CN106632285A - Method for synthesizing zidovudine-1,2,3-triazole compound - Google Patents
Method for synthesizing zidovudine-1,2,3-triazole compound Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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Abstract
The invention discloses a method for synthesizing a zidovudine-1,2,3-triazole compound, belonging to the technical field of antibacterial active medicines. According to the technical scheme of the invention, the specific route of the method for synthesizing the zidovudine-1,2,3-triazole compound is as shown in the specification. According to the method, on the basis that zidovudine molecules comprise azide groups, click reaction can be performed to enable zidovudine to react with aniline allylene compounds with different substituent groups so as to obtain the zidovudine-1,2,3-triazole compound, moreover gram-positive bacterium-staphylococcus aureus, gram-negative bacterium-escherichia coli and fungus-candida albicans are selected to perform in-vitro antibacterial activity testing on the zidovudine-1,2,3-triazole compound, and the results show that the compound has relatively good antibacterial activity.
Description
Technical field
The invention belongs to have the synthesis technical field of antimicrobial active medicament, and in particular to a kind of Zidovudine -1,2,3-
The synthetic method of triazole compound.
Background technology
Folic acid is the transfer that one carbon unit is provided in cell metabolism, is the synthesis of thymidine, purine, some amino acid and pantothenic acid
Important confactor.Higher eucaryote can obtain folic acid and folic acid by folic acid transfer protein on cell membrane from food
Polyglutamic acid, and the prokaryotes such as bacterium and some lower eukaryotes then need itself synthesis to obtain folic acid to participate in carefully
Born of the same parents DNA synthesizes, and promotes division and the maturation of cell.When folic acid deficiency, DNA synthesis is slow, directly result in bacterium nucleic acid and
The synthesis of protein is reduced, and is ultimately resulted in bacterial growth and is stagnated and dead.Microorganism Folic Acid biosynthetic enzyme is in mammal
In do not exist, therefore these enzymes can be used as the outstanding drug targets of bacterial-infection resisting.At present, by studying and summarizing folic acid
The structure and scheme information of available enzyme in route of synthesis, finds dihydrofolate synthetase (dihydropteroate
Synthase, DHPS) and dihyrofolate reductase (dihydrofolate reductase, DHFR) be bacteria living institute it is required
Enzyme.There is significant difference in the amino acid sequence of both enzymes, homology is less than 30% between bacterium and mammal, and
Active site between bacterium and mammal has very big difference.Therefore, DHPS and DHFR are the important of bacterium infection clinical treatment
Target.
Triazole class compounds have the advantages that biologically active height and to human body cell small toxicity, and its medical value is increasingly received
To concern, Jing is often introduced into polypeptide, DNA, RNA and saccharide compound as effective functional group.Recent study finds, many
Ring derivatives containing triazole to the pathogen targets such as HIV-TR and lanosterol 14 α-demethylase have stronger compatibility and
Specificity.Wherein 1,2,3- 3-triazole compounds are because with broad-spectrum biological activities such as AntiHIV1 RT activity, antibacterial, antihyperglycemic and anti-spasms
And become the focus of current triazole class compounds research, such as classical treatment fungal disease medicine Fluconazole has two 1, and 2,
3- triazole rings, therefore activity is high, toxicity is low, have use value medicine and agricultural chemicals new product are found from triazole class compounds
It is one of current study hotspot to plant.In order to obtain the efficient antibacterials of new class, the present invention is according in Zidovudine molecule
Containing azido group, by click reactions it can be made to obtain with the reaction of the anilino- propine compound with different substituents
Zidovudine -1,2,3- triazole compounds.
The content of the invention
Present invention solves the technical problem that it is simple and convenience operation with antibacterial activity to there is provided a kind of synthesis technique
Zidovudine -1,2,3- triazole compounds synthetic method.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of Zidovudine -1,2,3- triazoles
The synthetic method of compound, it is characterised in that concretely comprise the following steps：
(1) hydroxy propanal carries out heat condensation reaction under triethylamine effect and obtains compound with malonic acid
(2) by compoundIt is heated to slough carbon dioxide and water, and rearranged rear shape
Compound HOH is obtained into double bond2CCH2CH=CHCOOH；
(3) by compound HOH2CCH2CH=CHCOOH carry out in the presence of HY type molecular sieves intramolecular cyclization obtain β-
Methylol-gamma-butyrolacton；
(4) by β-methylol-gamma-butyrolacton, Jing chlorinations obtain the chloro- 5- (hydroxyls of 3- under the effect of catalyst phosphorus trichloride
Methyl) tetrahydrofuran -2 (3H) -one；
(5) by 3- chloro- 5- (methylol) tetrahydrofuran -2 (3H) -one, Jing elimination reactions obtain 5- under potassium hydroxide effect
(methylol) dihydrofuran -2 (3H) -one；
(6) reaction of 5- (methylol) dihydrofuran -2 (3H) -one Jing azide substitution is obtained into 4- nitrine -5- (methylol) two
Hydrogen furans -2 (3H) -one；
(7) it is 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one is etherified anti-under iodomethane and triethylamine effect
4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one should be obtained；
(8) reaction of 4- nitrine -5- (diformazan ether) (3H) -one Jing of dihydrofuran -2 carbonyl reduction is obtained into 4- nitrine -5-
(diformazan ether) dihydrofuran -2 (3H)-acetic acid esters；
(9) by 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid esters and pyrimidine ring reaction obtain 3- deoxidations -
3- azido -5-O- methyl ether base thymidines；
(10) 3- deoxidation -3- azido -5-O- methyl ether base thymidines are sloughed into first under KBr effect
Base obtains Zidovudine；
(11) be there is into click reactions in Zidovudine and anilino- acetylene compound and obtains target product Zidovudine -1,
2,3- triazole compounds.
Further preferably, the building-up process of step (1) is：Hydroxy propanal and malonic acid are placed in reaction vessel, are added
Analysis pure toluene, adds triethylamine, is heated to back flow reaction, is poured into water reactant liquor after reaction completely, uses ethyl acetate
Extraction is multiple, merges organic phase, is evaporated off obtaining compound after solvent
Further preferably, the detailed process of step (2) is：By compoundAdd molten
In agent toluene, then the concentrated sulfuric acid is added dropwise, is heated to back flow reaction, on reaction unit plus water knockout drum and when separate reaction produced by
Water, adds saturated sodium carbonate solution neutralization reaction liquid after reaction 2h, then is extracted with ethyl acetate reactant liquor repeatedly, merges organic
Phase, is evaporated off obtaining compound HOH after solvent2CCH2CH=CHOOH.
Further preferably, the detailed process of step (3) is：By compound HOH2CCH2It is pure that CH=CHCOOH is added to analysis
In DMF, HY molecular sieves are added, be heated to back flow reaction, after reaction completely room temperature is down to, added water and filtering reacting liquid, filtrate
It is extracted with ethyl acetate repeatedly, merges organic phase, is evaporated off obtaining β-methylol-gamma-butyrolacton, wherein compound after solvent
HOH2CCH2CH=CHCOOH is 12 with the mass ratio of HY molecular sieves:5, HY molecular sieves are zeolite-HY molecular sieves or AlCl3- HY point
Son sieve.
Further preferably, the detailed process of step (4) is：β-methylol-gamma-butyrolacton is added in solvent chloroform,
Add phosphorus trichloride, by the air in nitrogen displacement reactor, then chlorine be passed through in reactant liquor, at ambient temperature and
React under illumination condition, be evaporated off after solvent the purification of Jing column chromatography for separation obtain 3- chloro- 5- (methylol) tetrahydrofurans -2 (3H) -
Ketone, wherein β-methylol-gamma-butyrolacton are 8 with the mass ratio of phosphorus trichloride:1；The detailed process of step (5) is：3- is chloro-
5- (methylol) tetrahydrofuran -2 (3H) -one is added in solvent toluene, adds potassium hydroxide, is heated to back flow reaction, instead
Answer after 5h pressurization that toluene is evaporated off, remaining reactant liquor is poured into water, with chloroform extraction reactant liquor 3 times, merge dense after organic phase
Contracting obtains crude product, then the purification of Jing column chromatography for separation obtains 5- (methylol) dihydrofuran -2 (3H) -one, the chloro- 5- (hydroxyls of wherein 3-
Methyl) mass ratio of (3H) -one of tetrahydrofuran -2 and potassium hydroxide is 1:1.
Further preferably, the detailed process of step (6) is：5- (methylol) dihydrofuran -2 (3H) -one is added to molten
In agent DMF, sodium azide is added, reaction 4h is stirred at room temperature, then be warming up to 50 DEG C of reaction 2h, raw material reaction adds afterwards completely dilute
Hydrochloric acid adjusts the pH of reactant liquor to acidity, then is extracted with ethyl acetate reactant liquor, and Jing column chromatography for separation purification after concentration obtains 4-
Nitrine -5- (methylol) dihydrofuran -2 (3H) -one, wherein 5- (methylol) dihydrofuran -2 (3H) -one and sodium azide
Mass ratio 3:2；The detailed process of step (7) is：4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one is added into solvent
In tetrahydrofuran, iodomethane and triethylamine are added, be warming up to 45 DEG C of reactions, added water after raw material reaction is complete and be quenched, separation has
Machine phase, water is mutually extracted with ethyl acetate, and merges organic phase, and washing is removed under reduced pressure and obtain after solvent 4- nitrine -5- (diformazan ether)
Dihydrofuran -2 (3H) -one, the wherein quality of 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one, iodomethane and triethylamine
Than for 3:4:4.
Further preferably, the detailed process of step (8) is：By 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one
In being added to solvent DMF, triphenylphosphine and ethyl acetate are added, acetic acid is added dropwise at room temperature, azo is added after dripping
Dicarboxylate, reaction is evaporated off solvent after terminating, and after adding ethyl acetate extraction, is evaporated off obtaining 4- nitrine -5- after solvent
(diformazan ether) dihydrofuran -2 (3H)-acetic acid esters, wherein 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one, triphen
Base phosphine is 13 with the mass ratio of diethyl azodiformate:10:5.
Further preferably, the detailed process of step (9) is：By 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-second
Acid esters is added in solvent toluene with thymidine, adds triethylamine, and in 70 DEG C of reactions, reaction pours into reactant liquor after terminating
Solid is separated out in frozen water, suction filtration post-drying obtains 3- deoxidation -3- azido -5-O- methyl ether base thymidines, wherein
The mass ratio of 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid esters, thymidine and triethylamine is 1:1:2.
Further preferably, the detailed process of step (10) is：By 3- deoxidation -3- azido -5-O- methyl ether base thymidines
Deoxyribonucleoside is added in solvents tetrahydrofurane, adds lithium bromide, and in room temperature reaction, TLC monitoring raw material reactions are complete, Jing Guozheng
Except solvents tetrahydrofurane, acetone, the complete molten rear cooling crystallization of heating are added, then gained solid suction filtration post-drying is obtained into here many husbands
Fixed, wherein 3- deoxidations -3- azidos -5-O- methyl ether base thymidines and the mass ratio of lithium bromide are 2:1.
Further preferably, the detailed process of step (11) is：Zidovudine and anilino- acetylene compound are added to molten
In the agent tert-butyl alcohol, stannous chloride is added, in room temperature reaction, after TLC monitoring raw material reactions are complete, through washing, extraction, concentration
Afterwards again Jing column chromatography chromatograms separating-purifying obtains target product Zidovudine -1, wherein 2,3- triazole compounds, Qi Duofu
The mass ratio of fixed, anilino- acetylene compound and stannous chloride is 4:1.5:0.5, wherein anilino- acetylene compound is anilino-
Acetylene, o-toluidine ethyl-acetylene, o ethyl aniline ethyl-acetylene, adjacent fluoroanilino acetylene, o-chloraniline ethyl-acetylene, to methylbenzene
Amido acetylene, to MEA ethyl-acetylene, N, N- diacetylene anilines, N, N- diacetylene o-toluidines, N, N- diacetylenes
Base open-chain crown ether, N, N- diacetylene o ethyl anilines, N, N- diacetylenes are to MEA, N, N- diacetylenes neighbour's chlorobenzene
Amine or N, N- diacetylene neighbour's fluoroaniline.
The synthetic route of Zidovudine -1,2,3- triazole compounds of the present invention is：
The present invention contains azido group according in Zidovudine molecule, makes it by click reactions and carries different replacements
The acetylene compound of anilino- third reaction of base obtains Zidovudine -1,2,3- triazole compounds, and selects gram sun
Property bacterium-Staphylococcus aureus, Gram-negative bacteria-Escherichia coli and fungi-candida albicanses to synthesized Zidovudine-
1,2,3- triazole compound has carried out antibacterial activity in vitro measure, as a result shows that such compound is respectively provided with preferable antibacterial
Activity.
Specific embodiment
The above of the present invention is described in further details by the following examples, but this should not be interpreted as this
The scope for inventing above-mentioned theme is only limitted to below example, and all technologies realized based on the above of the present invention belong to this
Bright scope.
Embodiment 1
Weigh during hydroxy propanal 7.5g (0.1mol) and malonic acid 13g (0.12mol) is placed in reaction vessel, plus analyze pure first
Benzene 50mL, adds triethylamine 10mL, is heated to back flow reaction, pours reactant liquor in 300mL water into after reaction 5h, then uses acetic acid
Ethyl ester 200mL is extracted 3 times, merges organic phase, is evaporated off obtaining compound after solvent15g。
Embodiment 2
Weigh CompoundDuring 35g (0.20mol) is placed in container, toluene 100mL is added,
Be slowly added dropwise concentrated sulfuric acid 20g again, be heated to back flow reaction, on reaction unit plus water knockout drum and when separate reaction produced by
Water, after reaction 2h, adds a certain amount of saturated sodium carbonate solution neutralization reaction liquid, then with ethyl acetate 300mL extractive reactions liquid 3
It is secondary, merge organic phase, it is evaporated off obtaining compound HOH after solvent2CCH2CH=CHCOOH27g.
Embodiment 3
Weigh Compound HOH2CCH2During CH=CHCOOH12g (0.1mol) is placed in reaction vessel, analysis is added
DMF100mL, adds zeolite-HY molecular sieve 5g, is heated to back flow reaction, and after reaction 6h room temperature is down to, and adds 500mL water, mistake
Filter reactant liquor, filtrate is extracted 3 times with ethyl acetate 300mL, merges organic phase, be evaporated off being obtained after solvent product β-methylol-γ-
Butyrolactone 9g.
Embodiment 4
In the reactor with good ventilation system, β-methylol-gamma-butyrolacton 8g (0.07mol) is added into chlorine
In imitative 50mL, phosphorus trichloride 1g is added, by the air in nitrogen displacement reactor, then chlorine is slowly introducing in reactant liquor
Gas, reacts 3h with illumination condition at ambient temperature, Jing column chromatography for separation purification after solvent is evaporated off and obtains 3- chloro- 5- (hydroxyl first
Base) tetrahydrofuran -2 (3H) -one 6.2g.
Embodiment 5
In reaction bulbs of the 500mL with agitator, 3- chloro- 5- (methylol) tetrahydrofuran -2 (3H) -one 10g
(0.06mol) in being added to toluene 100mL, potassium hydroxide 10g is added, is heated to backflow, after reaction 5h, pressurization is evaporated off first
Benzene, pours residual reaction liquid in water 200mL into, with chloroform 100mL extractive reactions liquid 3 times, after merging organic phase, is concentrated to give thick
Product, then Jing column chromatography for separation purification obtain 5- (methylol) dihydrofuran -2 (3H) -one 4.6g.
Embodiment 6
In reaction bulbs of the 250mL with agitator, compound 5- (methylol) dihydrofuran -2 (3H) -one 15g is added
Enter in DMF 100mL, add sodium azide 10g, reaction 4h is stirred at room temperature, then be warming up to 50 DEG C of reaction 2h, raw material
Add watery hydrochloric acid to adjust the pH of reactant liquor to subacidity after reaction completely, then pour into 10 times of water, stir, use ethyl acetate
100mL is extracted twice, then with saturated common salt water washing to neutrality, anhydrous sodium sulfate drying, 4- nitrine -5- (hydroxyls is obtained after concentration
Methyl) dihydrofuran -2 (3H) -one 13g.
Embodiment 7
In reaction bulbs of the 250mL with agitator, 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one 15g is added
Enter in tetrahydrofuran 100mL, add iodomethane 20g and triethylamine 20g, after being warming up to 45 DEG C of reaction 5h, raw material reaction is complete
Entirely, add water and be quenched, separate organic phase, water is mutually extracted 2 times with ethyl acetate 100mL, merge organic phase, washing is removed under reduced pressure molten
4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one 11g is obtained after agent.
Embodiment 8
In reaction bulbs of the 250mL with agitator, by 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one 13g
In being added to DMF 100mL, triphenylphosphine 10g and ethyl acetate 20mL is added, acetic acid 20mL is added dropwise at room temperature, dripped
Room temperature reaction 1h is kept afterwards, DEAD (diethyl azodiformate) 5g is added, and keeps room temperature to continue to react 3h, reaction after adding
Solvent is evaporated off after end, ethyl acetate 200mL is added, solvent is evaporated off after washing and is obtained 4- nitrine -5- (diformazan ether) two
Hydrogen furans -2 (3H)-acetic acid esters 9g.
Embodiment 9
In reaction bulbs of the 500mL with agitator, by 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid
Ester 15g and thymidine 15g is added in toluene 100mL, adds triethylamine 30g, and 4h is reacted in 70 DEG C, and reaction terminates rear
Reactant liquor is poured into frozen water, has a large amount of solids to separate out, and suction filtration post-drying obtains 3- deoxidation -3- azido -5-O- methyl ether base thymus gland
Fudr 10g.
Embodiment 10
In reaction bulbs of the 100mL with agitator, by 3- deoxidation -3- azido -5-O- methyl ether base thymidine deoxidations
Nucleosides 10g is added in tetrahydrofuran 50mL, adds lithium bromide 5g, and 5h, TLC monitoring raw material reactions are reacted at ambient temperature
Completely, then through solvents tetrahydrofurane is evaporated off, acetone 30mL, the complete molten rear cooling crystallization of heating, by gained solid suction filtration are added
Post-drying obtains Zidovudine 6.7g.
Embodiment 11
In reaction bulbs of the 100mL with agitator, Zidovudine 4g and N, N- diacetylene aniline 1.5g are added to
In tert-butyl alcohol 30mL, stannous chloride 0.5g is added, after room temperature reaction 10h, TLC monitoring raw material reaction is complete, through washing, extraction
Take, again Jing column chromatography chromatograms separating-purifying obtains target product Zidovudine -1,2,3- triazoles-amino acetylenylbenzene after concentration
3.5g；1H NMR(600Mz,CDCl3):11.34 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.25 (d, J=12.0Hz,
1H), 7.11 (t, J=12.0Hz, 1H), 6.79 (d, J=6.0Hz, 1H), 6.59 (t, J=12.0Hz.1H), 6.41 (t, J=
12.0Hz.1H), 5.87 (t, J=12.0Hz.1H), 5.35-5.25 (m, 2H), 4.44 (d, J=6.0Hz, 2H), 4.20-4.17
(m,1H),3.70-3.56(m,2H),2.73-2.59(m,2H)1.80(s,3H).
Embodiment 12
Biological activity determination
The present embodiment is from Escherichia coli (Gram-negative brevibacterium) and golden yellow glucose coccus (gram-positive bacteria)
As antibacterial activity test object.First it is to prepare fluid nutrient medium (by peptone 1g, yeast extract 0.5g, sodium chloride 1g and steaming
Distilled water 100mL is placed in 250mL conical flasks, is placed on electric furnace and is heated while stirring, it is to be mixed clarification it is uniform when, stop heating,
Bottleneck gauze and brown paper are sealed into successively stand-by) and solid medium (by peptone 1g, yeast extract 0.5g, sodium chloride 1g,
Agar 2g and distilled water 100mL are placed in 250mL conical flasks, are placed on electric furnace and are heated while stirring, it is to be mixed clarification it is uniform when,
Stop heating, bottleneck gauze and brown paper are sealed into successively stand-by)；Then culture medium is sterilized by high-pressure sterilizing pot
Process.Next to that the preparation of bacterium solution, Escherichia coli and golden yellow glucose coccus actication of culture after, pipette 100 μ L with liquid-transfering gun
Bacterium solution after activation, is placed in the 100mL distilled water of bacterium of having gone out and is well mixed.Flat board is sterilized finally by uviol lamp,
Then culture medium is quickly poured into flat board while hot, thickness about 0.15cm is uniformly paved, stood, allow its slow solidification, after solidification
It is put into culture in 37 DEG C of incubator to do without Detection for one day.
Synthesized target compound and control compound solution is prepared respectively with DMF, is placed in stand-by in volumetric flask.With beating
Hole device punches on filter paper, and aperture is 5mm, during the sample solution that concentration is 10mg/mL is immersed in after then filter paper is sterilized
It is stand-by.
On superclean bench, alcolhol burner is lighted, the nutrient solution for taking 10 μ L dilutions with liquid-transfering gun is added to solid culture base table
Face, and be coated with uniform.The garden filter paper for soaking is taken with aseptic nipper and is taped against media surface.Each flat board puts 4, carries out 3
Secondary parallel laboratory test, wherein a piece of carry out blank.The flat board for being placed with tablet is placed in 37 DEG C of insulating boxs and cultivates 24h, observed
Phenomenon.By occurring different size of transparent ring-inhibition zone on agar medium respectively, can by measuring antibacterial circle diameter
To find out the bacteriostatic activity size of each sample.
General principle, principal character and the advantage of the present invention is embodiment above describes, the technical staff of the industry should
Understand, the present invention is not restricted to the described embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope without departing from the principle of the invention, the present invention also has various changes and modifications, and these changes and improvements each fall within
In the scope of protection of the invention.
Claims (10)
1. a kind of Zidovudine -1, the synthetic method of 2,3- triazole compounds, it is characterised in that concretely comprise the following steps：
(1) hydroxy propanal carries out heat condensation reaction under triethylamine effect and obtains compound with malonic acid
(2) by compoundIt is heated to slough carbon dioxide and water, and rearranged rear formation is double
Key obtains compound HOH2CCH2CH=CHCOOH；
(3) by compound HOH2CCH2CH=CHCOOH carries out intramolecular cyclization in the presence of HY type molecular sieves and obtains β-hydroxyl first
Base-gamma-butyrolacton；
(4) by β-methylol-gamma-butyrolacton, Jing chlorinations obtain 3- chloro- 5- (hydroxyl first under the effect of catalyst phosphorus trichloride
Base) tetrahydrofuran -2 (3H) -one；
(5) by 3- chloro- 5- (methylol) tetrahydrofuran -2 (3H) -one, Jing elimination reactions obtain 5- (hydroxyls under potassium hydroxide effect
Methyl) dihydrofuran -2 (3H) -one；
(6) reaction of 5- (methylol) dihydrofuran -2 (3H) -one Jing azide substitution is obtained into 4- nitrine -5- (methylol) dihydro furans
Mutter -2 (3H) -one；
(7) 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one etherified is reacted under iodomethane and triethylamine effect
To 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one；
(8) reaction of 4- nitrine -5- (diformazan ether) (3H) -one Jing of dihydrofuran -2 carbonyl reduction is obtained into 4- nitrine -5- (diformazans
Ether) dihydrofuran -2 (3H)-acetic acid esters；
(9) 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid esters and pyrimidine ring reaction are obtained into 3- deoxidations -3- to fold
Nitrogen base -5-O- methyl ether base thymidines；
(10) by 3- deoxidation -3- azido -5-O- methyl ether base thymidines, demethylating is obtained under KBr effect
To Zidovudine；
(11) be there is into click reactions in Zidovudine and anilino- acetylene compound and obtain target product Zidovudine -1,2,3-
Triazole compound.
2. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that step
Suddenly the building-up process of (1) is：Hydroxy propanal and malonic acid are placed in reaction vessel, analysis pure toluene is added, three second are added
Amine, is heated to back flow reaction, is poured into water reactant liquor after reaction completely, is extracted with ethyl acetate repeatedly, merges organic phase, steams
Except obtaining compound after solvent
3. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that step
Suddenly the detailed process of (2) is：By compoundIn adding solvent toluene, then dense sulphur is added dropwise
Acid, is heated to back flow reaction, on reaction unit plus water knockout drum and when separate reaction produced by water, reaction 2h after add saturation
Sodium carbonate liquor neutralization reaction liquid, then it is extracted with ethyl acetate reactant liquor repeatedly, merge organic phase, it is evaporated off obtaining chemical combination after solvent
Thing HOH2CCH2CH=CHCOOH.
4. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that step
Suddenly the detailed process of (3) is：By compound HOH2CCH2CH=CHCOOH is added in the pure DMF of analysis, adds HY molecular sieves,
Back flow reaction is heated to, after reaction completely room temperature is down to, added water and filtering reacting liquid, filtrate is extracted with ethyl acetate repeatedly, closed
And organic phase, it is evaporated off obtaining β-methylol-gamma-butyrolacton, wherein compound HOH after solvent2CCH2CH=CHCOOH and HY molecules
The mass ratio of sieve is 12:5, HY molecular sieves are zeolite-HY molecular sieves or AlCl3- HY molecular sieves.
5. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that step
Suddenly the detailed process of (4) is：β-methylol-gamma-butyrolacton is added in solvent chloroform, phosphorus trichloride is added, by nitrogen
Air in gas metathesis reactor, then chlorine is passed through in reactant liquor, at ambient temperature with reaction under illumination condition, it is evaporated off molten
Jing column chromatography for separation purification after agent obtains 3- chloro- 5- (methylol) tetrahydrofuran -2 (3H) -one, wherein β-methylol-γ-Ding Nei
Ester is 8 with the mass ratio of phosphorus trichloride:1；The detailed process of step (5) is：By 3- chloro- 5- (methylol) tetrahydrofurans -2
(3H) -one is added in solvent toluene, adds potassium hydroxide, is heated to back flow reaction, and pressurization after reaction 5h is evaporated off toluene, will
Remaining reactant liquor is poured into water, and with chloroform extraction reactant liquor 3 times, to merge and be concentrated to give crude product, then Jing post layers after organic phase
Analysis separating-purifying obtains 5- (methylol) dihydrofuran -2 (3H) -one, and wherein 3- chloro- 5- (methylol) tetrahydrofurans -2 (3H) -
Ketone is 1 with the mass ratio of potassium hydroxide:1.
6. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that step
Suddenly the detailed process of (6) is：5- (methylol) dihydrofuran -2 (3H) -one is added in solvent DMF, Azide is added
Sodium, be stirred at room temperature reaction 4h, then be warming up to 50 DEG C reaction 2h, raw material reaction completely afterwards add watery hydrochloric acid adjust reactant liquor pH to
Acidity, then reactant liquor is extracted with ethyl acetate, Jing column chromatography for separation purification after concentration obtains 4- nitrine -5- (methylol) dihydro furans
Mutter -2 (3H) -one, the mass ratio 3 of wherein 5- (methylol) dihydrofuran -2 (3H) -one and sodium azide:2；The tool of step (7)
Body process is：4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one is added in solvents tetrahydrofurane, iodine first is added
Alkane and triethylamine, are warming up to 45 DEG C of reactions, add water after raw material reaction is complete and are quenched, and separate organic phase, and water is extracted with ethyl acetate
Take, merge organic phase, washing is removed under reduced pressure and obtain after solvent 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one, its
The mass ratio of middle 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one, iodomethane and triethylamine is 3:4:4.
7. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that step
Suddenly the detailed process of (8) is：4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one is added in solvent DMF, then is added
Enter triphenylphosphine and ethyl acetate, acetic acid is added dropwise at room temperature, diethyl azodiformate is added after dripping, reaction terminates
After solvent is evaporated off, add ethyl acetate extraction after, be evaporated off obtaining 4- nitrine -5- (diformazan ether) dihydrofuran -2 after solvent
(3H)-acetic acid esters, wherein 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one, triphenylphosphine and azoformic acid diethyl
The mass ratio of ester is 13:10:5.
8. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that step
Suddenly the detailed process of (9) is：4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid esters is added to thymidine
In solvent toluene, triethylamine is added, in 70 DEG C of reactions, reactant liquor is poured into frozen water and separates out solid by reaction after terminating, suction filtration
Post-drying obtains 3- deoxidation -3- azido -5-O- methyl ether base thymidines, wherein 4- nitrine -5- (diformazan ether)
The mass ratio of dihydrofuran -2 (3H)-acetic acid esters, thymidine and triethylamine is 1:1:2.
9. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that step
Suddenly the detailed process of (10) is：3- deoxidation -3- azido -5-O- methyl ether bases thymidine is added into solvent tetrahydrochysene furan
In muttering, lithium bromide is added, in room temperature reaction, TLC monitoring raw material reaction completely, through solvents tetrahydrofurane is evaporated off, is added
Acetone, the complete molten rear cooling crystallization of heating, then gained solid suction filtration post-drying is obtained into Zidovudine, wherein 3- deoxidations -3- nitrine
Base -5-O- methyl ether base thymidines are 2 with the mass ratio of lithium bromide:1.
10. Zidovudine -1 according to claim 1, the synthetic method of 2,3- triazole compounds, it is characterised in that
The detailed process of step (11) is：Zidovudine and anilino- acetylene compound are added in solvent tertiary butanol, chlorine is added
Change is cuprous, and in room temperature reaction, after TLC monitoring raw material reactions are complete, through washing, extraction, again Jing column chromatography chromatograms divide after concentration
Target product Zidovudine -1,2,3- triazole compounds, wherein Zidovudine, anilino- acetylene compound are obtained from purification
It is 4 with the mass ratio of stannous chloride:1.5:0.5, wherein anilino- acetylene compound be N, N- diacetylene anilines, N, N- diethyls
Alkynyl o-toluidine, N, N- diacetylene open-chain crown ethers, N, N- diacetylene o ethyl anilines, N, N- diacetylenes are to second
Base aniline, N, N- diacetylenes o-chloraniline or N, N- diacetylene neighbour's fluoroaniline.
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| CN109485611A (en) * | 2018-12-28 | 2019-03-19 | 河南师范大学 | A kind of preparation method of triazole derivatives |
| CN110407830A (en) * | 2019-08-21 | 2019-11-05 | 河南师范大学 | A method of synthesis N- aryl phenothiazine compound |
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| CN110407830A (en) * | 2019-08-21 | 2019-11-05 | 河南师范大学 | A method of synthesis N- aryl phenothiazine compound |
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