Chiral 2,2'-disubstituted indoline compounds, methods of synthesis and uses thereof

Abstract

The application provides a chiral 2-position disubstituted indoline compound and a synthesis method and application thereof. The application uses a simple structure palladium catalyst and a chiral ligand as a catalyst system, and uses a newly designed allyl benzoxazinone as a raw material to perform a palladium catalyzed intramolecular asymmetric cyclization reaction, so that efficient asymmetric synthesis of the chiral 2-position disubstituted indoline compound is realized. The synthesis method is simple, the reaction condition is mild, the cost is low, and the efficiency is high; the raw material is cheap and easy to obtain, atom economy is good, and the substrate is widely applicable; the target product has high yield and high enantioselectivity; the chiral 2-position disubstituted indoline compound obtained by the application has excellent inhibition effect on bladder cancer cells, provides a scientific basis for developing a new candidate drug for treating bladder cancer, and has important significance for the treatment of bladder cancer.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of chiral 2-position disubstituted indoline compound and its synthesis method and application, belong to organic synthesis technical field. BACKGROUND

[0002] Chiral indoline as an important skeleton mainly exists in the form of polycyclic or annular in a variety of chiral indole alkaloids, wherein 2-position substituted chiral indoline skeleton is the important component of many natural products and in-research drugs, and is also widely used in chiral auxiliary for asymmetric synthesis and common motif of biologically significant compounds, which makes the asymmetric construction of this kind of skeleton become a constantly researched and improved goal and difficulty in synthesis field. Although a variety of methods for constructing chiral indoline skeleton have been reported in the literature, such as kinetic resolution, indole direct functionalization, asymmetric synthesis using chiral reagents and asymmetric catalytic reaction, etc., but the 2-position of indoline synthesized by these methods is mostly monosubstituted, i.e. tertiary carbon chiral center, and the report on 2-position chiral quaternary carbon center is relatively less. Chiral indoline derivatives containing 2-position quaternary carbon center also widely exist in in-research drugs or natural products, such as (+)-Benzastatin E, (+)-Deriglidole, etc.

[0003] At present, there are relatively few reports on asymmetric construction of chiral indoline 2-position quaternary carbon center, and most of the methods for constructing 2-position quaternary carbon center alone are realized through intramolecular coupling reaction. In 2012, Cai Qian's group reported asymmetric intramolecular Ullmann carbon-nitrogen coupling reaction under the catalysis of CuI and BINOL chiral ligand (J. Am. Chem. Soc. 2012, 134, 14326-14329), and the construction of indoline skeleton with 2-position quaternary carbon center was realized by desymmetrization strategy, but the stereoselectivity of the product was general. In 2016, Baudoin et al. realized the synthesis of various chiral indolines by carbon-hydrogen bond activation strategy using palladium catalyst and chiral phosphoric acid catalysis system (Chem. Sci. 2017, 8, 1344-1349), although indoline compounds with 2-position tertiary carbon chiral center were synthesized with good enantioselectivity by this method, but the construction and asymmetric synthesis control of indoline 2-position quaternary carbon chiral center were relatively poor.

[0004] Therefore, developing novel, simple and efficient asymmetric synthesis reaction for the synthesis of ring compounds can not only effectively make up for the deficiency of the synthesis method of indoline skeleton with 2-position chiral quaternary carbon center, but also provide theoretical basis and methodological foundation for the total synthesis of related natural products, and provide a new way for the synthesis of related drug intermediates and other functional molecules. SUMMARY

[0005] In view of the deficiencies of the prior art, the present application provides a chiral 2-position disubstituted indoline compound and a synthesis method and application thereof. The present application uses a simple-structured palladium catalyst and a chiral ligand as a catalyst system, and performs a palladium-catalyzed intramolecular asymmetric cyclization reaction on an allyl benzoxazinone newly designed as a raw material, so as to realize efficient asymmetric synthesis of the chiral 2-position disubstituted indoline compound. The synthesis method of the present application is simple, the reaction condition is mild, the cost is low, and the efficiency is high; the raw material is cheap and easy to obtain, the atomic economy is good, and the substrate is widely applicable; the target product of the present application has high yield and high enantioselectivity; the chiral 2-position disubstituted indoline compound obtained by the present application has excellent inhibition effect on bladder cancer cells, which provides a scientific basis for developing a new candidate drug for treating bladder cancer, and has important significance for the treatment of bladder cancer.

[0006] Term explanation:

[0007] Room temperature: has the meaning known in the art, refers to 25±5℃.

[0008] The technical scheme adopted by the present application is as follows:

[0009] A chiral 2-position disubstituted indoline compound has the structure shown in the following formula II:

[0010]

[0011] wherein, R 1 is selected from alkyl, halogen, nitro, alkoxy, phenyl, ester, hydrogen; R 2 is selected from substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted methylthiophene, and substituted or unsubstituted methylnaphthalene, wherein the substituent is selected from halogen, C1-C3 alkyl, methoxy.

[0012] According to the present application, preferably, R 1 is 5-methyl, 5-fluoro, 5-chloro, 6-acetate, 6-yl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl) acetate, 6-yl 4-(N,N-dipropylsulfamoyl) benzoate, 5-phenyl, hydrogen or 6-methoxy; R 2 is benzyl, 2-fluorobenzyl, 3,5-dichlorobenzyl, 2-o-methylphenyl, 3,5-dichlorophenyl, methylthiophene or methylnaphthalene.

[0013] According to the present application, preferably, the chiral 2-position disubstituted indoline compound is selected from the following compounds:

[0014]

[0015] The synthesis method of the above-mentioned chiral 2-position disubstituted indoline compound comprises the following steps:

[0016] The chiral 2-substituted indoline compound II is obtained by asymmetric allylation reaction of the allyl benzoxazepinone compound I in a solvent under catalysis of a palladium catalytic system; the palladium catalytic system is composed of a palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct (Pd2(dba)3.CHCl3) and a chiral ligand having the structure shown in formula III;

[0017]

[0018] In the structural formulae of the compounds of formula I and II, R 1 is selected from alkyl, halogen, nitro, alkoxy, phenyl, ester, hydrogen; R 2 is selected from substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted methylthiophene, and substituted or unsubstituted methylnaphthalene, wherein the substituents are selected from halogen, C1-C3 alkyl, methoxy.

[0019] According to the application, preferably, in the structural formulae of the compounds of formula I and II, R 1 is 5-methyl, 5-fluoro, 5-chloro, 6-acetate, 6-yl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate, 6-yl 4-(N,N-dipropylsulfamoyl)benzoate, 5-phenyl, hydrogen, or 6-methoxy; R 2 is benzyl, 2-fluorobenzyl, 3,5-dichlorobenzyl, 2-ortho-methylphenyl, 3,5-dichlorophenyl, methylthiophene, or methylnaphthalene.

[0020] According to the application, preferably, the solvent is N,N-dimethylformamide (DMF); the ratio of the volume of the solvent to the number of moles of the allyl benzoxazepinone compound I is 3-10 mL:1 mmol; and the solvent is anhydrous.

[0021] According to the application, preferably, the molar ratio of the palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct to the allyl benzoxazepinone compound I is 0.01-0.03:1; and the molar ratio of the palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct to the chiral ligand is 1:3-5.

[0022] According to the application, the chiral ligand can be prepared by the method in the prior art, which can be prepared according to the literature (ACS Catal. 2021, 11, 2684-2690).

[0023] According to the application, preferably, in the reaction system of the allyl benzoxazepinone compound I, a molecular sieve is further added; the molecular sieve has a mass to number of moles ratio of 1-3 g:1 mmol.

[0024] According to the application, preferably, the reaction is carried out under the protection of a protective gas, and the protective gas is nitrogen or argon.

[0025] According to the application, preferably, the reaction temperature is -20-0℃, and more preferably -10℃; the reaction time is 2-48h, and more preferably 12-24h. During the reaction, the reaction progress is monitored by HPLC, and when the allyl benzoxazepinone compound I in the system is completely converted, the reaction is ended.

[0026] According to the application, after the reaction of the allyl benzoxazepinone compound I, the product can be separated and characterized by conventional separation and purification methods; preferably, the specific post-reaction processing steps are as follows: the solvent of the reaction liquid is removed, and the obtained crude product is separated by silica gel column chromatography to obtain the chiral 2-position disubstituted indoline compound, and the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the mixed solvent is 0.02-0.2:1.

[0027] According to the application, one preferred embodiment comprises the following steps:

[0028] Under the protection of a protective gas, the palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct, the chiral ligand III and The molecular sieve is added into a flask, N,N-dimethylformamide is added, and after stirring at room temperature for 20-40 minutes, it is placed in a cold trap at -20-0℃; the allyl benzoxazepinone compound I is dissolved in N,N-dimethylformamide, and then added into the above flask, and continues to be stirred at -20-0℃ until the reaction is complete; the reaction liquid is concentrated under reduced pressure to remove the excess solvent, and then purified by silica gel column chromatography to obtain the chiral 2-position disubstituted indoline compound.

[0029] According to the application, preferably, the preparation method of the allyl benzoxazepinone compound I comprises the following steps:

[0030] (1) Under the protection of nitrogen, the tetrahydrofuran solution of the Boc-protected o-methyl aniline S1 is stirred at -20-(-30)℃ for 5-15 minutes, the sec-butyl lithium solution is added dropwise, and continues to be stirred for 5-15 minutes; the vinyl ketone S2 is added, and the stirring is continued until the reaction is complete; the saturated ammonium chloride aqueous solution is added to the reaction liquid at -20-(-30)℃ for quenching, the reaction liquid is concentrated, and then extracted with ethyl acetate; the organic phases are combined, washed with saturated brine, dried with anhydrous sodium sulfate, distilled under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain the amino alcohol intermediate.

[0031]

[0032] wherein, R 1selected from alkyl, halogen, nitro, alkoxy, phenyl, ester, hydrogen; R 2 selected from substituted or unsubstituted benzyl, substituted or unsubstituted phenyl, substituted or unsubstituted methylthiophene, substituted or unsubstituted methylnaphthalene, wherein the substituent is selected from halogen, C1-C3 alkyl, methoxy;

[0033] (2) under nitrogen protection, the tetrahydrofuran solution of the amino alcohol intermediate is stirred at -5-5℃ for 5-15 minutes, and a methyl lithium solution is added dropwise, after dropping, it is stirred at 45-55℃ until the reaction is complete; saturated ammonium chloride aqueous solution is added to quench the reaction, and then the reaction solution is concentrated and extracted with ethyl acetate, the organic phases are combined, the organic phase is washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent is removed by reduced pressure distillation, and then column chromatography on silica gel is carried out to purify to obtain the allyl benzoxazinone compound I.

[0034] Preferably, in step (1), the concentration of the tetrahydrofuran solution of the Boc-protected o-methyl aniline S1 is 0.1-0.3 mmol / mL; the molar ratio of the Boc-protected o-methyl aniline S1 to the sec-butyllithium is 1:1-3; and the molar ratio of the vinyl ketone S2 to the Boc-protected o-methyl aniline S1 is 1:1-2.

[0035] Preferably, in step (2), the concentration of the tetrahydrofuran solution of the amino alcohol intermediate is 0.1-0.3 mmol / mL; and the molar ratio of the amino alcohol intermediate to the methyl lithium is 1:1-3.

[0036] The chiral 2-position disubstituted indoline compound is used for preparing an anti-bladder cancer drug.

[0037] The technical features and beneficial effects of the present application are as follows:

[0038] 1. The present application uses a simple structure of palladium catalyst and a chiral ligand as a catalyst system, and a newly designed 1,5-dipole allyl benzoxazinone as a raw material for palladium-catalyzed intramolecular asymmetric cyclization reaction, to realize the efficient asymmetric synthesis of chiral 2-position disubstituted indoline compounds. The synthesis method is simple, the reaction conditions are mild, and the operation is convenient and simple; the amount of catalyst used is small, the cost of catalyst is low, and the efficiency is high; the raw materials are cheap and easy to obtain, the atomic economy is good, and the substrate is widely applicable.

[0039] 2. This invention uses a novel 1,5-dipolar allylbenzoxazine as a starting material. Currently, 1,3-dipolar and 1,4-dipolar molecules have been widely used in various intermolecular asymmetric cycloaddition reactions to construct a variety of chiral mesocyclic compounds, but they also have the following limitations: 1) Intermolecular reactions require the participation of both a dipole and a dipoleophile, which may lead to numerous side reactions; 2) Dipolarophiles are mostly electron-deficient alkenes or carbonyl derivatives, such as aldehydes and imines, which greatly limits the application range of the substrates. In contrast, research on 1,5-dipolar molecules is relatively limited, especially regarding the asymmetric intramolecular cyclization reaction of 1,5-dipolar molecules to construct chiral quaternary carbon centers, which has not yet been reported. Therefore, this invention can expand the application of 1,5-dipolar molecules in asymmetric cyclization reactions and develop a new strategy for constructing chiral quaternary carbon centers through decarboxylation intramolecular asymmetric cyclization reactions.

[0040] 3. The palladium catalyst used in this invention has a low dosage and low cost. Through screening and optimization of different palladium catalysts and chiral ligands, the palladium catalytic system of this invention was ultimately determined to be the optimal reaction condition. If other palladium catalysts or chiral ligands are used, or if the ratio of the two is unsuitable, the enantioselectivity of the product will decrease significantly. In this invention, the molecular sieve has a significant impact on the yield, but does not affect the enantioselectivity of the product.

[0041] 4. The present invention has high reaction yield and high enantioselectivity (up to 99% ee); the chiral 2-position disubstituted indoline compounds obtained by the present invention have excellent inhibitory effects on bladder cancer cells, providing a scientific basis for the development of new candidate drugs for the treatment of bladder cancer, and are of great significance for the treatment of bladder cancer patients. Attached Figure Description

[0042] Figure 1 The graph shows the inhibition rate of the compounds synthesized in Examples 1-13 against bladder cancer cells (T24).

[0043] Figure 2 To illustrate the inhibition rate and concentration-inhibition rate curves of different concentrations of compound IIe against bladder cancer cells (T24) in Example 2.

[0044] Figure 3 To illustrate the inhibition rate and concentration-inhibition rate curves of different concentrations of compound IIi against bladder cancer cells (T24) in Example 3.

[0045] Figure 4 To illustrate the inhibition rate and concentration-inhibition rate curves of different concentrations of compound IIj against bladder cancer cells (T24) in Example 4. Detailed Implementation

[0046] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited thereto.

[0047] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and raw materials described are commercially available or prepared according to known methods unless otherwise specified.

[0048] The solvents used in the examples are anhydrously treated, and the treatment method is a prior art.

[0049] The yield described in the examples is a molar yield.

[0050] In the examples, the preparation method of the chiral ligand III is a prior art, which can be prepared according to the literature (ACS Catal. 2021, 11, 2684-2690).

[0051] In the examples, the preparation steps of the allyl benzoxazepinone compound I are as follows:

[0052]

[0053] Into a dry and clean flask, add a solution of S1 (2 mmol) in tetrahydrofuran (0.2 mmol / mL), replace with nitrogen for three times, place the reaction in a cold trap at -25°C and stir for 10 minutes, then slowly add a solution of sec -butyl lithium (2.0 equiv.) and continue to stir for 10 minutes, finally add enone S2 (1.5 equiv.) and continue to stir until the reaction is complete. Add saturated aqueous ammonium chloride solution to the reaction at -25°C for quenching, concentrate the reaction liquid, extract with ethyl acetate for several times, combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, remove the excess solvent under reduced pressure, and purify by silica gel column chromatography (eluent PE / EA = 20:1 to 5:1) to obtain the amino alcohol intermediate S3 for the next step reaction.

[0054] Into a dry and clean flask, add a solution of the above obtained amino alcohol intermediate S3 in tetrahydrofuran (0.2 mmol / mL), replace with nitrogen for three times, place the reaction in a cold trap at 0°C and stir for 10 minutes, then slowly add a solution of methyl lithium (2.0 equiv.). After the addition is completed, the reaction is raised to 50°C and stirred overnight until the reaction is complete. Add saturated aqueous ammonium chloride solution to the reaction for quenching, concentrate the reaction liquid, extract with ethyl acetate for several times, combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, remove the excess solvent under reduced pressure, and purify by silica gel column chromatography (eluent PE / EA = 20:1 to 3:1) to obtain the allyl benzoxazepinone compound I. The overall yield of the two steps is about 60% to 70%.

[0055] Example 1

[0056] Synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa)

[0057] The reaction scheme is as follows:

[0058]

[0059] The procedure is as follows:

[0060] Under nitrogen atmosphere, palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg of allylbenzoxazepinone compound Ia (58.6 mg, 0.2 mmol) were added to a 5 mL vial. After stirring at room temperature for 30 min, the vial was placed in a cold trap at -10 °C. The reaction was complete after stirring at -10 °C for 12 h. The reaction was concentrated under reduced pressure to remove excess solvent. The crude product was purified by silica gel column (eluent: EA / PE = 0.02-0.1:1, v / v) to give the target product IIa (39 mg, 78% yield). Molecular sieves were added to a 5 mL vial, 0.5 mL of N,N-dimethylformamide was added, and after stirring at room temperature for 30 min, the vial was placed in a cold trap at -10 °C. After dissolving allylbenzoxazepinone compound Ia (58.6 mg, 0.2 mmol) in 0.5 mL of N,N-dimethylformamide, it was added to the above vial, and stirring was continued at -10 °C for 12 h until the reaction was complete. The reaction was concentrated under reduced pressure to remove excess solvent. The crude product was purified by silica gel column (eluent: EA / PE = 0.02-0.1:1, v / v) to give the target product IIa (39 mg, 78% yield).

[0061] The characterization data of the product (IIa) are as follows:

[0062] Colorless oily liquid (39 mg, 78% yield). Daicel Chiral OJ-3 column, (Hexane / i-PrOH = 70 / 30, v = 1 mL / min, λ = 254 nm), t(minor) = 6.1 min, t(major) = 10.8 min, 94% ee. (c = 0.1 in CH2Cl2). (c = 0.1 in CH2Cl2).

[0063] 1 H NMR (400 MHz, CDC13) δ 7.29-7.20 (m, 3H), 7.16-7.14 (m, 2H), 6.89 (s, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 5.98 (dd, J = 17.4, 10.4 Hz, 1H), 5.02 (d, J = 17.4 Hz, 1H; d, J = 10.4 Hz, 1H), 3.69 (s, 1H), 3.02 (d, J = 15.3 Hz, 1H), 2.98 (d, J = 15.3 Hz, 1H), 2.94 (d, J = 13.0 Hz, 1H), 2.89 (d, J = 13.0 Hz, 1H), 2.24 (s, 3H).

[0064] 13 C NMR (100 MHz, CDC13) δ 147.5, 142.4, 137.2, 130.5, 128.1, 127.8, 127.6, 126.6, 125.9, 113.0, 108.9, 68.5, 45.9, 42.3, 20.9.

[0065] HRMS (ESI) calcd (m / z) for C 18 H 19 N[M+H] + : 250.159, found: 250.1585

[0066] Example 2

[0067] Synthesis of (S)-2-benzyl-5-chloro-2-vinyldihydroindole (IIb)

[0068] The reaction scheme is as follows:

[0069]

[0070] The operation steps are as follows:

[0071] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieves are added to a 5 mL tomato bottle, 0.5 mL N,N-dimethylformamide is added, and after stirring at room temperature for 30 minutes, it is placed in a cold trap at -10°C. After dissolving the allyl benzoxazepinone compound Ib (62.8 mg, 0.2 mmol) in 0.5 mL N,N-dimethylformamide, it is added to the above-mentioned tomato bottle, and stirring is continued at -10°C for 12 h until the reaction is complete. The reaction solution is concentrated under reduced pressure to remove excess solvent, and the obtained crude product is separated and purified by silica gel column (eluent is EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIb (44 mg, 82% yield).

[0072] The characterization data of the obtained product (IIb) are as follows:

[0073] Colorless oily liquid, 44 mg, 82% yield, Daicel OJ-3 column, (Hexane / i-PrOH = 70 / 30, v = 1 mL / min, λ = 254 nm), t(minor) = 5.7 min, t(major) = 6.4 min, 98% ee. (c = 0.05 in CH2Cl2).

[0074] 1 H NMR (400 MHz, CDC13) δ 7.28-7.23 (m, 3H), 7.16-7.07 (m, 2H), 7.06-6.86 (m, 2H), 6.49 (d, J = 8.2 Hz, 1H), 5.96 (dd, J = 17.2, 10.6 Hz, 1H), 5.08-4.93 (d, J = 17.1 Hz, 1H; d, J = 10.5 Hz, 1H), 3.03 (d, J = 15.5 Hz, 1H), 2.95 (d, J = 15.6 Hz, 1H), 2.94 (d, J = 13.0 Hz, 1H), 2.89 (d, J = 13.1 Hz, 1H).

[0075] 13 C NMR (100 MHz, CDC13) δ 148.5, 141.9, 136.8, 130.4, 129.3, 128.1, 127.3, 126.7, 125.2, 122.9, 113.3, 109.6, 68.9, 45.9, 42.1.

[0076] HRMS (ESI) calcd (m / z) for C 18 H 19 N[M+H] + : 270.1044, found: 270.1046.

[0077] Example 3

[0078] Synthesis of (S)-2-benzyl-6-methoxy-2-vinyldihydroindole (lie)

[0079] The reaction scheme is as follows:

[0080]

[0081] The procedure is as follows:

[0082] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieve was added into a 5 mL vial, 0.5 mL of N,N-dimethylformamide was added, and the mixture was stirred at room temperature for 30 min and then placed in a cold trap at -10 °C. Allylbenzoxazepinone compound Ic (61.9 mg, 0.2 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide and added into the above vial, and the mixture was stirred at -10 °C for 12 h until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the obtained crude product was purified by silica gel column (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIc (41 mg, 78% yield).

[0083] The characterization data of the obtained product (IIc) are as follows:

[0084] Colorless oily liquid, 41 mg, 78% yield, Daicel OJ-3 column, (Hexane / i-PrOH = 70 / 30, v = 1 mL / min, λ = 254 nm), t(minor) = 9.6 min, t(major) = 11.6 min, 96% ee. (c = 0.1 in CH2Cl2).

[0085] 1 H NMR (400 MHz, CDC13) δ 7.30-7.23 (m, 3H), 7.19-7.11 (m, 2H), 6.93 (d, J = 7.9 Hz, 1H), 6.30-6.17 (m, 2H), 5.98 (dd, J = 16.9, 10.8 Hz, 1H), 5.10-4.94 (d, J = 16.9 Hz, 1H; d, J = 10.8 Hz, 1H), 3.75 (s, 3H; s, 1H), 3.01-2.88 (m, 4H).

[0086] 13 C NMR (100 MHz, CDC13) δ 160.1, 151.2, 142.4, 137.1, 130.5, 128.1, 126.6, 125.2, 119.7, 113.1, 103.1, 96.0, 69.0, 55.4, 46.0, 41.7.

[0087] HRMS (ESI) calcd (m / z) for C 18 H 19 N[M+H] + : 266.1539, found: 266.1542.

[0088] Example 4

[0089] Synthesis of (S)-2-benzyl-2-vinylindoline-6-acetate (II d)

[0090] The reaction scheme is as follows:

[0091]

[0092] The operation steps are as follows:

[0093] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieves are added to a 5 mL tomato bottle, 0.5 mL N,N-dimethylformamide is added, and after stirring at room temperature for 30 minutes, it is placed in a cold trap at -10°C. After dissolving the allyl benzoxazepinone compound Id (67.5 mg, 0.2 mmol) in 0.5 mL N,N-dimethylformamide, it is added to the above-mentioned tomato bottle, and stirring is continued at -10°C for 12 h until the reaction is complete. The reaction solution is concentrated under reduced pressure to remove excess solvent, and the obtained crude product is separated and purified by silica gel column (eluent is EA / PE = 0.02-0.1:1, v / v) to obtain the target product Id (45 mg, 77% yield).

[0094] The characterization data of the obtained product (Id) are as follows:

[0095] Colorless oily liquid, 45 mg, 77% yield, Daicel OJ-3 column, (Hexane / i-PrOH = 70 / 30, v = 1 mL / min, λ = 254 nm), t(minor) = 7.6 min, t(major) = 8.2 min, 96% ee. (c = 0.1 in CH2Cl2).

[0096] 1 H NMR (400 MHz, CDCI3 δ 7.39-7.21 (m, 3H), 7.20-7.10 (m, 2H), 6.99 (d, J = 7.9 Hz, 1H), 6.37 (dd, J = 7.8, 2.1 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 5.98 (dd, J = 17.0, 10.8 Hz, 1H), 5.17-4.91 (m, 2H), 3.83 (s, 1H), 3.03 (d, J = 15.3 Hz, 1H), 2.99-2.93 (d, J = 15.3 Hz, 1H; d, J = 13.1 Hz, 1H), 2.90 (d, J = 13.1 Hz, 1H), 2.26 (s, 3H).

[0097] 13 C NMR (100 MHz, CDC13) δ 169.8, 150.9, 150.8, 142.2, 136.9, 130.5, 128.2, 126.7, 125.2, 124.8, 113.3, 110.9, 102.5, 69.1, 46.1, 41.8, 21.3.

[0098] HRMS (ESI) calcd (m / z) for C 18 H 19 N[M+H] + : 294.1489, found: 294.1485.

[0099] Example 5

[0100] Synthesis of (R)-2-(2-fluorobenzyl)-2-vinyldihydroindole (lie)

[0101] The reaction scheme is as follows:

[0102]

[0103] The operation steps are as follows:

[0104] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieves are added to a 5 mL tomato bottle, 0.5 mL N,N-dimethylformamide is added, and after stirring at room temperature for 30 minutes, it is placed in a cold trap at -10°C. After dissolving the allyl benzoxazepinone compound le (59.5 mg, 0.2 mmol) in 0.5 mL N,N-dimethylformamide, it is added to the above-mentioned tomato bottle, and stirring is continued at -10°C for 12 h until the reaction is complete. The reaction solution is concentrated under reduced pressure to remove excess solvent, and the obtained crude product is separated and purified by silica gel column (eluent is EA / PE = 0.02-0.1:1, v / v) to obtain the target product le (38 mg, 75% yield).

[0105] The characterization data of the obtained product (lie) are as follows:

[0106] Colorless oily liquid, 38 mg, 75% yield, Daicel OJ-3 column, (Hexane / i-PrOH = 70 / 30, v = 1 mL / min, λ = 254 nm), t(minor) = 9.3 min, t(major) = 11.1 min, 97% ee. (c = 0.1 in CH2Cl2).

[0107] 1 H NMR (400 MHz, CDC13) δ 7.23 - 7.15 (m, 2H), 7.02 (m, 4H), 6.67 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.03 (ddd, J = 17.1, 10.6, 1.6 Hz, 1H), 5.08 - 4.95 (d, J = 17.2 Hz, 1H; d, J = 10.5 Hz, 1H), 3.86 (s, 1H), 3.09 (d, J = 15.4 Hz, 1H), 3.06 - 2.93 (d, J = 15.3 Hz, 1H; m, 2H).

[0108] 13 C NMR (100 MHz, CDC13) δ 161.5 (d, 1 J C-F = 245.1 Hz), 149.9, 142.2, 132.6 (d, 3 J C-F = 4.7 Hz), 128.4 (d, 3 J C-F = 8.2 Hz), 127.5, 127.1, 124.9, 124.3 (d, 2 J C-F = 15.8 Hz), 123.7 (d, 4 J C-F = 3.6 Hz), 118.5, 115.4 (d, 2 J C-F = 23.0 Hz), 112.7, 108.9, 68.6, 42.0, 38.8.

[0109] HRMS (ESI) calcd (m / z) for C 17 H 16 FN [M + H] + : 254.134, found: 254.1340

[0110] Example 6

[0111] Synthesis of (S)-2-(naphthalen-2-ylmethyl)-2-vinyldihydroindole (II f)

[0112] The reaction scheme is as follows:

[0113]

[0114] The procedure is as follows:

[0115] Palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieve was added into a 5 mL vial, 0.5 mL N,N-dimethylformamide was added, and after stirring at room temperature for 30 min, it was placed in a cold trap at -10 °C. Allyl benzoxazepinone compound If (65.9 mg, 0.2 mmol) was dissolved in 0.5 mL N,N-dimethylformamide, and then added into the above vial, and continued to stir at -10 °C for 12 h until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the obtained crude product was separated and purified by silica gel column (eluent EA / PE = 0.02-0.1:1, v / v) to obtain the target product If (41 mg, 72% yield).

[0116] The characterization data of the obtained product (If) are as follows:

[0117] Colorless oily liquid, 41 mg, 72% yield. Daicel OJ-3 column, (Hexane / i-PrOH = 70 / 30, v = 1 mL / min, λ = 254 nm), t(minor) = 15.1 min, t(major) = 16.7 min, 94% ee. (c = 0.1 in CH2Cl2).

[0118] 1 H NMR (400 MHz, CDC13) δ 7.80 (td, J = 6.5, 2.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.59 (s, 1H), 7.41 - 7.49 (m, 2H), 7.31 (dd, J = 8.4, 1.7 Hz, 1H), 7.12 - 7.00 (m, 2H), 6.70 (t, J = 7.4 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.05 (dd, J = 17.1, 10.7 Hz, 1H), 5.04 (d, J = 10.7 Hz, 1H), 5.00 (d, J = 17.2 Hz, 1H), 3.83 (s, 1H), 3.20 - 3.05 (d, J = 15.2 Hz, 1H; m, 2H), 3.02 (d, J = 15.2 Hz, 1H).

[0119] 13C NMR (100 MHz, CDC13) δ 149.9, 142.4, 134.8, 133.3, 132.3, 129.0, 128.9, 127.7, 127.7, 127.6, 127.5, 127.3, 126.0, 125.6, 125.1, 118.6, 113.2, 109.0, 68.6, 46.2, 42.5.

[0120] HRMS (ESI) calcd (m / z) for C 21 H 19 N[M+H] + :286.159, found:286.1595.

[0121] Example 7

[0122] Synthesis of (R)-2-(thiophen-3-ylmethyl)-2-vinyldihydroindole (IIg)

[0123] The reaction scheme is as follows:

[0124]

[0125] The operation steps are as follows:

[0126] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieves are added to a 5 mL tomato bottle, 0.5 mL N,N-dimethylformamide is added, and after stirring at room temperature for 30 minutes, it is placed in a cold trap at -10°C. After dissolving the allyl benzoxazepine compound Ig (57.1 mg, 0.2 mmol) in 0.5 mL N,N-dimethylformamide, it is added to the above-mentioned tomato bottle, and stirring is continued at -10°C for 12 h until the reaction is complete. The reaction solution is concentrated under reduced pressure to remove excess solvent, and the obtained crude product is separated and purified by silica gel column (eluent is EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIg (29 mg, 60% yield).

[0127] The characterization data of the obtained product (IIg) are as follows:

[0128] Colorless oily liquid, 29 mg, 60% yield, Daicel OJ-3 column, (Hexane / i-PrOH = 70 / 30, v = 1 mL / min, λ = 254 nm), t(minor) = 8.0 min, t(major) = 8.9 min, 92% ee. (c = 0.1 in CH2Cl2).

[0129] 1 H NMR (400 MHz, CDC13) δ 7.29 - 7.19 (m, 1H), 7.09 - 6.97 (m, 3H), 6.94 (d, J = 4.8 Hz, 1H), 6.69 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.02 (dd, J = 17.3, 10.6 Hz, 1H), 5.10 (d, J = 17.3 Hz, 1H), 5.06 (d, J = 10.6 Hz, 1H), 3.84 (s, 1H), 3.08 - 2.98 (d, J = 13.8 Hz, 1H; m, 2H), 2.94 (d, J = 13.8 Hz, 1H).

[0130] 13 C NMR (100 MHz, CDC13) δ 149.9, 142.7, 137.6, 129.7, 127.6, 127.3, 125.1, 123.0, 118.6, 113.1, 109.0, 68.0, 42.3, 40.5.

[0131] HRMS (ESI) calcd (m / z) for C 15 H 15 NS[M+H] + : 242.0998, found: 242.0999.

[0132] Example 8

[0133] Synthesis of (S)-2-(3,5-dichlorobenzyl)-2-vinyldihydroindole (IIh)

[0134] The reaction scheme is as follows:

[0135]

[0136] The procedure is as follows:

[0137] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieve was added into a 5 mL vial, 0.5 mL of N,N-dimethylformamide was added, and the mixture was stirred at room temperature for 30 min and then placed in a cold trap at -10 °C. Allylbenzoxazepinone compound Ih (69.6 mg, 0.2 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide and added into the above vial, and the mixture was stirred at -10 °C for 12 h until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the obtained crude product was purified by silica gel column (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product Ih (46 mg, 76% yield).

[0138] The characterization data of the obtained product (Ih) are as follows:

[0139] Colorless oily liquid, 46 mg, 76% yield, Daicel OJ-3 column, (Hexane / i-PrOH = 80 / 20, v = 1 mL / min, λ = 254 nm), t(minor) = 5.8 min, t(major) = 6.2 min, 94% ee. (c = 0.1 in CH2Cl2).

[0140] 1 H NMR (400 MHz, CDC13) δ 7.23 (m, 1H), 7.10-6.99 (m, 4H), 6.70 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 7.7 Hz, 1H), 5.93 (dd, J = 17.2, 10.6 Hz, 1H), 5.08 (d, J = 10.5 Hz, 1H), 5.04 (d, J = 17.1 Hz, 1H), 3.74 (s, 1H), 3.02 (m, 2H), 2.92 (d, J = 13.1 Hz, 1H), 2.87 (d, J = 13.1 Hz, 1H).

[0141] 13 C NMR (100 MHz, CDC13) δ 149.6, 141.7, 140.6, 134.5, 128.9, 127.7, 126.9, 126.9, 125.1, 118.9, 113.8, 109.0, 68.2, 45.6, 42.3.

[0142] HRMS (ESI) calcd (m / z) for C 17 H 15 Cl2N [M+H] + : 304.0654, found: 304.0659.

[0143] Example 9

[0144] Synthesis of (S)-2-benzyl-2-vinyldihydroindol-6-yl 2-(11-oxo-6,11- dihydrodibenzo[b,e]oxepin-2-yl)acetate (IIi)

[0145] The reaction scheme is as follows:

[0146]

[0147] The operation steps are as follows:

[0148] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Add molecular sieves into a 5 mL tomato bottle, add 0.5 mL N,N- dimethylformamide, and stir at room temperature for 30 minutes, and then place in a cold trap at -10 °C. Dissolve allyl benzoxazepinone compound Ii (109.1 mg, 0.2 mmol) in 0.5 mL N,N-dimethylformamide, and then add into the above-mentioned tomato bottle, and continue to stir at -10 °C for 12 h until the reaction is complete. Concentrate the reaction solution under reduced pressure to remove the excess solvent, and the obtained crude product is separated and purified by silica gel column (eluent is EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIi (70 mg, 70% yield).

[0149] The characterization data of the obtained product (IIi) are as follows:

[0150] Colorless oily liquid, 70 mg, 70% yield. Daicel IH-3 column, (Hexane / i-PrOH = 60 / 40, v = 1 mL / min, λ = 254 nm), t(minor) = 15.8 min, t(major) = 18.8 min, 90% ee. (c = 0.3 in CH2Cl2).

[0151] 1H NMR (400 MHz, CDC13) δ 8.21 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 7.7, 1.4 Hz, 1H), 7.59 - 7.45 (m, 3H), 7.37 (dd, J = 7.4, 1.2 Hz, 1H), 7.29 - 7.22 (m, 3H), 7.17 - 7.10 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.36 (dd, J = 7.9, 2.1 Hz, 1H), 6.30 (d, J = 2.1 Hz, 1H), 5.97 (dd, J = 17.1, 10.7 Hz, 1H), 5.20 (s, 2H), 5.07 - 5.01 (dd, J = 17.2, 1.2 Hz, 1H), 4.99 (dd, J = 10.6, 1.2 Hz, 1H), 3.85 (s, 3H), 3.02 (d, J = 15.4 Hz, 1H), 2.97 - 2.91 (d, J = 15.4 Hz, 1H; d, J = 13.1 Hz, 1H), 2.89 (d, J = 13.1 Hz, 1H).

[0152] 13 C NMR (100 MHz, CDC13) δ 190.9, 170.1, 160.7, 150.9, 150.8, 142.2, 140.5, 136.9, 136.4, 135.6, 132.9, 132.7, 130.5, 129.6, 129.4, 128.2, 127.9, 127.6, 126.7, 125.3, 125.2, 124.9, 121.3, 113.2, 110.8, 102.4, 73.7, 69.1, 46.1 41.8, 40.5.

[0153] HRMS (ESI) calcd (m / z) for C 18 H 19 N[M+H] + : 502.2013, found: 502.2016.

[0154] Example 10

[0155] Synthesis of (S)-2-benzyl-2-vinyldihydroindol-6-yl 4-(N,N-dipropylsulfamoyl)benzoate (IIj)

[0156] The reaction scheme is as follows:

[0157]

[0158] The procedure is as follows:

[0159] Palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieve was added into a 5 mL vial, 0.5 mL N,N-dimethylformamide was added, and after stirring at room temperature for 30 min, it was placed in a cold trap at -10 °C. Allyl benzoxazepinone compound Ij (112.5 mg, 0.2 mmol) was dissolved in 0.5 mL N,N-dimethylformamide, and then added into the above vial, and continued to stir at -10 °C for 12 h until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the obtained crude product was separated and purified by silica gel column (eluent EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIj (71 mg, 68% yield).

[0160] The characterization data of the obtained product (IIj) are as follows:

[0161] Colorless oily liquid, 71 mg, 68% yield. Daicel IH-3 column, (Hexane / i-PrOH = 60 / 40, v = 1 mL / min, λ = 254 nm), t(minor) = 10.9 min, t(major) = 12.7 min, 90% ee. (c = 0.2 in CH2Cl2).

[0162] 1 H NMR (400 MHz, CDC13) δ 8.30 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 7.27 (dt, J = 14.0, 7.6 Hz, 3H), 7.16 (d, J = 6.9 Hz, 2H), 7.06 (d, J = 7.9 Hz, 1H), 6.50 (dd, J = 7.9, 1.9 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.00 (ddd, J = 17.0, 10.7, 1.1 Hz, 1H), 5.20-4.99 (d, J = 17.0 Hz, 1H; d, J = 10.7 Hz, 1H), 3.90 (s, 1H), 3.22-2.89 (m, 8H), 1.61-1.54 (m, 4H), 0.88 (t, J = 7.4 Hz, 6H).

[0163] 13C NMR (100 MHz, CDC13) δ 164.1, 151.1, 150.7, 144.8, 142.1, 136.8, 133.3, 130.8, 130.5, 128.2, 127.2, 126.7, 125.3, 125.3, 113.3, 110.8, 102.3, 69.1, 50.0, 46.1, 41.8, 22.0, 11.3.

[0164] HRMS (ESI) calcd (m / z) for C 18 H 19 N[M+H] + : 519.2312, found: 519.2310.

[0165] Example 11

[0166] Synthesis of (S)-5-methyl-2-(o-tolyl)-2-vinyldihydroindole (IIk)

[0167] The reaction scheme is as follows:

[0168]

[0169] The operation steps are as follows:

[0170] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieves are added to a 5 mL tomato bottle, 0.5 mL N,N-dimethylformamide is added, and after stirring at room temperature for 30 minutes, it is placed in a cold trap at -10°C. After dissolving the allyl benzoxazepinone compound Ik (58.7 mg, 0.2 mmol) in 0.5 mL N,N-dimethylformamide, it is added to the above-mentioned tomato bottle, and stirring is continued at -10°C for 12 h until the reaction is complete. The reaction solution is concentrated under reduced pressure to remove excess solvent, and the obtained crude product is separated and purified by silica gel column (eluent is EA / PE = 0.02-0.1:1, v / v) to obtain the target product IIk (39 mg, 78% yield).

[0171] The characterization data of the obtained product (IIk) are as follows:

[0172] Colorless oily liquid, 39 mg, 78% yield. Daicel IH-3 column, (Hexane / i-PrOH = 98 / 2, v = 1 mL / min, λ = 254 nm), t(minor) = 5.2 min, t(major) = 5.9 min, 95% ee. (c = 0.1 in CH2Cl2).

[0173] 1 H NMR (400 MHz, CDC13) δ 7.70 (dd, J = 5.8, 2.5 Hz, 1H), 7.26 - 7.14 (m, 3H), 6.97 - 6.81 (m, 2H), 6.61 (d, J = 7.8 Hz, 1H), 6.20 (dd, J = 17.2, 10.4 Hz, 1H), 4.99 (d, J = 10.4 Hz, 1H), 4.83 (d, J = 17.2 Hz, 1H), 4.05 (s, 1H), 3.56 (d, J = 15.7 Hz, 1H), 3.25 (d, J = 15.7 Hz, 1H), 2.37 (s, 3H), 2.24 (s, 3H).

[0174] 13 C NMR (100 MHz, CDC13) δ 146.5, 143.3, 142.5, 135.6, 131.9, 128.2, 128.0, 127.9, 127.0, 127.0, 125.8, 125.5, 112.9, 109.3, 71.1, 42.4, 22.1, 20.9.

[0175] HRMS (ESI) calcd (m / z) for C 18 H 19 N[M+H] + : 250.1590, found 250.1592.

[0176] Example 12

[0177] Synthesis of (S)-5-phenyl-2-(o-tolyl)-2-vinyldihydroindole (II m)

[0178] The reaction scheme is as follows:

[0179]

[0180] The procedure is as follows:

[0181] Under nitrogen protection, add palladium catalyst tris(dibenzylideneacetone)dichloropalladium-chloroform adduct (5.2 mg, 5 umol), chiral ligand III (11.5 mg, 0.02 mmol) and 300 mg Molecular sieve was added into a 5 mL vial, 0.5 mL of N,N-dimethylformamide was added, and it was stirred at room temperature for 30 min and then placed in a cold trap at -10 °C. Allyl benzoxazepinone compound Im (71.1 mg, 0.2 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide, and then added into the above vial, and it was continuously stirred at -10 °C for 12 h until the reaction was completed. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the obtained crude product was separated and purified by silica gel column (eluent: EA / PE = 0.02-0.1:1, v / v) to obtain the target product Im (45 mg, 72% yield).

[0182] The characterization data of the obtained product (Im) are as follows:

[0183] Colorless oily liquid, 45 mg, 72% yield, Daicel IH-3 column, (Hexane / i-PrOH = 98 / 2, v = 1 mL / min, λ = 254 nm), t(minor) = 15.7 min, t(major) = 8.8 min, 96% ee. (c = 0.1 in CH2Cl2).

[0184] 1 H NMR (400 MHz, CDC13) δ 7.77-7.66 (m, 1H), 7.56-7.48 (m, 2H), 7.37 (t, J = 7.7 Hz, 2H), 7.34-7.28 (m, 2H), 7.27-7.17 (m, 4H), 6.74 (d, J = 7.8 Hz, 1H), 6.24 (dd, J = 17.2, 10.3 Hz, 1H), 5.02 (d, J = 10.4 Hz, 1H), 4.85 (d, J = 17.2 Hz, 1H), 4.20 (s, 1H), 3.66 (d, J = 15.8 Hz, 1H), 3.33 (d, J = 15.8 Hz, 1H), 2.38 (s, 3H).

[0185] 13 C NMR (100 MHz, CDC13) δ 148.4, 143.1, 142.3, 141.7, 135.5, 132.3, 132.0, 128.7, 128.3, 127.2, 126.9, 126.8, 126.5, 126.1, 125.8, 123.6, 113.2, 109.4, 71.2, 42.5, 22.1.

[0186] HRMS (ESI) calcd (m / z) for C 23 H 21 N [M+H] +:312.1747, found 312.1750.

[0187] Example 13

[0188] Synthesis of (S)-5-chloro-2-(3,5-dichlorophenyl)-2-vinyldihydroindole (IIn)

[0189] The reaction route is as follows:

[0190]

[0191] The operation steps are as follows:

[0192] Under nitrogen protection, palladium catalyst tris(dibenzylacetone)dipalladium-chloroform adduct (5.2 mg, 5 μmol), chiral ligand III (11.5 mg, 0.02 mmol), and 300 mg of... Molecular sieves were added to a 5 mL round-bottom flask, followed by 0.5 mL of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes and then placed in a cold trap at -10°C. Allylbenzoxazine compound In (73.7 mg, 0.2 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide and added to the round-bottom flask. The mixture was stirred at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent. The crude product was purified by silica gel column chromatography (eluent: EA / PE = 0.02–0.1:1, v / v) to obtain the target product IIn (51 mg, 79% yield).

[0193] The characterization data of the obtained product (Ⅱn) are as follows:

[0194] Colorless oily liquid, 51 mg, 79% yield. Daicel IH-3 column, (Hexane / i-PrOH=98 / 2, v=1mL / min, λ=254nm), t(minor)=9.5min, t(major)=8.5min, 91%ee. (c = 0.1 in CH2Cl2).

[0195] 1H NMR (400 MHz, CDC13) δ 7.35 (d, J = 1.9 Hz, 2H), 7.26 (t, J = 1.9 Hz, 1H), 7.09 - 6.97 (m, 2H), 6.61 (d, J = 8.8 Hz, 1H), 6.09 (dd, J = 17.1, 10.5 Hz, 1H), 5.17 (d, J = 10.5 Hz, 1H), 5.10 (d, J = 17.1 Hz, 1H), 4.10 (s, 1H), 3.39 (d, J = 15.9 Hz, 1H), 3.18 (dt, J = 15.9, 1.1 Hz, 1H).

[0196] 13 C NMR (100 MHz, CDC13) δ 149.0, 147.7, 141.0, 135.1, 128.6, 127.7, 127.3, 124.9, 124.9, 124.0, 114.3, 110.3, 70.7, 43.4.

[0197] HRMS (ESI) calcd (m / z) for C 16 H 12 Cl3N[M+H] + : 324.0108, found 324.0109.

[0198] Comparative Example 1

[0199] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa) was carried out as described in Example 1 except that no palladium catalyst was added.

[0200] No reaction occurred in this comparative example because no palladium catalyst was added.

[0201] Comparative Example 2

[0202] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa) was carried out as described in Example 1 except that no chiral ligand III was added.

[0203] No reaction occurred in this comparative example because no chiral ligand was added. The yield of IIa was 30% and the product was not enantioselective.

[0204] Comparative Example 3

[0205] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa) was carried out as described in Example 1 except that the palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct was replaced by the same molar amount of palladium acetate.

[0206] The yield of IIa was 60% and the ee value was 33% in this comparative example because palladium acetate was added.

[0207] Comparative Example 4

[0208] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa) was carried out as described in Example 1, except that the chiral ligand III was replaced with an equimolar amount of the chiral ligand of the following structure.

[0209]

[0210] In this comparative example, the chiral ligand was replaced, and the yield of IIa was 45% with an ee value of 39%.

[0211] Comparative Example 5

[0212] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa) was carried out as described in Example 1, except that the amount of tris(dibenzylideneacetone)dipalladium-chloroform adduct was 0.02 umol.

[0213] In this comparative example, the amount of palladium catalyst added was 0.1 mmol%, and the yield of IIa was 53% with an ee value of 71%.

[0214] Comparative Example 6

[0215] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa) was carried out as described in Example 1, except that the solvent was dichloromethane.

[0216] In this comparative example, the solvent added was dichloromethane, and the yield of IIa was 51% with an ee value of 32%.

[0217] Comparative Example 7

[0218] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa) was carried out as described in Example 1, except that the solvent was tetrahydrofuran.

[0219] In this comparative example, the solvent added was tetrahydrofuran, and the yield of IIa was 42% with an ee value of 30%.

[0220] Comparative Example 8

[0221] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindole (IIa) was carried out as described in Example 1, except that no molecular sieves were added.

[0222] In this comparative example, no molecular sieves were added, and the yield of IIa was 56% with an ee value of 94%.

[0223] Application Example 1

[0224] Test of the inhibitory effect of the compounds synthesized in Examples 1-13 on bladder cancer cells (T24)

[0225] The bladder cancer cells (T24) were purchased from Shanghai Sailabkang Biotechnology Co., Ltd. The complete culture medium was prepared according to the ratio of 9:1 of the culture medium: fetal bovine serum, and the culture medium was RPMI1640.

[0226] The specific steps are as follows:

[0227] (1) Preparation of sample solution: the test compound was dissolved with DMSO, filtered with 0.22 μm to remove bacteria, and obtained a 100 μM sample stock solution, then diluted with complete culture medium to a concentration of 5 μM to obtain the sample solution; at the same time, the culture solution added with an equal volume of DMSO was used as the control solution.

[0228] (2) Cell recovery and subculture: open the water bath and adjust the temperature to 37°C. Take out the liquid nitrogen frozen cells, quickly place them in the 37°C water bath, and shake quickly. After the cells are completely melted, take out the frozen tube from the water bath. Take one 10 ml sterile centrifuge tube, add 4 ml of culture medium, then transfer the cells in the frozen tube to the centrifuge tube, centrifuge at 1000 rpm for 5 min at room temperature, take a new 25T cell culture bottle, and add 5 ml of culture medium. Discard the supernatant in the centrifuge tube, leave the precipitate, and add it all to the culture bottle. Under the condition of 5% CO2 and 37°C, stand for 8 h, then aspirate all the culture medium, add 5 ml of fresh culture medium, and continue to culture. When the cells grow to cover the culture bottle, discard the old culture medium, wash the cells with 2 ml of PBS, discard the PBS, add 1 ml of trypsin, and digest at room temperature for about 30 s. Gently tap around the culture bottle to make the digested cells fall off. The cells that are not easy to fall off are gently blown down with a gun head, and 2 ml of culture medium is added. Transfer the digested cells to a sterile centrifuge tube, centrifuge at 1000 rpm for 5 min at room temperature, discard the supernatant, add 1 ml of culture medium, mix well by blowing, and transfer to a new culture bottle for culture. When the cells grow to cover the culture bottle, the experiment can be performed.

[0229] (3) Detection of cell activity by sample: take T24 cells in the logarithmic growth phase, count the cells, adjust the cell concentration, and inoculate into a 96-well plate at a concentration of 6×10 3 cells / well. Continue to culture in a 37°C, 5% CO2 incubator. After 24 h of cell adhesion and growth, discard the cell culture medium, add 100 μL of sample solution and control solution to each well, and culture in a 37°C, 5% CO2 incubator for 72 h. Remove the culture medium, wash each well with PBS three times, add 100 μL / well of culture medium containing 10% CCK-8, and then incubate in a 37°C constant temperature incubator containing 5% CO2 for 2 h. Detect the absorbance value at 450 nm by an enzyme marker and calculate the cell survival rate. The experiment was repeated three times to take the average value, and the results are shown in Table 1. Figure 1 ​

[0230] From Figure 1 It can be seen that different compounds have different degrees of inhibition on bladder cancer cells (T24), and the application further determines the IC50 values of IIe, IIi and IIj on bladder cancer cells (T24).

[0231] Example 2: Inhibitory activity of compound IIe on bladder cancer cells (T24)

[0232] The specific steps are as follows:

[0233] The bladder cancer cells (T24) were purchased from Shanghai Sailabio Biotechnology Co., Ltd., and the complete culture medium was prepared according to the ratio of 9:1 (culture medium:fetal bovine serum), and the culture medium was RPMI1640.

[0234] (1) Preparation of sample solution: dissolve the test compound IIe with DMSO, filter bacteria with 0.22 μm, obtain 100 μM sample mother liquor, then dilute with complete culture medium to working concentration of 0.5, 1, 2, 3, 4, 5 μM, respectively, to obtain sample solution.

[0235] (2) Cell recovery and subculture: open the water bath and adjust the temperature to 37℃. Take out the liquid nitrogen frozen cells, quickly place them in a 37℃ water bath, and shake quickly. After the cells are completely melted, take out the frozen tube from the water bath. Take one 10 mL sterile centrifuge tube, add 4 mL culture medium, then transfer the cells in the frozen tube to the centrifuge tube, centrifuge at 1000 rpm for 5 min at room temperature, take a new 25T cell culture bottle, add 5 mL culture medium. Discard the supernatant in the centrifuge tube, leave the precipitate, and add it all to the culture bottle. Under the condition of 5% CO2 and 37℃, stand for 8h, then aspirate all the culture medium, add 5 mL fresh culture medium, and continue to culture. When the cells grow to cover the culture bottle, discard the old culture medium, wash the cells with 2 mL PBS, discard the PBS, add 1 mL trypsin, and digest at room temperature for about 30s. Gently tap around the culture bottle to make the digested cells fall off, and use a gun head to gently blow the cells that are not easy to fall off. Add 2 mL culture medium; transfer the digested cells to a sterile centrifuge tube, centrifuge at 1000 rpm for 5 min at room temperature, discard the supernatant, add 1 mL culture medium and mix well, transfer to a new culture bottle for culture, and when the cells grow to cover the bottle, the experiment can be carried out.

[0236] (3) Sample activity detection on cells: take T24 cells in logarithmic growth phase, count the cells, adjust the cell concentration, and adjust the cell concentration to 6×10 3The cells are inoculated into a 96-well plate at a cell / well inoculation amount and continue to be cultured in a 37°C, 5% CO2 incubator. After the cells are adherently cultured for 24 hours, the cell culture solution is discarded, 100 μL of sample solution and control solution (DMSO) are added to each well, and after 72 hours of culture in a 37°C, 5% CO2 incubator, the culture medium is removed, each well is washed three times with PBS, 100 μL / well of culture medium containing 10% CCK-8 is added, and then incubation is carried out in a 37°C constant-temperature incubator containing 5% CO2 for 2 hours. The absorbance value at 450 nm is detected by an enzyme-labeled instrument. The absorbance values of each group are input into Excel and the relative activity is calculated (relative activity % = (OD value of the experimental group - background OD value) / (OD value of the control group - background OD value) x 100%). The relative activity values are input into GraphPad Prism for plotting.

[0237] The test results are shown in Table 2, and as shown in Table 2, the synthetic compound IIe of the present application exhibits excellent inhibitory activity against bladder cancer cells (T24), with an IC50 value of 1.30 μM. Figure 2 Figure 2 The test results are shown in Table 2, and as shown in Table 2, the synthetic compound IIe of the present application exhibits excellent inhibitory activity against bladder cancer cells (T24), with an IC50 value of 1.30 μM.

[0238] Application Example 3: Inhibitory activity of synthetic compound IIi against bladder cancer cells (T24)

[0239] The specific test method is as shown in Application Example 2, except that the concentration of the sample solution is 0.01, 0.05, 0.1, 0.5, 1, 5 μM.

[0240] The test results are shown in Table 2, and as shown in Table 2, the synthetic compound IIe of the present application exhibits excellent inhibitory activity against bladder cancer cells (T24), with an IC50 value of 1.30 μM. Figure 3 Figure 3 The test results are shown in Table 2, and as shown in Table 2, the synthetic compound IIe of the present application exhibits excellent inhibitory activity against bladder cancer cells (T24), with an IC50 value of 1.30 μM.

[0241] Application Example 4: Inhibitory activity of synthetic compound IIj against bladder cancer cells (T24)

[0242] The specific test method is as shown in Application Example 2, except that the concentration of the sample solution is 1, 2, 3, 4, 5, 20, 50 μM.

[0243] The test results are shown in Table 2, and as shown in Table 2, the synthetic compound IIe of the present application exhibits excellent inhibitory activity against bladder cancer cells (T24), with an IC50 value of 1.30 μM. Figure 4 Figure 4 The test results are shown in Table 2, and as shown in Table 2, the synthetic compound IIe of the present application exhibits excellent inhibitory activity against bladder cancer cells (T24), with an IC50 value of 1.30 μM.

[0244] The above are only some embodiments of the present application and do not limit the present application in any form. Any simple modification, equivalent change or modification of the above embodiments according to the present application is within the scope of the technical solutions of the present application.​​​

Claims

1. A chiral 2,2'-disubstituted indoline compound, characterized in that, having the following formula II: Ⅱ wherein R 1 is 5-methyl, 5-fluoro, 5-chloro, 6-acetate, 6-yl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate, 6-yl 4-(N,N-dipropylsulfamoyl)benzoate, 5-phenyl, hydrogen, or 6-methoxy; R 2 is benzyl, 2-fluorobenzyl, 3,5-dichlorobenzyl, 2-o-tolyl, 3,5-dichlorophenyl, methylthiophene, or methyl naphthalene.

2. The chiral 2,2'-disubstituted indoline compound according to claim 1, wherein The chiral 2,2'-disubstituted indoline compound is selected from the following compounds: 。 3. The method for synthesizing the chiral 2,2'-disubstituted indoline compound according to any one of claims 1-2, comprising the steps of: The allyl benzoxazepin compound I is subjected to asymmetric allylation reaction in a solvent under catalysis of a palladium catalytic system to obtain the chiral 2,2'-disubstituted indoline compound II; the palladium catalytic system is composed of a palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct (Pd2(dba)3.CHCl3) and a chiral ligand having the following formula III; wherein, In the structural formula of the compounds of formula I, II, R 1 is 5-methyl, 5-fluoro, 5-chloro, 6-acetate, 6-yl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-2-yl)acetate, 6-yl 4-(N,N-dipropylsulfamoyl)benzoate, 5-phenyl, hydrogen or 6-methoxy; R 2 is benzyl, 2-fluorobenzyl, 3,5-dichlorobenzyl, 2-ortho-methylphenyl, 3,5-dichlorophenyl, methylthiophene or methyl naphthalene.

4. The method for synthesizing the chiral 2-position disubstituted indoline compound according to claim 3, characterized in that, The solvent is N,N-dimethylformamide (DMF); the ratio of the volume of the solvent to the molar number of the allyl benzoxazepin compound I is 3-10 mL:1 mmol.

5. The method for synthesizing the chiral 2-position disubstituted indoline compound according to claim 3, characterized in that, The molar ratio of the palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct to the allyl benzoxazepin compound I is 0.01-0.03:1; the molar ratio of the palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct to the chiral ligand is 1:3-5.

6. The method for synthesizing the chiral 2-position disubstituted indoline compound according to claim 3, characterized in that, The reaction system of the allyl benzoxazepin compound I further comprises 4Å molecular sieves; the ratio of the mass of the 4Å molecular sieves to the molar number of the allyl benzoxazepin compound I is 1-3 g:1 mmol.

7. The method for synthesizing the chiral 2-position disubstituted indoline compound according to claim 3, characterized in that, The reaction is carried out under protection of a protective gas, and the protective gas is nitrogen or argon; the temperature of the reaction is -20-0°C; and the time of the reaction is 2-48 h.

8. The method for synthesizing the chiral 2-position disubstituted indoline compound according to claim 3, characterized in that, The post-reaction treatment steps are as follows: the solvent of the reaction liquid is removed, and the obtained crude product is separated by silica gel column chromatography to obtain the chiral 2,2'-disubstituted indoline compound, and the eluent is a mixed solvent of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether in the mixed solvent is 0.02-0.2:

1.

9. The use of the chiral 2,2'-disubstituted indoline compound according to any one of claims 1-2 in the preparation of an anti-bladder cancer drug.

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