万艾可

万艾可(枸橼酸西地那非)的合成路线--E文转载 The synthesis of sildenafil citrate was first reported in the Bioorganic & Medicinal Chemistry Letters, Vol 6, pp. 1819, 1824, 1996. The reaction scheme is reproduced below. Sildenafil was reported in this journal as "a potent and selective inhibitor of type 5 PDE with utility for the treatment of male erectile dysfunction" The first step of the synthesis is the reaction of a diketoester (1) and hydrazine to give the pyrazole ring. The regioselective N-methylation of the pyrazole and hydrolysis gives a carboxylic acid (3). Compound (3) is then reacted with HNO3 and H2SO4 to give a nitrated product. This is then followed by a carboxamide formation and the reduction of the nitro group. The compound (4) is then acylated under basic conditions and this produces the pyrazolopyrimidinone (6). (6) is then chlorosulphonylated selectively on the 5'-position of the phenyl ring. This can then couple with an amine to give sildenafil (7). The yield of each step is given on the reaction scheme. This is the original synthesis which was reported in the literature when the molecule was first synthesised. A variant of the synthesis was published but the changes it involved only consisted in the change of a few reactants, and no major changes were reported. This synthesis appeared in the January 1999 issue of Chemistry in Britain. This journal only reported the original discovery synthesis and said that the synthesis used commercially had not been published. The drug is commercially manufactured by an alternative route. The reaction scheme is described in the patent which was published on 17 decembre 1997. However, the synthesis used in the commercial manufacture could be different to this. The patent was filed by the Pfizer Research and Development Company. The scheme is reproduced below. The synthesis was described in a lot of detail, including the solvents that were the best to use, however, these details have not been reproduced here. These and further details about the synthesis can be found on the original patent document. The reaction pathway is explained in more detail below. Compound 2 can be prepared by the chlorosulphonation of 2-ethoxybenzoic acid (1). The conversion of compound 2 to compound 4 is achieved by N-sulphonation of 1-methylpiperazine and may be conducted in a one or two step procedure. Coupling of compound 4 with compound 6 can be achieved by any of the known amide bond-forming reactions. The aminopyrazole (6) is obtainable by the conventional reduction of the corresponding nitropyrazole (5). The resulting solution of compound 6 may be used directly after filtration in the coupling reaction with compound 4. The cyclisation of compound 7 to give sildenafil has been achieved in yields up to 95%. Thus the overall yield of sildenafil based on compound 1 as a starting material, depending on whether the one or two step sulphonylation procedure is used can be as high as 51.7% or 47.8% respectively. This compares favourably with the first synthesis in which the overall yield is 27.6%. The cyclisation of compound 7 to sildenafil can be conducted under neutral or acidic conditions. Under neutral conditions, compound 7 is heated, optionally in the presence of a solvent and/or optionally in the presence of a dehydrating agent and/or mechanical water removal system. Under acidic conditions, the reaction is carried out with a prolic acid or Lewis acid optionally in the presence of a solvent. The reagents employed in the reactions can vary, but the following are among the ones recommended by the submitters of the patent: The first step is the chlorosulphonylation of 2-ethoxybenzoic acid. This can be achieved by reacting 1 equivalent mole of thionyl chloride with 4 equivalent mole of chlorosulphonic acid. Addition of 1-methylpiperazine to an aqueous suspension of compound 2 is a suitable reaction to obtain compound 4 in one step. The carboxylic function of compound 4 can be activated using a 5% excess of N,N'-carbonyldiimidazole in ethyl acetate. This intermediate can then be reacted with imidazolide and compound 6. Compound 6 is obtainable by reduction of the corresponding nitropyrazole 5 for example by using palladium catalysed hydrogenation in ethyl acetate. Compound 7 is then cyclised to complete the reaction scheme and give sildenafil. Information about the synthesis used to manufatcure Viagra was not available, and the two presented above are only the ones which were published. It is not surprising that the commercial manufacture of the drug is by a pathway that is not published. 本帖最近评分： 共 4 条评分 科创币 +90 隐藏 dx毁灭者 科创币 +5 10-22 强大滴转帖 托尼史塔克 科创币 +30 10-22 这个不错。 焓熵` 科创币 +50 10-22 高质量发帖 火箭爱好者 科创币 +5 10-22 囧 回复 引用 举报 HYPERLINK "javascript:scroll(0,0)" \o "顶端" 顶端 ca-139 UID：20780 · 注册时间2011-04-17 · 最后登录2011-12-27 · 在线时间268小时 · 发帖257 · 搜Ta的帖子 · 精华 1 · 科创币-760 · 学术分1 访问TA的空间 HYPERLINK "javascript:;" 加好友 HYPERLINK "javascript:;" 用道具 级别: 十步芳草 INCLUDEPICTURE "http://bbs.kechuang.org/images/wind8purple/level/10.gif" \* MERGEFORMATINET 发帖 257 科创币 -760 学术分 1 · 关注Ta · 发消息 只看该作者 1楼 发于: 10-22 好吧，我就翻译下吧。。。。。。 合成枸橼酸西地那非首次在有机和药物化学字母,第六卷,- 1819页,1824年。下面是转载的反应计划。昔多芬在这一本日记中报道了“一种潜在的和选择性乙酰胆碱酯酶抑制剂,运用效用5型气治疗男性勃起功能障碍” 　　 （第一张图） 第一步合成的反应的一个diketoester(1)和肼给吡唑环。这regioselective N-methylation吡唑和水解的给羧酸(3)。复合(3)然后硝酸和硫酸反应强烈,给人一种产品。 　　这是一个carboxamide然后,形成和减少硝基组。复合(4)下然后类型为基本条件和这产生了pyrazolopyrimidinone(6)。(6)则是chlorosulphonylated selec （图二） 这个药物是商业生产的另一种可选择的途径。反应计划中描述的专利decembre发表于1997年17。然而,合成用于商业生产是不一样的。提出专利是辉瑞公司研制开发。下面是转载的。 　　 （图三） 综合介绍了许多细节,包括溶剂,是最好的使用,然而,这些细节还没有复制这里。这些和进一步的详情的合成可以发现在原专利文件。 　　反应途径在下面详细说明。 　　复合2可以做准备的chlorosulphonation 2-ethoxybenzoic酸(1)。转换的化合物2到4的获得是通过N-sulphonation化合物的1-methylpiperazine和可以通过一个或两个步骤的程序。以复合耦合的复合四6可以达到任何已知氨基bond-forming反应。(六)的aminopyrazole可减少由传统的相应的nitropyrazole(5),其结果可能是解决复合6直接使用过滤后的化合物偶联反应4。 cyclisation的复合7给西地那非已经达到产量上升到95%。因此,总收率为西化合物1的基础上作为一个起始资料,取决于一个或两个步骤程序使用sulphonylation可高达51.7%或47.8%。这个价格相比,是较为便宜的第一合成总收率为27.6%。 cyclisation的复合7西可进行中性或酸性条件下。在中性条件下,复合7加热,可选的存在和/或可选用溶剂中出现脱水代理和/或机械除湿法系统。在弱酸性条件下,反应的进行prolic酸或刘易斯酸选择性地在存在大量的溶剂。 采用反应的反应物能变化,但以下的中间而是推荐的专利： 第一步是2-ethoxybenzoic chlorosulphonylation的酸。这可以达到反应thionyl氯的等效鼹鼠1和4 chlorosulphonic等效鼹鼠的酸。一加1-methylpiperazine水悬架的化合物2是一种适合于反应机理得到复合4在一个步骤。功能的羧酸化合物4能够激活使用5%过量的N,N ' -carbonyldiimidazole在乙酸乙酯。这中间就可以表现出imidazolide和复合6。通过减少复合6获得相应的nitropyrazole 5例如用钯催化加氢在乙酸乙酯。然后cyclised复合7是完成反应计划和给西地那非。 　　信息用于大规模合成伟哥是无效的,只是两个上述那些被出版。也就不足为奇了商业生产的药物是由一个路径,是没有发布。 　　 　　 [ 此帖被ca-139在2011-10-22 22:26重新编辑 ]