Chiral 2-position disubstituted indoline compound as well as synthesis method and application thereof

Abstract

The invention provides a chiral 2-position disubstituted indoline compound as well as a synthesis method and application thereof. According to the invention, a palladium catalyst with a simple structure and a chiral ligand are taken as a catalyst system, and allyl benzoxazaketone with brand new design is taken as a raw material to carry out 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, mild in reaction condition, low in cost and high in efficiency; the raw materials are cheap and easily available, the atom economy is good, and the substrate application range is wide; the target product is high in yield and high in enantioselectivity; the obtained chiral 2-position disubstituted indoline compound has an excellent inhibition effect on bladder cancer cells, provides a scientific basis for developing new candidate drugs for treating bladder cancer, and has important significance on treatment of bladder cancer.

Description

Technical Field

[0001] The invention relates to a chiral 2-position disubstituted indoline compound and a synthesis method and application thereof, belonging to the technical field of organic synthesis. Background Art

[0002] Chiral indoline is an important skeleton that exists in a variety of chiral indole alkaloids in the form of multiple rings or parallel rings. Among them, the chiral indoline skeleton substituted at the 2-position is an important component of many natural products and drugs under development. It is also widely used as a chiral auxiliary in asymmetric synthesis and a common motif of compounds with biological significance, which makes the asymmetric construction of this type of skeleton a goal and difficulty that is constantly studied and improved in the field of synthesis. Although the literature has reported a variety of methods for constructing chiral indoline skeletons, such as kinetic resolution, direct functionalization of indole, asymmetric synthesis using chiral reagents, and asymmetric catalytic reactions, the indoline synthesized by these methods is mostly monosubstituted at the 2-position, that is, a tertiary carbon chiral center, and there are relatively few reports on chiral quaternary carbon centers at the 2-position. Chiral indoline derivatives containing quaternary carbon centers at the 2-position are also widely present in drugs under development or natural products, such as (+)-BenzastatinE, (+)-Deriglidole, etc.

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

[0004] Therefore, the development of novel, simple and efficient asymmetric synthesis reactions for the synthesis of medium-ring compounds can not only effectively make up for the shortcomings of the synthesis method of indoline skeleton with a 2-chiral quaternary carbon center, but also provide a theoretical basis and methodological foundation for the total synthesis of related natural products, and provide a new route for the synthesis of related drug intermediates and other functional molecules. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a chiral 2-disubstituted indoline compound and a synthesis method and application thereof. The present invention uses a simple palladium catalyst and a chiral ligand as a catalyst system, and uses a newly designed allylbenzoxazepinone as a raw material to carry out a palladium-catalyzed intramolecular asymmetric cyclization reaction to achieve efficient asymmetric synthesis of chiral 2-disubstituted indoline compounds. The synthesis method of the present invention is simple, the reaction conditions are mild, the cost is low, and the efficiency is high; the raw materials are cheap and easy to obtain, the atom economy is good, and the substrate has a wide range of applications; the target product of the present invention has a high yield and high enantioselectivity; the chiral 2-disubstituted indoline compound obtained by the present invention has an excellent inhibitory effect on bladder cancer cells, provides a scientific basis for the development of new candidate drugs for the treatment of bladder cancer, and is of great significance for the treatment of bladder cancer.

[0006] Terminology Note:

[0007] Room temperature: has the well-known meaning in the art, referring to 25±5°C.

[0008] The technical solution adopted by the present invention is as follows:

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

[0010]

[0011] Among them, R 1 is selected 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.

[0012] According to the preferred embodiment of the present invention, R 1 is 5-methyl, 5-fluoro, 5-chloro, 6-acetate, 6-methyl-2-(11-oxo-6,11-dihydrodibenzo[b,e]oxane-2-yl)acetate, 6-methyl-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 invention, the chiral 2-disubstituted indoline compound is preferably selected from the following compounds:

[0014]

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

[0016] In a solvent, under the catalysis of a palladium catalyst system, an allylbenzoxazepinone compound I undergoes an asymmetric allylation reaction to obtain a chiral 2-disubstituted indoline compound II; the palladium catalyst system is composed of a palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct (Pd2(dba)3.CHCl3) and a chiral ligand, and the chiral ligand has a structure shown in the following formula III;

[0017]

[0018] Among them, in the structural formula of the compound of formula I and II, R 1 is selected 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.

[0019] According to the preferred embodiments of the present invention, in the structural formula of the compound of formula I and II, R 1 is 5-methyl, 5-fluoro, 5-chloro, 6-acetate, 6-methyl-2-(11-oxo-6,11-dihydrodibenzo[b,e]oxane-2-yl)acetate, 6-methyl-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.

[0020] Preferably according to the present invention, the solvent is N,N-dimethylformamide (DMF); the ratio of the volume of the solvent to the molar number of the allylbenzoxazepinone compound I is 3-10 mL:1 mmol; and the solvent is anhydrous.

[0021] Preferably according to the present invention, the molar ratio of the palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct to the allylbenzoxazepin 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.

[0022] According to the present invention, the preparation method of the chiral ligand is a prior art and can be prepared with reference to the literature (ACS Catal. 2021, 11, 2684-2690).

[0023] According to the preferred embodiment of the present invention, the reaction system of the allylbenzoxazepinone compound I is further added Molecular sieve; The ratio of the mass of the molecular sieve to the molar number of the allylbenzoxazepinone compound I is 1 to 3 g:1 mmol.

[0024] Preferably according to the present invention, the reaction is carried out under the protection of a protective gas, and the protective gas is nitrogen or argon.

[0025] According to the preferred embodiment of the present invention, the reaction temperature is -20 to 0°C, more preferably -10°C; the reaction time is 2 to 48 hours, more preferably 12 to 24 hours. During the reaction, the reaction progress is monitored by HPLC, and the reaction is terminated when all the allylbenzoxazepinone compound I in the system is completely converted.

[0026] According to the present invention, after the allylbenzoxazepinone compound I is reacted, the product can be separated and characterized by a conventional separation and purification method; preferably, the specific post-reaction treatment steps are as follows: the reaction solution is freed from the solvent, and the obtained crude product is separated by silica gel column chromatography to obtain a chiral 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 to 0.2:1.

[0027] According to the present invention, a preferred embodiment comprises the following steps:

[0028] Under the protection of protective gas, palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct, chiral ligand III and Molecular sieves are added to an eggplant-shaped bottle, and N,N-dimethylformamide is added. After stirring at room temperature for 20-40 minutes, the mixture is placed in a cold trap at -20 to 0°C. Allylbenzoxazepinone compound I is dissolved in N,N-dimethylformamide, and then added to the above-mentioned eggplant-shaped bottle. Stirring is continued at -20 to 0°C until the reaction is complete. The reaction solution is concentrated under reduced pressure to remove excess solvent, and a chiral 2-disubstituted indole compound is obtained by purification by silica gel column chromatography.

[0029] Preferably, according to the present invention, the preparation method of the allylbenzoxazepinone compound I comprises the steps of:

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

[0031]

[0032] Among them, R 1is 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, substituted or unsubstituted methylnaphthalene, wherein the substituent is selected from halogen, C1-C3 alkyl, methoxy;

[0033] (2) Under nitrogen protection, a tetrahydrofuran solution of the amino alcohol intermediate is stirred at -5 to 5°C for 5 to 15 minutes, and a methyl lithium solution is added dropwise. After the addition is completed, the mixture is stirred at 45 to 55°C until the reaction is complete. A saturated aqueous ammonium chloride solution is added to the reaction solution for quenching. The reaction solution is concentrated and extracted with ethyl acetate. The organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent is removed by distillation under reduced pressure. The allylbenzoxazepinone compound I is purified by silica gel column chromatography.

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

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

[0036] Application of the chiral 2-disubstituted indoline compound in the preparation of anti-bladder cancer drugs.

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

[0038] 1. The present invention uses a simple palladium catalyst and a chiral ligand as a catalyst system, and uses a newly designed 1,5-dipolar allylbenzoxazepinone as a raw material to carry out a palladium-catalyzed intramolecular asymmetric cyclization reaction to achieve efficient asymmetric synthesis of chiral 2-position disubstituted indoline compounds. The synthesis method of the present invention is simple, the reaction conditions are mild, and the operation is convenient and simple; the amount of catalyst used is small, the catalyst cost is low, and the efficiency is high; the raw materials are cheap and easy to obtain, the atom economy is good, and the substrate has a wide range of applicability.

[0039] 2. The present invention uses a newly designed 1,5-dipole allylbenzoxazepine as a raw material. Currently, 1,3-dipole and 1,4-dipole have been widely used in various intermolecular asymmetric cycloaddition reactions to construct a variety of chiral mid-ring compounds, but there are also the following limitations: 1) Intermolecular reactions require the participation of dipoles and dipolephiles, and many side reactions may occur; 2) Dipolephiles are mostly electron-deficient olefins or carbonyl derivatives, such as aldehydes, imines, etc., which greatly limits the application range of the substrate. In contrast, there are relatively few studies on 1,5-dipoles, especially for the asymmetric intramolecular cyclization reaction of 1,5-dipole to construct a chiral quaternary carbon center. There is no report yet. Therefore, the present invention can expand the application of 1,5-dipole in asymmetric cyclization reactions and develop a new strategy for constructing a chiral quaternary carbon center through a decarboxylation intramolecular asymmetric cyclization reaction.

[0040] 3. The amount of palladium catalyst used in the palladium catalytic system of the present invention is low, and the catalyst cost is low; by screening and optimizing different palladium catalysts and chiral ligands, the palladium catalytic system of the present invention is finally determined to be the optimal reaction condition. If other palladium catalysts or chiral ligands are used, or the ratio of the two is not suitable, the enantioselectivity of the product will be greatly reduced. In the present invention, the molecular sieve has a greater impact on the yield, but does not affect the enantioselectivity of the product.

[0041] 4. The reaction yield of the present invention is high and the enantioselectivity is high (up to 99% ee); the chiral 2-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 having important significance for the treatment of bladder cancer patients. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0043] Figure 2 The inhibition rate of different concentrations of compound IIe on bladder cancer cells (T24) in Application Example 2 and the concentration-inhibition rate curve are shown.

[0044] Figure 3 The inhibition rate of different concentrations of compound IIi on bladder cancer cells (T24) in Application Example 3 and the concentration-inhibition rate curve are shown.

[0045] Figure 4 The inhibition rate of different concentrations of compound IIj on bladder cancer cells (T24) in Application Example 4 and the concentration-inhibition rate curve are shown. DETAILED DESCRIPTION

[0046] The present invention is further described in detail below in conjunction with 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 can be obtained from commercial sources or prepared according to known methods unless otherwise specified.

[0048] The solvents used in the examples were treated with anhydrous solvents, and the treatment method is the prior art.

[0049] The yields described in the examples are molar yields.

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

[0051] In the embodiment, the preparation steps of allylbenzoxazepinone compound I are as follows:

[0052]

[0053] A tetrahydrofuran solution (0.2 mmol / mL) of S1 (2 mmol) was added to a dry and clean eggplant-shaped bottle, and the atmosphere was replaced with nitrogen three times. The reaction was placed in a cold trap at -25°C and stirred for 10 minutes, followed by a slow dropwise addition of a sec-butyl lithium solution (2.0 equiv.) and continued stirring for 10 minutes. Finally, an enone S2 (1.5 equiv.) was added and continued stirring until the reaction was complete. A saturated aqueous ammonium chloride solution was added to the reaction solution at -25°C for quenching, the reaction solution was concentrated and extracted with ethyl acetate for multiple times, the organic phases were combined, washed with saturated brine in turn, dried over anhydrous sodium sulfate, and the excess solvent was removed under reduced pressure distillation, and purified 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] Add the tetrahydrofuran solution (0.2 mmol / mL) of the amino alcohol intermediate S3 obtained above to a dry and clean eggplant-shaped bottle, replace with nitrogen three times, place the reaction solution in a cold trap at 0°C and stir for 10 minutes, then slowly add methyl lithium solution (2.0 equiv.). After the addition is completed, the reaction is heated to 50°C and stirred overnight until the reaction is complete. Add saturated aqueous ammonium chloride to the reaction solution for quenching, concentrate the reaction solution and extract it with ethyl acetate for multiple times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, remove excess solvent under reduced pressure distillation, and purify by silica gel column chromatography (eluent PE / EA=20:1 to 3:1) to obtain allylbenzoxazepinone compound I. The total yield of the two steps is about 60% to 70%.

[0055] Example 1

[0056] Synthesis of (S)-2-Benzyl-5-methyl-2-vinylindoline (Ⅱa)

[0057] The reaction route is as follows:

[0058]

[0059] The steps are as follows:

[0060] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰa (58.6 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱa (39 mg, 78% yield).

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

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

[0063] 1 H NMR (400MHz, CDCl3) δ7.29-7.20(m,3H),7.16-7.14(m,2H),6.89(s,1H),6.83 (d,J=7.8Hz,1H),6.52(d,J=7.8Hz,1H),5.98(dd,J=17.4,10.4Hz,1H),5.02( d,J=17.4Hz,1H; d,J=10.4Hz,1H),3.69(s,1H),3.02(d,J=15.3Hz,1H),2.98( d,J=15.3Hz,1H),2.94(d,J=13.0Hz,1H),2.89(d,J=13.0Hz,1H),2.24(s,3H).

[0064] 13 C NMR (100MHz, CDCl3) δ147.5,142.4,137.2,130.5,128.1,127.8,127.6,126.6,125.9,113.0,108.9,68.5,45.9,42.3,20.9.

[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 route is as follows:

[0069]

[0070] The steps are as follows:

[0071] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰb (62.8 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱb (44 mg, 82% yield).

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

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

[0074] 1 H NMR (400MHz, CDCl3) δ7.28-7.23(m,3H),7.16-7.07(m,2H),7.06-6.86(m,2H),6.49(d,J=8.2Hz,1H),5.96(dd,J=17.2,10.6Hz,1H),5.08 -4.93(d,J=17.1Hz,1H; d,J=10.5Hz,1H),3.03(d,J=15.5Hz,1H),2.95(d,J=15.6Hz,1H),2.94(d,J=13.0Hz,1H),2.89(d,J=13.1Hz,1H).

[0075] 13 C NMR (100MHz, CDCl3) δ148.5,141.9,136.8,130.4,129.3,128.1,127.3,126.7,125.2,122.9,113.3,109.6,68.9,45.9,42.1.

[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 (Ⅱc)

[0079] The reaction route is as follows:

[0080]

[0081] The steps are as follows:

[0082] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰc (61.9 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱc (41 mg, 78% yield).

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

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

[0085] 1 H NMR (400MHz, CDCl3) δ7.30-7.23(m,3H),7.19-7.11(m,2H),6.93(d,J=7.9Hz,1H),6.30-6.17(m,2H),5.98(d d,J=16.9,10.8Hz,1H),5.10-4.94(d,J=16.9Hz,1H; d,J=10.8Hz,1H),3.75(s,3H;s,1H),3.01-2.88(m,4H).

[0086] 13 C NMR (100MHz, CDCl3) δ160.1,151.2,142.4,137.1,130.5,128.1,126.6,125.2,119.7,113.1,103.1,96.0,69.0,55.4,46.0,41.7.

[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 (Ⅱd)

[0090] The reaction route is as follows:

[0091]

[0092] The steps are as follows:

[0093] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰd (67.5 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the resulting 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 Ⅱd (45 mg, 77% yield).

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

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

[0096] 1 H NMR (400MHz, CDCl3δ7.39-7.21(m,3H),7.20-7.10(m,2H),6.99(d,J=7.9Hz ,1H),6.37(dd,J=7.8,2.1Hz,1H),6.31(d,J=2.0Hz,1H),5.98(dd,J=17.0,1 0.8Hz,1H),5.17-4.91(m,2H),3.83(s,1H),3.03(d,J=15.3Hz,1H),2.99-2 .93(d,J=15.3Hz,1H; d,J=13.1Hz,1H),2.90(d,J=13.1Hz,1H),2.26(s,3H).

[0097] 13 C NMR (100MHz, CDCl3) δ169.8,150.9,150.8,142.2,136.9,130.5,128.2,126.7,125.2,124.8,113.3,110.9,102.5,69.1,46.1,41.8,21.3.

[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 (Ⅱe)

[0101] The reaction route is as follows:

[0102]

[0103] The steps are as follows:

[0104] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰe (59.5 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱe (38 mg, 75% yield).

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

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

[0107] 1 H NMR (400MHz, CDCl3) δ7.23-7.15(m,2H),7.02(m,4H),6.67(t,J=7.4Hz,1H),6.60(d,J=7.7Hz,1H),6.03(ddd,J=17.1,10.6,1.6 Hz, 1H), 5.08-4.95 (d, J = 17.2Hz, 1H; d, J = 10.5Hz, 1H), 3.86 (s, 1H), 3.09 (d, J = 15.4Hz, 1H), 3.06-2.93 (d, J = 15.3Hz, 1H; m, 2H).

[0108] 13 C NMR (100MHz,CDCl3)δ161.5(d, 1 J C-F =245.1Hz),149.9,142.2,132.6(d, 3 J C-F =4.7Hz),128.4(d, 3 J C-F =8.2Hz),127.5,127.1,124.9,124.3(d, 2 J C-F =15.8Hz),123.7(d, 4 J C-F =3.6Hz),118.5,115.4(d, 2 J C-F =23.0Hz),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 (Ⅱf)

[0112] The reaction route is as follows:

[0113]

[0114] The steps are as follows:

[0115] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10 °C. Allylbenzoxazepinone compound Ⅰf (65.9 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10 °C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱf (41 mg, 72% yield).

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

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

[0118] 1 H NMR (400MHz, CDCl3) δ7.80 (td, J=6.5, 2.4Hz, 2H), 7.75 (d, J=8.4Hz, 1H), 7.59 (s, 1H), 7 .41-7.49(m,2H),7.31(dd,J=8.4,1.7Hz,1H),7.12-7.00(m,2H),6.70(t,J=7.4Hz,1H) ,6.61(d,J=7.7Hz,1H),6.05(dd,J=17.1,10.7Hz,1H),5.04(d,J=10.7Hz,1H),5.00(d, J=17.2Hz,1H),3.83(s,1H),3.20-3.05(d,J=15.2Hz,1H; m,2H),3.02(d,J=15.2Hz,1H).

[0119] 13C NMR (100MHz, CDCl3) δ149.9,142.4,134.8,133.3,132.3,129.0,128.9,127.7,127. 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-(Thien-3-ylmethyl)-2-vinyldihydroindole (Ⅱg)

[0123] The reaction route is as follows:

[0124]

[0125] The steps are as follows:

[0126] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰg (57.1 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide, added to the above eggplant-shaped bottle, and stirred at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱg (29 mg, 60% yield).

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

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

[0129] 1 H NMR (400MHz, CDCl3) δ7.29-7.19(m,1H),7.09-6.97(m,3H),6.94(d,J=4.8Hz,1H),6.69(t,J=7.4Hz,1H),6.60(d,J=7.7Hz,1H),6.02(dd,J= 17.3, 10.6Hz, 1H), 5.10 (d, J = 17.3Hz, 1H), 5.06 (d, J = 10.6Hz, 1H), 3.84 (s, 1H), 3.08-2.98 (d, J = 13.8Hz, 1H; m, 2H), 2.94 (d, J = 13.8Hz, 1H).

[0130] 13 C NMR (100MHz, CDCl3) δ149.9,142.7,137.6,129.7,127.6,127.3,125.1,123.0,118.6,113.1,109.0,68.0,42.3,40.5.

[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 route is as follows:

[0135]

[0136] The steps are as follows:

[0137] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰh (69.6 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the resulting 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 Ⅱh (46 mg, 76% yield).

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

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

[0140] 1 H NMR (400MHz, CDCl3) δ7.23(m,1H),7.10-6.99(m,4H),6.70(t,J=7.4Hz,1H),6.63(d,J=7.7Hz,1H),5.93(dd,J=17.2,10.6Hz, 1H), 5.08 (d, J = 10.5Hz, 1H), 5.04 (d, J = 17.1Hz, 1H), 3.74 (s, 1H), 3.02 (m, 2H), 2.92 (d, J = 13.1Hz, 1H), 2.87 (d, J = 13.1Hz, 1H).

[0141] 13 C NMR (100MHz, CDCl3) δ149.6,141.7,140.6,134.5,128.9,127.7,126.9,126.9,125.1,118.9,113.8,109.0,68.2,45.6,42.3.

[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-vinylindoline-6-yl 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxan-2-yl)acetate (Ⅱi)

[0145] The reaction route is as follows:

[0146]

[0147] The steps are as follows:

[0148] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰi (109.1 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱi (70 mg, 70% yield).

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

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

[0151] 1H NMR (400MHz, CDCl3) δ8.21(d,J=2.4Hz,1H),7.90(dd,J=7.7,1.4Hz,1H),7.59-7.45(m,3H),7.37(dd,J=7.4,1.2Hz,1H ),7.29-7.22(m,3H),7.17-7.10(m,2H),7.06(d,J=8.4Hz,1H),6.98(d,J=7.9Hz,1H),6.36(dd,J=7.9,2.1Hz,1H),6.3 0(d,J=2.1Hz,1H),5.97(dd,J=17.1,10.7Hz,1H),5.20(s,2H),5.07-5.01(dd,J=17.2,1.2Hz,1H),4.99(dd,J=10.6,1 .2Hz, 1H), 3.85 (s, 3H), 3.02 (d, J = 15.4Hz, 1H), 2.97-2.91 (d, J = 15.4Hz, 1H; d, J = 13.1Hz, 1H), 2.89 (d, J = 13.1Hz, 1H).

[0152] 13 C NMR (100MHz, CDCl3) δ190.9,170.1,160.7,150.9,150.8,142.2,140.5,136.9,136.4,135.6,132.9,132.7,130. 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-vinylindoline-6-yl 4-(N,N-dipropylsulfamoyl)benzoate (Ⅱj)

[0156] The reaction route is as follows:

[0157]

[0158] The steps are as follows:

[0159] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰj (112.5 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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, 71mg, 68% yield.Daicel IH-3 column, (Hexane / i-PrOH=60 / 40, v=1mL / min, λ=254nm), t(minor)=10.9min, t(major)=12.7min, 90%ee. (c = 0.2 in CH2Cl2).

[0162] 1 H NMR (400MHz, CDCl3) δ8.30(d,J=8.4Hz,2H),7.93(d,J=8.4Hz,2H),7.27(dt,J=14.0,7. 6Hz,3H),7.16(d,J=6.9Hz,2H),7.06(d,J=7.9Hz,1H),6.50(dd,J=7.9,1.9Hz,1H),6.45 (d,J=2.0Hz,1H),6.00(ddd,J=17.0,10.7,1.1Hz,1H),5.20-4.99(d,J=17.0Hz,1H; d,J =10.7Hz,1H),3.90(s,1H),3.22-2.89(m,8H),1.61-1.54(m,4H),0.88(t,J=7.4Hz,6H).

[0163] 13C NMR (100MHz, CDCl3) δ164.1,151.1,150.7,144.8,142.1,136.8,133.3,130.8,130.5,128 .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] Embodiment 11

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

[0167] The reaction route is as follows:

[0168]

[0169] The steps are as follows:

[0170] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound Ⅰk (58.7 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱk (39 mg, 78% yield).

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

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

[0173] 1 H NMR (400MHz, CDCl3) δ7.70(dd,J=5.8,2.5Hz,1H),7.26-7.14(m,3H),6.97-6.81(m,2H),6.61(d,J=7.8Hz,1H),6.20(dd,J=17.2,10.4Hz,1 H), 4.99 (d, J = 10.4Hz, 1H), 4.83 (d, J = 17.2Hz, 1H), 4.05 (s, 1H), 3.56 (d, J = 15.7Hz, 1H), 3.25 (d, J = 15.7Hz, 1H), 2.37 (s, 3H), 2.24 (s, 3H).

[0174] 13 C NMR (100MHz, CDCl3) δ146.5,143.3,142.5,135.6,131.9,128.2,128.0,127.9,127.0,127.0,125.8,125.5,112.9,109.3,71.1,42.4,22.1,20.9.

[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 (Ⅱm)

[0178] The reaction route is as follows:

[0179]

[0180] The steps are as follows:

[0181] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound IM (71.1 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide, added to the above eggplant-shaped bottle, and stirred at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱm (45 mg, 72% yield).

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

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

[0184] 1 H NMR (400MHz, CDCl3) δ7.77-7.66(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=7.8Hz,1H),6.24 (dd,J=17.2,10.3Hz,1H),5.02(d,J=10.4Hz,1H),4.85(d,J=17.2Hz,1H), 4.20(s,1H),3.66(d,J=15.8Hz,1H),3.33(d,J=15.8Hz,1H),2.38(s,3H).

[0185] 13 C NMR (100MHz, CDCl3) δ148.4,143.1,142.3,141.7,135.5,132.3,132.0,128.7,128. 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] Embodiment 13

[0188] Synthesis of (S)-5-Chloro-2-(3,5-dichlorophenyl)-2-vinyldihydroindole (Ⅱn)

[0189] The reaction route is as follows:

[0190]

[0191] The steps are as follows:

[0192] Under nitrogen protection, 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 were added to a 5 mL eggplant-shaped bottle, and 0.5 mL N, N-dimethylformamide was added. After stirring at room temperature for 30 minutes, the mixture was placed in a cold trap at -10°C. Allylbenzoxazepinone compound In (73.7 mg, 0.2 mmol) was dissolved in 0.5 mL N, N-dimethylformamide and added to the above eggplant-shaped bottle. Stirring was continued at -10°C for 12 hours until the reaction was complete. The reaction solution was concentrated under reduced pressure to remove excess solvent, and the 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 Ⅱn (51 mg, 79% yield).

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

[0194] Colorless oily liquid, 51mg, 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 (400MHz, CDCl3) δ7.35(d,J=1.9Hz,2H),7.26(t,J=1.9Hz,1H),7.09-6.97(m,2H),6.61(d,J=8.8Hz,1H),6.09(dd,J=17.1, 10.5Hz,1H),5.17(d,J=10.5Hz,1H),5.10(d,J=17.1Hz,1H),4.10(s,1H),3.39(d,J=15.9Hz,1H),3.18(dt,J=15.9,1.1Hz,1H).

[0196] 13 C NMR (100MHz, CDCl3) δ149.0,147.7,141.0,135.1,128.6,127.7,127.3,124.9,124.9,124.0,114.3,110.3,70.7,43.4.

[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-vinyldihydroindoline (IIa) is as shown in Example 1, except that no palladium catalyst is added.

[0200] In this comparative example, no palladium catalyst was added and no reaction occurred.

[0201] Comparative Example 2

[0202] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindoline (IIa) is as shown in Example 1, except that the chiral ligand III is not added.

[0203] In this comparative example, no chiral ligand was added, the yield of IIa was 30%, and the product had no enantioselectivity.

[0204] Comparative Example 3

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

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

[0207] Comparative Example 4

[0208] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindoline (IIa) is as shown in Example 1, except that the chiral ligand III is replaced by an equimolar amount of a chiral ligand of the following structure.

[0209]

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

[0211] Comparative Example 5

[0212] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindoline (IIa) is as shown in Example 1, except that the amount of tris(dibenzylideneacetone)dipalladium-chloroform adduct used is 0.02 umol.

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

[0214] Comparative Example 6

[0215] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindoline (IIa) is as shown in Example 1, except that the solvent is dichloromethane.

[0216] The solvent added in this comparative example is dichloromethane, the yield of IIa is 51%, and the ee value is 32%.

[0217] Comparative Example 7

[0218] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindoline (IIa) is as shown in Example 1, except that the solvent is tetrahydrofuran.

[0219] The solvent added in this comparative example is tetrahydrofuran, the yield of IIa is 42%, and the ee value is 30%.

[0220] Comparative Example 8

[0221] The synthesis of (S)-2-benzyl-5-methyl-2-vinyldihydroindoline (IIa) is as shown in Example 1, except that no molecular sieve is added.

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

[0223] Application Example 1

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

[0225] Bladder cancer cells (T24) were purchased from Shanghai Saibaikang Biotechnology Co., Ltd. The culture medium used was a complete cell culture medium prepared in a ratio of (culture medium: fetal bovine serum = 9:1), and the culture medium type was RPMI1640.

[0226] The specific steps are as follows:

[0227] (1) Preparation of sample solution: The compound to be tested was dissolved with DMSO and sterilized by 0.22 μm filtration to obtain a 100 μM sample stock solution, which was then diluted with complete culture medium to a concentration of 5 μM to obtain a sample solution. At the same time, a culture medium to which an equal volume of DMSO was added was used as a control solution.

[0228] (2) Cell recovery and passaging: Open the water bath and adjust the temperature to 37°C. Take out the cells frozen in liquid nitrogen, quickly place the cells in a 37°C water bath, and shake quickly. After the cells are completely thawed, take out the cryotube from the water bath. Take a 10ml sterile centrifuge tube, add 4mL of culture medium, then transfer the cells in the cryotube to the centrifuge tube, centrifuge at 1000rpm at room temperature for 5min, take a new 25T cell culture flask, and add 5mL of culture medium. Discard the supernatant in the centrifuge tube, leave the precipitate, and add it all to the culture flask. Under 5% CO2 and 37°C conditions, let it stand for 8h, then aspirate all the culture medium, add 5mL of fresh culture medium, and continue culturing. Wait until the cells have grown all over the culture flask, discard the old culture medium, add 2mL PBS to wash the cells, discard PBS, add 1mL trypsin, digest at room temperature for about 30s, tap the area around the culture flask to let the digested cells fall off, and gently blow off the cells that are not easy to fall off with the tip of a gun, add 2mL culture medium; transfer the digested cells to a sterile centrifuge tube, centrifuge at 1000rpm at room temperature for 5min, discard the supernatant, add 1mL culture medium, blow and mix, transfer to a new culture flask, culture, and conduct experiments when it is full.

[0229] (3) Sample cell activity test: Take T24 cells in the logarithmic growth phase, count the cells, and adjust the cell concentration to 6×10 3 The cells were inoculated into a 96-well plate at a volume of 100 cells / well and continued to be cultured in a 37°C, 5% CO2 incubator. After the cells adhered to the wall for 24 hours, the cell culture medium was discarded, and 100 μL of sample solution and control solution were added to each well. After 72 hours of culture in a 37°C, 5% CO2 incubator, the culture medium was removed, each well was washed three times with PBS, and the culture medium containing 10% CCK-8 was added at 100 μL / well, and then cultured in a 37°C constant temperature incubator containing 5% CO2 for 2 hours. The absorbance value at 450nm was detected by an enzyme reader and the cell survival rate was calculated. The experiment was repeated 3 times and the average value was taken. The results are shown in the figure. Figure 1 .

[0230] from Figure 1 It can be seen that different compounds have different degrees of inhibitory effects on bladder cancer cells (T24). The present invention further determines the IC50 values ​​of IIe, IIi and IIj on bladder cancer cells (T24).

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

[0232] The specific steps are as follows:

[0233] Bladder cancer cells (T24) were purchased from Shanghai Saibaikang Biotechnology Co., Ltd. The culture medium used was a complete cell culture medium prepared in a ratio of (culture medium: fetal bovine serum = 9:1), and the culture medium type was RPMI1640.

[0234] (1) Preparation of sample solution: Compound IIe to be tested was dissolved with DMSO and sterilized by 0.22 μm filtration to obtain a 100 μM sample stock solution, which was then diluted with complete culture medium to working concentrations of 0.5, 1, 2, 3, 4, and 5 μM, respectively, to obtain sample solutions.

[0235] (2) Cell recovery and passaging: Open the water bath and adjust the temperature to 37°C. Take out the cells frozen in liquid nitrogen, quickly place the cells in a 37°C water bath, and shake quickly. After the cells are completely thawed, take out the cryotube from the water bath. Take a 10mL sterile centrifuge tube, add 4mL of culture medium, and then transfer the cells in the cryotube to the centrifuge tube. Centrifuge at 1000rpm at room temperature for 5min. Take a new 25T cell culture flask and add 5mL of culture medium. Discard the supernatant in the centrifuge tube, leave the precipitate, and add it all to the culture flask. Let it stand for 8h at 5% CO2 and 37°C, then aspirate all the culture medium, add 5mL of fresh culture medium, and continue culturing. Wait until the cells have grown all over the culture flask, discard the old culture medium, add 2mL PBS to wash the cells, discard PBS, add 1mL trypsin, digest at room temperature for about 30s, tap the area around the culture flask to let the digested cells fall off, and gently blow off the cells that are not easy to fall off with the tip of a gun, add 2mL culture medium; transfer the digested cells to a sterile centrifuge tube, centrifuge at 1000rpm at room temperature for 5min, discard the supernatant, add 1mL culture medium, blow and mix, transfer to a new culture flask, culture, and conduct experiments when it is full.

[0236] (3) Sample cell activity test: Take T24 cells in the logarithmic growth phase, count the cells, and adjust the cell concentration to 6×10 3The cells / well were inoculated into a 96-well plate and continued to be cultured in a 37°C, 5% CO2 incubator. After the cells adhered to the wall for 24 hours, the cell culture medium was discarded, and 100 μL of sample solution and control solution (DMSO) were added to each well. After 72 hours of culture in a 37°C, 5% CO2 incubator, the culture medium was removed, each well was washed three times with PBS, and a culture medium containing 10% CCK-8 was added at 100 μL / well, and then cultured in a 37°C constant temperature incubator containing 5% CO2 for 2 hours. The absorbance value at 450nm was detected by an enzyme marker. The absorbance values ​​of each group were entered into Excel and the relative activity was calculated (relative activity % = (OD value of the experimental group - background OD value) / (OD value of the control group - background OD value) × 100%), where the background OD value is the absorbance of only adding CCK8 reagent and culture medium. The relative activity values ​​were entered into GraphPad Prism for graphing.

[0237] The test results are in Figure 2 As shown in Figure 2 As shown, the synthetic compound IIe of the present invention 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 on bladder cancer cells (T24)

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

[0240] The test results are in Figure 3 As shown in Figure 3 As shown, the synthetic compound IIi of the present invention exhibits good inhibitory activity against bladder cancer cells (T24), with an IC50 value of 0.64 μM.

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

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

[0243] The test results are in Figure 4 As shown in Figure 4 As shown, the synthetic compound IIj of the present invention exhibited good inhibitory activity against bladder cancer cells (T24), with an IC50 value of 25.08 μM.

[0244] The above are only some embodiments of the present invention, and are not intended to limit the present invention in any form. Any simple modification, equivalent change or modification made to the above embodiments according to the invention shall fall within the scope of the technical solution of the present invention.

Claims

1. A chiral 2-disubstituted indoline compound, characterized in that: It has the structure shown in the following formula II: Among them, R 1 is selected 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.

2. The chiral 2-disubstituted indoline compound according to claim 1, characterized in that: R 1 is 5-methyl, 5-fluoro, 5-chloro, 6-acetate, 6-methyl-2-(11-oxo-6,11-dihydrodibenzo[b,e]oxane-2-yl)acetate, 6-methyl-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.

3. The chiral 2-disubstituted indoline compound according to claim 1, characterized in that: The chiral 2-disubstituted indoline compound is selected from the following compounds:

4. A method for synthesizing a chiral 2-disubstituted indoline compound as claimed in any one of claims 1 to 3, comprising the steps of: In a solvent, under the catalysis of a palladium catalyst system, an allylbenzoxazepinone compound I undergoes an asymmetric allylation reaction to obtain a chiral 2-disubstituted indoline compound II; the palladium catalyst system is composed of a palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct (Pd2(dba)3.CHCl3) and a chiral ligand, and the chiral ligand has a structure shown in the following formula III; in, In the structural formula of the compounds of formula Ⅰ and Ⅱ, R 1 is selected 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.

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

6. The method for synthesizing a chiral 2-disubstituted indoline compound according to claim 4, characterized in that: The molar ratio of the palladium catalyst tris(dibenzylideneacetone)dipalladium-chloroform adduct to the allylbenzoxazepinone 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.

7. The method for synthesizing a chiral 2-disubstituted indoline compound according to claim 4, characterized in that: The reaction system of the allylbenzoxazepinone compound I is also added Molecular sieve; The ratio of the mass of the molecular sieve to the molar number of the allylbenzoxazepinone compound I is 1 to 3 g:1 mmol.

8. The method for synthesizing a chiral 2-disubstituted indoline compound according to claim 4, characterized in that: The reaction is carried out under the protection of a protective gas, wherein the protective gas is nitrogen or argon; the reaction temperature is -20 to 0°C, more preferably -10°C; the reaction time is 2 to 48 hours, more preferably 12 to 24 hours.

9. The method for synthesizing a chiral 2-disubstituted indoline compound according to claim 4, characterized in that: The post-reaction treatment steps are as follows: the reaction solution is freed of solvent, and the obtained crude product is separated by silica gel column chromatography to obtain a chiral 2-disubstituted indoline compound, 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.

10. Use of the chiral 2-disubstituted indoline compound according to any one of claims 1 to 3 in the preparation of anti-bladder cancer drugs.

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