拉帕替尼的合成工艺改进

目的改进拉帕替尼的合成工艺。方法以N-(3-氯-4-((3-氟苯基)甲氧基)苯基)-6-碘喹唑啉-4-胺为原料,经Suzuki偶联,再与对甲苯磺酸成单盐。再经加成,还原,与对甲苯磺酸成双盐。四氢呋喃/水中自然降温,生成拉帕替尼。结果通过熔点测定、HPLC、质谱、1H NMR、元素分析、红外分析、对甲苯磺酸含量和水分含量测定等方法确证目标物结构。结论本工艺操作简单,适合工业化生产。     

LC-MS/MS法测定遗传毒性杂质4-(3-氟苯甲氧基)-3-氯苯胺

目的建立液质联用方法测定甲苯磺酸拉帕替尼及片中遗传毒性杂质4-(3-氟苯甲氧基)-3-氯苯胺的含量。方法采用C_8色谱柱(4.6 mm×250 mm,5μm),以水(A)-甲醇(B)为流动相,采用梯度洗脱(0~3min,40%B→90%B;3~8 min,90%B→95%B),流速0.7 ml/min,柱温30℃;ESI离子源,正离子扫描方式,多反应监测(MRM)模式扫描,检测离子通道为m/z:252.1→143.1。结果 4-(3-氟苯甲氧基)-3-氯苯胺浓度在0.24~103.89 ng/ml范围内与峰面积呈良好线性关系(r=0.9996);定量限为0.24 ng/ml;检出限为0.072 ng/ml;平均加样回收率为100.98%,RSD为2.58%(n=9)。结论本方法专属性强、灵敏度高、准确度好,可用于甲苯磺酸拉帕替尼及片中杂质4-(3-氟苯甲氧基)-3-氯苯胺的测定。     

丁酸氯维地平4种杂质的合成

目的合成丁酸氯维地平的4个杂质。方法以2, 3-二氯苯甲醛、乙酰乙酸乙酯、双乙烯酮、3-羟基丙腈、丁酸氯甲酯为起始原料,经酯化、缩合、环合得到4-(2, 3-二氯苯基)-1, 4-二氢-2, 6-二甲基-3, 5-吡啶二羧酸乙酯氰乙基酯(A);A在丙酮中经氢氧化钠选择性水解得到4-(2, 3-二氯苯基)-1, 4-二氢-2, 6-二甲基-3, 5-吡啶二羧酸单乙酯(B);B在乙腈和碳酸钾的混合溶液中与丁酸氯甲酯发生酯化反应生成4-(2, 3-二氯苯基)-1, 4-二氢-2, 6-二甲基-3, 5-吡啶二羧酸乙酯丁酰氧基甲酯(C)。C氧化得到杂质4-(2, 3-二氯苯基)-2, 6-二甲基-3, 5-吡啶二羧酸乙酯丁酰氧基甲酯(D)。结果 4个目标物经质谱(MS),核磁共振氢谱(~1H-NMR),核磁共振碳谱(~(13)C-NMR)确证其化学结构。结论合成的4个杂质可作为丁酸氯维地平质量控制对照品。本工艺操作可行,原料易得。     

新型高倍二肽甜味剂的制备与表征

N-{N-[3-甲基-3-(3,4-亚甲二氧基苯基)丁基]-α-L-天冬氨酰}-L-苯丙氨酸甲酯是一种新型纽甜类似物甜味剂。以3,4-亚甲基苯硼酸,3,3-二甲基丙烯酸为原料,经过Heck反应、酯化反应及DIBAL-H还原得到了3-甲基-3-(3,4-亚甲二氧基苯基)丁醛中间体。然后该中间体与阿斯巴甜在钯/碳催化作用下进行氢化还原氨化反应,成功制备了目标产物N-{N-[3-甲基-3-(3,4-亚甲二氧基苯基)丁基]-α-L-天冬氨酰}-L-苯丙氨酸甲酯。产物采用了核磁共振(NMR)、红外光谱(IR)和高分辨质谱(HRMS)等技术进行结构鉴定和分析,最后确证无误。经感官评定,测得其甜度约为蔗糖的3万倍。     

一种新型纽甜类似物甜味剂的合成及表征

为合成新型二肽类甜味剂,以甲醇、3,3-二甲基丙烯酸为初始原料,经Fischer酯化反应得到3,3-二甲基丙烯酸甲酯,再与2,5-二甲酚、甲烷磺酸发生Friedel-Crafts烷基化反应得到4,4,5,8-四甲基-3,4-二氢香豆素,产物以LiAlH_4为还原剂还原得到3-(2-羟基-3,6-二甲基苯基)-3-甲基丁醇,经2步保护反应分别保护醇羟基和酚羟基之后,用CH_3COOH脱掉叔丁基二甲基硅基(TBS)得到乙酰基保护的醇,用Dess-Martin periodinane氧化醇得到纽甜类似物的中间体3-(2-乙酰基-3,6-二甲基苯基)-3-甲基丁醛,最后将中间体与阿斯巴甜在硼氢化钠(Na BH_4)的还原胺化作用下合成高倍甜味剂纽甜类似物N-[N-[3-(2-乙酰基-3,6-二甲基苯基)-3-甲基丁基]-L-α-天冬氨酰]-L-苯丙氨酸1-甲酯。采用红外光谱(IR)、质谱(MS)以及核磁共振(NMR)对终产物进行结构鉴定和表征,结果确定其为目标终产物,并测得其甜度约为蔗糖的70 000倍。     

醇脱氢酶不对称还原2-[3-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基]-3-羟基丙基]苯甲酸甲酯

孟鲁司特钠是主要的抗哮喘药物之一,2-[3-(S)-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基]-3-羟基丙基]苯甲酸甲酯是孟鲁斯特钠的关键手性砌块.以实验室筛选到的醇脱氢酶不对称还原2-[3-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基-3-羟基丙基]苯甲酸甲酯,制备2-[3-(S)-[3-[2-(7-氯-2-喹啉基)乙烯基]苯基-3-羟基丙基]苯甲酸甲酯.在辅酶添加量为0.1 g/L,底物浓度为219.3 mmol/L,菌体用量为30 g/L,pH 7.5,45 ℃反应7h后,底物转化率达到100％,时空产率为31.2 mmol/(L·h),产物e.e.值大于99.9％.通过分批补料,反应5h,底物转化率达到100％,e.e.＞99.9％,时空产率达43.7 mmol/(L,h),是一次性投料的1.4倍.     

高甜度二肽甜味剂的合成与特性

以异香兰素为原料,经Wittig反应、常温常压催化氢化、二异丁基氢化铝还原制得中间体3-(3-羟基-4-甲氧基苯基)丙醛。S-叔丁基-L-半胱氨酸甲酯与N-叔丁氧羰基-L-天冬氨酸-4-叔丁酯经1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐以及1-羟基苯并三唑水合物缩合制得二肽化合物N-(N-叔丁氧羰基-4-叔丁酯-L-α-天冬氨酰)-S-叔丁基-L-半胱氨酸-1-甲酯,并在氯化氢-二氧六环溶液中脱保护制得二肽化合物N-(L-α-天冬氨酰)-S-叔丁基-L-半胱氨酸-1-甲酯;然后将中间体3-(3-羟基-4-甲氧基苯基)丙醛与N-(L-α-天冬氨酰)-S-叔丁基-L-半胱氨酸-1-甲酯通过亚胺化钯碳氢气常压催化氢化得到目标化合物N-[N-[3-(3-羟基-4-甲氧基苯基)丙基]-L-α-天冬氨酰基]-S-叔丁基-L-半胱氨酸-1-甲酯。经红外光谱、质谱以及核磁共振仪对产物进行结构鉴定,确定目标产物结构。     

2-[(4-甲基-1,2-苯并吡喃酮-7-基)氧基]丙酸钠对高倍甜味剂后苦味抑制效果研究

采用感官分析法,研究了不同浓度2-[(4-甲基-1,2-苯并吡喃酮-7-基)氧基]丙酸钠的苦味和涩味,2-[(4-甲基-1,2-苯并吡喃酮-7-基)氧基]丙酸钠对糖精钠、安赛蜜和甜菊糖苷这3种甜味剂后苦味的抑制效果,以及对5种基本味感的影响。结果表明:2-[(4-甲基-1,2-苯并吡喃酮-7-基)氧基]丙酸钠浓度较高时会有苦涩味;当其浓度为200mg/kg时可以使糖精钠、安赛蜜和甜菊糖苷的后苦味有一定程度的下降,但对每一种苦味物质的作用效果有所不同;2-[(4-甲基-1,2-苯并吡喃酮-7-基)氧基]丙酸钠有一定的增咸效果,对咖啡的苦味有一定程度的抑制作用,对酸味、甜味、鲜味基本无影响。     

一种可降解的双子季铵盐的合成及抑菌性研究

以N,N-二甲基乙醇胺和癸酸为原料制备了N-[2-(癸酰氧基)乙基]-N,N-二甲基胺,然后利用其与反-1,4-二氯-2-丁烯进行季铵化反应得到了双子季铵盐,并借助傅立叶变换红外光谱(FT-IR)、核磁共振氢谱(1H NMR)以及质谱对其结构进行了验证。抑菌试验表明,该季铵盐对革兰氏阳性菌(金黄色葡萄球菌)和革兰氏阴性菌(大肠杆菌)均有较好的抑菌性。     

溴化1-苄基-3-乙基苯并咪唑离子液体的合成

以邻苯二胺、甲酸为起始原料,通过缩合反应合成苯并咪唑,在碱性条件下苯并咪唑与苄基氯反应合成N-苄基苯并咪唑,然后将其与溴乙烷反应,得到溴化1-苄基-3-乙基苯并咪唑盐离子液体。所得产品结构经FTIR、1H NMR、13CNMR以及LC-MS表征,证明为目标产物。     

Kinetic resolution of an indan derivative using Bacillus sp. SUI-12: synthesis of a key intermediate of the melatonin receptor agonist TAK-375

The chiral indan derivative (S)-2 (2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl-amine) was synthesized by enzyme-catalyzed asymmetric hydrolysis of the racemic acetamide 1 (N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]acetamide). The reaction was carried out using Bacillus sp. SUI-12 screened for the ability to hydrolyze 1 to give (S)-2 with high enantioselectivity. In a scaled-up experiment, a low reaction rate was observed. However, by changing the culture medium and the reaction conditions, it became possible to run the reaction to 40% conversion on a 10-g or more scale, obtaining (S)-2 at >;99% enantiomeric excess (ee). The (S)-2 obtained was available for the synthesis of the melatonin receptor agonist TAK-375 (N-[2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl]propanamide).     

Structural determination of subsidiary colors in commercial Food Green No. 3 (fast green FCF, FD & C Green No. 3).

HPLC analysis revealed that eight subsidiary colors existed in commercial Food Green No. 3 (fast green FCF, FD & C Green No. 3). Among them, four subsidiary colors C, F, G, and H were isolated by using preparative HPLC and their structures were determined by MS and NMR. They were the disodium salt of 2-[[4-[N-ethyl-N-(3- sulfophenylmethyl)amino]phenyl][4-[N-ethyl-N-(4- sulfophenylmethyl)amino]phenyl]methylio]-4-hydroxybenzenesulfonic acid (abbreviated as m,p-G-3), the sodium salt of 2-[[(4-N-ethylamino)phenyl][4-[N-ethyl-N-(3- sulfophenylmethyl)amino]-phenyl]methylio]-4-hydroxybenzenesulfonic acid [abbreviated as HSBA-(EA) (m-EBASA)], the sodium salt of 2-[[(4-N-diethylamino)phenyl][4-[N-ethyl-N-(3- sulfophenylmethyl)amino]phenyl]-methylio]-4-hydroxybenzenesulfonic acid [abbreviated as HSBA-(di-EA) (m-EBASA)], and the sodium salt of 2-[[4-[N-ethyl-N-(phenylmethyl)amino]phenyl][4-[N-ethyl-N-(3- sulfophenylmethyl)-amino]phenyl]methylio]-4-hydroxybenzenesulfonic acid [abbreviated as HSBA-(EBA)(m-EBASA)], respectively. HSBA-(di-EA) (m-EBASA) was a subsidiary color newly found in commercial Food Green No. 3.     

Structure determination of new analogues of vardenafil and sildenafil in dietary supplements

New analogues of vardenafil and sildenafil illegally added to dietary supplements were detected by high-performance liquid chromatography (HPLC) analysis with a photodiode array detector (PDA). These compounds were isolated and their structures elucidated by mass spectrometry (MS), infrared (IR) spectroscopy, one- and two-dimensional nuclear magnetic resonance (NMR). One of the new analogues given the trivial name pseudovardenafil (compound 1) was structurally elucidated and shown to be 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-piperidine. It was a vardenafil analogue isolated from a dietary supplement capsule. Compared with vardenafil, the piperidine ring was substituted for the ethylpiperazine group. The second new analogue, trivially named hydroxyhongdenafil (compound 2), was separated from bulk powder used as a raw material for a dietary supplement. The piperazine and phenyl groups were connected through an acetyl group instead of a sulfonyl group, and hydroxyethylpiperazine was substituted for the methylpiperazine of sildenafil. It was structurally elucidated as 5-[2-ethoxy-5-[[4-(2-hydroxyethyl)-1-piperazinyl]acetyl]phenyl]-1,4-dihydro-1-methyl-3-propyl-7H-pyrazolo[4,3-d]pyrimidin-7-one.     

新型不对称咪唑类离子液晶化合物的微波法合成和液晶性能研究

使用微波辅助的方法高效合成了两种未见报道的不对称咪唑盐类离子液晶化合物,1-[4-(十二烷氧基)苯基]-3-己基咪唑溴盐和1-[4-(十二烷氧基)苯基]-3-辛基咪唑溴盐,并通过POM和DSC对它们的液晶性能进行了充分研究。实验表明,两种咪唑盐呈现出典型的和良好的近晶相织构。     

一种新的均三嗪类紫外线吸收剂ZLG-1的合成及表征

以三聚氯氰、间二甲苯为原料,经过Friedel-Craft反应,合成了2-氯-4,6-二（2＇,4＇二甲基苯基）-1,3,5-均三嗪（Ⅰ）,化合物Ⅰ在三氯化铝作用下再与间苯二酚反应,得到了2-（2’,4＇-二羟苯基）-4,6-二（2”,4”-二甲基苯基）-1,3,5-均三嗪（Ⅱ）．化合物Ⅱ在碱性条件下与环氧氯丙烷缩合并水解得到了该均三嗪类的紫外线吸收剂2-[2’-羟基-4’-（2＇＇＇,3＇＇＇）-二羟基丙烷氧基苯基]-4,6-二（2”,4”）-二甲基苯基-1,3,5-均三嗪（ZLG-1）,总收率为61．8％．讨论了反应温度、时间及反应物配比对各步反应收率的影响;并对化合物Ⅱ和ZLG-1的结构用IR、^1HNMR、MS进行了表征．由ZLG-1的UV光谱数据表明其紫外线吸收性能和三嗪-425相当．     

三唑类配体及其 Co（Ⅱ）配合物晶体的水热合成及表征

用水热法培养出3-（吡啶-4-基）-5-（1H-1,2,4-三唑-3-基）-1,2,4-三唑（简写成PYTZ）的晶体及其与过渡金属Co（Ⅱ）的配合物晶体：PYTZ · H2O （1）、[Co（PYTZ）2（H2O）2]·4H2O （2）,并通过X射线单晶衍射、元素分析、红外光谱、热重分析对其进行了表征。晶体结构表明,晶体1属于单斜晶系,P2（1）/c空间群;配合物晶体2属于单斜晶系,P2（1）/c空间群。配合物2中Co （Ⅱ）离子六配位呈八面体构型,N-H？O、O-H？N和O-H？O氢键将单个分子连接成二维超分子网络结构,并对其热分解过程进行了研究。     

氟虫腈亚砜荧光衍生化、HPLC-FLD检测方法的建立及应用

建立了氟虫腈代谢物-氟虫腈亚砜的柱前荧光衍生化方法,并将其应用于鸡蛋中的残留检测。优化后的柱前荧光衍生化反应主要条件如下:催化缩合剂为EDC/DMAP;反应溶剂为二氯甲烷;氟虫腈亚砜与荧光衍生试剂的用量比为1:8;45 ℃水浴中反应75 min。衍生产物为N-（3-氰基-1-（2, 6-二氯-4-（三氟甲基）苯基)-4-（（三氟甲基）硫代）-1H-吡唑-5-基）-4-（2-（9-乙基-9H-咔唑-3-基）-1H-菲并[9, 10-d]咪唑-1-基）丁酰胺（DX1）,具有很高的荧光强度。衍生化产物DX1的高效液相色谱-荧光检测（HPLC-FLD）的主要条件如下:C₁₈色谱柱;等度洗脱;流动相:乙腈/水（80/20,v/v）;流速:1.0 mL/min;λex=310 nm,λem=404 nm;进样量20 μL;柱温40 ℃。在上述检测条件下,氟虫腈亚砜HPLC-FLD检测方法的检测限为0.033 μg/L,定量限为0.092 μg/L。在此基础上,建立了鸡蛋残留氟虫腈亚砜提取和检测的HPLC-FLD方法,检测限和定量限分别达到了0.052和0.132 μg/kg,精密度、稳定性和重现性在保留时间和峰面积上的RSD分别小于0.04%和2.7%,上机检测可在20 min内完成。该方法具有较好的灵敏度、精确性和可靠性,可应用于鸡蛋中残留氟虫腈亚砜的检测。     

NP-HPLC分离测定1-[3,5-双（三氟甲基）苯基]乙醇对映异构体

目的 研究1-[3,5-双（三氟甲基）苯基]乙醇对映异构体分离测定的方法.方法 采用CHIRALPAK AD-3 （0.46cm×15 cm,5μm）色谱柱,以正己烷-异丙醇（200：1）为流动相,流速0.5 mL/min,柱温25℃.结果 采用本方法能完全分离对映异构体,灵敏方便,检出限为0.2011 μg/mL,约为供试品溶液浓度的0.04％,供试品溶液在12h内稳定.结论 本方法简单,专属性强,可有效控制1-[3,5-双（三氟甲基）苯基]乙醇中对映异构体含量.     

Identification of (furan-2-yl)methylated benzene diols and triols as a novel class of bitter compounds in roasted coffee

Preliminary studies demonstrated that the identification of unknown bitter taste compounds in roasted coffee, by means of an analytical fractionation approach, is hampered by their limited oxidative, as well as chemical stability. A synthetic-constructive strategy was followed in the present investigation by performing targeted reactions of putative coffee-related precursors to give candidate bitter taste molecules. Binary mixtures of a di and trihydroxybenzene, namely pyrogallol, hydroxyhydroquinone, catechol, or 3- and 4-methylcatechole, and a furan derivative, namely furfuryl alcohol, furan-2-aldehyde, or 5-(hydroxymethyl)furan-2-aldehyde, all of which are known to be present in roasted coffee, were thermally treated. The reaction products were identified as (furan-2-yl)methylated benzene diols and triols, by means of LC–MS and NMR experiments, and their bitter taste thresholds determined by means of sensory analysis. Finally, LC–MS/MS studies verified the natural occurence of 4-(furan-2-ylmethyl)benzene-1,2-diol, 4-(furan-2-ylmethyl)benzene-1,2,3-triol, 4-(furan-2-ylmethyl)-5-methylbenzene-1,2-diol, and 3-(furan-2-ylmethyl)-6-methylbenzene-1,2-diol as a novel class of bitter taste compounds in roasted coffee. Depending on their chemical structure, the bitter taste recognition threshold of these compounds ranged between 100 and 537 μmol/l.