CN100395251C - Sucralose synthesis method - Google Patents
Sucralose synthesis method Download PDFInfo
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- CN100395251C CN100395251C CNB2006100232678A CN200610023267A CN100395251C CN 100395251 C CN100395251 C CN 100395251C CN B2006100232678 A CNB2006100232678 A CN B2006100232678A CN 200610023267 A CN200610023267 A CN 200610023267A CN 100395251 C CN100395251 C CN 100395251C
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Abstract
The present invention discloses a method for preparing sucralose. In the method, sucrose is added in pyridine solvent to obtain 3-trityl sucrose; then, the 3-trityl sucrose is protected by acetylation and is hydrolyzed to obtain 5-acetyl sucrose which is in chlorination reaction in mixed solvent containing DMF and thionyl chloride to obtain 5-acetyl sucralose which is hydrolyzed to obtain sucralose. The method of the present invention has the advantages of low cost, high yield, convenient solvent recovery and industrialized production.
Description
Technical field
The present invention relates to food technology field.Be specifically related to a kind of sweetening agent---Synthetic Method of Sucralose.
Background technology
Sucralose (Sucralose, molecular formula C12H19O8Cl13, molecular weight 397.64) is a kind of novel high sugariness non-nutritive sweeting agent (I), its chemical name is 4,1 ', 6 '-three chloro-4,1 ', 6 '-three deoxidation sucralose 4,1 ', 6 '-trichlorogalactosucrose1,6-dichloro-1,6-dideoxy-β-D-fructofurannosyl-4-chloro-4-deoxy-α-D-galactopyranoside
Chemical structural formula is:
(I)
The sugariness of Sucralose is about 600 times of sucrose, does not participate in metabolism in human body, is not absorbed by the body, and heat is 0, is diabetics's ideal sweet taste surrogate.In addition, Sucralose can not be utilized by the carious tooth germ, can not cause carious tooth.Now used as sweetening agent by more than 20 state approvals.
Britain Tate ﹠amp in 1975; Lyle company synthesizes Sucralose.It is the single radical protection method and full radical protection method two classes of raw material that its chemical synthesis process mainly contains with sucrose.
Single radical protection method: 6 hydroxyls in the sucrose molecules are more active.Adopt 6 hydroxyls of acetyl or benzoyl based selective protection, and then selective chlorination, Sucralose obtained after the hydrolysis.Wherein intermediate cane sugar-6-acetic ester (benzoyl ester) preparation mainly contains; The ethyl ester method (US 4,889, and 928; US 5,409, and 772) and Dibutyltin oxide method (US5,023,329; 4,950,746).
1, single functional group method is a 6-ethyl ester sucrose at the key intermediate of chlorination reaction; because the not protection of 7 hydroxyls of residue, the chlorination reaction conditional request is than higher, and side reaction is many; main side reaction is by products such as dichloro sucrose and tetrachloro sucrose, and the impurity separating difficulty of finished product is bigger.Intermediate needs repeatedly just can meet the quality product requirement behind the purifying.
2, full radical protection method: utilize in the sucrose molecules difference of 8 hydroxyls on sterically hindered, with the bigger group (three methyl-phenoxide bases) of volume less relatively primary hydroxyl of guard space steric hindrance optionally, then with the whole acetylizes of remaining hydroxyl, under acidic conditions, slough trityl then, 4 ethanoyl are displaced to 6, make three chloro positions meet particular requirement (Hough L., Carbobydr.Res., 1975,40:285; US 4,343, and 934; US4,362,869; US 4,783, and 526; US 4,801, and 700).Three hydroxyls of chlorination again, deacetylation obtains Sucralose.Full radical protection method reactions steps is more, but the intermediate before the chlorination except three hydroxyls of needs chlorating are not protected, other hydroxyls are all protected, so the chlorination reaction mild condition.Side reaction is less.
US4343934 discloses a kind of preparation 6, the method for 1 ', 6 '-three oxygen-trityl five acetylated sucroses, the employing pyridine is a solvent, and room temperature reaction 4 days obtains 6,1 ', 6 '-three oxygen-trityl sucrose, hydrolysis in acetate, 4 migrate to 6, overall yield of reaction is on the low side, side reaction simultaneously is many, especially the reaction times oversize, have the hydroxyl of a large amount of other positions to be replaced by trityl.US4362869 discloses a kind of method of carrying out 4 migrations 6 with pyridine again, and the actual experiment effect is undesirable.US4801700 discloses a kind of chloridization process, owing to adopt phosgene as chlorination reagent, uses hypertoxicity gas, and actual production requires than higher, requires to add a kind of trichloroethane solvent when adopting sulfur oxychloride, increases solvent recuperation difficulty and solvent consumption cost.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, designs a kind of industrialized synthetic method that is suitable for.
The invention provides a kind of Synthetic Method of Sucralose, this method comprises the following steps:
(1) sucrose and triphenylmethyl chloride carry out optionally etherificate and acetylize in the solvent of pyridine or triethylamine, obtain 6,1 ', 6 '-three oxygen-trityl five acetylated sucroses.The yield of product can be increased to about 85%.
(2) 6,1 ', 6 '-three oxygen-trityl five acetylated sucroses add the normal tosic acid three methyl-phenoxide base hydrolysis of catalysis in methyl alcohol; and 4 ethanoyl migrate to 6 and obtain key intermediate 2 under alkaline condition; 3,6,3 ' 4 '-five oxy-acetyl sucrose (6-PAS).Select for use catalysis equivalent tosic acid hydrolysis trityl to adopt the acetate selectivity that is hydrolyzed good than US4362869, adopt simultaneously TERTIARY BUTYL AMINE carry out 4 migrate to 6 reaction temperature and, overall yield is significantly improved.
(3) 2,3,6,3 ', 4 '-five oxygen-penta-acetyl sucrose (6-PAS) is at sulfur oxychloride and N ', and 115 degree reactions are 1.5 to 4 hours in N '-dimethyl formamide.Obtain five acetyl Sucraloses, content is 88.2%.US5122601 employing phosphorus oxychloride and DMF or phosgene and DMF carry out chlorination reaction.Or the adding trichloroethane is a solvent.This technology directly adopts DMF and sulfur oxychloride to react, and reaction result is satisfied, and the solvent recuperation ratio is easier to.Reduced production cost.
(4) obtain crude product with ethyl acetate refining after, the content of five acetyl Sucraloses can reach 99.1%.
(5) 2,3,6,3 ', 4 ' five acetyl Sucraloses are used sodium hydroxide hydrolysis in methanol system, and crystallization obtains Sucralose in the aqueous solution.Content reaches more than 98.0%
Its chemical process is
The concrete following characteristics of method of the present invention: the 1. reaction yield height of each step; 2. the finished product content that obtains of reaction is up to more than 98.0%; 3. in preparation during five acetyl Sucraloses during reaction conditions, solvent recuperation is easy; 4. production cost is low.Therefore method of the present invention is suitable for suitability for industrialized production.
Embodiment:
Embodiment 1
6,1 ', 6 '-three oxygen-trityl five acetylated sucroses synthetic:
Get 150g sucrose (0.41mol) and 360g (1.25mol) triphenylmethyl chloride joins in the 500ml pyridine, 30-35 ℃ of stirring reaction 30hr, be cooled to 10 ℃, add 600ml diacetyl oxide stirring at normal temperature reaction 6-12hr, reaction product is under agitation slowly added again and separate out white depositions in the frozen water, filtration drying obtains 480g 6,1 ', 6 '-three oxygen-trityl five acetylated sucroses (yield 85%), HPLC checks purity 94.0%.
Embodiment 2
6,1 ', 6 '-three oxygen-trityl five acetylated sucroses synthetic:
Get 150g sucrose (0.41mol) and 360g (1.25mol) triphenylmethyl chloride joins in the 600ml triethylamine, 30-35 ℃ of stirring reaction 30hr, be cooled to 10 ℃, add 600ml diacetyl oxide stirring at normal temperature reaction 6-12h, reaction product is under agitation slowly added again and separate out white depositions in the frozen water, filtration drying obtains 465g 6,1 ', 6 '-three oxygen-trityl five acetylated sucroses (yield 81.4%), HPLC checks purity 92.1%.
Embodiment 3
2,3,4,3 ', 4 '-five oxygen-penta-acetyl sucrose synthetic:
Get 200g6,1 ', 6 '-three oxygen-trityl sucrose pentaacetate is dissolved in the 1000ml methyl alcohol, adds the 5.0g p-methyl benzenesulfonic acid, and 40-45 ℃ was reacted TLC detection reaction terminal point 2-4 hour.Sodium hydroxide neutralization with 2N after reaction finishes obtains the solid trityl alcohol, filters.Mother liquor is evaporated to and driedly obtains 2,3,4,3 ', 4 '-five oxygen-penta-acetyl sucrose ((4-PAS) 84.0g, yield 96.0%).
Embodiment 4
2,3,4,3 ', 4 '-five oxygen-penta-acetyl sucrose (4-PAS) synthetic:
Get 200g6,1 ', 6 '-three oxygen-trityl sucrose pentaacetate is dissolved in the 1000ml methyl alcohol, adds 15ml30% hydrochloric acid, and 40-45 ℃ was reacted TLC detection reaction terminal point 2.5 hours.Reaction finishes the sodium hydroxide neutralization of back with 2N.Filter.Mother liquor is evaporated to and driedly obtains 2,3,4, and 3 ', 4 '-five oxygen-penta-acetyl sucrose (4-PAS) (81.5g).
Embodiment 5
2,3,6, synthetic (6-PAS) of 3 ', 4 '-five oxygen-penta-acetyl sucrose:
Get 200.0g2,3,4,3 ', 4 '-five oxygen-five acetylated sucroses are dissolved in the 1000ml DMF solution, add the 10.0g TERTIARY BUTYL AMINE, 20-25 degree reaction 2.0-2.5 hour, and HPLC shows that 6-PAS content reaches 81.0%, 4-PAS content is 8.9%.Be evaporated to driedly, obtain 225.0g syrupy shape material, wherein contain 6-PAS (75.3%).4-PAS (8.0%), sucrose (4.5%), DMF (7.9%).Add the 500mlDMF dissolving, be directly used in chlorination reaction.
Embodiment 6
2,3,6, synthetic (6-PAS) of 3 ', 4 '-five oxygen-penta-acetyl sucrose:
Experimental technique is suitable with embodiment five, replaces TERTIARY BUTYL AMINE with the 9.5g triethylamine, obtains 220.0g syrupy shape material, wherein contains 6-PAS (73.3%).4-PAS (8.5%), sucrose 4.9%, DMF7.7%.Add the 500mlDMF dissolving, be directly used in chlorination reaction.
Embodiment 7
Obtain 2,3,6 according to embodiment five, 3 ', 4 '-five oxygen-penta-acetyl sucrose (6-PAS) is the syrupy shape material (81.5g); add the 320ml ethyl acetate, crystallisation by cooling obtains 65.5g 2,3; 6,3 ', 4 '-five oxygen-penta-acetyl sucrose (6-PAS), HPLC purity is 95.3%.
Embodiment 8
2,3,6,3 ', 4 '-five oxygen-penta-acetyl Sucralose synthetic:
In the there-necked flask of a 2000ml, nitrogen protection adds DMF900.0ml, is cooled to below 0 ℃, slowly adds sulfur oxychloride 162g (1.36mol).Add, keep the DMF mixing solutions that adds 150g6-PAS (0.302mol) and 330ml below 0 ℃.Add, 60min is warming up to 115 degree.115 degree stirring reactions 1.5-4.0 hour.Be cooled to below 20 ℃ the neutralization of 30% sodium hydroxide solution.Concentrating under reduced pressure reclaims DMF.Add entry 400ml.Ethyl acetate extraction five acetyl Sucraloses.Obtain five acetyl Sucraloses (121.5g) behind the organic layer concentrating under reduced pressure, HPLC check content is 88.2%.
Embodiment 9
2,3,6,3 ', 4 '-five oxygen-penta-acetyl Sucralose refining
In the there-necked flask of a 1000ml, nitrogen protection, adding content is 88.2% five acetyl Sucralose 150g, ethyl acetate 400.0ml; the reflux dissolving adds activated carbon 5.0g and filters, and is cooled to 0～5 ℃; filter, drying obtains five acetyl Sucraloses of 90.2g content 99.1%.Mother liquor can reclaim 20.5g five acetyl Sucraloses.
Embodiment 10
Synthesizing of Sucralose
In the there-necked flask of a 1000ml; nitrogen protection; adding content is 99.1% five acetyl Sucralose 100.0g; methyl alcohol 400.0ml adds 5.0g sodium hydroxide, and 40～45 ℃ of reactions are after 1.5～2.0 hours; Zeo-karb is neutralized to neutrality; remove by filter resin, add activated carbon 5.0g decolouring, be evaporated to dried.Add entry 200ml, concentrating under reduced pressure boils off residual methanol.When moisture reaches 70.0～75.0%.Stop to concentrate, kept 40～50 ℃ of stirred crystallization 4 hours, be cooled to 25 ℃ again, filter.40 ℃ of vacuum-dryings.Obtain the 41.0g Sucralose.HPLC check content reaches 98.8%.Can obtain the 9.1g Sucralose behind the mother liquor concentrating under reduced pressure.
Claims (2)
1. a Synthetic Method of Sucralose is characterized in that this method comprises the following steps:
(1), sucrose and triphenylmethyl chloride in 30-35 ℃, react and carried out optionally etherificate and acetylize in 30 hours in the solvent of pyridine or triethylamine, obtains 6,1 ', 6 '-three oxygen-trityl five acetylated sucroses;
(2), 6,1 ', 6 '-three oxygen-trityl five acetylated sucroses adopt the normal tosic acid of catalysis to make catalyzer, in 40-45 ℃ of reaction three methyl-phenoxide base hydrolysis in 2-4 hour, 4 ethanoyl migrate to 6 and obtain key intermediate 2,3,6 in the presence of TERTIARY BUTYL AMINE or triethylamine again, 3 ' 4 '-five oxygen-penta-acetyl sucrose do not need purifying promptly to can be used for the next step;
(3), 2,3,6,3 ', 4 '-five oxygen-penta-acetyl sucrose is at sulfur oxychloride and N ', 115 ℃ of reactions are 1.5-4 hour in N '-dimethyl formamide, obtain five acetyl Sucraloses;
(4), obtain content after refining with ethyl acetate be 99.1% five acetyl Sucraloses to five acetyl Sucraloses;
(5), five acetyl Sucraloses use the sodium hydroxide solution hydrolysis in methyl alcohol, obtain Sucralose.
2. a kind of Synthetic Method of Sucralose according to claim 1 is characterized in that sulfur oxychloride and 2,3,6 in the wherein said step (3), and the ratio of 3 ', 4 '-five oxygen-penta-acetyl sucrose is 3.0～10.0mol: 1.0mol.
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| CNB2006100232678A CN100395251C (en) | 2006-01-12 | 2006-01-12 | Sucralose synthesis method |
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| CNB2006100232678A CN100395251C (en) | 2006-01-12 | 2006-01-12 | Sucralose synthesis method |
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100415762C (en) * | 2006-08-28 | 2008-09-03 | 江南大学 | Preparation method of intermediate for synthesizing trichloro saccharose |
| CN100480252C (en) * | 2006-10-13 | 2009-04-22 | 恩滋药业(南京)有限公司 | Sucrose derivative and preparing method thereofr, and method for synthesizing trichloro sucrose utilizing same |
| CN101012253B (en) * | 2007-02-06 | 2010-04-14 | 启东东岳药业有限公司 | Method of preparing 6-PAS |
| KR20080073879A (en) * | 2007-02-07 | 2008-08-12 | 주식회사 일신케미칼 | Preparation method of sucralose |
| CN101367849B (en) * | 2007-08-15 | 2012-03-21 | 常州市牛塘化工厂有限公司 | Preparation method for sucrose trichloride -2,3,6,3',4'-pentaacetate |
| CN105707831A (en) * | 2016-03-03 | 2016-06-29 | 李云军 | Environment-friendly sucralose |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4362869A (en) * | 1907-12-02 | 1982-12-07 | Talres Development (N.A.) N.V. | Process for the preparation of 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4362869A (en) * | 1907-12-02 | 1982-12-07 | Talres Development (N.A.) N.V. | Process for the preparation of 4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose |
Non-Patent Citations (6)
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| 三氯蔗糖的基团迁移法合成研究. 李晔等.食品科学，第25卷第1期. 2004 |
| 三氯蔗糖的基团迁移法合成研究. 李晔等.食品科学，第25卷第1期. 2004 * |
| 全基团保护法制备三氯蔗糖的原理. 郑建仙等.食品与发酵工业，第27卷第7期. 2001 |
| 全基团保护法制备三氯蔗糖的原理. 郑建仙等.食品与发酵工业，第27卷第7期. 2001 * |
| 全基团保护法制备三氯蔗糖的研究. 郑建仙等.食品与发酵工业，第28卷第2期. 2002 |
| 全基团保护法制备三氯蔗糖的研究. 郑建仙等.食品与发酵工业，第28卷第2期. 2002 * |
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Effective date of registration: 20111220 Address after: 201203 Shanghai Zhangjiang High Tech Park of Pudong New Area Cailun Road No. 780 building 214 room 2 Co-patentee after: Dafeng Haijianuo Pharmaceutical Co., Ltd. Patentee after: Shanghai Hegno Pharmaceuticals Holding Co., Ltd. Co-patentee after: Shanghai Disainuo Vitamin Co., Ltd. Address before: 201203 north head of Binhai Industrial Area, Nanhui District, Shanghai Patentee before: Shanghai Disainuo Vitamin Co., Ltd. |
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