CN114437148B - Preparation method of sodium salt or potassium salt of pharmaceutical auxiliary material - Google Patents
Preparation method of sodium salt or potassium salt of pharmaceutical auxiliary material Download PDFInfo
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- CN114437148B CN114437148B CN202011208049.8A CN202011208049A CN114437148B CN 114437148 B CN114437148 B CN 114437148B CN 202011208049 A CN202011208049 A CN 202011208049A CN 114437148 B CN114437148 B CN 114437148B
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- salt
- potassium
- reaction
- sodium
- sodium salt
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- 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 36
- 239000000463 material Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 72
- 238000001914 filtration Methods 0.000 claims abstract description 23
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 20
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 16
- 229940124531 pharmaceutical excipient Drugs 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims abstract description 8
- 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 20
- 239000000243 solution Substances 0.000 claims description 19
- 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
- 239000008213 purified water Substances 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- 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
- 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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 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
- 230000000171 quenching effect Effects 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 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
- 150000001768 cations Chemical group 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 239000011347 resin Substances 0.000 abstract description 6
- 229920005989 resin Polymers 0.000 abstract description 6
- 238000007670 refining Methods 0.000 abstract description 4
- 239000002894 chemical waste Substances 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 238000005119 centrifugation Methods 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 229910017053 inorganic salt Inorganic materials 0.000 abstract description 2
- 238000004321 preservation Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 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 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001514 detection 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
- 235000013305 food Nutrition 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 229940013883 sucrose octaacetate Drugs 0.000 description 2
- 238000003786 synthesis reaction 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
- 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
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- 239000012159 carrier gas Substances 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000004090 dissolution Methods 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
- 238000005187 foaming Methods 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 239000007788 liquid 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
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 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
- 230000000638 stimulation Effects 0.000 description 1
- -1 sucrose ester Chemical class 0.000 description 1
- 150000003445 sucroses Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of sodium salt or potassium salt of pharmaceutical excipients, which is characterized in that calcium salt with low water solubility is selected to remove acid in a reaction system, and unreacted calcium salt and calcium sulfate generated by reaction are compounds which are slightly soluble in water and can be removed by filtration or centrifugation, so that the influence of inorganic salt on the purity of a product is reduced. The sodium salt or potassium salt of the pharmaceutical auxiliary material prepared by the synthesis method of the invention has few impurities and little cation residue, does not need to be further refined, avoids the need of repeated refining 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 sodium salt or potassium salt of a pharmaceutical adjuvant.
Background
Sucrose Esters (SE) are a generic term for a class of nonionic surfactants synthesized from sucrose and higher fatty acids, typically 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 the functions of viscosity adjustment, aging prevention, crystallization prevention and the like. Is easy to be absorbed by human body, has no sensitization, and can be well compounded with a plurality of anionic, nonionic and amphoteric surfactants so as to reduce the stimulation effect of the surfactants. SE has been recommended by the United nations grain and agricultural organization/world health organization (FAO/WHO) as a high-efficiency and safe food additive, and is now widely applied to the fields of medicine, food, bioengineering, daily chemicals, agriculture and the like. The application is continuously developed, so that the market potential is huge, and the development prospect is very good.
In the prior art, the synthesis methods reported so far of the sodium salt or the potassium salt of the pharmaceutical auxiliary material all need to pass through a sodium type or potassium type resin column, and the sodium salt or the potassium salt of the pharmaceutical auxiliary material with higher purity can be obtained through passing through a cation resin column for multiple times, so that the operation is complex and the production efficiency is low.
Patent US5447919 reports a method for synthesizing the pharmaceutical excipients. The university of northwest university journal, volume 27, hua, 2005 et al published a study on the preparation of high purity sucrose octaacetate to successfully synthesize high purity sucrose octaacetate. The patent 200510200609 discloses the directional synthesis of sucrose-6-higher fatty acid monoester by a two-step method, 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 at solving the following problems in the prior art: in the preparation of the sodium salt or potassium salt of the pharmaceutical auxiliary material in the prior art, the sodium salt or potassium salt of the pharmaceutical auxiliary material with higher purity can be obtained only by passing through a cation resin column for multiple 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:
the preparation method of the sodium salt or potassium salt of the pharmaceutical auxiliary material comprises the following steps:
(1) Adding calcium salt into the solution of the pharmaceutical excipients, controlling the reaction temperature, stirring and reacting, reacting the calcium salt with the solution to generate calcium sulfate slightly soluble in water, and filtering;
(2) Adding 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) And (3) controlling the temperature of the filtrate in the step (2), stirring for crystallization, filtering and drying to obtain the sodium salt or potassium salt of the pharmaceutical auxiliary material.
Further, the method also comprises the following steps:
adding sucrose, sulfur trioxide-pyridine complex, 2-methylpyridine and dimethylformamide into a reaction vessel, stirring and mixing uniformly, heating to 60-65 ℃ and stirring for reaction, cooling the system solution after the reaction, and adding purified water for quenching reaction to obtain the solution of the pharmaceutical auxiliary material.
The calcium salt used in the step (1) is at least one of calcium hydroxide, calcium oxide and calcium carbonate.
The theoretical amount of the calcium salt and the pharmaceutical excipients in the step (1) is 4-16 in molar ratio.
The reaction temperature in the step (1) is controlled to be 0-60 ℃.
The stirring reaction time in the step (1) is 0.5-12h.
The sodium salt in the 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.
The molar ratio of the theoretical amount of the sodium salt or the potassium salt to the pharmaceutical auxiliary material 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 0.5-12h.
The temperature of the filtrate in the step (3) is controlled to be 0-60 ℃.
And (3) stirring and crystallizing for 0-24h.
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, is convenient to operate, has high yield, does not generate any toxic and harmful substances, is environment-friendly and economical, is suitable for commercial production, and has good market application prospect.
(2) The sodium salt or potassium salt of the pharmaceutical auxiliary material prepared by the method has high purity, excellent performance and high quality, meets the international industrial requirements, and can reach the international advanced level in various indexes.
(3) The sodium salt or potassium salt of the pharmaceutical auxiliary material prepared by the synthesis method of the invention has few impurities and little cation residue, does not need to be further refined, avoids the need of repeated refining or passing through a cation resin column, reduces the operation complexity, greatly reduces the production cost of enterprises and reduces the discharge of chemical wastes.
(4) In the preparation process, firstly, low water-solubility calcium salt is selected to remove acid in a reaction system, and unreacted calcium salt and calcium sulfate generated by the reaction are compounds which are slightly soluble in water and can be removed by filtration or centrifugation, so that the influence of inorganic salt on the purity of a product is reduced. And secondly, sodium salt or potassium salt which can generate insoluble calcium salt with calcium ions is selected as a raw material, so that the calcium salt after the reaction is precipitated and separated from a product, and the purity of the product is further improved.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The following are specific examples:
example 1
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine complex, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-port reaction flask, the temperature is raised to 60-65 ℃, and the reaction is stirred for 4 hours.
2. Cooling the reaction system to 0-10 ℃, and adding 150mL of purified water to quench the reaction; the temperature of the solution is controlled to be 0-10 ℃, 4.33g of calcium hydroxide is added in batches under stirring, and the reaction is carried out for 2h under heat preservation and stirring after the addition.
3. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, controlling the temperature to 50-60 ℃, dropwise adding 9.35g of solution of sodium hydroxide dissolved in 20mL of purified water under stirring, controlling the reaction temperature to 50-60 ℃, and carrying out heat preservation and stirring reaction for 6h after the completion of the dripping.
4. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, stirring and crystallizing for 16 hours at the temperature of 30-40 ℃, filtering, and drying to obtain 15.96g of white powdery solid, wherein the yield is: 94.23%.
Example 2
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine complex, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-port reaction flask, the temperature is raised to 60-65 ℃, and the reaction is stirred for 4 hours.
2. Cooling the reaction system to 20-30 ℃, adding 150mL of purified water to quench the reaction, controlling the temperature of the solution to 20-30 ℃, adding 8.67g of calcium hydroxide in batches under stirring, and carrying out heat preservation and stirring reaction for 0.5h after the addition is completed.
3. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, cooling to 20-30 ℃, dropwise adding 50mL of solution of sodium carbonate dissolved in purified water under stirring, controlling the reaction temperature to 20-30 ℃, and carrying out heat preservation and stirring reaction for 12h after the completion of the dripping.
4. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, cooling to 0-10 ℃, filtering, and drying to obtain 16.12g of white powdery solid with the yield: 95.17 percent.
Example 3
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine complex, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-port reaction flask, the temperature is raised to 60-65 ℃, and the reaction is stirred for 4 hours.
2. Cooling the reaction system to 50-60 ℃, adding 150mL of purified water for quenching reaction, controlling the temperature of the solution to 50-60 ℃, adding 13.11g of calcium oxide in batches under stirring, and carrying out heat preservation and stirring reaction for 12h after the addition is completed.
3. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, controlling the temperature to 0-10 ℃, adding 12.11g of potassium carbonate in batches under stirring, controlling the reaction temperature to 0-10 ℃, and carrying out heat preservation and stirring reaction for 8h after dripping.
4. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, stirring and crystallizing for 8 hours at the temperature of 10-20 ℃, filtering, and drying to obtain 18.19g of white powdery solid, wherein the yield is as follows: 96.72%.
Example 4
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine complex, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-port reaction flask, the temperature is raised to 60-65 ℃, and the reaction is stirred for 4 hours.
2. Cooling the reaction system to 50-60 ℃, adding 150mL of purified water for quenching reaction, controlling the temperature of the solution to 40-50 ℃, adding 17.53g of calcium carbonate in batches under stirring, and carrying out heat preservation and stirring reaction for 10h after the addition is completed.
3. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, cooling to 40-50 ℃, dropwise adding 9.83g of potassium hydroxide solution dissolved in 20mL of purified water under stirring, controlling the reaction temperature to 40-50 ℃, and carrying out heat preservation and stirring for reaction for 0.5h.
4. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, stirring and crystallizing for 4 hours at the temperature of 50-60 ℃, filtering, and drying to obtain 17.56g of white powdery solid, wherein the yield is: 93.37%.
Example 5
1. 5g of sucrose, 20.92g of sulfur trioxide-pyridine complex, 20mL of 2-methylpyridine and 100mL of Dimethylformamide (DMF) are added into a 250mL four-port reaction flask, the temperature is raised to 60-65 ℃, and the reaction is stirred for 4 hours.
2. Cooling the reaction system to 30-40 ℃, adding 150mL of purified water for quenching reaction, controlling the temperature of the solution to 30-40 ℃, adding 10.82g of calcium hydroxide in batches under stirring, and carrying out heat preservation and stirring reaction for 8h after the addition is completed.
3. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, controlling the temperature to 30-40 ℃, dropwise adding 60mL of solution of 8.30g of sodium sulfate dissolved in purified water under stirring, controlling the reaction temperature to 30-40 ℃, and carrying out heat preservation and stirring reaction for 2h after the completion of the dripping.
4. Filtering, transferring the filtrate into a 500mL four-port reaction bottle, stirring and crystallizing for 24 hours at the temperature of 20-30 ℃, filtering, and drying to obtain 15.76g of white powdery solid, wherein the yield is: 93.05%.
The sodium salt or potassium salt of the pharmaceutical excipients in the above example is detected by the following method:
[ related substances ]
Chromatographic column: waters μbond ak,3.9mm×30cm,10 μm
Column temperature: 30 DEG C
Flow rate: 1.0mL/min
Sample injection volume: 50 mu L
Sample tray temperature: 15 DEG C
Run time: 40minutes (the time of the main peak can be properly adjusted)
Differential refractive detector temperature: 30 DEG C
Detector sensitivity: 256
Elution mode: isocratic elution
Sample preparation: precisely weighing 0.2g of potassium salt of the pharmaceutical auxiliary material, placing the potassium salt into a 20ml volumetric flask, and adding 20ml of mobile phase solution for dissolution;
preparing a reference substance: precisely weighing potassium salt reference substance 0.1g of USP pharmaceutical adjuvant, placing into a 10ml measuring flask, adding mobile phase, dissolving to scale, and shaking.
[ Metal ions ]
Instrument: inductively coupled plasma mass spectrometer (Agilent 7800)
Carrier gas: argon (purity not less than 99.999%)
Mode: high matrix mode
The data analysis method comprises the following steps: full quantitative analysis
The measuring method comprises the following steps: the standard curve method is characterized by measuring standard curve solutions with different concentrations under the selected analysis condition, taking a response value as an ordinate, measuring the concentration as an abscissa, drawing a standard curve, calculating a regression equation, and performing a blank test under the same analysis condition with relevant linear data not lower than 0.99 and eliminating blank interference.
Sodium salt and potassium salt detection information table of pharmaceutical auxiliary materials
As can be seen from the detection data result information of the table, the sodium salt or potassium salt product of the pharmaceutical adjuvant prepared by the synthesis process has good purity, no impurity is detected, the cation residue is very small, no further refining is needed, the condition that repeated refining or passing through a cation resin column is needed is avoided, the operation complexity is reduced, the production cost of enterprises is greatly reduced, and the emission of chemical wastes is reduced.
The preferred embodiments of the invention disclosed above are intended only to assist in the explanation of the invention. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise form 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 and utilize the invention. The invention is limited only by the claims and the full scope and equivalents thereof.
Claims (10)
1. The preparation method of the sodium salt or the potassium salt of the pharmaceutical auxiliary material is characterized by comprising the following steps:
(1) Adding sucrose, sulfur trioxide-pyridine complex, 2-methylpyridine and dimethylformamide into a reaction vessel, stirring and mixing uniformly, heating to 60-65 ℃ and stirring for reaction, cooling the system solution after the reaction, and adding purified water for quenching reaction to obtain a solution of pharmaceutical excipients; adding calcium salt into the solution of the pharmaceutical auxiliary materials, wherein the calcium salt is at least one of calcium hydroxide, calcium oxide and calcium carbonate, controlling the reaction temperature, stirring and reacting, reacting the calcium salt with the solution to generate calcium sulfate which is slightly soluble in water, and filtering;
(2) Adding 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 sodium salt or potassium salt of the pharmaceutical auxiliary material;
wherein the structure of the pharmaceutic adjuvant is as follows:
2. the method for preparing sodium salt or potassium salt of pharmaceutical excipients according to claim 1, wherein the molar ratio of the theoretical amount of the calcium salt to the pharmaceutical excipients in the step (1) is 4-16.
3. The method for preparing the sodium salt or the potassium salt of the pharmaceutical excipient according to claim 1, wherein the reaction temperature is controlled to be 0-60 ℃ in the step (1).
4. The method for preparing the sodium salt or the potassium salt of the pharmaceutical excipient according to claim 1, wherein the stirring reaction time in the step (1) is 0.5-12h.
5. The method for preparing the sodium salt or the potassium salt of the pharmaceutical auxiliary material according to claim 1, wherein the sodium salt in the 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.
6. The method for preparing sodium salt or potassium salt of pharmaceutical excipients according to claim 1, wherein the molar ratio of the theoretical amount of sodium salt or potassium salt of pharmaceutical excipients in the step (2) is 4-16.
7. The method for preparing a sodium salt or potassium salt of a pharmaceutical excipient according to claim 1, wherein the reaction temperature in the step (2) is 0 to 60 ℃.
8. The method for preparing the sodium salt or the potassium salt of the pharmaceutical excipient according to claim 1, wherein the stirring reaction time in the step (2) is 0.5-12h.
9. The method for preparing the sodium salt or the potassium salt of the pharmaceutical excipient according to claim 1, wherein the temperature of the filtrate in the step (3) is controlled to be 0-60 ℃.
10. The method for preparing the sodium salt or the potassium salt of the pharmaceutical excipient according to claim 1, wherein the stirring crystallization time in the step (3) is 0-24h.
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| 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 |
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| 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 |
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| 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 |
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