Indeno isoquinoline compounds and preparation method thereof
阅读说明：本技术 茚并异喹啉类化合物及其制备方法 (Indeno isoquinoline compounds and preparation method thereof ) 是由 徐允河 邱圣祺 李曼 于 2019-10-22 设计创作，主要内容包括：本发明公开了茚并异喹啉类化合物及其制备方法,特征是以预制官能团的联烯分子,在钯催化剂、配体和碱金属醋酸盐(如醋酸钠)的作用下发生分子内双芳基化反应,得到茚并异喹啉类化合物。本发明采用一步法,通过钯催化实现联烯分子的分子内双芳基化反应,体系简单,无需经过额外处理即可得到茚并异喹啉类化合物,简便易行,易于操作,底物适用性广,能耐受多种官能团,且产物收率显著高于传统合成方法。本发明成功实现了茚并异喹啉类化合物的合成,很容易制得高产率的茚并异喹啉类化合物。该类茚并异喹啉类化合物,可直接或经过进一步修饰后作为抗肿瘤药物前体。本发明为发展一类新型抗肿瘤药物提供了新的合成手段,具有经济实用性和工业应用前景。(The invention discloses indenoisoquinoline compounds and a preparation method thereof, which are characterized in that a diene molecule with a prefabricated functional group is subjected to intramolecular diarylation reaction under the action of a palladium catalyst, a ligand and alkali metal acetate (such as sodium acetate) to obtain the indenoisoquinoline compounds. The method adopts a one-step method, realizes intramolecular diarylation reaction of allene molecules through palladium catalysis, has a simple system, can obtain the indeno isoquinoline compounds without additional treatment, is simple and easy to operate, is easy to operate, has wide substrate applicability, can tolerate various functional groups, and has a product yield remarkably higher than that of the traditional synthetic method. The invention successfully realizes the synthesis of the indeno isoquinoline compounds, and the indeno isoquinoline compounds with high yield can be easily prepared. The indenoisoquinoline compound can be directly used as an antitumor drug precursor or used as an antitumor drug precursor after being further modified. The invention provides a new synthesis means for developing a novel anti-tumor drug, and has economic practicability and industrial application prospect.)
1. An indeno isoquinoline compound, which is characterized by having an indeno [1,2-c ] isoquinoline skeleton structure shown in a formula II:
wherein R is1、R2、R3、R4、R6、R7、R8、R9And R12Each independently selected from alkyl, alkoxy, halogen or hydrogen, and
R10、R11each independently selected from hydrogen, alkyl, aryl or heteroaryl.
2. The compound of claim 1, wherein the compound is selected from the group consisting of:
3. a compound selected from
4. A method for preparing indenoisoquinoline compounds,
the method is characterized in that:
adding the compound shown in the formula 1, a palladium catalyst, a ligand and alkali metal acetate into an organic solvent, and synthesizing the indenoisoquinoline compound shown in the formula II or a corresponding product marked by an enantiomer, a racemate, a diastereoisomer or an isotope thereof by adopting a one-step method:
wherein R is1、R2、R3、R4、R6、R7、R8、R9And R12Each independently selected from alkyl, alkoxy, halogen or hydrogen;
R5selected from acyl, sulfonyl or sulfinyl;
R10and R11Each independently selected from hydrogen, alkyl, aryl or heteroaryl;
x is halogen.
5. The method of claim 4, wherein the molar ratio of the compound of formula 1 to the palladium catalyst is from 100:1 to 10:1, the molar ratio of the palladium catalyst to the ligand is from 1:1 to 1:2, and the molar ratio of the compound of formula 1 to the alkali metal acetate is from 2:1 to 1: 5.
6. The process of claim 4, wherein the palladium catalyst is tetrakistriphenylphosphine palladium, bis (dibenzylideneacetone) palladium, or tris (dibenzylideneacetone) dipalladium, or
Wherein the ligand is triphenylphosphine, tri (m-methoxyphenyl) phosphine, tri (p-dimethylaminophenyl) phosphine or 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene.
7. The process according to claim 4, wherein the alkali metal acetate is sodium acetate or the organic solvent is selected from polar organic solvents such as N, N-dimethylformamide, N-dimethylacetamide or dimethylsulfoxide, preferably N, N-dimethylformamide.
8. The method according to claim 4, wherein the method is performed under a protective atmosphere, preferably the protective atmosphere is nitrogen, argon or helium.
9. The process of claim 4, wherein the reaction temperature is 80-140 ℃, or the reaction time is 8-36 hours.
10. The method of claim 4, wherein the indenoisoquinoline-based compound is a compound according to any one of claims 1 to 3.
Technical Field
The invention belongs to the technical field of indeno isoquinoline compounds, and particularly relates to an indeno isoquinoline compound and a preparation method thereof.
Background
The indenoisoquinoline and the derivatives thereof, as potential anti-tumor active compounds, have the advantages of more stable activity, lower cytotoxicity and the like compared with camptothecin topoisomerase I inhibitors (topotecan and the like). Some of the indenoisoquinoline derivatives have been subjected to preliminary antitumor activity tests (Song, Y., Shao, z., Dexheimer, t.s., Scher, e.s., Pommier, Y. & Cushman, m.j.med.chem.2010,53, 1979-:
regarding the construction of indenoisoquinoline skeleton, the currently reported synthesis method mainly uses (2, 2-dimethoxyethyl) benzylamine and benzaldehyde or aryl imine to condense in hydrochloric acid. However, the synthesis yield of the reaction is very low, the substrate universality is also narrow, and the research and the application of the indeno isoquinoline compounds are limited. Therefore, a simple and efficient preparation method of the indeno isoquinoline compound is urgently needed to be developed.
Disclosure of Invention
The invention aims to provide an indeno isoquinoline compound and a preparation method thereof, and the preparation of the indeno isoquinoline compound is realized through a allene intramolecular diarylation reaction so as to overcome the defects in the prior art.
The invention relates to an indeno isoquinoline compound, which is characterized in that the indeno [1,2-c ] isoquinoline skeleton structure is shown as a formula II:
substituent R in indenoisoquinoline compounds of formula II1、R2、R3、R4、R6、R7、R8、R9And R12Each independently selected from alkyl, alkoxy, halogen or hydrogen; substituent R10And R11Each independently selected from hydrogen, alkyl, aryl or heteroaryl.
In a particular embodiment, R10And R11One of which is hydrogen and the other is tert-butyl.
In a particular embodiment, R10And R11One of which is hydrogen and the other is phenyl.
In a particular embodimentIn the scheme, R10And R11One of which is hydrogen and the other is heteroaryl.
Specifically, the indenoisoquinoline compounds comprise compounds with the following structures:
specifically, the indenoisoquinoline compounds include the following compounds:
the invention also relates to a preparation method of the indenoisoquinoline compound, which is characterized by comprising the following steps: using allene molecules with prefabricated functional groups, adopting a one-step method to synthesize an indenoisoquinoline skeleton,
wherein the substituent R1、R2、R3、R4、R6、R7、R8、R9And R12Each independently selected from alkyl, alkoxy, halogen or hydrogen;
wherein the substituent R5Selected from acyl, sulfonyl or sulfinyl;
wherein the substituent R10And R11Each independently selected from hydrogen, alkyl, aryl or heteroaryl;
wherein the substituent X is halogen;
as used herein, acyl refers to alkyl-C (═ O) -or aryl-C (═ O) -.
As used herein, sulfonyl means alkyl-S (═ O)2-or aryl-S (═ O)2-。
As used herein, sulfinyl refers to alkyl-S (═ O) -or aryl-S (═ O) -.
As used herein, alkyl includes, but is not limited to, C1-6Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl, n-hexyl, and the like.
As used herein, alkoxy includes, but is not limited to, C1-6Alkoxy, such as methoxy, ethoxy, isopropoxy, and the like.
As used herein, halogen includes fluorine, chlorine, bromine and iodine.
As used herein, aryl groups may be selected from phenyl, naphthyl, and substituted aryl (e.g., substituted phenyl); the substituted aryl group includes, but is not limited to, alkyl groups, alkoxy groups, halogen groups, and the like substituted aryl groups (e.g., phenyl groups), such as methyl groups, methoxy groups, fluorine atoms, or chlorine atoms substituted aryl groups (e.g., phenyl groups).
The term "heteroaryl" denotes a monovalent aromatic heterocyclic mono-or polycyclic ring system of 5 to 12 ring atoms comprising 1,2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, and the like,
In a particular embodiment, R5Selected from acetyl or p-toluenesulfonyl. In a particular embodiment, R10And R11One of which is hydrogen and the other is phenyl.
The specific operation steps are as follows:
under the protective atmosphere, a divinyl compound and a derivative thereof, namely a compound of a formula 1 are used as reaction substrates, the compound of the formula 1, a palladium catalyst, a ligand and alkali metal acetate are added into an organic solvent, wherein the molar ratio of the compound of the formula 1 to the palladium catalyst is 100: 1-10: 1, the molar ratio of the palladium catalyst to the ligand is 1: 1-1: 2, the molar ratio of the compound of the formula 1 to the acetate is 2: 1-1: 5, an arylation reaction is carried out for 8-36 hours at 80-140 ℃, a reaction end point is determined by a thin-layer chromatography dot plate, and then column chromatography is carried out to obtain a corresponding indeno-isoquinoline compound II or a corresponding product marked by an enantiomer, a racemate, a diastereoisomer or an isotope thereof.
In some embodiments, the palladium catalyst is tetrakistriphenylphosphine palladium, bis (dibenzylideneacetone) palladium, or tris (dibenzylideneacetone) dipalladium.
In some embodiments, the ligand is triphenylphosphine, tris (m-methoxyphenyl) phosphine, tris (p-dimethylaminophenyl) phosphine, or 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene.
In some embodiments, the protective atmosphere is nitrogen, argon, or helium.
In some embodiments, the molar ratio of the compound of formula 1 to the palladium catalyst is from 100:1 to 10:1, preferably 10: 1.
In some embodiments, the molar ratio of palladium catalyst to ligand is from 1:1 to 1:2, preferably 1: 1.
In some embodiments, the molar ratio of the compound of formula 1 to alkali metal acetate is from 2:1 to 1:5, preferably 1: 3.
In some embodiments, the alkali metal acetate is selected from sodium acetate, potassium acetate, and the like, preferably sodium acetate.
In some embodiments, the organic solvent is selected from polar organic solvents such as N, N-dimethylformamide, N-dimethylacetamide or dimethylsulfoxide, preferably N, N-dimethylformamide.
In some embodiments, the reaction temperature is 80-140 ℃, preferably 100 ℃.
In some embodiments, the reaction time is 8 to 36 hours, preferably 8 hours.
According to the synthesis method of the indenoisoquinoline compound, a one-step method is adopted, allene molecules with prefabricated functional groups are subjected to intramolecular diarylation reaction under the action of a palladium catalyst, a ligand and alkali metal acetate (such as sodium acetate), and the indenoisoquinoline compound is obtained; the existing synthesis method of the indenoisoquinoline compound is realized by using (2, 2-dimethoxyethyl) benzylamine and benzaldehyde or aryl imine through condensation reaction, so that the reaction yield of the final step is low, and the waste of valuable raw materials is serious. Because the invention adopts a one-step method, realizes intramolecular diarylation reaction of allene molecules by palladium catalysis, has simple system, can obtain indeno isoquinoline compounds without additional treatment, is simple and easy to operate, wide in substrate applicability, capable of tolerating various functional groups, and has the product yield remarkably higher than that of the traditional synthetic method (the total synthetic yield is generally lower than 10%). The invention not only successfully realizes the synthesis of the indeno isoquinoline compounds, but also simplifies the traditional synthesis method, and the indeno isoquinoline compounds with high yield can be easily prepared. The indenoisoquinoline compound can be directly used as an antitumor drug precursor or used as an antitumor drug precursor after being further modified. The invention provides a new synthesis means for developing a novel anti-tumor drug, and has economic practicability and industrial application prospect.
Detailed Description