CN103172682B - The preparation method of 2-deoxidation-L-ribofuranose - Google Patents
The preparation method of 2-deoxidation-L-ribofuranose Download PDFInfo
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- CN103172682B CN103172682B CN201310081196.7A CN201310081196A CN103172682B CN 103172682 B CN103172682 B CN 103172682B CN 201310081196 A CN201310081196 A CN 201310081196A CN 103172682 B CN103172682 B CN 103172682B
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Abstract
The invention provides a kind of preparation method of 2-deoxidation-L-ribofuranose, this preparation method comprises: methylated L-arabinose through 3,5 hydroxyl protections, then goes protection to be prepared from through 2 deoxidations, the hydroxyl of 3,5.This preparation method has that raw material is easy to get, synthetic route is short, simple to operate, product yield and the advantage such as purity improves and production cost is lower.
Description
Technical field
The invention belongs to field of medicaments, particularly, relate to a kind of preparation method of pharmaceutical intermediate 2-deoxidation-L-ribofuranose.
Background technology
L-nucleoside medicine, as antiviral, anti-AIDS and antitumor drug, because its enantiomorph of its toxicity ratio is low, starts from the fifties in last century the common concern being just subject to people.2-deoxidation-L-ribofuranose, its structural formula is as follows:
It has the important intermediate of the L-nucleoside medicine of new biological activity as synthesis, is exactly the study hotspot of every field scientists all the time.
But 2-deoxidation-L-ribofuranose is a kind of non-natural ribose, only have and synthesized by chemistry or biological method, existing synthetic method mainly contains: 1) with 2-deoxy-D-ribofuranose for raw material is through transposition synthesis 2-deoxidation-L-ribofuranose; 2) with L-ribose through reduction synthesis 2-deoxidation-L-ribofuranose; 3) take xitix as Material synthesis 2-deoxidation-L-ribofuranose; 4) take L-arabinose as Material synthesis 2-deoxidation-L-ribofuranose.
But, with 3 kinds of methods or the expensive starting materials of going forward, if the market value of L-ribose is up to 6000 yuan/about Kg; Step is oversize, and yield is too low, and production cost is too high, and market cannot accept.By contrast, what be most suitable for practicality is take L-arabinose as Material synthesis 2-deoxidation-L-ribofuranose, but reported be in the route of Material synthesis 2-deoxidation-L-ribofuranose with L-arabinose, because intermediate reaction thing benzene oxygen thio-carbonyl chloride is expensive and not easily obtain, or because use CS
2raw material is inflammable.In addition, follow-up reductive agent also also exists the problem that expensive starting materials is not easy to obtain equally, makes whole production cost higher.
Publication number is that the Chinese patent of CN102108089 discloses a kind of method preparing 2-deoxidation-L-ribose, and the reaction mechanism of the method is as follows:
Wherein, AmberliteIR-120 represents the type of catalyst resin, and the 2-deoxidation-L-ribose obtained by the method is a kind of ribose of pyrans type of six-ring, but pyranoid ribose is not the main raw material of synthetic nucleosides.
Be the preparation method disclosing a kind of 2-deoxidation-L-ribose in the Chinese patent of CN102153600 at publication number, the reaction mechanism of the method is as follows:
The 2-deoxidation-L-ribose obtained by the method is also a kind of ribose of pyrans type of six-ring.
Due to the main raw material that pyranoid ribose is not synthetic nucleosides, the main raw material of synthetic nucleosides is pentacyclic furan type ribose, so need a kind of method of synthesizing furan type ribose.
Summary of the invention
The object of this invention is to provide a kind of method preparing 2-deoxidation-L-ribofuranose, this preparation method has the advantage that raw material is easy to get, synthetic route is short, simple to operate, product yield purity improves and production cost is lower.
The preparation method of 2-deoxidation-L-ribofuranose provided by the invention comprises the following steps:
A. shown in formula 1, shown in compound and formula 2, compound reacts compound shown in production 3 in the presence of a catalyst, in organic solvent;
B. compound shown in formula 3 reacts compound shown in production 4 with Methanesulfonyl chloride in the presence of a base, in organic solvent;
C. compound shown in formula 4 in the presence of a catalyst, in organic solvent through compound shown in hydrogenation production 5;
D. compound shown in formula 5 HCl exist under, in first alcohol and water, react compound shown in production 6.
Preferably, in described step a, described catalyzer is organic acid; Described organic solvent is selected from DMF or tetrahydrofuran (THF); Described temperature of reaction can be 30-90 DEG C.
More preferably, described catalyzer is tosic acid; Described temperature of reaction is 50 DEG C.
Preferably, described step a also comprise described reaction complete after distillation removing remaining formula 2 shown in compound and organic solvent, then add toluene dissolve and be adjusted to neutrality with sodium bicarbonate aqueous solution.
More preferably, described step a also comprise described reaction complete after distillation removing remaining formula 2 shown in compound and organic solvent, add toluene again dissolve and be adjusted to neutrality with sodium hydrogen carbonate solution, underpressure distillation is except desolventizing again for organic phase, and product carries out crystallization with methyl alcohol.
Preferably, in described step b, described alkali is one or more in pyridine, diisopropyl ethyl amine and triethylamine; Described organic solvent can be selected from one or more in 1,2-ethylene dichloride, methylene dichloride, chloroform, tetracol phenixin, acetonitrile, tetrahydrofuran (THF) and dioxane; Described temperature of reaction can be-10 ~ 40 DEG C.
More preferably, described alkali is triethylamine; Described organic solvent is chloroform; Described temperature of reaction is 0 DEG C.
Preferably, described step b also comprises after described reaction completes and is washed to neutrality with 0.5mol/L sulfuric acid or 1mol/L aqueous hydrochloric acid.
More preferably, described step b also comprises after described reaction completes and is washed to neutrality with 1mol/L aqueous hydrochloric acid, and carries out crystallization in methyl alcohol, ethanol, Virahol or acetone.
Wherein most preferably, in Virahol, crystallization is carried out.
Preferably, in described step c, described catalyzer is palladium carbon or Raney's nickel catalyst; Described organic solvent is selected from one or more in methyl alcohol, ethanol and Virahol; Described temperature of reaction is 0-80 DEG C.
Preferably, described organic solvent is methyl alcohol; Described temperature of reaction is 20 DEG C.
Preferably, described step c also comprises after described reaction completes and carries out recrystallization with dehydrated alcohol.
Preferably, in described steps d, the concentration of described HCl is 0.1-2mol/L; Described temperature of reaction is 20-80 DEG C.
More preferably, described temperature of reaction is 30 DEG C.
Preferably, described steps d also comprise described reaction complete after with ethyl acetate washing, through ethyl alcohol recrystallization after water layer evaporate to dryness.
Preferably, shown in described formula 1, the preparation method of compound comprises the following steps:
Compound shown in formula 7 reacts compound shown in production 1 with methyl alcohol under HCl exists;
The concentration of described HCl is 0.01mol/L, and described temperature of reaction is 0-35 DEG C, and after described reaction completes with sodium carbonate in and, filter, evaporate to dryness.
Preferably, described temperature of reaction is room temperature.
Prepared by the preparation method that the preparation method of compound shown in above-mentioned formula 1 is similar to 1-O-alkyl-L-arabinose glycosides disclosed in Chinese patent application 201010110944.6.
Specifically, the synthetic route of 2-deoxidation-L-ribofuranose (compound 6) of the present invention is as follows:
(1) methylate: drop into L-arabinose and methyl alcohol in a kettle., drip HCl methanol solution after stirring and dissolving, room temperature reaction 5 hours, add sodium carbonate neutralization after completion of the reaction, filter, after solution is spin-dried for, drops into the next step;
The protection of (2) 3,5 hydroxyls: walk product on dropping in a kettle., add tetrahydrofuran (THF), benzaldehyde dimethyl acetal and catalyzer, and react at 50 DEG C.React complete, the distillation remaining benzaldehyde dimethyl acetal of removing and tetrahydrofuran (THF), add toluene and dissolve, and wash or use NaHCO
3be adjusted to neutrality, underpressure distillation except desolventizing, and drops into the next step with after methanol crystallization;
(3) 2 deoxidations: when temperature of reaction is down to below 20 DEG C, add triethylamine and chloroform, cool to 0 DEG C after stirring, start to drip Methanesulfonyl chloride, after completion of the reaction, aqueous hydrochloric acid is washed till neutrality, and in Virahol crystallization purifying;
(4) hydrogenation: above product is dropped into hydrogenation reaction cauldron, adds methyl alcohol, palladium-carbon catalyst, catalytic hydrogenation at 20 DEG C, use dehydrated alcohol recrystallization after completion of the reaction;
The going of the hydroxyl of (5) 3,5 is protected: the compound obtained to step (4) adds methyl alcohol, water and hydrochloric acid; be warming up to 30 DEG C of reactions, after with ethyl acetate washing, point go organic phase; water layer evaporate to dryness, and obtain product 2-deoxidation-L-ribose with ethyl alcohol recrystallization.
The invention provides a kind of preparation method of 2-deoxidation-L-ribofuranose, the method with methoxyl group-L-arabinofuranose for raw material has obtained 2-deoxidation-L-ribofuranose by step such as protection hydroxyl, deoxidation, deprotection base etc.Prepared by the present invention is 2-deoxidation-L-ribofuranose, and what be different from prepared by most prior art is 2-deoxidation-L-ribopyranose, and this furan type ribose can be used as the main raw material synthesizing L-nucleoside medicine at present.
Unlike the prior art, the present invention adopts hydrochloric acid to carry out the protective reaction of 3,5 hydroxyls, and prior art uses acetic acid more in protective reaction.The advantage adopting hydrochloric acid to carry out protective reaction is: temperature of reaction is usually at 20-80 DEG C, and side reaction is few, so the yield of the reaction product 2-deoxidation-L-arabinofuranose obtained can reach 95%.So after the completion of reaction, only need with ethyl acetate washing reaction thing, remove organic phase, with product in ethyl alcohol recrystallization aqueous phase, just can obtain 2-deoxidation-L-ribofuranose, the purity of product is 99%; But the technique of prior art then needs reaction soln underpressure distillation, and distill the product that obtains and also will carry out recrystallization in sherwood oil or ether and just can obtain 2-deoxidation-L-ribose, and the L-ribose obtained is inadequate due to purity, also needs further purifying.
In addition, have employed benzaldehyde dimethyl acetal as protective material in preparation method of the present invention, existing protective material is then isopropylidene.The benzaldehyde dimethyl acetal that the present invention uses is as protective material, and its selectivity is better, and after step a terminates, find through inspection, the ratio of free hydroxyl group is 0.5%, and shown in the formula 1 of this explanation 99.5%, compound is all protected by benzaldehyde dimethyl acetal.
Embodiment
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But these embodiments are only exemplary, do not form any restriction to scope of the present invention.It will be understood by those skilled in the art that and can modify to the details of technical solution of the present invention and form or replace down without departing from the spirit and scope of the present invention, but these amendments and replacement all fall within the scope of protection of the present invention.
If no special instructions, described in following examples, method is ordinary method, and described starting material all can obtain from open commercial sources.
Embodiment 1
(1) methylate: input L-arabinose 100g and concentration are the methyl alcohol 800mL of 95% in a kettle., HCl methanol solution is dripped after stirring and dissolving, HCl concentration is wherein 0.01mol/l, room temperature reaction 5 hours, add sodium carbonate neutralization after completion of the reaction, filter, after solution is spin-dried for, drops into the next step;
The protection of (2) 3,5 hydroxyls: walk product on dropping in a kettle., add tetrahydrofuran (THF) 400mL, benzaldehyde dimethyl acetal 110g and catalyzer p-methyl benzenesulfonic acid 5g, and react at 50 DEG C.React complete, the distillation remaining benzaldehyde dimethyl acetal of removing and tetrahydrofuran (THF), add toluene and be washed till neutrality with sodium hydrogen carbonate solution, and underpressure distillation except desolventizing, and drops into the next step with after methanol crystallization;
(3) 2 deoxidations: when temperature of reaction is down to below 20 DEG C, add triethylamine 25mL and chloroform 600mL, cool to 0 DEG C after stirring, start to drip Methanesulfonyl chloride, after completion of the reaction, are washed till neutrality, crystallization purifying with the aqueous hydrochloric acid of 1mol/L;
(4) 2 deoxidations: above product is dropped into hydrogenation reaction cauldron, adds methyl alcohol 600mL, at palladium-carbon catalyst, catalytic hydrogenation at 20 DEG C, uses dehydrated alcohol recrystallization after completion of the reaction;
The going of the hydroxyl of (5) 3,5 is protected: the compound obtained to step (4) adds methyl alcohol 400mL, water 100mL and hydrochloric acid 100mL (0.5mol/L); be warming up to 30 DEG C of reactions; after wash by ethyl acetate; divide and go organic phase; water layer evaporate to dryness; and obtaining product 2-deoxidation-L-ribose 45g with ethyl alcohol recrystallization, yield is 50.3%, purity 99%.2-deoxidation-L-ribose is off-white powder, fusing point 69-72 DEG C.
Claims (14)
1. a preparation method for 2-deoxidation-L-ribofuranose, this preparation method comprises the following steps:
A. shown in formula 1, shown in compound and formula 2, compound reacts compound shown in production 3 in the presence of a catalyst, in organic solvent, wherein said catalyzer is organic acid, described organic solvent is selected from DMF or tetrahydrofuran (THF), and temperature of reaction is 30-90 DEG C;
B. compound shown in formula 3 reacts compound shown in production 4 with Methanesulfonyl chloride in the presence of a base, in organic solvent, wherein said alkali is selected from one or more in pyridine, diisopropyl ethyl amine and triethylamine, described organic solvent is selected from 1, one or more in 2-ethylene dichloride, methylene dichloride, chloroform, tetracol phenixin, acetonitrile, tetrahydrofuran (THF) and dioxane, temperature of reaction is-10 ~ 40 DEG C;
C. compound shown in formula 4 in the presence of a catalyst, in organic solvent through compound shown in hydrogenation production 5, wherein said catalyzer is palladium carbon or Raney's nickel catalyst, described organic solvent is selected from one or more in methyl alcohol, ethanol and Virahol, and temperature of reaction is 0-80 DEG C;
D. compound shown in formula 5 HCl exist under, in first alcohol and water, react compound shown in production 6, wherein the concentration of HCl is 0.1-2mol/L, and temperature of reaction is 20-80 DEG C;
2. preparation method according to claim 1, is characterized in that, in described step a, described catalyzer is tosic acid, and described temperature of reaction is 50 DEG C.
3. preparation method according to claim 1 and 2, is characterized in that, described step a also comprise described reaction complete after distillation removing remaining formula 2 shown in compound and organic solvent, then add toluene dissolve and be adjusted to neutrality with sodium hydrogen carbonate solution.
4. preparation method according to claim 1 and 2, it is characterized in that, described step a also comprise described reaction complete after distillation removing remaining formula 2 shown in compound and organic solvent, add toluene again dissolve and be adjusted to neutrality with sodium hydrogen carbonate solution, underpressure distillation is except desolventizing again for organic phase, and product carries out crystallization with methyl alcohol.
5. preparation method according to claim 1 and 2, is characterized in that, in described step b, described alkali is triethylamine, and described organic solvent is chloroform, and described temperature of reaction is 0 DEG C.
6. preparation method according to claim 1 and 2, is characterized in that, described step b also comprises after described reaction completes and is washed to neutrality with 0.5mol/L sulfuric acid or 1mol/L aqueous hydrochloric acid.
7. preparation method according to claim 1 and 2, is characterized in that, described step b also comprises after described reaction completes and is washed to neutrality with 1mol/L aqueous hydrochloric acid, and carries out crystallization in methyl alcohol, ethanol, Virahol or acetone.
8. preparation method according to claim 1 and 2, is characterized in that, described step b also comprises after described reaction completes and is washed to neutrality with 1mol/L aqueous hydrochloric acid, and carries out crystallization in Virahol.
9. preparation method according to claim 1 and 2, is characterized in that, in described step c, described organic solvent is methyl alcohol, and described temperature of reaction is 20 DEG C.
10. preparation method according to claim 1 and 2, is characterized in that, described step c also comprises after described reaction completes and carries out recrystallization with dehydrated alcohol.
11. preparation methods according to claim 1 and 2, is characterized in that, in described steps d, described temperature of reaction is 30 DEG C.
12. preparation methods according to claim 1 and 2, is characterized in that, described steps d also comprises after described reaction completes washs, through ethyl alcohol recrystallization after water layer evaporate to dryness with ethyl acetate.
13. preparation methods according to claim 1 and 2, is characterized in that, shown in described formula 1, the preparation method of compound comprises the following steps:
Compound shown in formula 7 reacts compound shown in production 1 with methyl alcohol under HCl exists;
The concentration of described HCl is 0.01mol/L, and described temperature of reaction is 0-35 DEG C, and after described reaction completes with sodium carbonate in and, filter, evaporate to dryness.
14. preparation methods according to claim 13, is characterized in that, described temperature of reaction is room temperature.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5753789A (en) * | 1996-07-26 | 1998-05-19 | Yale University | Oligonucleotides containing L-nucleosides |
| CN1724553A (en) * | 2005-06-17 | 2006-01-25 | 华东师范大学 | Synthesis method of 2-deoxy-2',2'-difluoro cytidine |
| CN102153600A (en) * | 2010-02-12 | 2011-08-17 | 何遂庆 | Method for preparing 2-deoxidation-L-ribose |
| CN102300464A (en) * | 2008-11-17 | 2011-12-28 | 安那迪斯药品股份有限公司 | Method Of Preparing Deoxyribofuranose Compounds |
-
2013
- 2013-03-14 CN CN201310081196.7A patent/CN103172682B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5753789A (en) * | 1996-07-26 | 1998-05-19 | Yale University | Oligonucleotides containing L-nucleosides |
| CN1724553A (en) * | 2005-06-17 | 2006-01-25 | 华东师范大学 | Synthesis method of 2-deoxy-2',2'-difluoro cytidine |
| CN102300464A (en) * | 2008-11-17 | 2011-12-28 | 安那迪斯药品股份有限公司 | Method Of Preparing Deoxyribofuranose Compounds |
| CN102153600A (en) * | 2010-02-12 | 2011-08-17 | 何遂庆 | Method for preparing 2-deoxidation-L-ribose |
Non-Patent Citations (2)
| Title |
|---|
| A stereospecific synthesis of L-deoxyribose, L-ribose and L-ribosides;Zhen-Dan Shi，等;《Tetrahedron》;20020415;第58卷(第16期);第3288页方案1 * |
| 抗肿瘤药物卡培他滨的合成新方法;赵明礼，等;《高等学校化学学报》;20120831;第33卷(第8期);第1733-1737页 * |
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Effective date of registration: 20221104 Address after: No. 25, Zone D, Mingxi Economic Development Zone, Sanming, Fujian 365299 Patentee after: Fujian Ruibo Technology Co.,Ltd. Address before: 710, Floor 7, New Materials Venture Building, No. 7, Fenghui Middle Road, Haidian District, Beijing 100094 Patentee before: BEIJING RIBIO BIOTECH Co.,Ltd. |