CN102558250B - Preparation method of iduronic acid and its derivative - Google Patents
Preparation method of iduronic acid and its derivative Download PDFInfo
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- CN102558250B CN102558250B CN201110062010.4A CN201110062010A CN102558250B CN 102558250 B CN102558250 B CN 102558250B CN 201110062010 A CN201110062010 A CN 201110062010A CN 102558250 B CN102558250 B CN 102558250B
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Abstract
The invention provides a preparation method of iduronic acid and its derivative, which is characterized by comprising the following steps: an oxidation method for oxidizing furans glucoside to acid comprises that under the existence of TEMPO (2,2,6,6-tetramethyl-1-piperidine oxide), iodobenzene diacetate is taken as an oxidizing agent for oxidation. The mol ratio of TEMPO to furans glucoside is 0.01-0.1, the mol ratio of oxidizing agent iodobenzene diacetateto to glucofuranose glycoside is 2.0-3.0. The method of the invention has the advantages that furans glucoside primary hydroxyl group is selectively oxidized through a weak oxidizing agent, protection and deprotection for other groups can be omitted, and the technology is simple; heavy metal chromium is not used as the oxidizing agent, thereby harm iduronic acid and its derivative to human body and circumference environment can be minimized during the preparation process.
Description
Technical field
The present invention relates to the preparation method of a kind of iduronic acid and derivative thereof, particularly relate to the chemical synthesis process of a kind of iduronic acid and derivative thereof.
Background technology
Heparin is a kind of mucopolysaccharide extracted from animal body, has anti-freezing, antithrombotic effect, and the derivative of heparin and heparin is comparatively extensive in the use of field of medicaments.The method of current synthetic heparin has chemosynthesis, chemoenzymatic synthesis, enzymatic clarification three kinds of methods.Before three more than ten years, more American-European scientists are when studying anti-freezing, the anti thrombotic action of heparin, and the effective fragment establishing heparin is a structure containing iduronic acid.
At occurring in nature, iduronic acid exists with the polysaccharide form combined with other carbohydrates, do not have free idose.Therefore, chemosynthesis hyparinoids from animal organs, first must synthesize iduronic acid.The most typically 1980s, French scientist J.Choay etc., utilize that glucofuranose glycosides is oxidized to acid by heavy metal chromium in acid condition, resterification, hydroxyl replace, and last acidifying becomes iduronic acid and derivative thereof.Because heavy metal chromium oxidation susceptibility is strong, can not elective oxidation of primary alcohols hydroxyl, so need before oxidation to protect other hydroxyls, after oxidation, esterification, carry out deprotection, the rate of recovery of complex process whole reaction simultaneously is also affected; Employ stronger acidity and relatively large heavy metal chromium simultaneously, harm is produced to human body and surrounding enviroment.
Summary of the invention
The object of this invention is to provide a kind of method of elective oxidation of primary alcohols hydroxyl, thus a kind of technique is simple, environmental pollution is little iduronic acid and derivative preparation method thereof are provided.
The technical solution adopted in the present invention is as follows:
The preparation method of a kind of iduronic acid and derivative thereof, comprise the steps: that being oxidized to acid method for oxidation used from glucofuranose glycosides is at TEMPO (2,2,6,6-tetramethyl--1-piperidine oxide) exist under, the oxidation carried out as oxygenant with iodobenzene diacetate.The mol ratio of TEMPO and glucofuranose glycosides is 0.01 ~ 0.1, and the mol ratio of oxygenant iodobenzene diacetate and glucofuranose glycosides is 2.0 ~ 3.0.
The esterification of above-mentioned glucofuranose acid is in dimethyl formamide (DMF), in the basic conditions, carries out with halohydrocarbon.Used alkali is the mineral alkalis such as sodium carbonate, salt of wormwood, sodium bicarbonate, and the consumption of alkali is 2 ~ 3 times (mol ratios) of glucofuranose acid; Halohydrocarbon is bromide or iodide, and as methyl iodide or bromobenzyl, its consumption is 1.2 ~ 1.5 times (mol ratios) for glucofuranose acid.
The carboxylate of above-mentioned glucofuranose acid carries out 5 hydroxyl transpositions under trifluoromethanesulfanhydride anhydride, sodium trifluoroacetate effect, temperature of reaction be room temperature to 60 DEG C, finally under the effect of the dilute sulphuric acid of 0.1 ~ 0.2M or the trifluoroacetic acid acid of 90% generate iduronic acid or derivatives thereof.
Beneficial effect of the present invention is: the primary hydroxyl group taking iodobenzene diacetate as oxygenant selective oxidation glucofuranose glycosides, and eliminate the step of protection to other groups and deprotection, technique is comparatively simple; Simultaneously do not use heavy metal chromium as oxygenant, decrease iduronic acid and derivative thereof in preparation process to the harm that human body and surrounding enviroment produce.
Embodiment
A kind of iduronic acid and the preferred preparation method of derivative thereof are as follows:
(1) 15.5 grams of 3-oxygen benzyls-1, are got, 2-oxygen-isopropylidene-α-D-glucofuranose (molecular weight is 343), be dissolved in the aqueous solution (1: 1 of 150 milliliters of acetonitriles, volume ratio), under stirring at room temperature, add 0.16 gram of TEMPO (molecular weight is 170), then add 37 grams of iodobenzene diacetates (molecular weight 322.10), react after 3 hours, add 20 ml methanol termination reactions; Be spin-dried under decompression.
The mol ratio of above-mentioned TEMPO and 3-oxygen benzyl-1,2-oxygen-isopropylidene-α-D-glucofuranose is 0.05, and the mol ratio of iodobenzene diacetate and 3-oxygen benzyl-1,2-oxygen-isopropylidene-α-D-glucofuranose is 2.5;
(2), the product that obtains in above-mentioned (1) is dissolved in 100 milliliters of DMF (dimethyl formamide), and add 12 grams of Anhydrous potassium carbonates, then add 10 milliliters of methyl iodide, stirred at ambient temperature is placed and spent the night; Solids removed by filtration thing, under low temperature, decompression is spin-dried for.Get residue with after a small amount of acetone solution, be placed in silicagel column upper end, by ethyl acetate: sherwood oil=1: 1 (volume ratio) wash-out, obtains 13.1 grams of carboxylates;
(3), by 8 milliliters of trifluoromethanesulfanhydride anhydrides, be dissolved in 160 milliliters of methylene dichloride, be chilled to-20 DEG C in advance; Then slowly add 80 milliliters containing the dichloromethane solution of pyridine 10%, after being added dropwise to complete, be slowly warming up to-10 DEG C; Slowly add the dichloromethane solution that 80 milliliters are dissolved with 8 grams of above-mentioned carboxylates again, be warming up to-5 DEG C, react 1 hour.After reaction terminates, reaction mixture is poured into the ice water solution (80 milliliters) containing 1.6 grams of sodium bicarbonates, separate organic phase; Organic phase uses dilute hydrochloric acid, water, saturated common salt water washing successively, anhydrous sodium sulfate drying, and filter, decompression is spin-dried for, and obtains syrup.Be dissolved in by the syrup obtained in 100 milliliters of DMF, add 16 grams of sodium trifluoroacetates, and be heated to 80 DEG C, react after 3 hours, decompression is spin-dried for; Add 100 milliliters of methylene dichloride, wash with water, anhydrous sodium sulfate drying, decompression is spin-dried for; Add 100 ml methanol in residue, stir after 1 hour, decompression is spin-dried for again; Cross silicagel column, with ether: sherwood oil=2: 1 (volume ratio) wash-out, obtain the glucofuranose acid esters compound 4.5 grams after hydroxyl transposition;
The glucofuranose acid esters compound of getting after above-mentioned 4 grams of hydroxyls transposition is dissolved in the trifluoroacetic acid of 90%, and at room temperature stir after 30 minutes, decompression is spin-dried for, residue with Ethyl acetate/sherwood oil recrystallization, obtains the iduronic acid derivative of 2.3 grams.
In the present embodiment, the reaction process of iduronic acid derivative is as follows:
Wherein, R is benzyl, R
1for methyl
In addition, as the preparation method of iduronic acid involved in the present invention and derivative thereof, be not limited to the content of the present embodiment, if R in above-mentioned reaction formula can be hydrogen or methyl, R
1can be methyl or benzyl.Meanwhile, in above-mentioned preparation process, the mol ratio of TEMPO and glucofuranose glycosides can be arbitrary value between 0.01 ~ 0.1, the mol ratio of iodobenzene diacetate and glucofuranose glycosides also can be 2.0 ~ 3.0 between arbitrary value.
Claims (5)
1. a preparation method for iduronic acid and ester thereof, wherein, the chemical structure of described ester is shown below:
In formula, R is hydrogen, methyl or benzyl, R
1for methyl or benzyl,
It is characterized in that comprising the steps:
(1), glucofuranose glycosides TEMPO exist under, be oxidized to glucofuranose acid with iodobenzene diacetate;
(2) the glucofuranose acid, in above-mentioned (1) in the basic conditions, carries out esterification with halohydrocarbon;
(3) the carboxylate trifluoromethanesulfanhydride anhydride, in above-mentioned (2), sodium trifluoroacetate generate iduronic acid or derivatives thereof after carrying out glucofuranose acid 5 hydroxyls transpositions under the action of an acid;
Wherein, the glucofuranose glycosides described in step (1) is 3-oxygen benzyl-1,2-oxygen-isopropylidene-α-D-glucofuranose, and the halohydrocarbon described in step (2) is methyl iodide.
2. according to the preparation method of iduronic acid described in claim 1 and ester thereof, it is characterized in that: the mol ratio of preparation process (1) described TEMPO and glucofuranose glycosides is 0.01 ~ 0.1, the mol ratio of described iodobenzene diacetate and glucofuranose glycosides is 2.0 ~ 3.0.
3., according to the preparation method of iduronic acid described in claim 1 and ester thereof, it is characterized in that: described in preparation process (2), alkali is mineral alkali.
4., according to the preparation method of iduronic acid described in claim 1 and ester thereof, it is characterized in that: acid described in preparation process (3) is the trifluoroacetic acid of 90%, and temperature of reaction is that room temperature is to 60 DEG C.
5. according to the preparation method of iduronic acid described in claim 1 and ester thereof, it is characterized in that: the mol ratio of preparation process (1) described TEMPO and glucofuranose glycosides is 0.02 ~ 0.05, the mol ratio of described iodobenzene diacetate and glucofuranose glycosides is 2.2 ~ 2.5.
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| CN110577559B (en) * | 2019-08-19 | 2023-02-17 | 江西科技师范大学 | Synthesis method of fluorosidase substrate for alpha-L-iduronidase determination |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1284953A (en) * | 1997-12-19 | 2001-02-21 | G·D·瑟尔公司 | Method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides |
| CN101096377A (en) * | 2006-06-26 | 2008-01-02 | 重庆华邦制药股份有限公司 | Monoglycosides acid purification method |
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| NL194919C (en) * | 1993-09-07 | 2003-07-04 | Tno | Process for oxidizing carbohydrates. |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1284953A (en) * | 1997-12-19 | 2001-02-21 | G·D·瑟尔公司 | Method of preparing enantiomerically-enriched tetrahydrobenzothiepine oxides |
| CN101096377A (en) * | 2006-06-26 | 2008-01-02 | 重庆华邦制药股份有限公司 | Monoglycosides acid purification method |
Non-Patent Citations (1)
| Title |
|---|
| 《Synthesis of Iduronic Acid Building Blocks》;Gregory J. S. Lohman;《J.ORG.CHEM》;20031231;第7559-7561页 * |
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