WO2023284262A1 - 3,4-fused seven-membered heterocyclic oxindole, synthesis method therefor and application thereof - Google Patents

Abstract

Disclosed is a 3,4-fused seven-membered heterocyclic oxindole, a synthesis method therefor and an application thereof. A structure of a 3,4-fused seven-membered nitrogen heterocyclic oxindole is provided in the present invention. A method for synthesizing same is also provided, comprising the following steps: reacting propargyl alcohol containing an isatin framework with a nucleophile under specific conditions to prepare a 3,4-fused seven-membered nitrogen heterocyclic oxindole. A pharmaceutical composition is provided in the present invention. Also provided in the present invention is an application of a 3,4-fused seven-membered nitrogen heterocyclic oxindole in the preparation of a drug for treating cancer. Provided in the present invention is a method for efficiently synthesizing 3,4-fused seven-membered nitrogen heterocyclic oxindoles having different structures. This is the first time achieving efficient synthesis of bioactive molecules containing both benzazepine and 3,4-fused heterooxidized oxindole structures on the basis of a hydrogen migration strategy.

Description

A 3,4-position condensed heterocyclic seven-membered heterocyclic indoline compound and its synthesis method and application

This application is required to be submitted to the Chinese Patent Office on July 13, 2021. The application number is CN202110788322.7, and the title of the invention is "a biologically active 3,4-position condensed heterocyclic seven-membered heterocyclic oxindole structure and The priority of the Chinese patent application for its synthetic method and application", the entire content of which is incorporated in this application by reference.

technical field

The invention relates to the technical field of pharmaceutical intermediates and chemical synthesis, in particular to a 3,4-position fused seven-membered heterocyclic oxindole compound and its synthesis method and application.

Background technique

Benzazepines are the core skeleton of many drugs. For example, mianserin and mirtazapine are psychotropic drugs with a dual mechanism of action. Compared with tricyclic inhibitors, mianserin has less cardiovascular toxicity and anti Cholinergic side effects are mild, and mirtazapine is one of the eight major antidepressants in the world. Therefore, several methods have been developed in recent years for the efficient construction of benzazepine structures.

For example, in 2019, the team of Professor Li Shuaishuai quickly and efficiently synthesized the benzazepine skeleton by using the hydrogen transfer strategy and using cheap and easy-to-obtain starting materials. The team selected indole and o-aminobenzaldehyde as the starting materials, and used hexafluoroisopropanol as the solvent to achieve dearomatization of the indole ring in one step, and further realized p-toluenesulfonic acid by using aromatization as the driving force. The catalyzed ring expansion reaction driven by aromatization has efficiently synthesized benzazepine compounds containing indole structures, providing a new method for the efficient synthesis of such drugs and analogs (Org.Lett., 2019, 21, 6225-6230).

In addition, the 3,4-position fused indole/oxindole is the core structure of many natural products and drugs, and plays a prominent role in the structure-activity relationship of drugs. However, the synthesis of such structures has always been a difficult point in the field of organic synthesis, and most of them are currently achieved through expensive transition metal catalysis.

For example, in 2013, Professor Zhu Jieping’s research group reported the activation of C(sp ² )-H and C(sp ³ )-H catalyzed by transition metal palladium, and achieved 3,4- Efficient synthesis of oxindole compounds with six-membered heterocycles (Angew. Chem. Int. Ed., 2013, 52, 12385-12389).

In 2018, Professor Xu Tao's research group reported a transition metal rhodium-catalyzed carbon-carbon bond activation reaction based on the strained ring opening process, and a one-step efficient synthesis of 3,4-position and six-membered heterocyclic oxindole compounds (Org. Lett., 2018, 20, 7689-7693).

Most of the reported synthesis of 3,4-position fused oxindole requires transition metal catalysis, and most of the constructed structures are limited to 3,4-position fused six-membered rings.

Contents of the invention

The purpose of the present invention is to address the deficiencies of the prior art, and to provide a 3,4-position condensed seven-membered heterocyclic oxindole compound and its synthesis method and application. The novel 3,4-position fused seven-membered nitrogen-heterocyclic oxindole compound will provide a new model molecule for drug development.

The method for synthesizing the 3,4-position condensed heterocyclic nitrogen-heterocyclic indolene compound in one step efficiently synthesizes the skeleton based on the hydrogen migration process, and the operation is simple, efficient and practical, and the constructed skeleton contains many This kind of functional group is beneficial to the later synthesis application of the skeleton.

Technical scheme of the present invention is realized like this:

The 3,4-position condensed heterocyclic seven-membered nitrogen-heterocyclic indoline compound has a structural formula as shown in formula 1, formula 2 or formula 3:

In formula 1, R is any ^one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl, preferably, when R in formula ¹ is alkyl, the alkane The group is an alkyl group with 1 to 5 carbon atoms;

R ² is any one of an alkyl group and a benzyl group, preferably, when R ² in formula 1 is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms;

^R3 is any one of alkyl, benzyl and aryl, preferably, when ^R3 in formula 1 is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms;

R ⁴ is any one of alkyl, phenyl, thienyl, and substituted phenyl, preferably, when R ⁴ in formula 1 is an alkyl group, the alkyl group is an alkyl group with 1 to 8 carbon atoms;

R is any one of alkyl, deuterated methyl, propargyl, butynyl, benzyl, aryl, hydrogen atom, preferably, when R in ^{formula 1} is an alkyl, the alkyl is an alkyl group with 1 to 10 carbon atoms;

R6 is any one of a methyl group, an ethyl group, a halogen atom, or a hydrogen atom ^;

X is an oxygen atom or a sulfur atom;

Preferably, in formula 1, R ¹ is any one of methyl, ethyl, benzyl, allyl; R ² is any one of methyl, ethyl, propyl; R ³ is methyl, ethyl Any one of base and propyl; R4 is any one of phenyl, ² -thienyl, and cyclopropyl; R5 is ethyl, ^{deuteromethyl} , haloethyl, propargyl, butynyl Any one of base, benzyl, aryl, hydrogen atom; R ⁶ is a hydrogen atom; X is an oxygen atom. Among them, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are the same or different from each other, and each independently represents a substituent. In addition, the carbons of adjacent R ² and R ³ may be linked to each other to form a ring .

In formula 2, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl, preferably, when R ¹ in formula 2 is an alkyl group, the alkane The group is preferably an alkyl group with 1 to 5 carbon atoms; R ² is any one of an alkyl group and a benzyl group, preferably, when R ² in formula 2 is an alkyl group, the alkyl group is preferably an alkyl group with a number of carbon atoms is an alkyl group of 1 to 10; ^R3 is any one of alkyl, benzyl, and aryl, preferably, when ^R3 in formula 2 is an alkyl group, the alkyl group is preferably 1 to 10 carbon atoms Alkyl of 10; R ⁴ is any one of alkyl, halogen, alkoxy, thioether, carboxylate, aryl, aryl ether, preferably, when R ⁴ in formula 2 is an alkyl group, the The alkyl group is preferably an alkyl group with 1 to 8 carbon atoms; preferably, R in the formula ² is a carboxylate group, and the carboxylate group is preferably a benzoate group, furan-2-methanol Any of ester group, phenylpropiolate group, salicylate group, ferrocene carboxylate group, indole acetate group, carboxylate group of naproxen, carboxylate group of ibuprofen One ^; R6 is any one of methyl, ethyl, halogen atom, hydrogen atom; more preferably, in ^{formula 2} , R1 is benzyl; R2 is any one of methyl, ethyl, propyl species; ^R3 is any one of methyl, ethyl, and propyl; R4 is benzoate, furan- ² -carboxylate, phenylpropiolate, salicylate, di Any one of ferrocene carboxylate group, indole acetate group, naproxen carboxylate group, and ibuprofen carboxylate group ^; R6 is a hydrogen atom. Among them, R ¹ , R ² , R ³ , R ⁴ , and R ⁶ are the same or different from each other, and each independently represents a substituent, and carbons of adjacent R ² and R ³ may be connected to each other to form a ring.

In formula 3, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl, preferably, when R ¹ in formula 3 is an alkyl group, the alkane The group is preferably an alkyl group with ¹ to 5 carbon atoms; R2 is any one of an alkyl group and a benzyl group, preferably, when R2 in formula ³ is an alkyl group, the alkyl group is preferably an alkyl group with a number of carbon atoms is an alkyl group of 1 to 10; R ³ is any one of alkyl, benzyl, and aryl, preferably, when R ³ in formula 3 is an alkyl group, the alkyl group is preferably 1 to 10 carbon atoms ¹⁰ 's alkyl group; R6 is any one of methyl group, ethyl group, halogen atom and hydrogen atom. Preferably, in formula 3, R ¹ is any one of benzyl and allyl; R ² is any one of methyl, ethyl, propyl; R ³ is any of methyl, ethyl, propyl One; R ⁶ is a hydrogen atom. Among them, R ¹ , R ² , R ³ , and R ⁶ are the same or different from each other, and each independently represents a substituent, and carbons of adjacent R ² and R ³ may be linked to each other to form a ring.

The compounds involved in the present invention may exist in the form of one or more stereoisomers. Various isomers include tautomers, geometric isomers, enantiomers, diastereomers, and the like. These isomers and mixtures of these isomers are within the protection scope of the present invention.

Based on the same inventive concept, the present invention also provides a synthesis method of the 3,4-position condensed heterocyclic seven-membered nitrogen-heterocyclic indolene compound. The synthesis process route diagram of the present invention is shown in Figure 1, comprising the following steps:

Mix propargyl alcohol containing isatin skeleton and nucleophilic reagent in a solvent evenly, and react under the condition of 25-90°C in the presence of a catalyst to obtain the oxidation of 3,4-position condensed seven-membered nitrogen heterocyclic ring Indole compounds;

Wherein, the structural formula of the propargyl alcohol containing isatin skeleton is as shown in formula 4:

In formula 4, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl and cyclobutylmethyl, preferably, when R ¹ in formula 4 is an alkyl group, the alkane The group is preferably an alkyl group with ¹ to 5 carbon atoms; R2 is any one of an alkyl group and a benzyl group, preferably, when R2 in formula ⁴ is an alkyl group, the alkyl group is preferably an alkyl group with a number of carbon atoms is an alkyl group of 1 to 10; R ³ is any one of alkyl, benzyl and aryl, preferably, when R ³ in formula 4 is an alkyl group, the alkyl group is preferably 1 to 10 carbon atoms 10 alkyl; R ⁴ is any one of alkyl, halogen, alkoxy, thioether, carboxylate, aryl, aryl ether and trimethylsilyl, preferably, R ^{4 in formula 4} When it is a carboxylate group, the carboxylate group is preferably a benzoate group, a furan-2-formate group, a phenylpropiolate group, a salicylate group, a ferrocene carboxylate group, an indole Any one in the carboxylate group of indole acetate group, the carboxylate group of naproxen and the carboxylate group of ibuprofen, preferably, when R in the formula ⁴ is an alkyl group, the said alkyl group is preferably a carbon atom An alkyl group whose number is 1 to ⁸ ; R6 is any one of a methyl group, an ethyl group, a halogen atom and a hydrogen atom. Among them, R ¹ , R ² , R ³ , R ⁴ , and R ⁶ are the same or different from each other, and each independently represents a substituent, and carbons of adjacent R ² and R ³ may be connected to each other to form a ring.

The above reaction conditions can be detected by thin-layer chromatography, and after the reaction is completed, purification is carried out to obtain a purified product of the 3,4-position fused seven-membered nitrogen-heterocyclic oxindole compound.

Above-mentioned reaction process is specifically:

The active molecules of propynyl alcohol generate allene cations under acid catalysis, and then the nucleophiles in the system attack to form allene intermediates, and the electron-deficient allenes trigger intramolecular hydrogen migration under acid catalysis to form zwitterion intermediates, and then pass through The intramolecular cyclization reaction generates a benzo seven-membered nitrogen-heterocyclic structure, and obtains the 3,4-position condensed seven-membered nitrogen-heterocyclic oxide indole compound. The synthetic principle route is as follows:

Preferably, in the synthesis method mentioned above, the reaction is carried out at 60°C.

As mentioned above, the nucleophile is alcohols, thiols or water. Preferably, the nucleophile is alcohol or water. More preferably, the nucleophile is water, because water is pollution-free and cheap, and the yield of the target product is high when water is used as the nucleophile.

According to the above synthesis method, the molar ratio of the isatin-containing propargyl alcohol to the nucleophile is 1:(10-50). Preferably, the molar ratio of the propargyl alcohol containing isatin skeleton to the nucleophile is 1:10.

In the above synthesis method, the solvent is toluene or halogenated hydrocarbon. Preferably, the solvent is toluene or dichloromethane. More preferably, the solvent is dichloromethane.

In the synthesis method described above, the amount of the solvent used is: 10-25 L of solvent is added per mole of propargyl alcohol containing isatin skeleton. Preferably, the amount of the solvent is: 20L of solvent is added per mole of propargyl alcohol containing isatin skeleton.

In the above synthesis method, the catalyst is added before the reaction, and the catalyst is a Bronsted acid or a Lewis acid. Preferably, the catalyst is trifluoromethanesulfonate, diphenyl phosphate or binaphthol phosphate.

According to the above synthesis method, the catalyst is used in an amount of 5-50 mol%. Preferably, the catalyst is used in an amount of 30 mol%.

Based on the same inventive concept, the present invention also provides a pharmaceutical composition, which comprises the above-mentioned 3,4-position fused seven-membered nitrogen-heterocyclic oxindole compound and pharmaceutically acceptable salts thereof, Solvates, hydrates, polycrystals, co-crystals, tautomers, geometric isomers, enantiomers, diastereomers or their mixtures or prodrugs, and pharmaceutically acceptable carriers , diluents, excipients or combinations thereof. In the present invention, the carrier, diluent, and excipient are not particularly limited, and may be carriers, diluents, and excipients suitable for pharmaceutical compositions well known to those skilled in the art.

Based on the same inventive concept, the present invention also provides 3,4-position fused seven-membered nitrogen-heterocyclic oxindole compounds for the preparation and treatment of cancer, atherosclerosis, tuberculosis, cardiovascular disease, epilepsy, and mental diseases. , Parkinson's, Alzheimer's disease drugs.

The beneficial effects of the present invention are:

1. The present invention efficiently synthesizes the 3,4-position condensed seven-membered nitrogen heterocyclic oxide indole skeleton under mild temperature conditions in one step. The technical scheme of the present invention is the 3,4-position condensed seven-membered The oxindole skeleton of the nitrogen heterocycle provides a convenient and concise synthesis method, and for the first time realized the efficient construction of the 3,4-position condensed seven-membered nitrogen heterocycle oxindole skeleton through the hydrogen transfer process.

2. The present invention has developed a method for efficiently synthesizing 3,4-position condensed heterocyclic seven-membered nitrogen-heterocyclic oxindole compounds containing multiple functional groups, and provides structurally diverse 3,4- The compound library of indole oxide skeleton with fused seven-membered nitrogen heterocycle provides a new model molecule for drug development.

3. The method has mild reaction conditions and is suitable for a variety of propynyl alcohol raw materials, and the propynyl alcohol raw materials can be prepared in situ from various terminal alkynes with a wide range of sources. The invention provides an experimental basis for the high-efficiency construction of the 3,4-position fused seven-membered nitrogen-heterocycle oxindole skeleton with good biological activity, and has good practical significance and application value.

Instructions attached

Fig. 1 is a synthesis process roadmap of the present invention.

detailed description

The technical solutions in the embodiments of the present invention will be clearly and completely described below in combination with the contents of the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the technical field of the invention. The terminology used in the description of the present invention is only for the purpose of describing specific embodiments, and is not used to limit the present invention. The term "and/or" used in this specification includes any and all combinations of one or more of the associated listed items.

The experimental methods used in the following examples, if no special instructions, are conventional methods; the reagents, materials, instruments, etc. used in the following examples, if no special instructions, can be obtained from commercial sources; the following examples The reaction vessel used in is a 25mL thick-walled pressure-resistant tube.

Example 1

This example provides a method for synthesizing the 3,4-position fused seven-membered nitrogen-heterocyclic indoline compound, which comprises the following steps:

Take 0.1mmol propargyl alcohol containing isatin skeleton in the reaction tube, add 1mL toluene in turn, add 1mmol nucleophilic reagent, in this example, _H2O is the nucleophilic reagent, and finally add 0.03mmol binaphthol phosphoric acid ester catalyst. The reaction temperature of the control system is 25°C, and the stirring is continued, and the reaction is tracked by spotting samples on a thin-layer chromatographic plate until the reaction of the raw materials is complete. After the reaction was completed, a silica gel column was used for separation and purification, and the purified product was rotary evaporated to obtain the target product Formula 1-1 with a yield of 50%. The reaction formula is as follows:

Example 2

The method of this embodiment is basically the same as that of Example 1, except that the reaction temperature is 40° C., and the yield is 58%.

Example 3

The method of this embodiment is basically the same as that of Example 1, except that the reaction temperature is 60° C., and the yield is 70%.

Example 4

The method of this embodiment is basically the same as that of Example 1, except that the reaction temperature is 80° C., and the yield is 67%.

Example 5

The method of this embodiment is basically the same as that of Example 1, except that the reaction solvent is 1 mL of dichloromethane, the reaction temperature is 60° C., and the yield is 88%.

Example 6

The method of this embodiment is basically the same as that of Example 1, except that the reaction solvent is 2 mL of dichloromethane, the reaction temperature is 60° C., and the yield is 90%.

Example 7

The method of this example is basically the same as that of Example 1, except that 0.03 mmol of scandium trifluoromethanesulfonate is added as a catalyst, the reaction temperature is 60° C., and the yield is 20%.

Example 8

The method of this example is basically the same as that of Example 1, except that 0.03 mmol of diphenyl phosphate is added as a catalyst, the reaction temperature is 60° C., and the yield is 85%.

Example 9

The method of this embodiment is basically the same as that of Example 1, except that 0.01 mmol of binaphthol phosphate catalyst is added, the reaction temperature is 60° C., and the yield is 29%.

Example 10

The method of this embodiment is basically the same as that of Example 1, except that 0.02 mmol of binaphthol phosphate catalyst is added, the reaction temperature is 60° C., and the yield is 58%.

Example 11

The method of this embodiment is basically the same as that of Example 1, except that 0.05 mmol of binaphthol phosphate catalyst is added, the reaction temperature is 60° C., and the yield is 82%.

According to the analysis of the above parallel test results, it can be seen that when the synthesis reaction of the present invention is carried out under the conditions of Example 6, the yield of the target product is the highest.

In the following Examples 12 to 36, the reaction was carried out according to the operation steps of Example 6; 0.1 mmol of propargyl alcohol containing isatin skeleton was put in a reaction tube, 2 mL of dichloromethane was added successively, 1 mmol of nucleophilic reagent was added, and finally Add 0.03 mmol binaphthol phosphate catalyst. The reaction temperature of the control system is 60°C, and the stirring is continued, and the reaction is tracked by spotting samples on a thin-layer chromatographic plate until the reaction of the raw materials is complete. After the reaction is completed, a silica gel column is used for separation and purification, and the purified products are rotary-evaporated to obtain the target products.

Example 12

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₇ H ₂₄ N ₂ O ₂

Molecular weight: 408.1838

Structural formula:

Yield: 90%

¹ H NMR (500MHz, CDCl ₃ ) δ7.29(d, J=4.4Hz, 2H), 7.23(t, J=11.6Hz, 8H), 7.15(t, J=8.0Hz, 1H), 7.08(dd ,J=7.0,3.0Hz,1H),6.46(d,J=8.4Hz,1H),6.30(d,J=7.6Hz,1H),5.08(d,J=15.7Hz,1H),4.84(d ,J=15.7Hz,1H),3.62-3.39(m,1H),3.36-3.23(m,2H),3.09(t,J=8.1Hz,1H),2.39(dd,J=13.4,7.4Hz, 1H), 1.95(dd, J＝14.5, 6.1Hz, 1H), 1.53-1.43(m, 1H), 0.47-0.31(m, 1H). ¹³ C NMR(125MHz, CDCl ₃ ) δ168.4, 143.6, 143.3, 141.6, 138.3, 136.4, 130.2, 128.7, 127.4, 127.3, 127.3, 127.1, 126.8, 126.1, 108.2, 106.6, 99.0, 76.5, 66.8, 49.7, 43.8, 27.8, 22.8. HRMS (ESI) m/z: [M +H] ⁺ calcd for C ₂₇ H ₂₅ N ₂ O ₂ 409.1911; found: 409.1922.

Example 13

raw material:

CH ₃ OH is a nucleophile

Product: Chemical formula: C ₃₈ H ₂₆ N ₂ O ₂

Molecular weight: 422.1994

Structural formula:

Yield: 70%

¹ H NMR (500MHz, CDCl ₃ ) δ7.38(d, J=7.3Hz, 2H), 7.32(dd, J=14.4,6.7Hz, 2H), 7.28(d, J=4.7Hz, 1H), 7.23 -7.18(m,4H),7.17-7.11(m,3H),6.44(d,J=8.4Hz,1H),6.30(d,J=7.6Hz,1H),5.12(d,J=15.6Hz, 1H), 4.89(d, J=15.6Hz, 1H), 3.52(s, 3H), 3.49(d, J=8.6Hz, 1H), 3.33(m, 1H), 3.05(t, J=8.2Hz, 1H), 2.40(dd, J＝13.2, 7.5Hz, 1H), 2.02-1.92(m, 1H), 1.55-1.46(m, 1H), 0.44(dd, J＝7.5, 4.4Hz, 1H). ¹³ C NMR (125MHz, CDCl ₃ ) δ167.8, 143.6, 143.4, 141.0, 136.6, 136.3, 130.3, 129.1, 128.7, 127.5, 127.5, 127.2, 127.2, 127.2, 108.1, 106.8, 98.8, 80.5, 64.7, 43.9, 26.9, 22.9. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₈ H ₂₇ N ₂ O ₂ 423.2067; found: 423.2074.

Example 14

raw material:

CH ₃ CH ₂ OH is a nucleophile

Product: Chemical formula: C ₂₉ H ₂₈ N ₂ O ₂

Molecular weight: 436.2151

Structural formula:

Yield: 72%

¹ H NMR (500MHz, CDCl ₃ ) δ7.38(d, J=7.5Hz, 2H), 7.31(t, J=7.5Hz, 2H), 7.27–7.16(m, 7H), 7.13(t, J= 8.0Hz, 1H), 6.43(d, J=8.4Hz, 1H), 6.29(d, J=7.6Hz, 1H), 5.11(d, J=15.6Hz, 1H), 4.87(d, J=15.6Hz ,1H),3.69(dt,J=15.5,8.5Hz,2H),3.46(d,J=9.1Hz,1H),3.32(m,1H),3.05(t,J=8.2Hz,1H),2.41 (dd,J=13.1,7.5Hz,1H),1.96(m,1H),1.54–1.44(m,1H),1.33(t,J=6.9Hz,3H),0.42(m,1H). ¹³ C NMR (125MHz, CDCl ₃ ) δ167.9, 143.6, 143.4, 141.4, 137.2, 136.7, 130.2, 128.7, 128.7, 127.5, 127.5, 127.2, 127.2, 127.1, 108.1, 106.9, 98.9, 80.4, 94.1, 95 , 27.1, 22.9, 16.4. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₉ N ₂ O ₂ 437.2224; found: 437.2235.

Example 15

raw material:

CD ₃ OD is a nucleophile

Product: Chemical formula: C ₂₈ H ₂₃ D ₃ N ₂ O ₂

Molecular weight: 425.2183

Structural formula:

Yield: 71%

¹ H NMR (500MHz, CDCl ₃ ) δ7.38(d, J=7.4Hz, 2H), 7.32(t, J=7.5Hz, 2H), 7.26(d, J=7.3Hz, 1H), 7.22–7.18 (m,4H),7.17–7.12(m,3H),6.43(d,J=8.4Hz,1H),6.30(d,J=7.6Hz,1H),5.11(d,J=15.6Hz,1H) ,4.88(d,J=15.6Hz,1H),3.48(d,J=8.9Hz,1H),3.38–3.27(m,1H),3.04(t,J=8.2Hz,1H),2.40(dd, J＝13.2,7.5Hz,1H),2.05–1.91(m,1H),1.56–1.46(m,1H),0.49–0.37(m,1H). ¹³ C NMR(125MHz,CDCl ₃ )δ167.8,143.6, 143.4,143.4,141.1,136.6,136.4,130.3,130.2,129.1,128.7,127.5,127.5,127.2,127.2,127.2,108.1,106.8,98.9,80.4,63.8,49.8,43.9,29.8 m/z: [M+H] ⁺ calcd for C ₂₈ H ₂₄ D ₃ N ₂ O ₂ 426.2255; found: 426.2263.

Example 16

raw material:

CF ₃ CH ₂ OH is a nucleophile

Product: Chemical formula: C ₂₉ H ₂₅ F ₃ N ₂ O ₂

Molecular weight: 490.1868

Structural formula:

Yield: 62%

¹ H NMR (500MHz, CDCl ₃ ) δ7.38(d, J=7.5Hz, 2H), 7.33(t, J=7.5Hz, 2H), 7.28(d, J=7.2Hz, 1H), 7.25-7.13 (m,6H),7.08(s,1H),6.46(d,J=8.4Hz,1H),6.32(d,J=7.6Hz,1H),5.12(d,J=15.6Hz,1H),4.86 (d, J=15.6Hz, 1H), 4.09(m, 1H), 4.03-3.90(m, 1H), 3.49-3.31(m, 2H), 3.09(t, J=8.2Hz, 1H), 2.42( dd,J＝13.4,7.5Hz,1H),2.01(m,1H),1.57-1.49(m,1H),0.51-0.36(m,1H). ¹³ C NMR(125MHz,CDCl ₃ )δ167.5,143.6, 143.4, 139.8, 136.4, 132.9, 130.8, 129.8, 128.7, 127.6, 127.5, 127.4, 126.9, 124.0(q, J=276.3Hz), 108.3, 106.5, 99.3, 80.5, 63.8, 61.9(q, J=34.7Hz ), 49.9, 43.9, 27.1, 22.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₆ F ₃ N ₂ O ₂ 491.1941; found: 491.1950.

Example 17

raw material:

2-Bromoethanol as a nucleophile

Product: Chemical formula: C ₂₉ H ₂₇ BrN ₂ O ₂

Molecular weight: 514.1256

Structural formula:

Yield: 62%

¹ H NMR (500MHz, CDCl ₃ ) δ7.37(t, J=7.2Hz, 2H), 7.32(t, J=7.5Hz, 2H), 7.29–7.22(m, 2H), 7.20(d, J= 7.7Hz, 4H), 7.15(dd, J=10.8, 5.1Hz, 2H), 6.44(d, J=8.4Hz, 1H), 6.31(d, J=7.6Hz, 1H), 5.11(d, J= 15.6Hz, 1H), 4.87(d, J=15.6Hz, 1H), 4.03(m, 1H), 3.88(m, 1H), 3.72–3.48(m, 2H), 3.44(d, J=8.8Hz, 1H), 3.34(m, 1H), 3.07(t, J=8.2Hz, 1H), 2.46(dd, J=13.2, 7.5Hz, 1H), 1.99(m, 1H), 1.60–1.46(m, 1H ),0.42(m,1H) ^.13 C NMR(125MHz,CDCl ₃ )δ167.6,143.6,143.3,140.8,136.5,135.6,130.4,129.1,128.7,127.5,127.5,127.3,127.2,127.1,108.1,106. 99.1, 80.1, 63.8, 63.4, 49.9, 43.9, 31.6, 27.1, 22.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₈ BrN ₂ O ₂ 515.1329; found: 515.1338.

Example 18

raw material:

propynyl alcohol as a nucleophile

Product: Chemical formula: C ₃₀ H ₂₆ N ₂ O ₂

Molecular weight: 446.1994

Structural formula:

Yield: 67%

¹ H NMR (500MHz, CDCl ₃ ) δ7.38(d, J=7.4Hz, 2H), 7.34(d, J=7.3Hz, 2H), 7.32–7.26(m, 2H), 7.21(dd, J= 7.0,2.9Hz,3H),7.20–7.13(m,3H),6.44(d,J=8.4Hz,1H),6.31(d,J=7.6Hz,1H),5.11(d,J=15.6Hz, 1H), 4.88(d, J=15.6Hz, 1H), 4.42(dd, J=15.5, 2.4Hz, 1H), 4.34(dd, J=15.5, 2.3Hz, 1H), 3.49(d, J=9.1 Hz, 1H), 3.34(m, 1H), 3.06(t, J＝8.2Hz, 1H), 2.49(t, J＝2.4Hz, 1H), 2.49–2.43(m, 1H), 2.10–1.96(m ,1H),1.55–1.45(m,1H),0.48–0.28(m,1H). ¹³ C NMR(125MHz,CDCl ₃ )δ167.7,143.7,143.5,140.4,136.5,134.6,130.5,129.4,128.8,127.5 ,127.5,127.4,127.3,127.2,108.2,106.7,99.1,81.2,80.6,74.5,64.1,52.4,49.9,43.9,27.9,22.9.HRMS(ESI)m/z:[M+H] ⁺ calcd for C ₃₀ H ₂₇ N ₂ O ₂ 447.2067; found: 447.2090.

Example 19

raw material:

Butynol as a nucleophile

Product: Chemical formula: C ₃₁ H ₂₈ N ₂ O ₂

Molecular weight: 460.2151

Structural formula:

Yield: 68%

¹ H NMR (500MHz, CDCl ₃ ) δ7.38(d, J=7.4Hz, 2H), 7.32(t, J=7.5Hz, 2H), 7.30-7.26(m, 1H), 7.24(s, 1H) ,7.19(d,J=7.3Hz,5H),7.14(t,J=8.0Hz,1H),6.44(d,J=8.4Hz,1H),6.30(d,J=7.6Hz,1H),5.11 (d,J=15.6Hz,1H),4.87(d,J=15.6Hz,1H),3.85-3.78(m,1H),3.73(dd,J=15.2,6.9Hz,1H),3.46(d, J＝9.1Hz, 1H), 3.34(m, 1H), 3.06(t, J＝8.2Hz, 1H), 2.60(m, 2H), 2.44(dd, J＝13.2, 7.5Hz, 1H), 2.04( dd,J＝5.9,3.4Hz,1H),1.98(m,1H),1.57-1.46(m,1H),0.42(m,1H). ¹³ C NMR(125MHz,CDCl ₃ )δ167.7,143.7,143.4, 141.0, 136.6, 136.2, 130.3, 129.0, 128.7, 128.6, 127.5, 127.2, 127.2, 127.2, 126.9, 108.1, 106.8, 99.0, 81.4, 80.3, 69.6, 63.9, 61.7, 49.9, 41.2.9, 29.27 HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₁ H ₂₉ N ₂ O ₂ 461.2224; found: 461.2232.

Example 20

raw material:

tryptophan as nucleophile

Product: Chemical formula: C ₃₇ H ₃₃ N ₃ O ₂

Molecular weight: 551.2573

Structural formula:

Yield: 77%

¹ H NMR (500MHz, CDCl ₃ ) δ8.10(s, 1H), 7.62(d, J=7.8Hz, 1H), 7.36(t, J=7.3Hz, 2H), 7.34–7.27(m, 3H) ,7.23(dd,J=16.4,7.0Hz,3H),7.16(t,J=6.1Hz,5H),7.14–7.08(m,2H),7.07(t,J=3.9Hz,1H),6.41( t,J=6.8Hz,1H),6.28(t,J=7.3Hz,1H),5.11(d,J=15.6Hz,1H),4.85(d,J=15.6Hz,1H),3.92(dd, J＝15.5, 7.2Hz, 1H), 3.85(dd, J＝15.6, 7.3Hz, 1H), 3.42(d, J＝9.1Hz, 1H), 3.28(m, 1H), 3.15(t, J＝7.0 Hz, 2H), 3.02(t, J=8.1Hz, 1H), 2.32(dd, J=13.1, 7.5Hz, 1H), 1.83(m, 1H), 1.52–1.35(m, 1H), 0.36(m ,1H). ¹³ C NMR (125MHz, CDCl ₃ ) δ167.9, 143.6, 143.4, 141.4, 136.9, 136.6, 136.2, 130.2, 128.8, 128.7, 127.7, 127.5, 127.3, 127.2, 127.1, 126.8, 1292.3, ,118.9,112.9,111.2,108.1,106.9,98.9,80.4,63.9,63.8,49.9,43.9,26.9,26.9,22.9.HRMS(ESI)m/z:[M+H] ⁺ calcd for C ₃₇ H ₃₄ N ₃ O ₂ 552.2646; found: 552.2655.

Example 21

raw material:

Citronellol is a nucleophile

Product: Chemical formula: C ₃₇ H ₄₂ N ₂ O ₂

Molecular weight: 546.3246

Structural formula:

Yield: 72%

¹ H NMR (500MHz, CDCl ₃ ) δ7.31(d, J=7.5Hz, 2H), 7.25(t, J=7.5Hz, 2H), 7.18(dd, J=8.9, 5.5Hz, 2H), 7.15 –7.09(m,5H),7.08–7.04(m,1H),6.36(d,J=8.4Hz,1H),6.23(d,J=7.6Hz,1H),5.03(dd,J=15.7,8.4 Hz,2H),4.86–4.74(m,1H),3.71–3.51(m,2H),3.43(t,J＝11.1Hz,1H),3.32–3.19(m,1H),2.99(t,J＝ 8.1Hz,1H),2.32(dd,J＝13.0,7.5Hz,1H),2.04–1.83(m,3H),1.73–1.64(m,2H),1.62(s,3H),1.55(s,3H ),1.53–1.46(m,2H),1.46–1.37(m,2H),1.37–1.28(m,1H),1.17–1.09(m,1H),0.94–0.85(m,3H),0.44–0.25 (m,1H) ^.13 C NMR(125MHz,CDCl ₃ )δ167.8,143.6,143.3,141.6,137.4,137.4,136.7,131.3,130.2,128.7,128.6,127.5,127.5,127.2,127.2,127.1,108.09 ESI )m/z: [M+H] ⁺ calcd for C ₃₇ H ₄₃ N ₂ O ₂ 547.3319; found: 547.3330.

Example 22

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₃ H ₂₀ N ₂ O ₂

Molecular weight: 356.1525

Structural formula:

Yield: 64%

¹ H NMR (500MHz, CDCl ₃ ) δ7.28(d, J=7.9Hz, 1H), 7.24–7.17(m, 5H), 7.01(s, 1H), 6.58(d, J=7.6Hz, 1H) ,6.51(d,J=8.4Hz,1H),4.54(dt,J=17.7,8.9Hz,2H),3.35(m,1H),3.28(d,J=8.7Hz,1H),3.15(s, 1H), 3.11(t, J=8.2Hz, 1H), 2.40(dd, J=13.4, 7.4Hz, 1H), 2.23(t, J=2.5Hz, 1H), 2.07–1.94(m, 1H), 1.55–1.45(m,1H),0.39(d,J=11.9Hz,1H). ¹³ C NMR(125MHz,CDCl ₃ )δ167.4,143.6,142.3,141.5,138.3,130.3,127.4,127.2,126.7,125.9, 108.5, 106.7, 99.0, 76.5, 72.1, 66.8, 49.8, 29.3, 27.9, 22.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₃ H ₂₁ N ₂ O ₂ 357.1598; found: 357.1606.

Example 23

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₃₁ H ₃₀ N ₂ O ₂

Molecular weight: 462.2307

Structural formula:

Yield: 72%

¹ H NMR (500MHz, CDCl ₃ ) δ7.25–7.18(m,7H),7.17–7.12(m,2H),7.10(dd,J=12.8,4.7Hz,3H),6.45(d,J=8.4 Hz, 1H), 6.27(d, J=7.6Hz, 1H), 5.11(d, J=15.8Hz, 1H), 4.76(d, J=15.7Hz, 1H), 4.17(d, J=30.6Hz, 1H), 3.40(dd, J＝11.7, 8.9Hz, 1H), 2.96–2.84(m, 2H), 2.48(m, 1H), 1.62–1.50(m, 2H), 1.38(d, J＝14.2Hz ,2H),1.28–1.12(m,3H),0.90(dd,J＝13.8,9.1Hz,2H). ¹³ C NMR(125MHz,CDCl ₃ )δ168.6,144.1,143.1,141.9,139.3,136.3,130.0, 128.7, 127.3, 127.0, 126.9, 126.6, 125.5, 108.2, 106.6, 98.8, 75.1, 50.4, 43.7, 39.7, 33.3, 29.2, 26.9, 25.4, 24.0, 21.3. HRMS (ESI) m/z: [M+H ] ⁺ calcd for C ₃₁ H ₃₁ N ₂ O ₂ 463.2380; found: 463.2408.

Example 24

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₂ H ₁₉ BrN ₂ O

Molecular weight: 406.0681

Structural formula:

Yield: 80%

¹ H NMR (500MHz, CDCl ₃ ) δ7.56(s, 1H), 7.25–7.20(m, 4H), 7.19–7.14(m, 1H), 6.97(t, J=8.0Hz, 1H), 6.57( s,1H),6.24(d,J=8.4Hz,1H),6.10(d,J=7.6Hz,1H),4.95(d,J=15.7Hz,1H),4.80(d,J=15.7Hz, 1H), 3.94(d, J＝8.5Hz, 1H), 3.47–3.34(m, 2H), 2.51(dd, J＝13.5, 5.9Hz, 1H), 2.17–2.07(m, 1H), 2.03(dt , J＝11.5, 5.8Hz, 1H), 1.90 (td, J＝11.9, 6.0Hz, 1H). ¹³ C NMR (125MHz, CDCl ₃ ) δ168.1, 144.4, 143.5, 140.4, 136.5, 130.9, 130.1, 129.8, _Found ^_ _{_ _} :407.0764.

Example 25

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₄ H ₂₄ N ₂ O ₂

Molecular weight: 372.1838

Structural formula:

Yield: 72%

1H NMR (500MHz, CDCl ₃ )δ7.21–7.10(m, 5H), 7.00(t, J=8.0Hz, 1H), 6.83(s, 1H), 6.34(d, J=8.4Hz, 1H), 6.11(d, J=7.6Hz, 1H), 4.92(d, J=15.8Hz, 1H), 4.75(d, J=15.8Hz, 1H), 3.45(t, J=8.2Hz, 1H), 3.40– 3.31(m, 1H), 3.14(d, J＝8.5Hz, 1H), 2.80(dd, J＝48.4, 6.7Hz, 1H), 2.51(t, J＝9.7Hz, 1H), 2.14–1.99(m ,1H),1.91(td,J=15.3,8.5Hz,2H),0.79(m,1H),0.73–0.63(m,1H),0.41–0.27(m,2H),0.24(m,1H). ¹³ C NMR (125MHz, CDCl ₃ ) δ168.7, 144.3, 143.6, 140.7, 136.9, 130.6, 129.1, 127.9, 127.7, 126.5, 108.4, 106.8, 99.3, 74.6, 66.9, 50.4, 44.5, 28.5, 25.0, .HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₄ H ₂₅ N ₂ O ₂ 373.1911; found: 373.1922.

Example 26

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₉ H ₂₄ N ₂ O ₃

Molecular weight: 448.1784

Structural formula:

Yield: 80%

¹ H NMR (500MHz, CDCl ₃ ) δ8.13(d, J=7.4Hz, 2H), 7.83(s, 1H), 7.77(s, 1H), 7.57(t, J=7.4Hz, 1H), 7.45 (t, J=7.7Hz, 2H), 7.25–7.21(m, 3H), 7.18(d, J=8.4Hz, 2H), 6.97(t, J=8.0Hz, 1H), 6.28(d, J= 8.4Hz, 1H), 6.12(d, J=7.6Hz, 1H), 4.97(d, J=15.8Hz, 1H), 4.84(d, J=15.8Hz, 1H), 4.03(d, J=8.3Hz ,1H), 3.46(dd,J=10.2,5.9Hz,2H),2.61(d,J=5.6Hz,1H),2.21(s,1H),2.12–1.98(m,2H). ¹³ C NMR( 125MHz, CDCl ₃ )δ168.2, 163.1, 144.9, 143.3, 136.6, 136.3, 134.0, 130.3, 130.3, 128.8, 128.7, 128.4, 127.4, 127.3, 126.9, 123.4, 108.6, 107.2, 93.6, 7 , 49.8, 43.8, 27.9, 24.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₅ N ₂ O ₃ 449.1860; found: 449.1871.

Example 27

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₇ H ₂₂ N ₂ O ₄

Molecular weight: 438.1580

Structural formula:

Yield: 81%

¹ H NMR (500MHz, CDCl ₃ ) δ7.76(s, 1H), 7.67(s, 1H), 7.61(s, 1H), 7.38(d, J=3.3Hz, 1H), 7.23(q, J= 7.5Hz, 4H), 7.18–7.14(m, 1H), 6.96(t, J=8.0Hz, 1H), 6.51(dd, J=3.5, 1.6Hz, 1H), 6.26(d, J=8.4Hz, 1H), 6.11(d, J=7.6Hz, 1H), 4.89(dd, J=59.0, 15.8Hz, 2H), 3.99(d, J=8.3Hz, 1H), 3.44(dd, J=9.6, 5.8 Hz, 2H), 2.58(dd, J＝13.4, 5.8Hz, 1H), 2.26–2.12(m, 1H), 2.00(m, 2H). ¹³ C NMR(125MHz, CDCl ₃ ) δ168.2, 154.9, 147.9, 144.8,143.3,142.9,136.6,135.6,130.4,128.7,128.5,127.4,127.3,126.9,123.5,120.4,112.4,108.5,107.2,99.4,59.4,49.8,43.7,27.9m/MS(ESI) z: [M+H] ⁺ calcd for C ₂₅ H ₂₃ N ₂ O ₄ 439.1652; found: 439.1659.

Example 28

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₃₁ H ₂₄ N ₂ O ₃

Molecular weight: 472.1787

Structural formula:

Yield: 75%

¹ H NMR (500MHz, CDCl ₃ )δ7.76(s,1H),7.63–7.59(m,2H),7.57(s,1H),7.43–7.38(m,1H),7.32(t,J=7.6 Hz, 2H), 7.24–7.20(m, 4H), 7.17–7.13(m, 1H), 6.94(t, J＝8.0Hz, 1H), 6.24(d, J＝8.4Hz, 1H), 6.10(d ,J=7.6Hz,1H),4.93(d,J=15.8Hz,1H),4.82(d,J=15.8Hz,1H),3.95(d,J=8.3Hz,1H),3.48–3.34(m ,2H),2.51(dd,J＝13.4,5.7Hz,1H),2.14(m,1H),2.05–1.86(m,2H). ¹³ C NMR(125MHz,CDCl ₃ )δ168.3,150.3,144.8,143.4 ,136.6,135.8,132.9,131.2,130.5,128.7,128.7,128.7,127.4,127.3,126.9,123.6,119.1,108.5,107.3,99.4,89.6,79.8,59.3,49.8,43.8,47.8 )m/z: [M+H] ⁺ calcd for C ₃₁ H ₂₅ N ₂ O ₃ 473.1860; found: 473.1870.

Example 29

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₉ H ₂₄ N ₂ O ₄

Molecular weight: 464.1736

Structural formula:

Yield: 63%

¹ H NMR (500MHz, CDCl ₃ ) δ10.31(s, 1H), 8.00(dd, J=8.0, 1.5Hz, 1H), 7.77(s, 1H), 7.70(s, 1H), 7.50–7.43( m,1H),7.26–7.21(m,3H),7.18(d,J=6.2Hz,1H),7.02–6.85(m,3H),6.28(d,J=8.4Hz,1H),6.13(d ,J=7.6Hz,1H),4.96(d,J=15.8Hz,1H),4.84(d,J=15.8Hz,1H),4.01(d,J=8.2Hz,1H),3.46(dd,J =9.5,5.9Hz,2H),2.59(dd,J=13.4,5.8Hz,1H),2.27–2.16(m,1H),2.08(dd,J=11.9,5.7Hz,1H),2.03–1.93( m,1H). ¹³ C NMR (125MHz, CDCl ₃ ) δ168.2, 166.6, 162.3, 144.8, 143.4, 136.9, 136.5, 135.2, 130.6, 130.4, 128.9, 128.7, 127.5, 127.3, 126.3, 124.1, 117.9, 111.0, 108.5, 107.3, 99.5, 59.4, 49.9, 43.8, 27.9, 24.8. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₂₉ H ₂₅ N ₂ O ₄ 465.1809; found: 465.1825.

Example 30

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₃₃ H ₂₈ FeN ₂ O ₃

Molecular weight: 556.1449

Structural formula:

Yield: 70%

¹ H NMR (500MHz, CDCl ₃ )δ7.78(s,1H),7.68(s,1H),7.24(q,J=7.5Hz,4H),7.18(d,J=7.0Hz,1H),6.97 (t, J=7.9Hz, 1H), 6.28(d, J=8.3Hz, 1H), 6.13(d, J=7.5Hz, 1H), 4.99(d, J=15.7Hz, 1H), 4.91(s ,2H),4.83(d,J=15.8Hz,1H),4.45(s,2H),4.20(s,5H),4.02(d,J=8.3Hz,1H),3.51–3.40(m,2H) , 2.59 (d, J=12.8Hz, 1H), 2.18 (dd, J=16.9, 10.1Hz, 1H), 2.00 (dd, J=17.6, 11.8Hz, 2H). ¹³ C NMR (125MHz, CDCl ₃ ) ( z: [M+H] ⁺ calcd for C ₃₃ H ₂₉ FeN ₂ O ₃ 557.1522; found: 557.1533.

Example 31

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₃₂ H ₂₇ N ₂ O ₃

Molecular weight: 501.2052

Structural formula:

Yield: 80%

¹ H NMR (500MHz, CDCl ₃ ) δ8.26(s, 1H), 7.68(s, 1H), 7.57(d, J=7.5Hz, 1H), 7.50(s, 1H), 7.27(d, J= 7.4Hz, 1H), 7.25–7.20(m, 4H), 7.19–7.15(m, 1H), 7.14–7.06(m, 3H), 6.94(dd, J＝11.7, 4.3Hz, 1H), 6.23(d ,J=8.4Hz,1H),6.10(d,J=7.6Hz,1H),4.96(d,J=15.7Hz,1H),4.82(d,J=15.7Hz,1H),3.91(d,J ＝8.5Hz,1H),3.87(s,2H),3.44–3.32(m,2H),2.45(dd,J＝13.1,5.0Hz,1H),2.17–2.04(m,1H),2.01–1.79( m,2H). ¹³ C NMR (125MHz, CDCl ₃ )δ168.4, 168.3, 144.8, 143.3, 136.6, 136.4, 136.2, 130.3, 128.7, 128.1, 127.4, 127.3, 127.2, 127.1, 123.6, 122.9, 1192.9, 118.8, 111.4, 108.5, 107.2, 107.1, 99.4, 59.4, 49.8, 43.7, 31.2, 27.8, 24.7. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₂ H ₂₈ N ₃ O ₃ 502.2125; found: 502.2134.

Example 32

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₃₆ H ₃₂ N ₂ O ₄

Molecular weight: 556.2362

Structural formula:

Yield: 52%

¹ H NMR (500MHz, CDCl ₃ )δ7.73–7.61(m,4H),7.47(d,J=9.6Hz,1H),7.44–7.36(m,1H),7.23–7.20(m,3H), 7.21–7.12(m,2H),7.10–6.99(m,2H),6.92(dt,J=11.4,8.0Hz,1H),6.20(dd,J=14.3,8.4Hz,1H),6.08(dd, J=9.9,7.7Hz,1H), 4.95(d,J=15.7Hz,1H),4.81(dd,J=15.7,4.6Hz,1H),3.98(dd,J=15.1,7.4Hz,1H), 3.92–3.85(m,1H),3.82(d,J=7.4Hz,3H),3.37(m,2H),2.50–2.41(m,1H),2.09(dt,J=13.1,6.2Hz,1H) ,2.01–1.79(m,2H),1.60(dd,J＝7.1,3.0Hz,3H). ¹³ C NMR(125MHz,CDCl ₃ )δ171.3,171.3,168.3,168.2,157.8,157.8,144.8,143.3,143.2 ,136.6,136.3,134.2,133.9,133.9,130.3,130.3,129.5,128.9,128.9,128.7,128.2,128.2,127.5,127.5,127.4,127.3,127.1,127.1,126.3,126.2,126.2,123.1,122.9,119.2 ,119.1,108.5,107.2,105.6,105.6,99.4,59.4,55.4,49.8,49.8,45.3,45.3,43.7,27.8,27.7,24.7,24.7,18.3,18.3.HRMS(ESI)m/z:[M+ H] ⁺ calcd for C ₃₆ H ₃₃ N ₂ O ₄ 557.2435; found: 557.2445.

Example 33

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₃₅ H ₃₆ N ₂ O ₃

Molecular weight: 532.2726

Structural formula:

Yield: 60%

¹ H NMR (500MHz, CDCl ₃ ) δ7.63(d, J=13.8Hz, 1H), 7.48(d, J=7.5Hz, 1H), 7.27–7.19(m, 7H), 7.05(dd, J= 15.0,7.9Hz,2H),6.94(dd,J=14.2,7.9Hz,1H),6.23(t,J=7.9Hz,1H),6.10(dd,J=7.3,5.9Hz,1H),4.96( dd,J=15.7,2.3Hz,1H),4.81(dd,J=15.8,3.2Hz,1H),3.92(t,J=9.2Hz,1H),3.87–3.80(m,1H),3.46–3.35 (m,2H),2.53–2.44(m,1H),2.37(dd,J＝12.0,7.1Hz,2H),2.12(dd,J＝14.0,5.9Hz,1H),2.03–1.88(m,2H ),1.77(m,1H),1.52(dd,J＝7.1,4.0Hz,3H),0.82(dd,J＝9.4,6.7Hz,6H). ¹³ C NMR(125MHz,CDCl ₃ )δ171.4,168.2, 144.8,143.3,141.1,136.6,136.3,130.3,129.6,129.6,128.7,127.4,127.3,127.3,123.0,122.9,108.5,107.1,99.4,99.3,59.4,49.8,45.4,327,27,7,3 24.7, 22.4, 18.3. HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₅ H ₃₇ N ₂ O ₃ 533.2799; found: 533.2810.

Example 34

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₁ H ₁₈ N ₂ O ₂

Molecular weight: 330.1368

Structural formula:

Yield: 70%

¹ H NMR (500MHz, CDCl ₃ )δ7.36–7.27(m,5H),7.22–7.15(m,2H),6.52(d,J=8.5Hz,1H),6.25(d,J=7.5Hz, 1H), 5.06(d, J＝15.7Hz, 1H), 4.84(d, J＝15.7Hz, 1H), 3.70–3.58(m, 2H), 3.56–3.48(m, 1H), 3.02(d,J =6.1Hz, 1H), 2.11(t, J=5.3Hz, 1H), 2.01–1.90(m, 2H); ¹³ C NMR (125MHz, CDCl ₃ ) δ186.4, 168.2, 144.9, 144.7, 138.4, 135.9, 133.6 ,128.8,127.7,127.4,126.9,108.9,108.3,99.9,65.3,50.1,43.9,25.3,24.6.HRMS(ESI)m/z:[M+H] ⁺ calcd for C ₂₁ H ₁₉ N ₂ O ₂ 331.1441 ;found: 331.1430.

Example 35

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₁₇ H ₁₆ N ₂ O ₂

Molecular weight: 280.1212

Structural formula:

Yield: 78%

¹ H NMR (500MHz, CDCl ₃ )δ7.24(s,1H),7.14(s,1H),6.55(d,J=8.5Hz,1H),6.34(d,J=7.5Hz,1H),5.87 (m,1H),5.30–5.20(m,2H),4.52–4.42(m,1H),4.35–4.24(m,1H),3.64(m,2H),3.58–3.49(m,1H),3.02 (t, J = 5.1Hz, 1H), 2.11 (t, J = 5.5Hz, 1H), 2.04–1.90 (m, 2H); ¹³ C NMR (125MHz, CDCl ₃ ) δ186.4, 167.8, 144.9, 144.7, 138.4 ,133.6,131.7,126.8,117.6,108.8,108.3,99.7,65.4,50.1,42.5,25.3,24.6.HRMS(ESI)m/z:[M+H] ⁺ calcd for C ₁₇ H ₁₇ N ₂ O ₂ 281.1285 ;found: 281.1302.

Example 36

raw material:

_H2O is a nucleophile

Product: Chemical formula: C ₂₅ H ₂₀ N ₂ O ₂

Molecular weight: 380.1525

Structural formula:

Yield: 66%

¹ H NMR (500MHz, CDCl ₃ ) δ7.59 (dd, J = 14.4, 7.4Hz, 4H), 7.31–7.19 (m, 3H), 7.05 (d, J = 20.5Hz, 1H), 6.96 (t, J=7.9Hz, 1H), 6.31(d, J=8.5Hz, 1H), 6.09(d, J=7.5Hz, 1H), 5.03(d, J=15.7Hz, 1H), 4.80(d, J= 15.7Hz, 1H), 3.42(dd, J=16.2, 8.9Hz, 2H), 3.36–3.28(m, 1H), 2.83(d, J=5.9Hz, 1H), 1.89(dd, J=17.3, 12.2 Hz, 1H), 1.80–1.70 (m, 2H); ¹³ C NMR (125MHz, CDCl ₃ ) δ186.4, 168.3, 144.9, 144.7, 138.4, 133.6, 133.5, 133.3, 132.9, 128.8, 127.8, 127.7, 126.9, 126.4 _found ^_ _{_ _ _} :381.1607.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of the present invention. within the scope of protection.

Claims (25)

1. The 3,4-position condensed heterocyclic seven-membered nitrogen-heterocyclic indoline compound is characterized in that its structural formula is as shown in formula 1, formula 2 or formula 3:

   

   In formula ¹ , R1 is any ^one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl; R2 is any one of alkyl and benzyl; ^R3 is alkane Any one of radical, benzyl, aryl; R4 is any one of alkyl, phenyl, thienyl, substituted phenyl ^; R5 is any one of alkyl, ^{deuteromethyl} , propargyl, butynyl , benzyl, aryl, hydrogen atom ^; R6 is any one of methyl, ethyl, halogen atom, hydrogen atom; X is any one of oxygen atom or sulfur atom;

   

   In formula 2, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl; R ² is any one of alkyl and benzyl; R ³ is alkane Any one of base, benzyl, aryl ^; R4 is any one of alkyl, halogen, alkoxy, thioether, carboxylate, aryl, aryl ether ^; R6 is methyl, ethyl Any one of , halogen atom and hydrogen atom;

   

   In formula ³ , R1 is any ^one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl; R2 is any one of alkyl and benzyl; ^R3 is alkane Any one of base, benzyl, aryl ^; R6 is any one of methyl, ethyl, halogen atom, hydrogen atom.
2. According to claim 1, the 3,4-position condensed heterocyclic nitrogen-heterocyclic indolene compound, is characterized in that, when R in formula ¹ is an alkyl group, the alkyl group is that the number of carbon atoms is 1 to 5 alkyl groups;

   When R in formula ¹ is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms;

   When R in formula ¹ is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms;

   When R in formula ¹ is an alkyl group, the alkyl group is an alkyl group with 1 to 8 carbon atoms;

   When R ⁵ in Formula 1 is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms.
3. According to claim 1, the 3,4-position condensed heterocyclic seven-membered nitrogen-heterocyclic indolene oxide compound is characterized in that, in formula ¹ , R is any of methyl, ethyl, benzyl, allyl A sort of;

   R ² is any one of methyl, ethyl, propyl;

   R ³ is any one of methyl, ethyl, propyl;

   R is any one of phenyl, ² -thienyl, and cyclopropyl;

   R is any one of ethyl, ^{deuteromethyl} , haloethyl, propargyl, butylynyl, benzyl, aryl, hydrogen atom;

   R ⁶ is a hydrogen atom;

   X is an oxygen atom.
4. According to claim 1, the 3,4-position fused seven-membered nitrogen-heterocyclic indoline oxide compound is characterized in that, in formula 1, the carbons of adjacent R ² and R ³ are connected to each other to form a ring .
5. According to claim 1, the 3,4-position condensed heterocyclic nitrogen-heterocyclic indolene compound, is characterized in that, when R in formula ² is an alkyl group, the alkyl group is that the number of carbon atoms is 1 to 5 alkyl groups;

   When R in formula ² is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms;

   When R in formula ² is an alkyl group, the alkyl group is preferably an alkyl group with 1 to 8 carbon atoms;

   R in the formula ² is a carboxylate group, and the carboxylate group is preferably a benzoate group, a furan-2-formate group, a phenylpropiolate group, a salicylate group, a dioxin Any of an iron formate group, an indole acetate group, a carboxylate group of naproxen, and a carboxylate group of ibuprofen.
6. According to claim 1, the indoline compound of 3,4-position condensed heterocyclic seven-membered nitrogen heterocycle is characterized in that, in formula 2, R ¹ is benzyl;

   R ² is any one of methyl, ethyl, propyl;

   R ³ is any one of methyl, ethyl, propyl;

   R ⁴ is benzoate group, furan-2-carboxylate group, phenylpropiolate group, salicylate group, ferrocene formate group, indole acetate group, carboxylate group of naproxen Any one of ester group and carboxylate group of ibuprofen;

   R ⁶ is a hydrogen atom.
7. According to claim 1, the 3,4-position fused seven-membered nitrogen-heterocyclic indoline oxide compound is characterized in that, in formula 2, the carbons of adjacent R ² and R ³ are connected to each other to form a ring .
8. According to claim 1, the indoline compound of 3,4-position condensed heterocyclic seven-membered nitrogen heterocyclic ring is characterized in that, when R in formula ³ is an alkyl group, the alkyl group is that the number of carbon atoms is 1 to 5 alkyl groups;

   When R ² in Formula 3 is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms.
9. The 3,4-position condensed heterocyclic seven-membered nitrogen-heterocyclic indolene compound according to claim 1, characterized in that, in formula 3,

   R ¹ is any one of benzyl and allyl;

   R ² is any one of methyl, ethyl, propyl;

   R ³ is any one of methyl, ethyl, propyl;

   R ⁶ is a hydrogen atom.
10. The 3,4-position fused seven-membered nitrogen-heterocyclic indoline oxide compound according to claim 1, characterized in that, in formula 3, the carbons of adjacent R ² and R ³ are linked to each other to form a ring .
11. According to claim 1, the 3,4-position fused seven-membered nitrogen-heterocyclic indoline oxide compound is characterized in that its structural formula is as follows: 1-1～1-14, 2-1～2-9, Any one of 3-1～3-3 shows:

    

    
12. The stereoisomers of the 3,4-position condensed heterocyclic seven-membered nitrogen-heterocyclic indolene compound of any one of claims 1 to 11, characterized in that the stereoisomers include tautomerism isomers, geometric isomers, enantiomers or diastereomers.
13. Oxidation of the 3,4-position condensed heterocyclic seven-membered nitrogen heterocycle of any one of claims 1 to 11 or the oxidation of the 3,4-position condensed seven-membered nitrogen heterocycle according to claim 12 The synthetic method of the stereoisomer of indoleene compound is characterized in that, comprises the following steps:

    Mix propargyl alcohol containing isatin skeleton and nucleophilic reagent uniformly in a solvent, and react at 25-90°C in the presence of a catalyst to prepare the 3,4-position condensed seven-membered nitrogen heterocyclic ring Indoline oxide compounds;

    Wherein, the structural formula of the propargyl alcohol containing isatin skeleton is as shown in formula 4:

    

    In formula 4, R ¹ is any one of alkyl, benzyl, allyl, propargyl, cyclopropylmethyl, cyclobutylmethyl; R ² is any one of alkyl and benzyl; R ³ is alkane Any one of base, benzyl, aryl ^; R4 is any one of alkyl, halogen, alkoxy, thioether, carboxylate, aryl, aryl ether, trimethylsilyl ^; R6 Any one of methyl group, ethyl group, halogen atom and hydrogen atom;

    The nucleophiles are alcohols, thiols or water.
14. The synthetic method according to claim 13, wherein, when R in formula ⁴ is an alkyl group, the alkyl group is an alkyl group with 1 to 5 carbon atoms;

    When R in formula ⁴ is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms;

    When R in formula ⁴ is an alkyl group, the alkyl group is an alkyl group with 1 to 10 carbon atoms;

    When R in formula ⁴ is a carboxylate group, the carboxylate group is preferably a benzoate group, a furan-2-carboxylate group, a phenylpropiolate group, a salicylate group, a dihydrogenate group Any one of iron formate group, indole acetate group, carboxylate group of naproxen and carboxylate group of ibuprofen;

    When R ⁴ in Formula 4 is an alkyl group, the alkyl group is preferably an alkyl group with 1 to 8 carbon atoms.
15. The synthesis method according to claim 13, characterized in that, in Formula 4, the carbons of adjacent R ² and R ³ are connected to each other to form a ring.
16. The synthetic method according to claim 13, characterized in that, when the nucleophile is an alcohol, the alcohol is methanol, ethanol, tritiated methanol, 2,2,2-trifluoroethanol, 2-bromo Ethanol, propynyl alcohol, butynol, tryptophanol, or citronellol.
17. The synthetic method according to claim 13 or 16, characterized in that, the mol ratio of the propargyl alcohol containing isatin skeleton to the nucleophile is 1:(10～50).
18. The synthesis method according to claim 13, characterized in that, the solvent is toluene or halogenated hydrocarbon.
19. The synthesis method according to claim 13 or 18, characterized in that the amount of the solvent is: adding 10-25L of solvent per mole of propargyl alcohol containing isatin skeleton.
20. The synthetic method according to claim 13, characterized in that, the catalyst is added before the reaction, and the catalyst is a Bronsted acid or a Lewis acid.
21. The synthesis method according to claim 13 or 20, characterized in that the catalyst is used in an amount of 5-50 mol%.
22. A pharmaceutical composition, comprising the 3,4-position condensed seven-membered nitrogen-heterocyclic oxidindole compound and pharmaceutically acceptable salts, solvates, and hydrates thereof according to any one of claims 1 to 11 , polycrystals, co-crystals, tautomers, geometric isomers, enantiomers, diastereomers or their mixtures or prodrugs, and pharmaceutically acceptable carriers, diluents, excipients Formulations or their combination.
23. Oxidation of the 3,4-position condensed heterocyclic seven-membered nitrogen heterocycle of any one of claims 1 to 11 or the oxidation of the 3,4-position condensed seven-membered nitrogen heterocycle according to claim 12 The application of the stereoisomers of indoleene compounds in the preparation of drugs for treating cancer, atherosclerosis, tuberculosis, cardiovascular diseases, epilepsy, mental diseases, Parkinson's disease and Alzheimer's disease.
24. Oxidation of the 3,4-position condensed heterocyclic seven-membered nitrogen heterocycle of any one of claims 1 to 11 or the oxidation of the 3,4-position condensed seven-membered nitrogen heterocycle according to claim 12 The application of stereoisomers of indoleene compounds in the treatment of cancer, atherosclerosis, tuberculosis, cardiovascular diseases, epilepsy, mental diseases, Parkinson's disease, and Alzheimer's disease.
25. The application of the pharmaceutical composition according to claim 22 in the treatment of cancer, atherosclerosis, tuberculosis, cardiovascular disease, epilepsy, mental disease, Parkinson's disease, and Alzheimer's disease.

Images