CN112898356A - Preparation method of glucosamine sulfate sodium chloride double salt - Google Patents
Preparation method of glucosamine sulfate sodium chloride double salt Download PDFInfo
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Abstract
The invention discloses a preparation method of glucosamine sulfate and sodium chloride double salt, which relates to the technical field of preparation of glucosamine sulfate and sodium chloride double salt, and specifically comprises the following steps: s1, preparing D-glucosamine, S2, preparing D-glucosamine sulfate, S3, dissolving the D-glucosamine sulfate in a solvent with the mass ratio of 1: adding sodium chloride into water at the ratio of 2-1: 5, stirring at room temperature until the sodium chloride is completely dissolved, filtering, concentrating the filtrate in a water bath by an oil pump under reduced pressure, adding acetone, stirring, standing at room temperature, filtering, and washing with acetone; the solid product is pumped by a water pump to remove acetone, and is dried in a water bath by an oil pump under reduced pressure to constant weight to obtain the glucosamine sulfate sodium chloride double salt.
Description
[ technical field ] A method for producing a semiconductor device
The invention relates to the technical field of double salt preparation, and particularly relates to a preparation method of glucosamine sulfate and sodium chloride double salt.
[ background of the invention ]
Glucosamine, a substance synthesized in the human body, is an important nutrient for forming chondrocytes, and is a natural tissue component of healthy articular cartilage. With age, the deficiency of glucosamine in the human body becomes more severe, and articular cartilage is continuously degenerated and worn. A number of medical studies in the united states, europe and japan have shown that: glucosamine can help repair and maintain cartilage, and can stimulate the growth of chondrocytes.
The glucosamine compounds are mainly present in the form of N-acetylglucosamine, its hydrochloride and sulfate. The indications include knee joint degenerative arthritis, hyperosteogeny, meniscus injury, rheumatic arthritis, etc. The human joint important component containing sulfate (such as chondroitin sulfate, etc.) is more close to glucosamine containing sulfate, and the absorption is better. Glucosamine containing sulfate is preferably used for treating osteoarthritis. Glucosamine sulfate is extremely easy to absorb moisture, easy to oxidize and unstable in property, and the double salt of sodium chloride is stable in property and easy to prepare into various preparations, so that the main commercially available product is glucosamine sulfate sodium chloride double salt.
The prior preparation process of glucosamine sulfate products comprises the following steps:
the first one is reported in Tanzhiyou in CN 106749436A, natural chitin is hydrolyzed with 40-90% sulfuric acid to break glycosidic bond and produce glucosamine sulfate, which is then reacted with sodium chloride to produce glucosamine sulfate and sodium chloride double salt. The method has the problems that the chitin is easy to react incompletely, the chitin is subjected to a reaction again, the contents of sulfate and sodium chloride are difficult to control, impurities with dark colors are easy to exceed standards, and the like;
secondly, as reported in Chenliqiong of Chinese patent CN 106967131A, the glucosamine hydrochloride aqueous solution is dechlorinated by anion exchange resin to produce free glucosamine aqueous solution, which is concentrated and then added with sulfuric acid to form glucosamine sulfate. The method can react with sodium chloride to prepare double salt, and the method generates a large amount of water after dechlorination by using an ion resin exchange method, has low glucosamine concentration, needs concentration or freeze drying after salification, has high cost and large production difficulty;
and the third is that glucosamine sulfate is obtained by using glucosamine hydrochloride as a raw material and reacting the glucosamine hydrochloride with strong alkali sodium methoxide, filtering solid sodium chloride generated in the reaction and adding fuming sulfuric acid, wherein the glucosamine sulfate is reported in Liu Xianhua in the research progress of glucosamine sulfate. Finally, the glucosamine sulfate is reacted with sodium chloride to prepare glucosamine sulfate sodium chloride double salt. The sodium chloride generated in the method has certain solubility in a methanol solution, so that the prepared glucosamine has high chlorine content, and high-purity glucosamine sulfate cannot be prepared;
in conclusion, the existing preparation method of glucosamine sulfate and sodium chloride double salt has the disadvantages of incomplete reaction, difficult quality control, color change and high freeze-drying cost; the glucosamine chloride content of the strong alkali neutralization method is high, and the like.
[ summary of the invention ]
In view of the above problems, the present invention provides a method for preparing glucosamine sulfate sodium chloride double salt. The invention adopts the method of directly adding sodium chloride, and the prepared glucosamine sulfate sodium chloride double salt meets the pharmacopoeia standard and has complete reaction.
In order to achieve the purpose, the technical scheme provided by the invention is as follows: a preparation method of glucosamine sulfate and sodium chloride double salt comprises the following steps:
S1S1, D-glucosamine preparation: adding D-glucosamine hydrochloride and an alcohol solvent into a reactor, stirring, adding di-n-propylamine, adding dichloromethane after the reaction is complete, stirring, standing, filtering, washing a product with absolute ethyl alcohol, adding a silver nitrate solution into a washing liquid to determine that no chloride ion exists, and then drying the product under reduced pressure to obtain high-purity white powder crystal D-glucosamine;
s2, D-glucosamine sulfate preparation: dissolving the D-glucosamine into water, stirring and dropwise adding dilute sulfuric acid at the internal temperature of-1-10 ℃ until the pH value is 3.30-4.50, and obtaining D-glucosamine sulfate aqueous solution; concentrating D-glucosamine sulfate by an oil pump under reduced pressure, adding methanol or ethanol or acetone, stirring magnetically until the excessive half product becomes powder crystal, adding acetone, stirring magnetically until the product becomes powder crystal, filtering, and washing with acetone and diethyl ether; drying the product in a water bath water pump under reduced pressure to remove the organic solvent, and drying the water bath oil in a water bath oil pump under reduced pressure to constant weight to obtain D-glucosamine sulfate;
s3, preparation of glucosamine sulfate and sodium chloride double salt: dissolving D-glucosamine sulfate into a solution with a mass ratio of 1: adding sodium chloride into water at the ratio of 2-1: 5, stirring at room temperature until the sodium chloride is completely dissolved, filtering, concentrating the filtrate in a water bath by an oil pump under reduced pressure, adding acetone, stirring, standing at room temperature, filtering, and washing with acetone; and removing the acetone from the solid product by a water pump under reduced pressure, and drying the solid product in a water bath by an oil pump under reduced pressure to constant weight to obtain the glucosamine sulfate sodium chloride double salt.
Further, in S1, the mass ratio of D-glucosamine hydrochloride to the alcohol solvent is 1: 2-1: 10, the alcohol solvent is one of methanol and ethanol, and the molar ratio of the D-glucosamine hydrochloride to the di-n-propylamine is 1:1 to 2.
Further, in S1, the mass ratio of the D-glucosamine hydrochloride to the alcohol solvent is 1: 2-1: 4.
Further, in S2, the mass ratio of D-glucosamine to water is 1: 3-1: 10, wherein the mass concentration of the dilute sulfuric acid is 5% -30%, and the mass concentration of methanol, ethanol or acetone is 4-20 times of the theoretical yield.
Further, in S2, the mass ratio of D-glucosamine to water is 1:2 to 1:4, and the mass concentration of the dilute sulfuric acid is 20%.
Further, in S3, the mass ratio of D-glucosamine sulfate to water is 1: 2-1: 5; adding sodium chloride with the equivalent ratio of 1.0: 1.0-1.2; concentrating the residue to 1.0-2.0 times of the theoretical yield of the product; the mass of the added acetone is 2-7 times of the theoretical yield of the product.
Compared with the prior art, the invention has the beneficial effects that:
1. compared with an ion exchange column method, the method has the advantages that the D-glucosamine hydrochloride is used as a raw material and is prepared by replacing D-glucosamine hydrochloride with di-n-propylamine, so that the method has less solvent consumption, high yield and simple process;
2. the concentrated D-glucosamine sulfate is subjected to a water transfer agent, a methanol (or ethanol or acetone) crystallization process, a D-glucosamine sulfate solution is generated by adding sulfuric acid into the D-glucosamine sulfate solution, and sodium chloride is added to directly prepare the glucosamine sulfate and sodium chloride double salt, so that the method has the characteristics of low cost and simple and convenient process;
3. the preparation process of the glucosamine sulfate sodium chloride double salt has controllable quality and high yield; the glucosamine content, the sulfate radical content, the pH value and the impurity limit all accord with the pharmacopoeia standard.
[ description of the drawings ]
FIG. 1 is a High Performance Liquid Chromatography (HPLC) chromatogram of glucosamine sulfate, which is a preparation method of a glucosamine sulfate sodium chloride double salt according to a first embodiment of the present invention;
FIG. 2 is an HPLC chromatogram of glucosamine sulfate obtained by the method for preparing a glucosamine sulfate-sodium chloride double salt according to the first embodiment of the present invention;
FIG. 3 is an HPLC chromatogram of a double salt of a method for preparing a glucosamine sulfate sodium chloride double salt according to an embodiment of the present invention;
FIG. 4 is an HPLC chromatogram of glucosamine prepared by the method for preparing a glucosamine sulfate-sodium chloride double salt according to the second embodiment of the present invention;
FIG. 5 is an HPLC chromatogram of glucosamine sulfate obtained by the method for preparing a glucosamine sulfate-sodium chloride double salt according to the second embodiment of the present invention;
FIG. 6 is an HPLC chromatogram of a double salt of a method for preparing a glucosamine sulfate sodium chloride double salt according to a second embodiment of the present invention;
FIG. 7 is an HPLC chromatogram of glucosamine prepared by the method for preparing a glucosamine sulfate-sodium chloride double salt according to the third embodiment of the invention;
FIG. 8 is an HPLC chromatogram of glucosamine sulfate obtained by the method for preparing a glucosamine sulfate-sodium chloride double salt according to the third embodiment of the present invention;
FIG. 9 is an HPLC chromatogram of a double salt of a method for preparing a glucosamine sulfate sodium chloride double salt according to a third embodiment of the present invention;
FIG. 10 is an HPLC chromatogram of glucosamine prepared by the method for preparing a glucosamine sulfate-sodium chloride double salt according to the fourth embodiment of the present invention;
FIG. 11 is an HPLC chromatogram of a double salt of a method for preparing a glucosamine sulfate sodium chloride double salt according to a fourth embodiment of the present invention;
FIG. 12 is an HPLC chromatogram of glucosamine prepared by the method for preparing a glucosamine sulfate-sodium chloride double salt in the fifth embodiment of the invention;
FIG. 13 is an HPLC chromatogram of a double salt of a method for preparing a glucosamine sulfate sodium chloride double salt in a fifth embodiment of the present invention;
FIG. 14 is an HPLC chromatogram of glucosamine prepared by the method for preparing a glucosamine sulfate-sodium chloride double salt according to the sixth embodiment of the present invention;
FIG. 15 is an HPLC chromatogram of a double salt of a method for preparing a glucosamine sulfate sodium chloride double salt in a sixth embodiment of the present invention;
fig. 16 is an HPLC chromatogram of a double salt according to embodiments one to six of the present invention.
[ detailed description ] embodiments
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further explained below;
d-glucosamine hydrochloride, manufactured by xxx, under the reference of lot No. WYS2019-115 (the following examples use undried products, content 98.6%, content 99.3% after drying), the reagents used were either analytically pure or the instruments are not indicated to the manufacturer, and all are conventional products commercially available.
Implementation mode one
Referring to fig. 1-3, a method for preparing glucosamine sulfate sodium chloride double salt includes the following steps:
s1, preparation of D-glucosamine: adding 80.00g of D-glucosamine hydrochloride and 250ml of methanol into a 500ml single-neck flask, stirring, adding 56.00g of di-n-propylamine, and reacting at the internal temperature of 15-20 ℃ for 2h until the reaction is complete; adding 200ml dichloromethane, stirring for 2min, standing at 10 deg.C for 2 h; filtration and washing of the product with absolute ethanol (4 × 40 ml); detecting by using 0.1M silver nitrate solution, and finally dropping a washing solution without chloride ions; drying the product in water bath at 40 deg.C under reduced pressure for 2 hr, in water bath at 50 deg.C under reduced pressure for 4 hr; the product, namely white powder crystal D-glucosamine, is 63.29g, the yield is 95.2 percent, and the content of HPLCD-glucosamine is determined as follows: 97.8% (no impurity peak), specific rotation (solvent, water): 51.5; detecting a chloride ion silver nitrate solution: standing for 5 minutes, sucking solid and liquid at the bottom of a reaction bottle, putting the reaction bottle into a 1ml syringe filled with cotton at the bottom, filtering out about 0.2g of the solid, washing with absolute ethyl alcohol 3x1ml, dissolving with 1.5ml of water, dropwise adding 5 drops of 0.1mol of silver nitrate solution, immediately observing no color change, and completely reacting;
s2, D-glucosamine sulfate preparation: weighing 55.00g of D-glucosamine and 165.0g of water, and adding the D-glucosamine and the water into a 250ml three-necked bottle with a thermometer and a dropping funnel; dropwise adding dilute sulfuric acid at the internal temperature of between 1 ℃ below zero and 3 ℃ until the pH value is 3.35 to obtain a D-glucosamine sulfate aqueous solution, transferring the D-glucosamine sulfate aqueous solution to a 1000ml round-bottom flask, performing rotary evaporation and concentration under reduced pressure of an oil pump, adding 450ml of methanol, performing vigorous magnetic stirring at room temperature for 4 hours, adding 500ml of acetone, stirring for 10 minutes, and performing magnetic stirring for 1.5 hours; filtering, washing the crystallized product by using 100ml of acetone and 100ml of diethyl ether; and (3) drying the product in a 35 ℃ water bath water pump under reduced pressure to remove the organic solvent, and drying the 50 ℃ water bath oil in a pump under reduced pressure to constant weight to obtain 72.00g of D-glucosamine sulfate, wherein the yield is as follows: 102.7%, 91.6% D-glucosamine sulphate content by HPLC (two peaks of impurities with retention times less than that of the product, total content of impurities xxx%), 20.0% sulphate SO4-2 (barium sulphate gravimetric method), specific rotation (solvent, water): 61.6; wherein the dilute sulfuric acid is 15.04g of concentrated sulfuric acid diluted by 60g of water, and the electric stirring is a stainless steel stirring paddle with the diameter of 50 mm;
s3, preparation of glucosamine sulfate and sodium chloride double salt: weighing 50.39g of D-glucosamine sulfate, 138.0g of water and 12.47g of sodium chloride, adding the D-glucosamine sulfate into a 500ml round-bottom flask, stirring the mixture at room temperature until the D-glucosamine sulfate is completely dissolved, filtering the mixture, concentrating the filtrate in a water bath at 40 ℃ under reduced pressure by an oil pump, adding 187ml of acetone, stirring the mixture for 2.5 hours, standing the mixture at room temperature for 1 hour, filtering the mixture, and washing the mixture by 30ml of acetone; removing acetone from a solid product by a water pump under reduced pressure, drying the solid product in a water bath at 50 ℃ by an oil pump under reduced pressure to constant weight to obtain 58.21g of glucosamine sulfate and sodium chloride double salt, wherein the yield is 100.4%, the glucosamine sulfate and sodium chloride double salt content is 98.0% by HPLC (two impurity peaks with retention time smaller than that of the product and total impurity content xxx%), the sulfate radical SO4-2 content is 17.1% (barium sulfate weight method), and the specific rotation (solvent and water): 52.1, pH 4.09.
Second embodiment
Referring to fig. 4-6, a method for preparing glucosamine sulfate sodium chloride double salt includes the following steps:
s1, preparation of D-glucosamine: adding 80.00g of D-glucosamine hydrochloride and 250ml of methanol into a 500ml single-neck flask, stirring, adding 56.00g of di-n-propylamine, and reacting at the internal temperature of 9-12 ℃ for 3 hours till the reaction is complete; adding 200ml dichloromethane, stirring for 2min, standing at 10 deg.C for 2 h; filtration and washing of the product with absolute ethanol (4 × 40 ml); detecting by using 0.1M silver nitrate solution, and finally dropping a washing solution without chloride ions; drying the product in water bath at 40 deg.C under reduced pressure for 2 hr, in water bath at 50 deg.C under reduced pressure for 4 hr; 64.27g of white powdery crystal D-glucosamine is obtained, the yield is 96.7%, and the content of D-glucosamine determined by HPLC is as follows: 97.5% (no impurity peak), specific rotation (solvent, water): 51.7; detecting a chloride ion silver nitrate solution: standing for 5 minutes, sucking solid and liquid at the bottom of a reaction bottle, putting the reaction bottle into a 1ml syringe filled with cotton at the bottom, filtering out about 0.2g of the solid, washing with absolute ethyl alcohol 3x1ml, dissolving with 1.5ml of water, dropwise adding 5 drops of 0.1mol of silver nitrate solution, immediately observing no color change, and completely reacting;
s2, D-glucosamine sulfate preparation: 51.33g of the D-glucosamine and 154.0g of water are taken and added into a 250ml three-mouth bottle provided with a thermometer and a dropping funnel; dropwise adding dilute sulfuric acid at the internal temperature of 0-5 ℃ until the pH value is 3.59 to obtain a D-glucosamine sulfate aqueous solution, transferring the D-glucosamine sulfate aqueous solution to a 1000ml round-bottom flask, performing reduced pressure concentration by an oil pump, adding 400ml of methanol, vigorously stirring at room temperature for 5 hours under electric action, adding 350ml of acetone, and magnetically stirring for 1.5 hours; filtering, washing the crystallized product by using 100ml of acetone and 100ml of diethyl ether; and (3) drying the product at 35 ℃ by a water pump under reduced pressure to remove the organic solvent, and drying the water bath oil at 50 ℃ by a pump under reduced pressure to constant weight to obtain 65.43g of D-glucosamine sulfate, wherein the yield is as follows: 100.1%, D-glucosamine sulphate content 92.7% by HPLC (two peaks of impurities with retention times less than that of the product, total content of impurities xxx%), sulphate SO4-2 content 20.3% (barium sulphate gravimetric method), specific rotation (solvent, water): 63.6; wherein the dilute sulfuric acid is obtained by diluting 14.04g of concentrated sulfuric acid with 56.5g of water, and the electric stirring is a stainless steel stirring paddle with the diameter of 50 mm;
s3, preparation of glucosamine sulfate and sodium chloride double salt: weighing 41.67g of D-glucosamine sulfate, 116.0g of water and 10.44g of sodium chloride, adding the D-glucosamine sulfate into a 500ml round-bottom flask, stirring the mixture at room temperature until the D-glucosamine sulfate is completely dissolved, filtering the mixture, carrying out decompression rotary evaporation and concentration on the filtrate in a water bath at 40 ℃ by using an oil pump, adding 157ml of acetone, stirring the mixture for 2.5 hours, standing the mixture at room temperature for 1 hour, filtering the mixture, and washing the mixture by using 30ml of acetone; removing acetone from a solid product by a water pump under reduced pressure, drying the solid product in a water bath at 50 ℃ by an oil pump under reduced pressure to constant weight to obtain 48.76g of glucosamine sulfate and sodium chloride double salt, wherein the yield is 100.5%, the glucosamine sulfate and sodium chloride double salt content is 98.9% by HPLC (two retention times are less than the impurity peaks of the product, the total content of impurities is xxx%), the sulfate radical SO4-2 content of barium sulfate is 17.1% (by weight method of barium sulfate), and the specific rotation (solvent and water): 52.9, pH 4.08.
Third embodiment
Referring to fig. 7-9, a method for preparing glucosamine sulfate sodium chloride double salt includes the following steps:
s1, preparation of D-glucosamine: adding 80.00g of D-glucosamine hydrochloride and 250ml of methanol into a 500ml single-neck flask, stirring, adding 56.00g of di-n-propylamine, and reacting at the internal temperature of 9-12 ℃ for 3 hours till the reaction is complete; adding 200ml dichloromethane, stirring for 2min, standing at 10 deg.C for 2 h; filtration and washing of the product with absolute ethanol (4 × 40 ml); detecting by using 0.1M silver nitrate solution, and finally dropping a washing solution without chloride ions; drying the product in water bath at 40 deg.C under reduced pressure for 2 hr, in water bath at 50 deg.C under reduced pressure for 4 hr; 64.22g of white powdery crystal D-glucosamine is obtained, the yield is 96.6%, and the content of D-glucosamine determined by HPLC is as follows: 98.2% (no impurity peak), specific rotation (solvent, water): 51.7; detecting a chloride ion silver nitrate solution: standing for 5 minutes, sucking solid and liquid at the bottom of a reaction bottle, putting the reaction bottle into a 1ml syringe filled with cotton at the bottom, filtering out about 0.2g of the solid, washing with absolute ethyl alcohol 3x1ml, dissolving with 1.5ml of water, dropwise adding 5 drops of 0.1mol of silver nitrate solution, immediately observing no color change, and completely reacting;
s2, D-glucosamine sulfate preparation: 51.97g of D-glucosamine and 153.0g of water are taken and added into a 250ml three-mouth bottle provided with a thermometer and a dropping funnel; at the internal temperature of 0-5 ℃, dropwise adding dilute sulfuric acid until the pH value is 3.58 to obtain D-glucosamine sulfate aqueous solution, transferring the D-glucosamine sulfate aqueous solution to a 1000ml round-bottom flask, carrying out reduced pressure concentration by an oil pump, adding 400ml of methanol, carrying out vigorous electric stirring at room temperature for 5h, adding 350ml of acetone, and carrying out magnetic stirring for 1.5 h. Filtration and washing of the crystalline product with 100ml of acetone. And (3) drying the product at 35 ℃ by a water pump under reduced pressure to remove the organic solvent, and drying the water bath oil at 50 ℃ by a pump under reduced pressure to constant weight to obtain 65.34g of D-glucosamine sulfate, wherein the yield is as follows: 100.7%, D-glucosamine sulphate content 92.5% by HPLC (two peaks of impurities with retention times less than that of the product, total content of impurities xxx%), sulphate SO4-2 content 20.2% (barium sulphate gravimetric method), specific rotation (solvent, water): 62.8 of the total weight of the alloy; wherein the dilute sulfuric acid is obtained by diluting 13.94g of concentrated sulfuric acid with 56.0g of water, and the electric stirring is a stainless steel stirring paddle with the diameter of 50 mm;
s3, preparation of glucosamine sulfate and sodium chloride double salt: weighing 40.46g of D-glucosamine sulfate, 112.0g of water and 10.11g of sodium chloride, adding into a 500ml round-bottom flask, stirring at room temperature until the D-glucosamine sulfate is completely dissolved, filtering, performing decompression rotary evaporation and concentration on the filtrate in a water bath at 40 ℃ by an oil pump, adding 152ml of acetone, stirring for 2.5h, standing at room temperature for 1h, filtering, and washing by 30ml of acetone; removing acetone from a solid product by a water pump under reduced pressure, drying the solid product in a water bath at 50 ℃ by an oil pump under reduced pressure to constant weight to obtain 46.80g of glucosamine sulfate and sodium chloride double salt, wherein the yield is 99.6%, the glucosamine sulfate and sodium chloride double salt is 98.2% by HPLC (two retention times are less than the impurity peaks of the product, the total content of impurities is xxx%), the sulfate radical SO4-2 content of barium sulfate is 17.1% (by weight method of barium sulfate), and the specific rotation (solvent and water): 52.3, pH 4.09.
Embodiment IV
Referring to fig. 10-11, a method for preparing glucosamine sulfate sodium chloride double salt includes the following steps:
s1, preparation of D-glucosamine: adding 195.27g of D-glucosamine hydrochloride and 585ml of methanol into a 2000ml single-neck flask, stirring, adding 137.45g of di-n-propylamine, and reacting in a water bath at 15 ℃ for 3.5h until the reaction is complete; adding 490ml of dichloromethane, stirring for 2min, standing for 2 at 10 ℃, filtering, washing the product with 250ml of dichloromethane and washing with absolute ethyl alcohol (4x95 ml); detecting by using 0.1M silver nitrate solution, and finally dropping a washing solution without chloride ions; drying the product in a water bath at 25 ℃ for 2h under reduced pressure by a water pump, drying in a water bath at 50 ℃ for 4h under reduced pressure by an oil pump; 158.08g of white powdery crystal D-glucosamine is obtained, the yield is 97.4%, and the content of D-glucosamine determined by HPLC is: 97.7% (no impurity peak), specific rotation (solvent, water); detecting a chloride ion silver nitrate solution: standing for 5 minutes, sucking solid and liquid at the bottom of a reaction bottle, putting the reaction bottle into a 1ml syringe filled with cotton at the bottom, filtering out about 0.2g of the solid, washing with absolute ethyl alcohol 3x1ml, dissolving with 1.5ml of water, dropwise adding 5 drops of 0.1mol of silver nitrate solution, immediately observing no color change, and completely reacting;
s2, preparation of glucosamine sulfate and sodium chloride double salt: taking 50.00g of D-glucosamine and 150.0g of water, and adding the D-glucosamine and the water into a 250ml three-necked bottle with a thermometer and a dropping funnel; dripping dilute sulphuric acid at the internal temperature of between 1 ℃ below zero and 5 ℃ until the pH value is 3.80 to obtain D-glucosamine sulfate aqueous solution; pouring the D-glucosamine sulfate aqueous solution into a 500ml round-bottom flask, adding 16.30g of sodium chloride, stirring at room temperature until the D-glucosamine sulfate aqueous solution is completely dissolved, filtering, concentrating the filtrate in a water bath at 40 ℃ by using an oil pump to reduce pressure and carry out rotary evaporation, adding 200ml of acetone, stirring for 1h, filtering, and washing the product by using 80ml of acetone; and (3) decompressing the solid product by using a water bath water pump at 25 ℃ to remove acetone, decompressing and drying the water bath at 50 ℃ by using an oil pump to constant weight to obtain 78.61g of glucosamine sulfate and sodium chloride double salt, wherein the yield is 98.3%, the glucosamine sulfate and sodium chloride double salt is 100.7% by HPLC (two retention time are less than the impurity peak and the total impurity content xxx%), the sulfate radical SO4-2 content barium sulfate is 17.0% (barium sulfate gravimetric method), and the specific rotation (solvent and water): 53.4, pH 4.06; wherein the dilute sulfuric acid is obtained by diluting 13.67g of concentrated sulfuric acid with 55.0g of water.
Fifth embodiment
Referring to fig. 12-13, a method for preparing glucosamine sulfate sodium chloride double salt includes the following steps:
s1, preparation of D-glucosamine: adding 120.00g of D-glucosamine hydrochloride and 360ml of methanol into a 1000ml single-neck flask, stirring, adding 84.47g of di-n-propylamine, and reacting in a water bath at 15 ℃ for 3.5h until the reaction is complete; adding dichloromethane 300ml, stirring for 2min, standing at 10 deg.C for 2 hr, standing at 5 deg.C for 1 hr, filtering, washing the product with dichloromethane 80ml, and washing with anhydrous ethanol (4 × 70 ml); and detecting by using 0.1M silver nitrate solution, wherein the finally dripped washing solution is free of chloride ions. Drying the product in a water bath at 25 ℃ for 2h under reduced pressure by a water pump, drying in a water bath at 50 ℃ for 8h under reduced pressure by an oil pump; the obtained product is white powder crystal D-glucosamine with 96.72g, the yield is 97.0 percent, and the content of D-glucosamine determined by HPLC is as follows: 99.3% (no impurity peak), specific rotation (solvent, water); detecting a chloride ion silver nitrate solution: standing for 5 minutes, sucking solid and liquid at the bottom of a reaction bottle, putting the reaction bottle into a 1ml syringe filled with cotton at the bottom, filtering out about 0.2g of the solid, washing with absolute ethyl alcohol 3x1ml, dissolving with 1.5ml of water, dropwise adding 5 drops of 0.1mol of silver nitrate solution, immediately observing no color change, and completely reacting;
s2, preparation of glucosamine sulfate and sodium chloride double salt: taking 50.00g of D-glucosamine and 150.0g of water, and adding the D-glucosamine and the water into a 250ml three-necked bottle with a thermometer and a dropping funnel; dripping dilute sulphuric acid at the internal temperature of between 1 ℃ below zero and 5 ℃ until the pH value is 3.80 to obtain D-glucosamine sulfate aqueous solution; pouring the D-glucosamine sulfate aqueous solution into a 500ml round-bottom flask, adding 16.30g of sodium chloride, stirring at room temperature until the D-glucosamine sulfate aqueous solution is completely dissolved, filtering, concentrating the filtrate in a water bath at 40 ℃ by using an oil pump to reduce pressure and carry out rotary evaporation, adding 200ml of acetone, stirring for 1h, filtering, and washing the product by using 80ml of acetone; and (3) decompressing the solid product by using a water bath water pump at 25 ℃ to remove acetone, decompressing and drying the water bath at 50 ℃ by using an oil pump to constant weight to obtain 78.61g of glucosamine sulfate and sodium chloride double salt, wherein the yield is 98.3%, the glucosamine sulfate and sodium chloride double salt is 100.7% by HPLC (two retention time are less than the impurity peak and the total impurity content xxx%), the sulfate radical SO4-2 content barium sulfate is 17.0% (barium sulfate gravimetric method), and the specific rotation (solvent and water): 53.4, pH 4.06; wherein the dilute sulfuric acid is obtained by diluting 13.67g of concentrated sulfuric acid with 55.0g of water.
Sixth embodiment
Referring to fig. 14-15, a method for preparing glucosamine sulfate sodium chloride double salt includes the following steps:
s1, preparation of D-glucosamine: adding 120.00g of D-glucosamine hydrochloride and 360ml of methanol into a 1000ml single-neck flask, stirring, adding 84.47g of di-n-propylamine, and reacting in a water bath at 15 ℃ for 3.5h until the reaction is complete; adding dichloromethane 300ml, stirring for 2min, standing at 10 deg.C for 2 hr, standing at 5 deg.C for 1 hr, filtering, washing the product with dichloromethane 80ml, and washing with anhydrous ethanol (4 × 70 ml); detecting by using 0.1M silver nitrate solution, and finally dropping a washing solution without chloride ions; drying the product in a water bath at 25 ℃ for 2h under reduced pressure by a water pump, drying in a water bath at 50 ℃ for 8h under reduced pressure by an oil pump; the obtained product is white powder crystal D-glucosamine with 96.72g, the yield is 97.0 percent, and the content of D-glucosamine determined by HPLC is as follows: 99.3% (no impurity peak), specific rotation (solvent, water); detecting a chloride ion silver nitrate solution: standing for 5 minutes, sucking solid and liquid at the bottom of a reaction bottle, putting the reaction bottle into a 1ml syringe filled with cotton at the bottom, filtering out about 0.2g of the solid, washing with absolute ethyl alcohol 3x1ml, dissolving with 1.5ml of water, dropwise adding 5 drops of 0.1mol of silver nitrate solution, immediately observing no color change, and completely reacting;
s2, preparation of glucosamine sulfate and sodium chloride double salt: 50.00g of the above D-glucosamine and 150.0g of water were taken and put into a 250ml three-necked flask equipped with a thermometer and a dropping funnel. Dilute sulfuric acid (13.80g of concentrated sulfuric acid diluted with 55.0g of water) was added dropwise at an internal temperature of minus 1 to 5 ℃ to a pH of 3.83(21 ℃) to give an aqueous solution of D-aminoglucose sulfate; pouring the D-glucosamine sulfate aqueous solution into a 500ml round-bottom flask, adding 16.61g of sodium chloride, stirring at room temperature until the D-glucosamine sulfate aqueous solution is completely dissolved, filtering, concentrating the filtrate in a water bath at 40 ℃ by using an oil pump to reduce pressure and carry out rotary evaporation, adding 200ml of acetone, stirring for 1h, filtering, and washing the product by using 80ml of acetone. And (3) removing acetone from the solid product by a water bath water pump at 25 ℃ under reduced pressure, drying the solid product in a water bath at 50 ℃ under reduced pressure by an oil pump to constant weight to obtain 78.90g of glucosamine sulfate and sodium chloride double salt, wherein the yield is 98.6%, the glucosamine sulfate and sodium chloride double salt is 100.4% by HPLC (two retention times are less than the impurity peak and the total impurity content xxx%), the sulfate radical SO4-2 content barium sulfate is 17.0% (barium sulfate gravimetric method), and the specific rotation (solvent and water): 52.8, pH 3.97; wherein the dilute sulfuric acid is obtained by diluting 13.80g of concentrated sulfuric acid with 55.0g of water.
As can be seen from experimental drawings 1-12, the prepared double salt has controllable quality and high yield.
The foregoing has described the general principles and principal features of the invention and its advantages; the present invention is not limited to the above-described embodiments, which are described in the specification and illustrated only for illustrating the principle of the present invention, but various changes and modifications may be made within the scope of the present invention as claimed without departing from the spirit and scope of the present invention; the scope of the invention is defined by the appended claims and equivalents thereof.
Claims (7)
1. A preparation method of glucosamine sulfate and sodium chloride double salt is characterized in that: the method comprises the following steps:
s1, preparation of D-glucosamine: adding D-glucosamine hydrochloride and an alcohol solvent into a reactor, stirring, adding di-n-propylamine, adding dichloromethane after the reaction is complete, stirring, standing, filtering, washing a product with absolute ethyl alcohol, adding a silver nitrate solution into a washing liquid to determine that no chloride ion exists, and then drying the product under reduced pressure by a water bath water pump to obtain high-purity white powder crystal D-glucosamine;
s2, D-glucosamine sulfate preparation: dissolving the D-glucosamine into water, stirring and dropwise adding dilute sulfuric acid at the internal temperature of-1-10 ℃ until the pH value is 3.30-4.50, and obtaining D-glucosamine sulfate aqueous solution; concentrating D-glucosamine sulfate by an oil pump under reduced pressure, adding methanol or ethanol or acetone, stirring magnetically until the excessive half product becomes powder crystal, adding acetone, stirring magnetically until the product becomes powder crystal, filtering, and washing with acetone and diethyl ether; drying the product in a water bath water pump under reduced pressure to remove the organic solvent, and drying the water bath oil in a water bath oil pump under reduced pressure to constant weight to obtain D-glucosamine sulfate;
s3, preparation of glucosamine sulfate and sodium chloride double salt: dissolving D-glucosamine sulfate into a solution with a mass ratio of 1: adding sodium chloride into water at the ratio of 2-1: 5, stirring at room temperature until the sodium chloride is completely dissolved, filtering, concentrating the filtrate in a water bath by an oil pump under reduced pressure, adding acetone, stirring, standing at room temperature, filtering, and washing with acetone; and removing the acetone from the solid product by a water pump under reduced pressure, and drying the solid product in a water bath by an oil pump under reduced pressure to constant weight to obtain the glucosamine sulfate sodium chloride double salt.
2. The method for preparing glucosamine sulfate sodium chloride double salt as claimed in claim 1, wherein: in S1, the mass ratio of D-glucosamine hydrochloride to the alcohol solvent is 1: 2-1: 10, the alcohol solvent is one of methanol and ethanol, and the molar ratio of the D-glucosamine hydrochloride to the di-n-propylamine is 1:1 to 2.
3. The method for preparing glucosamine sulfate sodium chloride double salt as claimed in claim 2, wherein: in S1, the mass ratio of the D-glucosamine hydrochloride to the alcohol solvent is 1: 2-1: 4.
4. The method for preparing glucosamine sulfate sodium chloride double salt as claimed in claim 1, wherein: in S2, the mass ratio of D-glucosamine to water is 1: 3-1: 10, wherein the mass concentration of the dilute sulfuric acid is 5% -30%, and the mass concentration of methanol, ethanol or acetone is 4-20 times of the theoretical yield.
5. The method for preparing glucosamine sulfate sodium chloride double salt as claimed in claim 4, wherein: in S2, the mass ratio of D-glucosamine to water is 1:2 to 1:4, and the mass concentration of the dilute sulfuric acid is 20%.
6. The method for preparing glucosamine sulfate sodium chloride double salt as claimed in claim 1, wherein: in S3, the mass ratio of D-glucosamine sulfate to water is 1: 2-1: 5; adding sodium chloride with the equivalent ratio of 1.0: 1.0-1.2; concentrating the residue to 1.0-2.0 times of the theoretical yield of the product; the mass of the added acetone is 2-7 times of the theoretical yield of the product.
7. A preparation method of glucosamine sulfate and sodium chloride double salt is characterized in that: the method comprises the following steps:
s1, preparation of D-glucosamine: adding D-glucosamine hydrochloride and an alcohol solvent into a reactor, stirring, adding di-n-propylamine, adding dichloromethane after the reaction is complete, stirring, standing, filtering, washing a product by dichloromethane and absolute ethyl alcohol in sequence, adding a silver nitrate solution into a washing solution to determine that no chloride ion exists, drying the product by a water bath water pump under reduced pressure in sequence, and drying the product by an oil pump under reduced pressure to obtain high-purity white powder crystalline D-glucosamine;
s2, preparation of glucosamine sulfate and sodium chloride double salt: dissolving the D-glucosamine into water, stirring and dropwise adding dilute sulfuric acid at the internal temperature of-1-10 ℃ until the pH value is 3.30-4.50, and obtaining D-glucosamine sulfate aqueous solution; adding sodium chloride into D-glucosamine sulfate water solution, stirring at room temperature to dissolve completely, filtering, concentrating the filtrate in water bath by oil pump under reduced pressure, adding acetone, stirring, filtering, and washing the product with acetone; and removing the acetone from the solid product by a water bath water pump under reduced pressure, and drying the water bath oil by the pump under reduced pressure to constant weight to obtain the glucosamine sulfate sodium chloride double salt.
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| CN101012251A (en) * | 2007-01-11 | 2007-08-08 | 庄建华 | Method of preparing aminoglucose composite sulphate |
| CN101830939A (en) * | 2010-05-19 | 2010-09-15 | 王松叶 | Preparation method of high-purity D-glucosamine sulfate |
| CN102850412A (en) * | 2012-10-12 | 2013-01-02 | 江苏澳新生物工程有限公司 | Preparation method of D-glucosamine sulfate sodium chloride salt |
| CN106749436A (en) * | 2015-11-20 | 2017-05-31 | 广东先强药业有限公司 | A kind of preparation method of Glucosamine Sulphate sodium chloride double salt |
| CN106967131A (en) * | 2017-05-17 | 2017-07-21 | 山西同达药业有限公司 | A kind of Glucosamine Sulphate product and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012251A (en) * | 2007-01-11 | 2007-08-08 | 庄建华 | Method of preparing aminoglucose composite sulphate |
| CN101830939A (en) * | 2010-05-19 | 2010-09-15 | 王松叶 | Preparation method of high-purity D-glucosamine sulfate |
| CN102850412A (en) * | 2012-10-12 | 2013-01-02 | 江苏澳新生物工程有限公司 | Preparation method of D-glucosamine sulfate sodium chloride salt |
| CN106749436A (en) * | 2015-11-20 | 2017-05-31 | 广东先强药业有限公司 | A kind of preparation method of Glucosamine Sulphate sodium chloride double salt |
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