Heterogeneous synthesis method of chiral quinoxalinone and derivatives thereof

Abstract

The invention relates to a heterogeneous synthesis method of chiral quinoxalinone and a derivative thereof, and the heterogeneous synthesis method comprises the following steps: under the action of a heterogeneous catalyst, mixing a reaction substrate, hydrogen, an acidic compound and a solvent, and carrying out asymmetric hydrogenation reaction to prepare the chiral quinoxalinone and the derivative thereof. According to the method, the catalyst which is difficult to separate in the reaction is immobilized, and the hydrogen and the solvent can be easily separated after the reaction is completed to obtain a target product with relatively high purity. Besides, the supported catalyst is used for continuous flow research, safe and continuous production of high-risk hydrogenation reaction is achieved, the activity of the catalyst is kept unchanged after the continuous reaction is conducted for 100 h, and important reference is provided for industrial production of the chiral compound.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a heterogeneous synthesis method of chiral quinoxalinone and its derivatives. Background Art

[0002] Chiral quinoxalinones and their derivatives are important structures in natural products, synthetic bioactive molecules and drugs. Compounds with them as substructures have been used to treat inflammation and pain in sepsis, as well as non-nucleoside HIV-1 reverse transcriptase inhibitors.

[0003] Therefore, the synthesis of chiral quinoxalinones and their derivatives has attracted widespread attention, and many synthetic strategies have been successfully developed.

[0004] So far, various efficient methods have been successfully developed to construct these important chiral skeletons, including hetero-Diels-Alder reaction, asymmetric nucleophilic addition reaction, Mannich reaction, za-henry reaction, allylic CH amination reaction, etc. Catalytic asymmetric hydrogenation reaction has been widely studied for its efficient and green synthesis of high optical purity chiral quinoxalone and its derivatives.

[0005] Asymmetric organocatalytic transfer hydrogenations of quinoxalinones and oxoquinoxalinones have been widely reported since 2010. These hydrogenations have performed well with moderate to excellent enantioselectivities but have limited substrate scope.

[0006] Recently, Zhou et al. used simple achiral urea or A chiral and renewable NAD(P)H model was developed for the enantioselective biomimetic catalytic reduction of quinoxalinones using acid as transfer catalyst.

[0007] Although impressive progress has been made in the synthesis of this class of compounds, current research is mostly limited to the study of homogeneous reactions, which require expensive small molecule catalysts or precious metal catalysis, which not only greatly increases the cost of the reaction but also may result in serious metal residues. Further efforts to seek a more efficient, green and universal method to construct structurally diverse optically active dihydroquinolinones are still highly desirable. Summary of the invention

[0008] Based on this, it is necessary to provide a heterogeneous synthesis method for chiral quinoxalinone and its derivatives.

[0009] To achieve the above object, the present invention provides a technical solution:

[0010] A heterogeneous synthesis method for chiral quinoxalinone and its derivatives, the heterogeneous synthesis method comprising the steps of: mixing a reaction substrate, hydrogen, an acidic compound and a solvent under the action of a heterogeneous catalyst, and performing an asymmetric hydrogenation reaction to prepare chiral quinoxalinone and its derivatives, the reaction equation being as follows:

[0011]

[0012] in, is the reaction substrate;

[0013] Chiral quinoxalinone and its derivatives;

[0014] R is methyl, ethyl, phenyl, halogen or trifluoromethyl;

[0015] R1 is methyl, ethyl, butyl or phenyl;

[0016] R2 is methyl, ethyl, butyl or phenyl;

[0017] The heterogeneous catalyst is a complex of a supported ferrocene ligand and a metal, wherein the metal comprises [Rh(cod)Cl] 2、 [Rh(cod)2]BF4, [Rh(cod)2]SbF 6、 At least one of [Rh(nbd)]2BF4 and [Rh(cod)2]BARF.

[0018] The supported ferrocene ligand is a SL-CF3 ligand or a SL-Ar ligand, and the structural formula is as follows

[0019]

[0020] Wherein, R3 is a conjugated olefin group, R4 is methyl or hydrogen, R5 is hydrogen, 3,5-dimethyl or 4-methyl, X is nitrogen, oxygen or sulfur, a ranges from 1 to 99, and b ranges from 1 to 99. Further, the specific steps of the heterogeneous synthesis method include:

[0021] filling a heterogeneous catalyst into a fixed bed reactor;

[0022] A reaction substrate, an acidic compound and a solvent are prepared into a solution, and the solution is placed in a reaction bottle to undergo an asymmetric hydrogenation reaction to obtain a chiral quinoxalinone and a derivative thereof;

[0023] Before feeding, the pipeline is cleaned with inert gas, solvent and hydrogen in sequence;

[0024] The system pressure was set to 1 MPa-5 MPa, the liquid flow rate was set to 0.01 mL / min-2 mL / min, and the gas flow rate was set to 5 sccm-50 sccm. After the system was stabilized, the chiral quinoxalinone and its derivatives were collected.

[0025] More specifically, the amount of the heterogeneous catalyst is 100 mg to 1000 mg;

[0026] The substrate concentration is 0.01M to 1M; M refers to molarity (M), and its unit is mole per liter (mol / L).

[0027] Furthermore, the liquid flow rate is 0.01 mL / min-0.1 mL / min, and the gas flow rate is 15 sccm-50 sccm.

[0028] Furthermore, the specific steps of the heterogeneous synthesis method include:

[0029] Weigh a heterogeneous catalyst (0.1-5 mmol%) and quinoxalinone and its derivatives into a reaction tube;

[0030] An acidic compound and a solvent are added to the reaction tube, and after stirring at room temperature, hydrogen is charged to a pressure of 0.5 MPa to 5 MPa to cause an asymmetric hydrogenation reaction. After the reaction is completed, the reaction tube is filtered, the filter cake is washed with a detergent, and an alkaline substance is added to quench the reaction to prepare chiral quinoxalinone and its derivatives.

[0031] Furthermore, the specific steps of the heterogeneous synthesis method include:

[0032] The quinoxalinone and its derivatives are mixed with an acidic compound to obtain acidified quinoxalinone and its derivatives;

[0033] Weigh the acidified quinoxalinone and its derivatives and heterogeneous catalyst (0.1-5 mmol%) in a reaction tube;

[0034] Adding a solvent to a reaction tube, stirring at room temperature, filling with hydrogen to a pressure of 0.5 MPa to 5 MPa, causing an asymmetric hydrogenation reaction, filtering after the reaction, washing the filter cake with a detergent, and adding an alkaline substance for quenching to prepare chiral quinoxalinone and its derivatives;

[0035] The reaction equation is as follows:

[0036]

[0037] in, It is the acidified quinoxalinone and its derivatives.

[0038] Furthermore, the detergent includes at least one of anhydrous ethanol, anhydrous methanol, dichloromethane, ethyl acetate and tetrahydrofuran.

[0039] Further, the alkaline substance includes at least one of sodium bicarbonate, sodium carbonate, potassium carbonate and triethylamine.

[0040] Furthermore, the reaction temperature of the asymmetric hydrogenation reaction is 25°C to 80°C, and the reaction time is 8h to 72h.

[0041] Furthermore, the acidic compound includes at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, phosphoric acid, hydrochloride, sulfate, phosphate and trifluoromethanesulfonate.

[0042] Furthermore, the solvent includes at least one of tetrahydrofuran, dichloromethane, chloroform, 1,4-dioxane, anhydrous ethanol, anhydrous methanol and isopropanol.

[0043] Beneficial effects of the present invention:

[0044] The present invention immobilizes the catalyst which is difficult to separate in the reaction, and after the reaction is completed, the hydrogen and the solvent can be easily separated to obtain the target product with higher purity.

[0045] In addition, the present invention also uses the loaded catalyst for continuous flow research to achieve safe and continuous production of high-risk hydrogenation reactions. After 100 hours of continuous reaction, the catalyst activity remains unchanged, and the TON value is greater than 2000, providing an important reference for the industrial production of such chiral compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 This is a diagram of the heterogeneous catalyst cycle results. DETAILED DESCRIPTION

[0047] In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments.

[0048] In the examples, the test methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are all commercially available unless otherwise specified.

[0049] A heterogeneous synthesis method for chiral quinoxalinone and its derivatives, the heterogeneous synthesis method comprising the steps of: mixing a reaction substrate, hydrogen, an acidic compound and a solvent under the action of a heterogeneous catalyst, and performing an asymmetric hydrogenation reaction to prepare chiral quinoxalinone and its derivatives, the reaction equation being as follows:

[0050]

[0051] in, is the reaction substrate;

[0052] Chiral quinoxalinone and its derivatives;

[0053] R is methyl, ethyl, phenyl, halogen or trifluoromethyl;

[0054] R1 is methyl, ethyl, butyl or phenyl;

[0055] R2 is methyl, ethyl, butyl or phenyl;

[0056] The heterogeneous catalyst is a complex of a supported ferrocene ligand and a metal, wherein the metal comprises [Rh(cod)Cl] 2、 [Rh(cod)2]BF4, [Rh(cod)2]SbF 6、 At least one of [Rh(nbd)]2BF4 and [Rh(cod)2]BARF.

[0057] The supported ferrocene ligand is a SL-CF3 ligand or a SL-Ar ligand, and the structural formula is as follows

[0058]

[0059] in,

[0060] R3 is a conjugated olefin group, R4 is methyl or hydrogen, R5 is hydrogen, 3,5-dimethyl or 4-methyl, X is nitrogen, oxygen or sulfur, a ranges from 1 to 99, and b ranges from 1 to 99. In some embodiments, R3 includes at least one of divinylphenyl, 1,3-butadienyl, isoprenyl, ethylene-trans-butenyl, acryl and styryl and their derivative groups.

[0061] The present invention immobilizes the catalyst which is difficult to separate in the reaction, and after the reaction is completed, the hydrogen and the solvent can be easily separated to obtain the target product with higher purity.

[0062] In addition, the present invention also uses the loaded catalyst for continuous flow research to achieve safe and continuous production of high-risk hydrogenation reactions. After 100 hours of continuous reaction, the catalyst activity remains unchanged, and the TON value is greater than 2142, providing an important reference for the industrial production of this type of chiral compounds.

[0063] TON (Turnover Number) is an important indicator in catalytic chemistry, which is used to measure the efficiency of a catalyst. It refers to the number of moles of reactants that can be converted or the number of moles of products that can be generated before each mole of catalyst loses its activity.

[0064] In some embodiments, the specific steps of the heterogeneous synthesis method include:

[0065] filling a heterogeneous catalyst into a fixed bed reactor;

[0066] A reaction substrate, an acidic compound and a solvent are prepared into a solution, and the solution is placed in a reaction bottle to undergo an asymmetric hydrogenation reaction to obtain a chiral quinoxalinone and a derivative thereof;

[0067] Before feeding, the pipeline is cleaned with inert gas, solvent and hydrogen in sequence; hydrogen must be introduced during the pipeline cleaning process. The introduction of inert gas is used to remove oxygen in the system and stabilize the pressure. In some embodiments, the inert gas is nitrogen.

[0068] The system pressure was set to 1 MPa-5 MPa, the liquid flow rate was set to 0.01 mL / min-2 mL / min, and the gas flow rate was set to 5 sccm-50 sccm. After the system was stabilized, the chiral quinoxalinone and its derivatives were collected.

[0069] Specifically, the gas velocity determines the solubility and distribution of the gas in the liquid. If the gas is a reactant, a higher gas velocity will increase the gas mass transfer rate, thereby accelerating the reaction rate. If the gas velocity is too high, it may cause uneven gas-liquid separation, affect the mixing effect in the reactor, and thus reduce the reaction efficiency. Higher gas velocities may increase the pressure drop of the equipment, increase the burden on the equipment, and the equipment design must be optimized to maintain good fluid dynamics performance.

[0070] The liquid rate determines the residence time of the liquid in the reactor. A higher liquid rate usually means a shorter residence time, which may lead to incomplete reaction, while a lower rate may help the reaction to proceed completely. A higher liquid rate helps mixing and mass transfer, reduces local concentration gradients, and promotes uniform reactions. However, if the rate is too high, it may cause excessive turbulence and affect a stable reaction environment. The liquid rate is closely related to the volume of the reactor. A high liquid rate requires a larger reactor volume to maintain sufficient reaction time.

[0071] Residence time is the average time that materials stay in the reactor. Longer residence time usually means that reactants have more time to react, thereby increasing reaction conversion and yield. Different reactions have different kinetics. Shorter residence time may be more suitable for fast reactions and single-step reactions, while longer residence time is suitable for multi-step reactions and equilibrium reactions that require longer time. Too long residence time may increase the probability of side reactions, especially for some systems with competing side reactions.

[0072] In continuous flow reactions, controlling these parameters requires a combination of specific reaction kinetics, mass transfer characteristics, and equipment design to achieve the best reaction results.

[0073] In some embodiments, the liquid flow rate is 0.01 mL / min-0.1 mL / min, and the gas flow rate is 15 sccm-50 sccm.

[0074] In some embodiments, the specific steps of the heterogeneous synthesis method include:

[0075] Weighing heterogeneous catalyst and quinoxalinone and its derivatives into a reaction tube;

[0076] An acidic compound and a solvent are added to the reaction tube, and after stirring at room temperature, hydrogen is charged to a pressure of 0.5 MPa to 5 MPa to cause an asymmetric hydrogenation reaction. After the reaction is completed, the reaction tube is filtered, the filter cake is washed with a detergent, and an alkaline substance is added to quench the reaction to prepare chiral quinoxalinone and its derivatives.

[0077] In some embodiments, the specific steps of the heterogeneous synthesis method include:

[0078] The quinoxalinone and its derivatives are mixed with an acidic compound to obtain acidified quinoxalinone and its derivatives;

[0079] Weigh the acidified quinoxalinone and its derivatives and the heterogeneous catalyst into a reaction tube;

[0080] Adding a solvent to a reaction tube, stirring at room temperature, filling with hydrogen to a pressure of 0.5 MPa to 5 MPa, causing an asymmetric hydrogenation reaction, filtering after the reaction, washing the filter cake with a detergent, and adding an alkaline substance for quenching to prepare chiral quinoxalinone and its derivatives;

[0081] The reaction equation is as follows:

[0082]

[0083] in, It is the acidified quinoxalinone and its derivatives.

[0084] In some embodiments, the detergent comprises at least one of anhydrous ethanol, anhydrous methanol, dichloromethane, ethyl acetate, and tetrahydrofuran.

[0085] In some embodiments, the alkaline substance includes at least one of sodium bicarbonate, sodium carbonate, potassium carbonate, and triethylamine.

[0086] In some embodiments, the reaction temperature of the asymmetric hydrogenation reaction is 25° C. to 80° C., and the reaction time is 8 h to 72 h.

[0087] In some embodiments, the acidic compound includes at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, phosphoric acid, hydrochloride, sulfate, phosphate, and trifluoromethanesulfonate.

[0088] In some embodiments, the solvent includes at least one of tetrahydrofuran, dichloromethane, chloroform, 1,4-dioxane, anhydrous ethanol, anhydrous methanol and isopropanol.

[0089] In the embodiment of the present invention, the preparation steps of the heterogeneous catalyst are as follows:

[0090] Under the conditions of Lewis acid and solvent, a ferrocene ligand or a complex of a ferrocene ligand and a metal is loaded on a carrier through Friedel-Crafts alkylation reaction to obtain a loaded ferrocene ligand;

[0091] Wherein, the structural formula of the carrier is

[0092] The structural formula of the ferrocene ligand is

[0093] R includes styryl, divinylphenyl, 1,3-butadiene or isoprene.

[0094] The reaction equation is as follows:

[0095]

[0096] The reaction temperature of the Friedel-Crafts alkylation reaction is -50°C to 80°C. The reaction time of the Friedel-Crafts alkylation reaction is. The solvent includes at least one of dichloromethane, chloroform, dichloroethane, nitromethane, nitrobenzene and carbon tetrachloride. The Lewis acid includes at least one of aluminum trichloride, ferric chloride, tin tetrachloride, concentrated sulfuric acid and trifluoromethanesulfonic acid.

[0097] Example 1

[0098] The reaction equation is as follows:

[0099]

[0100] The structural formula of the heterogeneous catalyst is as follows:

[0101]

[0102] Weigh the heterogeneous catalyst (20 mg, 1 mmol%, containing 0.5 mmol% Rh) and the reaction substrate (28 mg, 0.5 mmol) into a reaction tube, move to a glove box, add 2 ml of anhydrous ethanol and a dioxane solution of hydrochloric acid (4 M), stir at room temperature for 10 min, then move out of the glove box, fill with hydrogen to 2 MPa, react at room temperature for 16 h, then release the pressure, filter, wash the filter cake alternately with anhydrous ethanol and dichloromethane, quench the filtrate with saturated sodium bicarbonate aqueous solution, extract twice with ethyl acetate, and evaporate the organic phase to dryness under reduced pressure to obtain the target product, which can be directly detected without further purification, and the nuclear magnetic conversion rate is greater than 99%.

[0103] HPLC: ee=98%, AD H-85-15-1-30, RT=7.73min, 8.15min

[0104] 1H NMR(400MHz,Chloroform-d)δ6.96–6.88(m,2H),6.88–6.82(m,1H),6.70(dd,J =7.8,1.6Hz,1H),3.95(q,J=6.6Hz,2H),3.35(s,3H),1.43(d,J=6.6Hz,3H).13C NMR (101MHz, CDCl3) δ168.47,135.14,129.27,123.55,119.78,114.78,114.31,52.28,29.18,17.96.

[0105] Example 2

[0106] The reaction equation is as follows:

[0107]

[0108] Among them, the supported ferrocene ligand and Rh + Used as a catalyst, the structural formula of the supported ferrocene ligand is as follows:

[0109]

[0110] In a glove box, weigh the loaded ferrocene ligand (20 mg, 1 mmol%) and [Rh(cod)Cl]2 (0.5 mg, 0.5 mmol%) into a reaction tube, add 2 ml of anhydrous tetrahydrofuran, stir at room temperature for 30 min, then add the reaction substrate (30 mg, 0.5 mmol) and aqueous sulfuric acid solution (0.5 eq), stir at room temperature for 10 min, then move out of the glove box, fill with hydrogen to 4 MPa, react at room temperature for 12 h, then release the pressure, filter, wash the filter cake alternately with anhydrous ethanol and dichloromethane, quench the filtrate with saturated potassium bicarbonate aqueous solution, extract twice with ethyl acetate, and evaporate the organic phase to dryness under reduced pressure to obtain the target product, which can be directly detected without further purification, and the NMR conversion rate is greater than 99%.

[0111] HPLC: ee=99%, AD H-85-15-1-30, RT=7.09min, 8.18min

[0112] 1H NMR (400MHz, Chloroform-d) δ6.97–6.81(m,3H),6.71(d,J=7.6Hz,1H),3.98(ddq,J=27.4,13.2,6.9Hz,3H),1.42(d,J=6.6Hz,3H),1.25(d,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ167.78,135.40,128.03,123.42,119.83,114.68,114.64,52.24,37.14,17.80,12.70.

[0113] Example 3

[0114] The reaction equation is as follows:

[0115]

[0116] Among them, the supported ferrocene ligand and Rh + Used as a catalyst, the structural formula of the supported ferrocene ligand is as follows:

[0117]

[0118] In a glove box, the loaded ligand (20 mg, 1 mmol%) and [Rh(cod)Cl]2 (1 mg, 1 mmol%) were weighed into a reaction tube, 2 ml of anhydrous ethanol was added, and the reaction substrate (32 mg, 0.5 mmol) and aqueous sulfuric acid solution (0.5 eq) were added after stirring at room temperature for 30 min. After stirring at room temperature for 10 min, the glove box was removed, and hydrogen was filled to 5 MPa. The reaction was carried out at room temperature for 10 h and then the pressure was released. The filter cake was washed alternately with anhydrous ethanol and dichloromethane. The filtrate was quenched with saturated potassium bicarbonate aqueous solution and extracted twice with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure to obtain the target product. No further purification was required and it was directly detected. The NMR conversion rate was greater than 99%.

[0119] HPLC: ee=98%, AD H-85-15-1-30, RT=7.73min, 8.15min,

[0120] 1 H NMR(400MHz,Chloroform-d)δ6.91(ddd,J=13.1,7.6,1.5Hz,2H),6.83(td,J=7.6,1.6Hz,1H),6.70(dd ,J=7.5,1.6Hz,1H),3.97–3.83(m,3H),1.68–1.55(m,2H),1.40(t,J=6.9Hz,5H),0.95(t,J=7.3Hz,3H).13 C NMR (101MHz, CDCl3) δ167.97,135.42,128.15,123.35,119.69,114.79,114.65,52.20,41.86,29.33,20.21,17.77,13.91.

[0121] Example 4

[0122] The reaction equation is as follows:

[0123]

[0124] The structural formula of the heterogeneous catalyst is as follows:

[0125]

[0126] In a glove box, a heterogeneous catalyst (20 mg, 1 mmol%, containing 1 mmol% Rh) and a reaction substrate (42 mg, 0.5 mmol) were weighed into a reaction tube, and 2 ml of anhydrous dichloromethane and an ethyl acetate solution of hydrochloric acid (0.2 eq) were added. After stirring at room temperature for 10 min, the glove box was removed, and hydrogen was filled to 2 MPa. After reacting at room temperature for 20 h, the pressure was released and filtered. The filter cake was washed alternately with anhydrous ethanol and dichloromethane. The filtrate was quenched with a saturated potassium bicarbonate aqueous solution and extracted twice with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure to obtain the target product. No further purification was required and it was directly detected. The nuclear magnetic conversion rate was greater than 99%.

[0127] HPLC: ee=98%, OD H-10-90-0.6-30, RT 15.78 / 16.57min

[0128] 1 H NMR(400MHz,Chloroform-d)δ7.78(s,1H),7.67(s,2H),6.97–6.91(m,1H),6.79–6.73(m,2H) ,6.69(dd,J=8.4,1.4Hz,1H),5.31–5.15(m,2H),4.11(q,J=6.6Hz,1H),1.51(d,J=6.7Hz,3H). 13 C NMR (101MHz, CDCl3) δ168.67,139.83,135.34,132.44,132.10,127.92,126.76,126 .73,124.65,124.35,121.93,121.58,120.13,115.01,114.99,52.42,45.45,17.71.

[0129] Example 5

[0130] The reaction equation is as follows:

[0131] Among them, the supported ferrocene ligand and Rh + Used as a catalyst, the structural formula of the supported ferrocene ligand is as follows:

[0132]

[0133] In a glove box, weigh the loaded ferrocene ligand (20 mg, 1 mmol%) and [Rh(cod)BF4]2 (1 mg, 1 mmol%) into a reaction tube, add 2 ml of anhydrous isopropanol, stir at room temperature for 30 min, then add the reaction substrate (30 mg, 0.5 mmol) and phosphoric acid aqueous solution (0.5 eq), stir at room temperature for 10 min, then move out of the glove box, fill with hydrogen to 5 MPa, react at room temperature for 10 h, then release the pressure, filter, wash the filter cake alternately with anhydrous ethanol and dichloromethane, quench the filtrate with saturated potassium bicarbonate aqueous solution, extract twice with ethyl acetate, and evaporate the organic phase to dryness under reduced pressure to obtain the target product, which can be directly detected without further purification, and the NMR conversion rate is greater than 99%.

[0134] HPLC:ee=96%, AD H-15-85-1-30, RT=7.42 / 9.64min

[0135] 1 H NMR (400MHz, Chloroform-d) δ6.69(s,1H),6.50(s,1H),3.89(q,J=6.6Hz,1H),3.33(s,3H),2.20(s,3H),2.17(s,3H),1.40(d,J=6.6Hz,3H). 13 CNMR (101MHz, CDCl3) δ168.49,132.80,131.51,127.67,127.19,116.14,115.91,52.57,29.16,19.40,17.84.

[0136] Example 6

[0137] The reaction equation is as follows:

[0138]

[0139] The structural formula of the heterogeneous catalyst is as follows:

[0140]

[0141] The heterogeneous catalyst (20 mg, 1 mmol%, containing 2 mmol% Rh) and the reaction substrate (29 mg, 0.5 mmol) were weighed into a reaction tube, moved to a glove box, and 2 ml of anhydrous dichloromethane and a solution of hydrochloric acid in ethyl acetate (1 eq) were added. After stirring at room temperature for 10 min, the glove box was moved out, and hydrogen was filled to 1 MPa. The reaction was carried out at room temperature for 24 h and then the pressure was released. The filter cake was washed alternately with anhydrous ethanol and dichloromethane. The filtrate was quenched with a saturated aqueous sodium carbonate solution and extracted twice with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure to obtain the target product. No further purification was required and it was directly detected. The NMR conversion rate was 90%.

[0142] HPLC:ee=96%, AD H-15-85-1-30, RT=7.65 / 8.89min

[0143] 1 H NMR(400MHz,Chloroform-d)δ6.91(ddd,J=8.9,7.2,1.6Hz,2H),6.83(ddd,J=8.4,7.1,1.4Hz,1H),6.73–6.66(m,1H),3.80( dd,J=8.1,4.6Hz,1H),3.36(s,3H),1.83(dtd,J=15.0,7.4,4.7Hz,1H),1.71(dt,J=14.4,7.4Hz,1H),1.00(t,J=7.5Hz,3H). 13 CNMR (101MHz, CDCl3) δ167.96,134.68,129.00,123.63,119.56,114.68,114.36,77.16,57.96,29.11,24.88,9.90.

[0144] Example 7

[0145] The reaction equation is as follows:

[0146] The structural formula of the heterogeneous catalyst is as follows:

[0147]

[0148] The loaded ligand (20 mg, 1 mmol%, containing 0.7 mmol% Rh) and the reaction substrate (35 mg, 0.5 mmol) were weighed into a reaction tube, moved to a glove box, and 2 ml of anhydrous dichloromethane / isopropanol (1:1) mixed solvent was added. After stirring at room temperature for 10 min, the glove box was moved out, and hydrogen was filled to 4 MPa. The reaction was carried out at room temperature for 18 h and then the pressure was released. The filter cake was washed alternately with anhydrous ethanol and dichloromethane. The filtrate was quenched with saturated sodium carbonate aqueous solution and extracted twice with ethyl acetate. The organic phase was evaporated to dryness under reduced pressure to obtain the target product. No further purification was required and it was directly detected. The NMR conversion rate was 45%.

[0149] HPLC: ee=94%, AD H-20-80-1-30, RT=10.74 / 13.56min.

[0150] Example 8

[0151] Synthesis using a continuous flow reaction system:

[0152]

[0153] The structural formula of the heterogeneous catalyst is as follows:

[0154]

[0155] Wherein, a=99, b=1, and R3 is divinylbenzene.

[0156] 300 mg of heterogeneous catalyst was filled into the fixed bed reactor, and a dichloromethane solution of the acidified reaction substrate with a concentration of 0.025 M was prepared in the reaction bottle. The pipeline was cleaned with nitrogen, solvent and hydrogen for 1 hour before feeding, and the system was adjusted to 4MPa, and the liquid flow rate was set to 0.1mL / min and the gas to 20sccm. After the system was stable for 0.5 hours, the product was collected and sampled after 100 hours of continuous production, with a yield of 96% and ee = 96%.

[0157] Example 9

[0158] The conditions of the continuous flow reaction were optimized, and the optimization results are shown in Table 1. The reaction steps are the same as those in Example 1.

[0159] Table 1 Condition optimization results

[0160]

[0161] Example 10

[0162] The recycling effect of heterogeneous catalysts was experimentally verified, and the results are as follows Figure 1 shown.

[0163] It should be noted that the specific parameters or some reagents in the above embodiments are specific embodiments or preferred embodiments of the present invention, rather than limiting the present invention; those skilled in the art can make adaptive adjustments within the scope of the present invention.

Claims

1. A heterogeneous synthesis method of chiral quinoxalinone and its derivatives, characterized in that: The heterogeneous synthesis method comprises the steps of: mixing a reaction substrate, hydrogen, an acidic compound and a solvent under the action of a heterogeneous catalyst to undergo an asymmetric hydrogenation reaction to prepare chiral quinoxalinone and its derivatives, and the reaction equation is as follows: in, As reaction substrate; Chiral quinoxalinone and its derivatives; R is methyl, ethyl, phenyl, halogen or trifluoromethyl; R1 is methyl, ethyl, butyl or phenyl; R2 is methyl, ethyl, butyl or phenyl; The heterogeneous catalyst is a supported ferrocene ligand and a complex of the ligand and a metal, wherein the metal includes [Rh(cod)Cl] 2、 [Rh(cod)]2BF4, [Rh(cod)2]SbF 6， [Rh(nbd)]2BF4 and [Rh(cod)] At least one of 2BARF. The supported ferrocene ligand is a SL-CF3 ligand or a SL-Ar ligand, and the structural formula is as follows Wherein, R3 is a conjugated olefin group; R4 is methyl or hydrogen; R5 is hydrogen, 3,5-dimethyl or 4-methyl; X is oxygen or sulfur, a is in the range of 1-99, and b is in the range of 1-99.

2. The heterogeneous synthesis method according to claim 1, characterized in that The specific steps of the heterogeneous synthesis method include: filling a heterogeneous catalyst into a fixed bed reactor; A reaction substrate, an acidic compound and a solvent are prepared into a solution, and the solution is placed in a reaction bottle to undergo an asymmetric hydrogenation reaction to obtain a chiral quinoxalinone and a derivative thereof; Before feeding, the pipeline is cleaned with inert gas, solvent and hydrogen in sequence; Set the system pressure to 1MPa-5MPa, set the liquid flow rate to 0.01mL / min-2mL / min, the gas flow rate to 5sccm-50sccm, adjust to an appropriate temperature of 25°C-80°C, and start collecting chiral quinoxalinone and its derivatives after the system is stable.

3. The heterogeneous synthesis method according to claim 2, characterized in that The liquid flow rate is 0.01mL / min-0.1mL / min, and the gas flow rate is 15sccm-50sccm.

4. The heterogeneous synthesis method according to claim 1, characterized in that The specific steps of the heterogeneous synthesis method include: Weighing heterogeneous catalyst and quinoxalinone and its derivatives into a reaction tube; An acidic compound and a solvent are added to the reaction tube, and after stirring at room temperature, hydrogen is charged to a pressure of 0.5 MPa to 5 MPa to cause an asymmetric hydrogenation reaction. After the reaction is completed, the reaction tube is filtered, the filter cake is washed with a detergent, and an alkaline substance is added to quench the reaction to prepare chiral quinoxalinone and its derivatives.

5. The heterogeneous synthesis method according to claim 1, characterized in that The specific steps of the heterogeneous synthesis method include: The quinoxalinone and its derivatives are mixed with an acidic compound to obtain acidified quinoxalinone and its derivatives; Weigh the acidified quinoxalinone and its derivatives and the heterogeneous catalyst into a reaction tube; Adding a solvent to a reaction tube, stirring at room temperature, filling with hydrogen to a pressure of 0.5 MPa to 5 MPa, causing an asymmetric hydrogenation reaction, filtering after the reaction, washing the filter cake with a detergent, and adding an alkaline substance for quenching to prepare chiral quinoxalinone and its derivatives; The reaction equation is as follows: in, It is the acidified quinoxalinone and its derivatives.

6. The heterogeneous synthesis method according to claim 4 or 5, characterized in that: The detergent includes at least one of anhydrous ethanol, anhydrous methanol, dichloromethane, ethyl acetate and tetrahydrofuran.

7. The heterogeneous synthesis method according to claim 4 or 5, characterized in that: The alkaline substance includes at least one of sodium bicarbonate, sodium carbonate, potassium carbonate and triethylamine.

8. The heterogeneous synthesis method according to claim 4 or 5, characterized in that: The reaction temperature of the asymmetric hydrogenation reaction is 25°C to 80°C, and the reaction time is 8h to 72h.

9. The heterogeneous synthesis method according to claim 1, characterized in that The acidic compound includes at least one of hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, phosphoric acid, hydrochloride, sulfate, phosphate and trifluoromethanesulfonate.

10. The heterogeneous synthesis method according to claim 1, characterized in that: The solvent includes at least one of tetrahydrofuran, dichloromethane, chloroform, 1,4-dioxane, anhydrous ethanol, anhydrous methanol and isopropanol.

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