(N-(R)-α-phenylethyl) nitrilotriacetamide and its preparation method and application

Abstract

The invention belongs to the technical field of organic chemistry, and specifically relates to (N-(R)-α-phenylethyl) nitrilotriacetamide and a preparation method and application thereof. The structure of the (N-(R)-α-phenylethyl) nitrilotriacetamide is shown in formula (I): The preparation method of the (N-(R)-α-phenylethyl) nitrilotriacetamide provided by the invention does not require complicated organic synthesis reactions, is simple to operate, is cheap and easy to obtain, and has high yield. The (N-(R)-α-phenylethyl) nitrilotriacetamide of the invention has chiral recognition ability for o-chloromandelic acid enantiomers.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemistry, and specifically relates to (N-(R)-α-phenylethyl) nitrilotriacetamide and a preparation method and application thereof. Background Art

[0002] Due to the development of technology, the properties and preparation techniques of chiral compounds have been widely studied and applied in various fields. Optically pure compounds are increasingly important in the pharmaceutical and fine chemical industries as raw materials, intermediates and final products. In the laboratory and production process, there are three main ways to obtain optically pure enantiomeric compounds: extraction from natural products, asymmetric synthesis and racemic separation. Although many asymmetric catalytic reactions have been studied and developed by scholars in recent years, racemic separation is more widely used in the pharmaceutical industry.

[0003] Optically pure phenethylamine (PEA) is widely used as a chiral base resolving agent in the resolution of acidic racemic compounds. Although optically pure phenethylamine is widely used, its solubility in water is relatively high, which limits its application in the chiral resolution of racemic compounds.

[0004] Currently, the preparation methods of optically pure phenylethylamine derivatives still have the following problems: (1) there are many types of reactions and the reaction steps are relatively complicated; (2) the product yield is not high; (3) the raw materials are not easy to obtain and are expensive. Summary of the invention

[0005] The present invention aims to solve the above technical problems and provides (N-(R)-α-phenylethyl) nitrilotriacetamide and a preparation method and application thereof.

[0006] The technical solution of the present invention is:

[0007] (N-(R)-α-phenylethyl) nitrilotriacetamide, the structure is shown in formula (I):

[0008]

[0009] Furthermore, the preparation method of (N-(R)-α-phenylethyl)nitrilotriacetamide comprises the following steps:

[0010] (1) Take nitrilotriacetic acid, add dichloromethane, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, stir to react, and then add 1-hydroxybenzotriazole to obtain a reaction system A;

[0011] (2) dissolving 4-dimethylaminopyridine in dichloromethane, adding the mixture to reaction system A, and stirring the mixture to obtain reaction system B;

[0012] (3) R-α-phenylethylamine (R-α-PEA) was diluted with dichloromethane and added to reaction system B. The temperature was raised to room temperature for reaction. The reaction solution was extracted with 1M HCl, saturated NaHCO3, and saturated NaCl, respectively, and then dried over anhydrous sodium sulfate. The solution was separated by silica gel column chromatography and dried to obtain a solid, namely (N-(R)-α-phenylethyl)triethylamide.

[0013] Its synthetic route is as follows:

[0014]

[0015] Furthermore, in step (1), the stirring reaction is carried out in an ice bath for 10 minutes.

[0016] Furthermore, in step (2), the stirring reaction is carried out in an ice bath for 30 minutes.

[0017] Furthermore, in step (3), the eluent for the silica gel column chromatography separation is petroleum ether-ethyl acetate in a volume ratio of 1:2.

[0018] The invention provides application of (N-(R)-α-phenylethyl) nitrilotriacetamide in chiral recognition. The (N-(R)-α-phenylethyl) nitrilotriacetamide can chirally recognize propranolol, binaphthol, valsartan, camphorsulfonic acid, ibuprofen, benzoin, N-acetyl-DL-phenylalanine, o-chloromandelic acid and ketoprofen enantiomers.

[0019] The present invention also provides the use of (N-(R)-α-phenylethyl) nitrilotriacetamide in the separation of o-chloromandelic acid enantiomers. The use comprises the following steps:

[0020] (1) weighing the o-chloromandelic acid enantiomers to prepare an o-chloromandelic acid enantiomer aqueous solution, adding a phosphate buffer to adjust the pH value to prepare an aqueous phase for later use;

[0021] (2) Weigh (N-(R)-α-phenylethyl) nitrilotriacetamide, dissolve it in 1,2-dichloroethane, and prepare an organic phase for later use;

[0022] (3) The aqueous phase and the organic phase are placed in the same container, shaken in a constant temperature water bath, and allowed to stand to separate into layers. After the solution is completely separated, the aqueous phase solution is taken, filtered, and analyzed by high performance liquid chromatography.

[0023] The beneficial effects of the present invention are:

[0024] Compared with the prior art, the preparation method of (N-(R)-α-phenylethyl) nitrilotriacetamide provided by the present invention does not require complicated organic synthesis reactions, is simple to operate, is cheap and easy to obtain, and has a high yield. The (N-(R)-α-phenylethyl) nitrilotriacetamide of the present invention has chiral recognition ability for the enantiomer of o-chloromandelic acid. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the infrared spectrum of (N-(R)-α-phenylethyl)nitrilotriacetamide of the present invention;

[0026] Figure 2 It is the (N-(R)-α-phenylethyl) nitrilotriacetamide of the present invention. 1 H NMR spectrum;

[0027] Figure 3 It is the (N-(R)-α-phenylethyl) nitrilotriacetamide of the present invention. 13 C NMR spectrum;

[0028] Figure 4 It is a mixture of equal volumes of (N-(R)-α-phenylethyl) nitrilotriacetamide and a chiral compound racemate of the present invention. 1 HNMR spectrum;

[0029] Figure 5 is the HPLC chromatogram of o-chloromandelic acid enantiomers before chiral separation;

[0030] Figure 6 It is the HPLC chromatogram after chiral separation of o-chloromandelic acid enantiomers. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] Example 1 Preparation of (N-(R)-α-phenylethyl) nitrilotriacetamide

[0033] (1) 0.5 g (2.5 mmol) of nitrilotriacetic acid (NTA) was added to 20 mL of dichloromethane, and 1.53 g (8 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. The mixture was stirred in an ice bath for 10 min, and 1.08 g (8 mmol) of 1-hydroxybenzotriazole (HOBT) was added to obtain a reaction system A.

[0034] (2) 0.98 g (8 mmol) of 4-dimethylaminopyridine (DMAP) was dissolved in 10 mL of dichloromethane and then slowly added dropwise to reaction system A. The mixture was stirred in an ice bath for 30 min to obtain reaction system B.

[0035] (3) 0.97 g (8 mmol) of R-α-phenylethylamine (R-α-PEA) was diluted with 10 mL of dichloromethane and slowly added dropwise to the reaction system B. The temperature was raised to room temperature and the reaction was allowed to react for 12 h. The reaction solution was extracted with 1 M HCl, saturated NaHCO3, and saturated NaCl, respectively, and then dried over anhydrous sodium sulfate overnight. The solution was then chromatographed on a silica gel column, eluted with petroleum ether-ethyl acetate in a volume ratio of 1:2, and dried to obtain a white solid, namely (N-(R)-α-phenylethyl)triethylamide.

[0036] The results of infrared spectroscopy are as follows Figure 1 As shown by Figure 1 It can be seen that the carbonyl stretching vibration peak of the raw material carboxylic acid in the infrared spectrum is 1738.73 cm -1 Disappeared, transformed into the product of 1653.09cm -1 The stretching vibration peak of the amide carbonyl group and the deformation vibration peak of the secondary amide NH at 1543.49 cm-1 and 3268.00 cm-1 were produced in the product. -1 The stretching vibration peak of the amide NH group indicates the synthesis of the chiral monomer.

[0037] The results of NMR are as follows Figure 2-3 As shown, the analysis is as follows: 1 H NMR (500MHz, CDCl3) δ (ppm): 1.43 (d, 3H, H-3), 3.23 (s, 2H, H-1), 5.08 (s, 1H, H-2), 7.29-7.18 (m, 5H, H-4), 7.61 (s, 1H, H-5). 13 CNMR(126MHz,CDCl3)δ(ppm):169.53(-NH- C =O), 143.26(Ar- C -CH),128.67(Ar- C ),127.34(Ar- C ),126.18(Ar- C ),60.71(N- C H2-),49.05(-NH- C H-),22.10(- C H3).

[0038] Example 2 Application of (N-(R)-α-phenethyl)nitrilotriacetamide in the selective recognition of enantiomers of several chiral compounds.

[0039] CDCl3 solutions of (N-(R)-α-phenylethyl) nitrilotriacetamide and enantiomeric compounds were prepared at a concentration of 15 mmol / L, and the concentrations of (N-(R)-α-phenylethyl) nitrilotriacetamide, enantiomeric compounds and an equal volume mixture of the two were determined. 1 HNMR spectra can distinguish the different configurations of enantiomeric compounds based on the difference in chemical shifts.

[0040] like Figure 4 The results showed that in CDCl3 solution, (N-(R)-α-phenylethyl)triacetamide had chiral recognition effect on propranolol, binaphthol, valsartan, camphorsulfonic acid, ibuprofen, benzoin, N-acetyl-DL-phenylalanine, o-chloromandelic acid, and ketoprofen enantiomers.

[0041] As shown in Table 1, when (N-(R)-α-phenylethyl) nitrilotriacetamide and o-chloromandelic acid enantiomers, the host molecule and the guest molecule were mixed at a molar ratio of 1:1, the chemical shift of the hydrogen atom (δ5.6778ppm,s) on the chiral carbon connected to the benzene ring in the guest molecule moved upfield to δ5.6023ppm and δ5.5874ppm, and the chemical shift difference Δδ was 0.0755ppm and 0.0904ppm, respectively. There is π-π stacking between the host and guest molecules, and the carbonyl group of the amide in the host molecule forms a hydrogen bond with the hydrogen atom of the guest molecule, which reduces the electron cloud density of the hydrogen atom and enhances the deshielding effect, thereby generating a chemical shift.

[0042] Table 1

[0043]

[0044]

[0045] Example 3 Application of (N-(R)-α-phenylethyl)nitrilotriacetamide in liquid-liquid extraction separation of o-chloromandelic acid enantiomers.

[0046] (1) Weigh 10 mg of o-chloromandelic acid enantiomer, dissolve it in water and dilute it to a 100 mL volumetric flask. Use a pipette to transfer a certain volume of o-chloromandelic acid enantiomer aqueous solution, add 0.02 mol / L phosphate buffer to prepare a 0.1 mg / mL o-chloromandelic acid aqueous solution with a pH of 2 as the aqueous phase for later use.

[0047] (2) Weigh 250 mg of (N-(R)-α-phenylethyl) nitrilotriacetamide, dissolve it in 1,2-dichloroethane and dilute it to a 10 mL volumetric flask to prepare a 0.05 mol / L (N-(R)-α-phenylethyl) nitrilotriacetamide 1,2-dichloroethane solution as the organic phase for later use.

[0048] (3) When performing the extraction experiment, 2 mL of the aqueous phase and 2 mL of the organic phase were taken in a 10 mL reagent bottle and placed in a constant temperature water bath oscillator at a speed of 220 r / min and a temperature of 25°C. After oscillation extraction for 5 h, the extraction was allowed to stand for 1 h. After the solution was completely separated, the volumes of the upper and lower phases were read. The aqueous phase solution was taken and filtered with a 0.45 μm filter membrane. The enantiomer concentration was determined by HPLC chromatography. The results are as follows: Figure 6 HPLC chromatogram after chiral separation of o-chloromandelic acid enantiomers.

[0049] The application of this embodiment sets up a control group, and the steps of the control group are as follows: 2 mL of the aqueous phase and the organic phase (blank) are each taken into a 10 mL reagent bottle, placed in a constant temperature water bath oscillator, and shaken and extracted for 5 hours at a speed of 220 r / min and a temperature of 25°C, and then allowed to stand for 1 hour to separate the phases. After the solution is completely separated, the volumes of the upper and lower phases are read, the aqueous phase solution is taken, filtered with a 0.45 μm filter membrane, and the enantiomer concentration is determined by HPLC chromatography. The results are as follows: Figure 5 HPLC chromatogram of o-chloromandelic acid enantiomers before chiral separation.

[0050] Among them, HPLC chromatographic analysis conditions: Phenol MZ (2) (250mm×4.6mm, 5μm); mobile phase: n-hexane:isopropanol=93:7 (v / v, 0.1% TFA); detection wavelength: 230nm; flow rate: 1mL / min; injection volume: 20μL.

[0051] Depend on Figure 5 and Figure 6 The HPLC chromatogram analysis results show that the enantiomers of o-chloromandelic acid are extracted in an aqueous solution with pH = 2 and a temperature of 25°C using a 1,2-dichloroethane solution of (N-(R)-α-phenylethyl)triethylamide as the organic phase. The ee values ​​of the R and S configurations are 70% after extraction. The results show that the synthesized (N-(R)-α-phenylethyl)triethylamide can be used to construct a liquid-liquid extraction system and chiral liquid-liquid extraction to separate the enantiomers of o-chloromandelic acid.

[0052] The above description is a detailed description of the preferred feasible embodiments of the invention, but the embodiments are not intended to limit the scope of the patent application of the present invention. All equivalent changes or modified changes completed under the technical spirit suggested by the present invention should fall within the patent scope covered by the present invention.

Claims

1. Application of (N-(R)-α-phenylethyl)triacetamide in chiral recognition, characterized in that: The (N-(R)-α-phenylethyl) nitrilotriacetamide can chirally identify propranolol, binaphthol, valsartan, camphorsulfonic acid, ibuprofen, benzoin, N-acetyl-DL-phenylalanine, o-chloromandelic acid, and ketoprofen enantiomers; the (N-(R)-α-phenylethyl) nitrilotriacetamide has a structure as shown in formula (I):

2. Application of (N-(R)-α-phenylethyl)triacetamide in the separation of o-chloromandelic acid enantiomers.

3. The use according to claim 2, characterized in that: The following steps are involved: (1) weighing the o-chloromandelic acid enantiomers to prepare an o-chloromandelic acid enantiomer aqueous solution, adding a phosphate buffer to adjust the pH value to prepare an aqueous phase for later use; (2) Weigh (N-(R)-α-phenylethyl) nitrilotriacetamide, dissolve it in 1,2-dichloroethane, and prepare an organic phase for later use; (3) The aqueous phase and the organic phase are placed in the same container, shaken in a constant temperature water bath, and allowed to stand to separate into layers. After the solution is completely separated, the aqueous phase solution is taken, filtered, and analyzed by high performance liquid chromatography.

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