CN104829495B - A kind of method that two-component solvent prepares high-purity high-yield Metformin hydrochloride - Google Patents
A kind of method that two-component solvent prepares high-purity high-yield Metformin hydrochloride Download PDFInfo
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- CN104829495B CN104829495B CN201510197624.1A CN201510197624A CN104829495B CN 104829495 B CN104829495 B CN 104829495B CN 201510197624 A CN201510197624 A CN 201510197624A CN 104829495 B CN104829495 B CN 104829495B
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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
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- 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 method that two-component solvent prepares high-purity high-yield Metformin hydrochloride, including：Prepared by dimethylamine hydrochloride and prepared by Metformin hydrochloride；It is prepared by dimethylamine hydrochloride, reacted using dimethylamine gas and 31% hydrochloric acid as raw material, cooler is set to cool together with reacting kettle jacketing, by the way of pump beats circulation, spray-absorption dimethylamine tail gas and absorption by Hydrochloric Acid dimethylamine tail gas, the utilization rate of raw material is ensure that to greatest extent, the loss of raw material is reduced, product yield is improved.Prepared by Metformin hydrochloride, the use of dimethylformamide and ethylene glycol propyl ether two-component is solvent, using the synergy of two kinds of heterogeneity solvents, obtained Metformin hydrochloride, and product yield is more than 95%, and purity is more than 99.90%.
Description
Technical field
The invention belongs to technical field of organic synthesis, concretely relate to a kind of using two-component solvent preparation high-purity
The production method of Metformin hydrochloride in high yield.
Background technology
Metformin hydrochloride is as other guanidine materials, with very strong physiologically active, it is possible to decrease type II diabetes is suffered from
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, reduction blood plasma free fatty acid and triglyceride levels, secondary
Effect is small, safe, is 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 by the intake of intestines and stomach by improving the sensitiveness of insulin, and suppresses liver, kidney mistake
The gluconeogenesis of degree.Body weight generally mitigates during this product does not reduce the blood sugar level of non-diabetic patients, patient medication, blood plasma courage
Sterol, triglycerides and the reduction of pre-β lipoprotein level, periphery glucose metabolism are 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
Plus the sensitiveness of insulin.
Prepared by existing Metformin hydrochloride is mainly：Dimethylamine and hydrochloric acid reaction generate dimethylamine hydrochloride, and then two
Methylamine hydrochloride generates Metformin hydrochloride with dicyandiamide addition.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 concentration, crystallization, drying；The need for having to dimethylamine hydrochloride concentrate add such as EDTA with except
Decontamination；Part producer adds solvent when dimethylamine hydrochloride is concentrated into almost no moisture and dicyandiamide progress addition is anti-
Should, cause final Metformin hydrochloride purity low（Content 95% or so）.
The method that dimethylamine hydrochloride prepares Metformin hydrochloride with dicyandiamide addition in industry mainly has two kinds：One is wet
Method, i.e., in the presence of an organic, dimethylamine hydrochloride are reacted with dicyandiamide；One is 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 because organic compound can be dissolved well, it as reaction medium when,
Reaction can be promoted to occur in homogeneous；（2）It can guarantee that material is well mixed and heat exchange is stable, accelerate reaction rate, and
Reaction rate is improved to a certain extent；（3）Reaction is more complete, and process is easy to control；
Shortcoming：（1 ）The organic solvent used in current technique has cyclohexanol, tert-pentyl alcohol, benzene class etc., its toxicity and is difficult to
Reclaim and make environmentally harmful factor again；（2）Reaction temperature is higher, generally 130~160 DEG C, consumes energy larger；（3）
Reaction time is long, easily occurs multiple side reactions；（4）Amount of impurities, impurity content are more in obtained Metformin hydrochloride crude product,
It is refined need to consume the low boiling point solvents such as substantial amounts of ethanol or methanol cause product cost higher.
（Two）Dry process
Advantage：（1 ）Flux synthesis procedure is a kind of new synthetic method, and it is under the synthetic environment of solvent-free presence, to incite somebody to action
The method that solid matter heating melting is chemically reacted.This method needs to use poisonous and hazardous molten compared with solvent method, neither
Agent, and without considering the problems such as solvent recovery, waste are handled, the discharge of pollutant thing can be eliminated from source；（2）Technical process letter
Singly, required equipment is few, yield is higher, cost is low.
Shortcoming：（1 ）Stir resistance big, 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 to, in frit reaction, due to the addition without 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 is not lived, and will be sent out more than required temperature
Multiple side reactions such as raw polymerization, oxidation are very big on product quality and yield influence；（3）Product purification is difficult, before reaction
Phase, latter stage are heterogeneous reaction, only in the reaction the phase be homogeneous reaction, material mixing uniformity, reaction homogeneity all by
To different degrees of influence, unreacting material is more, it is necessary to which secondary crystallization can just obtain qualified products.
There is following defect in prior art production Metformin hydrochloride：
（1）Toxic solvent, produces dusty gas, causes environmental pollution；
（2）Reaction temperature is high, causes high energy consumption and security poor；
（3）Reaction time is long, and single device production capacity is poor；
（4）Easily occurs side reaction；
（5）Product purity is low；
（6）Reaction yield is low.
The content of the invention
The present invention is not enough for more than, and there is provided the work that a kind of two-component solvent prepares high-purity high-yield Metformin hydrochloride
Industry production method, realizes 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, reaction by 130~160 DEG C of existing process
20 DEG C lower than solvent boiling point or so of temperature, 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, production cost is reduced, finished product per ton reduces cost more than 300 yuan.
For deficiency present in the production of current Metformin hydrochloride, the present invention is adopted the following technical scheme that：
A kind of method that two-component solvent prepares high-purity high-yield Metformin hydrochloride, including：Dimethylamine hydrochloride system
It is prepared by standby and Metformin hydrochloride;The dimethylamine hydrochloride preparation process, including：Part hydrochloric acid and dimethylamine gas plus
Enter, material enters blow-down pipe, add dimethylamine and hydrochloric acid, reaction second;The Metformin hydrochloride preparation process, including：
Add raw material and solvent, heat temperature raising, cooling, second of cooling, centrifugation, washing, crystallization, dry.
The following is the further improvement to above-mentioned technical proposal：
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, is first put into salt-forming reaction kettle by the hydrochloric acid of total amount 60% and enters
Row reaction.
The material enter 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, continues to react 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, adjusts 60~100 revs/min of speed of agitator, starts 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 kept for 1~1.5 hour for finished product crystallization kettle temperature is down into 0~15 DEG C in 30~50 revs/min, 2~4 hours.
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, add
The difference of the polarity of used solvent, dissolubility etc. during decrease temperature crystalline, its supersaturation point range restraint difficulty is larger.It is different molten
The supersaturated point of agent is different, and Crystallization Process varies, and bad choosing is put using single solvent supersaturation, and degree of supersaturation is inadequate, very
Difficult crystallization, let alone growing the grain.Crystallized in the presence of double solvents, adjust supersaturated interval, by controlling process conditions, analysis
Brilliant process is easy to control.The Crystallization Procedure time shortens, and obtained crystalline solid its crystalline form, size distribution, hardness etc. are superior to use
Single solvent.Crystallization condition and the follow-up process for refining such as mixing speed, cooling rate, temperature residence time are effectively controlled, really
Protect finished product purity and crystal grain distribution.
2nd, product yield is high, and yield reaches 95%, reacts 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, substitutes and 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 rapid can be separated out from solvent, be reacted 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%.Solve one-component anti-to one of which
The problem of dissolution of raw material degree is poor is answered, the use of dimethylformamide and ethylene glycol propyl ether two-component is solvent, two kinds of solvent associations
Same-action makes dicyandiamide add 20% with dimethylamine hydrochloride inventory.One-component is used in existing process as solvent, or
Dissolve dicyandiamide ability stronger, 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 is improved.
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, adds into the cooling effect of salt synthesis reactor chuck cooling water, can be with
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, two using being concentrated in vacuo
Methylamine hydrochloride purity and yield are improved, and integrated cost is than existing process reduction by 3% or so；The energy has been saved, dimethylamine is used
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 declines 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,
Added after reaction to a certain extent from head tank and play circulation in remaining hydrochloric acid, 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；From emptying discharge
Tail gas enter absorption by Hydrochloric Acid tank and absorb dimethylamine therein into gas, no dimethylamine gas is discharged into air, environmentally safe.
8th, more accurate control salt-forming reaction terminal.It is 2.2~3.6 by the control of salt-forming reaction endpoint pH, sampling detection pH
PH value is sampled again and is met the requirements within 15 minutes after value is qualified, then stop dimethylamine and be passed through, pump is continued 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
In the description and interpretation present invention, it 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 first measures the hydrochloric acid of the 560Kg in head tank
Salt-forming reaction kettle is put into, stirring is opened, is passed through chilled brine to reacting kettle jacketing, treats that kettle temperature is down to 10 DEG C, to cooler shell side
Chilled brine is passed through, starts to be passed through dimethylamine gas to salt-forming reaction kettle, adjusts dimethylamine gas charging rate, dimethylamine gas
Addition is 200Kg or so, keeps kettle temperature to 20 DEG C.
2nd, material enters blow-down pipe
Open the circulation pump, and open and lead to the high-end valve of blow-down pipe and make material equally distributed three from tube wall circumference
Mouth spray sprays into 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 detects pH value for 4~5 at pump circulation mouthful sampling, is started
Remaining 360Kg hydrochloric acid is added dropwise from head tank, during which dimethylamine charging valve door is not closed, remaining hydrochloric acid time for adding is 1
~1.5 hours.
4th, react
Hydrochloric acid completion of dropping, samples detection at pump circulation mouthful sampling, continue to react 15 if pH value is 2.2~3.6~
Stop dimethylamine within 30 minutes to add.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 to stir 20 minutes.
Material in concentration kettle is put into centrifuge, dried.
7th, dry
Solid material is put into the drying of double-cone type drier, controls vacuum 0.064MPa, is passed through the steaming of double-cone type drier chuck
Steam pressure 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,
Raw material is sequentially added under stirring condition：350Kg dimethylamine hydrochlorides and 380Kg dicyandiamides.
2nd, heat temperature raising
Steam is passed through to addition kettle chuck, is heated, 80 revs/min of speed of agitator is adjusted, kettle temperature was risen to 110 DEG C in 40 minutes,
Kept for 20 minutes, continue to heat up, temperature is risen into 119 DEG C, insulation reaction 2 hours at 20 minutes.
3rd, cool
Material in addition kettle is pressed into crystallization kettle with compressed air, starts hot water circulating pump, using steam heater by water
It is heated to 40 DEG C to start to cool to crystallization kettle, crystallization kettle temperature is down to 60 DEG C in 60 revs/min, 4 hours of speed of agitator of regulation,
Kept for 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, is down to crystallization kettle temperature in 3 hours
30 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, started logical to crystallization kettle chuck
Enter 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.Solid material is put into washing kettle by preparation.
6th, wash
With vacuum by concentration be 80%（Mass percent concentration）Ethanol 2200Kg be pumped into washing kettle, open stirring, add
Centrifugal solids material, is heated to 60 DEG C, is kept for 60 minutes.
7th, crystallize
Material in washing kettle is pressed into finished product crystallization kettle after accurate filter with compressed air.Adjust speed of agitator 60
Rev/min, 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.
Regulation speed of agitator is 40 revs/min again, puts finished product crystallization kettle chuck recirculated water, starts to be passed through to finished product crystallization kettle chuck
Chilled brine, 5 DEG C are down in 2 hours by finished product crystallization kettle temperature, are kept for 1 hour.
8th, dry
Material is put into centrifuge, dried, solid is put into vacuum desiccator in centrifuge, is 80 DEG C of vacuums in temperature
To be dried 2 hours under the conditions of 0.08MPa, finished product 678.1Kg, yield 95.4% are obtained（The product in mother liquor is not calculated）.
Filtrate, which continues cycling through, to be used, 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
Reacting kettle jacketing is passed through chilled brine, treats that kettle temperature is down to 10~20 DEG C, chilled brine is passed through to cooler shell side, starts into salt
Reactor is passed through dimethylamine gas, and dimethylamine gas addition is 2/3rds or so of total amount, regulation dimethylamine gas charging
Speed keeps kettle temperature 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 open and lead to the high-end valve of blow-down pipe and make material equally distributed three from tube wall circumference
Mouth spray sprays into 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 detects pH value for 4~5 at pump circulation mouthful sampling, from head tank
The hydrochloric acid of remaining about total amount 40% is added dropwise（Period dimethylamine continues to be passed through salt-forming reaction kettle）, remaining hydrochloric acid time for adding is 1
~1.5 hours.
4th, react
Hydrochloric acid completion of dropping, addition all after the dimethylamine gas of metering, are sampled at pump circulation mouthful sampling and detected, if pH
It is worth for 2.2~3.6, then continuation 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, closing vacuum, continuation stirring 20~
30 minutes.
Material is put into centrifuge, dried, Recycling Mother Solution is used（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 double-cone type drier folder
Cover steam pressure and be less than 0.3MPa, drying time 2~2.5 hours.
Dimethylamine hydrochloride is obtained, yield is 97.7-97.9%.
（Two）It is prepared by Metformin hydrochloride
1st, raw material and solvent are added
Vavuum pump is opened, addition kettle, stirring condition will be pumped into after dimethylformamide and ethylene glycol propyl ether metering
Under sequentially add the dimethylamine hydrochloride and dicyandiamide of 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, 80~130 revs/min of speed of agitator is adjusted.30~50 minutes by kettle temperature liter
To 110~115 DEG C, kept for 10~30 minutes, continue to heat up rises to 118~125 DEG C, insulation reaction in 15~30 minutes by temperature
1.5~2.5 hours.
3rd, cool
Material in addition kettle is pressed into crystallization kettle with compressed air, starts hot water circulating pump, using steam heater by water
It is heated to 40-65 DEG C to start to cool to crystallization kettle, kettle temperature will be crystallized in 60~100 revs/min, 3~6 hours of speed of agitator of regulation
Degree is down to 60~75 DEG C, is 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, kettle temperature will be crystallized in 3.5~5 hours
Degree is down to 30~50 DEG C, is 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,
Start to be passed through chilled brine to crystallization kettle chuck, interior in 2~4 hours that crystallization kettle temperature is down into 0~10 DEG C, holding 1~2.5 is small
When.
5th, centrifuge
Crystallization kettle baiting valve is opened, material is put into centrifuge from crystallization kettle dries, and solid material is put into washing kettle, and centrifugation is female
Liquid is used for 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 consumption of ethanol
For 6~10 times of dimethylamine 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.Adjust 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.
Regulation speed of agitator is 30~50 revs/min 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, which continues cycling through, to be used, circulation is post-processed to a certain extent；From
Solid is put into vacuum desiccator in scheming, temperature be 60~90 DEG C of vacuums be dry 2 under the conditions of 0.06~0.08MPa~
2.5 hours, obtain finished product.
Filtrate, which continues cycling through, to be used, 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, with advantages below：
1st, prepared by dimethylamine hydrochloride, is reacted using dimethylamine gas and 31% hydrochloric acid as raw material, sets cooler and anti-
Kettle chuck is answered to cool together, by the way of pump beats circulation, spray-absorption dimethylamine tail gas and absorption by Hydrochloric Acid dimethylamine tail gas, most
Limits 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, adds the inventory of single batch, reduces reaction temperature, when shortening reaction
Between, dicyandiamide is uniform with dimethylamine hydrochloride addition reaction, and processing safety is improved.
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 is separated out easily from solvent, refined middle solvent is easy to wash away from finished product, so that
It ensure that finished product can reach pharmaceutical quality standard.
4th, addition reaction is finished, to ensure to separate out crystallization, ensureing crystal formation and grain graininess, it is determined that mixing speed, cooling
Speed, temperature residence time three are while the operation for being optimal, produces hydrochloric acid two that is pure and having 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 to 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 (3)
1. a kind of method that two-component solvent prepares high-purity hydrochloric acid melbine, it is characterised in that：Including：Dimethylamine hydrochloride
Prepare and be 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 addition of the part hydrochloric acid and dimethylamine gas, is first put into salt-forming reaction kettle by the hydrochloric acid of total amount 60% and is reacted, to
Dimethylamine gas is passed through in hydrochloric acid solution；
The dimethylamine：The weight ratio of 31% technical hydrochloric acid is 1：2.75~2.98；
The reaction, reaction end pH value control is 2.2~3.6, and pH value is sampled again within 15 minutes after sampling detection pH value is qualified
Meet the requirements, then stop dimethylamine and be passed through, pump is continued cycling through 2 hours can terminating reaction progress subsequent concentration；
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 addition raw material and solvent, the raw material of addition is dimethylamine hydrochloride, dicyandiamide；The solvent of addition is dimethyl formyl
Amine and ethylene glycol propyl ether；
The addition raw material and solvent, the part by weight dimethylamine hydrochloride fed intake：Dicyandiamide:Dimethylformamide：Ethylene glycol
Single positive propyl ether=1:1.06~1.11:0.8~1.65:0.2~1.2；
The Metformin hydrochloride preparation process, reaction temperature is 118~125 DEG C；
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 knot
Brilliant kettle chuck is passed through chilled brine, interior in 2~4 hours that crystallization kettle temperature is down into 0~10 DEG C, is kept for 1~2.5 hour；
Crystallisation step in prepared by the Metformin hydrochloride, adjusts 60~100 revs/min of speed of agitator, starts to crystallization kettle chuck
Recirculated water is passed through, finished product crystallization kettle temperature is down to 30~50 DEG C in 2~3 hours, is kept for 1~1.5 hour；Regulation stirring again
Rotating speed is kept for 1~1.5 hour for finished product crystallization kettle temperature is down into 0~15 DEG C in 30~50 revs/min, 2~4 hours；
Drying steps in prepared by the Metformin hydrochloride, are that 60~90 DEG C of vacuums are 0.06~0.08MPa conditions in temperature
Lower drying 2~2.5 hours, finished product.
2. the method that a kind of two-component solvent as claimed in claim 1 prepares high-purity hydrochloric acid melbine, it is characterised in that：
The material enters blow-down pipe step, open the circulation pump, and opening and leads to the high-end valve of blow-down pipe and make material from tube wall circumference
Upper equally distributed three mouth sprays spray into blow-down pipe.
3. the method that a kind of two-component solvent as claimed in claim 1 prepares high-purity hydrochloric acid melbine, it is characterised in that：
Using Metformin hydrochloride made from methods described, product yield is more than 95%, and purity is more than 99.90%.
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| CN201710507363.8A CN107245042B (en) | 2015-04-24 | 2015-04-24 | A kind of method of double solvents production Metformin hydrochloride |
| CN201510197624.1A CN104829495B (en) | 2015-04-24 | 2015-04-24 | A kind of method that two-component solvent prepares high-purity high-yield Metformin hydrochloride |
| CN201710507365.7A CN107337618B (en) | 2015-04-24 | 2015-04-24 | Production method for simultaneously improving purity and yield of metformin hydrochloride |
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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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| CN101450918B (en) * | 2007-11-30 | 2011-08-10 | 山东方兴科技开发有限公司 | Metformin hydrochloride purification method |
| 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 |
| WO2010146604A2 (en) * | 2009-06-18 | 2010-12-23 | Exemed Pharmaceuticals | Processes for preparing metformin hydrochloride |
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