CN1844093A - Process for preparing metformin hydrochloride - Google Patents
Process for preparing metformin hydrochloride Download PDFInfo
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- CN1844093A CN1844093A CN 200610081627 CN200610081627A CN1844093A CN 1844093 A CN1844093 A CN 1844093A CN 200610081627 CN200610081627 CN 200610081627 CN 200610081627 A CN200610081627 A CN 200610081627A CN 1844093 A CN1844093 A CN 1844093A
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- walaphage
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Abstract
The invention relates to a method of diabecron, using dimethylamine aqueous solution of 40% concentration one value, dropping hydrochloric acid in dimethylamine aqueous solution until the PH value is 2, stopping drop acid, vacuum concentrating solution, cooling to 50deg C after there is crystal in reactor, adding ethanol 0.3 shares, dicyandiamide 0.62-0.67 shares, heating to 80deg C,doing vacuum distillation to distill ethanol, reacting to produce diabecron when heating to 130deg C, adding ethanol 2-3 shares when cooling to 50deg C, discharging when cooling to 5deg C, centrifugal rinsing and drying, drying, recovering ethanol, getting diabecron crude product, drying crude product, adding deionized water 2.5-3 shares, activated char 0.02 shares, ethylene diamine tetraacetic acid disodium 0.003 shares, heating-up to 75-80deg C, cooling to 50deg C again after agitating, adsorbing, filtering, concentrating, adding ethanol 2 shares and agitating, cooling to 5deg C, discharging and centrifugal rinsing and drying, drying to recover the ethanol, getting diabecron completed product, on-spec product's yield of this invention is 75% -80%,the cost is decreased 15%-25% compared with primal method, hasing advantages of high product yield and low cost.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to a kind of production method of Walaphage.
Background technology
China is a big country that has 1,300,000,000 populations, and sickness rate every year of diabetes, the speed with 20% increased progressively.Up to now, also do not develop the specifics that can effect a radical cure diabetes in the world, and Walaphage is obvious to control the second stage of diabetes effect, cheap, ordinary people all afford to consume and is accepted by most of people.Along with the cumulative year after year of onset diabetes number, the demand of this medicine will constantly rise.Reach at home on the world market vast market will be arranged.In existing Walaphage production technology, the product yield of Walaphage low (average about 70%), and thick substances appears when reaction generates, influence quality product; Used ethanol consumption is big, the product cost height.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art and the production method of a kind of product yield height, Walaphage that cost is low is provided.
The object of the present invention is achieved like this:
The first step: get concentration and be 40% dimethylamine agueous solution and add in the anticorrosion reaction vessel for 1 part, hydrochloric acid is added dropwise in the dimethylamine agueous solution, being stirred to aqueous ph value is 2 o'clock, stops to drip acid.
Second step: above-mentioned solution is concentrated, when in the anticorrosion reaction vessel crystallization being arranged, be cooled to 50 ℃ after, add 0.3 part of ethanol, Dyhard RU 100 0.62-0.67 part.
The 3rd step: more above-mentioned solution is distilled, steam ethanol, and then whole solution is heated to 130 ℃ reacts and obtain the Walaphage crude product.
Above-mentioned reaction is obtained the Walaphage crude product, be cooled to 50 ℃ again, add ethanol 2-3 part, stir and be cooled to 5 ℃, discharging from anticorrosion reaction vessel is dried, and reclaims ethanol.
Crude product after the oven dry is added in the anticorrosion reaction vessel once more, add deionized water 2.5-3 part, 0.02 part of gac, 0.003 part of disodium ethylene diamine tetraacetate, be warming up to 75-80 ℃, be cooled to 50 ℃ again after stirring, adsorb, filter, concentrating, add 2 parts of ethanol and stir, cool to 5 ℃ the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains the Walaphage finished product.
Walaphage finished product after the oven dry is added in the anticorrosion reaction vessel, dissolve, add 3 parts, 0.03 part gac of deionized water and 0.002 part of disodium ethylene diamine tetraacetate, be warming up to 75-80 ℃, be cooled to 50 ℃ again after stirring, adsorb, filter, concentrating, add 3 parts of ethanol and stir, cool to 5 ℃, the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains fusing point and be 225 ℃ elaboration.
To being that the mother liquor of generation carries out air distillation respectively in 225 ℃ the elaboration process at Walaphage crude product, Walaphage finished product and fusing point, reclaim ethanol, and the residue mother liquor is through the recyclable Walaphage of crystallization.
Above-described anticorrosion reaction vessel is the anticorrosion reactor that has chuck, temperature, stirring, reflux and vacuum extractor, chuck is communicated with refrigerated brine and vapor phase respectively by valve control, when in step 2, step 3, salt manufacturing acid N1,N1-Dimethylbiguanide finished product and fusing point are 225 ℃ elaboration process, concentrating, all drive vacuum pump and carry out concentrating under reduced pressure.
In step 3, it is a kind of vigorous reactions that whole solution is heated to 130 ℃ of reactions of carrying out.
Qualified yield of the present invention is at 75%-80%, and cost is than the original 15%-25% that reduces.Therefore the present invention has product yield height, advantage that cost is low.
Embodiment
Technological process of the present invention is as follows:
The first step: get concentration and be 40% dimethylamine agueous solution and add in the anticorrosion reaction vessel for 1 part, hydrochloric acid is added dropwise in the dimethylamine agueous solution, being stirred to aqueous ph value is 2 o'clock, stops to drip acid.
Second step: above-mentioned solution is concentrated, when in the anticorrosion reaction vessel crystallization being arranged, be cooled to 50 ℃ after, add 0.3 part of ethanol, Dyhard RU 100 0.62-0.67 part.
The 3rd step: more above-mentioned solution is distilled, steam ethanol, and then whole solution is heated to 130 ℃ reacts and obtain the Walaphage crude product.
Above-mentioned reaction is obtained the Walaphage crude product, be cooled to 50 ℃ again, add ethanol 2-3 part, stir and be cooled to 5 ℃, discharging from anticorrosion reaction vessel is dried, and reclaims ethanol.
Crude product after the oven dry is added in the anticorrosion reaction vessel once more, add deionized water 2.5-3 part, 0.02 part of gac, 0.003 part of disodium ethylene diamine tetraacetate, be warming up to 75-80 ℃, be cooled to 50 ℃ again after stirring, adsorb, filter, concentrating, add 2 parts of ethanol and stir, cool to 5 ℃ the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains the Walaphage finished product.
Walaphage finished product after the oven dry is added in the anticorrosion reaction vessel, dissolve, add 3 parts, 0.03 part gac of deionized water and 0.002 part of disodium ethylene diamine tetraacetate, be warming up to 75-80 ℃, be cooled to 50 ℃ again after stirring, adsorb, filter, concentrating, add 3 parts of ethanol and stir, cool to 5 ℃, the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains fusing point and be 225 ℃ elaboration.
To being that the mother liquor of generation carries out air distillation respectively in 225 ℃ the elaboration process at Walaphage crude product, Walaphage finished product and fusing point, reclaim ethanol, and the residue mother liquor is through the recyclable Walaphage of crystallization.
Described anticorrosion reaction vessel is the anticorrosion reactor that has chuck, temperature, stirring, reflux and vacuum extractor, chuck is communicated with refrigerated brine and vapor phase respectively by valve control, when in step 2, step 3, salt manufacturing acid N1,N1-Dimethylbiguanide finished product and fusing point are 225 ℃ elaboration process, concentrating, all drive vacuum pump and carry out concentrating under reduced pressure.
In step 3, it is a kind of vigorous reactions that whole solution is heated to 130 ℃ of reactions of carrying out.
Embodiment 1: in testing laboratory, get concentration and be 40% dimethylamine agueous solution 500g and add in the anticorrosion reaction vessel, dripping concentration and be 31% hydrochloric acid, to be stirred to the dimethylamine agueous solution pH value be 2 o'clock, stops to drip acid, and then stirred 2 hours.Above-mentioned solution is concentrated, when in the anticorrosion reaction vessel crystallization being arranged, be cooled to 50 ℃ after, add ethanol 150g, Dyhard RU 100 310g, and be heated to 80 ℃, carry out vacuum distilling, steam ethanol, and then whole solution is heated to 130 ℃ reacts and obtain the Walaphage crude product.
Above-mentioned reaction is obtained the Walaphage crude product, be cooled to 50 ℃ again, add ethanol 1000g, stirring cools to 5 ℃, and discharging from anticorrosion reaction vessel is dried, and reclaims ethanol.
Crude product after the oven dry is added in the anticorrosion reaction vessel once more, add deionized water 1250g, gac 10g, disodium ethylene diamine tetraacetate 1.5g, be warming up to 75-80 ℃, stir, adsorption filtration,, be cooled to 50 ℃ again after concentrating, add 1000g ethanol and stir, cool to 5 ℃ the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains the Walaphage finished product.
React to such an extent that the Walaphage finished product is 478.7g through above-mentioned, yield is 78.38%.
Walaphage finished product after the oven dry is added in the anticorrosion reaction vessel, dissolve, add deionized water 1500g, 15g gac and 1g disodium ethylene diamine tetraacetate, be warming up to 75-80 ℃, be cooled to 50 ℃ again after stirring, filter, adsorb, concentrating, add 1500g ethanol and stir, cool to 5 ℃, the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains fusing point and be 225 ℃ elaboration.Wherein the whip attachment time is 40 minutes.
Embodiment 2: adopt industrial anticorrosion reactor to produce.
Is concentration that 40% dimethylamine agueous solution 180Kg squeezes into the corrosion resistant chuck that has, temperature stirring and refluxing device and vacuum extractor anticorrosion reactor in, is concentration that 31% hydrochloric acid slowly is added dropwise in the reactor, being stirred to aqueous ph value is 2 o'clock, stop to drip acid, stirred dimethylamine agueous solution then 5 hours, measure dimethylamine agueous solution PH=2, keep its PH be 2 stable after, open the vacuum of anticorrosion reactor and carry out concentrating under reduced pressure, when in the reactor crystallization being arranged, stop to concentrate, be cooled to 50 ℃ then, add ethanol 54Kg, Dyhard RU 100 120.6Kg distills above-mentioned solution again, steam ethanol, and then whole solution is heated to 130 ℃ reacts and obtain the Walaphage crude product.
In above-mentioned reaction, in steaming the alcoholic acid still-process, need to open temperature stirring and refluxing device, open vacuum extractor simultaneously and steam ethanol, be warming up to 130 ℃ then, answer to engender vigorous reaction in the still, be cooled to 50 ℃ then, add ethanol 540Kg, stir, cool off, reflux (promptly open agitator and cooling return channel on the reactor, stir cooling for reflux); Discharging when cooling, the discharging crude product that must wet to 5 ℃, behind the centrifuge dripping crude product, ethanol is reclaimed in oven dry then.
Crude product after the oven dry is added in the anticorrosion reaction vessel once more, add deionized water 540Kg, gac 3.6Kg, disodium ethylene diamine tetraacetate 0.54Kg, be warming up to 80 ℃, be cooled to 50 ℃ after stirring, filter, adsorb, distilling again, add 360Kg ethanol and stir, cool to 5 ℃ the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains the Walaphage finished product.Dry to such an extent that the Walaphage finished product is 178.73Kg, yield is 75.22%.
Walaphage finished product after the oven dry is added in the anticorrosion reaction vessel, dissolve, add 540Kg deionized water, 5.4Kg gac, the 0.36Kg disodium ethylene diamine tetraacetate is warming up to 75-80 ℃, be cooled to 50 ℃ again after stirring, adsorb, filter, concentrating, add 540Kg ethanol and stir, cool to 5 ℃ the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains fusing point and be 225 ℃ elaboration.
The various mother liquors that get rid of after the filter are carried out air distillation respectively, recyclable ethanol, and the residue mother liquor reclaims through crystallization, can make with extra care to be the Walaphage finished product, secondary mother liquid can repeatedly centralized and unified processing.
Claims (8)
1, a kind of production method of Walaphage is characterized in that:
The first step: get concentration and be 40% dimethylamine agueous solution and add in the anticorrosion reaction vessel for 1 part, hydrochloric acid is added dropwise in the dimethylamine agueous solution, being stirred to aqueous ph value is 2 o'clock, stops to drip acid,
Second step: above-mentioned solution is concentrated, when in the anticorrosion reaction vessel crystallization being arranged, be cooled to 50 ℃ after, add 0.3 part of ethanol, Dyhard RU 100 0.62-0.67 part,
The 3rd step: more above-mentioned solution is distilled, steam ethanol, and then whole solution is heated to 130 ℃ reacts and obtain the Walaphage crude product.
2, the production method of a kind of Walaphage according to claim 1, it is characterized in that: above-mentioned reaction is obtained the Walaphage crude product, be cooled to 50 ℃ again, add ethanol 2-3 part, stirring is cooled to 5 ℃, discharging from anticorrosion reaction vessel is dried behind the centrifuge dripping, reclaims ethanol.
3, the production method of a kind of Walaphage according to claim 2, it is characterized in that: the crude product after the oven dry is added in the anticorrosion reaction vessel once more, add deionized water 2.5-3 part, 0.02 part of gac, 0.003 part of disodium ethylene diamine tetraacetate, be warming up to 75-80 ℃, be cooled to 50 ℃ again after stirring, adsorb, filter, concentrating, add 2 parts of ethanol and stir, cool to 5 ℃, the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains the Walaphage finished product.
4, the production method of a kind of Walaphage according to claim 3, it is characterized in that: the Walaphage finished product after will drying adds in the anticorrosion reaction vessel, dissolve, add 3 parts, 0.03 part gac of deionized water and 0.002 part of disodium ethylene diamine tetraacetate, be warming up to 75-80 ℃, be cooled to 50 ℃ again after stirring, adsorb, filter, concentrating, adding 3 parts of ethanol stirs, cool to 5 ℃, the discharging centrifuge dripping, ethanol is reclaimed in oven dry, obtains fusing point and be 225 ℃ elaboration.
5, according to the production method of claim 2,3 or 4 described a kind of Walaphages, it is characterized in that: to being in 225 ℃ the elaboration process at Walaphage crude product, Walaphage finished product and fusing point, the mother liquor that produces carries out air distillation respectively, reclaim ethanol, and the residue mother liquor is through the recyclable Walaphage of crystallization.
6, the production method of a kind of Walaphage according to claim 1, it is characterized in that: described anticorrosion reaction vessel is the anticorrosion reactor that has chuck, temperature, stirring, reflux and vacuum extractor, chuck is connected with refrigerated brine and vapor phase respectively by valve control, when in step 2, step 3, salt manufacturing acid N1,N1-Dimethylbiguanide finished product and fusing point are 225 ℃ elaboration process, concentrating, all open vacuum and carry out concentrating under reduced pressure.
7, the production method of a kind of Walaphage according to claim 1 is characterized in that: in step 3, it is a kind of vigorous reactions that whole solution is heated to 130 ℃ of reactions of carrying out.
8, the production method of a kind of Walaphage according to claim 1 is characterized in that: in step 1, the time that is stirred to aqueous ph value and is the 2 o'clock restir aqueous solution was at least 20 minutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610081627XA CN100391939C (en) | 2006-05-10 | 2006-05-10 | Process for preparing metformin hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610081627XA CN100391939C (en) | 2006-05-10 | 2006-05-10 | Process for preparing metformin hydrochloride |
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| CN1844093A true CN1844093A (en) | 2006-10-11 |
| CN100391939C CN100391939C (en) | 2008-06-04 |
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| CNB200610081627XA Expired - Fee Related CN100391939C (en) | 2006-05-10 | 2006-05-10 | Process for preparing metformin hydrochloride |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010146604A3 (en) * | 2009-06-18 | 2011-02-10 | Exemed Pharmaceuticals | Processes for preparing metformin hydrochloride |
| 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 |
| CN102153489A (en) * | 2011-02-21 | 2011-08-17 | 寿光富康制药有限公司 | Novel crystal form of metformin hydrochloride and preparation method thereof |
| CN101450919B (en) * | 2007-11-30 | 2011-11-09 | 山东方兴科技开发有限公司 | Metformin hydrochloride purification method |
| 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 |
| WO2016059507A1 (en) * | 2014-10-13 | 2016-04-21 | Kamavarapu Sarath Kumar | Improved process for the preparation of high pure metformine |
| CN107245042A (en) * | 2015-04-24 | 2017-10-13 | 韩光琨 | A kind of method that double solvents produces Metformin hydrochloride |
| CN107474246A (en) * | 2017-08-15 | 2017-12-15 | 武汉桀升生物科技有限公司 | The method that one kettle way prepares ide polymers |
| CN110256299A (en) * | 2019-07-25 | 2019-09-20 | 凯莱英生命科学技术(天津)有限公司 | The preparation method of Metformin hydrochloride |
| CN110256300A (en) * | 2019-06-26 | 2019-09-20 | 武汉大学 | A kind of Metformin hydrochloride compound and metformin hydrochloride tablet composition |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN117658870A (en) | 2018-02-07 | 2024-03-08 | 默克专利股份有限公司 | Method for preparing metformin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3174901A (en) * | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
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2006
- 2006-05-10 CN CNB200610081627XA patent/CN100391939C/en not_active Expired - Fee Related
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101450919B (en) * | 2007-11-30 | 2011-11-09 | 山东方兴科技开发有限公司 | Metformin hydrochloride purification method |
| WO2010146604A3 (en) * | 2009-06-18 | 2011-02-10 | Exemed Pharmaceuticals | Processes for preparing metformin hydrochloride |
| CN102153489A (en) * | 2011-02-21 | 2011-08-17 | 寿光富康制药有限公司 | Novel crystal form of metformin hydrochloride and preparation method thereof |
| 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 |
| CN103435518B (en) * | 2013-08-26 | 2015-02-18 | 青岛黄海制药有限责任公司 | Preparation method of metformin hydrochloride |
| WO2016059507A1 (en) * | 2014-10-13 | 2016-04-21 | Kamavarapu Sarath Kumar | Improved process for the preparation of high pure metformine |
| CN106795104A (en) * | 2014-10-13 | 2017-05-31 | 瑟勒特·库玛·卡玛瓦拉普 | The improved method for preparing high-purity melbine |
| CN107245042A (en) * | 2015-04-24 | 2017-10-13 | 韩光琨 | A kind of method that double solvents produces Metformin hydrochloride |
| CN107245042B (en) * | 2015-04-24 | 2019-03-05 | 韩光琨 | A kind of method of double solvents production Metformin hydrochloride |
| CN107474246A (en) * | 2017-08-15 | 2017-12-15 | 武汉桀升生物科技有限公司 | The method that one kettle way prepares ide polymers |
| CN110256300A (en) * | 2019-06-26 | 2019-09-20 | 武汉大学 | A kind of Metformin hydrochloride compound and metformin hydrochloride tablet composition |
| CN110256300B (en) * | 2019-06-26 | 2022-04-05 | 武汉大学 | Metformin hydrochloride compound and metformin hydrochloride tablet composition |
| CN110256299A (en) * | 2019-07-25 | 2019-09-20 | 凯莱英生命科学技术(天津)有限公司 | The preparation method of Metformin hydrochloride |
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| CN100391939C (en) | 2008-06-04 |
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