CN106632285B - A kind of synthetic method of Zidovudine -1,2,3- triazole compound - Google Patents
A kind of synthetic method of Zidovudine -1,2,3- triazole compound Download PDFInfo
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Abstract
The invention discloses a kind of Zidovudine -1,2, the synthetic method of 3- triazole compound belongs to the synthesis technical field with antimicrobial active medicament.Technical solution of the present invention main points are as follows: a kind of Zidovudine -1,2, the synthetic method of 3- triazole compound, specific synthetic route are as follows:
Description
Technical field
The invention belongs to the synthesis technical fields with antimicrobial active medicament, and in particular to a kind of Zidovudine -1,2,3-
The synthetic method of triazole compound.
Background technique
Folic acid is to provide the transfer of one carbon unit in cell metabolism, is thymidine, purine, some amino acid and pantothenic acid synthesis
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, it is thin to participate in
Born of the same parents DNA synthesis promotes the division and maturation of cell.When folic acid deficiency, DNA synthesis slowly, directly result in bacterium nucleic acid and
The synthesis of protein is reduced, and eventually leads to bacterial growth stagnation and death.Folic acid biosynthetic enzyme is in mammal in microorganism
In and be not present, therefore these enzymes can be used as the outstanding drug targets of bacterial-infection resisting.Currently, by studying and summarizing folic acid
The structure and scheme information of available enzyme in route of synthesis find dihydrofolate synthetase (dihydropteroate
Synthase, DHPS) and dihyrofolate reductase (dihydrofolate reductase, DHFR) be bacteria living institute it is required
Enzyme.The amino acid sequence of both enzymes between bacterium and mammal there are significant difference, homology less than 30%, and
Active site between bacterium and mammal has very big difference.Therefore, DHPS and DHFR is the important of bacterium infection clinical treatment
Target.
Triazole class compounds have many advantages, such as that bioactivity is high and to human body cell small toxicity, medical value increasingly by
To concern, polypeptide often is introduced into, in DNA, RNA and saccharide compound as effective functional group.Recent study discovery, it is 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 having the broad-spectrum biological activities such as AntiHIV1 RT activity, antibacterial, antihyperglycemic and anti-spasm
And become the hot spot of current triazole class compounds research, such as 1,2 there are two classical treatment fungal disease drug Fluconazole tools,
3- triazole ring, therefore the medicine and pesticide new product that activity is high, toxicity is low, has use value are found from triazole class compounds
Kind is current one of research hotspot.The efficient antibacterials of new class in order to obtain, the present invention is according in Zidovudine molecule
Containing azido group, can be reacted by click makes it react to obtain with the anilino- propine compound with different substituents
Zidovudine -1,2,3- triazole compound.
Summary of the invention
It is simple the technical problem to be solved by the present invention is to provide a kind of synthesis technology and facilitate operation has antibacterial activity
Zidovudine -1,2,3- triazole compound synthetic method.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of Zidovudine -1,2,3- triazole
The synthetic method of compound, it is characterised in that specific steps are as follows:
(1) hydroxy propanal with malonic acid react to obtain compound by the progress heat condensation under triethylamine effect
(2) by compoundIt is heated to slough carbon dioxide and water, and it is rearranged after
It forms double bond and obtains compound HOH2CCH2CH=CHCOOH；
(3) by compound HOH2CCH2CH=CHCOOH carries out intramolecular cyclization in the presence of HY type molecular sieve and obtains β-
Methylol-gamma-butyrolacton；
(4) β-methylol-gamma-butyrolacton is obtained into the chloro- 5- (hydroxyl of 3- through chlorination under the effect of catalyst phosphorus trichloride
Methyl) tetrahydrofuran -2 (3H) -one；
(5) 3- chloro- 5- (methylol) tetrahydrofuran -2 (3H) -one is obtained into 5- through elimination reaction under potassium hydroxide effect
(methylol) dihydrofuran -2 (3H) -one；
(6) 5- (methylol) dihydrofuran -2 (3H) -one is reacted to obtain 4- nitrine -5- (methylol) two through azide substitution
Hydrogen furans -2 (3H) -one；
(7) 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one is etherified anti-under iodomethane and triethylamine effect
It should obtain 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one；
(8) it reacts 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one to obtain 4- nitrine -5- through carbonyl reduction
(diformazan ether) dihydrofuran -2 (3H)-acetic acid esters；
(9) it reacts 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid esters to obtain 3- deoxidation-with pyrimidine ring
3- azido -5-O- methyl ether base thymidine；
(10) 3- deoxidation -3- azido -5-O- methyl ether base thymidine is sloughed into first under lithium bromide effect
Base obtains Zidovudine；
(11) by Zidovudine and N, N- dipropargyl aniline occurs click and reacts to obtain target product Zidovudine -1,
2,3- triazole compound.
Further preferably, the synthesis process of step (1) are as follows: hydroxy propanal and malonic acid are placed in reaction vessel, are added
Pure toluene is analyzed, triethylamine is added, is heated to back flow reaction, is poured into water reaction solution after fully reacting, use ethyl acetate
Extraction repeatedly, merges organic phase, obtains compound after solvent is evaporated off
Further preferably, the detailed process of step (2) are as follows: by compoundIt is added molten
In agent toluene, then the concentrated sulfuric acid is added dropwise, is heated to back flow reaction, on reaction unit bonus point hydrophone and when separate caused by reaction
Saturated sodium carbonate solution neutralization reaction liquid is added after reacting 2h in water, then to be extracted with ethyl acetate reaction solution multiple, merges organic
Phase obtains compound HOH after solvent is evaporated off2CCH2CH=CHOOH.
Further preferably, the detailed process of step (3) are as follows: by compound HOH2CCH2It is pure that CH=CHCOOH is added to analysis
In DMF, HY molecular sieve is added, back flow reaction is heated to, is down to room temperature after fully reacting, adds water and filtering reacting liquid, filtrate
It is extracted with ethyl acetate repeatedly, merges organic phase, obtain β-methylol-gamma-butyrolacton after solvent is evaporated off, wherein compound
HOH2CCH2CH=CHCOOH and the mass ratio of HY molecular sieve are 12:5, and HY molecular sieve is zeolite-HY molecular sieve or AlCl3- HY points
Son sieve.
Further preferably, the detailed process of step (4) are as follows: β-methylol-gamma-butyrolacton is added in solvent chloroform,
Add phosphorus trichloride, by the air in nitrogen metathesis reactor, then be passed through chlorine into reaction solution, at room temperature and
It is reacted under illumination condition, purifies to obtain 3- chloro- 5- (methylol) tetrahydrofuran -2 (3H)-through column chromatography for separation after solvent is evaporated off
Ketone, wherein the mass ratio of β-methylol-gamma-butyrolacton and phosphorus trichloride is 8:1；The detailed process of step (5) are as follows: 3- is chloro-
5- (methylol) tetrahydrofuran -2 (3H) -one is added in solvent toluene, is added potassium hydroxide, is heated to back flow reaction, instead
It answers pressurization after 5h that toluene is evaporated off, remaining reaction solution is poured into water, extracted reaction solution 3 times with chloroform, it is dense after merging organic phase
Contracting obtains crude product, then purifies to obtain 5- (methylol) dihydrofuran -2 (3H) -one through column chromatography for separation, wherein the chloro- 5- (hydroxyl of 3-
Methyl) mass ratio of (3H) -one of tetrahydrofuran -2 and potassium hydroxide is 1:1.
Further preferably, the detailed process of step (6) are as follows: be added to 5- (methylol) dihydrofuran -2 (3H) -one 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, is added after raw material fully reacting dilute
Hydrochloric acid adjusts the pH of reaction solution to acidity, then reaction solution is extracted with ethyl acetate, and purifies to obtain 4- through column chromatography for separation after concentration
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) are as follows: 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one is added to solvent
In tetrahydrofuran, iodomethane and triethylamine are added, is warming up to 45 DEG C of reactions, after raw material fully reacting plus water quenching is gone out, and separation has
Machine phase, water phase are extracted with ethyl acetate, and merge organic phase, wash, and obtain 4- nitrine -5- (diformazan ether) after evaporating solvent under reduced pressure
Dihydrofuran -2 (3H) -one, wherein 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one, the quality of iodomethane and triethylamine
Than for 3:4:4.
Further preferably, the detailed process of step (8) are as follows: by 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one
It is added in solvent DMF, adds triphenylphosphine and ethyl acetate, acetic acid is added dropwise at room temperature, add azo after dripping
Solvent is evaporated off in dicarboxylate after reaction, after adding ethyl acetate extraction, obtains 4- nitrine -5- after solvent is evaporated off
(diformazan ether) dihydrofuran -2 (3H)-acetic acid esters, wherein 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one, triphen
The mass ratio of base phosphine and diethyl azodiformate is 13:10:5.
Further preferably, the detailed process of step (9) are as follows: by 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-second
Acid esters and thymidine are added in solvent toluene, add triethylamine, are reacted in 70 DEG C, are after reaction poured into reaction solution
Solid is precipitated in ice water, drying obtains 3- deoxidation -3- azido -5-O- methyl ether base thymidine after suction filtration, wherein
4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid esters, thymidine and triethylamine mass ratio is 1:1:2.
Further preferably, the detailed process of step (10) are as follows: by 3- deoxidation -3- azido -5-O- methyl ether base thymidine
Deoxyribonucleoside is added in solvents tetrahydrofurane, adds lithium bromide, and in room temperature reaction, TLC monitors raw material fully reacting, by steaming
Except solvents tetrahydrofurane, acetone, the complete molten rear cooling crystallization of heating are added, then dries to obtain here more husbands after obtained solid is filtered
Fixed, wherein the mass ratio of 3- deoxidation -3- azido -5-O- methyl ether base thymidine and lithium bromide is 2:1.
Further preferably, the detailed process of step (11) are as follows: by Zidovudine and N, N- dipropargyl aniline is added to molten
In the agent tert-butyl alcohol, stannous chloride is added, in room temperature reaction, after TLC monitors raw material fully reacting, by washing, is extracted, concentration
Target product Zidovudine -1,2 is obtained through column chromatography chromatogram separating-purifying again afterwards, 3- triazole compound, wherein Qi Duofu
The mass ratio of fixed, N, N- dipropargyl aniline and stannous chloride is 4:1.5:0.5.
The synthetic route of Zidovudine -1,2,3- triazole compound of the present invention are as follows:
The present invention contains azido group according in Zidovudine molecule, by click reaction make its from different substitutions
The third acetylene compound of anilino- of base reacts to obtain Zidovudine -1,2,3- triazole compound, and selects gram positive
Property bacterium-Staphylococcus aureus, Gram-negative bacteria-Escherichia coli and fungi-candida albicans are to synthesized Zidovudine-
1,2,3- triazole compound has carried out antibacterial activity in vitro measurement, the results showed that such compound all has preferable antibacterial
Activity.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
It weighs hydroxy propanal 7.5g (0.1mol) and malonic acid 13g (0.12mol) is placed in reaction vessel, bonus point analyses pure first
Benzene 50mL adds triethylamine 10mL, is heated to back flow reaction, pours into reaction solution in 300mL water after reacting 5h, then use acetic acid
Ethyl ester 200mL is extracted 3 times, is merged organic phase, is obtained compound after solvent is evaporated off
Embodiment 2
Weigh Compound(0.20mol) is placed in container, and toluene 100mL is added,
Concentrated sulfuric acid 20g is slowly added dropwise again, is heated to back flow reaction, on reaction unit bonus point hydrophone and when separate caused by reaction
After reacting 2h, a certain amount of saturated sodium carbonate solution neutralization reaction liquid is added, then extract reaction solution 3 with ethyl acetate 300mL in water
It is secondary, merge organic phase, obtains compound HOH after solvent is evaporated off2CCH2CH=CHCOOH27g.
Embodiment 3
Weigh Compound HOH2CCH2CH=CHCOOH12g (0.1mol) is placed in reaction vessel, and analysis is added
DMF100mL adds zeolite-HY molecular sieve 5g, is heated to back flow reaction, is down to room temperature after reacting 6h, 500mL water, mistake is added
Reaction solution is filtered, filtrate is extracted 3 times with ethyl acetate 300mL, is merged organic phase, is obtained product β-methylol-γ-after solvent is evaporated off
Butyrolactone 9g.
Embodiment 4
In the reactor with good ventilation system, β-methylol-gamma-butyrolacton 8g (0.07mol) is added to chlorine
In imitative 50mL, phosphorus trichloride 1g is added, by the air in nitrogen metathesis reactor, then is slowly introducing chlorine into reaction solution
Gas, at room temperature with react 3h under illumination condition, purify to obtain 3- chloro- 5- (hydroxyl first through column chromatography for separation after solvent is evaporated off
Base) (3H) -one of tetrahydrofuran -2 6.2g.
Embodiment 5
In reaction flask of the 500mL with blender, 3- chloro- 5- (methylol) (3H) -one of tetrahydrofuran -2 10g
(0.06mol) is added in toluene 100mL, adds potassium hydroxide 10g, is heated to flowing back, and after reacting 5h, first is evaporated off in pressurization
Benzene pours into residual reaction liquid in water 200mL, is extracted reaction solution 3 times with chloroform 100mL, after merging organic phase, is concentrated to get thick
Product, then purify to obtain 5- (methylol) (3H) -one of dihydrofuran -2 4.6g through column chromatography for separation.
Embodiment 6
In reaction flask of the 250mL with blender, compound 5- (methylol) (3H) -one of dihydrofuran -2 15g is added
Enter into 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
Dilute hydrochloric acid is added after fully reacting and adjusts the pH of reaction solution to subacidity, then pours into 10 times of water, stirs, uses ethyl acetate
100mL is extracted twice, then with saturated common salt water washing to neutrality, and anhydrous sodium sulfate is dry, and 4- nitrine -5- (hydroxyl is obtained after concentration
Methyl) (3H) -one of dihydrofuran -2 13g.
Embodiment 7
In reaction flask of the 250mL with blender, 4- nitrine -5- (methylol) (3H) -one of dihydrofuran -2 15g is added
Enter into tetrahydrofuran 100mL, add iodomethane 20g and triethylamine 20g, after being warming up to 45 DEG C of reaction 5h, raw material has reacted
Entirely, add water quenching to go out, separate organic phase, water phase is extracted 2 times with ethyl acetate 100mL, merges organic phase, and washing removes under reduced pressure molten
4- nitrine -5- (diformazan ether) (3H) -one of dihydrofuran -2 11g is obtained after agent.
Embodiment 8
In reaction flask of the 250mL with blender, by 4- nitrine -5- (diformazan ether) (3H) -one of dihydrofuran -2 13g
It is added in DMF 100mL, adds triphenylphosphine 10g and ethyl acetate 20mL, acetic acid 20mL is added dropwise at room temperature, drips
Room temperature reaction 1h is kept afterwards, adds DEAD (diethyl azodiformate) 5g, and room temperature the reaction was continued 3h, reaction are kept after adding
After solvent is evaporated off, add ethyl acetate 200mL, solvent be evaporated off after washing and obtains 4- nitrine -5- (diformazan ether) two
Hydrogen furans -2 (3H)-acetic acid esters 9g.
Embodiment 9
In reaction flask of the 500mL with blender, by 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid
Ester 15g and thymidine 15g are added in toluene 100mL, add triethylamine 30g, in 70 DEG C of reaction 4h, after reaction
Reaction solution pours into ice water, has a large amount of solids to be precipitated, and drying obtains 3- deoxidation -3- azido -5-O- methyl ether base thymus gland after suction filtration
Fudr 10g.
Embodiment 10
In reaction flask of the 100mL with blender, by 3- deoxidation -3- azido -5-O- methyl ether base thymidine deoxidation
Nucleosides 10g is added in tetrahydrofuran 50mL, adds lithium bromide 5g, reacts 5h at room temperature, and TLC monitors raw material reaction
Completely, using solvents tetrahydrofurane is evaporated off, acetone 30mL is added, the complete molten rear cooling crystallization of heating filters obtained solid
Drying obtains Zidovudine 6.7g afterwards.
Embodiment 11
In reaction flask of the 100mL with blender, by Zidovudine 4g and N, N- dipropargyl aniline 1.5g is added to
In tert-butyl alcohol 30mL, stannous chloride 0.5g is added, reacts at room temperature 10h, after TLC monitors raw material fully reacting, by washing, extraction
It takes, obtains target product Zidovudine -1,2,3- triazole-amino acetylenylbenzene through column chromatography chromatogram separating-purifying again 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 selects Escherichia coli (Gram-negative brevibacterium) and golden yellow glucose coccus (gram-positive bacteria)
As antibacterial activity test object.It is to prepare fluid nutrient medium (by peptone 1g, yeast extract 0.5g, sodium chloride 1g and steaming first
Distilled water 100mL is placed in 250mL conical flask, 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 successively sealed 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 flask, 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 successively sealed for use)；Then it is sterilized by high-pressure sterilizing pot to culture medium
Processing.The followed by preparation of bacterium solution pipettes 100 μ L with liquid-transfering gun after Escherichia coli and golden yellow glucose coccus actication of culture
Bacterium solution after activation is placed in sterilized 100mL distilled water and is uniformly mixed.It sterilizes finally by ultraviolet lamp to plate,
Then culture medium is quickly poured into plate while hot, thickness about 0.15cm is uniformly paved, and is stood, is allowed its slow solidification, after solidification
It is put into cultivate one day in 37 DEG C of incubator and does no Detection.
It prepares synthesized target compound and control compound solution respectively with DMF, is placed in volumetric flask stand-by.With beating
Hole device punches on filter paper, aperture 5mm, is immersed in the sample solution that concentration is 10mg/mL after then filter paper sterilizes
For use.
On superclean bench, alcolhol burner is lighted, takes the 10 diluted culture solutions of μ L to be added to solid culture base table with liquid-transfering gun
Face, and be coated with uniform.The garden filter paper impregnated is taken to be taped against media surface with aseptic nipper.Each plate puts 4, carries out 3
Secondary parallel laboratory test, wherein a piece of carry out blank control.The plate for being placed with tablet is placed in 37 DEG C of insulating boxs and is cultivated for 24 hours, observation
Phenomenon.It, can by measurement antibacterial circle diameter by occurring different size of transparent ring-inhibition zone on agar medium respectively
To find out the bacteriostatic activity size of each sample.
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. a kind of Zidovudine -1,2, the synthetic method of 3- triazole compound, it is characterised in that specific steps are as follows:
(1) hydroxy propanal with malonic acid react to obtain compound by the progress heat condensation under triethylamine effect
(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 sieve and obtains β-hydroxyl first
Base-gamma-butyrolacton；
(4) β-methylol-gamma-butyrolacton is obtained into 3- chloro- 5- (hydroxyl first through chlorination under the effect of catalyst phosphorus trichloride
Base) tetrahydrofuran -2 (3H) -one；
(5) 3- chloro- 5- (methylol) tetrahydrofuran -2 (3H) -one is obtained into 5- (hydroxyl through elimination reaction under potassium hydroxide effect
Methyl) dihydrofuran -2 (3H) -one；
(6) 5- (methylol) dihydrofuran -2 (3H) -one is reacted to obtain 4- nitrine -5- (methylol) dihydro furan through azide substitution
It mutters -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) 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one is reacted to obtain 4- nitrine -5- (diformazan through carbonyl reduction
Ether) dihydrofuran -2 (3H)-acetic acid esters；
(9) it reacts 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid esters to obtain 3- deoxidation-with thymidine ring
3- azido -5-O- methyl ether base thymidine；
(10) by 3- deoxidation -3- azido -5-O- methyl ether base thymidine, demethylating is obtained under lithium bromide effect
To Zidovudine；
(11) by Zidovudine and N, N- dipropargyl aniline occurs click and reacts to obtain target product Zidovudine -1,2,3-
Triazole compound；
The corresponding synthetic route of entire synthesis process are as follows:
WhereinSpecially
2. Zidovudine -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that step
Suddenly the synthesis process of (1) are as follows: hydroxy propanal and malonic acid are placed in reaction vessel, analysis pure toluene is added, adds three second
Amine is heated to back flow reaction, is poured into water reaction solution after fully reacting, is extracted with ethyl acetate repeatedly, merges organic phase, steams
Except obtaining compound after solvent
3. Zidovudine -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that step
Suddenly the detailed process of (2) are as follows: by compoundIt is added in solvent toluene, then dense sulphur is added dropwise
Acid is heated to back flow reaction, on reaction unit bonus point hydrophone and when separate reaction caused by water, react 2h after be added saturation
Sodium carbonate liquor neutralization reaction liquid, then to be extracted with ethyl acetate reaction solution multiple, merges organic phase, obtains chemical combination after solvent is evaporated off
Object HOH2CCH2CH=CHCOOH.
4. Zidovudine -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that step
Suddenly the detailed process of (3) are as follows: by compound HOH2CCH2CH=CHCOOH is added in the pure DMF of analysis, adds HY molecular sieve,
It is heated to back flow reaction, is down to room temperature after fully reacting, adds water and filtering reacting liquid, filtrate is extracted with ethyl acetate repeatedly, closes
And organic phase, β-methylol-gamma-butyrolacton is obtained after solvent is evaporated off, wherein compound HOH2CCH2CH=CHCOOH and HY molecule
The mass ratio of sieve is 12:5, and HY molecular sieve is zeolite-HY molecular sieve or AlCl3- HY molecular sieve.
5. Zidovudine -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that step
Suddenly the detailed process of (4) are as follows: β-methylol-gamma-butyrolacton is added in solvent chloroform, phosphorus trichloride is added, passes through nitrogen
Air in gas metathesis reactor, then chlorine is passed through into reaction solution, at room temperature with reacted under illumination condition, be evaporated off molten
It purifies to obtain 3- chloro- 5- (methylol) tetrahydrofuran -2 (3H) -one through column chromatography for separation after agent, wherein β-methylol-γ-Ding Nei
The mass ratio of ester and phosphorus trichloride is 8:1；The detailed process of step (5) are as follows: by 3- chloro- 5- (methylol) tetrahydrofuran -2
(3H) -one is added in solvent toluene, adds potassium hydroxide, is heated to back flow reaction, and toluene is evaporated off in pressurization after reacting 5h, will
Remaining reaction solution is poured into water, and is extracted reaction solution 3 times with chloroform, is concentrated to get crude product after merging organic phase, then through column layer
Analysis separating-purifying obtains 5- (methylol) dihydrofuran -2 (3H) -one, wherein the chloro- 5- of 3- (methylol) tetrahydrofuran -2 (3H) -
The mass ratio of ketone and potassium hydroxide is 1:1.
6. Zidovudine -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that step
Suddenly the detailed process of (6) are as follows: 5- (methylol) dihydrofuran -2 (3H) -one is added in solvent DMF, adds Azide
Sodium, is stirred at room temperature reaction 4h, then is warming up to 50 DEG C of reaction 2h, be added after raw material fully reacting the pH of dilute hydrochloric acid adjusting reaction solution to
Acidity, then reaction solution is extracted with ethyl acetate, it purifies to obtain 4- nitrine -5- (methylol) dihydro furan through column chromatography for separation after concentration
It mutters -2 (3H) -one, wherein the mass ratio 3:2 of 5- (methylol) dihydrofuran -2 (3H) -one and sodium azide；The tool of step (7)
Body process are as follows: 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one is added in solvents tetrahydrofurane, adds iodine first
Alkane and triethylamine are warming up to 45 DEG C of reactions, and after raw material fully reacting plus water quenching is gone out, and separates organic phase, and water phase is extracted with ethyl acetate
It takes, merges organic phase, wash, obtain 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one after evaporating solvent under reduced pressure,
The mass ratio of middle 4- nitrine -5- (methylol) dihydrofuran -2 (3H) -one, iodomethane and triethylamine is 3:4:4.
7. Zidovudine -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that step
Suddenly the detailed process of (8) are as follows: 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H) -one is added in solvent DMF, then plus
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, obtain 4- nitrine -5- (diformazan ether) dihydrofuran -2 after solvent is evaporated off
(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 -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that step
Suddenly the detailed process of (9) are as follows: be added to 4- nitrine -5- (diformazan ether) dihydrofuran -2 (3H)-acetic acid esters with thymidine
In solvent toluene, triethylamine is added, is reacted in 70 DEG C, reaction solution is poured into solid is precipitated in ice water after reaction, is filtered
Drying obtains 3- deoxidation -3- azido -5-O- methyl ether base thymidine afterwards, wherein 4- nitrine -5- (diformazan ether)
Dihydrofuran -2 (3H)-acetic acid esters, thymidine and triethylamine mass ratio is 1:1:2.
9. Zidovudine -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that step
Suddenly the detailed process of (10) are as follows: solvent tetrahydro furan is added in 3- deoxidation -3- azido -5-O- methyl ether base thymidine
In muttering, lithium bromide is added, in room temperature reaction, TLC monitoring raw material fully reacting is added by solvents tetrahydrofurane is evaporated off
Acetone heats complete molten rear cooling crystallization, then dries after obtained solid is filtered and obtain Zidovudine, wherein 3- deoxidation -3- nitrine
The mass ratio of base -5-O- methyl ether base thymidine and lithium bromide is 2:1.
10. Zidovudine -1,2 according to claim 1, the synthetic method of 3- triazole compound, it is characterised in that
The detailed process of step (11) are as follows: by Zidovudine and N, N- dipropargyl aniline is added in solvent tertiary butanol, adds chlorine
Change it is cuprous, in room temperature reaction, after TLC monitors raw material fully reacting, by washing, extraction, again through column chromatography chromatogram point after concentration
Target product Zidovudine -1,2 is obtained from purification, 3- triazole compound, wherein Zidovudine, N, N- dipropargyl aniline
Mass ratio with stannous chloride is 4:1.5:0.5.
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