公开(公告)号：US07551088B2

公开(公告)日：2009-06-23

申请号：US11786592

申请日：2007-04-12

申请人： W. David Findlay ,  Brian Bannister

发明人： W. David Findlay ,  Brian Bannister

IPC分类号： G08B13/14 ,  G08B5/22

CPC分类号： G06K19/07749 ,  G01S13/825

摘要： The present invention consists of an electronic vehicle tag (EVT), which is preferably 12×6 inches. It consists of an encasement mountable by 4 screws to a motor vehicle. The front face is comprised of an electronic paper display technology, which requires no power consumption to maintain its image. The electronic paper display will hold a high resolution full color graphic design relating to the vehicle tag selected and tag information depending on the state of issuances requirements. The display is reflective and can be easily read in sunlight or dimly lit environments and at virtually any angle. The plate has an electronic paper technology for display, wireless communication transmitter/receiver, logic board for electronic paper manipulation, high impact encasement, and a battery pack. The battery pack is used to change the display when required. The electronic vehicle tag is independent of the vehicle in which it is attached.

摘要翻译： 本发明由电子车辆标签（EVT）组成，其优选为12×6英寸。 它由一个可由4个螺钉安装到汽车上的外壳组成。 前脸由电子纸显示技术组成，不需要耗电来维持其图像。 电子纸显示器将保持与所选择的车辆标签和标签信息相关的高分辨率全色图形设计，这取决于发布要求的状态。 显示器是反射性的，可以在阳光或昏暗的环境中以几乎任何角度轻松读取。 该板具有用于显示的电子纸技术，无线通信发送器/接收器，用于电子纸操作的逻辑板，高冲击装置和电池组。 电池组用于在需要时更换显示屏。 电子车辆标签独立于其附接的车辆。

公开(公告)号：US4031304A

公开(公告)日：1977-06-21

申请号：US653938

申请日：1976-01-30

申请人： Brian Bannister

发明人： Brian Bannister

IPC分类号： C07H15/14 ,  C07H15/16

CPC分类号： C07H15/16

摘要： Alkyl 7-deoxy-7-.omega.-substituted alkylthio-.alpha.-thiolincos-aminides useful as intermediates for preparing anti-bacterially active 7-deoxy-7-.omega.-substituted alkylthiolincomycins are prepared by heating alkyl N-acyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminides with an appropriate thiol in the presence of an anhydrous lower hydrocarbon carboxylic acid.BRIEF DESCRIPTION OF THE INVENTIONThis invention relates to methods for making alkyl (7R,S) 7-deoxy-7-.omega.-substituted alkylthio-.alpha.-thiolincosaminides of Formula I: ##STR1## wherein Alk is alkyl of not more than 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, sec.- butyl, isobutyl, and tert.-butyl; R.sub.1 is hydrogen, methyl or ethyl; R.sub.2 is hydrogen, methyl or ethyl; R.sub.3 is hydrogen, methyl or ethyl; n is 0 or 1; and R is hydrogen, alkyl of 1 to 6 carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive.The wavy line joining the substituent to the carbon atoms at position number 7 in Formulae I, IVa, IVb, V, and VII indicates that the compounds exist in both (7R) and (7S) epimeric forms.The wavy line joining the methyl group and the hydrogen to the carbon atom at position number 7 in Formulae IIa, IIb and VI indicates that the compounds exist in both (6R,7R) and (6R,7S) epimeric forms.The term "carboxacyl" as used throughout the specification and claims means the acyl radical of a hydrocarbon carboxylic acid or of a hydrocarbon carboxylic acid substituted with an inert group. Preferred as carboxacyl groups are the acyl radicals of hydrocarbon carboxylic acids and inert group substituted hydrocarbon carboxylic acids having from 2 to about 18 carbon atoms, inclusive, in their structure. Representative of such carboxyacyl groups are those of formula: ##STR2## wherein E is hydrocarbyl of from 1 to about 17 carbpon atoms, inclusive, or hydrocarbyl of from 1 to 17 carbon atoms, inclusive, wherein a hydrogen atom has been replaced with an inert substituent group. Illustrative of acyl radicals of a hydrocarbon carboxylic acid wherein E is hydrocarbyl are the acyl radicals of (a) saturated or unsaturated, straight or branched chain aliphatic carboxylic acids, for example, acetic, propionic, butyric, isobutyric, tert-butylacetic, valeric, isovaleric, caproic, caprylic, decanoic, dodecanoic, lauric, tridecanoic, myristic, pentadecanoic, palmitic, margaric, stearic, acrylic, crotonic, undecylenic, oleic, hexynoic, heptynoic, octynoic acids and the like; (b) saturated or unsaturated, alicyclic carboxylic acids, for example, cyclobutanecarboxylic acid, cyclopentanecarboxylic acids, cyclopentenecarboxylic acid, methylcyclopentenecarboxylic acid, cyclohexanecarboxylic acid, dimethylcyclohexenecarboxylic acid, dipropylcyclohexanecarboxylic acid, and the like; (c) saturated or unsaturated, alicyclic aliphatic carboxylic acids, for example, cyclopentaneacetic acid, cyclopentanepropionic acid, cyclohexanebutyric acid, methylcyclohexaneacetic acid, and the like; (d) aromatic carboxylic acids, for example, benzoic acid, toluic acid, naphthoic acid, ethylbenzoic acid, isobutylbenzoic acid, methylbutylbenzoic acid, and the like; and (e) aromatic-aliphatic carboxylic acids, for example, phenylacetic acid, phenylpropionic acid, phenylvaleric acid, cinnamic acid, phenylpropionic acid, and naphthylacetic acid, and the like.The term "hydrocarbon carboxylic acid substituted with an inert group" is used herein to mean a hydrocarbon carboxylic acid wherein one or more hydrogen atoms attached directly to a carbon atom have been replaced with a group inert to reaction under the conditions hereinafter described for preparing compounds (I) of the invention. Illustrative of such substituent groups are halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, or alkoxy-groups. Illustrative of halo-, nitro-, hydroxy-, amino-, cyano-, thiocyano-, and alkoxy-substituted hydrocarbon carboxylic acids are mono-, di-, and trichloroacetic acid; .alpha.- and .beta.-chloropropionic acid; .alpha.- and .gamma.-bromobutyric acid; .alpha.- and .delta. iodovaleric acid; mevalonic acid; 2- and 4-chlorocyclohexanecarboxylic acid; shikimic acid; 2-nitro-1-methylcyclobutanecarboxylic acid; 1,2,3,4,5,6-hexachlorocyclohexanecarboxylic acid; 3-bromo-2-methylcyclohexanecarboxylic acid; 4- and 5-bromo-2-methylcyclohexanecarboxylic acid; 5- and 6-bromo-2-methylcyclohexanecarboxylic acid; 2,3-dibromo-2-methylcyclohexanecarboxylic acid; 2,5-dibromo-2-methylcyclohexanecarboxylic acid; 4,5-dibromo-2-methylcyclohexanecarboxylic acid; 5,6-dibromo-2-methylcyclohexanecarboxylic acid; 3-bromo-3-methylcyclohexanecarboxylic acid; 6-bromo-3-methylcyclohexanecarboxylic acid; 1,6-dibromo-3-methylcyclohexanecarboxylic acid; 2-bromo-4-methylcyclohexanecarboxylic acid; 1,2-dibromo-4-methylcyclohexanecarboxylic acid; 3-bromo-2,2,3-trimethylcyclopentanecarboxylic acid; 1-bromo-3,5-dimethylcyclohexanecarboxylic acid; homogentisic acid; o-, m-, and p-chlorobenzoic acid; anisic acid; salicyclic acid; p-hydroxybenzoic acid; .beta.-resorcylic acid; gallic acid, veratric acid, trimethoxybenzoic acid; trimethoxycinnamic acid; 4,4'-dichlorobenzilic acid; o-, m-, and p-nitrobenzoic acid; cyanoacetic acid; 3,4- and 3,5-dinitrobenzoic acids, 2,4,6-trinitrobenzoic acid; thiocyanoacetic acid; cyanopropionic acid; lactic acid; ethoxyformic acid (ethyl hydrogen carbonate); butyloxyformic acid; pentyloxyformic acid, hexyloxyformic acid; dodecyloxyformic acid; hexadecyloxyformic acid and the like.The term "aralkyl" as used in the specification and claims means an aralkyl of from 7 to 12 carbon atoms, inclusive. Illustrative of aralkyl of from 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, .alpha.-phenylpropyl, and .alpha.-naphthylmethyl. The invention comprises methods of preparing the compounds of Formula I and Formula IV. These methods of preparation will be described in greater detail hereinafter.DETAILED DESCRIPTION OF THE INVENTIONThe process of the invention is carried out according to the following procedures.PROCESS AThe compounds of Formula I can be obtained by heating an alkyl N-acyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide of the formula: ##STR3## in which Ac.sub.1 and Y are carboxacyl, and Alk is alkyl of 1 to 4 carbon atoms, inclusive, with a thiol of the formula: ##STR4## wherein R.sub.1 is hydrogen, methyl or ethyl; R.sub.2 is hydrogen, methyl or ethyl; R.sub.3 is hydrogen, methyl or ethyl; n is 0 or 1; and R is hydrogen, alkyl of 1 to 6 carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive, in the presence of glacial acetic acid or other anhydrous lower hydrocarbon carboxylic acid. Opening of the aziridine ring is thus effected yielding an acylated alkyl 7-deoxy-7-substituted-.alpha.-thiolincosaminide of the following formula: ##STR5## wherein Ac.sub.1, Y, Alk, n, R, R.sub.1, R.sub.2 and R.sub.3 are as defined above.The acyl groups (Ac.sub.1 and Y) are then removed by hydrazinolysis, for example, by following the procedure set forth in U.S. Pat. No. 3,179,565, to obtain the corresponding compound of Formula I: ##STR6## wherein Alk, n, R, R.sub.1, R.sub.2 and R.sub.3 are as defined above.The compounds of Formula I are useful for the same purposes as methyl .alpha.-thiolincosaminide (methyl 6-amino-6,8-dideoxy-1-thio-D-erythro-.alpha.-D-galacto-octopyranoside, .alpha.-MTL) as disclosed in U.S. Pat. No. 3,380,992 and as methyl 6-amino-7-chloro-6,7,8-trideoxy-1-thio-L-threo-and D-erythro-.alpha.-D-galacto-octopyranosides (U.S. Patents 3,496,163 and 3,502,648), and moreover can be acylated with trans-1-methyl-4-propyl-L-2-pyrrolidine carboxylic acid to form 7-deoxy-7-(.omega.-substituted alkylthio)lincomycins and with other L-2-pyrrolidine carboxylic acids as disclosed in these patents, or with an N-(2-hydroxyethyl)-L-2-pyrrolidine carboxylic acid to form compounds of the formula: ##STR7## wherein Alk, n, R, R.sub.1, R.sub.2 and R.sub.3 are as given and Ac is L-2-pyrrolidinecarboxacyl or an N-methyl, N-ethyl, or N-(2-hydroxyethyl)-L-2-pyrrolidinecarboxacyl any or all of which can be substituted in the 4-position with lower alkyl or lower alkylidene.The compounds of Formula IIa undergo thiolysis when heated with a suitable thiol in glacial acetic acid or anhydrous benzoic acid or other anhydrous lower hydrocarbon carboxylic acid.Suitable thiols have the formula: ##STR8## wherein R.sub.1 is hydrogen, methyl or ethyl; R.sub.2 is hydrogen, methyl or ethyl; R.sub.3 is hydrogen, methyl or ethyl; n is 0 or 1; and R is hydrogen, alkyl of 1 to 6 carbon atoms, inclusive, or aralkyl of 7 to 12 carbon atoms, inclusive.Illustrative examples of suitable thiols according to the invention areTABLE I2-hydroxyethane-1-thiol,3-hydroxypropane-1-thiol,2-hydroxypropane-1-thiol,1-hydroxypropane-2-thiol,3-hydroxybutane-1-thiol,1-hydroxybutane-3-thiol,2-(hydroxymethyl)propane-1-thiol,2-hydroxybutane-1-thiol,1-hydroxybutane-2-thiol,3-hydroxypentane-1-thiol,2-(hydroxymethyl)butane-1-thiol,1-hydroxypentane-3-thiol,2-methoxyethane-1-thiol,3-methoxypropane-1-thiol,2-methoxypropane-1-thiol,1-methoxypropane-2-thiol,3-methoxybutane-1-thiol,1-methoxybutane-3-thiol,2-(methoxymethyl)propane-1-thiol,2-methoxybutane-1-thiol,1-methoxybutane-2-thiol,3-methoxypentane-1-thiol,2-(methoxymethyl)butane-1-thiol,1-methoxypentane-3-thiol,2-ethoxyethane-1-thiol,3-ethoxypropane-1-thiol,2-ethoxypropane-1-thiol,1-ethoxypropane-2-thiol,3-ethoxybutane-1-thiol,1-ethoxybutane-3-thiol,2-(ethoxymethyl)propane-1-thiol,2-ethoxybutane-1-thiol,1-ethoxybutane-2-thiol,3-ethoxypentane-1-thiol,2-(ethoxymethyl)butane-1-thiol,1-ethoxypentane-3-thiol,2-propoxyethane-1-thiol,3-propoxypropane-1-thiol,2-propoxypropane-1-thiol,1-propoxypropane-2-thiol,3-propoxybutane-1-thiol,1-propoxybutane-3-thiol,2-(propoxymethyl)propane-1-thiol,2-propoxybutane-1-thiol,1-propoxybutane-2-thiol,3-propoxypentane-1-thiol,2-(propoxymethyl)butane-1-thiol,1-propoxypentane-3-thiol,2-butoxyethane-1-thiol,3-butoxypropane-1-thiol,2-butoxypropane-1-thiol,1-butoxypropane-2-thiol,3-butoxybutane-1-thiol,1-butoxybutane-3-thiol,2-(butoxymethyl)propane-1-thiol,2-butoxybutane-1-thiol,1-butoxybutane-2-thiol,3-butoxypentane-1-thiol,2-(butoxymethyl)butane-1-thiol,1-butoxypentane-3-thiol,2-pentyloxyethane-1-thiol,3-pentyloxypropane-1-thiol,2-pentyloxypropane-1-thiol,1-pentyloxypropane-2-thiol,3-pentyloxybutane-1-thiol,1-pentyloxybutane-3-thiol,2-(pentyloxymethyl)propane-3-thiol,2-pentyloxybutane-1-thiol,1-pentyloxybutane-2-thiol,3-pentyloxypentane-1-thiol,2-(pentyloxymethyl)butane-1-thiol,1-pentyloxypentane-3-thiol,2-hexyloxyethane-1-thiol,3-hexyloxypropane-1-thiol,2-hexyloxypropane-1-thiol,1-hexyloxypropane-2-thiol,3-hexyloxybutane-1-thiol,1-hexyloxybutane-3-thiol,2-(hexyloxymethyl)propane-1-thiol,2-hexyloxybutane-1-thiol,1-hexyloxybutane-2-thiol,3-hexyloxypentane-1-thiol,2-(hexyloxymethyl)butane-1-thiol,1-hexyloxypentane-3-thiol,2-benzyloxyethane-1-thiol,3-benzyloxypropane-1-thiol,2-benzyloxypropane-1-thiol,1-benzyloxypropane-2-thiol,3-benzyloxybutane-1-thiol,1-benzyloxybutane-3-thiol,2-(benzyloxymethyl)propane-1-thiol,2-benzyloxybutane-1-thiol,1-benzyloxybutane-2-thiol,3-benzyloxypentane-1-thiol,2-(benzyloxymethyl)butane-1-thiol,1-benzyloxypentane-3-thiol,2-[(ar-methylbenzyl)oxy]ethane-1-thiol,3-[(ar-methylbenzyl)oxy]propane-1-thiol,2-[(ar-methylbenzyl)oxy]propane-1-thiol,1-[(ar-methylbenzyl)oxy]propane-2-thiol,3-[(ar-methylbenzyl)oxy]butane-1-thiol,1-[(ar-methylbenzyl)oxy]butane-3-thiol,2-{[(ar-methylbenzyl)oxy]methyl}propane-1-thiol,2[(ar-methylbenzyl)oxy]butane-1-thiol,1-[(ar-methylbenzyl)oxy]butane-2-thiol,3-[(ar-methylbenzyl)oxy]pentane-1-thiol,2-{[(armethylbenzyl)oxy]methyl}butane-1-thiol,1-[(ar-methylbenzyl)oxy]pentane-3-thiol,2-[(ar-ethylbenzyl)oxy]ethane-1-thiol,3-[(ar-ethylbenzyl)oxy]propane-1-thiol,2-[(ar-ethylbenzyl)oxy]propane-1-thiol,1-[(ar-ethylbenzyl)oxy]propane:2-thiol,3-[(ar-ethylbenzyl)oxy]butane-1-thiol,1-[(ar-ethylbenzyl)oxy]butane-3-thiol,2-{[(ar-ethylbenzyl)oxy]methyl}propane-1-thiol,2-[(ar-ethylbenzyl)oxy]butane-1-thiol,1-[(ar-ethylbenzyl)oxy]butane-2-thiol,3-[(ar-ethylbenzyl)oxy]butane-1-thiol,2-{[(ar-ethylbenzyl)oxy]methyl}butane-1-thiol,1-[-(ar-ethylbenzyl)oxy]pentane-3-thiol,2-[(ar-methyl-2-phenyl)ethoxy]ethane-1-thiol,3-[(ar-methyl-2-phenyl)ethoxy]propane-1-thiol,2-([ar-methyl-2-phenyl)ethoxy]propane-1-thiol,1-[(ar-methyl-2-phenyl)ethoxy]propane-2-thiol,3-[(ar-methyl-2-phenyl)ethoxy]butane-1-thiol,1-[(ar-methyl-2-phenyl)ethoxy]butane-3-thiol,2-{[(ar-methyl-2-phenyl)ethoxy]methyl}propane-1-thiol,2-[(ar-methyl-2-phenyl)ethoxy]butane-1-thiol,1-[(ar-methyl-2-phenyl)ethoxy]butane-2-thiol,3-[(ar-methyl-2-phenyl)ethoxy]pentane-1-thiol,2-{[(ar-methyl-2-phenyl)methoxy]methyl}butane-1-thiol,1-[(ar-methyl-2-phenyl)ethoxy]pentane-3-thiol,2-[(ar-ethyl-2-phenyl)ethoxy]ethane-1-thiol,3-[(ar-ethyl-2-phenyl)ethoxy]propane-1-thiol,2-[(ar-ethyl-2-phenyl)ethoxy]propane-1-thiol,1-[(ar-ethyl-2-phenyl)ethoxy]propane-2-thiol,3-[(ar-ethyl-2-phenyl)ethoxy]butane-1-thiol,1-[(ar-ethyl-2-phenyl)ethoxy]butane-3-thiol,2-{[(ar-ethyl-2-phenyl)ethoxy]methyl}propane-1-thiol,2-[(ar-ethyl-2-phenyl)ethoxy]butane-1-thiol,1-[(ar-ethyl-2-phenyl)ethoxy]butane-2-thiol,3-[(ar-ethyl-2-phenyl)ethoxy]pentane-1-thiol,2-{[(ar-ethyl-2-phenyl)ethoxy]methyl}butane-1-thiol,1-[(ar-ethyl-2-phenyl)ethoxy]pentane-3-thiol,2-[(ar-methylnaphthyl)methoxy]ethane-1-thiol,3-[(ar-methylnaphthyl)methoxy]propane-1-thiol, 2-(ar-methylnaphthyl)methoxy]propane-1-thiol,1-[(arm-methylnaphthyl)methoxy]propane-2-thiol,3-[(ar-methylnaphthyl)methoxy]butane-1-thiol,1-[(ar-methylnaphthyl)methoxy]butane-3-thiol,2-{[(ar-methylnaphthyl)methoxy]methyl}propane-1-thiol,2-[(ar-methylnaphthyl)methoxy]butane-1-thiol,1-[(ar-methylnaphthyl)methoxy]butane-2-thiol,3-[(armethylnaphthyl)methoxy]pentane-1-thiol,2-{[ar-methylnaphthyl)methoxy]methyl}butane-1-thiol,1-[(ar-methylnaphthyl)methoxy]pentane-3-thiol,2-[(2-naphthyl)ethoxy]ethane-1-thiol,3-[(2-naphthyl)ethoxy]propane-1-thiol,2-[(2-naphthyl)ethoxy]propane-1-thiol,1-[(2-naphthyl)ethoxy]propane-2-thiol,3-[(2-naphthyl)ethoxy]butane-1-thiol,1-[(2-naphthyl)ethoxy]butane-3-thiol,2-{[(2-naphthyl)ethoxy]methyl}propane-1-thiol,2-[(2-naphthyl)ethoxy]butane-1-thiol,1-[(2-naphthyl)ethoxy]butane-2-thiol,3-[(2-naphthyl)ethoxy]pentane-1-thiol,2-{[(2-naphthyl)ethoxy]methyl}butane-1-thiol, and1-[(2-naphthyl)ethoxy]pentane-3-thiol.The term "ar" as used in naming the thiols described in Table I denotes that the substituent is on the aromatic ring.With any of the thiols described in Table I, the desired thiolysis can be obtained simply by heating an alkyl N-acetyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide with the appropriate thiol in glacial acetic acid or other anhydrous lower hydrocarbon carboxylic acid. The reaction proceeds satisfactorily under a broad range of temperature conditions, i.e., within a range of from about 25.degree. C. to about 180.degree. C. Preferably, the process of the invention is carried out within a temperature range of from about 60.degree. C. to about 150.degree. C. and most preferably within a temperature range of from about 80.degree. C. to about 110.degree. C. The proportions of reactants (IIa) and (III) are not critical to the process of reaction, but influence the yields of product compounds (I). The proportions employed may be stoichiometric, i.e., substantially equimolar. Optimum yields are obtained by employing the thiol reactant (III) in excess, i.e., a molar excess and preferably in a proportion of at least 2 molar equivalents, and most preferably within a range of from about 5 molar equivalents to about 60 molar equivalents. The reaction is acid catalyzed. Thus, the reaction is effected under acidic conditions such as are obtained with an anhydrous lower hydrocarbon carboxylic acid, such as glacial acetic acid. The anhydrous lower hydrocarbon carboxylic acid is advantageously employed in a molar proportion of from 1 to 7 relative to the acyl aziridine.Advantageously, the above described reaction is carried out in the presence of a suitable organic solvent. A suitable organic solvent is defined for the purpose of this invention as an organic solvent which will at least partially solubilize the thiolincosaminide reactant (IIa) and which does not in any way adversely affect the desired course of the reaction. Illustrative of suitable organic solvents are dioxane, carbon tetrachloride, chloroform, methylene chloride, benzene, toluene, n-hexane and like organic solvents. Preferred as the organic solvent is an excess of thiol compound (III), i.e., in a proportion beyond that required for the above described reaction, provided said thiol compound (III) meets the above criteria for solubilizing reactant (IIa) at the temperature selected for carrying out the process.In general, the above described reaction is complete in from about 1 to about 20 hours, depending upon the nature of the groups Ac.sub.1, Y, R, R.sub.1, R.sub.2, and R.sub.3 in the formulae (IIa) and (III). Completion of the reaction may be ascertained by conventional analytical procedures such as, for example, by vapor-phase chromatography, thin-layer chromatography and like procedures which will indicate the disappearance of starting compounds (IIa) and the appearance of the desired product compounds (IVa).Upon completion of the reaction, the reaction mixture can be subjected to procedures well known in the art such as countercurrent distribution, chromatography, and solvent extraction or crystallization to isolate the reaction product, if desired.Illustrative of anhydrous lower hydrocarbon carboxylic acids are dry lower alkanoic acids having 2 to 8 carbon atoms, inclusive, such as acetic acid, propionic acid and octanoic acid; arenoic acids having 7 to 8 carbon atoms, inclusive, such as benzoic acid and toluic acid. Preferred as the anhydrous hydrocarbon carboxylic acid is glacial acetic acid.The reaction which occurs is conveniently illustrated by the schematic formulae: ##STR9## wherein Ac.sub.1, Y, AlK, R.sub.1, R.sub.2, R.sub.3, R and n are as defined above.The starting compounds exist in two epimeric forms as follows: ##STR10## The R and S refer to the 7-position as the 6-position is always in the R-form. In the reaction an inversion takes place. For example, an alkyl (6R,7)R-N-acyl 6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide is converted to the corresponding (7S)-derivative, as a result of the inversion of the (7R)-position in the (6R,7R)-form during the course of the reaction. This inversion which occurs is conveniently illustrated by the schematic formulae: ##STR11## wherein Ac.sub.1, Y, Alk, R, R.sub.1, R.sub.2, R.sub.3 and n are as defined above, In a like manner, an alkyl (6R,7S)-N-acyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide is converted to the corresponding (7R)-derivative, as a result of the inversion of the (7S)-position in the (6R,7S)-form during the course of the reaction. This inversion is conveniently illustrated by the schematic formulae: ##STR12## wherein Ac.sub.1, Y, Alk, R, R.sub.1, R.sub.2, R.sub.3 and n are as defined above.The starting aziridino compounds of Formula IIa are well-known compounds, see for example U.S. Pat. Nos. 3,671,647 and 3,702,322, and are obtained by acylating a compound of the formula: ##STR13## with a carboxacyl acylating agent, such as acetic anhydride or other lower alkanoic acid anhydride or benzoyl chloride or like carboxacyl halide, in a manner already known in the art. Since the amino and hydroxy groups acylate at different rates the N-acyl, Ac.sub.1, and the O-acyl, Y, can be the same or different.Inasmuch as these acyl groups (Ac.sub.1 and Y) do not appear in the final product but are removed in the processing, it is immaterial what they are as long as they are carboxacyl.The starting compounds of Formula VI can be prepared by the dehydrohalogenation of a compound of the formula: ##STR14## which are known in the art; U.S. Pat. 3,502,648. The dehydrohalogenation is effected by heating a compound of Formula VII in an inert solvent in the presence of an acid acceptor. A suitable process is to heat a reaction mixture of starting compound, anhydrous sodium carbonate and dimethylformamide at reflux for a short time, remove the solvent, and crystallize from a suitable solvent, for example, methanol. See U.S. Pat. No. 3,544,551.By acylating the compounds of Formula I with an L-2-pyrrolidine carboxylic acid, compounds of Formula V in which Ac is the acyl of the L-2-pyrrolidine carboxylic acid are obtained. When Alk is methyl, n is O, R, R.sub.1 and R.sub.2 are hydrogen, and the L-2-pyrrolidinecarboxylic acid is trans-1-methyl-4-propyl-L-2-pyrrolidinecarboxylic acid and the configuration is (S), the compound is (7S)-7-deoxy-7-(2-hydroxyethylthio)lincomycin.PROCESS BThe compounds of Formula I can also be prepared by heating an alkyl N-acyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide of the formula: ##STR15## wherein Ac.sub.1, Alk and the wavy lines have the meanings previously described to them, with a thiol of the formula: ##STR16## wherein R, R.sub.1, R.sub.2, R.sub.3 and n are as previously defined, in the presence of glacial acetic acid or other anhydrous lower hydrocarbon carboxylic acid to form ##STR17## wherein Ac.sub.1, Alk, R, R.sub.1, R.sub.2, R.sub.3, and n are as previously defined, acylating the alcoholic hydroxyl groups of said compound with a carboxyacyl acylating agent, such as acetic anhydride or other lower alkanoic acid anhydride or benzoyl chloride or like carboxacyl halide to form the corresponding alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-acyloxyalkylthio)-.alpha.-thiolincosaminide when R is hydrogen, alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-alkoxyalkylthio)-.alpha.-thiolincosaminide when R is alkyl, or alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-aralkoxyalkylthio)-.alpha.-thiolincosaminide when R is aralkyl, deacylating the latter to form the corresponding compound of Formula I: ##STR18## wherein Alk, n, R, R.sub.1, R.sub.2, and R.sub.3 are as defined above.With any of the thiols described in Table I of Process A, the desired thiolysis can be obtained simply by heating an alkyl N-acetyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide with the appropriate thiol in glacial acetic acid or other anhydrous lower hydrocarbon carboxylic acid. The reaction proceeds satisfactorily under a broad range of temperature conditions, i.e., within a range of from about about 25.degree. C. to about 180.degree. C. Preferably, the process of the invention is carried out within a temperature range of from about 60.degree. C. to about 150.degree. C. and most preferably within a temperature range of from about 80.degree. C. to about 110.degree. C. The proportions of reactants (IIb) and (III) are not critical to the process of reaction, but influence the yields of product compounds (I). The proportions employed may be stoichiometric, i.e., substantially equimolar. Optimum yields are obtained by employing the thiol reactant (III) in excess, i.e., a molar excess and preferably in a proportion of at least 2 molar equivalents, and most preferably within a range of from about 5 molar equivalents to about 60 molar equivalents. The reaction is acid catalyzed. Thus, the reaction is effected under acidic conditions such as are obtained with an anhydrous lower hydrocarbon carboxylic acid, such as glacial acetic acid. The anhydrous lower hydrocarbon carboxylic acid is advantageously employed in a molar proportion of from 1 to 7 relative to the acyl aziridine.Advantageously, the above described reaction is carried out in the presence of a suitable organic solvent. A suitable organic solvent is defined for the purpose of this invention as an organic solvent which will at least partially solubilize the thiolincosaminide reactant (IIb) and which does not in any way adversely affect the desired course of the reaction. Illustrative of suitable organic solvents are dioxane, carbon tetrachloride, chloroform, methylene chloride, benzene, toluene, n-hexane and like organic solvents. Preferred as the organic solvent is an excess of thiol compound (III), i.e., in a proportion beyond that required for the above described reaction, provided said thiol compound (III) meets the above criteria for solubilizing reactant (IIb) at the temperature selected for carrying out the process.In general, the above described reaction is complete in from about 1 to about 20 hours, depending upon the nature of the groups Ac.sub.1, R, R.sub.1, R.sub.2, and R.sub.3 in the formulae (IIb) and (III). Completion of the reaction may be ascertained by conventional analytical procedures such as, for example, by vapor-phase chromatography, thin-layer chromatography and like procedures which will indicate the disappearance of starting compounds (IIB) and the appearance of the desired product compounds (IVb).Upon completion of the thiolysis, the excess solvent and reactant (III) can be removed from the reaction mixture and without separating the intermediate compound of Formula (IVb) the reaction mixture is acylated with an acylating reagent selected from acyl halides and acid anhydrides of hydrocarbon carboxylic acids containing from 2 to 12 carbon atoms, inclusive, such as acetic anhydride, in a manner known in the art, to form the corresponding alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-acyloxyalkylthio)-.alpha.-thiolincosaminide when R is hydrogen, alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-alkoxyalkylthio)-.alpha.-thiolincosaminide when R is alkyl, or alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-aralkoxyalkylthio)-.alpha.-thiolincosaminide when R is aralkyl.Upon completion of the acylation, the reaction mixture can be subjected to procedures well known in the art such as countercurrent distribution, chromatography, and solvent extraction or crystallization to isolate the corresponding alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-acyloxyalkylthio)-.alpha.-thiolincosaminide when R is hydrogen, alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-alkoxyalkylthio)-.alpha.-thiolincosaminide when R is alkyl, or alkyl N-acyl-2,3,4-tri-O-acyl-7-deoxy-7-(.omega.-aralkoxyalkylthio)-.alpha.-thiolincosaminide when R is aralkyl. In a manner known in the art, the latter is deacylated to form the corresponding compound of Formula I.The starting aziridino compounds of Formula IIb are known compounds and are obtained by acylating a compound of the formula (VI): ##STR19## with a carboxacyl acylating agent, such as acetic anhydride or other lower alkanoic acid anhydride or benzoyl chloride or like carboxacyl halide.The following examples are illustrative of the process of the present invention, but are not to be construed as limiting.EXAMPLE 1Part A-1 - Methyl (7S)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-(2-methoxyethylthio)-.alpha.-thiolincosaminide ##STR20##5.0 Grams (1 molar equivalent ) of methyl (6R,7R)-N-acetyl-2,3,4-tri-O-acetyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide is dissolved in 50 grams (44 molar equivalents) of 2-methoxyethanethiol by stirring in an oil-bath at 100.degree. C. 2,61 Grams (2.50 ml.; 3.5 molar equivalents) of glacial acetic acid are added, and the mixture heated at 100.degree. C. for 17 hours with exclusion of moisture. At the end of this period, the volatile materials are removed from the reaction mixture by distillation under high vacuum (ca. 0.2 mm Hg) at a temperature of 80.degree. C. (oil-bath temperature), giving a colorless solid residue showing by TLC [silica gel, acetone:Slellysolve R (1:1 v/v)] a major zone of R.sub.f 0.48. TLC refers to thin layer chromatography and Skellysolve B to essentially n-hexane, b.p. 60.degree.-68.degree. C., Skelly Oil Co., Inc.The above colorless solid residue is subjected to countercurrent distribution in the system ethanol:water:ethyl acetate:cyclohexane (1:1:1:2, v/v) to yield a major product at a K value of 0.81. Combination of material from tubes 190-250, inclusive, after 500 transfers, and removal of the solvent gives 2.61 grams (43% yield) of methyl (7S)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-(2-methoxyethylthio)-.alpha.-thiolincosaminide as a colorless solid. It is obtained as colorless needles upon crystallization from ethyl acetate, m.p. 225.degree.-227.degree. C., undepressed on admixture with material derived from 2-methoxyethyl methyl sulfide (Example 21, Part A-21 of U.S. Pat. No. 3,915,954) and identical with this compound in I.R. and N.M.R. spectra.Part B-1 - Methyl (7S)-7-deoxy-7-(2-methoxyethylthio)-.alpha.-thiolincosaminideMethyl (7S)-7-deoxy-7-(2-methoxyethylthio)-.alpha.-thiolincosaminide can be obtained from methyl (7S)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-(2-methoxyethylthio)-.alpha.-thiolincosaminide by following the procedure of Example 1, Part B-1 of U.S. Pat. No. 3,915,954.Part C-1 - (7S)-7-deoxy-7-(2-methoxyethylthio)lincomycin hydrochloride(7S)-7-deoxy-7-(2-methoxyethylthio)lincomycin hydrochloride can be obtained from methyl (7S)-7-deoxy-(2-methoxyethylthio)-.alpha.-thiolincosaminide by following the procedure of Example 1, Part C-1 of U.S. Pat. No. 3,915,954.EXAMPLE 2Part A-2 - Methyl (7S)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-(2-hydroxyethylthio)-.alpha.-thiolincosaminide ##STR21##7.0 Grams (1 molar equivalent) of methyl (6R,7R)-N-acetyl-2,3,4-tri-O-acetyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide is dissolved in 70.0 grams (52 molar equivalents) of 2-hydroxyethanethiol by stirring in an oil bath at 100.degree. C. 7.35 Grams (7.0 ml.; 7 molar equivaletns) of glacial acetic acid are added, and the mixture heated at 100.degree. C. for 17 hours with the exclusion of moisture. At the end of this period, the volatile materials are removed from the reaction mixture by distillation under high vacuum (ca. 0.2 mm) at a temperature of 80.degree. C. (oil-bath temperature), giving a semi-crystalline residue showing by TLC [silica gel, acetone:Skellysolve B (1:1 v/v)] a major zone of R.sub.f 0.34.The above semi-crystalline solid is subjected to countercurrent distribution in the system ethanol-water-ethyl acetate-cyclohexane (1:1:1:0.5, v/v/v/v) to yield a major product at a K value of 0.91. Combination of material from tubes 210-263 after the 500 transfers, inclusive, and removal of the solvent gives 4.57 grams (55% yield) of methyl (7S)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-(2-hydroxyethylthio)-.alpha.-thiolincosaminide as a colorless solid. It is obtained as needles on crystallization from ethyl acetate-Skellysolve B, m.p. 226.degree.-8.degree. C., undepressed on admixture with material derived from 2-hydroxyethyl methyl sulfide (Example 10, Part A-10a of U.S. Pat. No. 3,915,954) and identical with this compound in I.R. and N.M.R. spectra.Part B-2 - Methyl (7S)-7-deoxy-(2-hydroxyethylthio)-.alpha.-thiolincosaminideMethyl (7S)-7-deoxy-(2-hydroxyethylthio)-.alpha.-thiolincosaminide can be obtained from methyl (7S)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-(2-hydroxyethylthio)-.alpha.-thiolincosaminide by following the procedure of Example 1, Part B-1 of U.S. Pat. No. 3,915,954.Part C-2 - (7S)-7-deoxy-(2-hydroxyethylthio)lincomycin hydrochloride(7S)-7-deoxy-(2-hydroxyethylthio)lincomycin hydrochloride can be obtained from methyl (7S)-7-deoxy-(2-hydroxyethylthio)-.alpha.-thiolincosaminide by following the procedure of Example 1, Part C-1 of U.S. Pat. No. 3,915,954.EXAMPLE 3Part A-3 - Methyl (7S)-N-acetyl-7-deoxy-7-(2-hydroxyethylthio)lincosaminide ##STR22##5.0 Grams (1 molar equivalent) of methyl (6R,7R)-N-acetyl-6,7-aziridino-6-deamino-7-deoxy-.alpha.-thiolincosaminide is dissolved in 50 grams (35 molar equivalents) of 2-hydroxyethanethiol by stirring in an oil bath at 100.degree. C. 7.56 Grams (7.2 ml., 7 molar equivalents) of glacial acetic acid are added, and the mixture heated at 100.degree. C. for 17 hours, with the exclusion of moisture. At the end of this time, volatile materials are removed from the reaction solution by distillation under high vacuum (ca. 0.2 mm Hg) from an oil-bath at 100.degree. C., yielding a syrupy residue showing by tlc [silica gel, methanol-chloroform (1:5 v/v)] a major zone of R.sub.f 0.28. Chromatography on silica gel in methanol-methylene chloride (1:8, v/v) (column dimensions 5.8 .times. 99 cm., 1200 grams of silica) gives the desired material in fractions nos. 152-255, inclusive (collecting 50 ml. fractions after a forerun of 1450 ml.) obtained as a non-crystalline solid (2.98 grams) on removal of the solvent. Rechromatography to remove additional traces of impurity is conducted with a high performance liquid chromatogram (silica gel, 241 grams, dimensions 2.8 .times. 104 mm) in methanol-methylene chloride (1:8, v/v) at a flow rate of 3.5 ml./min. under a pressure of 12 p.s.i. Fractions of 50 ml. are collected, and the desired crude material is present in fractions nos. 21-27, inclusive, and is isolated as a colorless amorphous solid on removal of solvent in vacuo.Part B-3 - Methyl (7)-N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7-(2-acetoxyethylthio)-.alpha.-thiolincosaminide ##STR23##The solid obtained from Example 3, Part A-3, is acetylated by dissolving in pyridine (10 ml.), adding acetic anhydride (5 ml.), and allowing the solution to stand at room temperature for 48 hours with exclusion of moisture. Volatile materials are removed in vacuo, and the residue is dissolved in methylene chloride, washed with dilute aqueous hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water, and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo yields a colorless solid showing a single zone of R.sub.f 0.44 by tlc [silica gel, acetone:Skellysolve B (1:1, v/v)].The above solid is subjected to countercurrent distribution in the system ethanol-water-ethyl acetatecyclohexane (1:1:1:3, v/v) to yield a major product at a K value of 0.48. Combination of material from tubes 130-199, inclusive, after 500 transfers, and removal of the solvent in vacuo gives 1.60 grams (16%) of methyl (7S)-N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7-(2-acetoxyethylthio)-.alpha.-thiolincosaminide as a colorless solid. It is obtained as needles on crystallization from ethyl acetate-Skellysolve B, m.p. 206-207.degree. C., undepressed on admixture with material derived from 2-acetoxyethyl methyl sulfide (Example 10, Part A-10B, of U.S. Pat. No. 3,915,954) and from ethylene sulfide (Example 1, Part A-1 of U.S. Pat. No. 3,767,649) and identical with this compound in the I.R. and N.M.R. spectra.Part C-3 - Methyl (7S)-7-deoxy-7-(2-hydroxyethylthio)-.alpha.-thiolincosaminideMethyl (7S)-7-deoxy-7-(2-hydroxyethylthio)-.alpha.-thiolincosaminide can be obtained from methyl (7S)-N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7-(2-acetoxyethylthio)-.alpha.-thiolincosaminide by following the procedure of Example 1, Part B-1 of U.S. Pat. No. 3,767,649.Part D-3 - (7S)-7-deoxy-7-(2-hydroxyethylthio)lincomycin hydrochloride(7S)-7-Deoxy-7-(2-hydroxyethylthio)lincomycin hydrochloride can be obtained from methyl (7S)-7-deoxy-7-(2hydroxyethylthio)-.alpha.-thiolincosaminide by following the procedure of Example 1, Part C-1 of U.S. Pat. No. 3,915,954.EXAMPLE 4Following the procedure above of Example 1, Part A-1, but replacing the 2-methoxyethanethiol as used herein, by any other thiol shown in Table I, there can be obtained the corresponding methyl (7S)-N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7-(.omega.-substituted alkylthio)-.alpha.-thiolincosaminide.

摘要翻译： 可用作制备抗细菌活性7-脱氧-7-ω-取代的烷基硫醇新霉素的中间体的7-脱氧-7-ω-取代的烷硫基-α-硫代吗啉 - 氨基酯是通过加热N-酰基-6,7-氮丙啶 -6-脱氨基-7-脱氧-α-硫代氨基甲烷与适当的硫醇在无水低级烃羧酸的存在下反应。

公开(公告)号：USRE29558E

公开(公告)日：1978-02-28

申请号：US730835

申请日：1976-10-08

申请人： Brian Bannister

发明人： Brian Bannister

IPC分类号： C07H5/02 ,  C07D327/04 ,  C07D327/06 ,  C07H3/02 ,  C07H5/08 ,  C07H15/16

CPC分类号： C07H15/16 ,  C07D327/04 ,  C07D327/06 ,  Y02P20/55

摘要： Compounds of the formula: ##STR1## are disclosed, wherein R.sub.1 taken independently is hydrogen; R.sub.2 taken independently is the moiety ##STR2## wherein Ac is carboxacyl or an acyl group of formula: ##STR3## wherein Z is hydrogen, lower alkyl or a protective group removable by hydrogenolysis; R.sub.5 is lower alkyl; R.sub.1 and R.sub.2 when together are the divalent group; ##STR4## wherein Z and R.sub.5 are as defined above; R.sub.3 is hydrogen when R.sub.1 and R.sub.2 are taken together and is a monovalent thio group of formula: ##STR5## located in the 7(S)-position when R.sub.1 and R.sub.2 are taken independently, A represents hydrogen or hydroxyl, B represents hydrogen or hydroxyalkyl, n is the integer 0 when B is hydroxyalkyl and n is an integer of 0 to 1, inclusive, when B is hydrogen, X is oxygen .[.or sulfur.]., D is the acyl radical of a lower hydrocarbon carboxylic acid; R.sub.4 is lower alkyl and Y is carboxacyl or hydrogen.Disclosed also are methods of making and using the novel compounds of the invention, which are useful intermediates in the chemical synthesis of useful antibacterial lincomycin analogs. Certain of the compounds of the invention are also active as antibacterial agents.

公开(公告)号：US20080252457A1

公开(公告)日：2008-10-16

申请号：US11786592

申请日：2007-04-12

申请人： W. David Findlay ,  Brian Bannister

发明人： W. David Findlay ,  Brian Bannister

IPC分类号： G08B29/00 ,  G08B13/14

CPC分类号： G06K19/07749 ,  G01S13/825

摘要： The present invention consists of an electronic vehicle tag (EVT), which is preferably 12×6 inches. It consists of an encasement mountable by 4 screws to a motor vehicle. The front face is comprised of an electronic paper display technology, which requires no power consumption to maintain its image. The electronic paper display will hold a high resolution full color graphic design relating to the vehicle tag selected and tag information depending on the state of issuances requirements. The display is reflective and can be easily read in sunlight or dimly lit environments and at virtually any angle. The plate has an electronic paper technology for display, wireless communication transmitter/receiver, logic board for electronic paper manipulation, high impact encasement, and a battery pack. The battery pack is used to change the display when required. The electronic vehicle tag is independent of the vehicle in which it is attached.

摘要翻译： 本发明由电子车辆标签（EVT）组成，其优选为12×6英寸。 它由一个可由4个螺钉安装到汽车上的外壳组成。 前脸由电子纸显示技术组成，不需要耗电来维持其图像。 电子纸显示器将保持与所选择的车辆标签和标签信息相关的高分辨率全色图形设计，这取决于发布要求的状态。 显示器是反射性的，可以在阳光或昏暗的环境中以几乎任何角度轻松读取。 该板具有用于显示的电子纸技术，无线通信发送器/接收器，用于电子纸操作的逻辑板，高冲击装置和电池组。 电池组用于在需要时更换显示屏。 电子车辆标签独立于其附接的车辆。

公开(公告)号：US4022889A

公开(公告)日：1977-05-10

申请号：US586232

申请日：1975-06-12

申请人： Brian Bannister ,  Clarence DeBoer ,  Harold E. Renis

发明人： Brian Bannister ,  Clarence DeBoer ,  Harold E. Renis

IPC分类号： C07H19/12 ,  A61K31/71

CPC分类号： C07H19/12

摘要： Pharmaceutical compositions of antibiotic U-44,590 and derivatives thereof which can be used to treat Gram-negative and Gram-positive bacterial and viral diseases in humans and animals.

摘要翻译： 抗生素U-44,590及其衍生物的药物组合物可用于治疗人和动物中的革兰氏阴性和革兰氏阳性细菌和病毒性疾病。