CN100480252C - Sucrose derivative and preparing method thereofr, and method for synthesizing trichloro sucrose utilizing same - Google Patents
Sucrose derivative and preparing method thereofr, and method for synthesizing trichloro sucrose utilizing same Download PDFInfo
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Abstract
The invention discloses sucrose derivative, its method of preparation, and the method used it to compound sucralose. The sucrose derivative (I) is 1', 6'-protective sucrose alkyl 4, 6-ortho ester whose method of preparation is that the 4, 6-ortho ester reacts with the protective group corresponding R1-C1 or R1-Br and alkali in organic solvent. The sucrose derivative (II) is 2, 3, 1', 3', 4', 6'-protective sucrose alkyl 4, 6-ortho ester whose method of preparation is that the sucrose derivative I reacts with acid anhydride, or acyl chloride and alkali in organic solvent. The method of preparation of the sucralose is that the compound II reacts in acid and water or acid and organic solvent to produce compound III which reacts with thionyl chloride in organic solvent to produce compound IV whose alcoholic solution is added alkali to react. The invention has the advantages of high yield, and high purity.
Description
One, technical field
The present invention relates to sucrose derivative, and preparation method thereof and the application in Sucralose is synthetic.
Two, background technology
Sucralose (chemical name is 4,1 ', 6 '-three chloro-, 4,1 ', 6 '-three deoxidation sucralose, and commodity are called Sucralose, structural formula is as follows) be a kind of novel sweetener.Sweeting agent is the foodstuff additive of giving the food sweet taste, and is extensive in Applications in Food Industry.Characteristics such as sucrose is the most ancient sweeting agent in broad terms, and it is good to have mouthfeel, inexpensive.Sucralose behind the sucrose part chloro had both been kept the characteristics of sucrose, had more plurality of advantages such as the high and low calorific value of sugariness, nontoxic, anti-dental caries, thereby become the most competitive a kind of sweeting agent.
Compare with traditional sweeting agent, the sugariness of Sucralose is 600 times of sucrose, and its sweet taste is pure, and mouthfeel and be similar to natural sucrose does not have common offending smell or the mouthfeel of bringing of other sweeting agents.What is more important, Sucralose have absolute security, without any the query of safety toxicity aspect.In addition, the Sucralose caloric value is zero, thereby can supply adiposis patient, cardiovascular patient and the elderly etc. edible; Simultaneously, edible Sucralose can not cause blood glucose fluctuation, and is favourable to the diabetics; Can not cause that dental caries become, and help dental health; Have good solvability and stability, range of application is very extensive.
Sucralose just was found as far back as nineteen seventies.But for synthesizing of Sucralose, especially industrialization at present, is gone back very ideal technology of none.This is because the uniqueness of Sucralose structure determines.Eight hydroxyls are arranged in the sucrose molecules, Sucralose optionally replaces three hydroxyls wherein and keeps other five with chlorine, the position and the configuration that replace all have specific requirement, the replacement of different positions and isomorphism type will be to the mouthfeel and the sugariness important influence of Sucralose.Therefore, how to guarantee that the regioselectivity that replaces is the key point of every kind of route of synthesis.
People know that in sucrose molecules, position that each hydroxyl is got and activity are different, and it is in proper order: 6 '-C〉6-C〉4-C〉1 '-C〉2-C〉3-C〉3 '-C〉4 '-C.With regard to chlorination; in the superincumbent order, 6 '-C, 4-C, 1 '-C is needed position, and 6-C then is the position of not wishing chloro; and the core of ester method manages to make the 6-C position to be protected exactly, obtains Sucralose through reactions such as chloro, deacetylations more afterwards.
At present, difference different with the kind of the formed intermediate of hydroxyl in the sucrose and guard method is divided into ether method and ester method to the method for synthesizing trichloro according to blocking group.The ether method is put forward by British Hugh L., and this also is a synthesizing trichloro method the earliest.Through the development of decades, the ether method has had the intermediate convenient separation, advantages such as easy control of reaction conditions, but simultaneously, its shortcoming is also very obvious, and that is exactly that step is many, cost of material height, productive rate low (being no more than 30%), production cost height.Compare with the ether method, the productive rate of ester method increases, and still, because need to use the reagent of comparison costliness in the step of ester method, as dibutyl tin oxide, therefore, the ester method also is unfavorable for reducing cost.
Three, summary of the invention
1, goal of the invention: the purpose of this invention is to provide a kind of new sucrose derivative (general formula I, II), and preparation method thereof with the method for utilizing the sucrose derivative synthesizing trichloro.
2, technical scheme: the structural molecule formula and the building-up process of sucrose derivative of the present invention are expressed as follows:
Sucrose derivative structural molecule formula with general formula (I) (the sucrose alkyl 4 of 1 ', 6 '-protection, 6-ortho ester) is:
R wherein
1For aromatic base or alkyl, as methyl or phenyl; R
1' be alkyl, as methyl or ethyl; R
2Be trityl, or contain silica-based protecting group, silica-based as tert-butyl diphenyl.
Sucrose derivative structural molecule formula with general formula (II) (the sucrose alkyl 4 of 2,3,1 ', 3 ', 4 ', 6 '-protection, 6-ortho ester) is:
R wherein
1For aromatic base or alkyl, as methyl or phenyl; R
1' be alkyl, as methyl or ethyl; R
2Be trityl, or contain silica-based protecting group, silica-based as tert-butyl diphenyl; R
3Be ethanoyl, or benzoyl.
Building-up process is expressed as follows:
R
1Expression alkyl or aromatic base; R
1' the expression alkyl; R
2Expression trityl (CPh
3, English Trityl by name) or contain silica-based protecting group; R
3Expression ethanoyl, or benzoyl.
The preparation method of sucrose derivative I of the present invention may further comprise the steps:
Sucrose alkyl 4, the organic solvent solution of 6-ortho ester A (0.1 mole), as pyridine, tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, chloroform, methylene dichloride or N in the dinethylformamide solution, add excessive and the muriate R protecting group correspondence
1-Cl or bromide R
1-Br, as tri-benzoyl chlorine or chlorination tert-butyl diphenyl silicon (0.2 mole to 0.5 mole, wherein, with 0.4 mole for well, 0.22 mole is best), and add alkali, as imidazoles, pyridine, triethylamine or diisopropylethylamine (0.2 mole to 0.5 mole, wherein, with 0.4 mole for well, 0.22 mole is best), 5 to 30 degree (wherein, for well, 25 degree are best with 15 degree) stirring 4 to 16 hours (wherein, with 12 hours for well, 4 hours the bests).Reaction finishes, and concentrates, and adds ethyl acetate, chloroform or methylene dichloride and water, and organic layer concentrates, and drying obtains sucrose derivative I (productive rate〉95%) under the vacuum.
The preparation method of sucrose derivative II of the present invention may further comprise the steps:
The organic solvent solution of sucrose derivative I (0.1 mole), as pyridine, toluene, tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, chloroform, methylene dichloride or N, N '-dimethyl formamide (wherein, toluene is for well, pyridine the best) adds acid anhydrides in the solution, as four below the carbon acid anhydrides or the fragrant acid anhydrides (with benzoyl oxide, propionic anhydride is for well, diacetyl oxide the best) or acyl chlorides, as four below the carbon acyl chlorides or the fragrant acyl chlorides (with Acetyl Chloride 98Min., Benzoyl chloride is for well), and alkali, as pyridine, triethylamine or imidazoles reaction, 5 to 30 degree (wherein, for well, 25 degree are best with 15 degree) stirring 12 to 28 hours (wherein, with 12 hours for well, 16 hours the bests), concentrate, drying obtains sucrose derivative II (productive rate〉95%) under the vacuum.
The preparation method of Sucralose of the present invention may further comprise the steps:
A, sucrose derivative II (0.1 mole) is in water and acid, as acetate, tosic acid, mixing solutions (the volume ratio 1/2 to 1/8 of hydrochloric acid or sulfuric acid (acetate the best), wherein, with 1/5 for well, 1/2 the best), or at organic solvent, as the first tertbutyl ether, ether, tetrahydrofuran (THF), alcohol less than 10 carbon, (with Virahol for well, methyl alcohol the best) and acid, as acetate, tosic acid, the mixing solutions of sulfuric acid or hydrochloric acid (sulfuric acid for well, hydrochloric acid is good), 5 to 30 degree are (wherein, with 15 degree for well, 25 degree are best) stir 12 to 28 hours (wherein, with 12 hours for well, 16 hours the bests), concentrate, drying obtains sucrose derivative III (productive rate〉95%) under the vacuum.
B; the organic solvent solution of sucrose derivative III (0.1 mole); as N, N '-dimethyl formamide solution or pyridine are under nitrogen protection; be cooled to-10～0 degree (wherein; with 0 degree for well ,-10 degree the bests), thionyl chloride (0.4 mole); stir after 1 hour; be warming up to the 50-70 degree (wherein, with 50 degree for well, 70 degree the bests); stir 2 to 4 hours (wherein; with 2 hours for well, 4 hours the bests), be cooled to 0 degree; add the neutralization of NaOH solution; add ethyl acetate; chloroform or dichloromethane extraction, organic layer concentrate, and drying obtains sucrose derivative IV (productive rate〉90%) under the vacuum.
C, the alcoholic solution of sucrose derivative IV (0.1 mole), as less than the alcoholic solution of 10 carbon (with Virahol, ethanol is for well, methyl alcohol the best) adds alkali in, as sodium alkoxide less than 10 carbon, potassium alcoholate or caustic alkali, (0.55 mole, with sodium hydroxide, lithium hydroxide, hydrated barta, sodium ethylate is for well, sodium methylate or potassium hydroxide the best), 5 to 30 degree (wherein, for well, 25 degree are best with 15 degree) reaction stirring 12 to 28 hours (wherein, with 12 hours for well, 16 hours the bests), add the weakly acidic resin neutralization, filter, concentrate, be drying to obtain Sucralose (productive rate〉90%) under the vacuum.
3, beneficial effect: the present invention compared with prior art; its remarkable advantage is: position and active difference that this patent utilizes each hydroxyl to get; with sucrose alkyl 4,6-ortho ester (literature method, U.S. Pat 4889928) is respectively with two kinds of different blocking group protections.The intermediate that whole hydroxyls have been protected is being sloughed blocking group on the higher carbon of three activity earlier under the acidic conditions, after the chlorination more in addition all blocking groups slough, can high yield obtain highly purified Sucralose.
Four, embodiment
The following examples can more fully be understood the present invention, but do not limit the present invention in any way.
Embodiment 1:
Step 1: in pyridine (200mL) solution of compound 1 (0.1 mole), add tri-benzoyl chlorine (0.22 mole).25 degree stirred 16 hours down, concentrated, and added ethyl acetate and water, and organic layer concentrates, and drying obtains compound 2 (productive rate〉95%) under the vacuum.
Step 2: add diacetyl oxide (0.45 mole) in pyridine (200mL) solution of compound 2 (0.1 mole), 5 degree stirred 28 hours down, concentrated, and drying obtains compound 3 (productive rate〉95%) under the vacuum.
Step 3: (1/5,300mL) solution 20 degree stirred 12 hours down water/the acetate of compound 3 (0.1 mole), concentrated, and drying obtains compound 4 (productive rate〉95%) under the vacuum.
Step 4: the N of compound 4 (0.1 mole); N '-dimethyl formamide (150mL) solution is cooled to-10 degree, thionyl chloride (0.4 mole) under nitrogen protection; stir after 1 hour; be warming up to 70 degree, stirred 4 hours, be cooled to 0 degree; add the neutralization of NaOH solution; add ethyl acetate extraction, organic layer concentrates, and drying obtains compound 5 (productive rate 91%) under the vacuum.
Step 5: add potassium hydroxide (0.55 mole) in methyl alcohol (200mL) solution of compound 5 (0.1 mole), 5 degree reaction down stirred 12 hours, added weakly acidic resin and were neutralized to pH=6.0, filtered, concentrate, be drying to obtain Sucralose (productive rate 92%) under the vacuum.
Embodiment 2:
Step 1: add the pyridine solution of Benzoyl chloride (0.5 mole) in pyridine (200mL) solution of compound 2 (0.1 mole), 5 degree down reaction stirred 12 hours, concentrated, and drying obtains compound 6 (productive rate〉95%) under the vacuum.
Step 2: add concentrated hydrochloric acid (10mL) in methyl alcohol (300mL) solution of compound 6 (0.1 mole), 30 degree reaction down stirred 16 hours.The reaction reactant that finishes concentrates, and drying obtains compound 7 (productive rate〉95%) under the vacuum.
Step 3: identical with the step 4 among the embodiment 1, obtain compound 8 (productive rate 95%).
Step 4: add sodium methylate (0.55 mole) in methyl alcohol (200mL) solution of compound 8 (0.1 mole), 5 degree reaction down stirred 12 hours, added weakly acidic resin and were neutralized to pH=6.0, filtered, and concentrated, and were drying to obtain Sucralose (productive rate 91%) under the vacuum.
Claims (22)
1, a kind of sucrose derivative with following general formula (I):
R wherein
1Be phenyl or alkyl; R
1' be alkyl; R
2Be trityl, or tert-butyl diphenyl is silica-based.
2, sucrose derivative according to claim 1 is characterized in that wherein R
1The expression carbonatoms is less than 4 alkyl, or phenyl; R
1' the expression carbonatoms is less than 4 alkyl.
3, the preparation method of the described sucrose derivative of claim 1, it is characterized in that this method may further comprise the steps: sucrose alkyl 4 with following general formula, 6-ortho ester A is in organic solvent, and alkali, muriate or bromide with trityl, or silica-based muriate or the bromide reaction of tert-butyl diphenyl, obtain required product;
4, the preparation method of sucrose derivative according to claim 3 is characterized in that wherein said organic solvent is a pyridine, tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, chloroform, methylene dichloride or N, dinethylformamide.
5, the preparation method of sucrose derivative according to claim 3 is characterized in that wherein said alkali is imidazoles, pyridine, triethylamine, or diisopropylethylamine.
6, a kind of sucrose derivative with following general formula (II):
R wherein
1Be phenyl or alkyl; R
1' be alkyl; R
2Be trityl, or tert-butyl diphenyl is silica-based; R
3Be the acetyl or benzoyl base.
7, sucrose derivative according to claim 6 is characterized in that wherein R
1The expression carbonatoms is less than 4 alkyl, or phenyl; R
1' the expression carbonatoms is less than 4 alkyl.
8, the preparation method of the described sucrose derivative of claim 6 is characterized in that this method may further comprise the steps: the described sucrose derivative with general formula (I) of claim 1 is in organic solvent, and alkali, and acid anhydrides or acyl chloride reaction, obtains required product.
9, preparation method according to claim 8 is characterized in that wherein said acid anhydrides is a carbonatoms less than 4 acid anhydrides or benzoyl oxide; Acyl chlorides is a carbonatoms less than 4 acyl chlorides or Benzoyl chloride.
10, preparation method according to claim 9 is characterized in that wherein said acid anhydrides is diacetyl oxide or benzoyl oxide; Acyl chlorides is Acetyl Chloride 98Min. or Benzoyl chloride.
11, preparation method according to claim 8 is characterized in that wherein said organic solvent is a pyridine, tetrahydrofuran (THF), ethyl acetate, acetonitrile, acetone, chloroform, methylene dichloride or N, N '-dimethyl formamide.
12, preparation method according to claim 8 is characterized in that wherein said alkali is pyridine, triethylamine, or imidazoles.
13, a kind of method of utilizing the sucrose derivative synthesizing trichloro is characterized in that this method may further comprise the steps:
(1) will have the sucrose derivative of general formula (II)
R wherein
1Be phenyl, or alkyl; R
1' be alkyl; R
2Be trityl, or contain silica-based protecting group; R
3Be the acetyl or benzoyl base;
Reaction obtains compound III in acid and water or acid and organic solvent;
(2) compound III and thionyl chloride are reacted in organic solvent and are obtained compound IV;
(3) add alkali reaction in the alcoholic solution of compound IV, obtain Sucralose.
14, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 13 is characterized in that in step (1) acid is acetate, tosic acid, hydrochloric acid or sulfuric acid.
15, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 13 is characterized in that in step (1), and organic solvent is a carbonatoms less than 10 alcohol, ether, first tertbutyl ether or tetrahydrofuran (THF).
16, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 15 is characterized in that in step (1), organic solvent is methyl alcohol or ethanol.
17, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 13 is characterized in that in step (2), organic solvent is N, N '-dimethyl formamide or pyridine.
18, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 13 is characterized in that in step (3), and alcohol is carbonatoms less than 10 alcohol.
19, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 18 is characterized in that in step (3) alcohol is methyl alcohol or ethanol.
20, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 13 is characterized in that in step (3), and alkali is carbonatoms less than 10 sodium alkoxide or potassium alcoholate.
21, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 20 is characterized in that in step (3), alkali is sodium methylate or sodium ethylate.
22, the method for utilizing the sucrose derivative synthesizing trichloro according to claim 13 is characterized in that in step (3), alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide or hydrated barta.
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| CNB2006100967621A CN100480252C (en) | 2006-10-13 | 2006-10-13 | Sucrose derivative and preparing method thereofr, and method for synthesizing trichloro sucrose utilizing same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2009005889A (en) | 2006-12-05 | 2009-08-12 | Tate & Lyle Technology Ltd | Trityl chloride recovery. |
| CN105707830A (en) * | 2016-03-03 | 2016-06-29 | 李云军 | Sucralose |
| CN107417744B (en) * | 2016-05-23 | 2020-05-12 | 中国人民解放军第二军医大学 | Sucrose derivative, preparation method thereof and application of sucrose derivative as anti-cancer drug |
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| US4889928A (en) * | 1986-09-17 | 1989-12-26 | Tate & Lyle Public Limited Company | Sucrose alkyl 4,6-orthoacylates |
| CN1316428A (en) * | 2001-04-12 | 2001-10-10 | 河南兴泰科技实业有限公司 | Process for prparing trichlorosucrose-6-ester |
| CN1453285A (en) * | 2003-05-23 | 2003-11-05 | 广东省食品工业研究所 | Synthesis of sucrose-6-acetate |
| CN1800194A (en) * | 2006-01-12 | 2006-07-12 | 上海迪赛诺维生素有限公司 | Sucralose synthesis method |
-
2006
- 2006-10-13 CN CNB2006100967621A patent/CN100480252C/en not_active Expired - Fee Related
Patent Citations (4)
| 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 |
| CN1316428A (en) * | 2001-04-12 | 2001-10-10 | 河南兴泰科技实业有限公司 | Process for prparing trichlorosucrose-6-ester |
| CN1453285A (en) * | 2003-05-23 | 2003-11-05 | 广东省食品工业研究所 | Synthesis of sucrose-6-acetate |
| CN1800194A (en) * | 2006-01-12 | 2006-07-12 | 上海迪赛诺维生素有限公司 | Sucralose synthesis method |
Non-Patent Citations (4)
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| 单酯化法合成高甜度甜味剂－三氯蔗糖的研究. 马志玲等.食品科学，第23卷第5期. 2002 |
| 单酯化法合成高甜度甜味剂－三氯蔗糖的研究. 马志玲等.食品科学，第23卷第5期. 2002 * |
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