CN114437148A - Preparation method of sodium salt or potassium salt of pharmaceutic adjuvant - Google Patents
Preparation method of sodium salt or potassium salt of pharmaceutic adjuvant Download PDFInfo
- Publication number
- CN114437148A CN114437148A CN202011208049.8A CN202011208049A CN114437148A CN 114437148 A CN114437148 A CN 114437148A CN 202011208049 A CN202011208049 A CN 202011208049A CN 114437148 A CN114437148 A CN 114437148A
- Authority
- CN
- China
- Prior art keywords
- salt
- potassium
- sodium
- sodium salt
- pharmaceutic adjuvant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000546 pharmaceutical excipient Substances 0.000 title claims abstract description 40
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 title claims abstract description 39
- 159000000000 sodium salts Chemical class 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 238000001914 filtration Methods 0.000 claims abstract description 23
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 40
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 22
- 239000000243 solution Substances 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 18
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229930006000 Sucrose Natural products 0.000 claims description 9
- 239000008213 purified water Substances 0.000 claims description 9
- 239000005720 sucrose Substances 0.000 claims description 9
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 8
- -1 sulfur trioxide-pyridine compound Chemical class 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 5
- 239000000920 calcium hydroxide Substances 0.000 claims description 5
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000292 calcium oxide Substances 0.000 claims description 3
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- 239000004111 Potassium silicate Substances 0.000 claims description 2
- 239000004115 Sodium Silicate Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- NNHHDJVEYQHLHG-UHFFFAOYSA-N potassium silicate Chemical compound [K+].[K+].[O-][Si]([O-])=O NNHHDJVEYQHLHG-UHFFFAOYSA-N 0.000 claims description 2
- 229910052913 potassium silicate Inorganic materials 0.000 claims description 2
- 235000019353 potassium silicate Nutrition 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 claims description 2
- 235000011151 potassium sulphates Nutrition 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052911 sodium silicate Inorganic materials 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 7
- 150000001768 cations Chemical group 0.000 abstract description 7
- 238000007670 refining Methods 0.000 abstract description 6
- 239000011347 resin Substances 0.000 abstract description 6
- 229920005989 resin Polymers 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000002894 chemical waste Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 238000005119 centrifugation Methods 0.000 abstract description 2
- 229910017053 inorganic salt Inorganic materials 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 6
- 235000013305 food Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- ZIJKGAXBCRWEOL-SAXBRCJISA-N Sucrose octaacetate Chemical compound CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@@]1(COC(C)=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1 ZIJKGAXBCRWEOL-SAXBRCJISA-N 0.000 description 1
- 239000001344 [(2S,3S,4R,5R)-4-acetyloxy-2,5-bis(acetyloxymethyl)-2-[(2R,3R,4S,5R,6R)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxyoxolan-3-yl] acetate Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940013883 sucrose octaacetate Drugs 0.000 description 1
- 150000003445 sucroses Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of sodium salt or potassium salt of a pharmaceutic adjuvant, wherein a calcium salt with low water solubility is selected to remove acid in a reaction system, and both the unreacted calcium salt and calcium sulfate generated by the reaction are slightly water-soluble compounds and can be removed by filtration or centrifugation, so that the influence of inorganic salt on the purity of a product is reduced. The pharmaceutical adjuvant prepared by the synthetic method has less sodium salt or potassium salt impurities and less cation residues, does not need further refining, avoids the need of refining for many times or passing through a cation resin column, reduces the complexity of operation, greatly reduces the production cost of enterprises and reduces the discharge of chemical wastes.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, in particular to a preparation method of a sodium salt or a potassium salt of a pharmaceutic adjuvant.
Background
Sucrose Esters (SE) are a generic name for a class of nonionic surfactants synthesized from sucrose and higher fatty acids, and are generally white to ivory-colored powdery, lumpy, waxy solids, or colorless to yellowish viscous or resinous liquids. Has no odor and peculiar smell, and has good emulsifying, dispersing, wetting, foaming and washing performances, and effects of viscosity regulation, aging prevention, crystallization prevention and the like. Is easily absorbed by human body, has no sensitization, and can be well compounded with many anionic, nonionic and amphoteric surfactants to reduce the irritation of those surfactants. SE has been recommended by the food and agriculture organization/world health organization (FAO/WHO) of the United nations as an efficient and safe food additive, and is widely applied to the fields of medicine, food, bioengineering, daily chemicals, agriculture and the like. The application of the compound is continuously developed, so the compound has huge market potential and extremely wide development prospect.
In the prior art, the sodium salt or the potassium salt of the pharmaceutic adjuvant needs to pass through a sodium type or potassium type resin column in the hitherto reported synthesis methods, and the sodium salt or the potassium salt of the pharmaceutic adjuvant with higher purity can be obtained only by passing through a cation resin column for multiple times, so the operation is complex and the production efficiency is low.
Patent US5447919 reports a method for synthesizing the pharmaceutical adjuvant. The research on the preparation of high-purity sucrose octaacetate was successfully synthesized in the journal of northwest university, vol.27, Qiuhua, 2005. The patent 200510200609 discloses a two-step method for directionally synthesizing sucrose-6-higher fatty acid monoester, and also specifically mentions that sucrose ester is widely used in the fields of chemical industry, medicine, food and the like.
Disclosure of Invention
The invention aims to solve the following problems in the prior art: in the prior art, during the preparation of the sodium salt or the potassium salt of the pharmaceutic adjuvant, the sodium salt or the potassium salt of the pharmaceutic adjuvant with higher purity can be obtained only by passing through a cationic resin column for many times, the operation is complex, and the production efficiency is low.
In order to solve the technical problems, the invention is realized by the following technical scheme:
a preparation method of a sodium salt or a potassium salt of a pharmaceutic adjuvant comprises the following steps:
(1) adding calcium salt into the solution of the pharmaceutic adjuvant, controlling the reaction temperature, stirring for reaction, reacting the calcium salt with the solution to generate calcium sulfate slightly soluble in water, and filtering;
(2) adding a sodium salt or potassium salt aqueous solution into the filtrate prepared in the step (1), controlling the reaction temperature, stirring for reaction, reacting the sodium salt or potassium salt aqueous solution with the filtrate prepared in the step (1) to generate water-insoluble calcium salt, and filtering after the reaction is finished;
(3) controlling the temperature of the filtrate in the step (2), stirring for crystallization, filtering, and drying to obtain the sodium salt or the potassium salt of the pharmaceutic adjuvant.
Further, the method also comprises the following steps:
adding sucrose, sulfur trioxide-pyridine compound, 2-methylpyridine and dimethylformamide into a reaction vessel, stirring and mixing uniformly, heating to 60-65 ℃, stirring and reacting, cooling the system solution after the reaction is finished, and adding purified water to quench and react to obtain the solution of the pharmaceutic adjuvant.
The calcium salt used in the step (1) is at least one of calcium hydroxide, calcium oxide and calcium carbonate.
The molar ratio of the calcium salt to the pharmaceutical adjuvant food in the step (1) is 4-16.
In the step (1), the reaction temperature is controlled to be 0-60 ℃.
The stirring reaction time in the step (1) is 0.5-12 h.
In the step (2), the sodium salt is at least one of sodium carbonate, sodium sulfate, sodium silicate, sodium phosphate and sodium hydroxide; the potassium salt is at least one of potassium carbonate, potassium sulfate, potassium silicate, potassium phosphate and potassium hydroxide.
The molar ratio of the sodium salt or the potassium salt to the pharmaceutical auxiliary food in the step (2) is 4-16.
The reaction temperature in the step (2) is 0-60 ℃.
The stirring reaction time in the step (2) is 0.5-12 h.
And (4) controlling the temperature of the filtrate in the step (3) to be 0-60 ℃.
The stirring crystallization time in the step (3) is 0-24 h.
The chemical reaction equation of the invention is as follows:
the invention has the following beneficial effects:
(1) the method adopts an advanced process route, improves the reaction yield, reduces the energy consumption and the material cost, has mild conditions, convenient operation, high yield, no generation of any toxic and harmful substances, environmental protection, economy, suitability for commercial production and good market application prospect.
(2) The sodium salt or the potassium salt of the pharmaceutic adjuvant prepared by the method has high purity, excellent performance and high quality, meets the international industrial requirements, and can reach the international advanced level.
(3) The pharmaceutical adjuvant prepared by the process synthesis method has less sodium salt or potassium salt impurities and less cation residues, does not need further refining, avoids the need of refining for many times or passing through a cation resin column, reduces the complexity of operation, greatly reduces the production cost of enterprises and reduces the discharge of chemical wastes.
(4) In the preparation process, the calcium salt with low water solubility is selected to remove acid in a reaction system, unreacted calcium salt and calcium sulfate generated by reaction are all compounds which are slightly soluble in water, and the calcium salt can be removed by filtration or centrifugation, so that the influence of inorganic salt on the purity of the product is reduced. And secondly, selecting sodium salt or potassium salt which can generate insoluble calcium salt with calcium ions as raw materials, precipitating the calcium salt after reaction, and separating the calcium salt from the product to further improve the purity of the product.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The following are specific examples:
example 1
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine compound, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-mouth reaction bottle, the temperature is raised to 60-65 ℃, and the mixture is stirred and reacted for 4 hours.
2. Cooling the reaction system to 0-10 ℃, and adding 150mL of purified water to quench and react; controlling the temperature of the solution to be 0-10 ℃, adding 4.33g of calcium hydroxide in batches under stirring, keeping the temperature and stirring for reacting for 2 hours after the addition is finished.
3. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, controlling the temperature to be 50-60 ℃, dropwise adding 20mL of solution of 9.35g of purified water dissolved sodium hydroxide while stirring, controlling the reaction temperature to be 50-60 ℃, keeping the temperature and stirring for reacting for 6 hours after dropwise adding.
4. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, controlling the temperature to be 30-40 ℃, stirring, crystallizing for 16h, filtering, and drying to obtain 15.96g of white powdery solid, wherein the yield is as follows: 94.23 percent.
Example 2
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine compound, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-mouth reaction bottle, the temperature is raised to 60-65 ℃, and the mixture is stirred and reacted for 4 hours.
2. And cooling the reaction system to 20-30 ℃, adding 150mL of purified water to quench and react, controlling the temperature of the solution to 20-30 ℃, adding 8.67g of calcium hydroxide in batches under stirring, preserving the temperature, stirring and reacting for 0.5 h.
3. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, cooling to 20-30 ℃, dropwise adding 50mL of solution of sodium carbonate 15.48g dissolved in purified water while stirring, controlling the reaction temperature to be 20-30 ℃, keeping the temperature and stirring for reacting for 12 hours after dropwise adding.
4. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, cooling to 0-10 ℃, filtering, and drying to obtain 16.12g of white powdery solid, wherein the yield is as follows: 95.17 percent.
Example 3
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine compound, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-mouth reaction bottle, the temperature is raised to 60-65 ℃, and the mixture is stirred and reacted for 4 hours.
2. Cooling the reaction system to 50-60 ℃, adding 150mL of purified water to quench and react, controlling the temperature of the solution to 50-60 ℃, adding 13.11g of calcium oxide in batches under stirring, and keeping the temperature and stirring for reaction for 12 hours after the addition is finished.
3. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, controlling the temperature to be 0-10 ℃, adding 12.11g of potassium carbonate in batches under stirring, controlling the reaction temperature to be 0-10 ℃, after dripping, keeping the temperature and stirring for reacting for 8 hours.
4. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, controlling the temperature to be 10-20 ℃, stirring, crystallizing for 8 hours, filtering, and drying to obtain 18.19g of white powdery solid, wherein the yield is as follows: 96.72 percent.
Example 4
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine compound, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-mouth reaction bottle, the temperature is raised to 60-65 ℃, and the mixture is stirred and reacted for 4 hours.
2. Cooling the reaction system to 50-60 ℃, adding 150mL of purified water to quench and react, controlling the temperature of the solution to be 40-50 ℃, adding 17.53g of calcium carbonate in batches under stirring, preserving the temperature and stirring to react for 10 hours after the addition is finished.
3. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, cooling to 40-50 ℃, dropwise adding 20mL of a solution of 9.83g of purified water-soluble potassium hydroxide while stirring, controlling the reaction temperature to 40-50 ℃, keeping the temperature and stirring for reacting for 0.5h after dropwise adding.
4. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, controlling the temperature to be 50-60 ℃, stirring, crystallizing for 4 hours, filtering, and drying to obtain 17.56g of white powdery solid, wherein the yield is as follows: 93.37 percent.
Example 5
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine compound, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-mouth reaction bottle, the temperature is raised to 60-65 ℃, and the mixture is stirred and reacted for 4 hours.
2. Cooling the reaction system to 30-40 ℃, adding 150mL of purified water to quench the reaction, controlling the temperature of the solution to 30-40 ℃, adding 10.82g of calcium hydroxide in batches under stirring, preserving the temperature, stirring and reacting for 8 hours.
3. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, controlling the temperature to be 30-40 ℃, dropwise adding 60mL of a solution of 8.30g of purified water-soluble sodium sulfate while stirring, controlling the reaction temperature to be 30-40 ℃, keeping the temperature and stirring for reacting for 2 hours after dropwise adding.
4. Filtering, transferring the filtrate into a 500mL four-mouth reaction bottle, controlling the temperature to be 20-30 ℃, stirring, crystallizing for 24 hours, filtering, and drying to obtain 15.76g of white powdery solid, wherein the yield is as follows: 93.05 percent.
The sodium salt or the potassium salt of the pharmaceutic adjuvant in the embodiment is detected, and the detection method comprises the following steps:
[ related substances ]
A chromatographic column: waters. mu. bondapak,3.9 mm. times.30 cm,10 μm
Column temperature: 30 deg.C
Flow rate: 1.0mL/min
Sample introduction volume: 50 μ L
Temperature of the sample pan: 15 deg.C
Operating time: 40minutes (the time of the main peak can be adjusted properly)
Refractive index detector temperature: 30 deg.C
Detector sensitivity: 256
And (3) an elution mode: isocratic elution
Preparing a test sample: precisely weighing 0.2g of sylvite of pharmaceutic adjuvant, placing the sylvite in a 20ml volumetric flask, and adding 20ml of mobile phase solution for dissolving;
preparation of a reference substance: accurately weighing 0.1g of potassium salt reference substance of USP pharmaceutic adjuvant, placing the reference substance into a 10ml measuring flask, adding the mobile phase, dissolving until scales are reached, and shaking up to obtain the product.
[ METAL ION ]
The instrument comprises the following steps: inductively coupled plasma mass spectrometer (Agilent 7800)
Carrier gas: argon (purity not less than 99.999%)
Mode (2): high matrix mode
The data analysis method comprises the following steps: full quantitative analysis
The determination method comprises the following steps: the standard curve method comprises the steps of measuring standard curve solutions with different concentrations under selected analysis conditions, taking response values as vertical coordinates, measuring concentrations as horizontal coordinates, drawing a standard curve, calculating a regression equation, enabling relevant linear data to be not less than 0.99, carrying out a blank test under the same analysis conditions, and eliminating blank interference.
Detection information table of sodium salt and potassium salt of pharmaceutic adjuvant
According to the detection data result information in the table above, the sodium salt or potassium salt product of the pharmaceutic adjuvant prepared by the synthesis process method has good purity, no impurities are detected, the cation residue is very little, further refining is not needed, multiple refining or cation resin column passing is avoided, the operation complexity is reduced, the production cost of enterprises is greatly reduced, and the discharge of chemical waste is reduced.
The preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best understand the invention for and utilize the invention. The invention is limited only by the claims and their full scope and equivalents.
Claims (12)
1. A preparation method of a sodium salt or a potassium salt of a pharmaceutic adjuvant is characterized by comprising the following steps:
(1) adding calcium salt into the solution of the pharmaceutic adjuvant, controlling the reaction temperature, stirring for reaction, reacting the calcium salt with the solution to generate calcium sulfate slightly soluble in water, and filtering;
(2) adding a sodium salt or potassium salt aqueous solution into the filtrate prepared in the step (1), controlling the reaction temperature, stirring for reaction, reacting the sodium salt or potassium salt aqueous solution with the filtrate prepared in the step (1) to generate water-insoluble calcium salt, and filtering after the reaction is finished;
(3) controlling the temperature of the filtrate in the step (2), stirring for crystallization, filtering, and drying to obtain the sodium salt or the potassium salt of the pharmaceutic adjuvant.
Wherein the structure of pharmaceutic adjuvant is:
2. the method for preparing a sodium salt or a potassium salt of a pharmaceutical excipient according to claim 1, further comprising the steps of: adding sucrose, sulfur trioxide-pyridine compound, 2-methylpyridine and dimethylformamide into a reaction vessel, stirring and mixing uniformly, heating to 60-65 ℃, stirring and reacting, cooling the system solution after the reaction is finished, and adding purified water to quench and react to obtain the solution of the pharmaceutic adjuvant.
3. The method for preparing a sodium salt or a potassium salt of a pharmaceutical excipient according to claim 1, wherein the calcium salt used in step (1) is at least one of calcium hydroxide, calcium oxide and calcium carbonate.
4. The method for preparing a sodium salt or a potassium salt of a pharmaceutical excipient according to claim 1, wherein the molar ratio of the calcium salt to the pharmaceutical excipient in step (1) is 4 to 16.
5. The method for preparing a sodium salt or a potassium salt of a pharmaceutic adjuvant according to claim 1, characterized in that the reaction temperature in step (1) is controlled to be 0-60 ℃.
6. The method for preparing a sodium salt or a potassium salt of a pharmaceutic adjuvant according to claim 1, wherein the stirring reaction time in step (1) is 0.5-12 h.
7. The method for preparing a sodium salt or a potassium salt of a pharmaceutic adjuvant according to claim 1, wherein the sodium salt in step (2) is at least one of sodium carbonate, sodium sulfate, sodium silicate, sodium phosphate and sodium hydroxide; the potassium salt is at least one of potassium carbonate, potassium sulfate, potassium silicate, potassium phosphate and potassium hydroxide.
8. The method for producing a sodium salt or potassium salt of a pharmaceutical excipient according to claim 1, wherein the molar ratio of the sodium salt or potassium salt to the pharmaceutical excipient in step (2) is 4 to 16.
9. The method for preparing a sodium salt or a potassium salt of a pharmaceutic adjuvant according to claim 1, characterized in that the reaction temperature in the step (2) is up to 0-60 ℃.
10. The method for preparing a sodium salt or a potassium salt of a pharmaceutical excipient according to claim 1, wherein the stirring reaction time in the step (2) is 0.5 to 12 hours.
11. The method for preparing a sodium salt or a potassium salt of a pharmaceutic adjuvant according to claim 1, characterized in that the temperature of the filtrate in the step (3) is controlled to be 0-60 ℃.
12. The method for preparing a sodium salt or a potassium salt of a pharmaceutic adjuvant according to claim 1, characterized in that the stirring crystallization time in the step (3) is 0-24 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011208049.8A CN114437148B (en) | 2020-11-03 | 2020-11-03 | Preparation method of sodium salt or potassium salt of pharmaceutical auxiliary material |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011208049.8A CN114437148B (en) | 2020-11-03 | 2020-11-03 | Preparation method of sodium salt or potassium salt of pharmaceutical auxiliary material |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114437148A true CN114437148A (en) | 2022-05-06 |
| CN114437148B CN114437148B (en) | 2023-12-01 |
Family
ID=81361470
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011208049.8A Active CN114437148B (en) | 2020-11-03 | 2020-11-03 | Preparation method of sodium salt or potassium salt of pharmaceutical auxiliary material |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114437148B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115974938A (en) * | 2022-12-19 | 2023-04-18 | 辅必成（上海）医药科技有限公司 | Synthesis method of sucrose heptasulfate |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3432489A (en) * | 1965-11-05 | 1969-03-11 | Chugai Pharmaceutical Co Ltd | Disaccharide polysulfate aluminium compound and method |
| ES519512A0 (en) * | 1983-02-03 | 1984-06-16 | Elmu Sa | PROCEDURE FOR OBTAINING HEXADECA-HIDROXITETRACOSAHIDROXI 1,3,4,6-TETRA-O-SULFO-D-FRUCTOFURANOSIL-D-GLUCOPYRANOSIDE TETRAKIS (HYDROGEN-SULPHATE) (8-) HEXADECA ALUMINUM. |
| EP0230023A2 (en) * | 1985-12-24 | 1987-07-29 | Marion Merrell Dow Inc. | Pharmaceutical compositions for the enhancement of wound healing |
| HUT53912A (en) * | 1987-12-17 | 1990-12-28 | Gyogyszerkutato Intezet | New process for producing disaccharid -octasulfate- aluminium-complexes and their hydrates |
| US5447919A (en) * | 1991-03-13 | 1995-09-05 | Hoffmann-La Roche Inc. | Sulfated oligosaccharides |
| CN103193835A (en) * | 2013-04-18 | 2013-07-10 | 安徽赛诺医药化工有限公司 | Novel method for synthesizing and purifying sucrose octasulphonate sodium salt |
| CN108530498A (en) * | 2018-04-03 | 2018-09-14 | 安徽赛诺制药有限公司 | A kind of new method eight sulphonic acid ester potassium of sucrose synthesis and purified |
-
2020
- 2020-11-03 CN CN202011208049.8A patent/CN114437148B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3432489A (en) * | 1965-11-05 | 1969-03-11 | Chugai Pharmaceutical Co Ltd | Disaccharide polysulfate aluminium compound and method |
| ES519512A0 (en) * | 1983-02-03 | 1984-06-16 | Elmu Sa | PROCEDURE FOR OBTAINING HEXADECA-HIDROXITETRACOSAHIDROXI 1,3,4,6-TETRA-O-SULFO-D-FRUCTOFURANOSIL-D-GLUCOPYRANOSIDE TETRAKIS (HYDROGEN-SULPHATE) (8-) HEXADECA ALUMINUM. |
| EP0230023A2 (en) * | 1985-12-24 | 1987-07-29 | Marion Merrell Dow Inc. | Pharmaceutical compositions for the enhancement of wound healing |
| HUT53912A (en) * | 1987-12-17 | 1990-12-28 | Gyogyszerkutato Intezet | New process for producing disaccharid -octasulfate- aluminium-complexes and their hydrates |
| US5447919A (en) * | 1991-03-13 | 1995-09-05 | Hoffmann-La Roche Inc. | Sulfated oligosaccharides |
| CN103193835A (en) * | 2013-04-18 | 2013-07-10 | 安徽赛诺医药化工有限公司 | Novel method for synthesizing and purifying sucrose octasulphonate sodium salt |
| CN108530498A (en) * | 2018-04-03 | 2018-09-14 | 安徽赛诺制药有限公司 | A kind of new method eight sulphonic acid ester potassium of sucrose synthesis and purified |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115974938A (en) * | 2022-12-19 | 2023-04-18 | 辅必成（上海）医药科技有限公司 | Synthesis method of sucrose heptasulfate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114437148B (en) | 2023-12-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5336765A (en) | Process of preparing N-substituted aldobionamides | |
| Miller et al. | Benzyl Esters of Amino Acids1 | |
| CN114437148A (en) | Preparation method of sodium salt or potassium salt of pharmaceutic adjuvant | |
| CN105218486A (en) | A kind of method preparing epoxy chloropropane and calcium chloride | |
| CN114685570B (en) | Preparation method of green surfactant alkyl glycoside | |
| CN114436858A (en) | Preparation method of triethylamine salt of pharmaceutic adjuvant | |
| CN110003074A (en) | A kind of preparation method of levetiracetam intermediate | |
| CN109438250A (en) | A kind of preparation method of high purity dimethyl diallyl ammonium chloride monomer high yield | |
| CN109836399A (en) | A kind of synthetic method of biological buffer-morpholinoethanesulfonic acid | |
| CN114437149A (en) | Preparation method of key intermediate calcium salt of pharmaceutic adjuvant salt | |
| CN1041200C (en) | Alkyl xanthogenate type xanthate | |
| JP3874820B2 (en) | Method for producing taurine analogs | |
| US4369144A (en) | Preparation and use of alkali metal isethionates from ethionic acid | |
| CN112521269B (en) | Preparation method of magnesium succinate | |
| RU2756956C2 (en) | Method for obtaining crystalline form of calcium cis-2,3-epoxysuccinate | |
| CN112552338B (en) | Comprehensive recycling method of phosphorus-containing composite salt as byproduct in organic phosphine production | |
| RU2757039C2 (en) | Method for producing a crystalline form of calcium cis-2,3-epoxysuccinate | |
| US11926585B2 (en) | Process for the production of aluminum salts of a fatty acid | |
| US4435328A (en) | Preparation and use of alkali metal isethionates from ethionic acid | |
| CN112939789B (en) | Preparation method of methyl tributyl ammonium chloride | |
| CA1151394A (en) | Method of producing crystalline sodium aluminum phosphate | |
| CN112574007B (en) | Novel cyclohexylimine ionic liquid and method for catalyzing synthesis of butyl citrate and bisphenol F | |
| SU1525167A1 (en) | Method of obtaining mixture of ribonucleoside-2ъ and 3ъ monophosphates | |
| EP0111569B1 (en) | Hydroxyalkanesulfonic acids and their derivatives, and process for their preparation | |
| CN110256266B (en) | Preparation method and detection method of hydroxyethyl iminodiacetic acid disodium salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |