CN107245072A - A kind of preparation method of the triazole compound of Tarceva 1,2,3 - Google Patents
A kind of preparation method of the triazole compound of Tarceva 1,2,3 Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of the triazole compound of Tarceva 1,2,3, belong to the synthesis technical field with anti-tumor activity medicine.Technical scheme main points are：A kind of preparation method of the triazole compound of Tarceva 1,2,3, specific synthetic route is：
Description
Technical field
The invention belongs to the synthesis technical field with anti-tumor activity medicine, and in particular to a kind of Tarceva -1,2,
The preparation method of 3- triazole compounds.
Background technology
EGF-R ELISA (epidermal growth factor receptor, EGFR) is proto-oncogene HER-
1 expression product, is the more LCK transmembrane receptor of a class research, in many tumours, EGFR can be different
Often activation.It can be bred after binding of receptor and ligand by acting on cellular signal transduction, cell, apoptosis regulation and blood vessel are given birth to
Into and to tumour generation and propagation work.Therefore, EGFR signaling transduction network is occupied in the formation and development of tumour
Consequence, by the studies have shown that EGFR since cloning first has been to treat one of tumour to have very much from EGFR gene before 30 years
The target molecule of prospect.Tarceva (Erlotinib) is more representational medicine in targeting EGFR, for non-small cell lung
The existing more clear and definite curative effect such as cancer, head and neck cancer and colorectal cancer.Tarceva can be suppressed by occupying ATP binding cavities
EGFR receptor auto-phosphorylations, so as to block downstream signal transduction process.Tarceva is analyzed to send out with EGFR albumin crystals structure
Existing, the quinazoline ring of Tarceva occupies EGFR albumen hydrophobic pockets, this cavity by Leu694, Val702, Val718,
The amino acid residues such as Ala719 and Leu820 are constituted.Two N atoms on Tarceva quinazoline ring can be formed hydrogen bond with
Acceptor amino acid residue Met769 and Thr766 interact.Therefore, it is presumed that, by increasing N atoms in compound molecule
Number, preferably can be combined with EGFR acceptor amino acid residues, so improve inhibitory activity.
Triazole is as the important nitrogen-containing heterocycle compound of a class, with the potentiality as new type antineoplastic medicine, into
The focus and emphasis researched and developed for pharmaceutical chemistry.Such as, triazole compound can be as arimedex, by suppressing
Activity of aromatizing enzyme, prevents male sex hormone in human female from being converted into female hormone, so as to reduce serum estrogen level, reaches treatment
The purpose of menopausal women breast cancer disease.In order to obtain the efficient EGFR inhibitor of new class, the present invention is according to Tarceva point
Contain end-group alkyne in son, can be reacted by click makes it obtain strategic point with the azide compounds reaction with different substituents
Replace Buddhist nun's -1,2,3- triazole compounds in Lip river.
The content of the invention
Present invention solves the technical problem that it is simple and convenience operation with antitumor work to there is provided a kind of synthesis technique
The preparation method of the Tarceva -1,2,3- triazole compounds of property.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, a kind of Tarceva -1,2,3- triazoles
The preparation method of compound, it is characterised in that concretely comprise the following steps：
(1) in acetic anhydride solvent, 3,4- 3,5-dimethoxybenzoic alcohols are obtained under nitric acid effect in room temperature through nitration reaction
2- nitro -4,5- 3,5-dimethoxybenzoic alcohols；
(2) 2- nitros -4,5- 3,5-dimethoxybenzoic alcohol is used as catalysis in solvent benzol using cupric sulfate pentahydrate and potassium hydroxide
Agent, 2- nitro -4,5- dimethoxybenzoic acids are obtained through potassium permanganate oxidation；
(3) in methanol solvate, 2- nitros -4,5- dimethoxybenzoic acid is under hydrazine hydrate and Raney's nickel effect through nitro
It is reduced to amino and obtains 2- amino -4,5- dimethoxybenzoic acids；
(4) 2- amino -4,5- dimethoxybenzoic acids are obtained with formamide under the effect of catalyst ammonium formate through ring-closure reaction
To 6,7- dimethoxyquinazoline -4- ketone；
(5) 6,7- dimethoxyquinazolines -4- ketone obtains the chloro- 6,7- dimethoxys quinoline azoles of 4- under thionyl chloride effect
Quinoline；
(6) the chloro- 6,7- dimethoxyquinazolines of 4- are substituted reaction with m-aminophenyl ethyl ketone and obtain 4- aminoacetophenone -6,
7- dimethoxyquinazolines；
(7) 4- aminoacetophenones -6,7- dimethoxyquinazoline is sloughed in tetrahydrofuran solvent under lithium bromide effect
Methyl obtains 4- aminoacetophenone -6,7- dihydroxy base quinazolines；
(8) 4- aminoacetophenones -6,7- dihydroxy quinazoline and 2- methoxy ethyls bromine and azide compounds, in alkalescence
Occur substitution reaction under catalyst action simultaneously and click reactions obtain target product Tarceva -1,2,3- triazoles
Compound, wherein base catalyst are potassium carbonate, DBU, triethylamine or diethylamine.
Further preferably, the azide compounds described in step (8) are phenylazide, to methyl azide benzene, a nitroazide
Benzene, adjacent chlorine phenylazide or adjacent hydroxyl phenylazide.
Further preferably, the detailed process of step (1) is：3,4- 3,5-dimethoxybenzoic alcohols are added to solvent acetic acid acid anhydride
In, 0 DEG C of dropwise addition nitric acid is cooled to, stirring reaction liquid is warming up to room temperature, acetic anhydride is removed under reduced pressure after reaction completely after dripping,
The pH for adding saturated sodium carbonate solution regulation reaction solution is neutrality, with dichloromethane extractive reaction liquid, is evaporated off obtaining after solvent
2- nitro -4,5- 3,5-dimethoxybenzoic alcohols.
Further preferably, the detailed process of step (2) is：2- nitro -4,5- 3,5-dimethoxybenzoic alcohols are added to solvent
In benzene, potassium permanganate, cupric sulfate pentahydrate and potassium hydroxide are added, back flow reaction is heated to, after TLC monitoring raw material reactions completely
Reaction solution is poured into frozen water, the pH that reaction solution is adjusted with glacial acetic acid is 9, with chloroform extractive reaction liquid, is evaporated off obtaining after solvent
2- nitro -4,5- dimethoxybenzoic acids, wherein 2- nitros -4,5- 3,5-dimethoxybenzoic alcohol, potassium permanganate, cupric sulfate pentahydrate with
The mass ratio of potassium hydroxide is 20:15:1.5:5.
Further preferably, the detailed process of step (3) is：2- nitro -4,5- dimethoxybenzoic acids are added to solvent
In methanol, hydrazine hydrate and Raney's nickel are added, nitrogen protection reaction system is warming up to 50 DEG C of reactions, and TLC monitoring raw materials have reacted
Entirely, filtering reacting liquid, is evaporated off solvent methanol and obtains 2- amino -4,5- dimethoxybenzoic acids, wherein 2- nitros -4,5- dimethoxy
The mass ratio of yl benzoic acid, hydrazine hydrate and Raney's nickel is 16:105:0.4.
Further preferably, the detailed process of step (4) is：2- amino -4,5- dimethoxybenzoic acids and formamide are added
Enter the in the mixed solvent to ethanol and benzene, add catalyst ammonium formate, back flow reaction, TLC prisons are heated under nitrogen protection
Control raw material reaction complete, be evaporated off after solvent, wash, extraction is evaporated off solvent and obtains 6,7-dimethoxyquinazolin-4(3H)-one, wherein
The volume ratio of the in the mixed solvent ethanol and benzene of ethanol and benzene is 1:3.
Further preferably, the detailed process of step (5) is：6,7- dimethoxyquinazoline -4- ketone is added to protochloride
In sulfone, nitrogen protection reaction system is heated to back flow reaction, thionyl chloride, which is evaporated off, after reaction completely obtains chloro- 6, the 7- diformazans of 4-
Epoxide quinazoline.
Further preferably, the detailed process of step (6) is：By the chloro- 6,7- dimethoxyquinazolines of 4- and m-aminophenyl second
Ketone is added in solvent acetone, adds potassium carbonate, is heated to back flow reaction, and TLC monitoring raw material reactions are complete, and solvent third is evaporated off
Washed after ketone, extraction is evaporated off obtaining 4- aminoacetophenone -6,7- dimethoxyquinazolines after organic phase, chloro- 6, the 7- bis- of wherein 4-
The mass ratio of methoxyquinazoline hydrochloride, m-aminophenyl and potassium carbonate is 22:12:30.
Further preferably, the detailed process of step (7) is：By 4- aminoacetophenone -6,7- dimethoxyquinazolines and bromine
Change lithium to be added in solvents tetrahydrofurane, react at room temperature, TLC monitoring raw material reactions are complete, are evaporated off after solvent adding third
Ketone, is cooled to 0 DEG C, stirring separates out solid, and 4- aminoacetophenone -6,7- dihydroxy quinazolines are obtained after the drying of suction filtration solid, its
The mass ratio of middle 4- aminoacetophenones -6,7- dimethoxyquinazolines and lithium bromide is 3:1.
Further preferably, the detailed process of step (8) is：By 4- aminoacetophenone -6,7- dihydroxy bases quinazoline, 2- first
Epoxide bromic ether and phenylazide are added in acetone, add base catalyst, are heated to back flow reaction, and TLC monitoring raw materials are anti-
After answering completely, solvent acetone is evaporated off, the pH for adding water and adjusting reaction solution with watery hydrochloric acid is neutral, then uses dichloromethane extractive reaction
Liquid, is concentrated to give crude product, then obtains pure target compound Lip river in distress through column chromatography chromatogram separating-purifying and replace after organic phase washing
Buddhist nun -1,2, it is 3- triazole compounds, wherein 4- aminoacetophenones -6,7- dihydroxy base quinazoline, 2- methoxy ethyls bromine, folded
The mass ratio of nitrogen compound and base catalyst is 7:10:5:20.
The synthetic route of Tarceva -1,2,3- triazole compounds of the present invention is：
The present invention contain end-group alkyne according in Tarceva molecule, by click reaction make its with different substituents
Azidomethyl phenyl nitrogen compound reaction obtain Tarceva -1,2,3- triazole compounds, by making the N atoms in its molecule
Quantity is doubled, and has carried out antitumor activity test to it, it is found that such compound has to hepatoma Hep G 2 cells preferable
Inhibitory activity.
Embodiment
The above to the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
In many mouthfuls of bottle of 500mL, 3,4- 3,5-dimethoxybenzoic alcohols 16.8g (0.1mol) is added, acetic anhydride 150g is added,
It is cooled to 0 DEG C or so and nitric acid 6g is slowly added dropwise, be slowly stirred reaction solution, is warming up to depressurize after room temperature, reaction 6h after dripping and steams
Except acetic anhydride, distilled water 300mL is added, then saturated sodium carbonate solution is slowly added dropwise, the pH of regulation reaction solution is neutrality, with two
Chloromethanes 200mL extractive reactions liquid three times, merges organic phase, is evaporated off obtaining 2- nitro -4,5- 3,5-dimethoxybenzoic alcohols after solvent
20g。
Embodiment 2
In reaction bulbs of the 500mL with agitator, by 2- nitro -4,5- 3,5-dimethoxybenzoic alcohol 20g (0.093mol)
It is added in benzene 150mL, adds potassium permanganate 15g, after stirring, adds cupric sulfate pentahydrate 1.5g and potassium hydroxide
5g, is heated to after back flow reaction, reaction 10h, and TLC monitoring raw material reactions are complete, and reaction solution is poured into frozen water 500mL, stirred
After 1h, the pH for adjusting reaction solution with glacial acetic acid is 9, with chloroform 200mL extractive reactions liquid three times, merges organic phase, solvent is evaporated off
After obtain 2- nitro -4,5- dimethoxybenzoic acids 13g.
Embodiment 3
In reaction bulbs of the 500mL with agitator, 2- nitro -4,5- dimethoxybenzoic acids 16g is added to solvent
In methanol 150mL, hydrazine hydrate 105g and Raney's nickel 0.4g are added, nitrogen protection reaction system is warming up to 50 DEG C of reactions, reacted
After 5h, TLC monitoring raw material reactions are complete, and filtering reacting liquid is evaporated off solvent methanol and obtains 2- amino -4,5- dimethoxybenzoic acids
11g。
Embodiment 4
In reaction bulbs of the 500mL with agitator, by 2- amino -4,5- dimethoxybenzoic acid 20g and formamide 9g
Be added in the mixed solvent 200mL of ethanol and benzene (volume ratio of ethanol and benzene be 1:3) ammonium formate 10g, is added, in nitrogen
Under protection, it is heated to after back flow reaction, reaction 10h, TLC monitoring raw material reactions are complete, are evaporated off after solvent, add saturated aqueous common salt
150mL, then with chloroform 100mL extractive reactions liquid 3 times, merge organic phase, solvent is evaporated off and obtains 6,7- dimethoxyquinazolines -4-
Ketone 17g.
Embodiment 5
In 250mL there-necked flasks, 6,7-dimethoxyquinazolin-4(3H)-one 20g is added, thionyl chloride 100mL, nitrogen is added
Gas shielded reaction system, is heated to after back flow reaction, reaction 3h, thionyl chloride is evaporated off and obtains chloro- 6, the 7- dimethoxys quinoline azoles of 4-
Quinoline 13g.
Embodiment 6
Acetone 200mL is added in reaction bulb, chloro- 6, the 7- dimethoxyquinazolines 22g of 4- and m-aminophenyl is added
12g, adds potassium carbonate 30g after stirring, be heated to back flow reaction, and TLC monitoring raw material reactions are complete, and solvent acetone is evaporated off
Water 100mL is added afterwards, then is extracted twice with ethyl acetate 200mL, is merged organic phase, is evaporated off obtaining 4- aminobenzene second after organic phase
Ketone -6,7- dimethoxyquinazolines 20g.
Embodiment 7
Tetrahydrofuran 200mL is added in reaction bulb, 4- aminoacetophenone -6,7- dimethoxyquinazolines 30g is added
With lithium bromide 10g, 6h is reacted at room temperature, and TLC monitoring raw material reactions are complete, are evaporated off adding acetone 70mL, temperature after solvent
0 DEG C is down to, is slowly stirred, gradually has solid precipitation, 4- aminoacetophenone -6,7- dihydroxy base quinolines is obtained after the drying of suction filtration solid
Oxazoline 26g.
Embodiment 8
In reaction bulbs of the 250mL with agitator, by 4- aminoacetophenone -6,7- dihydroxy base quinazoline 7g, 2- first
Epoxide bromic ether 10g and phenylazide 5g are added in acetone 100mL, add potassium carbonate 20g, are heated to back flow reaction, TLC prisons
Control after raw material reaction completely, solvent acetone is evaporated off, the pH for adding water 100mL and adjusting reaction solution with watery hydrochloric acid is neutral, then
With three merging organic phases of dichloromethane 100mL extractive reactions liquid, 4- aminobenzene second is obtained through column chromatography for separation purification after concentration
Base -1,2,3- triazoles-benzene -6,7- two (2- methoxy ethoxies) quinazoline 6.7g.
Embodiment 9
In reaction bulbs of the 250mL with agitator, by 4- aminoacetophenone -6,7- dihydroxy base quinazoline 7g, 2- first
Epoxide bromic ether 10g and phenylazide 5g are added in solvent acetone 100mL, add DBU 20g, are heated to back flow reaction, TLC
Monitor after raw material reaction completely, solvent acetone be evaporated off, the pH for adding water 100mL and adjusting reaction solution with watery hydrochloric acid is neutrality,
Again with three merging organic phases of dichloromethane 100mL extractive reactions liquid, 4- aminobenzenes are obtained through column chromatography for separation purification after concentration
Ethyl -1,2,3- triazoles-benzene -6,7- two (2- methoxy ethoxies) quinazoline 5.1g.
Embodiment 10
In reaction bulbs of the 250mL with agitator, by 4- aminoacetophenone -6,7- dihydroxy base quinazoline 7g, 2- first
Epoxide bromic ether 10g and phenylazide 5g are added in solvent acetone 100mL, are added triethylamine 20g, are heated to back flow reaction,
After TLC monitoring raw material reactions completely, solvent acetone is evaporated off, during the pH for adding water 100mL and adjusting reaction solution with watery hydrochloric acid is
Property, then with three merging organic phases of dichloromethane 100mL extractive reactions liquid, 4- amino is obtained through column chromatography for separation purification after concentration
Phenethyl -1,2,3- triazoles-benzene -6,7- two (2- methoxy ethoxies) quinazoline 5.6g.1H NMR(400MHz,DMSO-d6)
δ:9.77 (s, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 7.97-7.94 (m, 1H), 7.81 (t, J=4Hz, 2H), 7.79-
7.61(m,3H),7.48(s,1H),4.58(s,1H),4.35(s,2H),3.89(s,2H),3.80(s,2H),3.41-3.34
(m,10H),
Embodiment 11
Antitumor activity is tested
Growth period liver cancer HepG2 is collected, the active anticancer of following compound is determined with MTS methods, by cell with debita spissitudo
(every milliliter 4 × 104Individual cell) be added in 96 porocyte culture plates (calf serum of tire containing 10wt% obtain nutrient solution be made into it is single thin
Born of the same parents' suspension), cultivate after 24h, in 37 DEG C, the CO that volumetric concentration is 5%2Under the conditions of compound effects 72h with various concentrations, so
MTS (final mass concentration 2mg/mL) and DMS (final 30 μM of molar concentration) mixture are directly added into celliferous training afterwards
Support in base, continue to put incubator incubation 4h.Act on after 4h, abandoning supernatant, 150 μ L DMSO are added per hole, vibration, cell is deposited
Absorptivity of the metabolin that motility rate is acted on MTS by it under enzyme linked immunological monitor 490nm wavelength is determined.
Biological activity test shows that such compound has certain inhibitory action in liver cancer HepG2 to cancer cell.To sum up
Described, the invention provides a kind of Tarceva -1,2 with bioactivity, the synthetic method of 3- triazole compounds is first
It is secondary to be found that such compound has preferable inhibitory activity to hepatoma Hep G 2 cells, therefore with great research and development potentiality.
Embodiment above describes general principle, principal character and the advantage of the present invention, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, the original for simply illustrating the present invention described in above-described embodiment and specification
Reason, under the scope for not departing from the principle of the invention, various changes and modifications of the present invention are possible, and these changes and improvements are each fallen within
In the scope of protection of the invention.
Claims (10)
1. a kind of Tarceva -1,2, the preparation method of 3- triazole compounds, it is characterised in that concretely comprise the following steps：
（1）In acetic anhydride solvent, 3,4- 3,5-dimethoxybenzoic alcohols obtain 2- nitre in room temperature under nitric acid effect through nitration reaction
Base -4,5- 3,5-dimethoxybenzoic alcohols；
（2）2- nitro -4,5- 3,5-dimethoxybenzoic alcohols are in solvent benzol, using cupric sulfate pentahydrate and potassium hydroxide as catalyst,
2- nitro -4,5- dimethoxybenzoic acids are obtained through potassium permanganate oxidation；
（3）In methanol solvate, 2- nitros -4,5- dimethoxybenzoic acid is reduced under hydrazine hydrate and Raney's nickel effect through nitro
2- amino -4,5- dimethoxybenzoic acids are obtained for amino；
（4）2- amino -4,5- dimethoxybenzoic acids obtain 6 under the effect of catalyst ammonium formate with formamide through ring-closure reaction,
7- dimethoxyquinazoline -4- ketone；
（5）6,7- dimethoxyquinazoline -4- ketone obtains the chloro- 6,7- dimethoxyquinazolines of 4- under thionyl chloride effect；
（6）The chloro- 6,7- dimethoxyquinazolines of 4- are substituted reaction with m-aminophenyl ethyl ketone and obtain 4- aminoacetophenones -6,7- two
Methoxyquinazoline hydrochloride；
（7）4- aminoacetophenone -6,7- dimethoxyquinazolines are in tetrahydrofuran solvent, the demethylating under lithium bromide effect
Obtain 4- aminoacetophenone -6,7- dihydroxy base quinazolines；
（8）4- aminoacetophenone -6,7- dihydroxy quinazolines and 2- methoxy ethyls bromine and azide compounds, in base catalysis
The lower generation substitution reaction simultaneously of agent effect and click react and obtain target product Tarceva -1,2,3- triazole compounds,
Wherein base catalyst is potassium carbonate, DBU, triethylamine or diethylamine.
2. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（8）Described azide compounds are phenylazide, to methyl azide benzene, a nitroazide benzene, adjacent chlorine phenylazide or adjacent hydroxyl
Base phenylazide.
3. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（1）Detailed process be：3,4- 3,5-dimethoxybenzoic alcohols are added in solvent acetic acid acid anhydride, 0 DEG C of dropwise addition nitric acid is cooled to,
Stirring reaction liquid, is warming up to room temperature, acetic anhydride is removed under reduced pressure after reaction completely after dripping, add saturated sodium carbonate solution tune
It is neutrality to save the pH of reaction solution, with dichloromethane extractive reaction liquid, is evaporated off obtaining 2- nitro -4,5- dimethoxy benzene first after solvent
Alcohol.
4. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（2）Detailed process be：2- nitro -4,5- 3,5-dimethoxybenzoic alcohols are added in solvent benzol, add potassium permanganate,
Cupric sulfate pentahydrate and potassium hydroxide, are heated to back flow reaction, pour into reaction solution in frozen water after TLC monitoring raw material reactions completely,
The pH that reaction solution is adjusted with glacial acetic acid is 9, with chloroform extractive reaction liquid, is evaporated off obtaining 2- nitro -4,5- dimethoxys after solvent
Benzoic acid, the mass ratio of wherein 2- nitros -4,5- 3,5-dimethoxybenzoic alcohol, potassium permanganate, cupric sulfate pentahydrate and potassium hydroxide is
20:15:1.5:5。
5. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（3）Detailed process be：2- nitro -4,5- dimethoxybenzoic acids are added in solvent methanol, hydrazine hydrate is added
And Raney's nickel, nitrogen protection reaction system, 50 DEG C of reactions are warming up to, TLC monitoring raw material reactions are complete, and filtering reacting liquid is evaporated off
Solvent methanol obtains 2- amino -4,5- dimethoxybenzoic acids, wherein 2- nitros -4,5- dimethoxybenzoic acid, hydrazine hydrate with
The mass ratio of Raney's nickel is 16:105:0.4.
6. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（4）Detailed process be：The mixing that 2- amino -4,5- dimethoxybenzoic acids and formamide are added into ethanol and benzene is molten
In agent, catalyst ammonium formate is added, back flow reaction is heated under nitrogen protection, TLC monitoring raw material reactions are complete, are evaporated off molten
After agent, wash, the in the mixed solvent second that solvent obtains 6,7-dimethoxyquinazolin-4(3H)-one, wherein ethanol and benzene is evaporated off in extraction
The volume ratio of alcohol and benzene is 1:3.
7. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（5）Detailed process be：6,7-dimethoxyquinazolin-4(3H)-one is added in thionyl chloride, nitrogen protection reactant
System, is heated to back flow reaction, and thionyl chloride, which is evaporated off, after reaction completely obtains chloro- 6, the 7- dimethoxyquinazolines of 4-.
8. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（6）Detailed process be：Chloro- 6, the 7- dimethoxyquinazolines of 4- and m-aminophenyl ethyl ketone are added in solvent acetone,
Potassium carbonate is added, back flow reaction is heated to, TLC monitoring raw material reactions are complete, are evaporated off washing after solvent acetone, extraction is evaporated off
4- aminoacetophenone -6,7- dimethoxyquinazolines, chloro- 6, the 7- dimethoxyquinazolines of wherein 4-, an ammonia are obtained after organic phase
The mass ratio of base benzene and potassium carbonate is 22:12:30.
9. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（7）Detailed process be：4- aminoacetophenone -6,7- dimethoxyquinazolines and lithium bromide are added to solvent tetrahydrochysene furan
In muttering, react at room temperature, TLC monitoring raw material reactions are complete, are evaporated off after solvent adding acetone, are cooled to 0 DEG C, stirring is separated out
Solid, 4- aminoacetophenone -6,7- dihydroxy quinazolines, wherein 4- aminoacetophenones -6,7- bis- are obtained after the drying of suction filtration solid
The mass ratio of methoxyquinazoline hydrochloride and lithium bromide is 3:1.
10. Tarceva -1,2 according to claim 1, the preparation method of 3- triazole compounds, it is characterised in that：
Step（8）Detailed process be：By 4- aminoacetophenone -6,7- dihydroxy bases quinazoline, 2- methoxy ethyls bromine and phenylazide
It is added in acetone, adds base catalyst, is heated to back flow reaction, after TLC monitoring raw material reactions completely, solvent third is evaporated off
Ketone, the pH for adding water and adjusting reaction solution with watery hydrochloric acid is neutral, then with dichloromethane extractive reaction liquid, is concentrated after organic phase washing
Crude product is obtained, then obtains through column chromatography chromatogram separating-purifying pure target compound Tarceva -1,2,3- triazoles
Compound, wherein 4- aminoacetophenones -6,7- dihydroxy base quinazoline, 2- methoxy ethyls bromine, azide compounds and alkalescence are urged
The mass ratio of agent is 7:10:5:20.
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| CN113493443A (en) * | 2020-04-21 | 2021-10-12 | 侯延生 | Erlotinib derivative with killing performance on wild lung cancer tumor cells and preparation method thereof |
| CN113493443B (en) * | 2020-04-21 | 2023-06-27 | 侯延生 | Application of erlotinib derivative in preparation of medicines for treating esophageal cancer |
| CN114213350A (en) * | 2021-12-29 | 2022-03-22 | 江苏福瑞康泰药业有限公司 | Preparation method of statin drug intermediate |
| CN114213350B (en) * | 2021-12-29 | 2024-03-19 | 江苏福瑞康泰药业有限公司 | Preparation method of statin drug intermediate |
| CN114634487A (en) * | 2022-03-31 | 2022-06-17 | 河南湾流生物科技有限公司 | Preparation method of quinoline feed additive with function of improving immunity |
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