CN101972669B - Nucleoside preparation technology by using solvent-free melting method and catalyst used thereby - Google Patents
Nucleoside preparation technology by using solvent-free melting method and catalyst used thereby Download PDFInfo
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Abstract
The invention relates to a catalyst used by a nucleoside preparation technology by using a solvent-free melting method, which is characterized in that the catalyst takes acidic or meta-acidic ionic liquid as the catalyst; the ionic liquid catalyst is quaternary ammonium salt type ionic liquid at constant temperature. The invention also discloses a nucleoside preparation technology utilizing the catalyst by using a solvent-free melting method, which is characterized in that carbohydrate derivatives and purines or miazines protected by silicon armour and other heterocyclic compounds of the same molar weights are heated to a melting state to prepare the corresponding nucleoside under the condition that the ionic liquid catalyst is used for catalysis. The invention has the advantages that the raw materials of the catalyst have wide sources and are easy acquired; the catalyst is taken as the technological catalyst for preparing various nucleosides by utilizing the solvent-free melting method, the reaction substrate is easily converted into the melting state because the catalyst is liquid at the constant temperature and has high boiling point; the heating temperature is low; the reaction is stable; and the carbonization degree of reaction mixture is low to be beneficial to the enhancement of the yield.
Description
Technical field
The present invention relates to a kind of preparation method of nucleosides, particularly a kind of solvent-free fusion method prepares nucleosides technology; The invention still further relates to the catalyst that aforementioned technology is used.
Background technology
After carbohydrate derivative and other heterocycle compound (often the being called as nucleoside base) fusions such as purine class or miazines that fusion method prepares the acyl group protection of nucleosides method almost equimolar amounts commonly used stir; The Lewis acid of cold slightly adding catalysis; Be heated to molten after the mixing once more; Reaction temperature is higher, and wider range is everlasting between 130-195 ℃.Feed way is heated to molten after also can two key reaction raw materials and little amount of catalyst Lewis acid being mixed together again.(negative pressure is less demanding under negative pressure; Higher because of reaction temperature, water commonly used is towards pump in the laboratory, and available water is towards pump or vavuum pump in the industry); Stoichiometric number minute or do not wait in several hours under negative pressure; Decide according to factors such as reaction raw materials and catalyst, reaction is carried out separating treatment after finishing again, can obtain corresponding nucleosides product.Negative pressure is mainly taken out the carboxylic acid that produces in the dereaction.
The acid of catalytic reaction is commonly used has p-TsOH, ZnCl
2, TiCl
4, chloroacetic acid, monochloroacetic acid, dibromo acetic acid, sulfuric acid, sulfamic acid (H
2NSO
3H), p-nitrophenol, di(2-ethylhexyl)phosphate (p-nitrophenol) ester [(p-O
2NC
6H
4O)
2P (O) OH], and iodine (I
2).When on the anomeric carbon of glycosyl halogenic substituent being arranged, also useful NaI and KI make catalyst.Prepare in the nucleosides at fusion method, add which kind of catalyst, one highly necessary with carbohydrate and the character of nucleoside base of protection, with and the result that tests decide (referring to Yao Qizheng, nucleosides chemical synthesis, Beijing: Chemical Industry Press, 2005, p215～217).
Though preparing nucleosides, above-mentioned fusion method avoids the use of the Silyl-Hilbert-Johnson method (referring to Vorbrueggen H, Run-Pohlenz C.Synthesis of Nucleosides, in Organic Reaction; Paquette LA, et al.eds, John Wiley & Sons:New York; 2000; Vol 55:154-284) Lewis acid catalyst such as heavy metal inorganic salts has reduced the pollution to environment, still in; In the fusion method can usefulness catalyst---acid compounds kind and quantity still are limited, can not adapt to the demand of variation of carbohydrate and the nucleoside base of protection.Obviously, the diversity of development catalyst is very necessary.
Summary of the invention
Technical problem to be solved by this invention is the deficiency to prior art, provide a kind of with wide material sources, preparation is convenient, structure is various, post processing is easy to solvent-free fusion method and prepares the employed ionic-liquid catalyst of nucleosides technology.
Another technical problem to be solved by this invention has provided a kind of solvent-free fusion method of above-mentioned ionic-liquid catalyst that uses and has prepared nucleosides technology.
Technical problem to be solved by this invention can also further realize through following technical scheme.The present invention is that a kind of solvent-free fusion method prepares the catalyst that nucleosides technology is used; Be characterized in: described catalyst is to make catalyst with the ionic liquid of acidity or slant acidity; Described ionic-liquid catalyst is that normal temperature is liquid quaternary ammonium salt ion liquid, and their molecular structure is selected from:
Wherein, Cation is selected from and is following five types of quaternary ammonium ions: imidazoles quaternary ammonium cation, imidazole radicals third/fourth sulfonic acid type quaternary ammonium cation, pyrazoles quaternary ammonium cation, pyridine quaternary ammonium cation, tetraalkyl quaternary ammonium cation; They all are the substituted quaternary ammonium ion of alkyl R, and R is the positive alkyl of C2～C9; Anion Y
-Inorganic acid or organic acid for negative monovalence are selected from: bisulfate ion, sulfuric acid one methyl esters anion, ethyl sulfuric acid anion, acetate, chloroacetate root, dichloroacetic acid root, trifluoroacetic acid root, propionate, seven fluorine propionates, butyric acid root, pentanoate, methanesulfonate, ethyl sulfonic acid root, TFMS root or p-methyl benzenesulfonic acid root.
In the described catalyst of above technical scheme: in said ionic-liquid catalyst, R is preferably the positive alkyl of C3～C6.
Technical problem to be solved by this invention can also further realize through following technical scheme.The invention also discloses a kind of solvent-free fusion method of the described catalyst of above technical scheme that uses and prepare nucleosides technology; Be characterized in: do at described ionic-liquid catalyst under the condition of catalysis with the purine class of the carbohydrate derivative of equimolar amounts and the protection of silicon first or miazines and other heterocycle compound (also being nucleoside base); Be heated to molten; Make corresponding nucleosides, heating and temperature control is at 85～120 ℃; Described carbohydrate derivative is the saccharide compound of acyl group protection.
Above-described solvent-free fusion method prepares in the nucleosides technology: described saccharide compound can be D-/L-carbohydrate acyclic or ring-type; Comprise: triose glycerine, dihydroxyacetone (DHA), four carbofuran cyclohexanol classes, oxa-ring tetrose, 2-oxa--1; 4-two butanols, 2-oxa--3-methylol-1; 4-two butanols, five yuan of furans/pyranoses, 2-deoxidation-five yuan furans/pyranose, 2; Two deoxidation-five yuan furans/the pyranoses of 3-, hexa-atomic furans/pyranose, 2-deoxidation-hexa-atomic furans/pyranose, 2, the two deoxidations of 3--hexa-atomic furans/pyranose; Preferred triose glycerine, oxa-ring tetrose, 2-oxa--1 wherein; 4-two butanols, 2-oxa--3-methylol-1,4-two butanols, five yuan of furans/pyranoses, 2-deoxidation-five yuan furans/pyranose, hexa-atomic furans/pyranose, 2-deoxidation-hexa-atomic furans/pyranose.
Above-described solvent-free fusion method prepares in the nucleosides technology: in the saccharide compound of described acyl group protection; The acyl group of protection saccharide compound can be the acyl group of routine, and is preferred: acetyl group, propiono, bytyry, isobutyryl, benzoyl, phenylacetyl group.
Above-described solvent-free fusion method prepares in the nucleosides technology: the preferable amount of described ionic-liquid catalyst is 0.05～0.5% of a substrate carbohydrate derivative mole; Further be preferably 0.05～0.2%.
Compared with prior art, the solvent-free fusion method of the present invention prepares nucleosides technology and catalyst has following technique effect:
(1) catalyst of the present invention is the ionic liquid of a kind of acidity or slant acidity; It is that multiple inorganic acid or organic acid by multiple quaternary ammonium cation and negative monovalence combines; Its raw material sources extensively, be easy to get; So the kind of catalyst is numerous and jumbled very big with quantity, can satisfy the synthetic needs of various nucleosides fully.
(2) because ionic liquid normal temperature is liquid state down, and boiling point is higher, shows through experimental study; Solvent-free fusion method of the present invention prepares the technology of all kinds nucleosides, the very easy molten that transfers to of its reaction substrate, and its heating-up temperature is generally at 85～120 ℃; The heating-up temperature for preparing nucleosides than conventional fusion method is low, so, its reacting balance; The carbonizing degree of reactant mixture is low, helps productive rate and improves.
The specific embodiment
Below further describe concrete technical scheme of the present invention,, and do not constitute restriction its right so that those skilled in the art understands the present invention further.
Embodiment 1.A kind of solvent-free fusion method prepares the catalyst that nucleosides technology is used, and described catalyst is to make catalyst with the ionic liquid of acidity or slant acidity, and described ionic-liquid catalyst is that normal temperature is liquid quaternary ammonium salt ion liquid, and their molecular structure is selected from:
Wherein, Cation is selected from and is following five types of quaternary ammonium ions: imidazoles quaternary ammonium cation, imidazole radicals third/fourth sulfonic acid type quaternary ammonium cation, pyrazoles quaternary ammonium cation, pyridine quaternary ammonium cation, tetraalkyl quaternary ammonium cation; They all are the substituted quaternary ammonium ion of alkyl R, and R is the positive alkyl of C2～C9; Anion Y
-Inorganic acid or organic acid for negative monovalence are selected from: bisulfate ion, sulfuric acid one methyl esters anion, ethyl sulfuric acid anion, acetate, chloroacetate root, dichloroacetic acid root, trifluoroacetic acid root, propionate, seven fluorine propionates, butyric acid root, pentanoate, methanesulfonate, ethyl sulfonic acid root, TFMS root or p-methyl benzenesulfonic acid root.
Embodiment 2.In the embodiment 1 described catalyst: in the said ionic-liquid catalyst, R is the positive alkyl of C3～C6.
Embodiment 3.The solvent-free fusion method of a kind of embodiment of use 1 or 2 described catalyst prepares nucleosides technology; The steps include: to do under the condition of catalysis at described ionic-liquid catalyst with the purine class of the carbohydrate derivative of equimolar amounts and the protection of silicon first or miazines and other heterocycle compound; Be heated to molten; Make corresponding nucleosides, heating and temperature control is at 85～120 ℃; Described carbohydrate derivative is the saccharide compound of acyl group protection.
Embodiment 4.In the embodiment 3 described technologies: described saccharide compound is a D-/L-carbohydrate acyclic or ring-type; Comprise: triose glycerine, dihydroxyacetone (DHA), four carbofuran cyclohexanol classes, oxa-ring tetrose, 2-oxa--1; 4-two butanols, 2-oxa--3-methylol-1; 4-two butanols, five yuan of furans/pyranoses, 2-deoxidation-five yuan furans/pyranose, 2; Two deoxidation-five yuan furans/the pyranoses of 3-, hexa-atomic furans/pyranose, 2-deoxidation-hexa-atomic furans/pyranose, 2, the two deoxidations of 3--hexa-atomic furans/pyranose.
Embodiment 5.In the embodiment 3 described technologies: in the saccharide compound of described acyl group protection, the acyl group of protection saccharide compound is selected from: acetyl group, propiono, bytyry, isobutyryl, benzoyl, phenylacetyl group.
Embodiment 6.In the embodiment 3 described technologies: the consumption of described ionic-liquid catalyst is 0.05% of a substrate carbohydrate derivative mole.
Embodiment 7.In the embodiment 3 described technologies: the consumption of described ionic-liquid catalyst is 0.5% of a substrate carbohydrate derivative mole.
Embodiment 8.In the embodiment 3 described technologies: the consumption of described ionic-liquid catalyst is 0.2% of a substrate carbohydrate derivative mole.
Embodiment 9.In the embodiment 3 described technologies: the consumption of described ionic-liquid catalyst is 0.1% of a substrate carbohydrate derivative mole.
Experimental example 1.Preparation of catalysts.
The ionic liquid of acidity or slant acidity (Ionic Liquid; Be abbreviated as: IL) compound mode of catalyst according to the form below 1 has prepared that a collection of (its preparation method is referring to Deng Youquan, ionic liquid---character, preparation and application, Beijing: Sinopec publishing house; 2006, p 11～18) as representative.
Table 1 (ionic liquid of acidity or slant acidity) catalyst
Annotate: the R in the table is a normal-butyl.
Experimental example 2.The preparation of Ribavirin (Ribavirin).
Reaction equation is following:
6.35g (0.05mol) 1H-1; 2; 4-triazole-3-carboxylate methyl ester and 16.54g (0.052mol) tetrem acyl ribose are mixed and heated to 90 ℃, add the about 12mg of catalyst 1a (0.052mmol) that states of experimental example 1 after the fusion, are heated with stirring to 105～110 ℃ under the negative pressure; The thin plate chromatography detects behind the 20min, and reaction is accomplished.After being chilled to room temperature, add the 80mL carrene, behind the stirring 15min, pour out solution, residue is continued to dissolve and wash away (80mL * 2) twice with carrene, merge organic facies, water washed twice (70mL * 2), organic facies is used anhydrous Na
2SO
4After the drying, concentrate under the negative pressure and reclaim solvent, get the dope intermediate.Add 180mL concentration subsequently and be 6% NH
3-MeOH solution, at 20 ℃ of reaction 4～5h, the adularescent solid produces therebetween; Under the negative pressure and be lower than under 40 ℃ of conditions, be concentrated into the half the of original volume, the back adds 30mL water; 50 ℃ of solids down to generation dissolve fully, add the about 40mL of methyl alcohol again, and mixture is put into refrigerator overnight.The white solid sedimentation and filtration that produces, and, get Ribavirin 6.22g (white crystalline powder) after the drying with a spot of ice methanol wash twice, yield is 51%, 173～175 ℃ of mp.
Use above proportioning raw materials and reaction condition, and method of operating, transformation catalyst, the Ribavirin productive rate of gained sees the following form 2:
Ribavirin productive rate under the table 2 different catalysts condition
Annotate: "-" expression is not done.
Experimental example 3.The preparation of 5-methyluridine (5-MU).
Reaction equation is following:
Preparation method, the step of 5-methyluridine (5-MU) are consistent with experimental example 2; Different only is that used nucleoside base methyl uracil need at first use TMS (TMS) to protect; With the dissolubility and reactivity that increases the raw material methyl uracil, more longer on the reaction time; In addition, in when base protection in the one step desugar of back, the concentration of used ammonia-methyl alcohol is higher slightly, about 8%, does not add water after the saponification, concentrates and boils off half methyl alcohol, can cool off product 5-MU.The 5-MU yield is different and different with catalyst, and concrete experimental result is seen table 3.5-MU is the off-white color crystalline powder, mp 181-185 ℃.
5-methyluridine productive rate under the table 3 different catalysts condition
Annotate: "-" expression is not done.
Experimental example 4.The preparation of adenosine (A).
Its reaction equation is following:
The preparation method of adenosine, step are consistent with experimental example 2; Different only is that used nucleoside base adenine need at first use TMS (TMS) to protect; With the dissolubility and reactivity that increases the raw material adenine; More longer on the reaction time, only select for use excellent catalytic effect 3i to make catalyst in this example.In addition, adenosine dissolubility in methyl alcohol is little, separates out morely, last after the saponification, and the yield of adenosine is 61%, white crystalline powder, mp 234-236 ℃.
Experimental example 5.6-methyl-4H, [1,2,5] oxadiazoles are [3,4-d] pyrimidine-5 also, the preparation of the oxide-based glycoside derivates 6～9 of 7-diketone 1-for 6H-.
To answer equation following
With the following formula is example, the 6-methyl-4H in the application formula, and 6H-[1; 2,5] oxadiazoles are [3,4-d] pyrimidine-5 also; 7-diketone 1-oxide is a raw material, and under the catalysis of ionic-liquid catalyst 3a, the cyclohexanol (seeing table 4) with multiple acyl group protection reacts under melting condition respectively; Reaction temperature is between 115～125 ℃, and the reaction time is 1～2h, after the cooling; With carrene gradation stripping product, after concentrating, with purification by silica gel column chromatography [eluant, eluent is an ethyl acetate: benzinum=1: 1 (V/V) and ethyl acetate: benzinum=5: 1 (V/V)]; Concrete experimental result is seen table 4, and a made class glycoside derivates 6～9 is brand-new compound, their structure all through mass spectrum (MS), infrared spectrum (IR), nucleus magnetic hydrogen spectrum (
1H NMR) with elementary analysis methods such as (EA) conclusive evidence.
Table 4 6-methyl-4H, [1,2,5] oxadiazoles are [3,4-d] pyrimidine-5 also, the glycoside derivative 6～9 of 7-diketone 1-oxide for 6H-
Annotate: [giving an example] compound 6:6-methyl-4-(2,3,5-three-O-acetyl group-1-β-D-furyl xylose base)-[1,2,5] oxadiazoles [3,4-d] pyrimidines-5 (4H), 7 (6H)-diketone 1-oxides, [α]
D 25+ 16.56 (c 2.50, CHCl
3);
1H NMR (CDCl
3, 300MHz) δ: 6.12 (d, J=5.4Hz, 1H, H-1 '), 5.96～5.93 (m, 1H, H-2 '), 5.46～5.43 (m, 1H, H-3 '), 4.51～4.48 (m, 1H, H-4 '), 4.42～4.31 (m, 2H, H-5 '), 3.38 (s, 3H, CH
3-6), 2.19 (s, 3H, CH
3-Ac), 2.11 (s, 3H, CH
3-Ac), 2.08 (s, 3H, CH
3-Ac); IR (KBr) v:3465,2960,1747,1703,1645,1583,1531,1429,1373,1311,1229,1050cm
-1ESI-MS (70V) m/z:443.2 (M+H)
+, 465.1 (M+Na)
+, C
16H
18N
4O
11(M
r=442.1); Anal.calcd for C
16H
18N
4O
11: C43.44, H4.10, N12.67; Found:C43.25, H4.24, N12.31.
Experimental example 6.4H, [1,2,5] oxadiazoles are [3,4-d] pyrimidine-5 also, the preparation of the oxide-based glycoside derivates 10～12 of 7-diketone 1-for 6H-.
Reaction equation is following:
With the following formula is example, the 4H in the application formula, and 6H-[1; 2,5] oxadiazoles are [3,4-d] pyrimidine-5 also; 7-diketone 1-oxide is a raw material, and under the catalysis of ionic-liquid catalyst 3a, the cyclohexanol (seeing table 5) with multiple acyl group protection reacts under melting condition respectively; Reaction temperature is between 115～125 ℃, and the reaction time is 1～2h, after the cooling; With carrene gradation stripping product, after concentrating, with purification by silica gel column chromatography [eluant, eluent is an ethyl acetate: benzinum=1: 1 (V/V) and ethyl acetate: benzinum=5: 1 (V/V)]; Concrete experimental result is seen table 4, and a made class glycoside derivates 10～12 is new compound, their structure all through mass spectrum (MS), infrared spectrum (IR), nucleus magnetic hydrogen spectrum (
1H NMR) with elementary analysis methods such as (EA) conclusive evidence.
Table 5 4H, [1,2,5] oxadiazoles are [3,4-d] pyrimidine-5 also, the oxide-based glycoside derivates 10～12 of 7-diketone 1-for 6H-
Annotate: [giving an example] compound 11:4-(2-acetoxyethoxy methyl)-[1,2,5] oxadiazoles [3,4-d] pyrimidine-5,7-diketone 1-oxide; H NMR (CDCl
3, 300MHz) δ: 8.73 (s, 1H, N-H), 5.47 (s, 2H, N-CH
2-), 4.18 (t, 2H ,-O-CH
2-), 3.85 (t, 2H ,-CH
2-OC=O), 2.00 (s, 1H ,-CH
3); ESI-MS:309.0 [M+Na]
+, C
9H
10N
4O
7(MW:286.05); Anal.Calcd for C
15H
16N
4O
111/2CH
3OH (302.2): C37.75, H4.00, N18.54; Found:C38.24, H3.69, N18.24.
Claims (6)
1. a solvent-free fusion method prepares nucleosides technology; It is characterized in that: do under the condition of catalysis at ionic-liquid catalyst with the purine class of the carbohydrate derivative of equimolar amounts and the protection of silicon first or miazines and other heterocycle compound; Be heated to molten; Make corresponding nucleosides, heating and temperature control is at 85～120 ℃; Described carbohydrate derivative is the saccharide compound of acyl group protection;
Described ionic-liquid catalyst is that normal temperature is liquid quaternary ammonium salt ion liquid, and their molecular structure is selected from:
Wherein, Cation is selected from and is following five types of quaternary ammonium ions: imidazoles quaternary ammonium cation, imidazole radicals third/fourth sulfonic acid type quaternary ammonium cation, pyrazoles quaternary ammonium cation, pyridine quaternary ammonium cation, tetraalkyl quaternary ammonium cation; They all are the substituted quaternary ammonium ion of alkyl R, and R is the positive alkyl of C2～C9; Anion Y
-Inorganic acid or organic acid for negative monovalence are selected from: bisulfate ion, sulfuric acid one methyl esters anion, ethyl sulfuric acid anion, acetate, chloroacetate root, dichloroacetic acid root, trifluoroacetic acid root, propionate, seven fluorine propionates, butyric acid root, pentanoate, methanesulfonate, ethyl sulfonic acid root, TFMS root or p-methyl benzenesulfonic acid root.
2. technology according to claim 1 is characterized in that: in the said ionic-liquid catalyst, R is the positive alkyl of C3～C6.
3. technology according to claim 1; It is characterized in that: described saccharide compound is a D-/L-carbohydrate acyclic or ring-type; Be selected from dihydroxyacetone (DHA), four carbofuran cyclohexanol classes, oxa-ring tetrose, 2-oxa--1; 4-two butanols, 2-oxa--3-methylol-1; 4-two butanols, five yuan of furans/pyranoses, 2-deoxidation-five yuan furans/pyranose, 2, the two deoxidation-five yuan furans/pyranoses of 3-, hexa-atomic furans/pyranose, 2-deoxidation-hexa-atomic furans/pyranose, 2, the two deoxidations of 3--hexa-atomic furans/pyranose.
4. technology according to claim 1 is characterized in that: in the saccharide compound of described acyl group protection, the acyl group of protection saccharide compound is selected from: acetyl group, propiono, bytyry, isobutyryl, benzoyl, phenylacetyl group.
5. technology according to claim 1 is characterized in that: the consumption of described ionic-liquid catalyst is 0.05～0.5% of a substrate carbohydrate derivative mole.
6. technology according to claim 5 is characterized in that: the consumption of described ionic-liquid catalyst is 0.05～0.2% of a substrate carbohydrate derivative mole.
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| CN101456813A (en) * | 2007-12-13 | 2009-06-17 | 中国科学院兰州化学物理研究所 | Method for synthesizing polyatomic alcohol fatty acid ester |
| CN101747311A (en) * | 2008-12-02 | 2010-06-23 | 中国科学院兰州化学物理研究所 | Method for synthesizing glycerol formal through reaction of glycerol and formaldehyde |
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| CN101456813A (en) * | 2007-12-13 | 2009-06-17 | 中国科学院兰州化学物理研究所 | Method for synthesizing polyatomic alcohol fatty acid ester |
| CN101747311A (en) * | 2008-12-02 | 2010-06-23 | 中国科学院兰州化学物理研究所 | Method for synthesizing glycerol formal through reaction of glycerol and formaldehyde |
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| Medicinal Chemistry Letters》.2008,(第18期),5640-5642. * |
| Vineet Kumar et al.,.Synthesis of nucleoside-based antiviral drugs in ionic liquids.《Bioorganic& * |
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