CN117800981A - Preparation method of chiral dihydroquinolone compound - Google Patents

Preparation method of chiral dihydroquinolone compound Download PDF

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CN117800981A
CN117800981A CN202311799243.1A CN202311799243A CN117800981A CN 117800981 A CN117800981 A CN 117800981A CN 202311799243 A CN202311799243 A CN 202311799243A CN 117800981 A CN117800981 A CN 117800981A
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chiral
compound
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dihydroquinolone
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陈兴宽
李志颖
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Jinan University
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Jinan University
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Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of chiral dihydroquinolone compounds. According to the invention, N-heterocyclic carbene (NHC) is used as a catalyst, and chloral and aza-o-benzoquinone precursor react under the action of NHC and an alkaline reagent to generate chiral dihydroquinolone through aza-diene Diels-Alder reaction. The preparation method of the invention does not need to use transition metal as a catalyst, can carry out reaction under milder conditions, and has the advantages of environmental protection, low cost, wide substrate selectivity, mild reaction conditions and the like. In addition, the reaction condition of the preparation method is optimized to ensure that the product has high yield and purity, and has unique cis-selectivity and excellent enantioselectivity. The invention provides a brand new route and a new thought for chiral dihydroquinolone compounds, can play an important role in the fields of medicine intermediates and the like, and has good application value and potential.

Description

Preparation method of chiral dihydroquinolone compound
Technical Field
The invention belongs to the technical field of organic synthesis. More particularly, to a method for preparing chiral dihydroquinolone compounds.
Background
Quinolone frameworks are one of the important frameworks of natural products and are called as dominant frameworks in the medical field, and due to their unique structure and excellent activity, the compounds have become important members in a huge database of bioactive molecules. Among them, dihydroquinolones are an important representative of quinolones, which are widely present in natural products and on-market drugs, exhibiting remarkable biological activity. For example, aripiprazole (antipsychotic), carteolol hydrochloride (non-selective beta blocker), visna Lin Tong (cardiotonic), and cilostazol (phosphodiesterase-3 inhibitor) are all pharmaceutically or medically useful natural products, all containing a dihydroquinolone group structure. In addition, the dihydroquinolone medicines can be multifunctional intermediates, can be further converted into other common heterocycles, such as tetrahydroquinoline or quinolone medicines, and the like, and have good application prospects.
Currently, the method for synthesizing chiral dihydroquinolones is mainly based on the following two strategies: 1) Asymmetric intermolecular 1,4 addition of quinolones by organometallic reagents; 2) By the aza-michael addition of an aminophalcone. Although the above strategies are effective synthetic strategies, they are harsh in reaction conditions and tedious in steps. For example, chinese patent application CN112239456A discloses a substitution of 2,3The synthesis method takes N-pyridine sulfonyl-o-iodoaniline as a raw material to react with olefin, takes a complex compound formed by palladium salt and ligand as a catalyst, and also needs to add a reaction auxiliary agent and an oxidant, and can react in a reaction medium at 100-120 ℃ to obtain the dihydroquinolone, so that the reaction is complicated, more reagents are needed, the cost is high, and the selectivity still has room for improvement.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of complicated synthesis method, high reaction condition requirement, high cost, limited yield and selectivity and the like of the prior art, and provides a preparation method of chiral dihydroquinolone compounds, which is environment-friendly, low in cost, mild in reaction condition, simple in reaction and high in yield and selectivity.
The invention also aims to provide the application of the preparation method in preparing the medicines containing the dihydro-quinolone structural element, tetrahydroquinoline or quinolone.
The above object of the present invention is achieved by the following technical scheme:
the invention discloses a preparation method of a chiral dihydroquinolone compound, which comprises the following steps: the compound 1, the compound 2, a catalyst NHC, an alkaline reagent and Lewis acid are reacted completely in an organic solvent at 20-35 ℃ under the protection of inert gas, and then the compound 3 (chiral dihydroquinolone compound) is obtained after separation and purification;
the synthetic route is as follows:
wherein R is disubstituted and each is independently C 1～5 An alkoxy group, or a methylenedioxy group, two alkoxy groups of which are respectively connected with two adjacent carbon atoms on the benzene ring; ar is aryl or substituted aryl, wherein the substituent in the substituted aryl is C 1～12 Alkyl or C 1～5 One or more of alkoxy groups; r is R 1 Selected from C 1～12 One of alkyl, aryl or substituted aryl, wherein the substituents in the substituted aryl are selected from C 1～12 Alkyl, C 1～5 Alkoxy, C 1～3 One of haloalkyl and halogen;
the carbon number of the aryl is 5-10.
According to the invention, N-heterocyclic carbene (NHC) is used as a catalyst, and chloral and aza-o-benzoquinone precursor react under the actions of NHC, alkaline reagent and Lewis acid to generate chiral dihydroquinolone through aza-diene Diels-Alder reaction, wherein the reaction mechanism is as follows:
chiral NHC catalysts first chemically selectively attack the favored carbonyl carbon to form enolates; then, the intermediate III is formed by the action of aza-o-methylene benzoquinone in Lewis acid to promote Diels-Alder reaction; finally, the intermediate IV generates chiral dihydroquinolone as a target product through intramolecular electron transfer, and simultaneously NHC catalyst release is continuously used for catalytic circulation; wherein, lithium ions in the added Lewis acid and two reaction intermediates of enolate and aza-o-methylene benzoquinone form lithium bonds, thereby enhancing the reactivity and the product yield, region and enantioselectivity.
Preferably, R is disubstituted, each independently C 1～5 An alkoxy group, or a methylenedioxy group, two alkoxy groups of which are respectively connected with two adjacent carbon atoms on the benzene ring; ar is selected from one of phenyl, substituted phenyl and naphthyl, wherein the substituent in the substituted phenyl is C 1～8 Alkyl or C 1～4 One or more of alkoxy groups; r is R 1 Selected from C 1～12 One of alkyl, phenyl or substituted phenyl, naphthyl and furyl, wherein the substituent in the substituted phenyl is selected from C 1～8 Alkyl, C 1～4 Alkoxy, C 1～3 Haloalkyl, halogen.
More preferably, R is disubstituted, each independently methoxy, or methylenedioxy, the two alkoxy groups of which are each attached to two adjacent carbon atoms on the benzene ring; ar is selected from phenyl or one of substituted phenyl and naphthyl, wherein the substituent in the substituted phenyl is one or more of methyl or methoxy; r is R 1 The substituent in the substituted phenyl is selected from one of methyl, methoxy, trifluoromethyl and halogen.
Further, the catalyst NHC is selected from any one of the following structures:
still further, the alkaline reagent is selected from one or more of 1, 8-diazabicyclo undec-7-ene, potassium tert-butoxide, cesium carbonate.
Preferably, the alkaline agent is selected from one or two of cesium carbonate or potassium tert-butoxide.
Further, the organic solvent is selected from one of dichloromethane, tetrahydrofuran, toluene, methyl tertiary butyl ether and acetonitrile.
Preferably, the organic solvent is selected from dichloromethane or toluene.
Preferably, the lewis acid is lithium fluoride or lithium chloride.
Further, the reaction time is 12-24 hours.
Still further, the inert gas is nitrogen or argon.
Further, the mol ratio of the compound 1, the compound 2, the catalyst N-heterocyclic carbene, the alkaline reagent and the Lewis acid is = (0.5-1)/(1-2)/(0.1-0.2)/(1.5-3)/(0.25-0.5).
Preferably, the molar ratio of compound 1, compound 2, catalyst N-heterocyclic carbene, basic agent, lewis acid=1:2:0.2:3:0.5.
The chiral dihydroquinolone compound prepared by the preparation method can remove the p-toluenesulfonyl protecting group to obtain free lactam through simple treatment, and can be easily converted into chiral tetrahydroquinolinone and quinolinone derivatives.
In addition, the invention also protects the application of the preparation method of the chiral dihydroquinolone compound in the preparation of the medicines containing the dihydroquinolone structural element, tetrahydroquinoline or quinolone.
The invention has the following beneficial effects:
the invention provides a preparation method of chiral dihydroquinolone compounds, which uses NHC as a catalyst, reacts with chloral, aza-o-benzoquinone precursor, alkaline reagent and lithium fluoride in an organic solvent under the protection of inert gas at 20-35 ℃ to generate chiral dihydroquinolone through aza-diene Diels-Alder reaction. The method does not need to use transition metal as a catalyst, can perform the reaction under milder conditions, and has the advantages of environmental protection, low cost, wide substrate selectivity (when the reaction substrates of the reaction are aromatic alpha-chloral and aliphatic alpha-chloral, the reaction substrates have better synthesis effect), mild reaction conditions and the like. In addition, the reaction conditions of the preparation method can be optimized to ensure that the product has high yield and purity, and has unique cis-selectivity and excellent enantioselectivity. The invention provides a brand new route and a new thought for chiral dihydroquinolone compounds, can play an important role in the fields of medicine intermediates and the like, and has good application value and potential.
Drawings
FIG. 1 is a diagram showing a reaction mechanism of chiral dihydroquinolone.
FIG. 2 is an H-spectrum of chiral dihydroquinolone compound 3a prepared in example 1.
FIG. 3 is a C-chart of a chiral dihydroquinolone compound 3a prepared in example 1.
FIG. 4 is an HPLC chart of chiral dihydroquinolone compound 3a prepared in example 1; wherein A is an HPLC spectrum of racemic dihydroquinolone compound 3a, and B is an HPLC spectrum of chiral dihydroquinolone compound 3a.
FIG. 5 is a diagram showing the structural formulae of the compounds 3a to 3o and the related data.
FIG. 6 is a diagram showing the structural formulae of the compounds 3p to 3u and the related data.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
The NHC catalyst structure adopted in the embodiment of the invention is any one of the following structures:
the reaction mechanism diagram for preparing chiral dihydroquinolone is shown in figure 1. Specifically, under basic conditions, the chiral NHC catalyst first chemoselectively attacks the favored carbonyl carbon (compound 2) to form an enolate (intermediate II), and then forms intermediate III with azao-methylenebenzoquinone (intermediate I formed by compound 1 losing TsH) under lewis acid to promote diels-alder reaction; finally, intermediate IV generates chiral dihydroquinolones as target products by intramolecular electron transfer, while NHC catalyst release continues for catalytic cycling.
Examples 1 to 9 and comparative examples 1 to 7 preparation of chiral dihydroquinolone 3a
The preparation method of the chiral dihydroquinolone 3a comprises the following steps:
to a 120mL dry Schlenk tube equipped with a magnetic stirring bar was added chiral catalyst NHC (251.4 mg,0.6 mmol), azao-benzoquinone precursor 1a (1.6950 g,3 mmol), α -chlorobenzopropanal 2a (1.0080 g,6 mmol), basic reagent (2.9250 g,9 mmol) and Lewis acid (38.9 mg,1.5 mmol), sealed with a septum, evacuated and refilled with nitrogen (3 cycles); solvent (40 ml,0.1 m) was added and the reaction mixture was stirred at 25 ℃ (oil bath temperature); after complete consumption of 1a (monitored by TLC), the reaction mixture was concentrated under reduced pressure, the residue was subjected to column chromatography on silica gel, and the residue was chromatographed using petroleum ether/EtOAc (v/v) =10/1 as eluent to give chiral dihydroquinolone 3a.
Among them, the chiral catalysts NHC type, basic reagent type, lewis acid type, solvent type and stirring reaction time during the preparation of examples 1 to 9 and comparative examples 1 to 7 are specifically shown in Table 1. The chiral dihydroquinolone 3a yield, dr value and ee value obtained are shown in table 1.
TABLE 1 conditions and yields for the preparation of chiral dihydroquinolone 3a of examples 1 to 9 and comparative examples 1 to 7
Note that: "-" means none, none; the yield was determined for the isolated product, trace was trace, np was no product, dr was determined by nuclear magnetic resonance crude spectroscopy and ee was analyzed by high performance liquid chromatography. DBU is 1, 8-diazabicyclo undec-7-ene, TEA is triethylamine, DABCO is 1, 4-diazabicyclo [ 2.2.2 ] octane, THF is tetrahydrofuran, MTBE is methyl tert-butyl ether, and Toluene is Toluene.
As can be seen from Table 1, when cesium carbonate and potassium tert-butoxide are used as the alkaline reagents, the yield is high and the selectivity is good; the solvent can be selected from dichloromethane and toluene. The yields were lower without the addition of lewis acid for comparative examples 1-4; the alkaline reagents added in comparative examples 5 to 7 were sodium acetate, tetrahydrofuran and 1, 4-diazabicyclo [ 2.2.2 ] octane, and the 3a compound could not be obtained.
The H spectrum of compound 3a was determined (see in particular fig. 2). From the figure, it can be seen that the chemical shift of the hydrogen spectrum peak of compound 3a 1 H NMR(300MHz,Chloroform-d)δ8.02(d,J＝8.4Hz,2H),7.42(s,1H),7.37(d,J＝8.1Hz,2H),7.28(d,J＝6.6Hz,1H),7.26-7.16(m,2H),7.04(d,J＝6.3Hz,2H),6.87(d,J＝8.7Hz,2H),6.69(d,J＝8.7Hz,2H),6.59(s,1H),5.95(d,J＝4.7Hz,2H),3.77(s,3H),3.73(d,J＝5.7Hz,1H),3.35(dd,J＝14.7,4.2Hz,1H),3.24-2.99(m,1H),2.49(s,4H)；
The carbon spectrum of compound 3a was determined (see in particular fig. 3). From the figure, it can be seen that the chemical shift of the carbon spectrum peak of compound 3a 13 C NMR(75MHz,Chloroform-d)δ171.88,158.72,146.58,145.49,145.11,138.80,136.36,129.45,129.42,129.35,129.07,128.93,128.63,128.54,127.36,126.50,114.15,107.81,105.05,101.74,55.20,49.44,44.34,32.35,21.77；
HRMS(ESI,m/z):calcd.for C 31 H 27 NO 6 S[M+H] + 542.1632,found 542.1631。
High performance liquid chromatography analysis data are 99% ee, [ chiral column IB N-5; the flow rate was 0.5 ml/min; mobile phase: isopropanol/n-hexane=20/80; retention time 28.4 min (secondary), 26.6 min (primary) ]. The HPLC spectrum of the compound 3a obtained by the measurement is shown in FIG. 4.
Examples 9 to 27 preparation of chiral dihydroquinolones 3b to 3u
The specific synthesis process is as follows:
specific preparation steps refer to the preparation method of the chiral dihydroquinolone 3a.
In the chiral dihydroquinolone 3 b-3 o compound, R substituent is 3, 4-methylenedioxy and substituent Ar is 4-methoxyphenyl; wherein when R is 1 When the substituent is 2-methylphenyl, preparing and obtaining a compound 3b; when R is 1 When the substituent is 2-bromophenyl, preparing a compound 3c; when R is 1 When the substituent is 2-trifluoromethyl phenyl, preparing a compound 3d; when R is 1 When the substituent is 3-chlorophenyl, preparing a compound 3e; when R is 1 When the substituent is 3-methoxyphenyl, preparing and obtaining a compound 3f; when R is 1 When the substituent is 4-fluorophenyl, 3g of a compound is prepared; when R is 1 When the substituent is 4-chlorophenyl, preparing a compound for 3h; when R is 1 When the substituent is 4-bromophenyl, preparing a compound 3i; when R is 1 When the substituent is 4-methylphenyl, preparing and obtaining a compound 3j; when R is 1 When the substituent is 4-methoxyphenyl, preparing and obtaining a compound 3k; when R is 1 When the substituent is naphthyl, preparing 3l of a compound; when R is 1 When the substituent is furyl, preparing a compound 3m; when R is 1 When the substituent is amyl, preparing and obtaining a compound 3n; when R is 1 When the substituent is nonyl, the compound 3o is prepared. The structural formulae, yields, dr values and ee values of the compounds 3a to 3o are shown in FIG. 5.
R in chiral dihydroquinolone 3 p-3 u compound 1 The substituent is phenyl; wherein, when R substituent is 3, 4-methylenedioxy and Ar is phenyl, preparing and obtaining a compound 3p; when the R substituent is 3, 4-methylenedioxy and Ar is 3-methylphenyl, preparing a compound 3q; when the R substituent is 3, 4-methylenedioxy and Ar is 4-methylphenyl, preparing a compound 3R; when the R substituent is 3, 4-methylenedioxy and Ar is 2-methyl-4-methoxyphenyl, preparing and obtaining a compound 3s; when the R substituent is 3, 4-methylenedioxy, ar is 2-naphthyl, compound 3t is prepared; when the R substituent is 3, 4-dimethoxy and Ar is 4-methoxyphenyl, the compound 3u is prepared. The structural formulae, yields, dr values and ee values of the compounds 3p to 3u are shown in FIG. 6.
Wherein the structure of the compound is characterized by:
compound 3b: 1 H NMR(300MHz,Chloroform-d)δ8.02(d,J＝8.1Hz,2H),7.43-7.33(m,3H),7.17-7.04(m,3H),6.89(dd,J＝16.6,7.6Hz,3H),6.69(d,J＝8.5Hz,2H),6.64(s,1H),5.95(d,J＝6.9Hz,2H),3.78(s,4H),3.33(dd,J＝14.9,4.1Hz,1H),3.13(dt,J＝10.0,5.0Hz,1H),2.61(dd,J＝15.0,10.0Hz,1H),2.50(s,3H),2.10(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ172.09,158.68,146.56,145.52,145.12,136.81,136.55,136.32,130.65,129.50,129.44,129.31,129.18,129.05,128.38,127.40,126.58,125.99,114.24,107.74,105.14,101.77,55.22,47.64,44.36,29.42,21.79,19.50；
HRMS(ESI,m/z):calcd.for C 32 H 29 NO 6 S[M+H] + 556.1789,found 556.1786; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 23.9 min (minor peak), 21.0 min (major peak)].
Compound 3c: 1 H NMR(300MHz,Chloroform-d)δ7.99(d,J＝8.4Hz,2H),7.48(dd,J＝7.8,1.4Hz,1H),7.41-7.31(m,3H),7.19-7.11(m,1H),7.05(ddd,J＝10.2,8.2,2.0Hz,2H),6.98-6.85(m,2H),6.75-6.61(m,3H),6.02-5.89(m,2H),3.80(d,J＝5.6Hz,1H),3.77(s,3H),3.35(dd,J＝13.8,5.8Hz,1H),3.26(dt,J＝7.4,5.7Hz,1H),2.76(dd,J＝13.9,7.3Hz,1H),2.48(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.64,158.71,146.56,145.53,145.03,138.35,136.29,132.90,132.05,129.45,129.40,129.29,129.15,128.40,128.30,127.32,124.61,114.24,107.67,105.24,101.75,55.21,47.38,45.46,33.77,21.76；
HRMS(ESI,m/z):calcd.for C 31 H 26 BrNO 6 S[M+Na] + 642.0557,found 642.0542; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 25.3 min (minor peak), 23.1 min (major peak)].
Compound 3d: 1 H NMR(300MHz,Chloroform-d)δ7.96(d,J＝8.1Hz,2H),7.59(d,J＝7.7Hz,1H),7.54-7.21(m,6H),6.91(d,J＝8.4Hz,2H),6.67(d,J＝6.6Hz,3H),5.94(d,J＝3.8Hz,2H),3.89(d,J＝5.5Hz,1H),3.76(s,3H),3.47(dd,J＝14.8,5.9Hz,1H),3.09(q,J＝6.1Hz,1H),2.87(dd,J＝14.8,6.8Hz,1H),2.47(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.61,158.73,146.62,145.62,145.08,137.85,136.20,132.16,131.84,129.46,129.40,129.12,129.03,128.42,127.38,126.74,126.37,114.26,107.59,105.35,101.80,55.19,49.02,45.58,29.98,21.74；
HRMS(ESI,m/z):calcd.for C 35 H 29 F 3 NO 6 S[M+H] + ,found 556.1786；
HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 20.5 min (minor peak), 18.1 min (major peak) ].
Compound 3e: 1 H NMR(300MHz,Chloroform-d)δ8.02(d,J＝8.1Hz,2H),7.43(s,1H),7.37(d,J＝8.1Hz,2H),7.18(d,J＝4.7Hz,2H),7.03(s,1H),6.96-6.85(m,3H),6.71(d,2H),6.60(s,1H),5.93(d,J＝5.9,1.4Hz,2H),3.76(s,3H),3.73(d,J＝5.7Hz,1H),3.30(dd,J＝14.6,4.6Hz,1H),3.18-3.05(m,1H),2.48(s,4H)； 13 C NMR(75MHz,Chloroform-d)δ171.53,158.84,146.67,145.58,145.23,141.04,136.28,134.31,129.91,129.47,129.42,129.29,129.01,128.91,128.46,127.24,127.09,126.76,114.26,107.84,105.06,101.83,55.22,49.28,44.74,32.38,21.77；
HRMS(ESI,m/z):calcd.for C 31 H 26 ClNO 6 S[M+Na] + 598.1062,found 598.1068; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 29.7 min (minor peak), 26.4 min (major peak)]。
Compound 3f: 1 H NMR(300MHz,Chloroform-d)δ8.01(d,J＝8.0Hz,2H),7.36(d,J＝8.5Hz,3H),7.28(s,1H),6.95(d,J＝8.5Hz,2H),6.76-6.63(m,3H),6.54(s,1H),5.97(d,J＝6.7Hz,2H),3.77(s,4H),3.70(s,3H),3.33-3.18(m,2H),2.73(dt,J＝12.1,5.7Hz,1H),2.49(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.72,158.86,153.38,146.66,145.62,145.14,136.36,136.13,130.28,129.43,129.31,129.25,129.14,128.25,127.05,125.15,121.30,115.48,114.30,107.66,105.12,101.79,56.22,55.25,46.97,45.76,31.95,21.75；
HRMS(ESI,m/z):calcd.for C 32 H 29 NO 7 S[M+H] + ,found 556.1786；
HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 39.6 min (minor peak), 29.4 min (major peak) ].
Compound 3g: 1 H NMR(300MHz,Chloroform-d)δ8.01(d,J＝8.4Hz,2H),7.41(s,1H),7.36(d,J＝8.2Hz,2H),7.00-6.90(m,4H),6.86(d,J＝8.7Hz,2H),6.72-6.64(m,2H),6.60(s,1H),6.00-5.91(m,2H),3.77(s,3H),3.70(d,J＝5.8Hz,1H),3.28(dd,J＝14.6,4.6Hz,1H),3.14-3.01(m,1H),2.49(s,4H)； 13 C NMR(101MHz,Chloroform-d)δ171.72,161.55(d,J＝242.9Hz),158.76,146.62,145.54,145.16,136.30,134.35(d,J＝3.3Hz),130.34(d,J＝7.8Hz),129.43,129.25,129.07,128.96,128.47,127.19,115.41(d,J＝21.0Hz),114.20,107.77,105.06,101.77,55.21,49.52,44.52,31.75,21.77；
HRMS(ESI,m/z):calcd.for C 31 H 26 FNO 6 S[M+Na] + 582.1358,found 582.1348; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 32.9 min (minor peak), 26.5 min (major peak)]。
Compound 3h: 1 H NMR(300MHz,Chloroform-d)δ8.01(d,J＝8.4Hz,2H),7.44-7.31(m,3H),7.25-7.18(m,2H),6.95(d,J＝8.4Hz,2H),6.89-6.81(m,2H),6.73-6.63(m,2H),6.60(s,1H),5.96(dd,J＝6.2,1.4Hz,2H),3.77(s,3H),3.69(d,J＝5.8Hz,1H),3.27(dd,J＝14.6,4.6Hz,1H),3.14-3.02(m,1H),2.49(s,4H)； 13 C NMR(75MHz,Chloroform-d)δ171.60,158.79,146.64,145.16,137.28,136.30,132.26,130.28,129.42,129.25,128.88,128.72,128.45,127.11,114.21,107.77,105.05,101.78,55.21,49.34,44.57,31.96,21.77；
HRMS(ESI,m/z):calcd.for C 31 H 26 ClNO 6 S[M+Na] + 598.1062,found 598.1048; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 41.8 min (minor peak), 33.7 min (major peak)]。
Compound 3i: 1 H NMR(300MHz,Chloroform-d)δ8.01(d,J＝8.4Hz,2H),7.44-7.31(m,5H),6.94-6.81(m,4H),6.75-6.64(m,2H),6.60(s,1H),6.00-5.91(m,2H),3.76(s,3H),3.70(d,J＝5.7Hz,1H),3.25(dd,J＝14.6,4.6Hz,1H),3.14-3.02(m,1H),2.48(s,4H)； 13 C NMR(75MHz,Chloroform-d)δ171.59,158.80,146.65,145.57,145.20,137.85,136.28,131.68,130.71,129.45,129.42,129.27,128.88,128.46,127.11,120.31,114.22,107.80,105.05,101.80,55.21,49.27,44.61,32.08,21.78；
HRMS(ESI,m/z):calcd.for C 31 H 26 BrNO 6 S[M+Na] + 642.0557,found 642.0541; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 45.8 min (minor peak), 34.2 min (major peak)]。
Compound 3j: 1 H NMR(300MHz,Chloroform-d)δ8.02(d,J＝8.4Hz,2H),7.42(s,1H),7.37(d,J＝8.2Hz,2H),7.07(d,J＝7.8Hz,2H),6.97-6.83(m,4H),6.69(d,J＝8.7Hz,2H),6.59(s,1H),5.99-5.91(m,2H),3.77(s,4H),3.31(dd,J＝14.7,4.2Hz,1H),3.17-3.05(m,1H),2.54-2.39(m,4H),2.32(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.95,158.70,146.55,145.47,145.08,136.40,136.02,135.61,129.44,129.40,129.37,129.31,129.12,128.79,128.57,127.44,114.12,107.82,105.04,101.73,55.20,49.51,44.22,31.85,21.76,21.05；
HRMS(ESI,m/z):calcd.for C 32 H 29 NO 6 S[M+Na] + 578.1608,found 578.1594; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 26.8 min (minor peak), 25.1 min (major peak)]。
Compound 3k: 1 H NMR(300MHz,Chloroform-d)δ8.02(d,J＝8.4Hz,2H),7.42(s,1H),7.36(d,J＝8.2Hz,2H),6.97-6.85(m,4H),6.80(d,J＝8.6Hz,2H),6.68(d,J＝8.7Hz,2H),6.59(s,1H),5.95(d,J＝4.9Hz,2H),3.77(d,J＝4.0Hz,6H),3.73(d,J＝5.7Hz,1H),3.28(dd,J＝14.6,4.3Hz,1H),3.14-3.01(m,1H),2.48(s,3H),2.47-2.35(m,1H)； 13 C NMR(75MHz,Chloroform-d)δ171.97,158.70,158.20,146.55,145.48,145.09,136.38,130.62,129.88,129.43,129.41,129.34,129.14,128.54,127.43,114.13,114.01,107.81,105.04,101.74,55.27,55.20,49.62,44.26,31.46,21.77；
HRMS(ESI,m/z):calcd.for C 37 H 29 NO 7 S[M+Na] + 594.1557,found 594.1546; HPLC analysis 99% ee, [ chiral IA column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=30/70; retention time 55.4 min (minor peak), 31.7 min (major peak)]。
Compound 3l: 1 H NMR(300MHz,Chloroform-d)δ8.30(d,J＝8.4Hz,1H),8.04(d,J＝8.1Hz,2H),7.82(d,J＝8.4Hz,1H),7.67-7.30(m,7H),6.93(dd,J＝15.5,8.0Hz,3H),6.71(d,J＝8.2Hz,2H),6.54(s,1H),5.90(s,2H),3.89(dd,J＝14.7,3.7Hz,1H),3.80(s,3H),3.68(d,J＝5.8Hz,1H),3.28-3.16(m,1H),2.92(dd,J＝14.8,9.8Hz,1H),2.52(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.83,158.77,146.54,145.48,145.24,136.21,134.07,132.66,131.14,131.07,129.58,129.47,129.22,129.17,128.14,127.26,127.02,126.83,125.59,125.44,123.88,114.37,107.68,105.05,101.74,55.25,48.06,44.67,29.34,21.81；
HRMS(ESI,m/z):calcd.for C 35 H 29 NO 6 S[M+H] + 592.1789,found 592.1799; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 35.2 min (minor peak), 29.5 min (major peak)]。
Compound 3m: 1 H NMR(300MHz,Chloroform-d)δ8.03(d,J＝8.4Hz,2H),7.44(s,1H),7.35(d,J＝8.0Hz,2H),7.31(d,J＝1.9Hz,1H),7.00-6.89(m,2H),6.75-6.66(m,2H),6.64(s,1H),6.29(dd,J＝3.2,1.9Hz,1H),6.05-5.92(m,3H),3.87(d,J＝5.3Hz,1H),3.75(s,3H),3.30-3.14(m,2H),2.64-2.52(m,1H),2.47(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.14,158.83,152.71,146.70,145.57,145.11,141.52,136.45,129.61,129.42,129.31,128.85,128.56,127.07,114.08,110.33,107.98,107.07,105.01,101.77,55.18,47.45,44.62,25.15,21.73；
HRMS(ESI,m/z):calcd.for C 29 H 25 NO 7 S[M+Na] + 554.1244,found 554.1249; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 27.2 min (minor peak), 24.3 min (major peak)]。
Compound 3n:yield:34mg (63%), white solid; 1 H NMR(300MHz,Chloroform-d)δ7.96(d,J＝8.4Hz,2H),7.43(s,1H),7.31(d,J＝7.9Hz,2H),6.97-6.83(m,2H),6.70(s,1H),6.69-6.60(m,2H),6.04-5.83(m,2H),3.93(d,J＝5.5Hz,1H),3.74(s,3H),2.77-2.60(m,1H),2.45(s,3H),1.89-1.74(m,1H),1.41-1.30(m,3H),1.24(m,6H),0.89-0.79(m,3H)； 13 C NMR(75MHz,Chloroform-d)δ172.22,158.66,146.55,145.50,144.88,136.52,129.32,129.29,129.08,128.89,127.42,114.00,107.73,105.21,101.74,55.17,48.42,45.21,31.59,29.18,27.41,26.67,22.57,21.71,14.04；
HRMS(ESI,m/z):calcd.for C 30 H 33 NO 6 S[M+Na] + ,found 578.1594；
HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 26.0 min (minor peak), 18.0 min (major peak) ].
Compound 3o: 1 H NMR(300MHz,Chloroform-d)δ7.96(d,J＝8.4Hz,2H),7.43(s,1H),7.31(d,J＝8.2Hz,2H),6.95-6.81(m,2H),6.74-6.60(m,3H),6.02-5.93(m,2H),3.93(d,J＝5.6Hz,1H),3.74(s,3H),2.69(q,J＝6.6,5.9Hz,1H),2.45(s,3H),1.86-1.74(m,1H),1.31-1.18(m,17H),0.88(d,J＝6.5Hz,3H)； 13 C NMR(75MHz,Chloroform-d)δ172.22,158.65,146.55,145.50,144.87,136.52,129.32,129.28,129.07,128.88,127.42,114.00,107.73,105.22,101.73,55.16,48.42,45.18,31.90,29.56,29.50,29.39,29.31,27.43,26.64,22.68,21.71,14.12；
HRMS(ESI,m/z):calcd.for C 34 H 41 NO 6 S[M+Na] + 614.2547,found 614.2533; HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80The method comprises the steps of carrying out a first treatment on the surface of the Retention time 23.7 min (minor peak), 16.1 min (major peak)]。
Compound 3q: 1 H NMR(300MHz,Chloroform-d)δ8.03(d,J＝8.4Hz,2H),7.28(d,J＝6.6Hz,1H),7.25-7.18(m,2H),7.08-7.00(m,4H),6.97(s,1H),6.76-6.69(m,1H),6.62(s,1H),6.00-5.91(m,2H),3.76(d,J＝5.8Hz,1H),3.37(dd,J＝14.7,4.2Hz,1H),3.20-3.07(m,1H),2.53(dd,J＝14.7,10.1Hz,1H),2.48(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.91,146.62,145.46,145.05,138.87,138.59,136.93,136.62,129.47,129.27,129.18,128.95,128.61,128.18,127.19,126.49,125.10,107.91,104.94,101.74,49.41,44.97,32.40,21.76,21.41；
HRMS(ESI,m/z):calcd.for C 31 H 27 NO 5 S[M+Na] + 548.1503,found 548.1493；
HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 17.2 min (minor peak), 14.8 min (major peak) ].
Compound 3r: 1 H NMR(300MHz,Chloroform-d)δ8.01(d,J＝8.4Hz,2H),7.42(s,1H),7.36(d,J＝8.1Hz,2H),7.28(t,J＝2.0Hz,1H),7.26-7.19(m,2H),7.07-6.99(m,2H),6.95(d,J＝8.0Hz,2H),6.84(d,J＝8.2Hz,2H),6.60(s,1H),6.02-5.80(m,2H),3.74(d,J＝5.7Hz,1H),3.35(dd,J＝14.6,4.2Hz,1H),3.20-3.07(m,1H),2.60-2.40(m,4H),2.29(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.84,146.58,145.47,145.05,138.86,136.94,136.37,134.00,129.46,129.38,128.94,128.61,128.09,127.25,126.48,107.83,105.04,101.72,49.37,44.71,32.35,21.75,21.04；
HRMS(ESI,m/z):calcd.for C 31 H 27 NO 5 S[M+Na] + 548.1503,found 548.1494；
HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 22.5 min (minor peak), 20.7 min (major peak) ].
Compound 3s: 1 H NMR(300MHz,Chloroform-d)δ8.08(d,J＝8.4Hz,2H),7.44-7.37(m,3H),7.20(d,J＝7.0Hz,3H),6.89-6.82(m,2H),6.73(d,J＝8.6Hz,1H),6.68(d,J＝2.8Hz,1H),6.60(s,1H),6.42(dd,J＝8.6,2.9Hz,1H),5.94(dd,J＝9.7,1.4Hz,2H),3.97(d,J＝6.3Hz,1H),3.76(s,4H),3.28(dd,J＝14.2,4.6Hz,1H),3.22-3.13(m,1H),2.51(s,3H),2.03(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ172.51,158.18,146.36,145.39,145.20,138.49,137.78,136.34,129.54,129.46,128.79,128.58,128.24,127.95,126.92,126.49,116.89,111.71,107.70,105.08,101.70,55.08,49.21,39.10,32.46,21.78,20.68；
HRMS(ESI,m/z):calcd.for C 32 H 29 NO 6 S[M+Na] + 578.1608,found 578.1600；
HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 24.8 min (minor peak), 22.8 min (major peak) ].
Compound 3t: 1 H NMR(300MHz,Chloroform-d)δ7.94(d,J＝8.4Hz,2H),7.83-7.73(m,1H),7.65(t,J＝7.8Hz,2H),7.56-7.38(m,4H),7.28(d,J＝6.4Hz,1H),7.25-7.22(m,2H),7.20(s,1H),7.15(dd,J＝8.5,2.0Hz,1H),7.08-7.00(m,2H),6.71(s,1H),5.97(dd,J＝8.0,1.4Hz,2H),3.96(d,J＝5.6Hz,1H),3.45(dd,J＝14.6,4.3Hz,1H),3.31-3.14(m,1H),2.65(dd,J＝14.7,10.1Hz,1H),2.43(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ171.92,146.74,145.55,145.00,138.82,136.45,134.55,133.33,132.48,129.40,129.17,128.93,128.67,128.50,128.23,127.44,127.09,126.93,126.57,126.38,126.12,126.08,107.94,105.24,101.79,49.50,44.92,32.62,21.74；
HRMS(ESI,m/z):calcd.for C 34 H 27 NO 5 S[M+Na] + 584.1503,found 584.1496；
HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 26.5 min (minor peak), 22.5 min (major peak) ].
Compound 3u: 1 H NMR(300MHz,Chloroform-d)δ8.01(d,J＝8.4Hz,1H),7.56(s,1H),7.37(d,J＝8.2Hz,2H),7.32-7.26(m,2H),7.26-7.16(m,3H),7.10-7.01(m,2H),6.83-6.72(m,2H),6.67-6.54(m,3H),3.95(s,3H),3.78(d,J＝12.8Hz,7H),3.33(dd,J＝14.6,4.2Hz,1H),3.24-3.13(m,1H),2.52-2.36(m,4H)； 13 C NMR(75MHz,Chloroform-d)δ171.78,158.66,147.54,146.98,145.07,138.89,136.29,129.57,129.42,129.36,129.31,129.01,128.62,128.14,126.45,125.65,114.07,110.69,107.76,56.35,56.05,55.17,49.57,44.32,32.31,21.76；
HRMS(ESI,m/z):calcd.for C 32 H 31 NO 6 S[M+Na] + 580.1756,found 580.1765；
HPLC analysis 99% ee, [ chiral IH column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time 31.9 min (minor peak), 42.1 min (major peak) ].
EXAMPLE 28 Process for the preparation of chiral dihydroquinolone derivative 4
Test materials: chiral dihydroquinolone 3a compound prepared in any one of examples 1 to 8.
To 2mL of a THF solution containing chiral dihydroquinolone 3a compound (108.2 mg,0.20mmol,99% ee) was added 0.4mL of Na/naphthalene THF solution (Na/naphthalene solution was added 3mL of THF as 5mmol of Na,5mmol of naphthalene), and the reaction was stirred at-78℃for 10 minutes. Then add H 2 O (2 mL) quench reaction with CH 2 Cl 2 (1 mL. Times.2) the resulting mixture was extracted. The combined organic layers were taken up in Na 2 SO 4 Drying above, filtering, concentrating under reduced pressure at 40deg.C, and drying. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=8:1 to 3:1) to give the desired product 4 as a white solid (70.4 mg,0.182mmol,91% yield,>20：1dr，99％ee)。
the structure of compound 4 is shown below:
compound 4: 1 H NMR(300MHz,Chloroform-d)δ8.48(s,1H),7.31(t,J＝7.2Hz,2H),7.22(d,J＝7.5Hz,1H),7.17-7.08(m,2H),7.05-6.99(m,2H),6.85-6.71(m,2H),6.51(s,1H),6.39(s,1H),5.85(dd,J＝14.9,1.4Hz,2H),3.76(s,4H),3.47(dd,J＝14.5,4.5Hz,1H),3.29(ddd,J＝10.6,6.5,4.3Hz,1H),2.44(dd,J＝14.6,10.3Hz,1H)； 13 C NMR(75MHz,Chloroform-d)δ172.06,158.76,147.07,143.50,139.74,132.02,130.16,129.06,128.46,126.25,121.22,114.21,108.42,101.22,97.80,55.20,46.14,44.73,31.75；
HRMS(ESI,m/z):calcd.for C 24 H 21 NO 4 S[M+H] + 388.1544,found 388.1558；
HPLC analysis of 99% ee, [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time: 23.9 minutes (minor peak), 18.0 minutes (major peak) ].
EXAMPLE 29 Process for the preparation of chiral dihydroquinolone derivative 5
Test materials: chiral dihydroquinolone 3a compound prepared in any one of examples 1 to 8.
LiAlH is prepared 4 (22.8 mg,0.6mmol,3.0 equiv) was added to anhydrous THF (1 mL) at 0deg.C, N 2 Under an atmosphere, chiral dihydroquinolone 3a compound (108.2 mg,0.20mmol,99% ee,1.0 equiv) was added again slowly. The reaction was stirred at 0deg.C for 2h and then quenched with 0.1M HCl solution. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases are in Na 2 SO 4 Drying, filtering, and concentrating under reduced pressure. Purification by silica gel column chromatography (petroleum ether/ethyl acetate=6:1) gave 5 (80.1 mg,0.125mmol,76% yield,>20：1dr，99％ee)。
the structure of compound 5 is shown below:
compound 5: 1 H NMR(300MHz,Chloroform-d)δ7.78(d,J＝8.3Hz,2H),7.33(d,J＝8.1Hz,2H),7.28(d,J＝7.4Hz,1H),7.24(s,1H),7.22-7.12(m,3H),6.83(s,1H),6.71(q,J＝8.8Hz,4H),6.57(s,1H),5.85(dd,J＝10.3,1.4Hz,2H),4.05(d,J＝11.7Hz,1H),3.77(s,3H),3.49(d,J＝10.9Hz,1H),3.15(d,J＝12.0Hz,1H),2.75-2.60(m,2H),2.49(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ158.03,146.64,145.93,143.51,140.77,137.97,134.46,133.12,129.93,129.39,128.95,128.50,127.47,127.43,126.07,113.94,107.71,101.42,60.23,55.23,46.03,45.27,34.77,21.63；
HRMS(ESI,m/z):calcd.for C 31 H 29 NO 5 S[M+H] + 528.1840,found 528.1824；
HPLC analysis: 99% ee; [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time: 26.4 minutes (minor peak), 24.2 minutes (major peak) ].
EXAMPLE 30 Process for the preparation of chiral dihydroquinolone derivative 6
Test materials: chiral dihydroquinolone 3a compound prepared in any one of examples 1 to 8.
DDQ (45.4 mg,0.20mmol,2.0 equiv) was added to a solution of 3a compound (54.1 mg,0.10mmol,99% ee,1.0 equiv) in 1, 4-dioxane (1 mL), stirred at 100deg.C for 12H, then H was added 2 O (2 ml), the resulting mixture was extracted with ethyl acetate (2 ml. Times.2), and the combined organic layers were taken up in Na 2 SO 4 Drying above, filtering, concentrating under reduced pressure at 40deg.C, and drying. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10:1 to 5:1) to give compound 6 (46.8 mg,0.087mmol,87% yield) as a white solid.
The structure of compound 6 is shown below:
compound 6: 1 H NMR(300MHz,Chloroform-d)δ7.88(d,J＝8.4Hz,2H),7.30(d,J＝8.0Hz,2H),7.18-7.09(m,4H),7.07-7.01(m,2H),7.00-6.93(m,2H),6.90(dd,J＝7.4,2.1Hz,2H),6.62(s,1H),6.02(s,2H),3.93(s,2H),3.86(s,3H),2.44(s,3H)； 13 C NMR(75MHz,Chloroform-d)δ159.52,154.16,150.72,150.46,147.73,144.80,142.57,139.71,134.81,130.43,129.29,129.07,128.44,128.15,125.90,124.41,121.52,114.06,105.01,102.28,101.81,55.36,33.34,21.73；
HRMS(ESI,m/z):calcd.for C 31 H 25 NO 6 S[M+H] + 540.1476,found 540.1491；
HPLC analysis: 99% ee; [ chiral IB N-5 column; the flow rate was 0.5 ml/min; mobile phase isopropanol/n-hexane=20/80; retention time: 26.4 minutes (minor peak), 24.2 minutes (major peak) ].
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (10)

1. The preparation method of the chiral dihydroquinolone compound is characterized by comprising the steps of reacting a compound 1, a compound 2, a catalyst N-heterocyclic carbene, an alkaline reagent and Lewis acid in an organic solvent under the protection of inert gas at 20-35 ℃ completely, separating and purifying to obtain the chiral dihydroquinolone compound 3;
the synthetic route is as follows:
wherein R is disubstituted and each is independently C 1～5 An alkoxy group, or a methylenedioxy group, two alkoxy groups of which are respectively connected with two adjacent carbon atoms on the benzene ring; ar is aryl or substituted aryl, wherein the substituent in the substituted aryl is C 1～12 Alkyl or C 1～5 One or more of alkoxy groups; r is R 1 Selected from C 1～12 One of alkyl, aryl or substituted aryl, wherein the substituents in the substituted aryl are selected from C 1～12 Alkyl, C 1～5 Alkoxy, C 1～3 One of haloalkyl and halogen;
the carbon number of the aryl is 5-10.
2. The method of claim 1, wherein R is disubstituted, each independently is C 1～5 Alkoxy, or methylenedioxy, the two alkoxy groups of which are each bound to a benzene ringTwo adjacent carbon atoms are connected; ar is selected from one of phenyl, substituted phenyl and naphthyl, wherein the substituent in the substituted phenyl is C 1～8 Alkyl or C 1～4 One or more of alkoxy groups; r is R 1 Selected from C 1～12 One of alkyl, phenyl or substituted phenyl, naphthyl and furyl, wherein the substituent in the substituted phenyl is selected from C 1～8 Alkyl, C 1～4 Alkoxy, C 1～3 Haloalkyl, halogen.
3. The method of claim 2, wherein R is disubstituted, each independently is methoxy, or methylenedioxy, wherein two alkoxy groups of the methylenedioxy are each attached to two adjacent carbon atoms on the benzene ring; ar is selected from phenyl or one of substituted phenyl and naphthyl, wherein the substituent in the substituted phenyl is one or more of methyl or methoxy; r is R 1 The substituent in the substituted phenyl is selected from one of methyl, methoxy, trifluoromethyl and halogen.
4. The method of claim 1, wherein the catalyst N-heterocyclic carbene is selected from any one of the following structures:
5. the preparation method according to claim 1, wherein the alkaline reagent is one or more selected from 1, 8-diazabicyclo undec-7-ene, potassium tert-butoxide and cesium carbonate.
6. The preparation method according to claim 1, wherein the organic solvent is selected from one of dichloromethane, tetrahydrofuran, toluene, methyl tert-butyl ether and acetonitrile.
7. The method of claim 1, wherein the lewis acid is lithium fluoride or lithium chloride.
8. The method according to claim 1, wherein the reaction time is 12 to 24 hours.
9. The method according to claim 1, wherein the inert gas is nitrogen or argon.
10. Use of the preparation method according to any one of claims 1 to 9 for the preparation of a medicament containing a dihydroquinolone structural element, tetrahydroquinoline or quinolone.
CN202311799243.1A 2023-12-25 2023-12-25 Preparation method of chiral dihydroquinolone compound Pending CN117800981A (en)

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