPa, drying time 2~2.5 hours.
Obtain dimethylamine hydrochloride, yield 97.7-97.9%.
（Two）It is prepared by Metformin hydrochloride
1st, raw material and solvent are added
Open vavuum pump, addition kettle will be pumped into after dimethylformamide and ethylene glycol propyl ether metering, under stirring condition according to
The secondary dimethylamine hydrochloride and dicyandiamide for adding metering.
Ingredient proportion（Weight ratio）Dimethylamine hydrochloride：Dicyandiamide:Dimethylformamide：Ethylene glycol propyl ether=1:
1.06~1.11:0.8~1.65:0.2~1.2.
2nd, heat temperature raising
Steam is passed through to addition kettle chuck, is heated, adjusts 80~130 revs/min of speed of agitator.Kettle temperature was risen in 30~50 minutes
110~115 DEG C, kept for 10~30 minutes, continue heating and temperature was risen to 118~125 DEG C in 15~30 minutes, insulation reaction 1.5
~2.5 hours.
3rd, cool
Material in addition kettle is pressed into crystallization kettle with compressed air, starts hot water circulating pump, is heated water using steam heater
Start to cool to crystallization kettle to 40-65 DEG C, drop crystallization kettle temperature in 60~100 revs/min, 3~6 hours of speed of agitator of regulation
To 60~75 DEG C, kept for 1~1.5 hour.
4th, second of cooling
The kettle chuck hot water that decrystallizes is put, starts to be passed through recirculated water to crystallization kettle chuck, drops crystallization kettle temperature in 3.5~5 hours
To 30~50 DEG C, kept for 1~1.5 hour.30~50 revs/min of speed of agitator is adjusted, puts the kettle chuck recirculated water that decrystallizes, is started
Chilled brine is passed through to crystallization kettle chuck, it is interior in 2~4 hours that crystallization kettle temperature is down to 0~10 DEG C, kept for 1~2.5 hour.
5th, centrifuge
Crystallization kettle baiting valve is opened, material is put into centrifuge from crystallization kettle is dried, and solid material is put into washing kettle, and centrifuge mother liquor is used
In addition reaction next time.
6th, wash
By concentration it is 75-90% with vacuum（Mass ratio）Ethanol be pumped into washing kettle, 75-90%（Mass ratio）The dosage of ethanol is two
6~10 times of methylamine hydrochloride inventory.Stirring is opened, centrifugation gained all solids material is added, is heated to 60~70
DEG C, kept for 40~80 minutes.
7th, crystallize
Material in washing kettle is pressed into finished product crystallization kettle after accurate filter with compressed air.Regulation speed of agitator 60~
100 revs/min, start to be passed through recirculated water to crystallization kettle chuck, it is interior in 2~3 hours that finished product crystallization kettle temperature is down to 30~50
DEG C, kept for 1~1.5 hour.
It is 30~50 revs/min to adjust speed of agitator again, puts finished product crystallization kettle chuck recirculated water, starts to finished product knot
Brilliant kettle chuck is passed through chilled brine, finished product crystallization kettle temperature is down into 0~15 DEG C in hour in 2~4 hours, holding 1~1.5 is small
When.
8th, dry
Material is put into centrifuge, dried, filtrate continues cycling through use, and circulation is post-processed to a certain extent；Centrifuge
Interior solid is put into vacuum desiccator, is that drying 2~2.5 is small under the conditions of 60~90 DEG C of vacuums are 0.06~0.08MPa in temperature
When, obtain finished product.
Filtrate continues cycling through use, and partial solvent is added after recycling 4 times.
Product yield is all higher than 95%, and purity is more than 99.90%, and all technical is excellent.
Through experiment, embodiment 1 is preferred embodiment, and yield, purity and every technical performance index are best.
Using technical solution of the present invention, there is advantages below：
1st, prepared by dimethylamine hydrochloride, is reacted using dimethylamine gas and 31% hydrochloric acid as raw material, sets cooler and reactor
Chuck cools, by the way of pump beats circulation, spray-absorption dimethylamine tail gas and absorption by Hydrochloric Acid dimethylamine tail gas together, maximum limit
Degree ensure that the utilization rate of raw material, reduces the loss of raw material, improves product yield.
Solution containing dimethylamine hydrochloride uses vacuum evaporation, and other side reactions do not occur for dimethylamine hydrochloride,
Plus control cooling rate and mixing speed, crystalline particle good evenness, crystallization Mother liquor is integrated.
2nd, prepared by Metformin hydrochloride, the use of dimethylformamide and ethylene glycol propyl ether two-component is solvent, utilizes
The synergy of two kinds of heterogeneity solvents, the inventory of single batch is added, reduces reaction temperature, when shortening reaction
Between, dicyandiamide and dimethylamine hydrochloride addition reaction are uniform, and processing safety improves.
3rd, dicyandiamide and dimethylamine hydrochloride carry out addition reaction under using two-component solvent condition, and solvent viscosity is almost
It is not affected by temperature and viscosity is relatively low, finished product separates out easily from solvent, and refined middle solvent is easy to wash away from finished product, so as to
It ensure that finished product can reach pharmaceutical quality standard.
4th, addition reaction finishes, to ensure to separate out crystallization, ensureing crystal formation and grain graininess, it is determined that mixing speed, cooling
The operation of speed, temperature residence time three while being optimal, produce hydrochloric acid two that is pure and thering is certain particle size to be distributed
First biguanides crystal.The granularity of Metformin hydrochloride crystal product and its distribution, depend primarily on nucleus generating rate, crystal growth
The mean residence time of speed and crystal in a crystallizer.In suitable mixing speed, cooling rate, temperature residence-time conditions
Under, Metformin hydrochloride degree of supersaturation is normally controlled in Metastable zone, and now condensing crystallizing kettle has higher production capacity, again
A certain size crystal product is can obtain, and product purity is high.
In the above-described embodiments, the preferred forms of the present invention are described, it is obvious that in the invention structure of the present invention
Under think of, many changes can be still made.Here, it should be noted that any change made under the inventive concept of the present invention all will
Fall within the scope of protection of the present invention.
Claims (7)
- It is 1. a kind of while improve Metformin hydrochloride purity and the production method of yield, it is characterised in that：Including：Dimethylamine hydrochloric acid Prepared by salt and prepared by Metformin hydrochloride；The Metformin hydrochloride preparation process, including：Add raw material and solvent, heat temperature raising, cooling, second of cooling, from The heart, washing, crystallization, drying；The cooling, material in addition kettle is pressed into crystallization kettle with compressed air, starts hot water circulating pump, utilizes steam heater 40-65 DEG C is heated water to start to cool to crystallization kettle, will crystallization in 60~100 revs/min, 3~6 hours of speed of agitator of regulation Kettle temperature degree is down to 60~75 DEG C, is kept for 1~1.5 hour.
- It is 2. according to claim 1 a kind of while improve Metformin hydrochloride purity and the production method of yield, its feature It is：Second of cooling, starts to be passed through recirculated water to crystallization kettle chuck, crystallization kettle temperature is down into 30 in 3.5~5 hours ~50 DEG C, kept for 1~1.5 hour；30~50 revs/min of speed of agitator is adjusted, the kettle chuck recirculated water that decrystallizes is put, starts to be passed through freezing salt to crystallization kettle chuck Water, crystallization kettle temperature is down to 0~10 DEG C in 2~4 hours, kept for 1~2.5 hour.
- It is 3. according to claim 1 a kind of while improve Metformin hydrochloride purity and the production method of yield, its feature It is：The addition raw material and solvent, the raw material of addition is dimethylamine hydrochloride, dicyandiamide；The solvent of addition is dimethyl methyl Acid amides and ethylene glycol propyl ether.
- It is 4. according to claim 3 a kind of while improve Metformin hydrochloride purity and the production method of yield, its feature It is：The addition raw material and solvent, the part by weight dimethylamine hydrochloride to feed intake：Dicyandiamide:Dimethylformamide：Ethylene glycol Single positive propyl ether=1:1.06~1.11:0.8~1.65:0.2~1.2.
- It is 5. according to claim 1 a kind of while improve Metformin hydrochloride purity and the production method of yield, its feature It is：The Metformin hydrochloride preparation process, reaction temperature are 118~125 DEG C.
- It is 6. according to claim 1 a kind of while improve Metformin hydrochloride purity and the production method of yield, its feature It is：Prepared by the dimethylamine hydrochloride, raw material dimethylamine：The weight ratio of 31% technical hydrochloric acid is 1：2.75~2.98.
- It is 7. according to claim 6 a kind of while improve Metformin hydrochloride purity and the production method of yield, its feature It is：It is prepared by the dimethylamine hydrochloride, including：The addition of part hydrochloric acid and dimethylamine gas；The addition of the part hydrochloric acid and dimethylamine gas, the hydrochloric acid of total amount 60% is first put into salt-forming reaction kettle and reacted, to 2/3rds dimethylamine gas is passed through in hydrochloric acid solution, keeps kettle temperature to 15~25 DEG C.
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| CN107445869A (en) * | 2017-07-18 | 2017-12-08 | 山东科源制药股份有限公司 | A kind of synthetic method of Metformin hydrochloride |
| 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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| CN101450918A (en) * | 2007-11-30 | 2009-06-10 | 山东方兴科技开发有限公司 | Metformin hydrochloride purification method |
| CN101450920A (en) * | 2007-11-30 | 2009-06-10 | 山东方兴科技开发有限公司 | Method for producing metformin hydrochloride large particle crystal |
| WO2010146604A2 (en) * | 2009-06-18 | 2010-12-23 | Exemed Pharmaceuticals | Processes for preparing metformin hydrochloride |
| CN102516130A (en) * | 2011-11-26 | 2012-06-27 | 赤峰万泽制药有限责任公司 | Preparation method of metformin hydrochloride |
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| CN100391939C (en) * | 2006-05-10 | 2008-06-04 | 翟树军 | Process for preparing metformin hydrochloride |
| WO2014041566A2 (en) * | 2012-09-17 | 2014-03-20 | Laurus Labs Private Limited | An improved process for the preparation of metformin hydrochloride |
| CN104119250A (en) * | 2014-07-15 | 2014-10-29 | 徐晓宁 | Production method of high-purity metformin hydrochloride |
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| CN101450918A (en) * | 2007-11-30 | 2009-06-10 | 山东方兴科技开发有限公司 | Metformin hydrochloride purification method |
| CN101450920A (en) * | 2007-11-30 | 2009-06-10 | 山东方兴科技开发有限公司 | Method for producing metformin hydrochloride large particle crystal |
| WO2010146604A2 (en) * | 2009-06-18 | 2010-12-23 | Exemed Pharmaceuticals | Processes for preparing metformin hydrochloride |
| CN102516130A (en) * | 2011-11-26 | 2012-06-27 | 赤峰万泽制药有限责任公司 | Preparation method of metformin hydrochloride |
| CN103435518A (en) * | 2013-08-26 | 2013-12-11 | 青岛黄海制药有限责任公司 | Preparation method of metformin hydrochloride |
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| CN107245042A (en) | 2017-10-13 |
| CN107245042B (en) | 2019-03-05 |
| CN104829495B (en) | 2017-07-21 |
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