6,7-二甲氧基-1,2,3,4-四氢异喹啉-3-羧酸甲酯的制备——介绍一个大学药物化学综合实验

介绍了我校制药工程专业和药物制剂专业开展的一个综合药物化学实验,该实验以合成PARP1抑制剂的关键中间体6,7-二甲氧基-1,2,3,4-四氢异喹啉-3-羧酸甲酯为目标分子,该化合物是作者课题组目前正在研究的PARP1抑制剂的关键中间体,其合成方法是以L-3,4-二甲氧基苯丙氨酸为原料,甲醇为溶剂,二氯亚砜为脱水剂,室温条件下合成L-3,4-二甲氧基苯丙氨酸甲酯,再以多聚甲醛为原料,二氯甲烷为溶剂,三氟乙酸为催化剂,经Pictet-Spengler反应合成6,7-二甲氧基-1,2,3,4-四氢异喹啉-3-羧酸甲酯,目标化合物的结构使用1H NMR、MS等分析方法进行表征。本实验有益于激发学生独立思考能力和研究意识,训练学生的综合实验操作技能和有机化合物的结构鉴定能力,培养学生掌握药物合成科学研究的基本思路和基本方法。     

2-甲氧基-3-氟-4-碘吡啶的合成

2-甲氧基-3-氟-4-碘吡啶是一个重要的医药化工中间体,其合成路线未见文献报道。以2-甲氧基-3-氟-5-氯吡啶为起始原料,经氢解和碘代两步反应合成标题化合物,总收率62.8%,其结构经¹H NMR, ¹³C NMR和MS确证。     

2-氨基-4-甲氧基氯代苯甲酸的合成研究

以2-氨基-4-甲氧基苯甲酸甲酯为原料,通过氯代反应,再分别通过酯水解反应得到化合物2-氨基-5-氯-4-甲氧基苯甲酸和2-氨基-3-氯-4-甲氧基苯甲酸。其中间体及产物结构经~1H NMR、~(13)C NMR和ESI-MS确证,并考察了最佳氯代反应条件。结果表明:物料配比为n(2-氨基-4-甲氧基苯甲酸甲酯)∶n(NCS)=1∶1. 2,反应溶剂为N,N-二甲基甲酰胺,反应时间为16 h,两种氯代产物2-氨基-5-氯-4-甲氧基苯甲酸甲酯和2-氨基-3-氯-4-甲氧基苯甲酸甲酯收率分别为47%和39%。     

2-烷基-6-甲氧基-1,4-苯醌的全合成

3,5-二甲氧基苯甲醛经格氏、氧化反应制到3,5-二甲氧基苯基烷基酮, 然后在微波辐射下经黄鸣龙还原和选择性脱甲基化、Teuber氧化反应制得目标化合物, 产率均在50%以上. 产物结构经IR, 1H NMR, 元素分析等进行了表征.     

4-(7-甲氧基-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-苄亚氨基噻唑的合成与生物活性

呋喃酚经醚化、傅克酰化、α-溴代、噻唑环化和亚胺化等反应合成了16种4-(7-甲氧基-2,2-二甲基-2,3-二氢苯并呋喃-5-基)-2-苄亚氨基噻唑新化合物.化合物的结构经1H NMR、质谱和元素分析等确证.杀虫活性实验结果表明,化合物2a和2i在500 mg/L对棉红蜘蛛死亡率分别为53.10%和67.71%,杀菌活性实验结果表明,化合物2a和2k在25 mg/L对油菜菌核病菌抑制率分别为57.9%和59.8%,除草活性实验结果表明,2l在2250 g.ai/ha浓度下对苘麻、刺苋、藜具有一定的除草活性.     

新型N^C^N三齿配体1,3-二(2′-嘧啶基)-5-甲氧基苯的合成

以1,1,3,3-四甲氧基丙烷为起始原料,经Stille偶联等五步反应合成了新型N^C^N三齿配体——1,3-二(2′-嘧啶基)-5-甲氧基苯,其结构经1H NMR,13C NMR和EI-MS表征.     

5-溴-1,3-二氟-2-甲氧基苯的合成

以5-溴-1,2,3-三氟苯为原料,经氰化取代,甲氧基化,氰基酸性水解,霍夫曼降级重排,重氮化和Gattermann反应,高效合成了5-溴-1,3-二氟-2-甲氧基苯,其结构经¹H NMR, 13C NMR和MS(EI)确证。并利用气相色谱（GC）和高效液相色谱（HPLC）实时监测反应进程,优化了合成条件。     

2,5-二甲氧基-4-[(1E)-2-(1H-苯并咪唑-2-基)乙烯基]苯甲醛的合成

以2-甲基苯并咪唑(1)和2,5-二甲氧基-1,4-对苯二甲醛(3)为原料,经缩合反应合成了新化合物——2,5-二甲氧基-4-[(1E) -2-( 1H-苯并咪唑-2-基)乙烯基]苯甲醛(4),其结构经1H NMR,IR和ESI-MS表征.较佳缩合反应条件为:1 11 mol,n(1)∶n(3)=1.1∶1.0,回流反应6h,收率75.2％.     

2,5-二甲氧基-4-氯硝基苯与硫化钠的反应

硫化钠和二硫化钠分别在95%乙醇中与2,5-二甲氧基-4-氯硝基苯反应, 原本期望得到2,5-二甲氧基-4-氯苯胺, 然而对产物结构的1H NMR, 13C NMR, MS以及元素分析结果表明, 2,5-二甲氧基-4-氯硝基苯中的硝基没有被硫化钠和二硫化钠还原成氨基, 而是其中的氯原子被硫离子(或二硫离子)取代, 分别生成了4,4’-硫代-2,2’,5,5’-四甲氧基-双硝基苯和4,4’-双硫代-2,2’,5,5’-四甲氧基-双硝基苯. 根据这个实验事实, 讨论了上述亲核取代反应的机理.     

2-[2-(4,6-二甲氧基嘧啶-2-氧)苯基]-2-(取代苯胺)乙氰类化合物的合成及除草活性研究

以水杨醛为原料,所得中间体2-(4,6-二甲氧基嘧啶-2-氧基)苯甲醛经三组分反应合成了12个2-[2-(4,6-二甲氧基嘧啶-2-氧基)苯基]-2-(取代苯胺)乙氰类化合物,通过1H NMR,MS和元素分析对所合成的化合物进行了结构表征.初步生物活性测试结果表明,在试验浓度下合成化合物均具有良好的除草活性.     

Photochemische reaktionen von übergangsmetall-organyl-komplexen mit Olefinen XII. Photochemisch induzierte [5 + 2, 3 + 2]-cycloadditionen von alkinen an tricarbonyl-η-cyclohexadienly-mangan

Upon UV irradiation in hexane at 243 K tricarbonyl-η⁵-cyclohexadienyl-manganese (1) and two equivalents of 2-butyne (2) or diphenylacetylene (4) yield in successive [5 + 2, 3 + 2] cycloadditions tricarbonyl-η^2:2:1-1,2,3,10-tetramethyl-tricyclo[5.2.1.0^4,9]-deca-2,5-dien-10-yl-manganese (6), or tricarbonyl-η^2:2:1-1,2,3,10-tetraphenyl-tricyclo[5.2.1.0^4,9]-deca-2,5-dien-10-yl-manganese (8), respectively. 3-Hexyne (3) reacts with 1 under the same conditions by successive [5 + 2, 3 + 2] cycloadditions and 1,4-H-shift to tricarbonyl-η^2:2:1-1,2,3-triethyl-10-ethylidene-tricyclo[5.2.1.0^4,9]dec-2-en-5-yl-manganse (7). Identical products are also obtained when 1 is first irradiated in THF at 208 K and the thermolabile intermediate, dicarbonyl-η⁵-cyclohexadienyl-tetrahydrofurane-manganese (11), is treated with an excess of the alkynes 2–4. In contrast, bis(trimethylsily)acetylene (5) substitutes photochemically in 1 only a CO ligand to yield dicarbonyl-η⁵-cyclohexadienyl-η²-bis(trimethylsily)Acetylene-manganese (9). The crystal and molecular structure of 7 was determined by an X-ray diffraction analysis. Complex 7 crystallizes in the triclinic space group , a = 822.6(2) pm, B = 882.5(2) pm, C = 1344.6(2) pm, = 92.36(2)°, β = 107.13(2)°, γ = 99.71(2)°, V = 0.9152(3) nm³, Z = 2. The complexes 6–9 were studied in solution by IR and NMR spectroscopy. The structures of 6,8 and 9 were elucidated from the NMR spectra. A possible formation mechanism for the complexes 6–9 will be discussed.     

手性有机小分子催化剂6,7-二氢-5H-吡咯并[1,2-a]咪唑的合成 ——介绍一个大学有机化学综合实验

介绍一个由科研成果转化形成的综合有机化学实验——一类手性双环咪唑类亲核有机小分子催化剂的合成及结构表征。该合成实验以咪唑和丙烯醛为原料,在催化量的乙酸存在下,合成手性双环咪唑醇外消旋体。然后利用固定化酶Nov435对该外消旋体进行乙酰化动力学拆分获得光学纯双环咪唑醇酯及醇类化合物。最后通过测定熔点、旋光度、红外(IR)光谱、核磁共振(~1H NMR、~(13)C NMR)和高分辨质谱仪(HRMS)对产物结构进行表征,并利用高效液相色谱仪(HPLC)对光学纯双环咪唑醇酯及醇类化合物的光学纯度进行了测定。本实验涵盖了合成、结构表征和光学纯度测定等实验技能训练及动力学拆分及不对称催化酶促反应等专业知识的学习,不仅有益于提高学生的综合实验能力,也可以开拓学生的视野。     

New N′-alkylidene/cycloalkylidene derivatives of 5-methyl-3-phenyl-1H-indole-2-carbohydrazide: synthesis, crystal structure, and quantum mechanical calculations

The condensation products of 5-methyl-3-phenyl-1H-indole-2-carbohydrazide (1) with 2-butanone, 3-pentanone and cyclopentanone were prepared. The adducts (2a-c) were characterized by microanalysis, UV, IR, ¹H NMR, ¹³C NMR and EI mass spectrometry. ¹H NMR spectra of 2a and 2b revealed rotational restriction about the C–N bond in solution (DMSO-d₆) and displayed double resonances associated with the CH₃ and CH₂CH₃ residues of the alkylidene moieties. A variable temperature ¹H NMR experiment was run on 2a to overcome the rotational barriers and thus determine the coalescence temperature but no coalescence was observed up to 77 °C. The structural analysis of 2a and 2c were also carried out by single crystal X-ray diffraction and confirmed by theoretical calculations (semiempirical PM3 and ab initio RHF/6-31G(d)).     

Microstructure determination of N-vinyl-2-pyrrolidone/butyl acrylate copolymers by NMR spectroscopy

The copolymer composition of N-vinyl-2-pyrrolidone/butyl acrylate (V/B) copolymers was determined from the quantitative ¹³C{¹H} NMR spectra. The monomer reactivity ratios for N-vinyl-2-pyrrolidone (V) and butyl acrylate (B) were found to be r_V=0.11±0.07, r_B=0.54±0.19, using the Kelen–Tudos and non-linear least-square error-in-variable (EVM) methods. The ¹³C{¹H} and ¹H NMR spectra of these copolymers are overlapping and complex. The complete spectral assignment of the carbon and proton NMR spectra were done by employing distortionless enhancement by polarization transfer (DEPT) and two-dimensional (2D) ¹³C–¹H heteronuclear single quantum correlation spectroscopy experiments. The 2D total correlation spectroscopy (TOCSY) (¹H–¹H homonuclear TOCSY) NMR spectrum was used to ascertain the various geminal and vicinal couplings in the copolymer.     

Some further studies of estertin compounds. crystal structures of [NEt4][MeO2CCH2CH2Sn(dmio)2] (dmio = 1,3-dithiole-2-one-4,5-dithiolato) and (MeO2CCH2CH2)2SnX2[X2 = I2, (NCS)2 or Cl, Br]

Estertn compounds, (MeO₂CCH₂CH₂)₂SnX₂ [X₂ = I₂ (2); X₂ = Br₂ (9); X₂ = Cl, Br (4)) or X₂ = (NCS)₂ (3)] have been obtained by halide exchange reactions of (MeO₂CCH₂CH₂)₂SnCl₂. Crystal structure determinations of 2–4 revealed chelating MeO₂CCH₂CH₂ units with distorted octahedral geometries at tin. The Sn---O bond lengths in the isothiocyanato complex, 3, are shorter [2.390(11) to 2.498(12), mean 2.439 Å], with the chelate bite angles, C---Sn---O, larger [74.3(7) to 78.2(6), mean 76.0°] than those in the halide analogues 2 and 4 [Sn---O = 2.519(2) to 2.541(8), mean 2.530 Å; C---Sn---O 72.8(3) to 73.9(4), mean 73.3°]. ¹H, ¹³C and ¹¹⁹Sn NMR and IR spectra of 2–4 and 9 were determined in CDCl₃ solution: the NMR spectra of (MeO₂CCH₂CH₂)₂SnX₂ show the following trends: (i) both δ¹H and δ¹³C, increase and (ii) both ²J (Sn---H) and ¹J(Sn---C) decrease in the sequence X₂ = (NCS)₂, Cl₂, ClBr, Br₂ and I₂. The MeO₂CCH₂CH₂ and dmio groups (dmio = 1,3-dithiole-2-one-4,5-dithiolato) are all chelating groups in (MeO₂CCH₂CH₂)₂Sn(dmio) (5). As shown by X-ray crystallography, the tin atom in the anion of solid [Q][MeO₂CCH₂CH₂Sn(dmio)₂] 6 (Q = NEt₄) forms 5 strong bonds [to C and the 4 thiolato S atoms, Sn---S 2.459(2) to 2.559(2) Å], arranged in a near trigonal bipyramidal array. There is an additional Intramolecular but weaker, interaction with the carbonyl oxygen atom [Sn---O = 3.111(5) Å]; v(C=O) = 1714 cm⁻¹ in solid 6 (Q = NEt₄). NMR spectra of 5 and 6 are also reported.     

K3PO4-promoted Cyclopropanation of Electron-deficient Alkenes with 2-Bromo-1,3-propanedione Compounds

An easy and efficient method for the synthesis of multisubstituted cyclopropane derivatives from electron-deficicent alkenes with 2-bromo-1,3-propanedione compounds was described. For this method, ethyl α-cyanocinnamate derivatives 1 and β,β-dicyanostyrene derivatives 4 can all smoothly react with 2-bromo-1,3-propanedione compounds 2 to afford the corresponding multisubstituted cyclopropane derivatives 3 and 5 in good to excellent yields(up to 100%) promoted by anhydrous K₃PO₄ in DMF at room temperature, respectively. A possible mechanism of this reaction was proposed. Structures of all the products were confirmed by ¹H NMR, ¹³C NMR and HRMS.     

部分还原二氧化钛的NMR和EPR研究

Partially reduced TiO₂ nanomaterials have attracted significant interest because of their visible-light activity for catalysis and photodegradation. Herein, we prepared a partially reduced anatase TiO₂ (Re-A-TiO₂) nanoparticle material using a fast combustion method, demonstrating good activity toward decomposing methyl orange under visible light irradiation. The surface structure of the prepared material, after being surface-selectively ¹⁷O-labeled with H₂¹⁷O (¹⁷O-enriched water), was studied via ¹⁷O and ¹H solid-state magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy and electron paramagnetic resonance (EPR) spectroscopy, and the obtained results were compared to those of non-reduced anatase TiO₂ (A-TiO₂). The EPR results showed that the concentrations of paramagnetic species (i.e., oxygen vacancies (OV) and Ti³⁺) in Re-A-TiO₂ were much higher than that in A-TiO₂, while the former was associated with a higher OV/Ti³⁺ ratio. The intensities of the EPR signals were significantly affected by the adsorbed water, and this phenomenon was explored in combination with ¹H NMR spectroscopy. The ¹H species on Re-A-TiO₂ appeared at larger chemical shifts, denoting the increased acidity of the sample, and these ¹H species on Re-A-TiO₂ were more difficult to remove than those on A-TiO₂. On the other hand, different features were observed for the signals arising from the two-coordinated oxygen atoms (μ₂-O) in ¹⁷O NMR, suggesting a typical anatase TiO₂(101) surface on A-TiO₂, but a more complex surface environment for Re-A-TiO₂. Furthermore, a larger amount of hydroxyl groups (OH) were observed on Re-A-TiO₂ compared to that on A-TiO₂, indicating a larger proportion of exposed (001) facets on Re-A-TiO₂. However, the μ₂-O signals broadened and became similar when the drying temperature was increased to 100 ℃, indicating a non-faceted anatase TiO₂ surface in such conditions. Based on the EPR and NMR results, a significant fraction of the OH species is believed to be formed from the reaction of the paramagnetic centers and adsorbed water molecules. The ¹H→¹⁷O cross polarization (CP) MAS and two-dimensional heteronuclear correlation (2D HETCOR) NMR spectra were used to verify the spatial proximity of the hydrogen and oxygen species, confirming the spectral assignments of a strongly adsorbed water and one type of surface OH species. In particular, the ¹H NMR signals at approximately 11 ppm were ascribed to the hydrogen species in the intramolecular hydrogen bond. In summary, this study investigated the paramagnetic species and surface structure of anatase TiO₂ materials by combining EPR along with ¹H and ¹⁷O solid-state NMR spectroscopy. The differences in the surface structures of Re-A-TiO₂ and A-TiO₂ should be closely related to their different properties toward the photodegradation of methyl orange.     

Synthesis,bioactivities and 3D-QSAR of novel avermectin B2a aglycon derivatives

Fourteen avermectin B2 a aglycon derivatives were designed and synthesized after removing the oleandrose disaccharide of avermectin B2 a.Their structures were characterized by’H NMR,13 C NMR,HMRS.Preliminary bioassays indicated that these compounds exhibited good insecticidal activity against diamondback moth at 200 mg/L,with mortality no less than 90%.Compounds 10 b,12 a,12 c,17 demonstrated good acaricidal activity against the adult mites,larvae,and good inhibition rate of hatching to mite eggs of Tetranychus cinnabarinus.Compounds 5,10 b,10 c exhibited excellent fungicidal activity against fourteen fungal pathogens in vitro.3 D-QSAR analysis showed that the fungicidal activity of avermectin B2 a aglycon derivatives would be increased when a negatively charged and bulky group was introduced at 13-position,which will be instructive for the further modification of avermectin B2 aaglycon.     

Neodymium Complex Obtained from Reductive-coupling of Carbodiimide: Synthesis and Structure of [(Cp")2Nd(NR)2C-C(NR)2Nd(Cp")2]

A bimetallic oxalamidino complex of neodymium [(Cp")₂Nd(NR)₂C-C(NR')₂Nd(Cp")₂][Cp"=η⁵-C₅H₃-1,3-(SiMe₃)₂, R=C₆H₁₁](2) was obtained via reaction between NdI₂ and carbodiimide[RN=C=NR] (R=C₆H₁₁)(molar ratio 1:1) in tetrahydrofuran(THF) solution, followed by the addition of [KCp"(THF)](1)(molar ratio 1:2) at a low temperature through a reductive-coupling reaction with carbodiimide. The structure of the intermediate product was confirmed by means of elemental analysis, ¹H NMR and ¹³C NMR. Characterization of the product by single crystal X-ray diffraction confirmed the diamidinate type of structure.     

新型含哌嗪-磺酰胺的2(5H)-呋喃酮类化合物的合成及其抗癌活性

以糠醛为原料,经氧化、醚化和重结晶制得5-甲氧基-3,4-二溴-2(5H)-呋喃酮（4）; 4与哌嗪经Michael加成消除反应制得5-甲氧基-4-哌嗪基-3-溴-2(5H)-呋喃酮（5）; 5与取代磺酰氯经磺酰化反应合成了7 个新型的含哌嗪-磺酰胺的2(5H)-呋喃酮类化合物(7a~7g),其结构经¹H NMR, ¹³C NMR, IR和HR-MS表征。初步的生物活性研究(MTT法)表明,7a~7g均能显著抑制人宫颈癌Hela细胞的增殖,其中5-甲氧基-4-(对乙酰氨基苯磺酰基-哌嗪基)-3-溴-2(5H)-呋喃酮（7f）的抑制活性最佳,其IC₅₀为0.03 μM(24 h)。