ERYTHROMYCIN A DERIVATIVES AND METHOD FOR THE PREPARATION OF THE SAME

Abstract: Erythromycin A derivativ es represented by the general formula wherein R¹ is a group of the formula R⁷CH₂- (wherein R⁷ is a hydrogen group or a lower alkyl group) or a group of the formula R⁸O- (wherein R⁸ is a lower alkyl group), R² is R⁸, a cycloalkyl group, a phenyl group or an aralkyl group, or R² and R₇ together form an alkylene group, R³ is a hydrogen atom, a lower alkyl group, a phenyl group or an aralkyl group, or R³ and R⁷ together form an alkylene group, or R² and R³ together form an alkylene group, R⁴ is a lower alkyl group, R⁵ is a substituted silyl group, and R⁶ is a hydrogen atom or R₅, are useful as intermediates for the synthesis of antibacterial agents.

Description: The present invention relates to erythromycin A derivatives and a method for their preparation. 6-O-Alkylerythromycins are useful as antibacterial agents or intermediates for synthesis of antibacterial agents. For example, 6-O-methylerythromycin A is not only stable under acidic conditions but also has a strong antibacterial activity when compared with erythromycin A. In particular, this compound shows an excellent effect for treatment of infections by oral administration, and therefore it is a useful antibacterial agent. There are known methods for preparing 6-O-methylerythromycin A, for example, (1) a method which comprises substituting the hydrogen atom of the hydroxy group at the 2'-position and the methyl group of the dimethylamino group at the 3'-position of an erythromycin A derivative by a benzyloxycarbonyl group, and thereafter, carrying out methylation of the hydroxy group at the 6-position, elimination of the benzyloxy carbonyl group, and methylation of the methylamino group at the 3'-position (US-A-4,331,803), and (2) an improved method for the selective methylation of the hydroxy group at the 6-position of an erythromycin A derivative which comprises converting the erythromycin A derivative having the protected hydroxy group at the 2'-position and/or the protected dimethylamino group at the 3'-position into any of various kinds of substituted oxime derivative, and thereafter, carrying out methylation of the hydroxy group at the 6-position, elimination of the protecting groups, deoximation at the 9-position and reproduction of the dimethylamino group at the 3'-position to give 6-O-methylerythromycin A (EP-A-158 467). However, since erythromycin A has many hydroxy groups, various kinds of erythromycin A derivative which are methylated on hydroxy groups other than at the 6-position are obtained as by-products by the method of item (1). Accordingly, this method requires a complicated procedure for purification of the 6-O-methylerythromycin A derivative, and has the drawback of causing low yield of the derivative. Although it is possible to methylate selectively the 6-hydroxy group by the method of item (2), this method requires complicated procedures such as catalytic reduction for elimination of the protecting groups after methylation. As a result of the various researches to solve the drawbacks of the above known methods, we have found a method for the preparation of 6-O-alkylerythromycin A derivatives by which the hydroxy group at the 6-position of erythromycin A derivatives can be methylated selectively, and introduction and elimination of the protecting groups can be easily carried out. According to one aspect, the present invention provides an erythromycin A derivative represented by the general formula wherein R¹ is a group of the formula R⁷CH₂- (wherein R⁷ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) or a group of the formula R⁸O- (wherein R⁸ is an alkyl group having 1 to 6 carbon atoms), R² is the same alkyl group as that of R⁸ or is a cycloalkyl group having 5 to 7 carbon atoms, a phenyl group or an aralkyl group, or R² and R⁷ together form an alkylene group having 2 or 3 carbon atoms, R³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or an aralkyl group, or R³ and R⁷ together form an alkylene group having 3 to 5 carbon atoms which is optionally substituted by 1 to 3 alkyl groups each having 1 to 3 carbon atoms, or R² and R³ together form an alkylene group having 3 or 4 carbon atoms, R⁴ is an alkyl group having 1 to 3 carbon atoms, R⁵ is a substituted silyl group of formula -SiR⁹R¹⁰R¹¹ (wherein R⁹, R¹⁰ and R¹¹ are the same or different, and each is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a phenyl substituted alkyl group in which the alkyl moiety has 1 to 3 carbon atoms, a cycloalkyl group having 5 to 7 carbon atoms or an alkenyl group having 2 to 5 carbon atoms, with the proviso that at least one of R⁹, R¹⁰ and R¹¹ is other than hydrogen atom) and R⁶ is a hydrogen atom or is the same silyl group as that of R⁵. According to another aspect, the present invention provides an erythromycin A derivative represented by the general formula wherein R¹, R², R³, R⁵ and R⁶ are as defined above. According to yet another aspect, the present invention provides a method for preparing an erythromycin A derivative represented by the general formula (I) which comprises reacting erythromycin A 9-oxime, in any desired sequence, with a compound of formula represented by the general formula wherein R¹, R² and R³ are as defined above, and R¹² is a group of formula -OR⁸ (wherein R⁸ is as defined above), or R¹ and R¹² together form a group of formula R⁷CH= (wherein R⁷ is as defined above), and with a silylating agent having R⁵ to give a compound of formula II, and then reacting the resulting compound with an alkylating agent having R⁴. In this specification, the term "alkyl group" refers to a linear or branched chain alkyl group, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group or a n-hexyl group. The term "aralkyl group" means a benzyl group, a benzyl group the phenyl moiety of which is substituted by a methyl group, an α-methylbenzyl group or a phenethyl group. Examples of the alkylene group having 2 or 3 carbon atoms are an ethylene group, a propylene group and a trimethylene group. Examples of the alkylene group having 3 to 5 carbon atoms substituted by 1 to 3 alkyl groups each having 1 to 3 carbon atoms are a 2-methyltrimethylene group, a 3-methyltrimethylene group, a 1-methyltetramethylene group, a 3-methyltetramethylene group, a 2,2,4-trimethyltetra-methylene group, a 2,4,4-trimethyltetramethylene group and a 1-isopropyl-4-methyltetramethylene group. The term "halogen atom" means a chlorine atom, a bromine atom or an iodine atom. Examples of the substituted silyl group are a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a (triphenylmethyl)dimethylsilyl group, a tert-butyldiphenylsilyl group, a diphenylmethylsilyl group, diphenylvinylsilyl group, a methyldiisopropylsilyl group, a tribenzylsilyl group, a tri(p-xylyl)silyl group, a triphenylsilyl group, a diphenylsilyl group and a dimethyloctadecylsilyl group. Processes embodying the present invention are illustrated below in more detail. At first, erythromycin A 9-oxime is reacted with a compound of formula III to protect the hydroxy group at the 9-oxime position. This reaction may be the same as those usually employed for introduction of the protecting groups of acetal-type to a hydroxyl group. For example, erythromycin A 9-oxime is reacted with a compound of formula III in a solvent in the presence of a catalyst with stirring to give a compound of the general formula wherein R¹, R² and R³ are as defined above. In this reaction, the amount of the compound of formula III is 2 to 20 equivalents, preferably 2 to 10 equivalents relative to erythromycin A 9-oxime. Examples of the compound of formula III are methyl vinyl ether, ethyl vinyl ether, n-propyl vinyl ether, isopropyl vinyl ether, n-butyl vinyl ether, isobutyl vinyl ether, 2-methoxypropene, 2-ethoxypropene, 2-n-propoxypropene, 2-isopropoxypropene, 2-n-butoxypropene, 2-isobutoxypropene, 2-sec-butoxypropene, 2-n-pentoxypropene, 2-n-hexyloxypropene, 2-benzyloxypropene, 2-methoxy-1-butene, 2-ethoxy-1-butene, 2-n-propoxy-1-butene, 2-isopropoxy-1-butene, 2-n-butoxy-1-butene, 2-methoxy-2-butene, 2-ethoxy-2-butene, 2-n-propoxy-2-butene, 2-isopropoxy-2-butene, 2-n-butoxy-2-butene, 2-methoxy-3-methyl-1-butene, 2-ethoxy-3-methyl-1-butene, 2-n-propoxy-3-methyl-1-butene, 2-isopropoxy-3-methyl-1-butene, 2-n-butoxy-3-methyl-1-butene, 2-methoxy-3,3-dimethyl-1-butene, 2-ethoxy-3,3-dimethyl-1-butene, 2-n-propoxy-3,3-dimethyl-1-butene, 3-methoxy-2-pentene, 3-ethoxy-2-pentene, 3-n-propoxy-2-pentene, 2-methoxy-4-methyl-2-pentene, 2-ethoxy-4-methyl-2-pentene, 2-n-propoxy-4-methyl-2-pentene, 1-methoxy-1-cyclopentene, 1-ethoxy-1-cyclopentene, 1-n-propoxy-1-cyclopentene, 1-n-butoxy-1-cyclopentene, 1-methoxy-3-methyl-1-cyclopentene, 1-methoxy-4-methyl-1-cyclopentene, 1-methoxy-1-cyclohexene, 1-ethoxy-1-cyclohexene, 1-n-propoxy-1-cyclohexene, 1-n-butoxy-1-cyclohexene, 1-methoxy-4-methyl-1-cyclohexene, 1-methoxy-6-methyl-1-cyclohexene, 1-methoxy-3,5,5-trimethyl-1-cyclohexene, 1-methoxy-3,3,5-trimethyl-1-cyclohexene, 1-methoxy-3-methyl-6-isopropyl-1-cyclohexene, 1-methoxy-1-cycloheptene, 1-ethoxy-1-cycloheptene, 1-n-propoxy-1-cycloheptene, 1-n-butoxy-1-cycloheptene, 1,1-dimethoxycyclopentane, 1,1-diethoxycyclopentane, 1,1-dimethoxycyclohexane, 1,1-diethyloxycyclohexane, 1,1-dimethoxycycloheptane, 1,1-diethoxycycloheptane, 2-methylenetetrahydrofuran, 5-methyl-2,3-dihydrofuran, 2-methylenetetrahydropyran, 6-methyl-3,4-dihydro-2H-pyran, 2,2-dimethoxypropane, 2,2-diethoxypropane, 2,2-di-n-propoxypropane, 2,2-diisopropoxypropane, 2,2-di-n-butoxypropane, 2,2-diisobutoxypropane, 2,2-di-sec-butoxypropane, 2,2-di-n-pentoxypropane, 2,2-di-n-hexyloxypropane, 2,2-dimethoxybutane, 2,2-diethoxybutane, 2,2-di-n-propoxybutane, 2,2-diisopropoxybutane, 2,2-di-n-butoxybutane, 2,2-dimethoxy-3-methylbutane, 2,2-diethoxy-3-methylbutane, 2,2-di-n-propoxy-3-methylbutane, 2,2-diisopropoxy-3-methylbutane, 2,2-dimethoxypentane, 2,2-diethoxypentane, 2,2-di-n-propoxypentane, 2,2-diisopropoxypentane, 2,2-di-n-butoxypentane, 3,3-dimethoxypentane, 3,3-diethoxypentane, 3,3-di-n-propoxypentane, 3,3-diisopropoxypentane, 3,3-di-n-butoxypentane, 2,2-dimethoxy-4-methylpentane, 2,2-diethoxy-4-methylpentane, 2,2-di-n-propoxy-4-methylpentane, 2,2-diisopropoxy-4-methylpentane, 2,2-di-n-butoxy-4-methylpentane, 2,4-dimethyl-3,3-dimethoxypentane, 2,4-dimethyl-3,3-diethoxypentane, 2,4-dimethyl-3,3-di-n-propoxypentane, 2,4-dimethyl-3,3-diisopropoxypentane, 2,4-dimethyl-3,3-di-n-butoxypentane, 2,2-dimethoxyhexane, 2,2-diethoxyhexane, 2,2-di-n-propoxyhexane, 2,2-diisopropoxyhexane, 2,2-di-n-butoxyhexane, 3,3-dimethoxyhexane, 3,3-diethoxyhexane, 3,3-di-n-propoxyhexane, 3,3-diisopropoxyhexane, 3,3-di-n-butoxyhexane, trimethyl orthoformate, trimethyl orthoacetate, trimethyl orthopropionate, trimethyl orthobutyrate, trimethyl orthobenzoate, trimethyl orthophenylacetate, triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionate, triethyl orthobutyrate, triethyl orthobenzoate, triethyl orthophenylacetate, tri-n-propyl orthoformate, triisopropyl orthoformate, tri-n-butyl orthoformate, tri-n-pentyl orthoformate and tri-n-hexyl orthoformate. The compound of formula I wherein both R¹ and R³ are methyl groups may be also prepared in the presence of 2-methoxypropene with an alcohol having R², for example, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, n-pentanol, isopentanol, hexanol, cyclopentanol, cyclohexanol, cycloheptanol, phenol, benzyl alcohol, phenethyl alcohol, α-methylbenzyl alcohol, o-methylbenzyl alcohol or p-methylbenzyl alcohol. Examples of the solvent used for the reaction of erythromycin A 9-oxime with the compound of formula III are dichloromethane, chloroform, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, nitroethane and toluene. Examples of the catalyst are salts of tert-amines (e.g., pyridine or triethylamine) with, for example, hydrochloric acid, sulfonic acid or p-toluenesulfonic acid, preferably pyridine hydrochloride and pyridinium p-toluenesulfonate. The amount of the catalyst is 1.5 to 5 equivalents, preferably 1.5 to 2 equivalents relative to erythromycin A 9-oxime. The reaction temperature is from 0°C to the reflux temperature of the solvent, but usually the reaction proceeds sufficiently at room temperature. The reaction of the compound of formula IV with the silylating agent is carried out in a solvent at 0°C to the reflux temperature of the solvent, preferably at room temperature with stirring. Examples of the silylating agent used are chlorosilanes such as trimethylchlorosilane and tert-butyldimethylchlorosilane; silylamines such as 1,1,1,3,3,3-hexamethyldisilazane, trimethylsilylimidazole and N,N-dimethylaminotrimethylsilane; silylamides such as bis(trimethylsilyl)acetamide, trimethylsilyldiphenylurea and bis(trimethylsilyl)urea and mixtures thereof. When using one of the chlorosilanes only, it is preferable to add a base. The amount of the silylating agent used is 1 to 10 equivalents, preferably 1 to 5 equivalents relative to the compound of formula IV. Examples of the solvent used for the reaction are acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, 1,2-dimethoxyethane, dichloromethane and chloroform. Examples of the base are inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate; and organic bases such as trimethylamine, triethylamine, tri-n-butylamine, tribenzylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 1,8-diazabicyclo[5,4,0]unde-7-cene and imidazole. The silylamines are preferably used together with the chlorosilanes or together with ammonium chloride or pyridine hydrochloride. Alternatively, the compound of formula II can be obtained by acetalization after silylation of erythromycin A 9-oxime. Namely, erythromycin A 9-oxime is reacted with the silylating agent under the same silylation conditions as described above, and then the resulting compound is reacted with the compound of formula III under the same acetalization conditions as described above to give the compound of formula II. The alkylation of the 6-hydroxy group can be carried out by the reaction of the compound of formula II with the alkylating agent in a solvent in the presence of a base at -15°C to room temperature, preferably at 0°C to room temperature with stirring. Examples of the alkylating agent are methyl bromide, ethyl bromide, n-propyl bromide, methyl iodide, ethyl iodide, n-propyl iodide, dimethyl sulfate, diethyl sulfate, di-n-propyl sulfate, methyl p-toluenesulfonate, ethyl p-toluenesulfonate, n-propyl p-toluenesulfonate, methyl methanesulfonate, ethyl methanesulfonate and n-propyl methanesulfonate. It is sufficient to use 1 to 3 molar equivalents of the methylating agent relative to the compound of formula II. Examples of the solvents used are polar aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, a mixture thereof or a mixture of one of these solvents and a solvent such as tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile or ethyl acetate. Examples of the base are sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide and potassium hydride. The amount of the base used is usually 1 to 2 equivalents relative to the compound of formula II. Although erythromycin A 9-oxime derivatives of the present invention exist in two isomeric forms (syn- and anti-forms), for the purpose of the present invention, these compounds may exist in either of the isomeric forms or in a mixture thereof. According to the method of the present invention, since the 2'-hydroxy group is silylated, steric hindrance prevents quaternization of the 3'-dimethylamino group during alkylation of the 6-hydroxy group. Therefore, it is not necessary to protect the 3'-dimethylamino group. The methylation of the hydroxy group at the 6-position by the method of the present invention provides as good a selective methylation at that position as that of known methods. Furthermore, the protecting groups of the hydroxy groups at the oxime, 2'- and 4"-positions of the compound of formula II of the present invention can be easily eliminated under acidic conditions. Moreover, since the reproduction of ketone by deoximation can be carried out under acidic conditions in good yield, this process can be done conveniently at the same time as the above elimination of the protecting groups. Therefore, according to the method of the present invention, the reaction procedure is extremely simplified and 6-O-alkylerythromycin A can be obtained in high yield and economically. Namely, the compound of formula I can be converted to a 6-O-alkylerythromycin A, for example, by the following method. The protecting groups of the hydroxy groups at the oxime, 2'- and 4"-positions of the compound of formula I can be easily eliminated in a suitable organic solvent in the presence of water and an acid at room temperature to the reflux temperature of the solvent with stirring. Examples of the acid are formic acid, acetic acid, n-propionic acid, oxalic acid, malonic acid and succinic acid. Examples of the organic solvent are hydrophilic solvents such as methanol, ethanol, isopropanol, dioxane, tetrahydrofuran and N,N-dimethylformamide. 6-O-Alkylerythromycin A 9-oxime thus obtained can be easily converted into 6-O-alkylerythromycin A by reaction with a deoximating agent. Examples of the deoximating agent are inorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium hydrogen sulfite, potassium thiosulfate and potassium metabisulfite. Examples of the solvent used in the reaction are the same hydrophilic solvents as those used for the elimination of the silyl groups described above. Coexistence of an acid makes the speed of the reaction much faster. In the present invention, the reaction of the compound of formula I with the deoximating agent in the presence of the acid brings about conveniently the deoximation together with the elimination of the protecting groups described above. For example, to the compound of formula I is added formic acid or sodium hydrogen sulfite in aqueous ethanol, and the mixture is stirred at 50°C to the reflux temperature to give 6-O-alkylerythromycin A. The amount of formic acid is 1.5 to 10 equivalents, preferably 2 to 5 equivalents relative to the compound of formula I, and the amount of sodium hydrogen sulfite is 1 to 10 equivalents, preferably 4 to 7 equivalents relative to the compound of formula I. The intermediates in any steps can be isolated from the reaction solution, for example, by extraction, and further can be purified, for example by recrystallization or column chromatography. However, it is not essential to carry out these isolation and purification steps. Since the progress of the reaction can be monitored by using thin layer chromatoaraphy or high speed liquid chromatography, the reaction may be stopped after the disappearance of the starting material. Next, the present invention will be illustrated in more detail by the following Examples. Example 1 (1) To a solution of 5 g of erythromycin A 9-oxime in 100 ml of dichloromethane were added 6.4 ml of 2-methoxypropene and 1.15 g of pyridine hydrochloride, and the mixture was stirred at room temperature for 15 minutes. After completion of the reaction, 100 ml of a saturated aqueous sodium bicarbonate solution was poured, the mixture was throughly stirred, and the organic layer was separated from the aqueous layer. The aqueous layer was extracted once more with 50 ml of dichloromethane. The combined organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. To the residue was added 50 ml of benzene, and the solvent was evaporated under reduced pressure. The procedure was repeated three times to give 5.15 g of erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime] as a foam. m.p. 113 - 116°C (recrystallized from diethyl etherpetroleum ether) ¹H-NMR (CDCl₃); δ (ppm)= 2.30 [3′-N(CH₃)₂], 3.23 [-OC(CH₃)₂OC H ₃], 3.33 (3″-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 23.9 and 24.0 [-O-C( C H₃)₂OCH₃], 40.3 [3′-N(CH₃)₂], 49.5 [-O-C(CH₃)₂O C H₃ and 3″-OCH₃], 103.7 [-O- C (CH₃)₂OCH₃] (2) To a solution of 4.1 g of the compound, obtained above, in 40 ml of dichloromethane was added a solution of 1.8 ml of trimethylsilylimidazole and 1.0 ml of trimethylchlorosilane in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 10 minutes. To the reaction solution was added 60 ml of n-hexane, and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. To the residue was added 50 ml of a saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (50 ml x 2). The organic layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 4.5 g of 2′, 4″-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime] as a foam. m.p. 124 - 126.5°C (recrystallized from acetone) ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2′-O-TMS), 0.14 (4″-O-TMS), 2.23 [3′-N(CH₃)₂], 3.22 [-O-C(CH₃)₂OC H ₃], 3.31 (3″-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 0.9 (4″-O-TMS), 1.0 (2′-O-TMS), 23.9 and 24.0 [-O-C( C H₃)₂OCH₃], 41.0 [3′-N(CH₃)₂], 49.3 [-O-C(CH₃)₂O C H₃], 49.6 (3″-OCH₃), 103.5 [-O C (CH₃)₂OCH₃] TMS as used above and hereinafter is a trimethylsilyl group. (3) To a solution of 2 g of the compound, obtained above, in 100 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1) were added 0.208 ml of methyl iodide and 178 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 100 minutes. To the reaction solution was added 1 ml of 50% aqueous dimethylamine solution, and the mixture was stirred for 1 hour. To the reaction solution was added 100 ml of water, and the mixture was extracted with ethyl acetate (100 ml and 50 ml). The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 2 g of 2′,4″-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime] as a foam. m.p. 134.5 - 137°C (recrystallized from chloroform-acetone) ¹H-NMR (CDCl₃); δ (ppm)= 0.09 (2′-O-TMS), 0.15 (4″-O-TMS), 2.23 [3′-N(CH₃)₂], 3.09 (6-OCH₃), 3.24 [-O-C(CH₃)₂OC H ₃], 3.33 (3″-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 0.9 (4″-O-TMS), 1.0 (2′-O-TMS), 23.5 and 24.4 [-O-C( C H₃)₂OCH₃], 41.0 [3′-N(CH₃)₂], 49.0 [-O-C(CH₃)₂O C H₃], 49.7 (3″-OCH₃), 51.0 (6-OCH₃), 102.9 [-O- C (CH₃)₂OCH₃] Example 2 (1) To a solution of 14.98 g of erythromycin A 9-oxime in 300 ml of dichloromethane were added 15.36 ml of 2-methoxypropene and 3.47 g of pyridine hydrochloride, and the mixture was stirred at room temperature for 20 minutes. Subsequently, a solution of 5.08 ml of trimethylchlorosilane and 5.6 of trimethylsilylimidazole in 10 ml of dichloromethane was added, and the mixture was stirred at room temperature for 30 minutes. After addition of water, the mixture was made basic with 2 N aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with, in turn, water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 18.78 g of a foam, which was identical to the compound obtained in Example 1 (2). (2) To a solution of 3.86 g of the compound obtained above, in a mixture of 28 ml of dimethyl sulfoxide and 56 ml of tetrahydrofuran, were added 0.37 ml of methyl iodide and 342 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added 2 ml of 50% aqueous dimethylamine solution, and the mixture was stirred for 30 minutes and extracted with n-hexane (150 ml and 100 ml). The organic layer was washed with, in turn, water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from chloroform - acetone to give 3.0 g of 2',4"-O-bis-(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime], which was identical to the compound obtained in Example 1(3). Example 3 (1) To a solution of 7.75 g of the compound, obtained in Example 1(1), in 70 ml of N,N-dimethylformamide was added 2.17 ml of triethylamine. Then, 1.89 ml of trimethylchlorosilane was added dropwise, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was poured into water and extracted with diethyl ether (150 ml x 2). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized twice from n-hexane to give 2.3 g of 2'-O-trimethylsilylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime]. m.p. 113.5 - 115°C ¹H-NMR (CDCl₃) δ (ppm)= 0.13 (2'-O-TMS), 2.24 [3'-N(CH₃)₂], 3.23 [-O-C(CH₃)₂OC H ₃], 3.33 (3"-OCH₃) (2) To a solution of 1.79 g of the compound obtained above, in 36 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1:1), were added, under ice-cooling with stirring, 0.19 ml of methyl iodide and then 171 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution was added 1 ml of 50% aqueous dimethylamine solution, and stirring was continued for 30 minutes. The reaction solution was poured into water and extracted with n-hexane (70 ml x 2), and the organic layer was washed with, in turn, water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from acetone to give 1.32 g of 6-O-methyl-2'-O-trimethyl-silylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime]. m.p. 123 - 125.5°C ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-O-TMS), 2.23 [3'-N(CH₃)₂], 3.09 (6-OCH₃), 3.23 [-O-C(CH₃)₂OC H ₃], 3.34 (3"-OCH₃) Example 4 (1) To a solution of 2 g of erythromycin A 9-oxime in 40 ml of dichloromethane were added 2.3 g of 2-ethoxypropene and 0.46 g of pyridine hydrochloride, and the mixture was stirred at room temperature for 15 minutes. Then, following a procedure similar to that of Example 1 (1), there was obtained 2.03 g of erythromycin A 9-[O-(1-ethoxy-1-methylethyl)oxime] as a foam. m.p. 106.5 - 107.5°C (recrystallized from dichloromethane - diisopropyl ether) ¹H-NMR (CDCl₃); δ (ppm)= 2.29 [3'-N(CH₃)₂], 3.33 (3"-OCH₃), 3.48 (-OC H ₂CH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 15.4 (-OCH₂ C H₃), 24.2 and 24.5 [-O-C( C H₃)₂O-], 40.3 [3'-N(CH₃)₂], 49.5 (3"-OCH₃), 57.5 (-O C H₂CH₃), 103.6 [-O- C (CH₃)₂O-] Mass (FAB): m/z=835 (MH⁺) (2) To a solution of 4.18 g of the compound, obtained above, in 30 ml of dichloromethane was added a solution of 1.4 g of trimethylsilylimidazole and 1.25 ml of trimethylchlorosilane in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 20 minutes. Then, following a procedure similar to that of Example 1(2), the resulting product was recrystallized from chloroform-acetone to give 3.9 g of 2',4"-O-bis(trimethyl)silyl)-erythromycin A 9-[O-(1-ethoxy-1-methylethyl)oxime]. m.p. 120 - 122°C ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-O-TMS), 0.14 (4"-O-TMS), 2.23 [3'-N(CH₃)₂], 3.31 (3"-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 0.6 (4"-O-TMS), 0.7 (2'-O-TMS), 24.0 and 26.3 [-O-C( C H₃)₂O-], 40.7 [3'-N(CH₃)₂] 49.3 (3"-OCH₃), 57.0 (-O- C H₂CH₃), 103.1 [-O- C (CH₃)₂O-] Mass (EI): m/z=978 (M⁺) (3) To a solution of 1.96 g of the compound obtained above, in 100 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1), were added 0.19 ml of methyl iodide and 171 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 1(3), the resulting product was recrystallized from acetone to give 1.63 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-ethoxy-1-methylethyl)oxime]. m.p. 127.5 - 128°C ¹H-NMR (CDCl₃); δ (ppm)= 0.08 (2'-O-TMS), 0.14 (4"-O-TMS), 2.22 [3'-N(CH₃)₂], 3.08 (6-OCH₃), 3.32 (3"-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 0.6 (4"-O-TMS), 0.8 (2'-O-TMS), 23.8 and 24.6 (-O-C( C H₃)₂O-], 40.7 [3'-N(CH₃)₂], 49.4 (3"-OCH₃), 50.6 (6-OCH₃), 56.3 (-O- C H₂CH₃), 102.4 [-O- C (CH₃)₂O-] Mass (EI); m/z=992 (M⁺) Example 5 (1) To a solution of 2 g of erythromycin A 9-oxime in 40 ml of dichloromethane were added 2.67 g of 2-isopropoxypropene and 0.46 g of pyridine hydrochloride, and the mixture was stirred at room temperature for 15 minutes. Then, following a procedure similar to that of Example 1(1), there was obtained 2.05 g of erythromycin A 9-{O-[1-(1-methylethoxy)-1-methylethyl]oxime}. m.p. 105 - 108°C (recrystallized from dichloromethane - diisopropyl ether) ¹H-NMR (CDCl₃): δ (ppm)= 2.29 [3'-N(CH₃)₂], 3.33 (3"-OCH₃), 4.00 [-O-C H (CH₃)₂] ¹³C-NMR (CDCl₃); δ (ppm)= 24.1, 24.3, 24.5 and 25.6 [-O-C( C H₃)₂O-CH( C H₃)₂), 40.3 [3'-N(CH₃)₂], 49.5 (3"-OCH₃), 64.6 [-O C H(CH₃)₂], 103.9 [-O- C (CH₃)₂O-] Mass (FAB); m/z=849 (MH⁺) (2) To a solution of 3 g of the compound obtained above, in 30 ml of dichloromethane, was added a solution of 1.04 ml of trimethylsilylimidazole and 0.90 ml of trimethylchlorosilane in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 10 minutes. To the reaction solution were added 2 N aqueous sodium hydroxide solution and water, and the organic layer was collected. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with, in turn, water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from aqueous acetone to give 2.46 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-{O-[1-(1-methylethoxy)-1-methylethyl]oxime}. m.p. 93 - 96°C (recrystallized from aqueous acetone) ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-O-TMS), 0.15 (4"-O-TMS), 2.23 (3'-N(CH₃)₂], 3.30 (3"-OCH₃) 4.00 [-OC H (CH₃)₂] ¹³C-NMR (CDCl₃); δ (ppm)= 0.7 (4"-O-TMS), 0.8 (2'-O-TMS), 23.9, 24.0, 24.4 and 25.3 [-O-C( C H₃)₂O-CH( C H₃)₂], 40.8 [3'-N(CH₃)₂], 49.5 (3"-OCH₃), 64.2 [-O- C H(CH₃)₂] 103.5 [-O- C (CH₃)₂O-] Mass (EI); m/z=992 (M⁺) (3) To a solution of 1 g of the compound obtained above, in 10 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1), were added under ice-cooling 0.08 ml of methyl iodide and 73 mg of 85% potassium hydroxide powder, and the mixture was stirred for 90 minutes. Then, following a procedure similar to that of Example 1(3), there was obtained 0.95 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-{O-[1-(1-methylethoxy)-1-methylethyl]oxime}. m.p. 115.5 - 118.5°C (recrystallized from aqueous acetone) ¹H-NMR (CDCl₃); δ (ppm)= 0.09 (2'-O-TMS), 0.15 (4"-O-TMS), 2.23 [3'-N(CH₃)₂], 3.08 (6-OCH₃), 3.32 (3"-OCH₃), 4.08 [-OC H (CH₃)₂] ¹³C-NMR (CDCl₃); δ (ppm)= 0.8 (4"-O-TMS), 0.9 (2'-O-TMS), 24.0, 24.3, 24.7 and 25.6 [-O-C( C H₃)₂O-CH( C H₃)₂], 40.9 [3'-N(CH₃)₂], 49.6 (3"-OCH₃), 50.8 (6-OCH₃), 63.5 (-O- C H(CH₃)₂], 102.9 [-O- C (CH₃)₂O-] Mass (EI); m/z=1006 (M⁺) Example 6 To a solution of 1 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-methoxy-1-methylethyl)-oxime], obtained in Example 1(2), in 20 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1), were added 0.09 ml of methyl iodide and 45 mg of 60% oily sodium hydride, and the mixture was stirred at room temperature for 2 hours. After the reaction, 0.5 ml of 50% aqueous dimethylamine solution was added, and stirring was continued for 30 minutes. 50 ml of water was added, the mixture was extracted with ethyl acetate (50 ml and 25 ml), and the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 0.9 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime], which was identical to the compound obtained in Example 1(3). Example 7 In 10 ml of N,N-dimethylformamide were dissolved 2.46 g of erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime] obtained in Example 1(1) and 3.0 ml of 1,1,1,3,3,3-hexamethyldisilazane, and the solution was stirred at 60 - 70°C for 8 hours. After stirring, the mixture was allowed to stand at room temperature for 2 days, and 200 ml of ethyl acetate was added to the reaction solution, and the organic layer was washed 3 times with 100 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 2.6 g of 2′,4″-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime] as a foam, which was identical to the compound obtained in Example 1(2). Example 8 To a solution of 7.49 g of erythromycin A 9-oxime in 100 ml of dichloromethane was added 9.0 ml of 2-methoxypropene. 1.74 g of pyridine hydrochloride was added at room temperature with stirring, and the mixture was stirred at room temperature for 1 hour. To the mixture was added 1.25 ml of 1,1,1,3,3,3-hexamethyldisilazane, and stirring was continued for a further 3 hours. 100 ml of dichloromethane and 100 ml of a saturated aqueous sodium carbonate solution were added, and the mixture was stirred throughly. The dichloromethane layer was collected, washed twice with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting foam was recrystallized from acetone to give 8.74 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime], which was identical to the compound obtained in Example 1(2). Example 9 To a solution of 1 g of erythromycin A 9-oxime in 7 ml of dichloromethane were added, under ice-cooling, 0.23 g of pyridine hydrochloride and then a solution of 1.3 g of 2,2-dimethoxypropane in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 24 hours. After the reaction, the mixture was added to 2 N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with, in turn, water and a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 0.65 g of erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime] as a foam, which was identical to the compound obtained in Example 1(1). Example 10 (1) To a solution of 10 g of erythromycin A 9-oxime in 50 ml of N,N-dimethylformamide were added 2.31 g of pyridine hydrochloride and then 5.6 ml of 1,1,1,3,3,3-hexamethyldisilazane under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After the reaction, 50 ml of 2 N aqueous sodium hydroxide solution and 50 ml of water were added, and the mixture was extracted with ethyl acetate (100 ml and 50 ml). The organic layer was washed with, in turn, water (50 ml x 2) and a saturated aqueous sodium chloride solution (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 11.9 g of 2′,4″-O-bis(trimethylsilyl)erythromycin A 9-oxime, which was then purified by recrystallization from aqueous acetone. ¹H-NMR (CDCl₃); δ (ppm)= 0.11 (2′-O-TMS), 0.15 (4″-O-TMS), 2.21 [3′-N(CH₃)₂], 3.30 (3″-OCH₃), 8.05 (=N-OH) ¹³C-NMR (CDCl₃); δ (ppm)= 0.9 (4″-OTMS), 1.0 (2′-OTMS), 41.0 [3′-N(CH₃)₂], 49.8 (3″-OCH₃) Mass (EI); m/z=892 (M⁺) (2) To a solution of 1 g of the compound, obtained above, in 7 ml of dichloromethane were added under ice-cooling 194 mg of pyridine hydrochloride and then 1.17 g of 2,2-dimethoxypropane, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into dilute aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 0.70 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime], which was identical to the compound obtained in Example 1(2). Example 11 To a solution of 330 mg of erythromycin A 9-oxime in 2.3 ml of dichloromethane were added under ice-cooling 80 mg of pyridine hydrochloride and then a solution of 0.7 g of 2,2-diisopropoxypropane in 1 ml of dichloromethane, and the mixture was stirred at room temperature for 30 minutes. Then, following a procedure similar to that of Example 9, there was obtained 370 mg of erythromycin A 9-{O-[1-(1-methylethoxy)-1-methylethyl]oxime}, which was identical to the compound obtained in Example 5(1). Example 12 To a solution of 1 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-oxime, obtained in Example 10(1), in 5 ml of dichloromethane were added, under ice-cooling, 194 mg of pyridine hydrochloride and then a solution of 449 mg of 2,2-diisopropoxypropane in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 1.5 hours. Then, following a procedure similar to that of Example 10(2), there was obtained 1.1 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-{O-[1-(1-methylethoxy-1-methylethyl]oxime}, which was identical to the compound obtained in Example 5(2). Example 13 (1) To a solution of 10 g of erythromycin A 9-oxime in 40 ml of dichloromethane were added, under ice-cooling, 2.3 g of pyridine hydrochloride and then a solution of 6.1 g of 2-n-butoxypropene in 30 ml of dichloromethane, and the mixture was stirred at room temperature for 1 hour. Then, following a procedure similar to that of Example 1(1), there was obtained 2.75 g of erythromycin A 9-[O-(1-n-butoxy-1-methylethyl)oxime]. m.p. 93 - 95°C (recrystallized from diethyl ether - petroleum ether) ¹H-NMR (CDCl₃); δ (ppm)= 0.91 [-O(CH₂)₃C H ₃], 2.28 [3'-N(CH₃)₂], 3.32 (3"-OCH₃), 3.40 (-OC H ₂CH₂CH₂CH₃) Mass (FAB); m/z=865 (MH⁺) (2) To a solution of 2 g of the compound, obtained above, in 20 ml of dichloromethane was added a solution of 0.68 ml of trimethylsilylimidazole and 0.59 ml of trimethylchlorosilane in 5 ml of dichloromethane, and the mixture was stirred at room temperature for 10 minutes. Then, following a procedure similar to that of Example 1(2), a residue was obtained, which was then purified by Florisil column chromatography (eluent, acetone : n-hexane : triethylamine = 1 : 5 : 0.01) to give 2.32 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-n-butoxy-1-methylethyl)oxime]. ¹H-NMR (CDCl₃); δ(ppm)= 0.09 (2'-O-TMS), 0.14 (4"-O-TMS), 0.90 [-O(CH₂)₃C H ₃], 2.22 [3'-N(CH₃)₂], 3.30 (3"-OCH₃), 3.40 [-OC H ₂CH₂CH₂CH₃] Mass (FAB); m/z=1009 (MH⁺) (3) Following a procedure similar to that of Example 1(3), there was obtained 1.00 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-n-butoxy-1-methylethyl)oxime] from 1 g of the compound obtained above. ¹H-NMR (CDCl₃); δ (ppm)= 0.08 (2'-O-TMS), 0.14 (4"-O-TMS), 2.21 [3'-N(CH₃)₂], 3.06 (6-OCH₃), 3.30 (3"-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm) = 0.9 (4"-O-TMS), 1.1 (2'-O-TMS), 41.0 [3'-N(CH₃)₂], 49.7 (3'-OCH₃), 50.9 (6-OCH₃), 61.2 [-O C H₂CH₂CH₂CH₃], 102.7 [-O- C (CH₃)₂O-] Mass (FAB); m/z=1023 (MH⁺) Example 14 (1) To a solution of 10 g of erythromycin A 9-oxime in 70 ml of dichloromethane were added, under ice-cooling, 2.3 g of pyridine hydrochloride and then a solution of 8.58 g of 1-methoxy-1-cyclohexene in 30 ml of dichloromethane. After stirring at room temperature overnight, the reaction solution was poured into 100 ml of 2 N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with, in turn, water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent, chloroform : methanol : aqueous ammonia = 10 : 1 : 0.1) and recrystallized from chloroform - diisopropyl ether to give 2.40 g of erythromycin A 9-[O-(1-methoxycyclohexyl)oxime]. m.p. 117 - 118°C ¹H-NMR (CDCl₃); ¹³C-NMR (CDCl₃); Mass (FAB); m/z=861 (MH⁺) (2) To a solution of 2.2 g of the compound, obtained above, in 11 ml of N,N-dimethylformamide were added, under ice-cooling, 1.65 g of 1,1,1,3,3,3-hexamethyldisilazane and then 0.44 g of pyridine hydrochloride, and the mixture was stirred at room temperature for 4 hours. Then, following a procedure similar to that of Example 10(1), there was obtained 2.55 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-methoxycyclohexyl)oxime]. ¹H-NMR (CDCl₃); ¹³C-NMR (CDCl₃); Mass (CI); m/z=1005 (MH⁺) (3) To a solution of 2.2 g of the compound, obtained above, in 22 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1) were added, under ice-cooling, 0.23 ml of methyl iodide and 190 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 3 hours. Then, following a procedure similar to that of Example 1(3), there was obtained 2.01 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-methoxycyclohexyl)oxime]. ¹H-NMR (CDCl₃); ¹³C-NMR (CDCl₃); Mass (CI); m/z=1019 (MH⁺) Example 15 To a solution of 1 g of erythromycin A 9-oxime in 10 ml of dichloromethane were added 0.23 g of pyridine hydrochloride and then a solution of 1.1 g of 1,1-dimethoxycyclohexane in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 24 hours. Then, following a procedure similar to that of Example 9, there was obtained 0.65 g of erythromycin A 9-[O-(1-methoxycyclohexyl)oxime], which was identical to the compound obtained in Example 14(1). Example 16 (1) To a solution of 5 g of erythromycin A 9-oxime and 1.16 g of pyridine hydrochloride in 25 ml of dichloromethane was added dropwise, under ice-cooling, 11.1 ml of triethyl orthoformate. After the reaction, stirring was continued at room temperature for 4.5 hours. Then, following a procedure similar to that of Example 14(1), the resulting crude product was purified by silica gel column chromatography (eluent, acetone : n-hexane : triethylamine = 3 : 10 : 0.2) to give 3.44 g of erythromycin A 9-[O-(diethoxymethyl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 2.28 [3'-N(CH₃)₂], 3.32 (3"-OCH₃), 5.64 [-C H (OC₂H₅)₂] ¹³C-NMR (CDCl₃); δ (ppm)= 40.3 [3'-N(CH₃)₂], 49.5 (3"-OCH₃), 60.9 and 62.5 [-OCH(O C H₂CH₃)₂] 115.7 [-O C H(OC₂H₅)₂] Mass (FAB); m/z=851 (MH⁺) (2) Following a procedure similar to that of Example 5(2) using a solution of 2.5 g of the compound obtained above, in 25 ml of dichloromethane, 0.86 ml of trimethylsilylimidazole and 0.75 ml of trimethylchlorosilane, the resulting product was purified by silica gel column chromatography (eluent, acetone : n-hexane : triethylamine = 1 : 5 : 0.01) to give 1.55 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(diethoxymethyl)oxime]. m.p. 98 - 103°C (recrystallized from n-hexane) ¹H-NMR (CDCl₃); δ (ppm)= 0.1 (2'-O-TMS), 0.15 (4"-O-TMS), 2.23 [3'-N(CH₃)₂], 3.30 (3"-OCH₃), 5.65 [-C H (OC₂H₅)₂] ¹³C-NMR (CDCl₃); δ (ppm)= 0.9 (4"-OTMS), 1.0 (2'-OTMS), 41.0 [3'-N(CH₃)₂], 49.8 (3''-OCH₃), 60.8 and 62.3 [-OCH(O C H₂CH₃)₂], 115.7 [-O C H(OC₂H₅)₂] Mass (FAB); m/z=995 (MH⁺) (3) Following a procedure similar to that of Example 5(3) using 1 g of the compound obtained above, there was obtained 0.99 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(diethoxymethyl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 0.09 (2'-O-TMS), 0.15 (4"-O-TMS), 2.21 [3'-N(CH₃)₂], 3.10 (6-OCH₃), 3.30 (3"-OCH₃), 5.65 [-C H (OC₂H₅)₂] ¹³C-NMR (CDCl₃); δ (ppm)= 0.9 (4"-O-TMS), 1.1 (2'-O-TMS), 41.0 [3'-N(CH₃)₂], 49.7 (3"-OCH₃), 50.9 (6-OCH₃), 60.2 and 61.4 [-OCH(O C H₂CH₃)₂], 115.9 [-O C H(OC₂H₅)₂] Mass (FAB); m/z=1009 (MH⁺) Example 17 Following a procedure similar to that of Example 10(2) using 1 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-oxime, obtained in Example 10(1), 1.86 ml of triethyl orthoformate and 194 mg of pyridine hydrochloride, there was obtained 0.60 g of 2',4"-O-bis(trimethylsilyl)erythromycin A 9-[O-(diethoxymethyl)oxime], which was identical to the compound obtained in Example 16(2). Example 18 To a solution of 10 g of erythromycin A 9-oxime in 50 ml of N,N-dimethylformamide were added 1.07 g of ammonium chloride and then 5.6 ml of 1,1,1,3,3,3-hexamethyldisilazane, and stirring was continued at room temperature for 20 hours. Then, following a procedure similar to that of Example 10(1), there was obtained 11.0 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-oxime, which was identical to the compound obtained in Example 10(1). Example 19 To a solution of 5 g of erythromycin A 9-oxime in 100 ml of dichloromethane were added 5 ml of isopropyl alcohol, 6.4 ml of 2-methoxypropene and 1.15 g of pyridine hydrochloride, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 5.4 g of erythromycin A 9-{O-[1-(1-methylethoxy)-1-methylethyl]oxime}, which was identical to the compound obtained in Example 5(1). Example 20 (1) To a solution of 7.49 g of erythromycin A 9-oxime in 100 ml of dichloromethane were added 10.4 ml of cyclohexyl alcohol, 9.6 ml of 2-methoxypropene and 1.74 g of pyridine hydrochloride, and the mixture was stirred at room temperature for 1 hour. Then, following a procedure similar to that of Example 19, the resulting residue was purified by silica gel column chromatography (eluent, acetone : n-hexane : triethylamine = 1 : 5 : 0.1 - 3 : 10 : 0.2) and recrystallized from aqueous acetone to give 5.7 g of erythromycin A 9-[O-(1-cyclohexyloxy-1-methylethyl)oxime]. m.p. 107 - 109.5°C ¹H-NMR (CDCl₃); δ (ppm)= 2.29 [3'-N(CH₃)₂], 3.30 (3"-OCH₃), ¹³C-NMR (CDCl₃); Mass (FAB); m/z=889 (MH⁺) (2) To a solution of 3 g of the compound obtained above, in 30 ml of ethyl acetate, was added a solution of 1.2 ml of trimethylsilylimidazole and 0.72 ml of trimethylchlorosilane in 5 ml of ethyl acetate, and the mixture was stirred at room temperature for 10 minutes. Then, following a procedure similar to that of Example 5(2), there was obtained 3.22 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-cyclohexyloxy-1-methylethyl)oxime]. m.p. 98 - 103°C (recrystallized from n-hexane) ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-O-TMS), 0.15 (4"-O-TMS), 2.24 [3'-N(CH₃)₂], 3.32 (3"-OCH₃), ¹³C-NMR (CDCl₃); Mass (CI); m/z=1033 (MH⁺) (3) Following a procedure similar to that of Example 1(3) using a solution of 2 g of the compound, obtained above, in 100 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1), 0.18 ml of methyl iodide and 160 mg of 85% potassium hydroxide powder, the resulting residue was recrystallized from acetone to give 1.2 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-cyclohexyloxy-1-methylethyl)oxime]. m.p. 202 - 203°C (recrystallized from acetone) ¹H-NMR (CDCl₃); δ (ppm)= 0.08 (2'-O-TMS), 0.14 (4"-O-TMS), 2.22 [3'-N(CH₃)₂], 3.07 (6-OCH₃), 3.32 (3"-OCH₃) ¹³C-NMR (CDCl₃); Mass (EI); m/z=1046 (M⁺) Example 21 (1) To a solution of 7 g of 2' , 4"-O-bis(trimethylsilyl)-erythromycin A 9-oxime, obtained in Example 10(1), in 35 ml of dichloromethane were added, under ice-cooling, 1.36 g of pyridine hydrochloride and then a solution of 3.41 g of 2,2-diisopropoxybutane in 14 ml of dichloromethane, and the mixture was stirred at room temperature for 1.5 hours. Then, following a procedure similar to that of Example 10(2), there was obtained 7.5 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-{O-[1-(1-methylethoxy)-1-methylpropyl]oxime}. ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-O-TMS), 0.15 (4"-O-TMS), 2.24 [3'-N(CH₃)₂], 3.31 (3"-OCH₃), 4.03 [-O-C H (CH₃)₂] ¹³C-NMR (CDCl₃); Mass (CI); m/z=1007 (MH⁺) (2) Following a procedure similar to that of Example 1(3) using a solution of 4 g of the compound obtained above, in 40 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1), 0.73 g of methyl iodide and 245 mg of 85% potassium hydroxide powder, there was obtained 3.87 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-{O-(1-(1-methylethoxy)-1-methylpropyl]oxime}. ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-O-TMS), 0.15 (4"-O-TMS), 2.23 [3'-N(CH₃)₂], 3.09 (6-OCH₃), 3.33 (3"-OCH₃) ¹³C-NMR (CDCl₃); Mass (CI); m/z=1021 (MH⁺) Example 22 To a solution of 1 g of erythromycin A 9-oxime in 7 ml of dichloromethane were added under ice-cooling 0.23 g of pyridine hydrochloride and a solution of 2.51 g of 2,2-di-n-butoxypropane in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 24 hours. Then, following a procedure similar to that of Example 10(2), there was obtained 0.83 g of erythromycin A 9-[O-(1-n-butoxy-1-methylethyl)oxime], which was identical to the compound obtained in Example 13(1). Example 23 To a solution of 1 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-oxime, obtained in Example 10(1), in 7 ml of dichloromethane were added under ice-cooling 194 mg of pyridine hydrochloride and then 2.11 g of 2,2-di-n-butoxypropane, and the mixture was stirred at room temperature for 5 hours. Then, following a procedure similar to that of Example 10(2), there was obtained 0.42 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-n-butoxy-1-methylethyl)oxime], which was identical to the compound obtained in Example 13(2). Example 24 (1) To a solution of 2.48 g of erythromycin A 9-oxime in 17 ml of dichloromethane were added 0.58 g of pyridine hydrochloride and then a solution of 1.7 g of 2-methylenetetrahydrofuran in 7.5 ml of dichloromethane, and the mixture was stirred at room temperature for 3 hours. Then, following a procedure similar to that of Example 5(1), the resulting product was purified by silica gel column chromatography (eluent, acetone : n-hexane : triethylamine = 3 : 10 : 0.2) to give 2.25 g of erythromycin A 9-[O-(2-methyl-2-tetrahydrofuryl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 1.54 and 1.55 [-OC(CH₃)₂O-], 2.29 [3'-N(CH₃)₂], 3.32 (3"-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 23.82 and 24.62 [OC( C H₃)O-], 40.32 [3'-N(CH₃)₂], 49.49 (3"-OCH₃), 68.90 (-OCH₂-) (2) To a solution of 2 g of the compound obtained above, in 10 ml of N,N-dimethylformamide, were added, under ice-cooling, 416 mg of pyridine hydrochloride and 970 mg of 1,1,1,3,3,3-hexamethyldisilazane, and the mixture was stirred at room temperature for 6 hours. Then, following a procedure similar to that of Example 10(1), there was obtained 2.18 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(2-methyl-2-tetrahydrofuryl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-O-TMS), 0.15 (4"-O-TMS), 1.54 and 1.55 [-OC(CH₃)₂O-], 2.23 [3'-N(CH₃)₂], 3.30 (3"-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 1.46 (4"-O-TMS), 1.56 (2'-O-TMS), 24.31 and 24.94 [OC( C H₃)O-], 41.54 [3'-N(CH₃)₂], 50.28 (3"-OCH₃), 69.37 (-OCH₂-) Mass (CI); m/z= 977 (MH⁺) (3) Following a procedure similar to that of Example 1(3) using a solution of 1.9 g of the compound obtained above, in 19 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1), 360 mg of methyl iodide and 154 mg of 85% potassium hydroxide powder, there was obtained 1.64 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(2-methyl-2-tetrahydrofuryl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 0.09 (2'-O-TMS), 0.15 (4"-O-TMS), 1.53 and 1.56 [O-C(CH₃)O-], 2.21 [3'-N(CH₃)₂], 3.08 (6-OCH₃), 3.31 (3"-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 0.90 (4"-O-TMS), 1.06 (2'-O-TMS), 23.53 and 24.17 [OC( C H₃)O-], 40.99 [3'-N(CH₃)₂], 49.72 (3"-OCH₃), 50.91 (6-OCH₃), 69.08 (-OCH₂-) Mass (CI); m/z=991 (MH⁺) Example 25 To a solution of 4.45 g of erythromycin A 9-oxime in 31 ml of dichloromethane were added 1.03 g of pyridine hydrochloride and then a solution of 4.75 g of 5-methyl-2,3-dihydrofuran in 13 ml of dichloromethane, and the mixture was stirred at room temperature for 24 hours. Then, following a procedure similar to that of Example 5(1), there was obtained 3.0 g of erythromycin A 9-[O-(2-methyl-2-tetrahydrofuryl)oxime], which was identical to the compound obtained in Example 24(1). Example 26 To a solution of 3.86 g of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime], obtained in Example 1(2), in 200 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1), were added 1.6 ml of ethyl iodide and 780 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 1.5 hours. Then, following a procedure similar to that of Example 1(3), the resulting residue was recrystallized from methanol to give 1.55 g of 2',4"-O-bis(trimethylsilyl)-6-O-ethylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime]. Mass (FAB); m/z=993 (MH⁺) Example 27 (1) To a solution of 3.74 g of erythromycin A 9-oxime in 150 ml of dichloromethane were added 3.0 ml of ethyl vinyl ether and 1.73 g of pyridine hydrochloride, and the mixture was stirred at room temperature for 1 week. Then, following a procedure similar to that of Example 1(1), there was obtained 3.5 g of erythromycin A 9-[O-(1-ethoxyethyl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 1.42 [-OCH(C H ₃)O-], 2.30 [3'-N(CH₃)₂], 3.34 (3"-OCH₃) ¹³C-NMR (CDCl₃); δ (ppm)= 15.5 (-OCH₂ C H₃), 20.2 [-OCH( C H₃)O-] 40.3 [3'-N(CH₃)₂], 49.5 (3"-OCH₃), Mass (FAB); m/z=821 (MH⁺) (2) To a solution of 820 mg of the compound obtained above, in 5 ml of N,N-dimethylformamide, were added 0.41 ml of 1,1,1,3,3,3-hexamethyldisilazane and 80 mg of ammonium chloride, and the mixture was stirred at room temperature for 4 hours. Then, following a procedure similar to that of Example 10(1), there was obtained 700 mg of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-ethoxyethyl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-O-TMS), 0.15 (4"-O-TMS), 1.53 [O-CH(C H ₃)O-], 2.20 [3'-N(CH₃)₂], 3.31 (3"-OCH₃) Mass (FAB); m/z=965 (MH⁺) (3) To a solution of 650 mg of the compound obtained above, in 14 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1), were added, under ice-cooling, 0.06 ml of methyl iodide and 58 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 1 (3), there was obtained 610 mg of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-ethoxyethyl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 0.09 (2'-O-TMS), 0.16 (4"-O-TMS), 1.10 [O-CH(C H ₃)O-], 2.22 [3'-N(CH₃)₂], 3.07 (6-OCH₃), 3.32 (3"-OCH₃) Mass (FAB); m/z=979 (MH⁺) Example 28 (1) To a solution of 804 mg of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-oxime, obtained in Example 10(1), and 156 mg of pyridine hydrochloride in 4 ml of dichloromethane was added under ice-cooling a solution of 338 mg of 3,3-diisopropoxypentane in 1.6 ml of dichloromethane, and the mixture was stirred at room temperature for 6 hours. Then, following a procedure similar to that of Example 10(2), there was obtained 860 mg of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-{O-[1-(1-methylethoxy)-1-ethylpropyl]oxime}. ¹H-NMR (CDCl₃) δ (ppm)= 0.11 (2'-O-TMS), 0.15 (4"-O-TMS), 2.25 [3'-N(CH₃)₂], 3.30 (3"-OCH₃), 4.04 [-O-C H (CH₃)₂] ¹³C-NMR (CDCl₃); δ (ppm)= 0.91 (4"-O-TMS), 1.02 (2'-O-TMS), 40.99 [3'-N(CH₃)₂], 49.73 (3"-OCH₃), 108.32 [-O- C (C₂H₅)₂O-] Mass (FAB); m/z=1021 (MH⁺) (2) To a solution of 669 mg of the compound, obtained above, in 6.6 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1) were added under ice-cooling 0.06 ml of methyl iodide and 55 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to than of Example 1(3), there was obtained 630 mg of 2',4"-O-bis(trimethylsilyl)-6-O-methyl erythromycin A 9-{O-(1-(1-methylethoxy)-1-ethylpropyl]oxime}. ¹H-NMR (CDCl₃); δ (ppm)= 0.11 (2'-O-TMS), 0.15 (4"-O-TMS), 2.27 [3'-N(CH₃)₂], 3.10 (6-OCH₃), 3.31 (3"-OCH₃), 4.10 [-O-C H (CH₃)₂] ¹³C-NMR (CDCl₃); δ (ppm)= 0.91 (4"-O-TMS), 1.13 (2'-O-TMS), 40.99 [3'-N(CH₃)₂], 49.70 (3"-OCH₃), 51.22 (6-OCH₃), 107.87 [-O- C (C₂H₅)₂O-] Mass (FAB); m/z=1035 (MH⁺) Example 29 (1) To a solution of 468 mg of erythromycin A 9-oxime in 5 ml of dichloromethane were added 108 mg of pyridine hydrochloride and then a solution of 367 mg of 2-benzyloxypropene in 2 ml of dichloromethane, and the mixture was stirred at room temperature for 2.5 hours. Then, following a procedure similar to that of Example 1(1), the resulting residue was purified by silica gel column chromatography (eluent, chloroform : methanol : aqueous ammonia = 30 : 1 : 0.1 - 10 : 1 : 0.1) to give 510 mg of erythromycin A 9-[O-(1-benzyloxy-1-methylethyl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 2.28 [3'-N(CH₃)₂], 3.32 (3"-O-CH₃), 4.50 (-OC H ₂C₆H₅), 7.20-7.40 (-O-CH₂C₆ H ₅) Mass (FAB): m/z=897 (MH⁺) (2) To a solution of 470 mg of the compound obtained above and 90 mg of pyridine hydrochloride in 4 ml of N,N-dimethylformamide was added a solution of 294 mg of 1,1,1,3,3,3-hexamethyldisilazane in 1 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature overnight. Then, following a procedure similar to that of Example 10(1), there was obtained 503 mg of 2',4"-O-bis(trimethylsilyl)-erythromycin A 9-[O-(1-benzyloxy-1-methylethyl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-OTMS), 0.15 (4"-OTMS), 2.22 [3'-N(CH₃)₂], 3.30 (3"-OCH₃), 4.50 (-OC H ₂C₆H₅), 7.20-7.40 [-OCH₂C₆ H ₅] Mass (FAB); m/z=1041 (MH⁺) (3) To a solution of 388 mg of the compound obtained above and 0.035 ml of methyl iodide in 5 ml of a mixture of dimethyl sulfoxide and tetrahydrofuran (1 : 1) was added under ice-cooling 29 mg of 85% potassium hydroxide powder, and the mixture was stirred at room temperature for 2 hours. Then, following a procedure similar to that of Example 1(3), there was obtained 376 mg of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-benzyloxy-1-methylethyl)oxime]. ¹H-NMR (CDCl₃); δ (ppm)= 0.10 (2'-OTMS), 0.15 (4"-OTMS), 2.22 [3'-N(CH₃)₂], 3.10 (6-O-CH₃), 3.32 (3"-O-CH₃), 4.52 (-O-C H ₂C₆H₅), 7.20-7.40 (-O-CH₂C₆ H ₅) Mass (FAB); m/z=1055 (MH⁺) Referential Example 1 (1) To a solution of 3.46 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime], obtained in Example 1(3), in 60 ml of ethanol/water (1/1) was added 1.5 ml of 99% formic acid, and the mixture was stirred at room temperature for 30 minutes. Then, most of the ethanol was evaporated under reduced pressure, and water was added to the residue. The mixture was made basic with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with, in turn, water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 2.53 g of 6-O-methylerythromycin A 9-oxime. m.p. 248 - 251°C (recrystallized from ethoanol - petroleum ether) (2) To a solution of 2 g of the compound obtained above, and 1.1 g of sodium hydrogen sulfite in 20 ml of ethanol/water (1/1), was added 0.25 ml of 99% formic acid, and the mixture was refluxed for 100 minutes. To the reaction solution was added 30 ml of water, 5 ml of 2N aqueous sodium hydroxide solution was added dropwise, and then the mixture was stirred under ice-cooling for 2 hours. The precipitate which formed was collected by filtration and recrystallized from ethanol to give 1.51 g of 6-O-methylerythromycin A. m.p. 223 - 225°C Referential Example 2 To a solution of 9.8 g of 2',4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime], obtained in Example 1(3), in 100 ml of ethanol/water (1/1), were added 6.7 g of sodium hydrogen sulfite and 1.6 ml of 99% formic acid, and then the mixture was refluxed with stirring for 60 minutes. To the reaction solution was added 150 ml of water, and then the mixture was adjusted to pH about 10 by adding dropwise 2 N aqueous sodium hydroxide solution and stirred under ice-cooling for 1 hour. The precipitate which formed was collected by filtration, washed with water and recrystallized from ethanol to give 5.15 g of 6-O-methylerythromycin A, which was identical to the compound obtained in Referential Example 1(2). Referential Example 3 To a solution of 980 mg of 2',4"-O-bis(trimethylsilyl)-6-O-ethylerythromycin A 9-[O-(1-methoxy-1-methylethyl)oxime], obtained in Example 26, in 10 ml of ethanol/water (1/1), were added 2 g of sodium hydrogen sulfite and 0.23 ml of 99% formic acid, and the mixture was refluxed with stirring for 60 minutes. Then, following a procedure similar to that of Referential Example 2, the resulting residue was recrystallized from ethanol to give 610 mg of 6-O-ethylerythromycin A. m.p. 213.5 - 214.5°C; ¹H-NMR (CDCl₃); δ (ppm)= 1.01 (6-OCH₂C H ₃), 2.23 [3'-N(CH₃)₂], 3.33 (3"-OCH₃), 3.45 (6-OC H ₂CH₃) Mass (FAB); m/z=761 (MH⁺)

Claims: Erythromycin A derivative represented by the general formula wherein R¹ is a group of the formula R⁷CH₂- (wherein R⁷ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) or a group of the formula R⁸O-(wherein R⁸ is an alkyl group having 1 to 6 carbon atoms), R² is the same alkyl group as that of R⁸ or is a cycloalkyl group having 5 to 7 carbon atoms, a phenyl group, a benzyl group in which the phenyl moiety is optionally substituted by a methyl group, an α-methyl benzyl group or a phenethyl group, or R² and R⁷ together form an alkylene group having 2 or 3 carbon atoms, R³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group in which the phenyl moiety is optionally substituted by a methyl group, an α-methyl benzyl group or a phenethyl group, or R³ and R⁷ together form an alkylene group having 3 to 5 carbon atoms which is optionally substituted by 1 to 3 alkyl groups each having 1 to 3 carbon atoms, or R² and R³ together form an alkylene group having 3 or 4 carbon atoms, R⁴ is an alkyl group having 1 to 3 carbon atoms, R⁵ is a substituted silyl group of formula -SiR⁹R¹⁰R¹¹ (wherein R⁹, R¹⁰ and R¹¹ are the same or different, and each is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a phenyl substituted alkyl group in which the alkyl moiety has 1 to 3 carbon atoms, a phenyl group, a cycloalkyl group having 5 to 7 carbon atoms or an alkenyl group having 2 to 5 carbon atoms, with the proviso that at least one of R⁹, R¹⁰ and R¹¹ is other than a hydrogen atom), and R⁶ is a hydrogen atom or is the same silyl group as that of R⁵. Erythromycin A derivative represented by the general formula wherein R¹ is a group of the formula R⁷CH₂- (wherein R⁷ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) or a group of the formula R⁸O- (wherein R⁸ is an alkyl group having 1 to 6 carbon atoms), R² is the same alkyl group as that of R⁸ or is a cycloalkyl group having 5 to 7 carbon atoms, a phenyl group, a benzyl group in which the phenyl moiety is optionally substituted by a methyl group, an α-methyl benzyl group or a phenethyl group, or R² and R⁷ together form an alkylene group having 2 or 3 carbon atoms, R³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group in which the phenyl moiety is optionally substituted by a methyl group, an α-methyl benzyl group or a phenethyl group, or R³ and R⁷ together form an alkylene group having 3 to 5 carbon atoms which is optionally substituted by 1 to 3 alkyl groups each having 1 to 3 carbon atoms, or R² and R₃ together form an alkylene group having 3 or 4 carbon atoms, R⁵ is a substituted silyl group of formula -SiR⁹R¹⁰R¹¹ (wherein R⁹, R¹⁰ and R¹¹ are the same or different, and each is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a phenyl substituted alkyl group in which the alkyl moiety has 1 to 3 carbon atoms, a phenyl group, a cycloalkyl group having 5 to 7 carbon atoms or an alkenyl group having 2 to 5 carbon atoms, with the proviso that at least one of R⁹, R¹⁰ and R¹¹ is other than a hydrogen atom), and R⁶ is a hydrogen atom or is the same silyl group as that of R⁵. A method for preparing an erythromycin A derivative represented by the general formula wherein R¹ is a group of the formula R⁷CH₂- (wherein R⁷ is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms) or a group of the formula R⁸O- (wherein R⁸ is an alkyl group having 1 to 6 carbon atoms), R² is the same alkyl group as that of R⁸ or is a cycloalkyl group having 5 to 7 carbon atoms, a phenyl group, a benzyl group in which the phenyl moiety is optionally substituted by a methyl group, an α-methyl benzyl group or a phenethyl group, or R² and R⁷ together form an alkylene group having 2 or 3 carbon atoms, R³ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, a benzyl group in which the phenyl moiety is optionally substitued by a methyl group, an α-methyl benzyl group or a phenethyl group, or R³ and R⁷ together form an alkylene group having 3 to 5 carbon atoms which is optionally substituted by 1 to 3 alkyl groups each having 1 to 3 carbon atoms, or R² and R³ together form an alkylene group having 3 or 4 carbon atoms, R⁴ is an alkyl group having 1 to 3 carbon atoms, R⁵ is a substitued silyl group of formula -SiR⁹R¹⁰R¹¹ (wherein R⁹, R¹⁰ and R¹¹ are the same or different, and each is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a phenyl substituted alkyl group in which the alkyl moiety has 1 to 3 carbon atoms, a phenyl group, a cycloalkyl group having 5 to 7 carbon atoms or an alkenyl group having 2 to 5 carbon atoms, with the proviso that at least one of R⁹, R¹⁰ and R¹¹ is other than a hydrogen atom), and R⁶ is a hydrogen atom or is the same silyl group as that of R⁵, which comprises reacting erythromycin A 9-oxime, in any desired sequence, with a compound of formula represented by the general formula wherein R¹, R² and R³ are as defined above, and R¹² is a group of formula -OR⁸ (wherein R⁸ is as defined above), or R¹ and R¹² together form a group of formula R⁷CH= (wherein R⁷ is as defined above), and with a silylating agent having R⁵ to give a compound represented by the general formula wherein R¹, R², R³, R⁵ and R⁶ are as defined above, and then reacting the resulting compound with an alkylating agent having R⁴.

Inventors: ADACHI, TAKASHI, ASAKA, TOSHIFUMI, KASHIMURA, MASATO, MATSUNAGA, TOHRU, MORIMOTO, SHIGEO, SEKIUCHI, KAZUTO, SOTA, KAORU, WATANABE, YOSHIAKI
Applicants: TAISHO PHARMACEUTICAL CO. LTD
Application year: 1987
Main classification: C07H17
IPC codes: C07H17