CN102603925A - Method for directly producing enoxaparin sodium from crude product heparin sodium - Google Patents
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Abstract
The invention relates to a preparation method for directly producing enoxaparin sodium from crude product heparin sodium. The preparation method comprises the following steps of: taking the crude product heparin sodium as a raw material, performing fractionated precipitation through an organic solvent to remove most of impurities in the crude product heparin sodium, and then removing part of residual impurity proteins, pigments and other impurities by oxidation through hydrogen peroxide so as to get the high-purity heparin sodium which is in line with the production requirements of the enoxaparin sodium; and taking the high-purity heparin sodium as an intermediate product, preparing a heparin quaternary ammonium salt, preparing heparin benzyl ester, performing alkaline depolymerization on the heparin benzyl ester, neutralizing with an acid, performing alcohol precipitation, refining, decoloring, dehydrating and drying to get an enoxaparin sodium finished product. By adopting the method disclosed by the invention, the use of the organic solvent is greatly reduced, the production efficiency is improved, the influences on the environment are reduced, the enoxaparin sodium finished product which achieves or is better than European Pharmacopoeia 7.0 version is obtained, and the method is simple to operate and can realize industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of Yi Nuo heparin sodium, more particularly, the present invention relates to a kind of method by crude heparin sodium direct production Enoxaparin Sodium.
Background technology
European Pharmacopoeia (EP) 7.0 editions definition Enoxaparin Sodium (enoxaparin sodium) is a kind of sodium salt of Low molecular heparin; Do not form by also there being complicated fully qualitatively oligose; Its constructional feature is that most of components have the structure of a 4-according to promise pyranose aldehydic acid at the non-reducing end of sugar chain; The component of 15%-25% has the structure of 1,6 acid anhydride at reducing end.The averagemolecular wt weight range of EP7.0 regulation Enoxaparin Sodium is 3800～5000, and eigenwert is about 4500, and molecular weight should be 12.0%～20.0% less than the level branch ratio of 2000D, and the level branch ratio of 2000D～8000D should be 68.0%～82.0%.
Enoxaparin Sodium is mainly used in illnesss such as antithrombotic, anticoagulation, treatment acute myocardial infarction and unstable angina pectoris.The main mechanism of enoxaparin is to strengthen the restraining effect to Xa factor and zymoplasm (the IIa factor) through combining with Thrombin inhibitor and mixture thereof, hinders Fibrinogen and changes scleroproein into, prevents platelet aggregation.Enoxaparin can change blood viscosity, protection vascular endothelial cell, prevention thrombus and atherosclerosis through reducing LDL, VLDL and rising HDL, improve effect such as coronary artery circulation.Compare with unfractionated heparin, advantage such as enoxaparin has that clinical indication is wide, bioavailability is high, long half time, spinoff are little receives the favor of doctor and extensive patients deeply, and its share of market has reached more than 2/3 of heparin and Low molecular heparin at present.
The method of producing Enoxaparin Sodium at present in the world is mainly alkaline lysis.The production technique of relevant enoxaparin is disclosed by many pieces of patent documentations.For example US4440926A discloses the process method of utilizing the quaternary ammonium salt esterification to prepare enoxaparin.Primary process that US5389618A discloses Enoxaparin Sodium and simple reference mark, its flow process comprises the preparation of the preparation of heparin quaternary ammonium salt, heparin benzyl ester, to heparin benzyl ester process step such as carry out that alkaline hydrolysis gathers.CN100436483C discloses a kind of production method for purifying of Enoxaparin Sodium, and with long chain quaternary salinization heparin, depolymerization obtains the enoxaparin bullion under alkaline condition in hydrophily is situated between for it, and obtains the Enoxaparin Sodium finished product through behind the adsorption bleaching.CN102050888B discloses a kind of preparation method of Enoxaparin Sodium, and it adopts hydrophilic liquid phase reaction and hydrophobic liquid phase reaction and solid state reaction, the macromole heparin sodium is degraded to the low molecular sodium heparin with ad hoc structure.CN100582123C discloses a kind of preparation method of Yi Nuo heparin, and it uses heparin sodium to be raw material, through quaternized, esterification, obtains enoxaparin through filter membrane, drying after eliminating in the alkaline solution again.
Yet, one of which, the step that comprises organic solvent among the disclosed preparation technology of above-mentioned patent is many, and consumption is big, and is serious to environmental hazard; They are two years old; The structure of Enoxaparin Sodium and composition more complicated; In structural confirmation and quality standard control, there is certain uncertainty; Thereby the research of starting raw material and production process just must be strict with control, and raw material has direct influence to the MWD of the Enoxaparin Sodium finished product in later stage, so yet normally used in the above-mentioned patent documentation be heparin sodium; In addition; The applicant is also noted that in the Enoxaparin Sodium production process; It is qualified that important indicator once-used degradeables such as MWD are difficult to; Also need complicated process steps such as follow-up essence filter, must have corresponding operation to solve that alkaline hydrolysis gathers problems such as the free sulfate that causes comes off in the Enoxaparin Sodium production process.
Summary of the invention
In order to solve the above-mentioned technical problem that exists in the prior art; The object of the present invention is to provide a kind of method by crude heparin sodium direct production Enoxaparin Sodium; It is big to have overcome original production technique organic solvent usage quantity; Not strict to starting raw material control, production process is complicated, sulfate radical content technical problems of high in the finished product.Method of the present invention can effectively reduce production costs, and is easy to realize commercial scale prodn, constant product quality.
To achieve these goals, the present invention has adopted following technical scheme:
A kind of method by crude heparin sodium direct production Enoxaparin Sodium, it may further comprise the steps:
(1) crude heparin sodium is added purified water and be dissolved into the crude heparin sodium aqueous solution that concentration is 10wt%～15wt%; Working concentration is that the hydrochloric acid of 2～6mol/L or the pH value of sodium hydrate regulator solution are 5.0～7.0, adds the medicinal alcohol of 0.3～0.8 times of liquor capacity then, adjustment temperature to 0～10 ℃; Placed collecting precipitation thing a, the purified water of 5～15 times of volumes of adding throw out a 5～24 hours; Fully after the dissolving; The hydrogen peroxide oxidation of adding liquor capacity 0.2v%～1v% 6～12 hours is used membrane filtration, adds the ethanol sedimentation of 2 times of amounts of liquor capacity; Deposition was placed 6～12 hours, obtained throw out b;
(2) in throw out b, add purified water and be dissolved into the heparin sodium aqua that concentration is 10wt%～15wt%, the benzethonium chloride of 2-4 times of weight of taking precipitate b slowly is added to it in heparin sodium aqua centrifugal collecting precipitate c in the time of stirring; Throw out c with water washing after 60～70 ℃ of dryings, obtain heparin benzethonium chloride salt;
(3) taking heparin benzethonium chloride salt added N, and dinethylformamide is dissolved into the solution that concentration is 15wt%～35wt% with heparin benzethonium chloride salt, adds the Benzyl Chloride of 0.5～0.8 times of weight of heparin benzethonium chloride salt, 25～30 ℃ of reactions 10～15 hours; The ethanolic soln that adds the saturated sodium acetate trihydrate of 2～2.5 times of material liquid volumes after reaction finishes, visual inspection stop to stir after obvious sediment thing d is arranged, and leave standstill solution centrifugal after 2 hours, and collecting precipitation thing d obtains the heparin benzyl ester;
(4) the taking heparin benzyl ester uses purified water to be dissolved into the solution of concentration as 3wt%～5wt%; Add the solid sodium hydroxide account for heparin benzyl ester weight 10wt%～15wt%, 60 ℃～65 ℃ stirring reactions 15～70 minutes; Adding 2mol/L hydrochloric acid soln adjust pH then is 6.0～8.0 back membrane filtrations, in filtrating, adds to stop to stir after the ethanol that accounts for 2～3 times of amounts of material liquid volume is cooled to 0 ℃～10 ℃, places 12h, and collecting precipitation thing e obtains the Enoxaparin Sodium bullion;
(5) purified water of 5～15 times of volumes of adding throw out e after the dissolving, adds the resin of the absorption sulfate radical that accounts for throw out e weight 0.5wt%～1wt% fully; 30 ℃～50 ℃ whip attachment 1～2 hour, behind 0.22 μ m membrane filtration, add the hydrogen peroxide oxidation 6～12 hours of the 0.2v%～1v% of liquor capacity; Use membrane filtration; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 6～12 hours, obtained throw out f; Use purified water to be dissolved into the solution of concentration as 10wt%～15wt% throw out f, behind 0.1 μ m membrane filtration, spraying drying gets the Enoxaparin Sodium finished product.
As preferably, the specific conductivity of described purified water in the time of 25 ℃ is 1.3uS/cm.
As preferably, described medicinal alcohol is the aqueous ethanolic solution of 95v%.
As preferably, in step (1), crude heparin sodium is added purified water and be dissolved into the crude heparin sodium aqueous solution that concentration is 10wt%; Working concentration is that the hydrochloric acid of 4mol/L or the pH value of sodium hydrate regulator solution are 5.2, adds the medicinal alcohol of 0.4 times of liquor capacity then, adjustment temperature to 0.5 ℃; Placed collecting precipitation thing a, the purified water of 5 times of volumes of adding throw out a 6 hours; After the dissolving, the hydrogen peroxide oxidation of adding liquor capacity 0.2v% 6 hours is used membrane filtration fully; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 6 hours, obtained throw out b.
As preferably, at the consumption of the Benzyl Chloride described in the step (3) 0.5～0.7 times of heparin benzethonium chloride salt weight.
As preferably, taking heparin benzethonium chloride salt in step (3) added N, and dinethylformamide is dissolved into the solution that concentration is 20wt% with heparin benzethonium chloride salt, adds the Benzyl Chloride of 0.5 times of weight of heparin benzethonium chloride salt, 28 ℃ of reactions 12 hours; The ethanolic soln that adds the saturated sodium acetate trihydrate of 2.2 times of material liquid volumes after reaction finishes, visual inspection stop to stir after obvious sediment thing d is arranged, and leave standstill solution centrifugal after 2 hours, and collecting precipitation thing d obtains the heparin benzyl ester.
As preferably, in step (4), the taking heparin benzyl ester uses purified water to be dissolved into the solution of concentration as 4wt%; Add the solid sodium hydroxide account for heparin benzyl ester weight 12wt%, 62 ℃ of stirring reactions 30 minutes; Adding 2mo l/L hydrochloric acid soln adjust pH then is 6.5～7.5 back membrane filtrations, in filtrating, adds to stop to stir after the ethanol that accounts for 2.5 times of amounts of material liquid volume is cooled to 0.5 ℃～2.5 ℃, places 12h, and collecting precipitation thing e obtains the Enoxaparin Sodium bullion.
As preferably, in step (5), add the purified water of 10 times of volumes of throw out e; After the dissolving, add the resin of the absorption sulfate radical account for throw out e weight 0.5wt% fully, 40 ℃ of whip attachment 1.5 hours; Behind 0.22 μ m membrane filtration, add 0.25% the hydrogen peroxide oxidation 8 hours of liquor capacity, use membrane filtration; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 10 hours, obtained throw out f; Use purified water to be dissolved into the solution of concentration as 10wt% throw out f, behind 0.1 μ m membrane filtration, spraying drying gets the Enoxaparin Sodium finished product.
As preferably, in step (5), the resin of described absorption sulfate radical is a resin anion(R.A).And further preferably, the resin of said absorption sulfate radical is selected from a kind of in D318 resin, D354 resin or the D314 resin.
Compared with prior art, the present invention has following beneficial effect:
1. the present invention has reduced middle environment by crude heparin sodium direct production Enoxaparin Sodium.The present invention removes the most of impurity such as CHS, heparan or LMWDS in the crude heparin sodium through deposition is arranged; Remove impurity such as residual foreign protein of part and pigment then through hydrogen peroxide oxidation, obtain to meet the high purity heparin sodium that Enoxaparin Sodium is produced.In heparin, contain too much macromolecule impurity, will prepare process to the depolymerization sequential scheduling of heparin like CHS, heparan or LMWDS etc. and cause disadvantageous effect, and these impurity can LMWDS be that index property material is controlled.It is thus clear that can effectively control the foreign matter content in the Enoxaparin Sodium product, constant product quality through preparation technology of the present invention.
2. in the present invention, the heparin benzyl ester obtains through the Benzyl Chloride that adds 0.5～0.8 times of heparin benzethonium chloride salt weight.At N, SN2 nucleophilic substitution reaction generation heparin benzyl ester takes place in the carboxyl of heparin benzethonium chloride salt and Benzyl Chloride in the N N (DMF), and the esterification yield of heparin benzyl ester is relevant with factors such as reactant concn, temperature of reaction and times.Production technique is in the past all thought: the price of heparin benzethonium chloride salt is very high; The general excessive adding of Benzyl Chloride; But we find that the residual of Benzyl Chloride has very big influence to later reaction, also need also can influence the quality and the effect of product in addition through repeatedly ethanol sedimentation removal.So the add-on of technology Benzyl Chloride in the past is all greater than 1.0 weight part heparin benzyl esters.Find and we are unexpected; The heparin benzyl ester obtains through the Benzyl Chloride that adds heparin benzethonium chloride salt 0.5～0.8 weight part; Esterification yield is when 10.5%-12.5%, and the molecular weight of product meets the officinal standard, and can significantly save the use of reagent and the PT of product; Improved production efficiency and practiced thrift cost, and the negative impact of environment has also been had tangible minimizing.
3. process method of the present invention is easy to accomplish scale production, and constant product quality is controlled; Not only can enhance productivity, reduce production cost, and can not produce destruction the structure of Enoxaparin Sodium.
Description of drawings
Fig. 1 process flow diagram of the present invention.
Embodiment
Below will combine accompanying drawing and specific embodiment that technical scheme of the present invention is done further explanation.
Embodiment 1
As shown in Figure 1, the described process of present embodiment may further comprise the steps:
Get crude heparin sodium 100Kg, add purified water and be dissolved into the crude heparin sodium aqueous solution that concentration is 10wt%; Working concentration is that the hydrochloric acid of 4mol/L or the pH value of sodium hydrate regulator solution are 5.2, adds the medicinal alcohol of 0.4 times of liquor capacity then, adjustment temperature to 0.5 ℃; Placed collecting precipitation thing a, the purified water of 5 times of volumes of adding throw out a 6 hours; After the dissolving, the hydrogen peroxide oxidation of adding liquor capacity 0.2v% 6 hours is used membrane filtration fully; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 6 hours, obtained throw out b; In throw out b, add purified water and be dissolved into the heparin sodium aqua that concentration is 10wt%, the benzethonium chloride of 2 times of weight of taking precipitate b slowly is added to it in heparin sodium aqua in the time of stirring, centrifugal collecting precipitate c; Throw out c with water washing after 60 ℃ of dryings, obtain heparin benzethonium chloride salt; Taking heparin benzethonium chloride salt adds N, and dinethylformamide is dissolved into the solution that concentration is 15wt% with heparin benzethonium chloride salt; The Benzyl Chloride that adds 0.5 times of weight of heparin benzethonium chloride salt 25 ℃ of reactions 10 hours, adds the ethanolic soln of the saturated sodium acetate trihydrate of 2 times of material liquid volumes after reaction finishes; Visual inspection stops to stir after obvious sediment thing d is arranged; Leave standstill solution centrifugal after 2 hours, collecting precipitation thing d obtains the heparin benzyl ester; The taking heparin benzyl ester uses purified water to be dissolved into the solution of concentration as 3wt%; Add the solid sodium hydroxide account for heparin benzyl ester weight 10wt%, 60 ℃ of ℃ of stirring reactions 15 minutes; Add 2mol/L hydrochloric acid soln adjust pH then and be 6.3 back membrane filtrations to clear liquid, in filtrating, add and stop to stir after the ethanol that accounts for 2 times of amounts of material liquid volume is cooled to 0.8 ℃, place 12h, collecting precipitation thing e obtains the Enoxaparin Sodium bullion; The purified water that adds 5 times of volumes of throw out e after the dissolving, adds the D318 resin that accounts for throw out e weight 0.5wt% fully; 30 ℃ of whip attachment 1 hour, behind 0.22 μ m membrane filtration, add the hydrogen peroxide oxidation 6 hours of the 0.2v% of liquor capacity; Use membrane filtration; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 6 hours, obtained throw out f; Use purified water to be dissolved into the solution of concentration as 10wt% throw out f, behind 0.1 μ m membrane filtration, spraying drying gets the Enoxaparin Sodium finished product.
Detected result: A231nm=16.7, anti-Xa IU:112.4, anti-IIa IU:24.8.The anti-IIa=4.5 of anti-Xa/.Molecular weight: average 4334, the ratio less than 2000: 17.6%, 2000～8000 ratio: 74.6%.Free sulfate radical: 0.2%.1,6-dehydrated structure content 21.0%.All the other each item indexs all meet the European Pharmacopoeia quality standard.
Embodiment 2
Enoxaparin Sodium is realized through following technology, gets crude heparin sodium 100Kg, adds purified water and is dissolved into the crude heparin sodium aqueous solution that concentration is 15wt%; Working concentration is that the hydrochloric acid of 4mol/L or the pH value of sodium hydrate regulator solution are 6.7, adds the medicinal alcohol of 0.8 times of liquor capacity then, adjustment temperature to 9.5 ℃; Placed collecting precipitation thing a, the purified water of 15 times of volumes of adding throw out a 24 hours; After the dissolving, the hydrogen peroxide oxidation of adding liquor capacity 1v% 12 hours is used membrane filtration fully; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 12 hours, obtained throw out b; In throw out b, add purified water and be dissolved into the heparin sodium aqua that concentration is 15wt%, the benzethonium chloride of 4 times of weight of taking precipitate b slowly is added to it in heparin sodium aqua in the time of stirring, centrifugal collecting precipitate c; Throw out c with water washing after 70 ℃ of dryings, obtain heparin benzethonium chloride salt; Taking heparin benzethonium chloride salt adds N, and dinethylformamide is dissolved into the solution that concentration is 35wt% with heparin benzethonium chloride salt; The Benzyl Chloride that adds 0.8 times of weight of heparin benzethonium chloride salt 30 ℃ of reactions 15 hours, adds the ethanolic soln of the saturated sodium acetate trihydrate of 2.5 times of material liquid volumes after reaction finishes; Visual inspection stops to stir after obvious sediment thing d is arranged; Leave standstill solution centrifugal after 2 hours, collecting precipitation thing d obtains the heparin benzyl ester; The taking heparin benzyl ester uses purified water to be dissolved into the solution of concentration as 5wt%; Add the solid sodium hydroxide account for heparin benzyl ester weight 15wt%, 65 ℃ of stirring reactions 70 minutes; Add 2mol/L hydrochloric acid soln adjust pH then and be 7.6 back membrane filtrations to clear liquid, in filtrating, add and stop to stir after the ethanol that accounts for 3 times of amounts of material liquid volume is cooled to 9.5 ℃, place 12h, collecting precipitation thing e obtains the Enoxaparin Sodium bullion; The purified water that adds 5 times of volumes of throw out e after the dissolving, adds the D314 resin that accounts for throw out e weight 1wt% fully; 30 ℃ of whip attachment 1 hour, behind 0.22 μ m membrane filtration, add the hydrogen peroxide oxidation 12 hours of the 0.1v% of liquor capacity; Use membrane filtration; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 12 hours, obtained throw out f; Use purified water to be dissolved into the solution of concentration as 15wt% throw out f, behind 0.1 μ m membrane filtration, spraying drying gets the Enoxaparin Sodium finished product.
Detected result: A231nm=16.4, anti-Xa IU:114.8, anti-IIa IU:24.6.The anti-IIa=4.7 of anti-Xa/.Molecular weight: average 4380, the ratio less than 2000: 17.4%, 2000～8000 ratio: 75.4%.Free sulfate radical: 0.2%.1,6-dehydrated structure content 20.8%.All the other each item indexs all meet the European Pharmacopoeia quality standard.
Claims (10)
1. method by crude heparin sodium direct production Enoxaparin Sodium is characterized in that may further comprise the steps:
(1) crude heparin sodium is added purified water and be dissolved into the crude heparin sodium aqueous solution that concentration is 10wt%～15wt%; Working concentration is that the hydrochloric acid of 2～6mol/L or the pH value of sodium hydrate regulator solution are 5.0～7.0, adds the medicinal alcohol of 0.3～0.8 times of liquor capacity then, adjustment temperature to 0～10 ℃; Placed collecting precipitation thing a, the purified water of 5～15 times of volumes of adding throw out a 5～24 hours; Fully after the dissolving; The hydrogen peroxide oxidation of adding liquor capacity 0.2v%～1v% 6～12 hours is used membrane filtration, adds the ethanol sedimentation of 2 times of amounts of liquor capacity; Deposition was placed 6～12 hours, obtained throw out b;
(2) in throw out b, add purified water and be dissolved into the heparin sodium aqua that concentration is 10wt%～15wt%, the benzethonium chloride of 2-4 times of weight of taking precipitate b slowly is added to it in heparin sodium aqua centrifugal collecting precipitate c in the time of stirring; Throw out c with water washing after 60～70 ℃ of dryings, obtain heparin benzethonium chloride salt;
(3) taking heparin benzethonium chloride salt added N, and dinethylformamide is dissolved into the solution that concentration is 15wt%～35wt% with heparin benzethonium chloride salt, adds the Benzyl Chloride of 0.5～0.8 times of weight of heparin benzethonium chloride salt, 25～30 ℃ of reactions 10～15 hours; The ethanolic soln that adds the saturated sodium acetate trihydrate of 2～2.5 times of material liquid volumes after reaction finishes, visual inspection stop to stir after obvious sediment thing d is arranged, and leave standstill solution centrifugal after 2 hours, and collecting precipitation thing d obtains the heparin benzyl ester;
(4) the taking heparin benzyl ester uses purified water to be dissolved into the solution of concentration as 3wt%～5wt%; Add the solid sodium hydroxide account for heparin benzyl ester weight 10wt%～15wt%, 60 ℃～65 ℃ stirring reactions 15～70 minutes; Adding 2mol/L hydrochloric acid soln adjust pH then is 6.0～8.0 back membrane filtrations, in filtrating, adds to stop to stir after the ethanol that accounts for 2～3 times of amounts of material liquid volume is cooled to 0 ℃～10 ℃, places 12h, and collecting precipitation thing e obtains the Enoxaparin Sodium bullion;
(5) purified water of 5～15 times of volumes of adding throw out e after the dissolving, adds the resin of the absorption sulfate radical that accounts for throw out e weight 0.5wt%～1wt% fully; 30 ℃～50 ℃ whip attachment 1～2 hour, behind 0.22 μ m membrane filtration, add the hydrogen peroxide oxidation 6～12 hours of the 0.2v%～1v% of liquor capacity; Use membrane filtration; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 6～12 hours, obtained throw out f; Use purified water to be dissolved into the solution of concentration as 10wt%～15wt% throw out f, behind 0.1 μ m membrane filtration, spraying drying gets the Enoxaparin Sodium finished product.
2. the method by crude heparin sodium direct production Enoxaparin Sodium according to claim 1 is characterized in that the specific conductivity of described purified water in the time of 25 ℃ is 1.3uS/cm.
3. according to each described method of claim 1-2, it is characterized in that in step (1), crude heparin sodium being added purified water is dissolved into the crude heparin sodium aqueous solution that concentration is 10wt% by crude heparin sodium direct production Enoxaparin Sodium; Working concentration is that the hydrochloric acid of 4mol/L or the pH value of sodium hydrate regulator solution are 5.2, adds the medicinal alcohol of 0.4 times of liquor capacity then, adjustment temperature to 0.5 ℃; Placed collecting precipitation thing a, the purified water of 5 times of volumes of adding throw out a 6 hours; After the dissolving, the hydrogen peroxide oxidation of adding liquor capacity 0.2v% 6 hours is used membrane filtration fully; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 6 hours, obtained throw out b.
4. according to each described method of claim 1-2, it is characterized in that consumption at the Benzyl Chloride described in the step (3) is 0.5～0.7 times of heparin benzethonium chloride salt weight by crude heparin sodium direct production Enoxaparin Sodium.
5. the method by crude heparin sodium direct production Enoxaparin Sodium according to claim 4 is characterized in that consumption at the Benzyl Chloride described in the step (3) is 0.5 times of heparin benzethonium chloride salt weight.
6. according to each described method of claim 1-2 by crude heparin sodium direct production Enoxaparin Sodium; It is characterized in that taking heparin benzethonium chloride salt in step (3); Add N; Dinethylformamide was dissolved into the solution that concentration is 20wt% with heparin benzethonium chloride salt, adds the Benzyl Chloride of 0.5 times of weight of heparin benzethonium chloride salt, 28 ℃ of reactions 12 hours; The ethanolic soln that adds the saturated sodium acetate trihydrate of 2.2 times of material liquid volumes after reaction finishes, visual inspection stop to stir after obvious sediment thing d is arranged, and leave standstill solution centrifugal after 2 hours, and collecting precipitation thing d obtains the heparin benzyl ester.
7. according to each described method of claim 1-2, it is characterized in that in step (4) that the taking heparin benzyl ester uses purified water to be dissolved into the solution of concentration as 4wt% by crude heparin sodium direct production Enoxaparin Sodium; Add the solid sodium hydroxide account for heparin benzyl ester weight 12wt%, 62 ℃ of stirring reactions 30 minutes; Adding 2mol/L hydrochloric acid soln adjust pH then is 6.5～7.5 back membrane filtrations, in filtrating, adds to stop to stir after the ethanol that accounts for 2.5 times of amounts of material liquid volume is cooled to 0.5 ℃～2.5 ℃, places 12h, and collecting precipitation thing e obtains the Enoxaparin Sodium bullion.
8. according to each described method of claim 1-2, it is characterized in that in step (5), add the purified water of 10 times of volumes of throw out e by crude heparin sodium direct production Enoxaparin Sodium; After the dissolving, add the resin of the absorption sulfate radical account for throw out e weight 0.5wt% fully, 40 ℃ of whip attachment 1.5 hours; Behind 0.22 μ m membrane filtration; Add 0.25% the hydrogen peroxide oxidation 8 hours of liquor capacity, use membrane filtration, the ethanol sedimentation of 2 times of amounts of adding liquor capacity; Deposition was placed 10 hours, obtained throw out f; Use purified water to be dissolved into the solution of concentration as 10wt% throw out f, behind 0.1 μ m membrane filtration, spraying drying gets the Enoxaparin Sodium finished product.
9. according to each described method of claim 1-2, it is characterized in that in step (5) that the resin of said absorption sulfate radical is selected from a kind of in D318 resin, D354 resin or the D314 resin by crude heparin sodium direct production Enoxaparin Sodium.
10. method by crude heparin sodium direct production Enoxaparin Sodium is characterized in that may further comprise the steps:
(1) get crude heparin sodium adding purified water and be dissolved into the crude heparin sodium aqueous solution that concentration is 10wt%, working concentration is that the hydrochloric acid of 4mol/L or the pH value of sodium hydrate regulator solution are 5.2, adds the medicinal alcohol of 0.4 times of liquor capacity then; Adjustment temperature to 0.5 ℃ was placed collecting precipitation thing a 6 hours; The purified water that adds 5 times of volumes of throw out a, after dissolving fully, the hydrogen peroxide oxidation of adding liquor capacity 0.2v% 6 hours; Use membrane filtration; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 6 hours, obtained throw out b;
(2) in throw out b, add purified water and be dissolved into the heparin sodium aqua that concentration is 10wt%, the benzethonium chloride of 2 times of weight of taking precipitate b slowly is added to it in heparin sodium aqua centrifugal collecting precipitate c in the time of stirring; Throw out c with water washing after 60 ℃ of dryings, obtain heparin benzethonium chloride salt;
(3) taking heparin benzethonium chloride salt adds N, and dinethylformamide is dissolved into the solution that concentration is 15wt% with heparin benzethonium chloride salt; The Benzyl Chloride that adds 0.5 times of weight of heparin benzethonium chloride salt 25 ℃ of reactions 10 hours, adds the ethanolic soln of the saturated sodium acetate trihydrate of 2 times of material liquid volumes after reaction finishes; Visual inspection stops to stir after obvious sediment thing d is arranged; Leave standstill solution centrifugal after 2 hours, collecting precipitation thing d obtains the heparin benzyl ester;
(4) the taking heparin benzyl ester uses purified water to be dissolved into the solution of concentration as 3wt%; Add the solid sodium hydroxide account for heparin benzyl ester weight 10wt%, 60 ℃ of stirring reactions 15 minutes; Add 2mol/L hydrochloric acid soln adjust pH then and be 6.3 back membrane filtrations to clear liquid, in filtrating, add and stop to stir after the ethanol that accounts for 2 times of amounts of material liquid volume is cooled to 0.8 ℃, place 12h, collecting precipitation thing e obtains the Enoxaparin Sodium bullion;
(5) purified water of 5 times of volumes of adding throw out e after the dissolving, adds the D318 resin that accounts for throw out e weight 0.5wt% fully; 30 ℃ of whip attachment 1 hour, behind 0.22 μ m membrane filtration, add the hydrogen peroxide oxidation 6 hours of the 0.2v% of liquor capacity; Use membrane filtration; The ethanol sedimentation that adds 2 times of amounts of liquor capacity, deposition was placed 6 hours, obtained throw out f; Use purified water to be dissolved into the solution of concentration as 10wt% throw out f, behind 0.1 μ m membrane filtration, spraying drying gets the Enoxaparin Sodium finished product.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104507972A (en) * | 2012-08-02 | 2015-04-08 | 罗维药品实验室有限公司 | Method for obtaining low molecular weight and very low molecular weight heparins |
| CN104530257A (en) * | 2014-12-24 | 2015-04-22 | 青岛九龙生物医药有限公司 | Method for separating dermatan sulfate in heparin sodium |
| CN104592421A (en) * | 2013-10-31 | 2015-05-06 | 江苏万邦生化医药股份有限公司 | Refining method of enoxaparin sodium |
| CN106243246A (en) * | 2015-08-21 | 2016-12-21 | 苏州融析生物科技有限公司 | A kind of sheep Enoxaparin Sodium and preparation method and application |
| CN106432547A (en) * | 2016-09-14 | 2017-02-22 | 苏州天马精细化学品股份有限公司 | Method for preparing enoxaparin sodium through heparin benzyl ester |
| CN108219031A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of process for purification of Enoxaparin Sodium |
| CN108219030A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of preparation method of Enoxaparin Sodium crude product |
| CN109666086A (en) * | 2018-11-05 | 2019-04-23 | 上海宝维医药技术有限公司 | A kind of preparation method and applications of High-purity heparin quaternary ammonium salt |
| WO2019116217A2 (en) | 2017-12-11 | 2019-06-20 | Biological E Limited | Process for the preparation of low molecular weight heparin |
| CN116284499A (en) * | 2022-07-28 | 2023-06-23 | 河北常山生化药业股份有限公司 | Preparation method of sheep-derived low-molecular heparin sodium |
| CN117777321A (en) * | 2023-11-27 | 2024-03-29 | 深圳市天道医药有限公司 | Synthesis method of low-impurity enoxaparin sodium |
| CN117946294A (en) * | 2023-11-13 | 2024-04-30 | 河北常山凯库得生物技术有限公司 | Preparation method of energy-saving and environment-friendly enoxaparin sodium |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5389618A (en) * | 1990-06-26 | 1995-02-14 | Rhone-Poulenc Rorer S.A. | Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events |
| CN101942040A (en) * | 2010-09-16 | 2011-01-12 | 山东海科化工集团有限公司 | Method for removing oversulfated chondroitin sulfate in heparin sodium |
-
2012
- 2012-03-21 CN CN2012100744243A patent/CN102603925B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5389618A (en) * | 1990-06-26 | 1995-02-14 | Rhone-Poulenc Rorer S.A. | Mixtures of particular LMW heparinic polysaccharides for the prophylaxis/treatment of acute thrombotic events |
| CN101942040A (en) * | 2010-09-16 | 2011-01-12 | 山东海科化工集团有限公司 | Method for removing oversulfated chondroitin sulfate in heparin sodium |
Non-Patent Citations (1)
| Title |
|---|
| 张利赟: "两种低分子肝素（LMWH）生产工艺及质量标准研究", 《中国优秀硕士学位论文全文数据库》 * |
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| CN108219031A (en) * | 2016-12-21 | 2018-06-29 | 鲁南制药集团股份有限公司 | A kind of process for purification of Enoxaparin Sodium |
| WO2019116217A2 (en) | 2017-12-11 | 2019-06-20 | Biological E Limited | Process for the preparation of low molecular weight heparin |
| US11299558B2 (en) | 2017-12-11 | 2022-04-12 | Biological E Limited | Process for the preparation of low molecular weight heparin |
| CN109666086A (en) * | 2018-11-05 | 2019-04-23 | 上海宝维医药技术有限公司 | A kind of preparation method and applications of High-purity heparin quaternary ammonium salt |
| CN109666086B (en) * | 2018-11-05 | 2020-12-22 | 上海宝维医药技术有限公司 | Preparation method and application of high-purity heparin quaternary ammonium salt |
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