CN101092438A - Method for preparing 6 U benzoyl tri-chloro galactose type cane sugar tetra-ethyl ester - Google Patents
Method for preparing 6 U benzoyl tri-chloro galactose type cane sugar tetra-ethyl ester Download PDFInfo
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- CN101092438A CN101092438A CNA2006100933771A CN200610093377A CN101092438A CN 101092438 A CN101092438 A CN 101092438A CN A2006100933771 A CNA2006100933771 A CN A2006100933771A CN 200610093377 A CN200610093377 A CN 200610093377A CN 101092438 A CN101092438 A CN 101092438A
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- benzoyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/30—Artificial sweetening agents
- A23L27/33—Artificial sweetening agents containing sugars or derivatives
- A23L27/37—Halogenated sugars
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/02—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to halogen
Abstract
This invention discloses a method for preparing 6-O-benzoyl trichlorosucrose tetraacetate. The method comprises: (1) performing 6-O-benzoylation coordination selective reaction between sucrose and tricarboxyl borate (complexing agent) in DMF solvent to obtain 6-O-benzoyl sucrose solution, vacuum-distilling DMF, and extracting with ethyl acetate to obtain pure 6-O-benzoyl sucrose; (2) chlorinating with phosphorus oxychloride at a low temperature in nitrogen flow in DMF solvent to obtain 6-O-benzoyl trichlorosucrose solution, distilling DMF, and extracting with ethyl acetate to obtain pure 6-O-benzoyl trichlorosucrose; (3) ethyl-esterifying pure 6-O-benzoyl trichlorosucrose with acetic anhydride/sodium acetate, and recrystallizing with toluene to obtain highly pure 6-O-benzoyl trichlorosucrose tetraacetate.
Description
The present invention relates to organic chemistry filed, particularly, the present invention relates to the preparation method that food adds Sweetener Sucralose key intermediate 6-O-benzoyl tri-chloro galactose type type cane sugar tetra-ethyl ester.
Background technology
Sucralose has another name called Sucralose, CAS:[56038-13-2], English name Sucralose has another name called 1 ', 4,6 '-trichlorogalactosucrose; TGS.
It is documented: 1975 in the world first preparation method who publishes Sucralose be P.H.Fairclough, (Carbohyd.Res, 40.285-298,1975).
Subsequently, L.Hough and R.A.Khan etc. has synthesized a series of compounds again, and these compounds (comprising Sucralose) are carried out sugariness assessment experiment and the design of chewing gum prescription, and has applied for patent (U.S.4,380,476,1983 in 1976; U.S.4,435,440,1984).
Have high sugariness based on Sucralose, low heat value, advantage such as nontoxic and mouthfeel is good becomes the focus of sweeting agent research and production.Wherein the sucralose-6-ester class is a key intermediate, and it carries out chlorination reaction by the sucrose-6-ester class and gets.
Sucralose is 4 in 8 hydroxyls of sucrose molecules, 1 ', 6 '-trihydroxy-is replaced by the chlorine atom, and numerous studies show that: sucrose 6-position hydroxyl must keep, because the 6-hydroxyl has great effect for the sucrose chlorinated derivatives, it is necessary for synthetic high-intensity sweetener.Therefore before chlorination, must manage 6-position hydroxyl protection, again 6-position hydroxyl be reduced after the chlorination.
Trityl methyl chloride that L.Hough and R.A.Khan propose and sucrose reaction, through polystep reaction, the production cycle is long, and productive rate is low, has any problem in actual production.
Using the orientation selective reaction, is reagent with Dibutyltin oxide, and the document of preparation Sucralose mainly contains: J.L.Navia (U.S; 4,950,746); D.S.Neiditch (U.S, 5,023; 329), R.E.Walkup (U.S, 5; 089,608), improved the orientation selectivity of acidylate; but final product has residual organotin as sweetening agent, is this class methods obvious defects.
Have multiplely about the chlorination reaction bibliographical information of sucrose-6-ethyl ester, conclude and get up to mainly contain three classes:
1. sulfur oxychloride method, R.A.Khan etc. (GB 2222827) for example, K.S.Mufti etc. (EP043649) will use pyridine, and operating environment is more abominable.
2.Vilsmerier method, K.S.Mufti (U.S4,380,476), Liu Xiaozhen etc. (CN1316428), method is more numerous and diverse.
3. phosgenation, R.E.Walkup etc. (U.S498043), Shen Bin etc. (CN1660868), well-known phosgene is toxic to environment to the people.
More than three kinds of methods its saving grace is all arranged, but the chlorating result is all undesirable.
Summary of the invention
In order to overcome the residual organotin or the deficiencies such as poor selectivity or separation difficulty of prior art, the invention provides a kind of preparation method of 6-O-benzoyl tri-chloro galactose type type cane sugar tetra-ethyl ester.Wherein react, remove DMF, use ethyl acetate extraction in vacuum with the DMF medium; Particularly utilize the orientation selective reaction of tricarboxylic ylboronic acid ester, carry out the benzoylation reaction of sucrose 6-position, shown significant advantage.
What J.L.Navia proposed generates 1 with Dibutyltin oxide and sucrose reaction, 3-two-6-O-sucrose-1,1,3, and 3-tetrabutyl distannoxane (DBSS), structural formula is as follows:
Suc-O-Sn(Bu)
2-O-Sn(Bu)
2-O-Suc
With reference to people such as N.TaKagi (U.S5,157,117) the preparation quinolizidine morpholine carboxylic acid two of Ti Chuing (the boric acid ester method of acetyl oxygen-O), we with tricarboxylic ylboronic acid ester and sucrose reaction generate sucrose 4-O-6-O-two (boric acid ester (DABS) of acetyl oxygen-O), its structural formula is as follows:
Technical solution of the present invention is divided three steps:
The first step: with the reaction of sucrose and tricarboxylic ylboronic acid ester (not being to use Dibutyltin oxide), (boric acid ester of acetyl oxygen-O) without separation, is an acylating agent generation 6-O-benzoyl sucrose with Benzoyl chloride/Sodium Benzoate or benzoyl oxide to generate sucrose 4-O-6-O-two.It is characterized in that orientation optionally carries out benzoylation on the 6-position, and introduced phenyl ring in the sucrose, be easy in reaction process, follow the tracks of and detect with HPLC with strong uv-absorbing;
Contain DMF, sucrose, dibenzoyl sucrose, dimethyl amine hydrochloride in the general crude product 6-O-benzoyl sucrose solution.With crude product 6-O-benzoyl sucrose solution, under high vacuum, boil off DMF with the rotating thin film evaporation unit.Use ethyl acetate extraction again, layering, combined ethyl acetate washes the class that desalts with water, obtains purer sucrose-6-benzoic ether (purity 94.6%).If DMF is not removed, because layering and assignment cause mutually, only with the ethyl acetate extraction 6-O-benzoyl sucrose of can't purifying.
Second step, 6-O-benzoyl sucrose that will be purer with phosphorus oxychloride in DMF solution, under the lesser temps under nitrogen gas stream, stir certain hour, be evaporated to driedly, obtain crude product 6-O-benzoyl sucralose solution.
The 3rd step: with crude product 6-O-benzoyl sucralose solution, boil off DMF in high vacuum, extract for three times with ethyl acetate, and wash with water, drying boils off ethyl acetate; Carry out full ethyl esterization with aceticanhydride/sodium-acetate or Acetyl Chloride 98Min./sodium acetate or Acetyl Chloride 98Min./pyridine, promptly get 6-O-benzoyl Sucralose tetra-ethyl ester.
In order to verify that the 6-O-benzoyl Sucralose-tetra-ethyl ester thing that is obtained by the present invention can obtain quite pure Sucralose, in the checking example detailed description is arranged.With 6-O-benzoyl Sucralose tetra-ethyl ester; in sodium methylate/methanol solution; stirring at room under nitrogen; hydrolysis (deacetylate) reaction is finished, generated the Sucralose crude product, through decolorizing and refining; add the Sucralose crystal seed; stirring is spent the night, and can obtain Sucralose, and quality index such as content and specific optical rotation all meet the standard of U.S.FCCIV.
The invention will be further described below by embodiment.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention, down preparation method's of the present invention simple modifications is all belonged to the scope of protection of present invention in advance in design of the present invention.Except as otherwise noted, the percentage ratio among the present invention is weight percentage.
Embodiment one
In whipping temp meter and water trap 1000ml three-necked bottle are housed, add sucrose 68.5g, (200m mol) 400ml Glacial acetic acid, tricarboxylic ylboronic acid ester 64.5g (0.3mol) and 200ml normal heptane with the suspended substance reflux, shift out the moisture content in the water trap.
Reaction solution is cooled to 0-5 ℃, drips the solution that benzoyl oxide 49.7g (220mol) is dissolved in cold 350ml DMF, dropwise, stirred 1 hour in about 5 ℃, follow the tracks of according to HPLC, 6-O-benzoyl sucrose generates, and sucrose has disappeared.
Under protection of nitrogen gas, stirred overnight at room temperature adds the 150ml water treatment in reaction solution, use rotatory evaporator, and evaporate to dryness obtains the syrup thing to remove DMF.Know with the HPLC analysis, contain 80.5g 6-O-benzoyl sucrose, use the methyl tert-butyl ether recrystallization, filtration, drying.Purity 94.6%, mp106-107 ℃, yield 90.2%.
Embodiment two
Sucrose 68.5g (200m mol) and sodium acetate 5.7g (70m mol) are dissolved in the 50ml acetate, add tricarboxylic ylboronic acid ester 64.5g (0.3mol), adding is added drop-wise to Benzoyl chloride 31.0g (220m mol is dissolved in the 40ml methylene dichloride) in the above-mentioned solution, stirs 3 hours in the greenhouse.Branch vibration layer, with the dilute hydrochloric acid neutralization, reduction vaporization obtains the mixture (both ratios are 8: 1) of unreacted sucrose and two single benzoyl sucrose to doing, by silicagel column separate two single benzoyl sucrose, moving phase is ethyl acetate/acetone=10: 10: 1.Know with the HPLC analysis, contain 78.5g 6-O-benzoyl sucrose, use the methylene dichloride recrystallization, purity 94.3%, yield 88.0%.
Embodiment three
The 1000ml three neck round-bottomed flasks that stirring, thermometer, dropping funnel and atmospheric condenser are being housed, feed nitrogen, add 200ml DMF, be chilled to-5 ℃, drip 68ml (0.72mol) phosphorus oxychloride, to keep the interior temperature of bottle below 10 ℃, dropwise, be chilled to-10 ℃, drip 6-O-benzoyl sucrose 50g (purity 90-92%, 0.1mol) being dissolved in the solution of 100ml DMF, temperature is no more than 5 ℃.Dropwise, with 60 ℃ of clarifying reaction solution heating, kept 30 minutes, 85 ℃ of reheat were kept 1 hour.Concentrating under reduced pressure is removed excessive phosphorus oxychloride and DMF, obtains the syrupy shape object, is chilled to room temperature, transfers to neutrality with liquid caustic soda, and ethyl acetate extraction concentrates, and measures through HPLC, contains 6-O-benzoyl Sucralose 95.6%, 33.6g, yield 65.8%.
Embodiment four
The 6-O-benzoyl Sucralose 51.1g (0.1mol) that embodiment three is obtained is dissolved in the 500mol ethyl acetate, adds pyridine 50ml, is cooled to 0 ℃.Divide three times and add aceticanhydride 50ml, stir, heated solution to 30 ℃, reaction process is detected by HPLC, reacts completely in about 3 hours.
Add 250ml water to destroy unreacted aceticanhydride, twice adding 100ml 1N hydrochloric acid merges organic layer, respectively washes once with saturated sodium carbonate solution and water.The vacuum concentration evaporate to dryness.Use the toluene recrystallization, obtain 6-O-benzoyl Sucralose tetra-ethyl ester, 62.4g measures purity 95.2%, yield 93.5% through HPLC.
The checking example
Purity according to embodiment four preparations is 95.2%6-O-benzoyl Sucralose tetra-ethyl ester 70.2g (0.1mol), put in the 1000ml three neck round-bottomed flasks (be equipped with and stir and nitrogen ingress pipe), add the making beating of 500ml methyl alcohol, add 30.0g 20% sodium methylate (6.0g, 0.11mol) methanol solution, stirring at room under nitrogen again, after 20 minutes, reaction mixture is homogeneous phase, follows the tracks of and detects with HPLC, determines that Sucralose is completed into.
Reactant is added acetate 18.4g (0.12mol), chilling, the rotating thin film evaporation, water temperature is no more than 30 ℃, removes methyl alcohol as far as possible, ethyl acetate and acetate.
Sucralose solids 54.5g (containing sodium acetate) with obtaining is dissolved in the 60ml water, is warmed to 70-80 ℃, adds activated carbon decolorizing, and is overanxious, stirs, and is chilled to room temperature, adds standard Sucralose crystal seed.Stirring is spent the night, with a small amount of cold distilled water washing, vacuum-drying, (20-25 ℃, 10mmHg) 12 hours.Xln Sucralose 34.5g is measured by HPLC: content 99.2%, yield 86.9%, specific optical rotation [α]=+ 68.2 ° (C=1.1, methyl alcohol).
Claims (12)
1. prepare the method for 6-O-benzoyl tri-chloro galactose type type cane sugar tetra-ethyl ester, comprise following process:
(1) with sucrose is starting raw material,, in the DMF medium, carries out 6-O-benzoylation orientation selective reaction, obtain 6-O-benzoyl sucrose solution with acylating agent with orientation selective reaction reagent; Under vacuum, boil off DMF with the rotating thin film water distilling apparatus, must purelyr get 6-O-benzoyl sucrose with ethyl acetate extraction again.
(2) use phosphorus oxychloride at low temperature, nitrogen gas stream is carried out chlorination and is obtained 6-O-benzoyl tri-chloro galactose type type sucrose solution in the DMF medium; Use the rotating thin film device, boil off DMF, use ethyl acetate extraction, obtain purer 6-O-benzoyl tri-chloro galactose type type sucrose.
(3) 6-O-benzoyl tri-chloro galactose type type sucrose that will be purer carries out full ethyl esterization with aceticanhydride/sodium-acetate, uses the toluene recrystallization again, prepares quite pure 6-O-benzoyl tri-chloro galactose type type tetra-ethyl ester.
2. according to the method for claim 1, comprise the acidylate of going of 6-O-benzoyl tri-chloro galactose type sugar tetra-ethyl ester, preparation Sucralose (TGS).
3. according to the method for claim 1, the reagent of orientation selective reaction is tricarboxylic ylboronic acid ester.
4. according to the method for claim 1,6-position acylating agent is benzoyl oxide and Benzoyl chloride.
5. according to the process of claim 1 wherein that the reaction medium of step (1) is DMF.
6. according to the process of claim 1 wherein that the reaction medium of step (2) is DMF.
7. according to the process of claim 1 wherein that step (1) comprises that using the rotating thin film evaporation unit removes reaction medium DMF.
8. according to the process of claim 1 wherein that step (2) comprises that using the rotating thin film evaporation unit removes reaction medium DMF.
9. according to the process of claim 1 wherein that step (3) comprises toluene solvant, carry out recrystallization, obtain the method for quite pure 6-O-benzoyl Sucralose tetra-ethyl ester.
10. according to the method for claim 5 and 7, wherein step (1) comprise remove DMF after, with the method for organic solvent ethyl acetate extraction 6-O-benzoyl sucrose.
11. according to the method for claim 6 and 8, wherein step (2) comprise remove DMF after, with the method for organic solvent ethyl acetate extraction 6-O-benzoyl Sucralose.
12. according to the method for claim 1～11, wherein the acylating agent of tetrem esterification is Acetyl Chloride 98Min./acetyl sodium or Acetyl Chloride 98Min./pyridine or aceticanhydride/sodium acetate.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100933771A CN101092438A (en) | 2006-06-22 | 2006-06-22 | Method for preparing 6 U benzoyl tri-chloro galactose type cane sugar tetra-ethyl ester |
| PCT/CN2006/001829 WO2008006251A1 (en) | 2006-06-22 | 2006-07-24 | Preparation of 6-o-benzoyl sucralose tetra-acetate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006100933771A CN101092438A (en) | 2006-06-22 | 2006-06-22 | Method for preparing 6 U benzoyl tri-chloro galactose type cane sugar tetra-ethyl ester |
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| CN101092438A true CN101092438A (en) | 2007-12-26 |
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|---|---|---|---|
| CNA2006100933771A Pending CN101092438A (en) | 2006-06-22 | 2006-06-22 | Method for preparing 6 U benzoyl tri-chloro galactose type cane sugar tetra-ethyl ester |
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| WO (1) | WO2008006251A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732338A (en) * | 2016-03-23 | 2016-07-06 | 浙江理工大学 | Preparation method of m-PEG (m-polyethylene glycol) polymer |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4950746A (en) * | 1988-07-18 | 1990-08-21 | Noramco, Inc. | Process for synthesizing sucrose derivatives by regioselective reaction |
| US4980463A (en) * | 1989-07-18 | 1990-12-25 | Noramco, Inc. | Sucrose-6-ester chlorination |
| US5298611A (en) * | 1993-03-12 | 1994-03-29 | Mcneil-Ppc, Inc. | Sucralose pentaester production |
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2006
- 2006-06-22 CN CNA2006100933771A patent/CN101092438A/en active Pending
- 2006-07-24 WO PCT/CN2006/001829 patent/WO2008006251A1/en active Application Filing
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732338A (en) * | 2016-03-23 | 2016-07-06 | 浙江理工大学 | Preparation method of m-PEG (m-polyethylene glycol) polymer |
| CN105732338B (en) * | 2016-03-23 | 2018-07-06 | 浙江理工大学 | A kind of preparation method of m-PEG polymer |
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| Publication number | Publication date |
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| WO2008006251A1 (en) | 2008-01-17 |
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