CN105777746A - Preparation method for 5,6,7,8- tetrahydropyrido[3,4-d] pyrimidine derivative with antifungal activity - Google Patents
Preparation method for 5,6,7,8- tetrahydropyrido[3,4-d] pyrimidine derivative with antifungal activity Download PDFInfo
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a preparation method for a 5,6,7,8- tetrahydropyrido[3,4-d] pyrimidine derivative with antifungal activity, and belongs to the technical field of organic synthesis. According to the technical scheme, the key point is that a target product 5,6,7,8- tetrahydropyrido[3,4-d] pyrimidine derivative with antifungal activity is obtained through reactions such as substitution, cyclization, reduction, esterification, hydrolysis, substitution and deprotection by taking commercialized o-nitro benzenesulfonyl chloride as a raw material. The preparation method is simple in preparation process and is easy to control, and the target product is high in yield and is good in repeatability; and prepared five 5,6,7,8- tetrahydropyrido[3,4-d] pyrimidine derivatives have relative inhibitory percentage of higher than 50% on original bacteria of the tobacco powdery mildew.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to the preparation method of a kind of 5,6,7,8-tetrahydropyridines also [3,4-d] pyrimidine derivatives with antifungal activity.
Background technology
Nitrogen-containing heterocycle compound due to have widely biological activity and extremely pay attention to, be widely used at present in medical research.Novel 5 reported herein, 6,7,8-tetrahydropyridine also [3,4-d] pyrimidine derivatives is a kind of important nitrogen heterocyclic ring, having developed many antibacterial of nitrogen heterocyclic ring class, herbicide, insecticide and medical, this compounds has become agrochemicals and the study hotspot of medicine, has broad application prospects.Such as, its derivant can have certain preventive and therapeutic effect by bacterium former to Powdery Mildew in Tobacco.
At present, existing about 5,6,7, in the synthesis report of 8-tetrahydropyridine also [3,4-d] pyrimidine compound, it is mostly with pyridone as raw material, first it is condensed in carbonyl α position with DMF-DMA, then carries out guanidine cyclization and obtain, but obtained compound is difficult to 4 introducing substituent groups.Publication No. CN
The patent of 104910158A, with benzylamine as raw material, obtains 5 through nine step reactions, and 6,7,8-tetrahydropyridines also [3,4-d] pyrimidine compound wherein uses benzyl to do protection group, and when last removing, operation is complicated and by-product proportion is higher.
Summary of the invention
Present invention solves the technical problem that there is provided that a kind of operation is simple, cheaper starting materials is easy to get, reaction efficiency is higher and reproducible has the 5 of antifungal activity; 6; 7; 8-tetrahydropyridine also [3; 4-d] preparation method of pyrimidine derivatives; the method, with the ortho-nitrophenyl sulfonic acid chloride that has been commercialized as raw material, is substituted, is cyclized, reduces, is esterified, hydrolyzes, replaces, the reaction such as deprotection obtains the target product with antifungal activity.
The present invention solves that above-mentioned technical problem adopts the following technical scheme that, have the 5 of antifungal activity, the preparation method of 6,7,8-tetrahydropyridines also [3,4-d] pyrimidine derivatives, it is characterised in that concretely comprise the following steps:
Step a, amido protecting: obtain compound 2-nitrobenzenesulfonyl glycine ethyl ester with the amino of ortho-nitrophenyl sulfonic acid chloride protection glycine ethyl ester; wherein the nitro on ortho-nitrophenyl sulfonic acid chloride produces vucubak effectl alpha effect to chlorine atom; make chlorine atom activation easily be replaced, reaction rate and conversion ratio can be improved；
Step b, nucleophilic displacement of fluorine: 4-neoprene acid ethyl ester obtains compound N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide as nucleopilic reagent and compound 2-nitrobenzenesulfonyl glycine ethyl ester generation substitution reaction; wherein chlorine atomic electronegativity is bigger; it is easy to be combined with proton; and finally making carbochain be linked on nitrogen-atoms, the by-product obtained is few；
nullStep c、Cyclization: compound N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide and sodium hydride reacting generating compound 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate in dioxane，Compound 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate is in the mixed solution of amitraz hydrochloride and dioxane，Reacting generating compound 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5 under the catalytic action of sodium,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine，The cyclisation of this two step broadly falls into radical reaction，Radical reaction is caused under organometallic catalysis，The strongest reaction rate of alkalescence is the fastest，When generating compound 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate at amitraz hydrochloride，Because six-membered ring structure is more stable，It is partial to generate hexa-atomic tetrahydro pyridine ring；
Step d, reductive halogenation react: compound 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5; 6,7,8-tetrahydropyridines also [3; 4-d] pyrimidine sequentially passes through reduction, halogenating reaction obtains compound 7-(2-nitrobenzenesulfonyl)-4-chloro-5; 6,7,8-tetrahydropyridines also [3; 4-d] pyrimidine; the reducing agent wherein selected and halogenating agent are thionyl chloride, and carbonyl reduction is first become the intermediate of ethers by thionyl chloride, slough ether group generation halogenating reaction the most again；
Step e, esterification: organic metal palladium compound PdCl2(PPh3)2It is dissociated into part and compound 7-(2-the nitrobenzenesulfonyl)-4-chloro-5 of dechlorination; 6; also [3,4-d] pyrimidine generation additive reaction of 7,8-tetrahydropyridines; carbonylation is there is the most again with CO; finally obtained compound 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5 by the nucleophilic attack generation esterification of ethanol, 6,7; 8-tetrahydropyridine also [3,4-d] pyrimidine；
Step f, hydrolysis: compound 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5,6,7; 8-tetrahydropyridine also [3; 4-d] pyrimidine microwave action generation hydrolysis under alkaline environment obtains compound 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5, and 6,7; 8-tetrahydropyridine also [3; 4-d] pyrimidine, wherein the reaction of this step employs microwave technology, by heat effect and non-thermal effect; reaction only needs 10min, greatly reduces the response time；
Step g, substitution reaction: compound 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5; 6; 7; 8-tetrahydropyridine also [3,4-d] pyrimidine first reacts with ClOCCOCl and generates chloride compounds, and chloride compounds reacts with Pentamethylene., pyrroles, hexamethylene, cyclopropane or cyclopropylamine and obtains 7-(2-nitrobenzenesulfonyl)-4-and replace formoxyl-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidines；
Step h, deprotection: under weakly alkaline environment; formoxyl-5 is replaced with sulfydryl benzene removing 7-(2-nitrobenzenesulfonyl)-4-; 6; the blocking group of 7,8-tetrahydropyridines also [3,4-d] pyrimidines obtains target product 4-and replaces formoxyl-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidines.
Further preferably; the detailed process of step a is: join in dichloromethane by ortho-nitrophenyl sulfonic acid chloride in reaction vessel; drip the mixed solution of glycine ethyl ester and triethylamine again; drip complete post-heating back flow reaction; after TLC monitoring raw material reaction is complete; it is cooled to room temperature, post-treated obtains 2-nitrobenzenesulfonyl glycine ethyl ester.
Further preferably; the detailed process of step b is: added by 2-nitrobenzenesulfonyl glycine ethyl ester in oxolane; add 4-neoprene acid ethyl ester and Anhydrous potassium carbonate; room temperature reaction; TLC monitoring raw material reaction is complete, post-treated obtains N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide.
Further preferably; the detailed process of step c is: join in dioxane by N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide and sodium hydride in reaction vessel; room temperature reaction; TLC monitoring raw material reaction is complete, post-treated obtains 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate；Then in reaction vessel; nitrogen is protected and under the conditions of 0 DEG C; sodium is dividedly in some parts in dioxane; drip the mixed solution of amitraz hydrochloride and dioxane again; it is warmed to room temperature after dripping; 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate is added after being uniformly mixed; react complete to TLC monitoring raw material reaction; adding acetic acid in reactant liquor, then decompression steams solvent, post-treated obtains 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidine.
Further preferably, the detailed process of step d is: by compound 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5,6; 7,8-tetrahydropyridines also [3,4-d] pyrimidine and thionyl chloride add N; in dinethylformamide, it is warming up to 85 DEG C of reactions, after TLC monitoring raw material reaction is complete; decompression steams thionyl chloride; post-treated obtain 7-(2-nitrobenzenesulfonyl)-4-chloro-5,6,7; 8-tetrahydropyridine also [3,4-d] pyrimidine.
Further preferably, the detailed process of step e is: by chloro-for 7-(2-nitrobenzenesulfonyl)-4-5,6,7,8-tetrahydropyridines also [3,4-d] pyrimidine, PdCl in autoclave2(PPh3) and N-Methyl pyrrolidone add in ethanol; it is passed through pressure in CO makes autoclave and reaches 0.3MPa; it is heated to 60 DEG C of reactions; TLC monitoring raw material reaction is complete, is cooled to room temperature, post-treated obtains 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidine.
Further preferably, the detailed process of step f is: addition 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5 in reaction vessel, 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidine, sodium hydroxide and methanol; put in microwave reactor; arranging power is 560W, is cooled to room temperature after reaction 10min, post-treated obtains 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidine.
Further preferably; the detailed process of step g is: add 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5 in reaction vessel; 6; 7; 8-tetrahydropyridine also [3; 4-d] pyrimidine, ClOCCOCl, alkane or amine substance and N; dinethylformamide, is stirred at room temperature reaction, and TLC monitoring raw material reaction is complete; post-treated 7-(2-the nitrobenzenesulfonyl)-4-that obtains replaces formoxyl-5; 6,7,8-tetrahydropyridines also [3; 4-d] pyrimidines, described alkane or amine substance are Pentamethylene., pyrroles, hexamethylene, cyclopropane or cyclopropylamine.
Further preferably, the detailed process of step h is: adds 7-(2-nitrobenzenesulfonyl)-4-in reaction vessel and replaces formoxyl-5,6; 7,8-tetrahydropyridines also [3,4-d] pyrimidines, sulfydryl benzene, potassium carbonate and N; dinethylformamide; at room temperature reacting, TLC monitoring raw material reaction is complete, and the post-treated 4-that obtains replaces formoxyl-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidines.
Preparation technology of the present invention is simple, it is easy to controlling, target product yield is high and reproducible, and five kinds of novel 5,6,7,8-tetrahydropyridines all former to the Powdery Mildew in Tobacco bacterium of also [3,4-d] pyrimidine derivatives prepared all reaches more than 50% relative to inhibition percentage.
Detailed description of the invention
Being described in further details the foregoing of the present invention by the following examples, but this should not being interpreted as, the scope of the above-mentioned theme of the present invention is only limitted to below example, all technology realized based on foregoing of the present invention belong to the scope of the present invention.
Embodiment 1
2-nitrobenzenesulfonyl glycine ethyl ester2Synthesis
By ortho-nitrophenyl sulfonic acid chloride 46.0g(0.20mol in reaction bulb) join in dichloromethane 200mL, it is slowly added dropwise glycine ethyl ester 20.6g(0.20mol again) and the mixed solution of triethylamine 40g, drip and be heated to reflux complete follow-up continuing, after TLC monitoring raw material reaction is complete, it is cooled to room temperature, dichloromethane 500mL extractive reaction liquid is used after adding a certain amount of water, merge organic facies, with saturated sodium bicarbonate solution washing reaction liquid, separate organic facies, after solvent is evaporated off, through silica gel column chromatography separating-purifying (eluant: PE:EA=20:1), obtain 2-nitrobenzenesulfonyl glycine ethyl ester 51.8g, yield 90%.
Embodiment 2
N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide3Synthesis
By 2-nitrobenzenesulfonyl glycine ethyl ester 57.1g(0.20mol) add in oxolane 300mL; add 4-neoprene acid ethyl ester 30.2g(0.20mol) and Anhydrous potassium carbonate 55.0g(0.40mol); room temperature reaction is overnight; TLC monitoring raw material reaction is complete; filtering reacting liquid; through silica gel column chromatography separating-purifying (eluant: PE:EA=10:1) after filtrate concentration, obtain product N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide 68.2g, yield 85%.
Embodiment 3
1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate4Synthesis
In reaction bulb; N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide 80.4g(0.20mol) and sodium hydride 4.8g(0.20mol) join in dioxane 500mL; room temperature reaction 5h; TLC monitoring raw material reaction is complete; decompression is cooled to room temperature after steaming dioxane; add water 500mL; with ethyl acetate 100mL extractive reaction liquid 2 times; merge organic facies; organic facies is washed again with a certain amount of saturated nacl aqueous solution; steam organic phase solvent and obtain 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate 56.9g, yield 80%.
Embodiment 4
7-(2-nitrobenzenesulfonyl)-4-carbonyl-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine5Synthesis
nullIn reaction bulb，Nitrogen is protected，Under the conditions of 0 DEG C，Sodium 2.5g(0.11mol) it is slowly added to dioxane 200mL in batches，It is slowly added dropwise amitraz hydrochloride 4.0g(0.05mol again) and the mixed solution of dioxane 300mL，It is warmed to room temperature after dripping，1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate 14.2g(0.04mol is added) after stirring 30min，Reaction is overnight，TLC monitoring raw material reaction is complete，Acetic acid 2.4g is added in reactant liquor，Then decompression steams solvent，Add water 500mL，With dichloromethane 200mL extractive reaction liquid 2 times，Merge organic facies，Organic facies is washed with a certain amount of saturated nacl aqueous solution，Solvent is evaporated off and obtains 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine 12.7g，Yield 95%.
Embodiment 5
7-(2-nitrobenzenesulfonyl)-4-chloro-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine6Synthesis
In reaction bulb, 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine 16.8g(0.05mol) and thionyl chloride 23.8g(0.20mol) add 200mL N, in dinethylformamide, it is warming up to 85 DEG C, reaction 5h, TLC monitoring raw material reaction is complete, decompression steams thionyl chloride, add a certain amount of saturated sodium bicarbonate solution, with dichloromethane extractive reaction liquid, merge organic facies, after solvent is evaporated off, thick product is through silica gel column chromatography separating-purifying (eluant: PE:EA=10:1), obtain 7-(2-nitrobenzenesulfonyl)-4-chloro-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine 12.0g, yield 85%.
Embodiment 6
7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine7Synthesis
By 7-(2-nitrobenzenesulfonyl)-4-chloro-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine 24.8g(0.07mol in autoclave), PdCl2(PPh3) 56.0g(0.08mol) and N-Methyl pyrrolidone 0.99g(0.01mol) add in ethanol 100mL; it is passed through pressure in CO makes still and reaches 0.3MPa; it is heated to 60 DEG C; reaction is overnight; TLC monitoring raw material reaction is complete; it is cooled to room temperature; filtering reacting liquid, filtrate decompression is evaporated off solvent, and crude product is through silica gel column chromatography separating-purifying (eluant: PE:EA=10:1); obtain 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5; 6,7,8-tetrahydropyridines also [3; 4-d] pyrimidine 21.9g, yield 80%.
Embodiment 7
7-(2-nitrobenzenesulfonyl)-4-carboxyl-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine8Synthesis
7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5 is added in reaction bulb, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine 7.84g(0.02mol), sodium hydroxide 0.4g(0.01mol) and methanol 80mL, put in microwave reactor, arranging power is 560W, it is cooled to room temperature after reaction 10min, add a certain amount of water, regulating reactant liquor pH with hydrochloric acid solution again is 3-4, dichloromethane extractive reaction liquid is used after steaming methanol, merge organic facies, 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5 is obtained after solvent is evaporated off, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine 6.5g, yield 90%.
Embodiment 8
7-(2-nitrobenzenesulfonyl)-4-cyclopenta formoxyl-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine9aSynthesis
null7-(2-nitrobenzenesulfonyl)-4-carboxyl-5 is added in reaction bulb,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine 25.4g(0.07mol)、ClOCCOCl 17.5g(0.14mol) and N,Dinethylformamide 200mL，At room temperature add Pentamethylene. 5.4g(0.08mol after reaction 5h) continue reaction to be stirred at room temperature overnight，TLC monitoring raw material reaction is complete，Add water 100mL，Separate organic facies，Aqueous phase dichloromethane 100mL*3 extracts，Merge organic facies，The thick product obtained after solvent is evaporated off (eluant: PE:EA=10:1) after silica gel column chromatography separating-purifying obtains brown solid 7-(2-nitrobenzenesulfonyl)-4-cyclopenta formoxyl-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine 20.4g，Yield 70%.
Embodiment 9
4-cyclopenta formoxyl-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine10aSynthesis
7-[(2-nitrobenzophenone) sulfonyl]-4-cyclopenta formoxyl-5 is added in reaction bulb, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine 4.3g(0.01mol), sulfydryl benzene 1.2g(0.011mol), potassium carbonate 1.5g(0.011mol) and N, dinethylformamide 100mL, at room temperature react overnight, the completely rear sucking filtration of TLC monitoring raw material reaction, water 50mL is added in filtrate, reactant liquor chloroform 50mL extracts 3 times, merge organic facies, organic facies obtains yellow oily liquid 4-cyclopenta formoxyl-5 through silica gel column chromatography separating-purifying after steaming, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine10a1.9g (yield 85%),1H NMR (400 MHz, DMSO-d 6 ) δ: 9.18 (s, 1H), 4.24 (s, 2H), 3.36
(t, 2H), 2.97 (dd, 2H), 2.83 – 2.63 (m, 1H), 2.01 – 1.48 (m, 8H), 1.35 (s, 1H)。
Embodiment 10
7-(2-nitrobenzenesulfonyl)-4-pyrroyl group-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine9bSynthesis
null7-(2-nitrobenzenesulfonyl)-4-carboxyl-5 is added in reaction bulb,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine 25.4g(0.07mol)、ClOCCOCl 17.5g(0.14mol)、Pyrroles 5.3g(0.08mol) and N,Dinethylformamide 200mL，Reaction is stirred at room temperature overnight，TLC monitoring raw material reaction is complete，Add water 100mL，Separate organic facies，Aqueous phase dichloromethane 100mL*3 extracts，Merge organic facies，The thick product obtained after solvent is evaporated off (eluant: PE:EA=10:1) after silica gel column chromatography separating-purifying obtains brown solid 7-(2-nitrobenzenesulfonyl)-4-pyrroyl group-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine 23.0g，Yield 80%.
Embodiment 11
4-pyrroyl group-5,6,7,8-tetrahydropyridine also [3,4-d] pyrimidine10bSynthesis
7-[(2-nitrobenzophenone) sulfonyl]-4-pyrroyl group-5 is added in reaction bulb, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine 4.1g(0.01mol), sulfydryl benzene 1.2g(0.011mol), potassium carbonate 1.5g(0.011mol) and N, dinethylformamide 100mL, at room temperature react overnight, the completely rear sucking filtration of TLC monitoring raw material reaction, water 50mL is added in filtrate, reactant liquor chloroform 50mL extracts 3 times, merge organic facies, organic facies obtains yellow oily liquid 4-pyrroyl group-5 through silica gel column chromatography separating-purifying after steaming, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine10b1.8g (yield 83%),1H NMR (400 MHz, DMSO-d 6 ) δ: 9.34 (s, 1H), 7.56 (dt, 2H), 6.40 – 6.08 (m, 2H),
4.24 (s, 2H), 3.37 (dd, 2H), 2.98 (t, 2H), 1.42 (s, 1H)。
Embodiment 12
Antifungal activity is tested
Use colony growth diameter method, testing compound is dissolved in dimethyl sulfoxide and is configured to certain density mother solution, and mother solution is added in 50 DEG C of PDA culture medium and is allowed to dispersed, be prepared as the pastille culture medium that concentration is 10mg/L.Cooling is followed by the white lead pathogen that grows tobacco, and then cultivates in 25 DEG C of calorstats, measures the colony diameter cultivating 24h, 48h respectively, in triplicate, takes its meansigma methods.Length according to bacterium colony extension diameter compares with matched group, obtains relative inhibition percentage.Result shows that the relative inhibition percentage of five kinds of oxazole compounds bacterium former to Powdery Mildew in Tobacco all reaches more than 50%.
Embodiment above describes the ultimate principle of the present invention, principal character and advantage; skilled person will appreciate that of the industry; the present invention is not restricted to the described embodiments; the principle that the present invention is simply described described in above-described embodiment and description; 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 the scope of protection of the invention.
Claims (9)
1. have the 5 of antifungal activity, the preparation method of 6,7,8-tetrahydropyridines also [3,4-d] pyrimidine derivatives, it is characterised in that concretely comprise the following steps:
Step a, amido protecting: obtain compound 2-nitrobenzenesulfonyl glycine ethyl ester with the amino of ortho-nitrophenyl sulfonic acid chloride protection glycine ethyl ester；
Step b, nucleophilic displacement of fluorine: 4-neoprene acid ethyl ester obtains compound N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide as nucleopilic reagent and compound 2-nitrobenzenesulfonyl glycine ethyl ester generation substitution reaction；
Step c, cyclization: compound N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide and sodium hydride reacting generating compound 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate in dioxane; compound 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate is in the mixed solution of amitraz hydrochloride and dioxane; reacting generating compound 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5 under the catalytic action of sodium; 6; 7; 8-tetrahydropyridine also [3,4-d] pyrimidine；
Step d, reductive halogenation react: compound 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5; 6; 7; 8-tetrahydropyridine also [3,4-d] pyrimidine sequentially passes through reduction, halogenating reaction obtains compound 7-(2-nitrobenzenesulfonyl)-4-chloro-5,6; 7; 8-tetrahydropyridine also [3,4-d] pyrimidine, reducing agent and the halogenating agent wherein selected are thionyl chloride；
Step e, esterification: organic metal palladium compound PdCl2(PPh3)2It is dissociated into part and compound 7-(2-the nitrobenzenesulfonyl)-4-chloro-5 of dechlorination; 6; also [3,4-d] pyrimidine generation additive reaction of 7,8-tetrahydropyridines; carbonylation is there is the most again with CO; finally obtained compound 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5 by the nucleophilic attack generation esterification of ethanol, 6,7; 8-tetrahydropyridine also [3,4-d] pyrimidine；
Step f, hydrolysis: compound 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5; 6; 7; 8-tetrahydropyridine also [3; 4-d] pyrimidine microwave action generation hydrolysis under alkaline environment obtains compound 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5,6,7; 8-tetrahydropyridine also [3,4-d] pyrimidine；
Step g, substitution reaction: compound 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5; 6; 7; 8-tetrahydropyridine also [3,4-d] pyrimidine first reacts with ClOCCOCl and generates chloride compounds, and chloride compounds reacts with Pentamethylene., pyrroles, hexamethylene, cyclopropane or cyclopropylamine and obtains 7-(2-nitrobenzenesulfonyl)-4-and replace formoxyl-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidines；
Step h, deprotection: under weakly alkaline environment; formoxyl-5 is replaced with sulfydryl benzene removing 7-(2-nitrobenzenesulfonyl)-4-; 6; the blocking group of 7,8-tetrahydropyridines also [3,4-d] pyrimidines obtains target product 4-and replaces formoxyl-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidines.
The most according to claim 1 have the 5 of antifungal activity; 6; the preparation method of 7,8-tetrahydropyridines also [3,4-d] pyrimidine derivatives; it is characterized in that: the detailed process of step a is: join in dichloromethane by ortho-nitrophenyl sulfonic acid chloride in reaction vessel; drip the mixed solution of glycine ethyl ester and triethylamine again, drip complete post-heating back flow reaction, after TLC monitoring raw material reaction is complete; it is cooled to room temperature, post-treated obtains 2-nitrobenzenesulfonyl glycine ethyl ester.
The most according to claim 1 have the 5 of antifungal activity; 6; 7; the preparation method of 8-tetrahydropyridine also [3,4-d] pyrimidine derivatives, it is characterised in that: the detailed process of step b is: added by 2-nitrobenzenesulfonyl glycine ethyl ester in oxolane; add 4-neoprene acid ethyl ester and Anhydrous potassium carbonate; room temperature reaction, TLC monitoring raw material reaction is complete, post-treated obtains N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide.
The most according to claim 1 have the 5 of antifungal activity; 6; 7; 8-tetrahydropyridine also [3; 4-d] preparation method of pyrimidine derivatives, it is characterised in that: the detailed process of step c is: join in dioxane by N-ethyl n-butyrate. base-N-ethyl acetate base-2-nitrobenzene sulfonamide and sodium hydride in reaction vessel, room temperature reaction; TLC monitoring raw material reaction is complete, post-treated obtains 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate；Then in reaction vessel; nitrogen is protected and under the conditions of 0 DEG C; sodium is dividedly in some parts in dioxane; drip the mixed solution of amitraz hydrochloride and dioxane again; it is warmed to room temperature after dripping; 1-(2-nitrobenzenesulfonyl)-3-carbonyl-4-piperidine ethyl formate is added after being uniformly mixed; react complete to TLC monitoring raw material reaction; adding acetic acid in reactant liquor, then decompression steams solvent, post-treated obtains 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidine.
The most according to claim 1 have the 5 of antifungal activity, 6, 7, 8-tetrahydropyridine also [3, 4-d] preparation method of pyrimidine derivatives, it is characterized in that: the detailed process of step d is: by compound 7-(2-nitrobenzenesulfonyl)-4-carbonyl-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine and thionyl chloride add N, in dinethylformamide, it is warming up to 85 DEG C of reactions, after TLC monitoring raw material reaction is complete, decompression steams thionyl chloride, post-treated obtain 7-(2-nitrobenzenesulfonyl)-4-chloro-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine.
The most according to claim 1 have the 5 of antifungal activity; 6; 7; the preparation method of 8-tetrahydropyridine also [3,4-d] pyrimidine derivatives, it is characterised in that: the detailed process of step e is: by 7-(2-nitrobenzenesulfonyl)-4-chloro-5 in autoclave; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidine, PdCl2(PPh3) and N-Methyl pyrrolidone add in ethanol; it is passed through pressure in CO makes autoclave and reaches 0.3MPa; it is heated to 60 DEG C of reactions; TLC monitoring raw material reaction is complete, is cooled to room temperature, post-treated obtains 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5; 6; 7,8-tetrahydropyridines also [3,4-d] pyrimidine.
The most according to claim 1 have the 5 of antifungal activity, 6, 7, 8-tetrahydropyridine also [3, 4-d] preparation method of pyrimidine derivatives, it is characterized in that: the detailed process of step f is: in reaction vessel, add 7-(2-nitrobenzenesulfonyl)-4-group-4 ethyl formate-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine, sodium hydroxide and methanol, put in microwave reactor, arranging power is 560W, it is cooled to room temperature after reaction 10min, post-treated obtain 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine.
The most according to claim 1 have the 5 of antifungal activity, 6, 7, 8-tetrahydropyridine also [3, 4-d] preparation method of pyrimidine derivatives, it is characterized in that: the detailed process of step g is: in reaction vessel, add 7-(2-nitrobenzenesulfonyl)-4-carboxyl-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidine, ClOCCOCl, alkane or amine substance and N, dinethylformamide, reaction is stirred at room temperature, TLC monitoring raw material reaction is complete, post-treated 7-(2-the nitrobenzenesulfonyl)-4-that obtains replaces formoxyl-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidines, described alkane or amine substance are Pentamethylene., pyrroles, hexamethylene, cyclopropane or cyclopropylamine.
The most according to claim 1 have the 5 of antifungal activity, 6, 7, 8-tetrahydropyridine also [3, 4-d] preparation method of pyrimidine derivatives, it is characterized in that: the detailed process of step h is: in reaction vessel, add 7-(2-nitrobenzenesulfonyl)-4-replace formoxyl-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidines, sulfydryl benzene, potassium carbonate and N, dinethylformamide, at room temperature react, TLC monitoring raw material reaction is complete, the post-treated 4-that obtains replaces formoxyl-5, 6, 7, 8-tetrahydropyridine also [3, 4-d] pyrimidines.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010120996A1 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses |
| US20140275120A1 (en) * | 2013-03-14 | 2014-09-18 | Janssen Pharmaceutica Nv | P2x7 modulators |
| CN104910158A (en) * | 2015-06-15 | 2015-09-16 | 河南师范大学 | 5,6,7,8-tetrahydropyrido[3,4-d] pyrimidine compound with bioactivity as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010120996A1 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their syntheses |
| US20140275120A1 (en) * | 2013-03-14 | 2014-09-18 | Janssen Pharmaceutica Nv | P2x7 modulators |
| CN104910158A (en) * | 2015-06-15 | 2015-09-16 | 河南师范大学 | 5,6,7,8-tetrahydropyrido[3,4-d] pyrimidine compound with bioactivity as well as preparation method and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| GEORGE E. MAGOULAS ET AL.: "Synthesis and antioxidative/anti-inflammatory activity of novel fullereneepolyamine conjugates", 《TETRAHEDRON》 * |
| JAMES F. BLAKE ET AL.: "Discovery of 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine inhibitors of Erk2", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| M. GREDICAK ET AL.: "Novel chloroenyne-modified amino acid derivatives", 《AMINO ACIDS》 * |
| 李世宁等: "5,6,7,8-四氢吡啶并[3,4-d]嘧啶衍生物的合成", 《化学研究与应用》 * |
| 陆国元编著: "《有机反应与有机合成》", 30 June 2009, 科学出版社 * |
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