CN101613379A - A kind of preparation method of Sucralose - Google Patents

Abstract

A kind of preparation method of Sucralose, to compare operation more simple with the traditional preparation process method for it.Wherein in removing the process of protecting group, use easy volatile bases compound, only need then just can obtain the pure product of Sucralose that ignition residue content and purity all meet the American market standard through primary crystallization as catalyzer.

Description

A kind of preparation method of Sucralose

Technical field

The present invention relates to a kind of preparation method of Sucralose, more specifically, relate to the preparation method of the more simple Sucralose of a kind of preparation process.

Background technology

Sucralose, chemical name are 4,1 ', 6 '-three chloro-, 4,1 ', 6 '-three deoxidation sucralose.

Sucralose is a kind of sugariness height, no calorific value, pure taste, stable in properties, novel sweetener safe in utilization, be the most excellent sweeting agent kind of over-all properties of generally acknowledging at present, be widely used in the numerous food such as beverage, cake, pickles, ice-creams, assembled alcoholic drinks, chewing gum, healthcare products.Because Sucralose not by metabolism, does not provide any heat, and do not cause carious tooth etc., be fit to therefore comprise that diabetic subject, children's etc. various crowds are edible in human body.

The U.S. uses the maximum country of Sucralose at present in the world, can use Sucralose, the U.S. to formulate strict quality standard safely in order to guarantee people.At present, these standards of being formulated by the U.S. are extensively adopted by Sucralose manufacturing firm, and become industry standard.Sucralose by manufacturing firm's preparation must reach above-mentioned quality standard when dispatching from the factory, otherwise can't come into the market.

The Sucralose quality standard that the U.S. formulates is all on the books in FCC4 (U.S. food chemical code) and USP 28 (American Pharmacopeia), its particular content following (percentage composition all is weight percentage):

Proterties powder (white is to the near-white crystallinity)

Content % 98.0～102.0

Moisture %≤2.0

Ignition residue %≤0.7

Methyl alcohol %≤0.1

Heavy metal (in Pb) mg/kg≤10

Specific rotation (in anhydride)+84.0 °～+ 87.5 °

Hydrolysate is qualified

Related substance is qualified

In above-mentioned quality standard, the content of ignition residue is an important indicator, if the content of ignition residue does not reach above-mentioned standard (≤0.7%) in the Sucralose, can't come into the market to sell.In traditional sucralose production method,, need through loaded down with trivial details treating processes usually for the content that makes ignition residue reaches above-mentioned standard.

Synthetic Method of Sucralose mainly contains three kinds at present, that is: raffinose method, full radical protection method and monoesters method.In three kinds of synthetic methods, all be to form suc as formula the compound shown in (I) earlier.

Wherein, R is the acyl group of 2-7 carbon; R1, R2, R3, R4 are all H or ethanoyl.

By transesterification reaction or hydrolysis reaction, slough the protecting group in the formula (I) then, form the Sucralose shown in the formula (II), and then, obtain the pure product of Sucralose by purification steps such as recrystallizations.

In traditional deprotection based method, generally use alkali metal containing ionic alkaline matter as catalyzer, for example sodium methylate or alkali metal hydroxide etc.Conventional way is, exsiccant formula (I) compound is dissolved in the lower alcohol, adds basic catalysts such as quantitative sodium methylate, reacts the regular hour under suitable temperature, can remove protecting group.Such method is at US4380476, and US4980463 all has description in the documents such as CN1176094C.

But; in above-mentioned traditional preparation method; owing to used alkali metal containing ionic alkaline matter in deprotection base process, and these alkalimetal ions can remain in the follow-up product, cause the ignition residue content in the Sucralose not reach above-mentioned quality standard.For the content that makes ignition residue meets the requirements, the essential content that reduces alkalimetal ion.In order to reach this purpose, the technician can carry out crystallization treatment repeatedly with the Sucralose product that obtains after the deprotection base usually, perhaps by behind the residual alkalimetal ion of ion exchange resin removal, carries out crystallization treatment again.No matter take above-mentioned which kind of post-treating method, all can make production cycle prolongation, more complicated, the production cost increase of production operation.

Summary of the invention

In order to address the above problem, in the process of deprotection base, the present invention uses easy volatile bases compound as catalyzer, found that, can carry out deprotection reaction to formula (I) compound easily equally, and adopt this method, and have following clear superiority: (1) reaction conditions gentleness, simple to operate; (2) the easy volatile bases compound of Jia Ruing can be easy to be removed, and carries out the primary crystallization processing ignition residue content of product is met the requirements.

Above-mentioned easy volatile bases compound mainly comprises a series of nitrogenous organic bases compounds, as ammonia, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, butylamine, TERTIARY BUTYL AMINE, quadrol etc., these bases compounds can use separately, also can be dissolved in other solvent and using, as ammoniacal liquor etc., two kinds or this type of two or more compound can also be used.The addition of bases is on concrete kind and alkalescence is strong and weak decide, the ph value of system is remained between the 9-10 get final product, if the ph value is low excessively, it is difficult then to react generation; Otherwise, if the ph value is too high, then not only can increase production cost, also may bring difficulty to subsequent disposal.

Concrete operations are as follows: formula (I) compound is dissolved in the mixed solvent of lower alcohol or lower alcohol and water, add a certain amount of easy volatile bases compound, react the regular hour at a certain temperature, formula (I) compound can be converted into Sucralose, solution is through decolouring, filtration, the filtrate reconcentration is to certain concentration, and crystallisation by cooling can obtain crystalline sucralose.

In theory, all formulas (I) compound all can remove protecting group by this method and obtain Sucralose, and the formula here (I) compound mainly is meant Sucralose carboxylic acid esters with practical value; specifically comprise: sucralose-6-acetic ester, Sucralose-6-propionic ester, Sucralose-6-butyric ester; Sucralose-6-valerate, Sucralose-6-benzoic ether, 4; 1 ', 6 '-three chloro-4,1 '; 6 '-three deoxidation sucralose-2,3,6; 3 ', 4 '-pentaacetate etc.

In this reaction process, alcohols not only plays the effect of dissolution type (I) compound as solvent, also participate in reaction simultaneously as reagent, wherein, alcohols can be under the effect of basic catalyst and formula (I) compound generation transesterification reaction, and then obtains Sucralose.Wherein alcohols is generally selected lower alcohols for use, as methyl alcohol, ethanol, propyl alcohol, butanols, amylalcohol etc.The consumption of alcohols is The more the better in theory, and among the present invention, the consumption of alcohols generally is 2-8 a times of formula (I) compound weight, is preferably 2-5 doubly.

In this reaction process, the content of water is few more good more in theory.But we find also can contain a certain proportion of water in the reaction system, are not higher than at about 40% o'clock at the content of water, reaction is not had disadvantageous effect, no matter water enters system by which kind of approach, is that material is carried secretly and entered, still artificial the introducing, the result is the same.

This type of reaction pair temperature of reaction requires also not strict, all can react between room temperature and reflux temperature, and when temperature was high, the reaction times was shorter, and when temperature was hanged down, the reaction times will be grown relatively, generally is advisable due to 20-60 ℃.

Reaction times is relevant because of the kind and the temperature of reaction of volatile bases, generally gets final product at 2-8 hour.

For the product that obtains after the deprotection base, only need carry out primary crystallization, just can obtain the satisfactory Sucralose product of ignition residue content and purity.Wherein, being used for crystalline solution can be organic solvent and water, also can be the mixture of the two, preferred organic solvent wherein, and organic solvent can be pure organic solvent, also can be the mixture of different organic solvents.Preferred organic comprises ethyl acetate, butylacetate, butanols, dimethylbenzene etc.

Describe the present invention in detail with embodiment below:

Embodiment

Embodiment 1

Trichloro-cane-6-ethyl ester 20g is added in the 70ml methyl alcohol, is heated to 40-50 ℃, treat that material dissolves fully after, add 5ml 40% aqueous methylamine solution, insulation reaction 2-3 hour, stopped reaction.Activated carbon decolorizing, filtration.Filtrate is concentrated into pulpous state, adds the 100ml ethyl acetate, continues to be concentrated into crystallization to occur.Filter the dry Sucralose (purity 99.1%, ignition residue 0.08%) that gets.

Embodiment 2

Trichloro-cane-6-ethyl ester 20g is added in the 70ml methyl alcohol, is heated to 40-50 ℃, treat that material dissolves fully after, add the 2ml TERTIARY BUTYL AMINE, insulation reaction 2-3 hour, stopped reaction.Activated carbon decolorizing, filtration.Filtrate is concentrated into pulpous state, adds the 100ml butylacetate, continues to be concentrated into crystallization to occur.Filter the dry Sucralose (purity 99.2%, ignition residue 0.1%) that gets.

Embodiment 3

Trichloro-cane-6-ethyl ester 20g is added in 50ml methyl alcohol and the 20ml water, is heated to 40-50 ℃, treat that material dissolves fully after, add the 2ml TERTIARY BUTYL AMINE, insulation reaction 2-3 hour, stopped reaction.Activated carbon decolorizing, filtration.Filtrate is concentrated into pulpous state, adds the 100ml ethyl acetate, continues to concentrate and constantly add ethyl acetate to crystallization occurring.Filter the dry Sucralose (purity 98.7%, ignition residue 0.18%) that gets.

Embodiment 4

Trichloro-cane-6-ethyl ester 20g is added in the 70ml methyl alcohol, is heated to 40-50 ℃, treat that material dissolves fully after, add the ammoniacal liquor of 4ml 30%, insulation reaction 2-3 hour, stopped reaction.Activated carbon decolorizing, filtration.Filtrate is concentrated into pulpous state, adds the 100ml ethyl acetate, continues to be concentrated into crystallization to occur.Filter the dry Sucralose (purity 98.9%, ignition residue 0.15%) that gets.

Embodiment 5

Trichloro-cane-6-ethyl ester 20g is added in the 80ml ethanol, is heated to 40-50 ℃, treat that material dissolves fully after, add the 3ml TERTIARY BUTYL AMINE, insulation reaction 2-3 hour, stopped reaction, activated carbon decolorizing, filtration.Filtrate is concentrated into pulpous state, adds the 100ml ethyl acetate, continues to be concentrated into crystallization to occur.Filter the dry Sucralose (purity 99.0%, ignition residue 0.12%) that gets.

Embodiment 6

With 4,1 ', 6 '-three chloro-, 4,1 ', 6 '-three deoxidation sucralose-2,3,6,3 ', 4 '-pentaacetate 30g is added in the 90ml methyl alcohol, is heated to 40-50 ℃, treat that material dissolves fully after, add the 4ml TERTIARY BUTYL AMINE, insulation reaction 6-7 hour, stopped reaction.Activated carbon decolorizing, filtration.Filtrate is concentrated into pulpous state, adds the 100ml ethyl acetate, continues to concentrate and constantly add ethyl acetate to crystallization occurring.Filter the dry Sucralose (purity 98.6%, ignition residue 0.2%) that gets.

Embodiment 7

Sucralose-6-benzoic ether 40g is added in the 150ml methyl alcohol, is heated to 40-50 ℃, treat that material dissolves fully after, add the 5ml TERTIARY BUTYL AMINE, insulation reaction 2-3 hour, stopped reaction.Activated carbon decolorizing, filtration.Filtrate is concentrated into pulpous state, adds the 100ml ethyl acetate, continues to concentrate and constantly add ethyl acetate to crystallization occurring.Filter the dry Sucralose (purity 98.5%, ignition residue 0.2%) that gets.

Comparative examples 1

Trichloro-cane-6-ethyl ester 20g is added in the 50ml methyl alcohol, is heated to 40-50 ℃, treat that material dissolves fully after, add the sodium methoxide solution of 2ml 30%, insulation reaction 2-3 hour, stopped reaction.Activated carbon decolorizing, filtration.Filtrate is concentrated into pulpous state, adds the 100ml ethyl acetate, continues to be concentrated into crystallization to occur.Filter the dry Sucralose (purity 97.8%, ignition residue 0.8%) that gets.

Claims (10)

1. method by formula (I) compound Sucralose, comprise steps such as removing protecting group and crystallization, it is characterized in that, with formula (I) compound and alcoholic solvent and a certain amount of easy volatile bases compound, under suitable temperature, react for some time, slough the protecting group of formula (I) compound, be translated into Sucralose;

Wherein, R is the acyl group of 2-7 carbon; R1, R2, R3, R4 are all H or ethanoyl.

2. method according to claim 1, its Chinese style (I) compound comprises: sucralose-6-acetic ester, Sucralose-6-propionic ester, Sucralose-6-butyric ester, Sucralose-6-valerate, Sucralose-6-benzoic ether and 4,1 ', 6 '-three chloro-, 4,1 ', 6 '-three deoxidation sucralose-2,3,6,3 ', 4 '-pentaacetate.

3. method according to claim 1, wherein alcoholic solvent comprises the mixture of lower alcohol, lower alcohol, or the mixture of lower alcohol and water.

4. method according to claim 3, wherein lower alcohol comprises methyl alcohol, ethanol.

5. according to the described method of claim 3-4, wherein total consumption of alcoholic solvent be formula (I) compound weight 2-8 doubly.

6. method according to claim 1, wherein volatile bases comprises ammonia, methylamine, dimethylamine, Trimethylamine 99, ethamine, diethylamine, triethylamine, butylamine, TERTIARY BUTYL AMINE, quadrol.

7. method according to claim 1, the weight ratio of its Chinese style (I) compound and volatile bases is 100: 0.5 to 100: 30.

8. method according to claim 1, the temperature of reaction that wherein removes protecting group is 20-60 ℃.

9. according to the described method of claim 1-4, wherein with an organic solvent carry out crystallization to removing the Sucralose that obtains after the protecting group.

10. method according to claim 9, organic solvent wherein comprises ethyl acetate, butylacetate.