CN107245042B - A kind of method of double solvents production Metformin hydrochloride - Google Patents
A kind of method of double solvents production Metformin hydrochloride Download PDFInfo
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- CN107245042B CN107245042B CN201710507363.8A CN201710507363A CN107245042B CN 107245042 B CN107245042 B CN 107245042B CN 201710507363 A CN201710507363 A CN 201710507363A CN 107245042 B CN107245042 B CN 107245042B
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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
Abstract
The invention discloses a kind of methods of double solvents production Metformin hydrochloride, comprising: dimethylamine hydrochloride preparation and Metformin hydrochloride preparation；The Metformin hydrochloride preparation step, comprising: raw material and solvent, heat temperature raising, cooling, for the second time cooling, centrifugation, washing, crystallization, drying is added；The heat temperature raising: Xiang Jiacheng kettle collet is passed through steam, and heating adjusts 80~130 revs/min of speed of agitator, kettle temperature was risen to 110~115 DEG C in 30~50 minutes, it is kept for 10~30 minutes, continues temperature to be risen to 118~125 DEG C, insulation reaction 1.5~2.5 hours in heating 15~30 minutes.Metformin hydrochloride preparation, is solvent using dimethylformamide and ethylene glycol propyl ether two-component, and using the synergistic effect of two kinds of heterogeneity solvents, Metformin hydrochloride obtained, product yield is greater than 95%, and purity is greater 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 relate to a kind of using two-component solvent preparation high-purity
The production method of high yield Metformin hydrochloride.
Background technique
Metformin hydrochloride has very strong physiological activity as other guanidine substances, can reduce type II diabetes trouble
Person is on an empty stomach and postprandial hyperglycemia, glycosylated hemoglobin (HbAlc) can decline 1%~2%, has unique treatment to make diabetes B
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 highly-safe, be current clinically most common antidiabetic drug.There are many mechanism of action for the medical instrument, including delay grape
For sugar by the intake of gastrointestinal tract, the sensibility by improving insulin increases the utilization of periphery glucose, and inhibits liver, kidney mistake
The gluconeogenesis of degree.This product does not reduce the blood glucose level of non-diabetic patients, and weight usually mitigates during patient medication, blood plasma gallbladder
Sterol, triglycerides and pre-β lipoprotein level reduce, and periphery glucose metabolism is improved.It is confirmed through clinical test, it can be effective
Reduce blood glucose and prevention coronary heart disease.The combination of insulin and target organ receptor can be increased and reinforce the effect after receptor simultaneously, increased
Add the sensibility of insulin.
The preparation of existing Metformin hydrochloride is mainly: dimethylamine reacts generation dimethylamine hydrochloride with hydrochloric acid, and then two
Methylamine hydrochloride and dicyandiamide addition generate Metformin hydrochloride.Dimethylamine hydrochloride and dicyandiamide synthesis condition and purification operations
Difference, obtained product purity, it is molten away from, dissolution clarity, feed stock conversion, product benefit etc. differ widely.
It is most that existing dimethylamine reacts generation dimethylamine hydrochloride production technology with hydrochloric acid are as follows: water-soluble to 40% dimethylamine
Hydrochloric acid is added dropwise in liquid, by concentration, crystallization, drying；Such as EDTA is added to dimethylamine hydrochloride concentrate to remove in some need
Decontamination；Solvent is added when dimethylamine hydrochloride is concentrated into almost no moisture by part of the manufacturer and dicyandiamide progress addition is anti-
It answers, causes final Metformin hydrochloride purity low (content 95% or so).
Dimethylamine hydrochloride and dicyandiamide addition are prepared there are mainly two types of the methods of Metformin hydrochloride in industry: first is that wet
Method, i.e., in the presence of an organic, dimethylamine hydrochloride are reacted with dicyandiamide；First is that dry method, i.e. dimethylamine hydrochloride with
Dicyandiamide reacts in the molten state, and the strengths and weaknesses analysis of the two is as follows:
(1) wet processing
Advantage: (1) organic solvent selected is because organic compound can be dissolved well, when it is as the medium reacted,
Reaction can be promoted in homogeneous middle generation；(2) it can guarantee that material is uniformly mixed and heat exchange is stablized, accelerate reaction rate, and
Reaction rate is improved to a certain extent；(3) react more complete, process is convenient for control；
Disadvantage: (1) organic solvent used in technique at present has cyclohexanol, tert-pentyl alcohol, benzene class etc., toxicity and is difficult to
Recycling makes environmentally harmful factor again；(2) reaction temperature is higher, generally 130~160 DEG C, consumes energy larger；(3)
Reaction time is long, and multiple side reactions easily occur；(4) amount of impurities, impurity content are more in the Metformin hydrochloride crude product obtained,
Purification needs to consume the low boiling point solvents such as a large amount of ethyl alcohol or methanol and causes product cost higher.
(2) dry process
Advantage: (1) flux synthesis procedure is a kind of novel synthetic method, it is incited somebody to action under solvent-free existing synthetic environment
The method that solid matter heating melting is chemically reacted.This method does not both need compared with solvent method using poisonous and hazardous molten
Agent, and do not have to the problems such as considering solvent recovery, waste processing, the discharge of pollutant object can be eliminated from source；(2) technical process letter
List, required equipment is few, yield is higher, at low cost.
Disadvantage: (1) it is big to stir resistance, and due to not having a solvent, reactant is in the molten state at 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 not no solvent, reactant
It is heated to after dissolving, heat loss is slower, it is difficult to control reaction temperature.Just in case temperature is lost control of, and is more than that required temperature will be sent out
Multiple side reactions such as raw polymerization, oxidation influence product quality and yield very big；(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
It is influenced to different degrees of, unreacting material is more, needs secondary crystallization that can just obtain qualified products.
Prior art production Metformin hydrochloride has the following deficiencies:
(1) toxic solvent generates polluted gas, causes environmental pollution；
(2) reaction temperature is high, causes energy consumption height and safety poor；
(3) reaction time is long, and single device production capacity is poor；
(4) Yi Fasheng side reaction；
(5) product purity is low；
(6) reaction yield is low.
Summary of the invention
The present invention against the above deficiency, provides 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 by 130~160 DEG C of prior art, reaction temperature
20 DEG C lower than solvent boiling point or so of degree, improves production security；
(4) shorten the production cycle, the reaction time shortens 2 hours than prior art；
(5) no pollution to the environment；
(6) single device production capacity is improved, separate unit inventory improves 20%；
(7) energy saving, production cost is reduced, finished product per ton reduces by 300 yuan of cost or more.
For deficiency present in the production of current Metformin hydrochloride, the present invention adopts the following technical scheme:
A kind of method that two-component solvent prepares high-purity high-yield Metformin hydrochloride, comprising: dimethylamine hydrochloride system
The preparation of standby and Metformin hydrochloride；
The dimethylamine hydrochloride preparation step, comprising: the addition of part hydrochloric acid and dimethylamine gas, material enter emptying
Dimethylamine and hydrochloric acid, reaction is added second in pipe；
The Metformin hydrochloride preparation step, comprising: raw material and solvent is added, heat temperature raising, cooling, drops for second
Temperature, centrifugation, washing, crystallization, drying.
It is to be advanced optimized to above-mentioned technical proposal below:
The dimethylamine hydrochloride preparation step, raw material dimethylamine: the weight ratio of 31% technical hydrochloric acid be 1: 2.75~
2.98。
The addition step of the part hydrochloric acid and dimethylamine gas, by the hydrochloric acid of total amount 60% be first put into salt-forming reaction kettle into
Row reaction.
The material enters blow-down pipe step, opens circulating pump, and open lead to the high-end valve of blow-down pipe make material from
Equally distributed three spray ports spray into blow-down pipe on tube wall circumference.
The reaction step, sample detection, if pH value is 2.2~3.6, the reaction was continued 15~30 minutes.
Raw material and solvent step is added in the Metformin hydrochloride preparation, ingredient proportion dimethylamine hydrochloride: dicyandiamide:
Dimethylformamide: ethylene glycol propyl ether=1:1.06~1.11:0.8~1.65:0.2~1.2.
Second of cooling step in Metformin hydrochloride preparation: crystallization kettle temperature is down to 30 in 3.5~5 hours~
It 50 DEG C, is kept for 1~1.5 hour；30~50 revs/min of speed of agitator are adjusted, crystallization kettle temperature is then down to 0 in 2~4 hours
It~10 DEG C, is kept for 1~2.5 hour.
Crystallisation step in the Metformin hydrochloride preparation, adjusts 60~100 revs/min of speed of agitator, starts to crystallization kettle
Collet is passed through recirculated water, and finished product crystallization kettle temperature is down to 30~50 DEG C in 2~3 hours, is kept for 1~1.5 hour；It adjusts again
Speed of agitator is that finished product crystallization kettle temperature is down to 0~15 DEG C in 30~50 revs/min, 2~4 hours, is kept for 1~1.5 hour.
It is 0.06~0.08MPa that drying steps in the Metformin hydrochloride preparation, which are 60~90 DEG C of vacuum degrees in temperature,
Under the conditions of dry 2~2.5 hours, finished product.
Using Metformin hydrochloride made from the method, product yield is greater than 95%, and purity is greater than 99.90%.
Compared with the prior art, the present invention has the following beneficial effects:
1, product purity is high, reaches 99.90%.Due to the unique chemical structure of melbine and physicochemical properties, in addition
The difference of polarity, dissolubility of used solvent etc. when decrease temperature crystalline, supersaturation point range restraint difficulty are larger.It is different molten
The supersaturation point of agent is different, and Crystallization Process is multifarious, and using the bad choosing of single solvent supersaturation point, degree of supersaturation is inadequate, very
Difficult crystallization, let alone growing the grain.It is crystallized in the presence of double solvents, adjusts supersaturated section, by controlling process conditions, analysis
Brilliant process is convenient for control.The Crystallization Procedure time shortens, obtained crystalline solid its crystalline form, size distribution, hardness etc. be superior to using
Single solvent.Effectively crystallization conditions and the follow-up process for refining such as control mixing speed, cooling rate, temperature residence time, really
Protect finished product purity and crystal grain distribution.
2, 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, and substitution uses one-component such as isoamyl at present
Alcohol, benzene class, dimethyl acetamide single solvent are reacted；Using single solvent, solubility is small when raw material low temperature, and temperature is higher
When solubility it is big, since the dissolution of product Metformin hydrochloride in a solvent is smaller, once misoperation or technique refer to when synthesis
Mark control is bad, and unreacted raw material dicyandiamide, dimethylamine hydrochloride and product can be precipitated from solvent rapidly, reacts endless
Entirely.Subsequent purification difficulty is big, and product purity is low, or even secondary refining product is needed to can be only achieved medical standard, and product is caused to be received
Rate is low, of poor benefits.Using preparation method of the present invention, product yield is increased to 95% or more by the 90% of prior art.
3, single device production capacity is improved, separate unit inventory improves 20%.One-component is solved to one of anti-
The problem for answering dissolution of raw material degree difference is solvent, two kinds of solvent associations using dimethylformamide and ethylene glycol propyl ether two-component
Same-action makes dicyandiamide and dimethylamine hydrochloride inventory increase 20%.Use one-component as solvent in prior art, or
Dissolve that dicyandiamide ability is stronger or dimethylamine hydrochloride solubility is big in a solvent, to the molten of final products Metformin hydrochloride
Solution situation also differs widely.
4, reaction temperature reduces by 20 DEG C or so, improves safety.Reaction temperature is dropped by 130~160 DEG C of prior art
It is 118~125 DEG C.20 DEG C lower than solvent boiling point of reaction temperature or so, be not in slug in reaction, and production security improves.
5, shorten the production cycle.Reaction time shortens 2 hours than prior art.40% is used using dimethylamine gas substitution
Dimethylamine solution and 31% hydrochloric acid carry out salt-forming reaction, have increase accordingly the concentration of reaction mass in reaction system, dimethylamine per ton
Hydrochloride concentration and evaporation discharge reduction shortens the production cycle close to 1000Kg.
6, energy saving, dimethylamine hydrochloride production cost per ton reduces by 300 yuan or more.When carrying out Matter Transfer with pump,
Cooler is provided in pump discharge pipeline to cool down to reaction solution, it, can be in addition at the cooling effect of salt synthesis reactor collet cooling water
Guarantee that reaction temperature meets technique requirement, does not need chilled brine and cool down to reaction system, saved the energy；Dimethylamine hydrochloride
Solution reduces evaporating temperature using vacuum concentration, reduces the generation of decomposition and the other side reactions of dimethylamine hydrochloride, and two
Methylamine hydrochloride purity and yield improve, and overall cost reduces by 3% or so than prior art；The energy has been saved, dimethylamine is used
Gas instead carries out salt-forming reaction using 40% dimethylamine solution and 31% hydrochloric acid, has increase accordingly reaction mass in reaction system
Concentration, dimethylamine hydrochloride concentration and evaporation discharge reduction per ton decline 300 yuan or more close to 1000Kg, cost.
7, no pollution to the environment.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, beats circulation always with pumping in reaction process, blow-down pipe top is set
In respect of the unreacted dimethylamine counter current contacting of equally distributed on tube wall circumference three spray ports and rising；It is discharged from emptying
Tail gas enter absorption by Hydrochloric Acid tank and absorb dimethylamine therein into gas, no dimethylamine gas is discharged into atmosphere, no pollution to the environment.
8, more acurrate control salt-forming reaction terminal.It is 2.2~3.6 by the control of salt-forming reaction endpoint pH, sample 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 continues cycling through can terminate instead for 2 hours
It should carry out subsequent concentration.
Specific embodiment:
Hereinafter, preferred embodiments of the present invention will be described, it should be understood 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, comprising the following steps:
(1) prepared by dimethylamine hydrochloride
1, 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
It is put into salt-forming reaction kettle, stirring is opened, is passed through chilled brine to reacting kettle jacketing, is down to 10 DEG C to kettle temperature, to cooler shell side
It is passed through chilled brine, starts to be passed through dimethylamine gas to salt-forming reaction kettle, adjusts dimethylamine gas charging rate, dimethylamine gas
Additional amount is 200Kg or so, keeps kettle temperature to 20 DEG C.
2, material enters blow-down pipe
Circulating pump is opened, and opening leads to the high-end valve of blow-down pipe and makes material equally distributed three from tube wall circumference
Spray port sprays into blow-down pipe；Observation tail gas enters the bubbling situation of absorption by Hydrochloric Acid tank.
3, dimethylamine and hydrochloric acid is added second
From dimethylamine steel cylinder be added dimethylamine gas, from pump circulation mouth sampling place sample detection pH value be 4~5 after, start
The hydrochloric acid of remaining 360Kg is added dropwise from head tank, during which dimethylamine charging valve door is not closed, and remaining hydrochloric acid time for adding is 1
~1.5 hours.
4, it reacts
Hydrochloric acid is added dropwise, from pump circulation mouth sampling place sample detection, the reaction was continued if pH value is 2.2~3.6 15~
Stop dimethylamine within 30 minutes to be added.Dimethylamine gas total amount is added at this time should be 330Kg or so.
5, it crystallizes
The liquid in salt-forming reaction kettle is pumped into concentration kettle with vacuum, stirring is started, is passed through steam to concentration kettle collet.
Hydraulic jet pump is opened, control concentration kettle vacuum degree is 0.048MPa.
When observing in concentration kettle has crystallization to be precipitated, turns down concentration kettle collet and enter steam valve, speed of agitator is adjusted
For 400rpm.
When observing that the generation of cyclic annular zone of a crystal is arranged at concentration kettle bottom, concentration kettle vacuum degree is increased to 0.066MPa.
When observing that concentration kettle bottom annular crystal increases suddenly, closes concentration kettle collet and enter steam valve, it will be dense
Contracting kettle vacuum degree is increased to 0.08MPa.
6, it is centrifuged
It is passed through cooling water temperature to concentration kettle collet, when kettle temperature is down to 28 DEG C, vacuum is closed, continues stirring 20 minutes.
Material in concentration kettle is put into centrifuge, is dried.
7, it dries
Solid material is put into the drying of double-cone type drier, controls vacuum degree 0.064MPa, is passed through the steaming of double-cone type drier collet
Steam pressure 0.25MPa, drying time 2.5 hours.
Obtain dimethylamine hydrochloride 583.2Kg, yield 97.7%.
(2) prepared by Metformin hydrochloride
1, raw material and solvent is added
Vacuum pump is opened, 600Kg dimethylformamide and 110Kg ethylene glycol propyl ether solvent are pumped into addition kettle,
Raw material is sequentially added under stirring condition: 350Kg dimethylamine hydrochloride and 380Kg dicyandiamide.
2, heat temperature raising
It is passed through steam to addition kettle collet, is heated, 80 revs/min of speed of agitator is adjusted, kettle temperature was risen to 110 DEG C in 40 minutes,
It is kept for 20 minutes, continues to heat up, temperature is risen to 119 DEG C, insulation reaction 2 hours at 20 minutes.
3, cool down
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 down to crystallization kettle, adjusts in 60 revs/min of speed of agitator, 4 hours and crystallization kettle temperature is down to 60 DEG C,
It is kept for 1 hour.
4, cool down for second
The kettle collet hot water that decrystallizes is put, starts to be passed through recirculated water to crystallization kettle collet, is down to crystallization kettle temperature in 3 hours
It 30 DEG C, is kept for 1.5 hours.40 revs/min of speed of agitator are adjusted, the kettle collet recirculated water that decrystallizes is put, is started logical to crystallization kettle collet
Enter chilled brine, crystallization kettle temperature is down to 8 DEG C in 2.5 hours, is kept for 2 hours.
5, it is centrifuged
Crystallization kettle baiting valve is opened, material is put into centrifuge drying from crystallization kettle.Prepare solid material being put into washing kettle.
6, it washs
By concentration be 80%(mass percent concentration with vacuum) ethyl alcohol 2200Kg be pumped into washing kettle, open stirring, be added
Centrifugal solids material is heated to 60 DEG C, is kept for 60 minutes.
7, it crystallizes
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 collet, finished product crystallization kettle temperature is down to 35 DEG C in 3 hours, is kept for 1 hour.
Adjusting speed of agitator again is 40 revs/min, puts finished product crystallization kettle collet recirculated water, starts to be passed through to finished product crystallization kettle collet
Finished product crystallization kettle temperature was down to 5 DEG C in 2 hours by chilled brine, was kept for 1 hour.
8, dry
Material is put into centrifuge, is dried, solid is put into vacuum desiccator in centrifuge, is 80 DEG C of vacuum degrees in temperature
It is drying 2 hours under the conditions of 0.08MPa, obtains finished product 678.1Kg, yield 95.4%(does not calculate the product in mother liquor).
Filtrate continues cycling through use, adds partial solvent after being recycled 4 times.
Through detecting: the technical performance index of product obtained is as follows:
The technical performance index of 1 product of table
Embodiment 2
Through testing, the step of using embodiment 1, using following technological parameter:
(1) prepared by dimethylamine hydrochloride
1, 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, opens stirring, to
Reacting kettle jacketing is passed through chilled brine, is down to 10~20 DEG C to kettle temperature, is passed through chilled brine to cooler shell side, starts at salt
Reaction kettle is passed through dimethylamine gas, and dimethylamine gas additional amount is 2/3rds or so of total amount, adjusts dimethylamine gas charging
Speed keeps kettle temperature to 15~25 DEG C.
Dimethylamine: 31% technical hydrochloric acid (weight ratio)=1: 2.75~2.98.
2, material enters blow-down pipe
Circulating pump is opened, and opening leads to the high-end valve of blow-down pipe and makes material equally distributed three from tube wall circumference
Spray port sprays into blow-down pipe；Observation tail gas enters the bubbling situation of absorption by Hydrochloric Acid tank.
3, dimethylamine and hydrochloric acid is added second
Be added metered amount dimethylamine gas, from pump circulation mouth sampling place sample detection pH value be 4~5 after, from head tank
The hydrochloric acid (period dimethylamine continues to be passed through salt-forming reaction kettle) of remaining about total amount 40% is added dropwise, remaining hydrochloric acid time for adding is 1
~1.5 hours.
4, it reacts
After hydrochloric acid is added dropwise, the dimethylamine gas all measured is added, from pump circulation mouth sampling place sample detection, if pH
Value is 2.2~3.6, then the reaction was continued 15~30 minutes (suitably adding 2~3Kg dimethylamine gas if pH value is lower than 2).
5, it crystallizes
The liquid in salt-forming reaction kettle is pumped into concentration kettle with vacuum, stirring is started, is passed through steam to concentration kettle collet.
Hydraulic jet pump is opened, control concentration kettle vacuum degree is 0.04~0.056MPa.
When observing in concentration kettle has crystallization to be precipitated, turns down concentration kettle collet and enter steam valve, speed of agitator is adjusted
For 40~60rpm.
When observing that the generation of cyclic annular zone of a crystal is arranged at concentration kettle bottom, concentration kettle vacuum degree is increased to 0.06~
0.07MPa。
When observing that concentration kettle bottom annular crystal increases suddenly, closes concentration kettle collet and enter steam valve, it will be dense
Contracting kettle vacuum degree is increased to 0.076MPa or more.
6, it is centrifuged
Be passed through cooling water temperature to concentration kettle collet, when kettle temperature is down to 30 DEG C or less, close vacuum, continue stirring 20~
30 minutes.
Material is put into centrifuge, is dried, Recycling Mother Solution use (or the hydrochloric acid for being 31% for configuration concentration, or focus on
It is a certain amount of after centralized processing, using)；
Solid material is put into the drying of double-cone type drier, controls 0.06~0.07MPa of vacuum degree, is passed through double-cone type drier folder
Cover steam pressure be lower than 0.3MPa, drying time 2~2.5 hours.
Obtain dimethylamine hydrochloride, yield 97.7-97.9%.
(2) prepared by Metformin hydrochloride
1, raw material and solvent is added
Vacuum 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.
2, heat temperature raising
It is passed through steam to addition kettle collet, is heated, adjusts 80~130 revs/min of speed of agitator.30~50 minutes by kettle temperature liter
To 110~115 DEG C, is kept for 10~30 minutes, continue temperature to be risen to 118~125 DEG C in heating 15~30 minutes, insulation reaction
1.5~2.5 hours.
3, cool down
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 down to crystallization kettle, kettle temperature will be crystallized by adjusting in 60~100 revs/min of speed of agitator, 3~6 hours
Degree is down to 60~75 DEG C, is kept for 1~1.5 hour.
4, cool down for second
The kettle collet hot water that decrystallizes is put, starts to be passed through recirculated water to crystallization kettle collet, 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 are adjusted, the kettle collet recirculated water that decrystallizes is put,
Start to be passed through chilled brine to crystallization kettle collet, interior in 2~4 hours that crystallization kettle temperature is down to 0~10 DEG C, holding 1~2.5 is small
When.
5, it is centrifuged
Crystallization kettle baiting valve is opened, material is put into centrifuge drying from crystallization kettle, solid material is put into washing kettle, and centrifugation is female
Liquid is used for addition reaction next time.
6, it washs
By concentration be 75-90%(mass ratio with vacuum) ethyl alcohol be pumped into washing kettle, 75-90%(mass ratio) dosage of ethyl alcohol
It is 6~10 times of dimethylamine hydrochloride inventory.Stirring is opened, centrifugation gained all solids material is added, is heated to 60
It~70 DEG C, is kept for 40~80 minutes.
7, it crystallizes
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, starts to be passed through recirculated water to crystallization kettle collet, finished product crystallization kettle temperature is down to 30~50 in 2~3 hours
DEG C, it is kept for 1~1.5 hour.
Adjusting speed of agitator again is 30~50 revs/min, puts finished product crystallization kettle collet recirculated water, starts to finished product knot
Brilliant kettle collet is passed through chilled brine, finished product crystallization kettle temperature is down to 0~15 DEG C in hour in 2~4 hours, holding 1~1.5 is small
When.
8, dry
Material is put into centrifuge, is dried, filtrate continues cycling through use, and circulation is post-processed to a certain extent；From
Solid is put into vacuum desiccator in scheming, dry 2 under the conditions of temperature be 60~90 DEG C of vacuum degrees is 0.06~0.08MPa~
2.5 hours, obtain finished product.
Filtrate continues cycling through use, adds partial solvent after being recycled 4 times.
Product yield is all larger than 95%, and purity is greater than 99.90%, and all technical is excellent.
Through testing, embodiment 1 is preferred embodiment, and yield, purity and every technical performance index are best.
Using technical solution of the present invention, have the advantage that
1, dimethylamine hydrochloride prepare, reacted using dimethylamine gas and 31% hydrochloric acid as raw material, setting cooler with instead
Kettle collet is answered to cool down together, in such a way that 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,
In addition control cooling rate and mixing speed, crystalline particle good evenness, crystallization post mother liquor are integrated.
2, prepared by Metformin hydrochloride, the use of dimethylformamide and ethylene glycol propyl ether two-component is solvent, utilizes
The synergistic effect of two kinds of heterogeneity solvents increases the inventory of single batch, reduces reaction temperature, when shortening reaction
Between, dicyandiamide and dimethylamine hydrochloride addition reaction are uniform, and operational safety improves.
3, dicyandiamide and dimethylamine hydrochloride carry out addition reaction under using two-component solvent condition, and solvent viscosity is almost
It not being affected by temperature and viscosity is lower, finished product is precipitated from solvent to be easy, and solvent is easy to wash away from finished product in purification, thus
It ensure that finished product can reach pharmaceutical quality standard.
4, addition reaction finishes, to ensure to be precipitated crystallization, guaranteeing crystal form and grain graininess, it is determined that mixing speed, cooling
Hydrochloric acid two that is pure and having certain particle size to be distributed is produced in the operation of speed, temperature residence time three while being optimal
First biguanides crystal.The granularity and its distribution of Metformin hydrochloride crystal product, depend primarily on nucleus generating rate, crystal growth
The mean residence time of rate 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, at this time condensing crystallizing kettle production capacity with higher, again
A certain size crystal product can be obtained, and product purity is high.
In the above-described embodiments, preferred forms of the invention are described, it is obvious that in invention structure of the invention
Under think of, many variations can be still made.Here, it should be noted that any change made under inventive concept of the invention all will
It falls within the scope of protection of the present invention.
Claims (1)
1. a kind of method of double solvents production Metformin hydrochloride, it is characterised in that: include: dimethylamine hydrochloride preparation and salt
Sour melbine preparation；
The dimethylamine hydrochloride preparation step, comprising: the addition of part hydrochloric acid and dimethylamine gas, material enter blow-down pipe,
Second of addition dimethylamine and hydrochloric acid, reaction；
The dimethylamine hydrochloride preparation step, raw material dimethylamine: the weight ratio of 31% technical hydrochloric acid is 1: 2.75~2.98；
The hydrochloric acid of total amount 60% is first put into salt-forming reaction kettle and carried out instead by the addition step of the part hydrochloric acid and dimethylamine gas
It answers；
The material enters blow-down pipe step, opens circulating pump, and opening leads to the high-end valve of blow-down pipe and makes material from tube wall
Equally distributed three spray ports spray into blow-down pipe on circumference；
The reaction step, sample detection, if pH value is 2.2~3.6, the reaction was continued 15~30 minutes；
The Metformin hydrochloride preparation, comprising the following steps:
(1) raw material and solvent is added
Open vacuum 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 that metering is added；Ingredient proportion (weight ratio) dimethylamine hydrochloride: dicyandiamide: dimethyl
Formamide: ethylene glycol propyl ether=1:1.06~1.11:0.8~1.65:0.2~1.2；
(2) heat temperature raising
It is passed through steam to addition kettle collet, is heated, adjusts 80~130 revs/min of speed of agitator；Kettle temperature was risen in 30~50 minutes
It 110~115 DEG C, is kept for 10~30 minutes, continues temperature to be risen to 118~125 DEG C in heating 15~30 minutes, insulation reaction 1.5
~2.5 hours；
(3) cool down
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 down to crystallization kettle to 40-65 DEG C, adjusts and drop crystallization kettle temperature in 60~100 revs/min of speed of agitator, 3~6 hours
To 60~75 DEG C, kept for 1~1.5 hour；
(4) cool down for second
The kettle collet hot water that decrystallizes is put, starts to be passed through recirculated water to crystallization kettle collet, drops crystallization kettle temperature in 3.5~5 hours
To 30~50 DEG C, kept for 1~1.5 hour；Adjust 30~50 revs/min of speed of agitator, put the kettle collet recirculated water that decrystallizes, start to
Crystallization kettle collet is passed through chilled brine, interior in 2~4 hours that crystallization kettle temperature is down to 0~10 DEG C, is kept for 1~2.5 hour；
(5) it is centrifuged
Crystallization kettle baiting valve is opened, material is put into centrifuge drying from crystallization kettle, solid material is put into washing kettle, and centrifuge mother liquor is used
In addition reaction next time；
(6) it washs
By concentration be 75-90%(mass ratio with vacuum) ethyl alcohol be pumped into washing kettle, 75-90%(mass ratio) dosage of ethyl alcohol 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, it is kept for 40~80 minutes；
(7) it crystallizes
Material in washing kettle is pressed into finished product crystallization kettle after accurate filter with compressed air；Adjusting speed of agitator 60~
100 revs/min, starts to be passed through recirculated water to crystallization kettle collet, finished product crystallization kettle temperature is down to 30~50 DEG C in 2~3 hours,
It is kept for 1~1.5 hour；Again adjust speed of agitator be 30~50 revs/min, put finished product crystallization kettle collet recirculated water, start to
Finished product crystallization kettle collet is passed through chilled brine, and finished product crystallization kettle temperature is down to 0~15 DEG C in hour in 2~4 hours, keeps 1
~1.5 hours；
(8) dry
Material is put into centrifuge, is dried, filtrate continues cycling through use, and circulation is post-processed to a certain extent；Centrifuge
Interior solid is put into vacuum desiccator, and dry 2~2.5 is small under the conditions of temperature be 60~90 DEG C of vacuum degrees is 0.06~0.08MPa
When, obtain Metformin hydrochloride finished product.
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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 |
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| CN1844093A (en) * | 2006-05-10 | 2006-10-11 | 翟树军 | Process for preparing metformin hydrochloride |
| CN101450918A (en) * | 2007-11-30 | 2009-06-10 | 山东方兴科技开发有限公司 | Metformin hydrochloride purification method |
| 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 |
| CN104119250A (en) * | 2014-07-15 | 2014-10-29 | 徐晓宁 | Production method of high-purity metformin hydrochloride |
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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 |
| WO2014041566A2 (en) * | 2012-09-17 | 2014-03-20 | Laurus Labs Private Limited | An improved process for the preparation of metformin hydrochloride |
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|---|---|---|---|---|
| CN1844093A (en) * | 2006-05-10 | 2006-10-11 | 翟树军 | Process for preparing metformin hydrochloride |
| CN101450918A (en) * | 2007-11-30 | 2009-06-10 | 山东方兴科技开发有限公司 | Metformin hydrochloride purification method |
| 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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| CN104119250A (en) * | 2014-07-15 | 2014-10-29 | 徐晓宁 | Production method of high-purity metformin hydrochloride |
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| CN104829495A (en) | 2015-08-12 |
| CN107337618B (en) | 2020-06-16 |
| CN107337618A (en) | 2017-11-10 |
| CN107245042A (en) | 2017-10-13 |
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