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142 条记录 (耗时 0.021 秒)

    Esterification process using methoxymethyl-P-toluenesulfonate
    121.
    发明授权
    Esterification process using methoxymethyl-P-toluenesulfonate 失效
    酯化方法使用甲氧基甲基对甲苯磺酸盐

    公开(公告)号：US4247461A

    公开(公告)日：1981-01-27

    申请号：US95018

    申请日：1979-11-16

    申请人： Jeng S. Lin ,  Paul D. Sleezer

    发明人： Jeng S. Lin ,  Paul D. Sleezer

    IPC分类号： C07D499/00 ,  C07D499/32 ,  C07D501/04 ,  C07D499/08 ,  C07D501/02

    CPC分类号： C07D499/00

    摘要： A new esterifying agent, i.e. methoxymethyl tosylate, is provided for use in preparing methoxymethyl esters of organic carboxylic acids. The new esterifying agent is found to be particularly advantageous in the esterification of penicillin 3-carboxyl groups or cephalosporin 4-carboxyl groups to the methoxymethyl ester group.

    摘要翻译： 提供了一种新的酯化剂，即甲氧基甲苯磺酸甲酯，用于制备有机羧酸的甲氧基甲基酯。 发现新的酯化剂在将青霉素3-羧基或头孢菌素4-羧基酯化成甲氧基甲基酯基团方面特别有利。

    Stereospecific production of 6- or 7-carbon-substituted-.beta.-lactams
    122.
    发明授权
    Stereospecific production of 6- or 7-carbon-substituted-.beta.-lactams 失效
    6-或7-碳取代的β-内酰胺的立体特异性生产

    公开(公告)号：US4237051A

    公开(公告)日：1980-12-02

    申请号：US031286

    申请日：1979-04-19

    申请人： Stuart W. McCombie

    发明人： Stuart W. McCombie

    IPC分类号： C07D499/00 ,  C07D501/04 ,  C07D501/02

    CPC分类号： C07D499/00

    摘要： Reaction of 6- or 7-diazo-.beta.-lactams with allylic halides in the presence of a catalytic amount of metallic copper or a copper salt affords 6- or 7-carbon-substituted-.beta.-lactams with the desired stereochemical configuration at the 6- or 7-position. Subsequent reduction with a trialkyl stannane affords useful intermediates for further syntheses affording 6- or 7-carbon-substituted-.beta.-lactams.The present invention relates to a process for the production of 6- or 7-carbon-substituted-.beta.-lactams having the desired stereochemical configuration at the 6- or 7-position. More particularly, this invention provides a process for the preparation of a .beta.-lactam of the formula ##STR1## wherein R.sub.1 is cyano or COOR.sub.2 wherein R.sub.2 is a readily removable ester-forming moiety, hydrogen or an alkali-metal cation;R.sub.3 and R.sub.4 are independently hydrogen, lower alkyl, aryl or aralkyl;Z is a group of the formula ##STR2## wherein R.sub.5 is hydrogen, lower alkyl or aralkyl; and the dotted line indicates the optional presence of a double bond; which comprises(1) reacting a diazo-.beta.-lactam of the formula ##STR3## wherein Y is a sulfur or an oxygenated sulfur atom and Z, R.sub.1, R.sub.3, and R.sub.4 are as hereinbefore defined; with an allyl halide of the formula ##STR4## wherein R.sub.3 and R.sub.4 are as hereinbefore defined andX is bromo or iodo;in the presence of a catalytic amount of metallic copper or a copper salt; and where Y is an oxygenated sulfur atom, followed by transformation of the resultant oxygenated sulfur intermediate to a compound wherein Y is a sulfur atom; and(2) subjecting the resultant intermediate of the formula ##STR5## wherein X, Z, R.sub.1, R.sub.3, and R.sub.4 are as hereinabove defined, to reduction with a trialkyl stannane to afford the compound of formula I.The lower alkyl groups referred to contain 1 to 6 carbon atoms and are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl and the corresponding branched-chain isomers thereof.The lower alkoxy groups referred to above likewise contain 1 to 6 carbon atoms and are exemplified by methoxy, ethoxy, propoxy, and the like.The term "aryl" as used herein refers to phenyl substituted by one or more substituent groups selected from among chloro, bromo, fluoro, lower alkyl, hydroxy, nitro, amino, aminomethyl, lower monoalkylamino, lower dialkylamino, lower alkoxy and carboxy. Such aryl groups represented by R.sub.1 can be, for example, 4-hydroxyphenyl, 3,4-dichlorophenyl, 2,6-dimethoxyphenyl, 4-methylphenyl, 2-fluorophenyl, 4-carboxyphenyl, 3-nitrophenyl, 4-aminophenyl, 3-aminophenyl, 4-dimethylaminophenyl, 4-aminomethylphenyl and 4-ethoxyphenyl.The term "aralkyl" encompasses aryl-substituted lower alkyl groups such as benzyl, phenethyl, p-fluorobenzyl, o-tolylethyl and m-hydroxy-phenethyl.The process of this invention initially involves the reaction of a diazo-.beta.-lactam of formula II and the allyl halide of formula III in the presence of a catalytic amount of metallic copper or a copper salt to induce the decomposition of the diazo-.beta.-lactam at temperatures of about 0.degree.-50.degree. C. to provide the intermediate of formula IV. The diazo-.beta.-lactam utilizable in this step of the invention may be any type of readily removable ester-blocked acid, i.e., the compound of formula II wherein R.sub.1 is COOR.sub.2 or a nitrile, i.e., the compound of formula II wherein R.sub.1 is cyano. Preferably, benzyl or benzhydryl esters are employed in the reaction wherein R.sub.1 is COOR.sub.2. The starting materials of formula II wherein Y is oxygenated sulfur are preferred due to the stability of the starting compound. However, the reaction using the equivalent sulfide also proceeds with good yields and avoids the need for a subsequent deoxygenation step.The allyl halides of formula III utilizable in the present invention are those wherein the halogen is iodine or bromine with iodine being most particularly preferred. The allyl halide of formula III may be substituted by lower alkyl, aryl or aralkyl groups. Those compounds wherein R.sub.3 and R.sub.4 are methyl or phenyl are preferred.The copper compound utilizable as a catalyst for this step of the instant invention may be almost any copper salt or finely divided elemental copper. Preferably, 1-10 mole percent of the copper or copper salt is utilized. The most preferred catalysts are cuprous chloride and copper (II)-2,4-pentanedioate.In order to maximize the yield for this step of the instant invention, it is preferable to use a large excess of the allyl halide of formula III. Most preferably, allyl bromide or allyl iodide is used as the reaction medium. Substituted allyl halides of formula III are preferably diluted with a non-polar co-solvent such as methylene chloride. Polar solvents may also be used, e.g., dimethylformamide, dimethylsulfoxide or acetonitrile, but these provide poorer yields.The reaction is preferably carried out at room temperature; however, depending on the nature of the starting materials, the reaction temperatures may range from about 0.degree. to 50.degree. C. Occasionally, warming to about 40.degree. C. is utilized to initiate the reaction which is then continued without further heating.The stereochemistry at C-6 or C-7 of the intermediate of formula IV is generally a mixture of alpha and beta compounds. Generally, use of the bromides gives a higher ratio of beta to alpha compounds, i.e., 5 to 6:1. Use of the iodides gives more approximately equal amounts of the alpha and beta isomers.The reduction of step 2 to afford the cis product of formula I is accomplished using trialkyl stannane (trialkyl tin hydride). Preferably, tri-n-butyl stannane is utilized. The intermediate of formula IV is heated at about 60.degree.-100.degree. C. with 1-2 equivalents of the tin hydride in an inert solvent. Preferred solvents are tetrahydrofuran, benzene and toluene. Typically, the product is separated by chromatography in yields of greater than 80%.The compounds of formula II wherein Y is an oxygenated sulfur atom may be obtained from the corresponding compounds wherein Y is sulfur by any of the conventional oxidation procedures, e.g., ozone, iodobenzene dichloride in aqueous pyridine, etc. An oxygenated sulfur penicillin compound, i.e., wherein Z is ##STR6## may then be converted to the corresponding cephalosporin, i.e., wherein Y is S and Z is ##STR7## by various literature methods. See, for instance, Flynn, "Cephalosporins and Penicillins", Academic Press, pp. 193-199 and 670-673 (1972). By such methods benzyl 6.beta.-allyl-6.alpha.-bromopenicillanate-1.beta.-oxide may be converted to benzyl 7.beta.-allyl-6.alpha.-bromo-3-methyl-3-cephem-4-carboxylate. The sulfoxide compound is also particularly useful wherein it is desired to convert a mixture of 2- and 3-cephem compounds to a pure 3-cephem compound.The 6- or 7-diazo starting materials of formula II are preparable via a variety of literature methods or variations thereof. A preferred method involves degradation of the penicillin or cephalosporin side chain via the N-nitroso derivative as described by Hausler and Sigg, Helv. Chim. Acta., 1327 (1967); and Sheehan, J. Org. Chem., 39, 1444 (1974). This process involves treatment of the penicillin or cephalosporin, e.g., benzylpenicillin benzyl ester or benzhydryl ester, to form the N-nitroso derivative, followed by decomposition of the nitroso amide side chain with methylene chloride-pyridine or methylene chloride at about 40.degree. C. to afford the diazo compound. An improvement of this process, omitting the pyridine and allowing the reaction to proceed at room temperature in a polar solvent, e.g., dimethylsulfoxide or dimethylformamide, affords a cleaner reaction and better conversion, i.e., >90%. This reaction sequence may be represented by the following scheme: ##STR8## wherein Y, Z and R.sub.1 are as hereinbefore defined.Preferable by this route are the following:benzyl 6-diazopenicillanate;benzhydryl 6-diazopenicillanate;6-diazopenicillanonitrile; andbenzyl 7-diazo-3-methylcephalosporanate.Another modification of the decomposition step in the preparation of the starting materials of formula II is to utilize triphenylphosphine and water in place of the methylene chloride and pyridine according to the method of Sheehan, J. Org. Chem., 42, 1012 ( 1977) to afford the hydrazone of the formula: ##STR9## Oxidation of this hydrazone by the method of U.S. Pat. No. 3,880,837 affords the desired diazo compound. This route is particularly preferred for the cephalosporin starting materials of this invention. Preparable by this route are the following:benzhydryl 7-diazo-3-methylcephalosporinate;benzhydryl 7-diazo-3-acetoxymethylcephalosporinate; andbenzhydryl 6-diazopenicillanate.An additional method for preparing the 6- or 7-diazo compounds of formula II involves diazotisation of the corresponding amino compounds using nitrous acid according to the procedure originally carried out by Hausler and Sigg, Helv. Chim. Acta., 1327 (1967) and further delineated in J. Amer. Chem. Soc., 94, 1408 (1972) and J. Org. Chem., 41, 1578 (1976).Once prepared, the compounds of formula I are utilizable to prepare various 6- or 7-substituted-.beta.-lactams having useful antimicrobial activity, many of which are known in the art. For instance, ozonolysis of 6.beta.-(allyl)penicillanonitrile, benzyl 6.beta.-(allyl)penicillanate or benzhydryl 6.beta.-allylpenicillanate affords 6.beta.-(formylmethyl)-penicillanonitrile, benzyl 6.beta.-(formylmethyl)penicillanate and benzhydryl 6.beta.-(formylmethyl)penicillanate, respectively. This ozonolysis is carried out according to standard methodology.The aldehyde obtained by the ozonolysis described in the preceding paragraph may then be subjected to reduction utilizing a mild reducing agent such as sodium borohydride to afford the corresponding alcohol. For instance, obtainable by this reaction is 6.beta.-(2-hydroxyethyl)penicillanonitrile, benzyl 6.beta.-(2-hydroxyethyl)penicillanate and benzhydryl 6.beta.-(2-hydroxyethyl)penicillanate. The ester group of the preceding two compounds may, of course, be removed utilizing standard hydrogenolysis typically with a palladium catalyst to afford the resulting free acids. Workup with a weak base, e.g., potassium carbonate or sodium carbonate, will afford the potassium or sodium salts, e.g., potassium 6.beta.-(2-hydroxyethyl)penicillanate or sodium 6.beta.-(2-hydroxyethyl)penicillanate.Oxidation of the aldehydes obtainable by the ozonolysis procedure affords the corresponding carboxylic acids. For instance, benzhydryl 6.beta.-(formylmethyl)penicillanate treated with chromic acid in acetone and water affords benzhydryl 6.beta.-(carboxymethyl)penicillanate.Reaction of the foregoing carboxylic acids with suitable azides provides various homo-penicillanates. For instance, benzhydryl 6.beta.-(carboxymethyl)penicillanate treated with diphenylphosphoryl azide and triethylamine at a reaction temperature of about 80.degree. C. according to the method of Ninomiya, et. al., Chem. Pharm. Bull. Japan, 22, 1398 (1974), affords benzhydryl 6.beta.-(carbonylaminomethyl)penicillanate which is typically not isolated. Treatment of this intermediate with the desired acid or alcohol provides homopenicillanates which then may be optionally deblocked. Obtainable in this method are potassium 6.beta.-(phenylacetamidomethyl)penicillanate and potassium 6.beta.-(ethoxycarbonylaminomethyl)penicillanate.Treatment of benzhydryl 6.beta.-(carbonylaminomethyl)penicillanate with trichloroethanol followed by a zinc/acetic acid reduction affords benzhydryl 6.beta.-(aminomethyl)penicillanate. Conventional deblocking of this compound then affords 6.beta.-(aminomethyl)penicillanic acid.Several of the foregoing compounds are described by Sheehan, et. al. as having useful and interesting antimicrobial activity in German Pat. Nos. 2,416,492 and 2,643,085. However, 6.beta.-(aminomethyl)penicillanic acid has not heretofore been described in any publication and is therefore a novel compound.The 6.beta.-(aminomethyl)penicillanic acid produced by the process of this invention possesses antibacterial activity. Additionally, it is a penicillinase inhibitor which may be used concomitantly with other penicillin-type antibiotics in infection therapy.Thus, when tested in standardized microbiological assays, this compound exhibits activity vis-a-vis such organisms as Staphylococcus aureus, Klebsiella, Bacillus subtilis, and Pseudomonas aeruginosa at test levels of 0.1 to 100 .mu.cg/ml. Thus, as antibacterial agents this compound is conventionally formulated for oral, intramuscular, intravenous or topical therapy.Thus, the present invention includes within its scope pharmaceutical compositions comprising an antibacterially effective amount of the novel 6.beta.-(aminomethyl)penicillanic acid with a compatible pharmaceutical carrier therefor, and a method of using such compositions for the treatment of microbial infections.The dosage administered of this compound is dependent upon the age and weight of the animal species being treated, the mode of administration, and the type and severity of bacterial infection being prevented or reduced. Typically, the dosage administered per day will be in the range of 100-5000 mg with 500-1000 mg being preferred.For oral administration, this compound may be formulated in the form of tablets, capsules, elixirs or the like. For parenteral administration it may be formulated into solutions or suspensions for intramuscular injection. Topical formulations include creams, ointments, gels and the like.

    摘要翻译： 在催化量的金属铜或铜盐存在下，6-或7-重氮-β-内酰胺与烯丙基卤化物的反应，得到6-或7-碳取代的β-内酰胺，其具有所需的立体化学构型 - 或7位。 随后用三烷基锡烷还原，为进一步合成提供6-或7-碳取代的β-内酰胺提供了有用的中间体。

    3-Methylene cephalosporanic acid derivatives and process for preparation thereof
    125.
    发明授权
    3-Methylene cephalosporanic acid derivatives and process for preparation thereof 失效
    3-亚甲基头孢菌酸衍生物及其制备方法

    公开(公告)号：US4138553A

    公开(公告)日：1979-02-06

    申请号：US841321

    申请日：1977-10-11

    申请人： Sachio Ishimoto ,  Hisao Yamaguchi ,  Yoshinori Kato ,  Takeo Oba ,  Kenji Ozawa ,  Yataro Ichikawa ,  Koji Nakagawa ,  Hideki Tsuruta

    发明人： Sachio Ishimoto ,  Hisao Yamaguchi ,  Yoshinori Kato ,  Takeo Oba ,  Kenji Ozawa ,  Yataro Ichikawa ,  Koji Nakagawa ,  Hideki Tsuruta

    IPC分类号： C07D499/00 ,  C07D501/10 ,  C07D501/02

    CPC分类号： C07D499/00 ,  Y02P20/55

    摘要： Novel substituted hydrazide derivatives of 7-(substituted)amino-3-methylene-cepham-4-carboxylic acids expressed by the formula ##STR1## wherein R.sub.1 represents alkyl containing at least 3 carbon atoms, cycloalkyl, or optionally substituted aryl, and one of R.sub.2 and R.sub.3 represents hydrogen with the other being hydrogen or the same as R.sub.1 ; or R.sub.1 and R.sub.2 form a heterocyclic ring optionally through a hetero atom together with the attached nitrogen and R.sub.3 represents hydrogen atom; and Z.sub.1 represents amino or protected amino; and acid addition salts thereof, which are useful as intermediates for synthesizing cephalosporin antibiotics. These compounds can be prepared in high yields from the corresponding substituted hydrazide derivatives of 6-substituted amino-1-oxide-2, 2-dimethyl-penam-3-carboxylic acids, which are readily available at low costs, by heating them in the presence of a thermal rearrangement promotor such as organic sulfonic acids and optionally in the further presence of a tertiary nitrogen-containing cyclic compound, followed if desired by splitting off the amino-protecting group and converting the product to acid addition salts.

    摘要翻译： 由式“IMAGE”表示的7-（取代的）氨基-3-亚甲基 - 头孢烯-4-羧酸的新型取代的酰肼衍生物，其中R 1表示含有至少3个碳原子的烷基，环烷基或任选取代的芳基， R2和R3代表氢，另一个是氢或与R1相同; 或R 1和R 2与所连接的氮一起任选地通过杂原子形成杂环，并且R 3表示氢原子; Z1表示氨基或被保护的氨基; 其酸加成盐，其可用作合成头孢菌素抗生素的中间体。 这些化合物可以以相当于6-取代的氨基-1-氧化物-2,2-二甲基 - 对甲苯磺酸的取代的酰肼衍生物的高收率制备，它们以低成本容易获得，通过在 存在热重排促进剂如有机磺酸，并且任选地在另外存在叔氮气环状化合物的情况下，如果需要的话，分解氨基保护基并将产物转化成酸加成盐。

    Method of preparing a rapidly dissolving powder of crystalline cephalothin sodium for parenteral administration
    126.
    发明授权
    Method of preparing a rapidly dissolving powder of crystalline cephalothin sodium for parenteral administration 失效
    制备用于肠胃外给药的结晶头孢菌素钠的快速溶解粉末的方法

    公开(公告)号：US4132848A

    公开(公告)日：1979-01-02

    申请号：US847501

    申请日：1977-11-03

    申请人： Michael D. Cise ,  Michael L. Roy

    发明人： Michael D. Cise ,  Michael L. Roy

    IPC分类号： A61K31/545 ,  C07D501/34 ,  C07D501/02

    CPC分类号： A61K31/545

    摘要： Essentially crystalline cephalothin sodium for parenteral administration is prepared by a freeze-drying process wherein a (C.sub.1 -C.sub.3 alcohol or acetone)-water solution of cephalothin sodium containing from about 2 to about 10 percent of C.sub.1 -C.sub.3 alcohol or acetone by volume is chilled from room temperature to -20.degree. C., or below, preferably about -40.degree. C. over a 1-3 hour period and then warmed to from about -3.degree. C. to about -10.degree. C. and held for 3 hours or more, then cooled to -20.degree. C., or below, preferably about -40.degree. C., before subjecting said frozen solution to a high vacuum and a moderate amount of heat to sublime the frozen solvent therefrom. The resulting powder dissolves rapidly in acceptable pharmaceutical diluents. Alternatively, from about 2 to about 5 percent by weight of sodium bicarbonate, related to the amount of cephalothin sodium present, is added to the solution before freeze-drying.

    摘要翻译： 用于胃肠外给药的基本结晶头孢菌素钠通过冷冻干燥方法制备，其中将含有约2至约10％的C 1 -C 3醇或丙酮的（C 1 -C 3醇或丙酮） - 头孢噻吩钠的水溶液冷却 在1-3小时内从室温至-20℃，优选约-40℃，然后升温至约-3℃至约-10℃并保持3小时 然后冷却至-20℃或更低，优选约-40℃，然后将所述冷冻溶液进行高真空和适度的热量以使冻结的溶剂升华。 所得粉末在可接受的药物稀释剂中快速溶解。 或者，将约2-约5重量％的与头孢噻吩钠的量相关的碳酸氢钠加入冷冻干燥前的溶液中。