JPH0764867B2 - 6-O-methylerythromycin A derivative and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to an erythromycin A derivative and a method for producing the same.

BACKGROUND ART 6-O-methylerythromycins are important as antibacterial agents or intermediates for synthesizing antibacterial agents. For example, 6
-O-methylerythromycin A is erythromycin A
In addition to being more stable under acidic conditions, it has stronger antibacterial activity. In particular, this compound is a useful antibacterial agent because it shows a remarkable effect in treating infectious diseases by oral administration.

Heretofore, several methods have been known as a method for methylating the 6-position hydroxyl group of an erythromycin A derivative.

For example:

(1) A method of substituting a hydrogen atom of a hydroxyl group at the 2'position and a methyl group of a dimethylamino group at the 3'position of an erythromycin A derivative with a benzyloxycarbonyl group and then methylating (US Pat. No. 4,331,803).

(2) Method of methylating erythromycin A derivative in which one or both of 2'-position hydroxyl group and 3'-position dimethylamino group of erythromycin A derivative are protected into various substituted oxime derivatives (European Patent Publication No. 158,467) ).

Problems to be Solved by the Invention However, in the method (1), erythromycin A is used.
Has a large number of hydroxyl groups, a large number of by-products in which hydroxyl groups other than the 6-position are methylated are obtained, and a complicated operation is required for purification of the 6-O-methylerythromycin A derivative, and therefore the yield is low. There is a drawback that. Further, in the method (2), selective methylation of the 6-position hydroxyl group is possible,
Erythromycin A 9- with only the 2'-hydroxyl group protected
When methylation is carried out using an oxime derivative, the 3'-dimethylamino group becomes a methyl quaternary salt under ordinary methylation conditions, and it is considerably difficult to restore this to the original dimethylamino group. Therefore, as a practical production method, it is necessary to protect both the 2'-position hydroxyl group and the 3'-position dimethylamino group.

Means for Solving the Problems As a result of various studies to solve the above-mentioned drawbacks of the known method, the present inventors have found that when the 2′-position hydroxyl group of an erythromycin A derivative is protected with a silyl group, the adjacent 3′-dimethylamino group is protected. The present invention has been completed by finding that the group is not quaternized even under ordinary methylation conditions.

The object of the present invention is to provide a general formula [In the formula, R ¹ is a 2-alkenyl group having 3 to 15 carbon atoms,
Arylmethyl group or halogen atom, 1 to 1 carbon atoms
4 alkoxy groups, nitro groups and 2 to 6 carbon atoms
Shows an arylmethyl group substituted with 1 to 3 alkoxy carbonyl groups, R ² is of the formula —SiR ⁴ R ⁵ R ⁶ (wherein R ⁴ ,
R ⁵ and R ⁶ are the same or different and each is 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, or 5 carbon atoms.
Represents a cycloalkyl group having 7 to 7 or an alkenyl group having 2 to 5 carbon atoms. Provided that at least one of R ⁴ , R ⁵ and R ⁶ is not a hydrogen atom).
R ³ represents a hydrogen atom or R ² . ] 6-O- represented by
A methyl erythromycin derivative is provided.

It is a further object of the present invention to prepare erythromycin A 9-oxime in any order to prepare compounds of formula R ^1-
By reacting with a compound of X (in the formula, R ¹ has the same meaning as described above and X represents a halogen atom) and a silylating agent having R ² ; (Wherein R ¹ , R ² and R ³ have the same meanings as described above), and a method for producing a 6-O-methylerythromycin A derivative comprising reacting the compound with a methylating agent. Is to provide.

In the present invention, the term alkyl, alkoxy or alkenyl used alone or in combination with another group means a straight-chain or branched one, and an arylmethyl group means a benzyl group, a benzhydryl group or a trityl group. And naphthylmethyl group. Examples of the substituted arylmethyl group include p-methoxybenzyl group, p-chlorobenzyl group, m-chlorobenzyl group, o-chlorobenzyl group, 2,4-dichlorobenzyl group, p-bromobenzyl group, m -Nitrobenzyl group, p-nitrobenzyl group and the like. Examples of the 2-alkenyl group for R ¹ include an allyl group, a methallyl group, a crotyl group, a prenyl group, a 2-pentenyl group, a 2-ethyl-2-butenyl group, a geranyl group and a neryl group, and a halogen atom and Are chlorine, bromine, iodine atoms and the like. The substituted silyl group means, for example, a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a tertiary-butyldimethylsilyl group, a (triphenylmethyl) dimethylsilyl group,
Tertiary butyldiphenylsilyl group, diphenylmethylsilyl group, diphenylvinylsilyl group, methyldiisopropylsilyl group, tribenzylsilyl group, tri (p
-Xylyl) silyl group, triphenylsilyl group, diphenylsilyl group, dimethyloctadecylsilyl group and the like. Hereinafter, the present invention will be described in more detail. First, the reaction of erythromycin A 9-oxime with the compound of formula R ¹ -X is carried out according to a method known per se, for example, the method described in European Patent 158,467, and the compound of the general formula (In the formula, R ¹ has the same meaning.) A compound represented by the formula can be obtained.

The reaction of the compound of formula III with the silylating agent is then carried out by stirring in a solvent in the presence of a base at 0 ° C. to the reflux temperature of the solvent, preferably room temperature. As the silylating agent, chlorosilanes such as trimethylchlorosilane and tertiary-butyldimethylchlorosilane, 1,1,1,3,
It is possible to use silylamines such as 3,3-hexamethyldisilazane, trimethylsilylimidazole, and dimethylaminotrimethylsilane, bis (trimethylsilyl) acetamide, trimethylsilyldiphenylurea, bis (trimethylsilyl) urea, and the like. The amount of silylating agent used is 1 to 10 equivalents, preferably 1 to 10 equivalents, relative to the compound of formula III.
It is 5 equivalents.

The solvent used in this reaction includes acetone, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform and the like. As a base,
Inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,
Trimethylamine, triethylamine, pyridine, 1,8
-Organic bases such as diazabicyclo [5,4,0] unde-7-cene, imidazole can be used.

In this reaction, whether or not the compound of the formula III is silylated only at the 2'position or at the 2'and 4'positions depends on the reaction conditions, but the use of chlorosilanes is preferable for the silylation at the 2'position. The combined use of chlorosilanes and silylamines or the use of 1,1,1,3,3,3-hexamethyldisilazane is preferred for silylation at the 2'-position and the 4 "-position.

Alternatively, the compound of formula II is erythromycin A 9-
It can also be obtained by reacting an oxime with a silylating agent and then reacting a compound of the formula R ¹ -X. That is, erythromycin A 9-oxime is reacted with a silylating agent under the same conditions as in the silylation, and then the resulting compound is represented by the formula R ^1-
By reacting the compound of X under the above reaction conditions
The compound of II can be obtained.

The reaction for obtaining the compound of formula I by the compound of formula II and the methylating agent is carried out by stirring in a solvent in the presence of a base at -15 ° C to room temperature, preferably 0 ° C to room temperature. As the methylating agent, methyl bromide, methyl iodide, dimethylsulfate, paratoluenesulfonic acid methyl ester, methanesulfonic acid methyl ester, etc. are used, and the amount thereof is 1 to 3 molar equivalents relative to the compound of formula II. Is enough. Solvents that can be used include aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, N-methyl-
There are 2-pyrrolidone, hexamethylphosphoric triamide or mixtures thereof, or mixtures thereof with tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile or ethyl acetate. As the base, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide, potassium hydride and the like can be used. The amount of base used is usually 1 to 2 molar equivalents relative to the compound of formula II.

In the present invention, when methylating a compound of formula II, the essential condition for preventing the quaternization of the 3'-dimethylamino group is to protect the 2'-hydroxyl group with a substituted silyl ether.
-Substitutional silyl etherification of hydroxyl groups is not always essential.

The compound of formula II may also be reacted with a methylating agent after isolation or without isolation.

The erythromycin A 9-oxime derivative of the present invention has two isomers (syn-type and anti-type), but in the present invention, it may be either syn-type or anti-type,
It may also be a mixture of syn type and anti type.

EFFECTS OF THE INVENTION According to the present invention, in the synthesis of 6-O-methylerythromycin A derivative, protection of the 3'-dimethylamino group is not necessary, and therefore 3'-N-methylation is not necessary.

Further, the methylation to the 6-position hydroxyl group has good selectivity as in the conventional method.

Furthermore, the substituted silyl group used for protecting the hydroxyl groups at the 2'-position and the 4 "-position in the present invention is very easy to remove.

Therefore, the present invention makes it possible to provide 6-O-methylerythromycin A in a high yield and economically.

That is, the compound of formula I is converted to 6-O-methylerythromycin A as follows, for example.

First, the substituted silyl groups (R ² and R ³ ) at the 2′-position and the 4 ″ -position in the compound of the formula I are treated, for example, with formic acid in an alcohol solvent or by reaction with tetrabutylammonium fluoride in tetrahydrofuran. Easily removed.

Next, removal of the R ¹ group of the compound obtained above is easily carried out by a known homogeneous or heterogeneous hydrogenolysis reaction. For example, this reaction is carried out by stirring in an alcohol solvent (eg, methanol, ethanol, etc.) in the presence of a palladium black or palladium carbon catalyst in a hydrogen atmosphere. The presence of formic acid, acetic acid, etc. favors this process.

This reaction is also carried out in the presence of a suitable hydrogen source (eg ammonium formate, sodium formate or a mixture of these and formic acid) and a catalyst (eg palladium carbon, palladium black etc.) in an organic solvent (eg methanol,
It can be easily carried out by stirring in ethanol, N, N-dimethylformamide, etc.) at room temperature to 70 ° C.

Furthermore, this reaction can be carried out using a catalyst composed of a compound of a platinum group element and a ligand. Examples of the compound of the platinum group element include ruthenium, rhodium, palladium and platinum salts or complexes, and examples of the ligand include phosphorus compounds such as triphenylphosphine, trinormal butylphosphine, triethylphosphite and 1,2-
There is ethylene (diphenyl) phosphine, but it is usually used in combination with palladium acetate and triphenylphosphine. This reaction is usually carried out in the presence of formic acid or formate salts. As formate salts, ammonium formate, trimethylammonium formate, ammonium salts such as triethylammonium formate or sodium formate,
Examples thereof include alkali metal salts such as potassium formate.

The removal operation of R ² and R ^{3 and} the removal operation of R ¹ can be performed in the opposite order without any problem.

The obtained 6-O-methylerythromycin A 9-oxime is deoxime using sodium bisulfite, titanium trichloride-ammonium acetate, sodium nitrite-hydrochloric acid or sodium hydrosulfite (Na ₂ S ₂ O ₄ ). It can be easily converted to 6-O-methylerythromycin A. (See, for example, JP-A-61-103890) Next, the method for producing the compound of formula I of the present invention by way of examples and the method for producing 6-O-methylerythromycin A by way of the reference examples will be specifically explained. .

Example 1 2'-O-trimethylsilylerythromycin A 9-
Production of (O-benzyl oxime) Erythromycin A 9- (O-benzyl oxime) 3.36 g
And 0.7 ml of triethylamine were dissolved in 30 ml of N, N-dimethylformamide, 0.7 ml of trimethylchlorosilane was added dropwise at room temperature, and the mixture was stirred for 10 minutes. After the reaction, isopropyl ether was added, and the mixture was washed with water and then saturated saline, and then dried over anhydrous magnesium sulfate. Evaporate the solvent,
The obtained crude product was recrystallized from isopropyl ether to give 1.35 g of the title compound as colorless needles.

mp104~106 ℃ Mass (FAB); m / z: 911 (MH +) PMR (CDCl 3); δ (ppm) = 0.11 (2'-O-TMS), 2.23 [3'-N (CH 3) 2 ], 3.33 (3 ″ -OCH ₃ ) CMR (CDCl ₃ ); δ (ppm) = 1.0 (2′-O-TMS), 41.0 [3′-N (CH ₃ ) ₂ ], 49.5 (3 ″ -OCH ₃ ) (In the above, TMS represents a trimethylsilyl group. The same applies hereinafter.) Example 2 Preparation of 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- (O-benzyloxime) trimethylsilylimidazole 2.24 g And 1.74 g of trimethylchlorosilane dissolved in 20 ml of dry dichloromethane and erythromycin dissolved in 40 ml of dichloromethane.
6.72 g of A 9- (O-benzyl oxime) was added at once at room temperature, and the mixture was stirred at room temperature for 10 minutes. Add chloroform,
The extract was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the obtained crude product was recrystallized from acetone-water to give the title compound as colorless needles.
Got 27g.

mp97-100 ° C Mass (FAB); m / z: 983 (MH ⁺ ) PMR (CDCl ₃ ); δ (ppm) = 0.09 (2'-O-TMS), 0.15 (4 "-O-TMS), 2.22 _{[3'-N (CH 3)} 2], 3.31 (3 "-OCH 3) CMR (CDCl 3); δ (ppm) = 0.9 (4" -O-TMS), 1.0 (2'-O-TMS) , 41.0 [3'-N (CH 3) 2], 49.7 (3 "-OCH 3) example 3 2'-O-trimethylsilyl -6-O-methylerythromycin a 9-preparation of (O-benzyl-oxime) 2 '-O-trimethylsilylerythromycin A 9-
2.28 g of (O-benzyl oxime) was dissolved in 20 ml of a mixed solvent of dimethyl sulfoxide / tetrahydrofuran (1/1), 0.38 ml of methyl iodide and 280 mg of 85% potassium hydroxide powder were added, and the mixture was stirred at room temperature for 2 hours. . Ethyl acetate was added to the reaction solution, washed with water and then with saturated saline, and then dried over anhydrous magnesium sulfate. Evaporate the solvent,
2.32 g of the glassy title compound was obtained.

Mass (FAB); m / z: 925 (MH ⁺ ) PMR (CDCl ₃ ); δ (ppm) = 0.09 (2'-O-TMS), 2.23 [3'-N (CH ₃ ) ₂ ], 3.03 ( _{6-OCH 3), 3.34 (} 3 "-OCH 3) example 4 2 ', 4" -O- bis (trimethylsilyl) -6-O-methylerythromycin A 9-(O-benzyl-oxime)
Preparation of 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- (O-benzyloxime) 3.93 g was treated in the same manner as in Example 3 to obtain 3.89 g of the glassy title compound.

mp115-116 ° C (recrystallized from methanol) Mass (FAB); m / z: 997 (MH ⁺ ) PMR (CDCl ₃ ); δ (ppm) = 0.09 (2′-O-TMS), 0.15 (4 ″ − O-TMS), 2.21 [3' -N (CH 3) 2], 3.03 (6-OCH 3), 3.32 (3 "-OCH 3) CMR (CDCl 3); δ (ppm) = 0.9 (4" - O-TMS), 1.1 (2' -O-TMS), 41.0 [3'-N (CH 3) 2], 49.7 (3 "-OCH 3), 50.7 (6-OCH 3) example 5 2' O-trimethylsilylerythromycin A 9-
Production of (O-allyl oxime) 1 g of erythromycin A 9- (O-allyl oxime) was treated in the same manner as in Example 1, and the obtained crude product was subjected to alumina column chromatography (elution solvent; acetone / n-hexane). = 1/10 to 1/5) and the glassy title compound
0.35g was obtained.

mp93~96 ℃ (n- hexane recrystallized) Mass (EI); m / z: 860 (M +) PMR (CDCl 3); δ (ppm) = 0.11 (2'-O-TMS), 2.23 [3 _{'-N (CH 3) 2]} , 3.32 (3 "-OCH 3) CMR (CDCl 3); δ (ppm) = 1.0 (2'-O-TMS), 41.0 [3'-N (CH 3) 2 _{], 49.5 (3 "-OCH 3} ) example 6 2 ', 4" -O- bis out the production erythromycin a 9-(O-allyl-oxime) 1 g of (trimethylsilyl) erythromycin a 9-(O-allyl-oxime) After reacting in the same manner as in Example 2, the reaction solution was added with 100 m of n-hexane.
l was added and the insoluble material was filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting solvent: acetone / n-hexane / triethylamine = 1/10 / 0.1) to obtain 0.70 g of the glassy title compound.

mp85-89 ℃ (Recrystallized from acetone) Mass (EI); m / z: 932 (M ⁺ ) PMR (CDCl ₃ ); δ (ppm) = 0.10 (2′-O-TMS), 0.14 (4 ″- O-TMS), 2.22 [3' -N (CH 3) 2], 3.31 (3 "-OCH 3) example 7 2'-O-trimethylsilyl -6-O-methylerythromycin A 9-(O-allyl-oxime ) Erythromycin A 9- (O-allyl oxime) 4 g and triethylamine 1.4 ml are added to N, N-dimethylformamide.
It was dissolved in 20 ml, 1.35 ml of trimethylchlorosilane was added dropwise at room temperature, and the mixture was stirred for 20 minutes. After adding 100 ml of water and extracting with ethyl ether and washing the organic layer with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off and 2 '
-O-trimethylsilylerythromycin A 9- (O-
3.86 g of a crude product of allyl oxime) was obtained.

Dimethyl sulfoxide / tetrahydrofuran (1 /
It was dissolved in 30 ml of the mixed solvent of 1), 0.42 ml of methyl iodide and then 357 mg of 85% sodium hydroxide powder were added under ice cooling, and the mixture was stirred for 1.5 hours. After the reaction was completed, 0.5 ml of 50% dimethylamine aqueous solution was added, and after stirring for 1 hour, 100 ml of water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluting solvent: acetone / n-hexane / triethylamine = 1/5 / 0.1) to obtain 1.45 g of the glassy title compound.

mp155-158 ° C (recrystallized from n-hexane) Mass (EI); m / z: 874 (M ⁺ ) PMR (CDCl ₃ ); δ (ppm) = 0.10 (2'-O-TMS), 2.22 [3 _{'-N (CH 3) 2]} , 3.08 (6-OCH 3), 3.33 (3 "-OCH 3) CMR (CDCl 3); δ (ppm) = 1.1 (2'-O-TMS), 41.0 [3 _{'-N (CH 3) 2]} , 49.4 (3 "-OCH 3), 50.9 (6-OCH 3) example 8 2', 4" -O- bis (trimethylsilyl) -6-O-methylerythromycin A 9 Preparation of-(O-allyloxime) 3.51 ml of trimethylsilylimidazole and 3.04 ml of trimethylchlorosilane were dissolved in 25 ml of dry dichloromethane, and 9.5 g of erythromycin A 9- (O-allyloxime) dissolved in 125 ml of dichloromethane were added at once at room temperature. The mixture was stirred at room temperature for 10 minutes, and n-hexane was added to the reaction solution.
400 ml was added, the insoluble matter was filtered, and the filtrate was concentrated. 200 ml of n-hexane was added to the residue to remove insoluble matter,
The filtrate was concentrated.

Dimethyl sulfoxide / tetrahydrofuran (1 /
Dissolved in 75 ml of mixed solvent of 1), 1 ml of methyl iodide, then
854 mg of 85% potassium hydroxide powder was added under ice cooling, and the mixture was stirred for 1.5 hours. After the completion of the reaction, the same treatment as in Example 7 was carried out to obtain 10.2 g of the title compound.

mp96~101 ℃ (acetone - recrystallized from water) Mass (EI); m / z: 946 (M +) PMR (CDCl 3); δ (ppm) = 0.09 (2'-O-TMS), 0.15 (4 "-O-TMS), 2.22 [ 3'-N (CH 3) 2], 3.09 (6-OCH 3), 3.32 (3" -OCH 3) CMR (CDCl 3); δ (ppm) = 0.9 (4 "-O-TMS), 1.1 ( 2'-O-TMS), 41.0 [3'-N (CH 3) 2], 49.7 (3" -OCH 3), 50.9 (6-OCH 3) example 9 erythromycin Preparation of 2 ', 4 "-O-bis (trimethylsilyl) -6-O-methylerythromycin A 9- (O-allyl oxime) from A 9-oxime Erythromycin A 9-oxime 10 g was dissolved in tetrahydrofuran 75 ml to give allyl bromide. 1.25 ml and 970 mg of 85% potassium hydroxide powder were added, and the mixture was stirred at room temperature for 2 hours.
After stirring for 1 minute, the mixture was poured into ethanol / water (50 ml / 200 ml) and stirred for 30 minutes under ice cooling. The resulting precipitate was collected by filtration, washed with water, dissolved in chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off and crude erythromycin A 9
9.7 g of-(O-allyl oxime) was obtained.

Trimethylsilylimidazole (3.58 ml) and trimethylchlorosilane (3.10 ml) were dissolved in dry dichloromethane (25 ml), and the above erythromycin A 9- (O-allyl oxime (9.7 g) dissolved in dichloromethane (125 ml) was added at once at room temperature, followed by stirring at room temperature for 10 minutes. 200 ml of n-hexane was added to the reaction solution to remove insoluble matter, and the filtrate was concentrated, 200 ml of n-hexane was added to the residue to remove insoluble matter, and the filtrate was concentrated to obtain crude 2 ', 4 "-O. -Bis (trimethylsilyl) erythromycin A 9- (O-allyl oxime) 1
I got 0g.

10 g of the above crude 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- (O-allyl oxime) was dissolved in 75 ml of a mixed solvent of dimethyl sulfoxide / tetrahydrofuran (1/1), and then methyl iodide (1 ml) was added. After adding 837 mg of 85% potassium hydroxide powder and stirring for 1.5 hours under ice cooling, after completion of the reaction, 1 ml of 50% dimethylamine aqueous solution was added, and after stirring at room temperature for 1 hour, 200 ml of water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate.The solvent was distilled off to give crude 2 ', 4 ".
10.3 g of -O-bis (trimethylsilyl) -6-O-methylerythromycin A9- (O-allyl oxime) was obtained. Purification as in Example 8 gave the title compound.

The melting point, Mass, PMR and CMR of this compound were the same as those of the compound obtained in Example 8.

Example 10 2 ', 4 "-O-bis (trimethylsilyl)) erythromycin A 9- (O from erythromycin A 9-oxime
-Benzyl oxime) 3.erythromycin A 9-oxime 3.79 g and benzyl chloride 0.75 ml are dissolved in N, N-dimethylformamide 30 ml,
0.24 g of sodium hydride (60%) was added under ice cooling. Two
After stirring for 1,1,1,3,3,3-hexamethyldisilazane 2.5 ml
And pyridine hydrochloride 0.99 g were added, and the mixture was further stirred at room temperature for 6 hours. After standing overnight, the reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the crude product obtained by distilling off the solvent was recrystallized from water-containing acetone to obtain 3.0 g of the title compound. It was This compound was identical with the compound obtained in Example 2 in mp, PMR and Mass.

Example 11 Preparation of 2 ', 4 "-O-bis (trimethylsilyl) -6-O-methylerythromycin A 9- [O- (o-chlorobenzyl) oxime] (1) 90 g of erythromycin A 9-oxime was added to N, Dissolve in 500 ml of N-dimethylformamide, add 23.6 g of o-chlorobenzyl chloride and 9.7 g of 85% potassium hydroxide,
The mixture was stirred under ice cooling for 30 minutes. After the reaction, the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and erythromycin A was removed.
98 g of 9- [O- (o-chlorobenzyl) oxime] was obtained.

mp114 ° C-117 ° C (recrystallized from n-hexane) (2) 8.7 g of the above compound was dissolved in 80 ml of ethyl acetate, 2.53 ml of trimethylchlorosilane and 2.8 g of trimethylsilylimidazole were dissolved in 10 ml of ethyl acetate, and a solution was added at room temperature. Stir for 1 hour. n-Hexane was added, and the mixture was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and a glassy 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- [O- (o-
Chlorobenzyl) oxime] was obtained.

Mass (EI); m / z: 1016 (M ⁺ ) PMR (CDCl ₃ ); δ (ppm) = 0.10 (2'-O-TMS), 0.15 (4 "-O-TMS), 2.23 [3'- N (CH ₃ ) ₂ ], 3.30 (3 ″ -OCH ₃ ) (3) 2 ′, 4 ″ -O-bis (trimethylsilyl) erythromycin A 9- [O- (o-crocobenzyl) oxime] 5.09 g in dimethyl Dissolved in 100 ml of a mixed solvent of sulfoxide / tetrahydrofuran (1/1), methyl iodide 0.41
ml and then 360% of 85% potassium hydroxide powder, and under cooling
Stir for 1.5 hours. 50% dimethylamine aqueous solution 2 in the reaction solution
After adding ml and stirring for 30 minutes, n-hexane was added, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.3 g of the glassy title compound.

Mass (EI); m / z : 1030 (M +) PMR (CDCl 3); δ (ppm) = 0.10 (2'-O-TMS), 0.15 (4 "-O-TMS), 2.22 [3'- _{N (CH 3) 2],} 3.02 (6-OCH 3), 3.32 (3 "-OCH 3) example 12 erythromycin A 9-O- (o- chlorobenzyl) Okishimamu] from 2 ', 4" -O- Preparation of bis (trimethylsilyl) erythromycin A 9- [O- (o-chlorobenzyl) oxime] Erythromycin A 9 obtained in (11) of Example 11 above.
-[O- (o-chlorobenzyl) oxime] 15.27 g was added to N,
Dissolved in 150 ml of N-dimethylformamide, 1,1,1,3,3,3
-7.8 ml of hexamethyldisilazane and pyridine hydrochloride
2.6 g was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (14.5 g). This compound was identical with the compound of item (2) of Example 11 in Mass and PMR.

Example 13 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- [O-from erythromycin A 9-oxime
Preparation of (o-chlorobenzyl) oxime] 3 g of erythromycin A 9-oxime was dissolved in 15 ml of N, N-dimethylformamide, and o-chlorobenzyl chloride was added.
Add 773 g and 0.192 g of 60% sodium hydride, and under ice cooling 2
Stir for hours. Then, the reaction solution was returned to room temperature, and 1,1,1,3,3,
3-hexamethyldisilazane 1.69 ml and ammonium chloride
0.321 g was added and stirring was continued at room temperature for 20 hours. After the reaction, 50 ml of n-hexane and 100 ml of saturated saline were added, the organic layer was separated, washed with saturated saline (100 ml × 2), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.2 g of the title compound.

This compound was the same as the compound of the item (2) of Example 11 in terms of Mass and PMR.

Reference Example 1 Preparation of 6-O-methylerythromycin A from 2 ', 4 "-O-bis (trimethylsilyl) -6-O-methylerythromycin A 9- (O-allyloxime) Crude obtained in Example 9 2 ', 4 "-O-bis (trimethylsilyl) -6-O-methylerythromycin A 9-
10.3 g of (O-allyl oxime) was dissolved in 100 ml of methanol, 6.2 ml of 99% formic acid was added, and the mixture was stirred at 50 ° C. for 1 hour. 300 ml of water was added to the reaction solution, and the mixture was made alkaline with 2N aqueous potassium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 8.93 g of crude 6-O-methylerythromycin A 9- (O-allyl oxime).

The obtained crude 6-O-methylerythromycin A 9- (O
-Allyl oxime) 8.93 g was dissolved in a mixed solvent of 50 ml of dioxane and 7.5 ml of water, and 89 mg of palladium acetate, 539 mg of triphenylphosphine and triethylammonium formate of 9.7
g was added and refluxed for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure, 200 ml of ether was added, and the mixture was extracted with 10% acetic acid.
The acetic acid layer was washed with ether and then n-hexane, made alkaline with 5N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain 8.5 g of crude 6-O-methylerythromycin A 9-oxime. This known compound was reacted with sodium bisulfite and 99% formic acid by a conventional method to obtain a known 6-O-methylerythromycin A.

mp223 to 225 ° C Reference example 2 2 ', 4 "-O-bis (trimethylsilyl) -6-O-methylerythromycin A 9- [O- (o-chlorobenzyl) oxime] 6-O-methylerythromycin A
Preparation of crude 2 ', 4 "-O-bis (trimethylsilyl) -6-O-methylerythromycin A 9-obtained in Example 11 above
2.8 g of [O- (o-chlorobenzyl) oxime] was dissolved in 30 ml of methanol, and 450 mg of 10% palladium carbon and 1.8 mg of formic acid were dissolved.
ml and 300 mg of ammonium formate were added, and the mixture was stirred at 60 ° C. for 2 hours. The palladium catalyst was removed by filtration, 200 ml of water was added to the filtrate, and 2N
Basified with aqueous sodium hydroxide. The precipitated precipitate was collected by filtration, washed with water and dried to obtain 1.7 g of crude 6-O-methylerythromycin A 9-oxime.

The obtained 6-O-methylerythromycin A 9-oxime was reacted with sodium bisulfite and 99% formic acid in the same manner as in Reference Example 1 to obtain 1.17 g of crystals of 6-O-methylerythromycin.

m.p.223-225 ℃

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masato Kashimura 1-403 Yoshino-cho, Omiya-shi, Saitama, Taisho Pharmaceutical Research Institute (72) Inventor Yoshiaki Watanabe 1-403 Yoshino-cho, Omiya, Saitama Taisho (72) Inventor Kaoru Soda 1-403 Yoshino-cho, Omiya-shi, Saitama Taisho Pharmaceutical Research Institute

Claims (2)

[Claims] 1. A general formula (In the formula, R ¹ is a 2-alkenyl group having 3 to 15 carbon atoms,
Arylmethyl group or halogen atom, 1 to 1 carbon atoms
4 alkoxy groups, nitro groups and 2 to 6 carbon atoms
Shows an arylmethyl group substituted with 1 to 3 alkoxy carbonyl groups, R ² is of the formula —SiR ⁴ R ⁵ R ⁶ (wherein R ⁴ ,
R ⁵ and R ⁶ are the same or different and each is 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, or 5 carbon atoms.
Represents a cycloalkyl group having 7 to 7 or an alkenyl group having 2 to 5 carbon atoms. Provided that at least one of R ⁴ , R ⁵ and R ⁶ is not a hydrogen atom).
R ³ represents a hydrogen atom or R ² . ] 6-O- represented by
Methylerythromycin derivative. 2. General formula [In the formula, R ¹ is a 2-alkenyl group having 3 to 15 carbon atoms,
Arylmethyl group or halogen atom, 1 to 1 carbon atoms
4 alkoxy groups, nitro groups and 2 to 6 carbon atoms
Shows an arylmethyl group substituted with 1 to 3 of 4 alkoxycarbonyl groups, R ² is represented by formula —SiR ⁴ R ⁵ R ⁶ (wherein R ⁴ , R ⁵
And R ⁶ are the same or different and each is a hydrogen atom or a carbon atom
~ 15 alkyl groups, phenyl substituted alkyl groups having 1 to 3 carbon atoms, phenyl groups, 5 carbon atoms
7 cycloalkyl groups or alkenyl groups having 2 to 5 carbon atoms are shown. Provided that at least one of R ⁴ , R ⁵ and R ⁶ is not a hydrogen atom), and R ³
Represents a hydrogen atom or R ² . ] In the production of the 6-O-methylerythromycin derivative represented by the formula, erythromycin A 9-oxime is added in any order to the formula R ^1-
By reacting with a compound of X (wherein R ¹ has the same meaning as defined above, X represents a halogen atom) and a silylating agent having R ² ; (Wherein R ¹ , R ² and R ³ have the same meanings as described above), and a method for producing a 6-O-methylerythromycin A derivative comprising reacting the compound with a methylating agent. .