WO2024011921A1

WO2024011921A1 - Synthesis method for indolone derivative containing butenamine structure

Info

Publication number: WO2024011921A1
Application number: PCT/CN2023/078984
Authority: WO
Inventors: 王兴旺; 刘文凯
Original assignee: 苏州大学
Priority date: 2022-07-15
Filing date: 2023-03-01
Publication date: 2024-01-18
Also published as: CN115124450B; CN115124450A

Abstract

Disclosed in the present invention is a synthesis method for an indolone derivative containing a butenamine structure. Particularly, 3-arylindolone and 2-vinylaziridine are used as reactants and are synthesized in a solvent under the catalysis of Pd2(dba)3·CHCl3 and a chiral oxamide phosphine ligand so as to obtain a product. The method disclosed by the present invention uses simple and readily available raw materials and mild reaction conditions, has simple and convenient post-treatment, is suitable for a large scope of substrates, and has high yield and high enantioselectivity. The synthesized product can be used for synthesizing drug intermediates.

Description

A kind of synthesis method of indolone derivative containing butylene amine structure

Technical field

The present invention relates to the synthesis of indolinone derivatives containing butenylamine structure, and in particular to a catalytic synthesis method of indolone derivatives containing butenylamine structure.

Background technique

Indolinone derivatives are widely found in natural products, bioactive molecules, and drugs, and have significant physiological and pharmacological activities, such as sedation, antiviral, bactericidal, destroying biological cell membranes, inhibiting enzyme activity, antitumor, etc. Biologically active and widely present in natural products. It is also an indispensable and important structural unit in many drug molecules, and has attracted the attention of many scientists. Indolinone derivatives containing butylene amine structure also have good biological activity and medicinal value, and are commonly found in sedative drugs and biological receptors (Figure 1). There are many reports on the synthesis methods of indolinone derivatives in the prior art. Using a catalytic amount of catalyst to promote the generation of a large number of new synthetic substances is the most effective and economical method for synthesizing organic compounds. In the field of organic synthesis research, palladium and phosphine ligand catalysis can be used in the synthesis of many organic compounds; however, there are no literature reports on the efficient synthesis of indolinone derivatives containing butenamine structures through palladium and phosphine ligand catalysis. Therefore, it is necessary to invent a method for synthesizing chiral derivatives of indolinone containing butylene amine structure. This method not only has high yield and excellent enantioselectivity, but also requires mild reaction conditions and simple operation.

technical problem

The object of the present invention is to provide an indolinone derivative containing a butylene amine structure and a catalytic synthesis method thereof.

Technical solutions

In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is: a synthesis method of an indolinone derivative containing a butylene amine structure, including the following steps, using 3-aryl indolinone and 2-vinyl azapine Cyclopropane is used as the reactant, and palladium salt and phosphine ligand are used as the catalytic system to react to obtain an indolinone derivative containing a butenamine structure. Preferably, 3-aryl indolinone and 2-vinyl aziridine are used as reactants, palladium salt and phosphine ligand are used as the catalytic system, and the reaction is carried out in an organic solvent at -40°C to 30°C to obtain a compound containing Indolinone derivatives with butylamine structure.

In the present invention, the chemical structural formula of 3-aryl indolinone is: .

In the present invention, the structural formula of the indolinone derivative containing a butylene amine structure is: .

In the above chemical structural formula, R ¹ is selected from: hydrogen, 5-fluoro, chlorine, bromine, methyl, methoxy, 6-fluoro, chlorine, bromine, methoxy; R ² is selected from: hydrogen, 3-trifluoromethyl, fluorine, chlorine, methyl, methoxy, 4-fluoro, chlorine, bromine, methyl, ethyl, methoxy, dimethylamino, tert-butyl, phenyl, 2,3 ,4,5,6-pentafluoro, 3,5-dimethyl.

In the present invention, the chemical structural formula of 2-vinylaziridine is: .

In the above technical solution, the organic solvent is an ether solvent, a benzene solvent or an alcohol solvent; such as dichloromethane, diethyl ether, tetrahydrofuran, toluene, 1,2-dichloroethane, p-xylene, m-xylene, o-xylene, 1,4-dioxane, methyl tert-butyl ether or methanol, ethanol, isopropyl alcohol, tert-butanol; preferably methanol.

In the above technical solution, the dosage of the catalyst is 1% to 10% of 3-aryl indolone in molar terms; the dosage of 2-vinyl aziridine is 0.5 of 3-aryl indolone. ~2 times; the dosage of phosphine ligand is 2%~5% of 3-aryl indolone. Preferably, on a molar basis, the dosage of the catalyst is 2.5% of 3-aryl indolone; the dosage of 2-vinyl aziridine is 1 times of 3-aryl indolone; the phosphine ligand The dosage is 2.5% of 3-aryl indolone. The amount of catalyst used is based on palladium.

In the present invention, the catalyst is preferably Pd ₂ (dba) ₃ ·CHCl ₃ and chiral glufosinate ligand; wherein the chemical structural formula of the catalyst Pd ₂ (dba) ₃ ·CHCl ₃ is: .

The chemical structural formula of chiral glufosinate ligand is: .

Where R is selected from: one of isopropyl, phenyl, benzyl, 4-methoxybenzyl, 4-trifluoromethylbenzyl, and 3,5-dimethylbenzyl.

In the present invention, the reaction system uses methanol as the solvent and Pd ₂ (dba) ₃ ·CHCl ₃ and chiral glufosinate ligand as the catalyst to increase the reaction yield, which can reach a maximum yield of 99%.

The above reaction process is as follows:

.

beneficial effects

Due to the application of the above technical solutions, the present invention has the following advantages compared with the prior art:

1. For the first time, the present invention uses Pd ₂ (dba) ₃ ·CHCl ₃ and chiral glufosinate ligand as catalysts to catalyze the allylation reaction of 3-aryl indolone and 2-vinyl aziridine. A series of indolinone derivatives containing butenamine structures were synthesized with excellent enantioselectivity and high yields. This compound combines the effects of indolinone and 2-buten-1-amine structures with biological activity and pharmacological effects, providing more options for the development of organic synthesis and biomedicine.

2. The reaction disclosed in the invention for synthesizing an indolinone derivative containing a butylene amine structure has high catalytic efficiency, low catalyst dosage, simple post-processing, the reaction belongs to an allylation reaction, and no by-products are generated in the system.

3． The method disclosed in the present invention for synthesizing indolinone derivatives containing butylene amine structure is applicable to a wide range of substrates, and the raw materials are all industrial, cheap and easily available products without pollution; it is easy to operate, has high yield and is chemically selective. It has good reactivity; the reaction conditions are mild, it can react well at -10°C, and it has high functional group compatibility, excellent enantioselectivity, and high yield.

Description of drawings

Figure 1 is a schematic structural diagram of an existing indolinone derivative containing a butylene amine structure.

Figure 2 shows the results of different reaction conditions and products.

Figure 3 shows the results of different palladium salt conditions and products.

Figure 4 shows the results of different substrate ratio conditions and products.

Figure 5 shows the results of different palladium salt and phosphine ligand conditions and products.

Figure 6 is a schematic diagram of ligand synthesis.

Embodiments of the invention

The synthesis method of indolinone derivatives containing butenamine structure disclosed in the present invention is schematically as follows: add catalyst, 3-arylindolone, 2-vinylaziridine, and solvent to the reaction bottle in sequence, and then - The reaction is carried out at 40°C to 30°C, preferably -10°C, with conventional stirring (magnetic or mechanical) for 4 to 12 hours. After the reaction is completed, the reaction solution is subjected to simple column chromatography (the eluent is preferably ethyl acetate:petroleum ether= 1:5), the target product, an indolinone derivative containing a butylene amine structure, can be obtained; this type of compound is an analogue of many sedatives, antiviral drugs, bactericidal drugs and enzyme inhibitors, and has huge application value.

The present invention will be further described below in conjunction with the examples.

Example

Refer to Figure 2. Pd ₂ (dba) ₃ ·CHCl ₃ , chiral glufosinate ligands L, 1a, and 2a were added to the reaction bottle in sequence, 1 mL of methanol was added, and the reaction was stirred at 30°C for 12 hours. The reaction system passed through a simple The target product 3aa can be obtained by column chromatography (eluent is ethyl acetate: petroleum ether = 1:5). The yield and ee results are shown in Figure 2. Based on the reaction system with L14 as the ligand, the solvent was replaced with the same volume of ethanol, isopropyl alcohol or tert-butanol. The product yields were 88%, 83% and 77% respectively, and the ee % were 86% and 76 respectively. %, 65%. Based on the reaction system with L14 as the ligand, the solvent was replaced with the same volume of THF, Et ₂ O, MTBE, DCM, DCE, toluene, MeCN, and acetone. The product yield/ee values were 90%/80%, respectively. 71%/79%, 78%/79%, 85%/58%, 86%/45%, 86%/52%, 83%/65%, 85%/86%. Based on the reaction system with L14 as the ligand, 30°C was adjusted to an ice-water bath, and the product yield/ee value was 91%/90%. Based on the reaction system with L14 as the ligand, the 30°C was adjusted to -10°C, and 1 equivalent of K ₂ CO ₃ , CH ₃ ONa, and 3,5-Dinitrobenzoic Acid were added as additives respectively. The product yield/ee values were respectively 44%/55%, NR, NR.

Referring to Figure 3, add the metal compound catalyst, chiral glufosinate ligand L14 (structural formula shown in Figure 2), 1a, and 2a in the reaction bottle in sequence, add 1 mL of methanol, and stir for 12 hours at 30°C. The reaction system passes through a simple The target product 3aa can be obtained by column chromatography (eluent is ethyl acetate: petroleum ether = 1:5). The yield and ee results are shown in Figure 3.

Referring to Figure 4, add metal compound catalyst Pd ₂ (dba) ₃ ·CHCl ₃ , chiral glufosinate ligand L14 (see Figure 2 for structural formula), 1a, and 2a in sequence in the reaction bottle, add 1 mL of methanol, and heat at -10°C The reaction was stirred for 12 hours at high temperature. The reaction system was subjected to simple column chromatography (eluent was ethyl acetate: petroleum ether = 1:5) to obtain the target product 3aa. The yield and ee results are shown in Figure 4.

Referring to Figure 5, add metal compound catalyst Pd ₂ (dba) ₃ ·CHCl ₃ , chiral glufosinate ligand L14 (see Figure 2 for structural formula), 1a, and 2a in sequence in the reaction bottle. Add 1 mL of methanol and heat at -10°C. The reaction was stirred at high temperature for 12 hours. The reaction system was subjected to simple column chromatography (eluent was ethyl acetate: petroleum ether = 1:5) to obtain the target product 3aa. The yield and ee results are shown in Figure 5.

Synthesis example: See Figure 6. To a solution of (1R, 2R)-1,2-diphenylethane-1,2-diamine (20 g, 94.0 mmol) in methanol (250 mL) at room temperature, 47 % HBr aqueous solution (11 mL, 94 mmol). Then _H2O (30 mL) and _Boc2O (23 g, 104 mmol) were added. After stirring for 12 hours, _H2O (200 mL) was added to the mixture. The precipitated by-product (di-tert-butyl compound) was filtered off, and the methanol was removed under reduced pressure. The residue was basified with 25% NaOH solution until the pH exceeded 14. The mixture was further cooled to 0°C. After stirring for 1.0 hours, the precipitate was collected by suction filtration to obtain crude product S1. Under a nitrogen atmosphere, add 2-(diphenylphosphine)benzoic acid (1.53 g, 5.0 mmol) and anhydrous dichloromethane (50 mL) to a dry flask, followed by HOBT (0.92 g, 0.92 g, 6.0 mmol), EDCI (1.15 g, 6.0 mmol), and N-methylmorpholine (0.60 mL, 5.5 mmol). After stirring for 30 minutes, S1 (1.56 g, 5.0 mmol) was added to the mixture. The mixture was then stirred for a further 3 h at room temperature and then quenched with water (30 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 mL×3). The combined organic phases were washed with brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain crude product. Dissolve the crude product in dry dichloromethane (30 mL). Then, trifluoroacetic acid (10.0 mL, 134 mmol) was added at room temperature. After stirring for 2 hours, the mixture was poured into saturated sodium bicarbonate solution (50 mL). Separate the organic layer and extract the aqueous layer with dichloromethane (50 mL×3). The combined organic phases were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to obtain crude product S2. NHR ₂ (10 mmol) was dissolved in anhydrous dichloromethane (10 mL) and added dropwise to a solution of oxalyl chloride (1.29 mL, 15 mmol) in anhydrous dichloromethane (20 mL) at 0 °C. After stirring for 5 min, triethylamine (1.46 mL, 10.5 mmol) was added dropwise at 0 °C. Then, the mixture was stirred for further 6 hours at room temperature. Excess oxalyl chloride and solvent were removed under reduced pressure. Dissolve the crude product in dichloromethane (15 mL) and cool to 0 °C. A solution of compound S2 (2.5 g, 5 mmol) in dry dichloromethane (10 mL) was then added dropwise at 0 °C, followed by triethylamine (0.75 mL, 5.5 mmol). The mixture was then stirred at room temperature for 12 h and then quenched with water (20 mL). Separate the organic layer and extract the aqueous layer with dichloromethane (10 mL×3). The combined organic phases were washed with brine (20 mL) and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (DCM/EtOAc 100:1 v/v) to give the corresponding products L13–L15.

Using methanol as the solvent, Pd ₂ (dba) ₃ ·CHCl ₃ (1.25 mol%) as the catalyst, and the chiral glufosinate ligand L14 (structural formula shown in Figure 2, 2.5 mol%) as the ligand, the following substrate expansion experiment was carried out .

Embodiment 1

Pd ₂ (dba) ₃ ·CHCl ₃ (2.6 mg, 0.0025 mmol), chiral glufosinate ligand (4.2 mg, 0.005 mmol), 1a (61.9 mg, 0.2 mmol), 2 (44.7 mg) were added to the reaction bottle in sequence. , 0.2 mmol), add 2 mL methanol, stir and react at -10°C for 4 hours, the reaction system can be passed through simple column chromatography (eluent is ethyl acetate: petroleum ether = 1:5) to obtain the target product 3a (Yield: 96.9 mg, 91%), white solid, mp 51-52 ℃, 95% ee . The reaction was completed by stirring at -10°C for 4 hours.

Embodiment 2

Pd ₂ (dba) ₃ ·CHCl ₃ (2.6 mg, 0.0025 mmol), chiral glufosinate ligand (4.2 mg, 0.005 mmol), 1c (65.5 mg, 0.2 mmol), 2 (44.7 mg) were added to the reaction bottle in sequence. , 0.2 mmol), add 2 mL methanol, stir and react at -10°C for 4 hours, the reaction system can be passed through simple column chromatography (eluent is ethyl acetate: petroleum ether = 1:5) to obtain the target product 3c (Yield: 96.9 mg, 91%), white solid, mp 103-104 ℃, 95% ee .

Embodiment 3

Pd ₂ (dba) ₃ ·CHCl ₃ (2.6 mg, 0.0025 mmol), chiral glufosinate ligand (4.2 mg, 0.005 mmol), 1d (68.8mg, 0.2 mmol), 2 (44.7 mg) were added to the reaction bottle in sequence. , 0.2 mmol), add 2 mL methanol, stir and react at -10°C for 4 hours, the reaction system can be passed through simple column chromatography (eluent is ethyl acetate: petroleum ether = 1:5) to obtain the target product 3d (Yield: 109.0 mg, 96%), white solid, mp 46-47 ℃, 97% ee .

Embodiment 4

Pd ₂ (dba) ₃ ·CHCl ₃ (2.6 mg, 0.0025 mmol), chiral glufosinate ligand (4.2 mg, 0.005 mmol), 1f (67.9 mg, 0.2 mmol), 2 (44.7 mg) were added to the reaction bottle in sequence. , 0.2 mmol), add 2 mL methanol, stir and react at -10°C for 4 hours, and the reaction system can be passed through simple column chromatography (eluent is ethyl acetate: petroleum ether = 1:5) to obtain the target product 3f (Yield 101.4 mg, 90%), semi-solid, 93% ee .

Embodiment 5

Pd ₂ (dba) ₃ ·CHCl ₃ (2.6 mg, 0.0025 mmol), chiral glufosinate ligand (4.2 mg, 0.005 mmol), 1g (65.5mg, 0.2 mmol), 2 (44.7 mg) were added to the reaction bottle in sequence. , 0.2 mmol), add 2 mL methanol, stir and react at -10°C for 4 hours, the reaction system can be passed through simple column chromatography (eluent is ethyl acetate: petroleum ether = 1:5) to obtain 3g of the target product (Yield: 105.0 mg, 96%), white solid, mp 102-103 ℃, 91% ee .

Embodiment 6

Pd ₂ (dba) ₃ ·CHCl ₃ (2.6 mg, 0.0025 mmol), chiral glufosinate ligand (4.2 mg, 0.005 mmol), 1j (64.7mg, 0.2 mmol), 2 (44.7 mg) were added to the reaction bottle in sequence. , 0.2 mmol), add 2 mL methanol, stir and react at -10°C for 4 hours, the reaction system can be passed through simple column chromatography (eluent is ethyl acetate: petroleum ether = 1:5) to obtain the target product 3j (Yield: 108.9 mg, 99%), white solid, mp 46-47 ℃, 92% ee .

Embodiment 7

Pd ₂ (dba) ₃ ·CHCl ₃ (2.6 mg, 0.0025 mmol), chiral glufosinate ligand (4.2 mg, 0.005 mmol), 1k (67.9 mg, 0.2 mmol), 2 (44.7 mg) were added to the reaction bottle in sequence. , 0.2 mmol), add 2 mL methanol, stir and react at -10°C for 4 hours, the reaction system can be passed through simple column chromatography (eluent is ethyl acetate: petroleum ether = 1:5) to obtain the target product 3k (Yield: 101.1 mg, 89%), white solid, mp 51-52 ℃, 92% ee .

Claims

A method for synthesizing indolinone derivatives containing a butylene amine structure, which is characterized in that it includes the following steps: using 3-aryl indolinone and 2-vinyl aziridine as reactants, and using palladium salt and The phosphine ligand is the catalytic system, and the reaction yields an indolinone derivative containing a butylene amine structure.
The synthesis method of indolinone derivatives containing butylene amine structure according to claim 1, characterized in that the chemical structural formula of 3-aryl indolinone is:

The structural formula of indolinone derivatives containing butenamine structure is:

In the above chemical structural formula, R1 is selected from: hydrogen, 5-fluoro, chlorine, bromine, methyl, methoxy, 6-fluoro, chlorine, bromine, methoxy; R2 is selected from: hydrogen, 3- Trifluoromethyl, fluorine, chlorine, methyl, methoxy, 4-fluoro, chlorine, bromine, methyl, ethyl, methoxy, dimethylamino, tert-butyl, phenyl, 2,3,4 , 5,6-pentafluoro, 3,5-dimethyl.
The method for synthesizing an indolinone derivative containing a butenamine structure according to claim 1, wherein the chemical structural formula of 2-vinyl aziridine is:

.
The synthesis method of indolinone derivatives containing butenamine structure according to claim 1, characterized in that, 3-aryl indolinone and 2-vinyl aziridine are used as reactants, and palladium salt and The phosphine ligand is a catalytic system, which reacts in an organic solvent at -40°C to 30°C to obtain an indolinone derivative containing a butenamine structure.
The method for synthesizing an indolinone derivative containing a butylene amine structure according to claim 4, wherein the organic solvent is an ether solvent, a benzene solvent or an alcohol solvent.
The method for synthesizing an indolinone derivative containing a butylene amine structure according to claim 1, characterized in that: on a molar basis, the amount of the palladium salt is 1% to 10% of 3-aryl indolinone. ; The dosage of 2-vinyl aziridine is 0.5 to 2 times that of 3-aryl indolinone.
The synthesis method of indolinone derivatives containing butylene amine structure according to claim 1, characterized in that: the reaction time is 4 to 12 hours.
The method for synthesizing an indolinone derivative containing a butylene amine structure according to claim 1, characterized in that: the palladium salt is a palladium salt containing an organic group, and the phosphine ligand is a chiral phosphine phosphine ligand.
The indolinone derivative containing butenamine structure prepared according to the synthesis method of the indolone derivative containing butenylamine structure according to claim 1.
Application of palladium salt and phosphine ligand as catalytic system in the preparation of indolinone derivatives containing butenamine structure using 3-aryl indolinone and 2-vinyl aziridine as substrates. .