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CN-122010863-A - Heterogeneous asymmetric synthesis method of chiral benzo aromatic heterocycle compound

CN122010863ACN 122010863 ACN122010863 ACN 122010863ACN-122010863-A

Abstract

The invention relates to a heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds, which comprises the steps of dissolving a reaction substrate in a solvent for reaction under the catalysis of a heterogeneous catalyst SL-n or SL/M-n to obtain a target product; the invention develops a heterogeneous asymmetric synthesis method of chiral benzo aromatic heterocycle compounds, by using a heterogeneous catalyst, a target product can be obtained by simple distillation after the reaction is finished, the product separation process is greatly simplified, and the ICP-OES result shows that the catalyst has no metal leaching in the reaction process and has better stability. The method has better selectivity and catalytic activity for asymmetric hydrogenation of a series of benzoxazinone and quinoxalinone compounds, and has larger industrialized application potential.

Inventors

  • YOU HENGZHI
  • WANG CHAO
  • WU LIPING
  • HUANG JUNRONG
  • ZHU YUXIANG
  • CHEN FENER

Assignees

  • 深圳连续制药科技有限公司

Dates

Publication Date
20260512
Application Date
20251210
Priority Date
20250815

Claims (10)

  1. 1. A heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds is characterized by comprising the following steps: under the catalysis of heterogeneous catalyst SL-n or SL/M-n, dissolving the reaction substrate in a solvent to react with hydrogen to obtain a target product; The general formula of the reaction is as follows: Or (b) ; R is methyl, ethyl, phenyl or halogen trifluoromethyl; R 1 is methyl, ethyl, butyl or phenyl; r 2 is methyl, ethyl, butyl or phenyl; X comprises oxygen and nitrogen; the structural formula of the heterogeneous catalyst SL-n or SL/M-n is as follows: Or (b) ; Wherein x: y=1, (1-10); M is a metal salt comprising one of [Rh(COD)Cl] 2 、[Ir(COD)Cl] 2 、[Rh(COD) 2 ]BF 4 、[Rh(COD) 2 ]SbF 6 or [ Rh (COD) 2 ] BARF; R' is H, CH 3 ; R 3 is para or meta-H, -CF 3 , or-CH 3 ; R 4 is selected from one of the compounds C 1 -C 7 。
  2. 2. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 1, wherein the heterogeneous catalyst SL-n or SL/M-n has the following structural formula: 、 、 、 、 、 、 、 Or (b) 。
  3. 3. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 1, wherein the solvent comprises at least one of tetrahydrofuran, dichloromethane, chloroform, 1, 4-dioxane, absolute ethanol, absolute methanol and isopropanol.
  4. 4. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 1, wherein an acid is added to the reaction, the acid comprising at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid and phosphoric acid.
  5. 5. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 1, wherein the reaction temperature is 25 ℃ to 80 ℃.
  6. 6. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 1, wherein the reaction time is 8 h-72 h.
  7. 7. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 1, wherein the reaction pressure is 0.5 MPa-5 MPa.
  8. 8. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 1, wherein the reaction is quenched by addition of an alkaline substance comprising at least one of sodium bicarbonate, sodium carbonate, potassium carbonate and triethylamine.
  9. 9. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 1, wherein heterogeneous catalyst SL-n is used in combination with a metal salt comprising one of [Rh(COD)Cl] 2 、[Ir(COD)Cl] 2 、[Rh(COD) 2 ]BF 4 、[Rh(COD) 2 ]SbF 6 or [ Rh (COD) 2 ] BARF.
  10. 10. The heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds according to claim 9, wherein the equivalent ratio of heterogeneous catalyst SL-n to metal salt is (0.1-5): 0.05-5.

Description

Heterogeneous asymmetric synthesis method of chiral benzo aromatic heterocycle compound Technical Field The invention relates to the technical field of asymmetric catalytic reaction, in particular to a heterogeneous asymmetric synthesis method of chiral benzo aromatic heterocycle compounds. Background Chiral benzoheteroaromatic compounds (e.g., molecules containing fused structures such as benzoxazinones, quinoxalinones, benzopyridines, benzofurans, benzothiophenes, etc.) are an important class of organic molecules whose core structure is characterized by the presence of asymmetric centers or planar chiralities. Such structures are widely found in natural products (e.g., indole alkaloids, quinolines) and functional materials with significant biological activity, as well as in numerous drug molecules (e.g., antimalarial quinine, anticancer camptothecins and taxanes, vinblastine, etc.). Therefore, the development of efficient and highly selective chiral benzoheteroaromatic ring synthesis methods has extremely high value in the fields of organic synthesis chemistry, pharmaceutical chemistry and material science. With the vigorous development of asymmetric catalytic technologies (such as Sharpless epoxidation, noyori hydrogenation, etc.), the stereoselective synthesis of chiral benzoheteroaromatic compounds has been significantly advanced, particularly since 2000, by the widespread use of transition metal catalysis (such as palladium, rhodium-catalyzed asymmetric C-H activation) and small organic molecule catalysis (such as proline derivatives). However, these synthetic strategies of the prior art face fundamental challenges when moving from laboratory to industrial applications, and there are still a number of bottleneck problems that need to be solved: 1. The homogeneous system limits that the current synthesis method of the compounds is mainly based on a homogeneous catalytic reaction system. 2. The cost of the catalyst is high, the catalysts used (in particular asymmetric catalysts) are generally expensive and are mostly dependent on noble metals (such as Pd, rh, ru, etc.), resulting in a high overall catalytic cost. 3. The separation and purification are difficult, after the reaction is finished, the expensive homogeneous catalyst is difficult to effectively recycle, and the difficulty and cost of the separation and purification of the target product can be obviously increased due to the residual metal impurities of the catalyst. And the homogeneous system is difficult to adapt to industrial production modes such as continuous flow and the like with higher efficiency and easier control. 4. The defects, particularly the problems of high catalyst cost and metal residue in the product, severely limit the application potential of the high-efficiency synthesis method in large-scale industrial production. Disclosure of Invention Based on the above, it is necessary to provide a new method for synthesizing chiral benzo-heteroaromatic compounds (especially benzoxazinones and quinoxalinones) with high efficiency, high selectivity, easy separation and recovery of catalyst, controllable cost and environmental friendliness, so as to overcome the inherent defects of the existing homogeneous catalysis system and meet the actual demands of industrial production. In order to achieve the above object, the present invention provides a technical solution: a heterogeneous asymmetric synthesis method of chiral benzoheteroaromatic compounds comprises the following steps: under the catalysis of heterogeneous catalyst SL-n or SL/M-n, dissolving the reaction substrate in a solvent to react with hydrogen to obtain a target product; The general formula of the reaction is as follows: Or (b) ; R is methyl, ethyl, phenyl or halogen trifluoromethyl; R 1 is methyl, ethyl, butyl or phenyl; r 2 is methyl, ethyl, butyl or phenyl; X comprises oxygen and nitrogen; the structural formula of the heterogeneous catalyst SL-n or SL/M-n is as follows: Or (b) ; Wherein x: y=1, (1-10); M is a metal salt comprising one of [Rh(COD)Cl]2、[Ir(COD)Cl]2、[Rh(COD)2]BF4、[Rh(COD)2]SbF6 or [ Rh (COD) 2 ] BARF; R' is H, CH 3; R 3 is para or meta-H, CF 3 or-CH 3; r 4 is selected from one of the compounds C 1-C7: 。 Preferably, the heterogeneous catalyst SL-n or SL/M-n has the following structural formula: 、、 、、 、、 、 Or (b) 。 Preferably, the solvent includes at least one of tetrahydrofuran, dichloromethane, chloroform, 1, 4-dioxane, absolute ethanol, absolute methanol, and isopropanol. Preferably, when the reaction formula isWhen an acid is added to the reaction, the acid comprises at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid and phosphoric acid. The application provides two embodiments, namely, firstly, a reaction substrate in a salt form is directly reacted with hydrogen, and secondly, acid is added into a reaction system to enable the substrate to generate salt in situ and then react with hydrogen. Preferably, the reaction temper