苹果酸舒尼替尼的合成方法改进

目的 合成抗肿瘤药苹果酸舒尼替尼。方法 以二乙烯酮和乙酰乙酸叔丁基酯为起始原料,经酰胺化、Knorr 环合、脱羧、Vilsmeier甲酰化 4 步反应制得中间体N-[2-(二乙胺基)乙基]-2 ,4-二甲基-5-甲酰基-1H-吡咯-3-甲酰胺,该中间体与5-氟-吲哚-2-酮经羟醛缩合、无水乙醚中成盐2步反应制得目标物苹果酸舒尼替尼。结果与结论 目标化合物的结构经1H-NMR、HR-EI-MS谱确证,总收率为37.9%。     

抗肿瘤药物舒尼替尼的新合成方法

目的 研究抗肿瘤药物舒尼替尼的新合成路线。方法 以4-氟-2-碘苯胺（3）为原料,经氯乙酰化、膦酰化、Horner-Emmons-Wittig反应得N-[2-(二乙胺基)乙基]-5-[(E)-2-(4-氟-2-碘代-苯胺基甲酰基)-乙烯基]-2,4-二甲基-1H-吡咯-3-甲酰胺（6）;6在醋酸钯和三乙胺的作用下,通过分子内5-exo型环合反应得舒尼替尼。结果与结论 新中间体及舒尼替尼结构经核磁共振谱和质谱确证,合成路线未见报道。     

2,4-二甲基-5-甲酰基-1H-吡咯-3-甲酸的合成

乙酰乙酸叔丁酯经系列反应得到的氨基酮与乙酰乙酸乙酯经Knorr反应得2，4-二甲基-3-乙氧羰基-1H-吡咯-5-羧酸叔丁酯，再经甲酰化、水解得抗肿瘤药舒尼替尼的重要中间体2，4-二甲基-5-甲酰基-1H-吡咯-3-甲酸，总收率约为44％。     

硫酸铵梯度法制备苹果酸舒尼替尼脂质体

目的:采用跨膜硫酸铵梯度法制备苹果酸舒尼替尼脂质体并对制备工艺进行考察。方法:采用混合离子交换树脂建立跨膜硫酸铵[ammonium sulfate,(NH4)2SO4]梯度制备苹果酸舒尼替尼脂质体;阳离子交换树脂分离-可见分光光度法测定苹果酸舒尼替尼脂质体的包封率,激光散射粒径分析仪测定苹果酸舒尼替尼脂质体的粒径。结果:苹果酸舒尼替尼脂质体包封率大于96%,平均粒径为107.5 nm。结论:以(NH4)2SO4梯度法制备的苹果酸舒尼替尼脂质体包封率较高,方法简便易行。     

舒尼替尼的合成

乙酰乙酸乙酯经Knorr反应、水解脱羧、甲酰化、水解、酰胺化得N-（2-二乙胺基乙基）-2,4-二甲基-5-甲酰基-1H-吡咯-3-甲酰胺（8）;另以对氟苯胺、水合氯醛和盐酸羟胺经羰基化、环合、还原得5-氟-1,3-二氢吲哚-2-酮（13）。8和13在三乙胺存在下缩合得抗肿瘤药舒尼替尼,总收率约13%（以乙酰乙酸乙酯计）。     

苹果酸舒尼替尼脂质体药物含量及包封率的测定

目的:建立苹果酸舒尼替尼脂质体含量及包封率的测定方法。方法:采用可见分光光度法测定苹果酸舒尼替尼的含量。阳离子交换树脂法分离游离药物,分光光度法测定脂质体中苹果酸舒尼替尼的包封率。结果:苹果酸舒尼替尼在430 nm处有最大吸收,4.0～15.0μg.mL-1范围内线性关系良好(r=0.9998,n=7);苹果酸舒尼替尼脂质体的平均包封率为91.89%。结论:所用方法简便、准确,可用于苹果酸舒尼替尼脂质体的含量及包封率测定。     

乙二胺四乙酸铵梯度法制备苹果酸舒尼替尼脂质体

目的制备苹果酸舒尼替尼脂质体,并对制备工艺进行考察。方法采用混合离子交换树脂建立跨膜乙二胺四乙酸铵(triethylamine-ethylenediamine tetraacetate,Et3N-EDTA)梯度制备苹果酸舒尼替尼脂质体;可见分光光度法和激光粒度仪分别测定苹果酸舒尼替尼脂质体的包封率和粒径。结果苹果酸舒尼替尼脂质体包封率大于98%,平均粒径为120.2 nm。结论以Et3N-EDTA梯度法制备的苹果酸舒尼替尼脂质体包封率较高,方法可行。     

苹果酸舒尼替尼可能导致严重皮肤反应

2013年9月6日,加拿大卫生部向医务人员发出安全警告：苹果酸舒尼替尼可能导致Stevens-Johnson综合征和中毒性表皮坏死松解症等严重皮肤反应~（[1]）。苹果酸舒尼替尼被用于甲磺酸伊马替尼治疗失败或不能耐受的胃肠道间质瘤和不能手术的晚期肾细胞癌（[2]）。苹果酸舒尼替尼致严重皮肤反应的潜在风险是基于对已发表文献进行回顾而得出的,     

1-(5-取代糠基)吲哚啉-2-酮衍生物的合成和初步抗肿瘤活性

为了寻找具有较好抗肿瘤活性的新型吲哚啉-2-酮类化合物，本研究以5-甲酰基-2,4-二甲基-1H-吡咯-3-羧酸乙酯与5位不同取代的吲哚啉-2-酮(2a～2d)为原料，首先经缩合得3-吡咯亚甲基-吲哚啉-2-酮(3a～3d)，再经N烃化反应得到1-(5-甲酰基糠基)-3-(吡咯亚甲基)-吲哚啉-2-酮(4a～4d)，然后与吲哚啉-2-酮缩合得到以5-亚甲基糠基连接的双吲哚啉-2-酮化合物(5a～5d)。所合成的12个新型吲哚啉-2-酮类化合物的结构经核磁共振谱、质谱和元素分析确认。采用四氮唑盐(MTT)还原法测试所合成化合物的体外抗肿瘤活性，结果表明所合成的化合物均有一定的抗肿瘤作用，其中6个化合物对SPC-A1肺癌肿瘤株体外抑制活性优于舒尼替尼，特别是化合物5a～5d， IC₅₀值均小于5 μmol·L^-1，值得作为抗肿瘤药物先导化合物。     

苹果酸舒尼替尼致不良反应30例调查分析

目的:统计苹果酸舒尼替尼致不良反应(ADR)发生情况,促进临床安全合理用药。方法:对本院使用该药的肿瘤患者进行问卷调查与定期随访,搜集ADR信息,并进行整理、归纳和分析。结果:ADR最快在用药后2～3 d内发生,最迟在持续用药18个月后发生,用药后1个月内ADR发生率较高。苹果酸舒尼替尼致ADR可累及多个器官和系统,其中皮肤系统与消化道系统ADR最常见,短暂性血压升高常发生于早期,主观感觉丧失与心肌缺血较罕见与严重。结论:充分了解苹果酸舒尼替尼的ADR情况与掌握其防治措施对于避免药源性疾病的发生十分重要。     

Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide,a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase

To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.     

Synthesis and antidiarrheal activity of N-(aminoiminomethyl)-1H-pyrrole-1-acetamides related to guanfacine

A series of N-(aminoiminomethyl)-1H-pyrrole-1-acetamides, related to guanfacine, were prepared and tested for antidiarrheal activity in castor oil dosed rats. trans-N-(Aminoiminomethyl)-2,5-dihydro-2,5-dimethyl-1H-pyrrole-1-acetami de (2), in which the dichlorophenyl ring of guanfacine is replaced by 2,5-dimethyl-2,5-dihydropyrrole, showed potent antidiarrheal activity but possessed only minimal cardiovascular activity in rats.     

8-Methoxy-chinolin-5,6-dione, 2. Mitt

8-Methoxy-quinoline-5,6-diones, II Nine 8-methoxy-quinoline-5,6-diones with varying substituents in the 2-, 3-, and/or 4-position 3a-i were synthesized by oxidation of the corresponding 6-amino-5,8-dimethoxyquinolines 1a-i . By this oxidation quinones of type 3 are obtained only if the 8-position of the quinoline nucleus is substituted. Oxidation of 6-amino-2,4-dimethyl-5-methoxyquinoline ( 4 ) yields 2,4-dimethyl-8-((2,4-dimethyl-5-methoxy-6-quinolyl)amino)-quinoline-5,6-dione ( 5 ).     

Synthesis and properties of amides of 1-benzyl-3-methyl- and 1-butyl-3-phenyl-7-methyl-4-oxo-2-thioxo (2,4-dioxo)-1,2,3,4-tetrahydropyrido-[2,3-d]pyrimidine-6-carboxy lic acids

Amides of 1-benzyl-3,7-dimethyl-4-oxo-2-thioxo-1,2,3,4- tetrahydropyrido[2,3]pyrimidine-6-carboxylic acid were obtained by the condensation of ammonia, primary and secondary cyclic amines with the corresponding acid chloride. As by - products amides of 1-benzyl-3,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyr imidine-6- carboxylic acid were isolated as a result of desulfuration. The same reaction performed with chloride of 1-butyl-7-methyl-3-phenyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyri do[2,3- d]pyrimidine-6-carboxylic acid gave mainly the corresponding 2,4-dioxo-amides.     

抗肿瘤新药布立尼布的合成

目的:合成抗肿瘤新药布立尼布,并对其工艺进行改进。方法:以3-甲基-1H-吡咯-2,4-二甲酸乙酯为原料,经N-氨基化,环合,格氏反应,氧化重排,乙酰化,卤化,亲核取代,脱保护和亲核取代反应制得布立尼布。结果与结论:目标产物结构经1H-NMR和MS确证,总收率为21.6%,ee值为99.3%。改进后的制备工艺反应条件温和,适合工业化生产。     

2,4-Diamino-5-benzylpyrimidines and analogues as antibacterial agents. 12. 1,2-Dihydroquinolylmethyl analogues with high activity and specificity for bacterial dihydrofolate reductase

Twelve 2,4-diamino-5-[(1,2-dihydro-6-quinolyl)methyl]pyrimidines containing gem-dimethyl or fluoromethyl substituents at the 2-position of the dihydroquinoline ring were prepared by condensations of dihydroquinolines with 2,4-diamino-5-(hydroxymethyl)pyrimidine. The dihydroquinolines were produced from the reaction of anilines with mesityl oxide or fluoroacetone. In some cases, 1-aryl-2,4-dimethylpyrroles were obtained as byproducts. Most of these pyrimidines were highly inhibitory to Escherichia coli dihydrofolate reductase (DHFR) and also had high specificity for the bacterial enzyme. 2,4-Diamino-5-[[1,2-dihydro-2,4-dimethyl-3-fluoro-2-(fluoromethyl)-8- methoxy-6(1H)quinolyl]methyl]pyrimidine had an apparent Ki value for E. coli DHFR 13 times lower than that of the control, trimethoprim (1), and was 1 order of magnitude more selective for the bacterial enzyme. It had outstanding activity against Gram-positive organisms in vitro, as well as broad-spectrum antibacterial activity equivalent to that of 1. The results of in vivo testing will be reported elsewhere. The gem-dimethyl substituents of the dihydroquinoline derivatives are considered to be responsible for the high selectivity, as well as contributing to potent bacterial DHFR inhibition. Molecular models are presented which suggest the probable interactions with the bacterial enzyme.     

克拉维酸钾有关物质F的合成

为了保证克拉维酸钾(1)的质量,本研究合成了欧洲药典收载的有关物质F,即4-[[[4-(2-羟乙基)-1H-吡咯-3-羰基]-氧]甲基]-1H-吡咯-3-羧酸。4-氯乙酰乙酸甲酯(2)与原甲酸三乙酯反应得4-氯-2-(二乙氧基甲基)-3-氧代丁酸甲酯(3),3与甘氨酸反应得烯胺。烯胺在乙酸酐中回流,经环合、脱羧得4-(氯甲基)-1H-吡咯-3-羧酸甲酯(5)。5和1的降解产物4-(2-羟乙基)-1H-吡咯-3-羧酸(8)反应得[4-(甲氧基羰基)-1H-吡咯-3-基]甲基4-(2-羟乙基)-1H-吡咯-3-羧酸甲酯(6),6经水解得有关物质F。产物结构经MS、1H NMR和13C NMR确证。