Preparation method and application of series of chiral polydentate amino alcohol ligands

Abstract

The invention discloses a preparation method and application of a series of novel chiral polydentate amino alcohol ligands. The synthesis method comprises the following steps: preparing primary alcohol type chiral amino alcohol by taking L-amino alcohol and 2-halogenated heteroaromatic ring as raw materials and carrying out nucleophilic substitution reaction in one step; the tertiary alcohol type chiral amino alcohol is prepared by taking L-leucine as a raw material, and sequentially carrying out methyl esterification, Buchwald-Harwig cross-coupling reaction and phenyl magnesium bromide addition reaction to synthesize the tertiary alcohol type chiral amino alcohol. The method disclosed by the invention is simple in process, mild in reaction condition, cheap and easily available in raw materials, easy in product separation and purification and high in yield; and the prepared chiral polydentate amino alcohol ligand can be applied to identification of camphorsulfonic acid enantiomers and determination of enantiomer excess (ee value).

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and chiral analysis technology, specifically involving a series of chiral polydentate amino alcohol ligands and their synthesis methods, as well as the application of such ligands as nuclear magnetic resonance chiral solvents in the identification of camphor sulfonic acid enantiomers and the determination of enantiomer excess values. Background Technology

[0002] Chirality is a fundamental property of nature, crucial in living systems and medicinal chemistry. Different enantiomers of chiral drugs can exhibit significant differences in efficacy, metabolism, and toxicity, as exemplified by the classic thalidomide incident. Therefore, efficient and accurate enantiomer recognition and resolution of chiral molecules are key to ensuring drug safety and efficacy and advancing the development of asymmetric synthesis.

[0003] Nuclear magnetic resonance (NMR) is an important analytical method for chiral identification, offering advantages such as ease of operation and rich information. However, NMR itself lacks chiral discrimination capabilities, requiring the introduction of a chiral environment, typically achieved by adding chiral solubilizers (CSAs). Ideally, CSAs should be easy to synthesize, highly soluble, and capable of generating significant and resolvable diastereomeric interactions with guest molecules (such as hydrogen bonding, π-π stacking, and steric hindrance effects), thereby resulting in a sufficiently large chemical shift difference (Δδ) in the NMR spectrum to achieve baseline separation.

[0004] In the prior art, CSAs based on chiral amino alcohol skeletons have attracted much attention because they simultaneously possess N and O hydrogen bond donor / acceptor sites ([1] Bozkurt S et al. Tetrahedron: Asymmetry. 2011. 22(5):541-549; [2] Wenzel TJ and Chisholm CD. Chirality. 2010. 23(3):190-214.). However, existing CSAs generally suffer from insufficient chemical shift asymmetry splitting and difficulty in achieving baseline resolution ([3] Wenzel TJ and Wilcox JD. Chirality. 2003. 15(3):256-270.). Many reported CSAs are either too small in Δδ due to structural limitations, making baseline resolution impossible; or their complex synthesis and high cost limit their widespread application.

[0005] Camphorsulfonic acid, as a rigid bicyclic, strongly acidic, and sterically hindered chiral acid, exhibits complex NMR signals. Conventional CSAs struggle to generate sufficiently large chemical shift differences (Δδ) between its enantiomers, making enantiomer identification and content analysis of this important chiral molecule extremely difficult. Therefore, developing dedicated CSAs capable of efficient and accurate enantiomer identification and content analysis of complex and sterically hindered chiral acids such as camphorsulfonic acid is of significant practical importance for expanding the application scope of NMR chiral analysis.

[0006] Meanwhile, in the field of ligand chemistry, the fine structure of ligand molecules (such as the number of coordinating teeth, functional group type, and steric hindrance) has a decisive influence on their recognition and coordination performance. Studies have shown that multidentate or multi-site chiral ligands can achieve highly selective recognition of guests through synergistic hydrogen bonding and spatial matching ([2] Wenzel TJ and Chisholm CD.Chirality. 2010. 23(3):190-214.), and the steric hindrance near the chiral center of the ligand (such as tert-butyl, diphenylmethyl, etc.) can significantly regulate the stability and chemical shift difference (Δδ) of the host-guest complex ([2] Wenzel TJ and Chisholm CD. Chirality. 2010. 23(3):190-214; [4] Feuge N and Wilhelm R.Chirality. 2023. 35(12):993-1011.). For example, the type of hydroxyl group (primary or tertiary) in an amino alcohol ligand profoundly alters the ligand's spatial conformation, flexibility, and interaction pattern with guest molecules. While chiral amino alcohols have been extensively studied as NMR chiral shift reagents, current work is largely limited to testing single or a few structures. Systematic synthesis of a series of ligands with clear contrasts (e.g., primary and tertiary alcohol types) and in-depth investigation of the structure-activity relationship between their key structural units (e.g., the tertiary alcohol center) and chiral recognition performance (especially the enantiomeric discrimination ability against rigid acids such as camphorsulfonic acid) is not reported in the literature. This invention provides molecular design guidance for developing high-performance CSAs for specific chiral substrates. Summary of the Invention

[0007] The primary objective of this invention is to provide a series of novel, systematically designed chiral polydentate amino alcohol ligands and their efficient and reliable synthetic methods. A further objective is to provide the aforementioned ligands, particularly tertiary alcohol ligands, as NMR chiral solvents for the enantiomeric identification and analysis of camphorsulfonic acid. Another objective is to reveal, through comparative studies, the influence of the aforementioned ligands (especially the spatial and electronic properties determined by the differences in their alcohol hydroxyl types) on the chiral recognition performance of rigid, sterically hindered guest structures of camphorsulfonic acid. The ultimate objective is to provide a method for the identification and quantitative analysis of enantiomeric camphorsulfonic acid configurations using 1H NMR spectroscopy for preferred tertiary alcohol ligands selected based on the above principles.

[0008] To achieve the above-mentioned technical objectives, this invention provides a series of chiral polydentate amino alcohol ligands. Primary alcohol-type chiral polydentate amino alcohol ligands refer to compounds having the structure shown in general formula (II), and tertiary alcohol-type chiral polydentate amino alcohol ligands refer to compounds having the structure shown in general formula (VI).

[0009]

[0010] in:

[0011] Ar is or ;

[0012] - R: benzyl, methyl, isobutyl, sec-butyl, or isopropyl;

[0013] This invention provides a series of chiral polydentate amino alcohol ligands based on pyridine or quinoline aromatic ring skeletons designed as chiral amino alcohol derivatives. These ligands construct polydentate chiral recognition sites through the synergistic interaction of the aza-aryl ring, amino group, and hydroxyl group (primary / tertiary alcohol). Through various intermolecular forces such as intermolecular hydrogen bonds, steric hindrance, and π–π interactions, they can form diastereomeric associations with a pair of enantiomers of camphorsulfonic acid with varying stability. This difference in association leads to the generation of probe protons, resulting in significant differences in chemical shift, thereby enabling chiral analysis and recognition of camphorsulfonic acid enantiomers.

[0014] The present invention also provides two methods for preparing a series of chiral polydentate amino alcohol ligands, including primary alcohol-type chiral polydentate amino alcohol ligands and tertiary alcohol-type chiral polydentate amino alcohol ligands.

[0015] Synthetic method of primary alcohol-type chiral polydentate amino alcohol ligand of general formula (II): Starting with L-amino alcohol as starting material, a one-step nucleophilic substitution reaction is carried out with 2-halogenated heteroaryl ring to remove hydrogen halide and directly form the primary alcohol-type chiral polydentate amino alcohol ligand.

[0016]

[0017] Where: Ar is or ;

[0018] - R: benzyl, methyl, isobutyl, sec-butyl, or isopropyl;

[0019] In the preferred embodiment, the nucleophilic substitution reaction is initiated by L-amino alcohol and reacted with a 2-halogenated heteroaromatic ring at a reaction temperature of 160°C for 11-15 hours.

[0020] In a preferred embodiment, the L-amino alcohol is L-phenylalanine, L-alanine, L-leucine, L-isoleucine, or L-valine.

[0021] In a preferred embodiment, the 2-halogenated heterocyclic ring is 2-bromopyridine or 2-chloroquinoline.

[0022] In the preferred embodiment, the molar ratio of the compound shown in Formula I to the 2-halogenated heteroaryl ring is 1.2:1.

[0023] A method for tertiary alcohol-type chiral polydentate amino alcohol ligands of general formula (VI) includes the following steps:

[0024] (1) The L-leucine of Formula III and methanol undergo a condensation reaction under the action of thionyl chloride to generate L-leucine methyl ester hydrochloride of Formula IV.

[0025] (2) The process for preparing the compound shown in formula V from the compound shown in formula IV is as follows: in a dioxane solvent, using BINAP as a ligand, Pd(OAc)2 as a catalyst, and Cs2CO3 as a base, the compound shown in formula V is obtained through a Buchwald-Hartwig cross-coupling reaction to obtain the α-heteroaryl ester;

[0026] (3) The α-heteroaryl amino ester obtained in (2) is subjected to an addition reaction with phenyl magnesium bromide to obtain the tertiary alcohol type chiral polydentate amino alcohol ligand shown in Formula VI;

[0027]

[0028] in:

[0029] Ar is or ;

[0030] In the preferred embodiment, the condensation reaction is carried out by adding thionyl chloride dropwise to a methanol solution of L-leucine in a room temperature water bath, and then allowing the mixture to react at room temperature for 24 hours after the addition is complete.

[0031] In a preferred embodiment, the molar ratio of compound III to sulfoxide is 1:1.2 to 3.

[0032] The preferred method is to use dioxane as a solvent and react at 100°C for 3 hours for the Buchwald-Hartwig cross-coupling reaction.

[0033] In a preferred embodiment, the 2-halogenated heteroaryl ring is 2-bromopyridine or 2-chloroquinoline.

[0034] In the preferred embodiment, the molar ratio of 2-halogenated heteroaromatic ring to compound IV is 1:1.2.

[0035] In the preferred embodiment, the molar ratio of 2-halogenated heteroaryl rings to BINAP is 1:0.06.

[0036] In the preferred embodiment, the molar ratio of 2-halogenated heteroaryl ring to Pd(OAc)2 is 1:0.03.

[0037] In the preferred embodiment, the molar ratio of 2-halogenated heteroaryl rings to Cs2CO3 is 1:3.

[0038] In the preferred embodiment, the molar volume ratio of 2-halogenated heteroaryl ring to dioxane is 1 mmol: 3 mL.

[0039] In the preferred embodiment, the addition reaction is carried out at a temperature of 25–35°C for 15–24 h.

[0040] In a preferred embodiment, the molar ratio of compound V to magnesium phenyl bromide is 1:2 to 5.

[0041] The present invention also provides the application of the chiral polydentate amino alcohol ligand in the identification of camphor sulfonic acid enantiomers and the determination of enantiomer excess value (ee value).

[0042] In the application of this invention, the chiral polydentate amino alcohol ligand, due to its polydentate structural features and specific sterically hindered groups (such as diphenylmethyl), can form diastereomer complexes with enantiomers of camphorsulfonic acid that exhibit significant differences in stability. Through the synergistic regulation of various intermolecular forces, including hydrogen bonding, π–π stacking, dipole-dipole interactions, and van der Waals forces, these complexes can induce significant differences in the chemical shift (Δδ) of probe protons, ultimately leading to baseline separation of the enantiomers. This method provides a reliable means for the identification and quantitative analysis of camphorsulfonic acid enantiomers.

[0043] In the preferred embodiment, the molar ratio of chiral polydentate amino alcohol ligand to camphor sulfonic acid is 1:1, and the concentrations of both chiral polydentate amino alcohol ligand and camphor sulfonic acid are 8 mM.

[0044] Compared with the prior art, the technical solution of the present invention brings the following beneficial technical effects:

[0045] (1) A series of novel and systematically designed chiral tripentate amino alcohol ligands are provided, which enriches the structural library of chiral recognition ligands. In particular, they provide a new recognition platform and material basis for recognizing rigid and sterically hindered chiral acid compounds such as camphor sulfonic acid.

[0046] (2) An efficient method for synthesizing the ligand was developed. The synthetic route has the advantages of readily available raw materials, mild reaction conditions, easy separation and purification of post-processing products, and high yield.

[0047] (3) The mechanism of action of tertiary alcohol ligands in chiral recognition of camphorsulfonic acid was revealed. Through systematic study, the steric hindrance and electronic properties of the tertiary alcohol center were clarified, which can generate differential interaction with the rigid bicyclic structure of camphorsulfonic acid, thereby inducing a significant difference in chemical shift (Δδ) of the probe proton in the association.

[0048] (4) Highly sensitive and high-resolution identification and quantitative analysis of camphor sulfonic acid enantiomers were achieved. Based on the above mechanism, the selected tertiary alcohol ligand was used as a chiral NMR solvent, which can realize baseline separation, configuration identification and enantiomer excess value (ee value) determination of camphor sulfonic acid enantiomers under micro-scale conditions, providing a new method for rapid analysis of chiral drugs and related compounds. Attached Figure Description

[0049] Figure 1 The primary alcohol-type chiral polydentate amino alcohol ligand prepared in Example 1 of this invention enables chiral recognition of camphor sulfonic acid enantiomers. 1 H NMR spectrum;

[0050] Figure 2 The tertiary alcohol-type chiral polydentate amino alcohol ligand prepared in Example 4 of this invention enables chiral recognition of camphor sulfonic acid enantiomers. 1 H NMR spectrum;

[0051] Figure 3 The chiral polydentate amino alcohol ligand prepared in Example 4-1 of this invention was used for the qualitative identification of camphor sulfonic acid enantiomeric compounds. 1 H NMR spectrum;

[0052] Figure 4 This is a calibration curve for determining the enantiomeric excess value (ee value) of camphorsulfonic acid using the chiral polydentate amino alcohol ligand prepared in Example 4-1 of the present invention; wherein, (a) is a partial ee value of camphorsulfonic acid in the presence of the ligand with different ee values. 1 (a) is an HNMR spectrum; (b) is based on (a) 1 Linear relationship between the measured ee value and the theoretical ee value obtained by integrating the H NMR signal. Detailed Implementation

[0053] The present invention will be further described below with reference to specific embodiments, but this does not limit the scope of protection of the claims in any way.

[0054] Example 1: The compound shown in Formula I undergoes a nucleophilic substitution reaction with 2-bromopyridine or 2-chloroquinoline to obtain the primary alcohol-type chiral polydentate amino alcohol ligand shown in Formula II. The specific operating conditions are as follows:

[0055]

[0056] A mixture of the compound shown in Formula I (1.2 mmol) and 2-bromopyridine (1 mmol) or 2-chloroquinoline (1 mmol) was heated and stirred at 160°C for 11–15 hours. The reaction was monitored by TLC until completion. The reaction was quenched by adding saturated sodium bicarbonate solution (20 mL) and the solution was extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, washed once with saturated brine (50 mL), dried with anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by recrystallization from a mixed solvent of petroleum ether / ethyl acetate (V / V = 10:1), which yielded the compound shown in Formula II.

[0057] Example 1-1: Preparation of (S)-3-phenyl-2-(pyridin-2-ylamino)prop-1-ol (ligand a)

[0058]

[0059] (S)-3-phenyl-2-(pyridin-2-ylamino)propan-1-ol: white solid, 85% yield. 1 H NMR (500 MHz, CDCl3, ppm) δ 8.02 (dd,J=5.1, 1.1 Hz, 1H), 7.36 (ddd, J=8.7, 7.2, 1.8 Hz, 1H), 7.30 (t, J=7.3 Hz,2H), 7.25–7.19 (m, 3H), 6.61–6.52 (m, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.58 (d, J=5.2 Hz, 1H), 4.06 (dqd, J=12.5, 6.3, 2.7 Hz, 1H), 3.82 (dd, J=11.0, 2.7 Hz,1H), 3.66 (dd, J=11.0, 6.5 Hz, 1H), 2.97 (dd, J=13.9, 6.3 Hz, 1H), 2.88 (dd,J=13.9, 8.1 Hz, 1H). 13 C NMR (126 MHz, CDCl3, ppm) δ 158.37, 147.22, 138.25,137.76, 129.32, 128.70, 126.64, 113.22, 108.91, 65.90, 55.81, 37.72. HRMS(ESI-TOF): m / z [M+H] + calcd. for C 14 H 17 N2O + , 229.1335, found 229.1332.

[0060] Examples 1-2: Preparation of (S)-2-(pyridin-2-ylamino)prop-1-ol (ligand b)

[0061]

[0062] (S)-2-(pyridin-2-yl-amino)propan-1-ol: white solid, 90% yield. 1 H NMR (400 MHz, CDCl3, ppm) δ 8.00 (d, J=5.0 Hz, 1H), 7.39 (t, J=7.7 Hz, 1H), 6.61–6.52 (m, 1H), 6.44 (d, J=8.4 Hz, 1H), 4.57 (s, 1H), 4.06 (d, J=63.6 Hz, 2H), 3.73 (dd, J=10.8, 2.9 Hz, 1H), 3.56 (dd, J=10.8, 7.2Hz, 1H), 1.23 (d, J=6.8 Hz, 3H). 13 C NMR (126 MHz, CDCl3, ppm) δ 158.49,147.16, 137.66, 112.90, 108.52, 68.07, 50.14, 17.82. HRMS (ESI-TOF): m / z [M+H] + calcd. for C8H 13 N2O + , 153.1022, found 153.1019.

[0063] Examples 1-3: Preparation of (2S,3S)-3-methyl-2-(pyridin-2-ylamino)pentane-1-ol (ligand c)

[0064]

[0065] (2S,3S)-3-methyl-2-(pyridin-2-yl-amino)pentan-1-ol: white solid, 88% yield. ¹H NMR (400 MHz, CDCl₃, ppm): δ 8.01–7.97 (m, 1H), 7.41–7.36 (m, 1H), 6.57–6.53 (m, 1H), 6.46 (d, J=8.4 Hz, 1H), 4.59 (d, J=5.7 Hz, 1H), 3.82 (dd, J=10.4, 2.2 Hz, 1H), 3.70 (ddd, J=8.0, 6.6, 2.0 Hz, 1H), 3.64 (dd, J=8.0, 6.6, 2.0 Hz, 1H). J=10.4, 7.2 Hz, 1H), 1.78–1.64 (m, 1H), 1.56 (tdd, J=14.9, 7.5, 4.3 Hz, 1H), 1.24–1.17 (m, 1H), 0.97 (d, J=6.9 Hz, 3H), 0.92 (t, J=7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3, ppm) δ 159.02, 147.22,137.66, 112.72, 108.32, 64.35, 58.74, 36.89, 25.93, 15.50, 11.70. HRMS (ESI-TOF): m / z [M+H]+ calcd. for C11H19N2O+, 195.1492, found 195.1485.

[0066] Examples 1-4: Preparation of (S)-3-methyl-2-(pyridin-2-ylamino)but-1-ol (ligand d)

[0067]

[0068] (S)-3-methyl-2-(pyridin-2-yl-amino)butan-1-ol: white solid, 85% yield. 1 H NMR (400 MHz, CDCl3, ppm) δ 7.98 (dd, J=5.2, 1.0 Hz, 1H), 7.41 (ddd, J=8.8, 7.2, 1.9 Hz, 1H), 6.56 (dd, J=6.6, 5.7Hz, 1H), 6.49 (d, J=8.5 Hz, 1H), 4.74 (s, 1H), 3.82 (h, J=5.1 Hz, 1H), 3.67(t, J=5.2 Hz, 1H), 3.65–3.60 (m, 1H), 1.99 (tt, J=13.4, 6.9 Hz, 1H), 1.01 (d,J=2.2 Hz, 3H), 0.99 (d, J=2.2 Hz, 3H). 13 C NMR (126 MHz, CDCl3, ppm) δ 158.92,146.85, 137.51, 112.28, 108.02, 63.68, 59.41, 29.57, 19.26, 18.74. HRMS (ESI-TOF): m / z [M+H] + calcd. for C 10 H 17 N2O + , 181.1335, found 181.1338.

[0069] Examples 1-5: Preparation of (S)-3-phenyl-2-(quinolin-2-ylamino)prop-1-ol (ligand e)

[0070]

[0071] (S)-3-phenyl-2-(quinolin-2-yl-amino)propan-1-ol: white solid, 87% yield. 1H NMR (400 MHz, CD3OD, ppm) δ 7.79 (d, J=9.0 Hz, 1H), 7.56 (d, J=8.9 Hz, 2H), 7.52–7.44 (m, 1H), 7.30 (d, J=7.2 Hz,2H), 7.24 (t, J=7.5 Hz, 2H), 7.19–7.11 (m, 2H), 6.73 (d, J=9.0 Hz, 1H), 4.40–4.30 (m, 1H), 3.71 (dd, J=11.0, 4.4 Hz, 1H), 3.65 (dd, J=11.0, 5.3 Hz, 1H),3.04–2.98 (m, 1H), 2.95 (dd, J = 13.8, 7.4 Hz, 1H). 13 C NMR (126 MHz, CDCl3, ppm) δ 156.60, 146.65, 138.20, 137.26, 129.54, 129.04, 128.33, 127.27,126.25, 125.16, 123.04, 122.12, 112.39, 65.44, 55.62, 37.12. HRMS (ESI-TOF):m / z [M+H] + calcd. for C 18 H 19 N2O + , 279.1492, found 279.1468.

[0072] Examples 1-6: Preparation of (S)-2-(quinolin-2-ylamino)prop-1-ol (ligand f)

[0073]

[0074] (S)-2-(quinolin-2-yl-amino)propan-1-ol: white solid, 82% yield. 1 H NMR (500 MHz, CDCl3, ppm) δ 8.02 (dd, J=5.1, 1.1 Hz,1H), 7.36 (ddd, J=8.7, 7.2, 1.8 Hz, 1H), 7.30 (t, J=7.3 Hz, 2H), 7.25–7.19(m, 3H), 6.61–6.52 (m, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.58 (d, J=5.2 Hz, 1H), 4.06 (dqd, J=12.5, 6.3, 2.7 Hz, 1H), 3.82 (dd, J=11.0, 2.7 Hz, 1H), 3.66 (dd,J=11.0, 6.5 Hz, 1H), 2.97 (dd, J=13.9, 6.3 Hz, 1H), 2.88 (dd, J=13.9, 8.1 Hz, 1H). 13 C NMR (126 MHz, CDCl3, ppm) δ 156.98, 146.69, 137.87, 130.00, 127.48,125.61, 123.37, 122.69, 112.57, 69.95, 51.27, 18.16. HRMS (ESI-TOF): m / z [M+H] + calcd. for C 12 H 15 N2O + , 203.1179, found 203.1208.

[0075] Examples 1-7: Preparation of (S)-4-methyl-2-(quinolin-2-ylamino)pentan-1-ol (ligand g)

[0076]

[0077] (S)-4-methyl-2-(quinolin-2-yl-amino)pentan-1-ol: white solid, 86% yield. 1 H NMR (400 MHz, CDCl3, ppm) δ 7.79 (d, J=8.9 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.55–7.47 (m,1H), 7.25–7.19 (m, 1H), 6.65 (d, J=8.9 Hz, 1H), 4.88 (s, 1H), 4.22–4.15 (m,1H), 3.85 (dd, J=10.9, 2.4 Hz, 1H), 3.64 (dd, J=10.9, 7.7 Hz, 1H), 1.76 (m, J=13.1, 6.6 Hz, 1H), 1.53–1.47 (m, 1H), 1.47–1.41 (m, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H). 13 C NMR (126 MHz, CDCl3, ppm) δ 157.24, 146.80,137.70, 129.87, 127.43, 125.57, 123.33, 122.47, 112.54, 68.89, 53.42, 41.09,25.18, 23.13, 22.33. HRMS (ESI-TOF): m / z [M+H] + calcd. for C 15 H 21 N2O + ,245.1648, found 245.1664.

[0078] Examples 1-8: Preparation of (2S,3S)-3-methyl-2-(quinolin-2-ylamino)pentane-1-ol (ligand h)

[0079]

[0080] (2S,3S)-3-methyl-2-(quinolin-2-yl-amino)pentan-1-ol: white solid, 85% yield. 1 H NMR (400 MHz, CDCl3, ppm) δ 7.79(d, J=8.9 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.22 (t, J=7.3 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 4.93 (s, 1H),3.98–3.88 (m, 2H), 3.74 (dd, J=11.0, 7.5 Hz, 1H), 1.80 (dt, J=12.9, 6.5 Hz,1H), 1.67–1.51 (m, 1H), 1.35–1.22 (m, 1H), 1.01 (d, J=6.9 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H). 13 C NMR (126 MHz, CDCl3, ppm) δ 157.38, 146.83, 137.67, 129.84,127.42, 125.53, 123.28, 122.42, 112.60, 65.76, 59.53, 37.10, 26.11, 15.54,11.75. HRMS (ESI-TOF): m / z [M+H] + calcd. for C 15 H 21 N2O + , 245.1648, found245.1638.

[0081] Examples 1-9: Preparation of (S)-3-methyl-2-(quinolin-2-ylamino)but-1-ol (ligand i)

[0082]

[0083] (S)-3-methyl-2-(quinolin-2-yl-amino)butan-1-ol: white solid, 85% yield. 1 H NMR (500 MHz, CDCl3, ppm) δ 8.02 (dd, J=5.1, 1.1 Hz, 1H), 7.36 (ddd, J=8.7, 7.2, 1.8 Hz, 1H), 7.30 (t, J=7.3 Hz, 2H), 7.25–7.19 (m, 3H), 6.61–6.52 (m, 1H), 6.35 (d, J=8.4 Hz, 1H), 4.58 (d, J=5.2 Hz, 1H), 4.06 (dqd, J=12.5, 6.3, 2.7 Hz, 1H), 3.82 (dd, J=11.0, 2.7 Hz,1H), 3.66 (dd, J=11.0, 6.5 Hz, 1H), 2.97 (dd, J=13.9, 6.3 Hz, 1H), 2.88 (dd,J=13.9, 8.1 Hz, 1H). 13 C NMR (126 MHz, CDCl3, ppm) δ 157.39, 146.82, 137.71,129.86, 127.43, 125.53, 123.29, 122.45, 112.58, 66.14, 60.78, 29.99, 19.40,19.09. HRMS (ESI-TOF): m / z [M+H] + calcd. for C 14 H 19 N2O + , 231.1492, found231.1510.

[0084] Example 2: The L-leucine of Formula III and methanol underwent a condensation reaction in the presence of thionyl chloride to produce L-leucine methyl ester hydrochloride of Formula IV. The specific operating conditions were as follows: 10 mmol of leucine was suspended in 10 mL of anhydrous methanol and cooled in a water bath at room temperature. 20 mmol of thionyl chloride was slowly added dropwise over 30 minutes. After the addition was complete, the reaction mixture was brought to room temperature and stirred for 24 hours. The solvent was removed under reduced pressure to obtain a white solid L-leucine methyl ester hydrochloride.

[0085]

[0086] Example 3: In the preparation of compound V from compound IV, BINAP was added as a ligand, Pd(OAc)2 as a catalyst, and Cs2CO3 as a base to carry out a Buchwald-Hartwig cross-coupling reaction to obtain compound V, α-heteroaryl amino ester. The specific operating conditions were as follows: 2-bromopyridine or 2-chloroquinoline (1.00 mmol, 1.0 equivalent), the L-leucine methyl ester hydrochloride (1.20 mmol), Cs2CO3 (3.00 mmol), BINAP (0.06 mmol), and Pd(OAc)2 (0.03 mmol) were added sequentially to a dried reaction flask. After adding dioxane (3 mL), the reaction was stirred at 100 °C for 3 hours. After the reaction solution cooled to room temperature, it was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was then purified by recrystallization using a mixed solvent of petroleum ether / ethyl acetate (V / V=15:1).

[0087]

[0088] Example 3-1: Preparation of (S)-2-(pyridin-2-ylamino)-4-methylpentanoate methyl ester

[0089]

[0090] (S)-2-(pyridin-2-ylamino)-4-methylpentanoate: white solid, yield 88%. 1 H NMR (600 MHz, CDCl3, ppm) δ 8.07 (dd, J=5.1,1.1 Hz, 1H), 7.40 (ddd, J=8.8, 7.2, 1.9 Hz, 1H), 6.60 (ddd, J=7.0, 5.1, 0.8Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 4.79 (s, 1H), 4.55 (td, J=8.7, 5.7 Hz, 1H), 3.71 (s, 3H), 1.79 (ddt, J=19.6, 13.0, 6.5 Hz, 1H), 1.70 (ddd, J=13.6, 8.0,5.7 Hz, 1H), 1.64 (ddd, J=13.7, 8.9, 6.3 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H).

[0091] Example 3-2: Preparation of (S)-2-(quinolin-2-ylamino)-4-methylpentanoate methyl ester

[0092]

[0093] (S)-2-(quinolin-2-yl-amino)-4-methylpentanoate: white solid, yield 82%. 1 H NMR (600 MHz, CDCl3, ppm) δ 7.81 (dd, J=8.6,5.6 Hz, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 7.54–7.49 (m,1H), 7.22 (t, J=7.4 Hz, 1H), 6.67 (dd, J=8.8, 3.3 Hz, 1H), 5.04 (s, 1H), 4.96–4.86 (m, 1H), 3.74 (s, 3H), 1.83 (dt, J=20.5, 6.4 Hz, 1H), 1.76 (ddd, J=13.4, 7.9, 5.5 Hz, 1H), 1.73–1.66 (m, 1H), 1.00 (d, J=4.1 Hz, 3H), 0.99 (d, J=4.0 Hz, 3H).

[0094] Example 4: The α-heteroaryl amino ester of Formula V was subjected to an addition reaction with phenylmagnesium bromide to obtain the tertiary alcohol-type chiral polydentate amino alcohol ligand of Formula VI. The specific operating conditions were as follows: Magnesium shavings (40 mmol) and tetrahydrofuran (10 mL) were added to a dry 100 mL three-necked flask. Bromobenzene (40 mmol) was dissolved in tetrahydrofuran (10 mL) to prepare a solution. Approximately 2 mL of the bromobenzene solution was added dropwise to the flask to initiate the reaction. After the reaction started, the remaining bromobenzene solution was slowly added dropwise while maintaining a micro-reflux state. The addition process was completed within 10 minutes. Subsequently, the reaction mixture was heated under reflux for 30 minutes to generate a PhMgBr solution, which was then cooled to room temperature and used directly in the next reaction step. Within 10 minutes, α-heteroaryl amino ester (5 mmol) was slowly added in batches to the Grignard reagent solution in an ice-water bath. After the addition was complete, the reaction mixture was allowed to rise to room temperature naturally and stirred for 12 hours. The reaction was quenched with 5% NH4Cl aqueous solution. The reaction mixture was extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by recrystallization using a petroleum ether / ethyl acetate (V / V = 20:1) mixed solvent.

[0095]

[0096] Example 4-1: Preparation of (S)-4-methyl-1,1-diphenyl-2-(pyridin-2-ylamino)pentan-1-ol (ligand j)

[0097]

[0098] (S)-4-methyl-1,1-diphenyl-2-(pyridin-2-ylamino)pentan-1-ol: white solid, 84% yield. 1 H NMR (400 MHz, CDCl3, ppm) δ 7.92 (dd, J=5.1, 1.2 Hz, 1H), 7.54–7.44 (m, 4H), 7.29–7.23 (m,2H), 7.23–7.11 (m, 4H), 7.05 (t, J=7.3 Hz, 1H), 6.44 (dd, J=6.5, 5.4 Hz, 1H), 6.17 (d, J=8.4 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.42 (d, J=8.0 Hz, 1H), 1.77–1.67 (m, 1H), 1.60–1.48 (m, 1H), 1.31–1.23 (m, 1H), 0.86 (d, J=6.5 Hz, 3H), 0.73 (d, J=6.7 Hz, 3H). 13 C NMR (126 MHz, CDCl3, ppm) δ 158.00, 147.24,146.43, 145.49, 137.61, 127.99, 127.90, 126.70, 126.62, 126.59, 126.48,112.77, 109.46, 81.54, 58.81, 38.64, 25.42, 23.99, 21.71. HRMS (ESI-TOF): m / z[M+H] + calcd. for C 23 H 27 N2O + , 347.2118, found 347.2141.

[0099] Example 4-2: Preparation of (S)-4-methyl-1,1-diphenyl-2-(quinolin-2-ylamino)pentan-1-ol (ligand k)

[0100]

[0101] (S)-4-methyl-1,1-diphenyl-2-(quinolin-2-ylamino)pentan-1-ol: white solid, 82% yield. 1 H NMR (600MHz, CDCl3, ppm) δ 7.68 (d, J=8.2 Hz, 1H), 7.56 (t, J=8.5 Hz, 3H), 7.46 (t, J=9.2 Hz, 4H), 7.26 (t, J=7.7 Hz, 2H), 7.15 (dd, J=14.1, 6.8 Hz, 2H), 7.08 (t,J=7.6 Hz, 2H), 6.98 (t, J=7.1 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 4.77 (s, 1H),1.59–1.49 (m, 1H), 1.36–1.26 (m, 1H), 1.21–1.16 (m, 1H), 0.95 (d, J=6.4 Hz, 1H), 0.86 (d, J=6.5 Hz, 3H), 0.70 (d, J=6.6 Hz, 3H). 13 C NMR (126 MHz, CDCl3, ppm) δ 156.05, 147.56, 146.35, 145.64, 143.99, 137.62, 129.86, 128.60, 128.06, 127.93, 127.66, 127.41, HRMS (ESI-TOF): m / z [M+K] + calcd. for C 27 H 28 KN2O + , 435.1833, found 435.1849.

[0102] Example 5: Chiral polydentate amino alcohol ligands for enantiomeric chiral recognition of camphor sulfonic acid

[0103] Example 5-1 Chiral Recognition of Primary Alcohol Ligands Approximately 0.93 mg (0.004 mmol) of racemic camphor sulfonic acid was dissolved in 0.5 mL of deuterated chloroform. Then, the primary alcohol-type chiral polydentate amino alcohol ligand prepared in Example 1 (approximately 0.004 mmol, weighed at a 1:1 molar ratio) was added to the solution, and the mixture was shaken to dissolve, bringing the final concentrations of both camphor sulfonic acid and the ligand to 8 mM. Immediately after thorough mixing, ¹H NMR was performed, focusing on the proton signal region at the ortho-methylene position of the sulfonic acid group. The results showed that, as shown in the attached... Figure 1 As shown, in the presence of this primary alcohol ligand, the methylene proton signal of the camphor sulfonic acid enantiomer did not undergo significant splitting, and the maximum chemical shift difference Δδ was only 0.0398 ppm, failing to achieve baseline separation, indicating that the primary alcohol ligand has a weak chiral recognition effect.

[0104] Example 5-2 Chiral Recognition of Tertiary Alcohol Ligands Approximately 0.93 mg (0.004 mmol) of racemic camphor sulfonic acid was dissolved in 0.5 mL of deuterated chloroform. Then, the tertiary alcohol-type chiral polydentate amino alcohol ligand prepared in Example 4 (approximately 0.004 mmol, weighed at a 1:1 molar ratio) was added to the solution, and the mixture was shaken to dissolve, bringing the final concentrations of both camphor sulfonic acid and the ligand to 8 mM. Immediately after thorough mixing, ¹H NMR was performed, focusing on the proton signal region at the ortho-methylene position of the sulfonic acid group. The results showed that, as shown in the attached... Figure 2 As shown, in the presence of the chiral polydentate amino alcohol ligand prepared in Example 4-1, the methylene proton signal of the camphorsulfonic acid enantiomer split into two clear signals with a chemical shift difference Δδ of 0.19 ppm, achieving baseline separation. This result directly confirms that tertiary alcohol ligands have a significantly superior chiral recognition ability for camphorsulfonic acid enantiomers compared to primary alcohol ligands, highlighting the crucial role of the tertiary alcohol center in recognizing rigid, sterically hindered chiral acids.

[0105] Example 6: Chiral polydentate amino alcohol ligands for enantiomeric identification and ee value determination of camphor sulfonic acid

[0106] The chiral polydentate amino alcohol ligands prepared in Example 4-1 of this invention were used for enantiomeric identification and ee value determination of camphor sulfonic acid. The deuterated solvent used was CDCl3, and the nuclear magnetic resonance (NMR) measurements were performed at 25°C on a Bruker AVANCE III 500 MHz spectrometer.

[0107] Example 6-1: Qualitative Identification Experiment

[0108] Approximately 0.93 mg (0.004 mmol) each of the racemic mixture of camphorsulfonic acid, D-camphorsulfonic acid, or L-camphorsulfonic acid were dissolved in 0.5 mL of deuterated chloroform (CDCl3). Then, approximately 1.39 mg (0.004 mmol) of the chiral polydentate amino alcohol ligand prepared in Example 4-1 was added to each solution, and the mixture was shaken to dissolve. At this point, the final concentrations of both camphorsulfonic acid and the ligand in the solution were 8 mM. Immediately after thorough mixing, ¹H NMR was performed, focusing on the signal region of the ortho-methylene proton (CH₂SO₃H) of the sulfonic acid group. The results showed that, as shown in the attached... Figure 3 As shown, after the addition of the ligand to racemic camphorsulfonic acid, the original single proton signal split into two sets of signals; while the addition of the ligand to the single-configuration D-camphorsulfonic acid or L-camphorsulfonic acid resulted in only a single signal, and comparison confirmed that the low-field signal belonged to the D configuration (i.e., the S configuration). The chemical shift difference Δδ between the two sets of signals was 0.19 ppm, and baseline separation was achieved, indicating that this chiral polydentate amino alcohol ligand can clearly and rapidly distinguish camphorsulfonic acid enantiomers and can be used for absolute configuration identification and quantitative analysis of enantiomer composition.

[0109] Example 6-2: Quantitative Determination of Enantiomer Excess Value (ee Value) A series of camphor sulfonic acid standard samples with ee values ​​of 0%, 20%, 40%, 60%, 80%, and 95% were precisely prepared. Six NMR tubes were taken, and chiral polydentate amino alcohol ligands prepared in Example 4-1 (final concentration 8 mM) were added to each. Then, samples with different ee values ​​were added, maintaining a 1:1 molar ratio of chiral solvent to camphor sulfonic acid, and dissolved in 0.5 mL of CDCl3. ¹H NMR spectra of each sample were acquired in the same test sequence. Characteristic proton signals with baseline separation were selected for precise integration to obtain the signal areas I of the two enantiomers. S with I R According to the formula ee(%) = Calculate and measure the ee value.

[0110] The measured ee value is linearly fitted to the theoretical ee value, as shown in the attached figure. Figure 4 As shown in (a) and (b), the calibration curve equation is obtained as y = 0.9921x – 0.2438, with a correlation coefficient R² = 0.9997. This result demonstrates that the determination of camphorsulfonic acid ee value using a chiral solvent via NMR integration has extremely high accuracy and reliability, making it suitable for precise enantiomeric purity analysis of this chiral acid.

Claims

1. A series of chiral amino alcohols characterized in that, A chiral polydentate amino alcohol ligand of a primary alcohol type or a chiral polydentate amino alcohol ligand of a tertiary alcohol type, wherein the chiral polydentate amino alcohol ligand of the primary alcohol type has a structure as shown in general formula (II), and the chiral polydentate amino alcohol ligand of the tertiary alcohol type has a structure as shown in general formula (VI). wherein: Ar is or ; - R: benzyl, methyl, isobutyl, sec-butyl or isopropyl.

2. A method of synthesizing a chiral polydentate amino alcohol ligand of primary alcohol type according to claim 1, characterized in that, The method comprises the following steps: The L-amino alcohol (I) and 2-halogen heteroaromatic ring undergo nucleophilic substitution reaction to obtain primary alcohol type (II) chiral polydentate amino alcohol ligand. wherein: Ar is or ; - R: benzyl, methyl, isobutyl, sec-butyl or isopropyl.

3. The method of claim 2, wherein the chiral polydentate amino alcohol ligand is a primary alcohol. The nucleophilic substitution reaction is carried out at 160 DEG C for 11-15 h, the molar ratio of the 2-halogenated heteroaromatic ring to the compound (I) is 1:1.2, and the 2-halogenated heteroaromatic ring is 2-bromopyridine or 2-chloroquinoline.

4. A method of synthesizing a chiral polydentate amino alcohol ligand of tertiary alcohol type according to claim 1, characterized in that, The method comprises the following steps: (1) the L-leucine amino acid (III) and methanol are subjected to condensation reaction under the action of dichloro sulfoxide to generate L-leucine methyl ester hydrochloride (IV); (2) the compound (IV) is subjected to Buchwald-Hartwig cross-coupling reaction in dioxane solvent to generate compound (V) by taking BINAP as a ligand, Pd(OAc)2 as a catalyst and Cs2CO3 as a base; (3) the compound (V) obtained in (2) is subjected to addition reaction with phenyl magnesium bromide to generate a tertiary alcohol type (VI) chiral polydentate amino alcohol ligand; wherein Ar is or .

5. The method of claim 4, wherein the tertiary alcohol type chiral polydentate amino alcohol ligand is characterized by: The condensation reaction is carried out by slowly adding dichlorosulfoxide to an L-leucine amino acid methanol solution in a normal temperature water bath, and the reaction is carried out at room temperature for 24-40 h after the addition is completed. The molar ratio of the compound (III) to dichlorosulfoxide is 1:1.2-3, the Buchwald-Hartwig cross-coupling reaction is carried out in dioxane as a solvent at 100 DEG C for 3 h, the 2-halogenated heteroaromatic ring is 2-bromopyridine or 2-chloroquinoline, the molar ratio of the 2-halogenated heteroaromatic ring to the compound (IV) is 1:1.2, the molar ratio of the 2-halogenated heteroaromatic ring to BINAP is 1:0.06, the molar ratio of the 2-halogenated heteroaromatic ring to Pd(OAc)2 is 1:0.03, the molar ratio of the 2-halogenated heteroaromatic ring to Cs2CO3 is 1:3, and the molar volume ratio of the 2-halogenated heteroaromatic ring to dioxane is 1 mmol:3 mL.

6. The method for using tertiary alcohol-type chiral polydentate amino alcohol ligands according to claim 4, characterized in that: The addition reaction is carried out at 25-35 DEG C for 15-24 h, and the molar ratio of the compound (V) to phenylmagnesium bromide is 1:2-5.

7. A method for the identification of enantiomers of camphorsulfonic acid using a chiral polydentate amino alcohol ligand, characterized in that, The method comprises the following steps: (1) mixing the chiral polydentate amino alcohol ligand with a camphorsulfonic acid sample to be detected in deuterated chloroform at a molar ratio of 1:1 to form a test solution; (2) performing nuclear magnetic resonance hydrogen spectrum testing on the test solution; and (3) identifying the enantiomer composition of the camphorsulfonic acid by analyzing the signal of the sulfonic acid group ortho-methylene proton in the camphorsulfonic acid, wherein the ligand can split the signal of the proton in the test solution, and the chemical shift difference (Δδ) of the signals corresponding to the R-configuration and the S-configuration is not less than 0.1 ppm.

8. The method of claim 7, characterized in that, In the test solution, the concentrations of the chiral polydentate amino alcohol ligand and the camphorsulfonic acid are both 8 mM. The chemical shift difference (Δδ) is 0.19 ppm, and the two groups of signals are baseline-separated. The absolute configuration is distinguished by comparing the chemical shifts of the proton signals, wherein the proton signal corresponding to D-camphorsulfonic acid (S-configuration) appears at a lower field.

9. A method for determining the enantiomeric excess value (ee value) of camphorsulfonic acid by means of a chiral polydentate amino alcohol ligand, characterized in that, The method comprises the following steps: (1) mixing the chiral polydentate amino alcohol ligand with a sample of camphorsulfonic acid to be tested in a molar ratio of 1:1 in deuterated chloroform to form a test solution; (2) performing nuclear magnetic resonance hydrogen spectrum test on the test solution; wherein the ligand can split the signal of the methylene group proton adjacent to the sulfonic acid group in the camphorsulfonic acid into two signal peaks corresponding to R-configuration and S-configuration, and the chemical shift difference (Δδ) between the two signal peaks is not less than 0.1 ppm and baseline separation is achieved; (3) obtaining the peak areas I S and I R ; The enantiomeric excess value of the said camphorsulfonic acid sample is calculated according to the formula ee (%) = .

10. The method of claim 9, wherein, The chemical shift difference (Δδ) is 0.19 ppm; the concentration of the chiral multidentate amino alcohol ligand and camphorsulfonic acid in the test solution is 8 mM; the linear correlation coefficient R² of the calibration curve for measuring the enantiomeric excess value of camphorsulfonic acid established by the method is 0.9997; the calibration curve is established by camphorsulfonic acid standard samples with theoretical ee values of 0%, 20%, 40%, 60%, 80% and 95% respectively, and the linear regression equation is y = 0.9921x - 0.2438, wherein y is the measured ee value and x is the theoretical ee value.

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