瑞戈非尼的合成工艺改进

改进抗癌新药瑞戈非尼的合成工艺,以2-吡啶甲酸为原料通过卤化,酰胺化,得到4-氯-N-甲基吡啶-2-甲酰胺,成盐酸盐得到4-氯-N-甲基吡啶-2-甲酰胺盐酸盐,与3-氟-4-氨基苯酚亲核取代反应得到4-(4-氨基-3-氟苯氧基)-N-甲基吡啶-2-甲酰胺,然后和4-氯-3-三氟甲基苯异氰酸酯缩合反应得到瑞戈非尼,总收率为47%。     

吡嘧司特钾的合成

以氰乙酸乙酯为原料，与叠氮化钠环合得到四唑-5-乙酸乙酯，再与2-氨基-3-甲基吡啶缩合得到3-(3-甲基-2-吡啶氨基)-2-(1H-四唑-5-基)丙烯酸乙酯，之后经环合成盐得到吡嘧司特钾，总收率48％。     

抗肿瘤药物neratinib的合成

目的合成抗癌药neratinib。方法以2-氯-4-硝基苯酚和2-氯甲基吡啶为起始原料,经醚化、硝基还原得到3-氯-4-（吡啶-2-甲氧基）苯胺,3-氯-4-（吡啶-2-甲氧基）苯胺与3-氰基-6-乙酰氨基-7-乙氧基-4-氯喹啉反应得到3-氰基-6-乙酰氨基-4-[3-氯-4-（吡啶-2-甲氧基）苯氨基]-7-乙氧基喹啉,3-氰基-6-乙酰氨基-4-[3-氯-4-（吡啶-2-甲氧基）苯氨基]-7-乙氧基喹啉去乙酰保护基后,与（E）-4-二甲氨基-2-丁烯酰氯经酰化反应得到ner-atinib。结果与结论目标物neratinib的总收率为56.0%,其结构经核磁共振氢谱、质谱确证。     

盐酸普萘洛尔有关物质的合成

为加强盐酸普萘洛尔的质量控制，报道了可能存在于药品中的3个有关物质——3-（1-萘氧基）-1，2-丙二醇（1）、N，N-双[[2-羟基-3-（1-萘氧基）]丙基]异丙基胺（2）和双[2-羟基-3-（1-萘氧基）]丙基醚（3）的合成方法：1-萘酚与环氧氯丙烷经缩合和酸性开环得到1，收率58％；普萘洛尔与3-（1-萘氧基）-1，2-环氧丙烷缩合得到2，收率30％；烯丙基-2，3-环氧丙基醚经环氧化后，与1-萘酚缩合得到3，收率38％。     

沃塞洛托的合成工艺研究

目的 改进沃塞洛托的合成工艺。方法 以2,6-二羟基苯甲酸(2)为起始原料,与丙酮反应得到5-羟基-2,2-二甲基-4H-苯并[d][1,3]二氧六环-4-酮,其与3-溴丙烯反应得到5-(烯丙氧基)-2,2-二甲基-4H-苯并[d][1,3]二氧六环-4-酮,经DIBAL-H还原得到2-(烯丙氧基)-6-羟基苯甲醛,再经羟烷基化反应得到2-(烯丙氧基)-6-{[2-(1-异丙基-1H-吡唑-5-基)吡啶-3-基]甲氧基}苯甲醛,最后脱除烯丙基保护基得到沃塞洛托。结果与结论目标化合物及其中间体的结构经¹H-NMR和ESI-MS谱确证,总收率为64.3%(以化合物2计),纯度为98.3%(HPLC法)。本工艺操作简便,原料价廉易得,适合工业化生产。     

盐酸度洛西汀的合成

以2-乙酰噻吩、N-甲基苄胺和多聚甲醛为原料,经Mannich反应、硼氢化钠还原、与1-氟萘经O-烷基化反应制得(±)-N-苄基-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-1-丙胺,脱苄基后经L-二苯甲酰酒石酸拆分得到( )-(S)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)-1-丙胺-L-二苯甲酰酒石酸盐,用氢氧化钠游离后与盐酸成盐得到盐酸度洛西汀,总收率为13.5%。     

Idelalisib的合成工艺改进

目的对PI3K-δ抑制剂idelalisib的合成工艺进行研究。方法以2-氟-6-硝基苯甲酸为起始原料,经氯化、与苯胺缩合、水合肼还原、与(2S)-2-{[(1,1-二甲基乙氧基)羰基]氨基}丁酸缩合得到N-{(1S)-1-[({3-氟-2-[(苯基氨基)羰基]苯基}氨基)羰基]丙基}氨基甲酸-1,1-二甲基乙基酯,再经环合、脱保护基得到2-[(1S)-1-氨基丙基]-5-氟-3-苯基-4(3H)-喹唑啉酮,最后与6-溴-9H-嘌呤发生亲核取代反应得到目标化合物idelalisib。结果与结论idelalisib的总收率为30.8%(以2-氟-6-硝基苯甲酸计),纯度为99.9%,其结构经IR、MS、~1H-NMR、~(13)C-NMR确证。该路线未见文献报道,反应原料易得,反应条件温和,操作简便,为其中试放大奠定了基础。     

盐酸他喷他多的合成

间甲氧基苯丙酮与二甲胺盐酸盐发生Mannich反应生成消旋3-二甲胺基-1-(3-甲氧基苯基)-2-甲基-1-丙酮(13),经结晶诱导的非对映异构体转化得到S-型化合物14后,经格氏反应、酰化及催化氢解得到(2R,3R)-2-甲基3-(3-甲氧基苯基)-N,N-二甲基戊胺,最后经脱保护基、与盐酸成盐得到中枢镇痛药盐酸他喷他多,总收率约52%.     

5-羟色胺转运体放射性配基[11C]DAPA前体的合成

用2,5-二溴硝基苯和2-巯基苯甲酸在Cu/K2CO3作用下缩合得到2-(4-溴-2-硝基苯硫基)苯甲酸,与氯化亚砜反应得到的酰氯与甲胺或二甲胺反应得到相应的酰胺,依次经BH3-THF还原和SnCl2还原相应得到5-羟色胺转运体放射性配基[11C]DAPA的标记前体5-溴-2-[2-(甲胺基甲基苯硫基)]苯胺和5-溴-2-[2-(二甲胺基甲基苯硫基)]苯胺,总收率分别为37%和68%.     

奎扎替尼的合成

对硝基苯酚(2)与4-(2-氯乙基)吗啉盐酸盐(3)发生亲核取代反应得到4-[2-(4-硝基苯氧基)乙基]吗啉(4),4经10%钯炭氢化还原得到4-[2-(4-吗啉基)乙氧基]苯胺(5)。5经2步环化反应得到7-[2-(4-吗啉基)乙氧基]-2-(4-硝基苯基)咪唑并[2,1-b][1,3]苯并噻唑(8)。8经铁粉和氯化铵还原得到4-[7-[2-(4-吗啉基)乙氧基]咪唑并[2,1-b][1,3]-苯并噻唑-2-基]苯胺(9)。另以3-氨基-5-叔丁基异?唑(10)和氯甲酸苯酯反应得苯基(5-叔丁基异?唑-3-基)氨基甲酸酯(11)。用9与11反应得到奎扎替尼(1),终产物纯度为99.17%,总收率为55%(以2计)。该方法所使用起始原料2价廉易得,且3的用量大大降低,反应条件相对温和,后处理操作简便,可为工业化生产提供参考。     

吡嘧司特钾的合成

以氰乙酸乙酯为起始原料，先与叠氮化钠反应生成5-乙氧羰甲基-1H-四唑，再与2-氨基-3-甲基吡啶和原甲酸三乙酯缩合得到吡嘧司特，进而成盐得到吡嘧司特钾，总收率38．7％。     

An efficient large‐scale synthesis of 1H‐indazole‐[3‐14C]carboxylic acid

An efficient large‐scale carbon‐14 synthesis of 1H‐indazole‐[3‐¹⁴C]carboxylic acid starting from [¹⁴C]potassium cyanide is reported. Key transformations encountered during the synthesis include aromatic nucleophilic substitution of 2‐nitrofluorobenzene by ethyl [¹⁴C]cyanoacetate, a mild decarbethoxylation and an aniline nitrosation/cyclization. Copyright © 2007 John Wiley & Sons, Ltd.     

帕珠沙星的合成研究

以左氟沙星中间体（S）-9，10-二氟-3-甲基-7-氧代-2，3-二氢-7H-吡啶[1，2，3-de][1，4]苯并恶嗪-6-羧酸乙酯为原料，经与氰乙酸乙酯缩合、脱羧、环合、水解及Hoffman降解制得帕珠沙星，总收率43%。     

Synthesis and antileishmanial activity of alpha-cyano ethyl propenoates--a new class of antileishmanials

A number of alpha-cyano-beta-substituted ethyl propenoates were synthesised by condensation of appropriate aldehydes with ethyl cyanoacetate in basic medium. These compounds have been studied for their antileishmanial activities in vivo in hamsters. Two compounds exhibited 70-77% activities both by intramuscular and oral routes.     

氮芥型化合物2-甲基-4-[双-(2′-氯乙基)-氨甲基]噻唑盐酸盐的合成

本文证实了氰乙酸乙酯与硫化氢作用所得的反应液与1,3-二氯丙酮在无水乙醇中反应后,进行昇华,所得的产物是2-甲基-4-氯甲基噻唑盐酸盐。并由它合成了氮芥型化合物2-甲基-4-[双-(2′-氯乙基)氨甲基]噻唑盐酸盐,供作抗肿瘤的试验。     

Antiinflammatory properties of a series of 4-amino-5-arylpyrazoles

A series of ethyl 4-amino-5-arylpyrazol-3-yl carboxylates were prepared from arylacetonitriles and ethyl diazoacetate. The compounds were evaluated for their analgesic and antiinflammatory properties, that were not, however, sufficiently interesting to justify the further development of the compounds. The synthesis of the compounds could be a useful extension of the original report by A. Bertho on the reaction between ethyl cyanoacetate and ethyl diazoacetate to yield diethyl 4-aminopyrazole-3,5-dicarboxylate.     

2-氨基-6-环丙胺基-9H-嘌呤的合成

氰乙酸乙酯经亚硝化、与盐酸胍在乙醇钠存在下缩合闭环、Pd/C催化还原得2,4,5-三氨基-6-羟基嘧啶,与甲酸环合得鸟嘌呤,再经乙酰化、氯化、与环丙胺缩合得到抗病毒药阿巴卡韦中间体2-氨基-6-环丙胺基-9H-嘌呤,总收率约39%。     

Studies on aminopyrazoles: antibacterial activity of some novel pyrazol

Hydrazones 2a-d were prepared from diazotiazation of sulfanilamide or its derivatives followed by coupling with ethyl cyanoacetate. 3-Aminopyrazoles 3a-d were obtained by refluxing of 2a-d with hydrazine hydrate in ethanol. [Bis(-methylthio)methylene]malononitrile (4) was reacted with aminopyrazoles 3a-d in refluxing DMF containing triethylamine to yield the novel pyrazolo[1,5-a]pyrimidines 6a-d. The anilino derivatives 8a-h were obtained by fusion of compounds 6a-d with aromatic amines. When compounds 6a,c,d were subjected to the reaction with hydrazine hydrate, the hydrazino derivatives 9a-c were isolated. Also, the aminopyrazoles 3 were reacted with some electrophiles such as arylidenemalononitriles, ethoxymethylene malononitrile and ethyl ethoxymethylene cyanoacetate to yield the novel substituted pyrazolo[1,5-a]pyrimidines 13, 17 and 19, respectively. Structures of the new compounds were established by their elemental analyses and spectral data. Most of these compounds were also tested in vitro for their antibacterial activity against some gram positive and gram negative bacteria.     

Rapid and efficient ultrasound-assisted method for the combinatorial synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] derivatives

An efficient one-pot synthesis of spiro[indoline-3,4'-pyrano[2,3-c]pyrazole] derivatives by four-component reaction of hydrazine, β-keto ester, isatin, and malononitrile or ethyl cyanoacetate catalyzed by piperidine under ultrasound irradiation is described. This synthesis was confirmed to follow the group-assistant-purification chemistry (GAP) chemistry process, which can avoid traditional chromatography and recrystallization purifications.