CN103694208B - The preparation method of acetylize L-arabinose alkene - Google Patents
The preparation method of acetylize L-arabinose alkene Download PDFInfo
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- CN103694208B CN103694208B CN201310712856.7A CN201310712856A CN103694208B CN 103694208 B CN103694208 B CN 103694208B CN 201310712856 A CN201310712856 A CN 201310712856A CN 103694208 B CN103694208 B CN 103694208B
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- arabinose
- acetylize
- bromo
- pectinose
- alkene
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a kind of preparation method of acetylize L-arabinose alkene.Be raw material with L-arabinose, utilize acetyl bromide to obtain the triacetylated pectinose of Beta-bromo-L-for protecting group and brominated reagent; Then triacetylated for Beta-bromo-L-pectinose is joined in the reaction system containing zinc powder, sodium pyrosulfate, copper sulfate, water; room temperature reaction 1-3h, obtains through filtration, washing, concentrating under reduced pressure rectifying the acetylize L-arabinose alkene that purity is greater than 99% subsequently.The present invention is raw materials used is conventional reagent, greatly reduces production cost, reaction conditions is gentleer, working method is simple, product yield and purity all more satisfactory, this is that the suitability for industrialized production of acetylize L-arabinose alkene provides a kind of novel method.
Description
Technical field
The present invention relates to technical field of organic chemistry, is specifically the method that acetylize L-arabinose alkene prepared by raw material with L-arabinose.
Background technology
In organic compound and pharmaceutical synthesis process, acetylize L-arabinose alkene is very important intermediate, and it is the critical materials of synthesis 2-deoxidation-L-ribose and L-Nucleotide medicine.But because market price is higher, this just greatly limit its application in every respect.L-type Nucleotide medicine plays significant therapeutic action at antiviral, the anti-AIDS for the treatment of and anti-tumor aspect in recent years; its demand increases year by year; the technical study of acetylize L-arabinose alkene has been subject to people and has paid much attention to, to searching out the novel process of suitability for industrialized.Novel process is constantly had to report to the synthesis of acetylize L-arabinose alkene at present; but mainly obtain target product from 1-substituent; wherein the most classical method first free pectinose is converted into bromo Tang, then in acetic acid with Arabic thin malt sugar (the Collection Czechoslov. of the obtained acetylize of zinc powder reduction generation eliminative reaction
chem.Commun,
1964,
29, 2810-2813; CN102108089A).
。
The method produces that thin malt sugar yield is low, by product is many, difficult purifying.In addition owing to there is a large amount of HBr in system, add zinc powder reaction fierceness, wayward, remain zinc powder simultaneously and easily lump, not easily aftertreatment.
Patent be 2011102227786.7 Chinese invention patent disclose in same reactor, to add zinc, method that aqueous ammonium chloride solution, bromo sugar reaction generate the Arabic thin malt sugar of acetylize.
。
Publication number is that the Chinese invention patent of CN101289439A discloses the method for carrying out the Arabic thin malt sugar of reduction elimination generation acetylize in sodium dihydrogen phosphate buffer.
。
Carry out in nonaqueous phase reduce eliminate prepare acetylize Arab thin malt sugar method also have report.Chinese patent (CN102643257A), United States Patent (USP) (US2009/0292117A1) all disclose in ethyl acetate solvent with N-Methylimidazole be catalyzer, zinc powder obtains the Arabic thin malt sugar of acetylize for reductive agent heating reflux reaction.
。
Above-mentioned several method all can obtain acetylize L-arabinose alkene product, but it is low to there is product yield, not easily purifying, the different shortcoming such as complex operation.
Summary of the invention
Object of the present invention be exactly for solve above-mentioned preparation method exist yield low, not easily purifying, the different shortcoming such as complex operation.We will provide a kind of product yield high, easy purifying, and technique simply prepares the novel method of acetylize L-arabinose alkene.
The present invention realizes in the following way, and concrete steps are as follows:
(1) preparation of the triacetylated pectinose of Beta-bromo-L-(II): with L-arabinose (I) for raw material; acetyl bromide is acidylate and brominated reagent; acidylate/bromo-reaction is carried out in acetic acid solution; dchloromethane is added after having reacted; with the washing of water, sodium hydrogen carbonate solution and hypo solution, filter after dry, the yellow solid after vacuum distillation recovered solvent; use dehydrated alcohol recrystallization, white needle-like crystals (II) can be obtained.
。
(2) preparation of acetylize L-arabinose alkene (III): triacetylated for Beta-bromo-L-pectinose is joined in the reaction system containing zinc powder, sodium pyrosulfate, copper sulfate, water; room temperature reaction 1-3h, obtains through dilution, filtration, washing, concentrating under reduced pressure rectifying the acetylize L-arabinose alkene that purity is greater than 99% subsequently.
。
In the inventive method, L-arabinose (I), acetyl bromide, acetic acid mol ratio are 1:(4 ~ 6): 4.0; preferred 1:4.5:4; generate in the reaction of the triacetylated pectinose of Beta-bromo-L-(II), its temperature of reaction-5 ~ 40 DEG C, preferably 0 ~ 5 DEG C.The triacetylated pectinose of Beta-bromo-L-(II), zinc powder, sodium pyrosulfate mol ratio 1:3:6 in Arabic thin malt sugar (III) reaction system of preparation L-acetylize; the triacylate pectinose of Beta-bromo-L-, water, copper sulfate mol ratio are 1:(60 ~ 120): (0.01 ~ 0.1); preferred 1:100:0.05; room temperature reaction 1-3h, preferred 2h.
Embodiment
In order to understand summary of the invention of the present invention further, being described in more detail the present invention with reference to preferred example, providing described example to be only in the object of explanation, not forming any limitation of the invention.
embodiment 1β
the preparation of the triacetylated pectinose of-bromo-L-(II)
Acetic acid (252mL, 4.0mol) and L-arabinose (150g, 1.0mol) are mixed, then said mixture is placed in ice bath, drip the dichloromethane solution (4.0mol, 324mL) containing acetyl bromide lentamente.Add rear continuation and maintain 0-5 DEG C of stirring 4h.Add 300mL dchloromethane after having reacted, then add the washing of 300mL frozen water, organic layer saturated sodium bicarbonate solution washing produces to bubble, and the hypo solution washing of 5% is extremely substantially colourless, anhydrous sodium sulfate drying.Filter, the yellow solid after vacuum distillation recovered solvent, uses dehydrated alcohol recrystallization, obtains white needles 220.4g, 65%.
Acetic acid (252mL, 4.0mol) and L-arabinose (150g, 1.0mol) are mixed, then said mixture is placed in ice bath, drip the dichloromethane solution (4.5mol, 364mL) containing acetyl bromide lentamente.Add rear continuation and maintain 0-5 DEG C of stirring 4h.Add 300mL dchloromethane after having reacted, then add the washing of 300mL frozen water, organic layer saturated sodium bicarbonate solution washing produces to bubble, and the hypo solution washing of 5% is extremely substantially colourless, anhydrous sodium sulfate drying.Filter, the yellow solid after vacuum distillation recovered solvent, uses dehydrated alcohol recrystallization, obtains white needles 237.3g, 70%.
Acetic acid (252mL, 4.0mol) and L-arabinose (150g, 1.0mol) are mixed, then said mixture is placed in ice bath, drip the dichloromethane solution (6.0mol, 485mL) containing acetyl bromide lentamente.Add rear continuation and maintain 0-5 DEG C of stirring 4h.Add 300mL dchloromethane after having reacted, then add the washing of 300mL frozen water, organic layer saturated sodium bicarbonate solution washing produces to bubble, and the hypo solution washing of 5% is extremely substantially colourless, anhydrous sodium sulfate drying.Filter, the yellow solid after vacuum distillation recovered solvent, uses dehydrated alcohol recrystallization, obtains white needles 206.8g, 61%.
Acetic acid (252mL, 4.0mol) and L-arabinose (150g, 1.0mol) are mixed, then said mixture is placed in ice bath, drip the dichloromethane solution (4.5mol, 364mL) containing acetyl bromide lentamente.Add the bath of recession deicing, stirring at room temperature 4h.Add 300mL dchloromethane after having reacted, then add the washing of 300mL frozen water, organic layer saturated sodium bicarbonate solution washing produces to bubble, and the hypo solution washing of 5% is extremely substantially colourless, anhydrous sodium sulfate drying.Filter, the yellow solid after vacuum distillation recovered solvent, uses dehydrated alcohol recrystallization, obtains white needles 176.3g, 52%.
The triacetylated pectinose of Beta-bromo-L-(II): white needles, m.p. 136-138 DEG C. IR (KBr) v
max2973,1766,1434,1374,1245,1168,1139,1113,1071,1016,943,895cm
-1;
1h NMR (CDCl
3, 400MHz),
δppm:2.04 (s, 3H), 2.13 (s, 3H), 2.18 (s, 3H), 3.96 (dd, 1H,
j=13.6 and 2.1Hz), 4.24 (d, 1H,
j=13.2Hz), 5.06-5.26 (m, 1H), 5.38-5.44 (m, 2H), 6.71 (d, 1H,
j=3.6Hz);
13c NMR (CDCl
3, 100MHz),
δppm:170.3,170.0,169.8,89.6,68.0,67.8,67.6,64.7,20.8,20.6.
the preparation of embodiment 2 acetylize L-arabinose alkene (III)
Sodium pyrosulfate (36g is added successively in three-necked flask; 0.3mol), zinc powder (9.75g; 0.15mol), copper sulfate (0.4g; 0.0025mol) and the triacetylated pectinose (17.0g of Beta-bromo-L-of above-mentioned preparation; 0.05mol); drip 90.0g (5.0mol) water and start stirring, adding rear stirring at room temperature 2h.After TCL detection reaction is complete, in reaction solution, add ethyl acetate 100mL dilution, filter, filtrate washes 2 times, anhydrous sodium sulfate drying, then 85-90 DEG C of cut is collected in concentrating under reduced pressure rectifying, obtains colourless oil liquid 9.6g, yield 96%, purity 99.1%.
Sodium pyrosulfate (36g is added successively in three-necked flask; 0.3mol), zinc powder (9.75g; 0.15mol), copper sulfate (0.4g; 0.0025mol) and the triacetylated pectinose (17.0g of Beta-bromo-L-of above-mentioned preparation; 0.05mol); drip 54.0g (3.0mol) water and start stirring, adding rear stirring at room temperature 2h.After TCL detection reaction is complete, in reaction solution, add ethyl acetate 100mL dilution, filter, filtrate washes 2 times, anhydrous sodium sulfate drying, then 85-90 DEG C of cut is collected in concentrating under reduced pressure rectifying, obtains colourless oil liquid 8.9g, yield 89%, purity 99.0%.
Sodium pyrosulfate (36g is added successively in three-necked flask; 0.3mol), zinc powder (9.75g; 0.15mol), copper sulfate (0.4g; 0.0025mol) and the triacetylated pectinose (17.0g of Beta-bromo-L-of above-mentioned preparation; 0.05mol); drip 108.0g (6.0mol) water and start stirring, adding rear stirring at room temperature 2h.After TCL detection reaction is complete, in reaction solution, add ethyl acetate 100mL dilution, filter, filtrate washes 2 times, anhydrous sodium sulfate drying, then 85-90 DEG C of cut is collected in concentrating under reduced pressure rectifying, obtains colourless oil liquid 9.2g, yield 92%, purity 99.1%.
Acetylize L-arabinose alkene (III): colourless oil liquid. IR (KBr) v
max3075,2941,2894,1741,1643,1435,1371,1240,1148,1087,1055,1041,918,896,762cm
-1;
1h NMR (CDCl
3, 400MHz),
δppm: 2.08 (s, 3H), 2.08 (s, 3H), 3.95-4.06 (m, 2H), 4.86 (dd, 1H,
j=6.0 and 5.2Hz), 5.19 (dt, 1H,
j=9.2 and 4.0Hz), 5.42-5.47 (m, 1H), 6.51 (dd, 1H,
j=6.0 and 0.4Hz);
13c NMR (CDCl
3, 100MHz),
δppm:170.5,170.0,97.6,65.8,62.7,20.8,20.5.
Claims (1)
1. a preparation method for acetylize L-arabinose alkene, is characterized in that, the method comprises the steps:
(1) preparation of the triacetylated pectinose of Beta-bromo-L-: take L-arabinose as raw material, in acetic acid solution, acetylize and bromo-reaction is carried out with acidylate and brominated reagent, described acidylate and brominated reagent are acetyl bromide, L-arabinose in reaction system, acetyl bromide, acetic acid mol ratio is 1:(4 ~ 6): 4, temperature of reaction-5 ~ 40 DEG C, dchloromethane is added after having reacted, with water, sodium hydrogen carbonate solution and hypo solution washing, filter after organic phase drying, yellow solid is obtained after vacuum distillation recovered solvent, use dehydrated alcohol recrystallization, the triacetylated pectinose of white needle-like crystals Beta-bromo-L-can be obtained,
(2) preparation of acetylize L-arabinose alkene (III): triacetylated for Beta-bromo-L-pectinose is joined containing zinc powder, sodium pyrosulfate, copper sulfate, in the reaction system of water, the triacetylated pectinose of Beta-bromo-L-(II) in reaction system, zinc powder, sodium pyrosulfate mol ratio 1:3:6, the triacetylated pectinose of Beta-bromo-L-, water, copper sulfate mol ratio is 1:(60 ~ 120): (0.01 ~ 0.1), room temperature reaction 1-3h, subsequently through dilution, filter, washing, concentrating under reduced pressure rectifying obtains the acetylize L-arabinose alkene that purity is greater than 99%.
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| CN102702276A (en) * | 2012-06-08 | 2012-10-03 | 济南圣泉唐和唐生物科技有限公司 | Postprocessing method for glycal reaction solution |
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| CN102702276A (en) * | 2012-06-08 | 2012-10-03 | 济南圣泉唐和唐生物科技有限公司 | Postprocessing method for glycal reaction solution |
Non-Patent Citations (2)
| Title |
|---|
| One-step Halogenation at the 2’-Positon of Uridine, and Related Reactions of Cytidine and N4-Acetylcytidine;Ryuji Marumoto et al.;《Chem. Pharm. Bull.》;19740131;第22卷(第1期);第128页第28-30行、第130页图1及第132页第16-19行 * |
| 全乙酰-L-阿拉伯糖和全乙酰溴代-L-阿拉伯糖的合成;陈彦;《中国优秀硕士学位论文全文数据库 工程科技I辑》;20100615(第06期);全文 * |
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