A method for alkynylating indole at carbon position four based on activation of c-h bond

Abstract

The application provides a method for alkynylating indole at the fourth carbon position based on C-H bond activation, which comprises the following steps: under the condition of Pd catalyst, ligand, additive and solvent, reacting a reactant shown in formula I with terminal alkyne bromide shown in formula II to obtain an indole C4 alkynylated compound shown in formula III; wherein the structure of the reactant shown in formula I, the terminal alkyne bromide shown in formula II and the indole C4 alkynylated compound shown in formula III is as follows: wherein R1 is any one of an alkyl group and a benzyl group; R2 is any one of a guiding group Ns and a Tf group; R3 is a halogen atom, an alkyl group or an alkoxy group; and R4 is any one of TIPS, TBS, TES, TBDPS or the following structural group: the reaction condition of the method is relatively mild, the yield is relatively high, the reproducibility is good, and the application range is relatively wide.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, including the preparation of pharmaceutical intermediates and related chemical technologies, and specifically relates to a method for alkyneation at the fourth carbon position of indole based on CH bond activation. Background Technology

[0002] Indole heteroaryl scaffolds have always been among the most unique heterocycles due to their prevalence in a wide range of marketed drugs, bioactive compounds, and functional molecules. The development of selective functionalization methods has become an important research direction, with transition metal-catalyzed CH bond activation recently considered an attractive late-stage functionalization synthetic tool. The reaction core essentially provides six unique reaction sites for catalysis. Among these, the selective functionalization of benzene fragments at the highly reactive C2- and C3- positions remains a challenge. To address this issue, various catalytic schemes, including alkylation, olefination, aromatication, amination, and borylation, have been developed over the past decade with the aid of appropriate directing groups. [C. Sambiagio, D.] R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T. Wiesinger, MF Zia, J. Wencel-Delord, T. Besset, BUW Maes, M. Schngrch, Chem. Soc. Rev. 2018, 47, 6603.], but research on alkynylation is limited. In 2019, Masahiro Miura et al. developed a catalytic scheme for direct phenylation using TIPS-EBX as the alkynylating agent. [Chandrababu Naidu Kona, Yuji Nishii,*and Masahiro Miura*, Angew. Chem. Int. Ed. 2019, 58, 9856–9860], and specific compounds can be synthesized from the intermediates synthesized after alkynylation.

[0003] In 2013, Jia Yanxing's group reported the direct C4 alkenylation of tryptophan via Pd-catalyzed CH bond activation during the synthesis of syringic acid, mimicking the C4 alkenylation of L-tryptophan catalyzed by natural allyltransferases [Liu,Q.;Li,Q.;Ma,Y.;Jia,Y. Direct Olefination at the C-4 Position of Tryptophan via CH Activation: Application to Biomimetic Synthesis of Clavicipitic Acid. Org. Lett. 2013, 15, 4528-4531.]. Based on this, our aim is to expand the method of Pd-catalyzed alkenylation of indole ring C4 position via CH bond activation to obtain key products for certain pharmaceutical intermediates. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the purpose of this invention is to provide a method for alkynylation of indole at the C4 position based on CH bond activation. Using Ns, Tf, or other directing groups, and various alkynyl bromines as introduction precursors, the product with indole C4 alkynylation is obtained. This invention features relatively mild reaction conditions, high yield, good reproducibility, and wide applicability.

[0005] The objective of this invention is achieved through the following technical solution:

[0006] This invention provides a method for alkynylation at the fourth carbon position of indole based on CH bond activation, the specific route of which is as follows:

[0007]

[0008] Includes the following steps:

[0009] In the presence of a Pd catalyst, ligand, additive, and solvent, the reactant shown in Formula I is reacted with the terminal alkyne bromine shown in Formula II to obtain the indole C4 alkyne compound shown in Formula III.

[0010] The structural formulas of the reactant shown in Formula I, the terminal alkyne bromine shown in Formula II, and the indole C4 alkyne-modified compound shown in Formula III are as follows:

[0011]

[0012] Wherein, R1 is either alkyl or benzyl;

[0013] R2 is either a directing group Ns or a Tf group;

[0014] R3 is a halogen atom, an alkyl group, or an alkoxy group;

[0015] R4 is any one of TIPS, TBS, TES, TBDPS, or the following structural groups:

[0016]

[0017] Preferably, the reactants represented by Formula I can be commercially available, prepared using existing methods, or obtained using the following preparation methods:

[0018] The preparation method of the reactant shown in Formula I includes the following steps: in the presence of a solvent, tryptophan methyl ester hydrochloride is reacted with R2Cl, and then the resulting reactant is reacted with TIPSCl to obtain the reactant shown in Formula I (reaction formula as follows);

[0019]

[0020] Alternatively, the preparation method of the reactant shown in Formula I may include the following steps:

[0021] Tryptophan methyl ester hydrochloride was reacted with TIPSCl to give intermediate product a;

[0022] Intermediate product a was reacted with HBPin to obtain intermediate product b;

[0023] After reacting intermediate b with trifluoroacetic acid, 4-nitrobenzenesulfonyl chloride was added to react and give intermediate c.

[0024] The intermediate product c is reacted with copper acetate or copper halide to obtain the reactant shown in Formula I (as shown in the reaction process below).

[0025]

[0026] Preferably, the Pd catalyst is palladium acetate.

[0027] Preferably, the ligand is a pyridine ligand; the pyridine ligand is selected from at least one of pyridine, methylpyridine, methoxypyridine, pyrazine, fluoropyridine, cyanopyridine, trifluoromethylpyridine, dimethylpyridine, acetylpyridinequinoline, isoquinoline, methyl nicotinate, and methyl isonicotinate.

[0028] More preferably, the pyridine ligand is selected from at least one of pyridine, fluoropyridine, acetylpyridine, cyanopyridine, methyl isonicotinate, methyl nicotinate, and trifluoromethylpyridine.

[0029] Preferably, the additive is a silver salt or a combination of a silver salt and an inorganic base;

[0030] The silver salt is selected from at least one of AgOAc, AgOBz, Ag2O, Ag2CO3, and Ag3PO4;

[0031] The inorganic base is at least one of sodium acetate, lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate, and sodium hydrogen phosphate dodecahydrate.

[0032] The solvent is selected from at least one of toluene, dioxane, xylene, dichloroethane, and tert-amyl alcohol.

[0033] More preferably, the inorganic base is at least one of sodium acetate, lithium acetate, and potassium acetate.

[0034] Preferably, the reaction temperature is 90-120℃ and the reaction time is 12-48h.

[0035] More preferably, the reaction temperature is 100°C and the reaction time is 18 hours. Previous experiments have shown that the highest reaction yield can be obtained at a reaction temperature of 100°C; therefore, this optimal reaction temperature is used in all embodiments of this invention.

[0036] Preferably, the molar ratio of the reactant shown in Formula I, the terminal alkyne bromine shown in Formula II, the Pt catalyst, the ligand, and the additive is 1:3:0.1:0.2:2-4.

[0037] Preferably, after the reaction is completed, the reaction product is further subjected to steps of filtration, removal of organic solvents, and purification.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] 1. The reaction conditions of the method of the present invention are relatively mild, the yield is high, the reproducibility is good, and the application range is wide.

[0040] 2. The method of this invention expands the application of Pd-catalyzed alkynylation at the C4 position of indole. Attached Figure Description

[0041] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0042] Figure 1 The proton NMR spectrum of the product of Example 1;

[0043] Figure 2 The carbon NMR spectrum of the product of Example 1;

[0044] Figure 3 The proton NMR spectrum of the product of Example 2;

[0045] Figure 4 The carbon NMR spectrum of the product of Example 2;

[0046] Figure 5The 1H NMR spectrum of the product of Example 3;

[0047] Figure 6 The carbon NMR spectrum of the product of Example 3;

[0048] Figure 7 The 1H NMR spectrum of the product of Example 4;

[0049] Figure 8 The carbon NMR spectrum of the product of Example 4;

[0050] Figure 9 The proton NMR spectrum of the product of Example 5;

[0051] Figure 10 The carbon NMR spectrum of the product of Example 5;

[0052] Figure 11 The 1H NMR spectrum of the product of Example 6;

[0053] Figure 12 The carbon NMR spectrum of the product of Example 6;

[0054] Figure 13 The proton NMR spectrum of the product of Example 7;

[0055] Figure 14 The carbon NMR spectrum of the product of Example 7;

[0056] Figure 15 The proton NMR spectrum of the product of Example 11;

[0057] Figure 16 The carbon NMR spectrum of the product of Example 11;

[0058] Figure 17 The proton NMR spectrum of the product of Example 12;

[0059] Figure 18 The carbon NMR spectrum of the product of Example 12;

[0060] Figure 19 The proton NMR spectrum of the product of Example 13;

[0061] Figure 20 The carbon NMR spectrum of the product of Example 13;

[0062] Figure 21 The proton NMR spectrum of the product of Example 14;

[0063] Figure 22 The carbon NMR spectrum of the product of Example 14;

[0064] Figure 23 The proton NMR spectrum of the product of Example 15;

[0065] Figure 24 The nuclear magnetic resonance carbon spectrum of the product of Example 15. Detailed Implementation

[0066] The present invention will now be described in detail with reference to specific embodiments. These embodiments will help those skilled in the art to further understand the present invention, but do not limit the invention in any way. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention. These all fall within the scope of protection of the present invention.

[0067] Example 1

[0068] This embodiment provides a method for preparing the compound shown in Formula 3, and the reaction formula is as follows:

[0069]

[0070] The specific preparation steps are as follows:

[0071] 1) Starting with commercially available tryptophan methyl ester hydrochloride (1.0 eq), dichloromethane, N-methylmorpholine (2.25 eq), and NsCl (1.2 eq) were added to a reaction vessel at 0°C. After the addition was complete, the reaction was transferred to room temperature and stirred for another three hours. The reaction was quenched with 1M hydrochloric acid, extracted with dichloromethane:petroleum ether = 1:1, dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. The crude product was a brown solid. This crude product (1.0 eq) was then placed in a reaction vessel and cooled to -78°C. Triisopropylsilyl chloride (TIPSCl (1.2 eq)) and anhydrous tetrahydrofuran were then added, followed by LiHMDS (3.0 eq) under anhydrous and oxygen-free conditions. The second step reaction was carried out for 2-3 hours (the second step reaction must be strictly kept at -78℃, otherwise the reaction will be deteriorated). The reaction was monitored by TLC. After the reaction was completed, it was quenched with saturated ammonium chloride aqueous solution. Then, ethyl acetate was added to separate the layers. The aqueous phase was further extracted with ethyl acetate (twice) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum, and the product was purified by silica gel column chromatography to obtain the substrate shown in Formula 1.

[0072] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) shown in Formula 2 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction mixture was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reactants were then cooled to room temperature, and the reaction product was washed with ethyl acetate and filtered through diatomaceous earth to remove insoluble solids. The filtrate obtained by rotary evaporation of the organic solvent was concentrated under vacuum and purified by silica gel column chromatography (using a system of petroleum ether and ethyl acetate as the developing solvent) to obtain the product shown in Formula 3, with a gram-scale purification yield of 73%.

[0073] The resulting compound of formula 3 is

[0074] Methyl(S)-2-((4-nitrophenyl)sulfonamido)-3-(1-(triisopropylsilyl)-4-((triisopropylsilyl)ethynyl)-1H-indol-3-yl)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 1 ) and carbon spectrum ( Figure 2 )for:

[0075] 1 H NMR (400MHz, CDCl3) δ7.88(d,J=8.8Hz,1H),7.57(d,J=8.8Hz,1H),7.38(d,J=8.4Hz ,1H),7.17(d,J=7.2Hz,1H),7.15(s,1H),7.02(t,J=8.0Hz,1H),5.68(d,J=8.4Hz,1 H),4.35-4.29(m,1H),3.69(s,3H),3.57(dd,J=15.2,4.4Hz,1H),3.48(dd,J=14.8, 10.4Hz,1H),1.68-1.60(m,1H),1.20-1.15(m,20H),1.10(dd,J=7.6,2.8Hz,18zH).

[0076] 13C NMR (125MHz, CDCl3) δ171.9,149.3,145.3,141.3,131.6,129.1,127.6,127.2,123.5,121. 4,114.9,113.6,112.9,107.5,95.3,77.0,57.6,52.6,28.3,18.7,18.0,18.0,12.7,11.4.

[0077] HRMS-ESI m / z calcd for CHNO[M+X] + X; found X

[0078] Example 2

[0079] This embodiment provides a method for preparing the compound shown in Formula 5, and the reaction formula is as follows:

[0080]

[0081] The specific preparation steps are as follows:

[0082] The substrate (1.0 eq) of Formula 1 prepared in Example 1, Pd(OAc)2 (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) of Formula 4 were dissolved in toluene (0.1 M). The test tubes were sealed and placed in a preheated oil bath. The reaction mixture was stirred at 100°C (oil bath) for 18 hours. Note: The tubes were carefully capped and covered with a safety shield. The reaction product was then cooled to room temperature, washed with ethyl acetate, and filtered through diatomaceous earth to remove insoluble solids. The organic solvent was then evaporated to dryness. The resulting filtrate was concentrated under vacuum and purified by silica gel column chromatography (300-400 mesh, using a mixture of petroleum ether and ethyl acetate as the eluent) to give the product of Formula 5, with a gram-scale purification yield of 85%.

[0083] The resulting compound of formula 5 is

[0084] Methyl(S)-3-(4-((tert-butyldiphenylsilyl)ethynyl)-1-(triisopropylsilyl)-1H-indol-3-yl)-2-((4-nitrophenyl)sulfonamido)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 3 ) and carbon spectrum ( Figure 4 )for:

[0085] 1H NMR (400MHz, CDCl3) δ7.93-7.86(m,4H),7.84(d,J=8.8Hz,2H),7.51(d,J=8.4Hz,2H),7.48 -7.43(m,1H),7.43-7.38(m,1H),7.28(d,J=7.2Hz,1H),7.16(s,1H),7.06(t,J=8.0Hz,3H), 5.24(d,J=8.4Hz,1H),4.42-4.36(m,1H),3.66(dd,J=14.8,4.4Hz,1H),3.24(dd,J=15.1,10 .4Hz,0H),3.02(s,1H),1.67(p,J=7.6Hz,1H),1.18(s,9H),1.13(dd,J=7.6Hz,3.2Hz,18H).

[0086] 13 C NMR (101MHz, CDCl3) δ172.0,149.4,145.2,141.5,135.7,135.6,133.4,133.3,132.2,129.7,129.6,129.4,127.9,1 27.9,127.8,127.2,123.6,121.5,115.4,113.3,112.4,109.3,93.1,56.7,52.0,28.7,27.2,19.0,18.1,18.1,12.7.

[0087] HRMS-ESI m / z calcd for CHNO[M+X] + X; found X.

[0088] Example 3

[0089] This embodiment provides a method for preparing the compound shown in Formula 7, and the reaction formula is as follows:

[0090]

[0091] The specific preparation steps are as follows:

[0092] The substrate (1.0 eq) of Formula 1 prepared in Example 1, Pd(OAc)2 (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) of Formula 6 were dissolved in toluene (0.1 M). The test tubes were sealed and placed in a preheated oil bath. The reaction mixture was stirred at 100°C (oil bath) for 18 hours. Note: The tubes were carefully capped and covered with a safety shield. The reaction product was then cooled to room temperature, washed with ethyl acetate, and filtered through diatomaceous earth to remove insoluble solids. The organic solvent was then evaporated to dryness. The resulting filtrate was concentrated under vacuum and purified by silica gel column chromatography (300-400 mesh, using a mixture of petroleum ether and ethyl acetate as the eluent) to give the product of Formula 7, with a gram-scale purification yield of 60%.

[0093] The resulting compound of formula 7 is

[0094] Methyl(S)-3-(4-((tert-butyldimethylsilyl)ethynyl)-1-(triisopropylsilyl)-1H-indol-3-yl)-2-((4-nitrophenyl)sulfonamido)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 5 ) and carbon spectrum ( Figure 6 )for:

[0095] 1 H NMR (400MHz, CDCl3) δ7.82(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),7.37(d,J=8.2Hz,1H),7.15(d,J=7.2Hz,1H),7.09(s,1H),7.02(t,J=8.0,1H),5. 90(d,J=8.4Hz,1H),4.30-4.24(m,1H),3.75(s,3H),3.51-3.39(m,2H),1. 67-1.61(m,3H),1.08(dd,J=7.6,4.8Hz,18H),1.05(s,9H),0.289(s,6H).

[0096] 13 C NMR (100MHz, CDCl3) δ172.1,149.3,145.4,141.4,132.1,129.4,127.5,126.8,123.5,121. 4,115.1,113.3,112.9,106.4,58.1,52.6,28.2,26.2,18.0,18.0,16.9,12.7,-4.8,-4.8.

[0097] HRMS-ESI m / z calcd for CHNO[M+X] + X; found X.

[0098] Example 4

[0099] This embodiment provides a method for preparing the compound shown in Formula 9, and the reaction formula is as follows:

[0100]

[0101] The specific preparation steps are as follows:

[0102] 1) The substrate shown in Formula 8 was prepared according to the method in the references (Feng, Y.; Holte, D.; Zoller, J.; Umemiya, S.; Simke, LR; Baran, PS, J Am Chem Soc 2015, 137(32), 10160-3.).

[0103] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) shown in Formula 2 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction mixture was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction product was then cooled to room temperature, washed with ethyl acetate, and filtered through diatomaceous earth to remove insoluble solids. The organic solvent was then evaporated to dryness. The resulting filtrate was concentrated under vacuum and purified by silica gel column chromatography (300-400 mesh, using a mixture of petroleum ether and ethyl acetate as the eluent) to give the product shown in Formula 9, with a gram-scale purification yield of 75%.

[0104] The resulting compound of formula 9 is

[0105] Benzyl(S)-2-((4-nitrophenyl)sulfonamido)-3-(1-(triisopropylsilyl)-4-((triisopropylsilyl)

[0106] ethynyl)-1H-indol-3-yl)propanoate, its 1H nuclear magnetic resonance spectrum ( Figure 7 ) and carbon spectrum ( Figure 8 )for:

[0107] 1H NMR (400MHz, CDCl3) δ7.82(d,J=8.4Hz,2H),7.55(d,J=8.8Hz,2H),7.39(d,J=8.4Hz,1 H),7.38-7.32(m,3H),7.29-7.26(m,2H),7.19(d,J=7.2Hz,1H),7.17(s,1H),7.02(t,J =8.0,1H),5.71(d,J=8.8Hz,1H),5.09(d,J=2.0Hz,2H),4.39(td,J=10.0,4.4Hz,1H),3 .63-3.51(m,2H),1.68-1.58(m,4H),1.15-1.08(m,19H),1.09(dd,J=7.6,3.6Hz,19H).

[0108] 13 C NMR (100MHz, CDCl3) δ171.3,149.4,145.5,141.4,135.0,131.6,129.4,128.6,128.6,128.3,127.6,1 27.2,123.6,121.4,115.0,113.7,113.0,107.6,95.3,67.5,57.8,28.5,18.8,18.0,18.0,12.7,11.4.

[0109] HRMS-ESI m / z calcd for CHNO[M+X] + X; found X.

[0110] Example 5

[0111] This embodiment provides a method for preparing the compound shown in Formula 11, and the reaction formula is as follows:

[0112]

[0113] The specific preparation steps are as follows:

[0114] 1) The substrate shown in Formula 10 was prepared according to the method in the references (Dai, PF; Ning, XS; Wang, H.; Cui, XC; Liu, J.; Qu, JP; Kang, YB, Angew Chem Int Ed Engl 2019, 58(16), 5392-5395.).

[0115] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) shown in Formula 2 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction mixture was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction product was then cooled to room temperature, washed with ethyl acetate, and filtered through diatomaceous earth to remove insoluble solids. The organic solvent was then evaporated to dryness. The resulting filtrate was concentrated under vacuum and purified by silica gel column chromatography (300-400 mesh, using a mixture of petroleum ether and ethyl acetate as the eluent) to give the product shown in Formula 11, with a gram-scale purification yield of 73%.

[0116] The resulting compound of formula 11 is

[0117] Methyl-(S)-2-((trifluoromethyl)sulfonamido)-3-(1-(triisopropylsilyl)-4-((triisopropylsilyl)ethynyl)-1H-indol-3-yl)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 9 ) and carbon spectrum ( Figure 10 )for:

[0118] 1 H NMR (400MHz, CDCl3) δ7.48(d,J=8.4Hz,1H),7.33(d,J=7.2Hz,2H),7.24(s,1H),7.08(t,J=8.0Hz,1H),6.28(d,J=9.2Hz,1H),4.38(td,J =10.0,4.0Hz,1H),3.86(dd,J=15.2,10.8Hz,1H),3.78(s,3H),3.60(dd,J=15.2,4.0Hz,1H),1.68(p,J=7.6Hz,3H),1.21-1.12(m,39H).

[0119] 13 C NMR (101MHz, CDCl3) δ170.9,141.3,131.3,129.7,127.4,121.4,115.2,113.3,112.6,108.3,95.8,59.7,52.8,28.2,18.7,18.0,18.0,12.8,11.5.

[0120] HRMS-ESI m / z calcd for CHNO[M+X] + X; found X.

[0121] Example 6

[0122] This embodiment provides a method for preparing the compound shown in Formula 13, and the reaction formula is as follows:

[0123]

[0124] The specific preparation steps are as follows:

[0125] 1) Preparation of the compound shown in Formula 12:

[0126] The compound of Formula 14 (1.0 eq) and triisopropylsilyl chloride (TIPSCl) (1.1 eq) were slowly added to dilithium (trimethylsilyl)amide (LiHMDS) (THF 1M) in ultradry THF under a nitrogen atmosphere with stirring. After reacting at -78°C for 2 hours, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution, followed by the addition of ethyl acetate. The organic layer was separated, and the aqueous phase was further extracted twice with EtOAc. The organic phase was dried over anhydrous sodium sulfate. After solvent removal under vacuum, the mixture was purified by silica gel column chromatography to give the compound of Formula 15 (yield 80%).

[0127] Iridium catalyst ([Ir(cod)(OMe)]2) (5 mol%), 1,10-phenanthroline (10 mol%), and B2Pin2 (20.30 g) were placed in an oven-dried vial under an argon atmosphere. After dissolving in hexane, HBPin (25 mol%) was added. Then, a hexane solution containing the compound shown in Formula 15 (0.66 mol / L%) was added to the system. After reacting at 80 °C for 24 hours, the reaction mixture was poured into a separating funnel, diluted with ethyl acetate, and washed under a nitrogen atmosphere. The combined organic phase was dried on anhydrous sodium sulfate, filtered, and the solvent was concentrated under vacuum. Purification was performed by silica gel chromatography. Silica gel chromatography yielded the compounds shown in Formulas 16 and 16' as an indivisible mixture (16:16' = 4.5:1) in a yield of 64%.

[0128] Trifluoroacetic acid (1 mol / L) was added to a 1.0 eq solution of a mixture containing the compounds shown in Formulas 16 and 16' at room temperature. The reaction was stirred at room temperature for 2 hours, then quenched with a saturated aqueous sodium bicarbonate solution, and diluted with DCM. The organic phase was washed twice with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under vacuum. DCM was added to the DCM solution containing the crude product at 0 °C, and after stirring for 15 min, a 0 °C solution of 4-nitrobenzenesulfonyl chloride (NsCl, 1.5 eq) was slowly added. After the addition was complete, the reaction mixture was heated to room temperature and stirred for another 3 hours. The reaction was quenched with a saturated aqueous ammonium chloride solution, and the reaction was extracted three times with DCM. The organic layer was washed three times with brine, dried over anhydrous sodium sulfate, and recrystallized from ethyl acetate to give the purified product 6-boryltryptophan methyl ester of Formula 17, with an overall yield of 43%.

[0129] 6-Boro-2-tryptophan methyl ester (1.0 eq) was dissolved in MeOH, followed by the addition of Cu(OAc)₂ (2.0 eq) and Et₃N (2.0 eq). Oxygen was introduced into the flask at room temperature for 24 hours. The solution was filtered and concentrated under vacuum. Purification by silica gel chromatography (1:20 → 1:4, acetic acid / hexane) yielded the substrate 6-methoxytryptophan methyl ester as shown in Formula 12, in 43% yield.

[0130]

[0131] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) shown in Formula 2 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction mixture was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction product was then cooled to room temperature, washed with ethyl acetate, and filtered through diatomaceous earth to remove insoluble solids. The organic solvent was then evaporated to dryness. The resulting filtrate was concentrated under vacuum and purified by silica gel column chromatography (300-400 mesh, using a mixture of petroleum ether and ethyl acetate as the eluent) to give the product shown in Formula 13, with a gram-scale purification yield of 70%.

[0132] The resulting compound of formula 13 is

[0133] Methyl(S)-3-(6-methoxy-1-(triisopropylsilyl)-4-((triisopropylsilyl)ethynyl)-1H-indol-3-yl)-2-((4-nitrophenyl)sulfonamido)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 11 ) and carbon spectrum ( Figure 12 )for:

[0134] 1 H NMR(400MHz, CDCl3)δ7.92(d,J=8.8Hz,2H),7.60(d,J=8.8Hz,2H),7.03(s,1H), 6.90(d,J=2.0Hz,1H),6.81(d,J=2.0Hz,1H),5.63(d,J=8.4Hz,1H),4.35-4.30(m ,1H),3.81(s,3H),3.67(s,3H),3.53(dd,J=14.8,4.0Hz,1H),3.40(dd,J=15.2, 10.8Hz,1H),1.66-1.60(m,3H),1.19-1.15(m,20H),1.11(d,J=7.6,1.2Hz,19H).

[0135] 13 C NMR (101MHz, CDCl3) δ171.9,155.3,149.4,145.5,142.4,130.3,127.7,124.0,123.6,115 .2,113.8,112.7,107.1,99.9,95.2,57.5,55.7,52.6,28.4,18.7,18.1,18.1,12.7,11.5.

[0136] HRMS-ESI m / z calcd for CHNO[M+X] + X; found X.

[0137] Example 7

[0138] This embodiment provides a method for preparing the compound shown in Formula 18, and the reaction formula is as follows:

[0139]

[0140] The specific preparation steps are as follows:

[0141] 1) The compound of Formula 17 prepared in Example 6 (1.0 eq), copper chloride (3.0 eq), and a mixture of methanol / H2O / MeCN (mixing volume ratio 2:1:1) were mixed and stirred in air at 70°C for 16 hours. The mixture was then cooled to room temperature and diluted with diethyl ether. The bound organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. Purification was performed on silica gel by column chromatography (1:20→1:4, 1:4, ethyl acetate / hexane) to give the substrate of Formula 18 as a green solid (yield 87%).

[0142]

[0143] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) shown in Formula 2 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction mixture was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction product was then cooled to room temperature, washed with ethyl acetate, and filtered through diatomaceous earth to remove insoluble solids. The organic solvent was then evaporated to dryness. The resulting filtrate was concentrated under vacuum and purified by silica gel column chromatography (300-400 mesh, using a mixture of petroleum ether and ethyl acetate as the eluent) to give the product shown in Formula 19, with a gram-scale purification yield of 67%.

[0144] The resulting compound of formula 19 is

[0145] Methyl(S)-3-(6-chloro-1-(triisopropylsilyl)-4-((triisopropylsilyl)ethynyl)-1H-indol-3-yl)-2-((4-nitrophenyl)sulfonamido)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 13 ) and carbon spectrum ( Figure 14 )for:

[0146] 1H NMR (400MHz, CDCl3) δ8.05(d,J=8.8Hz,2H),7.71(d,J=8.8Hz,2H),7.35(d,J=1.6Hz,1H),7.19(s,1H),7.18(d,J=1.6Hz,1H),5.60(d,J=8.8 Hz,1H),4.36(td,J=8.8,5.6Hz,1H),3.60(s,3H),3.54-3.52(m,2H),1.64(p,J=7.6Hz,3H),1.19-1.15(m,21H),1.12(d,J=7.2,1.2Hz,18H).

[0147] 13 C NMR (101MHz, CDCl3) δ171.7,149.6,145.6,141.8,132.0,128.2,127.9,127.0,126.8 ,123.7,114.7,114.7,113.0,105.9,96.4,57.3,52.6,28.5,18.7,18.0,12.7,11.4.

[0148] HRMS-ESI m / z calcd for CHNO[M+X] + X; found X.

[0149] Example 8

[0150] This example compares the yields of the products shown in Formula 3 prepared with different pyridine ligands. The specific preparation steps are the same as in Example 1, only the types of ligands used are different. The results are shown in Table 1 below (other ligand types with yields below 45% are not listed).

[0151] Table 1

[0152]

[0153]

[0154] Example 9

[0155] This example compares the yields of the products shown in Formula 3 prepared by different types of silver salts. The specific preparation steps are the same as in Example 1, only the type of silver salt used is different. The results are shown in Table 2 below. It can be seen that the yield is very low or even zero when silver chloride, AgOTs, and AgTFA are used.

[0156] Table 2

[0157] 1 Silver benzoate 46％ 48％ 2 silver oxide 40％ 50％ 3 Silver carbonate 70％ 0％ 4 Silver phosphate 52％ 38％ 5 silver chloride 15％ 88％ 6 AgTFA - main 7 AgOTs - break down

[0158] Example 10

[0159] This example compares the yields of the products shown in Formula 3 prepared from different types of inorganic bases. The specific preparation steps are the same as in Example 1, only the types of bases used are different. The results are shown in Table 3 below.

[0160] Table 3

[0161] 1 - 74％ 2 Sodium bicarbonate 68％ 3 Sodium carbonate 64％ 4 Sodium hydrogen phosphate 66％ 5 Sodium hydrogen phosphate dodecahydrate 72％ 6 Sodium acetate 76％ 7 Potassium acetate 74％

[0162] Example 11

[0163] This embodiment provides a method for preparing the compound shown in Formula 20, and the reaction formula is as follows:

[0164]

[0165] The specific preparation steps are as follows:

[0166] 1) The preparation method of the substrate shown in Formula 1 is as shown in Example 1.

[0167] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) shown in Formula 19 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give product 20 g. The gram-scale purification yield was 50%.

[0168] The resulting compound 20 is

[0169] Methyl(S)-2-((4-nitrophenyl)sulfonamido)-3-(4-((triethylsilyl)ethynyl)-1-(triisopropyl-silyl)-1H-indol-3-yl)propanoate Its 1H NMR spectrum ( Figure 15 ) and carbon spectrum ( Figure 16 )for:

[0170] 1H NMR (400MHz, CDCl3) δ7.83(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),7.36(d,J=8.4Hz,1H),7.16(d,J=7.2Hz,1H),7.09(s,1H),7.01(t,J=8.0Hz, 1H),5.83(d,J=8.4Hz,1H),4.31-4.25(m,1H),3.74(s,3H),3.53-3.40( m,2H),1.63(p,J=7.6Hz,3H),1.12-1.07(m,27H),0.78(q,J=8.0Hz,4H).

[0171] 13C NMR (100MHz, CDCl3) δ172.2,149.4,145.5,141.5,132.1,129.5,127.6,127.1,123. 6,121.5,115.2,113.6,113.1,106.9,96.6,58.2,52.7,28.4,18.1,12.8,7.7,4.4.

[0172] HRMS-ESI m / z calcd for CHNO[M+X]+X; found X.

[0173] Example 12

[0174] This embodiment provides a method for preparing the compound shown in Formula 22, and the reaction formula is as follows:

[0175]

[0176] The specific preparation steps are as follows:

[0177] 1) The preparation method of the substrate shown in Formula 1 is as shown in Example 1.

[0178] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling starter (3.0 eq) shown in Formula 21 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give product 22. The gram-scale purification yield was 57%.

[0179] The resulting compound 22 is

[0180] Methyl(S)-2-((4-nitrophenyl)sulfonamido)-3-(1-(triisopropylsilyl)-4-(3,3,3-triphenylprop-1-yn-1-yl)-1H-indol-3-yl)propanoate, its 1H NMR spectrum ( Figure 17 ) and carbon spectrum ( Figure 18 )for:

[0181] 1H NMR(400MHz, CDCl3)δ7.85(d,J=8.8Hz,2H),7.50(d,J=8.8Hz,2H),7.42-7.38(m,6H),7 .37-7.33(m,7H),7.31-7.27(m,3H),7.21(d,J=7.2Hz,1H),7.10(s,1H),7.03(t,J=8.0 Hz,1H),4.98(d,J=8.0Hz,1H),4.29-4.23(m,1H),3.51(dd,J=15.2,5.6Hz,1H),3.27(s ,3H),3.10(dd,J=15.2,9.2Hz,1H),1.66(p,J=7.6Hz,2H),1.12(dd,J=7.2,3.6Hz,18H).

[0182] 13C NMR (101MHz, DMSO) δ171.8,149.6,145.4,145.3,141.5,131.2,129.3,128.3,127.9,127.1,12 6.3,123.8,121.7,114.6,114.1,112.4,98.7,85.6,56.7,56.5,52.5,28.8,18.2,18.2,12.9.

[0183] HRMS-ESI m / z calcd for CHNO[M+X]+X; found X.

[0184] Example 13

[0185] This embodiment provides a method for preparing the compound shown in Formula 24, and the reaction formula is as follows:

[0186]

[0187] The specific preparation steps are as follows:

[0188] 1) The preparation method of the substrate shown in Formula 1 is as shown in Example 1.

[0189] 2) Dissolve substrate 1 (1.0 eq), Pd(OAc)2 (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and coupling starter (3.0 eq) shown in Formula 23 in toluene (0.1 M). Seal the test tube and place it in a preheated oil bath. Stir the reaction at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give product 24. The gram-scale purification yield was 58%.

[0190] The resulting compound 24 is

[0191] Methyl(S)-3-(4-((1-((tert-butyldimethylsilyl)oxy)cyclohexyl)ethynyl)-1-(triisopropylsilyl)-1H-indol-3-yl)-2-((4-nitrophenyl)sulfonamido)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 19 ) and carbon spectrum ( Figure 20 )for:

[0192] 1H NMR (400MHz, CDCl3) δ7.91(d,J=8.8Hz,2H),7.58(d,J=8.8Hz,2H),7.39(d,J=8.0Hz,1H),7.13(s,1H),7. 11(d,J=6.8Hz,1H),7.04(t,J=8.0Hz,1H),5.47(d,J=8.4Hz,1H),4.33-4.27(m,1H),3.68(s,3H),3.56(dd ,J=15.2,4.4Hz,1H),3.37(dd,J=14.8,10.4Hz,1H),1.95-1.84(m,4H),1.80-1.71(m,2H),1.66(p,J=7.6 Hz,3H),1.59-1.48(m,3H),1.45-1.35(m,1H),1.11(d,J=7.6Hz,18H),0.93(s,9H),0.24(d,J=1.2Hz,4H).

[0193] 13C NMR (100MHz, CDCl3) δ172.2,149.6,145.4,141.6,131.8,131.7,129.3,127.8,126.0,123.8,121.7,114.7,113 .7,112.5,98.4,83.8,69.3,57.4,52.8,40.7,40.5,28.7,26.1,26.0,25.4,22.3,18.4,18.2,18.1,12.8,-2.6.

[0194] HRMS-ESI m / z calcd for CHNO[M+X]+X; found X.

[0195] Example 14

[0196] This embodiment provides a method for preparing the compound shown in Formula 26, and the reaction formula is as follows:

[0197]

[0198] The specific preparation steps are as follows:

[0199] 1) The preparation method of the substrate shown in Formula 1 is as shown in Example 1.

[0200] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling starter (3.0 eq) shown in Formula 25 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give product 26. The gram-scale purification yield was 57%.

[0201] The resulting compound of formula 26 is

[0202] Methyl(S)-3-(4-((1-((tert-butyldimethylsilyl)oxy)cycloheptyl)ethynyl)-1-(triisopropylsilyl)-1H-indol-3-yl)-2-((4-nitrophenyl)sulfonamido)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 21 ) and carbon spectrum ( Figure 22 )for:

[0203] 1H NMR (400MHz, CDCl3) δ7.92(d,J=8.8Hz,2H),7.59(d,J=8.8Hz,2H),7.38(d,J=8.4Hz,1H),7.13(s, 1H),7.11(d,J=7.2Hz,1H),7.04(t,J=8.0Hz,1H),5.52(d,J=8.0Hz,1H),4.33-4.27(m,1H),3.68(s ,3H),3.55(dd,J=15.2,4.6Hz,1H),3.39(dd,J=14.8,10.4Hz,1H),2.07(q,J=6.0Hz,4H),1.79-1. 70(m,2H),1.69-1.62(m,6H),1.58-1.53(m,3H),1.10(d,J=7.2Hz,18H),0.92(s,9H),0.23(s,6H).

[0204] 13C NMR (100MHz, CDCl3) δ172.1,149.6,145.5,141.6,131.6,129.4,127.8,126.0,123.8,121.7,114.7,113.8, 112.7,99.7,83.1,72.6,57.5,52.7,44.3,44.2,28.7,28.3,26.0,21.9,21.9,18.4,18.2,18.2,12.9,-2.6.

[0205] HRMS-ESI m / z calcd for CHNO[M+X]+X; found X.

[0206] Example 15

[0207] This embodiment provides a method for preparing the compound shown in Formula 28, and the reaction formula is as follows:

[0208]

[0209] The specific preparation steps are as follows:

[0210] 1) The preparation method of the substrate shown in Formula 1 is as shown in Example 1.

[0211] 2) The substrate (1.0 eq), Pd(OAc)₂ (0.1 eq), pyridine (0.2 eq), AgOAc (2.0 eq), LiOAc (2.0 eq), and the coupling agent (3.0 eq) shown in Formula 27 were dissolved in toluene (0.1 M). The test tube was sealed and placed in a preheated oil bath. The reaction was stirred at 100 °C (oil bath) for 18 hours. Note: The tube was carefully capped and covered with a safety shield. The reaction mixture was then cooled to room temperature and filtered through diatomaceous earth. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give product 28. The gram-scale purification yield was 62%.

[0212] The resulting compound 28 is

[0213] Methyl(S)-3-(4-((1-((tert-butyldimethylsilyl)oxy)cyclooctyl)ethynyl)-1-(triisopropylsilyl)-1H-indol-3-yl)-2-((4-nitrophenyl)sulfonamido)propanoate, its hydrogen nuclear magnetic resonance spectrum ( Figure 23 ) and carbon spectrum ( Figure 24 )for:

[0214] 1H NMR (400MHz, CDCl3) δ7.93(d,J=8.8Hz,2H),7.61(d,J=8.8Hz,2H),7.38(d,J=8.0Hz,1H),7.15(s,1H ),7.13(d,J=7.2Hz,1H),7.04(t,J=8.0Hz,1H),5.52(d,J=8.4Hz,1H),4.34-4.28(m,1H),3.67(s,3H) ,3.56(dd,J=15.2,4.4Hz,1H),3.43(dd,J=14.8,10.4Hz,1H),2.13-1.99(m,4H),1.83-1.71(m,2H),1 .69-1.59(m,8H),1.56-1.50(m,3H)1.11(dd,J=7.6,2.0Hz,18H),0.90(s,9H),0.22(d,J=3.2Hz,6H).

[0215] 13C NMR (100MHz, CDCl3) δ172.1,149.6,145.6,141.5,131.4,129.5,127.8,126.1,123.8,121.7,114.7,113.8,112 .8,99.1,83.4,72.8,57.6,52.7,39.1,39.0,28.7,28.2,28.1,26.0,24.5,21.9,21.8,18.3,18.2,12.9,-2.7.

[0216] HRMS-ESI m / z calcd for CHNO[M+X]+X; found X.

[0217] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A preparation method based on CH bond activation and alkyneation at the fourth C4 position of indole, characterized in that, Includes the following steps: In the presence of a Pd catalyst, ligand, additive, and solvent, the reactant shown in Formula I is reacted with the terminal alkyne bromine shown in Formula II to obtain the indole C4 alkyne compound shown in Formula III. The structural formulas of the reactant shown in Formula I, the terminal alkyne bromine shown in Formula II, and the indole C4 alkyne-modified compound shown in Formula III are as follows: I, II, III, Wherein, R1 is either alkyl or benzyl; R2 is either a directing group Ns or a Tf group; R3 is a halogen atom, an alkyl group, or an alkoxy group; R4 is any one of TIPS, TBS, TES, TBDPS, or the following structural groups: ； The ligand is a pyridine ligand; the pyridine ligand is selected from at least one of pyridine, methylpyridine, methoxypyridine, pyrazine, fluoropyridine, cyanopyridine, trifluoromethylpyridine, dimethylpyridine, acetylpyridinequinoline, isoquinoline, methyl nicotinate, and methyl isonicotinate; The Pd catalyst is palladium acetate; The additive is a silver salt or a combination of a silver salt and an inorganic base; The silver salt is selected from at least one of AgOAc, AgOBz, Ag2O, Ag2CO3, and Ag3PO4; The inorganic base is at least one of sodium acetate, lithium acetate, potassium acetate, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate, and sodium hydrogen phosphate dodecahydrate.

2. The preparation method according to claim 1, characterized in that, The preparation method of the reactant shown in Formula I includes the following steps: reacting tryptophan methyl ester hydrochloride with R2Cl in the presence of a solvent, and then reacting the resulting reactant with TIPSCl to obtain the reactant shown in Formula I; or The preparation method of the reactant shown in Formula I includes the following steps: Tryptophan methyl ester with an amino group protected by a Boc group was reacted with TIPSCl to give intermediate product a; Intermediate product a was reacted with HBPin to obtain intermediate product b; After reacting intermediate b with trifluoroacetic acid, 4-nitrobenzenesulfonyl chloride was added to react and give intermediate c. The intermediate product c is reacted with copper acetate or copper halide to obtain the reactant shown in Formula I.

3. The preparation method according to claim 1, characterized in that, The pyridine ligand is selected from at least one of pyridine, fluoropyridine, acetylpyridine, cyanopyridine, methyl isonicotinate, methyl nicotinate, and trifluoromethylpyridine.

4. The preparation method according to claim 1, characterized in that, The solvent is selected from at least one of toluene, dioxane, xylene, dichloroethane, and tert-amyl alcohol.

5. The preparation method according to claim 4, characterized in that, The inorganic base is at least one of sodium acetate, lithium acetate, and potassium acetate.

6. The preparation method according to claim 1, characterized in that, The reaction temperature is 90-120℃, and the reaction time is 12-48h.

7. The preparation method according to claim 1, characterized in that, The molar ratio of the reactant shown in Formula I, the terminal alkyne bromine shown in Formula II, the Pd catalyst, the ligand, and the additive is 1:3:0.1:0.2:2-4.

8. The preparation method according to claim 1, characterized in that, After the reaction is completed, the steps of filtering, removing organic solvents, and purifying the reaction products are also included.

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