[(chloromethyl)thio] acetic acid methyl ester | 57235-69-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [(chloromethyl)thio] acetic acid methyl ester
• 英文别名: chloromethyl methoxycarbonylmethyl sulfide；Methyl (chloromethylthio)acetate；methyl-4-chloro-3-thiabutanoate；chloromethylsulfanyl-acetic acid methyl ester；Chlormethylmercapto-essigsaeure-methylester；[(chloromethyl)thio]acetic acid methyl ester；Methyl [(chloromethyl)sulfanyl]acetate；methyl 2-(chloromethylsulfanyl)acetate
• CAS: 57235-69-5
• 化学式: C₄H₇ClO₂S
• mdl: MFCD19232162
• 分子量: 154.617
• InChiKey: HLDIIMXXHCPATI-UHFFFAOYSA-N

物化性质

• 沸点：
  98 °C(Press: 14 Torr)
• 密度：
  1.253±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  8
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  51.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  [(chloromethyl)thio] acetic acid methyl ester 在 双氧水 、 vanadia 作用下， 以 叔丁醇 为溶剂， 以68%的产率得到chloromethyl methoxycarbonylmethyl sulfoxide
  参考文献：
  名称：

  Convenient method for the selective oxidation of sulfide sulfur in alkylmercaptoalkyl esters of thio- and dithioacids of phosphorus

  摘要：

  DOI：

  10.1007/bf00953168
• 作为产物：
  描述：

  聚合甲醛 、 巯基乙酸甲酯 在 盐酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以3.846 g的产率得到[(chloromethyl)thio] acetic acid methyl ester
  参考文献：
  名称：

  Hancock, James Reid; Hardstaff, William Rayne; Johns, Paul Alan, Canadian Journal of Chemistry, 1983, vol. 61, p. 1472 - 1480

  摘要：

  DOI：

文献信息

• 3-Heterothio[(oxyalkyl)thioacetyl]cephalosporin derivatives
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US03989696A1

  公开（公告）日：1976-11-02

  3-Heterothio[(oxyalkyl)thioacetyl] cephalosporin derivatives which have the formula ##EQU1## wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, tri (lower alkyl) silyl, a salt forming ion, or the group ##EQU2## R.sub.1 is hydrogen, lower alkyl, phenyl, thienyl or furyl; R.sub.2 and R.sub.6 each is hydrogen or lower alkyl; R.sub.3 and R.sub.5 is lower alkyl, phenyl or phenyl-lower alkyl; and R.sub.4 is a five- or six-member nitrogen and/or sulfur or oxygen-containing ring system; are useful as antibacterial agents.

  3-杂硫[(氧烷基)硫乙酰]头孢菌素衍生物，其化学式为##EQU1##其中R为氢、低烷基、苯基-低烷基、三(低烷基)硅基、形成盐的离子，或者是基团##EQU2##R.sub.1为氢、低烷基、苯基、噻吩基或呋喃基；R.sub.2和R.sub.6各自为氢或低烷基；R.sub.3和R.sub.5为低烷基、苯基或苯基-低烷基；R.sub.4为含有五元或六元氮和/或硫或氧的环系统；这些化合物可用作抗菌剂。
• [(Oxyalkyl)thioacetyl]cephalosporin derivatives
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US03991051A1

  公开（公告）日：1976-11-09

  [(Oxyalkyl)thioacetyl] cephalosporin derivatives having the formula ##EQU1## wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, tri(lower alkyl)silyl, a salt forming ion, or the group ##EQU2## R.sub.1 is hydrogen, lower alkyl, phenyl, thienyl or furyl; R.sub.2 and R.sub.6 each is hydrogen or lower alkyl; R.sub.3 and R.sub.5 each is lower alkyl, phenyl or phenyl-lower alkyl; and R.sub.4 is hydrogen, hydroxy, lower alkanoyloxy, lower alkoxy or lower alkylthio; are useful as antimicrobial agents. SUMMARY OF THE INVENTION This invention relates to new [(oxyalkyl)thioacetyl]cephalosporin derivatives having the formula ##STR1## R represents hydrogen, lower alkyl, phenyl-lower alkyl, tri(lower alkyl)silyl, a salt forming ion or the group ##STR2## R.sub.1 represents hydrogen, lower alkyl, phenyl, thienyl or furyl; R.sub.2 and R.sub.6 each represents hydrogen or lower alkyl; R.sub.3 and R.sub.5 each represents lower alkyl, phenyl or phenyl-lower alkyl; and R.sub.4 represents hydrogen, hydroxy, lower alkanoyloxy, lower alkoxy or lower alkylthio. The especially preferred members within each group are as follows: R is hydrogen, alkali metal, diphenylmethyl or ##STR3## especially hydrogen, pivaloyloxy, sodium or potassium; R.sub.1 is hydrogen or phenyl; R.sub.2 is hydrogen; R.sub.3 is lower alkyl, especially methyl; R.sub.4 is hydrogen or acetoxy; and R.sub.5 is methyl or t-butyl. DETAILED DESCRIPTION OF THE INVENTION The various groups represented by the symbols have the meanings defined below and these definitions are retained throughout this specification. The lower alkyl groups are the straight and branched chain hydrocarbon groups in the series from methyl to heptyl, the C.sub.1 to C.sub.4 groups and especially methyl and ethyl being generally preferred. The lower alkoxy and lower alkylthio groups are of the same type and the same preferences apply. The lower alkanoyloxy groups represented by R.sub.4 include the acyl radicals of lower fatty acids containing alkyl radicals of the type described above, e.g., acetoxy, propionoxy, butyryloxy, etc., the C.sub.1 to C.sub.4 members being preferred and acetoxy being especially preferred. The phenyl-lower alkyl radicals include a phenyl ring attached to a lower alkyl group of the kind described above like benzyl and phenethyl as well as those containing two phenyl groups such as diphenylmethyl. The salt forming ions represented by R are metal ions, e.g., alkali metal ions such as sodium or potassium, alkaline earth metal ions such as calcium or magnesium or an amine salt ion, e.g., a (lower alkyl)amine like methylamine or triethylamine. The new [(oxyalkyl)thioacetyl)cephalosporin derivatives of this invention are produced by reacting a 7-aminocephalosporanic acid compound, e.g., 7-aminocephalosporanic acid (7-ACA), 7-amino-3-desacetoxycephalosporanic acid (7-ADCA) and other derivatives, having the formula ##STR4## or derivatives thereof with an [(oxyalkyl)thio]acetic acid of the formula ##STR5## or an acid halide, anhydride including mixed anhydrides, activated esters or the like. The derivatives of II referred to include, for example, the triethylamine derivative, benzhydryl ester or the like. The acid halide of III is preferably the chloride. Coupling agents like dicyclohexylcarbodiimide or the like can also be used. A preferred method is the reaction between the 7-aminocephalosporanic acid compound and the [(oxyalkyl)-thio]acetic acid, for example, by dissolving or suspending the latter in an inert organic solvent such as chloroform, tetrahydrofuran, methylene chloride, dioxane, benzene or the like, and adding, at a reduced temperature of about 0.degree. to -20.degree. C about an equimolar amount of the 7-ACA or 7-ADCA compound, preferably in the form of its diphenylmethyl ester, in the presence of an activating compound such as dicyclohexylcarbodiimide. The product of the reaction is then isolated by conventional procedures, e.g., by filtration and concentration or evaporation of the solvent. The diphenylmethyl ester is converted to the free acid, e.g., with trifluoroacetic acid and anisole. Any of the salts can then be produced by conventional treatment, e.g., with potassium ethyl hexanoate, sodium bicarbonate or the like. Another preferred method involves the reaction of a 7-aminocephalosporanic acid compound with the acid halide of the [(oxyalkyl)thio]acetic acid in aqueous alkaline medium. When R is the acyloxymethyl group ##STR6## this group may be introduced into the 7-aminocephalosporanic acid moiety prior to the reaction with the [(oxyalkyl)thio]-acetic acid or derivative by treatment with one to two moles of a halomethyl ester of the formula ##STR7## wherein hal is halogen, preferably chlorine or bromine, in an inert organic solvent such as dimethylformamide, acetone, dioxane, benzene or the like, at about ambient temperature or below. The [(oxyalkyl)thio]acetic acid of formula III is produced by reacting a mercaptoacetic acid of the formula ##STR8## with a halogenated compound of the formula ##STR9## in the presence of a base like triethylamine in a solvent like tetrahydrofuran and then hydrolyzing the ester formed in the process. Alternatively, when the acid halide is used to react with the 7-aminocephalosporanic acid compound, an alkoxide R.sub.3 -OMe (wherein Me is a metal like sodium or potassium) is made to react with a haloester of the formula ##STR10## to obtain the intermediate of the formula ##STR11## Treatment with a base, e.g., an alkali metal hydroxide like potassium hydroxide, converts the ester to a salt which is then converted to the acid chloride with a halogenating agent like oxalyl chloride. Further process details are provided in the illustrative examples. Certain of the compounds of this invention may exist in different optically active forms. The various stereoisomeric forms as well as the racemic mixtures are within the scope of the invention. The compounds of this invention have a broad spectrum of antibacterial activity against both gram positive and gram negative organisms such as Staphylococcus aureus, Salmonella schottmuelleri, Pseudomonas aeruginosa, Proteus vulgaris, Escherichia coli and Streptococcus pyrogenes. They can be used as antibacterial agents to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephradine and other cephalosporins. For example, a compound of formula I or a physiologically acceptable salt thereof can be used in various animal species in an amount of about 1 to 150 mg/kg, daily, orally or parenterally, in single or two to four divided doses to treat infections of bacterial origin, e.g., 7.0 mg/kg is used in mice. Up to about 600 mg. of a compound of formula I or a physiologically acceptable salt thereof is incorporated in an oral dosage form such as tablets, capsules or elixirs or in an injectable form in a sterile aqueous vehicle prepared according to conventional pharmaceutical practice.

  [(氧烷基)硫乙酰基]头孢菌素衍生物具有以下公式：##EQU1## 其中，R表示氢、低碳基、苯基-低碳基、三(低碳基)硅基、盐形成离子或基团##EQU2## R.sub.1表示氢、低碳基、苯基、噻吩基或呋喃基；R.sub.2和R.sub.6各表示氢或低碳基；R.sub.3和R.sub.5各表示低碳基、苯基或苯基-低碳基；R.sub.4表示氢、羟基、低烷酰氧基、低烷氧基或低硫代基；它们可用作抗微生物剂。本发明涉及新的[(氧烷基)硫乙酰基]头孢菌素衍生物，其具有以下公式：##STR1## R表示氢、低碳基、苯基-低碳基、三(低碳基)硅基、盐形成离子或基团##STR2## R.sub.1表示氢、低碳基、苯基、噻吩基或呋喃基；R.sub.2和R.sub.6各表示氢或低碳基；R.sub.3和R.sub.5各表示低碳基、苯基或苯基-低碳基；R.sub.4表示氢、羟基、低烷酰氧基、低烷氧基或低硫代基。在每个组内特别优选的成员如下：R为氢、碱金属、二苯甲基或##STR3## 尤其是氢、季戊酸酯氧基、钠或钾；R.sub.1为氢或苯基；R.sub.2为氢；R.sub.3为低碳基，尤其是甲基；R.sub.4为氢或乙酰氧基；R.sub.5为甲基或叔丁基。各符号所表示的各组的含义如下，并且这些定义在本说明书中得以保留。低碳基是从甲基到庚基的直链和支链烃基，C.sub.1到C.sub.4基团，尤其是甲基和乙基通常优选。低烷氧基和低硫代基是相同类型的，同样适用偏好。由R.sub.4表示的低烷酰氧基组包括含有上述类型的烷基基团的低脂肪酸酰基，例如，乙酰氧基、丙酰氧基、丁酰氧基等，其中C.sub.1到C.sub.4成员是优选的，特别是乙酰氧基。含有苯基-低碳基基团的基团包括连接到上述类型的低碳基团的苯环的基团，例如苄基和苯乙基，以及含有两个苯基的基团，例如二苯甲基。由R表示的盐形成离子是金属离子，例如，碱金属离子，如钠或钾，碱土金属离子，例如钙或镁，或胺盐离子，例如(低碳基)胺，例如甲胺或三乙胺。本发明的新[(氧烷基)硫乙酰基)头孢菌素衍生物是通过将7-氨基头孢菌素酸化合物，例如7-氨基头孢菌素酸(7-ACA)，7-氨基-3-去乙酰基头孢菌素酸(7-ADCA)和其他衍生物，具有以下公式：##STR4## 或其衍生物与以下公式的[(氧烷基)硫]乙酸反应制备的：##STR5## 或酸卤、酸酐包括混合酐、活性酯或类似物。所提到的II衍生物包括，例如，三乙胺衍生物，苯甲酰基酯或类似物。III的酸卤最好是氯化物。也可以使用偶联剂，例如二环己基碳二亚胺或类似物。一种首选的方法是在惰性有机溶剂，例如氯仿、四氢呋喃、二氯甲烷、二恶烷、苯或类似物中，将[(氧烷基)-硫]乙酸溶解或悬浮在约0℃至-20℃的降温条件下，在激活化合物，例如二环己基碳二亚胺的存在下，加入7-ACA或7-ADCA化合物的等摩尔量，优选以其二苯甲基酯的形式存在。然后通过传统的程序，例如过滤和浓缩或溶剂蒸发，分离反应产物。二苯甲基酯可以转化为自由酸，例如三氟乙酸和茴香醚。然后可以通过传统的处理方法，例如用乙基己酸钾、碳酸氢钠或类似物处理，制备任何盐。另一种首选的方法涉及7-氨基头孢菌素酸化合物与[(氧烷基)硫]乙酸酸卤在水性碱性介质中反应。当R为乙酰氧甲基基团##STR6## 该基团可以在与[(氧烷基)硫]-乙酸或其衍生物反应之前，通过用式的一到二摩尔的卤代甲酯处理来引入到7-氨基头孢菌素酸基团中。##STR7## 其中hal是卤素，优选是氯或溴，在惰性有机溶剂，例如二甲基甲酰胺、丙酮、二恶烷、苯或类似物中，以约室温或低于室温的温度进行。式III的[(氧烷基)硫]乙酸是通过在三乙胺等碱性介质和四氢呋喃等溶剂中，将式的巯基乙酸##STR8## 与式的卤代化合物##STR9## 反应，然后水解所形成的酯而制备的。或者，当使用酸卤与7-氨基头孢菌素酸化合物反应时，使R.sub.3-OMe（其中Me是诸如钠或钾之类的金属）与式的卤酯反应##STR10## 以获得式的中间体##STR11## 用碱，例如，氢氧化钾等碱金属氢氧化物，将酯转化为盐，然后用卤化试剂，例如草酸二乙酯，将盐转化为酸氯化物。更多的过程细节在说明性示例中提供。本发明的某些化合物可能存在不同的光学活性形式。各种立体异构体形式以及混合物均属于本发明的范围。本发明的化合物对革兰氏阳性和革兰氏阴性微生物具有广谱的抗菌活性，例如金黄色葡萄球菌、肠杆菌、假单胞菌、普通变形杆菌、大肠杆菌和链球菌。它们可用作抗菌剂来治疗由上述菌株引起的感染，并且通常可以像头孢啶和其他头孢菌素一样使用。例如，公式I的化合物或其生理上可接受的盐可以在各种动物物种中以每日1至150毫克/千克的剂量口服或静脉注射，单次或分2至4次分割，用于治疗细菌性感染，例如在小鼠中使用7.0毫克/千克。公式I的化合物或其生理上可接受的盐的剂量高达约600毫克，可包含在口服剂型，例如片剂、胶囊或甜酒中，或在无菌水性载体中制备的注射剂型中。
• Synthesis, reaction with esterases, and toxicity of O-alkyl S-(carbalkoxymethylmercapto)methyl methylthiophosphonates
  作者：T. A. Mastryukova、A. �. Shipov、Z. K. Emkuzheva、A. P. Brestkin、I. L. Brik、Yu. E. Mandel'shtam、A. N. Fedin、T. I. Nozhko、Z. Tilyabaev、S. A. Roslavtseva、Yu. S. Kagan、E. A. Ershova、M. I. Kabachnik

  DOI：10.1007/bf00949696

  日期：1980.5
• The Relative Acidifying Influence of Oxygen and Sulfur Atoms on α-Hydrogen Atoms¹
  作者：Warren J. Brehm、Theodore Levenson

  DOI：10.1021/ja01650a040

  日期：1954.11
• Some methylpropyldithiophosphinates as potential insecticides
  作者：T. A. Mastryukova、A. �. Shipov、G. V. Zhdanova、Yu. S. Kagan、E. A. Ershova、N. A. Guseva、M. I. Kabachnik

  DOI：10.1007/bf00923905

  日期：1978.2