JPH0276893A - Erythromycin-a derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is R<7>CH-(R<7> is H or 1-3C alkyl) or R<8>O-(R<8> is 1-6C alkyl); R<2> is R<8>, 5-7C cycloalkyl, phenyl, aralkyl, etc.; R<3> is H, 1-4C alkyl, phenyl, aralkyl, etc.; R<4> is H or 1-3C alkyl; R<5> is-SiR<9>R<10>R<11> (R<9>-R<11> are H, 1-15C alkyl, phenyl, etc.); R<6> is H or R<5>]. EXAMPLE:2',4''-0-bis(trimethylsylyl)-6-0-methylerythromycin A 9-[0-(1-methoxy-1- methylethyl)oxime]. USE:Used as antibacterial agent. PREPARATION:Erythromycin A 9-oxime is reacted with a compound expressed by formula II (R<12> is-OR<8>, etc.) and a sylylating agent containing R<6> in arbitrary turn. Or further, resultant compound is reacted with alkylating agent containing R<4> excepting H.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to erythromycin A derivatives and methods for producing the same.

6-0-alkyl erythromycins are important as antibacterial agents or intermediates for the synthesis of antibacterial agents. For example, 6-0-
Methylerythromycin A is not only more stable under acidic conditions than erythromycin A, but also has stronger antibacterial activity.

In particular, this compound is a useful antibacterial agent because it shows remarkable effects in treating infectious diseases when administered orally.

Conventionally, as a method for producing 6-0-methylerythromycin A, for example, the following method is known.

(υAfter substituting the hydrogen atom of the 2'-position hydroxyl group and the methyl group of the 3'-position dimethylamino group of erythromycin A with a benzyloxycarbonyl group, the 6-position hydroxyl group was methylated, and then the benzyloxycarbonyl group was removed. Method for obtaining 6-0-methylerythromycin A by methylating the methylamino group at the ' position (U.S. Pat. No. 4.331.80)
3 specification).

■Methyl to the 6-position hydroxyl group of erythromycin A derivative
As a method with improved selectivity of oxidation, an erythromycin A derivative in which one or both of the hydroxyl group at the 2'-position and the dimethylamino group at the 3'-position is preserved as S is converted into various substituted oxime derivatives. The 6-position hydroxyl group is methylated, then the protecting group is removed, the 9-position is deoximed, and the 3'-position dimethylamino group is regenerated.
Method for obtaining 0-methylerythromycin A (European Published Patent No. 158,467).

However, with method (1), erythromycin A
has a large number of hydroxyl groups, many by-products with methylated hydroxyl groups other than the 6-position are obtained, and the purification of the 6-0-methylerythromycin A derivative requires complicated operations, resulting in a low yield. There is a drawback. In addition, although method (2) enables selective methylation of the 6-position hydroxyl group, deprotection after methylation requires complicated operations such as catalytic reduction.

Means for Determining Problems As a result of various studies to solve the drawbacks of the above-mentioned known methods, the present inventors found that the hydroxyl group at the 6-position of erythromycin A can be selectively alkylated, and each protective group can be easily introduced and removed. They discovered a method for producing 6-0-alkyl erythromycin A, and completed the present invention.

The object of the present invention is to provide a group of the formula R'CHz- (wherein R7 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms) or 2 R'O- (wherein R' represents an alkyl group having 1 to 6 carbon atoms), R8 represents R9, a cycloalkyl group having 5 to 7 carbon atoms, a phenyl group, or an aralkyl group, or R1 and R7 together form a fullylene group having 2 or 3 carbon atoms, R3 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or an aralkyl group, or R3 and R7 together to form an alkylene group having 3 to 5 carbon atoms, which may be substituted with 1 to 3 alkyl groups having 1 to 3 carbon atoms,
Alternatively, R2 and R3 together form an alkylene group having 3 to 4 carbon atoms, R4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and RJt formula -5iR"R"R
(In the formula, Rt, Rla and R are the same or different and are a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group, a phenyl group, a carbon atom) Represents a cycloalkyl group having 5 to 7 carbon atoms or an alkenyl group having 2 to 5 carbon atoms, provided that R'l
At least one of R" and R" represents a substituted silyl group (at least one of which is not a hydrogen atom), R1 is a hydrogen atom or RA
An object of the present invention is to provide an erythromycin A derivative which can be expressed as follows.

Another object of the invention is the preparation of compounds of formula I, comprising erythromycin A 9-oxymura, in any order, -
Monna [In the formula, R1, R1 and R1 have the same meanings as above,
R'' is the formula -0bi (wherein, pi' has the same meaning as above).

) or R1 and R'' together represent a group of formula R'
It forms a CH- group (wherein R7 has the same meaning as above). ] and a silylating agent having R8, or further reacting the obtained compound with an alkylating agent having R4 other than a hydrogen atom.

The term alkyl group used in the present invention means a linear or branched group, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
Isobutyl group, 5ec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl L
Such as n-hexyl group. Also, an aralkyl group is
It means a benzyl group, a benzyl group substituted with a methyl group, an α-methylbenzyl group, a phenethyl group, etc. Examples of alkylene groups having 2 to 5 carbon atoms include ethylene group, propylene group, trimethylene group, tetramethylene group, and pentamethylene group. ~3 alkyl group 1~
Examples of the 3-substituted alkylene group having 3 to 5 carbon atoms include 2-methyltrimethylene group, 3-methyltrimethylene group, 1-methyltetramethylene group, 3-methyltrimethylene group,
Examples include methyltetramethylene group, 2.2.4-trimethyltetramethylene group, 2,4.4-trimethyltetramethylene group, and 1-isopropyl-4-methyltetramethylene group. Halogen atoms include chlorine, bromine, and iodine atoms. In addition, substituted silyl group is
For example, trimethylsilyl group, triethylsilyl group,
Isopropyldimethylsilyl group, tert-butyldimethylsilyl group, (triphenylmethyl)dimethylsilyl group, tert-butyldiphenylsilyl group, diphenylmethylsilyl group, diphenylvinylsilyl group, methyldiisopropylsilyl group, tribenzylsilyl group, tri( p-xylyl)silyl group, triphenylsilyl group,
These include diphenylsilyl group and dimethyloctadecylsilyl group.

The present invention will be explained in detail below. First, erythromycin A 9-oxime and compound 2) are reacted,
The reaction for protecting the hydroxyl group at the 9-oxime position may be a method normally used for introducing an acetal-type protecting group to a hydroxyl group. For example, erythromycin A9-oxime and the compound of formula By stirring, -Momonana (where R1, R1 and R1 have the same meanings as above).

) In the reaction to obtain the compound represented by formula (1), the compound of formula (1) is used in an amount of 2 to 20 equivalents, preferably 2 to 10 equivalents, relative to erythromycin A 9-oxime.

Examples of the compound of formula (1) include methyl vinyl ether, ethyl vinyl ether, n-propyl vinyl ether, isopropyl vinyl ether, n-butyl vinyl ether, imbutyl vinyl ether, 2-methoxypropene, 2-ethoxypropene, 2-n-propoxypropene, -inbroboxypropene, 2-n-butoxypropene, 2-isobutoxypropene, 2-5ec-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-isopropoxy-1-cyclopentene , 1-n-butoxy-1-cyclopentene, 1-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-isopropoxy-
1-cyclohexene, 1-n-butoxy-1-cyclohexene, 1-imbutoxy-1-cyclohexene, 1-
Methoxy-4-methyl-1-cyclohexene, 1-methoxy-6-methyl-1-cyclohexene, 1-methoxy-3,5,5-)rifthyl-1-cyclohexene, 1-
Methoxy-3,3,5-)rifthyl-1-cyclohexene, 1-methoxy-3-methyl-6-itubroby-1
-Cyclohexene, 1-methoxy-1-cycloheptene, 1-ethoxy-1-cycloheptene, 1-n-propoxy-1-cycloheptene, 1-inpropoxy-1-
Cycloheptene, 1-n-butoxy-1-cycloheptene, 1-isobutoxy-1-cycloheptene, 1.1-
Dimethoxycyclopenkune, 1.1-jethoxycyclopenkun, 1.1-di-n-propoxycyclopenkun, 1.1-diisopropoxycyclopenkun, 1.1-
Di-n-butoxycyclopenkune, 1.1-diisobutoxycyclopenkune, 1.1-dimethoxycyclohexane, 1.1-jethoxycyclohexane, 1,1-di-
n-propoxycyclohexane, 1,1-diisopropoxycyclohexane, 1,1-di-n-butoxycyclohexane, 1,1-diisobutoxycyclohexane, 1
．． 1-dimethoxycyclohebutane, 1,1-jethoxycyclohebutane, 1.1-di-n-propoxycyclohebutane, 1.1-diisopropoxycyclohebutane, 1
．． 1-di-n-butoxycyclohebutane, 1,1-diisobutoxycyclohebutane, 2-methylenetetrahydrofuran, 5-methyl-2,3-dihydrofuran, 2-methylenetetrahydropyran, 6-methyl-3,4 -dihydro-2H-pyran, 2,2-dimethoxypropane, 2
．． 2-jethoxypropane, 2.2-di-n-propoxypropane, 2.2-diisopropoxypropane, 2.
2-di-n-butoxypropane, 2,2-diisobutoxypropane, 2,2-di5eQ-butoxypropane,
2.2-di-n-pentoxypropane, 2.2-di-n
-hexyloxypropane, 2.2-dimethoxybutane, 2.2-jethoxybutane, 2゜2-di-n-propoxybutane, 2.2-diisopropoxybutane, 2.2
-di-n-butoxybutane, 2,2-dimethoxy-3-
Methylbutane, 2,2-jethoxy-3-methylbutane, 2,2-di-n-propoxy-3-methylbutane, 2
, 2-diisopropoxy-3-methylbutane, 2.2-
n-butoxy-3-methylbutane, 2.2-dimethoxypencune, 2.2-jethoxypencune, 2.2-di-
n-propoxypenkune, 2.2-diisopropoxypenkune, 2.2-di-n-butoxypenkune, 3.3-
Dimethoxypenkune, 3゜3-Jethoxypenkun, 3
．． 3-di-n-propoxypenkune, 3.3-diisopropoxypenkune, 3.3-di-n-butoxypenkune, 2.2-dimethoxy-4-methylpentane, 2.2-
Jetoxy-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-dimethoxypenkune, 2,4-dimethyl-3,3-jethoxypenkune, 2.4-dimethyl-3,3-di-n-propoxypenkune, 2.4 -dimethyl-3,3-diisopropoxypenkune, 2,4-dimethyl-3,3-di-
n-butoxypenkune, 2,2-dimethoxyhexane,
2.2-jethoxyhexane, 2.2-di-n-propoxyhexane, 2.2-diisopropoxyhexane, 2
, 2-di-n-butoxyhexane, 3゜3-dimethoxyhexane, 3.3-jethoxyhexane, 3,3-di-
n-propoxyhexane, 3.3-diisopropoxyhexane, 3.3-di-n-butoxyhexane, trimethylorthoformate, trimethylorthoacetate, trimethylorthopropionate, trimethylorthobutyrate, trimethylorthobenzoate, trimethyl Orthophenylacetate, triethyl orthoformate, triethyl orthoacetate, triethyl orthopropionate, triethyl orthobutyrate, triethyl orthobenzoate, triethyl orthophenylacetate, tri-n-propyl orthoformate, triisopropyl orthoformate, tri-n- These include butyl orthoforme, -, di-n-pentyl orthoformate, tri-n-hexyl orthoformate, and the like.

In addition, when obtaining a compound of formula I in which RI and R4 both represent a methyl group, an alcohol having 2-methoxypropene and R2, such as ethanol, propatool, isopropanol, phthanol, isobutanol, 5e
C-butanol, pentanol, isopentanol, hexanol, cyclopentanol, cyclohexanol, cycloheptatool, phenol, benzyl alcohol, phenethyl alcohol, α-methylbenzyl alcohol, 0-methylbenzyl alcohol, p-methylbenzylalfur This can also be done by coexisting appropriate amounts of such substances.

Solvents used for the reaction of erythromycin A 9-oxime and compound 2 include dichloroethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, N
, N-dimethylformamide, dimethyl sulfoxide,
Solvents such as acetone, acetonitrile, nitroethane, toluene can be used. In addition, the catalysts used include hydrochloric acid, sulfuric acid, para-toluenesulfonic acid, etc. and tertiary amines (for example, pyridine, α-pifrin,
Examples include salts with β-pifrin, 7-picoline, N,N-dimethylaniline, triethylamine, etc., and pyridine hydrochloride, pyridinium valatoluenesulfonate, etc. are preferred. These are used in an amount of 1.5 to 5 equivalents to erythromycin A 9-oxime,
Preferably from 1.5 to 3 equivalents, the reaction temperature is 0 °C
~ the reflux temperature of the solvent, but room temperature is usually sufficient.

Next, the reaction between the compound of formula (■) and the silylating agent is carried out in a solvent,
The reaction is carried out with stirring at 0° C. to the reflux temperature of the solvent, preferably 0° C. to room temperature, to obtain a compound of formula I in which R1 is a hydrogen atom. Examples of the silylating agent include chlorosilanes such as trimethylchlorosilane and tertiary-butyldimethylchlorosilane, silylamines such as 1.1.1.3.3.3-hexamethyldisilazane, trimethylsilylimidazole, and dimethylamino-7trimethylsilane. Silylamides such as bis(trimethylsilyl)acetamide, triethylamine, diphenylurea, bis(trimethylsilyl)urea, or mixtures thereof can be used. When using chlorosilanes alone, it is preferable to use a base.The amount of silylating agent used is determined by the formula
The amount is 1 to 10 equivalents, preferably 1 to 5 equivalents, based on the compound.

Examples of the solvent used in this reaction include acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, and chloroform. Examples of bases include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, triethylamine, tri-n-butylamine, tribenzylamine, diisopropylmethylamine, N, N -dimethylaniline, pyridine, 1,8-diazabicyclo[5,4,0]unde-7
-Organic bases such as sen, imidazole, etc. can be used.

When silylamines are used, they are preferably used in combination with chlorosilanes or ammonium chloride, pyridine hydrochloride, or the like.

Alternatively, compounds of formula I in which R4 is a hydrogen atom can be obtained by silylating erythromycin A 9-oxime and then acetalizing it. That is, erythromycin A 9-oxime and a silylating agent are allowed to react under the same conditions as in the silylation, and then the resulting compound is reacted with a compound of formula I under the same conditions as in the acetalization, so that R1 is hydrogen. Compounds of formula 1 which are atoms can be obtained.

The alkylation of the 6-position hydroxyl group is carried out using formula 1, where R4 is a hydrogen atom.
The alkylating agent is methyl bromide, ethyl bromide, n bromide, etc. -propyl, methyl iodide, ethyl iodide, n iodide
-propyl, dimethyl sulfate, diethyl sulfate, di-n-propyl sulfate, para-toluenesulfonic acid methyl ester,
Para-toluenesulfonic acid ethyl ester, para-toluenesulfonic acid n-propyl ester, methanesulfonic acid methyl ester, methanesulfonic acid ethyl ester, methanesulfonic acid n-propyl ester, etc. are used, and the amount used is determined when R4 is a hydrogen atom. Solvents that can be used include aprotic polar solvents, for example, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethyl, for which 1 to 3 equivalents are sufficient for a given compound of Phosphoric triamides or mixtures thereof, or mixtures thereof with tetrahydrofuran, acetone, 1,2-dimethoxyethane, acetonitrile or ethyl acetate. As the base, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxy, etc. can be used. The amount of the base used is usually 1 to 2 equivalents relative to the compound of formula (3) in which R4 is a hydrogen atom. The erythromycin A9-oxime derivative in the present invention has two isomers (syn type and anti type), but in the present invention, it may be either the syn type or the anti type, or it may be a mixture of the syn type and the anti type. It may be.

In the method of the present invention, the hydroxyl group at the 2'-position is silylated, thereby preventing quaternization of the dimethylamino group during methylation of the hydroxyl group at the 6'-position. Therefore, protection of the dimethylamino group at the 3'' position is not required.

Furthermore, the methylation of the 6-position hydroxyl group has good selectivity, similar to conventional methods.

Oxime positions, 2' and 4'' positions of compounds of formula I of the invention
The respective protecting groups for the hydroxyl groups at positions can be easily removed under acidic conditions.

Furthermore, since the regeneration of ketones by deoximation proceeds with good yield under acidic conditions, it can be carried out simultaneously with the removal of the above-mentioned protecting groups, which is more convenient.

Therefore, the method of the present invention is a method in which the reaction operation is significantly simplified and 6-0-alkylerythromycin A can be obtained in high yield and economically. That is, R
Compounds of formula I in which 4 is other than a hydrogen atom can, for example, be led to 6-0-alkylerythromycin A as follows.

First, the protecting groups for the 9-oxime hydroxyl group, the 2'-position hydroxyl group, and the 4''-position hydroxyl group of the compound of formula
It is easily removed by stirring in the presence of water and acid at room temperature to the reflux temperature of the solvent. Here, as the acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, etc. are used. Examples of organic solvents include methanol,
Hydrophilic solvents such as ethanol, isopropanol, dioxane, tetrahydrofuran, N,N-dimethylformamide are used.

The obtained 6-0-alkyl erythromycin A9-oxime can be easily converted to 6-0-alkyl erythromycin A by reacting with a deoximating agent. Deoximating agents include sodium bisulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfite, sodium hydrosulfide, sodium metabisulfite, sodium dithionate, potassium bisulfite, potassium thiosulfate, potassium metabisulfite, etc. In the 0-water reaction of salts of inorganic acid oxides, the solvent may be the hydrophilic solvent used for removing the lyle group described above, and the reaction proceeds quickly when carried out in the presence of an acid. The compound is more suitable in the present invention because it can be deoximed simultaneously with the removal of the protecting group by reacting with a deoximating agent in the presence of an acid. That is, for example, for a compound of formula I in which % R' is other than a hydrogen atom, in aqueous ethanol, the compound of formula I has a concentration of 1.
Add 5 to 10 equivalents, preferably 2 to 5 equivalents, and 1 to 10 equivalents, preferably 4 to 7 equivalents of sodium hydrogen sulfite.
6-0-alkyl erythromycin A can be obtained by stirring at a temperature of .degree. C. to reflux.The intermediates of each step are isolated from the reaction solution by a method such as extraction. It can be further purified by crystallization, column chromatography, etc. However, these isolations
Purification is not required.

Since the progress of the reaction can be monitored by thin layer chromatography, high performance liquid chromatography, etc., the reaction can be stopped after waiting for the disappearance of the raw materials.

Actual L example Next, the present invention will be specifically explained with reference to Examples.

Example 1 (1) Dissolve 5 g of erythromycin A 9-oxime in 100 ml of dichloromethane, and dissolve 2-methoxypropene 6
．． 4 ml of pyridine hydrochloride and 115 g of pyridine hydrochloride were added, and after the reaction was stirred at room temperature for 15 minutes, 100 ml of saturated sodium bicarbonate solution was poured and thoroughly stirred to separate an organic layer and an aqueous layer. The aqueous layer was extracted once again with 50 mfL of dichloromethane, then combined with the organic layer, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 50ml of benzene in the residue
was added, and the solvent was distilled off under reduced pressure. This operation was repeated three times to obtain 5.15 g of erythromycin A 9-[0-, (1-methoxy-1-methylethyl)oxime] as a foamy substance.

m, p, 113-116°C (recrystallized from ether-petroleum ether)'H-NMR (
CD(I3); l; (ppm)=2,' 30 [3'-N (
CHm)*].

3, 23 [-0-C(CH5)to, CHm]-
3,33 (3”-0CR,) Mouth C-NMR (CDCf3): 1; (ppm) = 23, 9 and 24.0 [-0
-C((≧Hs)zOcHsko.

40, 3 [3”-N (CHaL]).

49.5[-0-C(CH,), 0°H1 and 3''-
0CHI.

1 0 3.7[-0-(≧(CHa)-0CHAko(
2) 4.1 g of the compound obtained above was added to dichloromethane 4.
Add 1.8 ml of trimethylsilylimigsol dissolved in 5 ml of dichloromethane and 1.0 ml of trimethylchlorosilane, and stir at room temperature for 10 minutes. Add 60 ml of n-hexane to the reaction solution, and filter the precipitate. The filtrate was concentrated under reduced pressure. Add 50ml of saturated sodium bicarbonate solution to the residue.
1 was added and extracted with dichloromethane (50ml x 2). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, leaving a foamy 2
',4''-〇-bis(trimethylsilyl)-erythromycin A 9-[0-(1-methoxy-1-dimethyledel)oxime] 4.5 g was obtained.

m, p, 124-126.5°C (recrystallized from acetone)'H-NMR (CDCI23); 1; (ppm) -0, 10 (2'-0-IMS>.

o, 14 (4--o-IMS).

2, 23 [3'-N (CH'm)zl.

3. 2 2 [-0-C(CHA)tOCH, Co.

3, 31 (3”-OCHs) “C-NM　R(CDCf3): δ(ppm>-0,9(4''-0(MS).

1, 0 (2'-0-TMS).

23.9 and 24.0 [-0-C(danH-)tOCHi].

41, 0 [3'-N(CHaL]).

49, 3 [-o-c (c Ha) to Dan H3].

49, 6 (3”-OCHm).

103.5[-0-dan(CHs) to CHa] However, TMS represents a trimethylsilyl group. The same applies below.

(3) 2 g of the compound obtained above was mixed with 100 g of a mixed solvent of dimethyl sulfoxide/tetrahydrofuran (1/1).
0.208 ml of methyl iodide and 8
Add 178 mg of 5% potassium hydroxide powder and stir at room temperature for 10
1 ml of 50% dimethylamine aqueous solution was added to the 0 reaction solution that had been stirred for 0 minutes, and the mixture was stirred for 1 hour. 1 part water to the reaction solution
00ml and ethyl acetate (100rd and 50T
lllll). After washing the organic layer with saturated saline,
It was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 2',4''-〇-bis(trimethylsilyl)-a-O
2 g of methylerythromycin A 9-[0-(1-methoxy-1-methylethyl)oxime] were obtained as a foam.

m, p, 134.5-137°C (recrystallized from chloroform-acetone)'H-NMR (
CDCR3): S (ppm)-0,09 (2'-0-TMS).

0.15 (4”-0-TMS).

2, 23 [3'-N(CHm)zl.

3.09<6-OCHI).

3, 24 [-07C(CHl)tOCdan,].

3.33 (3”-〇CH,) IC-NMR (CDC et al.); S (ppm) = 0.9 (4-0-TMS).

1.0 (2°-0 (MS).

23.5 and 24.4 [-0-C (dan H1)! oCHB.

4 1.0 [3'-N(CHa)zko.

49, 0 [-0-C(CHa)todanH,].

49, 7 (3--OCHs).

s L, 0 (6-OCHi).

102.9 [-0-dan (CHa) to CH-] Example 2 (1) Erythromycin A 9-year-old xime 14.98 g
was dissolved in 300 ml of dichloromethane, 15.35 ml of 2-methoxypropene and 3.47 ml of pyridine hydrochloride.
[] was added and stirred at room temperature for 20 minutes. Combined, 5.08 ml of trimethylchlorosilane and 5.6 g of trimethylsilylimidazole in 10 ml of dichloromethane solution.
added. After stirring at room temperature for 30 minutes, water was added and 2N
The mixture was made alkaline with an aqueous sodium hydroxide solution, extracted with chloroform, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 18.78 g of a foamy substance.

This material was the same compound as that obtained in Example 1(2).

(2) 3.86 g of the compound obtained above was added to 28 ml of dimethyl sulfoxide and 56 ml of tetrahydrofuran.
0.37 ml of methyl iodide and 342 mg of 85% potassium hydroxide powder were added to the solution, and stirred at room temperature for 2 hours. To the reaction solution was added 2 mQ of 50% dimethylamine aqueous solution, and after stirring for 30 minutes, -hexane (150
Extracted in ml and 100ml. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-acetone to give 2',4''-〇-bis(trimethylsilyl)-6, which was the same as that obtained in Example 1 (3).
3.0 g of -0-methylerythromycin A9-[0-(1-methoxy-1-methylethyl)oxime] was obtained.

Example 3 (1) 7.75 g of the compound obtained in Example 1 (1) was heated with N
.

Dissolved in 70 ml of N-dimethylformamide and added 2.17 mm of triethylamine.Next, 1.89 ml of trimethylchlorosilane was added dropwise, and the mixture was stirred at room temperature for 10 minutes.
Extracted with X 2 ). Wash the organic layer with saturated saline,
It was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized twice from n-hexane to obtain 2.3 g of 2'-〇-trimethylsilylerythromycin A9-[0-(1-methoxy-1-methylethyl)oxime]. .

m, p, 113.5-115℃ 'H-NMR (CDCR3).

1; (ppnl)-0, 13<2'-0-TMS)
.

2, 24 [3=N(CHi)tl.

3.2 3[-0-C(CH-)tOcdan,ko.

3.33 (3″-OCHi) (2) 1.79 g of the compound obtained above was dissolved in a mixed solvent of dimethyl sulfoxide/tetrahydrofuran <1/1) 3
Dissolve in 6rnfL and 1. Methyl iodide 0.19 under water cooling
Then, 171 mg of 85% potassium hydroxide powder was added with stirring, and 1 ml of 50% dimethylamine aqueous solution was added to the reaction mixture, which was stirred at room temperature for 1.5 hours.
The reaction solution, which had been stirred for 30 minutes, was poured into water, extracted with n-hexane (70 ml x 2 ), and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from acetone to obtain 1.32 g of 6-0-methyl-2'-〇-trimethylsilylerythromycin A9-[0-methoxy-1-methylethyl)oxime]. Obtained.

m, p, 123-125.5℃ 'H-NMR (CDCI23); δ(ppm)-o, 10(2'-o-rhs).

2, '23 [3'-N(CHx)*].

3.09 (6-OCHi).

3, 23 [-0-C (CHs) to C day,].

]334 (3″-OCHi″) Example 4 (1) Erythromycin A 2 g of 9-oxime was dissolved in 40 ml of dichloromethane, and 2-ethoxypropene 2.
Add 3g and 0.46g of pyridine hydrochloride, and stir at room temperature.
Stir for 5 minutes. Hereinafter, erythromycin A 9-[0-(1-ethoxy-
2.03 g of 1-methylethyl) oxidiumco were obtained as a foam.

m, p, 106.5-107.5°C (recrystallized from dichloromethane-isopropyl ether) 'H-NMR (CDCp3); S (ppm) = 2.29 [3'-N(CHx)z]
.

3, 33 (3”-OCHm).

3.48 (-0CdanzCHi) “C-NM　R(CD(J’3); S (ppH1>-15,4(-0CHICHa).

24.2 and 24.5 [-0-C(danHs)to-].

40, 3 [3'-N(CHm)z].

49.5<3--0 CHI).

57.5 (-0 degrees H * CHs).

1 0 3.6[-0-C(CHI)! O-ko Mass
(FAB); m/z = 835 (MH") (2) Dissolve 18 g of the compound 4' obtained above in 30 ml of dichloromethane, and 1.4 g of trimethylsilylimidazole and 1.25 ml of trimethylchlorosilane dissolved in 5 ml of dichloromethane. was added and stirred at room temperature for 20 minutes.The following treatment was carried out in the same manner as in Example 1 (2), and the obtained residue was recrystallized from chloroform-acetone to obtain 2'
, 3.9 g of 4"-0-bis(trimethylsilyl)erythromycin A 9-[0-(1-ethoxy-1-methylethyl)oxime] was obtained.

m, p, 120-122°C' H-NMR (CDCf3): 8 (ppm)
= 0, 10 (2'-0-IMS).

0.14 (4″-〇-TMS).

2.2 3 [3'-N<CHa) Oko.

3.31 (3″-0CR,) Mouth C-NM　R(CDC4)3); S (ppm) -0, 6 (4--0-TMS).

0.7 (2°-0-, IMS>.

24.0 and 26.3 [-0-C (dan am), o].

40, 7 [3'-N<CHi)t].

49, 3 (3”-OCHm).

57, 0 (-0-CH! CHn).

1 0 3.1[-0-(≧(CHa)-0-koMas
s(EI); m/z=978 (M”) (3) 1.96 g of the compound obtained above was mixed with dimethyl sulfoxide/tetrahydrofuran <1/1) mixed solvent 1
00td, methyl iodide 0.19mQ and 8
171 mg of 5% potassium hydroxide powder was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, the treatment was carried out in the same manner as in Example 1 (3), and the obtained residue was recrystallized from acetone to obtain 2'.

4”-〇-bis(trimethylsilyl)-6-0-methylerythromycin A 9-[0-(1-ethoxy-1
-methylethyl)oxime] 1.63 g was obtained.

ff1. p, 127.5~b 'H-NMR (CDCj23); S (pptn)-0,08 (2'-0-IMS).

o, 14 (4--o-TMS).

2.2 2 [3'-N (CHz)t.

3.08 (6-OCHI).

3, 32 (3-OCHi) “C-NM　R(CDCc): S (ppm) - 0.5 (4'' - 0-TBS).

o, s (2'-0-ThS).

23.8 and 24.6' [-0-C(danHm)tO-].

40.7 [3″-N(CHm)z].

49.4 (3”-0CR,).

50.6 (6-OCHm).

56.3 (-0-dan H, CH,).

102.4[-0-dan(CHA)-0-]Mass(E
I); m/z = 99 2 (M”) Example 5 (1) Erythromycin A 9-oxime 2g was dissolved in dichloromethane 40rd, 2-impropoxypropene 2.67g and pyridine hydrochloride 0.46g was added and stirred at room temperature for 15 minutes.Hereinafter, Example 1 (1)
Erythromycin A 9-(0-[
2.05 g of 1-(1-methylethoxy)-1-methylethyl]oxime was obtained.

m, p, tos ~ 108°C (recrystallized from dichloromethane-isopropyl ether) ' R-N M R (CDC4+3); S (ppm
) = 2, 29 [3'-N(CHa)zl.

3.33 (3”-0CHI).

4,00 [-0-CH(,CHs)*]"C-NM
R (CDC et al.); 5(1)1)ffl)-24,1,24,3,24,5
and 25.6 [=OC(danHs)t O-CH(danHm)t]
.

40, 3 [3=N(CHsL]- 49,5 (3”-OCHs).

64.6[-0°H(CHi)zl.

103.9[-0-dan(CHs >x O-]Mass
(FAB); m/z=849<MH”) (2) 3 g of the compound obtained above was dissolved in 3 g of dichloromethane.
Add 1.04 td of trimethylsilylimidazole and 0.90 mfl of trimethylchlorosilane dissolved in 5 ml of dichloromethane,
2N-sodium hydroxide solution and water were added to the stirred reaction solution for 1 minute, the organic layer was separated, and the aqueous layer was evaporated with 20ml of dichloromethane.
Extracted with 1 liter.

The organic layers were combined, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from aqueous acetone to give 2゛,4''-〇-bis(
trimethylsilyl)-erythromycin A 9-(0
-[1-(1-methylethoxy)-1-methylethylcoxime) 2.46 g was obtained.

m, p, 93-96°C (recrystallized from hydrous acetone)'
H-NMR (CDCg3); S (ppm)
-o, 1o (2'-o-rMs).

0, 15 (4”-0-IMS).

2, 23 [3'-N (CHs)*].

3.30 (3”-〇CHD.

4.00 [-〇Gdan (CHi)zl IC-NMR (CDCR3); S (ppm>-0, 7 (4"-0=TMS).

0, 8 (2'-0-TMS).

2 3.9.2 4.0 24.4 and 25.3 [-0-C((≧Hs)to-CH(CHi)tco94
0,8 [3”-N<CHm)t]-49,5(3”
-OCHm).

64.2(-0-danH(CHs)xl.

103.5[-0-(≧(CHi)io-copiass
(EI) i m/z = 992 (M”) (3) 1 g of the compound obtained above was mixed with 10 rn of a mixed solvent of dimethyl sulfoxide/tetrahydrofuran (1/1).
0.08 ynO of methyl iodide and 73 mg of 85% potassium hydroxide powder were added under water cooling, and the mixture was stirred for 90 minutes. Hereafter, the same process as in Example 1 (3) was carried out.
',4''-〇-bis(trimethylsilyl)-6-0-methylerythromycin A 9-(0-[1-(1-methylethoxy)-1-methylethyl]oxime) 0.
95g was obtained.

m, p, 115.5-118.5°C (recrystallized from aqueous acetone) 'H-NMR (CDCI23); S (ppm) = 0, 09 <2'-0-TMs
).

0.15 (4°-0-TMS).

2.23[:3'-N(CHs)t].

3.08 (6-OCHM).

3.32 (3”-0CHI).

4,08 [-0CH(CHs)*]"C-NMR
(CD(J'3); S (ppm) -0, 8 (4=-○-TMS).

0, 9 (2'-0-TBS).

24.0, 24.3 24.7 and 25.6 [-〇-C(danHs) to -CH(danHi)t
].

4 0.9 [3-N (CHm)t.

49, 6 (3”-OCHm).

50.8 (6-OCHm).

63.5(-0-danH(CHi)tl.

102, 9 [-〇-〇 (CHs)to-1Mas
s(EI); m/z = 1006 (M") Example 6 2',4"-〇-bis(trimethylsilyl)-erythromycin A9-[0-(1-
Dissolve 1 g of methoxy-1-methylethyl)oxime in 20 ml of a mixed solvent of dimethyl sulfoxide/tetrahydrofuran (1/1), add 0.09 ml of methyl iodide and 45 mg of 60% oily sodium hydride, and stir at room temperature for 2 hours. After the 0 reaction, 0.5 ml of 50% dimethylamine aqueous solution was added, and stirring was continued for 30 minutes. water 50
Add ml and ethyl acetate (50mQ and 25ml)
After extraction, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the same compound 2゛,4''-〇- as obtained in Example 1 (3) was obtained.
Bis(trimethylsilyl)-6-〇-methylerythromycin A 9-[0-(1-methoxy-1-methylethyl)oxime] 0.9 g.

I got it.

Example 7 Erythromycin A9-[0
-(1-methoxy-1-methylethyl)oxime]2.
46 g, and 3.0 ml of 1.1.1.3,3.3-hexamethyldisilazane were dissolved in N,N-dimethylformamide 1
The solution was dissolved in 0ml and stirred at 60-70°C for 8 hours. After that, leave it at room temperature for 2 days, and add 200ml of ethyl acetate to the reaction solution.
1 was added thereto, washed three times with 100 ml of saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the same foamy substance 2' as the compound obtained in Example 1 (2) was obtained.
2.6 g of 4''-0-bis(trimethylsilyl)erythromycin A 9-[0-(1-methoxy-1-methylethyl)oxime] was obtained.

Example 8 Erythromycin A 9-oxime 7.49 g was dissolved in 100 ml of dichloromethane, 2-methoxypropene 9. Added omi. 1.74 g of pyridine hydrochloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. To this, 1.1.1.3.3.3-hexamethyldisilazane 1.
25 trdl was added and stirring continued for an additional 3 hours. 100 ml of dichloromethane and 1 liter of saturated sodium carbonate aqueous solution
After adding 00 mQ and stirring thoroughly, the dichloromethane layer was separated. The dichloromethane layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure, and the resulting foam was crystallized from acetone to give the same compound 2 as obtained in Example 1 (2).
8.74 g of 4''-0-bis(trimethylsilyl)-erythromycin A 9-[0-(1-methoxy-1-methylethyl)oxydimco was obtained.

Example 9 Erythromycin A 9-oxime (1 g) was dissolved in dichloromethane (7 mH), and pyridine was added under water cooling. Acid acid 0.23g
Then, 1.3 g of 2,2-dimethoxypropane dissolved in dichloromethane 3rd was added and stirred at room temperature for 24 hours. After the reaction, the mixture was added to a 2N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and erythromycin A9-[0-(1-methoxy-1
-methylethyl)oxime] was obtained as a foam.

This material was the same compound as that obtained in Example 1(1).

Example 10 (1) 10 g of erythromycin A 9-oxime was mixed with N,
Dissolved in 50ml of N-dimethylformamide, added 2.31g of pyridine hydrochloride, and then cooled with water for 1°1.1.
3.3. Added 5.6 ml of 3-hexamethyldisilazane and continued stirring at room temperature for 5 hours. After the reaction, 50 ml of 2N aqueous sodium hydroxide solution and 50 ml of water were added and extracted with ethyl acetate (100 mQ and 50+d). .

The organic layer was washed with water (<50 ml x 2) and 50 ml of saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under pressure to give 11.9 g of 2',4'-〇-bis(trimethylsilyl-erythromycin A 9-year-old xime). H! It was purified by recrystallization from aqueous acetone.

H-NMR (CDCj23)δ(ppm)-
0, 1 1 (2'-0-TMS)0,
15(4"-〇-TMS) 2 , 2 1 [3'-N(c Hs)tco3
．． 30 (3”-0CR,) 8.05 (=N-OH) IC-N MR (CDCj23) S (ppm) = 0, 9 <4--0-TM
S) 1, 0 (2'-0-TMS) 4 1. 0 [3'-N(CHmLko49.8(3
"-OCH,) Mass (EI); m/z = 892 (M") (2) 1 g of the compound obtained above was added to 7 m of dichloromethane.
194 mg of pyridine hydrochloride and then 1.17 g of 2,2-dimethoxypropane were added under ice-cooling and 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 saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.70 g of 2',4''-〇-bis(trimethylsilyl)-erythromycin A9-[0-(1-methoxy-1-methylethyl)oxime]. This was the same compound as that obtained in Example 1 (2).

Example 11 330 mg of erythromycin A 9-oxime was dissolved in 2.3 ml of dichloromethane, 80 mg of pyridine hydrochloride was dissolved in 2.3 ml of dichloromethane, and then dissolved in 1 ml of dichloromethane.
, 0.7 g of 2-diisopropoxypropane was added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, the same treatment as in Example 9 was carried out to obtain 370 mg of erythromycin A 9-(0-[1-(1-methylethoxy)-1-methylethylcoxime). This material was the same compound as that obtained in Example 5(1).

Example 12 1 g of 2',4''-〇-bis(trimethylsilyl)-erythromycin A 9-oxime obtained in Example 10 (1) was dissolved in 5 ml of dichloromethane, and 194 mB of pyridine hydrochloride was added under water cooling, followed by 2 ml of dichloromethane. 449 mg of 2,2-diisopropoxypropane dissolved in was added and stirred at room temperature for 1.5 hours.Hereinafter, Example 10 (2
) to give 2′,4″-O-bis(trimethylsilyl)-erythromycin A9-(O-[1-(1-
methylethoxy)-1-methylethylkoxime)1.
1g was obtained. This substance was the same compound as that obtained in Example 5(2).

Example 13 <1) 10 g of erythromycin A 9-oxime was dissolved in 40 mQ of dichloromethane, and 2-n- was dissolved in 2.3 g of pyridine hydrochloride and 30 ml of dichloromethane while cooling with water.
6.1 g of butoxypropene was added, followed by stirring at room temperature for 1 hour. Thereafter, erythromycin A 9-[0-(1-n-butoxy-1-
2.75 g of (methyl ethyl) oxyjimco was obtained.

m, p, 93-95 °C (recrystallized from ether-petroleum ether) 'H-NMR (CD (J3); S (ppm) = 0.9 1 [-0 (CHtL
CH, co2.28[3″-rBcHs)z].

3.32 (3”-0CR,).

3.40(-QCCHcutcHtcHm)Mass(
FAB); rn/z-865(MH”) (2) 2 g of the compound obtained above was dissolved in dichloromethane 20
0.68 mQ of trimethylsilylimidazole dissolved in 5 mQ of dichloromethane and 0.59 ml of trimethylchlorosilane were added thereto, and the mixture was stirred at room temperature for 10 minutes. Hereinafter, the residue obtained by the same treatment as in Example 1 (2) was subjected to florisil column chromatography (eluent: acetone: n-hexane: triethylamine-1:
5:0.01) to produce 2',4''-〇-bis(trimethylsilyl)-erythromycin A 9-[
0-(1-n-butoxy-1-methylethyl)oxime] 2.32 g was obtained.

'H-NMR (CDCρ3); S (ppm) = 0, 09 (2'-0-TMS>
.

0.14 (4"-〇-IMS).

0. 9 0 [-0(CHt)m CH, ko2, 2
2 [3”N(CHi)*].

3.30 (3--OCHI).

3.40 [-QCdan, CH, CH, CH,)Mass(
FAB): m/z=LOO9(MH") (3) 1 g of the compound obtained above was treated in the same manner as in Example 1 (3) to obtain 2',4"-〇-bis(trimethylsilyl)- 6-0-Methylerythromycin A 9-
1.00 g of [0-(1-n-butoxy-1-methylethyl)oxime] was obtained.

'H-NMR (CDCI+3); δ (ppm>= 0, 08 <2°-0-]: MS)
.

o, 14 (4--0-TMS).

2.2 1[3,', -N(CHm)*ko.

3, 06 (6-OCHi).

3, 30 (3”-OCHa) C-NMR (CDC4) 3): 6i (ppm>=0, 9<4”-0-
IMS).

1, 1 (2'-0-TMS>.

4 1. 0 [3'-N (CHi)tco.

49.7 (3”-0CHA).

50, 9 (,6-OCHm).

6 1.2 [-0-CHICHICHzc Hsko1
02.7 [-0-dan (cHn) to -] Mass (FA
R)" m/z = 1023 (MH") Example 14 (1) Erythromycin A 10 g of 9-oxime was dissolved in 70 ml of dichloromethane, 2.3 g of pyridine hydrochloride was added under water cooling, and then 1-methoxy was dissolved in 30 ml of dichloromethane. 8.58 g of -1-cyclohexene was added. After stirring overnight at room temperature, the reaction mixture was poured into 100 ml of 2N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform: methanol: aqueous ammonia - 10: 1: 0.1), and then recrystallized from chloroform-isopropyl ether to obtain erythromycin A 9-[0 -(1-methoxycyclohexyl)oxime] 2.40 g was obtained.

m, p, 117-118°C' H-NMR (CDCF3); & (ppm)
-2,28[3'-N(CHs)! ko 3.32 (3'-
〇 〇 Hm) IC-N MR (CD (Jls) & (ppm) -40,30 [3' -N (CHI)!]
Mass (FAB); m/z=861 (MH”) (2) 2.2 g of the compound obtained above was dissolved in 11 ml of feN, N-dimethylformamide, and heated to 1.1°1.3.3.3 under water cooling. - 1.65 g of hexamethyldisilazane.

Then, 0.44 g of pyridine hydrochloride was added, and the mixture was stirred at room temperature for 4 hours. Thereafter, the same procedure as in Example 10(1) was carried out to obtain 12.55 g of 2',4''-〇-bis(trimethylsilyl)-erythromycin A 9-[0-(1-methoxycyclohexyl)oxime.

'H-NMR (CDCf3); f; (ppm) -0, 10 (2'-0-TMS).

0, 15 (4-0-TMs).

2, 24 [3'-N(CHs)x].

3.30 (3″-〇 〇 HA) IC-NMR (CDCf+3); 1; (ppo+) -0, 91 (4″-0-IMS)
.

1, 02 (2-o-1Ms).

41, OOC3'-N (CH1) tl.

Mass (CI); +n/z-1005 (MH") (3) 2.2 g of the compound obtained above was dissolved in 22 ml of dimethyl sulfoxide, and 0.23 ml of methyl iodide was added under cooling with water.
mfl and 190 mg of 85% potassium hydroxide powder were added and stirred at room temperature for 3 hours. The following treatment was carried out in the same manner as in Example 1 (3) to obtain 2゛,4''-〇-bis(trimethylsilyl-〇-methylerythromycin A 9-[0-(1-
methoxycyclohexyl) oxyjimco2. 01 g was obtained.

'H-NM R (CDCI!3).

δ(1)pm)-0, 10(2'-0-TMS)0,
14 (4”-0-'fMs) 2 , 21 [3'-N(CHA)!] 3 , 11 (
8-OCHs) 3.31 (3'-OCHm) "C-NMR (CDCR3); S (ppm>-o, 90 (4"-o-rMs)
1.06 (2'-0-MS> 4 0.9 8 [3'-N (CHalt 49.71
(3' -0CR,) 51.17 (6-OCR,) Mass (CI) H rn/z-1019 (Mu") Example 15 Erythromycin A 9-oxime 1 g was dissolved in dichloromethane 10 ml, and pyridine hydrochloride 0 Next, 1.1 g of 1,1-dimethoxycyclohexane dissolved in 3 ml of dichloromethane was added, and the mixture was stirred at room temperature for 24 hours. cyclohexyl)oxime] 0.65 g was obtained. This material was obtained in Example 14 (1
) was the same compound as that obtained in .

Example 16 (1) 5 g of erythromycin A 9-oxime and 1.16 g of pyridine hydrochloride were added to 25 ml of dichloromethane.
triethyl orthoformate 11, dissolved in water and cooled with water.
After the reaction of adding lrd dropwise, stirring was continued for 4.5 hours at room temperature. Hereinafter, the crude product obtained by the same treatment as in Example 14 (1) was subjected to silica gel column chromatography (eluent: acetone, 20-hexane: triethylamine-3: 1).
Erythromycin A 9-[
0-(Jethoxymethyl>oxime) 3.44 g was obtained.

'H-NMR(CDCj)3);l;'(ppm)-2,28[3'-N (CHl)
! ].

3.32(3"-〇〇H,) 5.64[-Cdan(OCtHs)t] 1C-NMR(CDCR3); S (ppm)-40,3[3'-N(CHl)2 KO49.5(3”-0CR1) 60.9 and 62,5 [-0CH(OdanHt CHi)zl.

1 1 5.7[-04nH(OC*H*)xcoM
ass (FAB); m/z=851 (Ml”) (2) 2.5 g of the compound obtained above was dissolved in 25 ml of dichloromethane, and 0.5 g of trimethylsilylimidazole was added.
86ml and 0.75ml trimethylchlorosilane
Using silica gel column chromatography (
Eluent, acetone:n-hexane:triethylamine-
1:5:0.01) and purified with 2゛,4''-〇-bis(trimethylsilyl)-erythromycin A
9-[0-(jethoxymethyl)oxymco 1.55
I got g.

m, p, 98-103℃ (recrystallized from n-hexane)
"H-NMR (CDCff3).

8 (ppm) = 0, 10 (2'-0-TMS)
.

0, 15 (4”-0-TMS).

2.2 3 [3’-N(CHa)! Ko.

3.30 (3"-OCHm).

5, 65 [-CH(OCzHi)*]"C-NM
R(CDCff3); δ(ppm) = 0
, 9 (4′-OTMS).

1.0 (2'-0 engineering MS).

41,0 [3'-N(CHm)zl-49,8(3
”-OCHm).

60.8 and 62.3 [-0CH (Odan HICHs)! ]-115,7[-0CH(OCtHi)tlMasS(F
AB): m/z-995 (MH”) (3) Using 1 g of the compound obtained above, Example 5 (
3), 2',4''-〇-bis(trimethylsilyl)-6-0-methylerythromycin A
9-[0-(jethoxymethyl)oxime] 0.
I got 99g.

'H-NMR (CDC4)3); S (ppm)-o, 09 (2-o-rMs).

0.15 (4”-〇　-TMS).

2.2 1 [3’-N(CHl)! Ko.

3, IG (6-OCHs).

3.30 (3″-OCH,).

5.65 [-Cdan (OC*Hi)*] "C-NM R (CDCF3): δ (ppm) = 0.9 (4”-0-XMS).

1, 1 (2'-0-TMS).

4 1. 0 [3'-N(CHs)*ko.

49.7<3'-OCHm)- 50,9(6-OCHi).

60.2 and 61.4 [-0CH(OdanHt CHs)-]-115, 9[-
0CH(OCxHs)t]Mass(FAB); m/z=1009 (Ml('') Example 17 2°, 4''-0-bis(trimethylsilyl)-erythromycin A obtained in Example 10(1) 9 -oxime 1g1 Example 10 (2
), 2゛,4''-O-bis(trimethylsilyl)-erythromycin A9-[0
0.60 g of -(jethoxymethyl)oxymco was obtained. This material was the same compound as that obtained in Example 16(2).

Example 18 10 g of erythromycin A 9-oxime was dissolved in 50 ml of N,N-dimethylformamide, 1.07 g of ammonium chloride and 5.6 ml of 1.1.1.3,3.3-hexamethyldisilazane were added. Stirring was continued for 20 hours at room temperature. The following treatment was carried out in the same manner as in Example 10 (1) to obtain 11.0 g of 2',4'-0-bis(trimethylsilyl)-erythromycin A 9-year-old xime. It was the same compound as that obtained in .

Example 19 - Dissolve 5 g of erythromycin A 9-oxime in 100 ml of dichloromethane and add 5 ml of isopropyl alcohol.
Add 1 l, 6.4 g of 2-methoxypropene and 1.15 g of pyridine hydrochloride and stir at room temperature for 1 hour. Saturated sodium bicarbonate solution was added to the reaction mixture, extracted with chloroform, and the organic layer was washed with saturated brine. Afterwards, it was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and erythromycin A 9-(0-[1-(
1-methylethoxy)-1-methylethyl]oxime)
5.4g was obtained.

Example 20 (1) Erythromycin A 9-oxime 7, 49g was dissolved in dichloromethane 100, cyclohexyl alcohol 10.4d, 2-methoxypropene 9.6ml!
and 1.74 g of pyridine hydrochloride were added and stirred at room temperature for 1 hour. Thereafter, the residue obtained by the same treatment as in Example 19 was subjected to silica gel column chromatography (eluent: acetone: n-hexane: triethylamine - 1:5:0.1).
~3:10:0.2) and recrystallized from aqueous acetone to obtain erythromycin A9-[0-(1-cyclohexyloxy-1-methylethyl)oxime] 5
．． I got 73.

m, p, 107-109.5℃ 'H-NMR (CDCβ3); S(ppm)-2, 29[3'-N(CH8>2].

3,30 (3"-OCR's)"C-NMR (CDCI!3); S (ppm) = 40. 1 [3'-N<
CHs) x co.

1 0 3.7[-0-C(CHI)! O-ko Mass
(FAB); m/z =889 (MW”) (2) 3 g of the compound obtained above was added to 30 ml of ethyl acetate.
1.2 ml of trimethylsilylimidazole dissolved in 5 ml of ethyl acetate and 0.72+nl of trimethylchlorosilane were added, and the mixture was stirred at room temperature for 10 minutes.

Thereafter, the same process as in Example 5 (2) was carried out to obtain 2′, 4″-〇-
Bis(trimethylsilyl)erythromycin A9-[0
-(1-cyclohexyloxy-1-methylethyl)oxime] 3.22 g was obtained.

m, p, 98-103°C (recrystallized from n-hexane)'H-NMR (CDC4)3); S (ppm)-o, 10 (2°-0-TMS)
.

0.15 (4″-〇-IMS).

2.2 4 [3'-N (CHs>x).

3.32 (・3″-0CR,) Mouth C-NMR (CDCI23): S (ppm) -0,9 (4-0-TMS).

1, 0 (2'-0-IMS).

4 0. 9 [3’-N<CHa”)zko.

103.8[-0-dan(CHm)to-]I1ass(
CI);.

m/z = 1033 (MH") (3) 2 g of the compound obtained above was dissolved in 100 mil of dimethyl sulfoxide/tetrahydrofuran (1I1), and dissolved using 0.18 mu of methyl iodide and 160 μ of 85% potassium hydroxide powder. The treatment was carried out in the same manner as in Example 1 (3), and the obtained residue was recrystallized from acetone at 2° and 4°C.
1.2 g of "-0-bis(trimethylsilyl)-6-0-methylerythromycin A 9-[0-(1-cyclohexyloxy-1-methylethyl)oxime]" was obtained.

m, p, 202-203℃ (recrystallized from acetone)'
H-NMR (CDCI23); S (ppm) -o, o s (2'-o -r
hs).

0.14 (4"-〇-TMS).

2.2 2 C3'-N (CHm) i.

3, 07 (6-OCHs”)- 3, 32 (3”-OCHs) Eye C-NM　R(CDCI23); E (ppm > 0, 8 (4”-0-IMS).

0, 9 (2'-0-TMS).

4 0.9 [3'-N(CHaLko.

49, 6 (3”-OCHn).

50.8 (6-OCHm).

103.0[-Q-dan(CH,),0-]Mass(F
J) ; m/z = 1046 (M”) Example 21 (1) 7 g of 2゛,4“-〇-bis(trimedelsilyl)erythromycin A 9-oxime obtained in Example 10 (1) was added to 35 ml of dichloromethane. Dissolve and add 136 g of pyridine hydrochloride under water cooling, then 14 m of dichloromethane.
2,2-diisopropoxybutane dissolved in 1 3.41
g and stirred at room temperature for 1.5 hours. Example 10 below
2゛,4''-〇-bis(trimethylsilyl)erythromycin A9-(0-[1-(1)
-methylethoxy)-1-methylpropyl]oxime)
7.5g was obtained.

“H-NMR (CDCI23); S (ppm)-o, 10 (2-o-rMs).

0, 15 (4-0-TMS).

2.2 4[3'-N(CHaLko.

3, 31 (3-OCHm).

4, 0 3 [-0-Cdan(CHs)tkoIC-
NMR (CDCR3): S (ppm) = 0, 92 (4”-0-TMS
).

1, 02 (2'-0-TMS).

8.6 0 [0-CTCHA)CH,CHa Miko
1, OO[3'-N(CHa)zco.

49.73 (3-OCH,).

106 , 05 [-0-CCHs<CtHs)-]M
ass (CI); m/z = 1006 (M”) (2) 4 g of the compound obtained above was added to 40 ml of a mixed solvent of dimethyl sulfoxide/tetrahydrofuran (1/1).
2',4''-〇-bis(trimethylsilyl)-
6-0-methylerythromycin A 9-(0-[1
-(1-methylethoxy)-1-methylpropyl]oxime) 3.87 g was obtained.

'H-NM R (CDCR3): 8 (ppm)-0, 10 (2'-0-TMS).

0.15 (4″-〇-TMS).

2.23 [3’-N(CHI)! ].

3.09 (6-OCH,).

3.33 (3-OCHI) Mouth C-NMR (CDC1) 3): S (ppm) -0, 91<4''-0 (MS).

1, 07 < 2’-〇　-TMS).

8.64 and 8.83 ■ [0-C(CHI)CHtdanHm] 41.00 [3″-N(CHa)*].

4.9, 71 (3”’-OCHg).

50.95 and 51.19 (a -o CHs > 105.62 [-0-dan CHs (Cz Hs )-]
Mass (C engineering); m/z = 1021 (MH”) Example 22 Erythromycin A 9-oxime 1g was dissolved in dichloromethane 7ml, and pyridine hydrochloride 0.23g was added under water cooling.
, then 2,2-di-
Add 2.51 g of n-butoxypropane and stir at room temperature.
Stirred for 4 hours. Thereafter, the same treatment as in Example 10(2) was carried out to obtain 0.83 g of erythromycin A 9-[0-(1-n-butoxy-1-methylethyl)oxime]. This material was the same compound as that obtained in Example 13(1).

Example 23 2′,4″-〇-bis(trimethylsilyl)erythromycin A 9-oxime 1 obtained in Example 10(1)
Dissolve 194I of pyridine hydrochloride in 7rnll of dichloromethane and cool with water. Ig and then 2.11 g of 2.2-di-n-butoxypropane were added, and the mixture was stirred at room temperature for 5 hours. Thereafter, the same process as in Example 10 (2) was carried out.

0.42 g of 4″-〇-bis(trimethylsilyl)erythromycin A 9-[0-(1-n-butoxy)-1-methylethyl)oxime] was obtained. This material was obtained in Example 13(2). It was the same compound as the one.

Example 24 (1) Erythromycin A 9-year-old xime 2.48 g
was dissolved in 17 mfl of dichloromethane, 0.58 g of pyridine hydrochloride and then 1.7 g of 2-methylenetetrahydrofuran dissolved in 7.5 ml of dichloromethane were added, and the mixture was stirred at room temperature for 3 hours. Hereinafter, the product obtained by the same treatment as in Example 5 (1) was purified by silica gel column chromatography (eluent: acetone: n-hexane: triethylamine-3: 10: 0.2) to obtain erythromycin A 9- 2.25 g of [0-(2-methyl-2-tetrahydrofuryl)oxidimco] was obtained.

'H-NMR (CDC et al.); δ (ppm) -1,54 and 1.55 [-QC (CH
,)O-co2.29 [3'-N(CHI)! ].

3, 32 (3”-OCHi).

"C-NMR(CDCM);S(pP'O))-2a, s2 and 24.62
[OC(danH,)O-] 40 , 32 [3=N(CHi)zl.

49.49 (3″-OCH*).

68.90 [-00Ht- (furan ring)] (2) 2 g of the compound obtained above was dissolved in 1 N,N-dimethylformamide.
416mg of pyridine hydrochloride dissolved in 0ml and cooled with water.
and it, 1.3.3.3-hexamethyldisilazane 9
70o+g was added and stirred at room temperature for 6 hours. Thereafter, 2' was processed in the same manner as in Example 10 (1).

2.18 g of 4''-〇-bis(trimethylsilyl)erythromycin A 9-[0-<2-methyl-2-tetrahydrofuryl)oxidimco was obtained.

'H-NMR (CDCf3); &(ppm)=o, tO(2'-0-tech1is).

o, 15 (4-0-TMS).

1.54 and 1.55 [-0C(CH,)O-]2,23[3'-N<CHs)t13.30(3''
-0CHI) IC-NMR (CDCj23).

E (ppm) = 1.4 6 (4”-0-T
B.S.).

1, 58 (2'-0-TMS).

24.31 and 24.94 [-〇〇(Me≧H8)0-ko 41.54 [3-N(CH,), co.

50.28 (3”-0CR,).

69.37[-0CHt (7-run ring)]Mass(
CI): rn/z-977 (M") (3) 1.9 g of the compound obtained above was dissolved in a mixed solvent of dimethyl sulfoxide/tetrahydrofuran (1/1) 19
ml, and treated in the same manner as in Example 1 (3) using 360 mg of ethyl iodide and 154 mg of 85% potassium hydroxide powder to obtain 2',4''-〇-bis(trimethylsilyl)-6-0-methyl. Erythromycin A 9-[0
-(2-methyl-2-tetrahydrofuryl)oxime]
1.64g was obtained.

'H-NMR (CDCI23); 1; (ppm) -o, 09 (2'-o -T
MS).

0, 15 (4”-0-IMS>.

1.53 and 1.56 [0-C(CH,)O-] 2.21[3°-N(cHt>x] 3,08 (6-OCHa) 3.31(3"-0CR,) IC -NMR(CD(J'3); S (ppm) -0, 90(4''-0-IMS)1
, 06 <2'-0-IMS).

23.53 and 24.17 [0C((nH3)0-co 40, 99 [3'-N(CHa)].

49, 72 (3”-OCHm).

50.91 (6-OCHm) 69.08[-0CH! -(furan ring)]Mass(Q
); m/z=991 (MH”) Example 25 Erythromycin A 9-year-old xime 4.45g dissolved in cyclomethane 31mQ, pyridine hydrochloride 1.03g
1. Next, 4.75 g of 5-methyl-2,3-dihydrofuran dissolved in 13 ml of dichloromethane was added, and the mixture was stirred at room temperature for 24 hours. Erythromycin A 9-[0-(2-methyl-
3.0 g of 2-tetrahydrofuryl oxime was obtained.

This substance was the same as the metal compound obtained in Example 24(1).

Example 26 2′,4″-〇-bis(trimethylsilyl)erythromycin A obtained in Example 1(2) 9-[0-(1
-methoxy-1-methylethyl) oxyjimco 3,86
g in dimethyl sulfoxide/tetrahydrofuran (1/
Dissolve in 200 ml of mixed solvent of 1) and add ethyl iodide 1.
6 ml and 780 mg of 85% potassium hydroxide powder were added and stirred at room temperature for 1.5 hours. The following treatment was carried out in the same manner as in Example 1 (3), and the obtained residue was recrystallized from methanol to obtain 2',4''-〇-bis(trimethylsilyl)-6-0-
1.55 g of ethylerythromycin A 9-[0-(1-methoxy-1-methylethyl)oxymco was obtained.

Mass (FAB); m/z = 993 (MH”) Example 27 (1) Erythromasin A 9-oxime 3.74 g was dissolved in dichloromethane 150 ml, ethyl vinyl ether 3. OmQ and pyridine hydrochloride 1.73 fi was added and left at room temperature for one week.The following treatment was carried out in the same manner as in Example 1 (1) to obtain erythromycin A 9-[0-/1-
3.5 g of Oxijimco (methoxyethyl) was obtained.

"H-NMR(CDCF3); S(ppm)-1,42[0-CH(Cdan,)O-]2
, 30 [3'-N(CHx)*].

3.34 (3”-〇CHm) “C-NM　R(CDCff3); l; (pptn)-15, 5 (OCHtCHs).

20.2[0-CH(danH*)O-].

40, 3 [3'-N<CHm)tl.

49, 5 (3”-OCHz).

Mass (FAB): m/z = 821 (MH") (2) Dissolve the compound 820TIg obtained above in N,N-dimethylformamide 5r + tl, 1.1.1,
3.3° 0.41 mQ of 3-hexamethyldisilazane and 80 μm of ammonium chloride were added, and the mixture was stirred at room temperature for 4 hours. Thereafter, 2' was treated in the same manner as in Example 10 (1'),
4″-〇-bis(trimethylsilyl)erythromycin A-9-[0-(1-ethoxyethyl)oxime core 0
I got 0■.

'H-NMR(CDCF3) ;1; (pp
IIll)-0, 10 (2'-〇-Ding MS).

0, 15 < 4--0-TMS).

1. 5 3 [0-CH(CH,)O-co2.2
0 [3'-N (CH) hit] 3.31 (3''-〇 G,, Hs) Mass (FA
B); m/z = 965 (MH”) (3) The compound 650 obtained above was dissolved in a mixed solvent of dimethyl sulfoxide/tetrahydrofuran (<1/1) 14
ml of methyl iodide and 0.06ml of methyl iodide under water cooling. and 58 cm of 85% potassium hydroxide powder, and
Stir for hours. The following process was carried out in the same manner as in Example 1 (3).
10rrg of 4''-0-bis(trimethylsilyl)-6-0-methylerythromycin A9-[0-(1-ethoxyethyl)oxime coro was obtained.

”　H-NMR (CD (J’3): δ(ppm)-0,09(2'-0-'rMs).

Q, l 6 (4--0-TMS).

1 , 10 [0-CH(Cdan5)O-]2.2 2
[3'-N<CHa>t]3,07 (6-OCH
a) 3,32 (3′-OCHs) Mass (FAB); m/z=979 (MH”) Example 28 (1) 2′,4″-〇-bis obtained in Example 10(1) (Trimethylsilyl)erythromycin A 9-oxime 8041'Ig and 156 ng of pyridine hydrochloride were dissolved in 4 mQ of dichloromethane, and 1 mQ of dichloromethane was added under water cooling.
．． 338 ITg of 3,3-diisopropoxypenkune dissolved in 6 ml was added, and the mixture was stirred at room temperature for 6 hours. Thereafter, it was treated in the same manner as in Example 10 (2).
trimethylsilyl)-erythromycin A 9-(0
-[1-(1-methylethoxy)-1-ethelbropylcoxime) 860 ng were obtained.

'H-NMR (CDCj23); S (ppm) = 0, 11 (2'-0-TMS)
.

o, 1s (4--o-TMs>.

2, 25 [3'-N(CHi)t].

3, 30(3--OCHa) 4.0 4 [-0-CH(CHl)tth c -N
M R (cDcR3); S (ppm) = 0, 9
1 (4-10-TMS).

1, 02 (2'-0-TMS).

40.99[:3'-N(cHt)z].

49, 73 (3--OCHm).

108.32 [-0-dan (C, Hs)! O-]Mass
(FAB); m/z 1021 (crude) (2) The compound 669 obtained above was dissolved in a mixed solvent of dimethyl sulfoxide/natohydrofuran (1/1) 6.6
0.06rrIi of methyl iodide dissolved in mQ and cooled with water.
and 55 μm of 85% potassium hydroxide powder were added thereto, and the mixture was stirred at room temperature for 2 hours. The following treatment was carried out in the same manner as in Example 1 and 3).
, 4”-〇-bis(trimethylsilyl)-6-〇-methylerythromycin A 9-(0-[1-(1-methylethoxy)-1-ethylpropyl]oxime) 63
0 ng was obtained.

'H-NMR (CDC&+:s); S (ppm) = 0, 11 (2'-0-IMS)
.

0, 15 < 4 = -0-TMS).

2.2 7 [3'-N(CHi)*ko.

3, 10 (6-OCHs')- 3,31 (3”-0CHI).

4.1 0 [-0-Cdan (CHI) 1co”C-NMR
(CDC et al.); S (ppm) -0, 9t (4"-〇-TMS)
.

1, 13 (2'-〇-TMS).

40, 99 [3'-N<cHm)*].

49, 70 (3”-OCHm).

51.22 (6-OCHs).

107.87 [-0-dan (c, Hs) to-]Mass
(FAB): 01/Z-1035(MH”) Example 29 (1) Erythromycin A 9-oxime 468Trg
Dissolve in 5 ml of dichloromethane and add 1 ml of pyridine hydrochloride.
08 ml, then 367 ml of 2-benzyloxypropene dissolved in 2 ml of dichloromethane were added, and the mixture was stirred at room temperature for 2.5 hours. Thereafter, the residue obtained by the same treatment as in Example 1 (1) was subjected to silica gel column chromatography [eluent chloroform:methanol:aqueous ammonia-30: i
: o, t ~ 10: 1: Purified with 0.11, erythromycin A 9-[0-(1-benzyloxy-
1-methylethyl)oxime] 510μ was obtained.
'H-NMR (CDCj23);S (ppfQ)-
2,28[3'-N (CHm)*ko.

3, 32 (3-0-CHA).

4.5 0 [-0CH, C, H, Co.

7.2 0-7.4 0 [-0-CHx C-dan,] Mass (FAB); m/z-897(M)l'') (2) 470Tl1g of the compound obtained above and 90ni+ of pyridine hydrochloride was dissolved in 4 ml of N,N-dimethylformamide, and 294 μl of 1,1,1.3.3.3-hexamethyldisilazane dissolved in 1 m!I of N,N-dimethylformamide was added and stirred overnight at room temperature. Hereinafter, it was treated in the same manner as in Example 10 (1) to obtain 2',4''-〇-bis(trimethylsilyl)-erythromycin A 9-
[0-(1-benzyloxy-1-methylethyl)oxijimco 503■ was obtained.

'H-NMR (CDCi)3); S (ppm) -0, 10 (2'-0-IMS).

0, 15 (4”-0-TMS).

2. 2 2 [3”-N (CHm) zko.

3.30 (3"-0CR,).

4.50 (-QCdan!c, Hi).

7.20-7.40 [-0CH, C, Dan,] 11ass (FAR): m/z = 1041 (Ml”) (3) Compound 388■ obtained above and 0.035 mQ of methyl iodide were added together. The solution was dissolved in 5 ml of a mixed solvent of delsulfoxide/tetrahydrofuran (1/1), and 29 ng of 85% potassium hydroxide powder was added under water cooling, followed by stirring at room temperature for 2 hours. ′
, 4''-〇-bis(trimethylsilyl)-6-0-methylerythromycin A9-[0-(1-benzyloxy-1-methylethyl)oxime] 376 Wg was obtained.

"H-NMR (CDCf3); S (ppm) = o, 10 (2"-OTMS)
.

0.15 (4″-OTMS).

2.2 2 [3’-N (CIA)! Ko.

3, 10 (6-0-CHi).

3.32 (3”-〇-CH,).

4,52 (-0-CdantC*Hs>-7,20-7
, 40 [-0-CHsC-dan,] Mass (FAB); m/z = 1055 (Ml'') Example 30 (1) Erythromycin A 9-oxime 5g was dissolved in 35ml dichloromethane, and pyridine hydrochloride was added under water cooling. Then, a solution prepared by fermenting 1.16 g of 1.1-diisopropoxycyclohexane and 15 parts of dichloro and comethane was added, and the mixture was stirred at room temperature for 42.5 hours. Erythromycin A 9-(
5.1 g of 0-[1-(1-methylethoxy)cyclohexylkoxime) was obtained.

m, p, t14-116°C (recrystallized from dichloromethane-isopropyl ether) 'H-NMR (CDCb): S (ppm
) = 2.3 2 [3'-N(CHs)t.

3.32 (3”-〇CH*).

4.05 [-0-C Dan(CHs)t"C-NMR(CDCR3);δ(pl)I!l)" 24,33 [-0CH(C
Ha)tl.

40, 31 [3=N(CHa)zl.

49, 49 (3”-OCHm).

63.38 [-0 degrees H(CH,L].

104 , 22 [C””O〒-Pr ]Mass(
SXMS) ; m/z = 889 (MH”) (2) 4.45 g of the compound obtained above was dissolved in 15 ml of N,N-dimethylformamide, and pyridine hydrochloride 0
, 58g, and then 1.1.1, 3.3. under water cooling.
1.76 mQ of 3-hexamethyldisilazane was added. The mixture was stirred at room temperature for 5 hours and 40 minutes, and then treated in the same manner as in Example 10 (1) to obtain 2゛,4''-〇-bis(trimethylsilyl).
3.78 g of erythromycin A 9-(0-[1-(1-methylethoxy)cyclohexyl]oxime) was obtained.

'H-NMR (CDCI3); S (ppm)-0, 08 (2'-0-IMS).

0.12 (4"-〇-TMS).

2.2 0 [3'-N(CHs)*ko.

3,28 (3”-OCHa)-4,05[-ocdan(C)1.),]]RoC-NMR
CDCΩ3); 8 (ppm)-0,91 (4"-0-TMS).

1, OO (2'-0-TMS).

24.35[-0-CH(danHm)tl.

40, 99 [3'-N(cH,5)zl.

63.24[-0-danH(CHsL]).

1 0 4 , 0.7 [C””:W-pr ]M
ass (CI); m/z = 1 032 (M") Example 31 (1) 2',4"-〇-bis(trimethylsilyl)erythromycin A 9-year-old xime obtained in Example 10 (1) 9.8 g was dissolved in 45 ml of dichloromethane, 1.73 g of pyridine hydrochloride was added under water cooling, then 5.0 g of 1,1-diisopropoxycyclohexane dissolved in 15 ml of dichloromethane was added, and the mixture was heated at room temperature for 18 hours and 40 hours.
The mixture was stirred for a minute. Thereafter, the same treatment as in Example 9 was carried out.

10.7 g of 4"-0-bis(trimethylsilyl)erythromycin A 9-(0-[1-(1-methylethoxy)cyclohexyl]oxime) was obtained.

This substance was the same compound as the compound obtained in Example 30(2).

(2) 5.86 g of the compound obtained above was dissolved in a mixed solvent of dimethyl sulfoxide/tetrahydrofuran (1/1)
Dissolve in 3 ml and cool with water to add 0.915 methyl iodide.
Next, 0.38 g of 95% water-stained potassium powder was added to the mixture and stirred for 5 hours. Thereafter, treatment was carried out in the same manner as in Example 1 (3) to obtain 2゛,4''-〇-bis(trimethylsilyl)-6-〇-methylerythromycin A 9-(0-[1-<1
-methylethoxy)cyclohexyl]oxime) 5.6
4g was obtained.

'H-NMR (CDCI3); S(M)m)-0,09(2'-0-TMS).

0.15 (4″-〇-TMS).

2,21 [3'-N (CH5)zl-3,10(
6-OCHl) - 3,30(3''-OCHs).

4,10[-0-Cdan(cHn)tl''C-NMR
(CDCI: 8 (ppm) = 0, 90 (4"-0-1'M
S).

1, Q 6 (2'-0 (MS).

24.44 and 24.57 [-0-CH(danHm)x].

41, OO[3””-N (CHm)tl-51,
11 (6-OCHs).

6 2.8 2 [knee 0-(≧H(CH’sL).

103, 62 [CRI2] Example 32 5 g of erythromycin A 9-oxime was dissolved in 20 ml of acetonitrile, and 1.16 g of pyridine hydrochloride was added, followed by 3.35 g of 1,1-diisopropoxycyclohexane dissolved in 5 ml of acetonitrile. , 14 at room temperature
．． 1 of pyridine hydrochloride was added to the 0 reaction solution stirred for 5 hours under water cooling.
．． After adding 16 g and 5.6 ml of 1,1,1.3.3.3-hexamethyldisilazane and stirring for 30 minutes, the mixture was further stirred at room temperature for 1 hour and 30 minutes. Add 60ml of n-hexane to the reaction solution.
5 mQ of 2N aqueous sodium hydroxide solution and 50 ml of water were added, and the organic layer was separated, thoroughly washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2', 4
″-〇-bis(trimethylsilyl)erythromycin A
6.5 g of 9-(0-El-(1-methylethoxy)cyclohexyl]oxime) was obtained.

This material was the same compound as that obtained in Example 30(2).

Example 33 Erythromycin A 23.4 g of 9-year-old xime was dissolved in 160 ml of dichloromethane, and 5.48 s of pyridine hydrochloride was added under water cooling, followed by 15.3 g of 1-isopropoxy-1-cyclohexene dissolved in 40 ml of dichloromethane. Stir overnight at room temperature. The mixture was treated with Example 9 and P[ to obtain 20.5 g of erythromycin A9-(0-[1-(1-methylethoxy)cyclohexylcoxime).

This material was the same compound as that obtained in Example 30(1).

Reference Example 1 1) 2',4''-〇-his(trimethylsilylthromycin A 9-[0-(1-methoxy-1-methylethyl)oxime] 3 obtained by the method of Example 1 (3) .46g was dissolved in 60ml of ethanol/water (1/1), 1.5ml of 99% formic acid was added, and the mixture was stirred at room temperature for 30 minutes.Then, most of the ethanol was distilled off under reduced pressure, and water was added to the residue. added.

The mixture was made basic with a 2N aqueous sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and 6-0-methylerythromycin A-
9-year old Kisim 2. 53 g was obtained.

m. p. 248-251°C (recrystallized from ethanol-petroleum ether) (2) 2 g of the compound obtained above and 1.1 sodium bisulfite
Dissolve 99 g in 20 ml of ethanol/water (1/1).
% formic acid 0.25r+tll was added and refluxed for 100 minutes. After adding 30 ml of water to the reaction solution, 5 mQ of 2N aqueous sodium hydroxide solution was added dropwise, and the mixture was stirred for 2 hours under water cooling. The generated precipitate was collected by filtration, recrystallized from ethanol, and 6-
O-methylerythromycin A 1. 51 g was obtained.

m. p. 223-225°C Reference Example 2 2′,4″-〇-bis(trimethylsilyl)-6-0-methylerythromycin A obtained in Example 1 (3) 9-[0-(1-methoxy-1-methylethyl) ) 9.8g of Okijimco in ethanol/water (1/1) 10
0 mQ, 6.7 g of sodium bisulfite and 1.6 ml of 99% formic acid were added, and the mixture was stirred under reflux for 60 minutes.

150 ml of water was added to the reaction solution, and 2N aqueous sodium hydroxide solution was added dropwise to the reaction mixture to adjust the pH to approximately 10, followed by stirring for 1 hour under water cooling. After filtering the generated precipitate and washing with water,
Recrystallized from ethanol to give 6-O-methylerythromycin A5. 15 g was obtained. This substance is reference example 1 (
It was the same compound as that obtained in 2).

Reference Example 3 2゛,4''-〇-bis(trimethylsilyl)-6-0-ethylerythromycin A obtained in Example 26
9-[0-<1-methoxy-1-methylethyl)oxijimco 980 mg- in ethanol/water (1/1)
IOml! 2 g of sodium bisulfite and 0.23 rd of 99% formic acid were added, and the mixture was stirred under reflux for 60 minutes. Thereafter, the same procedure as in Reference Example 2 was carried out to obtain 610 mg of 6-0-ethylerythromycin A.

m. p. 2 1 3.5 to 2 1 4.5℃'H
- NMR (CDCI23); δ (ppm) - 1
, 0 '1 (6 -OC HxCdan.)2 ,
2 3 [3'-N (C H s)zl.

3, 33 (3”-〇 〇 H s> 3, 45 (6-QCdanz C H *) Mass (F
AB);

Claims (2)

[Claims] (1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ) or a group of the formula R^8O- (in the formula, R^8 represents an alkyl group having 1 to 6 carbon atoms), and R^2 is R
^8 represents a cycloalkyl group, phenyl group or aralkyl group having 5 to 7 carbon atoms, or R^2 and R^7 together form an alkylene group having 2 or 3 carbon atoms, R^ 3 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or an aralkyl group, or R^
3 and R^7 together have 3 to 5 carbon atoms, which may be substituted with 1 to 3 alkyl groups having 1 to 3 carbon atoms.
or R^2 and R^3 together form an alkylene group having 3 to 4 carbon atoms, and R
^4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R^6 has the formula -SiR^9R^1^0R^1^1 (
In the formula, R^9, R^1^0 and R^1^1 are the same or different and are a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group. group, phenyl group, cycloalkyl group having 5 to 7 carbon atoms, or alkenyl group having 2 to 5 carbon atoms. However, at least 1 of R^9, R^1^0 and R^1^1
is not a hydrogen atom), and R^6
represents a hydrogen atom or R^6. Erythromycin A derivative represented by (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 is the formula R^7CH_2- (In the formula, R^7 is a hydrogen atom or an alkyl having 1 to 3 carbon atoms. ) or a group of the formula R^3O- (in the formula, R^8 represents an alkyl group having 1 to 6 carbon atoms), and R^2 is R
^8 represents a cycloalkyl group, phenyl group or aralkyl group having 5 to 7 carbon atoms, or R^2 and R^7 together form an alkylene group having 2 or 3 carbon atoms, R^ 3 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or an aralkyl group, or R^
3 and R^7 together have 3 to 5 carbon atoms, which may be substituted with 1 to 3 alkyl groups having 1 to 3 carbon atoms.
or R^2 and R^3 together form an alkylene group having 3 to 4 carbon atoms, and R
^4 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and R^5 has the formula -SiR^9R^1^0R^1^1 (
In the formula, R^9, R^1^0 and R^1^1 are the same or different and are a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group. group, phenyl group, cycloalkyl group having 5 to 7 carbon atoms, or alkenyl group having 2 to 5 carbon atoms. However, at least 1 of R^9, R^1^0 and R^1^1
is not a hydrogen atom), and R^6
represents a hydrogen atom or R^5. ] In order to produce the erythromycin A derivative represented by erythromycin A9-oxime, the general formula ▲ includes numerical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^1, R^ 2 and R^3 have the same meanings as above, R^1^2 represents -OR^8, or R^1 and R^1^2 together form the formula R^7CH= (in the formula, R^
7 has the same meaning as above). ] and a silylating agent having R^5, or further reacting the obtained compound with an alkylating agent having R^4 other than a hydrogen atom.