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A new chalcone derivative: Synthesis, crystal structure, Hirshfeld surface, quantum chemical investigations, Druggability and human Cathepsin D inhibitory activity
一种新的查尔酮衍生物：合成、晶体结构、Hirshfeld 表面、量子化学研究、成药性和人组织蛋白酶 D 抑制活性

Ya-an Zhang a , 1 a , 1 ^(a,1){ }^{\mathrm{a}, 1}, Xiaowan Wang a , 1 a , 1 ^(a,1){ }^{\mathrm{a}, 1}, Ya-dian Pan a a ^(a){ }^{\mathrm{a}}, Xin-Zhu She b b ^(b){ }^{\mathrm{b}}, Yuan-Yuan Liu a , ∗ , a , ∗ ,  ^(a,^(**)", "){ }^{\mathrm{a},{ }^{*} \text {, }} Bai-Wang Sun c , ∗ c , ∗ ^(c,^(**)){ }^{\mathrm{c},{ }^{*}}
张 a , 1 a , 1 ^(a,1){ }^{\mathrm{a}, 1} 亚安 ， 王 a , 1 a , 1 ^(a,1){ }^{\mathrm{a}, 1} 小婉 ， 潘亚典 a a ^(a){ }^{\mathrm{a}} ， 佘 b b ^(b){ }^{\mathrm{b}} 欣柱 ， 刘媛媛 a , ∗ , a , ∗ ,  ^(a,^(**)", "){ }^{\mathrm{a},{ }^{*} \text {, }} Bai-Wang Sun c , ∗ c , ∗ ^(c,^(**)){ }^{\mathrm{c},{ }^{*}} a a ^(a){ }^{a} School of Pharmaceutical and Chemical Engineering, Chengxian College, Southeast University, Nanjing,210088, China
a a ^(a){ }^{a} 东南大学 城县学院 制药与化工学院， 江苏 南京 210088 b b  ^("b "){ }^{\text {b }} College of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, China
b b  ^("b "){ }^{\text {b }} 南京工业大学 食品科学与轻工业学院， 中国 南京 211816 c School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China c School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China  ^("c School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China "){ }^{\text {c School of Chemistry and Chemical Engineering, Southeast University, Nanjing, 211189, China }}

A R T IC L E I N F O

Keywords:  关键字：

Chalcones  查耳酮
Crystal structure  晶体结构
DFT
ADMET  亚美特
Hirshfeld surface  Hirshfeld 曲面
Molecular docking  分子对接

Abstract  抽象

This paper presents the synthesis of a novel chalcone derivative, and its molecular structure has been determined by NMR and single-crystal X-ray diffraction analysis. The molecules are connected via O − H ⋯ O , C − H ⋯ O O − H ⋯ O , C − H ⋯ O O-HcdotsO,C-HcdotsO\mathrm{O}-\mathrm{H} \cdots \mathrm{O}, \mathrm{C}-\mathrm{H} \cdots \mathrm{O}, and C − H ⋯ S C − H ⋯ S C-HcdotsS\mathrm{C}-\mathrm{H} \cdots \mathrm{S} hydrogen bonds along with C − H ⋯ π C − H ⋯ π C-Hcdots pi\mathrm{C}-\mathrm{H} \cdots \pi and π ⋯ π π ⋯ π pi cdots pi\pi \cdots \pi interactions. Hirshfeld surface studies have been conducted to comprehensively quantify the patterns of intermolecular interactions. DFT calculations provided insights into the nature of the molecule, including frontier molecular orbital, ADCH charge, Molecular Electrostatic Potential and Natural Bond Orbitals analysis using the optimized structure by B3LYP/6-311 G (d, p) level. The calculated HOMO-LUMO gap ( 3.23 eV ) indicates decent softness and reactivity of the target molecule. The molecular docking studies reveal that the target compound exhibits a high binding affinity with Human Cathepsin D (CatD), with a docking score of − 7.58 kcal / mol − 7.58 kcal / mol -7.58kcal//mol-7.58 \mathrm{kcal} / \mathrm{mol}. The assessment of drug-likeness properties and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles further support its potential as a potent CatD inhibitor candidate for medication development.
本文介绍了一种新型查尔酮衍生物的合成，其分子结构已通过 NMR 和单晶 X 射线衍射分析确定。分子通过 O − H ⋯ O , C − H ⋯ O O − H ⋯ O , C − H ⋯ O O-HcdotsO,C-HcdotsO\mathrm{O}-\mathrm{H} \cdots \mathrm{O}, \mathrm{C}-\mathrm{H} \cdots \mathrm{O} 、 C − H ⋯ S C − H ⋯ S C-HcdotsS\mathrm{C}-\mathrm{H} \cdots \mathrm{S} 氢键以及 C − H ⋯ π C − H ⋯ π C-Hcdots pi\mathrm{C}-\mathrm{H} \cdots \pi 和 π ⋯ π π ⋯ π pi cdots pi\pi \cdots \pi 相互作用连接。已经进行了 Hirshfeld 表面研究以全面量化分子间相互作用的模式。DFT 计算提供了对分子性质的见解，包括使用 B3LYP/6-311 G （d， p） 水平的优化结构进行前沿分子轨道、ADCH 电荷、分子静电势和自然键轨道分析。计算出的 HOMO-LUMO 间隙 （ 3.23 eV ） 表明目标分子具有良好的柔软度和反应性。分子对接研究表明，目标化合物与人组织蛋白酶 D （CatD） 表现出高结合亲和力，对接评分为 − 7.58 kcal / mol − 7.58 kcal / mol -7.58kcal//mol-7.58 \mathrm{kcal} / \mathrm{mol} .药物相似性特性和 ADMET （吸收、分布、代谢、排泄和毒性） 特征的评估进一步支持其作为药物开发的有效 CatD 抑制剂候选者的潜力。

1. Introduction  1. 引言

Chalcones, with 1, 3-diphenylpropenone as the basic skeleton, are natural products widely concerned for their unique chemical characteristics, easy synthesis, and varied biological activities [1-2]. In drug development, chalcone compounds have been proven to have various pharmacological benefits, including anti-tumor [3], antioxidant [4], anti-inflammatory[5], hypoglycemic [6], and antibacterial activities [7]. Despite these potential medicinal benefits, the poor water solubility, low bioavailability, and inadequate selectivity of chalcone compounds limit their clinical application [8-10]. Alpha-lipoic acid (LA), a natural bioactive product, is classified within the B vitamins [11]. Alpha-lipoic acid has a disulfide five-membered ring structure with substantial electron density, exhibiting strong antioxidant properties [12]. Moreover, lipoic acid possesses anti-glycation [13], liver protection [14], and anti-ageing properties [15], and it also plays a role in regulating cell metabolism and signal transduction [16], with high medical value.
查耳酮以 1,3-二苯丙烯酮为基本骨架，因其独特的化学特性、易合成和多种生物活性而被广泛关注的天然产物 [1-2]。在药物开发中，查尔酮化合物已被证明具有多种药理学益处，包括抗肿瘤 [3]、抗氧化 [4]、抗炎 [5]、降血糖 [6] 和抗菌活性 [7]。尽管具有这些潜在的药用价值，但查尔酮化合物的水溶性差、生物利用度低和选择性不足限制了它们的临床应用[8-10]。α-硫辛酸 （LA） 是一种天然生物活性产物，属于 B 族维生素 [11]。α-硫辛酸具有二硫键五元环结构，具有相当大的电子密度，表现出很强的抗氧化特性[12]。此外，硫辛酸具有抗糖化 [13]、保肝 [14] 和抗衰老 [15] 等特性，还发挥着调节细胞代谢和信号转导的作用 [16]，具有很高的医疗价值。
Recent studies have shown that esterification modification of lipoic acid can not only improve its lipophilicity but also effectively enhance its biological activity [17,18]. Alkynyl groups are important functional groups in many drugs, active natural products, and functional materials [19]. Among approved drugs on the market or clinical/preclinical evaluation, drugs containing terminal or internal alkynyl groups account for a large proportion, such as alkynyl steroid drugs [20-21]. Although alkynyl groups, both internal and terminal, tend to inhibit Cytochrome isoforms enzymes (CYP), they can serve diverse roles in medicinal chemistry research, such as increasing the hydrophobicity of molecules, enhancing interactions with target enzymes, and improving drug stability and oral activity [21]. Based on the above, a novel chalcone compound (compound 1 shown in Fig. 1) has been synthesized to combine the synergic effects of lipoic acid and propynyl structural fragments according to the drug hybridization principles.
最近的研究表明，硫辛酸的酯化修饰不仅可以提高其亲脂性，还可以有效增强其生物活性 [17,18]。炔基是许多药物、活性天然产物和功能材料中的重要官能团 [19]。在已上市或临床/临床前评价的已批准药物中，含有末端或内部炔基的药物占很大比例，例如炔基类固醇药物 [20-21]。尽管内部和末端炔基倾向于抑制细胞色素亚型酶 （CYP），但它们可以在药物化学研究中发挥多种作用，例如增加分子的疏水性、增强与靶酶的相互作用以及提高药物稳定性和口服活性 [21]。基于上述，根据药物杂交原理，合成了一种新的查尔酮化合物（化合物 1 如图 1 所示），以结合硫辛酸和丙炔结构片段的协同作用。
Cathepsin D (CatD), as a member of the aspartic protease family, plays a crucial role in the metabolism and degradation of intracellular
组织蛋白酶 D （CatD） 作为天冬氨酸蛋白酶家族的一员，在细胞内的代谢和降解中起着至关重要的作用
C#CCOc1ccc(C(=O)/C=C/c2ccc(OC(=O)CCCCC3CCSS3)cc2)c(O)c1OOOOSSOH

[R]OC(=O)O[C@H](C)O[Na]ROOOSHONa

CCCCCCCCNC(=O)COc1ccc2ccccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1NHOOOOOO
Fig. 1. The structures of compound 1-3.
图 1.化合物 1-3 的结构。
proteins, the activation of peptide hormones, and the regulation of apoptosis [22]. CatD has been identified as a potential target for cancer treatment, as its overexpression is closely related to the occurrence and development of various malignant tumours, such as breast cancer and ovarian cancer [23]. The well-known CatD inhibitor is Pepstatin A [24], a pentapeptide molecule that exhibits potent inhibitory activity. However, peptidomimetic inhibitors have shortcomings, including high molecular weight, poor membrane permeability, low oral bioavailability and rapid hydrolysis in vivo. Consequently, the development of efficient non-peptidomimetic inhibitors has emerged as an alternative potential strategy [25]. Numerous small molecule inhibitors of CatD have been reported and compound 2 [25] and compound 3 [26] are two of them (Fig. 1). The present work has selected these compounds as standard
蛋白质、肽激素的激活和细胞凋亡的调节 [22]。CatD 已被确定为癌症治疗的潜在靶点，因为它的过表达与各种恶性肿瘤（如乳腺癌和卵巢癌）的发生和发展密切相关 [23]。众所周知的 CatD 抑制剂是胃蛋白酶抑制剂 A [24]，这是一种具有有效抑制活性的五肽分子。然而，拟肽抑制剂存在分子量高、膜通透性差、口服生物利用度低和体内快速水解等缺点。因此，开发有效的非拟肽抑制剂已成为一种替代的潜在策略 [25]。已经报道了许多 CatD 的小分子抑制剂，化合物 2 [25] 和化合物 3 [26] 就是其中的两种（图 1）。目前的工作选择了这些化合物作为标准
inhibitors to compare the docking results with our target compound. To the best of our knowledge, no study has focused on chalcone compounds or their crystal structures that have inhibitory effects or biological activity on CatD in literature or the Cambridge Crystallographic Data Center (CCDC)
抑制剂，将对接结果与我们的目标化合物进行比较。据我们所知，在文献或剑桥晶体学数据中心 （CCDC） 中，没有研究关注对 CatD 具有抑制作用或生物活性的查尔酮化合物或其晶体结构
In this work, a new chalcone compound, 4-[(1E)-3-[2-hydroxy-4-(prop-2-ynyloxy)pH-enyl]-3-oxoprop-1-enyl]phenyl 5-(1,2-dithiolan- 3 − yl 3 − yl 3-yl3-\mathrm{yl} ) pentanoate (compound 1), has been synthesized to the route reported in Scheme 1, and then its crystal structure and intermolecular interactions have been investigated as well as DFT studies. Computer aided drug design methods have been used to comprehensively evaluate its drug-likeness properties. The inhibitory effect of the target compound on human CatD has been predicted using Autodock software to explore its potential application in treating related diseases.
在这项工作中，按照方案 1 中报道的路线合成了一种新的查尔酮化合物 4-[（1E）-3-[2-羟基-4-（丙-2-炔氧基）pH-烯基]-3-氧代丙-1-烯基]苯基 5-（1,2-二硫烷- 3 − yl 3 − yl 3-yl3-\mathrm{yl} ）五酸酯（化合物 1），然后研究了其晶体结构和分子间相互作用以及 DFT 研究。计算机辅助药物设计方法已被用于综合评价其药物相似性。使用 Autodock 软件预测了目标化合物对人 CatD 的抑制作用，以探索其在治疗相关疾病方面的潜在应用。

2. Experiment section  2. 实验部分

2.1. Materials and physical measurements
2.1. 材料和物理测量

All reagents used in the experiment were of commercially available analytical grade and were purified as required. Reactions were monitored by thin-layer chromatography with ethyl acetate /petroleum ether (3:1, v/v) using a ZF-20D black-box UV analyzer. 1 H 1 H ^(1)H{ }^{1} \mathrm{H} NMR and 13 C 13 C ^(13)C{ }^{13} \mathrm{C} NMR pectra of intermediates and target product were obtained by Bruker AV400 instrument in CDCl 3 CDCl 3 CDCl_(3)\mathrm{CDCl}_{3} or DMSO- d 6 d 6 d_(6)\mathrm{d}_{6} with TMS as an internal reference.
实验中使用的所有试剂均为市售分析级试剂，并根据需要进行纯化。使用 ZF-20D 黑盒紫外分析仪，通过乙酸乙酯/石油醚 （3：1， v/v） 的薄层色谱法监测反应。 1 H 1 H ^(1)H{ }^{1} \mathrm{H} 中间体和目标产品的 NMR 和 13 C 13 C ^(13)C{ }^{13} \mathrm{C} NMR pectra 通过 Bruker AV400 仪器 CDCl 3 CDCl 3 CDCl_(3)\mathrm{CDCl}_{3} 或 DMSO- d 6 d 6 d_(6)\mathrm{d}_{6} 以 TMS 作为内部参考获得。

2.2. Synthesis  2.2. 合成

Synthetic process of intermediate 2:
中间体 2 的合成工艺：
Under an atmosphere of nitrogen, 2, 4-dihydroxyacetophenone (1.52 g , 10 mmol g , 10 mmol g,10mmol\mathrm{g}, 10 \mathrm{mmol} ), potassium carbonate ( 2.07 g , 15 mmol 2.07 g , 15 mmol 2.07g,15mmol2.07 \mathrm{~g}, 15 \mathrm{mmol} ), and anhydrous DMF ( 10 mL ) were added sequentially, followed by the dropwise addition of propargyl bromide ( 1.43 g , 12 mmol 1.43 g , 12 mmol 1.43g,12mmol1.43 \mathrm{~g}, 12 \mathrm{mmol} ). After stirring at 60 ∘ C 60 ∘ C 60^(@)C60^{\circ} \mathrm{C} overnight, the reaction mixture was cooled to room temperature, followed by the addition of dichloromethane. It was washed with water and saturated salt water in sequence, dried with anhydrous magnesium sulfate, filtered, and concentrated. After silica gel column chromatography purification (ethyl acetate: petroleum ether = 1 : 2 − 2 : 1 , v / v = 1 : 2 − 2 : 1 , v / v =1:2-2:1,v//v=1: 2-2: 1, \mathrm{v} / \mathrm{v}, gradient elution), a light yellow solid (intermediate 2) was obtained with a yield of 60 % . 1 H 60 % . 1 H 60%.^(1)H60 \% .{ }^{1} \mathrm{H} NMR ( 400 MHz , CDCl 3 400 MHz , CDCl 3 400MHz,CDCl_(3)400 \mathrm{MHz}, \mathrm{CDCl}_{3} ) δ ( ppm ) : 12.69 ( s , 1 H δ ( ppm ) : 12.69 ( s , 1 H delta(ppm):12.69(s,1H\delta(\mathrm{ppm}): 12.69(\mathrm{~s}, 1 \mathrm{H}, OH ), 7.65 (s, 1H, Ar-H), 6.50 (m, 2H, Ar-H), 4.72 (s, 2H, CH2), 2.56 (s, 4 H , 三 CH , CH 3 CH , CH 3 CH,CH_(3)\mathrm{CH}, \mathrm{CH}_{3} ).
在氮气气氛下，依次加入 2,4-二羟基苯乙酮 （1.52 g , 10 mmol g , 10 mmol g,10mmol\mathrm{g}, 10 \mathrm{mmol} ）、碳酸钾 （ 2.07 g , 15 mmol 2.07 g , 15 mmol 2.07g,15mmol2.07 \mathrm{~g}, 15 \mathrm{mmol} ） 和无水 DMF （ 10 mL），然后滴加炔丙基溴 （ 1.43 g , 12 mmol 1.43 g , 12 mmol 1.43g,12mmol1.43 \mathrm{~g}, 12 \mathrm{mmol} ）。搅拌 60 ∘ C 60 ∘ C 60^(@)C60^{\circ} \mathrm{C} 过夜后，将反应混合物冷却至室温，然后加入二氯甲烷。依次用水和饱和盐水洗涤，用无水硫酸镁干燥，过滤，浓缩。硅胶柱色谱纯化后（乙酸乙酯：石油醚 = 1 : 2 − 2 : 1 , v / v = 1 : 2 − 2 : 1 , v / v =1:2-2:1,v//v=1: 2-2: 1, \mathrm{v} / \mathrm{v} ，梯度洗脱），得到浅黄色固体（中间体2），收率为 60 % . 1 H 60 % . 1 H 60%.^(1)H60 \% .{ }^{1} \mathrm{H} NMR（ 400 MHz , CDCl 3 400 MHz , CDCl 3 400MHz,CDCl_(3)400 \mathrm{MHz}, \mathrm{CDCl}_{3} ）、 δ ( ppm ) : 12.69 ( s , 1 H δ ( ppm ) : 12.69 ( s , 1 H delta(ppm):12.69(s,1H\delta(\mathrm{ppm}): 12.69(\mathrm{~s}, 1 \mathrm{H} OH ）、7.65 （s， 1H， Ar-H）、6.50 （m， 2H， Ar-H）、4.72 （s， 2H， CH2）、2.56 （s， 4 H ， 三 CH , CH 3 CH , CH 3 CH,CH_(3)\mathrm{CH}, \mathrm{CH}_{3} ）。
Synthetic process of intermediate 3:
中间体 3 的合成工艺：
Acetic acid ( 1.5 mL , 26.2 mmol 1.5 mL , 26.2 mmol 1.5mL,26.2mmol1.5 \mathrm{~mL}, 26.2 \mathrm{mmol} ) was mixed with pyrrolidine ( 2.15 mL , 26.2 mmol mL , 26.2 mmol mL,26.2mmol\mathrm{mL}, 26.2 \mathrm{mmol} ) in an ice bath and heated to 30 ∘ C 30 ∘ C 30^(@)C30^{\circ} \mathrm{C}. Then intermediate 2
将乙酸 （ 1.5 mL , 26.2 mmol 1.5 mL , 26.2 mmol 1.5mL,26.2mmol1.5 \mathrm{~mL}, 26.2 \mathrm{mmol} ） 与吡咯烷 （ 2.15 mL , 26.2 mmol mL , 26.2 mmol mL,26.2mmol\mathrm{mL}, 26.2 \mathrm{mmol} ） 在冰浴中混合并加热至 30 ∘ C 30 ∘ C 30^(@)C30^{\circ} \mathrm{C} 。然后是中间 2
Scheme 1. Synthetic route of compound 1.
方案 1.化合物 1 的合成路线。
Table 1  表 1
Crystal data and structure refinements for Compounds 1.
化合物 1 的晶体数据和结构优化。
Compound  复合 1
Formula  公式 C 26 H 26 O 5 S 2 C 26 H 26 O 5 S 2 C_(26)H_(26)O_(5)S_(2)\mathrm{C}_{26} \mathrm{H}_{26} \mathrm{O}_{5} \mathrm{~S}_{2}
Formula weight  配方重量 482.59
Crystal system  晶系 Triclinic  三斜晶系
Space group  空间组 P 1-  第 1 页-
Z 2
a/ Å 7.3057(9)
b/ Å 10.0144(13)
c/ Å Å "Å"\AAÅ
c/ Å		 17.263(2))
α / ∘ α / ∘ alpha//^(@)\alpha /{ }^{\circ} 103.464(3)
β / ∘ β / ∘ beta//^(@)\beta /{ }^{\circ} 92.738(3)
γ / ∘ γ / ∘ gamma//^(@)\gamma /{ }^{\circ} 91.397(3)
V, Å 3 Å 3 "Å"^(3)\AA^{3}Å
V, Å		 1226.1(3)
T/K  T/K （电汇） 296.15
μ ( mm − 1 ) μ mm − 1 mu(mm^(-1))\mu\left(\mathrm{mm}^{-1}\right) 0.251
D calc ( Mg m − 3 D calc  Mg m − 3 D_("calc ")(Mgm^(-3):}\mathrm{D}_{\text {calc }}\left(\mathrm{Mg} \mathrm{m}^{-3}\right. )   D calc ( Mg m − 3 D calc  Mg m − 3 D_("calc ")(Mgm^(-3):}\mathrm{D}_{\text {calc }}\left(\mathrm{Mg} \mathrm{m}^{-3}\right. ） 1.307
Cryst dimensions(mm)  晶粒尺寸（mm） 0.2 × 0.15 × 0.1 0.2 × 0.15 × 0.1 0.2 xx0.15 xx0.10.2 \times 0.15 \times 0.1
No. of reflns collected  不。收集的 refln 4311
No. of unique reflns  不。唯一 refln 的数量 2010
No. of params  不。参数 299
Goodness of fit on F 2 F 2 F^(2)\mathrm{F}^{2}
拟合 F 2 F 2 F^(2)\mathrm{F}^{2} 优度		 1.394
R 1 , wR 2 ( ( I > 2 σ ( I ) R 1 , wR 2 ( ( I > 2 σ ( I ) R_(1),wR_(2)((I > 2sigma(I)\mathrm{R}_{1}, \mathrm{wR}_{2}((I>2 \sigma(\mathrm{I}) )   R 1 , wR 2 ( ( I > 2 σ ( I ) R 1 , wR 2 ( ( I > 2 σ ( I ) R_(1),wR_(2)((I > 2sigma(I)\mathrm{R}_{1}, \mathrm{wR}_{2}((I>2 \sigma(\mathrm{I}) ） 0.1332, 0.3724
R 1 , wR 2 R 1 , wR 2 R_(1),wR_(2)\mathrm{R}_{1}, \mathrm{wR}_{2} (all data)   R 1 , wR 2 R 1 , wR 2 R_(1),wR_(2)\mathrm{R}_{1}, \mathrm{wR}_{2} （所有数据） 0.2397, 0.4362
CCDC No.  中央结算编号 2,381,071
Compound 1 Formula C_(26)H_(26)O_(5)S_(2) Formula weight 482.59 Crystal system Triclinic Space group P 1- Z 2 a/ Å 7.3057(9) b/ Å 10.0144(13) c/ "Å" 17.263(2)) alpha//^(@) 103.464(3) beta//^(@) 92.738(3) gamma//^(@) 91.397(3) V, "Å"^(3) 1226.1(3) T/K 296.15 mu(mm^(-1)) 0.251 D_("calc ")(Mgm^(-3):} ) 1.307 Cryst dimensions(mm) 0.2 xx0.15 xx0.1 No. of reflns collected 4311 No. of unique reflns 2010 No. of params 299 Goodness of fit on F^(2) 1.394 R_(1),wR_(2)((I > 2sigma(I) ) 0.1332, 0.3724 R_(1),wR_(2) (all data) 0.2397, 0.4362 CCDC No. 2,381,071| Compound | 1 | | :---: | :---: | | Formula | $\mathrm{C}_{26} \mathrm{H}_{26} \mathrm{O}_{5} \mathrm{~S}_{2}$ | | Formula weight | 482.59 | | Crystal system | Triclinic | | Space group | P 1- | | Z | 2 | | a/ Å | 7.3057(9) | | b/ Å | 10.0144(13) | | c/ $\AA$ | 17.263(2)) | | $\alpha /{ }^{\circ}$ | 103.464(3) | | $\beta /{ }^{\circ}$ | 92.738(3) | | $\gamma /{ }^{\circ}$ | 91.397(3) | | V, $\AA^{3}$ | 1226.1(3) | | T/K | 296.15 | | $\mu\left(\mathrm{mm}^{-1}\right)$ | 0.251 | | $\mathrm{D}_{\text {calc }}\left(\mathrm{Mg} \mathrm{m}^{-3}\right.$ ) | 1.307 | | Cryst dimensions(mm) | $0.2 \times 0.15 \times 0.1$ | | No. of reflns collected | 4311 | | No. of unique reflns | 2010 | | No. of params | 299 | | Goodness of fit on $\mathrm{F}^{2}$ | 1.394 | | $\mathrm{R}_{1}, \mathrm{wR}_{2}((I>2 \sigma(\mathrm{I})$ ) | 0.1332, 0.3724 | | $\mathrm{R}_{1}, \mathrm{wR}_{2}$ (all data) | 0.2397, 0.4362 | | CCDC No. | 2,381,071 |
( 1.0 g , 5.25 mmol 1.0 g , 5.25 mmol 1.0g,5.25mmol1.0 \mathrm{~g}, 5.25 \mathrm{mmol} ) and para hydroxybenzaldehyde ( 0.64 g , 5.25 mmol 0.64 g , 5.25 mmol 0.64g,5.25mmol0.64 \mathrm{~g}, 5.25 \mathrm{mmol} ) were added. After stirring for 2 h , the reaction mixture was cooled to room temperature and ethyl acetate ( 20 mL ) and 12 % NaCl 12 % NaCl 12%NaCl12 \% \mathrm{NaCl} aqueous solution ( 12 mL ) were added. The extracted portion of ethyl acetate was washed with saturated salt water and saturated sodium bisulfite solution sequentially, dried with anhydrous magnesium sulfate, filtered, and concentrated. After silica gel column chromatography purification (cyclohexane: acetone = 2 : 1 , v / v = 2 : 1 , v / v =2:1,v//v=2: 1, \mathrm{v} / \mathrm{v} ), a light yellow solid (intermediate 3) was obtained with a yield of 82 % . 1 H 82 % . 1 H 82%.^(1)H82 \% .{ }^{1} \mathrm{H} NMR ( 400 MHz, DMSO-d 6 6 _(6)_{6} ) δ δ delta\delta (ppm): 13.60 (s, 1 H , OH ) , 10.17 1 H , OH ) , 10.17 1H,OH),10.171 \mathrm{H}, \mathrm{OH}), 10.17 (s, 1 H , OH ) , 8.28 1 H , OH ) , 8.28 1H,OH),8.281 \mathrm{H}, \mathrm{OH}), 8.28 (d, J = 8.9 Hz , 1 H J = 8.9 Hz , 1 H J=8.9Hz,1HJ=8.9 \mathrm{~Hz}, 1 \mathrm{H}, = CH = CH =CH=\mathrm{CH} ), 7.91-7.77 (m, 4H, Ar-H), 6.85 (d, J = 8.4 Hz , 2 H , Ar − H ) , 6.60 J = 8.4 Hz , 2 H , Ar − H ) , 6.60 J=8.4Hz,2H,Ar-H),6.60J=8.4 \mathrm{~Hz}, 2 \mathrm{H}, \mathrm{Ar}-\mathrm{H}), 6.60 (d, J J JJ
（ 1.0 g , 5.25 mmol 1.0 g , 5.25 mmol 1.0g,5.25mmol1.0 \mathrm{~g}, 5.25 \mathrm{mmol} ） 和对羟基苯甲醛 （ 0.64 g , 5.25 mmol 0.64 g , 5.25 mmol 0.64g,5.25mmol0.64 \mathrm{~g}, 5.25 \mathrm{mmol}