CN108727440A - A kind of preparation method of tri--O- acetyl group -5- deoxidations-β of 1,2,3--D-ribose - Google Patents
A kind of preparation method of tri--O- acetyl group -5- deoxidations-β of 1,2,3--D-ribose Download PDFInfo
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Abstract
The invention discloses a kind of preparation methods of 1,2,3- tri--O- acetyl group -5- deoxidations-β-D-ribose, belong to nucleosides in organic chemistry and synthesize field.Its reaction step is as follows：Inosine 1 is reacted with triphenyl phosphite-halogen, obtains compound 2；Subsequent compound 2 hydrogenating reduction under palladium carbon catalysis；Then tri--O- acetyl group -5- deoxidations-β of 1,2,3--D-ribose is obtained by the reaction in compound 3 under inorganic boric acid catalysis in aceticanhydride.This synthetic method raw material is cheap, and step is short, is easy to industrialized production, has industrial applications foreground.
Description
Technical field
The invention belongs to nucleosides in organic chemistry to synthesize field, and in particular to 1,2,3- of one kind, tri--O- acetyl group -5- are de-
The method of the preparation method of oxygen-β-D-ribose.
Background technology
1,2,3- tri--O- acetyl group -5- deoxidations-β-D-ribose, CAS：62211-93-2 is mainly used for capecitabine
(Capecitabine) in synthesis.Capecitabine is the new antitumoral new drug developed by Roche Holding Ag, in 1998 by FDA
Approval lists in the U.S., trade name XELODA (Xeloda).One suitable for inoperable late period or metastatic gastric carcinoma
Line is treated, colon cancer adjuvant chemotherapy, and suitable for chemotherapy, breast cancer list medicine chemotherapy or the combined chemotherapy of colorectal cancer.
Open source information reports relatively more, representative patent WO2009071726A1 to the process route of capecitabine
Once the synthetic method for disclosing capecitabine uses 5-flurocytosine for starting material, by making the amino on pyrimidine ring send out
It is raw acylated to introduce non-polar sidechain, then with 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose is coupled, most afterwards through hydrolysis
Biacetyl group on removal glycosyl obtains capecitabine.
Currently, document about 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose synthetic route report, mainly have with
Under it is several：
United States Patent (USP) US4340729 is first translated into 5- deoxy-D-riboses, then occur using D-ribose as starting material
Triacetylated reaction prepares target product.This route is fairly simple, and more common method.Its shortcoming is that synthetic route
Long, intermediate is all grease, not easy purification, and total recovery is low, especially triacetyl of the final step to 5- deoxy-D-riboses
Change, 1 beta/alpha ratio is low, causes total recovery in 25-30%, in the industrial production without competitive advantage.
CN100432088 uses inosine for starting material, and 1 is prepared through three steps such as iodate, reduction, acetylation,
2,3-O- triacetyl -5- deoxidations-β-D-ribose.The starting material inosine cost of the route is low compared with D-ribose, but its deficiency
Be in：Using iodine as iodo reagent, molecule utilization rate is low, and generates more black during iodo and de- iodo
Waste water containing iodine increases the pressure of three-protection design；Expensive triphenyl phosphorus is largely used in iodide reaction, and reacts raw
At triphenylphosphinc oxide be difficult to eliminate, to post-reaction treatment, purifying bring difficulty；Total recovery is low, and practical operation total recovery does not surpass
Cross 60%.
CN102432642B using inosine as starting material, through paratoluensulfonyl chloride it is acylated 5 '-p-toluenesulfonyl -6- hydroxyls
Then base -9-D- purine nucleosides restores to obtain 5 '-deoxidation -6- hydroxyl -9- β-D- purine nucleosides, then under sodium borohydride effect
2,3-O- diacetyl -5- deoxyinosines are prepared through acylation reaction with acetic anhydride, last desugar glycosides is acetylating simultaneously that target is produced
Object 1,2,3-O- triacetyl -5- deoxy-D-ribofuranoses.It is poor using the sodium borohydride safety of equivalent in this method, it is quenched
The a large amount of hydrogen of Shi Anquan generate, and security risk is apparent.When simultaneously amplifying feather weight scale, even if using equivalent to toluene
When sulfonylation other than 5, hence it is evident that 2 tosylation by-products (about 12-14%) of amount generate, not easy purification, in this
Mesosome can be introduced directly into finished product, cause product list miscellaneous exceeded.
For amplification scale, all there is different degrees of deficiency in various routes, in addition the subtle structure change of nucleosides
In specific reaction, property can all have apparent difference.Still need to develop short through operating procedure at present, raw material sources are conveniently easy to get,
It is safely controllable in operating process, have the technology of industrial prospect synthesis 1,2,3- tri--O- acetyl group -5- deoxidations-β-D-ribose
Scheme.
Invention content
In order to overcome drawbacks described above, the invention discloses a kind of 1,2,3- tri--O- acetyl group -5- deoxidations-β-D-riboses
Preparation method.It using inosine as raw material, is reacted with triphenyl phosphite-halogen, 5 hydroxyls are changed into halogen, Qi Tawei by a step
It is unaffected to set hydroxyl, then the hydrogenating reduction under palladium carbon catalysis, is finally obtained by the reaction 1 under inorganic boric acid catalysis in aceticanhydride,
Tri--O- acetyl group -5- deoxidations-β of 2,3--D-ribose.
The preparation method of 1,2,3- of one kind, tri--O- acetyl group -5- deoxidations-β-D-ribose, which is characterized in that reaction equation
It is as follows：
Including following reaction step：Inosine 1 is reacted with triphenyl phosphite-halogen, obtains compound 2；Subsequent compound 2
The hydrogenating reduction under palladium carbon catalysis；Then tri--O- acetyl of 1,2,3- is obtained by the reaction in compound 3 under inorganic boric acid catalysis in aceticanhydride
Base -5- deoxidations-β-D-ribose.
Further, in the above-mentioned technical solutions, in the first step, halogen is selected from chlorine or bromine, reacts organic
It is carried out in the presence of alkali, reaction dissolvent is selected from dichloromethane, chloroform or 1,2- dichloroethanes.
Further, in the above-mentioned technical solutions, in the first step, organic base is selected from triethylamine or diisopropyl ethyl
Amine.
Further, in the above-mentioned technical solutions, the inosine, triphenyl phosphite, halogen, organic base molar ratio be
1:1-2.5:1-2.5:1.5-3.Preferably, triphenyl phosphite and halogen are equivalent, and organic alkali equivalent is more than phosphorous acid three
Phenyl ester or bromine equivalent.
In operation, using by inosine, triphenyl phosphite and organic base be added reaction system, be cooled to -40 DEG C to -
10 DEG C, starts to be passed through chlorine or bromine is added dropwise that reaction system cools down after completion of the reaction, after removing organic solvent, second is added
Alcohol removes phosphorous by-product and organic basis of hydrochloride/bromate crystallization under freezing.Reaction solution can be directly entered plus hydrogen step
Suddenly.
Further, in the above-mentioned technical solutions, the reduction adds in hydrogen, and palladium carbon addition is the 2- of 2 weight of compound
10%.After the completion of reaction, filtering can enter lower batch cycle to catalyst, but need to supplement 1-3% raw catelysts again, protect
The reaction efficiency for demonstrate,proving batch, after 5 cycles, concentration does catalyst activation treatment.
Further, in the above-mentioned technical solutions, compound 3, aceticanhydride and inorganic boric acid molar ratio are 1:10-15:0.05-
0.10, reaction carries out under reflux conditions.
Invention advantageous effect：
1. the present invention is common commercial raw materials and reagents, convenient sources are easy to industrialized production, have and answer well
Use foreground.
2. when in the present invention using triphenyl phosphite-halogen reaction, once builds 5 hydroxyls and be changed into halogen, while 2
It is unaffected with 3 hydroxyls, after reaction, by-product is removed by being added under ethyl alcohol freezing.
3. using palladium carbon reduction hydrogenation as most there are convenient dehalogenation means, item is hydrogenated by change for different halogens
It can smoothly be realized after part.
4. often step product can carry out directly down without further purification, finished product is using i.e. reachable after methanol aqueous systems recrystallization
To 99% or more purity.
Specific embodiment：The following contents is please voluntarily supplemented according to the condition of above-mentioned setting
Embodiment 1
The synthesis of 5 '-bromine inosines (2)
In the there-necked flask with blender and thermometer 1000mL, inosine (80g, 0.3mol), phosphorous triphenyl phosphate is added
Ester (139.5g, 0.45mol), triethylamine (50.6g, 0.5mol), dichloromethane 400mL are cooled to -15 DEG C, and bromine is added dropwise
(95.9g, 0.6mol) controls temperature at 0 DEG C hereinafter, being added dropwise, and room temperature reaction 2h after completion of the reaction drops reaction system
400mL ethyl alcohol is added in temperature, organic solvent concentration and recovery, crystallizes phosphorous by-product and organic basis of hydrochloride/bromate under freezing
It removes.Reaction solution can be directly entered hydrogenation step.
The synthesis of 5 '-deoxyinosines (3)
4g Palladium carbon will be added in upper step reaction solution, after triethylamine (30.4g, 0.3mol) reaction system replacing hydrogen, rise
Temperature filters after reaction to back flow reaction 4h, and Palladium carbon can be used for lower secondary response recycling, and reaction solution is concentrated into syrup addition
The stirring of 200mL water has solid precipitation, filters filter cake and is washed with a small amount, dries to obtain product 62g, two step yields (in terms of inosine)：
82.4%.
The preparation of 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose (4)
In with blender and thermometer 250mL there-necked flasks, 5 '-deoxyinosines (20g, 0.079mol), aceticanhydride is added
100mL heats up 100 DEG C and reacts 1 hour, and inorganic boric acid 0.23g (0.05eq) is added, and the reaction was continued 10 hours, there is solid precipitation,
10 DEG C of cooling is filtered except acetyl hypoxanthine solid, and filtrate decompression concentration is dry, and isopropanol 30mL bands are added once, add 45mL
Isopropanol crystallisation by cooling obtains 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose 17.3g, HPLC：99.6%, single miscellaneous 0.11%,
Yield：83.7%.
Embodiment 2
The synthesis of 5 '-bromine inosines (2)
In the there-necked flask with blender and thermometer 1000mL, inosine (80g, 0.3mol), phosphorous triphenyl phosphate is added
Ester (139.5g, 0.45mol), diisopropyl ethyl amine (64.7g, 0.5mol), dichloromethane 400mL are cooled to -15 DEG C, drop
Liquid feeding bromine (95.9g, 0.6mol) controls temperature at 0 DEG C hereinafter, being added dropwise, and 40 DEG C are reacted 2h, after completion of the reaction, by reactant
400mL ethyl alcohol is added, by phosphorous by-product and organic basis of hydrochloride/bromate under freezing in system's cooling, organic solvent concentration and recovery
Crystallization is removed.Reaction solution can be directly entered hydrogenation step.
The synthesis of 5 '-deoxyinosines (3)
4g Palladium carbon will be added in upper step reaction solution, diisopropyl ethyl amine (38.8g, 0.3mol) reaction system replaces hydrogen
After gas, it is warming up to back flow reaction 4h, is filtered after reaction, Palladium carbon can be used for lower secondary response recycling, and reaction solution is concentrated into
The stirring of 200mL water, which is added, in syrup a solid precipitation, filters filter cake and is washed with a small amount, and dries to obtain product 63g, two step yields (with
Inosine meter)：83.8%.
The preparation of 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose (4)
5 '-deoxyinosines (20g, 0.079mol), aceticanhydride are added in the 250mL there-necked flasks with blender and thermometer
110mL heats up 100 DEG C and reacts 1 hour, and boric acid (0.23g, 0.0039mol) is added, and the reaction was continued 10 hours, there is solid precipitation,
10 DEG C of cooling is filtered except acetyl hypoxanthine solid, and filtrate decompression concentration is dry, and isopropanol 30mL bands are added once, add 30mL
Isopropanol crystallisation by cooling obtains 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose 17.4g, HPLC：99.5%, single miscellaneous 0.13%,
Yield：84.1%.
Embodiment 3
The synthesis of 5 '-chlorine inosines (2)
In the there-necked flask with blender and thermometer 1000mL, inosine (80g, 0.3mol), phosphorous triphenyl phosphate is added
Ester (139.5g, 0.45mol), triethylamine (50.6g, 0.5mol), chloroform 400mL are cooled to -15 DEG C, be passed through chlorine (42.5g,
0.6mol) at 0 DEG C hereinafter, chlorine is passed through finishes, 40 DEG C of reaction 2h after completion of the reaction cool down reaction system control temperature, have
400mL ethyl alcohol is added in solvent concentration and recovery, removes phosphorous by-product and organic basis of hydrochloride/chlorate crystallization under freezing.
Reaction solution can be directly entered hydrogenation step.
The synthesis of 5 '-deoxyinosines (3)
4g Palladium carbon will be added in upper step reaction solution, after triethylamine (30.4g, 0.3mol) reaction system replacing hydrogen, rise
Temperature filters after reaction to back flow reaction 4h, and Palladium carbon can be used for lower secondary response recycling, and reaction solution is concentrated into syrup addition
The stirring of 200mL water has solid precipitation, filters filter cake and is washed with a small amount, dries to obtain product 52g, two step yields (in terms of inosine)：
69%.
The preparation of 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose (4)
5 '-deoxyinosines (20g, 0.079mol), aceticanhydride are added in the 250mL there-necked flasks with blender and thermometer
80mL heats up 100 DEG C and reacts 1 hour, and boric acid (0.23g, 0.0039mol) is added, and the reaction was continued 10 hours, there is solid precipitation, drops
10 DEG C of temperature is filtered except acetyl hypoxanthine solid, and filtrate decompression concentration is dry, and isopropanol 30mL bands are added once, it is different to add 30mL
Propyl alcohol crystallisation by cooling obtains 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose 16.2g, HPLC：99.6%, single miscellaneous 0.15%, it receives
Rate：78.45%.
Embodiment 4
The synthesis of 5 '-bromine inosines (2)
In the there-necked flask with blender and thermometer 1000mL, inosine (80g, 0.3mol), phosphorous triphenyl phosphate is added
Ester (139.5g, 0.45mol), triethylamine (50.6g, 0.5mol), dichloroethanes 400mL are cooled to -15 DEG C, and bromine is added dropwise
(95.9g, 0.6mol) controls temperature at 0 DEG C hereinafter, being added dropwise, and 40 DEG C of reaction 2h after completion of the reaction drop reaction system
400mL ethyl alcohol is added in temperature, organic solvent concentration and recovery, crystallizes phosphorous by-product and organic basis of hydrochloride/bromate under freezing
It removes.Reaction solution can be directly entered hydrogenation step.The synthesis of 5 '-deoxyinosines (3)
4g Palladium carbon will be added in upper step reaction solution, diisopropyl ethyl amine (38.8g, 0.3mol) reaction system replaces hydrogen
After gas, it is warming up to back flow reaction 4h, is filtered after reaction, Palladium carbon can be used for lower secondary response recycling, and reaction solution is concentrated into
The stirring of 200mL water, which is added, in syrup a solid precipitation, filters filter cake and is washed with a small amount, and dries to obtain product 63g, two step yields (with
Inosine meter)：84%.
The preparation of 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose (4)
5 '-deoxyinosines (20g, 0.079mol), aceticanhydride are added in the 250ml there-necked flasks with blender and thermometer
100mL heats up 100 DEG C and reacts 1 hour, and boric acid (0.35g, 0.0057mol) 0.24g is added, and the reaction was continued 10 hours, there is solid
It is precipitated, cools down 10 DEG C and filter except acetyl hypoxanthine solid, filtrate decompression concentration is dry, isopropanol 30mL bands is added once, then add
Enter 45mL isopropanol crystallisation by cooling and obtains 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose 17.3g, HPLC：99.2%, it is single miscellaneous
0.14%, yield：83.7%.
Embodiment 5
The synthesis of 5 '-bromine inosines (2)
In the there-necked flask with blender and thermometer 1000mL, inosine (80g, 0.3mol), phosphorous triphenyl phosphate is added
Ester (186g, 0.6mol), triethylamine (70.7g, 0.7mol), dichloromethane 400mL are cooled to -15 DEG C, be added dropwise bromine (120g,
0.75mol) at 0 DEG C hereinafter, being added dropwise, 40 DEG C of reaction 2h after completion of the reaction cool down reaction system control temperature, organic
Solvent concentration recycles, and 400mL ethyl alcohol is added, and removes phosphorous by-product and organic basis of hydrochloride/bromate crystallization under freezing.Instead
Answer solution that can be directly entered hydrogenation step.
The synthesis of 5 '-deoxyinosines (3),
Upper step reaction solution is added in the there-necked flask of 1000mL, adds 3g Palladium carbon, triethylamine (30.4g,
0.3mol) after reaction system replacing hydrogen, it is warming up to back flow reaction 4h, is filtered after reaction, Palladium carbon can be used for lower secondary response
Recycling, reaction solution, which is concentrated into syrup and 200mL water is added and stirs, solid precipitation, filters filter cake and is washed with a small amount, dries
Obtain product 62g, two step yields (in terms of inosine)：82.4%.
The preparation of 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose (4)
5 '-deoxyinosines (20g, 0.079mol), aceticanhydride are added in the 250mL there-necked flasks with blender and thermometer
100mL heats up 100 DEG C and reacts 1 hour, and boric acid (0.47g, 0.0078mol) is added, and the reaction was continued 10 hours, there is solid precipitation,
10 DEG C of cooling is filtered except acetyl hypoxanthine solid, and filtrate decompression concentration is dry, and isopropanol 30mL bands are added once, add 45mL
Isopropanol crystallisation by cooling obtains 1,2,3-O- triacetyl -5- deoxidations-β-D-ribose 17.3g, HPLC：99.2%, single miscellaneous 0.14%,
Yield：83.7%.
The above shows and describes the basic principles and main features of the present invention and the advantages of the present invention.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (6)
1. one kind 1,2, the preparation method of tri--O- acetyl group -5- deoxidations-β of 3--D-ribose, which is characterized in that reaction equation is such as
Under：
Including following reaction step：Inosine 1 is reacted with triphenyl phosphite-halogen, obtains compound 2；Subsequent compound 2 is in palladium
The lower hydrogenating reduction of carbon catalysis；Then tri--O- acetyl group of 1,2,3--is obtained by the reaction in compound 3 under inorganic boric acid catalysis in aceticanhydride
5- deoxidations-β-D-ribose.
2. a kind of preparation method of 1,2,3- tri--O- acetyl group -5- deoxidations-β-D-ribose according to claim 1, feature
It is：In the first step, halogen is selected from chlorine or bromine, and reaction carries out in the presence of an organic base, and reaction dissolvent is selected from dichloro
Methane, chloroform or 1,2- dichloroethanes.
3. a kind of preparation method of 1,2,3- tri--O- acetyl group -5- deoxidations-β-D-ribose according to claim 2, feature
It is：In the first step, organic base is selected from triethylamine or diisopropyl ethyl amine.
4. according to a kind of preparation method of 1,2,3- tri--O- acetyl group -5- deoxidations-β-D-ribose described in Claims 2 or 3,
It is characterized in that：The inosine, triphenyl phosphite, halogen, organic base molar ratio be 1:1-2.5:1-2.5:1.5-3.
5. a kind of preparation method of 1,2,3- tri--O- acetyl group -5- deoxidations-β-D-ribose according to claim 1, feature
It is：In the reduction plus hydrogen, palladium carbon addition is the 2-10% of 2 weight of compound.
6. according to the preparation method of arbitrary described a kind of 1,2, the 3- tri--O- acetyl group -5- deoxidations-β-D-riboses of claim 1-3,
It is characterized in that：Compound 3, aceticanhydride and inorganic boric acid molar ratio are 1:10-15:0.05-0.10, reaction under reflux conditions into
Row.
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| CN107827938A (en) * | 2017-10-27 | 2018-03-23 | 新乡拓新药业股份有限公司 | A kind of preparation method of the deoxidation β D ribose of 1,2,3 3 O acetyl group 5 |
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2018
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| CN101012252A (en) * | 2007-01-30 | 2007-08-08 | 王成举 | Method of synthesizing 1,2,3-tri-O-acetyl-5-deoxidation-D-ribose |
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