阅读说明：本技术 5-氨基-1,2,4-噁二唑类衍生物及其合成方法 (5- amino -1,2,4- furodiazole derivative and its synthetic method ) 是由 汪煦 付金萍 李利军 于 2019-09-12 设计创作，主要内容包括：本发明公开了一类5-氨基-1,2,4-噁二唑类衍生物及其合成方法。所述的5-氨基-1,2,4-噁二唑类衍生物具有如下式(I)所示结构,其合成方法为：在钯催化剂存在且氧气存在的条件下,由如下式(II)所示化合物和式(III)所示化合物在有机溶剂中,于加热或不加热条件下反应,制得目标化合物粗品。本发明所述合成方法简单易控,周期短,产率高。所述式(I)、式(II)和式(III)所示结构的化合物分别如下：<Image he="139" wi="700" file="DDA0002200784510000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a kind of 5- amino -1,2,4- furodiazole derivative and its synthetic methods.The 5- amino -1,2,4- furodiazole derivative has the structure as shown in following formula (I), its synthetic method are as follows: palladium catalyst exist and oxygen existing under the conditions of, the compound as shown in the compound as shown in following formula (II) and formula (III) is in organic solvent, it is reacted under the conditions of being heated or not heated, target compound crude product is made.Synthetic method of the present invention is simple and easy to control, and the period is short, and yield is high.The compound difference of structure shown in the formula (I), formula (II) and formula (III) is as follows:)

1. compound shown in following formula (I)s or its pharmaceutically acceptable salt:

Wherein:

R indicates the phenyl or naphthalene that phenyl, alkyl-substituted phenyl or vinyl that alkyl, phenyl, halogen atom replace replace Base or substituted naphthalene thienyl or substituted thienyl furyl or substituted furyl or pyrrole Piperidinyl or substituted pyridyl group, Huo person's Shi Benzyl base or substituted Benzyl base；

R ' indicates tert-butyl, adamantyl or 1,1,3,3- 4-methyl-butane base.

2. compound according to claim 1, it is characterised in that: R indicate alkyl, phenyl, 4- fluorophenyl, 4- chlorphenyl, 4- bromophenyl, 2- aminomethyl phenyl, 3- aminomethyl phenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- trifluoromethyl, 3,2- bis- Aminomethyl phenyl, 3,4- 3,5-dimethylphenyl, ethenylphenyl, naphthalene, thienyl, furyl, pyridyl group, Benzyl base or 4- methoxybenzyl Base.

3. the synthetic method of compound described in claim 1, it is characterised in that: mainly comprise the steps that and deposited in palladium catalyst And oxygen existing under the conditions of, the compound as shown in the compound as shown in following formula (II) and formula (III) in organic solvent, in It is reacted under the conditions of being heated or not heated, target compound crude product is made；

Wherein:

R indicate the phenyl that phenyl, alkyl-substituted phenyl or vinyl that phenyl, halogen atom replace replace or naphthalene or Substituted naphthalene thienyl or substituted thienyl furyl or substituted furyl or pyridyl group Or the pyridyl group replaced, Huo person's Shi Benzyl base or substituted Benzyl base；

R ' indicates tert-butyl, adamantyl or 1,1,3,3- tetramethyl butyl.

4. synthetic method according to claim 3, it is characterised in that: alkaline matter is added before reactions.

5. synthetic method according to claim 4, it is characterised in that: the alkaline matter be sodium acetate, tripotassium phosphate, Sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, fluorine Change the combination of one or more of potassium, cesium fluoride, pyridine, triethylamine and N, N- diisopropyl ethyl amine.

6. the synthetic method according to any one of claim 3-5, it is characterised in that: the palladium catalyst is selected from four (triphenylphosphine) palladium, palladium chloride, palladium acetate, two (triphenylphosphine) palladium chlorides, in two (cyano benzene) palladium chlorides and dibrominated palladium A combination of one or more.

7. the synthetic method according to any one of claim 3-5, it is characterised in that: the organic solvent be selected from In benzene, toluene, dimethyl sulfoxide, acetonitrile, n,N-Dimethylformamide, N-Methyl pyrrolidone, benzonitrile and Isosorbide-5-Nitrae dioxane A combination of one or more.

8. the synthetic method according to any one of claim 3-5, it is characterised in that: reaction under conditions of not heating into Row.

9. the synthetic method according to any one of claim 3-5, it is characterised in that: further include to target chemical combination obtained The step of object crude product is purified.

10. synthetic method according to claim 9, it is characterised in that: the step of purifying is by targeted obtained It closes object crude product and carries out silica gel column chromatography, obtain target compound after purification.

Technical field

The present invention relates to furodiazole compounds, and in particular to 5- amino -1,2,4- furodiazole derivative and its synthesis Method.

Background technique

In field of medicaments, for heterocyclic compound in occupation of very important status, chemical structure is ever-changing, each own Special property and important use.Wherein, nitrogen-containing heterocycle is many kinds of and exists extensively, is many biologically active days Very important structural unit in right and non-natural compound skeleton passes through compounding design in recent years and obtains variety classes and function Nitrogen-containing heterocycle compound have become pharmaceutical chemistry and synthesize chemical research hot spot.

Oxadiazoles heterocycle compound is widely paid close attention to because it has the characteristics that efficient, structure is changeable by researchers. Wherein, Vidal reports 3- glycosyl -5- amino -1,2,4- furodiazole compound table in terms of glycogen phosphorylase inhibitors Reveal excellent effect (Beilstein J.Org.Chem.2015,11,499-503)；Hamel reports amino -1,2 5-, 4- furodiazole compound is as effective Antitubulin, between tubulin binding and cell static mechanical performance There are good correlation (Bioorg.Med.Chem. Lett.2013,23,1262-1268)；Layton reports 5- amino- 1,2,4- furodiazole compound is shown good as effective NR2B- selective NMDA receptor antagonists in animal experiment Good selectivity, and do not have an adverse effect to motor function in patient's large dose oral administration, especially in Parkinson's sufferer Good efficiency (ACS Chem.Neurosci.2011,2,352-362) is shown after person is oral.But it has not yet to see with acyl Amidoxime and different cyanides are raw material, and synthesis obtains 5- amino -1,2,4- furodiazole chemical combination under the action of palladium catalyst The relevant report of object.

Summary of the invention

The technical problem to be solved in the present invention is to provide the 5- amino -1,2,4- furodiazole derivatives of a kind of structure novel And its synthetic method.

5- amino -1,2,4- furodiazole derivative of the present invention be with compound shown in following formula (I)s or its Pharmaceutically acceptable salt:

Wherein:

R indicates the phenyl that phenyl, alkyl-substituted phenyl or vinyl that alkyl, phenyl, halogen atom replace replace, or It is naphthalene or substituted naphthalene thienyl or substituted thienyl or furyl or substituted furyl, or It is pyridyl group or substituted pyridyl group, Huo person's Shi Benzyl base or substituted Benzyl base；

R ' indicates tert-butyl, adamantyl or 1,1,3,3- 4-methyl-butane base.

In above compound, R is more preferably alkyl, phenyl, 4- fluorophenyl, 4- chlorphenyl, 4- bromophenyl, 2- first Base phenyl, 3- aminomethyl phenyl, 4- aminomethyl phenyl, 4- methoxyphenyl, 4- trifluoromethyl, 3,2- 3,5-dimethylphenyl, 3,4- 3,5-dimethylphenyl, ethenylphenyl, naphthalene, thienyl, furyl, pyridyl group, Benzyl base or 4- methoxy-benzyl.

The synthetic method of compound shown in above-mentioned formula (I), mainly comprise the steps that palladium catalyst exist and oxygen deposit Under the conditions, the compound as shown in the compound as shown in following formula (II) and formula (III) in organic solvent, Yu Jiare or is not added It is reacted under heat condition, target compound crude product is made；

Wherein:

R indicates the phenyl or naphthalene that phenyl, alkyl-substituted phenyl or vinyl that phenyl, halogen atom replace replace Base or substituted naphthalene thienyl or substituted thienyl furyl or substituted furyl or pyrrole Piperidinyl or substituted pyridyl group, Huo person's Shi Benzyl base or substituted Benzyl base；

R ' indicates tert-butyl, adamantyl or 1,1,3,3- tetramethyl butyl.

In above-mentioned synthetic method, R's is preferably selected as previously described.

In synthetic method of the present invention, compound shown in the raw material formula (II) that is related to is amide 9 oxime derivate, be can refer to Existing literature (Li, S., Wan, P., Ai, J., Sheng, R., Hu, Y., &Hu, Y. (2017) .Pallad ium-Catalyzed, Silver-Assisted Direct C-5–H Arylation of 3-Substitute d 1,2,4-Oxadiazoles Under Microwave Irradiation.Advanced Synthesis&Catal ysis, 359 (5), 772-778.) into Row synthesis, can also free design synthetic route synthesized, this will not be detailed here.Compound shown in the raw material formula (III) being related to For isocyanide derivative, can be bought directly from the market.

In synthetic method of the present invention, the molar ratio of compound shown in compound shown in formula (II) and formula (III) is to change Metering ratio is learned, in actual operation, the molar ratio of compound shown in compound shown in formula (II) and formula (III) is usually 1:1- 1.2。

In order to improve reaction yield, alkaline matter is preferably added before reactions.The alkaline matter is that can expire The substance of hydrogen in compound shown in foot removing formula (II) in substituent R, specifically can be selected from sodium acetate, tripotassium phosphate, hydrogen Sodium oxide molybdena, potassium hydroxide, calcium hydroxide, cesium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, fluorination Potassium, cesium fluoride, pyridine, triethylamine and N, the combination of one or more of N- diisopropyl ethyl amine.The basic species The additional amount of matter is usually 1 times or more of compound mole shown in formula (II), and preferably 2-4 times.

In synthetic method of the present invention, the selection of the palladium catalyst is identical as existing technology, specifically can be selected from four (triphenylphosphine) palladium, palladium chloride, palladium acetate, two (triphenylphosphine) palladium chlorides, in two (cyano benzene) palladium chlorides and dibrominated palladium A combination of one or more.The additional amount of the palladium catalyst is usually 3% of compound mole shown in formula (II) More than, preferably 3-5%.

In synthetic method of the present invention, the organic solvent specifically can be selected from the organic solvent be selected from In benzene, toluene, dimethyl sulfoxide, acetonitrile, n,N-Dimethylformamide, N-Methyl pyrrolidone, benzonitrile and Isosorbide-5-Nitrae dioxane A combination of one or more.The dosage of the organic solvent is advisable with that can dissolve the raw material participated in and reacted, usual situation Under, on the basis of compound shown in the formula (II) of 0.5mmol, all raw materials for participating in reaction usually use that 0.5-5mL's is organic molten Agent is dissolved.

In synthetic method of the present invention, reaction is typically chosen under air conditions and carries out, and reaction can in heating or not Carried out under conditions of heating, preferably reaction be to be carried out under conditions of not heating, under conditions of more preferably 20~25 DEG C into Row.Whether reaction can be used TLC tracing detection completely.According to the experience of applicant, when reaction carries out under the conditions of 20~25 DEG C When, reaction time control is more suitable in 2-6h.

Prepared by the above method is the crude product of formula (I) compound, and existing conventional purification process can be used and carry out to it It purifies to improve the purity of formula (I) compound.The mode for generalling use silica gel column chromatography is purified, the elution in chromatography Agent can be the mixed solvent being made of ethyl acetate and petroleum ether by the volume ratio of 1:5-100.The in the mixed solvent, second The volume ratio of acetoacetic ester and petroleum ether is preferably 1:5-50, more preferably 1:5-20.

Compared with prior art, the present invention provides a series of 5- amino -1,2 of structure novels, 4- furodiazole is derivative Object and its synthetic method, and the synthetic method provided is simple and easy to control, the period is short, and yield is high.

Specific embodiment

The present invention is described in further detail combined with specific embodiments below, content to better understand the invention, but The present invention is not limited to following embodiments.