Preparation and application of an imidazole-derived column [5] aromatic chiral filler

Abstract

The present invention provides a preparation of an imidazole-derived column [5] aromatic chiral filler and its use in the separation of chiral aromatic and chiral aliphatic enantiomers. The present invention uses brominated column [5] aromatics bonded with aminopropyl porous silicon and further halogenated with chiral imidazole derivatives (S-histidinol, S-1-(5-phenyl-1H-imidazole-2-yl)ethylamine) to simply prepare a chiral imidazole-derived column [5] aromatic chiral filler, and can achieve high selectivity separation of chiral aromatic and chiral aliphatic enantiomers in normal phase and reverse phase modes, and obtain good temperature responsiveness and repeatability results. It is a new type of chiral filler with development potential.

Description

Technical Field

[0001] The present invention relates to a preparation technology of an imidazole-derived column [5] aromatic chiral filler and an evaluation of the separation performance of chiral aromatic and chiral fatty enantiomers, belonging to the field of chiral drug research and development. Background Art

[0002] Chirality involves many fields such as biopharmaceutical intermediates and chemical raw materials, but due to its enantiomeric specificity and different biological effects and activities, its selective separation is still very important. There are many separation methods at present, such as enzyme kinetic separation, crystallization separation, membrane separation, chromatographic separation, etc. Among them, the separation of new chiral fillers combined with liquid chromatography analysis is considered to be one of the most effective methods for enantiomeric separation. Chiral fillers are the key to achieving this efficient separation. According to the "three-point interaction" principle, the chiral stationary phase exhibits different binding abilities with enantiomers through some specific interactions (such as conjugation, hydrogen bonding, dipole-dipole interaction) to achieve selective separation. Therefore, the development of new chiral fillers with novel functional groups, strong chiral or stereo environments, and high separation has always been the goal pursued by chromatographers.

[0003] So far, multi-structure chiral fillers such as graphene oxide, metal organic frameworks, covalent organic frameworks, polysaccharides, crown ethers, and microporous polymers have been reported, but they have shortcomings such as weak chiral selection regions, few action sites, or weak solvent tolerance, which greatly limits their practical application in enantiomeric separation. Therefore, the complexity and subtlety of new chiral designs need to be further explored. Recently, the new generation of supramolecular macrocyclic pillar [n] aromatics has great research potential in the field of isomer separation or chirality research due to its rigid columnar structure, electron-rich hydrophobic cavity, and easy chiral modification.

[0004] In view of this, the purpose of the present invention is to provide an imidazole-derived column [5] aromatic chiral filler for the preparation and separation of chiral aromatic and chiral aliphatic enantiomers, and to investigate the responsiveness to different fluidity volume fractions, temperature responsiveness and repeatability evaluation, in order to apply this type of chiral imidazole-derived column [5] aromatic chiral filler to actual chiral drug separation and promote chiral research. Summary of the invention

[0005] 1. Preparation of chiral aromatic packing materials for imidazole-derived columns[5]

[0006] (1) Preparation of brominated pillar [5] aromatic hydrocarbons: 1,1-dibromophenylene diethyl ether was dissolved in anhydrous 1,2-dichloroethane solution, and paraformaldehyde was added as a polymerization reagent and boron trifluoride etherate as a catalyst. The mixture was stirred at room temperature for 1.0 to 1.5 hours. After the reaction was completed, the mixture was poured into methanol to quench the reaction. The solid obtained after filtration was washed with water and saturated sodium bicarbonate solution. The organic layer was then dried over anhydrous magnesium sulfate. The organic solvent was removed in vacuo and purified by column chromatography to obtain brominated pillar [5] aromatic hydrocarbons.

[0007] Among them, the mass ratio of 1,1-dibromophenylene diethyl ether to polyformaldehyde is 2:1~3:1; the mass ratio of 1,1-dibromophenylene diethyl ether to boron trifluoride is 1:1~2:1.

[0008] Preparation of imidazole-derived column [5] aromatic chiral filler: aminopropyl silica gel is dispersed in anhydrous toluene, brominated column [5] aromatic, S-histidinol or S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine are added, triethylamine is used as a catalyst, refluxed at 90-100°C for 20-24 hours, and after the reaction is completed, a light yellow solid is obtained by filtration, which is washed and vacuum dried to obtain an S-histidinol-modified column [5] aromatic chiral filler or an S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine-modified column [5] aromatic chiral filler. The mass ratio of the brominated column [5] aromatic hydrocarbon to aminopropyl silica gel is 1:1.5~1:2.5; the mass ratio of the brominated column [5] aromatic hydrocarbon to S-histidinol or S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic hydrocarbon chiral filler is 1.5:1~2.5:1; the mass ratio of the brominated column [5] aromatic hydrocarbon to triethylamine is 15:1~25:1.

[0009] 2. Characterization of chiral aromatic packing materials in imidazole-derived columns[5]

[0010] The imidazole-derivatized column [5] aromatic chiral filler was characterized by infrared spectroscopy, such as Figure 4As shown, the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler and the S-histidinol modified column [5] aromatic chiral filler have obvious silanol absorption peaks at 3434 wavenumbers, indicating that nucleophilic substitution has successfully occurred on the surface of the silica sphere. This is attributed to CH stretching, and the absorption peak is observed at 2923 wavenumbers. Adsorption peaks are observed at 1493 and 1402 wavenumbers, corresponding to the bending vibration of the benzene ring in the column [5] aromatics. In the wavenumber range of 1000~1200, the absorption peak corresponds to the stretching vibration absorption band of Si-O-Si. The absorption peaks at 944 and 682 wavenumbers are caused by the stretching vibration of the benzene ring skeleton, and the increased absorption band intensity at 1640 wavenumber is attributed to the stretching vibration and bending vibration of the N−H bond. The above infrared results confirm the successful preparation of (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler and S-histidinol modified column [5] aromatic chiral filler.

[0011] Simultaneous thermal analysis: Figure 5 The data of the simultaneous thermal analysis curves show that the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler and the S-histidinol modified column [5] aromatic chiral filler remain relatively stable before 205 degrees Celsius, and have good thermal stability. The significant weight loss of the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler and the S-histidinol modified column [5] aromatic chiral filler indicates that (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine, S-histidinol, and the bromo-column [5] aromatics are successfully bonded to the aminopropyl silica gel.

[0012] X-ray electron spectrum: The full spectrum of X-ray electron spectrum is as follows Figure 6 As shown, both the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler and the S-histidinol modified column [5] aromatic chiral filler have C, N, O and Si elements, confirming the successful preparation of the chiral imidazole derivative column [5] aromatic chiral filler.

[0013] 3. Evaluation of chiral separation of aromatic hydrocarbons using imidazole-derived columns [5]

[0014] 1. Reverse-phase mode: Evaluation of reverse-phase enantiomeric separation on (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral packing and S-histidinol modified column [5] aromatic chiral packing ( Figure 7 , Figure 8). The experimental results show that the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler has a good separation effect on the enantiomers of flavanone, metalaxyl, 2-phenyl-1-propanol, mandelic acid, furoin and clodinafop-butyl. The best separation effect for metalaxyl is under the conditions of a methanol-water volume ratio of 60:40 and a wavelength of 254 nm, with a resolution of 8.17 ( Figure 7 ). The S-histidinol modified column [5] aromatic chiral filler can achieve highly selective separation of 1,2-propylene glycol, flurbiprofen, methionine, epichlorohydrin and furfural. The separation degree of epichlorohydrin is 3.06 ( Figure 8 ).

[0015] 2. Normal phase mode: Evaluation of enantiomeric separation in normal phase mode on (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral packing and S-histidinol modified column [5] aromatic chiral packing ( Fig. 9 , Fig.10 ). The experimental results show that the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler can achieve high selective separation of eight racemic isomers including 1-(3-chlorophenyl)ethanol, 1-(4-methylphenyl)ethanol, 1-(p-tolyl)ethylamine, 1-phenyl-1-propanol, 1-phenyl-2-propanol, 1-phenylethanol, 2-phenyl-1-propanol and carprofen in normal phase mode. Among them, the separation degree of 1-(4-methylphenyl)ethanol is as high as 4.09 ( Fig. 9 ). The aromatic chiral filler of the S-histidinol modified column [5] achieves highly selective separation of benzoin, ketoprofen, 2-butanol and 2-pentanol. The separation degree of the aliphatic chiral compound 2-butanol is as high as 7.44 ( Fig.10 ).

[0016] 3. Temperature control and repeatability

[0017] The enantiomeric separation of clodinafop-butyl was evaluated on a (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column[5] using aromatic chiral filler in the temperature range of 35-55 degrees Celsius. Fig.11). Also in the temperature range of 35 to 55 degrees Celsius, the S-histidinol modified column [5] aromatic chiral filler was investigated for the evaluation of epichlorohydrin enantiomer separation. The experimental results showed that with the increase of temperature, the retention time and separation value of clodinafop-butyl and epichlorohydrin decreased. The results showed that the enantiomer separation process of (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler and S-histidinol modified column [5] aromatic chiral filler was an exothermic reaction. In addition, the reproducibility and stability of (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler were studied using the chiral aromatic compound clodinafop-butyl as the analyte. The experimental results showed that the retention time and peak area of ​​clodinafop-butyl did not change significantly after 6 repetitions, and the relative standard deviation of clodinafop-butyl separation was less than 0.82%. Similarly, the chiral aliphatic compound epichlorohydrin was used as the analyte to study the reproducibility and stability of the chiral aromatic packing of the S-histidinol modified column [5]. The experimental results showed that the retention time and peak area of ​​epichlorohydrin did not change significantly after 6 repetitions, and the relative standard deviation of the separation degree of epichlorohydrin was less than 0.32%. The repeatability experiment showed that this type of chiral imidazole-derived column [5] aromatic chiral packing has practical application value in enantiomeric separation.

[0018] In summary, the present invention provides a preparation technology of a chiral imidazole derivative column [5] aromatic chiral filler and a new application for separation of chiral aromatic and chiral aliphatic enantiomers. The results show that the chiral imidazole derivative column [5] aromatic chiral filler can achieve high selective separation of multi-structure aromatic and aliphatic chiral compounds in reverse phase and normal phase modes. In the reverse phase mode, the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler has the best separation effect on metalaxyl under the conditions of methanol-water volume ratio of 60:40 and wavelength of 254 nanometers, with a separation degree of 8.17; the S-histidinol modified column [5] aromatic chiral filler has a separation degree of 3.06 on epichlorohydrin under the conditions of acetonitrile-water volume ratio of 30:70 and wavelength of 210 nanometers. In normal phase mode, the separation of 1-(4-methylphenyl)ethanol with (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column[5] aromatic chiral filler was as high as 4.09 under the conditions of n-hexane-isopropanol volume ratio of 95:5 and wavelength of 260 nm; the separation of 1-(4-methylphenyl)ethanol with (S)-histidinol modified column[5] aromatic chiral filler was as high as 7.44 under the conditions of n-hexane-isopropanol volume ratio of 95:5 and wavelength of 210 nm. Temperature control experiments confirmed that the retention time and separation value of clodinafop-butyl and epichlorohydrin decreased with the increase of temperature. Six consecutive repeatability tests showed that the relative standard deviation of the separation of clodinafop-butyl using the (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] with aromatic chiral filler was less than 0.82%; the relative standard deviation of the separation of epichlorohydrin using the S-histidinol modified column [5] with aromatic chiral filler was less than 0.32%, indicating that the chiral imidazole-derived column [5] with aromatic chiral filler had good repeatability. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a synthetic route for brominated column[5]arene;

[0020] Figure 2 The synthetic route for the aromatic chiral filler of S-histidinol modified column [5];

[0021] Figure 3 Synthetic route for (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] Aromatic chiral filler

[0022] Figure 4 This is the infrared spectrum of the chiral imidazole-derivatized column [5] aromatic chiral filler;

[0023] Figure 5 It is a chiral imidazole-derivatized column [5] for simultaneous thermal analysis of aromatic chiral packing;

[0024] Figure 6 It is a chiral imidazole-derived column [5] aromatic chiral filler X-ray electron spectroscopy characterization;

[0025] Figure 7 Evaluation of the reverse phase separation of aromatic chiral hydrocarbons in a (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5];

[0026] Figure 8 Evaluation of the reverse phase separation of aromatic chiral fillers on S-histidinol modified columns[5];

[0027] Fig. 9 Evaluation of the normal phase separation of aromatic chiral packing materials on a (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5];

[0028] Fig.10 Evaluation of the normal phase separation of aromatic chiral packing materials on S-histidinol modified column [5];

[0029] Fig.11 Temperature control and repeatability of chiral imidazole-derivatized columns[5] with aromatic chiral packing. DETAILED DESCRIPTION

[0030] Example 1

[0031] Preparation of brominated column [5] aromatic hydrocarbons: Under mechanical stirring at room temperature, 1,1-dibromophenylene diethyl ether (3.0 g) was dissolved in 50 mL of anhydrous 1,2-dichloroethane solution, and paraformaldehyde (1.2 g) was added as a polymerization reagent and boron trifluoride ether as a catalyst (2.5 g). The mixture was stirred for 1.0 hour. After the reaction was completed, the mixture was poured into 80-100 mL of methanol to quench the reaction. The solid obtained after filtration was washed with 50-60 mL of water and 50-60 mL of saturated sodium bicarbonate solution. The organic layer was then dried with 45-50 g of anhydrous magnesium sulfate, and the organic solvent was removed in vacuo. Column chromatography was performed to purify the brominated column [5] aromatic hydrocarbons using a volume ratio of petroleum ether: ethyl acetate = 40:1-50:1. The synthetic route of brominated column [5] aromatic hydrocarbons is as follows: Figure 1 .

[0032] Preparation of S-histidinol modified column [5] aromatic chiral filler: Disperse aminopropyl silica gel (3.0 g) in 70 ml of anhydrous toluene, add brominated column [5] aromatic hydrocarbon (1.6 g), S-histidinol (0.9 g) and triethylamine (0.1 g) as catalyst, reflux at 95 ° C for 24 hours, and after the reaction is completed, filter to obtain a light yellow solid, wash with 50-60 ml of methanol and 50-60 ml of ethanol, and then vacuum dry at 55-60 degrees Celsius for 20-24 hours to obtain S-histidinol modified column [5] aromatic chiral filler. The synthetic route is as follows: Figure 2 The separation performance of the S-histidinol modified column [5] aromatic chiral filler is as follows Figure 8 , Fig.10 .

[0033] Example 2

[0034] The preparation of brominated column [5] aromatic hydrocarbon is the same as in Example 1.

[0035] Preparation of S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler: Disperse aminopropyl silica gel (2.5 g) in 70 ml of anhydrous toluene, add bromo-column [5] aromatic hydrocarbon (1.6 g), S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine (0.9 g), and triethylamine (0.1 g) as a catalyst, reflux at 95 degrees Celsius for 24 hours, and after the reaction is completed, filter to obtain a light yellow solid, wash with 50-60 ml of methanol and 50-60 ml of ethanol, and then vacuum dry at 55-60 degrees Celsius for 20-24 hours to obtain S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic chiral filler. The synthetic route is as follows: Figure 3 The separation performance of the aromatic chiral filler of S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] is shown in Figure 7 , Fig. 9 .

Claims

1. A method for preparing an imidazole-derivative column [5] aromatic chiral filler, comprising the following steps: Preparation of brominated pillar [5] aromatic hydrocarbons: 1,1-dibromophenylene diethyl ether is dissolved in anhydrous 1,2-dichloroethane solution, paraformaldehyde is added as a polymerization reagent, boron trifluoride ether is used as a catalyst, and the mixture is stirred at room temperature for 1.0 to 1.5 hours. After the reaction is completed, the mixture is poured into methanol to quench the reaction. The solid obtained after filtration is washed with water and saturated sodium bicarbonate solution, and the organic layer is then dried over anhydrous magnesium sulfate. The organic solvent is removed in vacuo, and the mixture is purified by column chromatography to obtain brominated pillar [5] aromatic hydrocarbons. Preparation of imidazole-derived column [5] aromatic chiral filler: aminopropyl silica gel is dispersed in anhydrous toluene, brominated column [5] aromatic, S-histidinol or S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine are added, triethylamine is used as a catalyst, refluxed at 90-100°C for 20-24 hours, and after the reaction is completed, a light yellow solid is obtained by filtration, which is washed and vacuum dried to obtain an S-histidinol-modified column [5] aromatic chiral filler or an S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine-modified column [5] aromatic chiral filler.

2. The method for preparing the imidazole-derivative column [5] aromatic chiral filler according to claim 1, characterized in that: In step (1), the mass ratio of 1,1-dibromophenylene diethyl ether to paraformaldehyde is 2:1-3:1; the mass ratio of 1,1-dibromophenylene diethyl ether to boron trifluoride is 1:1-2:

1.

3. The method for preparing the imidazole-derivative column [5] aromatic chiral filler according to claim 1, characterized in that: In step (2), the mass ratio of the brominated column [5] aromatic hydrocarbon to the S-histidinol or S-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] aromatic hydrocarbon chiral filler is 1.5:1 to 2.5:

1.

4. The method for preparing the imidazole-derivative column [5] aromatic chiral filler according to claim 1, characterized in that: In step (2), the mass ratio of the brominated column [5] aromatic hydrocarbon to the aminopropyl silica gel is 1:1.5 to 1:2.5; the mass ratio of the brominated column [5] aromatic hydrocarbon to triethylamine is 15:1 to 25:

1.

5. Use of the imidazole-derivative column [5] aromatic chiral filler prepared by the method of claim 1 in the separation of chiral aromatic and chiral fatty enantiomers.

6. The use of the imidazole-derivative column [5] aromatic chiral filler as claimed in claim 5 in the separation of chiral aromatic and chiral aliphatic enantiomers, characterized in that: The (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column [5] with aromatic chiral filler achieved highly selective separation of the enantiomers of flavanone, metalaxyl, 2-phenyl-1-propanol, mandelic acid, furoin, and clodinafop-butyl in reverse phase mode.

7. Use of the imidazole-derivative column [5] aromatic chiral filler as claimed in claim 5 in the separation of chiral aromatic and chiral aliphatic enantiomers, characterized in that: The S-histidinol modified column[5] with aromatic chiral filler can achieve highly selective separation of 1,2-propylene glycol, flurbiprofen, methionine, epichlorohydrin, and furfural enantiomers in reverse phase mode.

8. The use of the imidazole-derivative column [5] aromatic chiral filler as claimed in claim 5 in the separation of chiral aromatic and chiral fatty enantiomers, characterized in that: (S)-1-(5-phenyl-1H-imidazol-2-yl)ethylamine modified column[5] aromatic chiral filler can achieve highly selective separation of 1-(3-chlorophenyl)ethanol, 1-(4-methylphenyl)ethanol, 1-(p-tolyl)ethylamine, 1-phenyl-1-propanol, 1-phenyl-2-propanol, 1-phenylethanol, 2-phenyl-1-propanol, and carprofen enantiomers in normal phase mode.

9. The use of the imidazole-derivatized column [5] aromatic chiral filler as claimed in claim 5 in the separation of chiral aromatic and chiral aliphatic enantiomers, characterized in that: S-histidinol modified column[5] aromatic chiral filler can achieve highly selective separation of benzoin, ketoprofen, 2-butanol and 2-pentanol enantiomers in normal phase mode.

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