CN102040672B - Low-heat solid-phase synthesis method of heparin quaternary ammonium salt - Google Patents
Low-heat solid-phase synthesis method of heparin quaternary ammonium salt Download PDFInfo
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Abstract
The invention discloses a low-heat solid-phase synthesis method of a heparin quaternary ammonium salt. In the method, the heparin quaternary ammonium salt is prepared by a low-heat solid-phase reaction by using heparin sodium and benzethonium chloride as raw materials, using sodium chloride and ferric oxide as mineralizers and using inert gas as a protective agent. The method has the advantages of thorough reaction, high yield, low energy consumption and less pollution, and is applicable to industrial production, thereby being a promising preparation method.
Description
Technical field
The present invention relates to the synthetic method of a kind of compound, be specifically related to the low-heat solid phase synthesis process of heparin quaternary ammonium salt, belong to chemosynthesis technical field.
Background technology
Enoxaparin is a kind of anti-freezing and antithrombotic reagent, belongs to the verivate of low molecular sodium heparin.Normally, enoxaparin is to be raw material with the heparin, through quaternized, the esterification of heparin, finally obtains through β-elimination in alkaline solution.
The quaternized of heparin is one step of key of preparation enoxaparin.Chinese patent (grant number CN100582123C) discloses the quaternised method of a kind of heparin, as follows: under the normal temperature heparin sodium is dissolved in 7～11 times of water, transfers pH to 7.0～9.0; The benzethonium chloride of 2～3 times of heparin sodium amounts is dissolved in 3～7 times of water and stirs, the heparin sodium aqueous solution is added in the benzethonium chloride aqueous solution, fully after the reaction; Vacuum filtration, vacuum tightness >=0.08Mpa, solid are blunged and are washed the back suction filtration; Repeat twice; Solid with oven dry in 20～30 hours, gets the heparin quaternary ammonium salt of sodium-salt form in 45～60 ℃.Jin Fei, Xu Feihu etc. disclose the quaternised method of a kind of heparin in " preparation of Enoxaparin Sodium and purifying " (Chinese Journal of Pharmaceuticals, 2008,39-(1)), as follows: taking heparin sodium 10g adds water 50ml dissolving; Get among the water-soluble 100ml of benzethonium chloride 25g, stir down and it is slowly added in the heparin sodium aqua filtration.Filter cake is used water washing, and oven dry gets heparin benzethonium chloride salt 31.2g.The quaternized method of above-mentioned heparin all adopts conventional liquid-phase reaction system, has contaminated wastewater in the production process, and the yield of product is low, deficiencies such as the purifying technique complicacy of product.To the deficiency of existing heparin quaternary ammonium salt synthetic technology, efficient, the green compound method of exploitation heparin quaternary ammonium salt is necessary.
Low-heat solid state reaction method is a kind of new compound method that grows up the eighties in 20th century, develops very rapid.Its preparation technology is simple, and reaction conditions is gentle, save energy, and productive rate is high, pollutes advantages such as low, and it is come into one's own in the field of chemical synthesis day by day, is a kind of eco-friendly green synthesis method.Use the synthetic heparin quaternary ammonium salt of low-heat solid-phase synthesis, all do not appear in the newspapers both at home and abroad.
Summary of the invention
The object of the present invention is to provide a kind of green synthesis method of heparin quaternary ammonium salt, is that a kind of application low-heat solid-phase synthesis prepares the heparin quaternary ammonium salt specifically.
Technical scheme of the present invention is: a kind of low-heat solid phase synthesis process of heparin quaternary ammonium salt; It is characterized in that, be raw material with heparin sodium and benzethonium chloride, is mineralizer with sodium-chlor, red oxide of iron; With the rare gas element is protective material, prepares the heparin quaternary ammonium salt through low fever solid phase reaction.
Concrete steps are following:
1) mixes by 1: 0.001～0.005 weight ratio taking heparin sodium and sodium-chlor, fully grind;
2) 1～1.8 times benzethonium chloride of adding heparin sodium weight in said mixture;
3) 0.001～0.005 times red oxide of iron of adding benzethonium chloride weight in said mixture;
4) said mixture under 90 ± 5 ℃, under the nitrogen protection, fully ground 4～5 hours, reduced to room temperature, promptly got.
For normally carrying out of better protection reaction title product and reaction, the present invention has adopted inactive gas that reaction is protected, and preferred inactive gas is a nitrogen, and preferred nitrogen gas pressure is 0.0003～0.0015Mpa.
Traditional chemical reaction is in dissolving phase or gas phase, to carry out, and its reaction needed energy consumption is high, and the time is long, the serious and complex process of contaminate environment.Solid state reaction is one of human chemical reaction that uses the earliest.Solid phase synthesis process: refer to the reaction that those have solid matter to participate in.That is to say that reactant must be the reaction of solid matter, just can be called solid state reaction.The inapplicable solvent of solid state reaction has highly selective, high yield, simple technological process and other advantages, is one of people's main means of preparing novel solid material and compound.Comprise classical solid-solid reaction, also comprise solid-solid/liquid/gas reactions and solid-liquid reaction.
Low fever solid phase reaction is the room temperature solid state reaction again, refers under the condition of room temperature or nearly room temperature (≤100 ℃), and the chemical reaction that is carried out between the solid-phase compound has and is convenient to the advantage operating and control.In addition, low fever solid phase reaction does not use solvent in addition, highly selective, high yield, pollution less, save the energy, characteristics such as synthesis technique is simple.These characteristics meet the requirement of current social Green Chemistry development.
An innovative point of the present invention is to have added suitable mineralizer (sodium-chlor and red oxide of iron) in the preparation process.These mineralizers have effectively promoted some change of the crystalline structure of reaction-ure surface, have greatly promoted normally carrying out of reaction.
The heparin quaternary ammonium salt that contriver of the present invention adopts the present invention to prepare is the feedstock production enoxaparin, and gained final mean annual increment solution color meets 4.0 editions requirements of European Pharmacopoeia, and all the other quality index all meet European Pharmacopoeia 5.3 editions.Specific targets are following:
Molecular weight: 3000～6000 dalton
FXa/F?II?a：＞2.5
Heavy metal :≤30ppm
Bacterial endotoxin :≤0.01EU/ heparin unit
The present invention compared with prior art has following distinguishing feature:
1), product yield is high, yield can reach more than 97.5%, improves nearly 25 percentage points than prior art.
2), simple to operate, be easy to control.The reference mark of whole process of production has only temperature and nitrogen gas pressure, compare controlled variable than prior art and lack, and each parameter control is also than prior art easy handling.
3), solid state reaction, do not use solvent, pollution-free, plant factor is high, is environment amenable green synthesis method.Prior art all adopts liquid-phase reaction system, causes reaction system big, and plant factor is low, and contaminated wastewater is arranged, and the purifying technique of product is complicated.
Embodiment
Below do further detailed description through embodiment, but should this be interpreted as that the scope of above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Taking heparin sodium 12.0g, sodium-chlor 36mg mixes, and grinds 0.5 hour.Add benzethonium chloride 14.4g again, red oxide of iron 43.2mg, under nitrogen (pressure 0.0005Mpa) protection, 90 ℃ were ground 4 hours, got pressed powder 26.0g, yield 98.6%, performance liquid detects, purity 98.5%.
Embodiment 2
Taking heparin sodium 10.0g, sodium-chlor 30mg mixes, and grinds 0.5 hour.Add benzethonium chloride 12.0g again, red oxide of iron 36mg, under nitrogen (pressure 0.0005Mpa) protection, 90 ℃ were ground 4 hours, got pressed powder 21.8g, yield 98.8%, performance liquid detects, purity 99.5%.
Embodiment 3
Taking heparin sodium 12.0g, sodium-chlor 24mg mixes, and grinds 0.5 hour.Add benzethonium chloride 15.6g again, red oxide of iron 31.2mg, under nitrogen (pressure 0.0006Mpa) protection, 93 ℃ were ground 4 hours, got pressed powder 27.0g, yield 97.6%, performance liquid detects, purity 97.5%.
Embodiment 4
Taking heparin sodium 10.0g, sodium-chlor 20mg mixes, and grinds 0.5 hour.Add benzethonium chloride 13.0g again, red oxide of iron 26mg, under nitrogen (pressure 0.0006Mpa) protection, 93 ℃ were ground 4 hours, got pressed powder 22.4g, and yield 97.8% performance liquid detects, purity 99.6%.
Embodiment 5
Taking heparin sodium 12.0g, sodium-chlor 24mg mixes, and grinds 0.5 hour.Add benzethonium chloride 15.6g again, red oxide of iron 31.2mg, under nitrogen (pressure 0.0005Mpa) protection, 88 ℃ were ground 4 hours, got pressed powder 27.3g, yield 99.0%, performance liquid detects, purity 97.2%.
Embodiment 6
Taking heparin sodium 12.0g, sodium-chlor 24mg mixes, and grinds 0.5 hour.Add benzethonium chloride 15.6g again, red oxide of iron 31.2mg, under nitrogen (pressure 0.0005Mpa) protection, 88 ℃ were ground 4 hours, got pressed powder 27.0g, yield 99.2%, performance liquid detects, purity 97.8%.
Claims (2)
1. the low-heat solid phase synthesis process of a heparin quaternary ammonium salt, it is characterized in that: with heparin sodium and benzethonium chloride is raw material, is mineralizer with sodium-chlor, red oxide of iron, is protective material with the rare gas element, has prepared the heparin quaternary ammonium salt through low fever solid phase reaction; Concrete steps comprise:
1) weight ratio by 1:0.001～0.005 mixes heparin sodium and sodium-chlor, fully grinds;
2) 1～1.8 times benzethonium chloride of adding heparin sodium weight in said mixture;
3) 0.001～0.005 times red oxide of iron of adding benzethonium chloride weight in said mixture;
4) with said mixture, under 90 ± 5 ℃, under nitrogen protection, fully ground 4～5 hours, reduce to room temperature, promptly get.
2. the low-heat solid phase synthesis process of a kind of heparin quaternary ammonium salt as claimed in claim 1 is characterized in that: said nitrogen gas pressure is 0.0003～0.0015MPa.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1850865A (en) * | 2006-05-24 | 2006-10-25 | 杭州九源基因工程有限公司 | Production method for purifying enoxaparin sodium |
| CN101165071A (en) * | 2006-10-20 | 2008-04-23 | 江苏江山制药有限公司 | Clexane and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1850865A (en) * | 2006-05-24 | 2006-10-25 | 杭州九源基因工程有限公司 | Production method for purifying enoxaparin sodium |
| CN101165071A (en) * | 2006-10-20 | 2008-04-23 | 江苏江山制药有限公司 | Clexane and preparation method thereof |
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Effective date of registration: 20181130 Address after: 832000 Six Junken New Villages, Beiquan Town, Shihezi City, Xinjiang Uygur Autonomous Region, 153 Patentee after: Shihezi City, Yu Long Biological Technology Co. Ltd. Address before: 251400 West Head of Fuyang Road, Jiyang Development Zone, Jiyang County, Jinan City, Shandong Province Patentee before: Shandong Yucong Biotechnology Co., Ltd. |