Chiral catalyst as well as preparation method and application thereof

Abstract

The invention discloses a chiral catalyst with a chemical structural formula shown in the specification, the chiral catalyst is prepared from beta-cyclodextrin and (1S, 2S)-(+)-1, 2-cyclohexanediamine as raw materials, the catalyst is simple and convenient to prepare, can be used for an aqueous phase asymmetric aldol reaction, and has the advantages of easily available raw materials, high stability, good repeatability, greenness, safety and the like; the invention provides a new way for synthesizing important drug intermediates; and # imgabs0 #.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a chiral catalyst mono-3-(S,S-cyclohexanediamine)-β-cyclodextrin and a preparation method and application thereof. Background Art

[0002] Chiral compounds are widely present in nature. They not only play a key role in the life of animals and plants, but also play an important role in pharmaceutical, agricultural and other chemical industries. Chiral compounds and their mirror images are called enantiomers. They have the same chemical structure and therefore usually have the same physical properties. However, for organisms, the two enantiomers often show certain differences in biological activities such as toxicology, pharmacology, and pharmacokinetics, or even completely opposite. The most typical example is the "thalidomide incident". Thalidomide was originally a drug used to relieve morning sickness in pregnant women, but was later withdrawn from the market due to its significant impact on the normal development of the fetus. Therefore, it is of great significance to obtain chiral compounds with a single enantiomer. Asymmetric synthesis is one of the most effective methods to obtain chiral compounds with a single enantiomer. At present, many chiral ligands and their transition metal complexes have been used in asymmetric catalytic reactions. However, they have obvious disadvantages, including high cost, high toxicity, and difficulty in recycling.

[0003] Aldol reaction refers to the nucleophilic addition of an aldehyde or ketone with α-H to another aldehyde or ketone molecule under acid or base catalysis to generate β-hydroxyaldehyde or β-hydroxyketone, which can be thermally dehydrated to generate α, β-unsaturated aldehyde or ketone. Through the condensation of alcohol-aldehyde, new carbon-carbon bonds can be formed in the molecule and the carbon chain can be extended. Traditionally, the Aldol reaction is carried out by using acidic or basic substances, in many cases, in catalytic amounts. When aldehydes or asymmetric ketones are used as carbonyl acceptors, a new stereocenter is introduced on the β-carbon atom, and the asymmetric synthesis of β-hydroxycarbonyl compounds is achieved by controlling the absolute configuration of the β-carbon atom during the carbon-carbon bond formation process. Therefore, the asymmetric aldol reaction is considered to be one of the most reliable asymmetric carbon-carbon bonding reactions. In 2000, List et al. (J. Am. Chem. Soc., 2000, 122(10): 2395-2396) reported an asymmetric aldol reaction mediated by proline via an enamine intermediate, for which he was awarded the 2021 Nobel Prize in Chemistry.

[0004] In the early 1990s, Mukaiyama et al. first reported that a Lewis acid could enantioselectively catalyze aldol reactions with good enantioselectivity (Chem. Lett., 1990, 129). Since then, a variety of Lewis acids and Lewis bases have been synthesized and have good chiral catalytic effects on aldol reactions. The synthesis of chiral organic catalysts and metal catalysts has given aldol reactions more options and also improved the yield and ee value of aldol reactions. However, the above catalysts have problems such as cumbersome synthesis steps and environmental pollution (Chem. Soc. Rev., 2018, 47, 4388). In 2011, a similar catalyst reported by Luo Sanzhong et al. was a model of the combination of supramolecular and organic catalysis represented by cyclodextrin, but similar reports only studied the first side of cyclodextrin (J. Am. Chem. Soc., 2010(20): 7216-7228).

[0005] In summary, the development of a new, efficient and green chiral catalyst for asymmetric catalysis on the second side of cyclodextrin is of great significance in the fields of chemical synthesis and catalysis. Summary of the invention

[0006] The invention provides a novel green chiral catalyst, which is a solid compound mono-3-(S,S-cyclohexanediamine)-β-cyclodextrin prepared by using β-cyclodextrin (β-CD) and its derivative mono-2-p-toluenesulfonyl-β-cyclodextrin (mono-2-p-toluenesulfonyl-β-CD) and (1S,2S)-(+)-1,2-cyclohexanediamine as raw materials.

[0007] The β-cyclodextrin structural formula is as follows: .

[0008] The mono-2-toluenesulfonyl-β-cyclodextrin structural formula is as follows: .

[0009] The mono-3-(S,S-cyclohexanediamine)-β-cyclodextrin structural formula is as follows:

[0010] The chiral catalyst mono-3-(S,S-cyclohexanediamine)-β-cyclodextrin is prepared as follows: 1. Preparation of mono-2-p-toluenesulfonyl-β-CD β-CD was dissolved in N, N-dimethylformamide at 0°C, and after stirring and mixing, sodium hydride was added, and the mixture was reacted at 0°C for 2 h to obtain a β-cyclodextrin solution; a solution of p-toluenesulfonyl chloride (TsCl) in N, N-dimethylformamide was slowly added dropwise to the β-cyclodextrin solution, and then the mixture was reacted at room temperature for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to remove most of the N, N-dimethylformamide, and the concentrated solution was added dropwise to acetone, stirred for 1 h, and then filtered. The filter cake was heated and dissolved with deionized water, and the insoluble matter was removed by filtration. The filtrate was purified by a reverse phase silica gel column (eluted with methanol-water solution) to obtain mono-2-p-toluenesulfonyl-β-CD; The molar ratio of β-cyclodextrin to sodium hydride is 1:1-2; the molar ratio of β-cyclodextrin to p-toluenesulfonyl chloride is 1:1-2; the mass volume ratio of β-cyclodextrin to N,N-dimethylformamide g:mL is 1:8-11; the mass volume ratio of p-toluenesulfonyl chloride to N,N-dimethylformamide g:mL is 1:2-1:4; the reverse phase column eluent is a methanol aqueous solution with a volume concentration of 20-30%; 2. Preparation of mono-3-(S,S-cyclohexanediamine)-β-CD Dissolve mono-2-toluenesulfonyl-β-CD in N,N-dimethylformamide and add (1 S , 2 S )-(+)-1, 2-cyclohexanediamine, nitrogen protection, react at 70-80°C for 18-24h in a nitrogen atmosphere. After the reaction, cool the reaction solution to room temperature, add 1 mol / L sodium hydroxide aqueous solution, mix well, drop the mixture into acetone and stir for 1 h, filter, dissolve the filter cake with water, and then purify with a reverse phase silica gel column (eluted with methanol-water solution) to obtain a light yellow solid mono-3-S, S-cyclohexanediamine-β-CD; The molar ratio of mono-2-toluenesulfonyl-β-cyclodextrin to (1S, 2S)-(+)-1,2-cyclohexanediamine is 1:9-11; the mass volume ratio of mono-2-toluenesulfonyl-β-cyclodextrin to N,N-dimethylformamide is 1:3-5, and the reverse phase column eluent is a methanol aqueous solution with a volume concentration of 10-20%.

[0011] Another object of the present invention is to use the chiral catalyst in catalyzing asymmetric aldol reactions.

[0012] Advantages and technical effects of the present invention: The raw materials used in this method are p-toluenesulfonyl chloride, β-cyclodextrin, (1 S , 2 S)-(+)-1, 2-cyclohexanediamine and the reaction solvent are both cheap and easily available, and the experimental method is simple and easy to carry out. The catalyst of the present invention has the advantages of stable properties, high catalytic efficiency, reusability, high chiral selectivity, etc., and is expected to improve the use efficiency of cyclodextrin derivatives in chemical synthesis and catalysis. The novel green chiral catalyst of the present invention has a good application prospect. DETAILED DESCRIPTION

[0013] The method described in the present invention is further described below by examples, but the protection scope of the present invention is not limited by the examples. The reagents used in the present examples are conventional commercially available reagents or reagents prepared by conventional methods unless otherwise specified, and the methods used are conventional methods unless otherwise specified.

[0014] Example 1: Preparation of mono-3-(S,S-cyclohexanediamine)-β-CD 1. Dissolve β-CD (190 g, 159 mmol) in 1.7 L N, N-dimethylformamide at 0 ° C, stir for 10 min, add sodium hydride (11 g, 175 mmol), react at 0 ° C for 2 h to obtain β-cyclodextrin solution, slowly drop p-toluenesulfonyl chloride (53 g, 175 mmol) in N, N-dimethylformamide solution (150 mL) into the β-cyclodextrin solution, react at room temperature for 3 h, and concentrate to 90 mL under reduced pressure after the reaction to remove part of N, N-dimethylformamide. Add the concentrated solution dropwise to 2 L acetone, continue stirring for 1 h, and then filter. Heat the filter cake with 50 mL of deionized water at 100 ° C to dissolve it, filter to remove insoluble matter, and purify the filtrate with a reversed-phase silica gel C18 column, elute with 20% methanol aqueous solution, collect the eluate and spin dry at 75 ° C to obtain 52 g of white solid mono-2-toluenesulfonyl-β-CD with a yield of 24%; (2) Dissolve mono-2-toluenesulfonyl-β-CD (2 g, 1.55 mmol) in 8 mL of N,N-dimethylformamide, then add (1S,2S)-(+)-1,2-cyclohexanediamine (1.77 g, 15.5 mmol), and react at 80 °C in a nitrogen atmosphere for 24 h. After the reaction, cool the reaction solution to room temperature, add NaOH aqueous solution (2 mL, 1 mol / L), and then dropwise add the reaction solution into 200 mL of acetone and stir for 1 h. Filter with suction, dissolve the filter cake in 1 mL of water, and then purify it with a reverse phase silica gel column and elute with 10% methanol aqueous solution. Collect the eluate and spin dry it at 80 °C to obtain 1.2 g of light yellow solid mono-3-(S,S-cyclohexanediamine)-β-CD with a yield of 63%.

[0015] Mono-3-(S,S-cyclohexanediamine)-β-CD hydrogen spectrum: 1 H NMR (600 MHz, D2O) d5.01-4.73 (m,7H), 4.03 (d, J = 7.1 Hz, 1H), 3.94-3.01 (m, 39H), 2.64 (t, J = 11.8 Hz, 2H),2.29 (d, J = 11.8 Hz, 1H), 1.90 (m, 2H), 1.57 (m, 2H), 1.30-0.89 (m, 4H). Carbon spectrum: 13 C NMR (150 MHz, D2O) d HR-MS (ESI) m / z: calcd for C 48 H 82 N2O 34 [M+H] + :1231.4822, found [M+H] + : 1231.4836. Example 2: Use of chiral catalysts in catalytic asymmetric aldol reactions Add mono-3-(S,S-cyclohexanediamine)-β-CD (246 mg, 0.25 mmol) to a round-bottom flask, then add pH=3 citric acid buffer solution (4 mL) and acetone (0.37 mL, 5 mmol), and stir until clear. Then add p-nitrobenzaldehyde (75 mg, 0.5 mmol) to the reaction solution, and then stir the reaction solution at 0°C for 7 days. After the reaction is completed, extract with ethyl acetate and purify by column chromatography to obtain 75 mg of light yellow oil with a yield of 72% and an ee value of 92%; Product hydrogen spectrum: 1 H NMR (600 MHz, CDCl3) d 8.33-8.14 (d, J = 8.7 Hz, 2H), 7.55(d, J = 8.6 Hz, 2H), 5.27 (dd,J = 8.9, 3.5 Hz, 1H), 3.61 (s, 1H), 2.98-2.78(m, 2H), 2.23 (s, 3H); Carbon spectrum: 13 C NMR (150 MHz, CDCl3) d 208.66, 149.85, 147.29,126.41, 123.80, 68.89, 51.48, 30.74.t r (R) = 27.3 min, t r (S) = 36.9 min, ee =92% (Chiralcel AS-H, l = 254 nm, 30% i- PrOH / hexane, 0.5 mL / min, 25 ℃).

[0016] The substrate application range of the catalyst mono-3-(S,S-cyclohexanediamine)-β-CD catalyzed asymmetric aldol reaction in water phase was further explored below. The reaction conditions were the same as above. The detailed data are shown in Table 1. The reaction time in the synthesis of compound 2d in the table was 4 days. As can be seen from the table, the catalyst mono-3-(S,S-cyclohexanediamine)-β-CD can catalyze the asymmetric aldol reaction of electron-withdrawing benzaldehyde and polycyclic aromatic aldehydes with acetone, and obtain the product with high stereoselectivity and moderate yield; Table 1

[0017] .

Claims

1. A chiral catalyst, whose chemical structural formula is as follows: 。 2. The method for preparing a chiral catalyst according to claim 1, characterized in that: Here are the steps: (1) At 0°C, β-cyclodextrin is dissolved in N,N-dimethylformamide, mixed and then sodium hydride is added to obtain a β-cyclodextrin solution; at 0°C, a solution of p-toluenesulfonyl chloride in N,N-dimethylformamide is added dropwise to the solution of β-cyclodextrin in N,N-dimethylformamide, and the mixture is reacted at room temperature. After the reaction is completed, the mixture is concentrated under reduced pressure, and the concentrated solution is added dropwise to acetone for precipitation, filtered, and the filter cake is collected. After the filter cake is dissolved, it is purified by a reverse phase column to obtain mono-2-p-toluenesulfonyl-β-cyclodextrin; ； (2) Dissolve mono-2-toluenesulfonyl-β-cyclodextrin in N,N-dimethylformamide solution, add (1S,2S)-(+)-1,2-cyclohexanediamine, and react for 18-24 hours at 70-80°C in a nitrogen atmosphere. After the reaction is completed, cool to room temperature, add sodium hydroxide aqueous solution, mix well, drop the mixture into acetone, stir, filter, collect the filter cake, and after the filter cake is dissolved, purify it with a reverse phase column to obtain the chiral catalyst mono-3-(S,S-cyclohexanediamine)-β-cyclodextrin.

3. The method for preparing a chiral catalyst according to claim 2, characterized in that: In step (1), the molar ratio of β-cyclodextrin to sodium hydride is 1:1-2; the molar ratio of β-cyclodextrin to p-toluenesulfonyl chloride is 1:1-2.

4. The method for preparing a chiral catalyst according to claim 2, characterized in that: The eluent of the reverse phase column in step (1) is a methanol-water solution with a volume concentration of 20-30%.

5. The method for preparing a chiral catalyst according to claim 2, characterized in that: In step (2), the molar ratio of mono-2-toluenesulfonyl-β-cyclodextrin to (1S,2S)-(+)-1,2-cyclohexanediamine is 1:9-11.

6. The method for preparing a chiral catalyst according to claim 2, characterized in that: The concentration of sodium hydroxide in the sodium hydroxide aqueous solution is 1 mol / L.

7. The method for preparing a chiral catalyst according to claim 2, characterized in that: The eluent of the reverse phase column in step (2) is a methanol-water solution with a volume concentration of 10-20%.

8. Use of the chiral catalyst according to claim 1 in catalyzing an asymmetric aldol reaction.

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