化药新药研发检测

客户所提供三样品分别为氨基丁二酸与杂质A混合溶液、氨基丁二酸不同处理方法溶液及氨基丁二酸单标，由于使用CAPCELL PAK C8DD色谱柱无法将样品①中氨基丁二酸与杂质A分离，因此我们选择使用具有高表面极性、可以对极性样品有良好保留的CAPCELL PAK ADME色谱柱进行尝试

The syntheses of a diverse set of 2-aryl-4 quinolone derivatives were achieved by exposing corresponding acylated 20-aminoacetophenones to microwave irradiation in the presence of NaOH. The microwave accelerated cyclizations were complete within 10–22 min at 120 C giving 57–95% isolated yields.

We present the synthesis of new derivatives of natural products magnolol (1) and honokiol (2) and their evaluation as allosteric ligands for modulation of GABAA receptor activity. New derivatives were prepared via metal assisted cross-coupling reactions in two consecutive steps. Compounds were tested by means of two-electrode voltage clamp electrophysiology at the a1b2c2 receptor subtype at low GABA concentrations. We have identified several compounds enhancing GABA induced current (IGABA) in the range similar or even higher than the lead structures. At 3 lM, compound 8g enhanced IGABA by factor of 443, compared to 162 and 338 of honokiol and magnolol, respectively. Furthermore, 8g at EC10–20 features a much bigger window of separation between the a1b2c2 and the a1b1c2 subtypes compared to honokiol, and thus improved subtype selectivity。

We report here an efficient and expeditious microwave-assisted synthesis of cyclopentadiene ring-fused tetrahydroquinolines using the three-component Povarov reaction catalyzed by indium (III) chloride. This method has an advantage of shorter reaction time (10–15 min) with high and reproducible yields (up to 90%) and is suitable for parallel library synthesis. The optimization process is reported and the results from the microwave route are compared with those of the conventional synthetic route. In almost all cases, the microwave acceleration consistently provided improved yields favoring the cis-diastereomer.

作者利用聚四氟乙烯制造过程中产生的无法利用的副产物CHF3作为起始物料，采用连续流能够直接合成二氟甲基氨基酸，该类化合物是磷酸吡哆醛脱羧酶的高度选择性和强效抑制剂。 该反应所需的原料便宜易得，产物通过简单的水解和沉淀能够得到良好的收率和纯度。 由于原子经济性、可持续性、试剂成本和试剂可用性是工业化参考的重要因素，因此，该工艺展现出良好的工业化应用前景。

The discovery of potent benzimidazole stearoyl-CoA desaturase (SCD1) inhibitors by ligand-based virtual screening is described. ROCS 3D-searching gave a favorable chemical motif that was subsequently optimized to arrive at a chemical series of potent and promising SCD1 inhibitors. In particular, compound SAR224 was selected for further pharmacological profiling based on favorable in vitro data. After oral administration to male ZDF rats, this compound significantly decreased the serum fatty acid desaturation index, thus providing conclusive evidence for SCD1 inhibition in vivo by SAR224.

The Letter describes the investigation of an industrial reaction of N-methylphenylpiperazine and chloro nicotinonitrile, under microwave heating. Besides the formation of the expected 2-(4-methyl-2-phenylpiperazinyl)pyridine-3-carbonitrile (4), extension of the scale leads to unexpected by-products. A specific pathway due to the formation of a reactive ‘ionic alkylating intermediate’ formed in situ under microwave conditions is proposed to explain the results observed.

双特异性抗体（BsAbs）是同时可以结合两个靶点的抗体药物，可以将效应细胞直接作用于靶向肿瘤细胞，提高抗体的选择性，改善药物的安全性和有效性。与两种单抗混合治疗相比，双特异性抗体可以降低开发和临床成本，是当下抗体药物开发的香馍馍。

Mechanotransduction in the regulation of cellular responses has been previously studied using elastic hydrogels. Because cells interact only with the surface of biomaterials, we are focusing on the molecular mobility at the outermost surface of biomaterials. In this study, surfaces with the mobile Arg-Gly-Asp-Ser (RGDS) peptide have been constructed. Cell culture substrates were coated with ABA-type block copolymers composed of poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) segments (A) and a polyrotaxane (PRX) unit with RGDS bound to a-cyclodextrin (B). Adhesion, morphological changes and actin filament formation of human umbilical vein endothelial cells were reduced on the surfaces containing mobile PRX-RGDS in comparison to the immobile RGDS surfaces constructed from random copolymers with RGDS side groups (Prop-andom-RGDS). In the neurite outgrowth assay using rat adrenal pheochromocytoma cells (PC12), only 20% of adherent PC12 cells had neurites on PRX-RGDS surfaces, but more than 50% did on the Random-RGDS surface. The beating colony of dimethyl-sulfoxide-treated mouse embryonic carcinoma cells (P19CL6) were found 10 and 14 days after induction on PRX-RGDS and Random-RGDS surfaces, respectively. After 22 days, the beating colony disappeared on PRX-RGDS surfaces, but many colonies remained on Random-RGDS surfaces. These data suggest that the molecular mobility of the cell-binding ligand on the outermost surface of materials effectively suppresses the actin filament formation and differentiation of these functional cell lines, and may be used as a culture substrate for immature stem cells or progenitor cells.

An efficient route to dipyridone acid HIV integrase inhibitors is developed. The key steps include a onepot three-step formation of the core template (containing one point of structural diversity) followed by a regioselective benzylation and in situ deprotection to afford the title compounds.

An operationally simple and efficient method under mild acidic conditions was developed to convert fully protected amino acids to the corresponding zwitterions without either isoelectric precipitation or ion exchange chromatography.

本文简述利用Nexera UC和UC Prep开发超临界流体色谱制备方法的过程，介绍了重叠进样方式在手性化合物拆分制备系统中的应用方式。实际案例结果比对，使用重叠进样方式分离效率较传统提升2.3倍，时间和试剂的消耗量在相同制备量下减少134%，可显著提升工作效率。11次重叠进样过程中，各主要色谱峰对应的峰面积和面积/峰高比的RSD在5.5%以内，保留时间差RSD在0.6%以内，各峰峰宽和分离度变化在7%以内，体现出良好的系统稳定性。

吸入型药物具有吸收快、起效快及避免首过代谢的特点，近年来备受关注。然而，吸入性制剂药物通过肺部给药，避免了肝脏首过效应，直接作用于肺部组织，对其进行药物代谢特征研究选用肝细胞及其亚细胞组织并不完全适用，因其在肺部停留时间较长，通常认为应当考察其在肺部的代谢情况。

溶出仪的使用说明：   　　1.首先应给水浴箱注入蒸馏水至水线标志。   　　2.将电源插头接在有地线的220V电源插座中，并按下仪器底座右侧的电源开关指示灯亮，水泵启动水浴槽中的水开始循环流动。   　　3.再按加热键加热指示红灯亮，水开始加热。再按住选择键温，选绿灯依次循环闪亮到达设定的温度时释放选择键绿灯所对应的温度就是所需的温度。当温度达到设定温度是红灯灭表示停止加热。   　　4.按下电源开关后转速显示“P”按减速键转速降低反之增加。释放启动键转速停止再按则恢复。   　　5.取样针头和调整垫是为了方便取样。 当需要换水浴箱中的水时可在出水嘴上更换上附件箱中的放水管便可。   　　当仪器使用完毕后，应把溶出仪以及附件都清洗干净，保持清洁。

A microwave-promoted three-step tandem process for the synthesis of bicyclic c-lactams is developed. In all cases examined this led to significantly faster tandem processes producing the bicyclic c-lactams more cleanly and reproducibly compared to standard thermal conditions.

The palladium-catalyzed arylation of rac-(E)-3-acetoxy-1,3-diphenylprop-1-ene with arylboronic acids was studied under controlled microwave irradiation conditions. Avariety of different catalysts, bases, and solvents were explored in order to achieve optimum yields in the shortest possible reaction times. The best isolated yields were obtained using Pd2(dba)3$CHCl3/PPh3 as the catalytic system, potassium phosphate monohydrate as the base, and toluene/H2O as a solvent system. Microwave irradiation using 5 mol% of the palladium catalyst for 90 s (max. temp 170 C) generally afforded the cross-coupling products in good to excellent yields.

A microwave-assisted, sequential, one-pot protocol has been developed for the synthesis of a variety of benzothiadiazin-3-one-1,1-dioxides. This protocol utilizes a copper catalyzed N-arylation of a-bromobenzenesulfonamides with a number of amines to generate the corresponding 2 aminobenzenesulfonamides,which undergo cyclization to the desired sultams using carbonyl diimidazole (CDI). A range ofconditions was evaluated for the key C–N bond formation step with tolerance toward functionalized amines.

本文利用岛津GCMS-QP2020 NX气质联用仪，建立了止咳糖浆中6种多元醇类物质含量的检测方法。在5.0 ~ 100 μg/mL浓度范围内，各化合物标准曲线相关系数均大于0.999，线性关系良好，取浓度为5.0 µg/mL标准品溶液连续进样6针，各化合物峰面积RSD小于3.56%。对止咳糖浆基质进行了低、中、高（5.0、20和40 mg/kg）三水平的加标回收实验，回收率分布在87.27-107.72%之间。该方法操作简单，可用于止咳糖浆中六种多元醇类物质含量测定。

制备纳米晶药物中粒度表征和稳定性分析。

本文总结了 Genevac 快速溶剂蒸发工作站在 Protac 小分子开发过程中多方面的应用，在药物合成，药物纯化，晶型筛选等过程都能展示独特优势。

铃木-米亚乌拉钯偶联法被广泛用于制药和精细化工行业的生物芳烃和杂生物芳烃产品的合成中。通常，在批处理中，铃木偶联不能在反应溶剂的沸点以上进行，这可能导致反应时间过长，然而流动化学允许更高的操作压力，大大提高了安全性，允许更高的反应温度，以及更快的反应时间。

Abstract—Desymmetrization of pyridazine-3,6-diones by the use of N-benzyl protective groups leads to useful starting materials for building polysubstituted pyridazine libraries in a regioselective manner.

Microwave promoted indium trichloride (10 mol %) catalyzed sp3 C–H bond functionalization of 2-alkyl azaarenes 1 or 4 has been observed to construct C–C bond either with but-2-ene-1,4-diones 2 or (E)-3-(2-oxo-2-phenylethylidene)indolin-2-one (6) giving access to 2-((quinolin-2-yl)methyl)butane-1,4-diones 3, 2-((pyridin-2-yl)methyl)butane-1,4-diones 5, or 3-(quinolin-2-yl)propan-2-yl)indolin-2-ones 7 in good yields using 1,4-dioxane as solvent.

本应用介绍了使用 Agilent 1260 Infinity II SFC 系统与安捷伦方法筛选向导进行软件辅助的方法开发。在不同等度条件下对四根手性柱进行了自动筛选，快速鉴别出了最佳分离条件。对鉴别出的条件进行快速优化后，能够在 4 分钟内实现两种对映异构体的分离。这一分离速度通常比利用正相色谱分离对映异构体的经典方法快 10 倍。最后，结果表明所鉴别出的方法还可用于对映异构体的分析型制备分离。

Abstract—The palladium-catalyzed arylation of rac-(E)-3-acetoxy-1,3-diphenylprop-1-ene with arylboronic acids was studied under controlled microwave irradiation conditions. Avariety of different catalysts, bases, and solvents were explored in order to achieve optimum yields in the shortest possible reaction times. The best isolated yields were obtained using Pd2(dba)3$CHCl3/PPh3 as the catalytic system, potassium phosphate monohydrate as the base, and toluene/H2O as a solvent system. Microwave irradiation using 5 mol% of the palladium catalyst for 90 s (max. temp 170 C) generally afforded the cross-coupling products in good to excellent yields.

We report here the first example of an SRN1 reaction on propargylic chloride in heterocyclic series. The reaction of 4-(3-chloroprop-1-ynyl)-1,2-dimethyl-5-nitro-1H-imidazole with nitronate anions led to both the formation of the C-alkylated product through an SRN1 mechanism and the predominant ethylenic compound resulting from nitrous acid elimination on the C-alkylated product. Interestingly, in contrast to our previous works on SRN1 reactivity, no O-alkylated product was observed.

晶泰科技自主研发使用的自动化实验室，采用人机结合模式实现了实验过程的高度自动化和智能化，通过智能调度系统远程操控百台规模自动化工站和 AGV 小车，同时提升实验过程和物料传送的效率，可按照客户场景需求分阶段搭建专属自动化实验室。

乙醇中挥发性杂质的检测主要采用气相色谱法或气相色谱-质谱联用法。目前检测乙醇中挥发性杂质主要以《中国药典》2020版检验方法为主，系统适用性要求，乙醛峰与甲醇峰之间的分离度应当满足要求，即按照气相色谱法测定法（通则0521），待测物质色谱峰与相邻色谱峰之间的分离度应不小于1.5。本文根据《中国药典》2020版标准，利用东西分析GC-4100气相色谱仪建立测定乙醇中挥发性杂质含量的方法，该方法中乙醛和甲醇分离度R>2，完全符合药典中分离度大于1.5的要求，可供相关人员参考。

本应用介绍了利用 SFC/MS 对二肽和三肽、小分子肽和大分子肽的分析。在改性剂含量通常高达 50% 的梯度中，肽发生洗脱。测得的保留时间RSD 通常低于 0.2%，并且峰面积 RSD 通常低于 2%。作为示例，借助 Skyline 软件创建了用于八肽血管紧张素 I I 的 MRM 方法。本研究证明了 SFC/三重四极杆组合对肽的分析能力。最后，利用 SFC/MS 对大分子肽胰岛素进行了分析，并对测得的电荷态进行解卷积实现了对分子量的测定。

本应用简报介绍了 Agilent ChemStation 方法筛选向导软件在 Agilent 1260 Infinity 分 析型 SFC（超临界流体色谱）系统上自动开发针对药物的非手性 SFC 分离方法方面 的应用。SFC 系统配有溶剂选择阀和色谱柱选择阀，可以使用多达 12 种不同的溶剂 和 6 种不同的固定相进行筛选。ChemStation 方法筛选向导软件可以直观而方便地 创建方法和工作列表，从而实现全面、高效的方法开发。