CN102358739A - Synthetic method for imidazole[1,2-a]pyridine and 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde compounds - Google Patents

Synthetic method for imidazole[1,2-a]pyridine and 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde compounds Download PDF

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CN102358739A
CN102358739A CN2011102515600A CN201110251560A CN102358739A CN 102358739 A CN102358739 A CN 102358739A CN 2011102515600 A CN2011102515600 A CN 2011102515600A CN 201110251560 A CN201110251560 A CN 201110251560A CN 102358739 A CN102358739 A CN 102358739A
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CN102358739B (en
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朱强
王洪根
王勇
梁冬冬
刘兰英
张健存
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Guangzhou Institute of Biomedicine and Health of CAS
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Abstract

The invention discloses a novel synthetic method for 3-formyl-imidazole[1,2-a]pyridine and 2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde, and effective application of the method into synthesis of Necopidem and Saripidem. According to the invention, a 3-formyl-imidazole[1,2-a]pyridine system is established by using a cheap and low toxic Cu-catalyed O2 activated intramolecular olefin under dehydrogenation ammoxidation; conditions for the method are mild, reaction substrates are easily available, a catalytic system is simple, operation is simple, tolerance of functional groups is good, and the method is economical and effective and has very important scientific values and realistic significance.

Description

The compound method of imidazoles [1,2-a] pyridine and imidazole aldehyde compounds
Technical field
The present invention relates to the novel synthesis of 3-aldehyde radical-imidazoles [1,2-a] pyridine and imidazole aldehyde, and this method is applied in the middle of known drug molecule synthetic.
Background technology
Imidazoles [1,2-a] pyridine is one type of important heterocyclic system, extensively is present in the compound molecule of biologically active.As all containing this structural unit in alpidem, necopidem, the Saripidem medicine.Also few, especially single especially to the compound method of this heterocyclic system at present to 3-position alkyl imidazole [1,2-a] pyridine.And the existing method overwhelming majority exists substrate narrow application range, raw material synthetic route long, and productive rate is low, and product is difficult to shortcomings such as verivate.Therefore, develop one simpler, effectively, the method for green synthetic polysubstituted imidazoles [1,2-a] pyridine heterocycle, the possible pharmaceutical use for continuing excavation imidazoles [1,2-a] pyridine skeleton has crucial meaning.
Necopidem and Saripidem are two anxiolytic medicament, now to they synthetic main adopt be the 2-EL-970 with
The coupling process of-halo carbonyl compound.Shortcomings such as reaction exists route long, and productive rate is low.As at present the synthetic total recovery of necopidem being had only 25%.The intramolecularly dehydrogenation oxygen amination reaction that uses the alkene that we develop is as committed step, and the synthetic total recovery of Saripidem medicine can bring up to 50% from 25%.
Imidazoles extensively is present in natural product and the synthetic drugs molecule as a most important heterogeneous ring compound in the organic chemistry.In the medicine of 2009 annual sales amount Top200, what contain imidazole ring just reaches four.Bone metabolism medicine Zometa like the development of Novartis company; Antihypertensive drugs Cozaar and some similar medicines that Merk produces.In addition, also have many imidazoles and ring appears in the Top200 medicine like the medicine as core such as benzoglyoxaline.To the synthetic of imidazole ring a large amount of bibliographical informations is arranged, but be directed against the synthetic actually rare of the substituted imidazoles of aldehyde radical.Because the electron deficiency character of imidazole ring is introduced aldehyde radical through traditional Vilsmeier-Haack formylation reaction and can not be realized.The resourcefulness that adopts now is to slough acid proton under highly basic promotes to obtain with cancellation such as DMF again.Yet for 1, the 2-disubstituted imidazolium takes off alpha proton reaction and generally occurs in 5 all singlely, is difficult to the synthetic effectively substituted imidazoles of 4-aldehyde radical.
Summary of the invention
One of the object of the invention provides the novel synthesis of a kind of effective imidazoles [1,2-a] pyridine and imidazole aldehyde compounds.Concrete technical scheme is following:
Structural formula is
Figure BDA0000087034270000021
imidazoles [1; 2-a] the pyridine compounds compound method, may further comprise the steps:
(1) under alkaline condition, make N-allyl group-2-EL-970 by the 2-EL-970 with the allyl bromide 98 reaction:
Figure BDA0000087034270000022
Or obtain the substituted N-allyl group of allylic-2-EL-970 through one two step one kettle way reaction by 2-EL-970, corresponding aldehyde and vinyl Grignard reagent:
Figure BDA0000087034270000023
(2) prepare the purpose compound by the substituted N-allyl group of allylic-2-EL-970 again:
Figure BDA0000087034270000024
R in the said structure formula and R 1Be hydrogen, aryl, alkyl, or halogen; R 2Be hydrogen, aryl, alkyl or heterocycle.
At first be that the electrical and sterically hindered on the pyridine ring is investigated.The substituted methyl substrate of all places has all obtained yield preferably, wherein the methyl substituted yield in 3-position best (entry 2).In addition, 5-position methyl substituted does not have because of steric factor the too big influence of productive rate product (entry 4).Medium electrophilic chlorine, bromine substituent can tolerate this reaction conditions preferably, but need could transform down fully in higher temperature (120 ℃), and this also is that the further derivatize of imidazoles [1,2-a] pyridine provides space (entry 5,8).And isoquinoline 99.9 is a very good substrate of this reaction.
The substituted radical of allylic is not obvious to the influence of reaction.Various electrically (like OMe, Me, F, Cl, Br, CN, COOMe) and the substituted phenyl in position can both obtain good yield (entry 7-18).The yield of 3-pyridyl and 2-thienyl is relatively low.The substrate yield that alkyl replaces (like sec.-propyl, cyclohexyl) is good.
Structural formula is the compound method of
Figure BDA0000087034270000031
imidazole aldehyde compounds, may further comprise the steps:
(1) under lewis acid catalysis, carry out nucleophilic addition through itrile group compound and allylamine,
Figure BDA0000087034270000032
With the aluminum chloride is catalyzer, reacts half a hour at 120 ℃;
(2) preparation purpose compound:
Figure BDA0000087034270000033
With two (trifluoromethanesulfonic acid) copper is catalyzer, and potassiumphosphate is an alkali, the oxygen atmosphere, and DMAC N,N is a solvent, is heated to 105 ℃ of reactions;
R in the said structure formula and R 1Be H, aryl, alkyl, or halogen; R 2Be H, aryl, alkyl or heterocycle.
Multiple N substituting group substrate such as N-phenyl, the N-methyl, N-benzyl-N-allyl phenyl amidine all obtains to let satisfied yield (entry1-4).What deserves to be mentioned is that benzyl can conveniently remove, but increased the derivatize space (entry 3) of this product.It is various that electrically (Br) substituted benzene carbon amidine all can be applicable to this reaction for Me, MeO, and electrically not obvious (entry 4,6-8) to the influence of productive rate.In addition, acid amidine can also can successfully obtain product.
Another object of the present invention provides the compound method of a kind of anxiolytic medicament necopidem and Saripidem.
The technical scheme that realizes above-mentioned purpose is following:
The compound method of necopidem may further comprise the steps:
Figure BDA0000087034270000041
The first step; Synthesizing of N-(1-(4-ethylphenyl) allyl group)-5-picoline-2-amine: with 2-amido-5-picoline; 4-ethylbenzene formaldehyde; Tosic acid, molecular sieve places the exsiccant THF, back flow reaction 15-20 hour; Reaction cooled slowly drips the vinyl Grignard reagent then to-75 to-80 ℃ in reaction system; Reaction remains on-75 to-80 ℃ of reactions and rose to room temperature in 0.3-0.7 hour then; In reaction system, add saturated ammonium chloride and water successively, the extraction of ethyl ester ethyl ester; Water continues to use ethyl acetate extraction, merges organic phase, washing, drying; Remove and desolvate, residuum obtains N-(1-(4-ethylphenyl) allyl group)-5-picoline-2-amine through column chromatography purification;
Second step; 2-(4-ethylphenyl)-6-methyl-imidazoles [1; 2-a] pyridine-3-formaldehyde synthetic: under the oxygen atmosphere, N-(1-(4-ethylphenyl) allyl group)-5-picoline-2-amine, the N of two hexafluoroacetylacetone copper; N-N,N-DIMETHYLACETAMIDE mixed solution places under the 100-110 ℃ of condition and reacted 12-16 hour, and room temperature is reduced in reaction; In reaction, add saturated sodium bicarbonate, ETHYLE ACETATE, extraction; Water continues to use ethyl acetate extraction, merges organic phase, and washing, drying are removed and desolvated, and residuum obtains 2-(4-ethylphenyl)-6-methyl-imidazoles [1,2-a] pyridine-3-formaldehyde through column chromatography purification;
In the 3rd step, necopidem synthetic: with 2-(4-ethylphenyl)-6-methyl-imidazoles [1,2-a] pyridine-3-formaldehyde, methylamine hydrochloride, sodium hydrogencarbonate are suspended in the methyl alcohol, 60-70 ℃ of reaction 18-22 hour; Reaction solution is cooled to room temperature, disposable adding Peng Qinghuana, removal of solvent under reduced pressure after reaction finishes adds saturated sodium carbonate, ethyl acetate extraction in the residuum; Merge organic phase, washing, drying are removed and are desolvated, and add THF in the residuum, and sodium hydrogencarbonate drips 3-methylbutyryl chlorine under the argon gas atmosphere; The mixture room temperature reaction; In reaction, add saturated sodium bicarbonate, ETHYLE ACETATE, extraction; Water continues to use ethyl acetate extraction; Merge organic phase, with washing, drying; Remove and desolvate, residuum obtains necopidem through column chromatography purification.
The compound method of Saripidem may further comprise the steps:
Figure BDA0000087034270000051
The first step; Synthesizing of N-(1-(4-chloro-phenyl-) allyl group)-pyridine-2-amine: with 2-amido pyridine; The 4-chlorobenzaldehyde; Tosic acid,
Figure BDA0000087034270000052
molecular sieve places exsiccant THF, back flow reaction; Reaction finishes postcooling to-75 to-80 ℃, in reaction system, slowly drips the vinyl Grignard reagent then; Reaction remains on and rises to room temperature after-75 to-80 ℃ of reactions finish; In reaction system, add saturated ammonium chloride and water successively, the extraction of ethyl ester ethyl ester; Water continues to use ethyl acetate extraction; Merge organic phase, washing, drying are removed and are desolvated, and residuum obtains N-(1-(4-chloro-phenyl-) allyl group)-pyridine-2-amine through column chromatography purification;
Second step; Synthesizing of 2-(4-chloro-phenyl-)-imidazoles [1,2-a] pyridine-3-formaldehyde: under the oxygen atmosphere, N-(1-(4-chloro-phenyl-) allyl group)-pyridine-2-amine; The DMAC N,N mixed solution of two hexafluoroacetylacetone copper places under the 100-110 ℃ of condition and reacted 12-16 hour; Room temperature is reduced in reaction; In reaction, add saturated sodium bicarbonate, ETHYLE ACETATE, extraction; Water continues to use ethyl acetate extraction; Merge organic phase, washing, nothing drying; Remove and desolvate, residuum obtains 2-(4-chloro-phenyl-)-imidazoles [1,2-a] pyridine-3-formaldehyde through column chromatography purification;
In the 3rd step, Saripidem synthetic: with 2-(4-chloro-phenyl-)-imidazoles [1,2-a] pyridine-3-formaldehyde, methylamine hydrochloride, sodium hydrogencarbonate are suspended in the methyl alcohol, 60-70 ℃ of reaction; After reaction finishes reaction solution is cooled to room temperature, disposable adding Peng Qinghuana, removal of solvent under reduced pressure after reaction finishes adds saturated sodium carbonate, ethyl acetate extraction in the residuum; Merge organic phase, washing, nothing drying; Remove and desolvate, add THF in the residuum, sodium hydrogencarbonate drips n-butyryl chloride under the argon gas atmosphere; The mixture room temperature reaction adds saturated sodium bicarbonate after reaction finishes in reaction, ETHYLE ACETATE, extraction; Water continues with ethyl acetate extraction two times; Merge organic phase, washing, drying are removed and are desolvated, and residuum obtains Saripidem through column chromatography purification.
The present invention has the following advantages;
1, adopts the Cu catalysis O of cheap low toxicity first 2The dehydrogenation amine oxidizing reaction of activation/intramolecularly alkene has made up 3-aldehyde radical imidazoles [1,2-a] pyridine system, this method mild condition; Reaction substrate is easy to get, and catalystsystem is simple, and is easy and simple to handle; Functional group's tolerance number, economical and effective has crucial learning value and realistic meaning;
2, imidazoles is as short of electricity subbase heterocycle, and the method for introducing aldehyde radical is few, and only method condition is harsh, operates loaded down with trivial details.One of the existing method of present method conduct is replenished, when making up imidazole ring, introduces this chemical reaction variety rich functional groups of aldehyde radical.Should be one type of atom economy property, high step economy, mild condition and easy-operating reaction;
3, our compound method of development is applied to known anxiolytic effectively, promptly in the middle of the synthesizing of necopidem and saripidem, the yield previous methods that compares is significantly improved;
4, reaction need not to add any core ductant;
5, reaction uses the oxygen of green economy to be oxygenant, has reduced environmental pollution.
Embodiment
Embodiment 1,
One, imidazoles [1,2-a] pyridine compounds and their is synthetic
The synthetic of raw material can pass through dual mode:
First kind of mode:
For simple N-allyl group-2-EL-970, react down by 2-EL-970 alkaline condition and to make with allyl bromide 98.
Figure BDA0000087034270000061
Substituting group is methyl, chlorine on the pyridine ring, is alkali with n-Butyl Lithium or potassium tert.-butoxide, and THF is a solvent, obtains 6 raw materials altogether, and yield is between 24～77%.
The concrete operations step is following:
With the n-Butyl Lithium is alkali:
Under-78 ℃ of conditions, drip in THF (10mL) solution of 2-EL-970 (3.0mmol) n-Butyl Lithium (1.8mL, 2.5M in n-hexane, 1.5equiv.).After reaction places-78 ℃ to react half a hour, in reaction solution, slowly drip allyl bromide 98 solution (3.6mmol, 1.2equiv., diluted in 2mL of THF).Reaction continues to remain on-78 ℃ of reactions and slowly is warming up to room temperature after half a hour, toward reaction system in, once adds saturated ammonium chloride (1mL) and water, and ETHYLE ACETATE (30mL) extracts.Water continues with ethyl acetate extraction one time.Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, remove and desolvate, residuum promptly obtains pure compound through column chromatography purification.
With the potassium tert.-butoxide is alkali:
Under the Ar gas shiled, with 2-EL-970 (3.0mmol), (THF 1.5equiv.) (10mL) mixed solution placed room temperature reaction 1 hour to potassium tert.-butoxide for 504mg, 4.5mmol.In reaction solution, slowly drip allyl bromide 98 solution (3.6mmol, 1.2equiv., diluted in 2mL ofTHF).Reaction continued to remain on room temperature reaction 2 hours, added entry (30mL) cancellation.ETHYLE ACETATE (30mL) extraction.Water continues with ethyl acetate extraction one time.Merge organic phase, with the saturated common salt washing, anhydrous sodium sulfate drying removes on Rotary Evaporators and desolvates, and residuum obtains pure compound through column chromatography purification.
Figure BDA0000087034270000071
Figure BDA0000087034270000081
The second way:
The substituted N-allyl group of allylic-2-EL-970 is then obtained through one two step one kettle way reaction by 2-EL-970, corresponding aldehyde and vinyl Grignard reagent.
Figure BDA0000087034270000082
Substituting group is methyl or bromine on the pyridine ring; R 2For phenyl, substituted-phenyl, 2-naphthyl, 3-pyridine, 2-thienyl, sec.-propyl, cyclohexyl etc., obtain 17 raw materials altogether, yield is between 24～89%.
The concrete operations step is following:
With 2-EL-970 (3.0mmol); Aldehyde (3.0mmol); Tosic acid (10mg);
Figure BDA0000087034270000083
molecular sieve (2.0g) places exsiccant THF, back flow reaction 18 hours.Reaction cooled is to-78 ℃, then in the reaction system slowly dropping vinyl Grignard reagent (6mL, 1.0M in THF, 2.0equiv.).Remain on-78 ℃ of reactions and rise to room temperature after half a hour.In system, add saturated ammonium chloride (1mL), water, ETHYLE ACETATE (30mL) extraction successively.Water continues with ethyl acetate extraction one time.Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, remove and desolvate, residuum obtains pure compound through column chromatography purification.
Figure BDA0000087034270000084
Figure BDA0000087034270000091
Figure BDA0000087034270000101
Figure BDA0000087034270000111
Substrate spread scenarios such as following table:
Figure BDA0000087034270000112
Under oxygen atmosphere; With the substituted N-allyl group of allylic-2-EL-970 (0.5mmol), two (hexafluoroacetylacetone) copper (0.1mmol; DMF mixed solution 20mol%) places under 105 ℃ of conditions, after a plate shows that raw material runs out of basically, room temperature is reduced in reaction.In reaction, add saturated sodium bicarbonate solution (10mL), ETHYLE ACETATE (10mL) extraction.Water continues with twice of ethyl acetate extraction.Merge organic layer, with saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, remove and desolvate, residuum obtains pure compound through column chromatography purification.
Figure BDA0000087034270000121
Figure BDA0000087034270000131
Figure BDA0000087034270000141
The sign of product;
Figure BDA0000087034270000142
1H?NMR(400MHz，CDCl 3)δ10.06(s，1H)，9.65(d，J＝6.8Hz，1H)，7.85-7.80(m，3H)，7.61-7.51(m，4H)，7.14(t，J＝6.8Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ179.6，158.3，147.7，132.3，130.4，129.8，128.9，128.8，120.7，117.4，115.3；HRMS(ESI)：Exact?mass?calcd?for?C 14H 11N 2O[M+H] +223.0866，Found?223.0868.
Figure BDA0000087034270000151
1H?NMR(400MHz，CDCl 3)δ9.93(s，1H)，9.47(d，J＝6.8Hz，1H)，8.30(s，1H)，7.78(d，J＝8.8Hz，1H)，7.54(t，J＝8.4Hz，1H)，7.12(t，J＝6.8Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ177.8，149.3，146.8，130.1，128.7，125.0，117.8，115.4；HRMS(ESI)：Exact?mass?calcd?forC 8H 7N 2O[M+H] +147.0553，Found?147.0557.
Figure BDA0000087034270000152
1H?NMR(400MHz，CDCl 3)δ9.94(s，1H)，9.35(d，J＝6.4Hz，1H)，8.30(s，1H)，7.35(d，J＝6.8Hz，1H)，7.04(t，J＝7.2Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ177.9，149.5，146.2，129.1，127.9，126.4，125.4，115.5，16.8；HRMS(ESI)：Exact?mass?calcd?for?C 9H 9N 2O[M+H] +161.0709，Found?161.0712.
Figure BDA0000087034270000153
1H?NMR(400MHz，CDCl 3)δ9.91(s，1H)，9.33(s，1H)，8.26(s，1H)，7.68(d，J＝9.2Hz，1H)，7.40(d，J＝8.4Hz，1H)，2.42(s，3H)； 13C?NMR(125MHz，CDCl 3)δ177.7，148.4，146.8，133.0，126.7，125.7，124.8，117.0，18.2；HRMS(ESI)：Exact?mass?calcd?for?C 9H 9N 2O[M+H] +161.0709，Found?161.0714.
Figure BDA0000087034270000154
1H?NMR(400MHz，CDCl 3)δ9.89(s，1H)，8.39(s，1H)，7.64(d，J＝8.8Hz，1H)，7.45(t，J＝8.0Hz，1H)，6.89(d，J＝7.2Hz，1H)，2.96(s，3H)； 13C?NMR(125MHz，CDCl 3)δ175.9，152.0，149.7，140.1，130.0，128.2，116.2，115.7，23.0；HRMS(ESI)：Exact?mass?calcd?for?C 9H 9N 2O[M+H] +161.0709，Found?161.0710.
Figure BDA0000087034270000161
The?reaction?was?performed?at?120℃?for?24h，yield：51％. 1H?NMR(400MHz，CDCl 3)δ9.93(s，1H)，9.54(d，J＝1.2Hz，1H)，8.29(s，1H)，7.71(d，J＝9.6Hz，1H)，7.50(dd，J＝9.6Hz，J＝2.0Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ178.0，147.6，146.7，131.3，126.6，125.0，123.8，118.1；HRMS(ESI)：Exact?mass?calcd?for?C 8H 6ClN 2O[M+H] +181.0163，Found?181.0165.
Figure BDA0000087034270000162
1H?NMR(400MHz，CDCl 3)δ9.99(s，1H)，9.16(d，J＝7.2Hz，1H)，8.76-8.71(m，1H)，8.29(s，1H)，7.84-7.80(m，1H)，7.75-7.71(m，2H)，7.33(d，J＝7.2Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ178.5，147.5，145.2，131.4，130.3，128.8，127.0，126.6，124.6，124.2，122.7，115.5；HRMS(ESI)：Exact?mass?calcd?for?C 12H 9N 2O[M+H] +?197.0709，Found?197.0711.
Figure BDA0000087034270000163
1H?NMR(400MHz，CDCl 3)δ10.00(s，1H)，9.50(d，J＝7.2Hz，1H)，7.83-7.81(m，2H)，7.55-7.50(m，4H)，6.94(d，J＝6.4Hz，1H)，2.50(s，3H)； 13C?NMR(125MHz，CDCl 3)δ179.1，158.5，148.2，142.2，132.5，129.8，129.7，128.8，127.9，120.6，117.6，116.1，21.7；HRMS(ESI)：Exact?mass?calcd?for?C 15H 13N 2O[M+H] +?237.1022，Found?237.1026.
Figure BDA0000087034270000164
The?reaction?was?performed?at?120℃for?24h，yield：49％. 1H?NMR(400MHz，CDCl 3)δ10.06(s，1H)，9.52(d，J＝7.2Hz，1H)，7.99(d，J＝1.2Hz，1H)，7.83-7.80(m，2H)，7.57-7.53(m，3H)，7.22(dd，J＝7.2Hz，J＝2.0Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ179.7，158.7，147.9，131.9，130.1，129.8，129.0，128.8，124.7，120.7，119.9，119.1；HRMS(ESI)：Exactmass?calcd?for?C 14H 10BrN 2O[M+H] +?300.9971，Found?300.9972.
1H?NMR(400MHz，CDCl 3)δ10.04(s，1H)，9.65(d，J＝6.8Hz，1H)，7.81-7.76(m，3H)，7.59(t，J＝6.8Hz，1H)，7.53-7.49(m，2H)，7.13(t，J＝7.6Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ179.1，156.9，147.7，136.2，131.0，130.8，130.6，129.2，128.8，120.7，117.4，115.4；HRMS(ESI)：Exact?mass?calcd?for?C 14H 10ClN 2O[M+H] +?257.0476，Found?257.0478.
Figure BDA0000087034270000172
1H?NMR(400MHz，CDCl 3)δ10.04(s，1H)，9.65(d，J＝6.8Hz，1H)，7.79(d，J＝9.2Hz，1H)，7.72-7.65(m，4H)，7.59(t，J＝8.4Hz，1H)，7.12(t，J＝6.8Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ179.0，156.9，147.7，132.1，131.3，131.2，130.6，128.8，124.5，120.7，117.5，115.4；HRMS(ESI)：Exact?mass?calcd?for?C 14H 10BrN 2O[M+H] +?300.9971，Found?300.9971.
Figure BDA0000087034270000173
1H?NMR(400MHz，CDCl 3)δ10.00(s，1H)，9.46(s，1H)，7.76(d，J＝8.8Hz，2H)，7.66(d，J＝9.2Hz，1H)，7.40(d，J＝9.2Hz，1H)，7.03(d，J＝8.8Hz，1H)，3.87(s，3H)，2.42(s，3H)； 13C?NMR(125MHz，CDCl 3)δ179.3，161.0，158.1，146.7，133.2，131.1，126.8，125.2，125.0，120.3，116.4，114.3，55.4，18.3；HRMS(ESI)：Exact?mass?calcd?for?C 16H 15N 2O 2[M+H] +?267.1128，Found?267.1132.
Figure BDA0000087034270000174
1H?NMR(400MHz，CDCl 3)δ10.01(s，1H)，9.45(s，1H)，7.71-7.65(m，3H)，7.40(dd，J＝8.8Hz，J＝2.0Hz，1H)，7.31(d，J＝8.0Hz，1H)，2.42(s，3H)，2.41(s，3H)； 13CNMR(125MHz，CDCl 3)δ179.4，158.2，146.6，139.8，133.1，129.6，129.5，126.8，125.5，120.4，116.5，21.3，18.3；HRMS(ESI)：Exact?mass?calcd?for?C 11H 9N 2O[M+H] +?251.1179，Found251.1182.
Figure BDA0000087034270000175
1H?NMR(400MHz，CDCl 3)δ9.99(s，1H)，9.46(s，1H)，7.82-7.78(m，2H)，7.68(d，J＝9.2Hz，1H)，7.43(dd，J＝9.2Hz，J＝1.6Hz，1H)，7.23-7.19(m，2H)，2.44(s，3H)；? 13C?NMR(125MHz，CDCl 3)δ179.0，164.8，162.8，157.1，146.6，133.4，131.6，131.5，128.7，128.6，?126.8，125.6，120.5，116.6，116.5，115.9，18.3；HRMS(ESI)：Exact?mass?calcd?for?C 15H 12FN 2O[M+H] +?255.0928，Found?255.0928.
Figure BDA0000087034270000181
1H?NMR(400MHz，CDCl 3)δ10.06(s，1H)，9.51(s，1H)，7.97(d，J＝8.4Hz，2H)，7.84(d，J＝8.4Hz，2H)，7.75(d，J＝9.2Hz，1H)，7.50(dd，J＝9.2Hz，J＝1.6Hz，1H)，2.49(s，3H)； 13C?NMR(125MHz，CDCl 3)δ178.6，155.4，146.7，137.0，133.8，132.5，130.3，126.8，126.2，120.9，118.3，116.9，113.3，18.4；HRMS(ESI)：Exact?mass?calcd?for?C 16H 12N 3O[M+H] +262.0975，Found?262.0973.
Figure BDA0000087034270000182
1H?NMR(400MHz，CDCl 3)δ10.04(s，1H)，9.48(s，1H)，8.18(d，J＝8.4Hz，2H)，7.89(d，J＝8.4Hz，2H)，7.71(d，J＝9.2Hz，1H)，7.45(dd，J＝9.2Hz，J＝1.6Hz，1H)，3.96(s，3H)，2.45(s，3H)； 13C?NMR(125MHz，CDCl 3)δ179.0，166.6，156.6，146.7，136.8，133.5，131.0，130.0，129.7，126.8，125.9，120.8，116.7，52.3，18.3；HRMS(ESI)：Exact?mass?calcdfor?C 17H 15N 2O 3[M+H] +?295.1077，Found?295.1075.
Figure BDA0000087034270000183
1H?NMR(400MHz，CDCl 3)δ9.72(s，1H)，9.51(s，1H)，8.18(d，J＝8.0Hz，1H)，7.99(d，J＝8.0Hz，1H)，7.94-7.92(m，1H)，7.77(d，J＝9.2Hz，1H)，7.66(d，J＝6.8Hz，J＝1.2Hz，1H)，7.60-7.46(m，4H)，2.48(s，3H)； 13C?NMR(125MHz，CDCl 3)δ179.5，157.8，146.7，133.8，133.2，132.2，130.0，129.7，129.5，128.3，127.0，126.6，126.3，125.8，125.6，124.9，122.1，116.8，18.3；HRMS(ESI)：Exact?mass?calcd?for?C 19H 15N 2O[M+H] +?287.1179，Found?287.1178.
Figure BDA0000087034270000184
1H?NMR(400MHz，CDCl 3)δ10.05(s，1H)，9.48(s，1H)，7.71(d，J＝8.8Hz，1H)，7.44-7.40(m，2H)，7.37-7.35(m，2H)，7.06-7.03(m，1H)，3.89(s，3H)，2.45(s，3H)； 13C?NMR(125MHz，CDCl 3)δ179.5，159.9，158.0，146.6，133.8，133.3，129.8，126.8，125.5，122.4，120.6，116.6，115.9，114.6，55.5，18.3；HRMS(ESI)：Exact?mass?calcd?for?C 16H 15N 2O 2[M+H] +267.1128，Found?267.1131.
1H?NMR(400MHz，CDCl 3)δ9.74(s，1H)，9.42(s，1H)，7.72(d，J＝9.2Hz，1H)，7.59-7.53(m，2H)，7.45-7.38(m，3H)，2.45(s，3H)； 13C?NMR(125MHz，CDCl 3)δ179.2，155.3，146.7，133.6，133.0，132.5，131.6，130.7，130.1，126.8，126.6，125.8，121.1，116.9，18.3；HRMS(ESI)：Exact?mass?calcd?for?C 15H 12ClN 2O[M+H] +?271.0633，Found?271.0637.
Figure BDA0000087034270000192
1H?NMR(400MHz，CDCl 3)δ10.00(s，1H)，9.46(s，1H)，9.02(br，1H)，8.72(br，1H)，8.14(d，J＝8.4Hz，1H)，7.70(d，J＝8.8Hz，1H)，7.47-7.44(m，2H)，2.43(s，3H)； 13CNMR(125MHz，CDCl 3)δ178.5，154.6，150.6，150.1，146.9，136.8，128.7，126.8，126.0，123.7，120.9，116.7，18.3；HRMS(ESI)：Exact?mass?calcd?for?C 14H 12N 3O[M+H] +?238.0975，Found238.0977.
Figure BDA0000087034270000193
1H?NMR(400MHz，CDCl 3)δ10.26(s，1H)，9.43(s，1H)，7.64(d，J＝9.2Hz，1H)，7.59(dd，J＝3.6Hz，J＝0.8Hz，1H)，7.52(dd，J＝4.8Hz，J＝0.8Hz，1H)，7.39(dd，J＝9.2Hz，J＝1.6Hz，1H)，7.99(dd，J＝4.8Hz，J＝3.6Hz，1H)，2.41(s，3H)； 13C?NMR(125MHz，CDCl 3)δ178.3，151.2，146.7，135.0，133.5，128.8，128.6，128.1，126.8，125.5，119.9，116.4，18.3；HRMS(ESI)：Exact?mass?calcd?for?C 13H 11N 2OS[M+H] +?243.0587，Found?243.0588.
Figure BDA0000087034270000194
1H?NMR(400MHz，CDCl 3)δ10.03(s，1H)，9.50(d，J＝6.8Hz，1H)，7.69(d，J＝9.2Hz，1H)，7.48(t，J＝8.4Hz，1H)，7.02(t，J＝6.8Hz，1H)，3.56-3.46(m，1H)，1.42(d，J＝6.8Hz，6H)； 13C?NMR(125MHz，CDCl 3)δ176.7，166.5，147.9，129.9，128.6，119.6，116.9，114.8，27.0，?22.8；HRMS(ESI)：Exact?mass?calcd?for?C 11H 13N 2O[M+H] +?189.1022，Found?189.1025.
Figure BDA0000087034270000201
1H?NMR(400MHz，CDCl 3)δ10.02(s，1H)，9.36(s，1H)，7.60(d，J＝8.8Hz，1H)，7.34(dd，J＝8.8Hz，J＝1.6Hz，1H)，3.17-3.09(m，1H)，2.39(s，3H)，1.95-1.72(m，7H)，1.49-1.33(m，3H)； 13C?NMR(100MHz，CDCl 3)δ176.6，165.7，146.9，132.6，126.8，124.8，119.7，116.2，37.3，33.2，26.5，25.8，18.1；HRMS(ESI)：Exact?mass?calcd?for?C 15H 19N 2O[M+H] +243.1492，Found?243.1495.
At first be that the electrical and sterically hindered on the pyridine ring is investigated.The substituted methyl substrate of all places has all obtained yield preferably, wherein the methyl substituted yield in 3-position best (entry 2).In addition, 5-position methyl substituted does not have because of steric factor the too big influence of productive rate product (entry 4).Medium electrophilic chlorine, bromine substituent can tolerate this reaction conditions preferably, but need could transform down fully in higher temperature (120 ℃), and this also is that the further derivatize of imidazoles [1,2-a] pyridine provides space (entry 5,8).What deserves to be mentioned is that isoquinoline 99.9 is a very good substrate of this reaction.
The substituted radical of allylic is not obvious to the influence of reaction.Various electrically (like OMe, Me, F, Cl, Br, CN, COOMe) and the substituted phenyl in position can both obtain good yield (entry 7-18).The yield of 3-pyridyl and 2-thienyl is relatively low.The substrate yield that alkyl replaces (like sec.-propyl, cyclohexyl) is good.
Two, the imidazole aldehyde compounds is synthetic
The synthetic of raw material makes through itrile group compound and the nucleophilic addition of allylamine under the Lewis acid catalysis.
Figure BDA0000087034270000202
In reaction flask, add cyano compound (5.0mmol), aluminum chloride (5.0mmol) and allyl amine compound (6.0mmol; 1.2equiv.); Reaction places under 120 ℃ of conditions reacts half a hour; In reaction system, add frozen water (25mL), vigorous stirring add to be done sodium hydroxide solution again and is equaled 14 to pH.Ethyl acetate extraction (3x 30mL) merges organic layer and uses anhydrous sodium sulfate drying, concentrating under reduced pressure, and column chromatography obtains product.
Figure BDA0000087034270000211
Under the oxygen atmosphere, (0.75mmol, DMA 1.5equiv.) (1.5mL) mixed solution places under 105 ℃ of conditions and reacts with raw material (0.5mmol), copper trifluoromethanesulfcomposite (0.1mmol, 20%) and potassiumphosphate.The point plate is reduced to room temperature with reaction after showing that raw material consumption is intact, in reaction, adds saturated sodium bicarbonate (10mL), ETHYLE ACETATE (10mL), extraction.Water continues with twice of ethyl acetate extraction.Merge organic layer, with saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, remove and desolvate, residuum obtains pure compound through column chromatography purification.
Substrate spread scenarios such as following table:
Figure BDA0000087034270000221
Figure BDA0000087034270000222
Figure BDA0000087034270000231
The sign of product:
Figure BDA0000087034270000232
1H?NMR(400MHz，CDCl 3)δ9.96(s，1H)，7.79(s，1H)，7.40(d，J＝8.4Hz，2H)，7.32-7.12(m，5H)，7.08(d，J＝8.4Hz，2H)，2.38(s，3H)； 13C?NMR(125MHz，CDCl 3)δ186.0，148.4，141.2，139.1，134.7，130.1，129.1，128.9，128.6，128.1，128.0，125.2，21.0；HRMS(ESI)：Exact?mass?calcd?for?C 17H 15N 2O?[M+Na] +?285.0998，Found?285.0994.
Figure BDA0000087034270000241
1H?NMR(400MHz，CDCl 3)δ10.03(s，1H)，7.86(s，1H)，7.48-7.41(m，5H)，7.36-7.25(m，5H)； 13C?NMR(125MHz，CDCl 3)δ186.3，148.5，141.6，137.4，129.8，129.3，129.1，129.0，128.8，128.3，127.7，125.7；HRMS(ESI)：Exact?mass?calcd?for?C 16H 13N 2O[M+H] +?249.1022，Found?249.1036.
Figure BDA0000087034270000242
1H?NMR(400MHz，CDCl 3)δ9.93(s，1H)，7.67(s，1H)，7.61-7.58(m，2H)，7.48-7.45(m，3H)，7.39-7.35(m，3H)，7.12-7.10(m，2H)，5.25(s，2H)； 13C?NMR(125MHz，CDCl 3)δ186.2，149.9，141.3，135.3，129.7，129.2，129.0，128.7，128.5，127.0，126.5，125.0，51.1；HRMS(ESI)：Exact?mass?calcd?for?C 17H 15N 2O[M+Na] +?285.0998，Found?285.0994.
Figure BDA0000087034270000243
1H?NMR(400MHz，CDCl 3)δ9.91(s，1H)，7.70(s，1H)，7.66-7.64(m，2H)，7.51-7.48(m，3H)，3.81(s，3H)； 13C?NMR(125MHz，CDCl 3)δ186.1，149.6，141.0，129.6，129.1，128.8，128.7，127.1，35.1；HRMS(ESI)：Exact?mass?calcd?for?C 11H 11N 2O[M+H] +?187.0866，Found?187.0857.
Figure BDA0000087034270000244
1H?NMR(400MHz，CDCl 3)δ9.89(s，1H)，7.67(s，1H)，7.53(d，J＝8.4Hz，2H)，7.28(d，J＝8.4Hz，2H)，3.78(s，3H)，2.41(s，3H)； 13C?NMR(125MHz，CDCl 3)δ186.1，149.8，140.9，139.7，129.3，128.7，127.6，126.3，35.1，21.3；HRMS(ESI)：Exact?mass?calcd?for?C 12H 13N 2O[M+H] +?201.1022，Found?201.1006.
1H?NMR(400MHz，CDCl 3)δ9.87(s，1H)，7.65(s，1H)，7.56(d，J＝8.4Hz，2H)，6.98(d，J＝8.4Hz，2H)，3.85(s，3H)，3.77(s，3H)； 13C?NMR(125MHz，CDCl 3)δ186.1，160.6，149.6，140.8，130.2，127.5，121.5，114.1，55.3，35.1；HRMS(ESI)：Exact?masscalcd?for?C 12H 13N 2O 2[M+H] +?217.0972，Found?217.0965.
Figure BDA0000087034270000252
1H?NMR(400MHz，CDCl 3)δ9.88(s，1H)，7.68(s，1H)，7.62(d，J＝7.6Hz，2H)，7.52(d，J＝7.6Hz，2H)，3.80(s，3H)； 13C?NMR(125MHz，CDCl 3)δ185.9，148.5，141.1，132.0，130.3，128.1，127.9，124.2，35.2；HRMS(ESI)：Exact?mass?calcd?for?C 11H 10BrN 2O[M+Na] +286.9791，Found?286.9798.
Figure BDA0000087034270000253
1H?NMR(400MHz，CDCl 3)δ9.83(s，1H)，7.52(s，1H)，3.69(s，3H)，2.70-2.63(m，1H)，1.93-1.89(m，4H)，1.77-1.67(m，3H)，1.44-1.30(m，3H)； 13C?NMR(125MHz，CDCl 3)δ185.9，154.7，140.3，126.6，35.8，33.1，31.3，26.2，25.6；HRMS(ESI)：Exact?mass?calcd?for?C 11H 17N 2O[M+H] +?193.1335，Found193.1326.
Multiple N substituting group substrate such as N-phenyl, the N-methyl, N-benzyl-N-allyl phenyl amidine all obtains to let satisfied yield (entry1-4).What deserves to be mentioned is that benzyl can conveniently remove, but increased the derivatize space (entry 3) of this product.It is various that electrically (Br) substituted benzene carbon amidine all can be applicable to this reaction for Me, MeO, and electrically not obvious (entry 4,6-8) to the influence of productive rate.In addition, acid amidine can also can successfully obtain product.
Embodiment 2: the compound method of necopidem and Saripidem
The compound method of necopidem may further comprise the steps:
Figure BDA0000087034270000261
The first step; Synthesizing of N-(1-(4-ethylphenyl) allyl group)-5-picoline-2-amine: with 2-amido-5-picoline (1.081g; 10.0mmol), 4-ethylbenzene formaldehyde (1.610g, 12mmol; 1.2equiv); Tosic acid (30mg),
Figure BDA0000087034270000262
molecular sieve (10.0g) places the exsiccant THF, back flow reaction 18 hours.Reaction cooled is to-78 ℃, then in the reaction system slowly dropping vinyl Grignard reagent (6mL, 1.0M in THF, 2.0equiv).Reaction remains on-78 ℃ of reactions and rose to room temperature in 0.5 hour then.In reaction system, add saturated ammonium chloride (1mL) and water successively, ethyl ester ethyl ester (30mL) extraction.Water continues with ethyl acetate extraction one time.Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, remove and desolvate, residuum obtains pure article compound (1.802g, 77%) through column chromatography purification.
Second step, 2-(4-ethylphenyl)-6-methyl-imidazoles [1,2-a] pyridine-3-formaldehyde synthetic: under the oxygen atmosphere; N-(1-(4-ethylphenyl) allyl group)-5-picoline-2-amine (1.20g; 4.76mmol), two hexafluoroacetylacetone copper (454mg, 0.952mmol; DMAC N,N 20mol%) (14mL) mixed solution places under 105 ℃ of conditions and reacted 14 hours.Room temperature is reduced in reaction.In reaction, add saturated sodium bicarbonate (30mL), ETHYLE ACETATE (30mL), extraction.Water continues with ethyl acetate extraction two times.Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, remove and desolvate, residuum obtains pure article compound (905mg, 72%) through column chromatography purification.
The 3rd step, necopidem synthetic: with 2-(4-ethylphenyl)-6-methyl-imidazoles [1,2-a] pyridine-3-formaldehyde (905mg; 3.42mmol), methylamine hydrochloride (693mg, 10.26mmol; 3.0equiv), sodium hydrogencarbonate (859mg, 10.26mmol; 3.0equiv) be suspended in the methyl alcohol (20mL), 65 ℃ were reacted 20 hours.Reaction solution is cooled to room temperature, and (389mg, 10.26mmol 3.0equiv), reacted one hour disposable adding Peng Qinghuana.Removal of solvent under reduced pressure adds saturated sodium carbonate (20mL) in the residuum, ETHYLE ACETATE (30mL) extraction three times.Merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Desolvate revolving in the steaming to remove, add THF (20mL) in the residuum, sodium hydrogencarbonate (859mg, 10.26mmol, 3.0equiv), drip under the argon gas atmosphere 3-methylbutyryl chlorine (818mg, 6.8mmol, 2.0equiv).Mixture room temperature reaction 0.5 hour.In reaction, add saturated sodium bicarbonate (30mL), ETHYLE ACETATE (30mL), extraction.Water continues with ethyl acetate extraction two times.Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.Desolvate revolving in the steaming to remove, residuum obtains pure article compound (1.122g, three step yields 90%) through column chromatography purification.
The sign of product:
Figure BDA0000087034270000271
1H?NMR(400MHz，CDCl 3)δ7.91(s，1H)，7.29-7.26(m，2H)，7.22-7.16(m，3H)，6.28(d，J＝9.2Hz，1H)，6.09-6.01(m，1H)，5.29-5.28(m，3H)，4.79(br，1H)，2.66-2.61(m，2H)，2.16(s，3H)，1.25-1.20(m，3H).
Figure BDA0000087034270000272
1H?NMR(400MHz，CDCl 3)δ10.03(s，1H)，9.48(s，1H)，7.73(d，J＝8.0Hz，2H)，7.69(d，J＝9.2Hz，1H)，7.41(dd，J＝9.2Hz，J＝1.6Hz，1H)，7.35(d?J＝8.0Hz，2H)，2.73(q，J＝7.6Hz，2H)，2.44(s，3H)，1.29(t，J＝7.6Hz，3H)； 13C?NMR(125MHz，CDCl 3)δ179.5，158.3，146.7，146.2，133.2，129.8，129.7，128.4，126.8，125.3，120.5，116.5，28.7，18.3，15.4；HRMS(ESI)：Exact?mass?calcd?for?C 17H 17N 2O[M+H] +?265.1335，Found?265.1339.
Figure BDA0000087034270000273
1H?NMR(400MHz，CDCl 3)δ8.09(s，1H)，7.63(d，J＝7.6Hz，2H)，7.53(d，J＝9.2Hz，1H)，7.28(d，J＝8.0Hz，2H)，7.05(dd，J＝9.2Hz，J＝0.8Hz，1H)，5.18(s，2H)，2.70(q，J＝7.6Hz，2H)，2.59(s，3H)，2.30(s，3H)，2.18-2.15(m，3H)，1.27(t，J＝7.6Hz，3H)，0.95(d，J＝6.4Hz，6H)； 13C?NMR(125MHz，CDCl 3)δ172.9，145.9，144.2，144.0，131.6，128.7，128.1，128.0，123.0，122.0，116.5，115.2，42.3，38.6，33.6，28.6，25.6，22.6，18.2，15.4；HRMS(ESI)：Exactmass?calcd?for?C 23H 30N 3O[M+H] +?364.2383，Found?364.2382.
The compound method of Saripidem may further comprise the steps:
Figure BDA0000087034270000281
The first step; Synthesizing of N-(1-(4-chloro-phenyl-) allyl group)-pyridine-2-amine: with 2-amido pyridine (10.0mmol); 4-chlorobenzaldehyde (12mmol; 1.2equiv); Tosic acid (30mg),
Figure BDA0000087034270000282
molecular sieve (10.0g) places the exsiccant THF, back flow reaction 18 hours.Reaction cooled is to-78 ℃, then in the reaction system slowly dropping vinyl Grignard reagent (6mL, 1.0M inTHF, 2.0equiv).Reaction remains on-78 ℃ of reactions and rose to room temperature in 0.5 hour then.In reaction system, add saturated ammonium chloride (1mL) and water successively, ethyl ester ethyl ester (30mL) extraction.Water continues with ethyl acetate extraction one time.Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, remove and desolvate, residuum obtains pure article compound (, 65%) through column chromatography purification.
Second step; Synthesizing of 2-(4-chloro-phenyl-)-imidazoles [1,2-a] pyridine-3-formaldehyde: under the oxygen atmosphere, N-(1-(4-chloro-phenyl-) allyl group)-pyridine-2-amine (; 4.76mmol); (0.952mmol, DMAC N,N 20mol%) (14mL) mixed solution place under 105 ℃ of conditions and reacted 14 hours two hexafluoroacetylacetone copper.Room temperature is reduced in reaction.In reaction, add saturated sodium bicarbonate (30mL), ETHYLE ACETATE (30mL), extraction.Water continues with ethyl acetate extraction two times.Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.On Rotary Evaporators, remove and desolvate, residuum obtains pure article compound (74%) through column chromatography purification.
The 3rd step, Saripidem synthetic: with 2-(4-chloro-phenyl-)-imidazoles [1,2-a] pyridine-3-formaldehyde (3.42mmol); Methylamine hydrochloride (10.26mmol, 3.0equiv), sodium hydrogencarbonate (10.26mmol; 3.0equiv) be suspended in the methyl alcohol (20mL), 65 ℃ were reacted 20 hours.Reaction solution is cooled to room temperature, and (10.26mmol 3.0equiv), reacted one hour disposable adding Peng Qinghuana.Removal of solvent under reduced pressure adds saturated sodium carbonate (20mL) in the residuum, ETHYLE ACETATE (30mL) extraction three times.Merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying.Desolvate revolving in the steaming to remove, add THF (20mL) in the residuum, sodium hydrogencarbonate (10.26mmol, 3.0equiv), drip under the argon gas atmosphere n-butyryl chloride (6.8mmol, 2.0equiv).Mixture room temperature reaction 0.5 hour.In reaction, add saturated sodium bicarbonate (30mL), ETHYLE ACETATE (30mL), extraction.Water continues with ethyl acetate extraction two times.Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying.Desolvate revolving in the steaming to remove, residuum obtains pure article compound (three step yields 85%) through column chromatography purification.
The sign of product:
Figure BDA0000087034270000291
Following?the?general?procedure?C，yield：65％. 1H?NMR(400MHz，CDCl 3)δ8.08(d，J＝5.2Hz，1H)，7.43-7.31(m，5H)，6.61-6.58(m，1H)，6.30(d，J＝8.4Hz，1H)，6.08-6.00(m，1H)，5.32-5.22(m，3H)，4.87(br，1H)； 13C?NMR(100MHz，CDCl 3)δ157.7，148.1，140.0，138.2，137.4，133.0，128.7，128.4，116.2，113.4，107.0，57.7.
Figure BDA0000087034270000292
1H?NMR(400MHz，CDCl 3)δ10.04(s，1H)，9.65(d，J＝6.8Hz，1H)，7.81-7.76(m，3H)，7.59(t，J＝6.8Hz，1H)，7.53-7.49(m，2H)，7.13(t，J＝7.6Hz，1H)； 13C?NMR(125MHz，CDCl 3)δ179.1，156.9，147.7，136.2，131.0，130.8，130.6，129.2，128.8，120.7，117.4，115.4；HRMS(ESI)：Exact?mass?calcd?for?C 14H 10ClN 2O[M+H] +?257.0476，Found?257.0478.
Figure BDA0000087034270000293
1H?NMR(400MHz，CDCl 3)δ8.374-8.357(d，J＝6.8Hz，1H)，7.674-7.653(d，J＝8.4Hz，2H)，7.623-7.600(d，J＝9.2Hz，1H)，7.448-7.426(d，J＝8.8Hz，2H)，7.231(t，J＝8.0Hz，1H)，6.821(t，J＝6.4Hz，1H)，5.164(s，2H)，2.582(s，3H)，2.266(t，J＝7.6Hz，2H)，1.710-1.617(m，2H)，0.939(t，J＝7.2Hz，3H)。
More than be to the specifying of possible embodiments of the present invention, but this embodiment is not in order to limiting claim of the present invention, does not allly break away from the equivalence that skill spirit of the present invention does and implement or change, all should be contained in the claim of the present invention.

Claims (4)

1. structural formula is
Figure FDA0000087034260000011
imidazoles [1; 2-a] the pyridine compounds compound method; It is characterized in that, may further comprise the steps:
(1): under alkaline condition, make N-allyl group-2-EL-970 with the allyl bromide 98 reaction by the 2-EL-970:
Figure FDA0000087034260000012
With n-Butyl Lithium or potassium tert.-butoxide is alkali, and THF is a solvent;
Or obtain the substituted N-allyl group of allylic-2-EL-970 through one two step one kettle way reaction by 2-EL-970, corresponding aldehyde and vinyl Grignard reagent:
Figure FDA0000087034260000013
The first step is catalyzer with the tosic acid;
Figure FDA0000087034260000014
molecular sieve is a siccative; THF is a solvent, is heated to backflow; After reaction finishes, in reaction system, drip anhydrous vinyl Grignard reagent, remain on-75 to-80 ℃ of reactions and rose to room temperature reaction in 0.3-0.7 hour then;
(2) prepare the purpose compound by the substituted N-allyl group of allylic-2-EL-970 again:
Figure FDA0000087034260000015
With two (hexafluoroacetylacetone) copper is catalyzer, under the oxygen atmosphere, and N, dinethylformamide is a solvent, is heated to 100-110 ℃ of reaction;
R in the said structure formula and R 1Be hydrogen, aryl, alkyl, or halogen; R 2Be hydrogen, aryl, alkyl or heterocycle.
2. structural formula is the compound method of
Figure FDA0000087034260000021
imidazole aldehyde compounds; It is characterized in that, may further comprise the steps:
(1) under Louis acid catalysis, carry out nucleophilic addition through itrile group compound and allylamine,
Figure FDA0000087034260000022
With the aluminum chloride is catalyzer, is heated to 110-130 ℃, reacts under the condition of no solvent;
(2) preparation purpose compound:
Figure FDA0000087034260000023
With two (trifluoromethanesulfonic acid) copper is catalyzer, and potassiumphosphate is an alkali, the oxygen atmosphere, and DMAC N,N is a solvent, is heated to 100-110 ℃ of reaction;
R in the said structure formula and R 1Be hydrogen, aryl, alkyl, or halogen; R 2Be hydrogen, aryl, alkyl or heterocycle.
3. the compound method of
Figure FDA0000087034260000024
; It is characterized in that, may further comprise the steps:
Figure FDA0000087034260000031
The first step; Synthesizing of N-(1-(4-ethylphenyl) allyl group)-5-picoline-2-amine: with 2-amido-5-picoline; 4-ethylbenzene formaldehyde; Tosic acid;
Figure FDA0000087034260000032
molecular sieve places the exsiccant THF, back flow reaction 15-20 hour; Reaction cooled slowly drips the vinyl Grignard reagent then to-75 to-80 ℃ in reaction system; Reaction remains on-75 to-80 ℃ of reactions and rose to room temperature in 0.3-0.7 hour then; In reaction system, add saturated ammonium chloride and water successively, the extraction of ethyl ester ethyl ester; Water continues to use ethyl acetate extraction; Merge organic phase, washing, drying; Remove and desolvate, residuum obtains N-(1-(4-ethylphenyl) allyl group)-5-picoline-2-amine through column chromatography purification;
Second step; 2-(4-ethylphenyl)-6-methyl-imidazoles [1; 2-a] pyridine-3-formaldehyde synthetic: under the oxygen atmosphere; N-(1-(4-ethylphenyl) allyl group)-5-picoline-2-amine, the DMAC N,N mixed solution of two hexafluoroacetylacetone copper place under the 100-110 ℃ of condition and reacted 12-16 hour; Room temperature is reduced in reaction; In reaction, add saturated sodium bicarbonate, ETHYLE ACETATE, extraction; Water continues with ethyl acetate extraction two times; Merge organic phase, washing, drying; Remove and desolvate, residuum obtains 2-(4-ethylphenyl)-6-methyl-imidazoles [1,2-a] pyridine-3-formaldehyde through column chromatography purification;
In the 3rd step, necopidem synthetic: with 2-(4-ethylphenyl)-6-methyl-imidazoles [1,2-a] pyridine-3-formaldehyde, methylamine hydrochloride, sodium hydrogencarbonate are suspended in the methyl alcohol, 60-70 ℃ of reaction 18-22 hour; Reaction solution is cooled to room temperature, disposable adding Peng Qinghuana, removal of solvent under reduced pressure after reaction finishes adds saturated sodium carbonate, ethyl acetate extraction in the residuum; Merge organic phase, saturated common salt washing, anhydrous sodium sulfate drying; Desolvate revolving in the steaming to remove, add THF in the residuum, sodium hydrogencarbonate drips 3-methylbutyryl chlorine under the argon gas atmosphere; Mixture room temperature reaction 0.5 hour; In reaction, add saturated sodium bicarbonate, ETHYLE ACETATE, extraction; Water continues to use ethyl acetate extraction; Merge organic phase, with saturated common salt washing, anhydrous sodium sulfate drying; Remove and desolvate, residuum obtains necopidem through column chromatography purification.
4. the compound method of
Figure FDA0000087034260000041
; It is characterized in that, may further comprise the steps:
Figure FDA0000087034260000042
The first step; Synthesizing of N-(1-(4-chloro-phenyl-) allyl group)-pyridine-2-amine: with 2-amido pyridine; The 4-chlorobenzaldehyde; Tosic acid,
Figure FDA0000087034260000043
molecular sieve places the exsiccant THF, and it is anti-to reflux; Reaction finishes postcooling to-75 to-80 ℃, in reaction system, slowly drips the vinyl Grignard reagent then; Reaction remains on-75 to-80 ℃ of reactions, rises to room temperature after reaction finishes; In reaction system, add saturated ammonium chloride and water successively, the extraction of ethyl ester ethyl ester; Water continues to use ethyl acetate extraction; Merge organic phase, washing, drying; Remove and desolvate, residuum obtains N-(1-(4-chloro-phenyl-) allyl group)-pyridine-2-amine through column chromatography purification;
Second step; Synthesizing of 2-(4-chloro-phenyl-)-imidazoles [1,2-a] pyridine-3-formaldehyde: under the oxygen atmosphere, N-(1-(4-chloro-phenyl-) allyl group)-pyridine-2-amine; The DMAC N,N mixed solution of two hexafluoroacetylacetone copper places under the 100-110 ℃ of condition and reacted 12-16 hour; Room temperature is reduced in reaction; In reaction, add saturated sodium bicarbonate, ETHYLE ACETATE, extraction; Water continues to use ethyl acetate extraction; Merge organic phase, washing, drying; Remove and desolvate, residuum obtains 2-(4-chloro-phenyl-)-imidazoles [1,2-a] pyridine-3-formaldehyde through column chromatography purification;
In the 3rd step, Saripidem synthetic: with 2-(4-chloro-phenyl-)-imidazoles [1,2-a] pyridine-3-formaldehyde, methylamine hydrochloride, sodium hydrogencarbonate are suspended in the methyl alcohol, 60-70 ℃ of reaction 18-22 hour; Reaction solution is cooled to room temperature, disposable adding Peng Qinghuana, removal of solvent under reduced pressure after reaction finishes adds saturated sodium carbonate, ethyl acetate extraction in the residuum; Merge organic phase, washing, nothing drying; Remove and desolvate, add THF in the residuum, sodium hydrogencarbonate drips n-butyryl chloride under the argon gas atmosphere; The mixture room temperature reaction adds saturated sodium bicarbonate after reaction finishes in reaction, ETHYLE ACETATE, extraction; Water continues with ethyl acetate extraction two times; Merge organic phase, washing, drying are removed and are desolvated, and residuum obtains Saripidem through column chromatography purification.
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