CN114437146A - Production process of sucralose-6-acetate - Google Patents
Production process of sucralose-6-acetate Download PDFInfo
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- CN114437146A CN114437146A CN202210020727.0A CN202210020727A CN114437146A CN 114437146 A CN114437146 A CN 114437146A CN 202210020727 A CN202210020727 A CN 202210020727A CN 114437146 A CN114437146 A CN 114437146A
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- acetate
- sucrose
- acetic acid
- sucralose
- solution
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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 claims abstract description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 161
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 70
- 229960000583 acetic acid Drugs 0.000 claims abstract description 62
- 238000000034 method Methods 0.000 claims abstract description 42
- 239000000243 solution Substances 0.000 claims abstract description 42
- 229930006000 Sucrose Natural products 0.000 claims abstract description 39
- 239000005720 sucrose Substances 0.000 claims abstract description 39
- 239000000843 powder Substances 0.000 claims abstract description 37
- 239000003960 organic solvent Substances 0.000 claims abstract description 27
- 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 23
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 23
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 19
- 239000011259 mixed solution Substances 0.000 claims abstract description 17
- 150000001412 amines Chemical class 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 16
- 230000008569 process Effects 0.000 claims abstract description 16
- 238000005406 washing Methods 0.000 claims abstract description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 36
- UBOXGVDOUJQMTN-UHFFFAOYSA-N 1,1,2-trichloroethane Chemical compound ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 239000007787 solid Substances 0.000 claims description 20
- -1 N-dimethylethylamine Natural products 0.000 claims description 16
- 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 12
- 238000000967 suction filtration Methods 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 compound 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
- 238000010438 heat treatment Methods 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 7
- 238000001816 cooling 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
- 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
- 239000007788 liquid Substances 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
- 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
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 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
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 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
- 238000001914 filtration Methods 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 239000012670 alkaline solution Substances 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 150000003335 secondary amines Chemical class 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- 238000001291 vacuum drying Methods 0.000 claims 1
- 238000004821 distillation Methods 0.000 abstract description 5
- 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
- 239000012467 final product Substances 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 28
- 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
- 239000012452 mother liquor Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000005457 ice water Substances 0.000 description 8
- 238000005917 acylation reaction Methods 0.000 description 7
- 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
- 230000010933 acylation Effects 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 230000001376 precipitating effect Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002288 cocrystallisation Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000000105 evaporative light scattering detection Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- JLHADLTXDDGZFX-UHFFFAOYSA-L [[acetyloxy(dibutyl)stannyl]oxy-dibutylstannyl] acetate Chemical compound CCCC[Sn](CCCC)(OC(C)=O)O[Sn](CCCC)(CCCC)OC(C)=O JLHADLTXDDGZFX-UHFFFAOYSA-L 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001704 evaporation 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
- 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
- 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
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 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
- 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
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 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
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 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
- 239000002002 slurry Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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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
Abstract
The invention provides a production process of sucralose-6-acetate, which comprises the following steps: adding a mixed solution of glacial acetic acid and a first organic solvent into the sucrose acetate concentrated solution obtained by the 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, reacting with acetic acid to form a stable chemical bond, capturing acetic acid from a cocrystal skeleton, washing residual organic amine and a formed acetic acid-organic amine combination by using the second organic solvent, and drying completely to obtain sucrose-6-acetate powder with the content of more than 99.8%; the powder is dissolved in N, N-dimethylformamide solution and applied to the next step of regioselective chlorination reaction, so that the adverse effect of impurities on the chlorination reaction process is eliminated, the chlorination yield is improved, the purification process of sucralose-6-acetate is simplified, the final product quality of sucralose is improved, and the method has better industrial value.
Description
Technical Field
The invention relates to the field of sucrose-6-acetate crystallization separation in a chemical separation technology, in particular to a high-selectivity separation method for molecular identification of sucrose-6-acetate based on a supermolecule chemical technology, and belongs to the improvement of a high-efficiency 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 reactions of acylation, chlorination and deacylation. Among them, the preparation of sucralose-6-acetate by regiochlorination of the acylation product sucrose-6-acetate is the most critical step in the whole production process, and is considered to be the most complex and difficult-to-control one ring 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 usually directly used for the subsequent selective chlorination reaction, but the acetic acid synthesized by the dibutyltin oxide method has high content, and the synthesis yield of the sucralose-6-acetate can be directly influenced. Therefore, N-dimethylformamide is often used for reducing the acetic acid value of the acylation solution by multi-step distillation, but long-time distillation not only has high energy consumption, but also causes the content of sucrose-6-acetate to be reduced, and N, N-dimethylformamide and acetic acid can form the highest azeotrope, so that the post-treatment is complicated. Besides, the acylation solution contains various sucrose acetates with structural properties similar to those of sucrose-6-acetate, and such a complicated composition is one of the important reasons for the low production efficiency.
Sucrose-6-acetate is a compound with biodegradable and nontoxic characteristics, is used as an important chemical raw material, and is also an important intermediate for synthesizing a nonionic surfactant and a sucrose-based polymer. Therefore, the method for obtaining the acylation product sucrose-6-acetate with single composition has important significance for the production of sucralose and other additional value products.
Among the currently reported methods for the separation and purification of sucrose-6-acetate, 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 decrystallization process disclosed in US 20110168568 has poor selectivity; and the recrystallization processes 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 percent, so that the methods are not suitable for large-scale industrialization.
Disclosure of Invention
The invention aims to solve the existing technical bottleneck and provide a method for efficiently separating sucrose-6-acetate, particularly under the condition that the physicochemical properties of all components are extremely similar, the sucrose-6-acetate can be still separated from an acetylation solution in a high selectivity way, and the obtained sucrose-6-acetate with reagent grade purity is used for selective chlorination, so that the production cost is reduced, and the synthesis yield of the sucralose-6-acetate is improved.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a production process of sucralose-6-acetate comprises the following steps:
the first step is as follows: adding a mixed solution of glacial acetic acid and a first organic solvent into the sucrose acetate concentrated solution at 15-45 ℃, stirring, carrying out suction filtration on a precipitated white crystal, washing with glacial acetic acid to remove residual mother liquor, and drying in vacuum at 60-80 ℃ until the mother liquor is complete to obtain white powder with stable properties.
The second step is that: uniformly dispersing the white powder in a second organic solvent at 15-35 ℃, adding organic amine with the molar content of 1-10 times that of acetic acid into each gram of solid per 5-50 ml of solvent, filtering after the reaction is finished, washing by using the second organic solvent to remove residual organic amine and acetic acid-organic amine combination, and drying in vacuum at 30-50 ℃ until the mixture is complete to obtain high-purity sucrose-6-acetate powder.
The third step: 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 performing regioselective chlorination by using thionyl chloride to finally obtain the sucralose-6-acetate synthetic solution.
The sucrose acetate concentrated solution in the first step is a concentrated slurry obtained by rotationally evaporating sucrose acetylation synthetic solution under-0.01-0.2 MPa at 30-80 ℃ and 50-150 r/min to remove more than 80% of volatile organic solvent, 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 obtained by reacting a sucrose 6-hydroxyl selective acetylation method, and the sucrose 6-hydroxyl selective acetylation method is a dibutyltin oxide method.
The specific steps of producing the sucrose acetylation synthetic fluid by a dibutyltin oxide method are as follows: adding a catalyst 1, 3-di (acetyloxy) -1,1,3, 3-tetrabutyldistannoxane (DSDA) into a sucrose N, N-dimethylformamide solution, distilling at 80-90 ℃ under reduced pressure to continuously carry out water generated by the reaction until no liquid is distilled, supplementing a certain amount of N, N-dimethylformamide, cooling to low temperature, dropwise adding acetic anhydride, stirring for 3-6 h, and then adding deionized water for quenching. And finally, extracting and recovering the DSDA in the reaction solution by using cyclohexane to obtain the sucrose acetylation synthetic solution.
The invention uses glacial acetic acid as a co-crystallization solvent, and the glacial acetic acid as a small molecular object can be well embedded in a skeleton cavity formed by sucrose-6-acetate, and has excellent specific recognition effect. The glacial acetic acid and the first organic solvent are mixed for use, which is beneficial to improving the crystallization efficiency. However, the specific type and amount of the first organic solvent can affect the crystallization speed and the final yield, and the crystallization speed and the final yield can be improved by adopting a proper solvent combination. The first organic solvent is an organic solvent which is difficult to dissolve or slightly soluble in 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, t-butanol, isopropanol, and ethanol.
Preferably, the mass ratio of the sucrose acetate concentrated solution and 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 bond effect, the organic amine and the acetic acid are used for reaction to form a stable chemical bond, so that the organic amine has stronger acting force, and the acetic acid can be abstracted from a sucrose-6-acetate skeleton cavity without damaging a sucrose-6-acetate skeleton structure. The second organic solvent and the organic amine in the second step have different basicity per unit volume, and thus have a significant influence on the re-separation process.
Preferably, the second organic solvent of the second step is at least one of dichloromethane, chloroform, carbon tetrachloride, 1, 1-dichloroethane, 1, 2-dichloroethane, 1,1, 1-trichloroethane and 1,1, 2-trichloroethane.
Preferably, the amount of the second organic solvent used in the second step is 5-50 ml of the second organic solvent per gram of the white powder used in the first step.
Preferably, the organic amine of the second step is at least one of dimethylamine, diethylamine, diisopropylamine, diisobutylamine, diisoamylamine, 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 a powder having a molar ratio of about 1:1, wherein the actual content of the sucrose-6-acetate is 86-87%, the actual content of the acetic acid is 13-14%, and the acetic acid wrapped inside can be completely removed only by controlling the actual content of the sucrose-6-acetate and the acetic acid to be in a certain particle size. The third step is to obtain sucrose-6-acetate powder with high purity from the second step, which means that the actual content of sucrose-6-acetate is more than 99.8% and the actual content of acetic acid is less than 0.05%.
It should be noted that the first step of washing the precipitated crystals with glacial acetic acid resulted in only a small loss of sucrose-6-acetate. The second organic solvent is an insoluble organic solvent of sucrose-6-acetate, and the sucrose-6-acetate is hardly lost in this step.
The third step, namely performing regioselective chlorination by using thionyl chloride, comprises the following specific steps of: slowly dripping a N, N-dimethylformamide solution of sucrose-6-acetate into a mixed solution of 1,1, 2-trichloroethane and thionyl chloride at the temperature of-5 ℃, wherein the volume ratio of the 1,1, 2-trichloroethane to the thionyl chloride is 3: 1-4: 1; the volume ratio of the N, N-dimethylformamide solution of sucrose-6-acetate to the mixed solution of 1,1, 2-trichloroethane and thionyl chloride is 1: 2-1: 3; heating to 20-35 ℃, stirring for 0.5-1 h, heating to 70-85 ℃ at a speed of 1-2 ℃/min, reacting for 1-1.5 h, heating to 90-100 ℃ at a speed of 0.5-1 ℃/min, reacting for 1-1.5 h, and finally heating to 105-115 ℃ at a speed of 0.1-0.3 ℃/min, and performing reflux reaction 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 liquid.
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 co-crystallization process of the sucrose-6-acetate and the acetic acid in the first step is over 90 percent, the yield of the re-separation process of the sucrose-6-acetate and the acetic acid in the second step is over 99.8 percent, and the content of the finally obtained white powder sucrose-6-acetate is over 99.8 percent. The conditions required in the whole process are very mild, the requirement on equipment in industrial production is low, the operation is convenient, and the method is suitable for large-scale industrialization.
(2) Based on the high acetic acid content of the self-acylation synthetic liquid, after a certain amount of glacial acetic acid is supplemented to a proper cocrystallization concentration, cocrystallization is accurately formed with sucrose-6-acetate, and the selective identification capability of various similar sucrose acetates is remarkably improved. The sucrose-6-acetate powder obtained not only has an extremely high content but also contains almost no acetic acid. The process of separating sucrose-6-acetate and removing acetic acid is skillfully coupled, and the problems that the acetic acid is difficult to remove and the sucrose-6-acetate is difficult to purify are perfectly solved. Compared with the multi-step distillation treatment of the 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 over 10 percent, the dosage of chlorinated reagent and solvent, the energy consumption in the reaction process and the subsequent separation difficulty of sucralose-6-acetate are reduced, and the synthesis yield of sucralose-6-acetate can be improved.
Drawings
FIG. 1 is a schematic diagram of a 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 shows sucrose-6-acetate1H NMR spectrum;
FIG. 4 shows sucrose-6-acetate13C NMR spectrum;
FIG. 5 is a diagram of sucrose-6-acetate/acetic acid ORTEP;
FIG. 6 is a graph of hydrogen bonding in sucrose-6-acetate/acetic acid crystals, symmetry code: a is 1+ X, + Y, + Z, B is-X, 0.5+ Y, -Z, C is-1 + X, + Y, + Z;
FIG. 7 is a stacking diagram of the sucrose-6-acetate/acetic acid unit cell along the a-axis;
FIG. 8 is a FT-IR chart of a sucrose-6-acetate/acetic acid cocrystal before and after acetic acid removal, a-acetic acid; b-sucrose-6-acetate; c-sucrose-6-acetate/acetic acid;
FIG. 9 is XRD patterns before and after removal of acetic acid from sucrose-6-acetate/acetic acid co-crystals, a-sucrose-6-acetate/acetic acid; b-sucrose-6-acetate; c-sucrose-6-acetate/acetic acid single crystal data simulation;
FIG. 10 is SEM images of sucrose-6-acetate/acetic acid cocrystal before and after removal of acetic acid, the left side is sucrose-6-acetate/acetic acid cocrystal, and the right side is sucrose-6-acetate.
Detailed Description
The present invention will be described in detail with reference to specific examples.
Example 1
100g of dibutyltin oxide are initially heated to 85 ℃, 26g of acetic anhydride are added dropwise, and the mixture obtained is stirred for 4 hours. Then mixed with cyclohexane and vacuum distilled to dryness to remove excess acetic anhydride to obtain the catalyst 1, 3-bis (acetyloxy) -1,1,3, 3-tetrabutyldistannoxane (DSDA). Next, the prepared DSDA was completely dissolved in 720mL of N, N-dimethylformamide together with 68.5g of sucrose, and the water produced in the reaction was continuously taken up by distillation under reduced pressure at 85 ℃ until any liquid was not distilled off (about 2 hours). It was then cooled to 0 ℃, supplemented with a quantity of N, N-dimethylformamide and added dropwise with 30.5g of acetic anhydride, stirred for 3h to ensure complete conversion of the sucrose. Deionized water was then added to the mixture to terminate the reaction. Finally, the DSDA is extracted with cyclohexane to make it completely free of DSDA. To obtain the sucrose acetylation synthetic solution.
Rotary evaporating at 60 deg.C and 100r/min under-0.1 MPa for 3 hr to remove more than 80% of volatile organic solvent to obtain sucrose ester concentrate. The contents of N, N-dimethylformamide and acetic acid were measured by HPLC-PDA method, and the contents of sucrose-6-acetate and other sucrose acetates were measured by HPLC-ELSD method, and the results are shown in Table 1 and Table 2.
Example 2
Taking 200g of the sucrose ester concentrated solution in example 1, adding 150ml of N, N-dimethylformamide, completely mixing, performing rotary evaporation for 2h at 60 ℃ and 100r/min under-0.1 MPa, removing more than 80% of volatile organic solvent, and repeating the previous operation for 2 times to obtain the refined sucrose ester concentrated solution. The contents of N, N-dimethylformamide and acetic acid were measured by HPLC-PDA method, and the contents of sucrose-6-acetate and other sucrose acetates were measured by HPLC-ELSD method, and the results are shown in Table 1 and Table 2.
Example 3
Taking 50g of sucrose ester concentrated solution in example 1, adding a mixed solution of 150g of glacial acetic acid and 50g of n-butanol at normal temperature, mechanically stirring at the stirring speed of 1000r/min, immediately precipitating crystals, stopping stirring after 60min, performing suction filtration to obtain a light yellow solid, washing with glacial acetic acid to remove residual mother liquor, and drying in vacuum at 60 ℃ to complete to finally obtain white powder with stable properties. Uniformly dispersing white powder in 250ml of 1, 2-dichloroethane, adding 30g of diisopropylamine, stirring for 1h, performing suction filtration, washing the solid with 1, 2-dichloroethane for 2-3 times to remove residues, and drying in vacuum at 40 ℃ until the residue is completely removed, thereby finally obtaining sucrose-6-acetate powder with the purity of 99.61%, wherein the yield is 87.2%.
Example 4
Taking 50g of sucrose ester concentrated solution in example 1, adding a mixed solution of 150g of glacial acetic acid and 60g of ethyl acetate at normal temperature, mechanically stirring at the stirring speed of 1000r/min, immediately precipitating crystals, stopping stirring after 40min, performing suction filtration to obtain a light yellow solid, washing with glacial acetic acid to remove residual mother liquor, and drying in vacuum at 60 ℃ until the mother liquor is complete to finally obtain white powder with stable properties. Uniformly dispersing white powder in 300ml of dichloromethane, adding 40g of tripropylamine, stirring for 5 hours, performing suction filtration, washing the solid with dichloromethane for 2-3 times to remove residues, and drying in vacuum at 40 ℃ until the solid is completely removed, thereby finally obtaining sucrose-6-acetate powder with the purity of 98.73%, wherein the yield is 95.1%.
Example 5
Taking 50g of sucrose ester concentrated solution in example 1, adding a mixed solution of 100g of glacial acetic acid and 30g of tert-butyl alcohol at normal temperature, mechanically stirring at the stirring speed of 1000r/min, immediately precipitating crystals, stopping stirring after 80min, performing suction filtration to obtain a light yellow solid, washing with glacial acetic acid to remove residual mother liquor, and drying in vacuum at 60 ℃ until the mother liquor is complete to finally obtain white powder with stable properties. Uniformly dispersing white powder in 300ml of 1, 2-dichloroethane, adding 40g N, N-diisopropylethylamine, stirring for 1h, carrying out suction filtration, washing the solid with 1,1, 2-trichloroethane for 2-3 times to remove residues, and drying in vacuum at 50 ℃ till the solid is completely removed, thereby finally obtaining sucrose-6-acetate powder with the purity of 99.69%, wherein the yield is 82.1%.
Example 6
Taking 50g of sucrose ester concentrated solution in example 1, adding a mixed solution of 150g of glacial acetic acid and 40g of tetrahydrofuran at normal temperature, mechanically stirring at the 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 liquor, and drying in vacuum at 60 ℃ until the mother liquor is complete to finally obtain white powder with stable properties. Uniformly dispersing the white powder in 250ml of dichloromethane, adding 30g of triethylamine, stirring for 0.5h, performing suction filtration, washing the solid with dichloromethane for 2-3 times to remove residues, and drying in vacuum at 40 ℃ until the solid is completely removed, thereby finally obtaining the sucrose-6-acetate powder with the purity of 99.56%, wherein the yield is 90.3%.
Example 7
Taking 50g of sucrose ester concentrated solution in example 1, adding a mixed solution of 150g of glacial acetic acid and 50g of acetonitrile at normal temperature, mechanically stirring at the 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 liquor, and drying in vacuum at 60 ℃ until the mother liquor is complete to finally obtain white powder with stable properties. Uniformly dispersing the white powder in 300ml of dichloromethane, adding 35g of diisobutylamine, stirring for 1.5h, performing suction filtration, washing the solid with dichloromethane for 2-3 times to remove residues, and drying in vacuum at 40 ℃ until the solid is completely removed, thereby finally obtaining the sucrose-6-acetate powder with the purity of 99.91 percent, wherein the yield is 89.2 percent.
TABLE 1 Change in sucrose-6-acetate content before and after selective separation of acylated solution (area normalization from HPLC-ELSD)
TABLE 2 Change in N, N-dimethylformamide and acetic acid content before and after selective isolation of the acylation solution (external standard method from HPLC-PDA)
Example 8
58ml of thionyl chloride was first thoroughly mixed with 214ml of 1,1, 2-trichloroethane and placed in an ice-water bath at below 0 ℃. 46g of the sucrose ester concentrate obtained in example 1 was completely dissolved in 46ml of N, N-dimethylformamide and slowly added dropwise to a mixed solution of thionyl chloride and 1,1, 2-trichloroethane over 30 minutes. After the dropwise addition is finished, the mixture is stirred at normal temperature, after 0.5h, the mixture is heated to 85 ℃ at the speed of 1.5 ℃/min, the mixture is subjected to heat preservation reflux reaction for 1h, then the mixture is heated to 100 ℃ at the speed of 0.5 ℃/min, the mixture is subjected to heat preservation reflux reaction for 1h, and finally the mixture is heated to 110 ℃ at the speed of 0.2 ℃/min, and the heat preservation reflux reaction is performed for 1.5 h. And 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 be about =9, and after 10min, adjusting the mixture to be neutral by using hydrochloric acid to obtain a chlorination neutralized solution. The content of sucralose-6-acetate in the product was determined by HPLC-RID method, and the final yield was 49.8% by simple conversion.
Example 9
58ml of thionyl chloride was first thoroughly mixed with 214ml of 1,1, 2-trichloroethane and placed in an ice-water bath at below 0 ℃. 46g of the purified sucrose ester concentrate obtained in example 2 was completely dissolved in 46ml of N, N-dimethylformamide and slowly added dropwise to a mixed solution of thionyl chloride and 1,1, 2-trichloroethane over 30 minutes. After the dropwise addition is finished, the mixture is transferred to the room temperature and stirred, after 0.5h, the mixture is heated to 85 ℃ at the speed of 1.5 ℃/min, the mixture is subjected to heat preservation reflux reaction for 1h, then the mixture is heated to 100 ℃ at the speed of 0.5 ℃/min, the mixture is subjected to heat preservation reflux reaction for 1h, and finally the mixture is heated to 110 ℃ at the speed of 0.2 ℃/min, and the mixture is subjected to heat preservation reflux reaction for 100 min. And 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 be about =9, and after 10min, adjusting the mixture to be neutral by using hydrochloric acid to obtain a chlorination neutralized solution. The content of sucralose-6-acetate in the product is determined by an HPLC-RID method, and the final yield is 59.2 percent by simple conversion.
Example 10
58ml of thionyl chloride was first thoroughly mixed with 214ml of 1,1, 2-trichloroethane and placed in an ice-water bath at below 0 ℃. 38.4g of the sucrose-6-acetate solid powder purified in example 7 was completely dissolved in 55ml of N, N-dimethylformamide and slowly added dropwise to a mixed solution of thionyl chloride and 1,1, 2-trichloroethane over 30 minutes. After the dropwise addition is finished, the mixture is stirred at normal temperature, heated to 85 ℃ at a speed of 1.5 ℃/min after 0.5h, subjected to heat preservation reflux reaction for 1h, heated to 100 ℃ at a speed of 0.5 ℃/min, subjected to heat preservation reflux reaction for 1h, and finally heated to 110 ℃ at a speed of 0.2 ℃/min, subjected to heat preservation reflux reaction for 100 min. And 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 be about =9, and after 10min, adjusting the mixture to be neutral by using hydrochloric acid to obtain a chlorination neutralized solution. The content of sucralose-6-acetate in the product is determined by an HPLC-RID method, and the final yield is 68.5 percent by simple conversion.
Example 11
58ml of thionyl chloride was first thoroughly mixed with 214ml of 1,1, 2-trichloroethane and placed in an ice-water bath at below 0 ℃. 38.4g of the sucrose-6-acetate solid powder purified in example 6 was dissolved in 55ml of N, N-dimethylformamide and slowly added dropwise to a mixed solution of thionyl chloride and 1,1, 2-trichloroethane over 30 minutes. After the dropwise addition is finished, the mixture is stirred at normal temperature, heated to 85 ℃ at a speed of 1.5 ℃/min after 0.5h, subjected to heat preservation reflux reaction for 1h, heated to 100 ℃ at a speed of 0.5 ℃/min, subjected to heat preservation reflux reaction for 1h, and finally heated to 110 ℃ at a speed of 0.2 ℃/min, subjected to heat preservation reflux reaction for 100 min. And 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 be about =9, and after 10min, adjusting the mixture to be neutral by using hydrochloric acid to obtain a chlorination neutralized solution. The content of sucralose-6-acetate in the product was determined by HPLC-RID method, and the final yield was 67.2% by simple conversion.
TABLE 3 sucralose-6-acetate yield change before and after regioselective chlorination (external standard method from HPLC-RID)
The above detailed description of the sucralose-6-acetate production process with reference to examples is illustrative and not restrictive, and several examples can be cited within the scope of the present invention, so that variations and modifications without departing from the general concept of the present invention shall fall within the protection scope of the present invention.
Claims (10)
1. A production process of sucralose-6-acetate is characterized by comprising the following steps:
1) taking the sucrose acetylation synthetic solution, and performing rotary evaporation at a speed of 50-150 r/min under the conditions of-0.01-0.2 MPa and 30-80 ℃, removing more than 80% of volatile organic solvent in the sucrose acetylation synthetic solution to obtain a sucrose acetate concentrated solution;
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 ℃, 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 ℃, wherein the using amount ratio is that each gram of solid is 5-50 ml of solvent, adding organic amine with the molar content of acetic acid being 1-10 times that of the solid, stirring for 0.1-5 h, filtering, washing by using the second organic solvent to remove residual organic amine and acetic acid-organic amine combination, and drying in vacuum at 30-50 ℃ to obtain sucrose-6-acetate powder;
4) dissolving the 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.
2. The sucralose-6-acetate production process according to claim 1, wherein the step 2) of drying the precipitated white crystals to obtain white powder specifically comprises the following steps: stirring for 20-120 min, then carrying out suction filtration, washing with glacial acetic acid, and carrying out vacuum drying at 60-80 ℃ to obtain white powder.
3. The process for producing sucralose-6-acetate according to claim 1, wherein the sucrose acetylation synthetic solution is a synthetic solution obtained by a selective acetylation method of 6-hydroxy group of sucrose, and the selective acetylation method of 6-hydroxy group of sucrose is a dibutyltin oxide method.
4. The process of claim 1, wherein the first organic solvent comprises ethyl acetate, methyl acetate, acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1, 4-dioxane, n-butanol, t-butanol, isopropanol, or ethanol.
5. The process of claim 1, wherein the organic amine is a secondary or tertiary amine.
6. The process according to claim 5, wherein the organic amine is dimethylamine, diethylamine, diisopropylamine, diisobutylamine, diisoamylamine, trimethylamine, N-dimethylethylamine, triethylamine, N-diisopropylmethylamine, N-diisopropylethylamine or tripropylamine.
7. The process according to claim 1, wherein the second organic solvent is dichloromethane, chloroform, carbon tetrachloride, 1, 1-dichloroethane, 1, 2-dichloroethane, 1,1, 1-trichloroethane or 1,1, 2-trichloroethane.
8. The process for producing sucralose-6-acetate according to claim 1, wherein the "regioselective chlorination with thionyl chloride" in the step 4) specifically comprises: slowly dripping a N, N-dimethylformamide solution of sucrose-6-acetate into a mixed solution of 1,1, 2-trichloroethane and thionyl chloride at the temperature of-5 ℃, heating to 20-35 ℃, stirring for 0.5-1 h, heating to 70-85 ℃ at the speed of 1-2 ℃/min, reacting for 1-1.5 h, heating to 90-100 ℃ at the speed of 0.5-1 ℃/min, reacting for 1-1.5 h, and finally heating to 105-115 ℃ at the speed of 0.1-0.3 ℃/min, and performing reflux reaction 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 liquid.
9. The process for producing sucralose-6-acetate according to claim 8, wherein the volume ratio of 1,1, 2-trichloroethane to thionyl chloride is 3:1 to 4: 1; the volume ratio of the N, N-dimethylformamide solution of sucrose-6-acetate to the mixed solution of 1,1, 2-trichloroethane and thionyl chloride is 1: 2-1: 3.
10. The process of claim 8, wherein the alkaline solution is ammonia.
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