(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸的合成

目的 合成头孢唑兰中间体(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸。方法 以氰乙酰胺为起始原料,依次经甲氧亚氨化、加成、酯化、与硫氰化钾反应、构型转换和水解共6步反应制得目标化合物。结果和结论 目标化合物的结构经¹H-NMR和MS谱确证。该工艺路线原料易得,操作简便,总收率为29.8%,具有一定的工业化价值。     

(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸合成路线图解

（Z）-2-（5-氨基-1，2，4-噻二唑-3-基）-2-甲氧亚氨基乙酸（1）是合成头孢唑兰（cefozopran）和头孢克定（cefclidin）㈨等头孢菌素的关键中间体。1的合成路线按噻二唑环形成前或后引入甲氧亚氨基可分为两类，现分述如下：     

(Z)-2 - [(5-氨基-[1,2,4]噻二唑-3-基)-羧基-亚甲基氨基氧基]-2-甲基-丙酸叔丁酯的制备方法

摘要：本文探索头孢洛扎中间体的制备方法。首先将起始物料2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基乙酸与甲醇进行 反应得到化合物1,然后化合物1与盐酸羟胺反应得到化合物2,其次化合物2与α-溴代异丁酸叔丁酯进行缩合反应得到化合物3, 最后通过水解反应制备(Z)-2-[(5-氨基-[1,2,4]噻二唑-3-基)-羧基-亚甲基氨基氧基]-2-甲基-丙酸叔丁酯(简称TATD)。该产品的纯度 与总摩尔收率分别为99.1%、66.1%,且反应原料易得,适合工业化规模生产。     

盐酸头孢唑兰的合成

目的 研究抗生素盐酸头孢唑兰的合成方法.方法 以7-氨基头孢烷酸(7-ACA)为原料,在三乙胺催化下与(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧亚氨基硫代乙酸(S-2-苯并噻唑)酯缩合得7β-[(Z)-2-(5-氨基-1,2,4-噻二唑-3-基)-2-甲氧哑氨基乙酰氨基]头孢烷酸,再经六甲基二硅胺烷硅烷化保护,与咪唑并[1,2-b]哒嗪在三甲基碘硅烷(TMSI)催化下进行3-位取代反应,然后经甲醇脱保护,阴离子交换树脂除碘离子,最后与盐酸成盐得盐酸头孢唑兰.结果 目标化合物总收率为15%,结构经MS,IR和1H-NMR确证.结论 用本法合成盐酸头孢唑兰,原料易得,操作简便,易于工业化生产.     

2-(2-氨基-4-噻唑基)-2-(Z)-羟亚胺基乙酸的合成

以乙酰乙酸甲酯为原料,经亚硝化,硫酰氯氯化,环合,水解,精制五步反应制备了2-(2-氨基-4-噻唑基)-2-(Z)-羟亚胺基乙酸,总收率38.8%。本品是合成头孢克肟、头孢他啶、头孢地尼等的重要中间体。     

《中国医药工业杂志》2008年（第39卷）年度索引

主题索引Subject Index1抗微生物感染药物1A抗生素1A1A青霉素类青霉素V钾phenoxymethylpenicillin potassium片在健康人体内的药物动力学和生物等效性39:9141A1B头孢菌素类2-(5-氨基-1,2,4-噻二唑-3-基)-2-(Z)-甲氧亚氨基39:645头孢泊肟cefpodoxime人血浆中～的RP-HPLC法测定39     

(6R,7R)-7-[2-呋喃基(甲氧亚氨基)乙酰氨基]-3-羟甲基-8-氧代-5-硫杂-1-氮杂二环[420]辛-2-烯-2-甲酸的合成研究

目的　制备(6R,7R) - 7-[2 -呋喃基(甲氧亚氨基)乙酰氨基] - 3-羟甲基- 8-氧代- 5 -硫杂- 1-氮杂二环[4 2 0]辛- 2 -烯- 2 -甲酸。方法　通过7-氨基头孢烷酸的水解,生成去乙酰基7-氨基头孢烷酸,再与2 - (2 -呋喃基)- 2 -甲氧亚胺基乙酸氯反应进行7位氨基的酰化制备上述医药中间体。结果及结论　适宜的反应条件为:7-氨基头孢烷酸在- 2 5℃水解,与2 - (2 -呋喃基) - 2 -甲氧亚胺基乙酰氯在- 10℃反应,二者的摩尔比为1 0∶1. 15,收率可达80 %。     

2-(2-苄氧羰基氨基噻唑-4-基)-5-(3-甲基-2-丁烯氧羰基)-2-戊烯酸的合成

对头孢布烯的关键中间体2-(2-苄氧羰基氨基噻唑-4-基)-5-(3-甲基-2-丁烯氧羰基)-2-戊烯酸(1)的合成工艺进行了研究。选用国内易得的(2-氨基噻唑-4-基)乙酸甲酯(2)作为起始原料,经过氨基保护、M ichae l加成-消除和选择性酯化三步反应制得目标化合物1,反应总收率63.0%。该工艺操作简单,生产成本低,适合工业化生产。     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-[3-烷基-4-(烷氨基)烷氧基]苯酯的合成

前文报道的一系列二甲氨基甲酸间-(烷氨基)烷氧(烷硫)基苯酯类化合物(I,X=O,S)中,多数具有较强的抑酶作用,有的对实验动物的中麻催醒效果较好,且毒性和副作用小。其中二甲氨基甲酸间-(2-二甲氨基)-乙氧基苯酯(I,X=O,n=2,R=CH_3)已命名为“催醒     

可逆性胆碱酯酶抑制剂:二甲氨基甲酸-[2-(2-二甲氨基)乙氧基-4(或5)-特丁基]苯酯的合成

前报报道在“催醒安”的对位异构体的苯环上引入烷基,可以增强对胆碱酯酶的抑制作用。为了探索在邻位异构体(Ⅰ)的苯环上引入烷基对生理活性的影响,合成了二甲氨基甲酸-[2-(2-二甲氨基)乙氧基-4(或5)-特丁基]苯酯(Ⅱ)。     

Studies on anti-MRSA parenteral cephalosporins. I. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)- hydroxyiminoacetamido]-3-(substituted imidaz

In order to improve the antibacterial activity of cefozopran (CZOP) against methicillin-resistant Staphylococcus aureus (MRSA), we initiated chemical modification to introduce a 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-hydroxyimino acetyl group at the C-7 position and a 3- or 6-substituted imidazo[1,2-b]pyridazinium or 5-substituted imidazo[1,2-a]pyridinium group at the C-3' position. Although this approach successfully enhanced the anti-MRSA activity of CZOP two to eight times, a slight decrease in the activity against Gram-negative bacteria including Pseudomonas aeruginosa was involved. Among the novel derivatives, 3-(6-aminoimidazo[1,2-b]pyridazinium-1-yl)methyl-7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)hydroxyiminoacetamido]-3-cephem-4-carboxylate (44a) showed an excellent balance of activity against MRSA and Gram-negative bacteria.     

Studies on condensed-heterocyclic azolium cephalosporins. IV. Synthesis and antibacterial activity of 7 beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)- alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl cephalosporins including SCE-2787.

The synthesis and in vitro antibacterial activity of 7 beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetami do] cephalosporins bearing various condensed-heterocyclic azolium groups at the 3 position in the cephalosporin nucleus are described. The thiadiazolyl cephalosporins showed good antibacterial activity against both Gram-positive and Gram-negative bacteria and the MICs of the thiadiazolyl cephalosporins against Pseudomonas aeruginosa was more potent than that of the corresponding 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-alkoxyiminoacetamido]-3- (condensed-heterocyclic azolium)methyl cephalosporins. Also, the thiadiazolyl cephalosporins bearing (imidazo[1,2-b]-pyridazinium-1-yl)methyl groups at the 3 position showed antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Among the cephalosporins tested, 7 beta-[2-(5- amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamido]-3-(imidaz o[1,2- b]pyridazinium-1-yl)methyl-3- cephem-4-carboxylate (4, SCE-2787) which exhibited the most potent antibacterial activity and the broadest antibacterial spectrum was selected as a parenteral cephalosporin candidate for further biological evaluation.     

Studies on anti-MRSA parenteral cephalosporins. III. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido-3

In the course of our exploration for a novel cephalosporin derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we modified the C-3 linked spacers of cephem derivatives bearing a 1-methylimidazo[1,2-b]pyridazinium-6-yl group at the C-3' position and 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxy-iminoacetyl group at the C-7 position. The optimal spacers were the (E)-2-vinyl and (E)-2-thiovinyl groups seen in 19a and 29aa, respectively. Their anti-MRSA activity was 16 to 32 times as potent as that of cefozopran (CZOP). Focusing on the (E)-2-vinyl and (E)-2-thiovinyl spacers, we further modified the alkoxyimino groups in the C-7 acyl moiety and the 1-alkylimidazo[1,2-b]pyridazinium moieties at the C-3' position and investigated the structure-activity relationships (SAR) of the derivatives. Consequently, we selected 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (29ca) as a new anti-MRSA parenteral cephalosporin candidate for further biological evaluation. The selected 29ca showed anti-MRSA activity comparable to that of vancomycin (VCM) both in vitro and in vivo, high affinity (IC50)=2.7 microg/ml) for penicillin binding protein 2' (PBP2') of MRSA and potent activity against Gram-negative bacteria as well.     

Studies on condensed-heterocyclic azolium cephalosporins. V. Synthesis and antibacterial activity of 3-(condensed-triazolo-pyridinium, -pyrimidinium, and -pyridazinium)-methyl cephalosporins.

As a part of our studies on cephalosporins bearing condensed-heterocyclic azolium methyl groups at the 3 position in the cephalosporin nucleus, we describe here the synthesis and antibacterial activity of 7 beta-[2-(2-aminothiazol-4-yl)2(Z)-methoxyiminoacetamido] cephalosporins (1-16, 7 beta-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)- methoxyiminoacetamido] cephalosporins (17,18) and 7 beta-[2-(5-amino- 1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetamido) cephalosporins (19-23) containing a variety of condensed-heterocyclic triazolium methyl groups at the 3 position in the cephalosporin nucleus. These cephalosporins exhibited potent antibacterial activity, and it appears that condensed-heterocyclic triazolium as well as condensed-heterocyclic imidazolium rings are effective moieties for improving antibacterial activity and the spectrum of activity. Among the cephalosporins tested, 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(5- methyl[1,2,3]triazolo-[1,5-alpha]pyridinium-1-yl)methyl-3-cephem-4- carboxylate (9) and 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(6- methoxy[1,2,4]triazolo[1,5-alpha]pyridinium-1-yl)methyl-3-cephem-4- carboxylate (11) showed good antibacterial activity.     

Synthesis and antimycobacterial activity of (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives

[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-ylthio]acetic acid (3,4-diaryl-3H-thiazol-2-ylidene)-hydrazide derivatives were synthesized and tested for their in vitro antimycobacterial activity. Some compounds showed an interesting activity against a strain of Mycobacterium tuberculosis H(37)Rv and three clinical isolates of M. tuberculosis.     

Studies on anti-MRSA parenteral cephalosporins. II. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4- thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(substituted imidaz

In an effort to discover a novel cefozopran (CZOP) derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we performed chemical modification of the alkoxyimino moiety and imidazo[1,2-b]pyridazinium group of CZOP. Among the prepared compounds, the cyclopentyloxyimino derivative 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyiminoacetamido]-3-(3,6-diaminoimidazo[1,2-b]pyridazinium-1-yl)methyl-3-cephem-4-carboxylate (20 g) showed the most potent anti-MRSA activity, reflecting its high affinity (IC50 = 1.6 microg/ml) for penicillin binding protein 2' (PBP2'), although its anti-MRSA activity was slightly inferior to that of vancomycin (VCM). In experimental systemic infection in mice, however, 20 g showed activity comparable to that of VCM against MRSA. In addition, 20 g showed activity similar or slightly inferior to that of CZOP against Pseudomonas aeruginosa both in vitro and in vivo. Considering its favorable antibacterial activity profile, 20 g was considered to be the most promising CZOP derivative for further studies.     

头孢唑兰和头孢克定侧链酸合成研究

目的探讨侧链酸的合成工艺及结构确证。方法以氰基乙酰胺为起始原料,经烷化,羟肟化,环合、酰胺水解反应合成了头孢菌素类的关键中间体2-(5-氨基-12,4,-噻二唑-3-基)-2-甲氧基亚氨基乙酸。结果四步主要反应的收率分别是73.2%,66.3%6,2.5%3,3.3%,总收率为10.1%。结论该合成工艺操作简便,收率高,是合成侧链酸的较好方法。通过元素分析、红外吸收光谱及核磁共振谱确证了侧链酸的结构。