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Studies on the Development of New Reaction Modes for the Synthesis of New Drugs

新药合成新反应模式开发研究

基本信息

批准号：
08457585
负责人：
NAGAO Yoshimitsu
金额：
$ 4.54万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

We are extensively carrying out the development of new reaction modes useful for the synthesis of seed and lead compounds of new drugs by utilizing the latent active species. Recently, we have disclosed several new reactions as follows. A new reagent, 3,3'- (phenylphosphoryl) -bis (1,3-thiazolidine-2-thione) was exploited for intramolecular dehydration of various beta-amino acids to give the coreresponding beta-lactams, which could be useful for the monobactam antibiotics. New beta-lactamase inhibitors, thienamonobactams were successfully synthesized by utilizing the latent [2+2] cycloaddition reaction of diketene with an imine derivative. A unique heterocyclic compound, mercaptobicyclotriazolium chloride as the pendant molecule of a remarkable 1beta-methylcarbapenem antibiotic "biapenem", was efficiently synthesized via the reaction cascade employing a pyrazolidine derivative and ethyl formimidate hydrochloride. New angiotensin II (Ag II) receptor antagonists, (acylimino) thiadiazolines were synthesized by exploiting the latent regioselective activation of the nitrogen atom in the heterocyclic moiety of 2-trifluoroacetamido-1,3,4-thiadiazoles. 1,5-Type intramolecular nonbonding S・・・O interaction was clarified by X-ray crystallographic analyzes and abinito MO calculation of the Ag II receptor antagonists and their simple model compounds. We have also developed several new reactions useful for the drug syntheses such as a chemoselective Dieckmann-type reaction mode toward the enantiodivergent process, the Horner-Wadsworth-Emmons reaction of aryl alkyl ketones using tin (II) -triflate and N-ethylpiperidine, and syntheses of new strained [6] and [7] metacyclophanes utilizing the latent conjugated allenyl ketone systems.

我们正在广泛开展利用潜在活性物种合成新药种子和先导化合物的新反应模式的开发。最近，我们公开了如下几种新的反应。本文报道了一种新试剂3，3 ′-（苯磷酰基）-双（1，3-噻唑烷-2-基）对多种β-氨基酸进行分子内脱水，得到相应的β-内酰胺类化合物，可用于单内酰胺类抗生素的合成。利用双乙烯酮与亚胺衍生物的潜在[2+2]环加成反应，成功地合成了新型β-内酰胺酶抑制剂硫烯单内酰胺。以吡唑烷衍生物和亚胺酸乙酯盐酸盐为原料，通过级联反应，高效合成了1 β-甲基碳青霉烯类抗生素“比阿培南”的侧基巯基双环三唑氯化物。利用2-三氟乙酰氨基-1，3，4-噻二唑类化合物杂环部分氮原子的潜在区域选择性活化作用，合成了新型血管紧张素II（Ag II）受体拮抗剂（酰基亚氨基）噻二唑啉类化合物。通过对Ag Ⅱ受体拮抗剂及其简单模型化合物的X射线晶体学分析和abinito分子轨道计算，阐明了分子内1，5-型非键S···O相互作用。我们还开发了几个新的反应，如化学选择性Dieckmann型反应模式对映体发散过程，Horner-Wadsworth-Emmons反应的芳基烷基酮使用锡（II）-三氟甲磺酸酯和N-乙基哌啶，和合成新的应变[6]和[7]间环芳利用潜在的共轭联烯基酮系统。