CN114437146B - Production process of sucralose-6-acetate - Google Patents
Production process of sucralose-6-acetate Download PDFInfo
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- CN114437146B CN114437146B CN202210020727.0A CN202210020727A CN114437146B CN 114437146 B CN114437146 B CN 114437146B CN 202210020727 A CN202210020727 A CN 202210020727A CN 114437146 B CN114437146 B CN 114437146B
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- acetate
- sucrose
- acetic acid
- sucralose
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- FACOTAQCKSDLDE-YKEUTPDRSA-N [(2R,3R,4R,5R,6R)-6-[(2R,3S,4S,5S)-2,5-bis(chloromethyl)-3,4-dihydroxyoxolan-2-yl]oxy-3-chloro-4,5-dihydroxyoxan-2-yl]methyl acetate Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](COC(=O)C)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 FACOTAQCKSDLDE-YKEUTPDRSA-N 0.000 title claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 title abstract description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 160
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 71
- 229960000583 acetic acid Drugs 0.000 claims abstract description 62
- 229930006000 Sucrose Natural products 0.000 claims abstract description 39
- 239000005720 sucrose Substances 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 37
- 239000000843 powder Substances 0.000 claims abstract description 37
- 239000000243 solution Substances 0.000 claims abstract description 35
- 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 abstract description 28
- 239000003960 organic solvent Substances 0.000 claims abstract description 28
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 22
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 20
- 239000011259 mixed solution Substances 0.000 claims abstract description 17
- 150000001412 amines Chemical class 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 13
- 238000005406 washing Methods 0.000 claims abstract description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000003756 stirring Methods 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 21
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 17
- 239000013078 crystal Substances 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 15
- -1 N-dimethylethylamine Natural products 0.000 claims description 14
- 230000021736 acetylation Effects 0.000 claims description 14
- 238000006640 acetylation reaction Methods 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- 238000001291 vacuum drying Methods 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 5
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 3
- 238000002390 rotary evaporation Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- SPVVMXMTSODFPU-UHFFFAOYSA-N 3-methyl-n-(3-methylbutyl)butan-1-amine Chemical compound CC(C)CCNCCC(C)C SPVVMXMTSODFPU-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 238000004821 distillation Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 239000004376 Sucralose Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 4
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 abstract description 4
- 235000019408 sucralose Nutrition 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 2
- 230000002411 adverse Effects 0.000 abstract 1
- 230000005496 eutectics Effects 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 22
- 238000000926 separation method Methods 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 238000004321 preservation Methods 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 11
- 239000012141 concentrate Substances 0.000 description 9
- 239000005457 ice water Substances 0.000 description 8
- ZHBXLZQQVCDGPA-UHFFFAOYSA-N 5-[(1,3-dioxo-2-benzofuran-5-yl)sulfonyl]-2-benzofuran-1,3-dione Chemical compound C1=C2C(=O)OC(=O)C2=CC(S(=O)(=O)C=2C=C3C(=O)OC(C3=CC=2)=O)=C1 ZHBXLZQQVCDGPA-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000010413 mother solution Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000000105 evaporative light scattering detection Methods 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002288 cocrystallisation Methods 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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- 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)
- Saccharide Compounds (AREA)
Abstract
The invention provides a sucralose-6-acetate production process which comprises the following steps: adding glacial acetic acid and a first organic solvent mixed solution into the sucrose acetate concentrated solution obtained by primary distillation to obtain white eutectic powder of sucrose-6-acetate and acetic acid; uniformly dispersing the cocrystal in a second organic solvent, adding organic amine for treatment, enabling the cocrystal to react with acetic acid to form a stable chemical bond, extracting acetic acid from a cocrystal skeleton, washing residual organic amine and formed acetic acid-organic amine conjugate by using the second organic solvent, and drying completely to obtain sucrose-6-acetate powder with the concentration of more than 99.8%; the powder is dissolved in N, N-dimethylformamide solution, is applied to the next regional selective chlorination reaction, eliminates the adverse effect of impurities on the chlorination reaction process, improves the chlorination yield, simplifies the purification process of sucralose-6-acetate, improves the product quality of the final sucralose, and has better industrial value.
Description
Technical Field
The invention relates to the field of sucrose-6-acetate crystallization separation in chemical separation technology, in particular to a high-selectivity separation method for molecular identification of sucrose-6-acetate based on supermolecular chemistry technology, belonging to the improvement of efficient production technology of sucralose-6-acetate.
Background
Sucralose is an excellent non-nutritive sweetener, has the advantages of high sweetness, good stability, high safety and the like, is approved by more than 120 countries for use, and is applied to various foods, health care products, medical treatment and daily chemical products. The sucralose is produced by taking sucrose as a raw material and carrying out three steps of acylation, chlorination and deacylation. Among them, the preparation of sucralose-6-acetate by regional chlorination of the acylation product sucrose-6-acetate is the most critical step in the whole production process, and is considered as the most complex and difficult-to-control loop due to the problems of more byproducts, poor separation efficiency, low synthesis yield and the like.
In the prior art, the synthesized sucrose acetylation solution is generally directly used for the subsequent selective chlorination reaction, but the synthesis yield of the sucralose-6-acetate can be directly influenced due to the higher acetic acid content synthesized by the dibutyl tin oxide method. Therefore, N-dimethylformamide is often used for reducing the acetic acid value of an acylated solution by multi-step distillation, but long-time distillation not only has high energy consumption, but also can reduce the content of sucrose-6-acetate, and the N, N-dimethylformamide and acetic acid can form the highest azeotrope, so that the post-treatment is complex. In addition to this, the acylating solution contains various sucrose acetates having similar structural properties to sucrose-6-acetate, and such a complicated composition is one of the important causes of low production efficiency.
Sucrose-6-acetate is a compound with biodegradable and nontoxic properties, and is used as an important chemical raw material and an important intermediate for synthesizing nonionic surfactant and sucrose-based polymer. Thus, the acquisition of sucrose-6-acetate, a single composition of the acylated product, is of great significance for the production of sucralose and other value-added products.
Among the sucrose-6-acetate separation and purification methods reported so far, the ion exchange method disclosed in US 7626016 requires a large amount of solvent and the ion exchange resin treatment is troublesome; the column chromatography disclosed in CN 103288891 has the advantages of large solvent amount, small yield, complex operation and extremely high cost; the dichloromethane detrusion method disclosed in US 20110168568 is poor in selectivity; and the recrystallization methods disclosed in CN 103319548, CN 106946956, US 20070227897, US 7932380, US 4889928 and US 2011168568 have relatively large product losses; moreover, the purity of the sucrose-6-acetate obtained by the methods is low and is mostly between 85 and 96%, so that the method is not suitable for large-scale industrialization.
Disclosure of Invention
The invention aims to solve the existing technical bottleneck, and provides a high-efficiency separation method of sucrose-6-acetate, wherein sucrose-6-acetate can be separated from an acetylation solution with high selectivity under the condition that the physical and chemical properties of all the components are extremely similar, and the sucrose-6-acetate with reagent grade purity is used for selective chlorination so as to reduce the production cost and improve the synthesis yield of sucralose-6-acetate.
In order to achieve the above object, the technical scheme of the present invention is as follows:
the sucralose-6-acetate production process comprises the following steps:
the first step: and adding a mixed solution of glacial acetic acid and a first organic solvent into the concentrated sucrose acetate solution at 15-45 ℃, stirring, carrying out suction filtration on the precipitated white crystals, washing with glacial acetic acid to remove residual mother solution, and carrying out vacuum drying at 60-80 ℃ until the residual mother solution is completely removed, thus obtaining white powder with stable properties.
And a second step of: uniformly dispersing the white powder in a second organic solvent at 15-35 ℃, adding organic amine with the molar content of 1-10 times of acetic acid into the second organic solvent at the dosage ratio of per gram of solid per 5-50 ml of solvent, filtering after the reaction is finished, washing the second organic solvent to remove the residual organic amine and acetic acid-organic amine conjugate, and drying in vacuum at 30-50 ℃ until the mixture is completely dried to obtain the sucrose-6-acetate powder with high purity.
And a third step of: and dissolving the high-purity sucrose-6-acetate powder into an N, N-dimethylformamide solution, wherein the molar ratio of the sucrose-6-acetate to the N, N-dimethylformamide is 1:7-1:11, and carrying out regioselective chlorination by using thionyl chloride to finally obtain the sucralose-6-acetate synthetic solution.
The concentrated solution of the sucrose acetate in the first step is prepared by rotary evaporation of sucrose acetylation synthetic solution under the conditions of-0.01-0.2 MPa, 30-80 ℃ and 50-150 r/min, and removing more than 80% of volatile organic solvent, wherein the specific composition of the concentrated solution comprises sucrose-6-acetate, sucrose-2-acetate, sucrose-3-acetate, sucrose-2, 6-acetate, sucrose-3, 6-acetate, sucrose-4, 6-acetate, sucrose-1 ', 6-acetate, sucrose-6', 6-acetate, N-dimethylformamide and difficultly removed acetic acid, the solid content of the sucrose-6-acetate is 10% -96%, and the actual content of the acetic acid is 1% -10%. The sucrose acetylation synthetic liquid is synthetic liquid obtained by the reaction of a sucrose 6-position hydroxyl selective acetylation method, and the sucrose 6-position hydroxyl selective acetylation method is a dibutyl tin oxide method.
The method for producing the sucrose acetylation synthetic liquid by the dibutyl tin oxide method comprises the following specific steps: adding a catalyst 1, 3-bis (acetoxyl) -1, 3-tetrabutyl distannoxane (DSDA) into the N, N-dimethylformamide solution of sucrose, carrying out reduced pressure distillation at 80-90 ℃ to continuously take out water generated by the reaction until any liquid cannot be evaporated, adding a certain amount of N, N-dimethylformamide, cooling to low temperature, dropwise adding acetic anhydride, stirring for 3-6 h, and then adding deionized quenching. Finally, DSDA in the reaction liquid is recovered by cyclohexane extraction, and the sucrose acetylation synthesis liquid is obtained.
The invention uses glacial acetic acid as a co-crystallization solvent, can be well inlaid in a framework cavity formed by sucrose-6-acetate as a small molecule object, and has excellent specific recognition effect. The glacial acetic acid and the first organic solvent are mixed for use in the first step, which is helpful for improving crystallization efficiency. However, the specific type and amount of the first organic solvent will affect the crystallization rate and the final yield, and the crystallization rate and the final yield can be improved by using a suitable solvent combination. The first organic solvent is a poorly soluble or slightly soluble organic solvent of sucrose-6-acetate.
Preferably, the first organic solvent in the first step is at least one of ethyl acetate, methyl acetate, acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, n-butanol, tert-butanol, isopropanol and ethanol.
Preferably, the mass ratio of the sucrose acetate concentrated solution to the glacial acetic acid in the first step is 1:1-1:6.
Preferably, the mass ratio of the glacial acetic acid and the first organic solvent mixed solution in the first step is 3:1-3:3.
Preferably, the stirring time in the first step is 20-120 min.
Because the sucrose-6-acetate and the acetic acid have strong hydrogen bonding effect, the organic amine and the acetic acid are reacted to form a stable chemical bond, so that the organic amine-acetic acid compound has stronger acting force, and the acetic acid can be extracted from the cavity of the sucrose-6-acetate skeleton without damaging the sucrose-6-acetate skeleton structure. The second organic solvent type and amount, and the organic amine type and amount, described in the second step, all result in a difference in alkalinity per unit volume, thereby significantly affecting the re-isolation process.
Preferably, the second organic solvent of the second step is at least one of dichloromethane, chloroform, carbon tetrachloride, 1-dichloroethane, 1, 2-dichloroethane, 1-trichloroethane and 1, 2-trichloroethane.
Preferably, the second organic solvent is used in an amount of 5 to 50ml of the second organic solvent per gram of the white powder obtained in the first step.
Preferably, the organic amine in the second step is at least one of dimethylamine, diethylamine, diisopropylamine, diisobutylamine, diisopentylamine, trimethylamine, N-dimethylethylamine, triethylamine, N-diisopropylmethylamine or N, N-diisopropylethylamine or tripropylamine.
Preferably, the molar ratio of the organic amine used in the second step to acetic acid is 1:1-10:1.
Preferably, the reaction time of the second step is 0.1-5 h.
It should be noted that the white powder obtained from the first step in the second step means that the molar ratio is about 1:1, wherein the actual content of sucrose-6-acetate is 86-87%, and the actual content of acetic acid is 13-14%, and the complete removal of acetic acid wrapped inside can be ensured only by controlling the actual content of sucrose-6-acetate and acetic acid under a certain particle size. The sucrose-6-acetate powder of high purity obtained from the second step in the third step means that the sucrose-6-acetate actual content exceeds 99.8% and the acetic acid actual content is less than 0.05%.
It should be noted that the first step described using glacial acetic acid to wash the precipitated crystals has only a small loss of sucrose-6-acetate. The second organic solvent in the second step is an insoluble organic solvent for sucrose-6-acetate, and the sucrose-6-acetate is hardly lost in the second step.
The specific steps of the third step of 'using thionyl chloride for regioselective chlorination' are as follows: slowly dropwise adding an N, N-dimethylformamide solution of sucrose-6-acetate into a mixed solution of 1, 2-trichloroethane and thionyl chloride at the temperature of-5 ℃, wherein the volume ratio of 1, 2-trichloroethane to thionyl chloride is 3:1-4:1; the volume ratio of the N, N-dimethylformamide solution of the sucrose-6-acetate to the mixed solution of the 1, 2-trichloroethane and the thionyl chloride is 1:2-1:3; heating to 20-35 ℃ and stirring for 0.5-1 h, heating to 70-85 ℃ at 1-2 ℃/min for reacting for 1-1.5 h, heating to 90-100 ℃ at 0.5-1 ℃/min for reacting for 1-1.5 h, and heating to 105-115 ℃ at 0.1-0.3 ℃/min for reflux reacting for 1-2 h; cooling to-5 ℃, adjusting the pH to 9-10 with alkali liquor (ammonia water), adjusting the pH to be neutral with hydrochloric acid after 5-30 min, and obtaining the sucralose-6-acetate synthetic solution.
Compared with the prior art, the invention has the advantages and outstanding effects that:
(1) The method has the characteristics of high selectivity, no energy consumption, high yield, high speed and the like in the process of separating the sucrose-6-acetate, the whole process is carried out at normal temperature, the yield of the sucrose-6-acetate and acetic acid in the first step is more than 90 percent in the co-crystallization process, the yield of the sucrose-6-acetate and acetic acid in the second step is more than 99.8 percent in the re-separation process, and the content of the sucrose-6-acetate in the white powder is more than 99.8 percent. The whole process has mild condition, low equipment requirement in industrial production and convenient operation, and is suitable for large-scale industrialization.
(2) Based on the high acetic acid content of the self-acyl synthesis liquid, after a certain amount of glacial acetic acid is added to a concentration suitable for co-crystallization, the co-crystal is precisely formed with sucrose-6-acetate, and the selective identification capability of various similar sucrose acetate is remarkably improved. The sucrose-6-acetate powder obtained not only has an extremely high content but also contains almost no acetic acid. The method skillfully couples the sucrose-6-acetate separation and acetic acid removal processes, and perfectly solves the problems that acetic acid is difficult to remove and sucrose-6-acetate is difficult to purify. Compared with the multi-step distillation treatment of N, N-dimethylformamide, the method has lower acid content, reduces complicated steps and high energy loss, and has better industrial value.
(3) When the reagent grade sucrose-6-acetate powder obtained by the separation method is used for the next reaction, the production cost can be reduced by more than 10 percent, the consumption of chlorinated reagent and solvent, the energy consumption in the reaction process and the subsequent separation difficulty of the sucralose-6-acetate can be reduced, and the synthesis yield of the sucralose-6-acetate can be improved.
Drawings
FIG. 1 is a route diagram of the sucralose-6-acetate production process of the present invention;
FIG. 2 is a HPLC-ELSD chromatogram before and after selective crystallization separation of sucrose-6-acetate;
FIG. 3 is sucrose-6-acetate 1 H NMR spectrum;
FIG. 4 is sucrose-6-acetate 13 C NMR spectrum;
FIG. 5 is a sucrose-6-acetate/acetate ORTEP plot;
FIG. 6 is a graph of hydrogen bonding in sucrose-6-acetate/acetic acid crystals, symmetry codes: a is 1+X, +Y, +Z, B is-X, 0.5+Y, -Z, C is-1+X, +Y, +Z;
FIG. 7 is a sucrose-6-acetate/acetic acid unit cell stacking diagram along the a-axis;
FIG. 8 is a FT-IR chart of sucrose-6-acetate/acetic acid co-crystal acetic acid before and after removal of a-acetic acid; b-sucrose-6-acetate; c-sucrose-6-acetate/acetic acid;
FIG. 9 is an XRD pattern of sucrose-6-acetate/acetic acid co-crystal before and after acetic acid removal, a-sucrose-6-acetate/acetic acid; b-sucrose-6-acetate; c-sucrose-6-acetate/acetic acid single crystal data simulation;
FIG. 10 is an SEM image of sucrose-6-acetate/acetic acid co-crystal before and after acetic acid removal, with sucrose-6-acetate/acetic acid co-crystal on the left and sucrose-6-acetate on the right.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1
First, 100g of dibutyltin oxide was heated to 85℃and 26g of acetic anhydride was added dropwise, and the resulting mixture was stirred for 4 hours. After that, the mixture was mixed with cyclohexane, and distilled to dryness in vacuo to remove excess acetic anhydride, thereby obtaining 1, 3-bis (acetoxy) -1, 3-tetrabutyldistannoxane (DSDA) as a catalyst. Next, the prepared DSDA and 68.5g of sucrose were completely dissolved in 720mL of N, N-dimethylformamide, and the moisture generated by the reaction was continuously taken out by distillation under reduced pressure at 85℃until any liquid was not distilled out (about 2 hours). Then it was cooled to 0 ℃, a certain amount of N, N-dimethylformamide was added and 30.5g of acetic anhydride was added dropwise, and stirred for 3 hours to ensure complete conversion of sucrose. Deionized water was then added to the mixture to terminate the reaction. Finally, the DSDA was extracted with cyclohexane to be completely free of DSDA. To obtain the sucrose acetylation synthetic liquid.
And (3) rotary evaporating for 3 hours at 60 ℃ and 100r/min under the pressure of minus 0.1MPa, and removing more than 80% of volatile organic solvent to obtain sucrose ester concentrated solution. The N, N-dimethylformamide and acetic acid content were determined by HPLC-PDA method, and the sucrose-6-acetate and other sucrose acetate content were determined by HPLC-ELSD method, and the results are shown in tables 1 and 2.
Example 2
200g of sucrose ester concentrate in example 1 is taken, 150ml of N, N-dimethylformamide is added, the mixture is completely mixed, the mixture is subjected to rotary evaporation for 2 hours at the temperature of 60 ℃ below zero and the pressure of 100r/min, more than 80% of volatile organic solvent is removed, and the operation is repeated for 2 times to obtain refined sucrose ester concentrate. The N, N-dimethylformamide and acetic acid content were determined by HPLC-PDA method, and the sucrose-6-acetate and other sucrose acetate content were determined by HPLC-ELSD method, and the results are shown in tables 1 and 2.
Example 3
Taking 50g of sucrose ester concentrate in example 1, adding a mixed solution of 150g of glacial acetic acid and 50g of n-butanol at normal temperature, mechanically stirring at a stirring speed of 1000r/min, immediately precipitating crystals, stopping stirring after 60min, performing suction filtration to obtain a pale yellow solid, washing with glacial acetic acid to remove residual mother solution, and vacuum drying at 60 ℃ until the solution is completely dried to finally obtain white powder with stable properties. The white powder was uniformly dispersed in 250ml of 1, 2-dichloroethane, 30g of diisopropylamine was added, stirred for 1 hour, suction filtration was performed, the solid was washed with 1, 2-dichloroethane for 2-3 times to remove the residue, and vacuum drying was performed at 40 ℃ until completion, to finally obtain sucrose-6-acetate powder having a purity of 99.61% with a yield of 87.2%.
Example 4
Taking 50g of sucrose ester concentrate in example 1, adding a mixed solution of 150g of glacial acetic acid and 60g of ethyl acetate at normal temperature, mechanically stirring at a stirring speed of 1000r/min, immediately precipitating crystals, stopping stirring after 40min, performing suction filtration to obtain a pale yellow solid, washing with glacial acetic acid to remove residual mother solution, and vacuum drying at 60 ℃ until the solution is completely dried to finally obtain white powder with stable properties. The white powder was uniformly dispersed in 300ml of methylene chloride, 40g of tripropylamine was added, stirred for 5 hours, suction filtration was performed, the residue was removed by washing the solid with methylene chloride 2-3 times, and vacuum drying was performed at 40 ℃ until completion, finally obtaining sucrose-6-acetate powder with a purity of 98.73%, with a yield of 95.1%.
Example 5
Taking 50g of sucrose ester concentrate in example 1, adding a mixed solution of 100g of glacial acetic acid and 30g of tertiary butanol at normal temperature, mechanically stirring at a stirring speed of 1000r/min, immediately precipitating crystals, stopping stirring after 80min, performing suction filtration to obtain a pale yellow solid, washing with glacial acetic acid to remove residual mother solution, and vacuum drying at 60 ℃ until the solution is completely dried to finally obtain white powder with stable properties. The white powder was uniformly dispersed in 300ml of 1, 2-dichloroethane, 40g of N, N-diisopropylethylamine was added, stirred for 1 hour, suction filtration was performed, the solid was washed with 1, 2-trichloroethane 2-3 times to remove the residue, and vacuum drying was performed at 50℃until completion, whereby sucrose-6-acetate powder having a purity of 99.69% was finally obtained, with a yield of 82.1%.
Example 6
Taking 50g of sucrose ester concentrate in example 1, adding 150g of glacial acetic acid and 40g of tetrahydrofuran mixed solution at normal temperature, mechanically stirring at a stirring speed of 1000r/min, immediately precipitating crystals, stopping stirring after 100min, performing suction filtration to obtain a light yellow solid, washing with glacial acetic acid to remove residual mother solution, and vacuum drying at 60 ℃ until the mixture is complete to finally obtain white powder with stable properties. The white powder was uniformly dispersed in 250ml of dichloromethane, 30g of triethylamine was added, stirred for 0.5h, suction filtration was performed, the residue was removed by washing the solid with dichloromethane 2 to 3 times, and vacuum drying was performed at 40 ℃ until completion, finally sucrose-6-acetate powder with a purity of 99.56% was obtained, with a yield of 90.3%.
Example 7
Taking 50g of sucrose ester concentrate in example 1, adding a mixed solution of 150g of glacial acetic acid and 50g of acetonitrile at normal temperature, mechanically stirring at a stirring speed of 1000r/min, immediately precipitating crystals, stopping stirring after 100min, performing suction filtration to obtain a pale yellow solid, washing with glacial acetic acid to remove residual mother liquor, and vacuum drying at 60 ℃ until the solution is completely cooled to finally obtain white powder with stable properties. The white powder was uniformly dispersed in 300ml of methylene chloride, 35g of diisobutylamine was added, stirred for 1.5 hours, suction filtration was performed, the residue was removed by washing the solid with methylene chloride 2 to 3 times, and vacuum drying was performed at 40 ℃ until completion, finally obtaining sucrose-6-acetate powder with a purity of 99.91% and a yield of 89.2%.
TABLE 1 sucrose-6-acetate content variation before and after Selective separation of the acylating solution (area normalization method from HPLC-ELSD)
TABLE 2 variation of N, N-dimethylformamide and acetic acid content before and after selective separation of the acylating solution (external standard method from HPLC-PDA)
Example 8
58ml of thionyl chloride were thoroughly mixed with 214ml of 1, 2-trichloroethane and placed in an ice-water bath at a temperature below 0 ℃. 46g of the sucrose ester concentrate obtained in example 1 was taken and dissolved completely in 46ml of N, N-dimethylformamide and added slowly dropwise to the mixed solution of thionyl chloride and 1, 2-trichloroethane over 30 min. After the dripping is finished, the mixture is moved to normal temperature and stirred, after 0.5h, the mixture is heated to 85 ℃ at a speed of 1.5 ℃/min, the mixture is subjected to heat preservation and reflux reaction for 1h, then is heated to 100 ℃ at a speed of 0.5 ℃/min, the mixture is subjected to heat preservation and reflux reaction for 1h, and finally is heated to 110 ℃ at a speed of 0.2 ℃/min, and the mixture is subjected to heat preservation and reflux reaction for 1.5h. After the chlorination reaction is finished, placing the mixture in an ice-water bath, cooling to below 0 ℃, dropwise adding ammonia water, adjusting the pH to about 9, adjusting the pH to be neutral by hydrochloric acid after 10min, and obtaining a chlorination neutralization solution. The sucralose-6-acetate content was measured by HPLC-RID method and was converted simply to a final yield of 49.8%.
Example 9
58ml of thionyl chloride were thoroughly mixed with 214ml of 1, 2-trichloroethane and placed in an ice-water bath at a temperature below 0 ℃. 46g of the refined sucrose ester concentrate obtained in example 2 was taken and completely dissolved in 46ml of N, N-dimethylformamide and slowly added dropwise to the mixed solution of thionyl chloride and 1, 2-trichloroethane over 30 minutes. After the dripping is finished, the mixture is stirred at normal temperature, heated to 85 ℃ at 1.5 ℃ per minute for 0.5h, subjected to heat preservation and reflux reaction for 1h, heated to 100 ℃ at 0.5 ℃ per minute, subjected to heat preservation and reflux reaction for 1h, and finally heated to 110 ℃ at 0.2 ℃ per minute, subjected to heat preservation and reflux reaction for 100 min. After the chlorination reaction is finished, placing the mixture in an ice-water bath, cooling to below 0 ℃, dropwise adding ammonia water, adjusting the pH to about 9, adjusting the pH to be neutral by hydrochloric acid after 10min, and obtaining a chlorination neutralization solution. The sucralose-6-acetate content was measured by HPLC-RID method and was converted simply to 59.2% final yield.
Example 10
58ml of thionyl chloride were thoroughly mixed with 214ml of 1, 2-trichloroethane and placed in an ice-water bath at a temperature below 0 ℃. A further 38.4g of sucrose-6-acetate solid powder purified from example 7 was taken, completely dissolved in 55ml of N, N-dimethylformamide and slowly added dropwise to the mixed solution of thionyl chloride and 1, 2-trichloroethane over 30 min. After the dripping is finished, the mixture is stirred at normal temperature, heated to 85 ℃ at 1.5 ℃ per minute for 0.5h, subjected to heat preservation and reflux reaction for 1h, heated to 100 ℃ at 0.5 ℃ per minute, subjected to heat preservation and reflux reaction for 1h, and finally heated to 110 ℃ at 0.2 ℃ per minute, subjected to heat preservation and reflux reaction for 100 min. After the chlorination reaction is finished, placing the mixture in an ice-water bath, cooling to below 0 ℃, dropwise adding ammonia water, adjusting the pH to about 9, adjusting the pH to be neutral by hydrochloric acid after 10min, and obtaining a chlorination neutralization solution. The sucralose-6-acetate content was measured by HPLC-RID method and was converted simply to a final yield of 68.5%.
Example 11
58ml of thionyl chloride were thoroughly mixed with 214ml of 1, 2-trichloroethane and placed in an ice-water bath at a temperature below 0 ℃. A further 38.4g of sucrose-6-acetate solid powder purified from example 6 was taken, completely dissolved in 55ml of N, N-dimethylformamide and slowly added dropwise to the mixed solution of thionyl chloride and 1, 2-trichloroethane over 30 min. After the dripping is finished, the mixture is stirred at normal temperature, heated to 85 ℃ at 1.5 ℃ per minute for 0.5h, subjected to heat preservation and reflux reaction for 1h, heated to 100 ℃ at 0.5 ℃ per minute, subjected to heat preservation and reflux reaction for 1h, and finally heated to 110 ℃ at 0.2 ℃ per minute, subjected to heat preservation and reflux reaction for 100 min. After the chlorination reaction is finished, placing the mixture in an ice-water bath, cooling to below 0 ℃, dropwise adding ammonia water, adjusting the pH to about 9, adjusting the pH to be neutral by hydrochloric acid after 10min, and obtaining a chlorination neutralization solution. The sucralose-6-acetate content was measured by HPLC-RID, and was converted simply to 67.2% final yield.
TABLE 3 variation of yields of sucralose-6-acetate before and after regioselective chlorination (external standard method from HPLC-RID)
The foregoing detailed description of the process for producing sucralose-6-acetate with reference to the examples is illustrative and not limiting, and several examples may be enumerated in accordance with the defined scope of the present invention, and therefore, variations and modifications may be considered to be within the scope of the present invention.
Claims (5)
1. A process for producing sucralose-6-acetate, which is characterized by comprising the following steps:
1) Taking sucrose acetylation synthetic liquid, and performing rotary evaporation at a speed of 50-150 r/min under the conditions of-0.01-0.2 MPa and 30-80 ℃ to remove more than 80% of volatile organic solvents in the sucrose acetylation synthetic liquid to obtain sucrose acetate concentrated liquid;
2) Adding a mixed solution of glacial acetic acid and a first organic solvent in a mass ratio of 3:1-3:3 into the sucrose acetate concentrated solution at 15-45 ℃ and stirring, wherein the mass ratio of the sucrose acetate concentrated solution to the glacial acetic acid is 1:1-1:6, and drying the precipitated white crystals to obtain white powder;
3) Uniformly dispersing the white powder in a second organic solvent at 15-35 ℃, adding organic amine with the molar content of 1-10 times of acetic acid into the white powder per gram of solid per 5-50 ml of solvent, stirring for 0.1-5 hours, filtering, washing to remove residual organic amine and acetic acid-organic amine conjugate by using the second organic solvent, and vacuum drying at 30-50 ℃ to obtain sucrose-6-acetate powder;
4) Dissolving the sucrose-6-acetate powder into an N, N-dimethylformamide solution, wherein the dosage molar ratio of the sucrose-6-acetate to the N, N-dimethylformamide is 1:7-1:11; and performing regioselective chlorination by using thionyl chloride to finally obtain sucralose-6-acetate synthetic solution;
the sucrose acetylation synthetic liquid is synthetic liquid obtained by the reaction of a sucrose 6-position hydroxyl selective acetylation method, and the sucrose 6-position hydroxyl selective acetylation method is a dibutyl tin oxide method;
the first organic solvent is ethyl acetate, methyl acetate, acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, n-butanol, tertiary butanol, isopropanol or ethanol;
the organic amine is dimethylamine, diethylamine, diisopropylamine, diisobutylamine, diisopentylamine, trimethylamine, N-dimethylethylamine, triethylamine, N-diisopropylmethylamine, N-diisopropylethylamine or tripropylamine;
the second organic solvent is dichloromethane, chloroform, carbon tetrachloride, 1-dichloroethane, 1, 2-dichloroethane, 1-trichloroethane or 1, 2-trichloroethane.
2. The process for producing sucralose-6-acetate according to claim 1, wherein in step 2), "drying the precipitated white crystals to obtain white powder" specifically comprises: stirring for 20-120 min, filtering, washing with glacial acetic acid, and vacuum drying at 60-80 ℃ to obtain white powder.
3. The process for producing sucralose-6-acetate according to claim 1 wherein "regioselective chlorination with thionyl chloride" in step 4) specifically comprises: slowly dropwise adding an N, N-dimethylformamide solution of sucrose-6-acetate into a mixed solution of 1, 2-trichloroethane and thionyl chloride at the temperature of-5 ℃, stirring for 0.5-1 h at the temperature of 20-35 ℃, heating to 70-85 ℃ at 1-2 ℃/min for reacting for 1-1.5 h, heating to 90-100 ℃ at 0.5-1 ℃/min for reacting for 1-1.5 h, and finally heating to 105-115 ℃ at 0.1-0.3 ℃/min for reflux reacting for 1-2 h; cooling to-5 ℃, adjusting the pH to 9-10 with alkali liquor, adjusting the pH to be neutral with hydrochloric acid after 5-30 min, and obtaining the sucralose-6-acetate synthetic solution.
4. The process for producing sucralose-6-acetate according to claim 3, wherein the volume ratio of 1, 2-trichloroethane to thionyl chloride is 3:1 to 4:1; the volume ratio of the N, N-dimethylformamide solution of the sucrose-6-acetate to the mixed solution of the 1, 2-trichloroethane and the thionyl chloride is 1:2-1:3.
5. A process for producing sucralose-6-acetate according to claim 3 where the lye is aqueous ammonia.
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