Roxane mechanical interlocking molecule as well as preparation method and application thereof

Abstract

The invention provides rotaxane mechanical interlocking molecules as well as a preparation method and application thereof. The rotaxane mechanical interlocking molecule disclosed by the invention is used as a catalyst intermediate of a Michael addition reaction and is subjected to an acid-base neutralization reaction with DBU (1, 8-diazabicyclo [5.4. 0] undec-7-ene), and the obtained reaction product can be used as a catalyst of the Michael addition reaction, so that the conversion rate of the Michael addition reaction is increased, and the yield of the Michael addition reaction is increased. The method plays an important role in the fields of chemical medicine raw material medicine, preparation manufacturing and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical drug raw materials and preparation manufacturing. More specifically, it relates to a kind of rotaxane mechanical interlocking molecule and its preparation method and application. BACKGROUND

[0002] Michael Addition is a classical organic reaction that constructs carbon-carbon or carbon-heteroatom bond by 1,4-conjugate addition of nucleophilic carbon anion (or equivalent nucleophile) to the β-carbon of α,β-unsaturated carbonyl compound (Michael acceptor). The core mechanism is divided into three steps: 1) generation of carbon anion: base (such as sodium ethoxide, LDA) removes α-hydrogen from active methylene compound (such as malonate, nitroalkane) or heteroatom-containing donor (such as thiol, amine) to form a resonance-stable carbon anion or enolate anion; 2) 1,4-conjugate addition: carbon anion attacks the β-carbon of α,β-unsaturated carbonyl compound (such as acrolein, methyl vinyl ketone), and the negative charge is dispersed by conjugation effect to form an enolate intermediate; 3) product stabilization: the enolate intermediate is protonated or tautomerized to form a thermodynamically stable product.

[0003] Michael Addition plays an important role in the manufacture of chemical drug raw materials and preparations, and is occasionally used in the field of gene engineering drugs and vaccine manufacturing. For example: 1) synthesis of vitamin B6 intermediate: Michael Addition of α,β-unsaturated aldehyde derivative and dibenzoylmethane can produce 1,5-dicarbonyl compound, which can generate vitamin B6 after cyclization; 2) synthesis of key intermediates of steroid hormone drugs: Robinson cyclization reaction can construct a six-membered ring structure with angular methyl group (such as hydrocortisone skeleton) through Michael Addition and intramolecular aldol condensation, which is the core skeleton of testosterone, estrogen, and progesterone, etc. steroid hormones; 3) biological coupling: through thiol-Michael Addition reaction, drug molecules (such as microtubule inhibitor MMAE) can be covalently linked to antibody carriers (such as anti-HER2 antibody trastuzumab) to prepare antibody-drug conjugates (ADC) for targeted cancer therapy, etc. SUMMARY

[0004] The present application aims to provide a kind of rotaxane mechanical interlocking molecule as Michael Addition catalyst intermediate, which undergoes acid-base neutralization reaction with DBU (1,8-diazabicyclo [5.4.0] undecane-7-ene), and the reaction product obtained can be used as a catalyst for Michael Addition reaction to improve the conversion rate of Michael Addition reaction.

[0005] The first object of the present application is to provide a kind of rotaxane mechanical interlocking molecule.

[0006] The second object of the present application is to provide a preparation method of the wheel-like mechanically interlocked molecule.

[0007] The third object of the present application is to provide an application of the wheel-like mechanically interlocked molecule.

[0008] The fourth object of the present application is to provide a wheel-like mechanically interlocked catalyst.

[0009] The fifth object of the present application is to provide an application of the wheel-like mechanically interlocked catalyst in catalyzing Michael addition reaction.

[0010] The sixth object of the present application is to provide a preparation method of the wheel-like mechanically interlocked catalyst.

[0011] The seventh object of the present application is to provide a preparation method of 1,5-dicarbonyl compound.

[0012] The above objects of the present application are achieved by the following technical solutions. The present application provides a wheel-like mechanically interlocked molecule, the structural formula of which is selected from: (1) a hetero[5]wheel-like mechanically interlocked molecule: ; (2) a hetero[3]wheel-like mechanically interlocked molecule: .

[0013] The present application further provides a preparation method of the wheel-like mechanically interlocked molecule, which is obtained by reacting diphenyl-24-crown-8 (DB24C8), benzo-21-crown-7 (B21C7), an isocyanate derivative and a rod-shaped compound. The isocyanate derivative is 1,6-hexane diisocyanate or 3,5-dimethylphenyl isocyanate. The structural formula of the rod-shaped compound is: .

[0014] Mechanically Interlocked Molecules (MIMs) refer to a structure formed by mechanical interlocking between at least two components in a molecule, which is characterized in that there is no direct covalent bond between the components, but the components cannot be separated without cutting the covalent bond, thereby ensuring that the mechanically interlocked molecules have high conformational freedom (such as elongation, rotation, sliding and twisting, etc.), while maintaining structural integrity. Mechanically interlocked molecules can be divided into rotaxanes, molecular knots, catenanes and the like according to the structure. The rotaxane type mechanically interlocked molecule has a rod-shaped molecule as an axle component and a ring-shaped molecule as a ring component, the rod-shaped molecule passes through the cavity of the ring-shaped molecule, and the ends are combined with a large volume molecule to prevent the rod-shaped molecule from sliding out. The present application uses diphenyl-24-crown-8 and benzene-21-crown-7 as the ring component of the rotaxane type mechanically interlocked molecule, uses the rod-shaped compound as the axle component, and uses the isocyanate derivative as the blocking group. At the same time, the hydroxyl group of the rod-shaped compound is used as a reaction group, which overcomes the technical problems that the preparation process of the existing rotaxane type mechanically interlocked molecule often needs to use heavy metals (such as tin ions, etc.) as catalysts. Under the condition of not adding catalyst, the rotaxane type mechanically interlocked molecule is prepared by one-pot method. This method not only can achieve 100% atom economy, meet the requirements of green chemistry, but also can achieve a yield of more than 65%, realize the efficient preparation of the rotaxane type mechanically interlocked molecule.

[0015] Preferably, the molar ratio of diphenyl-24-crown-8, benzene-21-crown-7, isocyanate derivative and rod-shaped compound is 28-37:28-37:9-42:18-25.

[0016] Further preferably, the molar ratio of diphenyl-24-crown-8, benzene-21-crown-7, 1,6-hexane diisocyanate and rod-shaped compound is 33-37:33-37:9-11:21-25; or the molar ratio of diphenyl-24-crown-8, benzene-21-crown-7, 3,5-dimethylphenyl isocyanate and rod-shaped compound is 28-32:28-32:38-42:18-22.

[0017] Most preferably, the molar ratio of diphenyl-24-crown-8, benzene-21-crown-7, 1,6-hexane diisocyanate and rod-shaped compound is 35:35:10:23; or the molar ratio of diphenyl-24-crown-8, benzene-21-crown-7, 3,5-dimethylphenyl isocyanate and rod-shaped compound is 30:30:40:20.

[0018] Preferably, the preparation method is: after dibenzo-24-crown-8, benzo-21-crown-7 and rod-shaped compound are assembled to form pseudorotaxane, the rotaxane-based mechanically interlocked molecule is formed by capping with isocyanate derivative.

[0019] The synthesis route of the rotaxane-based mechanically interlocked molecule is as follows:

[0020] Or .

[0021] Further preferably, the temperature of the assembly is 20-30 ℃.

[0022] Further preferably, the assembly time is 1.8-2.2 h. Most preferably, it is 2 h.

[0023] Further preferably, the capping temperature is 20-30 ℃.

[0024] Further preferably, the capping time is 45-50 h. Most preferably, it is 48 h.

[0025] Preferably, the reaction is carried out in an organic solvent, which is chloroform and acetonitrile in a volume ratio of 4.8-5.2:1. The amount of the organic solvent is enough to dissolve the reaction raw materials.

[0026] Preferably, the reaction is carried out in an inert atmosphere.

[0027] Further preferably, the inert atmosphere is argon atmosphere, nitrogen atmosphere or helium atmosphere.

[0028] Preferably, the reaction is also carried out with stirring.

[0029] Further preferably, the stirring speed is 500-1000 rpm.

[0030] Preferably, after the reaction, washing, drying and purification are sequentially carried out.

[0031] Further preferably, the washing is washing with water.

[0032] Further preferably, the washing is 3-5 times.

[0033] Further preferably, the purification is carried out by column chromatography.

[0034] More preferably, the eluent used in the column chromatography is dichloromethane and methanol in a volume ratio of 19-21:1. Most preferably, it is dichloromethane and methanol in a volume ratio of 20:1.

[0035] More preferably, the packing used in the column chromatography is silica gel.

[0036] The wheel-like mechanical interlocking molecule as a catalyst intermediate of the Michael addition reaction, and the reaction product (wheel-like mechanical interlocking catalyst) obtained by the acid-base neutralization reaction with DBU can be used as a catalyst for the Michael addition reaction, and has a better catalytic effect on the Michael addition reaction. Therefore, the application also provides an application of the wheel-like mechanical interlocking molecule, which is specifically: synthesizing a wheel-like mechanical interlocking catalyst by the acid-base neutralization reaction with DBU.

[0037] Preferably, the molar ratio of the wheel-like mechanical interlocking molecule to DBU is 1:2-4.

[0038] Preferably, the temperature of the acid-base neutralization reaction is 20-30 ℃, and most preferably 25 ℃.

[0039] Preferably, the time of the acid-base neutralization reaction is 25-35 min, and most preferably 30 min.

[0040] Preferably, the acid-base neutralization reaction is also stirred at the same time, such as stirring at 500-1000 rpm.

[0041] Preferably, the acid-base neutralization reaction is carried out in an organic solvent, such as dichloromethane. The amount of the organic solvent is enough to dissolve the raw materials of the reaction.

[0042] The wheel-like mechanical interlocking catalyst has a better catalytic effect on the Michael addition reaction, and therefore the application also provides a wheel-like mechanical interlocking catalyst and its application in catalyzing the Michael addition reaction.

[0043] The structural formula of the wheel-like mechanical interlocking catalyst is selected from: (1) a hetero[5]wheel-like mechanical interlocking catalyst: ; (2) a hetero[3]wheel-like mechanical interlocking catalyst: .

[0044] Preferably, the Michael addition reaction is a Michael addition reaction of an α,β-unsaturated aldehyde derivative and dibenzoylmethane.

[0045] Further preferably, the structural formula of the α,β-unsaturated aldehyde derivative is: , wherein R=Me, Et or CH2Ph.

[0046] Preferably, the molar ratio of the wheel-like mechanical interlocking catalyst, the α,β-unsaturated aldehyde derivative and dibenzoylmethane is 0.8-1.2:1.8-2.2:1.

[0047] Preferably, the temperature of the Michael addition reaction is -25 to -15℃, and most preferably -20℃.

[0048] Preferably, the time of the Michael addition reaction is 30 to 40 h, and most preferably 36 h.

[0049] Preferably, the Michael addition reaction is accompanied by stirring, such as stirring at 500 to 1000 rpm.

[0050] Preferably, the Michael addition reaction is carried out in an organic solvent, such as dichloromethane. The amount of the organic solvent is sufficient to dissolve the raw materials of the reaction.

[0051] Preferably, the Michael addition reaction is followed by post-treatment, such as washing, drying, and purification in sequence.

[0052] Further preferably, the washing is washing with water.

[0053] Further preferably, the drying is drying with anhydrous sodium sulfate.

[0054] Further preferably, the purification is carried out by column chromatography.

[0055] More preferably, the eluent used in the column chromatography is petroleum ether and ethyl acetate in a volume ratio of 14 to 15:1. Most preferably, the eluent is petroleum ether and ethyl acetate in a volume ratio of 15:1.

[0056] More preferably, the packing material used in the column chromatography is silica gel.

[0057] Based on this, the application further provides a preparation method of the rotaxane mechanical interlocking catalyst, specifically: subjecting the rotaxane mechanical interlocking molecule to an acid-base neutralization reaction with DBU to obtain the rotaxane mechanical interlocking catalyst.

[0058] The synthetic route of the rotaxane mechanical interlocking catalyst is as shown below:

[0059] Alternatively .

[0060] In addition, the application further provides a preparation method of a 1,5-dicarbonyl compound, specifically: subjecting an α,β-unsaturated aldehyde derivative to a Michael addition reaction with dibenzoylmethane under the catalysis of the rotaxane mechanical interlocking catalyst to obtain the 1,5-dicarbonyl compound.

[0061] Preferably, the α,β-unsaturated aldehyde derivative has the following structural formula: , wherein R = Me, Et, or CH2Ph.

[0062] 1,5-dicarbonyl compound synthesis route is shown as follows: wherein, R = Me, Et or CH2Ph.

[0063] The present application has the following beneficial effects: 1. The wheel-shaped mechanical interlocking molecule of the present application as a catalyst intermediate of Michael addition reaction, undergoes acid-base neutralization reaction with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and the obtained reaction product can be used as a catalyst for Michael addition reaction, thereby improving the conversion rate of Michael addition reaction.

[0064] 2. The present application uses dibenzo-24-crown-8 and benzo-21-crown-7 as the ring component of the wheel-shaped mechanical interlocking molecule, uses a rod-shaped compound as the shaft component, uses an isocyanate derivative as the blocking group, and simultaneously uses the hydroxyl group of the rod-shaped compound as a reaction group to prepare the wheel-shaped mechanical interlocking molecule by one-pot method without adding a catalyst, thereby avoiding the environmental pollution risk caused by the use of heavy metal catalysts and having industrial feasibility. The preparation process of the present application is simple, the atomic economy reaches 100%, and meets the requirements of green chemistry. Moreover, under the process of the present application, the yield of the wheel-shaped mechanical interlocking molecule can reach more than 65%, thereby providing an efficient raw material preparation process for the fields of molecular machines, reaction intermediates, catalysts, drug delivery systems, etc. BRIEF DESCRIPTION OF DRAWINGS

[0065] Figure 1 NMR spectrum of the hetero[5] wheel-shaped mechanical interlocking molecule obtained in Example 1.

[0066] Figure 2 NMR spectrum of the hetero[5] wheel-shaped mechanical interlocking molecule obtained in Example 1.

[0067] Figure 3 High-resolution electrospray ionization mass spectrum of the hetero[5] wheel-shaped mechanical interlocking molecule obtained in Example 1.

[0068] Figure 4 Homonuclear hydrogen hydrogen correlation spectrum of the hetero[5] wheel-shaped mechanical interlocking molecule obtained in Example 1.

[0069] Figure 5 Homonuclear rotating coordinate system NOE spectrum of the hetero[5] wheel-shaped mechanical interlocking molecule obtained in Example 1.

[0070] Figure 6 NMR spectrum of the hetero[3] wheel-shaped mechanical interlocking molecule obtained in Example 4.

[0071] Figure 7NMR carbon spectrum of the hetero[3]rotaxane-based mechanically interlocked molecule obtained in Example 4.

[0072] Figure 8 High resolution electrospray ionization mass spectrum of the hetero[3]rotaxane-based mechanically interlocked molecule obtained in Example 4.

[0073] Figure 9 Homonuclear hydrogen hydrogen correlation spectrum of the hetero[3]rotaxane-based mechanically interlocked molecule obtained in Example 4.

[0074] Figure 10 Homonuclear rotating frame NOE spectrum of the hetero[3]rotaxane-based mechanically interlocked molecule obtained in Example 4.

[0075] Figure 11 NMR hydrogen spectrum of the main product dot obtained in Comparative Example 1.

[0076] Figure 12 NMR hydrogen spectrum of the main product dot obtained in Comparative Example 2.

[0077] Figure 13 NMR hydrogen spectrum of the main product dot obtained in Comparative Example 3.

[0078] Figure 14 NMR hydrogen spectrum of the main product dot obtained in Comparative Example 4.

[0079] Figure 15 NMR hydrogen spectrum of the main product dot obtained in Comparative Example 5. DETAILED DESCRIPTION

[0080] The present application will be further described with reference to the drawings and specific examples, but the examples do not limit the present application in any form. Unless otherwise specified, the reagents, methods and apparatus used in the present application are conventional reagents, methods and apparatus in the art.

[0081] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0082] Example 1 Preparation of a rotaxane-based mechanically interlocked molecule, a hetero[5]rotaxane-based mechanically interlocked molecule 0.35 mmol dibenzo-24-crown-8, 0.35 mmol benzo-21-crown-7 and 0.23 mmol rod-shaped compound were dissolved in 6 mL organic solvent (chloroform and acetonitrile in a volume ratio of 5:1). The mixture was stirred for 2 h at 25 °C and 800 rpm under an argon atmosphere. Then 0.10 mmol 1,6-hexamethylene diisocyanate was added, and the mixture was stirred for 48 h at 25 °C and 800 rpm under an argon atmosphere to obtain an organic phase. The organic phase was washed with 10 mL deionized water (repeated 3 times), dried with anhydrous sodium sulfate for 30 min, filtered, and the filtrate was evaporated to dryness. The filtrate was then purified by silica gel column chromatography (eluent was dichloromethane and methanol in a volume ratio of 20:1) to obtain 0.241 g of yellow solid hetero[5] rotaxane mechanically interlocked molecules (yield 66.8%).

[0083] The structure of the hetero[5]rotaxane mechanically interlocked molecules obtained in this embodiment was characterized: (1) Proton nuclear magnetic resonance spectrum 1 H NMR 10.0 mg of hetero[5]rotaxane mechanically interlocked molecules were dissolved in 0.6 mL of deuterated chloroform and measured using a Bruker AV-400 spectrometer. The protons of the molecules were assigned to the corresponding protons, and the resulting proton NMR spectrum was obtained. 1 H NMR, CDCl3, 400 MHz, 298K (e.g.) Figure 1 As shown.

[0084] (2) Carbon nuclear magnetic resonance spectrum 13 C NMR 10.0 mg of hetero[5] rotaxane mechanically interlocked molecules were dissolved in 0.6 mL of deuterated chloroform and measured using a Bruker AV-400 spectrometer. The carbon atoms were assigned to the molecules, and the resulting carbon NMR spectrum was obtained. 13 (C NMR, CDCl3, 100 MHz, 298K) Figure 2 As shown.

[0085] (3) High-resolution electrospray ionization mass spectrometry (HRESI-MS) The molecular weight of hetero[5]rotaxane mechanically interlocked molecules was analyzed using Waters LCT Premier XE high-resolution electrospray ionization mass spectrometry. The obtained high-resolution electrospray ionization mass spectra are shown below. Figure 3 As shown, [M-2PF6] can be seen. 2+ (1422.8095), [M-3PF6] 3+ (899.7936), [M-4PF6] 4+ (638.6031), [M+8D-8H-2PF6] 2+(1427.8439), [M+H2O-2PF6] 2+ (1431.7839), [M+6D-6H+H2O-2PF6] 2+ (1434.8253), [M+CH3OH-3PF6] 3+ (911.5356) molecular ion peak.

[0086] (4) Homonuclear hydrogen-hydrogen correlation spectrum 1 H- 1 H COSY The homonuclear hydrogen-hydrogen correlation spectra of hetero[5]rotaxane mechanically interlocked molecules were measured ( 1 H- 1 H COSY, CDCl3, 400MHz, 298K (e.g., H COSY, CDCl3, 400MHz, 298K) Figure 4 As shown in the figure. The cross peak CP1 indicates H d H f respectively with H e There is a correlation; the cross peak CP2 indicates that H i With H j There is a correlation; the cross peak CP3 indicates that H k With H j There is a correlation; the cross peak CP4 indicates that the protons H on the B21C7 ring are related to H. t There is a correlation; the cross peak CP5 indicates that H o With H n There is a correlation; the cross peak CP6 indicates that H p With H q There is a correlation; the cross peak CP7 indicates that H m With H l There is a correlation.

[0087] (5) NOE spectrum in a rotating coordinate system with the same nucleus HH ROESY The NOE spectra of hetero[5]rotaxane mechanically interlocked molecules in the same nucleus rotating coordinate system (HH ROESY, CDCl3, 400 MHz, 298 K) were measured as follows: Figure 5 As shown in the figure. The cross peak CP1 indicates H g H h There is a spatial correlation between H and the proton H on the DB24C8 ring, and the cross peak CP2 indicates that H d With H c Spatial correlation exists, and the cross-peak CP3 indicates that H o With H r Spatial correlation exists, and the cross-peak CP4 indicates that H a With H bThere is a spatial correlation, the cross peaks CP5, CP6 and CP7 indicate that the protons H on the B21C7 ring are correlated with H n , H m There is a spatial correlation.

[0088] In summary, the structure of the yellow solid obtained in this example can be determined by combining the results of the proton nuclear magnetic resonance spectrum 1 H NMR, carbon nuclear magnetic resonance spectrum 13 C NMR, high-resolution electrospray ionization mass spectrum HRESI-MS, homonuclear hydrogen correlation spectrum 1 H- 1 H COSY, homonuclear rotating frame NOE spectrum H-H ROESY, and the structure of the yellow solid obtained in this example is determined to be the hetero[5]rotaxane-based mechanically interlocked molecule, and the structure is as follows: ; The reaction equation of this example is shown as follows: .

[0089] Example 2 Preparation of a rotaxane-based mechanically interlocked molecule, a hetero[5]rotaxane-based mechanically interlocked molecule Dissolve 0.33 mmol of dicyclo-24-crown-8, 0.33 mmol of benzo-21-crown-7, and 0.21 mmol of the rod-shaped compound in 6 mL of an organic solvent (chloroform and acetonitrile in a volume ratio of 4.8:1), stir under an argon atmosphere at 20°C at 1000 rpm for 2.2 h, then add 0.09 mmol of 1,6-hexane diisocyanate, and continue to stir under an argon atmosphere at 20°C at 1000 rpm for 50 h to obtain an organic phase. Wash the organic phase with 10 mL of deionized water (repeat 3 times), then dry with anhydrous sodium sulfate for 25 min, then perform suction filtration, and then rotary evaporate the filtrate to obtain a yellow solid hetero[5]rotaxane-based mechanically interlocked molecule (yield 66.5%).

[0090] In this example, the same method as in Example 1 is used to determine the proton nuclear magnetic resonance spectrum 1 H NMR chart, carbon nuclear magnetic resonance spectrum 13 C NMR chart, high-resolution electrospray ionization mass spectrum HRESI-MS chart, homonuclear hydrogen correlation spectrum 1 H- 1 H COSY chart, homonuclear rotating frame NOE spectrum H-H ROESY chart, and it can be determined that the structure is the same as in Example 1.

[0091] Example 3 Preparation of a rotaxane-based mechanically interlocked molecule, a hetero[5]rotaxane-based mechanically interlocked molecule Dissolve 0.37 mmol of dibenzo-24-crown-8, 0.37 mmol of benzo-21-crown-7 and 0.25 mmol of the rod compound in 6 mL of organic solvent (volume ratio of chloroform to acetonitrile of 5.2:1), stir under argon atmosphere at 30 °C at 500 rpm for 1.8 h, then add 0.11 mmol of 1,6-hexane diisocyanate, continue to stir under argon atmosphere at 30 °C at 500 rpm for 45 h to obtain an organic phase. Wash the organic phase with 10 mL of deionized water (repeat 5 times), then dry with anhydrous sodium sulfate for 35 min, then suction filter, take the filtrate and rotary evaporate, then purify by silica gel column chromatography (eluent is volume ratio of dichloromethane to methanol of 21:1) to obtain 0.261 g of yellow solid hetero[5]rotaxane-based mechanically interlocked molecule (yield 66.6%).

[0092] In this example, the same method as in Example 1 was used to determine the nuclear magnetic resonance hydrogen spectrum of the product 1 H NMR chart, nuclear magnetic resonance carbon spectrum 13 C NMR chart, high-resolution electrospray ionization mass spectrum HR ESI-MS chart, homonuclear hydrogen hydrogen correlation spectroscopy 1 H- 1 H COSY chart, homonuclear rotating coordinate system NOE spectroscopy H-H ROESY chart, which can determine that the structure is the same as that of Example 1.

[0093] Example 4 Preparation of rotaxane-based mechanically interlocked molecule-hetero[3]rotaxane-based mechanically interlocked molecule Dissolve 0.30 mmol of dibenzo-24-crown-8, 0.30 mmol of benzo-21-crown-7 and 0.20 mmol of the rod compound in 6 mL of organic solvent (volume ratio of chloroform to acetonitrile of 5:1), stir under argon atmosphere at 25 °C at 800 rpm for 2 h, then add 0.40 mmol of 3,5-dimethylphenyl isocyanate, continue to stir under argon atmosphere at 25 °C at 800 rpm for 48 h to obtain an organic phase. Wash the organic phase with 10 mL of deionized water (repeat 3 times), then dry with anhydrous sodium sulfate for 30 min, then suction filter, take the filtrate and rotary evaporate, then purify by silica gel column chromatography (eluent is volume ratio of dichloromethane to methanol of 20:1) to obtain 0.236 g of yellow solid hetero[3]rotaxane-based mechanically interlocked molecule (yield 72.4%).

[0094] The structure of the hetero[3]rotaxane-based mechanically interlocked molecule obtained in this example was characterized: (1) Nuclear magnetic resonance hydrogen spectrum 1 H NMR 10.0 mg of hetero[3]rotaxane mechanically interlocked molecules were dissolved in 0.6 mL of deuterated chloroform and measured using a Bruker AV-400 spectrometer. The protons of the molecules were assigned to the corresponding protons, and the resulting proton NMR spectrum was obtained. 1 H NMR, CDCl3, 400 MHz, 298K (e.g.) Figure 6 As shown.

[0095] (2) Carbon nuclear magnetic resonance spectrum 13 C NMR 10.0 mg of hetero[3]rotaxane mechanically interlocked molecules were dissolved in 0.6 mL of deuterated chloroform and measured using a Bruker AV-400 spectrometer. The carbon atoms were assigned to the molecules, and the resulting carbon NMR spectrum was obtained. 13 (C NMR, CDCl3, 100 MHz, 298K) Figure 7 As shown.

[0096] (3) High-resolution electrospray ionization mass spectrometry (HRESI-MS) The molecular weight of hetero[3]rotaxane mechanically interlocked molecules was analyzed using Waters LCT Premier XE high-resolution electrospray ionization mass spectrometry. The obtained high-resolution electrospray ionization mass spectra are shown below. Figure 8 As shown, [M+2D-2H-PF6] can be seen. + (1486.5176), [M+H2O-PF6] + (1501.4092), [M+CH3OH-2PF6] 2+ (685.4321) molecular ion peak.

[0097] (4) Homonuclear hydrogen-hydrogen correlation spectrum 1 H- 1 H COSY The homonuclear hydrogen-hydrogen correlation spectra of hetero[3]rotaxane mechanically interlocked molecules were measured ( 1 H- 1 H COSY, CDCl3, 400MHz, 298K (e.g., H COSY, CDCl3, 400MHz, 298K) Figure 9 As shown in the figure. The cross peak CP1 indicates H d H f respectively with H e There is a correlation; the cross peak CP2 indicates that H j With H k There is a correlation; CP3 indicates that H v With H w There is a correlation; the cross peak CP4 indicates that H x With H w There is a correlation; the cross peak CP5 indicates that H o With Hn There is a correlation; the cross peak CP6 indicates that H k With H l There is a correlation.

[0098] (5) NOE spectrum in a rotating coordinate system with the same nucleus HH ROESY The NOE spectra of hetero[3]rotaxane mechanically interlocked molecules in the same nucleus rotating coordinate system (HH ROESY, CDCl3, 400 MHz, 298 K) were measured as follows: Figure 10 As shown in the figure. The cross peak CP1 indicates H d H f There is a spatial correlation between the H proton on the aromatic ring of B21C7 and the cross peak CP2, indicating that H... d With H c Spatial correlation exists, and the cross-peak CP3 indicates that H a With H b Spatial correlation exists, and the cross-peak CP4 indicates that H w With H r Spatial correlation exists, and the cross-peak CP5 indicates that the protons H on the B21C7 ring are related to H. i Spatial correlation exists, and the cross peak CP6 indicates that H k With H i Spatial correlation exists, and the cross peak CP7 indicates that H n With H o Spatial correlation exists, and the cross-peak CP8 indicates that H u With H o Spatial correlation exists, and the cross-peak CP9 indicates that the protons H on the B21C7 ring are related to H. m Spatial correlation exists, and the cross-peak CP10 indicates that H k With H u Spatial correlation exists.

[0099] In summary, combining the hydrogen nuclear magnetic resonance spectrum... 1 H NMR, carbon NMR spectrum 13 C10 NMR, high-resolution electrospray ionization mass spectrometry (HRESI-MS), homonuclear hydrogen-hydrogen correlation spectroscopy 1 H- 1 The results of H COSY and NOE spectra in the same nucleus rotating coordinate system confirm that the yellow solid obtained in this embodiment is a hetero[3]rotaxane mechanically interlocked molecule, and its structure is as follows: ; The reaction equation for this embodiment is shown below: .

[0100] Example 5 Preparation of a rotaxane-based mechanically interlocked molecule, a hetero[3]rotaxane-based mechanically interlocked molecule Dissolve 0.28 mmol of dibenzo-24-crown-8, 0.28 mmol of benzo-21-crown-7 and 0.18 mmol of the rod compound in 6 mL of an organic solvent (volume ratio of 4.8:1 of chloroform and acetonitrile), stir under argon atmosphere, 20 °C, 1000 rpm for 2.2 h, then add 0.38 mmol of 3,5-dimethylphenyl isocyanate, continue to stir under argon atmosphere, 20 °C, 1000 rpm for 50 h to obtain an organic phase. Wash the organic phase with 10 mL of deionized water (repeat 3 times), then dry with anhydrous sodium sulfate for 25 min, then suction filter, take the filtrate and rotary evaporate, then purify by silica gel column chromatography (eluent is volume ratio of 19:1 of dichloromethane and methanol) to obtain 0.212 g of yellow solid hetero[3]rotaxane-based mechanically interlocked molecule (yield 72.2%).

[0101] In this example, the same method as in Example 4 is used to determine the hydrogen nuclear magnetic resonance spectrum of the product 1 H NMR chart, carbon nuclear magnetic resonance spectrum 13 C NMR chart, high resolution electrospray ionization mass spectrum HR ESI-MS chart, homonuclear hydrogen hydrogen correlation spectroscopy 1 H- 1 H COSY chart, homonuclear rotating coordinate system NOE spectrum H-H ROESY chart, which can determine that the structure is the same as that of Example 4.

[0102] Example 6 Preparation of a rotaxane-based mechanically interlocked molecule, a hetero[3]rotaxane-based mechanically interlocked molecule Dissolve 0.32 mmol of dibenzo-24-crown-8, 0.32 mmol of benzo-21-crown-7 and 0.22 mmol of the rod compound in 6 mL of an organic solvent (volume ratio of 5.2:1 of chloroform and acetonitrile), stir under argon atmosphere, 30 °C, 500 rpm for 1.8 h, then add 0.42 mmol of 3,5-dimethylphenyl isocyanate, continue to stir under argon atmosphere, 30 °C, 500 rpm for 45 h to obtain an organic phase. Wash the organic phase with 10 mL of deionized water (repeat 5 times), then dry with anhydrous sodium sulfate for 35 min, then suction filter, take the filtrate and rotary evaporate, then purify by silica gel column chromatography (eluent is volume ratio of 21:1 of dichloromethane and methanol) to obtain 0.260 g of yellow solid hetero[3]rotaxane-based mechanically interlocked molecule (yield 72.5%).

[0103] In this example, the same method as in Example 4 is used to determine the hydrogen nuclear magnetic resonance spectrum of the product 1 H NMR chart, carbon nuclear magnetic resonance spectrum 13C NMR plot, high resolution electrospray ionization mass spectrometry HR ESI-MS plot, homonuclear hydrogen hydrogen correlation spectroscopy 1 H- 1 H COSY plot, homonuclear rotating frame NOE spectroscopy H-H ROESY plot, which confirmed the same structure as Example 4.

[0104] Comparative Example 1 The same as Example 1, except that 3 drops of dibutyltin dilaurate (DBTDL) were added at the same time as the 0.10 mmol 1,6-hexane diisocyanate. That is, the present comparative example is as follows: Dissolve 0.35 mmol dibenzo-24-crown-8, 0.35 mmol benzo-21-crown-7 and 0.23 mmol rod-shaped compound in 6 mL organic solvent (volume ratio 5:1 chloroform and acetonitrile), stir for 2 h under argon atmosphere, 25 °C, 800 rpm, then add 0.10 mmol 1,6-hexane diisocyanate and 3 drops of dibutyltin dilaurate (DBTDL), continue to stir under argon atmosphere, 25 °C, 800 rpm for 48 h, to obtain an organic phase. Wash the organic phase with 10 mL deionized water (repeat 3 times), then dry with anhydrous sodium sulfate for 30 min, then suction filter, take the filtrate and rotary evaporate, then purify by silica gel column chromatography (eluent is volume ratio 20:1 dichloromethane and methanol).

[0105] The main product point obtained by silica gel column chromatography is characterized by nuclear magnetic resonance hydrogen spectrum, and the obtained nuclear magnetic resonance hydrogen spectrum (400 MHz, CDC13, 298 K) is as shown in 1 H NMR, CDC13, 400 MHz, 298 K) as Figure 11 shown. It can be seen that the main product obtained in the present comparative example does not have a mechanical interlocking structure.

[0106] Comparative Example 2 The same as Example 1, except that 3 drops of stannous octoate were added at the same time as the 0.10 mmol 1,6-hexane diisocyanate. That is, the present comparative example is as follows: Dissolve 0.35 mmol dibenzo-24-crown-8, 0.35 mmol benzo-21-crown-7 and 0.23 mmol rod-shaped compound in 6 mL organic solvent (volume ratio 5:1 chloroform and acetonitrile), stir for 2 h under argon atmosphere, 25 °C, 800 rpm, then add 0.10 mmol 1,6-hexane diisocyanate and 3 drops of stannous octoate, continue to stir under argon atmosphere, 25 °C, 800 rpm for 48 h, to obtain an organic phase. Wash the organic phase with 10 mL deionized water (repeat 3 times), then dry with anhydrous sodium sulfate for 30 min, then suction filter, take the filtrate and rotary evaporate, then purify by silica gel column chromatography (eluent is volume ratio 20:1 dichloromethane and methanol).

[0107] The main product point obtained by silica gel column chromatography was characterized by nuclear magnetic resonance hydrogen spectrum, and the obtained nuclear magnetic resonance hydrogen spectrum (H NMR, CDC13, 400 MHz, 298 K) was as shown in Figure 2. 1 H NMR, CDC13, 400 MHz, 298 K) was as shown in Figure 2. Figure 12 As can be seen, the main product obtained in the present comparative example does not have a mechanical interlocking structure.

[0108] Comparative Example 3 The same as Example 1, except that 3 drops of dibutyltin diacetate were added at the same time as the addition of 0.10 mmol of 1,6-hexane diisocyanate. That is, the present comparative example is as follows: The 0.35 mmol of dibenzo-24-crown-8, 0.35 mmol of benzo-21-crown-7 and 0.23 mmol of rod-shaped compound were dissolved in 6 mL of organic solvent (volume ratio of chloroform to acetonitrile of 5:1), stirred under an argon atmosphere at 25 °C at 800 rpm for 2 h, then 0.10 mmol of 1,6-hexane diisocyanate and 3 drops of dimethyltin dilaurate were added, and stirring was continued under an argon atmosphere at 25 °C at 800 rpm for 48 h to obtain an organic phase. The organic phase was washed with 10 mL of deionized water (repeated 3 times), then dried with anhydrous sodium sulfate for 30 min, and then filtered under suction, and the filtrate was rotary evaporated, and then purified by silica gel column chromatography (eluent: volume ratio of dichloromethane to methanol of 20:1).

[0109] The main product point obtained by silica gel column chromatography was characterized by nuclear magnetic resonance hydrogen spectrum, and the obtained nuclear magnetic resonance hydrogen spectrum (H NMR, CDC13, 400 MHz, 298 K) was as shown in Figure 2. 1 H NMR, CDC13, 400 MHz, 298 K) was as shown in Figure 2. Figure 13 As can be seen, the main product obtained in the present comparative example does not have a mechanical interlocking structure.

[0110] Comparative Example 4 The same as Example 1, except that 3 drops of dibutyltin diacetate were added at the same time as the addition of 0.10 mmol of 1,6-hexane diisocyanate. That is, the present comparative example is as follows: Dissolve 0.35 mmol of dibenzo-24-crown-8, 0.35 mmol of benzo-21-crown-7 and 0.23 mmol of the rod compound in 6 mL of organic solvent (volume ratio of chloroform to acetonitrile of 5:1), stir under argon atmosphere at 25 °C at 800 rpm for 2 h, then add 0.10 mmol of 1,6-hexane diisocyanate and 3 drops of dibutyl tin diacetate, continue to stir under argon atmosphere at 25 °C at 800 rpm for 48 h to obtain an organic phase. Wash the organic phase with 10 mL of deionized water (repeat 3 times), then dry with anhydrous sodium sulfate for 30 min, then suction filter, take the filtrate to rotary evaporation, then purify by silica gel column chromatography (eluent is dichloromethane to methanol at a volume ratio of 20:1).

[0111] The main product point obtained by silica gel column chromatography is characterized by nuclear magnetic resonance hydrogen spectrum, and the obtained nuclear magnetic resonance hydrogen spectrum (H NMR, CDC13, 400 MHz, 298 K) is as shown in 1 H NMR, CDC13, 400 MHz, 298 K) is as shown in Figure 14 It can be seen that the main product obtained in the present example does not have a mechanical interlocking structure.

[0112] Comparative Example 5 The same as Example 1, except that 3 drops of dimethyl tin diacetate are added at the same time as 0.10 mmol of 1,6-hexane diisocyanate. That is, the present comparative example is as follows: Dissolve 0.35 mmol of dibenzo-24-crown-8, 0.35 mmol of benzo-21-crown-7 and 0.23 mmol of the rod compound in 6 mL of organic solvent (volume ratio of chloroform to acetonitrile of 5:1), stir under argon atmosphere at 25 °C at 800 rpm for 2 h, then add 0.10 mmol of 1,6-hexane diisocyanate and 3 drops of dibutyl tin diacetate, continue to stir under argon atmosphere at 25 °C at 800 rpm for 48 h to obtain an organic phase. Wash the organic phase with 10 mL of deionized water (repeat 3 times), then dry with anhydrous sodium sulfate for 30 min, then suction filter, take the filtrate to rotary evaporation, then purify by silica gel column chromatography (eluent is dichloromethane to methanol at a volume ratio of 20:1).

[0113] The main product point obtained by silica gel column chromatography is characterized by nuclear magnetic resonance hydrogen spectrum, and the obtained nuclear magnetic resonance hydrogen spectrum (H NMR, CDC13, 400 MHz, 298 K) is as shown in 1 H NMR, CDC13, 400 MHz, 298 K) is as shown in Figure 15 It can be seen that the main product obtained in the present example does not have a mechanical interlocking structure.

[0114] The aforementioned dibutyltin dilaurate, stannous octoate, dimethyltin dilaurate, dibutyltin diacetate and dimethyltin diacetate are commonly used to catalyze the preparation of rotaxane-based mechanically interlocked molecules, but in the present application, dibenzo-24-crown-8 and benzo-21-crown-7 are used as the ring component of the rotaxane-based mechanically interlocked molecules, a rod-shaped compound is used as the axle component, and an isocyanate derivative is used as the blocking group, and meanwhile, the hydroxyl group of the rod-shaped compound is used as the reaction group, and as a result, it is unexpectedly found that the process can achieve a rotaxane-based mechanically interlocked molecule yield of more than 65% without using a catalyst, which is significantly higher than the process using a catalyst.

[0115] Application Example 1 Application of Rotaxane-Based Mechanically Interlocked Molecules - Hetero[5]rotaxane-Based Mechanically Interlocked Molecules S1. Preparation of Hetero[5]rotaxane-Based Mechanically Interlocked Catalyst 1 mol of hetero[5]rotaxane-based mechanically interlocked molecules and 4 mol of DBU were dissolved in dichloromethane, stirred at 25 ℃ and 800 rpm for 30 min to obtain the hetero[5]rotaxane-based mechanically interlocked catalyst.

[0116] The synthesis route is as follows: .

[0117] S2. Preparation of 1,5-Dicarbonyl Compounds 1-3 1 / 10 volume of the product of S1 (containing 0.1 mol of hetero[5]rotaxane-based mechanically interlocked catalyst), 0.2 mol of α,β-unsaturated aldehyde derivative and 0.1 mol of dibenzoylmethane were added, stirred at -20 ℃ and 800 rpm for 36 h, and then sequentially subjected to water washing, anhydrous sodium sulfate drying and silica gel column chromatography purification (eluent: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain 1,5-dicarbonyl compounds 1-3; wherein the structure of the α,β-unsaturated aldehyde derivative is as follows: , and R is Me, Et or CH2Ph (corresponding to 1,5-dicarbonyl compounds 1-3, respectively).

[0118] The synthesis route is as follows: wherein R = Me, Et or CH2Ph.

[0119] Application Example 2 Application of Rotaxane-Based Mechanically Interlocked Molecules - Hetero[3]rotaxane-Based Mechanically Interlocked Molecules S1. Preparation of Hetero[3]rotaxane-Based Mechanically Interlocked Catalyst 1 mol of hetero[3]rotaxane-based mechanically interlocked molecules and 2 mol of DBU were dissolved in dichloromethane, stirred at 25 ℃ and 800 rpm for 30 min to obtain the hetero[3]rotaxane-based mechanically interlocked catalyst.

[0120] The synthetic route is as follows: .

[0121] S2. Preparation of 1,5-dicarbonyl compounds 4-6 Take 1 / 10 volume of the product of S1 (containing 0.1 mol of hetero[3]rotaxane mechanical interlocking catalyst), and then add 0.22 mol of α,β-unsaturated aldehyde derivative, 0.1 mol of dibenzoylmethane, stir at -20 ℃, 800 rpm for 36 h, and sequentially go through water washing, anhydrous sodium sulfate drying, silica gel column chromatography purification (eluent is petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain 1,5-dicarbonyl compounds 4-6; wherein the structural formula of the α,β-unsaturated aldehyde derivative is: , and R is Me, Et, CH2Ph respectively (corresponding to 1,5-dicarbonyl compounds 4-6 respectively).

[0122] The synthetic route is as follows: , wherein R=Me, Et or CH2Ph.

[0123] Test Example 1 Product conversion rate and er value of Michael addition reaction The conversion rate of 1,5-dicarbonyl compounds 1-6 is calculated according to “conversion rate (%) = actual product mass / theoretical product mass x 100%”, and the ratio of enantiomers is determined by chiral HPLC to obtain the er value, and the results are shown in Table 1. Wherein the eluent used in HPLC is 15% (v / v) acetonitrile aqueous solution. er v / v

[0124] Table 1

[0125] It can be seen that the rotaxane mechanical interlocking molecule of the present application as a catalyst intermediate of Michael addition reaction undergoes acid-base neutralization reaction with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), and the obtained reaction product can be used as a catalyst of Michael addition reaction, thereby increasing the conversion rate of Michael addition reaction to 28%-63%.

[0126] The above examples are the preferred embodiments of the present application, but the embodiments of the present application are not limited by the above examples, and any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present application shall be equivalent replacement methods, and all shall be included in the protection scope of the present application.​​

Claims

1. A rotaxane-based mechanically interlocked molecule, characterized in that, The structural formula is selected from: (1) a hetero[5]rotaxane type mechanically interlocked molecule: ； (2) a hetero[3]rotaxane type mechanically interlocked molecule: 。 2. The method of claim 1, wherein the preparation of the rotaxane-based mechanical interlocking molecule is characterized by, The rotaxane type mechanically interlocked molecule is obtained by reacting diphenal-24-crown-8, benzo-21-crown-7, an isocyanate derivative and a rod-shaped compound. The isocyanate derivative is 1,6-hexane diisocyanate or 3,5-dimethylphenyl isocyanate. The structural formula of the rod-shaped compound is: 。 3. The preparation method according to claim 2, characterized in that, After diphenal-24-crown-8, benzo-21-crown-7 and the rod-shaped compound are assembled to form a pseudo-rotaxane, the isocyanate derivative is used to cap to form the rotaxane type mechanically interlocked molecule.

4. Use of the rotaxane-based mechanical interlocking molecule according to claim 1, characterized in that, An acid-base neutralization reaction with DBU is used to synthesize a rotaxane mechanically interlocked catalyst.

5. A wheel-like mechanical interlocking catalyst characterized by, The structural formula is selected from: (1) a hetero[5]rotaxane mechanically interlocked catalyst: ； (2) a hetero[3]rotaxane mechanically interlocked catalyst: 。 6. The application of the rotaxane mechanically interlocked catalyst in claim 5 in catalyzing a Michael addition reaction.

7. Use according to claim 6, characterized in that, The Michael addition reaction is a Michael addition reaction of an α,β-unsaturated aldehyde derivative and dibenzoylmethane.

8. Use according to claim 7, characterized in that, The α,β-unsaturated aldehyde derivative has the structural formula: wherein R = Me, Et or CH2Ph.

9. A method for preparing the rotaxane mechanically interlocked catalyst of claim 5, characterized by, An acid-base neutralization reaction of the rotaxane type mechanically interlocked molecule in claim 1 with DBU is used to obtain the rotaxane mechanically interlocked catalyst.

10. A method for producing a 1,5-dicarbonyl compound, characterized by, Under the catalysis of the rotaxane mechanically interlocked catalyst in claim 5, a Michael addition reaction of an α,β-unsaturated aldehyde derivative and dibenzoylmethane is used to obtain the rotaxane mechanically interlocked catalyst.

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