CN103073606A - Method for synthesizing and preparing 5'-S-(4, 4'-dimethoxytriphenylmethyl)-2'-deoxyinosine - Google Patents
Method for synthesizing and preparing 5'-S-(4, 4'-dimethoxytriphenylmethyl)-2'-deoxyinosine Download PDFInfo
- Publication number
- CN103073606A CN103073606A CN2013100535242A CN201310053524A CN103073606A CN 103073606 A CN103073606 A CN 103073606A CN 2013100535242 A CN2013100535242 A CN 2013100535242A CN 201310053524 A CN201310053524 A CN 201310053524A CN 103073606 A CN103073606 A CN 103073606A
- Authority
- CN
- China
- Prior art keywords
- hypoxanthine deoxyriboside
- reaction
- dimethoxytrityl
- formula
- molar weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Saccharide Compounds (AREA)
Abstract
The invention discloses a method for synthesizing and preparing 5'-S-(4, 4'-dimethoxytriphenylmethyl)-2'-deoxyinosine. The method comprises the following steps of: under inert gas protection, carrying out mitsunobu reaction on 2'-deoxyinosine and 4, 4'-dimethoxytriphenylmethyl mercaptan in an organic solvent at room temperature under effects of an azo reagent, a phosphine coordination compound, organic alkali or protonic acid, i.e. carrying out intermolecular dehydration reaction on 5'-hydroxyl of the 2'-deoxyinosine and the 4, 4'-dimethoxytriphenylmethyl mercaptan to obtain a C-S bond, and obtaining the 5'-S-(4, 4'-dimethoxytriphenylmethyl)-2'-deoxyinosine. The method for synthesizing and preparing the 5'-S-(4, 4'-dimethoxytriphenylmethyl)-2'-deoxyinosine has the beneficial effects of being wide in raw material sources, low in price, high in yield, mild in reaction condition, good in selectivity, simple in operation process, convenient in post-treatment, and suitable for large-scale industrial production.
Description
Technical field
The present invention relates in the field of chemical synthesis 5 '-the synthetic and preparation method of S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.
Background technology
Along with the development of molecular biology and pharmaceutical industry, the research and development of nucleoside compound and derivative thereof becomes focus.Along with going deep into of research, nucleoside compound and derivative thereof being carried out the new nucleoside compound that obtains after functional group transforms and modifies has special curative effect in Cardiovarscular, central nervous system disease, circulation and urinary system and the aspect such as antiviral, antitumor, is widely used in molecular biology, medicine and other fields.Nucleoside compound being carried out structural modification introducing hetero-atoms sulphur, the antiviral activity of medicine is improved a lot, can also reduce the toxic side effect of medicine simultaneously, is one of approach of research and screening of medicaments.5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside is as to the intermediate of 2 '-Hypoxanthine deoxyriboside glycosyl introducing hetero-atoms sulfur modification, compound after the modification is proved conclusively in the biological activity that improves medicine, is increased antiviral spectrum, and there is positive effect the aspects such as reduction toxic side effect.To nucleoside compound 5 '-the position hydroxyl is with (MeO)
2It is one of more common modification that TrSH carries out the thioetherification modification, and the main method of modification is as follows:
By 5 ' of 2 '-deoxythymidine-position hydroxyl is activated with methylsulfonyl chloride, after the thioacetic acid potassium esterification, use again 4,4 '-dimethoxytrityl methyl mercaptan ((MeO)
2TrSH) replace rear (Efficient Solid Synthensis of Cleavable Oligodeoxynucleotides Based on a Novel Strategy for the Syhthesis of 5 '-S-(4 of realization, 4 '-Dimethoxytrityl)-2 '-deoxy-5 '-thionucleoside Phosphpramidites, Kerstin Jahn-Hofmann and Ioachin W.Engels, Helvetica Chimica Acta-Vol.87 (2004), 2812-2828)), yet the method is through polystep reaction, produce a plurality of intermediate products, finally obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-yield of deoxythymidine is on the low side, can only reach 38.3%, and wherein the 3rd step used 1,1,3,3-tetramethyl guanidine is as catalyzer, price, production cost is high, is unsuitable for suitability for industrialized production.Its synthetic route is as follows:
Summary of the invention
The invention provides that a kind of reaction conditions is gentle, selectivity is good, operating process is simple 5 '-S-(4,4 '-dimethoxytrityl)-2 '-synthetic method of Hypoxanthine deoxyriboside, and a kind of yield is high, aftertreatment is easy and be easy to 5 of suitability for industrialized production '-preparation method of S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.
Provided by the present invention 5 '-S-(4; 4 '-dimethoxytrityl)-2 '-synthetic method of Hypoxanthine deoxyriboside; under protection of inert gas; under the normal temperature; in organic solvent; in azo agents; the coordination phosphine compound; under the effect of organic bases or protonic acid; with 2 '-Hypoxanthine deoxyriboside (compound shown in the formula I) and 4; 4 '-dimethoxytrityl mercaptan (compound shown in the formula II) carry out light prolong (Mitsunobu) reaction; obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside (compound shown in the formula III):
Described synthetic method comprises following operation: pass into rare gas element in container, with 2 '-Hypoxanthine deoxyriboside, 4,4 '-dimethoxytrityl mercaptan, coordination phosphine compound, organic bases or protonic acid and organic solvent add in the reaction vessel, drip azo agents, stoichiometric number hour to thin-layer chromatography TLC detection reaction liquid to without 2 '-Hypoxanthine deoxyriboside.
The developping agent that described thin-layer chromatography TLC detects is methylene dichloride: methyl alcohol volume ratio 5: 1, and take Rf=0.3 as indication point.
In the building-up reactions, described 4,4 '-molar weight of dimethoxytrityl mercaptan (compound shown in the formula II) is 2 '-2-4 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight doubly, preferred 2 times.
Described azo agents is azo agents commonly used in the Mitsunobu reaction, such as in diethyl azodiformate, diisopropyl azodiformate, the tert-butyl azodicarboxylate one or more, be preferably tert-butyl azodicarboxylate or diisopropyl azodiformate; Described azo agents molar weight is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight doubly, the mol ratio of azo agents and coordination phosphine compound is 1: 1 during use.
Described coordination phosphine compound is one or more in triphenyl phosphorus, tributylphosphine, the trimethyl-phosphine, is preferably triphenyl phosphorus or tributylphosphine; The molar weight of described coordination phosphine compound is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight doubly, the mol ratio of coordination phosphine compound and azo agents is 1: 1 during use.
Described organic solvent is DMF or dimethyl sulfoxide (DMSO), is preferably DMF; The consumption of described organic solvent is 2 '-30-50 of Hypoxanthine deoxyriboside (compound shown in the formula I) (ml: g) doubly.
Described rare gas element is nitrogen.
Described organic bases is selected from triethylamine, DMAP, N-methylpyrrole or DMA, is preferably DMAP or DMA; The molar weight of described organic bases is 2 '-1-2 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly.
Described protonic acid is selected from one or more in formic acid, acetic acid, phenylformic acid, tosic acid, methylsulfonic acid and the oxalic acid, is preferably formic acid or methylsulfonic acid or oxalic acid; The molar weight of described protonic acid is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly.
The further purpose of the present invention is to provide 5 '-preparation method of S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.The method further comprises the process of abstraction reaction product from above-mentioned reaction solution, and concrete operations are:
In reaction solution, add ethyl acetate, add again the washing composition extracting and demixing, get upper organic phase, behind anhydrous sodium sulfate drying, revolve except organic solvent, through silica gel column chromatography, obtain white solid 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside; Described washing composition is saturated aqueous ammonium chloride (using the situation of organic bases in synthetic) or saturated sodium bicarbonate aqueous solution (using the situation of protonic acid in synthetic).
The above technical scheme of the present invention proposed a kind of synthetic and preparation 5 '-S-(4,4 '-dimethoxytrityl)-2 '-novel method of Hypoxanthine deoxyriboside, synthetic reaction mechanism is: in azo agents, the coordination phosphine compound, organic bases or protonic acid exist lower, 2 '-Hypoxanthine deoxyriboside 5 '-position hydroxyl and 4,4 '-dimethoxytrityl mercaptan generation condensation dehydration reaction formation compound 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside, azo agents in the reaction process is reduced to the hydrazine dicarboxylic diester, and the coordination phosphine compound is oxidized to the basic phosphine of oxidation three hydrocarbon (virtue).The present invention first with Mitsunobu reaction (light prolongs reaction) for 2 '-thioetherification reaction of Hypoxanthine deoxyriboside and obtained success, have following beneficial effect:
1, reaction scheme is short, take 2 '-Hypoxanthine deoxyriboside only can make target product through a step chemical reaction as initiator;
2, reaction conditions is gentle;
3, by product is few, and this is because the selectivity of reaction is high;
4, do not use corrosive materials in the whole preparation process, reduced the toxicity of operating process;
5, raw material sources are extensive and cheap, initiator 2 '-Hypoxanthine deoxyriboside is very easy in market obtain, thereby the cost of synthetic target product is lower;
6, target product yield is high, can reach more than 90%;
7, preparation technology is simple, and convenient post-treatment is suitable for large-scale industrial production.
In sum, the present invention will be 5 '-play a significant role in S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside suitability for industrialized production, have a extensive future.
Below in conjunction with specific embodiment the present invention is described in further details.
Embodiment
In compound group is modified, often need to carry out functional group and transform, makes up new chemical bond, such as chemical bonds such as C-O, C-N, C-S, C-C, P-S, the present invention to nucleoside compound 5 '-a position hydroxyl carries out the thioetherification modification, target is to obtain new C-S bonding.It is under azo agents and the basic phosphine effect of three alkane (virtue) that light prolongs (Mitsunobu) reaction, alcohol compound and the dehydration condensation that carries out with the various front nucleophilic reagent of active hydrogen are a kind of classical ways that makes up C-O, C-N, the chemical bonds such as C-S, C-C.Yet, the differential responses thing utilizes light to prolong the maximum difficult point of reaction and is the selection of solvent, catalyzer and determining of reaction conditions, be so limited, at present, 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside synthetic in, do not have to use up the research report that prolongs (Mitsunobu) reaction.
The present invention is by further investigation, find and successfully utilize the Mitsunobu single step reaction obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside, thus, research and probe of the present invention and provide that a kind of yield is high, reaction conditions is gentle, selectivity is good, operating process is simple, aftertreatment is easy and be easy to 5 of suitability for industrialized production '-the synthetic and preparation method of S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.
Synthetic method reaction mechanism of the present invention is: in the presence of azo agents, coordination phosphine compound, organic bases or protonic acid, reaction raw materials 2 '-Hypoxanthine deoxyriboside 5 '-position hydroxyl and another reaction raw materials 4,4 '-dimethoxytrityl mercaptan generation condensation dehydration reaction formation compound 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside, azo agents in the reaction process is reduced to the hydrazine dicarboxylic diester, and the coordination phosphine compound is oxidized to the basic phosphine of oxidation three hydrocarbon (virtue).Its synthetic route is as follows:
Synthetic method provided by the present invention is: under protection of inert gas; under the normal temperature; in organic solvent; in azo agents; under the existence of coordination phosphine compound and organic bases (or protonic acid); with 2 '-Hypoxanthine deoxyriboside (compound shown in the formula I) and 4; 4 '-dimethoxytrityl mercaptan (compound shown in the formula II) carry out light prolong (Mitsunobu) reaction; namely 2 '-Hypoxanthine deoxyriboside 5 '-position hydroxyl and 4; 4 '-intermolecular dehydration reaction occurs in dimethoxytrityl mercaptan; form the C-S key; obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside (compound shown in the formula III).
Above-mentioned 5 '-S-(4,4 '-dimethoxytrityl)-2 '-the Hypoxanthine deoxyriboside synthetic method in, described 4,4 '-molar weight of dimethoxytrityl mercaptan (compound shown in the formula II) is 2 '-2-4 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly, test example and embodiment have listed 2 times situation (excessive), but also are fine after amount.
In the present invention, the azo agents of using is azo agents commonly used in the Mitsunobu reaction, such as in diethyl azodiformate, diisopropyl azodiformate, the tert-butyl azodicarboxylate one or more, be preferably tert-butyl azodicarboxylate or diisopropyl azodiformate.Described azo agents mole dosage is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly; The mol ratio of azo agents and coordination phosphine compound is 1: 1 during use.
In the present invention, the coordination phosphine compound of using is one or more in triphenyl phosphorus, tributylphosphine, the trimethyl-phosphine, is preferably triphenyl phosphorus or tributylphosphine.The molar weight of described coordination phosphine compound is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly; The mol ratio of coordination phosphine compound and azo agents is 1: 1 during use.
In the present invention, to use organic bases or protonic acid especially.In the present invention, acting as of organic bases captures 4, and the hydrogen on 4 '-dimethoxytrityl methyl mercaptan promotes the condensation dehydration reaction.Therefore, the organic bases that can be used among the present invention needs special screening, and the present invention experimental results show that triethylamine, DMAP, N-methylpyrrole or DMA all can be selected and reach certain effect, and imidazoles, pyridine can't make reaction carry out; From the screening of reaction product yield, preferred organic bases is DMAP or DMA.The molar weight of described organic bases is 2 '-1-2 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly.
In the present invention, it is protonated that the acting as of protonic acid makes azo agents and the addition of coordination phosphorus compound generate the De quaternary alkylphosphonium salt, accelerates reaction process; Do not use protonic acid, designed light prolongs reaction and can not carry out.Can be used for protonic acid among the present invention and can be selected from formic acid, acetic acid, phenylformic acid, methylsulfonic acid, tosic acid and the oxalic acid one or more, but from the screening of reaction product yield, preferably formic acid or methylsulfonic acid or oxalic acid.The molar weight of described protonic acid is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly.
Described organic solvent is DMF or dimethyl sulfoxide (DMSO), is preferably DMF.The consumption of described organic solvent (volume, ml) be 2 '-(quality, 30-50 g) is (ml: g) doubly for Hypoxanthine deoxyriboside (compound shown in the formula I) consumption.
Described rare gas element is generally nitrogen.
Described temperature of reaction is gentle, and at normal temperatures reaction get final product, this temperature variation usually with the temperature for preparing environment 0-25 ℃ of variation.
The described reaction times with 2 '-till Hypoxanthine deoxyriboside (compound shown in the formula I) runs out of.
Concrete, provided by the invention 5 '-S-(4,4 '-dimethoxytrityl)-2 '-synthetic method of Hypoxanthine deoxyriboside (compound shown in the formula III), comprise following operation: in container, pass into rare gas element, with 2 '-Hypoxanthine deoxyriboside, 4,4 '-dimethoxytrityl mercaptan, coordination phosphine compound, organic bases or protonic acid and organic solvent add in the reaction vessel, drip azo agents, stoichiometric number hour, with thin-layer chromatography TLC detection reaction liquid to without 2 '-Hypoxanthine deoxyriboside (compound shown in the formula I) till.
The present invention further in conjunction with aftertreatment provide a kind of be suitable for 5 of suitability for industrialized production '-preparation method of S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside (compound shown in the formula III).The method is the process of abstraction reaction product from the reaction solution of above-mentioned reaction, concrete operations are: add ethyl acetate in reaction solution, add again washing composition saturated aqueous ammonium chloride (the corresponding synthetic middle organic bases situation of using) or unsaturated carbonate oxygen sodium (situation of use protonic acid during correspondence the is synthetic) aqueous solution, extracting and demixing, get upper organic phase and (comprise target compound in the organic phase, the soda acid that unreacted is complete, compound shown in the excessive formula III, the coordination phosphine compound, azo agents and organic solvent), use anhydrous sodium sulfate drying, behind the filtering solid organic solvent except is wherein revolved in organic phase decompression, revolve except behind the organic solvent, the thick crude product of remainder is carried out post (silicagel column) chromatography, obtain white solid 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.
Embodiment implements under take technical solution of the present invention as prerequisite, has provided detailed embodiment and concrete operating process, and embodiment will help to understand the present invention, but protection scope of the present invention is not limited to following embodiment.
Method therefor is ordinary method if no special instructions among the following embodiment.
The optimization of test example one, reagent and parameter (organic bases)
This test 2 '-charging capacity of Hypoxanthine deoxyriboside is 6.3g (0.025mol), 4,4 '-charging capacity of dimethoxytrityl mercaptan is 16.8g (0.05mol), investigates different azo agents, coordination phosphine compound, organic bases, organic solvent to the impact of reaction.Composition of raw materials and processing parameter are as shown in table 1.
Synthetic method: under the nitrogen protection; 5-10 ℃ of scope; press the listed raw material of table 1 and ingredient proportion; add 2 in the reaction flask '-Hypoxanthine deoxyriboside, 4; 4 '-dimethoxytrityl mercaptan, coordination phosphine compound, organic bases and organic solvent, splash into azo agents, holding temperature continues reaction at 5-10 ℃; with thin-layer chromatography TLC detection reaction liquid to without 2 '-(developping agent condition: methylene dichloride: methyl alcohol=5: 1, Rf=0.3) Indicator Reaction finishes Hypoxanthine deoxyriboside.
Product extracts: add ethyl acetate 200mL in reaction solution, add saturated aqueous ammonium chloride 0.5L * 3 washings, get upper organic phase, anhydrous sodium sulfate drying, revolve except column chromatography behind the organic solvent (ethyl acetate: methylene dichloride: methyl alcohol=10: 10: 1) separate, collect obtain white solid 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside, calculated yield (%)
Table 1 composition of raw materials and processing parameter
In the table 1: DIAD represents diisopropyl azodiformate, and DEAD represents diethyl azodiformate, and DBAD represents tert-butyl azodicarboxylate; TPP represents triphenylphosphine, and TMP represents trimethyl-phosphine, and TBuP represents tributylphosphine; DMAP represents the 4-dimethylamino pyridine; DMF represents DMF, and DMSO represents dimethyl sulfoxide (DMSO); Ingredient proportion (mol ratio) refers to 2 '-Hypoxanthine deoxyriboside: 4,4 '-dimethoxytrityl mercaptan: azo agents: coordination phosphine compound: organic bases; Compound used therefor purity is all greater than 98% in the table; Yield refer to synthetic product 5 '-yield of S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.
Table 1 is listed result show: the test explanation of numbering 1-3, azo agents select diisopropyl azodiformate (DIAD) or tert-butyl azodicarboxylate (DBAD) effect better; The test explanation of numbering 3-5, coordination phosphorus compound select triphenylphosphine (TPP) or tributylphosphine (TBuP) effect better; Numbering 3,6,7,9 test explanation, organic bases select DMAP (DMAP) or DMA effect better; The test explanation of numbering 7,8, the yield that organic solvent selects DMF (DMF) reaction to obtain is higher.
Embodiment 1-5, use organic bases prepare 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside
With 2 '-Hypoxanthine deoxyriboside 12.6g (0.05mol) and 4,4 '-dimethoxytrityl mercaptan 33.6g (0.1mol) preparation 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside, composition of raw materials and processing parameter are as shown in table 2:
Table 2 composition of raw materials and processing parameter
In the table 2: DIAD represents diisopropyl azodiformate, and DEAD represents diethyl azodiformate, and DBAD represents tert-butyl azodicarboxylate; TPP represents triphenylphosphine, and TMP represents trimethyl-phosphine, and TBuP represents tributylphosphine; DMAP represents the 4-dimethylamino pyridine; DMF represents DMF, and DMSO represents dimethyl sulfoxide (DMSO); Ingredient proportion (mol ratio) refers to 2 '-Hypoxanthine deoxyriboside: 4,4 '-dimethoxytrityl mercaptan: azo agents: coordination phosphine compound: organic bases; Product refers to 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside, purity, yield are product purity and yield.
Table 2 is the result show: use preferred azo agents, coordination phosphorus compound, organic bases and solvent to carry out the embodiment reaction of various combination, all obtain preferably yield; The molar weight of azo agents and coordination phosphorus compound is 2 '-2-6 of Hypoxanthine deoxyriboside molar weight doubly, little but multiple changes for the yield impact; Reaction at normal temperatures (such as common 5-25 ℃) is carried out, and the variation of temperature is little on the yield impact between each embodiment; The molar weight of organic bases is 2 '-1-2 of Hypoxanthine deoxyriboside molar weight is doubly.It can also be seen that by comparative example, the difference of organic bases has considerable influence to reaction: obtain product though use the N-methylpyrrole can prolong by designed light reaction, but yield is lower, carries out, can not obtain desired product and use imidazoles, pyridine can't make light prolong reaction at all.
The preparation process of embodiment 1-5 and comparative example is that (each example is listed data by table 2) operates under the normal temperature in the table 2, in reaction flask, continue to pass into nitrogen, add successively 2 in the reaction flask '-Hypoxanthine deoxyriboside, 4,4 '-dimethoxytrityl mercaptan, coordination phosphine compound, organic bases and organic solvent, splash into azo agents, continued reaction approximately 3-4 hour, with thin-layer chromatography TLC detection reaction liquid, until nothing 2 '-Hypoxanthine deoxyriboside (developping agent condition: methylene dichloride: methyl alcohol=5: 1, Rf=0.3) Indicator Reaction finishes; Reaction solution is transferred in the separating funnel, in reaction solution, adds ethyl acetate 400mL, add again saturated aqueous ammonium chloride 1L * 3 (washing altogether 3 times), extracting and demixing; Get upper organic phase, add anhydrous sodium sulfate drying, reduce pressure again behind the filtering anhydrous sodium sulphate solid and revolve except organic solvent, with silica gel column chromatography (column chromatography condition on the thick crude product that obtains, ethyl acetate: methylene dichloride: methyl alcohol=10: 10: 1), obtain white solid.
With H-NMR the gained white solid is identified, structure is correct.
1H-NMR(300MHz，d-DMSO)：12.38(s，1H，-NH)；8.26(s，1H，-CH(4))；7.99(s，1H，-CH(9))；7.16-7.23(m，9H，-PhH)；?6.85(m，4H，-PhH)；6.25(t，1H，-CH(1’))；5.38(s，1H，-OH(3’))；4.19(s，1H，-CH(4’))；3.74(m，6H，-OMe)；2.75(m，1H，-CH(3’))；2.51(m，2H，-CH
2(5’))；2.21-2.40(m，1H，-CH
2(2’))。Analytical results shows, embodiment 1-5 and comparative example 1 obtained structure correct 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.And comparative example 2,3 do not obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.
Purity detecting: detect with HPLC, the HPLC condition: chromatographic column is Promosil C18 4.6 * 250mm; Moving phase: acetonitrile: ammonium bicarbonate aqueous solution=60: 40; Column temperature is 25 ℃; Detect wavelength 254nm.What record the results are shown in Table 2, and purity all can reach 98%.
The optimization of test example two, reagent and parameter (protonic acid)
This test 2 '-charging capacity of Hypoxanthine deoxyriboside is 6.3g (0.025mol), 4,4 '-charging capacity of dimethoxytrityl mercaptan is 16.8g (0.05mol), investigate different azo agents, coordination phosphine compound, protonic acid, the impact of organic solvent on reacting, composition of raw materials and processing parameter are as shown in table 3:
Table 3 composition of raw materials and processing parameter
In the table 3: DIAD represents diisopropyl azodiformate, and DEAD represents diethyl azodiformate, and DBAD represents tert-butyl azodicarboxylate; TPP represents triphenylphosphine, and TMP represents trimethyl-phosphine, and TBuP represents tributylphosphine; DMF represents DMF, and DMSO represents dimethyl sulfoxide (DMSO); Ingredient proportion (mol ratio) refers to 2 '-Hypoxanthine deoxyriboside: 4,4 '-dimethoxytrityl mercaptan: azo agents: coordination phosphine compound: protonic acid; Compound used therefor purity is all greater than 98% in the table; Yield refer to synthetic product 5 '-yield of S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.
Synthetic method: under the nitrogen protection; holding temperature is under 5-10 ℃; press the listed raw material of table 3 and ingredient proportion; add 2 in the reaction flask '-Hypoxanthine deoxyriboside, 4; 4 '-dimethoxytrityl mercaptan, coordination phosphine compound, protonic acid and organic solvent, splash into azo agents, holding temperature continues reaction down at 5-10 ℃; with thin-layer chromatography TLC detection reaction liquid to without 2 '-(developping agent condition: methylene dichloride: methyl alcohol=5: 1, Rf=0.3) Indicator Reaction finishes Hypoxanthine deoxyriboside.
Product extracts: add ethyl acetate 200mL in reaction solution, add saturated sodium bicarbonate aqueous solution 0.5L*3, extracting and demixing, get upper organic phase, anhydrous sodium sulfate drying revolves except (the ethyl acetate: methylene dichloride: methyl alcohol=10: 10: 1), collect white solid of column chromatography behind the organic solvent, calculated yield (%)
Table 3 is listed result show: numbering 1-3 test explanation, and azo agents is selected diisopropyl azodiformate (DIAD) or tert-butyl azodicarboxylate (DBAD) better; Numbering 4-6 test explanation, the coordination phosphorus compound is selected triphenylphosphine (TPP) or tributylphosphine (TBuP) better; Numbering 3 and 9,7 and 10 comparative descriptions, the yield that solvent selects DMF to obtain is higher; Numbering 3,5,6,7 test explanations, protonic acid formic acid or methylsulfonic acid or oxalic acid effect are best, number 11-13 and more further show, and the oxalic acid effect is better than acetic acid and phenylformic acid.
Embodiment 6-10, use protonic acid prepare 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside
With 2 '-Hypoxanthine deoxyriboside 12.6g (0.05mol) and 4,4 '-dimethoxytrityl mercaptan 33.6g (0.1mol) preparation 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside, composition of raw materials and processing parameter are as shown in table 4:
Table 4 composition of raw materials and processing parameter
In the table 4: DIAD represents diisopropyl azodiformate, and DEAD represents diethyl azodiformate, and DBAD represents tert-butyl azodicarboxylate; TPP represents triphenylphosphine, and TMP represents trimethyl-phosphine, and TBuP represents tributylphosphine; DMF represents DMF, and DMSO represents dimethyl sulfoxide (DMSO); Ingredient proportion (mol ratio) refers to 2 '-Hypoxanthine deoxyriboside: 4,4 '-dimethoxytrityl mercaptan: azo agents: coordination phosphine compound: protonic acid; Product refers to '-S-(4,4 '-dimethoxytrityl-2 '-Hypoxanthine deoxyriboside, purity, yield are product purity and yield.
Table 4 has provided embodiment according to the optimum result variation kind of table 3 and the combination of different mol ratio, and the result shows: select preferred azo agents, coordination phosphorus compound, protonic acid and solvent to carry out various combination, all obtain preferably yield; The molar weight of azo agents and coordination phosphorus compound is 2 '-2-6 of Hypoxanthine deoxyriboside molar weight doubly, little but multiple changes for the yield impact; Reaction at normal temperatures (such as common 5-25 ℃) is carried out, and the variation of temperature is on not impact of yield between each embodiment; The molar weight of protonic acid is 2 '-2-6 of Hypoxanthine deoxyriboside molar weight is doubly; Can find out by reference examples, whether adding protonic acid has considerable influence to reaction, does not use the reference examples light of protonic acid to prolong reaction and can not carry out, and can not obtain product.
The operating process of embodiment 6-10 and reference examples is: under the normal temperature (each example is listed data by table 2), in reaction flask, continue to pass into nitrogen, add successively 2 in the reaction flask '-Hypoxanthine deoxyriboside, 4,4 '-dimethoxytrityl mercaptan, coordination phosphine compound, protonic acid (reference examples does not add) and organic solvent, splash into azo agents, continued reaction approximately 3-4 hour, with thin-layer chromatography TLC detection reaction liquid, until nothing 2 '-Hypoxanthine deoxyriboside (developping agent condition: methylene dichloride: methyl alcohol=5: 1, Rf=0.3) Indicator Reaction finishes; Reaction solution is transferred in the separating funnel, in reaction solution, add ethyl acetate 400mL, add again saturated sodium bicarbonate solution 1L * 3 (washing 3 times) extracting and demixing, get upper organic phase, through anhydrous sodium sulfate drying, the organic phase after the removal anhydrous sodium sulphate is revolved except organic solvent, with silica gel column chromatography (chromatography condition on the thick crude product that obtains, ethyl acetate: methylene dichloride: methyl alcohol=10: 10: 1), obtain white solid.
With H-NMR the gained white solid is identified, structure is correct.
1H-NMR(300MHz，d-DMSO)：12.37(s，1H，-NH)；8.22(s，1H，-CH(4))；7.98(s，1H，-CH(9))；7.15-7.32(m，9H，-PhH)；6.84(m，4H，-PhH)；6.24(t，1H，-CH(1’))；5.38(s，1H，-OH(3’))；4.19(s，1H，-CH(4’))；3.71(m，6H，-OMe)；2.74(m，1H，-CH(3’))；2.50(m，2H，-CH
2(5’))；2.18-2.39(m，1H，-CH
2(2’))。Analytical results shows, embodiment 6-10 obtained structure correct 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside.
Purity detecting: detect with HPLC, the HPLC condition: chromatographic column is Promosil C18 4.6 * 250mm; Moving phase: acetonitrile: ammonium bicarbonate aqueous solution=60: 40; Column temperature is 25 ℃; Detect wavelength 254nm.What record the results are shown in Table 4, and purity all can reach 97%.
Claims (10)
1.5 '-S-(4; 4 '-dimethoxytrityl)-2 '-synthetic method of Hypoxanthine deoxyriboside; under protection of inert gas; under the normal temperature; in organic solvent; under the effect of azo agents, coordination phosphine compound, organic bases or protonic acid; with 2 '-Hypoxanthine deoxyriboside (compound shown in the formula I) and 4; 4 '-dimethoxytrityl mercaptan (compound shown in the formula II) carry out light prolong (Mitsunobu) reaction; obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside (compound shown in the formula III):
2. synthetic method according to claim 1, it is characterized in that, comprise following operation: in container, pass into rare gas element, with 2 '-Hypoxanthine deoxyriboside, 4,4 '-dimethoxytrityl mercaptan, coordination phosphine compound, organic bases or protonic acid and organic solvent add in the reaction vessel, drip azo agents, stoichiometric number hour to thin-layer chromatography TLC detection reaction liquid to without 2 '-Hypoxanthine deoxyriboside.
3. synthetic method according to claim 1 and 2 is characterized in that, described 4,4 '-molar weight of dimethoxytrityl mercaptan (compound shown in the formula II) is 2 '-2-4 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly.
4. according to claim 1 and 2 or 3 described synthetic methods, it is characterized in that: described azo agents is azo agents commonly used in the Mitsunobu reaction, such as in diethyl azodiformate, diisopropyl azodiformate, the tert-butyl azodicarboxylate one or more, be preferably tert-butyl azodicarboxylate or diisopropyl azodiformate; Described azo agents molar weight is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight doubly, the mol ratio of azo agents and coordination phosphine compound is 1: 1 during use.
5. according to claim 1 to 4 arbitrary described synthetic methods, it is characterized in that: described coordination phosphine compound is one or more in triphenyl phosphorus, tributylphosphine, the trimethyl-phosphine, is preferably triphenyl phosphorus or tributylphosphine; The molar weight of described coordination phosphine compound is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight doubly, the mol ratio of coordination phosphine compound and azo agents is 1: 1 during use.
6. according to claim 1 to 5 arbitrary described synthetic methods, it is characterized in that: described organic solvent is DMF or dimethyl sulfoxide (DMSO), is preferably DMF; The consumption of described organic solvent is 2 '-30-50 of Hypoxanthine deoxyriboside (compound shown in the formula I) (ml: g) doubly.
7. according to claim 1 to 6 arbitrary described synthetic methods, it is characterized in that: described rare gas element is nitrogen; The developping agent that described thin-layer chromatography TLC detects is methylene dichloride: methyl alcohol volume ratio 5: 1, and take Rf=0.3 as indication point.
8. according to claim 1 to 7 arbitrary described synthetic methods, it is characterized in that: described organic bases is selected from triethylamine, DMAP, N-methylpyrrole or DMA, is preferably DMAP or DMA; The molar weight of described organic bases is 2 '-1-2 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly.
9. according to claim 1 to 7 arbitrary described synthetic methods, it is characterized in that: described protonic acid is selected from one or more in formic acid, acetic acid, phenylformic acid, tosic acid, methylsulfonic acid and the oxalic acid, is preferably formic acid or methylsulfonic acid or oxalic acid; The molar weight of described protonic acid is 2 '-2-6 of Hypoxanthine deoxyriboside (compound shown in the formula I) molar weight is doubly.
10.5 the preparation method of '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside is characterized in that, also further comprise the process of abstraction reaction product in Accessory Right requirement 2 to 9 arbitrary described reaction solutions, concrete operations are:
In reaction solution, add ethyl acetate, add again the washing composition extracting and demixing, get upper organic phase, behind anhydrous sodium sulfate drying, revolve except organic solvent, through silica gel column chromatography, obtain white solid 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Hypoxanthine deoxyriboside; Described washing composition is saturated aqueous ammonium chloride or saturated sodium bicarbonate aqueous solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310053524.2A CN103073606B (en) | 2013-02-05 | 2013-02-05 | Synthetic and the preparation method of 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310053524.2A CN103073606B (en) | 2013-02-05 | 2013-02-05 | Synthetic and the preparation method of 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103073606A true CN103073606A (en) | 2013-05-01 |
| CN103073606B CN103073606B (en) | 2016-05-18 |
Family
ID=48150323
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310053524.2A Active CN103073606B (en) | 2013-02-05 | 2013-02-05 | Synthetic and the preparation method of 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103073606B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187843A (en) * | 2015-05-04 | 2016-12-07 | 复旦大学 | One prepares the method for (S)-4-amino-5-mercaptopentanoic acid |
| CN106187844A (en) * | 2015-05-04 | 2016-12-07 | 复旦大学 | A kind of preparation method of (S)-4-amino-5-mercaptopentanoic acid |
| CN114426465A (en) * | 2020-10-29 | 2022-05-03 | 江苏和成新材料有限公司 | Method for carrying out mitsunobu reaction on alcoholic hydroxyl donor and active hydrogen donor |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003074083A1 (en) * | 2002-03-04 | 2003-09-12 | Pfizer Inc. | Combination therapies for treating methylthioadenosine phosphorylase deficient cells |
| CN1563006A (en) * | 2004-04-14 | 2005-01-12 | 中国科学院上海有机化学研究所 | Synthesizing nucleoside analog for antivirus |
| WO2008042688A2 (en) * | 2006-09-29 | 2008-04-10 | Lexicon Pharmaceuticals, Inc. | Phlorizin analogs as inhibitors of sodium glucose co-transporter 2 |
| JP4709959B2 (en) * | 2001-06-14 | 2011-06-29 | 国立大学法人東京工業大学 | Nucleoside phosphoramidite compounds |
-
2013
- 2013-02-05 CN CN201310053524.2A patent/CN103073606B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4709959B2 (en) * | 2001-06-14 | 2011-06-29 | 国立大学法人東京工業大学 | Nucleoside phosphoramidite compounds |
| WO2003074083A1 (en) * | 2002-03-04 | 2003-09-12 | Pfizer Inc. | Combination therapies for treating methylthioadenosine phosphorylase deficient cells |
| CN1563006A (en) * | 2004-04-14 | 2005-01-12 | 中国科学院上海有机化学研究所 | Synthesizing nucleoside analog for antivirus |
| WO2008042688A2 (en) * | 2006-09-29 | 2008-04-10 | Lexicon Pharmaceuticals, Inc. | Phlorizin analogs as inhibitors of sodium glucose co-transporter 2 |
Non-Patent Citations (2)
| Title |
|---|
| GIAN FILIPPO RUDA，等: "Modified 5′-Trityl Nucleosides as Inhibitors of Plasmodium falciparum dUTPase", 《CHEMMEDCHEM》, vol. 6, no. 2, 18 January 2011 (2011-01-18), pages 309 - 320 * |
| LÁSZLÓ KÜRTI，等: "《Strategic Applications of Named Reactions in Organic Synthesis》", 31 December 2005, article "Mitsunobu reaction", pages: 294-295 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187843A (en) * | 2015-05-04 | 2016-12-07 | 复旦大学 | One prepares the method for (S)-4-amino-5-mercaptopentanoic acid |
| CN106187844A (en) * | 2015-05-04 | 2016-12-07 | 复旦大学 | A kind of preparation method of (S)-4-amino-5-mercaptopentanoic acid |
| CN106187844B (en) * | 2015-05-04 | 2018-02-27 | 复旦大学 | A kind of preparation method of the mercaptopentanoic acid of (S) 4 amino 5 |
| CN106187843B (en) * | 2015-05-04 | 2018-05-25 | 复旦大学 | A kind of method for preparing (S) -4- amino -5- mercaptopentanoic acids |
| CN114426465A (en) * | 2020-10-29 | 2022-05-03 | 江苏和成新材料有限公司 | Method for carrying out mitsunobu reaction on alcoholic hydroxyl donor and active hydrogen donor |
| CN114426465B (en) * | 2020-10-29 | 2024-02-06 | 江苏和成新材料有限公司 | Method for carrying out photo-delay reaction on alcohol hydroxyl donor and active hydrogen donor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103073606B (en) | 2016-05-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2018090598A (en) | Pseudo solid phase protective group and nucleotide | |
| EP3712130B1 (en) | Method for synthesis of roxadustat and intermediate compounds thereof | |
| CN1903854B (en) | Method of synthesizing valaciclovir hydrochloride | |
| CN103121999A (en) | Method for synthesizing tyrosine kinase inhibitor PCI-32765 | |
| CN107235923B (en) | Preparation method of 3-aryl quinoxalinone derivatives | |
| EP2484671A1 (en) | Fluorescent molecule and method for detecting target nucleic acid | |
| CN102875537A (en) | Novel preparation method of antithrombosis medicine | |
| CN101555267A (en) | Synthesis method of clofarabine of nucleoside analogues | |
| Donga et al. | A novel approach to oligonucleotide synthesis using an imidazolium ion tag as a soluble support | |
| CN102702010A (en) | Photosensitive functionalized solid-supported phase, preparation method and application thereof | |
| CN103073606A (en) | Method for synthesizing and preparing 5'-S-(4, 4'-dimethoxytriphenylmethyl)-2'-deoxyinosine | |
| CN102260200B (en) | Method for synthesizing phenylsulfone compounds | |
| CN103788010B (en) | Febuxostat intermediate and preparation method thereof | |
| CN102603710A (en) | Preparation method of imatinib intermediate | |
| CN108409818B (en) | Method for synthesizing cytosine nucleoside | |
| CN104016915B (en) | A kind of preparation method of boscalid amine | |
| CN108794477A (en) | A kind of N2The preparation method of 9 substituted guanine class compound | |
| CN107383097A (en) | The preparation method of the phosphonylation derivative of the ketone of 3 benzylidene iso-indoles of N phenyl 1 | |
| CN102180755A (en) | Synthesis method of azide compounds | |
| JP7452549B2 (en) | Phosphoramidite activator | |
| CN103435586B (en) | Containing the polyamine derivative and its preparation method and application of flavones structure | |
| CN111116477A (en) | Synthesis process of doramelamine | |
| JP7298866B2 (en) | Solid phase carrier for nucleic acid synthesis and method for producing nucleic acid using the same | |
| CN104478883B (en) | A kind of C8-Heterocyclylalkyl purine nucleoside analogs and synthetic method thereof | |
| CN114920684B (en) | Selenium-containing benzamide compound and synthetic method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |