Method for asymmetric organic catalytic synthesis of spiro [indole-3, 4 '-pyrrole [3, 4-b] pyridine] derivative

Abstract

The invention provides a method for asymmetric organic catalytic synthesis of spiro [indole-3, 4-b] pyridine. The invention discloses a method for preparing an optically active spiro [indole-3, 4 '-pyrrole [3, 4-b] pyridine] derivative, which comprises the following steps of: mixing substituted isatin with a structure as shown in a formula 2, cyanoacetate with a structure as shown in a formula 3, 3-aminomaleimide with a structure as shown in a formula 4, chiral cinchona alkali and a Takemoto type catalyst in an organic solvent, and reacting to obtain the optically active spiro [indole-3, 4'-pyrrole [3, 4-b] pyridine] derivative with a structure as shown in a formula 5. The invention relates to a 1, 4-b] pyridine] derivative. According to the method, the high-optical-purity spiro [indole-3, 4 '-pyrrole [3, 4-b] pyridine] derivative can be obtained, the maximum enantiomeric excess value of the derivative reaches 99%, the yield is good (74%-91%), and it is determined that the absolute configuration of a target compound is S through an X-single crystal diffraction experiment.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for asymmetric organic catalytic synthesis of spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivatives. Background Art

[0002] Maleimide is a structural unit widely found in various natural alkaloids and bioactive drugs. In addition, maleimide can be converted into many important heterocyclic frameworks, such as succinimide, pyrrolidine and 2-pyrrolidone. Therefore, the synthesis and structural optimization of maleimide derivatives have become the focus of attention.

[0003] 1,4-Dihydropyridine (1,4-DHP) is a special nitrogen heterocyclic structure in medicinal chemistry and a key skeleton structure of calcium channel antagonist drugs. Studies have shown that a pair of chiral 1,4-DHPs often exhibit different pharmacological activities. For example, ( S )-Finerenone and ( S )-Amlodipine showed a higher R -enantiomer has better activity. Therefore, it is of great significance to synthesize optically pure 1,4-DHP to improve its pharmacological effects.

[0004] Optically pure spiro-oxidized indole derivatives containing heterocyclic structures have significant biological activities and are often used as key intermediates for the synthesis of alkaloids and clinical drugs. Based on the biological activities exhibited by the above three structures, an attempt was made to combine the three reactions into one molecule in order to obtain a series of optically active spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivatives. Summary of the invention

[0005] The purpose of the present invention is to provide a method for asymmetric organic catalytic synthesis of spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivatives. The present invention obtains 21 unreported optically active spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivatives for the first time through organic catalytic asymmetric tandem reactions, and obtains single crystals. The absolute configuration of the main product is determined by X-ray single crystal diffraction to be S The reaction conditions are mild, the raw materials are cheap and readily available, the catalyst system does not contain heavy metals, is safe and environmentally friendly, and is suitable for industrial production. The reaction yield is high (79-91%), and the enantioselectivity is as high as 99%, providing an important basis for the synthesis of pharmaceutical intermediates, such as chiral 1,4-dihydropyridine derivatives.

[0006] The present invention provides a method for asymmetric organic catalytic synthesis of spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivatives, comprising the following steps: The substituted isatin of the structure shown in Formula 2, the cyanoacetate of the structure shown in Formula 3, the 3-aminomaleimide of the structure shown in Formula 4, the chiral cinchona alkaloid and the Takemoto type catalyst are mixed in an organic solvent and reacted to obtain an optically active spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative of the structure shown in Formula 5; The chiral cinchona alkali and Takemoto-type catalyst have a structure shown in any one of Formulas 1a to 1g, ; In Formulae 2 to 5, R1 is hydrogen, halogen, methyl, methoxy, nitro or benzyl, R2 is methyl or ethyl, R3 is isobutyl or benzyl, and R4 is hydrogen or halogen.

[0007] Preferably, R1 is hydrogen, chlorine, bromine, methyl, methoxy, nitro or benzyl, and R4 is hydrogen or chlorine.

[0008] Preferably, the molar ratio of substituted isatin, cyanoacetate and 3-aminomaleimide is 1:(0.9-1.1):(0.9-1.1).

[0009] Preferably, the molar ratio of substituted isatin, cyanoacetate and 3-aminomaleimide is 1:1:1.

[0010] Preferably, the molar amount of the chiral cinchona alkaloid and the Takemoto-type catalyst is 5-20% of the molar amount of the substituted isatin.

[0011] Preferably, the molar amount of the chiral cinchona alkaloid and Takemoto-type catalyst is 10% of the molar amount of substituted indigo carmine.

[0012] Preferably, the organic solvent includes one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, ether, acetonitrile and ethyl acetate.

[0013] Preferably, the reaction temperature is 0-30° C., and the reaction time is 18-30 hours.

[0014] Preferably, after the reaction is completed, the product is separated and purified by column chromatography to obtain an optically active spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivative.

[0015] Preferably, the eluent used for the column chromatography separation and purification is n-hexane and ethyl acetate in a volume ratio of 2:1.

[0016] The invention provides a method for synthesizing a spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivative by asymmetric organic catalysis, comprising the following steps: mixing a substituted isatin with a structure shown in formula 2, a cyanoacetate with a structure shown in formula 3, a 3-aminomaleimide with a structure shown in formula 4, a chiral cinchona alkali and a Takemoto-type catalyst in an organic solvent, and reacting the mixture to obtain an optically active spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivative with a structure shown in formula 5; the chiral cinchona alkali and the Takemoto-type catalyst have a structure shown in any one of formulas 1a to 1g, wherein in formulas 2 to 5, R1 is hydrogen, halogen, methyl, methoxy, nitro or benzyl, R2 is methyl or ethyl, R3 is isobutyl or benzyl, and R4 is hydrogen or halogen. The present invention uses a chiral cinchona alkaloid-Takemoto type catalyst to catalyze the asymmetric Knoevenagel / Michael / cyclization tandem reaction of different substituted isatins, cyanoacetates and 3-amino 3-aminomaleimide. High optical purity spiro [indole-3,4'-pyrrole [3,4-b] pyridine] derivatives are obtained, and the enantiomeric excess value is up to 99%, and the yield is good (74%-91%). The absolute configuration of the target compound is determined by X-ray single crystal diffraction experiment. S .

[0017] Compared with the prior art, the present invention has the following advantages: 1. At present, there is no report on the asymmetric Knoevenagel / Michael / cyclization tandem reaction of different substituted isatins, cyanoacetates and 3-aminomaleimide.

[0018] 2. The reaction has high enantioselectivity, good yield, complete reaction, no by-products detected by H-NMR and C-NMR, and can obtain highly enantiomeric optically pure compounds.

[0019] 3. The method provided by the present invention has a wide range of substrate universality, and the spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivatives generated by the reaction are a class of potential biologically active molecules.

[0020] 4. Easy operation, mild reaction conditions and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0022] Figure 1This is the H NMR spectrum of compound 5aaa prepared in Example 18 of the present invention; Figure 2 This is the NMR carbon spectrum of compound 5aaa prepared in Example 18 of the present invention; Figure 3 This is a high-resolution mass spectrum of compound 5aaa prepared in Example 18 of the present invention; Figure 4 HPLC spectrum of compound 5aaa prepared in Example 18 of the present invention (racemic product); Figure 5 HPLC spectrum of compound 5aaa prepared in Example 18 of the present invention (S configuration); Figure 6 This is the H NMR spectrum of compound 5gaa prepared in Example 26 of the present invention; Figure 7 This is the NMR carbon spectrum of compound 5gaa prepared in Example 26 of the present invention; Figure 8 This is a high-resolution mass spectrum of the compound 5gaa prepared in Example 26 of the present invention; Fig. 9 HPLC spectrum of compound 5gaa prepared in Example 26 of the present invention (racemic product); Fig.10 This is the HPLC spectrum of compound 5gaa prepared in Example 26 of the present invention (S configuration); Fig.11 This is the X-ray single crystal diffraction test result of compound 5gaa prepared in Example 26 of the present invention. DETAILED DESCRIPTION

[0023] The present invention provides a method for asymmetric organic catalytic synthesis of spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivatives, comprising the following steps: The substituted isatin of the structure shown in Formula 2, the cyanoacetate of the structure shown in Formula 3, the 3-aminomaleimide of the structure shown in Formula 4, the chiral cinchona alkaloid and the Takemoto type catalyst are mixed in an organic solvent and reacted to obtain an optically active spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative of the structure shown in Formula 5; The chiral cinchona alkali and Takemoto-type catalyst have a structure shown in any one of Formulas 1a to 1g, ; In Formulae 2 to 5, R1 is hydrogen, halogen, methyl, methoxy, nitro or benzyl, R2 is methyl or ethyl, R3 is isobutyl or benzyl, and R4 is hydrogen or halogen.

[0024] In the present invention, the molar ratio of the substituted isatin, cyanoacetate and 3-aminomaleimide is preferably 1: (0.9-1.1): (0.9-1.1), more preferably 1:1:1; the molar amount of the chiral cinchona alkaloid and the Takemoto-type catalyst is preferably 5-20% of the molar amount of the substituted isatin, more preferably 10-15%, such as 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, preferably a range value with any of the above values ​​as the upper or lower limit.

[0025] In the present invention, the organic solvent is preferably one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, diethyl ether, acetonitrile and ethyl acetate.

[0026] In the present invention, the reaction temperature is preferably 0-30°C, more preferably 0-25°C, such as 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, preferably a range value with any of the above values ​​as the upper or lower limit; the reaction time is preferably 18-30 hours, more preferably 20-28 hours, and most preferably 24-26 hours.

[0027] After the reaction is completed, the present invention preferably separates and purifies the obtained reaction product by column chromatography to obtain a high optical purity spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivative.

[0028] In the present invention, n-hexane and ethyl acetate in a volume ratio of 2:1 are preferably used as the eluent for column chromatography separation and purification.

[0029] The chiral cinchona alkaloids and Takemoto-type catalysts used in the present invention can catalyze the asymmetric Knoevenagel / Michael / cyclization tandem reaction of substituted isatin, cyanoacetate and 3-aminomaleimide to obtain optically active spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivatives, and have the advantages of high reaction yield and high enantioselectivity.

[0030] To further illustrate the present invention, a method for asymmetric organic catalytic synthesis of spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivatives provided by the present invention is described in detail below in conjunction with examples, but it should not be construed as limiting the scope of protection of the present invention.

[0031] Example 1

[0032] 0.10 mmol 5-Cl indigo carmine, 0.10 mmol ethyl cyanoacetate, 0.10 mmol 3-aminomaleimide and 10 mol% chiral cinchona alkaloid-quadrilamide catalyst (1a) were placed in a dry and sealed reaction tube, a magnetic bar was added, 1 mL 1,2-dichloroethane was added by syringe, and the mixture was placed in a magnetic stirrer for reaction at room temperature (rt) for 24 h. The reaction progress was monitored by TLC. After the reaction was completed, the pure product, high optical purity spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative (5a), was separated by silica gel column chromatography, and the eluent was n-hexane:ethyl acetate 2:1.

[0033] The reaction formula and the structure of the chiral cinchona alkaloid-squaramide catalyst are as follows:

[0034] Embodiments 2 to 17 According to the steps in Example 1, a high optical purity spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared. The specific raw materials and parameter changes are shown in Table 1.

[0035] The products of Examples 1 to 17 were measured, and the yields were the isolated yields. The enantiomeric excess (ee) of the products was measured by HPLC chiral OD-H column.

[0036] Catalysts 1a-1g were applied to the asymmetric Knoevenagel / Michael / cyclization tandem reaction of 5-Cl isatin, ethyl cyanoacetate and maleimide. Using 1,2-dichloroethane as solvent, all catalysts can make the reaction proceed smoothly to obtain the target product 5a with a yield of 71%-82% and an enantioselectivity of 15%-60%. Among them, catalyst 1a showed the best catalytic performance, so 1a was determined to be the best catalyst. In order to further improve the enantioselectivity of the reaction, the best catalyst 1a was used to catalyze the reaction under different conditions. It can be seen from Table 1 that the solvent effect has a significant effect on the catalytic performance of the catalyst. Dichloromethane is the best solvent, while the reaction cannot proceed when toluene or ether is used as the solvent. The results of catalyst dosage screening show that 10 mol% equivalent is the best. When the catalyst dosage is reduced to 5 mol%, the enantioselectivity and yield decrease (Example 15 vs. Example 8), and increasing it to 20 mol% does not improve the stereoselectivity of the reaction (Example 16 vs. Example 8). When the temperature was decreased from room temperature to 0°C, the reaction failed to occur (Example 14). Adding 4 Å molecular sieves (4 ÅMS (100 mg)) did not improve the performance of the catalyst (Example 17). Therefore, the optimal reaction conditions were: dichloromethane as solvent, 10 mol% catalyst 1a, and room temperature reaction.

[0037] Embodiment 18

[0038] 0.10 mmol of substituted indigo carmine, 0.10 mmol of cyanoacetate, 0.10 mmol of 3-aminomaleimide (for specific structure, see Table 2) and 10 mol% of catalyst 1a were placed in a dry and sealed reaction tube, a magnetic bar was added, 1 mL of dichloromethane was added with a syringe, and the mixture was placed in a magnetic stirrer to react at room temperature for 24 h. The reaction progress was monitored by TLC. After the reaction was completed, the pure product was separated by silica gel column chromatography, and the eluent was n-hexane: ethyl acetate 2:1. The reaction formula and cat.1a structure are as follows: .

[0039] Compound 5aaa prepared in Example 18 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6',7'-tetrahydrospiro [indoline-3,4' -pyrrolo [3,4- b]-pyridine]-3'- carboxylate(5aaa): 11H NMR (500 MHz, Chloroform- d ) δ 8.07 (d, J J = 10.0 Hz, 1H), 7.64 – 7.58(m, 3H), 7.46 (d, J J = 5.5 Hz, 2H), 7.24 – 7.17 (m, 2H), 7.03 (td, J J = 7.5, 1.0Hz, 1H), 6.89 (d, J J = 7.5 Hz, 1H), 3.89 (dddd, J J = 17.8, 10.7, 7.1, 3.6 Hz, 2H),3.05 (d, J J = 7.0 Hz, 2H), 1.79 (dt, J J = 13.5, 7.0 Hz, 1H), 0.85 (t, J J = 7.0 Hz,3H), 0.74 (dd, J J = 12.0, 6.5 Hz, 6H); as Figure 1 ; 13 13C NMR (125 MHz, Chloroform- d ) δ 180.1, 168.9, 167.5, 163.6, 153.7,140.5, 137.2, 136.5, 134.0, 130.5, 130.2, 129.4, 128.5, 123.7, 122.5, 110.4,109.2, 59.8, 48.6, 45.1, 27.7, 20.0, 20.0, 13.2; as Figure 2 ; HRMS (ESI): calculated for C 27 H 27 N4O5[M+H] + : 487.1976, found 487.1976; as Figure 3 ; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R R = 22.3 min (minor), 26.2 min (major), as Figure 4~Figure 5.

[0040] Embodiment 19

[0041] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0042] The compound 5baa prepared in Example 19 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-5-chloro-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5baa): 1 H NMR (500 MHz, Chloroform- d ) δ 8.35 (d, J = 19.2 Hz, 1H), 7.69 – 7.57(m, 3H), 7.55 – 7.39 (m, 2H), 7.20 (ddd, J = 8.0, 2.0, 0.5 Hz, 1H), 7.16 (d, J =2.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 3.91 (qd, J = 7.0, 3.0 Hz, 2H), 3.07 (dd, J = 7.0, 1.0 Hz, 2H), 1.80 (dt, J = 13.5, 7.0 Hz, 1H), 0.89 (t, J = 7.0 Hz, 3H),0.83 – 0.63 (m, 6H); 13 C NMR (125 MHz, Chloroform- d) δ 179.9, 168.6, 167.5, 163.3, 153.8,139.3, 138.0, 137.4, 133.7, 130.6, 130.3, 129.3, 128.4, 127.7, 124.2, 110.3,109.6, 59.9, 48.8, 45.2, 27.7, 20.0, 20.0, 13.2; HRMS (ESI): calculated for C 27 H 25 ClN4NaO5[M+Na] + : 543.1406, found543.1410; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 17.6 min (minor), 20.4 min (major).

[0043] Embodiment 20

[0044] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0045] The compound 5caa prepared in Example 20 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-5-methyl-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5caa): 1 H NMR (500 MHz, Chloroform- d ) δ 8.26 (s, 1H), 7.67 – 7.55 (m, 3H), 7.47 (dd, J = 6.5, 3.0 Hz, 2H), 7.01 (dd,J = 8.0, 2.0 Hz, 1H), 6.97 (d, J = 2.0Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.89 (q, J = 7.0 Hz, 2H), 3.05 (dd, J = 7.0, 1.5Hz, 2H), 2.32 (s, 3H), 1.80 (dq, J = 13.5, 7.0 Hz, 1H), 0.87 (t, J = 7.0 Hz, 3H),0.75 (dd, J = 10.0, 6.5 Hz, 6H); 13 C NMR (125 MHz, Chloroform- d ) δ 180.3, 169.1, 167.6, 163.7, 153.7,138.3, 137.2, 136.6, 134.1, 131.9, 130.5, 130.3, 129.4, 128.8, 124.5, 110.6,109.0, 59.8, 48.7, 45.2, 27.8, 21.2, 20.1, 20.0, 13.2, HRMS (ESI): calculated for C 28 H 28 N4NaO5 [M+Na] + : 523.1952, found523.1958; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10,0.7 mL / min, λ= 254nm), t R = 18.9 min (minor), 22.1 min (major).

[0046] Embodiment 21

[0047] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0048] The compound 5daa prepared in Example 21 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-5-methoxy-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5daa): 1 H NMR (500 MHz, Chloroform- d ) δ 8.60 (s, 1H), 7.72 – 7.55 (m, 3H), 7.44 (dd, J = 6.5, 3.0 Hz, 2H), 6.80 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H),6.73 (dd, J = 8.5, 2.5 Hz, 1H), 3.89 (q, J = 7.0 Hz, 2H), 3.79 (s, 3H), 3.05 (d, J = 7.0 Hz, 2H), 1.79 (hept, J = 7.0 Hz, 1H), 0.87 (t, J = 7.0 Hz, 3H), 0.74 (dd, J =9.0, 6.5 Hz, 6H); 13 C NMR (125 MHz, Chloroform- d ) δ 180.2, 168.9, 167.5, 163.5, 155.8,153.6, 137.8, 137.2, 134.4, 133.9, 130.4, 130.2, 129.3, 112.2, 111.4, 110.3,109.6, 59.8, 55.7, 49.0, 45.1, 27.6, 20.0, 19.9, 13.1; HRMS (ESI): calculated for C 28 H28 N4NaO6[M+Na] + : 539.1901, found539.1906; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 25.6 min (minor), 29.8 min (major).

[0049] Embodiment 22

[0050] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0051] The compound 5eaa prepared in Example 22 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-5-nitro-2, 5', 7'-trioxo-1'-phenyl-1',5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5eaa): 1 H NMR (500 MHz, DMSO- d 6) δ 11.12 (s, 1H), 8.23 ​​(d, J = 2.4 Hz, 1H),8.17 (dd, J = 8.6, 2.4 Hz, 1H), 7.58 (s, 5H), 6.99 (d, J = 8.6 Hz, 1H), 3.71 (qd, J = 7.1, 5.4 Hz, 2H), 2.93 (dd, J = 7.2, 1.7 Hz, 2H), 1.62 (hept, J = 6.8 Hz, 1H),0.74 (t, J = 7.1 Hz, 3H), 0.65 (dd, J= 9.9, 6.7 Hz, 6H); 13 C NMR (126 MHz, DMSO- d 6) δ 180.4, 168.1, 167.5, 163.0, 154.6, 149.1,142.3, 138.1, 137.8, 134.2, 130.0, 129.9, 129.8, 125.7, 119.7, 108.8, 108.0,76.4, 59.1, 48.2, 44.4, 27.5, 19.9, 13.2; HRMS (ESI): calculated for C 27 H 24 N5NaO7 [M+Na] + : 553.1568, found553.1562; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 24.4 min (minor), 29.9 min (major).

[0052] Embodiment 23

[0053] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0054] The compound 5eab prepared in Example 23 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-ethyl-2'-amino-1'-(4-chlorophenyl)-6'-isobutyl-5-nitro-2,5',7'-trioxo-1',5',6',7'-tetrahydrospiro [indoline-3,4'-pyrrolo[3,4-b]pyridine]-3'-carboxylate (5faa): 1 H NMR (500 MHz, DMSO- d 6) δ 11.12 (s, 1H), 8.25 (d,J = 2.4 Hz, 1H),8.16 (dd, J = 8.6, 2.4 Hz, 1H), 7.63 (d, J = 7.6 Hz, 4H), 6.99 (d, J = 8.6 Hz, 1H), 3.78 – 3.64 (m, 2H), 2.94 (dd, J = 7.1, 2.0 Hz, 2H), 1.63 (hept, J = 6.8 Hz, 1H),0.74 (t, J = 7.0 Hz, 3H), 0.65 (dd, J = 10.2, 6.7 Hz, 6H); 13 C NMR (126 MHz, DMSO- d 6) δ 180.3, 168.2, 167.4, 163.1, 154.6, 149.1,142.4, 138.0, 137.8, 134.8, 133.2, 132.0, 129.9, 125.8, 119.8, 108.8, 108.1,76.4, 59.2, 48.2, 44.5, 27.5, 20.0, 13.2; HRMS (ESI): calculated for C 27 H 24 ClN5NaO7 [M+Na] + : 588.1256, found588.1250; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 25.6 min (minor), 30.7 min (major).

[0055] Embodiment 24

[0056] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0057] The compound 5eba prepared in Example 24 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Methyl-2'-amino-6'-isobutyl-5-nitro-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5eba): 1 H NMR (500 MHz, DMSO- d 6) δ 11.12 (s, 1H), 8.22 (d, J = 2.5 Hz, 1H),8.15 (dd, J = 8.5, 2.5 Hz, 1H), 7.58 (s, 5H), 7.01 (d, J = 8.5 Hz, 1H), 3.23 (s,3H), 2.94 (dd, J = 7.0, 2.0 Hz, 2H), 1.63 (hept, J = 7.0 Hz, 1H), 0.65 (dd, J =10.0, 6.5 Hz, 6H); 13 C NMR (125 MHz, DMSO- d 6) δ 180.2, 168.3, 167.3, 162.8, 154.4, 148.7,142.2, 137.9, 137.5, 134.1, 129.9, 129.8, 129.6, 125.7, 119.6, 108.7, 108.0,76.5, 50.2, 48.1, 44.3, 27.3, 19.8; HRMS (ESI): calculated for C 26 H 23 N5NaO7[M+Na] + : 540.1490, found540.1497; HPLC(Daicel Chiralcel OD-H, n-hexane / i-PrOH =70 / 30, 1.0 mL / min, λ=254 nm), t R = 5.2 min (minor), 6.3 min (major).

[0058] Embodiment 25

[0059] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0060] The compound 5faa prepared in Example 25 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-6-chloro-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5faa): 1 H NMR (500 MHz, Chloroform- d ) δ 8.68 (s, 1H), 7.67 – 7.58 (m, 3H), 7.45 (t, J = 4.5 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 2.0 Hz, 1H),6.93 (d, J = 2.0 Hz, 1H), 3.91 (q, J = 7.0 Hz, 2H), 3.08 (d, J = 7.5 Hz, 2H), 1.81(dq, J = 13.5, 7.0 Hz, 1H), 0.90 (t, J = 7.0 Hz, 3H), 0.76 (dd, J = 10.5, 6.5 Hz,6H); 13 C NMR (126 MHz, Chloroform- d) δ 180.3, 168.7, 167.6, 163.4, 153.7,141.9, 137.3, 134.9, 134.0, 133.8, 130.6, 130.3, 129.3, 124.5, 122.41, 110.0,109.8, 60.0, 48.3, 45.2, 27.7, 20.0, 19.9, 13.2; HRMS (ESI): calculated for C 27 H 25 ClN4NaO5[M+Na] + : 543.1406, found543.1412; HPLC(Daicel Chiralpak AS-H, n-hexane / i -PrOH =80 / 20, 1.0 mL / min, λ=254 nm), t R = 21.6 min (minor), 61.7 min (major).

[0061] Embodiment 26

[0062] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0063] The compound 5gaa prepared in Example 26 was subjected to X-ray single crystal diffraction test. Fig.11 As shown, its absolute configuration is determined as S .

[0064] The compound 5gaa prepared in Example 26 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-6-chloro-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5faa): 1 H NMR (500 MHz, Chloroform- d) δ 8.68 (s, 1H), 7.67 – 7.58 (m, 3H), 7.45 (t, J = 4.5 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 2.0 Hz, 1H),6.93 (d, J = 2.0 Hz, 1H), 3.91 (q, J = 7.0 Hz, 2H), 3.08 (d, J = 7.5 Hz, 2H), 1.81(dq, J = 13.5, 7.0 Hz, 1H), 0.90 (t, J = 7.0 Hz, 3H), 0.76 (dd, J = 10.5, 6.5 Hz,6H); Figure 6 ; 13 C NMR (126 MHz, Chloroform- d ) δ 180.3, 168.7, 167.6, 163.4, 153.7,141.9, 137.3, 134.9, 134.0, 133.8, 130.6, 130.3, 129.3, 124.5, 122.41, 110.0,109.8, 60.0, 48.3, 45.2, 27.7, 20.0, 19.9, 13.2; such as Figure 7 ; HRMS (ESI): calculated for C 27 H 25 ClN4NaO5[M+Na] + : 543.1406, found543.1412; Figure 8 ; HPLC(Daicel Chiralpak AS-H, n-hexane / i -PrOH =80 / 20, 1.0 mL / min, λ=254 nm), t R = 21.6 min (minor), 61.7 min (major), such as Figures 9-10 .

[0065] Embodiment 27

[0066] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0067] The compound 5gab prepared in Example 27 was subjected to NMR detection, mass spectrometry detection and HPLC detection, and the results were as follows: ( S )-ethyl-2'-amino-1'-(4-chlorophenyl)-6'-isobutyl-7-chloro-2,5',7'-trioxo-1',5',6',7'-tetrahydrospiro [indoline-3,4'-pyrrolo[3,4-b]pyridine]-3'-carboxylate (5gab): 1 H NMR (500 MHz, DMSO- d 6) δ 10.77 (s, 1H), 7.67 – 7.55 (m, 4H), 7.27(dt, J = 7.0, 1.0 Hz, 1H), 7.20 (dd, J = 8.0, 1.0 Hz, 1H), 6.92 (dd, J = 8.0, 7.5Hz, 1H), 3.82 – 3.59 (m, 2H), 3.02 – 2.89 (m, 2H), 1.64 (dt, J = 13.5, 7.0 Hz,1H), 0.76 (t, J = 7.0 Hz, 3H), 0.66 (dd, J = 8.5, 6.5 Hz, 6H); 13 C NMR (125 MHz, DMSO- d 6) δ 179.6, 168.3, 167.24, 163.1, 154.1,140.0, 138.6, 137.2, 134.7, 133.3, 131.8, 129.9, 127.9, 122.6, 122.5, 113.2,109.3, 77.2, 59.0, 48.8, 44.4, 27.4, 19.9, 12.9; HRMS (ESI): calculated for C 27 H24 Cl2N4NaO5 [M+Na] + : 577.1016, found577.1021; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 18.4 min (minor), 21.9 min (major).

[0068] Embodiment 28

[0069] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0070] The compound 5gac prepared in Example 28 was subjected to nuclear magnetic resonance detection, mass spectrometry detection and HPLC detection, and the results were as follows: ( S )-ethyl-2'-amino-1'-(3-chlorophenyl)-6'-isobutyl-7-chloro-2,5',7'-trioxo-1',5',6',7'-tetrahydrospiro [indoline-3,4'-pyrrolo[3,4-b]pyridine]-3'-carboxylate (5gac): 1 H NMR (500 MHz, DMSO- d 6) δ 10.78 (s, 1H), 7.79 (s, 1H), 7.64 (ddd, J =8.0, 2.0, 1.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.30(d, J = 7.5Hz, 1H), 7.21 (dd, J = 8.0, 1.0 Hz, 1H), 6.92 (dd, J = 8.0, 7.5 Hz, 1H), 3.78 – 3.63 (m, 2H), 2.96 (d, J= 7.0 Hz, 2H), 1.64 (hept, J = 7.0 Hz, 1H), 0.77(t, J = 7.0 Hz, 3H), 0.66 (dd, J = 8.5, 6.5 Hz, 6H); 13 C NMR (125 MHz, DMSO- d 6) δ 179.7, 168.4, 167.3, 163.1, 154.1, 140.0,138.6, 137.2, 135.7, 133.8, 131.3, 130.2, 130.2, 128.8, 128.0, 122.7, 113.3,109.4, 77.4, 59.1, 48.9, 44.4, 27.5, 19.9, 13.0; HRMS (ESI): calculated for C 27 H 24 Cl2N4NaO5[M+Na] + : 577.1016, found577.1020; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =70 / 30, 1.0 mL / min, λ=254 nm), t R = 4.7 min (minor), 5.6 min (major).

[0071] Embodiment 29

[0072] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0073] The compound 5gad prepared in Example 29 was subjected to NMR detection, mass spectrometry detection and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-benzyl-7-chloro-2, 5', 7'-trioxo-1'-phenyl-1',5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b]-pyridine]-3'-carboxylate (5gad): 1 H NMR (500 MHz, DMSO- d 6) δ 10.79 (s, 1H), 7.58-7.53 (m, 5H), 7.30 –7.18 (m, 5H), 7.12 – 7.03 (m, 2H), 6.93 (dd, J = 8.0, 7.5 Hz, 1H), 4.33 (s,2H), 3.90 – 3.61 (m, 2H), 0.78 (t, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, DMSO- d 6) δ 179.5, 168.2, 166.8, 162.4, 154.1, 139.9,138.5, 137.7, 136.5, 134.2, 129.9, 129.8, 129.6, 128.5, 127.9, 127.6, 127.5,122.6, 122.5, 113.2, 109.2, 77.2, 58.9, 48.8, 40.4, 12.8; HRMS (ESI): calculated for C 30 H 23 ClNaN4O5[M+Na] + : 577.1249, found577.1243; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =80 / 20, 1.0 mL / min, λ=254 nm), t R = 11.6 min (major), 15.3 min (minor).

[0074] Embodiment 30

[0075] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0076] The compound 5gba prepared in Example 30 was subjected to nuclear magnetic resonance detection, mass spectrometry detection and HPLC detection, and the results were as follows: ( S )-Methyl-2'-amino-6'-isobutyl-7-chloro-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5gba): 1 H NMR (500 MHz, DMSO- d 6) δ 10.76 (s, 1H), 7.67 – 7.48 (m, 5H), 7.25(dd, J = 8.0, 1.0 Hz, 1H), 7.20 (dd, J = 8.0, 1.0 Hz, 1H), 6.92 (dd, J = 8.0, 7.5Hz, 1H), 3.23 (s, 3H), 3.03 – 2.81 (m, 2H), 1.64 (hept, J = 7.0 Hz, 1H), 0.65(dd, J = 8.0, 6.5 Hz, 6H); 13 C NMR (125 MHz, DMSO- d 6) δ 179.4, 168.4, 167.1, 162.8, 154.1, 139.6,138.2, 137.2, 134.2, 129.9, 129.8, 129.5, 128.0, 122.6, 122.3, 113.0, 109.3,77.4, 50.1, 48.8, 44.2, 27.3, 19.7; HRMS (ESI): calculated for C 26 H 23 ClN4NaO5[M+Na] + : 529.1249, found529.1255; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 1.0 mL / min, λ=254 nm), t R= 10.8 min (minor), 17.5 min (major).

[0077] Embodiment 31

[0078] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0079] The compound 5haa prepared in Example 31 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-7-bromo-2, 5', 7'-trioxo-1'-phenyl-1',5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5haa): 1 H NMR (500 MHz, Chloroform- d ) δ 7.77 (s, 1H), 7.65 – 7.56 (m, 3H), 7.50 – 7.38 (m, 2H), 7.35 (dd, J = 8.0, 1.0 Hz, 1H), 7.13 (dt, J = 7.5, 1.0 Hz,1H), 6.92 (dd, J = 8.0, 7.5 Hz, 1H), 4.00 – 3.79 (m, 2H), 3.05 (d, J = 7.0 Hz,2H), 1.79 (dt, J = 13.5, 6.5 Hz, 1H), 0.89 (t, J = 7.0 Hz, 3H), 0.74 (dd, J = 12.0,6.5 Hz, 6H); 13 C NMR (125 MHz, Chloroform- d) δ 178.8, 168.6, 167.3, 163.3, 153.7,140.0, 137.6, 137.3, 133.7, 130.9, 130.5, 130.2, 129.2, 123.7, 122.5, 109.6,102.5, 59.5, 49.0, 45.0, 27.3, 20.0, 19.9, 13.1; HRMS (ESI): calculated for C 27 H 25 BrN4NaO5[M+Na] + : 587.0901, found587.0907; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 18.5 min (minor), 22.5 min (major).

[0080] Embodiment 32

[0081] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0082] The compound 5hab prepared in Example 32 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-ethyl-2'-amino-1'-(4-chlorophenyl)-6'-isobutyl-7-bromo-2,5',7'-trioxo-1',5',6',7'-tetrahydrospiro [indoline-3,4'-pyrrolo[3,4-b]pyridine]-3'-carboxylate(5hab): 1 H NMR (500 MHz, DMSO- d 6) δ 10.63 (s, 1H), 7.66 – 7.55 (m, 4H), 7.33(dd, J = 8.0, 1.0 Hz, 1H), 7.29 (dd, J= 7.5, 1.0 Hz, 1H), 6.86 (dd, J = 8.0, 7.5Hz, 1H), 3.78 – 3.62 (m, 2H), 3.03 – 2.89 (m, 2H), 1.63 (hept, J = 7.0 Hz, 1H),0.77 (t, J = 7.0 Hz, 3H), 0.66 (dd, J = 8.0, 6.5 Hz, 6H); 13 C NMR (126 MHz, DMSO- d 6) δ 179.6, 168.4, 167.3, 163.1, 154.2, 141.7,138.6, 137.3, 134.7, 133.3, 131.8, 130.8, 129.9, 123.1, 123.0, 109.4, 101.6,77.4, 59.1, 49.2, 44.4, 27.5, 19.93, 13.0; HRMS (ESI): calculated for C 27 H 24 BrClN4NaO5 [M+Na] + : 621.0511, found621.0515; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 19.3 min (minor), 23.1 min (major).

[0083] Embodiment 33

[0084] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0085] The compound 5had prepared in Example 33 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S)-Ethyl-2'-amino-6'-benzyl-7-bromo-2, 5', 7'-trioxo-1'-phenyl-1',5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5had): 1 H NMR (500 MHz, DMSO- d 6) δ 10.65 (s, 1H), 7.63 – 7.47 (m, 5H), 7.34(dd, J = 8.0, 1.0 Hz, 1H), 7.32 – 7.29 (m, 1H), 7.27 – 7.19 (m, 3H), 7.10 –7.04 (m, 2H), 6.87 (dd, J = 8.0, 7.5 Hz, 1H), 4.32 (s, 2H), 3.85 – 3.62 (m,2H), 0.78 (t, J = 7.0 Hz, 3H); 13 C NMR (125 MHz, DMSO- d 6) δ 179.3, 168.1, 166.6, 162.4, 154.0, 141.5,138.4, 137.6, 136.4, 134.2, 134.1, 130.6, 129.8, 129.7, 129.5, 128.4, 127.5,127.4, 122.9, 122.8, 109.3, 101.4, 77.4, 58.8, 49.0, 40.4, 12.8; HRMS (ESI): calculated for C 30 H 23 BrNaN4O5[M+Na] + : 621.0744, found621.0749; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R= 38.6 min (major), 52.7 min (minor).

[0086] Embodiment 34

[0087] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0088] The compound 5iaa prepared in Example 34 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-7-methyl-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5iaa): 1 H NMR (500 MHz, DMSO- d 6) δ 10.38 (s, 1H), 7.61 – 7.54 (m, 3H), 7.54 –7.48 (m, 2H), 7.05 (ddt, J = 7.5, 1.0, 0.5 Hz, 1H), 6.96 (ddd, J = 7.5, 1.5, 0.5Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H), 3.77 – 3.59 (m, 2H), 2.93 (d, J = 7.0 Hz, 2H),2.21 (s, 3H), 1.63 (hept, J = 7.0 Hz, 1H), 0.73 (t, J = 7.0 Hz, 3H), 0.65 (t, J =7.0 Hz, 6H); 13 C NMR (125 MHz, DMSO- d6) δ 180.2, 168.6, 167.3, 163.2, 154.1, 140.8,137.2, 136.7, 134.6, 130.0, 129.7, 129.3, 121.4, 121.2, 117.8, 110.4, 77.8,59.0, 48.3, 44.4, 27.5, 20.0, 16.4, 12.9; HRMS (ESI): calculated for C 28 H 28 N4NaO5 [M+Na] + : 523.1952, found523.1956; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 20.5 min (minor), 25.2 min (major).

[0089] Embodiment 35

[0090] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0091] The compound 5jaa prepared in Example 35 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-7-nitro-2, 5', 7'-trioxo-1'-phenyl-1',5', 6', 7'-tetrahydrospiro [indoline -3,4' -pyrrolo [3,4- b ]-pyridine]-3'-carboxylate (5jaa): 1 H NMR (500 MHz, Chloroform- d ) δ 9.22 (s, 1H), 8.08 (dd, J = 8.5, 1.0Hz, 1H), 7.66 – 7.61 (m, 3H), 7.51 (dt, J= 7.0, 1.0 Hz, 1H), 7.45 (s, 2H), 7.14 (dd, J = 8.5, 7.0 Hz, 1H), 3.89 (q, J = 7.0 Hz, 2H), 3.05 (d, J = 7.0 Hz, 2H),1.77 (dq, J = 14.0, 7.0 Hz, 1H), 0.83 (t, J = 7.0 Hz, 3H), 0.74 (dd, J = 13.5, 6.5Hz, 6H); 13 C NMR (125 MHz, Chloroform- d ) δ 179.0, 168.3, 167.3, 163.1, 154.0,130.8, 130.4, 129.4, 123.4, 122.1, 77.2, 60.0, 45.2, 27.7, 20.0, 19.9, 13.2; HRMS (ESI): calculated for C 27 H 24 N5NaO7 [M+Na] + : 553.1568, found553.1572; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 22.6 min (minor), 30.0 min (major).

[0092] Embodiment 36

[0093] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0094] The compound 5kaa prepared in Example 36 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S)-Ethyl-2'-amino-6'-isobutyl-1-methyl-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline- 3,4' -pyrrolo [3,4- b]-pyridine]-3'- carboxylate (5kaa): 1 H NMR (500 MHz, Chloroform- d ) δ 7.59 (ddt, J = 4.6, 2.9, 1.8 Hz, 3H),7.45 (dd, J = 6.3, 3.2 Hz, 2H), 7.29 (td, J = 7.7, 1.3 Hz, 1H), 7.20 (dd, J = 7.2,1.2 Hz, 1H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 6.85 (d, J = 7.7 Hz, 1H), 3.80 (qd, J = 7.1, 3.1 Hz, 2H), 3.33 (s, 3H), 3.01 (d, J = 7.3 Hz, 2H), 1.75 (dq, J = 13.7,6.5 Hz, 1H), 0.78 (t, J = 7.1 Hz, 3H), 0.71 (dd, J = 15.0, 6.7 Hz, 6H); 13 C NMR (126 MHz, Chloroform- d ) δ 178.3, 168.8, 167.4, 163.6, 153.8,143.5, 137.1, 135.9, 134.0, 130.4, 130.2, 129.3, 128.5, 123.2, 122.4, 110.7,107.4, 59.4, 48.1, 45.0, 27.6, 26.5, 20.0, 19.9, 13.4; HRMS (ESI): calculated for C 28 H 28N4NaO5 [M+Na] + : 523.1952, found523.1958; HPLC (Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R = 15.6 min (minor), 28.0 min (major).

[0095] Embodiment 37

[0096] A highly optically pure spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative was prepared according to the method in Example 18, except that the substituents R1, R2, R3 and R4 were different from those in Example 18, see Table 2 for details.

[0097] The compound 51a prepared in Example 37 was subjected to NMR, mass spectrometry and HPLC detection, and the results were as follows: ( S )-Ethyl-2'-amino-6'-isobutyl-1-benzyl-2, 5', 7'-trioxo-1'-phenyl-1', 5', 6', 7'-tetrahydrospiro [indoline- 3,4' -pyrrolo [3,4- b]-pyridine]-3'- carboxylate (5laa): 1 H NMR (500 MHz, Chloroform- d ) δ 7.69 – 7.56 (m, 5H), 7.47 (s, 2H),7.38 (t, J = 7.5 Hz, 2H), 7.34 – 7.29 (m, 1H), 7.23 – 7.15 (m, 2H), 7.01 (td, J =7.5, 1.0 Hz, 1H), 6.77 (d, J = 7.5 Hz, 1H), 5.16 (d, J = 15.5 Hz, 1H), 4.86 (d, J =15.5 Hz, 1H), 3.91 (dq, J = 10.5, 7.0 Hz, 1H), 3.52 (dq, J= 11.0, 7.0 Hz, 1H),3.05 (d, J = 7.5 Hz, 2H), 1.80 (hept, J = 7.0 Hz, 1H), 0.75 (dd, J = 11.0, 6.5 Hz,6H), 0.56 (t, J = 7.0 Hz, 3H); 13 C NMR (126 MHz, Chloroform- d ) δ 178.6, 168.9, 167.3, 163.6, 153.9,143.1, 137.3, 136.2, 136.1, 134.1, 130.5, 130.2, 129.4, 128.6, 128.3, 128.0,127.5, 123.3, 122.5, 110.5, 108.5, 59.3, 48.3, 45.0, 45.0, 27.7, 20.0, 13.6; HRMS (ESI): calculated for C 34 H 32 N4NaO5 [M+Na] + : 599.2265, found599.2269; HPLC(Daicel Chiralcel OD-H, n-hexane / i -PrOH =90 / 10, 0.7 mL / min, λ=254 nm), t R =17.0 min (minor), 22.3 min (major).

[0098] The products of Examples 18 to 37 were measured, and the yields were the isolated yields. The enantiomeric excess (ee) of the products was determined by HPLC chiral OD-H and AS-H columns.

[0099] The optimal catalyst system was applied to the asymmetric Knoevenagel / Michael / cyclization tandem reaction of different substituted isatins, ethyl cyanoacetate and maleimide. As shown in Table 2, the screened isatins can give the corresponding products in yields of 53-99% ee (Examples 18-37). The substituents and their positions significantly affect the enantioselectivity. The influence of different N-substituents (R1) was studied, and it was found that the unsubstituted isatin on N gave 92% enantioselectivity (Example 18), while N-methyl isatin or N-benzyl isatin as substrates resulted in significantly lower ee values ​​(Examples 36, 37 vs. Example 18). Next, various substituents (R2) on the benzene ring (C5 and C7) of the isatin were studied. The reaction of isatin with a weak electron-withdrawing group at C5 (5-Cl) gave moderate enantioselectivity (Example 19), while isatin with an electron-donating group at C5 (5-Me or 5-OMe) was beneficial to improve the enantioselectivity (Examples 21, 22). When isatin (5-NO2) with a strong electron-withdrawing group is used as a substrate, the ee value of the product is increased to 97% (Example 22). In addition, the substituent at the C7 position, especially the halogen group, is beneficial to improving the stereoselectivity of the reaction (Examples 26-35). According to the above experimental results, the best enantiomeric excess is obtained when isatin substituted with 5-NO2 and 7-halogen is used as a substrate (Examples 22, 26 and 31).

[0100] Next, the best substrates 5-NO2- and 7-Cl isatin were reacted with 1-isobutyl-3-phenylaminomaleimide and different cyanoacetic acid esters. Methyl cyanoacetate resulted in a significant decrease in enantioselectivity compared to ethyl cyanoacetate (Examples 24 and 30 vs. Examples 22 and 26).

[0101] Finally, the scope of 3-arylmaleimides was expanded. 7-Chloro or 7-bromoisatin and ethyl cyanoacetate were reacted in three components with different 3-arylaminomaleimides. When R4 was changed from isobutyl to benzyl, the enantioselectivity was significantly reduced (Examples 29 and 33 vs. Examples 26 and 31). In addition, when R5 was a 4-Cl- or 3-Cl-substituted phenyl, the reaction proceeded smoothly and excellent results were obtained (90%-99% ee, Examples 23, 27, 28, and 32).

[0102] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for asymmetric organic catalytic synthesis of spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivatives, comprising the following steps: The substituted isatin of the structure shown in Formula 2, the cyanoacetate of the structure shown in Formula 3, the 3-aminomaleimide of the structure shown in Formula 4, the chiral cinchona alkaloid and the Takemoto type catalyst are mixed in an organic solvent and reacted to obtain an optically active spiro[indole-3,4'-pyrrolo[3,4-b]pyridine] derivative of the structure shown in Formula 5; The chiral cinchona alkali and Takemoto-type catalyst have a structure shown in any one of Formulas 1a to 1g, ； In Formulae 2 to 5, R1 is hydrogen, halogen, methyl, methoxy, nitro or benzyl, R2 is methyl or ethyl, R3 is isobutyl or benzyl, and R4 is hydrogen or halogen.

2. The method according to claim 1, characterized in that R1 is hydrogen, chlorine, bromine, methyl, methoxy, nitro or benzyl, and R4 is hydrogen or chlorine.

3. The method according to claim 1, characterized in that The molar ratio of substituted isatin, cyanoacetate and 3-aminomaleimide is 1:(0.9~1.1):(0.9~1.1).

4. The method according to claim 3, characterized in that The molar ratio of substituted isatin, cyanoacetate and 3-aminomaleimide is 1:1:

1.

5. The method according to claim 1, characterized in that The molar amount of the chiral cinchona alkaloid and the Takemoto-type catalyst is 5-20% of the molar amount of the substituted indigo carmine.

6. The method according to claim 5, characterized in that The molar amount of the chiral cinchona alkali and Takemoto-type catalyst is 10% of the molar amount of the substituted indigo carmine.

7. The method according to claim 1, characterized in that The organic solvent includes one or more of dichloromethane, chloroform, 1,2-dichloroethane, toluene, ether, acetonitrile and ethyl acetate.

8. The method according to claim 1, characterized in that The reaction temperature is 0-30° C., and the reaction time is 18-30 hours.

9. The method according to claim 1, characterized in that: After the reaction is completed, the product is separated and purified by column chromatography to obtain an optically active spiro[indole-3,4'-pyrrole[3,4-b]pyridine] derivative.

10. The method according to claim 6, characterized in that The eluent used for column chromatography separation and purification is n-hexane and ethyl acetate in a volume ratio of 2:1.

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