阅读说明：本技术 一种n杂原子多取代苯并四元环酮的合成方法及应用 (Synthesis method and application of N heteroatom polysubstituted benzoquaternary cyclic ketone ) 是由 徐涛 邱波 张建宇 战俊玲 李晓彤 于 2018-08-22 设计创作，主要内容包括：本发明公开了一种N杂原子多取代苯并四元环酮的合成方法,合成路线从已知的苯胺化合物A开始,可以实现百克级规模的制备,收率可以达到90％以上,而该路线的每一个步骤都可以实现二十克级规模以上的反应,本发明提供的合成路线为这些具有生物活性的化合物的合成带来一条更为简洁有效的途径,并且收率高,可大规模制备。并且公开了N杂原子多取代苯并四元环酮的应用,与不同的酰氯反应,可以制得不同的产物,具有很广阔的应用前景。(The invention discloses a synthetic method of N heteroatom polysubstituted benzoquaternary cyclic ketone, which starts from a known aniline compound A, can realize preparation on a hectogram scale, and has the yield of over 90 percent, and each step of the route can realize reaction on a twenty gram scale. And discloses the application of N heteroatom polysubstituted benzoquaternary cyclic ketone, different products can be prepared by reacting with different acyl chloride, and the N heteroatom polysubstituted benzoquaternary cyclic ketone has a very wide application prospect.)

1. A synthetic method of N heteroatom polysubstituted benzotetracyclic ketone is characterized by comprising the following steps:

(1) dissolving the compound A in a THF solution, adding LDA, adding equivalent methyl iodide, ethyl iodide or benzyl bromide under the action of removing one molecule H on N by LDA, and stirring at room temperature for 1-4 hours to connect three different protecting groups of methyl, ethyl or benzyl to obtain a compound B;

(2) dissolving the compound B in a THF solution, adding LDA, adding excessive ethyl chloroformate under the action of LDA removing another molecule of H on N, and reacting at 40-60 ℃ to connect an ester side chain to obtain a compound C;

(3) adding n-butyllithium into a THF solution at the temperature of 0 ℃, stirring overnight at room temperature to obtain an alkenyloxy lithium solution, then adding a compound C into the prepared excessive alkenyloxy lithium solution, adding a 1.5-2 times of n-butyllithium solution, and stirring, wherein in the process, n-BuLi and the compound C are subjected to lithium halide exchange and cyclized with the alkenyloxy lithium to obtain a compound D;

(4) respectively adding excessive oxalyl chloride and DMSO DCM solution into a dry flask filled with nitrogen, then dropwise adding a compound D solution dissolved in DCM, reacting for 0.5-1.5 h, adding triethylamine, heating to room temperature, and oxidizing hydroxyl into carbonyl through Swern oxidation to obtain a compound E;

(5) adding excessive HBr/HAc solution into the HAc solution of the compound E, stirring to remove an ester side chain to obtain a compound F, namely the required N heteroatom polysubstituted benzoquaternary cyclic ketone;

the specific reaction process is as follows:

2. the method for synthesizing N heteroatom polysubstituted benzoquaternary ring ketone, according to claim 1, characterized in that in step (1) and step (2), LDA is added in equal amount at-78 ℃.

3. The method for synthesizing an N heteroatom polysubstituted benzotetracyclic ketone, according to claim 1, wherein in the step (3), the compound C is added into the prepared excess alkenyl oxy-lithium solution at-78 ℃, and then the N-butyl lithium solution is added and stirred for 0.5 hour.

4. The method for synthesizing N heteroatom polysubstituted benzotetracyclic ketone, according to claim 1, characterized in that in step (4), excess oxalyl chloride and DMSO respectively in DCM are added in dry flask filled with nitrogen at-78 ℃.

5. The method for synthesizing N-heteroatom-polysubstituted benzoquaternary ring ketone, according to claim 1, characterized in that in step (5), at 40 ℃, excess HBr/HAc solution is added into HAc solution of compound E, and the mixture is stirred for two days to remove the side chain.

6. The method for synthesizing N heteroatom polysubstituted benzotetracyclic ketone according to claim 1, wherein in step (1) and step (3), NH is used after the reaction is completed₄Quenched with aqueous Cl, extracted with ethyl acetate, washed with brine, MgSO₄Drying, concentrating and purifying by silica gel chromatography to obtain compound B or compound D.

7. The method as claimed in claim 1, wherein in step (2), NH is used after the reaction is completed₄Quenched with aqueous Cl, extracted with EA, washed with brine, MgSO₄Drying, concentration and purification by silica gel chromatography gave compound C.

8. The method for synthesizing N-heteroatom polysubstituted benzotetracyclic ketone in claim 1, wherein in step (4), after the reaction is completed, H is added₂Quench O, extract with ethyl acetate, wash the combined organic layers with brine and MgSO₄Drying, concentrating the organic layer under reduced pressure and purifying by silica gel column chromatography to give yellow compound E.

9. The method for synthesizing N-heteroatom polysubstituted benzoquaternary ring ketone, according to claim 1, wherein in step (5), after the reaction is completed, the solution is treated with NaHCO₃The solution was adjusted to alkaline pH, poured into ice water and extracted with DCM, washed with brine, and MgSO₄Drying, concentration and purification by silica gel chromatography gave compound F.

10. Use of N-heteroatom polysubstituted benzotetracyclic ketones characterized in that an acid chloride is added to a solution of compound F and DMAP in DCM at room temperature, the solution is stirred for 2 hours and quenched, NaHCO is extracted with DCM₃And is washed by brine,purifying to obtain a compound G, wherein the specific reaction process is as follows:

in the formula, R₅Comprises the following steps: ethyl, 2-methylbut-1-enyl, methylcyclopropyl, 3, 4-dihydro-2H-pyran, 1-methyl-1H-indolophenyl, 8-methoxy-2H-chromenyl, indenyl, tolyl, prop-1-en-1-ylphenyl, phenyl, anisole.

Technical Field

The invention relates to benzoquaternarycyclic ketone, in particular to a synthetic method and application of N heteroatom polysubstituted benzoquaternarycyclic ketone.

Background

The four-membered ring in the benzocyclobutene has larger ring tension, the compound of the type is widely used for activating carbon-carbon bonds at present, and different substituent benzocyclobutene can obtain various types of products, such as spiro, cyclo and other various types of compounds under appropriate conditions through the activation of the carbon-carbon bonds. However, the preparation of the benzocyclobutene with different substituents still has certain difficulty, the benzocyclobutene with the oxygen substituent has already been prepared on a large scale, and the N heteroatom polysubstituted benzocyclobutene is not reported yet.

Disclosure of Invention

In order to solve the technical problems, the invention provides a synthetic method and application of N heteroatom polysubstituted benzoquatermary cyclic ketone, so as to achieve the aim of preparing the N heteroatom polysubstituted benzoquatermary cyclic ketone on a large scale.

In order to achieve the purpose, the technical scheme of the invention is as follows:

a method for synthesizing N heteroatom polysubstituted benzotetracyclic ketone comprises the following steps:

(1) dissolving the compound A in a THF solution, adding LDA, adding equivalent methyl iodide, ethyl iodide or benzyl bromide under the action of removing one molecule H on N by LDA, and stirring at room temperature for 1-4 hours to connect three different protecting groups of methyl, ethyl or benzyl to obtain a compound B;

(2) dissolving the compound B in a THF solution, adding LDA, adding excessive ethyl chloroformate under the action of LDA removing another molecule of H on N, and reacting at 40-60 ℃ to connect an ester side chain to obtain a compound C;

(3) adding n-butyllithium into a THF solution at the temperature of 0 ℃, stirring overnight at room temperature to obtain an alkenyloxy lithium solution, then adding a compound C into the prepared excessive alkenyloxy lithium solution, adding a 1.5-2 times of n-butyllithium solution, and stirring, wherein in the process, n-BuLi and the compound C are subjected to lithium halide exchange and cyclized with the alkenyloxy lithium to obtain a compound D;

(4) respectively adding excessive oxalyl chloride and DMSO DCM solution into a dry flask filled with nitrogen, then dropwise adding a compound D solution dissolved in DCM, reacting for 0.5-1.5 h, adding triethylamine, heating to room temperature, and oxidizing hydroxyl into carbonyl through Swern oxidation to obtain a compound E;

(5) adding excessive HBr/HAc solution into the HAc solution of the compound E, stirring to remove an ester side chain to obtain a compound F, namely the required N heteroatom polysubstituted benzoquaternary cyclic ketone;

the specific reaction process is as follows:

in the scheme, in the step (1) and the step (2), the same amount of LDA is added at-78 ℃.

In the scheme, in the step (3), the compound C is added into the prepared excessive lithium alkenyloxide solution at the temperature of-78 ℃, and then the n-butyllithium solution is added and stirred for 0.5 hour.

In the above protocol, in step (4), an excess of oxalyl chloride and DMSO in DCM was added to each dry flask under nitrogen at-78 ℃.

In the above scheme, in the step (5), an excess amount of HBr/HAc solution is added to the HAc solution of the compound E at 40 ℃, and the mixture is stirred for two days to remove the ester side chain.

In the scheme, in the step (1) and the step (3), NH is used after the reaction is finished₄Quenched with aqueous Cl, extracted with ethyl acetate, washed with brine, MgSO₄Drying, concentrating and purifying by silica gel chromatography to obtain compound B or compound D.

In the scheme, in the step (2), after the reaction is finished, NH is used₄Quenched with aqueous Cl, extracted with EA, washed with brine, MgSO₄Drying, concentration and purification by silica gel chromatography gave compound C.

In the scheme, in the step (4), after the reaction is finished, H is added₂Quench O, extract with ethyl acetate, wash the combined organic layers with brine and MgSO₄Drying, concentrating the organic layer under reduced pressure and purifying by silica gel column chromatography to give yellow compound E.

In the above scheme, in the step (5), after the reaction is completed, the reaction solution is preparedNaHCO for solution₃The solution was adjusted to alkaline pH, poured into ice water and extracted with DCM, washed with brine, and MgSO₄Drying, concentration and purification by silica gel chromatography gave compound F.

The application of N heteroatom polysubstituted benzoquaternary cyclic ketone comprises the following steps:

to a solution of compound F and DMAP in DCM at room temperature was added the acid chloride, the solution was stirred for 2 hours and quenched, and NaHCO was extracted with DCM₃Washing with brine and purifying to obtain the compound G, wherein the specific reaction process is as follows:

wherein R5 is: ethyl, 2-methylbut-1-enyl, methylcyclopropyl, 3, 4-dihydro-2H-pyran, 1-methyl-1H-indolophenyl, 8-methoxy-2H-chromenyl, indenyl, tolyl, prop-1-en-1-ylphenyl, phenyl, anisole.

Through the technical scheme, the synthesis method of the N heteroatom polysubstituted benzoquaterphenyl cyclic ketone has high applicability, can be widely applied to synthesis of different substituted benzoquaterphenyl cyclic compounds, and is based on compound research, the benzoquaterphenyl cyclic compound containing cyano, phenyl and halogen substitution on a benzene ring is a basic structural element of a plurality of active compounds. Therefore, the synthetic route provided by the invention provides a simpler and more effective way for synthesizing the compounds with biological activity, has high yield and can be produced in a large scale.

The prepared N heteroatom polysubstituted benzoquaternary cyclic ketone can be subjected to acylation reaction with different acyl chlorides, and different substituent groups are connected to aniline to carry out application expansion.

Drawings

FIG. 1 shows Ga-Gv and the yield of products obtained by reacting N heteroatom polysubstituted benzotetracyclic ketone with different acyl chlorides.

Detailed Description

The technical scheme in the embodiment of the invention is clearly and completely described below with reference to the accompanying drawings.

The invention provides a synthesis method and application of N heteroatom polysubstituted benzoquaternary cyclic ketone, and the specific embodiment is as follows:

a first part: synthesis method of N heteroatom polysubstituted benzoquaternary cyclic ketone