CN103172682A - Preparation method of 2-deoxy-L-ribofuranose - Google Patents
Preparation method of 2-deoxy-L-ribofuranose Download PDFInfo
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- 0 CO[C@@]12[C@@](C(*C3)(C3S(C)(=O)=O)OC)OC(c3ccccc3)O[C@@]1C2 Chemical compound CO[C@@]12[C@@](C(*C3)(C3S(C)(=O)=O)OC)OC(c3ccccc3)O[C@@]1C2 0.000 description 1
- MHNOSFGFGRTSRA-YZNZAMEGSA-N OC(C1)[C@]11ONC[C@H]1O Chemical compound OC(C1)[C@]11ONC[C@H]1O MHNOSFGFGRTSRA-YZNZAMEGSA-N 0.000 description 1
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Abstract
The invention provides a preparation method of 2-deoxy-L-ribofuranose. The preparation method comprises the following steps: carrying out 3,5-site hydroxy protection on methylated L-arabinose; carrying out 2-site deoxygenation on the L-arabinose; and carrying out 3,5-site hydroxy deprotection on the obtained product. The preparation method has the advantages of available raw materials, short synthetic route, improved product yield and purity, low production cost and the like, and is simple to operate.
Description
Technical field
The invention belongs to field of medicaments, particularly, relate to the preparation method of a kind of pharmaceutical intermediate 2-deoxidation-L-ribofuranose.
Background technology
The L-nucleoside medicine because its toxicity is lower than its enantiomorph, begins just to be subject to people's common concern as antiviral, anti-AIDS and antitumor drug from the fifties in last century.2-deoxidation-L-ribofuranose, its structural formula is as follows:
It as synthetic important intermediate with L-nucleoside medicine of new biological activity, is exactly the study hotspot of every field scientists all the time.
Yet 2-deoxidation-L-ribofuranose is a kind of non-natural ribose, only has by chemistry or biological method and synthesizes, and existing synthetic method mainly contains: 1) synthesize 2-deoxidation-L-ribofuranose take the 2-deoxy-D-ribofuranose as raw material through transposition; 2) synthesize 2-deoxidation-L-ribofuranose with L-ribose through reducing; 3) synthetic 2-deoxidation-L-ribofuranose take xitix as raw material; 4) synthetic 2-deoxidation-L-ribofuranose take L-arabinose as raw material.
But, expensive with go forward 3 kinds of methods or raw material, as the market value of L-ribose up to 6000 yuan/Kg left and right; Step is oversize, and yield is too low, and production cost is too high, and market can't be accepted.By contrast, what be suitable for practicality most is synthetic 2-deoxidation-L-ribofuranose take L-arabinose as raw material, but reported take L-arabinose as raw material in the route of synthetic 2-deoxidation-L-ribofuranose, because the expensive and difficult acquisition of intermediate reaction thing benzene oxygen thio-carbonyl chloride, or because use CS
2Raw material is inflammable.In addition, follow-up reductive agent also exists the problem that the raw material costliness is not easy to obtain equally, makes whole production cost higher.
Publication number is a kind of method that the Chinese patent of CN102108089 discloses the 2-of preparation deoxidation-L-ribose, and the reaction mechanism of the method is as follows:
Wherein, Amberlite IR-120 represents the type of catalyst resin, and the 2-deoxidation-L-ribose that obtains by the method is a kind of ribose of pyrans type of six-ring, yet pyranoid ribose is not the main raw material of synthetic nucleosides.
Disclose a kind of preparation method of 2-deoxidation-L-ribose in publication number is the Chinese patent of CN102153600, the reaction mechanism of the method is as follows:
The 2-deoxidation-L-ribose that obtains by the method is also a kind of ribose of pyrans type of six-ring.
Be not the main raw material of synthetic nucleosides due to pyranoid ribose, the main raw material of synthetic nucleosides is pentacyclic furan type ribose, so need a kind of method of synthetic furan type ribose.
Summary of the invention
The method that the purpose of this invention is to provide a kind of 2-of preparation deoxidation-L-ribofuranose, this preparation method have advantages of 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 provided by the invention-L-ribofuranose comprises the following steps:
A. compound shown in compound shown in formula 1 and formula 2 reacts compound shown in production 3 under catalyzer exists, in organic solvent;
B. compound shown in formula 3 reacts compound shown in production 4 with Methanesulfonyl chloride under alkali exists, in organic solvent;
C. compound shown in formula 4 under catalyzer exists, in organic solvent through compound shown in hydrogenation production 5;
D. compound shown in formula 5 reacts compound shown in production 6 under HCl exists, in the first alcohol and water.
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 ℃.
More preferably, described catalyzer is tosic acid; Described temperature of reaction is 50 ℃.
Preferably, described step a also comprise described reaction complete after distillation remove compound and organic solvent shown in remaining formula 2, then add toluene dissolving and transfer to neutrality with sodium bicarbonate aqueous solution.
More preferably, described step a also comprise described reaction complete after distillation remove compound and organic solvent shown in remaining formula 2, add again the toluene dissolving and transfer to neutrality with sodium hydrogen carbonate solution, organic phase underpressure distillation desolventizing again, 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 ℃.
More preferably, described alkali is triethylamine; Described organic solvent is chloroform; Described temperature of reaction is 0 ℃.
Preferably, described step b also comprises after described reaction is completed 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 is completed and is washed to neutrality with the 1mol/L aqueous hydrochloric acid, and carry out crystallization in methyl alcohol, ethanol, Virahol or acetone.
Wherein most preferably, carry out crystallization in Virahol.
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 ℃.
Preferably, described organic solvent is methyl alcohol; Described temperature of reaction is 20 ℃.
Preferably, described step c also comprises after described reaction is completed 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 ℃.
More preferably, described temperature of reaction is 30 ℃.
Preferably, described steps d also comprises after described reaction is completed washs with ethyl acetate, and the water layer evaporate to dryness is by ethyl alcohol recrystallization.
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 ℃, and neutralizes with sodium carbonate after described reaction is completed, filtration, evaporate to dryness.
Preferably, described temperature of reaction is room temperature.
The preparation method that the preparation method of compound shown in above-mentioned formula 1 is similar to the disclosed 1-O-alkyl of Chinese patent application 201010110944.6-L-arabinose glycosides prepares.
The synthetic route of particularly, 2-deoxidation of the present invention-L-ribofuranose (compound 6) is as follows:
(1) methylate: drop into L-arabinose and methyl alcohol in reactor, drip the HCl methanol solution after stirring and dissolving, room temperature reaction 5 hours react and adds the sodium carbonate neutralization after complete, and filtration is spin-dried for rear input the next step until solution;
The protection of (2) 3,5 hydroxyls: go on foot product on dropping in reactor, add tetrahydrofuran (THF), phenyl aldehyde dimethyl acetal and catalyzer, and reaction under 50 ℃.React complete, remaining phenyl aldehyde dimethyl acetal and tetrahydrofuran (THF) are removed in distillation, add the toluene dissolving, and wash or use NaHCO
3Transfer to neutrality, the underpressure distillation desolventizing, and with dropping into the next step after methanol crystallization;
(3) 2 deoxidations: when temperature of reaction is down to below 20 ℃, add triethylamine and chloroform, cool to 0 ℃ after stirring, begin to drip Methanesulfonyl chloride, react complete after, aqueous hydrochloric acid is washed till neutrality, and in Virahol crystallization purifying;
(4) hydrogenation: above product is dropped into hydrogenation reaction cauldron, add methyl alcohol, palladium-carbon catalyst, 20 ℃ of lower catalytic hydrogenations are reacted the complete rear dehydrated alcohol recrystallization of using;
The hydroxyl of (5) 3,5 go the protection: the compound that makes to step (4) adds methyl alcohol, water and hydrochloric acid; be warming up to 30 ℃ of reactions, complete rear with the ethyl acetate washing, divide and go organic phase; the water layer evaporate to dryness, and obtain product 2-deoxidation-L-ribose with ethyl alcohol recrystallization.
The invention provides the preparation method of a kind of 2-deoxidation-L-ribofuranose, the method has made 2-deoxidation-L-ribofuranose take methoxyl group-L-furans pectinose as raw material by steps such as protection hydroxyl, deoxidation, deprotection bases.What the present invention prepared is 2-deoxidation-L-ribofuranose, and what be different from most prior art preparation is 2-deoxidation-L-ribopyranose, and this furan type ribose can be used as the main raw material of at present synthetic L-nucleoside medicine.
Unlike the prior art be that the present invention adopts hydrochloric acid to carry out the protective reaction of 3,5 hydroxyls, and prior art acetic acid that use in protective reaction more.The advantage that adopts hydrochloric acid to carry out protective reaction is: at 20-80 ℃, side reaction is few usually for temperature of reaction, so the yield of the reaction product 2-that obtains deoxidation-L-furans pectinose can reach 95%.So, after reaction finishes, only need to remove organic phase with ethyl acetate washing reaction thing, with ethyl alcohol recrystallization aqueous phase product, just can obtain 2-deoxidation-L-ribofuranose, the purity of product is 99%; Yet the technique of prior art needs the reaction soln underpressure distillation, and the product that distillation obtains also will carry out recrystallization and just can obtain the 2-deoxidation-L-ribose in sherwood oil or ether, and the L-ribose that obtains also needs further purifying because purity is inadequate.
In addition, adopted the phenyl aldehyde dimethyl acetal as protective material in preparation method of the present invention, existing protective material is isopropylidene.The phenyl aldehyde dimethyl acetal that the present invention uses is as protective material, and its selectivity is better, after step a finishes, finds through check, and 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 the phenyl aldehyde 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 embodiment are only exemplary, scope of the present invention are not consisted of any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can modify or replace details and the form of technical solution of the present invention, but these modifications and replacement all fall within the scope of protection of the present invention.
If no special instructions, the described method of following examples is ordinary method, and described starting material all can get from open commercial sources.
Embodiment 1
(1) methylate: input L-arabinose 100g and concentration are 95% methyl alcohol 800mL in reactor, drip the HCl methanol solution after stirring and dissolving, HCl concentration wherein is 0.01mol/l, room temperature reaction 5 hours, react and add the sodium carbonate neutralization after complete, filter, be spin-dried for rear input the next step until solution;
The protection of (2) 3,5 hydroxyls: go on foot product on dropping in reactor, add tetrahydrofuran (THF) 400mL, phenyl aldehyde dimethyl acetal 110g and catalyzer p-methyl benzenesulfonic acid 5g, and reaction under 50 ℃.React complete, remaining phenyl aldehyde dimethyl acetal and tetrahydrofuran (THF) are removed in distillation, and add toluene and be washed till neutrality with sodium hydrogen carbonate solution, the underpressure distillation desolventizing, and with dropping into the next step after methanol crystallization;
(3) 2 deoxidations: when temperature of reaction is down to below 20 ℃, add triethylamine 25mL and chloroform 600mL, cool to 0 ℃ after stirring, begin to drip Methanesulfonyl chloride, react complete after, be washed till neutrality, crystallization purifying with the aqueous hydrochloric acid of 1mol/L;
(4) 2 deoxidations: above product is dropped into hydrogenation reaction cauldron, add methyl alcohol 600mL, at palladium-carbon catalyst, 20 ℃ of lower catalytic hydrogenations are reacted the complete rear dehydrated alcohol recrystallization of using;
The hydroxyl of (5) 3,5 go the protection: the compound that makes to step (4) adds methyl alcohol 400mL, water 100mL and hydrochloric acid 100mL (0.5mol/L); be warming up to 30 ℃ of reactions; complete wash with ethyl acetate afterwards; divide and go organic phase; the water layer evaporate to dryness; and obtaining product 2-deoxidation-L-ribose 45g with ethyl alcohol recrystallization, yield is 50.3%, purity 99%.The 2-deoxidation-L-ribose is off-white powder, fusing point 69-72 ℃.
Claims (10)
1. the preparation method of 2-deoxidation-L-ribofuranose, this preparation method comprises the following steps:
A. compound shown in compound shown in formula 1 and formula 2 reacts compound shown in production 3 under catalyzer exists, in organic solvent;
B. compound shown in formula 3 reacts compound shown in production 4 with Methanesulfonyl chloride under alkali exists, in organic solvent;
C. compound shown in formula 4 under catalyzer exists, in organic solvent through compound shown in hydrogenation production 5;
D. compound shown in formula 5 reacts compound shown in production 6 under HCl exists, in the first alcohol and water
2. preparation method according to claim 1, is characterized in that, in described step a, described catalyzer is organic acid, and described organic solvent is selected from DMF or tetrahydrofuran (THF), and described temperature of reaction is 30-90 ℃; Preferably, described catalyzer is tosic acid, and described temperature of reaction is 50 ℃.
3. preparation method according to claim 1 and 2, is characterized in that, described step a also comprise described reaction complete after distillation remove compound and organic solvent shown in remaining formula 2, then add toluene dissolving and transfer to neutrality with sodium hydrogen carbonate solution; Preferably, described step a also comprise described reaction complete after distillation remove compound and organic solvent shown in remaining formula 2, then add toluene dissolving and transfer to neutrality with sodium hydrogen carbonate solution, organic phase underpressure distillation desolventizing again, product carries out crystallization with methyl alcohol.
4. the described preparation method of any one according to claim 1 to 3, it is characterized in that, in described step b, described 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, described temperature of reaction are-10～40 ℃; Preferably, described alkali is triethylamine, and described organic solvent is chloroform, and described temperature of reaction is 0 ℃.
5. the described preparation method of any one according to claim 1 to 4, is characterized in that, described step b also comprises after described reaction is completed and is washed to neutrality with 0.5mol/L sulfuric acid or 1mol/L aqueous hydrochloric acid; Preferably, described step b also comprises after described reaction is completed and is washed to neutrality with the 1mol/L aqueous hydrochloric acid, and carries out crystallization in methyl alcohol, ethanol, Virahol or acetone, most preferably, carries out crystallization in Virahol.
6. the described preparation method of any one according to claim 1 to 5, it is characterized in that, 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, and described temperature of reaction is 0-80 ℃, preferably, described organic solvent is methyl alcohol, and described temperature of reaction is 20 ℃.
7. the described preparation method of any one according to claim 1 to 6, is characterized in that, described step c also comprises after described reaction is completed and carries out recrystallization with dehydrated alcohol.
8. the described preparation method of any one according to claim 1 to 7, is characterized in that, in described steps d, the concentration of described HCl is 0.1-2mol/L, and described temperature of reaction is 20-80 ℃; Preferably, described temperature of reaction is 30 ℃.
9. the described preparation method of any one according to claim 1 to 8, is characterized in that, described steps d also comprises after described reaction is completed washs with ethyl acetate, and the water layer evaporate to dryness is by ethyl alcohol recrystallization.
10. the described preparation method of any one according to claim 1 to 9, 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 ℃, and neutralizes with sodium carbonate after described reaction is completed, filtration, evaporate to dryness; Preferably, 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 |
|---|
| ZHEN-DAN SHI，等: "A stereospecific synthesis of L-deoxyribose, L-ribose and L-ribosides", 《TETRAHEDRON》 * |
| 赵明礼，等: "抗肿瘤药物卡培他滨的合成新方法", 《高等学校化学学报》 * |
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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. |