CN103073606B - Synthetic and the preparation method of 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine - Google Patents
Synthetic and the preparation method of 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine Download PDFInfo
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Abstract
The invention discloses a kind of 5 '-S-(4, 4 '-dimethoxytrityl) the synthetic and preparation method of-2 '-deoxyinosine, under inert gas shielding, under normal temperature in organic solvent, in azo agents, coordination phosphine compound, under the effect of organic base or Bronsted acid, by 2 '-deoxyinosine and 4, 4 '-dimethoxytrityl mercaptan carries out light and prolongs (Mitsunobu) reaction, i.e. 5 of 2 '-deoxyinosine '-position hydroxyl and 4, there is intermolecular dehydration in 4 '-dimethoxytrityl mercaptan, form C-S key, obtain 5 '-S-(4, 4 '-dimethoxytrityl)-2 '-deoxyinosine. the present invention has following beneficial effect: raw material sources are extensive and cheap, yield is high, reaction condition is gentle, selectively good, operating process is simple, post processing is easy, be applicable to large-scale industrial production.
Description
Technical field
The present invention relates to closing of (4,4 '-dimethoxytrityl)-2 '-deoxyinosine of 5 '-S-in the field of chemical synthesisBecome and preparation method.
Background technology
Along with the development of molecular biology and pharmaceuticals industry, the research and development of nucleoside compound and derivative thereof becomesFocus. Along with going deep into of research, to nucleoside compound and derivative thereof carry out functional group's conversion and modify after obtain newNucleoside compound is in Cardiovarscular, central nervous system disease, circulation and disease in the urological system and antiviral, antitumorEtc. aspect have special curative effect, be widely used in molecular biology, medicine and other fields. Nucleoside compound is carried out to structure to be repaiiedDecorations introducing hetero-atoms sulphur, can make the antiviral activity of medicine improve a lot sometimes, can also reduce the poison of medicine simultaneouslySide effect is one of approach of research and screening medicine. 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine is doneFor the intermediate to 2 '-deoxyinosine glycosyl introducing hetero-atoms sulfur modification, the compound after modification is confirmed is improving medicineBiologically active, the antiviral spectrum that increases, there is positive effect the aspects such as reduction toxic and side effect. Nucleoside compound 5 '-position hydroxyl is used(MeO)2It is one of more common modification that TrSH carries out thioetherification modification, and the main method of modification is as follows:
Activate with mesyl chloride by the 5 '-position hydroxyl to 2 '-AZT, after thioacetic acid potassium esterification, then use 4,4 '-Dimethoxytrityl methyl mercaptan ((MeO)2TrSH) replace the rear (EfficientSolidSynthensisof of realizationCleavableOligodeoxynucleotidesBasedonaNovelStrategyfortheSyhthesisof5’-S-(4，4’-Dimethoxytrityl)-2’-deoxy-5’-thionucleosidePhosphpramidites，KerstinJahn-HofmannandIoachinW.Engels，HelveticaChimicaActa-Vol.87(2004), 2812-2828)), but the method is through multistep reaction, produces multiple intermediate products, finally obtain 5 '-S-(4,4 '-Dimethoxytrityl) yield of-2 '-AZT is on the low side, can only reach 38.3%, and wherein the 3rd step used 1,1,3,3-TMG is as catalyst, price, and production cost is high, is unsuitable for suitability for industrialized production. Its synthetic route is as follows:
Summary of the invention
The invention provides a kind of reaction condition gentleness, selective simple 5 '-S-(4, the 4 '-dimethoxy of good, operating processBase trityl) synthetic method of-2 '-deoxyinosine, and a kind of yield is high, post processing is easy and be easy to suitability for industrialized productionThe preparation method of 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine.
The synthetic method of 5 '-S-provided by the present invention (4,4 '-dimethoxytrityl)-2 '-deoxyinosine, beUnder inert gas shielding, under normal temperature, in organic solvent, at the work of azo agents, coordination phosphine compound, organic base or Bronsted acidWith under, by 2 '-deoxyinosine (compound shown in formula I) and 4,4 '-dimethoxytrityl mercaptan (compound shown in formula II)Carry out light and prolong (Mitsunobu) reaction, obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine (shown in formula IIICompound):
Described synthetic method comprises following operation: in container, pass into inert gas, by 2 '-deoxyinosine, 4,4 '-bis-Methoxyl group trityl mercaptan, coordination phosphine compound, organic base or Bronsted acid and organic solvent add in reaction vessel, drip evenNitrogen reagent, stoichiometric number hour extremely uses thin-layer chromatography TLC detection reaction liquid to nothing 2 '-deoxyinosine.
The solvent that described thin-layer chromatography TLC detects is carrene: methyl alcohol volume ratio 5: 1, and taking Rf=0.3 as instructionPoint.
In synthetic reaction, the mole of described 4,4 '-dimethoxytrityl mercaptan (compound shown in formula II) is 2 '-The 2-4 of deoxyinosine (compound shown in formula I) mole times, preferably 2 times.
Described azo agents is conventional azo agents in Mitsunobu reaction, as diethyl azodiformate, azo twoOne or more in formic acid diisopropyl ester, tert-butyl azodicarboxylate, are preferably tert-butyl azodicarboxylate or azoDioctyl phthalate diisopropyl ester; Described azo agents mole is 2-6 times of 2 '-deoxyinosine (compound shown in formula I) mole, makesThe mol ratio of used time azo agents and coordination phosphine compound is 1: 1.
Described coordination phosphine compound is one or more in triphenyl phosphorus, tributylphosphine, trimethyl-phosphine, is preferably threePhenyl phosphorus or tributylphosphine; The mole of described coordination phosphine compound is 2 '-deoxyinosine (compound shown in formula I) moleDoubly, when use, the mol ratio of coordination phosphine compound and azo agents is 1: 1 to 2-6.
Described organic solvent is DMF or dimethyl sulfoxide (DMSO), is preferably DMF; InstituteThe consumption of stating organic solvent is the doubly (ml: g) of 30-50 of 2 '-deoxyinosine (compound shown in formula I).
Described inert gas is nitrogen.
Described organic base is selected from triethylamine, DMAP, N-methylpyrrole or DMA, is preferablyDMAP or DMA; The mole of described organic base is 2 '-deoxyinosine (compound shown in formula I)The 1-2 of mole doubly.
Described Bronsted acid is selected from one or more in formic acid, acetic acid, benzoic acid, p-methyl benzenesulfonic acid, methanesulfonic acid and oxalic acid,Be preferably formic acid or methanesulfonic acid or oxalic acid; The mole of described Bronsted acid is 2 '-deoxyinosine (compound shown in formula I) mole2-6 doubly.
The further object of the present invention is to provide 5 '-S-(4, the 4 '-dimethoxytrityl) system of-2 '-deoxyinosinePreparation Method. The method further comprises the process of abstraction reaction product from above-mentioned reactant liquor, and concrete operations are:
In reactant liquor, add ethyl acetate, then add washing agent extracting and demixing, get upper organic phase, use anhydrous sodium sulfateAfter dry, revolve except organic solvent, through silica gel column chromatography, obtain white solid 5 '-S-(4,4 '-dimethoxytrityl)-2 '-Deoxyinosine; Described washing agent is saturated aqueous ammonium chloride (using the situation of organic base in synthetic) or saturated sodium bicarbonate waterSolution (using the situation of Bronsted acid in synthetic).
The above technical scheme of the present invention proposed a kind of synthetic and preparation 5 '-S-(4,4 '-dimethoxytrityl)-The new method of 2 '-deoxyinosine, synthetic reaction mechanism is: deposit at azo agents, coordination phosphine compound, organic base or Bronsted acidUnder, 5 of 2 '-deoxyinosine '-position hydroxyl and 4,4 '-dimethoxytrityl mercaptan generation condensation dehydration formationizationCompound 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine, the azo agents in course of reaction is reduced to hydrazine twoCarboxylic acid diesters, coordination phosphine compound is oxidized to oxidation three hydrocarbon (virtue) base phosphine. By Mitsunobu reaction, (light prolongs first in the present inventionReaction) for the thioetherification reaction of 2 '-deoxyinosine and obtained success, there is following beneficial effect:
1, reaction scheme is short, only can make target product through a step chemical reaction taking 2 '-deoxyinosine as starting material;
2, reaction condition gentleness;
3, accessory substance is few, and this is because the selective height of reaction;
4, in whole preparation process, do not use corrosive materials, reduced the toxicity of operating process;
5, raw material sources are extensive and cheap, and starting material 2 '-deoxyinosine is very easy to obtain on market, thereby closesBecome the cost of target product 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 in 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine suitability for industrialized productionIn play a significant role, have a extensive future.
Below in conjunction with specific embodiment, the present invention is described in further details.
Detailed description of the invention
In compound group is modified, often need to carry out functional group's conversion, build new chemical bond, as C-O, C-N, C-The chemical bonds such as S, C-C, P-S, the present invention carries out thioetherification modification to nucleoside compound 5 '-position hydroxyl, and target obtains newC-S bonding. Light prolong (Mitsunobu) reaction be under azo agents and the effect of three alkane (virtue) base phosphine, alcohol compound withThe dehydration condensation that the various front nucleopilic reagent of reactive hydrogen carries out is the one that builds the chemical bonds such as C-O, C-N, C-S, C-CClassical way. But differential responses thing utilizes light to prolong the maximum difficult point of reaction and is selection and the reaction condition of solvent, catalystDetermine, be so limited, at present, in 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine synthetic, should notUse up the research report that prolongs (Mitsunobu) reaction.
The present invention, by further investigation, finds and successfully utilizes Mitsunobu single step reaction to obtain 5 '-S-(4,4 '-diformazanOxygen base trityl)-2 '-deoxyinosine, thus, research and probe of the present invention and provide that a kind of yield is high, reaction condition is gentle,Selectively good, operating process is simple, post processing is easy and be easy to 5 of suitability for industrialized production '-S-(4,4 '-dimethoxy triphen firstBase) the synthetic and preparation method of-2 '-deoxyinosine.
Synthetic method reaction mechanism of the present invention is: exist at azo agents, coordination phosphine compound, organic base or Bronsted acidUnder, 5 of reaction raw materials 2 '-deoxyinosine '-position hydroxyl and another reaction raw materials 4,4 '-dimethoxytrityl mercaptan occurCondensation dehydration forms compound 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine, the idol in course of reactionNitrogen reagent is reduced to hydrazine dicarboxylic diester, and coordination phosphine compound is oxidized to oxidation three hydrocarbon (virtue) base phosphine. Its synthetic route asUnder:
Synthetic method provided by the present invention is: under inert gas shielding, under normal temperature, in organic solvent, at azoUnder the existence of reagent, coordination phosphine compound and organic base (or Bronsted acid), by 2 '-deoxyinosine (compound shown in formula I) and 4,4 '-dimethoxytrityl mercaptan (compound shown in formula II) carries out light and prolongs (Mitsunobu) reaction, i.e. 2 '-deoxyinosine5 '-position hydroxyl and 4,4 '-dimethoxytrityl mercaptan there is intermolecular dehydration, formation C-S key, obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine (compound shown in formula III).
In above-mentioned 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine synthetic method, described 4,4 '-bis-The mole of methoxyl group trityl mercaptan (compound shown in formula II) is 2 '-deoxyinosine (compound shown in formula I) mole2-4 doubly, test example and embodiment have listed the situation (excessive) of 2 times, but are also fine after amount.
In the present invention, the azo agents of using is conventional azo agents in Mitsunobu reaction, as azoformic acidOne or more in diethylester, diisopropyl azodiformate, tert-butyl azodicarboxylate, are preferably azoformic acid twoThe tert-butyl ester or diisopropyl azodiformate. Described azo agents mole dosage is that 2 '-deoxyinosine (compound shown in formula I) rubsThe 2-6 of your amount times; When use, the mol ratio of azo agents and coordination phosphine compound is 1: 1.
In the present invention, the coordination phosphine compound of using is a kind of or many in triphenyl phosphorus, tributylphosphine, trimethyl-phosphineKind, be preferably triphenyl phosphorus or tributylphosphine. The mole of described coordination phosphine compound is 2 '-deoxyinosine (chemical combination shown in formula IThing) mole 2-6 doubly; When use, the mol ratio of coordination phosphine compound and azo agents is 1: 1.
In the present invention, to use especially organic base or Bronsted acid. In the present invention, acting as of organic base captures 4,Hydrogen on 4 '-dimethoxytrityl methyl mercaptan, promotes condensation dehydration. Therefore, can be used for the organic base in the present inventionNeed special screening, the present invention experimental results show that triethylamine, DMAP, N-methylpyrrole or DMA all canSelect and reach certain effect, and imidazoles, pyridine cannot make reaction carry out; From the screening of product yield, preferred organic baseFor DMAP or DMA. The mole of described organic base is 2 '-deoxyinosine (chemical combination shown in formula IThing) mole 1-2 doubly.
In the present invention, acting as of Bronsted acid makes azo agents and the addition of coordination phosphorus compound generate quaternary alkylphosphonium salt protonChange, accelerate course of reaction; Do not use Bronsted acid, designed light prolongs reaction and can not carry out. Can be used for the Bronsted acid in the present inventionCan be selected from one or more in formic acid, acetic acid, benzoic acid, methanesulfonic acid, p-methyl benzenesulfonic acid and oxalic acid, but from product yieldScreening, preferably formic acid or methanesulfonic acid or oxalic acid. The mole of described Bronsted acid is 2 '-deoxyinosine (chemical combination shown in formula IThing) mole 2-6 doubly.
Described organic solvent is DMF or dimethyl sulfoxide (DMSO), is preferably DMF. InstituteThe consumption (volume, ml) of stating organic solvent is that (quality, 30-50 g) is (ml doubly for 2 '-deoxyinosine (compound shown in formula I) consumption∶g)。
Described inert gas is generally nitrogen.
Described reaction temperature is gentle, reaction at normal temperatures, and this variations in temperature is conventionally with the temperature of preparing environment0-25 DEG C of variation.
Till the described reaction time runs out of with 2 '-deoxyinosine (compound shown in formula I).
Concrete, 5 '-S-provided by the invention (4,4 '-dimethoxytrityl)-2 '-deoxyinosine is (shown in formula IIICompound) synthetic method, comprise following operation: in container, pass into inert gas, by 2 '-deoxyinosine, 4,4 '-diformazanOxygen base trityl mercaptan, coordination phosphine compound, organic base or Bronsted acid and organic solvent add in reaction vessel, drip azoReagent, stoichiometric number hour, uses thin-layer chromatography TLC detection reaction liquid extremely without till 2 '-deoxyinosine (compound shown in formula I).
The present invention further provides a kind of 5 of suitability for industrialized production '-S-(4,4 '-dimethoxy three that is suitable in conjunction with post processingBenzyl) preparation method of-2 '-deoxyinosine (compound shown in formula III). The method is to carry from the reactant liquor of above-mentioned reactionGet the process of product, concrete operations are: in reactant liquor, add ethyl acetate, then add washing agent saturated ammonium chloride water-solubleLiquid (the corresponding synthetic middle organic base situation that uses) or unsaturated carbonate oxygen sodium (situation of use Bronsted acid during correspondence the is synthetic) aqueous solution,Extracting and demixing, (organic phase comprises shown in the complete soda acid of target compound, unreacted, excessive formula III and changing to get upper organic phaseCompound, coordination phosphine compound, azo agents and organic solvent), with anhydrous sodium sulfate drying, after filtering solid, organic phase is reduced pressureRevolve the organic solvent removing wherein, revolve except after organic solvent, the thick crude product of remainder is carried out to post (silicagel column) chromatography, obtain whiteLook solid 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine.
Embodiment implements under taking technical solution of the present invention as prerequisite, has provided detailed embodiment and concreteOperating process, embodiment will contribute to understand the present invention, but protection scope of the present invention is not limited to following embodiment.
In following embodiment, method therefor is conventional method if no special instructions.
The optimization (organic base) of test example one, reagent and parameter
The inventory of this test 2 '-deoxyinosine is 6.3g (0.025mol), 4,4 '-dimethoxytrityl mercaptanInventory is 16.8g (0.05mol), investigates different azo agents, coordination phosphine compound, organic base, organic solvent to reactionImpact. Composition of raw materials and technological parameter are as shown in table 1.
Synthetic method: under nitrogen protection, 5-10 DEG C of scope, by the listed raw material of table 1 and ingredient proportion, add in reaction bulbEnter 2 '-deoxyinosine, 4,4 '-dimethoxytrityl mercaptan, coordination phosphine compound, organic base and organic solvent, splash into idolNitrogen reagent, holding temperature continues reaction at 5-10 DEG C, with extremely nothing 2 '-deoxyinosine (solvent of thin-layer chromatography TLC detection reaction liquidCondition: carrene: methyl alcohol=5: 1, Rf=0.3) Indicator Reaction finishes.
Product extracts: in reactant liquor, adds ethyl acetate 200mL, adds the washing of saturated aqueous ammonium chloride 0.5L × 3,Get upper organic phase, anhydrous sodium sulfate drying, revolve except column chromatography after organic solvent (ethyl acetate: carrene: methyl alcohol=10:10: 1) separate, collect and obtain white solid 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine, calculated yield(％)，
Table 1 composition of raw materials and technological parameter
In table 1: DIAD represents diisopropyl azodiformate, DEAD represents diethyl azodiformate, and DBAD represents evenNitrogen dicarboxylate; TPP represents triphenylphosphine, and TMP represents trimethyl-phosphine, and TBuP represents tributylphosphine; DMAP represents 4-Dimethylamino pyridine; DMF represents DMF, and DMSO represents dimethyl sulfoxide (DMSO); Ingredient proportion (mol ratio) refers to 2 '-Deoxyinosine: 4,4 '-dimethoxytrityl mercaptan: azo agents: coordination phosphine compound: organic base; Chemical combination used in tableThing purity is all greater than 98%; Yield refers to the receipts of synthetic product 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosineRate.
The listed result of table 1 shows: the test explanation of numbering 1-3, azo agents is selected diisopropyl azodiformate(DIAD) or tert-butyl azodicarboxylate (DBAD) effect better; The test explanation of numbering 3-5, coordination phosphorus compound selects threePhenylphosphine (TPP) or tributylphosphine (TBuP) effect are better; The test explanation of numbering 3,6,7,9, organic base is selected 4-diformazan ammoniaYl pyridines (DMAP) or DMA effect are better; The test explanation of numbering 7,8, organic solvent is selected N, N-dimethylIt is higher that formamide (DMF) reacts the yield obtaining.
Embodiment 1-5, use organic base are prepared 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine
Make with 2 '-deoxyinosine 12.6g (0.05mol) and 4,4 '-dimethoxytrityl mercaptan 33.6g (0.1mol)Standby 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine, composition of raw materials and technological parameter are as shown in table 2:
Table 2 composition of raw materials and technological parameter
In table 2: DIAD represents diisopropyl azodiformate, DEAD represents diethyl azodiformate, and DBAD represents evenNitrogen dicarboxylate; TPP represents triphenylphosphine, and TMP represents trimethyl-phosphine, and TBuP represents tributylphosphine; DMAP represents 4-Dimethylamino pyridine; DMF represents DMF, and DMSO represents dimethyl sulfoxide (DMSO); Ingredient proportion (mol ratio) refers to 2 '-Deoxyinosine: 4,4 '-dimethoxytrityl mercaptan: azo agents: coordination phosphine compound: organic base; Product refers to 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine, purity, yield are product purity and yield.
Table 2 result shows: use preferred azo agents, coordination phosphorus compound, organic base and solvent to carry out various combinationEmbodiment reaction, all obtain good yield; The mole of azo agents and coordination phosphorus compound is 2 '-deoxyinosine moleThe 2-6 of amount doubly, little but multiple changes for yield impact; Reaction at normal temperatures (as common 5-25 DEG C) is carried out, eachBetween embodiment, the variation of temperature is little on yield impact; The mole of organic base is 1-2 times of 2 '-deoxyinosine mole.It can also be seen that by comparative example, the difference of organic base has considerable influence to reaction: though it is set to use N-methylpyrrole to pass throughThe light of meter prolongs reaction and obtains product, but yield is lower, carries out and use imidazoles, pyridine cannot make light prolong reaction at all, can notObtain desired product.
In table 2, the preparation process of embodiment 1-5 and comparative example is that under normal temperature, (each example is listed data by table 2) operates,In reaction bulb, continue to pass into nitrogen, in reaction bulb, add successively 2 '-deoxyinosine, 4,4 '-dimethoxytrityl sulphurAlcohol, coordination phosphine compound, organic base and organic solvent, splash into azo agents, continues the about 3-4 hour of reaction, uses thin-layer chromatography TLCDetection reaction liquid, until without 2 '-deoxyinosine (solvent condition: carrene: methyl alcohol=5: 1, Rf=0.3) Indicator Reaction knotBundle; Reactant liquor is transferred in separatory funnel, in reactant liquor, adds ethyl acetate 400mL, then add saturated ammonium chloride water-solubleLiquid 1L × 3 (washing altogether 3 times), extracting and demixing; Get upper organic phase, add anhydrous sodium sulfate drying, filtering anhydrous sodium sulfate is solidAfter body, decompression is revolved except organic solvent again, by silica gel column chromatography (column chromatography condition, ethyl acetate: two on the thick crude product obtainingChloromethanes: methyl alcohol=10: 10: 1), obtain white solid.
Gained white solid is identified with H-NMR, 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，-CH2(5’))；2.21-2.40(m，1H，-CH2(2 ')). Analysis resultShow, embodiment 1-5 and comparative example 1 have obtained correct 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxidation flesh of structureGlycosides. And comparative example 2,3 does not obtain 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine.
Purity detecting: by HPLC detection, HPLC condition: chromatographic column is PromosilC184.6 × 250mm; Mobile phase:Acetonitrile: ammonium bicarbonate aqueous solution=60: 40; Column temperature is 25 DEG C; Detect wavelength 254nm. What record the results are shown in Table 2, the equal energy of purityReach 98%.
The optimization (Bronsted acid) of test example two, reagent and parameter
The inventory of this test 2 '-deoxyinosine is 6.3g (0.025mol), 4,4 '-dimethoxytrityl mercaptanInventory is 16.8g (0.05mol), investigates different azo agents, coordination phosphine compound, Bronsted acid, organic solvent to reactionImpact, composition of raw materials and technological parameter are as shown in table 3:
Table 3 composition of raw materials and technological parameter
In table 3: DIAD represents diisopropyl azodiformate, DEAD represents diethyl azodiformate, and DBAD represents evenNitrogen dicarboxylate; TPP represents triphenylphosphine, and TMP represents trimethyl-phosphine, and TBuP represents tributylphosphine; DMF represents N, N-Dimethyl formamide, DMSO represents dimethyl sulfoxide (DMSO); Ingredient proportion (mol ratio) refers to 2 '-deoxyinosine: 4,4 '-dimethoxy threeBenzyl mercaptan: azo agents: coordination phosphine compound: Bronsted acid; In table, compound used therefor purity is all greater than 98%; Yield refers toThe yield of synthetic product 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine.
Synthetic method: under nitrogen protection, holding temperature is at 5-10 DEG C, by the listed raw material of table 3 and ingredient proportion, to reactionIn bottle, add 2 '-deoxyinosine, 4,4 '-dimethoxytrityl mercaptan, coordination phosphine compound, Bronsted acid and organic solvent,Splash into azo agents, holding temperature continues reaction at 5-10 DEG C, with extremely nothing 2 '-deoxidation flesh of thin-layer chromatography TLC detection reaction liquidGlycosides (solvent condition: carrene: methyl alcohol=5: 1, Rf=0.3) Indicator Reaction finishes.
Product extracts: in reactant liquor, add ethyl acetate 200mL, add saturated sodium bicarbonate aqueous solution 0.5L*3, extractionGet layering, get upper organic phase, anhydrous sodium sulfate drying, revolves except (the ethyl acetate: carrene: first of column chromatography after organic solventAlcohol=10: 10: 1), collect white solid, calculated yield (%),
The listed result of table 3 shows: numbering 1-3 test explanation, azo agents is selected diisopropyl azodiformate (DIAD)Or tert-butyl azodicarboxylate (DBAD) is better; Numbering 4-6 test explanation, coordination phosphorus compound is selected triphenylphosphine (TPP)Or tributylphosphine (TBuP) is 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, Bronsted acid formic acid or methanesulfonic acid or oxalic acid effect are best, and number 11-13 and more further show,Oxalic acid effect is better than acetic acid and benzoic acid.
Embodiment 6-10, use Bronsted acid are prepared 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine
Make with 2 '-deoxyinosine 12.6g (0.05mol) and 4,4 '-dimethoxytrityl mercaptan 33.6g (0.1mol)Standby 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine, composition of raw materials and technological parameter are as shown in table 4:
Table 4 composition of raw materials and technological parameter
In table 4: DIAD represents diisopropyl azodiformate, DEAD represents diethyl azodiformate, and DBAD represents evenNitrogen dicarboxylate; TPP represents triphenylphosphine, and TMP represents trimethyl-phosphine, and TBuP represents tributylphosphine; DMF represents N,Dinethylformamide, DMSO represents dimethyl sulfoxide (DMSO); Ingredient proportion (mol ratio) refers to 2 '-deoxyinosine: 4,4 '-dimethoxyTrityl mercaptan: azo agents: coordination phosphine compound: Bronsted acid; Refer to '-S-of product (4,4 '-dimethoxytrityl-2 '-deoxyinosine, purity, yield are product purity and yield.
The combination that table 4 changes kind and different mol ratio according to the optimum results of table 3 has provided embodiment, and result shows:Select preferred azo agents, coordination phosphorus compound, Bronsted acid and solvent to carry out various combination, all obtain good yield; EvenThe mole of nitrogen reagent and coordination phosphorus compound is 2-6 times of 2 '-deoxyinosine mole, but multiple changes for yield shadowRing little; Reaction at normal temperatures (as common 5-25 DEG C) is carried out, and between each embodiment, the variation of temperature does not have shadow to yieldRing; The mole of Bronsted acid is 2-6 times of 2 '-deoxyinosine mole; Can find out by reference examples whether add Bronsted acidReaction is had to considerable influence, and not using the reference examples light of Bronsted acid to prolong reaction can not carry out, and can not obtain product.
The operating process of embodiment 6-10 and reference examples is: under normal temperature (each example is listed data by table 2), in reaction bulb, holdContinue and pass into nitrogen, in reaction bulb, add successively 2 '-deoxyinosine, 4,4 '-dimethoxytrityl mercaptan, coordination phosphine chemical combinationThing, Bronsted acid (reference examples does not add) and organic solvent, splash into azo agents, continues the about 3-4 hour of reaction, uses thin-layer chromatography TLCDetection reaction liquid, until without 2 '-deoxyinosine (solvent condition: carrene: methyl alcohol=5: 1, Rf=0.3) Indicator Reaction knotBundle; Reactant liquor is transferred in separatory funnel, in reactant liquor, adds ethyl acetate 400mL, then add saturated sodium bicarbonate moltenLiquid 1L × 3 (washing 3 times) extracting and demixing, gets upper organic phase, through anhydrous sodium sulfate drying, to removing having after anhydrous sodium sulfateMachine revolves mutually except organic solvent, by silica gel column chromatography (chromatography condition, ethyl acetate: carrene: first on the thick crude product obtainingAlcohol=10: 10: 1), obtain white solid.
Gained white solid is identified with H-NMR, 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，-CH2(5’))；2.18-2.39(m，1H，-CH2(2 ')). Analysis resultShow, embodiment 6-10 has obtained correct 5 '-S-(4,4 '-dimethoxytrityl)-2 '-deoxyinosine of structure.
Purity detecting: by HPLC detection, HPLC condition: chromatographic column is PromosilC184.6 × 250mm; Mobile phase:Acetonitrile: ammonium bicarbonate aqueous solution=60: 40; Column temperature is 25 DEG C; Detect wavelength 254nm. What record the results are shown in Table 4, the equal energy of purityReach 97%.
Claims (10)
- The synthetic method of 1.5'-S-(4,4'-dimethoxytrityl)-2'-deoxyinosine, is under inert gas shielding,Under normal temperature, in organic solvent, at azo agents, coordination phosphine compound and organic base or azo agents, coordination phosphine compound andUnder the effect of Bronsted acid, by compound 4 shown in compound 2'-deoxyinosine shown in formula I and formula II, 4'-dimethoxy triphen firstBase mercaptan carries out Mitsunobu reaction, obtains compound 5'-S-shown in formula III (4,4'-dimethoxytrityl)-2'-de-Oxygen inosine, described organic solvent is DMF or dimethyl sulfoxide (DMSO);Described azo agents is in diethyl azodiformate, diisopropyl azodiformate, tert-butyl azodicarboxylateOne or more; Described azo agents mole is 2-6 times of the deoxyinosine of compound 2'-shown in formula I mole, even when useThe mol ratio of nitrogen reagent and coordination phosphine compound is 1:1;Described coordination phosphine compound is one or more in triphenyl phosphorus, tributylphosphine, trimethyl-phosphine; Described coordination phosphine chemical combinationThe mole of thing is 2-6 times of the deoxyinosine of compound 2'-shown in formula I mole;Described organic base is triethylamine, DMAP, N-methylpyrrole or DMA; Described organic baseMole is 1-2 times of the deoxyinosine of compound 2'-shown in formula I mole;Described Bronsted acid is one or more in formic acid, acetic acid, benzoic acid, p-methyl benzenesulfonic acid, methanesulfonic acid and oxalic acid; Described matterThe mole of son acid is 2-6 times of the deoxyinosine of compound 2'-shown in formula I mole:
- 2. synthetic method according to claim 1, is characterized in that, comprises following operation: in container, pass into indifferent gasBody, by 2'-deoxyinosine, 4,4'-dimethoxytrityl mercaptan, coordination phosphine compound, organic base or Bronsted acid and organicSolvent adds in reaction vessel, drips azo agents, and stoichiometric number hour extremely extremely takes off without 2'-with thin-layer chromatography TLC detection reaction liquidOxygen inosine.
- 3. synthetic method according to claim 2, is characterized in that, compound 4 shown in described formula II, 4'-dimethoxyThe mole of trityl mercaptan is 2-4 times of the deoxyinosine of compound 2'-shown in formula I mole.
- 4. synthetic method according to claim 3, is characterized in that: described azo agents is tert-butyl azodicarboxylateOr diisopropyl azodiformate.
- 5. synthetic method according to claim 3, is characterized in that: described coordination phosphine compound is triphenyl phosphorus or threeButyl phosphine.
- 6. synthetic method according to claim 3, is characterized in that: described organic solvent is DMF;The consumption of the corresponding described organic solvent of compound 2'-deoxyinosine shown in the formula I of every g is 30-50ml.
- 7. synthetic method according to claim 6, is characterized in that: described inert gas is nitrogen; Described thin-layer chromatographyThe solvent that TLC detects is carrene: methyl alcohol volume ratio 5:1, and taking Rf=0.3 as indication point.
- 8. synthetic method according to claim 7, is characterized in that: described organic base is DMAP or N, N-Dimethylaniline.
- 9. synthetic method according to claim 7, is characterized in that: described Bronsted acid is formic acid or methanesulfonic acid or oxalic acid.
- 10. the synthetic method described in claim 2-7 any one, is characterized in that, also comprises from the arbitrary institute of claim 2 to 7State the process of abstraction reaction product in reactant liquor, concrete operations are:In reactant liquor, add ethyl acetate, then add washing agent extracting and demixing, get upper organic phase, use anhydrous sodium sulfate dryingAfter, revolve except organic solvent, through silica gel column chromatography, obtain white solid 5'-S-(4,4'-dimethoxytrityl)-2'-deoxidationInosine; Described washing agent is saturated aqueous ammonium chloride or saturated sodium bicarbonate aqueous solution.
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| WO2003074083A1 (en) * | 2002-03-04 | 2003-09-12 | Pfizer Inc. | Combination therapies for treating methylthioadenosine phosphorylase deficient cells |
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| WO2003074083A1 (en) * | 2002-03-04 | 2003-09-12 | Pfizer Inc. | Combination therapies for treating methylthioadenosine phosphorylase deficient cells |
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