CN101445524B - Method for preparing sucralose - Google Patents
Method for preparing sucralose Download PDFInfo
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- CN101445524B CN101445524B CN2008101658817A CN200810165881A CN101445524B CN 101445524 B CN101445524 B CN 101445524B CN 2008101658817 A CN2008101658817 A CN 2008101658817A CN 200810165881 A CN200810165881 A CN 200810165881A CN 101445524 B CN101445524 B CN 101445524B
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- sucrose
- sucralose
- benzoate
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- 238000000034 method Methods 0.000 title claims abstract description 43
- 235000019408 sucralose Nutrition 0.000 title claims abstract description 42
- 239000004376 Sucralose Substances 0.000 title claims abstract description 41
- 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 title claims abstract description 41
- 229930006000 Sucrose Natural products 0.000 claims abstract description 47
- 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 47
- 239000005720 sucrose Substances 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000001953 recrystallisation Methods 0.000 claims abstract description 13
- 238000006136 alcoholysis reaction Methods 0.000 claims abstract description 7
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 7
- 238000000605 extraction Methods 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- AFHCRQREQZIDSI-OVUASUNJSA-N [(2r,3s,4s,5r,6r)-6-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl benzoate 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](COC(=O)C=2C=CC=CC=2)O1 AFHCRQREQZIDSI-OVUASUNJSA-N 0.000 claims description 39
- AFHCRQREQZIDSI-UHFFFAOYSA-N sucrose-6-benzoate Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC(=O)C=2C=CC=CC=2)O1 AFHCRQREQZIDSI-UHFFFAOYSA-N 0.000 claims description 39
- -1 cyclic ester Chemical class 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 24
- 230000032050 esterification Effects 0.000 claims description 14
- 238000005886 esterification reaction Methods 0.000 claims description 14
- XEMRAKSQROQPBR-UHFFFAOYSA-N (trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=CC=C1 XEMRAKSQROQPBR-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000005711 Benzoic acid Substances 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 235000010233 benzoic acid Nutrition 0.000 claims description 6
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 230000008030 elimination Effects 0.000 claims description 6
- 238000003379 elimination reaction Methods 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000000920 calcium hydroxide Substances 0.000 claims description 5
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 5
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 4
- 239000001110 calcium chloride Substances 0.000 claims description 4
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 238000006386 neutralization reaction Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 6
- 235000013373 food additive Nutrition 0.000 abstract description 2
- 239000002778 food additive Substances 0.000 abstract description 2
- 150000003445 sucroses Chemical class 0.000 abstract description 2
- 235000010290 biphenyl Nutrition 0.000 abstract 1
- 239000004305 biphenyl Substances 0.000 abstract 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract 1
- 229960004793 sucrose Drugs 0.000 description 39
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 235000011116 calcium hydroxide Nutrition 0.000 description 4
- 150000001733 carboxylic acid esters Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000011148 calcium chloride Nutrition 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000005057 refrigeration Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- MUPFEKGTMRGPLJ-RMMQSMQOSA-N Raffinose Natural products O(C[C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O[C@@]2(CO)[C@H](O)[C@@H](O)[C@@H](CO)O2)O1)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 MUPFEKGTMRGPLJ-RMMQSMQOSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- MUPFEKGTMRGPLJ-UHFFFAOYSA-N UNPD196149 Natural products OC1C(O)C(CO)OC1(CO)OC1C(O)C(O)C(O)C(COC2C(C(O)C(O)C(CO)O2)O)O1 MUPFEKGTMRGPLJ-UHFFFAOYSA-N 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000003147 glycosyl group Chemical group 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- MUPFEKGTMRGPLJ-ZQSKZDJDSA-N raffinose 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[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)O1 MUPFEKGTMRGPLJ-ZQSKZDJDSA-N 0.000 description 2
- 238000002791 soaking Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 206010006514 bruxism Diseases 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Saccharide Compounds (AREA)
Abstract
The invention relates to a method for preparing sucralose, belonging to the technical field of food additive. The invention more particularly relates to a method for preparing a high purity sucrose single protection intermediate which is sucrose-6-benzoic ether and the method for preparing sucralose by taking the obtained sucrose-6-benzoic ether as the intermediate. The method is characterized in that firstly, sucrose is esterified to produce the sucrose-6-benzoic; then, the sucrose-6-benzoic is taken as the intermediate for deprotection group and recrystallization to be made into the sucralose after the reactions of extraction, concentration and alcoholysis. The sucrose-6-benzoic ether obtained by the method has high purity, and the composition proportion of sucrose derivative in HPLC analytical reaction liquid is about that the ratio of more than 92% of sucrose-6-benzoic ether: less than 1% of sucrose-4-benzoic ether: less than 5% of sucrose-6-6'- diphenyl formic ether, and no residual sucrose is available; the reaction yield of the sucrose-6-benzoic is more than 85%.
Description
Technical field
The invention belongs to technical field of food additives, especially a kind of Sucralose is commonly called as the industrialized process for preparing of Sucralose (TGS write a Chinese character in simplified form in English, trade(brand)name Sucralose).
Technical background
Sucralose is a kind of novel intense sweetener, is characterized in that sugariness is high, is 600 times of sucrose; Sweet taste is pure, and mouthfeel and sucrose are basically identical; Stable performance is difficult for being destroyed by severe environment such as soda acid, high temperature; Wide application almost can be used for all food, and is safe to use in food; Heat is low, without grinding tooth, be suitable for diabetics and odontopathy patients.
Have 8 hydroxyls in the molecular structure of sucrose.Optionally using 4,1 ', 6 ' hydroxyl in chlorine atom substituting saccharose molecule is the ultimate principle of making Sucralose.If at first in sucrose molecules except 4; 1 '; 6 all outer other hydroxyls of hydroxyl carry out the acidylate protection; again with chlorinating agent to 4; 1 ', 6 ' hydroxyl carries out chlorine and replaces, and sloughs at last the acidylate blocking group and obtains Sucralose; this is the full guard route of so-called preparation Sucralose, for example the method addressed of United States Patent (USP) 4362869 and English Patent 2182039.The full guard route prepares Sucralose, and operational path is long, and the raw material of use is various, and preparation cost is not suitable for suitability for industrialized production.
In the molecular structure of sucrose, the reactive behavior of 8 hydroxyls is different, and the descending order of its reactive behavior is:
6,6 '〉4〉1 '〉2〉3,3 ', 4 '
If at first only 6 hydroxyls the most active in sucrose molecules are carried out the acidylate protection; again with chlorinating agent to activity take second place 4; 1 '; 6 ' hydroxyl carries out chlorine and replaces; slough at last the acidylate blocking group and obtain Sucralose; this is single protection route of so-called preparation Sucralose, for example United States Patent (USP) 4380476,4889928 and 4980463 and the method addressed of European patent 0515145.Because the reactive behavior of 8 hydroxyls in sucrose molecules is different, so single guard method is short than the reaction scheme of full guard method, step is few, is more suitable for suitability for industrialized production.
But sucrose in single guard method-6 hydroxyl and 6 ' position hydroxyl is active close.How obtaining purity is enough to satisfy the key problem in technology that the sucrose of chloro requirement-6-carboxylicesters is single protection route.Various countries' patent discloses multiple correlation technique, but its defective is respectively arranged.The disclosed very low temperature esterification process of US4380476 for example, selectivity is not high, goes back the demand pole chromatographic separation, is not suitable for suitability for industrialized production; US4889928 and EP0515145 disclose original carboxylic acid ester's esterification process, but are attended by more side reaction, more sucrose 4-acetic ester is still arranged in the cane sugar-6-acetic ester that obtains and do not protect sucrose etc. to be difficult to remove, and have a strong impact on end product quality.
As: in the cane sugar-6-acetic ester that obtains with original carboxylic acid ester's esterification process of US4889928, sucrose and derivative ratio thereof are about: cane sugar-6-acetic ester 85%, sucrose-4-acetic ester 4%, sucrose 11%; Add the raw material trimethyl orthoacetate and be difficult for preparation, price is high, has affected the economic benefit of manufacture Sucralose; In addition, the crystallinity of cane sugar-6-acetic ester in solvent is poor, can further purify with the method for recrystallization, thereby greatly affect quality and the yield of follow-up preparation Sucralose.Although above-mentioned original carboxylic acid ester's esterification process patent has related to the precursor of Sucrose-6-benzoate, but do not provide specific examples, because according to the principle of original carboxylic acid ester's esterification process, the raw material of preparation Sucrose-6-benzoate should be former phenylformic acid trimethyl, and this material does not exist.
US5023329 and EP0352048 disclose the organotin activation method, use a large amount of organotins as the hydroxyl deactivated catalyst, and catalyst toxicity is large, and difficult the recovery is not suitable for making the food grade product.
In addition, also has the enzyme process route.For example: US4826962 discloses the enzyme process route of raffinose as the chloro precursor; raffinose can be regarded 6 sucrose that a glycosyl protection is arranged as; slough this glycosyl with enzymolysis process after chloro and just obtain Sucralose, so the method can be included into single protection route.US5470969 discloses with preparing sucrose-6-acetic ester by enzymatic and has then carried out the route of chloro, and the method obviously also can be included in single protection route.The more difficult preparation of the enzyme of using in enzyme process, and expensive, transformation efficiency is not high yet, is difficult to realize industrialization.
Summary of the invention
In order to overcome the deficiency that exists in existing Sucralose list protection route production technique; the invention provides a kind of preparation method of Sucralose; especially a kind of highly purified sucrose list protection intermediate: the preparation method of Sucrose-6-benzoate (Fig. 3), and prepare the method for Sucralose as intermediate with the Sucrose-6-benzoate that obtains subsequently.
The technical solution adopted for the present invention to solve the technical problems is: a kind of preparation method of Sucralose; comprise that (1) generates the method for Sucrose-6-benzoate and (2) with the sucrose esterification and Sucrose-6-benzoate made the method for Sucralose as intermediate through extraction, concentrated, alcoholysis reaction Deprotection and recrystallization again, it is characterized in that: the method that the sucrose esterification is generated Sucrose-6-benzoate comprises the following steps:
1. will encircle esterifying agent trichlorotoluene zotrichloride (Fig. 1) and splash in the polar aprotic solvent that contains sucrose, the cyclic ester reaction of carrying out under low temperature obtains cyclic ester compounds I (Fig. 2);
2. after cyclic ester reacts completely, add suitable quantity of water to keep the hydrolysis reaction that destroys the trichlorotoluene zotrichloride of traces of unreacted under low temperature and carry out cyclic ester compounds I, obtain Sucrose-6-benzoate and a small amount of sucrose-4 benzoic acid ester;
3. add in calcium hydroxide mineral alkali or pyridine organic bases and react with cyclic ester reaction and hydrolysis the HCl that produces, add again appropriate calcium hydroxide after the insoluble CaCl2 of elimination, sucrose-4 benzoic acid ester is transformed to Sucrose-6-benzoate under alkaline condition, obtain containing the Sucrose-6-benzoate reaction solution.
According to the method for Sucrose-6-benzoate sucrose that the sucrose esterification is generated described above, it is characterized in that: the mol ratio of ring esterifying agent trichlorotoluene zotrichloride and sucrose is 1～1.2 times;
The method of Sucrose-6-benzoate sucrose that the sucrose esterification is generated according to described above is characterized in that: the time for adding of ring esterifying agent trichlorotoluene zotrichloride is 1～6 hour;
According to the method that the sucrose esterification is generated Sucrose-6-benzoate sucrose described above, it is characterized in that: the cyclic ester reaction is carried out at low temperatures, temperature-30～10 ℃; 1～10 hour reaction times;
According to the method for Sucrose-6-benzoate sucrose that the sucrose esterification is generated described above, it is characterized in that: it is relative sucrose 3～12 molar equivalent ratios that hydrolysis reaction adds the water yield; Hydrolysis reaction carries out at low temperatures, temperature-30～10 ℃; 10～100 minutes reaction times;
According to the method that the sucrose esterification is generated Sucrose-6-benzoate sucrose described above, it is characterized in that: polar aprotic solvent is selected from dimethyl formamide, N,N-DIMETHYLACETAMIDE, Trimethylamine 99, triethylamine, Tributylamine, pyridine, piperidines, N-methylmorpholine, N-ethylmorpholine any one;
Preparation method according to a kind of Sucralose described above, it is characterized in that: carry out after the benzoyl transport reaction obtains containing pure Sucrose-6-benzoate reaction solution, the alkalescence that adds 35% hydrochloric acid neutralization reaction liquid, and the insoluble calcium chloride of elimination, remove again solvent under reduced pressure, and use acetone recrystallization, get pure Sucrose-6-benzoate solid; This Sucrose-6-benzoate solid is used for the Sucralose subsequent preparation process.Comprise the following steps: use the method that Sucrose-6-benzoate solution is splashed into Vilsmeier reagent; Sucrose-6-benzoate is carried out Selective chlorination obtain Sucralose-6-benzoic ether; through extraction, concentrated, alcoholysis reaction Deprotection and recrystallization are made Sucralose again.
The invention has the beneficial effects as follows, the purity that obtains Sucrose-6-benzoate with the method is high, the proportion of composing of sucrose derivative is about in HPLC analytical reaction liquid: Sucrose-6-benzoate is greater than 92%: sucrose-4 benzoic acid ester＜1%: sucrose-6-6 '-dibenzoate＜5%, and residual without sucrose; The reaction yield of Sucrose-6-benzoate is greater than 85%.
Reaction solution removes solvent again under reduced pressure, and use acetone recrystallization, the Sucrose-6-benzoate solid that has obtained being further purified.Further purifying is very favourable for the preparation process of follow-up Sucralose, can obtain highly purified Sucralose.
React in solvent with trichlorotoluene zotrichloride cheap and easy to get and sucrose in a word and can get novel cyclic ester compounds I, the transposition of hydrolysis and benzoyl by it can obtain purer Sucrose-6-benzoate.This Sucrose-6-benzoate can also be further purified with the method for recrystallization, and is very favourable to follow-up Sucralose preparation.Present method has the practicality of suitability for industrialized production.
Further illustrate the present invention below in conjunction with drawings and Examples
Fig. 1 trichlorotoluene zotrichloride structural formula
Fig. 2 cyclic ester compounds I
Fig. 3 Sucrose-6-benzoate
Embodiment
Embodiment one
In three mouthfuls of round-bottomed flasks that the 500ml band stirs, 51.3 grams (0.15mol) sucrose is dropped in 250mlDMF, first heat of solution a little, stir again lower refrigeration to-15 ℃～-10 ℃, begin to splash into trichlorotoluene zotrichloride (its structure is seen accompanying drawing 1) 23.4ml (32.3 grams, 0.165mol), dripped off in 2.5 hours, then insulation reaction 2.5 hours.Add water 20ml, stir and add in calcium hydroxide 40 grams after 20 minutes and HCl, the CaCl that elimination generates
2After add again approximately 2 gram calcium hydroxides, making solution PH is 8, continue to stir after 1.5 hours, add the alkalescence of a little 35% hydrochloric acid neutralization reaction liquid, and the insoluble calcium chloride of elimination obtains neutral reaction liquid.Reaction solution through HPLC detect wherein sucrose and the proportion of composing of derivative, and the reaction yield of sucrose 6-benzoic ether.
Reference examples 1 to 2: repeat the operation twice of embodiment 1, but cyclic ester and hydrolysising reacting temperature are changed into respectively 5～10 ℃ and 25～30 ℃
Below totally seven experimental results are as shown in the table
Illustrate:
In upper table, the proportion of composing of sucrose and derivative thereof is sequentially: S-6-B:S-4-B:S-6-6 '-BB: sucrose
● wherein S-6-B, S-4-B, S-6-6 '-BB represent respectively Sucrose-6-benzoate, sucrose-4 benzoic acid ester and sucrose-6-6 ' dibenzoate
Embodiment 6: the end reaction liquid that embodiment 1 is obtained removes solvent under reduced pressure, get approximately 70 grams of thick thing, use the 210ml acetone recrystallization, get the Sucrose-6-benzoate white solid, be weighed as 55.6 grams after vacuum drying, the sucrose 6-benzoic ether content that detects wherein through HPLC is 98.2%.
In three mouthfuls of round-bottomed flasks of the stirring of embodiment 7:1000ml band and logical nitrogen device, add DMF100ml, stir lower refrigeration to-2 ℃, dropping sulfur oxychloride 55ml (0.76mol) maintains the temperature at during dropping below-2 ℃, is added dropwise to complete rear stirring 15 minutes.Maintain the temperature at below-1 ℃, (purity 98.2% 0.107mol), is added dropwise to complete rear stirring 15 minutes to drip the 50 gram S-6-B that are dissolved in 200mlDMF.Be warmed up to 5 ℃ of reactions 30 minutes in 15 minutes, and then be warming up to 115 ℃ of reactions after 4 hours, chlorination is completed, cooling, refrigeration are stirred the downhill reaction system and are dripped 30% aqueous sodium hydroxide solution to 0 ℃, until the PH of reaction system is 9, reacted 1 hour, be 7 with the acetic acid PH that neutralizes.Detect through HPLC, the amount that contains Sucralose-6-benzoic ether in neutralizer is 37.7 grams, and yield is 70.2%.
Embodiment 8: repeat embodiment 7 twice, detect through HPLC, the amount that contains Sucralose-6-benzoic ether in the neutralizer that obtains is respectively 35.5 grams and 38.5 grams, and yield is respectively 70.5% and 71.7%.
Embodiment 9: the subsequent handling that the neutralizer that obtains from above-described embodiment 7 and 8 prepares Sucralose is:
After neutralizer is concentrated into volume and reduces half, add the ethyl acetate extraction of isopyknic water and 2 times of volumes, then use the ethyl acetate extraction twice of same volume, combining extraction liquid is concentrated into dried.
[0046] add the methyl alcohol that is equivalent to 8 times of weight of dry product, transfer PH to 9, alcoholysis reaction 1 hour with sodium methylate.After alcoholysis is completed, be neutralized to PH=7 with acidic resins, be concentrated into driedly, then with the ethyl acetate washing by soaking that is equivalent to 6 times of weight of dry product, take off dried; Use the same method again washing by soaking once after, take off dried; Takes off dry product recrystallization twice, use the water of 1 times of weight at every turn, then the ethyl alcohol recrystallization of using 1 times of weight is once, take off in final vacuum dry the Sucralose the finished product.
Claims (7)
1. the preparation method of a Sucralose; comprise that (1) generates the method for Sucrose-6-benzoate and (2) with the sucrose esterification and Sucrose-6-benzoate made the method for Sucralose as intermediate through extraction, concentrated, alcoholysis reaction Deprotection and recrystallization again, it is characterized in that: the method that the sucrose esterification is generated Sucrose-6-benzoate comprises the following steps:
1. will encircle the esterifying agent trichlorotoluene zotrichloride and splash in the polar aprotic solvent that contains sucrose, the cyclic ester reaction of carrying out under low temperature obtains cyclic ester compounds I, cyclic ester temperature of reaction-30～10 ℃,
2. after cyclic ester reacts completely, add suitable quantity of water to keep the hydrolysis reaction that destroys the trichlorotoluene zotrichloride of traces of unreacted under low temperature and carry out cyclic ester compounds I, obtain Sucrose-6-benzoate and a small amount of sucrose-4 benzoic acid ester, it is relative sucrose 3～12 molar equivalents that hydrolysis reaction adds the water yield, hydrolysis reaction carries out under temperature-30～10 ℃
3. add in calcium hydroxide mineral alkali or pyridine organic bases and react the HCl that produces, the CaCl that elimination is insoluble with cyclic ester reaction and hydrolysis
2After add again appropriate calcium hydroxide, sucrose-4 benzoic acid ester is transformed to Sucrose-6-benzoate under alkaline condition, obtain containing the Sucrose-6-benzoate reaction solution.
2. the preparation method of a kind of Sucralose according to claim 1 is characterized in that: the mol ratio of ring esterifying agent trichlorotoluene zotrichloride and sucrose is 1～1.2.
3. the preparation method of a kind of Sucralose according to claim 1 is characterized in that: the time for adding of ring esterifying agent trichlorotoluene zotrichloride is 1～6 hour.
4. the preparation method of a kind of Sucralose according to claim 1, is characterized in that: 1～10 hour cyclic ester reaction times.
5. the preparation method of a kind of Sucralose according to claim 1, is characterized in that: hydrolysis time 10～100 minutes.
6. the preparation method of a kind of Sucralose according to claim 1 is characterized in that: polar aprotic solvent is selected from a kind of in dimethyl formamide, N,N-DIMETHYLACETAMIDE, Trimethylamine 99, triethylamine, Tributylamine, pyridine, piperidines, N-methylmorpholine, N-ethylmorpholine.
7. the preparation method of a kind of Sucralose according to claim 1, it is characterized in that: carry out after the benzoyl transport reaction obtains containing pure Sucrose-6-benzoate reaction solution, the alkalescence that adds 35% hydrochloric acid neutralization reaction liquid, and the insoluble calcium chloride of elimination, remove again solvent under reduced pressure, and use acetone recrystallization, get pure Sucrose-6-benzoate solid; This Sucrose-6-benzoate solid is used for the Sucralose subsequent preparation process; subsequent preparation process comprises the following steps: use the method that Sucrose-6-benzoate solution is splashed into Vilsmeier reagent; carry out Selective chlorination and obtain Sucralose-6-benzoic ether; again through extraction; concentrated, alcoholysis reaction Deprotection and recrystallization are made Sucralose.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4889928A (en) * | 1986-09-17 | 1989-12-26 | Tate & Lyle Public Limited Company | Sucrose alkyl 4,6-orthoacylates |
| EP0515145A1 (en) * | 1991-05-21 | 1992-11-25 | TATE & LYLE PUBLIC LIMITED COMPANY | Continuous process for the preparation of sucrose 6-esters |
| CN1312164C (en) * | 2003-09-23 | 2007-04-25 | 李宝才 | Method for synthesizing sucralose by monoester method |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4889928A (en) * | 1986-09-17 | 1989-12-26 | Tate & Lyle Public Limited Company | Sucrose alkyl 4,6-orthoacylates |
| EP0515145A1 (en) * | 1991-05-21 | 1992-11-25 | TATE & LYLE PUBLIC LIMITED COMPANY | Continuous process for the preparation of sucrose 6-esters |
| CN1312164C (en) * | 2003-09-23 | 2007-04-25 | 李宝才 | Method for synthesizing sucralose by monoester method |
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