CN107445869A - A kind of synthetic method of Metformin hydrochloride - Google Patents
A kind of synthetic method of Metformin hydrochloride Download PDFInfo
- Publication number
- CN107445869A CN107445869A CN201710584225.XA CN201710584225A CN107445869A CN 107445869 A CN107445869 A CN 107445869A CN 201710584225 A CN201710584225 A CN 201710584225A CN 107445869 A CN107445869 A CN 107445869A
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- CN
- China
- Prior art keywords
- metformin hydrochloride
- synthetic method
- dimethylamine
- dicyandiamide
- solution
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
Abstract
The invention discloses a kind of synthetic method of Metformin hydrochloride, comprise the following steps：（1）Salt-forming stage；（2）Steam salt phase；（3）The condensation stage.The present invention is used as solvent, small toxicity low relative to traditional handicraft solvent cost by the use of toluene and DMF；Solvent repeats to apply mechanically, and reduces the discharge of waste liquid, is easy to industrialized production, greatly reduces production cost and Environmental costs；It is no in course of reaction to use catalyst, and the reaction time is short, is effectively improved stability of the dicyandiamide in reaction system, reduces the generation of dicyandiamide side reaction, simplify purifying technique.
Description
Technical field
The invention belongs to technical field of organic synthesis, more particularly to the preparation side of hypoglycemic drug Metformin hydrochloride
Method.
Background technology
Metformin hydrochloride, abbreviation DMBG, chemical name：1,1-Dimethylbiguanide hydrochloride is treatment merely by control
The type-II diabetes medicine of diet processed and uncontrollable blood sugar concentration, especially for obesity and with hyperinsulinemia patient
With it is fine the effect of.2006, ADA（American Diabetes Association）Guidelines for Management of Diabetes Mellitus points out, Metformin hydrochloride conduct
First-line treatment medicine simultaneously runs through treatment overall process, has been common people as a line of type-II diabetes and the remarkable status of whole medication
Attracted attention.
In recent years, with the continuous improvement of living standards of the people, some endanger the incidence of disease of the disease of people's health also with
Change there occurs corresponding, wherein outstanding aobvious protrude of becoming younger of the rising of diabetes morbidity and patient.Diabetes prevalence
Increase to the 3.62% of the mid-90 by the 1.21% of the eighties in last century, nearly 3 times are increased between 10 years, at present the estimation whole nation 20
Year, above diabetes number of patients was more than 20,000,000.
That reports earliest prepares Metformin hydrochloride, is Werner and Bell in 1922 melting methods used, by double cyanogen
Amine and dimethylamine mixing, dissolve by heating reaction, and temperature is 180 DEG C.Solid fusion method prepares hardly possible during Metformin hydrochloride
So that it is well mixed, progressively prepared later using solvent method, the solvent used is mostly high boiling solvent, such as：Isoamyl alcohol, the third three
Alcohol, n-amyl alcohol, cyclohexanol etc..
The content of the invention
In order to solve the above technical problems, the present invention provides a kind of synthetic method of Metformin hydrochloride, present invention synthesis salt
The method of sour melbine is adapted to continuous production, can reduce the reaction time, improves reaction yield and purity, reduces waste water
Discharge capacity.
The present invention is achieved through the following technical solutions, and the present invention provides a kind of synthetic method of Metformin hydrochloride,
Comprise the following steps：
（1）Salt-forming stage：In reactor, dimethylamine agueous solution is added, under cryogenic conditions, aqueous hydrochloric acid solution is added dropwise, obtains two
The methylamine hydrochloride aqueous solution；
（2）Steam salt phase：The dimethylamine hydrochloride aqueous solution is evaporated under reduced pressure, water is evaporated off, obtains dimethylamine hydrochloride solid；
（3）The condensation stage：DMF, toluene and dicyandiamide are added, heating response obtains Metformin hydrochloride, and cooling filters to obtain hydrochloric acid
Melbine crystal, baking material it is dry white hydrochloride melbine.
This technique uses DMF and toluene mixed solvent so that and reaction temperature reduces, at 125 DEG C or so, reaction yield
Up to more than 95%.The method of synthetic hydrochloric acid melbine is adapted to continuous production, can reduce the reaction time, improves reaction and receives
Rate and purity, reduce the discharge capacity of waste water.
Preferably, the step（1）In, the mass fraction of dimethylamine agueous solution is 40%.
Preferably, the step（1）In, the mass fraction of hydrochloric acid solution is 30%.
As preferred：The step（1）In, the mass ratio of dimethylamine agueous solution and hydrochloric acid solution is 1.0：（2.0~
3.0）, the PH of reaction solution is controlled between 1.0 ~ 6.0, the dimethylamine hydrochloride that the reaction obtains is strong acid weak base
Salt, easily hydrolysis so that the aobvious acidity of solution, therefore the hydrochloric acid content being added dropwise is more than dimethylamine in proportion, is reduced as far as product
Hydrolysis.
As preferred：The step（2）In, the water content of dimethylamine hydrochloride solid is 0.5%.The step preferably will
The dimethylamine hydrochloride aqueous solution is all evaporated, and turns into solid, can thus reduce dehydrating step before reaction.It is but finally solid
Body does not reach material steaming salt oven bottom caking, agitating paddle, be wrapped in material be evaporated off dry needing what is grown very much completely
Time.By considering in terms of time and the energy is saved, the water content of dimethylamine hydrochloride solid is not higher than 0.5%, so that it may
To carry out in next step.
Preferably, the step（3）In, DMF, toluene and dicyandiamide mass ratio are（1~2）：（1~2）：1.
Preferably, the step（3）In, DMF, toluene and dicyandiamide mass ratio are 1.4:1.2:1.Step（3）In
By DMF to the solubility experiment and DMF of dimethylamine hydrochloride and dicyandiamide to the solubility experiment of Metformin hydrochloride, selection
The mass ratio of DMF and dicyandiamide is 1.4:1.By consulting the azeotropic ratio of toluene and water, the quality of toluene and dicyandiamide is selected
Than for 1.2:1.
Preferably, the step（3）In, reaction temperature is 120 ~ 140 DEG C.Preferably, the step（3）In, instead
It is 3h between seasonable.Step（3）Medium temperature spends height, is swift in response, it is necessary to which the energy consumed is more；Temperature is too low, and reaction is slower, consumption
The longer time, consider, the reaction temperature is controlled at 120 ~ 140 DEG C, reacts 3h.
Preferably, the step（3）In, cool to 30 DEG C and filter to obtain Metformin hydrochloride crystal.
Beneficial effects of the present invention
The present invention is used as solvent, small toxicity low relative to traditional handicraft solvent cost by the use of toluene and DMF；Solvent repeats to apply mechanically,
The discharge of waste liquid is reduced, is easy to industrialized production, greatly reduces production cost and Environmental costs；Do not used in course of reaction
Catalyst, and the reaction time is short, is effectively improved stability of the dicyandiamide in reaction system, reduces dicyandiamide side reaction
Generation, simplify purifying technique.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
The application principle of the present invention is further described with reference to specific embodiment.
Embodiment 1：
（1）In 500ml four-hole bottles add 146.81g dimethylamine agueous solutions, cooling be slowly added dropwise hydrochloric acid to PH 1.0 ~ 6.0 it
Between；
（2）Open vacuum, decompression steam water, to four-hole bottle in material distilled-to-dryness；
（3）120g DMF is added into four-hole bottle, heating stirring, is all dissolved to solid, adds 100g dicyandiamides and 110g
Toluene, rise temperature separate moisture in phegma to flowing back, and until no moisture is separated, then steam toluene, will
After toluene is evaporated, control temperature reacts 3h within 120 ~ 140 DEG C, cools to 30 DEG C and filters to obtain Metformin hydrochloride crystal, dries
Expect dry white hydrochloride melbine 188.6g（With dicyandiamide rate of collecting 95.7%）.
Embodiment 2：
（1）In 500ml four-hole bottles add 146.81g dimethylamine agueous solutions, cooling be slowly added dropwise hydrochloric acid to PH 1.0 ~ 6.0 it
Between；
（2）Open vacuum, decompression steam water, to four-hole bottle in material distilled-to-dryness；
（3）140g DMF is added into four-hole bottle, heating stirring, is all dissolved to solid, adds 100g dicyandiamides and 120g
Toluene, rise temperature separate moisture in phegma to flowing back, and until no moisture is separated, then steam toluene, will
After toluene is evaporated, control temperature reacts 3h within 120 ~ 140 DEG C, cools to 30 DEG C and filters to obtain Metformin hydrochloride crystal, dries
Expect dry white hydrochloride melbine 193.1g（With dicyandiamide rate of collecting 97.97%）.
Contrast experiment：
（1）In 500ml four-hole bottles add 146.81g dimethylamine agueous solutions, cooling be slowly added dropwise hydrochloric acid to PH 1.0 ~ 6.0 it
Between；
（2）Open vacuum, decompression steam water, to four-hole bottle in material distilled-to-dryness；
（3）300g isopropanol is added into four-hole bottle, heating stirring, is all dissolved to solid, adds 100g dicyandiamides, rise
High-temperature separates moisture in phegma to flowing back, and until no moisture is separated, control temperature is 120 ~ 140
6h is reacted within DEG C, 30 DEG C is cooled to and filters to obtain Metformin hydrochloride crystal, baking material it is dry white hydrochloride melbine
142.6g（With dicyandiamide rate of collecting 72.4%）.
As a result show：Embodiment 1 and embodiment 2 are substantially low using technical solution of the present invention synthetic hydrochloric acid melbine cost
In the synthesis technique of contrast experiment, and embodiment 1 and embodiment 2 use toluene and DMF mixed solvents, reduce the reaction time,
Reaction yield is improved, avoids the generation of the side reaction of dicyandiamide for a long time under the high temperature conditions.
Certainly, described above is also not limited to the example above, the technical characteristic of the invention without description can by or
Realized, will not be repeated here using prior art；It is not to this that above example, which is merely to illustrate technical scheme,
The limitation of invention, the present invention is described in detail with reference to preferred embodiment, one of ordinary skill in the art should
Understand, the variations, modifications, additions or substitutions that those skilled in the art are made in the essential scope of the present invention
Without departure from spirit of the invention, it should also belong to claims of the invention.
Claims (10)
1. a kind of synthetic method of Metformin hydrochloride, comprises the following steps：
（1）Salt-forming stage：In reactor, dimethylamine agueous solution is added, under cryogenic conditions, aqueous hydrochloric acid solution is added dropwise, obtains two
The methylamine hydrochloride aqueous solution；
（2）Steam salt phase：The dimethylamine hydrochloride aqueous solution is evaporated under reduced pressure, water is evaporated off, obtains dimethylamine hydrochloride solid；
（3）The condensation stage：DMF, toluene and dicyandiamide are added, heating response obtains Metformin hydrochloride, and cooling filters to obtain hydrochloric acid
Melbine crystal, baking material it is dry white hydrochloride melbine.
A kind of 2. synthetic method of Metformin hydrochloride according to claim 1, it is characterised in that：The step（1）In,
The mass fraction of dimethylamine agueous solution is 40%.
A kind of 3. synthetic method of Metformin hydrochloride according to claim 1, it is characterised in that：The step（1）In,
The mass fraction of hydrochloric acid solution is 30%.
A kind of 4. synthetic method of Metformin hydrochloride according to claim 1, it is characterised in that：The step（1）In,
The mass ratio of dimethylamine agueous solution and hydrochloric acid solution is 1.0：（2.0~3.0）, the PH that finally makes reaction solution controls 1.0 ~
Between 6.0.
A kind of 5. synthetic method of Metformin hydrochloride according to claim 1, it is characterised in that：The step（2）In,
The water content of dimethylamine hydrochloride solid is 0.5%.
A kind of 6. synthetic method of Metformin hydrochloride according to claim 1, it is characterised in that：The step（3）In,
DMF, toluene and dicyandiamide mass ratio is（1~2）：（1~2）：1.
A kind of 7. synthetic method of Metformin hydrochloride according to claim 1 or 6, it is characterised in that：The step（3）
In, DMF, toluene and dicyandiamide mass ratio are 1.4:1.2:1.
A kind of 8. synthetic method of Metformin hydrochloride according to claim 1, it is characterised in that：The step（3）In,
Reaction temperature is 120 ~ 140 DEG C.
A kind of 9. synthetic method of Metformin hydrochloride according to claim 1, it is characterised in that：The step（3）In,
Reaction time is 3h.
A kind of 10. synthetic method of Metformin hydrochloride according to claim 1, it is characterised in that：The step（3）
In, cool to 30 DEG C and filter to obtain Metformin hydrochloride crystal.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710584225.XA CN107445869A (en) | 2017-07-18 | 2017-07-18 | A kind of synthetic method of Metformin hydrochloride |
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| CN201710584225.XA CN107445869A (en) | 2017-07-18 | 2017-07-18 | A kind of synthetic method of Metformin hydrochloride |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112028795A (en) * | 2020-09-17 | 2020-12-04 | 重庆医药高等专科学校 | Synthesis method of metformin hydrochloride |
| CN115353467A (en) * | 2022-08-26 | 2022-11-18 | 宁夏恒康科技有限公司 | Processing system of industrial hydrochloric acid in application of metformin hydrochloride |
| CN115974726A (en) * | 2022-10-28 | 2023-04-18 | 东北师范大学 | Method for separating metformin hydrochloride crude product |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104829495A (en) * | 2015-04-24 | 2015-08-12 | 青岛中科荣达新材料有限公司 | Method for preparation of high purity and high yield metformin hydrochloride by two-component solvent |
| CN106278953A (en) * | 2015-04-24 | 2017-01-04 | 泰山医学院 | A kind of production method improving metformin hydrochloride purity |
-
2017
- 2017-07-18 CN CN201710584225.XA patent/CN107445869A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN104829495A (en) * | 2015-04-24 | 2015-08-12 | 青岛中科荣达新材料有限公司 | Method for preparation of high purity and high yield metformin hydrochloride by two-component solvent |
| CN106278953A (en) * | 2015-04-24 | 2017-01-04 | 泰山医学院 | A kind of production method improving metformin hydrochloride purity |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112028795A (en) * | 2020-09-17 | 2020-12-04 | 重庆医药高等专科学校 | Synthesis method of metformin hydrochloride |
| CN115353467A (en) * | 2022-08-26 | 2022-11-18 | 宁夏恒康科技有限公司 | Processing system of industrial hydrochloric acid in application of metformin hydrochloride |
| CN115974726A (en) * | 2022-10-28 | 2023-04-18 | 东北师范大学 | Method for separating metformin hydrochloride crude product |
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