CN115974938A - Synthesis method of sucrose heptasulfate - Google Patents
Synthesis method of sucrose heptasulfate Download PDFInfo
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- CN115974938A CN115974938A CN202211632835.XA CN202211632835A CN115974938A CN 115974938 A CN115974938 A CN 115974938A CN 202211632835 A CN202211632835 A CN 202211632835A CN 115974938 A CN115974938 A CN 115974938A
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- sucrose
- aqueous solution
- heptasulfate
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- 239000005720 sucrose Substances 0.000 title claims abstract description 57
- 229930006000 Sucrose Natural products 0.000 title claims abstract description 15
- 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 title claims abstract description 15
- 238000001308 synthesis method Methods 0.000 title claims description 12
- 239000007864 aqueous solution Substances 0.000 claims abstract description 36
- 238000001914 filtration Methods 0.000 claims abstract description 28
- 239000012043 crude product Substances 0.000 claims abstract description 26
- 239000007787 solid Substances 0.000 claims abstract description 24
- 239000000243 solution Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 17
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims abstract description 17
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 16
- 229930195729 fatty acid Natural products 0.000 claims abstract description 16
- 239000000194 fatty acid Substances 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000005670 sulfation reaction Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 4
- 238000002156 mixing Methods 0.000 claims abstract description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 42
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 26
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- -1 sulfur trioxide compound Chemical class 0.000 claims description 13
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 150000007530 organic bases Chemical group 0.000 claims description 6
- YYHPEVZFVMVUNJ-UHFFFAOYSA-N n,n-diethylethanamine;sulfur trioxide Chemical compound O=S(=O)=O.CCN(CC)CC YYHPEVZFVMVUNJ-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 239000000047 product Substances 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 229960004793 sucrose Drugs 0.000 description 42
- 239000008213 purified water Substances 0.000 description 22
- 238000001816 cooling Methods 0.000 description 21
- 238000010438 heat treatment Methods 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 14
- WEPNHBQBLCNOBB-FZJVNAOYSA-N sucrose octasulfate Chemical compound OS(=O)(=O)O[C@@H]1[C@H](OS(O)(=O)=O)[C@H](COS(=O)(=O)O)O[C@]1(COS(O)(=O)=O)O[C@@H]1[C@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@@H](COS(O)(=O)=O)O1 WEPNHBQBLCNOBB-FZJVNAOYSA-N 0.000 description 12
- 239000012535 impurity Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000002502 liposome Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- HNUGYESUXKUUPM-UHFFFAOYSA-A tetradecasodium heptasulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O HNUGYESUXKUUPM-UHFFFAOYSA-A 0.000 description 4
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 229960002166 vinorelbine tartrate Drugs 0.000 description 3
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 3
- WXOMTJVVIMOXJL-BOBFKVMVSA-A O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)OS(=O)(=O)OC[C@H]1O[C@@H](O[C@]2(COS(=O)(=O)O[Al](O)O)O[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@@H]2OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@@H]1OS(=O)(=O)O[Al](O)O Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)O.O[Al](O)OS(=O)(=O)OC[C@H]1O[C@@H](O[C@]2(COS(=O)(=O)O[Al](O)O)O[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@@H]2OS(=O)(=O)O[Al](O)O)[C@H](OS(=O)(=O)O[Al](O)O)[C@@H](OS(=O)(=O)O[Al](O)O)[C@@H]1OS(=O)(=O)O[Al](O)O WXOMTJVVIMOXJL-BOBFKVMVSA-A 0.000 description 2
- 238000005034 decoration Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 241001065310 Bignonia Species 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000010005 growth-factor like effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229960004291 sucralfate Drugs 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- CILBMBUYJCWATM-HGBQGYOLSA-N vinorelbine D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.OC(=O)[C@@H](O)[C@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-HGBQGYOLSA-N 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Abstract
The invention provides a method for synthesizing sucrose heptasulfate, belonging to the technical field of synthesis of sucrose heptasulfate. The preparation method comprises the following steps: carrying out a sulfation reaction on the compound of 2-O-sucrose fatty acid ester and sulfur trioxide under the action of a catalyst to obtain a reaction solution; removing a solvent layer in the reaction solution, adjusting the pH of the solution to salify through an inorganic alkaline aqueous solution, and separating out a solid; mixing the solid and an inorganic alkali aqueous solution, carrying out hydrolysis reaction, and filtering to obtain a 2-O-sucrose heptasulfate crude product; crystallizing the crude 2-O-sucrose heptasulfate in a solvent, and drying in vacuum to obtain the purified 2-O-sucrose heptasulfate. The preparation process disclosed by the invention is mild in reaction conditions, simple and convenient to operate, high in yield, high in purity and good in product appearance.
Description
Technical Field
The invention relates to the technical field of synthesis of sucrose heptasulfate, in particular to a method for synthesizing sucrose heptasulfate.
Background
The sucrose octasulfate has the structure of C 12 H 14 O 35 S 8 -R 8 The compound is applied to the medicine mainly for treating ulcer in early stage, a new variety is added in the liposome industry in 2015, and with the fact that irinotecan liposome (trade name) is marketed in the United states, sucrose sulfate serving as a novel auxiliary material enters the eye curtains which are in the same phase in the medicine world.
1. Auxiliary material used for loading medicine into liposome
The vinorelbine bitartrate liposome prepared by the one-sucrose octasulfate triethylamine gradient method such as the Chinese Bignonia in 2010 has higher encapsulation rate and the method is feasible. The vinorelbine tartrate liposome injection is prepared by adopting a pH gradient method, an ammonium sulfate gradient method and a sucrose octasulfate triethylamine (SOS-TEA) gradient method in the Wangmai sea and the like in 2014 and combining a PEG external introduction method, and the result shows that the vinorelbine tartrate liposome injection has remarkable advantages and low toxicity in the aspect of antitumor cell growth compared with the traditional vinorelbine tartrate injection.
2. Used as active medicine of similar growth factor
The mechanism of the antiulcer activity was studied by Xzhu et al in 1993, and it was found that the mechanism of action is similar to that of growth factor. In 2001, janF et al used it to alleviate acute radiation skin and head and neck cancer mucosal reactions after radiotherapy on head and neck cancer. The mechanism of action of sucrose octasulfate, a growth factor-like, was further studied by briankk. The chinese pharmacopoeia, 2020 edition, page 1623, contains sucralfate (aluminum sucrose octasulfate) as a treatment for gastric and duodenal ulcers. An ointment with antibacterial and anti-inflammatory effects is prepared from cane sugar octasulfate silver. In 2017, M Smits et al apply sucrose octasulfate as a gastric mucosa protectant for children in the treatment of gastroesophageal reflux disease.
Sucrose octasulfate can be decomposed under specific conditions in the process, and the structure of the generated impurities is shown as formula I
Wherein R can represent metal elements such as K, na and the like. In order to develop the process research and quality research of sucrose octasulfate and improve the quality controllability and safety of auxiliary materials, researchers need to obtain sufficient impurity reference substances. At present, no commercial reference substance is supplied, no foreign matter synthesis method is reported in domestic and foreign documents and patents, and the accuracy of qualitative and quantitative determination is poor by adopting a self-comparison method at present. In order to improve the quality of sucrose octasulfate and reduce clinical risks, the research and monitoring of impurities in sucrose octasulfate are required, and the content of the impurities in the sucrose octasulfate is strictly controlled, so that the urgent need is to provide a synthetic method which can quickly, simply and efficiently obtain a reference substance of the impurity I.
Disclosure of Invention
The invention aims to provide a method for synthesizing sucrose heptasulfate, which aims to solve the technical problem that the purity of sucrose octasulfate cannot be accurately controlled in the prior art.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a method for synthesizing sucrose heptasulfate, which comprises the following steps:
1) Carrying out a sulfation reaction on the compound of 2-O-sucrose fatty acid ester and sulfur trioxide under the action of a catalyst to obtain a reaction solution;
2) Removing a solvent layer in the reaction solution, adjusting the pH of the solution to salify through an inorganic alkaline aqueous solution, and separating out a solid;
3) Mixing the solid with an inorganic alkali aqueous solution, then carrying out hydrolysis reaction, and filtering to obtain a crude product of the 2-O-sucrose heptasulfate;
4) Crystallizing the crude 2-O-sucrose heptasulfate in a solvent, and drying in vacuum to obtain the purified 2-O-sucrose heptasulfate.
Further, in the step 1), the 2-O-sucrose fatty acid ester is one or more of 2-O-sucrose laurate, 2-O-sucrose myristate and 2-O-sucrose stearate; the sulfur trioxide complex comprises sulfur trioxide pyridine and/or sulfur trioxide triethylamine.
Further, in the step 1), the catalyst is an organic base, and the organic base contains one or more of triethylamine, pyridine, 2-methylpyridine and 2, 6-dimethylpyridine;
the mass ratio of the 2-O-sucrose fatty acid ester, the sulfur trioxide compound and the catalyst is 1:1 to 4:0.5 to 20.
Further, in the step 1), the sulfation reaction is carried out in an organic solvent, and the organic solvent comprises one or more of pyridine, 2-methylpyridine and 2, 6-dimethylpyridine; the volume-mass ratio of the organic solvent to the 2-O-sucrose fatty acid ester is 10-60 mL:1g of the total weight of the composition.
Further, in the step 1), the temperature of the sulfation reaction is 45-85 ℃, and the time of the sulfation reaction is 2-4 h.
Further, in the step 2) and the step 3), the inorganic alkaline aqueous solution independently comprises a potassium hydroxide aqueous solution and/or a sodium hydroxide aqueous solution; the volume concentration of the inorganic alkaline aqueous solution is independently 10-30%.
Further, in the step 2), the pH value of the solution is adjusted to 8-11 by the inorganic alkaline aqueous solution.
Further, in the step 3), the temperature of the hydrolysis reaction is 20-30 ℃, and the time of the hydrolysis reaction is 2-4 h; the filtration is carried out at 0 to 30 ℃.
Further, in the step 4), the solvent comprises at least two of water, absolute ethyl alcohol, absolute n-propyl alcohol, absolute isopropyl alcohol and absolute n-butyl alcohol, and the crystallization temperature is 0-30 ℃.
Further, the mass-volume ratio of the 2-O-sucrose fatty acid ester to the solvent in the step 4) is 1g:5 to 7mL.
The invention has the beneficial effects that:
the method has the advantages of short reaction route, low energy consumption, low production cost and simple operation, and is suitable for industrial production; the sucrose heptasulfate prepared by the invention has high purity and good appearance and shape, and can be used as an impurity reference substance for the quality research of sucrose octasulfate auxiliary materials and preparations.
Detailed Description
The invention provides a method for synthesizing sucrose heptasulfate, which comprises the following steps:
1) Carrying out a sulfation reaction on the compound of 2-O-sucrose fatty acid ester and sulfur trioxide under the action of a catalyst to obtain a reaction solution;
2) Removing a solvent layer in the reaction solution, adjusting the pH of the solution to salify through an inorganic alkaline aqueous solution, and separating out a solid;
3) Mixing the solid and an inorganic alkali aqueous solution, carrying out hydrolysis reaction, and filtering to obtain a 2-O-sucrose heptasulfate crude product;
4) Crystallizing the crude 2-O-sucrose heptasulfate in a solvent, and drying in vacuum to obtain the purified 2-O-sucrose heptasulfate.
In the present invention, in the step 1), the 2-O-sucrose fatty acid ester is one or more of 2-O-sucrose laurate, 2-O-sucrose myristate and 2-O-sucrose stearate, preferably 2-O-sucrose laurate and/or 2-O-sucrose myristate; the sulfur trioxide complex comprises sulfur trioxide pyridine and/or sulfur trioxide triethylamine, preferably sulfur trioxide triethylamine.
In the present invention, in the step 1), the catalyst is an organic base, and the organic base comprises one or more of triethylamine, pyridine, 2-methylpyridine and 2, 6-dimethylpyridine, preferably one or more of triethylamine, pyridine and 2-methylpyridine, and more preferably triethylamine.
In the invention, the mass ratio of the 2-O-sucrose fatty acid ester, the sulfur trioxide compound and the catalyst is 1:1 to 4:0.5 to 20, preferably 1:2 to 3:1 to 18, more preferably 1:2.5:5 to 15.
In the present invention, in the step 1), the sulfation reaction is performed in an organic solvent comprising one or more of pyridine, 2-picoline and 2, 6-lutidine, preferably pyridine and/or 2-picoline.
In the invention, the volume-mass ratio of the organic solvent to the 2-O-sucrose fatty acid ester is 10-60 mL:1g, preferably 20 to 50mL:1g, more preferably 30 to 40mL:1g.
In the invention, in the step 1), the temperature of the sulfation reaction is 45-85 ℃, preferably 50-70 ℃, and more preferably 60-65 ℃; the time of the sulfation reaction is 2 to 4 hours, and preferably 3 hours.
In the invention, the solid obtained in the step 2) is heated, dissolved and cleaned, added with absolute ethyl alcohol, cooled and crystallized, filtered at the temperature of 0-10 ℃, and then the obtained filtered solid is treated in the step 3).
In the present invention, in the step 2) and the step 3), the inorganic alkaline aqueous solution independently comprises a potassium hydroxide aqueous solution and/or a sodium hydroxide aqueous solution, preferably a potassium hydroxide aqueous solution; the volume concentration of the aqueous inorganic alkali solution is independently 10 to 30%, preferably 15 to 25%, and more preferably 20%.
In the present invention, in the step 2), the pH of the aqueous solution of an inorganic base is adjusted to 8 to 11, preferably 9 to 10, and more preferably 9.5.
In the present invention, in the step 3), the temperature of the hydrolysis reaction is 20 to 30 ℃, preferably 22 to 28 ℃, and more preferably 25 ℃; the time of the hydrolysis reaction is 2 to 4 hours, preferably 3 hours; the filtration is carried out at 0 to 30 ℃, preferably 0 to 20 ℃, and more preferably 0 to 10 ℃.
In the present invention, in the step 4), the solvent includes at least two of water, anhydrous ethanol, anhydrous n-propanol, anhydrous isopropanol and anhydrous n-butanol, preferably water and anhydrous ethanol; the crystallization temperature is 0 to 30 ℃, preferably 0 to 20 ℃, and more preferably 0 to 10 ℃.
In the invention, in the step 4), the crude product of the 2-O-sucrose heptasulfate is crystallized in a solvent, washed once by purified water at 0-10 ℃, and then dried in vacuum.
In the invention, the mass-volume ratio of the 2-O-sucrose fatty acid ester to the solvent in the step 4) is 1g:5 to 7mL, preferably 1g:6mL.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Adding 75.0g of sulfur trioxide pyridine into 1.2L of 2-methylpyridine, then adding 60g of triethylamine, finally adding 30.0g of 2-O-sucrose laurate, heating to 65 ℃ under the protection of nitrogen, reacting for 3h, pouring out supernatant, adding 150mL of purified water, stirring, adding 20% potassium hydroxide aqueous solution, adjusting the pH to 10, separating out solid, heating to dissolve, dropwise adding 30mL of absolute ethyl alcohol, cooling and crystallizing, filtering at 5 ℃, adding 30mL of 20% potassium hydroxide aqueous solution into a filter cake at room temperature, reacting for 2h, cooling and crystallizing, and filtering at 5 ℃ to obtain a crude product of 2-O-sucrose heptasulfate potassium.
Dissolving the crude product in 90mL of purified water, heating to dissolve the crude product, adding 90mL of absolute ethyl alcohol, cooling and crystallizing, filtering at 5 ℃, washing a filter cake once with a small amount of purified water at 5 ℃, and drying a wet product in vacuum to obtain 22.3g of 2-O-sucrose heptasulfate potassium white solid with the purity of 97 percent and the yield of 33 percent.
Example 2
Adding 73.0g of triethylamine trioxide into 1.2L2, 6-dimethylpyridine, then adding 60g of pyridine, finally adding 30.0g of 2-O-sucrose myristate, heating to 65 ℃ under the protection of nitrogen, reacting for 2h, pouring out to remove supernatant, adding 150mL of purified water, stirring, adding 20% sodium hydroxide aqueous solution, adjusting the pH to 8, precipitating solid, heating to dissolve, dropwise adding 30mL of anhydrous ethanol, cooling and crystallizing, filtering at 0 ℃, adding 30mL of 20% sodium hydroxide aqueous solution into a filter cake at room temperature, reacting for 3h, cooling and crystallizing, and filtering at 0 ℃ to obtain a crude product of 2-O-sucrose heptasulfate sodium.
Dissolving the crude product in 90mL of purified water, heating to dissolve the crude product, adding 90mL of absolute ethyl alcohol, cooling and crystallizing, filtering at 0 ℃, washing a filter cake once with a small amount of purified water at 0 ℃, and drying a wet product in vacuum to obtain 21.6g of 2-O-sucrose sodium heptasulfate white solid with the purity of 97 percent and the yield of 50 percent.
Example 3
Adding 75.0g of pyridine trioxide into 1.2L of pyridine, then adding 60g of 2, 6-dimethylpyridine, finally adding 30.0g of 2-O-sucrose stearate, heating to 65 ℃ under the protection of nitrogen, reacting for 4h, pouring out to remove supernatant, adding 150mL of purified water, stirring, adding 20% sodium hydroxide aqueous solution, adjusting the pH to 10, precipitating solid, heating to dissolve, dropwise adding 30mL of anhydrous ethanol, cooling and crystallizing, filtering at 10 ℃, adding 30mL of 20% sodium hydroxide aqueous solution into a filter cake at room temperature, reacting for 2h, cooling and crystallizing, and filtering at 10 ℃ to obtain a crude product of 2-O-sucrose heptasulfate sodium.
Dissolving the crude product in 90mL of purified water, heating to dissolve the crude product, adding 90mL of absolute ethyl alcohol, cooling and crystallizing, filtering at 10 ℃, washing a filter cake once with a small amount of purified water at 10 ℃, and drying a wet product in vacuum to obtain 17.3g of 2-O-sucrose sodium heptasulfate white solid with the purity of 97 percent and the yield of 40 percent.
Example 4
Adding 75.0g of sulfur trioxide pyridine into 1.2L of pyridine, then adding 60g of 2-methylpyridine, finally adding 30.0g of 2-O-sucrose laurate, heating to 70 ℃ under the protection of nitrogen, reacting for 2h, pouring out supernatant, adding 150mL of purified water, stirring, adding 20% potassium hydroxide aqueous solution, adjusting pH to 9, precipitating solid, heating to dissolve, dropwise adding 30mL of absolute ethyl alcohol, cooling and crystallizing, filtering at 3 ℃, adding 30mL of 20% potassium hydroxide aqueous solution into a filter cake at room temperature, reacting for 2h, cooling and crystallizing, and filtering at 3 ℃ to obtain a crude product of 2-O-sucrose heptasulfate potassium.
Dissolving the crude product in 90mL of purified water, heating to dissolve the crude product, adding 90mL of absolute ethyl alcohol, cooling for crystallization, filtering at 3 ℃, washing a filter cake once with a small amount of purified water at 3 ℃, and drying a wet product in vacuum to obtain 28.3g of 2-O-sucrose heptasulfate potassium white solid with the purity of 97 percent and the yield of 42 percent
Example 5
Adding 75.0g of sulfur trioxide pyridine into 1.2L of pyridine, then adding 60g of 2-methylpyridine, finally adding 30.0g of 2-O-sucrose laurate, heating to 65 ℃ under the protection of nitrogen, reacting for 2h, pouring to remove supernatant, adding 150mL of purified water, stirring, adding 20% potassium hydroxide aqueous solution to adjust the pH value to 11, separating out solid, heating to dissolve, dropwise adding 30mL of absolute ethanol, cooling and crystallizing, filtering at 6 ℃, adding 30mL of 20% potassium hydroxide aqueous solution into filter cakes at room temperature, reacting for 3h, cooling and crystallizing, and filtering at 6 ℃ to obtain a crude product of 2-O-sucrose heptasulfate potassium.
Dissolving the crude product in 90mL of purified water, heating to dissolve the crude product, adding 90mL of anhydrous n-propanol, cooling for crystallization, filtering at 6 ℃, washing a filter cake once with a small amount of purified water at 6 ℃, and drying a wet product in vacuum to obtain 30.2g of 2-O-sucrose heptasulfate potassium white solid with the purity of 97 percent and the yield of 44 percent.
Example 6
Adding 75.0g of sulfur trioxide pyridine into 1.2L of pyridine, then adding 60g of 2-methylpyridine, finally adding 30.0g of 2-O-sucrose laurate, heating to 60 ℃ under the protection of nitrogen, reacting for 4h, pouring to remove supernatant, adding 150mL of purified water, stirring, adding 20% potassium hydroxide aqueous solution to adjust the pH value to 10, separating out solid, heating to dissolve, dropwise adding 30mL of absolute ethanol, cooling to crystallize, filtering at 5 ℃, adding 30mL of 20% potassium hydroxide aqueous solution to a filter cake at room temperature, reacting for 2h, cooling to crystallize, and filtering at 5 ℃ to obtain a crude product of 2-O-sucrose heptasulfate potassium.
Dissolving the crude product in 90mL of purified water, heating to dissolve the crude product, adding 90mL of anhydrous isopropanol, cooling for crystallization, filtering at 5 ℃, washing a filter cake once with a small amount of purified water at 5 ℃, and drying a wet product in vacuum to obtain 29.5g of 2-O-sucrose heptasulfate potassium white solid with the purity of 97 percent and the yield of 44 percent.
Example 7
Adding 75.0g of sulfur trioxide pyridine into 1.2L2-methylpyridine, then adding 60g of 2-methylpyridine, finally adding 30.0g of 2-O-sucrose laurate, heating to 65 ℃ under the protection of nitrogen, reacting for 2h, pouring out and removing supernatant, adding 150mL of purified water, stirring, adding 20% potassium hydroxide aqueous solution to adjust the pH to 8, separating out solid, heating to dissolve, dropwise adding 30mL of anhydrous ethanol, cooling and crystallizing, filtering at 0 ℃, adding 30mL of 20% potassium hydroxide aqueous solution into a filter cake at room temperature, reacting for 2h, cooling and crystallizing, and filtering at 0 ℃ to obtain a crude product of 2-O-sucrose heptasulfate potassium.
Dissolving the crude product in 90mL of purified water, heating to dissolve the crude product, adding 90mL of anhydrous n-butyl alcohol, cooling and crystallizing, filtering at 0 ℃, washing a filter cake once with a small amount of purified water at 0 ℃, and drying a wet product in vacuum to obtain 26.4g of 2-O-sucrose heptasulfate potassium white solid with the purity of 97 percent and the yield of 39 percent.
From the above examples, the present invention provides a method for synthesizing sucrose heptasulfate. The sucrose heptasulfate prepared by the invention has high purity and good appearance and shape, and can be used as an impurity reference substance for the quality research of sucrose octasulfate auxiliary materials and preparations.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A method for synthesizing sucrose heptasulfate is characterized by comprising the following steps:
1) Carrying out a sulfation reaction on the compound of 2-O-sucrose fatty acid ester and sulfur trioxide under the action of a catalyst to obtain a reaction solution;
2) Removing a solvent layer in the reaction solution, adjusting the pH of the solution to salify through an inorganic alkaline aqueous solution, and separating out a solid;
3) Mixing the solid and an inorganic alkali aqueous solution, carrying out hydrolysis reaction, and filtering to obtain a 2-O-sucrose heptasulfate crude product;
4) Crystallizing the crude 2-O-sucrose heptasulfate in a solvent, and drying in vacuum to obtain the purified 2-O-sucrose heptasulfate.
2. The synthesis method according to claim 1, wherein in the step 1), the 2-O-sucrose fatty acid ester is one or more of 2-O-sucrose laurate, 2-O-sucrose myristate and 2-O-sucrose stearate; the sulfur trioxide complex comprises sulfur trioxide pyridine and/or sulfur trioxide triethylamine.
3. The synthesis method according to claim 1 or 2, wherein in the step 1), the catalyst is an organic base, and the organic base comprises one or more of triethylamine, pyridine, 2-methylpyridine and 2, 6-dimethylpyridine;
the mass ratio of the 2-O-sucrose fatty acid ester, the sulfur trioxide compound and the catalyst is 1:1 to 4:0.5 to 20.
4. The synthesis method according to claim 3, wherein in the step 1), the sulfation reaction is carried out in an organic solvent, and the organic solvent comprises one or more of pyridine, 2-methylpyridine and 2, 6-dimethylpyridine; the volume mass ratio of the organic solvent to the 2-O-sucrose fatty acid ester is 10-60 mL:1g.
5. The synthesis method according to claim 1, 2 or 4, wherein in the step 1), the temperature of the sulfation reaction is 45-85 ℃, and the time of the sulfation reaction is 2-4 h.
6. The synthesis method according to claim 1 or 4, wherein in the step 2) and the step 3), the inorganic base aqueous solution independently comprises a potassium hydroxide aqueous solution and/or a sodium hydroxide aqueous solution; the volume concentration of the inorganic alkaline water solution is independently 10-30%.
7. The synthesis method according to claim 6, wherein in the step 2), the pH of the solution is adjusted to 8 to 11 by using an aqueous solution of an inorganic base.
8. The synthesis method according to claim 1 or 7, wherein in the step 3), the temperature of the hydrolysis reaction is 20-30 ℃, and the time of the hydrolysis reaction is 2-4 h; the filtration is carried out at 0 to 30 ℃.
9. The synthesis method according to claim 8, wherein in the step 4), the solvent comprises at least two of water, anhydrous ethanol, anhydrous n-propanol, anhydrous isopropanol and anhydrous n-butanol, and the crystallization temperature is 0-30 ℃.
10. The synthesis method of claim 9, wherein the mass-to-volume ratio of the 2-O-sucrose fatty acid ester to the solvent in step 4) is 1g:5 to 7mL.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07196702A (en) * | 1993-12-28 | 1995-08-01 | Shin Etsu Chem Co Ltd | Production of polysaccharide sulfate salt |
| WO2003038054A2 (en) * | 2001-10-31 | 2003-05-08 | New York University | Structure-based design and synthesis of fgf inhibitors and fgf modulator compounds |
| 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 |
| CN110741012A (en) * | 2017-04-14 | 2020-01-31 | 韩国普莱姆制药株式会社 | Synthesis method of sucralfate and sucralfate prepared by method |
| CN110981922A (en) * | 2019-12-17 | 2020-04-10 | 安徽赛诺制药有限公司 | Preparation method of sucrose octasulfonate potassium |
| CN114437149A (en) * | 2020-11-03 | 2022-05-06 | 江苏开元药业有限公司 | Preparation method of key intermediate calcium salt of pharmaceutic adjuvant salt |
| CN114436858A (en) * | 2020-11-03 | 2022-05-06 | 江苏开元药业有限公司 | Preparation method of triethylamine salt of pharmaceutic adjuvant |
| CN114437148A (en) * | 2020-11-03 | 2022-05-06 | 江苏开元药业有限公司 | Preparation method of sodium salt or potassium salt of pharmaceutic adjuvant |
-
2022
- 2022-12-19 CN CN202211632835.XA patent/CN115974938A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07196702A (en) * | 1993-12-28 | 1995-08-01 | Shin Etsu Chem Co Ltd | Production of polysaccharide sulfate salt |
| WO2003038054A2 (en) * | 2001-10-31 | 2003-05-08 | New York University | Structure-based design and synthesis of fgf inhibitors and fgf modulator compounds |
| 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 |
| CN110741012A (en) * | 2017-04-14 | 2020-01-31 | 韩国普莱姆制药株式会社 | Synthesis method of sucralfate and sucralfate prepared by method |
| 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 |
| CN110981922A (en) * | 2019-12-17 | 2020-04-10 | 安徽赛诺制药有限公司 | Preparation method of sucrose octasulfonate potassium |
| CN114437149A (en) * | 2020-11-03 | 2022-05-06 | 江苏开元药业有限公司 | Preparation method of key intermediate calcium salt of pharmaceutic adjuvant salt |
| CN114436858A (en) * | 2020-11-03 | 2022-05-06 | 江苏开元药业有限公司 | Preparation method of triethylamine salt of pharmaceutic adjuvant |
| CN114437148A (en) * | 2020-11-03 | 2022-05-06 | 江苏开元药业有限公司 | Preparation method of sodium salt or potassium salt of pharmaceutic adjuvant |
Non-Patent Citations (1)
| Title |
|---|
| POLAT, T ET AL.: "Synthesis of sulfosucrose derivatives for evaluation as regulators of fibroblast growth factor activity", TETRAHEDRON LETTERS, vol. 43, no. 45, 4 November 2002 (2002-11-04), pages 8047 - 8049, XP004387185, DOI: 10.1016/S0040-4039(02)01969-X * |
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