Patent Application
20070207246
This patent application claims the priority right of the Chinese patent application No. 200610038635.6, filed on Mar. 6, 2006.
The invention falls in chemical synthesis field. It is an improvement method of sucralose synthesis yield.
As one of chlor-sugar, sucralose is a kind of new sweetener. It is 600 times sweeter than cane sugar, and does not participate in human metabolism. Sucralose has high safety and strong ability of anti-acidolysis. All of these advantages make sucralose a most popular strong sweetener in the market. Up to present, it has been approved for use in more than thirty countries. The study of sucralose synthesis began from 1970s. At present, the main synthesis methods are mono-group protection method and omni-group protection method, of which the latter is not widely used because of its low yield and complicated operation. Many studies have been conducted about mono-group protection method, such as U.S. Pat. No. 4,889,928, U.S. Pat. No. 5,449,772, CN1453284 and CN1526716, which emphasize the synthesis of sugar-6-acetate but have little study about follow-up chlorination and alcoholysis.
The U.S. Pat. No. 4,977,254 disclosed the method of using chlorinated sulfoxide and a little benzyl tri-ethyl amchlor to react in DCE, but the synthesis yield is only 21%. In the European patent No. EP0043649, it uses chlorinated sulfoxide and pyridine react in chloroform, but the reaction conditions are −75° C. which is too critical to reach in production. What's more, pyridine is toxic and odorous. Most of the present chlorination processes need high temperature and has serious charring and low synthesis yield. In this invention, chlorination can be conducted under mild conditions with a synthesis yield of more than 80%. The genenral yield is about 50% after crystallization. Most studies (such as CN1453284 A) use sodium methylatesodium methoxide as catalyst in the alcoholysis of sucralose easter, but the disadvantage is they can not react completely. In this invention, we take KOH as catalyst, which can make complete reaction without creating any foreign materials, to alcoholize in methanol solution under proper temperature.
Aimed at the above technical problems, the purpose of this invention is to find out a sucralose synthesis yield improvement Method with low cost, high yield, good quality, brief process, mild reaction conditions and stable production.
The invention is realized with support of the following technical measures:
As an improvement method of sucralose synthesis yield, this invention takes azo reagent as catalyst, acetic acid as acylating agent and synthesizes the cane sugar into sugar-6-acetate under proper dissolvent; After being crystallized in a mixed solution of DMF & acetone, the sugar-6-acetate is then synthesized into sucralose-6-acetate with a proper chlorinated reagent under non-proton polar solvent with TCA as the catalyst. And the crude sucralose-6-acetate is recrystallized and purified in a mixed solution of water and alcohol. At last, the alcoholysis of sucralose-6-acetate is completed in KOH/methanol and then the product sucralose is synthesized.
In the above stated improvement method of sucralose synthesis yield, azo reagent is azo di-carboxylic di-ethylmaleate or N,N-cicyclohexylcarbodiimid (DCC).
In the above stated improvement method of sucralose synthesis yield, the dosage of acetic acid used during synthesis of sugar-6-acetate is 1.4-1.5 times of sugar mole, and catalyst dosage is 0.1-0.3 time of sugar mole.
In the above stated improvement method of sucralose synthesis yield, the reaction dissolvent used during synthesis of sugar-6-acetate is N,N-dimethylformamide (DMF) or hexamethyl phosphoramide as one of its feature.
In the above stated improvement method of sucralose synthesis yield, the temperature needed during synthesis of sugar-6-acetate is 10° C.-25° C.
In the above stated improvement method of sucralose synthesis yield, the temperature needed during crystallization of sugar-6-acetate in the mixed solution of DMF and acetone is 30° C.-50° C. And the proportion of acetone to DMF is 2:1˜5:1.
In the above stated improvement method of sucralose synthesis yield, the proper chlorinated reagent are phosphorous pentachloride, Phosphorus trichloride, phosphorus oxychloride, chlorinated sulfoxide or phosgene.
In the above stated improvement method of sucralose synthesis yield, the non-proton polar solvent are N,N-dimethylformamide (DMF), hexamethyl phosphoramide or dimethyl sulfoxide.
In the above stated improvement method of sucralose synthesis yield, the dosage of chlorinated reagent used during the chlorination process of sucralose-6-acetate from sugar-6-acetate is 4-7 times of the mole weight of sugar-6-acetate, and the dosage of TCA is 3-5 times of the mole weight of sugar-6-acetate.
In the above stated improvement method of sucralose synthesis yield, the temperature range needed during chlorination process of sucralose-6-acetate from sugar-6-acetate is −5° C.-80° C.
In the above stated improvement method of sucralose synthesis yield, the alcohol used in mixed solution of alcohol and water during crystallization and purification of the sucralose-6-acetate includes methanol, ethanol, propanol and isopropyl alcohol.
In the above stated improvement method of sucralose synthesis yield, the concentration of alcohol used in mixed solution of alcohol and water during crystallization and purification of the sucralose-6-acetate is 10%˜50%.
In the above stated improvement method of sucralose synthesis yield, the crystallization and purification temperature of sucralose-6-acetate by mixed solution of acetone/DMF is 55° C.˜75° C.
In the above-stated improvement method of sucralose synthesis yield, the PH value in alcoholysis reaction of sucralose-6-acetate is 10-11.
In the above stated improvement method of sucralose synthesis yield, the alcoholysis temperature range of sucralose-6-acetate is 45° C.˜50° C.
The synthesis process from cane sugar to high purity sucralose as follows:
1. Synthesis of Sugar-6-Acetate
In azo di-carboxylic diethylmaleate, sugar and acetic acid can be highly selectively reacted into sugar-6-acetate with very little esterification. The reaction conditions are mild and can be done in room temperature. Usually the reaction lasts 2-8 hours. Sugar transformation efficiency is over 95%. Under the same conditions, using N,N-cicyclohexylcarbodiimid (DCC) instead of azo di-carboxylic diethylmaleate, sugar transformation efficiency is still around 90%. The dosage of acetic acid is about 1.5 times of sugar mole. The more acetic acid, the more impurities.
2. Synthesis of Sucralose-6-Acetate
In the synthesis of sucralose-6-acetate, we were surprised to find that reaction temperature could be greatly reduced with the existance of TCA (80° C. will be OK). In DMF, chloridate reagents (such as phosphoric chloride) exist in ion form; their sublimate temperature is 160° C. and the reaction can be conducted successfully in 80° C. Chlorinaton process can be easily controlled. It can be completed in 8-12 hours without char phenomenon. The product has a good purity and can be crystallized by using of water.
3. Synthesis of Sucralose
The de-acetyl of sucralose-6-acetate will have high yield in methanol solution with KOH as catalyst. Its transformation efficiency is over 90%. In this process, PH value control is the key point. If PH value is higher than 11, impurities will be increased. If PH value is lower than 10, transformation efficiency will be very low. PH value is controlled by KOH addition. Reaction temperature should be controlled at 45° C.˜50° C.
Adopting the above synthesis process, the yield can be more than 35% of sugar on weight basis.
The benefits of this invention:
Compared with the reported sucralose production processes, the invention has features of low cost, high yield rate, good quality, brief process, mild reaction conditions, stable and easy production. It has been checked by a plant with annual capacity of 15 MT, and got perfect achievemnts. The product complies with FCC and USP standards, and the weight yield rate stablly more than 35%.
Although the following detailed description contains many specifics for the purposed of illustration, any one of ordinary skill in the art will appreciate that many variations and alterations to the following details are within the scope of the invention. Accordingly, the following preferred embodiment of the invention is set forth without any loss of generality to, and without imposing limitations upon, the claimed invention.
Practice 1: Synthesis of Sugar-6-Acetate
34.2 g cane sugar suspended on 200 ml DMF, added 3.5 g azo di-carboxylic diethylmaleate, and stir for 30 minutes in room temperature. Then add acetic acid 8.8 g, stir and react for 5 hours in room temperature. Decompress and evaporate the dissolvent and get the floccule 35 g. Under 40° C., add DMF 30 ml into the floccule, stirring. Then 100 ml acetone is dropped. Cooling, we will get crystalline named sugar-6-acetate.
Practice 2: Synthesis of Sugar-6-Acetate
34.2 g cane sugar suspended on 200 ml DMF, added 5 g N,N-cicyclohexylcarbodiimid (DCC), and stir for 30 minutes in room temperature. Then add acetic acid 8.8 g, stir and react for 4 hours in room temperature. Add water 10 ml, stir for 20 minutes. Decompress and evaporate the dissolvent and get floccule 35 g. Under 40° C., add DMF 30 ml into the floccule, stirring. Then 100 ml acetone is dropped. Cooling, we will get crystalline named sugar-6-acetate.
Practice 3: Synthesis of Sucralose-6-Acetate
Dissolve sugar-6-acetate 35 g and PC15 110 g in 300 ml N,N-dimethylformamide (DMF) and cool the dissolvent to −5° C. Add TCA 70 g. Improve the temperature to 80° C. in 6 hours and then keep temperature unchanged for 3 hours reaction. Cool down; add NaHCO3 water solution to neutralize the solution. Extract the product sucralose-6-acetate by using DCM. Use activated carbon to decolor and concentrate the product. Add water 250 ml to dissolve it in 75° C., cool and crystallize it. Then get crude sucralose-6-acetate 26.2 g.
Practice 4: Synthesis of Sucralose-6-Acetate
Dissolve sugar-6-acetate 35 g and PC15 125 g in 300 ml N,N-dimethylformamide (DMF) and cool the dissolvent to −5° C. Add TCA 90 g. Improve the temperature to 80° C. in 6 hours and then keep temperature unchanged for 3 hours reaction. Cool down; add NaHCO3 water solution to neutralize the solution. Extract the product sucralose-6-acetate by using DCM. Use activated carbon to decolor and concentrate the product. Add water 250 ml to dissolve it in 75° C., cool and crystallize it. Then get crude sucralose-6-acetate 25 g.
Practice 5: Purification of Sucralose-6-Acetate
Suspend 20 g crude Sucralose-6-acetate on 30 ml 10% methanol-water solution. Heat to 70° C. to dissolve. Cool it to room temperature slowly and get crystallization. Get pure Sucralose-6-acetate after filtering and drying.
Practice 6: Synthesis of Sucralose
Dissolve 20 g sucralose-6-acetate into 150 ml methanol. KOH controls the PH value of the solution at 11. Reaction lasts for 4 hours under 45° C. Use activated carbon to decolor. Filter and concentrate. Add water 6 ml to dissolve it in 70° C. Cool it gradually to room temperature. Make it standing. Filter and get the product sucralose 12.3 g. It is verified that the concentration is over 99%.
| Number | Date | Country | Kind |
|---|---|---|---|
| 200610038635.6 | Mar 2006 | CN | national |
