3-chloromethyl-7β-tert-butylcarbonylamino-3-cephem-4-carboxylic acid p-methoxybenzyl ester | 134866-27-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-chloromethyl-7β-tert-butylcarbonylamino-3-cephem-4-carboxylic acid p-methoxybenzyl ester
• 英文别名: p-methoxybenzyl 7β-t-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate；4-methoxybenzyl 7β-t-butoxycarbonylamino-3-chloromethyl-3-cephemcarboxylate；(4-methoxyphenyl)methyl (6R,7R)-3-(chloromethyl)-7-[(2-methylpropan-2-yl)oxycarbonylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
• CAS: 134866-27-6
• 化学式: C₂₁H₂₅ClN₂O₆S
• 分子量: 468.958
• InChiKey: VGJMCLYHFAGBCT-CRAIPNDOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  120
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-chloromethyl-7β-tert-butylcarbonylamino-3-cephem-4-carboxylic acid p-methoxybenzyl ester 在 sodium iodide 作用下， 以 丁酮 为溶剂， 反应 1.0h， 生成 4-methoxybenzyl 7β-t-butoxycarbonylamino-3-iodomethyl-3-cephemcarboxylate
  参考文献：
  名称：

  Studies on Anti-MRSA Parenteral Cephalosporins. III. Synthesis and Antibacterial Activity of 7.BETA.-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-[(E)-2-(1-alkylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylates and Related Compounds.

  摘要：

  在我们探索具有优异抗甲氧西林耐药金黄色葡萄球菌（MRSA）抗菌活性的新的头孢菌素衍生物的过程中，我们对具有l-甲基咪唑[1, 2-b]吡咯噻啉-6-基团的C-3链接间隔物进行了修改，其位于C-3'位置，以及具有2-(5-氨基-1, 2, 4-噻二唑-3-基)-2(Z)-环戊基氧基亚胺乙酰基团的C-7位置。最优间隔物是19a和29aa中的(E)-2-乙烯基和(E)-2-硫乙烯基，分别其抗MRSA活性是头孢佐芬（CZOP）活性的16到32倍。我们针对(E)-2-乙烯基和(E)-2-硫乙烯基间隔物，进一步修改了C-7酰基部分的烷氧亚胺基团和C-3'位置的1-烷基咪唑[1, 2-b]吡咯噻啉基团，并研究了这些衍生物的构效关系（SAR）。因此，我们选择了7β-[2-(5-氨基-1, 2, 4-噻二唑-3-基)-2(Z)-氟甲氧基亚胺乙酰氨基]-3-[(E)-2-(l-甲基咪唑[1, 2-b]吡咯噻啉-6-基)硫乙烯基]-3-头孢菌素-4-羧酸酯（29ca）作为新的抗MRSA注射用头孢菌素候选物进行进一步的生物评价。所选择的29ca在体外和体内的抗MRSA活性与万古霉素（VCM）相当，对MRSA的青霉素结合蛋白2'（PBP2'）具有高亲和力（IC50=2.7 μg/ml），并对革兰阴性细菌同样表现出强大的活性。

  DOI：

  10.7164/antibiotics.54.257
• 作为产物：
  描述：

  二碳酸二叔丁酯 、 p-methoxybenzyl 7-amino-3-chloromethyl-3-cephem-4-carboxylate 在 N-三甲基硅基乙酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 15.0h， 以5.1 mg的产率得到3-chloromethyl-7β-tert-butylcarbonylamino-3-cephem-4-carboxylic acid p-methoxybenzyl ester
  参考文献：
  名称：

  Studies on Anti-MRSA Parenteral Cephalosporins. III. Synthesis and Antibacterial Activity of 7.BETA.-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-[(E)-2-(1-alkylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylates and Related Compounds.

  摘要：

  在我们探索具有优异抗甲氧西林耐药金黄色葡萄球菌（MRSA）抗菌活性的新的头孢菌素衍生物的过程中，我们对具有l-甲基咪唑[1, 2-b]吡咯噻啉-6-基团的C-3链接间隔物进行了修改，其位于C-3'位置，以及具有2-(5-氨基-1, 2, 4-噻二唑-3-基)-2(Z)-环戊基氧基亚胺乙酰基团的C-7位置。最优间隔物是19a和29aa中的(E)-2-乙烯基和(E)-2-硫乙烯基，分别其抗MRSA活性是头孢佐芬（CZOP）活性的16到32倍。我们针对(E)-2-乙烯基和(E)-2-硫乙烯基间隔物，进一步修改了C-7酰基部分的烷氧亚胺基团和C-3'位置的1-烷基咪唑[1, 2-b]吡咯噻啉基团，并研究了这些衍生物的构效关系（SAR）。因此，我们选择了7β-[2-(5-氨基-1, 2, 4-噻二唑-3-基)-2(Z)-氟甲氧基亚胺乙酰氨基]-3-[(E)-2-(l-甲基咪唑[1, 2-b]吡咯噻啉-6-基)硫乙烯基]-3-头孢菌素-4-羧酸酯（29ca）作为新的抗MRSA注射用头孢菌素候选物进行进一步的生物评价。所选择的29ca在体外和体内的抗MRSA活性与万古霉素（VCM）相当，对MRSA的青霉素结合蛋白2'（PBP2'）具有高亲和力（IC50=2.7 μg/ml），并对革兰阴性细菌同样表现出强大的活性。

  DOI：

  10.7164/antibiotics.54.257

文献信息

• Studies on Anti-MRSA Parenteral Cephalosporins. III. Synthesis and Antibacterial Activity of 7.BETA.-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-[(E)-2-(1-alkylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylates and Related Compounds.
  作者：TOMOYASU ISHIKAWA、KEIJI KAMIYAMA、YUTAKA NAKAYAMA、YUJI IIZAWA、KENJI OKONOGI、AKIO MIYAKE

  DOI：10.7164/antibiotics.54.257

  日期：——

  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 l-methylimidazo[l, 2-b]pyridazinium-6-yl group at the C-3' position and 2-(5-amino-l, 2, 4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyiminoacetyl 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[l, 2-b]pyridazinium moieties at the C-3' position and investigated the structureactivity relationships (SAR) of the derivatives. Consequently, we selected 7β-[2-(5-aminol, 2, 4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(l-methylimidazo[l, 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 μg/ml) for penicillin binding protein 2' (PBP2') of MRSA and potent activity against Gram-negative bacteria as well.

  在我们探索具有优异抗甲氧西林耐药金黄色葡萄球菌（MRSA）抗菌活性的新的头孢菌素衍生物的过程中，我们对具有l-甲基咪唑[1, 2-b]吡咯噻啉-6-基团的C-3链接间隔物进行了修改，其位于C-3'位置，以及具有2-(5-氨基-1, 2, 4-噻二唑-3-基)-2(Z)-环戊基氧基亚胺乙酰基团的C-7位置。最优间隔物是19a和29aa中的(E)-2-乙烯基和(E)-2-硫乙烯基，分别其抗MRSA活性是头孢佐芬（CZOP）活性的16到32倍。我们针对(E)-2-乙烯基和(E)-2-硫乙烯基间隔物，进一步修改了C-7酰基部分的烷氧亚胺基团和C-3'位置的1-烷基咪唑[1, 2-b]吡咯噻啉基团，并研究了这些衍生物的构效关系（SAR）。因此，我们选择了7β-[2-(5-氨基-1, 2, 4-噻二唑-3-基)-2(Z)-氟甲氧基亚胺乙酰氨基]-3-[(E)-2-(l-甲基咪唑[1, 2-b]吡咯噻啉-6-基)硫乙烯基]-3-头孢菌素-4-羧酸酯（29ca）作为新的抗MRSA注射用头孢菌素候选物进行进一步的生物评价。所选择的29ca在体外和体内的抗MRSA活性与万古霉素（VCM）相当，对MRSA的青霉素结合蛋白2'（PBP2'）具有高亲和力（IC50=2.7 μg/ml），并对革兰阴性细菌同样表现出强大的活性。
• A fluorogenic probe using a catalytic reaction for the detection of trace intracellular zinc
  作者：Ippei Takashima、Yohei Inoue、Nobuyuki Matsumoto、Akira Takagi、Kensuke Okuda

  DOI：10.1039/d0cc05315e

  日期：——

  A reaction-based fluorescent probe with cephem scaffold has been applied for signal amplification system to detect trace intracellular zinc.

  一种基于反应的头孢菌素骨架荧光探针已被应用于信号放大系统，用于检测微量细胞内锌。
• 一类头孢中间体的制备方法
  申请人：南京工业大学

  公开号：CN103896964B

  公开（公告）日：2016-04-13

  本发明涉及一类头孢中间体的制备方法，采用3-氯甲基-7β-氨基-3-头孢烯-4-羧酸酯盐酸盐（3-氯甲基-7β-氨基-3-头孢烯-4-羧酸对甲氧苄酯盐酸盐（ACLE.HCl）或3-氯甲基-7β-氨基-3-头孢烯-4-羧酸二苯甲酯盐酸盐（ACLH.HCl））为原料，在溶剂中与缚酸剂中和后，然后与二碳酸二叔丁酯(Boc2O)在催化条件下反应生成3-氯甲基-7β-叔丁氧酰基氨基-3-头孢烯-4-羧酸酯（Cpd1和Cpd2）。本发明提供的一种实用的头孢母环原料制备方法，产品得率96%,纯度98.5%。
• JP2022031028A
  申请人：——

  公开号：——

  公开（公告）日：——
• A Mechanism-Based Inhibitor Targeting the <scp>dd</scp>-Transpeptidase Activity of Bacterial Penicillin-Binding Proteins
  作者：Mijoon Lee、Dusan Hesek、Maxim Suvorov、Wenlin Lee、Sergei Vakulenko、Shahriar Mobashery

  DOI：10.1021/ja038445l

  日期：2003.12.1

  Penicillin-binding proteins (PBPs) are responsible for the final stages of bacterial cell wall assembly. These enzymes are targets of beta-lactam antibiotics. Two of the PBP activities include DD-transpeptidase and DD-carboxypeptidase activities, which carry out the cross-linking of the cell wall and trimming of the peptidoglycan, the major constituent of the cell wall, by an amino acid, respectively. The activity of the latter enzyme moderates the degree of cross-linking of the cell wall, which is carried out by the former. Both these enzymes go through an acyl-enzyme species in the course of their catalytic events. Compound 6, a cephalosporin derivative incorporated with structural features of the peptidoglycan was conceived as an inhibitor specific for DD-transpeptidases. On acylation of the active sites of DD-transpeptidases, the molecule would organize itself in the two active site subsites such that it mimics the two sequestered strands of the bacterial peptidoglycan en route to their cross-linking. Hence, compound 6 is the first inhibitor conceived and designed specifically for inhibition of DD-transpeptidases. The compound was synthesized in 13 steps and was tested with recombinant PBP1b and PBP5 of Escherichia coli, a DD-transpeptidase and a DD-carboxypeptidase, respectively. Compound 6 was a time-dependent and irreversible inhibitor of PBP1b. On the other hand, compound 6 did not interact with PBP5, neither as an inhibitor (reversible or irreversible) nor as a substrate.