CN104693092B - Chirality 3,3-bis-replacement oxoindole derivative and synthetic method thereof and application - Google Patents

Abstract

The present invention relates to the chemical synthesis process of a kind of novel chirality 3,3 two replacement oxoindole derivative with PTP1B inhibitory action.The present invention is with diazonium isatin, indole, arylamine and aldehydic acid ester as raw material, with metallic catalyst as catalyst, with chiral phosphoric acid as co-catalyst, with organic solvent as solvent, with molecular sieve as additive, through single step reaction under the conditions of 25 DEG C, column chromatography purifies and i.e. obtains product.The present invention has the advantage that step economy, Atom economy, cis-selectivity and enantioselectivity are high and yield is high, and reaction condition is gentle, safety simple to operate.Optical voidness 3, the 3 two replacement oxoindole derivative with two chiral centres of present invention synthesis is important chemical industry, chemistry and medicine intermediate, has wide application prospect in field of medicine and chemical technology.

Description

Chiral 3,3-disubstituted oxindole derivatives and their synthesis methods and applications

technical field

The invention relates to a novel chiral 3,3-disubstituted oxindole derivative and its synthesis method and application, belonging to the field of preparation and application of pharmaceutical intermediates.

Background technique

Chiral 3,3-disubstituted oxindole derivatives are a kind of important skeleton structure units for the construction of natural products and synthetic drugs, and many natural product structures contain such skeleton structures. Cyclotryptamine widely has 3,3-disubstituted oxindole skeleton structure. For example, the natural compound (+)-WIN 64821 isolated from Aspergillus is a potential SP receptor antagonist of neurokinin (NK-1) receptor and cholecystokinin B (cholecystokinin B) receptor (J . Antibiot., 1994, 47, 411; J. Antibiot., 1994, 47, 399; J. Antibiot., 1994, 47, 391). Chaetocin not only has good antibacterial and cell growth inhibitory activity, but also is a potential histone lysine-specific methyltransferase (HMTs) inhibitor (Nat.Chem.Biol., 2005 ,1,143). The 3,3-disubstituted oxindole skeleton widely exists in epidithiodioxopiperazine (ETP) alkaloids. For example, leptosin D has cytotoxic effect on P-388 lymphocytic leukemia cell line (J. Antibiot., 1994, 47, 1242). Bionectins A and B (Bionectins A and B) have antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and quinolone-resistant Staphylococcus aureus (QRSA) (J.Nat.Prod.,2006,69 , 1816). In addition, 3,3-disubstituted oxindole derivatives can also be used in the synthesis of numerous other antineoplastic drugs, antibiotics, antifungal drugs, etc. The discovery and synthesis of new chiral 3,3-disubstituted oxindole derivatives provides a good basis for the physiological research of this important compound, and is a new opportunity for the discovery of new drug molecules (Angew.Chem.Int. Ed., 2013, 52, 2486).

In view of the important role of chiral 3,3-disubstituted oxindole derivatives, it is of great theoretical significance and economic value to develop a simple and practical synthesis method. The skeleton structure is relatively crowded in terms of spatial structure, the steric hindrance is very large, and the chiral control method is single, which greatly increases the difficulty of chiral synthesis of the skeleton. In recent years, organic chemists have developed a series of different routes and synthetic methods. For example, in the research on the total synthesis of Gliocladine C (Gliocladine C), the Overman research group successfully obtained the key 3,3-disubstituted oxindole structure using Fe catalysis for the first time (J.Am.Chem.Soc., 2011, 133,6549). Stephenson's research group also completed the construction of this type of important framework structure using photocatalyst Ru (Angew.Chem.Int.Ed., 2011, 50, 9655). Zhang Junliang's group successfully constructed a new class of chiral 3,3-disubstituted oxindole derivatives through the Michael addition reaction catalyzed by small molecule catalysts (Org. Lett., 2013, 15, 2266). Gong Liuzhu's research group developed a new method for the synthesis of chiral 3,3-disubstituted oxindole derivatives through the relay-catalyzed C-H functionalization/Michael addition reaction of Ru and chiral square amides (Angew.Chem.Int.Ed., 2014, 53, 10763). However, many of these routes and synthetic methods have disadvantages such as complex synthesis of raw materials, many reaction steps, long reaction time, high cost, low yield, cumbersome operation and post-treatment, etc., and their practical and economic value are greatly limited. Therefore, it is a new challenge for modern organic synthetic chemists to develop an efficient, practical and universal method for the synthesis of such 3,3-disubstituted oxindole derivatives.

Contents of the invention

The purpose of the present invention is to disclose a one-step synthesis of a novel compound with two adjacent chiral centers and PTP1B inhibition with low cost, high yield, mild reaction conditions, good selectivity, wide range of substrate application, and safe and simple operation. Chemical Synthesis of Active Optically Pure 3,3-Disubstituted Oxindole Derivatives. The chiral 3,3-disubstituted oxindole derivatives synthesized according to the present invention exhibit good PTP1B inhibitory effect.

Multicomponent reactions feature high convergence, high atom economy, and the ability to construct complex compounds efficiently. Compared with the traditional two-component reaction, the multi-component reaction is close to the ideal synthesis method. In recent years, with the increasing development of the concepts of atom economy and step economy, multicomponent reactions have increasingly become a research hotspot. Therefore, the application of multicomponent reactions in the field of drug synthesis has broad prospects and many potential advantages. For this reason, the present invention designs a four-component reaction co-catalyzed by a metal Lewis acid catalyst and a chiral phosphoric acid catalyst using diazoisatin compounds, indole compounds, aromatic amines, and alkyd esters as raw materials, and synthesizes a series of 3,3-Disubstituted oxindole derivatives with PTP1B inhibitory activity and high enantioselectivity. Its general formula is as follows:

in:

R is _an alkyl group; it includes benzyl, methyl, ethyl;

R ₂ is benzyl, tert-butoxycarbonyl, benzyloxycarbonyl;

R ₃ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a nitro group; wherein, the alkyl group includes a methyl group, an ethyl group, an isopropyl group; and the alkoxy group is a methoxy group, an ethoxy group, tert-butoxy;

R ₄ is a hydrogen atom, a halogen atom, an alkyl group, and an alkoxy group; wherein, the alkyl group includes methyl, ethyl, and isopropyl; and the alkoxy group is methoxy, ethoxy, or tert-butoxy base;

Ar is an aryl group; it includes phenyl, p-bromophenyl, p-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, p-fluorophenyl, p-tolyl.

The chemical reaction mechanism involved in the present invention is shown in the following formula: under the catalysis of metal Lewis acid, diazo decomposes to form metal carbene (I), and the zwitterion pair (IIa/IIb) formed by metal carbene and indole is catalyzed by chiral phosphoric acid. The imine (III) generated on-site by arylamine and aldehyde ester is trapped (Mannich-type trapping), and the obtained intermediate IV is formed in one step through the subsequent hydrogen transfer process (H transfer process) with high yield and high asymmetric Enantioselective, highly enantioselective 3,3-disubstituted oxindole derivatives.

The method for synthesizing novel chiral 3,3-disubstituted oxindole derivatives proposed by the present invention uses diazoisatin compounds, indole compounds, aromatic amines and alkyd esters as raw materials, and metal Lewis acids (MLn ) as catalyst, with chiral phosphoric acid (ChiralPPA) as co-catalyst, with organic solvent as solvent, with Molecular sieve ( MS) is an additive, which reacts at 25°C, and is characterized in that a chiral 3,3-disubstituted oxindole derivative with PTP1B inhibitory activity is obtained through a one-step four-component reaction; the reaction of the synthetic method The equation looks like this:

in:

R is alkyl, benzyl; _The alkyl includes methyl, ethyl;

R ₂ is benzyl, tert-butoxycarbonyl, benzyloxycarbonyl;

R ₃ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a nitro group; wherein, the alkyl group includes a methyl group, an ethyl group, an isopropyl group; and the alkoxy group is a methoxy group, an ethoxy group, tert-butoxy;

R ₄ is a hydrogen atom, a halogen atom, an alkyl group, and an alkoxy group; wherein, the alkyl group includes methyl, ethyl, and isopropyl; and the alkoxy group is methoxy, ethoxy, or tert-butoxy base;

Ar is an aryl group; it includes phenyl, p-bromophenyl, p-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, p-fluorophenyl, p-tolyl.

In the synthesis reaction of the present invention, metal carbene is decomposed under the catalysis of metal Lewis acid to form metal carbene, and the zwitterion pair formed by metal carbene and indole is captured by the imine generated on-site by aromatic amine and alkyd ester under the catalysis of chiral phosphoric acid. Formation of 3,3-disubstituted oxindole derivatives with high yield, high diastereoselectivity, and high enantioselectivity.

In the present invention, the diazoisatins include diazoisatins, various nitrogen-substituted diazoisatins, various aryl-substituted diazoisatins, etc.; the indole compounds include various nitrogen-substituted indoles Indole, various aryl substituted indoles, etc.; the arylamines include unsubstituted aniline, various substituted arylamines, etc.; the aldehyde esters are ethyl glyoxylate, etc.; the organic solvents include methylene chloride, three Chloromethane, toluene, 1,2-dichloroethane, xylene, etc.

In the present invention, the metal Lewis acid catalyst is all metal Lewis acid compounds that can catalyze the decomposition of diazo; for example, metal rhodium, metal copper, metal palladium, metal ruthenium, metal osmium, metal iridium, metal cobalt Types, metal iron, metal nickel, metal platinum, etc.

In the present invention, the chiral phosphoric acid used as a co-catalyst is S-type, and its structure is shown in formula (A), wherein, R is triphenylsilyl, 9-phenanthrenyl, phenyl, 3,4,5 -Trifluorophenyl, 3,5-difluorophenyl, 3,5-bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 2,4,6-triisopropylphenyl , p-methylphenyl, p-methoxyphenyl or 4-biphenyl;

The process of synthesizing chiral 3,3-disubstituted oxindole derivatives in the present invention comprises dissolving aromatic amine, aldehyde ester, metal Lewis acid catalyst and chiral phosphoric acid catalyst in an organic solvent at 25°C; and then dissolving A mixture of indole compounds and diazoisatin compounds dissolved in an organic solvent was added dropwise to the reaction system within 1 h at 25°C. After the dropwise addition was completed, the solvent was removed to obtain a crude product; The ratio is ethyl acetate:petroleum ether=1:30～1:10 solution is subjected to column chromatography, and high yield, high diastereoselectivity and high enantioselectivity obtain chiral 3,3-disubstituted oxidation Indole derivatives.

In the inventive method, the mol ratio of raw material and catalyzer is indole compound: diazoisatin compound: aromatic amine: alkyd ester: metal Lewis acid catalyst: chiral phosphoric acid=1.1:(1.0-1.1):(1.1 -1.2):(1.1-1.2):(0.01-0.02):(0.05-0.10); The added amount of the molecular sieve is 100 mg/mmol based on the diazoisatin compound; the added amount of the organic solvent is 1 ml/mmol based on the diazoisatin compound.

In the method of the present invention, the method for separating and purifying the crude product is to perform column chromatography with a mobile phase having a volume ratio of ethyl acetate:petroleum ether of 1:30 to 1:10.

In a specific embodiment, the synthesis method of the novel chiral 3,3-disubstituted oxindole derivatives of the present invention is as follows: arylamine (0.33mmol, 1.1eq), alkydate (0.36mmol, 1.2eq), Molecular sieves (300mg), metal Lewis acid catalysts (0.006mmol) and chiral phosphoric acid catalysts (0.015mmol) were dissolved in organic solvents (1.5ml) at 25°C; then, dissolved in organic solvents (1.5ml) The mixture of diazoisatin compound (0.30mmol, 1.0eq) and indole compound (0.33mmol, 1.1eq) was added dropwise to the reaction system at 25°C within 1h. solvent to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product.

The present invention also proposes a 3,3-disubstituted oxindole derivative prepared by the above synthesis method, the structure of which is shown in formula (5). The optically pure 3,3-disubstituted oxindole derivative with two chiral centers synthesized by the invention is an important chemical, chemical and pharmaceutical intermediate.

The present invention also proposes a new 3,3-disubstituted oxindole derivative, the structure of which is shown in formula (5),

in:

R is alkyl, benzyl; _The alkyl includes methyl, ethyl;

R ₂ is benzyl, tert-butoxycarbonyl, benzyloxycarbonyl;

R ₃ is a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a nitro group; wherein, the alkyl group includes a methyl group, an ethyl group, an isopropyl group; and the alkoxy group is a methoxy group, an ethoxy group, tert-butoxy;

R ₄ is a hydrogen atom, a halogen atom, an alkyl group, and an alkoxy group; wherein, the alkyl group includes methyl, ethyl, and isopropyl; and the alkoxy group is methoxy, ethoxy, or tert-butoxy base;

Ar is an aryl group; it includes phenyl, p-bromophenyl, p-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, p-fluorophenyl, p-tolyl.

Preferably, R ₁ is benzyl, methyl; R ₂ is benzyl, tert-butoxycarbonyl; R ₃ is hydrogen atom, halogen atom; R ₄ is hydrogen atom, halogen atom; Ar is phenyl, p-bromophenyl .

More preferably, R ₁ is benzyl; R ₂ is tert-butoxycarbonyl; R ₃ is a hydrogen atom; R ₄ is a hydrogen atom; Ar is p-bromophenyl.

Further, R ₁ is benzyl, methyl; R ₂ is benzyl, tert-butoxycarbonyl; R ₃ is hydrogen atom, halogen atom, methyl, methoxy, nitro; R ₄ is hydrogen atom, halogen atom, methyl; Ar is phenyl, p-bromophenyl, p-chlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, p-fluorophenyl, p-tolyl.

The present invention also proposes an application of the chiral 3,3-disubstituted oxindole derivative in the preparation of an inhibitory drug for obesity-specific target gene-protein tyrosine phosphatase 1B.

The reaction mechanism involved in the present invention is: under the catalysis of metal Lewis acid, diazo decomposes to form metal carbene, and the zwitterion pair formed by metal carbene and indole is formed by the imine generated on-site by aromatic amine and alkyd ester under the catalysis of chiral phosphoric acid. Capture, one-step formation of 3,3-disubstituted oxindole derivatives with high yield, high diastereoselectivity, and high enantioselectivity. The beneficial effects of the present invention include: constructing novel chiral 3,3-disubstituted oxindole derivatives with two adjacent chiral centers through a one-step multi-component reaction, the reaction conditions are mild, the yield is high, and the selectivity is good. The substrate has wide applicability, and the operation is safe and simple. The synthesized chiral 3,3-disubstituted oxindole derivative itself has important applications in the research of biological proteins and enzymes, and has strong economic applicability. The invention has the advantages of step economy, atom economy, high diastereoselectivity and enantioselectivity and high yield, and the reaction conditions are mild, and the operation is simple and safe. The novel optically pure 3,3-disubstituted oxindole derivatives with two chiral centers obtained in the present invention are important chemical, chemical and pharmaceutical intermediates, and are widely used in the field of pharmaceutical and chemical industries, so they have great applications prospect.

Description of drawings

Figure 1 shows that taking Example 25 as an example, the three-dimensional configuration of the 3,3-disubstituted oxindole derivative prepared by the present invention is determined as (2S,3S) by single crystal diffraction.

detailed description

The present invention will be described in further detail in conjunction with the following specific examples and accompanying drawings, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

Example 1:

Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in dichloromethane (1.5ml) at 25°C; A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in methane (1.5ml) was added dropwise to the reaction at 25°C within 1h In the system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 72%, the dr value was greater than 95:5, and the ee value was 86%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14(m,3H),7.12-7.08(m,1H),7.05(s,1H),7.03-6.99(m,3H),6.78-6.75(m,3H),5.38(d,J=10.6 Hz,1H),5.17(s,2H),4.69(d,J=10.3Hz,1H),3.77-3.70(m,2H),1.60(s,9H),0.65(t,J=7.1Hz,3H )； ¹³ C NMR(100MHz,CDCl ₃ )δ174.90,170.94,149.28,146.18,140.69,137.01,136.94,129.46,129.28,128.74,128.49,127.67,127.21,126.69,126.58,125.87,124.41,122.08,121.41,119.85 , 119.21, 115.38, 114.83, 111.05, 109.92, 84.49, 62.44, 60.93, 54.71, 50.20, 28.10, 13.29; HRMS (ESI) calcd for C ₃₈ H ₃₇ N ₃ NaO ₅ [M+Na] ⁺ ＝ 638.2631, found 6 .

Example 2:

Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.33mmol, 1.1eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in toluene (1.5ml) at 25°C; then, dissolved in toluene (1.5ml ) in the mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) was added dropwise to the reaction system within 1h at 25°C, dropwise After the addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 80%, the dr value was greater than 95:5, and the ee value was 86%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14(m,3H),7.12-7.08(m,1H),7.05(s,1H),7.03-6.99(m,3H),6.78-6.75(m,3H),5.38(d,J=10.6 Hz,1H),5.17(s,2H),4.69(d,J=10.3Hz,1H),3.77-3.70(m,2H),1.60(s,9H),0.65(t,J=7.1Hz,3H )； ¹³ C NMR(100MHz,CDCl ₃ )δ174.90,170.94,149.28,146.18,140.69,137.01,136.94,129.46,129.28,128.74,128.49,127.67,127.21,126.69,126.58,125.87,124.41,122.08,121.41,119.85 , 119.21, 115.38, 114.83, 111.05, 109.92, 84.49, 62.44, 60.93, 54.71, 50.20, 28.10, 13.29; HRMS (ESI) calcd for C ₃₈ H ₃₇ N ₃ NaO ₅ [M+Na] ⁺ ＝ 638.2631, found 6 .

Example 3:

Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and 3,5-difluorophenyl substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in xylene (1.5ml) was added dropwise to In the reaction system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 75%, the dr value was greater than 95:5, and the ee value was 92%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14(m,3H),7.12-7.08(m,1H),7.05(s,1H),7.03-6.99(m,3H),6.78-6.75(m,3H),5.38(d,J=10.6 Hz,1H),5.17(s,2H),4.69(d,J=10.3Hz,1H),3.77-3.70(m,2H),1.60(s,9H),0.65(t,J=7.1Hz,3H )； ¹³ C NMR(100MHz,CDCl ₃ )δ174.90,170.94,149.28,146.18,140.69,137.01,136.94,129.46,129.28,128.74,128.49,127.67,127.21,126.69,126.58,125.87,124.41,122.08,121.41,119.85 , 119.21, 115.38, 114.83, 111.05, 109.92, 84.49, 62.44, 60.93, 54.71, 50.20, 28.10, 13.29; HRMS (ESI) calcd for C ₃₈ H ₃₇ N ₃ NaO ₅ [M+Na] ⁺ ＝ 638.2631, found 6 .

Example 4:

Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and 9-phenanthrenyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in 1,2-dichloroethane (1.5ml) at 25°C; then, A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) dissolved in 1,2-dichloroethane (1.5ml) was It was added dropwise to the reaction system within 1 h at 25°C. After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 74%, the dr value was greater than 95:5, and the ee value was 66%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14(m,3H),7.12-7.08(m,1H),7.05(s,1H),7.03-6.99(m,3H),6.78-6.75(m,3H),5.38(d,J=10.6 Hz,1H),5.17(s,2H),4.69(d,J=10.3Hz,1H),3.77-3.70(m,2H),1.60(s,9H),0.65(t,J=7.1Hz,3H )； ¹³ C NMR(100MHz,CDCl ₃ )δ174.90,170.94,149.28,146.18,140.69,137.01,136.94,129.46,129.28,128.74,128.49,127.67,127.21,126.69,126.58,125.87,124.41,122.08,121.41,119.85 , 119.21, 115.38, 114.83, 111.05, 109.92, 84.49, 62.44, 60.93, 54.71, 50.20, 28.10, 13.29; HRMS (ESI) calcd for C ₃₈ H ₃₇ N ₃ NaO ₅ [M+Na] ⁺ ＝ 638.2631, found 6 .

Example 5:

Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), palladium acetate (0.006mmol) and p-methoxyphenyl substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) in (1.5ml) was added dropwise to the reaction system at 25°C within 1h After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 59%, the dr value was greater than 95:5, and the ee value was 73%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14(m,3H),7.12-7.08(m,1H),7.05(s,1H),7.03-6.99(m,3H),6.78-6.75(m,3H),5.38(d,J=10.6 Hz,1H),5.17(s,2H),4.69(d,J=10.3Hz,1H),3.77-3.70(m,2H),1.60(s,9H),0.65(t,J=7.1Hz,3H )； ¹³ C NMR(100MHz,CDCl ₃ )δ174.90,170.94,149.28,146.18,140.69,137.01,136.94,129.46,129.28,128.74,128.49,127.67,127.21,126.69,126.58,125.87,124.41,122.08,121.41,119.85 , 119.21, 115.38, 114.83, 111.05, 109.92, 84.49, 62.44, 60.93, 54.71, 50.20, 28.10, 13.29; HRMS (ESI) calcd for C ₃₈ H ₃₇ N ₃ NaO ₅ [M+Na] ⁺ ＝ 638.2631, found 6 .

Embodiment 6:

Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.1eq), Molecular sieves (300mg), cyclooctadienyl rhodium chloride (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, A mixture of N-tert-butoxycarbonyldiazoisatin (0.3mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) dissolved in xylene (1.5ml) was at 25°C within 1h Add it dropwise into the reaction system, and after the dropwise addition, remove the solvent by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 57%, the dr value was greater than 95:5, and the ee value was 73%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=8.1Hz, 1H), 7.51-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.27-7.22 (m, 4H), 7.20-7.14(m,3H),7.12-7.08(m,1H),7.05(s,1H),7.03-6.99(m,3H),6.78-6.75(m,3H),5.38(d,J=10.6 Hz,1H),5.17(s,2H),4.69(d,J=10.3Hz,1H),3.77-3.70(m,2H),1.60(s,9H),0.65(t,J=7.1Hz,3H )； ¹³ C NMR(100MHz,CDCl ₃ )δ174.90,170.94,149.28,146.18,140.69,137.01,136.94,129.46,129.28,128.74,128.49,127.67,127.21,126.69,126.58,125.87,124.41,122.08,121.41,119.85 , 119.21, 115.38, 114.83, 111.05, 109.92, 84.49, 62.44, 60.93, 54.71, 50.20, 28.10, 13.29; HRMS (ESI) calcd for C ₃₈ H ₃₇ N ₃ NaO ₅ [M+Na] ⁺ ＝ 638.2631, found 6 .

Embodiment 7:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction system within 1h at 25°C , After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 94%, the dr value was greater than 95:5, and the ee value was 97%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99(d, J=8.1Hz, 1H), 7.49-7.38(m, 3H), 7.26-7.16(m, 7H), 7.12-7.07(m, 1H), 7.00(t, J=6.9Hz, 4H), 6.66-6.57(m, 2H), 5.33-5.25(m, 1H), 5.16(s, 2H), 4.81(d, J=9.7Hz, 1H), 3.78 -3.70(m,2H),1.60(s,9H),0.67(t,J=7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ174.97,170.54,149.22,145.20,140.61,136.99,136.85, 132.06,129.58,128.79,128.24,127.77,127.11,126.81,126.45,125.77,124.52,122.19,121.20,119.95,116.31,115.44,111.02,110.94,109.99,84.64,62.41,61.13,54.48,50.19,28.12,13.34； HRMS (ESI) calcd for C ₃₈ H ₃₆ BrN ₃ NaO ₅ [M+Na] ⁺ = 716.1736, found 716.1682.

Embodiment 8:

P-chloroaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) at 25°C. It was added dropwise into the reaction system within 1 h. After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 70%, the dr value was greater than 95:5, and the ee value was 97%.

¹ H NMR (400MHz, CDCl3) δ7.99 (d, J = 8.1Hz, 1H), 7.49-7.38 (m, 3H), 7.26-7.16 (m, 7H), 7.12-7.07 (m, 1H), 7.00 (t,J=6.9Hz,4H),6.66-6.57(m,2H),5.33-5.25(m,1H),5.16(s,2H),4.81(d,J=9.7Hz,1H),3.78- 3.70(m,2H),1.60(s,9H),0.67(t,J=7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ174.93,170.60,149.20,144.73,140.61,136.97,136.84,129.54 ,129.14,128.76,128.25,127.74,127.05,126.77,126.45,125.77,124.47,123.87,122.16,121.25,119.91,115.90,115.41,110.91,109.94,84.61,62.53,61.08,54.54,50.18,28.09,13.29；HRMS (ESI) calcd for C ₃₈ H ₃₆ BrN ₃ NaO ₅ [M+Na] ⁺ ＝672.2241, found 672.2198.

Embodiment 9:

P-methylaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction system within 1h at 25°C , After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 58%, the dr value was greater than 95:5, and the ee value was 49%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99(d, J=8.2Hz, 1H), 7.54-7.40(m, 3H), 7.29-7.14(m, 6H), 7.12-7.07(m, 1H), 7.06-6.95(m,6H),6.68(d,J=8.4Hz,2H),5.36(d,J=10.9Hz,1H),5.17(s,2H),4.48(d,J=10.5Hz,1H ),3.77-3.67(m,2H),2.22(s,3H),1.59(s,9H),0.62(t,J＝7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ174.87,171.15, 149.32,143.88,140.77,137.07,136.96,129.78,129.43,128.74,128.58,128.57,127.66,127.20,126.68,126.66,125.94,124.35,122.07,121.60,119.82,115.38,115.21,111.07,109.90,84.43,62.89, 60.85, 54.95, 50.19, 28.11, 20.50, 13.28; HRMS (ESI) calcd for C ₃₉ H ₃₉ N ₃ NaO ₅ [M+Na] ⁺ ＝652.2787, found 652.2831.

Example 10:

P-fluoroaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction system within 1h at 25°C , After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 71%, the dr value was greater than 95:5, and the ee value was 78%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99(d, J=8.1Hz, 1H), 7.53-7.50(m, 2H), 7.46-7.41(m, 1H), 7.29-7.18(m, 5H), 7.13-7.09(m,1H),7.05-7.01(m,3H),6.98(s,1H),6.88-6.83(m,2H),6.71-6.68(m,2H),5.31(d,J=10.8 Hz,1H),5.22-5.13(m,2H),4.44(d,J=10.7Hz,1H),3.77-3.70(m,2H),1.59(s,9H),0.62(t,J=7.1Hz ,3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ174.90, 171.02, 156.94 (d, ¹ J _CF ＝237.2Hz), 149.25, 142.50 (d, ⁴ J _CF ＝2.1Hz), 140.75, 137.02, 136.97, 129.50 ,128.76,128.45,127.72,126.98,126.71,126.59,125.89,124.38,122.15,121.64,119.88,116.43(d, ³ J _CF ＝7.6Hz),115.71(d, ² J _CF ＝210.4Hz4),115 , 109.92, 84.53, 63.36, 60.98, 55.09, 50.17, 28.10, 13.26; HRMS (ESI) calcd for C ₃₈ H ₃₆ FN ₃ NaO ₅ [M+Na] ⁺ ＝656.2537, found 656.2568.

Example 11:

3,4-dichloroaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction system within 1h at 25°C , After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 86%, the dr value was greater than 95:5, and the ee value was 98%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99(d, J=8.0Hz, 1H), 7.46-7.40(m, 2H), 7.35(d, J=8.0Hz, 1H), 7.26-7.18(m, 5H), 7.16(d, J=8.7Hz, 1H), 7.12-7.08(m, 1H), 7.04-7.00(m, 3H), 6.98(s, 1H), 6.80(d, J=2.7Hz, 1H ),6.56(dd,J=8.8,2.8Hz,1H),5.22(d,J=10.2Hz,1H),5.20-5.12(s,2H),5.00(d,J=9.4Hz,1H),3.81 -3.71(m,2H),1.61(s,9H),0.70(t,J=7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ175.01,170.18,149.17,145.63,140.52,137.01,136.69, 132.91,130.77,129.67,128.80,128.05,127.84,127.07,126.91,126.34,125.68,124.62,122.26,121.73,120.96,120.04,115.72,115.48,114.07,110.83,110.03,84.75,62.19,61.30,54.15,50.21, 28.12, 13.38; HRMS (ESI) calcd for C ₃₈ H ₃₅ Cl ₂ N ₃ NaO ₅ [M+Na] ⁺ ＝706.1851, found 706.1829.

Example 12:

3,5-dichloroaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction system within 1h at 25°C , After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 88%, the dr value was greater than 95:5, and the ee value was 95%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (d, J=8.1Hz, 1H), 7.45-7.40 (m, 2H), 7.30-7.18 (m, 6H), 7.13-7.09 (m, 1H), 7.04-6.98(m,4H),6.72(t,J=1.6Hz,1H),6.59(d,J=1.7Hz,2H),5.19-5.14(m,4H),3.85-3.70(m,2H) ,1.62(s,9H),0.73(t,J=7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ174.97,169.94,149.15,147.74,140.44,136.96,136.65,135.59,129.68,128.80,128.00 ,127.86,127.06,126.91,126.26,125.63,124.66,122.26,120.76,120.07,118.80,115.48,112.44,110.77,110.03,84.78,61.81,61.37,53.83,50.23,28.11,13.39；HRMS(ESI)calcd for C ₃₈ H ₃₅ Cl ₂ N ₃ NaO ₅ [M+Na] ⁺ ＝706.1851, found 706.1879.

Example 13:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and 5-bromo-N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise at 25°C within 1h Into the reaction system, after the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 87%, the dr value was greater than 95:5, and the ee value was 89%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.97(d, J=8.1Hz, 1H), 7.59(s, 1H), 7.47-7.42(m, 2H), 7.24-7.21(m, 6H), 7.19- 7.16(m,1H),7.03(d,J=8.7Hz,1H),6.97-6.95(m,3H),6.61(d,J=8.8Hz,2H),5.25(d,J=7.3Hz,1H ), 5.12(s, 2H), 4.72(d, J=9.6Hz, 1H), 3.80-3.71(m, 2H), 1.62(s, 9H), 0.68(t, J=7.1Hz, 3H); ¹³ C NMR(100MHz,CDCl ₃ )δ174.91,170.42,149.00,145.06,140.56,136.32,135.66,132.09,129.79,129.34,128.88,128.01,127.97,126.70,126.62,125.64,125.20,124.59,123.96,116.44,115.56, 113.50, 111.46, 111.23, 110.64, 84.90, 62.38, 61.20, 54.41, 50.40, 28.11, 13.34; HRMS (ESI) calcd for C ₃₈ H ₃₅ Br ₂ N ₃ NaO ₅ [M+Na] ⁺ ＝794.0841, found 794.080 .

Example 14:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and 5-methoxy-N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) at 25°C within 1h Add it dropwise into the reaction system, and after the dropwise addition, remove the solvent by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 79%, the dr value was greater than 95:5, and the ee value was 57%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.97 (d, J=8.1Hz, 1H), 7.46-7.40 (m, 2H), 7.28-7.19 (m, 6H), 7.07-6.99 (m, 4H), 6.74(dd,J=8.9,2.4Hz,1H),6.64-6.60(m,3H),5.19(d,J=10.2Hz,1H),5.14(s,2H),4.98(d,J=9.5Hz ,1H),3.85-3.73(m,2H),3.64(s,3H),1.61(s,9H),0.75(t,J=7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ175. 14,170.37,154.01,149.13,145.13,140.59,136.86,132.07,129.53,128.77,128.55,127.74,127.28,126.77,126.69,125.84,124.58,116.10,115.26,112.46,110.89,110.68,110.26,102.44,84.68,62.42, 61.16, 55.60, 54.00, 50.41, 28.09, 13.42; HRMS (ESI) calcd for C ₃₉ H ₃₈ BrN ₃ NaO ₆ [M+Na] ⁺ ＝746.1842, found 746.1806.

Example 15:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and 5-nitro-N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was dropped at 25°C within 1h Added to the reaction system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 49%, the dr value was greater than 95:5, and the ee value was 90%.

¹ H NMR (400MHz, CDCl ₃ )δ8.37(s,1H),8.04-7.99(m,2H),7.51-7.43(m,2H),7.30-7.22(m,7H),7.18(s,1H ),7.02-7.00(m,2H),6.63(d,J＝8.9Hz,2H),5.24-5.21(m,3H),4.82(d,J＝9.5Hz,1H),3.81-3.75(m, 2H), 1.63(s, 9H), 0.71(t, J=7.1Hz, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ174.79, 170.02, 148.78, 144.84, 141.94, 140.57, 139.64, 135.48, 132.15, 131.15 ,130.12,129.06,128.32,126.78,126.22,125.64,125.41,124.73,118.62,117.86,116.36,115.75,113.93,111.37,110.00,85.18,62.60,61.30,54.10,50.75,28.05,13.40；HRMS(ESI)calcd for C ₃₈ H ₃₅ BrN ₄ NaO ₇ [M+Na] ⁺ ＝761.1587, found 761.1601.

Example 16:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and 6-bromo-N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise at 25°C within 1h Into the reaction system, after the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 86%, the dr value was greater than 95:5, and the ee value was 96%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.98(d, J=8.0Hz, 1H), 7.46-7.42(m, 2H), 7.35-7.20(m, 8H), 7.12(dd, J=8.7, 1.6 Hz,1H),7.01-6.99(m,2H),6.94(s,1H),6.61(d,J＝8.8Hz,2H),5.25-5.23(m,1H),5.12(s,2H),4.68 (d, J=9.8Hz, 1H), 3.79-3.73(m, 2H), 1.60(s, 9H), 0.68(t, J=7.1Hz, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ174. 76,170.41,149.08,145.04,140.62,137.85,136.22,132.07,129.74,128.91,128.83,127.99,126.72,126.63,125.68,125.31,124.55,123.29,122.67,116.42,116.01,115.52,112.85,111.34,111.25,84.80, 62.36, 61.18, 54.48, 50.23, 28.08, 13.37; HRMS (ESI) calcd for C ₃₈ H ₃₅ Br ₂ N ₃ NaO ₅ [M+Na] ⁺ ＝794.0841, found 794.0805.

Example 17:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and 7-methyl-N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was dropped at 25°C within 1h Added to the reaction system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 76%, the dr value was greater than 95:5, and the ee value was 82%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.98(d, J=8.1Hz, 1H), 7.44-7.39(m, 2H), 7.24-7.17(m, 7H), 6.95(s, 1H), 6.89- 6.80(m,4H),6.60(d,J=8.7Hz,2H),5.43(s,2H),5.26(d,J=10.1Hz,1H),4.93(d,J=9.4Hz,1H), 3.83-3.73(m,2H),2.44(s,3H),1.61(s,9H),0.76(t,J＝7.1Hz,3H); ¹³ CNMR(100MHz,CDCl ₃ )δ175.01,170.44,149.23,145.16 ,140.50,139.02,135.80,132.06,130.25,129.54,128.88,127.48,127.34,125.70,125.46,125.18,124.59,121.29,120.25,118.88,116.14,115.42,110.99,110.88,84.64,62.40,61.19,54.20,52.43 , 28.13, 19.62, 13.46; HRMS (ESI) calcd for C ₃₉ H ₃₈ BrN ₃ NaO ₅ [M+Na] ⁺ ＝730.1893, found 730.1897.

Example 18:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of 5-fluoro-N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise at 25°C within 1h Into the reaction system, after the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 77%, the dr value was greater than 95:5, and the ee value was 86%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.99 (dd, J=9.0, 4.6Hz, 1H), 7.41 (d, J=8.1Hz, 1H), 7.26-7.20 (m, 7H), 7.15-7.10( m,2H),7.05-7.00(m,3H),6.98(s,1H),6.64-6.60(m,2H),5.27(d,J＝10.4Hz,1H),5.18(s,2H),4.73 (d, J=10.0Hz, 1H), 3.81-3.73(m, 2H), 1.59(s, 9H), 0.68(t, J=7.1Hz, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ174. 57,170.43,159.72(d, ¹ J _CF ＝244.3Hz),149.17,145.02,137.03,136.69,136.64(d, ⁴ J _CF ＝2.3Hz),132.09,128.94(d, ³ J _CF ＝8.1Hz),128.82, 128.09, 127.83, 126.82, 126.25, 122.34, 121.04, 120.10, 116.76(d, ³ J _CF ＝7.8Hz), 116.38, 116.17(d, ² J _CF ＝22.8Hz), 113.39(d, ² J _CF ＝24.9Hz ), 111.25, 110.35, 110.08, 84.84, 62.26, 61.25, 54.80, 50.24, 28.08, 13.33; HRMS (ESI) calcd for C ₃₈ H ₃₅ FBrN ₃ NaO ₅ [M+Na] ⁺ ＝734.1642, found 734.1660.

Example 19:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of 5-methyl-N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzyl indole (0.33mmol, 1.1eq) in 1.5ml) was dropped at 25°C within 1h Added to the reaction system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 87%, the dr value was greater than 95:5, and the ee value was 96%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.85(d, J=8.2Hz, 1H), 7.30-7.18(m, 9H), 7.10(t, J=7.5Hz, 1H), 7.03-6.97(m, 4H), 6.61(d, J=8.8Hz, 2H), 5.22(d, J=10.2Hz, 1H), 5.18(s, 2H), 4.96(d, J=9.3Hz, 1H), 3.79-3.73( m,2H),2.34(s,3H),1.60(s,9H),0.72(t,J=7.1Hz,3H); ¹³ C NMR(101MHz,CDCl ₃ )δ175.21,170.37,149.24,145.16,138.12, 136.92,136.78,134.15,132.04,130.04,128.77,128.08,127.74,127.14,126.87,126.41,126.13,122.10,120.95,119.90,116.04,115.15,111.15,110.77,109.92,84.45,62.44,61.07,54.15,50.20, 28.11, 21.21, 13.36; HRMS (ESI) calcd for C ₃₉ H ₃₈ BrN ₃ NaO ₅ [M+Na] ⁺ = 730.1893, found 730.1929.

Example 20

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of 6-fluoro-N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise at 25°C within 1h Into the reaction system, after the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 87%, the dr value was greater than 95:5, and the ee value was 91%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.79 (dd, J=10.2, 2.4Hz, 1H), 7.47-7.42(m, 2H), 7.27-7.20(m, 6H), 7.15-7.11(m, 1H ),7.06-7.01(m,3H),6.96(s,1H),6.92(td,J＝8.6,2.5Hz,1H),6.64-6.60(m,2H),5.28(d,J＝10.5Hz, 1H), 5.18(s, 2H), 4.65(d, J=10.1Hz, 1H), 3.79-3.72(m, 2H), 1.59(s, 9H), 0.67(t, J=7.1Hz, 3H); ¹³ C NMR (100MHz, CDCl ₃ ) δ174.68, 170.60, 163.27 (d, ¹ J _CF ＝246.4Hz), 148.94, 145.05, 141.90 (d, ³ J _CF ＝12.5Hz), 137.03, 136.75, 132.08, 128.80, 128. ,127.81,127.00(d, ³ J _CF ＝9.5Hz),126.80,126.33,122.42(d, ⁴ J _CF ＝2.8Hz),122.30,121.20,120.04,116.45,111.16(d, ² J _CF ＝23.0Hz) ,110.64,110.02,104.22(d, ² J _CF ＝29.6Hz),85.11,62.33,61.19,54.43,50.21,28.04,13.32; HRMS(ESI) calcd for C ₃₈ H ₃₅ FBrN ₃ NaO ₅ [M+Na] ⁺ ＝734.1642, found 734.1636.

Example 21:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of 6-chloro-N-tert-butoxycarbonyldiazoisatin (0.3mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise at 25°C within 1h Into the reaction system, after the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 78%, the dr value was greater than 95:5, and the ee value was 82%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.08(d, J=1.9Hz, 1H), 7.49-7.42(m, 2H), 7.27-7.20(m, 7H), 7.13(t, J=7.3Hz, 1H),7.07-7.00(m,3H),6.94(s,1H),6.62(d,J=8.8Hz,2H),5.30(d,J=10.6Hz,1H),5.17(s,2H), 4.60(d, J=10.0Hz, 1H), 3.78-3.73(m, 2H), 1.59(s, 9H), 0.66(t, J=7.1Hz, 3H); ¹³ C NMR(100MHz, CDCl ₃ ) δ174 .38,170.58,148.98,145.05,141.63,137.06,136.74,135.40,132.08,128.81,128.19,127.83,126.80,126.76,126.30,125.36,124.54,122.35,121.27,120.09,116.51,116.18,111.36,110.33,110.05,85.15 , 62.22, 61.23, 54.63, 50.21, 28.04, 13.30; HRMS (ESI) calcd for C ₃₈ H ₃₅ ClBrN ₃ NaO ₅ [M+Na] ⁺ ＝750.1346, found 750.1332.

Example 22:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-tert-butoxycarbonyldiazoisatin (0.30mmol, 1.0eq) and N-methylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction system within 1h at 25°C , After the dropwise addition, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 73%, the dr value was greater than 95:5, and the ee value was 70%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.98(d, J=8.2Hz, 1H), 7.48(d, J=7.5Hz, 1H), 7.45-7.41(m, 1H), 7.35(d, J= 8.1Hz,1H),7.28-7.14(m,5H),7.02-6.99(m,1H),6.94(s,1H),6.67-6.64(m,2H),5.30(d,J=10.5,1H) ,4.86(d,J=10.2Hz,1H),3.83-3.72(m,2H),3.65(s,3H),1.59(s,9H),0.70(t,J=7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ174.96,170.52,149.19,145.17,140.54,137.40,132.04,129.53,128.87,127.25,126.15,125.77,124.49,121.96,121.03,119.68,116.34,115.38,111.00,110.21,109.41,84.59 , 62.33, 61.06, 54.37, 32.90, 28.09, 13.33; HRMS (ESI) calcd for C ₄₀ H ₃₄ BrN ₃ NaO ₃ [M+Na] ⁺ ＝706.1681, found 706.1689.

Example 23:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-benzyldiazoisatin (0.30mmol, 1.0eq) and N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction system within 1h at 25°C, dropwise After the addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 83%, the dr value was greater than 95:5, and the ee value was 87%.

¹ H NMR (400MHz, CDCl ₃ )δ7.48(d, J=7.1Hz, 2H), 7.29-7.16(m, 11H), 7.12-6.95(m, 6H), 6.80(d, J=7.8Hz, 1H), 6.63(d, J=8.8Hz, 2H), 5.40(d, J=10.3Hz, 1H), 5.19(s, 2H), 5.03(d, J=15.6Hz, 1H), 4.89-4.81( m,2H),3.78-3.71(m,2H),0.63(t,J=7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ176.94,171.11,145.38,143.72,137.13,137.06,135.49,132.05 ,129.22,128.75,128.70,128.04,128.01,127.69,127.61,127.58,126.74,126.53,126.28,122.59,122.13,121.50,119.74,116.08,110.84,110.74,109.92,109.59,61.58,60.95,54.38,50.14,44.29 , 13.37; HRMS (ESI) calcd for C ₃₂ H ₃₂ BrN ₃ NaO ₅ [M+Na] ⁺ ＝640.1423, found 640.1413.

Example 24:

P-bromoaniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-benzyldiazoisatin (0.30mmol, 1.0eq) and 6-bromo-N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction at 25°C within 1h In the system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 90%, the dr value was greater than 95:5, and the ee value was 94%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.45(d, J=7.4Hz, 1H), 7.39-7.36(m, 2H), 7.29-7.25(m, 8H), 7.22-7.16(m, 3H), 7.10-7.06(m, 2H), 7.02-7.00(m, 3H), 6.81(d, J=7.8Hz, 1H), 6.62(d, J=8.7Hz, 2H), 5.35(d, J=10.5Hz ,1H),5.15(s,2H),5.02(d,J=15.6Hz,1H),4.81(d,J=15.6Hz,1H),4.75(d,J=9.8Hz,1H),3.80-3.73 (m,2H),0.65(t,J=7.1Hz,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ176.72,170.96,145.23,143.70,137.97,136.43,135.34,132.08,129.42,128.89,128.74,128.62 ,127.93,127.69,127.53,126.65,126.18,125.41,123.07,122.95,122.66,116.17,115.96,112.82,111.29,110.97,109.72,61.57,61.03,54.34,50.17,44.28,13.44；HRMS(ESI)calcd forC ₄₀ H ₃₄ BrN ₃ NaO ₃ [M+Na] ⁺ ＝706.1681, found 706.1688.

Example 25:

Aniline (0.33mmol, 1.1eq), ethyl glyoxylate (0.36mmol, 1.2eq), Molecular sieves (300mg), rhodium acetate (0.006mmol) and triphenylsilyl-substituted chiral phosphoric acid catalyst (0.015mmol) were dissolved in xylene (1.5ml) at 25°C; then, dissolved in xylene ( A mixture of N-benzyldiazoisatin (0.30mmol, 1.0eq) and 5-bromo-N-benzylindole (0.33mmol, 1.1eq) in 1.5ml) was added dropwise to the reaction at 25°C within 1h In the system, after the dropwise addition was completed, the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:30～1:10) to obtain a pure product. The yield was 87%, the dr value was greater than 95:5, and the ee value was 95%.

¹ H NMR (400MHz, CDCl ₃ ) δ7.69(s, 1H), 7.49(d, J=7.3Hz, 1H), 7.30-7.24(m, 6H), 7.21-7.17(m, 6H), 7.12- 7.08(m,2H),7.05-6.99(m,3H),6.80-6.76(m,4H),5.42(d,J=10.7Hz,1H),5.17(s,2H),5.04(d,J= 15.8Hz, 1H), 4.82(d, J=15.8Hz, 1H), 4.67(d, J=10.0Hz, 1H), 3.79-3.71(m, 2H), 0.64(t, J=7.1Hz, 3H) ； ¹³ C NMR(100MHz,CDCl ₃ )δ176.82,171.34,146.17,143.87,136.68,135.74,135.39,129.45,129.38,129.33,128.82,128.80,128.31,127.83,127.64,127.53,127.30,126.56,126.28,125.07, _{124.34,122.60,119.19,114.73,113.28,111.36,110.73,109.74,61.67,60.85,54.53,50.37,44.30,13.37} ^; _{_ _ _ _} =784.0786, found 784.0790.

Taking the 3,3-disubstituted oxindole derivative prepared in Example 25 as an example, the absolute configuration of this type of compound was determined by single crystal diffraction. As shown in Figure 1, the test results showed that the stereo configuration of the 3,3-disubstituted oxindole derivative was determined as (2S,3S) by single crystal diffraction.

Application example: PTP1B inhibitory activity test

Screening model:

Name: PTP1B

Alias: PTPN1

English full name: protein tyrosine phosphatase 1B

Chinese full name: protein tyrosine phosphatase PTP1B

Introduction: PTP1B is the first identified protein tyrosine phosphatase (protein tyrosine phosphatase), through the PTP1B knockout mouse experiments show that PTP1B through the dephosphorylation of insulin receptors, and then in the regulation of insulin sensitivity and It plays a very important role in the process of fat metabolism. Therefore, selective and highly active PTP1B inhibitors are of great value in the treatment of diabetes and obesity.

Screening method:

Protocol id: 25

Protocol name: PTP1B activity assay, absorbance

Instrument: VERSAmax (Molecular Devices, USA).

Materials: PTP1B, the laboratory used E. coli expression system to obtain GST fusion protein.

Substrate, pNPP.

Procedure: Enzyme activity is detected in 96-well or 384-well flat-bottomed transparent microplates using light absorbance detection. The free product obtained by the hydrolysis of the substrate pNPP by PTP1B has a strong light absorption at 405nm. The change of light absorption intensity at 405 nm was monitored by a microplate reader, and the initial reaction velocity was calculated. The control compound used in the experiment was oleanolic acid.

Sample treatment: the sample was dissolved in DMSO, stored at low temperature, and the concentration of DMSO in the final system was controlled within the range that did not affect the detection activity.

Data processing and result explanation: The activity of the sample is tested under the condition of a single concentration, such as 20 μg/ml, for the primary screening. For samples that exhibit activity under certain conditions, for example, the inhibition rate %Inhibition is greater than 50, and the dose-dependent relationship of the test activity, that is, the IC ₅₀ /EC ₅₀ value, is obtained by nonlinear fitting of the sample activity to the sample concentration, and the software used for calculation is GraphpadPrism 4, the model used for fitting is Sigmoidaldose-response (variable slope). For most inhibitor screening models, set the bottom and top of the fitting curve to 0 and 100. In general, multiple holes (n≥2) are set for each sample in the test, and the results are represented by standard deviation (Standard Deviation, SD) or standard error (Standard Error, SE). In general, a reported compound is used as a reference for each test. All data are as credible, accurate, and correct as possible within the scope of knowledge in the field. The test results are shown in Table 1 below.

Table 1

Experimental results show that the 3,3-disubstituted oxindole derivatives of the present invention have significant PTP1B inhibitory effects, and are suitable for the preparation of inhibitory drugs for obesity-specific target gene-protein tyrosine phosphatase 1B.

The present invention is further described in detail, and the protection content of the present invention is not limited to the above detection results. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

Claims (6)

1. a chirality 3, the synthetic method of 3-bis-replacement oxoindole derivative, it is characterised in that with diazonium isatin compounds, Benzazole compounds, arylamine and aldehydic acid ester are raw material, with metal Lewis acids as catalyst, with chiral phosphoric acid as co-catalyst, With organic solvent as solvent, withMolecular sieve is additive, reacts, through step four component reaction and get final product under the conditions of 25 DEG C To the chirality 3,3-bis-replacement oxoindole derivative with PTP1B inhibitory activity；The reaction of described synthetic method is as follows:

Wherein:

R₁For alkyl, benzyl；Described alkyl is selected from methyl, ethyl；

R₂For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group；

R₃For hydrogen atom, halogen atom, alkyl, alkoxyl, nitro；Wherein, described alkyl is selected from methyl, ethyl, isopropyl；

Described alkoxyl is methoxyl group, ethyoxyl, tert-butoxy；

R₄For hydrogen atom, halogen atom, alkyl, alkoxyl；Wherein, described alkyl is selected from methyl, ethyl, isopropyl；Described Alkoxyl is methoxyl group, ethyoxyl, tert-butoxy；

Ar is aryl；Its selected from phenyl, p-bromophenyl, rubigan, 3,4-Dichlorobenzene base, 3,5-Dichlorobenzene base, to fluorophenyl, P-methylphenyl；

Wherein, described chiral phosphoric acid is S type, and shown in its structure such as formula (A), wherein, R is that triphenyl is silica-based, 9-phenanthryl, Phenyl, 3,4,5-trifluorophenyls, 3,5-difluorophenyls, 3,5-bis-(trifluoromethyl) phenyl, 3,5-Dichlorobenzene base, 2,4,6-tri-isopropyls Base phenyl, p-methylphenyl, p-methoxyphenyl or 4-xenyl；

Synthetic method the most according to claim 1, it is characterised in that

Described organic solvent is selected from dichloromethane, chloroform, toluene, 1,2-dichloroethanes, dimethylbenzene.

Synthetic method the most according to claim 1, it is characterised in that by arylamine, aldehydic acid ester, metal Lewis acids catalysis Agent and chiral phosphoric acid catalyst are dissolved in organic solvent under the conditions of 25 DEG C；Then the indoles chemical combination being dissolved in organic solvent Thing, the mixture of diazonium isatin compounds are added drop-wise in reaction system at 25 DEG C in 1h, after dropping, remove molten Agent, obtains crude product；It is ethyl acetate by crude product volume ratio: the solution of petroleum ether=1:30～1:10 carries out column chromatography, obtains Chirality 3,3-bis-replacement oxoindole derivative.

Synthetic method the most according to claim 1, it is characterised in that Benzazole compounds: diazonium isatin compounds: Arylamine: aldehydic acid ester: metal Lewis acids catalyst: the mol ratio=1.1:(1.0-1.1 of chiral phosphoric acid): (1.1-1.2): (1.1-1.2): (0.01-0.02):(0.05-0.10)；The addition of molecular sieve is 100mg/mmol diazonium isatin compounds；Described have The addition of machine solvent is 1ml/mmol diazonium isatin compounds.

5. a chirality 3,3-bis-replacement oxoindole derivative, it is characterised in that shown in its structure such as formula (5):

Wherein:

R₁For alkyl, benzyl；Described alkyl is selected from methyl, ethyl；

R₂For benzyl, tertbutyloxycarbonyl, benzyloxycarbonyl group；

R₃For hydrogen atom, halogen atom, alkyl, alkoxyl, nitro；Wherein, described alkyl is selected from methyl, ethyl, isopropyl；

Described alkoxyl is methoxyl group, ethyoxyl, tert-butoxy；

R₄For hydrogen atom, halogen atom, alkyl, alkoxyl；Wherein, described alkyl is selected from methyl, ethyl, isopropyl；Described Alkoxyl is methoxyl group, ethyoxyl, tert-butoxy；

Ar is aryl；Its selected from phenyl, p-bromophenyl, rubigan, 3,4-Dichlorobenzene base, 3,5-Dichlorobenzene base, to fluorophenyl, P-methylphenyl.

6. chirality 3,3-bis-replacement oxoindole derivative as claimed in claim 5 is at preparation obesity specific target protein enzyme-egg Application in the suppression medicine of white tyrosine phosphatase 1B.