JPS63183597A - 6-o-methylerythromycin a derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is 3-15C 2-alkenyl or (substituted) arylmethyl; R<2> is substituted silyl of formula -SiR<4>R<5>R<6> (R<4>-R<6> are H, 1-15C alkyl, phenyl-substituted 1-3C alkyl, phenyl, 5-7C cycloalkyl or 2-5C alkenyl; at least one of R<4>-R<6> is not H); R<3> is H or R<2>]. EXAMPLE:2'-0-trimethylsilyl-6-0-methylerythromycin A 9-(0-benzyloxime). USE:An antibacterial agent and a synthetic intermediate for antibacterial agent. PREPARATION:Erythromycin A 9-oxime is made to react with a compound of formula R<1>-X (X is halogen) and a silylation agent having R<2> group and the resultant compound of formula II is reacted with a methylation agent.

Description

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

BACKGROUND OF THE INVENTION 6-0-Methylerythromycins are important as antibacterial agents or intermediates for the synthesis of antibacterial agents. For example, 6
-〇-Methylerythromycin A is erythromycin A
It is not only more stable under acidic conditions, but also has stronger antibacterial activity. In particular, this compound is a useful antibacterial agent because it shows remarkable effects in the treatment of infectious diseases when administered orally.

Several methods for methylating the 6-position hydroxyl group of erythromycin A derivatives have been known.

Examples include:

(1) A method in which the hydrogen atom of the 2'-position hydroxyl group and the methyl group of the 3'-position dimethylamino group of an erythromycin A derivative are subjected to tS with a benzyloxycarbonyl group, and then methylated (US Pat. No. 4,331.803) .

(2) A method of methylating 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 are protected, using various substituted oxime derivatives (European Published Patent Application No. 158). No. 467).

Problems to be Solved by the Invention However, in 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) enabled selective methylation of the 6-position hydroxyl group,
Erythromycin A with only the 2' hydroxyl group protected 9
- When methylated using an oxime derivative, the 3'-dimethylamino group becomes a methyl quaternary salt under normal methylation conditions, and it is quite difficult to convert it back 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 The present inventors have made various studies to solve the shortcomings and points of the above-mentioned known methods. As a result, when the hydroxyl group at the 2' position of an erythromycin A derivative is protected with a silyl group, the adjacent 3°- The present invention was completed based on the discovery that dimethylamino groups are not quaternized even under normal methylation conditions.

The object of the present invention is to obtain a compound of the general formula [wherein R1 is a 2-alkenyl group having 3 to 15 carbon atoms, an arylmethyl group, or a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a nitro group, and a carbon atom] Number 2
- represents an arylmethyl group substituted with 1 to 3 of 6 alkoxycarbonyl groups, R2 is of the formula -5iR'R'R
'(In the formula, R4, RS 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, It represents a cycloalkyl group having 5 to 7 carbon atoms or an alkenyl group having 2 to 5 carbon atoms.

However, at least one of R4, R8 and R6 represents a substituted silyl group (not a hydrogen atom), and R8 represents a hydrogen atom or R2. An object of the present invention is to provide 6-0-methylerythromycin derivatives shown in Table 6 below.

A further object of the present invention is to prepare compounds of formula I by combining erythromycin A 9-oxime with formula R'-X (wherein R1 is as defined above and X is halogen) in any order. It is possible to react with a compound of the general formula (wherein R1, R2 and R8 have the same meanings as above) and a silylating agent having R2.

) and reacting it with methyl north side.

In the present invention, the term alkyl, alkoxy or alkenyl used alone or in combination with other groups means a linear or branched chain, and the arylmethyl group refers to a benzyl group, a benzhydryl group, a trityl group and means naphthylmethyl group. Examples of substituted arylmethyl groups include p-methoxybenzyl group, p,-chlorobenzyl group, m-chlorobenzyl group, 0-chlorobenzyl group, 2,4-dichlorobenzyl group, p-bromobenzyl group, m-nitrobenzyl group, p-nitro group, prenyl group, 2-pentenyl group, 2-ethyl-2-butenyl group, geranyl group, neryl group, etc., and halogen atoms include chlorine, bromine, iodine atoms, etc. be. In addition, substituted silyl groups include, for example, trimethylsilyl group, triethyl,
lucilyl 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, diphenylsilyl group, dimethyl Such as octadecylsilyl group. The present invention will be explained in more detail below. First, erythromycin A 9-oxime is prepared with the formula R
The reaction with the compound 1-X is carried out according to a method known per se, for example the method described in European Patent No. 158.467, and is carried out in the general formula (wherein R' has the same meaning as above). It is possible to obtain a compound that can be expressed.

Next, the reaction between the compound 2 and the silylating agent is carried out in a solvent.
The reaction is carried out by stirring in the presence of a base at 0°C to the reflux temperature of the solvent, preferably at room temperature. As the silylating agent, chlorosilanes such as trimethylchlorosilane, tert-butyldimethylchlorosilane, 1,1,1
．． Silylamines such as 3,3.3-hexamethyldisilazane, trimethylsilylimidazole, and dimethylaminotrimethylsilane, bis(trimethylsilyl)acetamide, trimethylsilyldiphenylurea, bis(trimethylsilyl)urea, and the like can be used. The amount of the silylating agent used is 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to the compound of formula (1).

Solvents used in this reaction include acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, 1,2-dimethoxyethane,
Examples include dichloromethane and chloroform. Examples of bases include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trimethylamine, triethylamine, pyridine,
Organic bases such as 1°8-diazabicyclo[5,4,0]unde-7-cene, imidazole, etc. can be used.

In this reaction, the compound of formula
Whether silylation is performed at the 2'-position or the 4'-position depends on the reaction conditions, but the use of chlorosilanes is preferable for silylation at the 2'-position, and the combination of chlorosilanes and silylamines or 1.1.1.3. 3. The use of 3-hexamethyldisilazane is preferred for silylation of the 2' and 4' positions.

Alternatively, the compound of formula ■ is erythromycin A 9
It can also be obtained by reacting a later compound of R'-X, which is obtained by reacting -oxime with a silylating agent. That is, erythromycin A 9-oxime and a silylating agent are reacted under the same conditions as for the silylation, and then the obtained compound is reacted with a compound of formula R''-X under the above reaction conditions to obtain the compound of formula 11 (1). compound can be obtained.

The reaction of the compound of formula (1) and the methylating agent to obtain the compound of formula (2) is carried out in a solvent in the presence of a base with stirring at -15°C to room temperature, preferably at 0°C to room temperature. As the methylating agent, methyl bromide, methyl iodide, dimethyl sulfate, p-toluenesulfonic acid methyl ester, methanesulfonic acid methyl ester, ster, etc. are used, and the amount used is 1 to 3 molar equivalents relative to the compound of formula H. is sufficient. Solvents that can be used include aprotic polar solvents such as N,
N-dimethylformamide, dimethyl sulfoxide, N
-Me, thi-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, tertiary butoxypotassium, potassium hydride, etc. can be used. The amount of base used is determined by the formula π
It is usually 1 to 2 molar equivalents per compound.

121 In the present invention, when methylating the compound of the formula ”
- Substituted silyl etherification of the hydroxyl group is not necessarily an essential condition.

Further, the compound of formula (1) may be reacted with a methylating agent after being isolated or without being isolated.

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.
It may also be a mixture of the syn type and the anti type.

According to the present invention, in the synthesis of 6-0-methylerythromycin A derivatives, protection of the 3'-dimethylamino group is not required, and therefore 3'-N-methylation is no longer necessary.

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

Furthermore, the substituted silyl groups used to protect the 2'- and 4''-position hydroxyl groups in the present invention are very easy to remove.

Therefore, the present invention has made it possible to provide 6-0-methylerythromycin A in high yield and economically.

That is, the compound of formula (1) is converted into 6-0-methylerythromycin A in the following manner, for example.

First, the substituted silyl groups (R2 and Rm) at the 2' and 4' positions in the compound of formula I can be easily removed by treatment with, for example, formic acid in an alcoholic solvent or by reaction with tetrabutylammonium fluoride in tetrahydrofuran. removed.

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

This reaction can also be carried out in an organic solvent (e.g., methanol, ethanol, , N,N-dimethylformamide, etc.) at room temperature to 70°C.

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

There is no problem even if the order of the removal operation of R2 and R1 and the removal operation of R1 is reversed.

The obtained 6-0-methylerythromycin A9-oxime can be prepared using sodium bisulfite, titanium trichloride-ammonium acetate, sodium nitrite-hydrochloric acid, or sodium hydrosulfide ('Na t's x Oa
), etc., to easily convert it to 6-0-methylerythromycin A.

Next, the method for producing the compound of formula (1) of the present invention will be specifically explained using Examples, and the method for producing 6-0-methylerythromycin A using Reference Examples.

・Example 1 Erythromycin A 9-(0-benzyloxime)
3.36g and 0.7mQ of triethylamine in N,N
- It was dissolved in 30 ml of dimethylformamide, 0.7 ml of trimethylchlorosilane was added dropwise at room temperature, and the mixture was stirred for 10 minutes. Isopropyl ether was added to the reaction mixture, which was washed with water and then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting crude product was recrystallized from isopropyl ether to obtain 1.35 g of the title compound in the form of colorless needles.

m, p, 1.04-106°C Mas 5 (FAB); m/z: 911 (MH
”)PMR(CDCj23); δ(ppm) −0, 11(2′-〇-TMS).

2, 2', 3 [3'7 N (CHa) shoulder.

3.33(3”-〇〇Hs) CMR(CD(J+3); δ(ppm)=1,0(2'-0-IMS)
.

41, O [3'-N (CH O) shoulder.

49.5 (3”-0CHI) (TMS in the above represents a trimethylsilyl group.

The same applies below. ) Preparation of Example 2 2.24 g of trimethylsilylimidazole and 1.74 g of trimethylchlorosilane are dissolved in 20 ml of dry dichloromethane, and 6.72 g of erythromycin A 9-(0-benzyloxime) dissolved in 40 ml of dichloromethane are added at once at room temperature. The mixture was added and stirred at room temperature for 10 minutes. After adding chloroform and washing with water and then saturated brine, it was dried over anhydrous magnesium sulfate.

The solvent was distilled off, and the resulting crude product was recrystallized from acetone-water to obtain 5.27 g of the title compound in the form of colorless needles.

m, p, 97-l 00'C Mas 5 (FAB); m/z: 983 (MH
”)PMR(CDC13);S(ppm)=0,09(2'-
0(MSn.

0.15 (4”-〇-T, MS).

2.2 2 [3'-N(CHs)*ko.

3.31 (3"-〇 〇 Hz) CMR(CD(J13): δ(pI)fil)=0.9<4"-0-TMS
).

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

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

49.7(3"-OCHi) Example 3 2'-〇~trimethylsilylerythromycin A 9
-(0-Benzyloxime) 2.28g was dissolved in 20ml of a mixed solvent of dimethyl sulfoxide/tetrahydrofuran (1/1), 0.38mjl of methyl iodide and then 280mg of 85% potassium hydroxide powder were added, and the mixture was heated to room temperature for 2 hours. Stir for hours. Add ethyl acetate to the reaction solution, add water,
The mixture was then washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the glassy title compound 2 was obtained.
．． 32g was obtained.

Mas 5 (FAB): m/z: 925 (MH
”) PM R (CDCρ3); S (ppm) = 0, 09 (2'-0-TMS)
.

2, 23 [3'-N(CHi)tl.

3.03 (6-OCHI).

3,34<3''-OCHm) Example 4 2',4''-bis(trimethylsilyl)erythromycin A 9-(0-benzyloxime) 3,93g
was treated as in Example 3 to obtain the glassy title compound 3.
．． 89g was obtained.

m, p, l15-116°C (recrystallized from methanol) Mas 5 (FAB); m/z: 997 (MH
”) PMR (CDCI13); δ (ppm) = 0, 09 (2'-0-TMS)
.

0.15 (4″-〇　-TMS).

2, 21 [3'-N(CHl)! ].

−20= 3.03 (6-OCHi).

3゜32 (3”-OCHs) CM　R(CDCj23); δ (ppm) = 0.9 (4”-0-IMS).

1.1 (2'-0-IMS>.

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

49.7 (3”-0CR,).

50.7(6-OCHm) Example 5 Erythromycin A 9-(0-allyloxime) I
g was treated in the same manner as in Example 1, and the obtained crude product was purified by alumina column chromatography (elution solvent: acetone/n-hexane = 1/10 to 115) to obtain the title compound in a glass form. 35g was obtained.

m, p, 93-96°C (recrystallized from n-hexane) Mass (E I): m/z: 860 (M”
)PMR(CDCj?3); δ(ppm>=0, 11 (2'-0-TMS)
.

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

3.32 (3"-OCHM) CM R<CDCR5); ε (ppm) = 1.0 (2'-0-TMS).

41, 0 [3'-N (CHs)t].

49.5(3”-OCHm) Example 6 Erythromycin A 9-(0-allyloxime) I
After reacting g in the same manner as in Example 2, 100 ml of n-hexane was added to the reaction solution and insoluble matter was filtered. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (elution solvent: acetone/n-hexane/triethylamine =
1/1010.1) to obtain 0.70 g of the glassy title compound.

m, p, 85-89°C (recrystallized from acetone) Ma8s (E I); m/Z,: 932 (M
”) PMR (CDC#3); S (ppm) = 0, 10 (2'-0-IMS)
.

0.14 (4"-〇　-TMS>.

2.22[3°-N(CHsL]).

3.31 (3″-OCHm) Example 7 Erythromycin A 9-(0-allyloxime)4
g and 1.4 ml of triethylamine were dissolved in 20 ml of N,N-dimethylformamide, 1.35 ml of trimethylchlorosilane was added dropwise at room temperature, and the mixture was stirred for 20 minutes. Add 100ml of water, extract with ethyl ether,
The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3.86 g of a crude product of 2'-0-trimethylsilylerythromycin A 9-(0-allyloxime).

This was mixed with dimethyl sulfoxide/tetrahydrofuran (1
0.42 Tnf1 of methyl iodide and then 357 mg of 85% potassium hydroxide powder were added under water 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 TnfL of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. Distill the solvent,
The residue was subjected to silica gel column chromatography (elution solvent: acetone/n-hexane/triethylamine = 1
/ 510.1) to give the glassy title compound 1.
45g was obtained.

m, p, 155-158°C (recrystallized from n-hexane) Mass (EI); m/z: 874 (M”) P M R
(CDCIIs): δ (ppm) = 0, 10 (2'-0-TMS)
.

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

3.08 (6-OCHm).

3.33 (3”-〇 CHm) CMR (CDCR3); δ (ppm) = 1, 1 (2'-0-IMS)
.

41,,O[3'-N(CHmL]- 49,4 (3″-〇〇〇Hx).

50.9 (6-OCHM) Example 8 3.51 mu of trimethylsilylimidazole and 3.04 mu of trimethylchlorosilane &! was dissolved in 25ml of dry dichloromethane, and 125mH of dichloromethane was added.
Add 9.5 g of erythromycin A 9-(0-allyloxime) dissolved in 9-(0-allyloxime) at room temperature,
Stir for a minute. 400 mQ of n-hexane was added to the reaction solution, insoluble matters were filtered off, and the filtrate was concentrated. 200 ml of n-hexane was added to the residue, the resulting insoluble matter was filtered, and the filtrate was concentrated.

This was mixed with dimethyl sulfoxide/tetrahydrofuran (1
/1) in 75 ml of mixed solvent, methyl iodide 1
ml and then 854 mg of 85% potassium hydroxide powder were added under water cooling and stirred for 1.5 hours. After the reaction was completed, the reaction mixture was treated in the same manner as in Example 7 to obtain 10.2 g of the title compound.

m, p, 96-101°C (recrystallized from acetone-water) Mass (EI); m/z: 946 (M”) P M R
(CD(J)3); S (ppm)=0,09 (2'-0-IMS)
.

0, 15 (4”-0-TMS>.

2, 22 [3'-N(CHiL]).

3.09 (6-OCHs).

3.32 (3”-0CH8) CMR (CDCff3); E (ppm>= 0, 9 (4”-〇-IMS
).

1.1 (2°-0-TMS).

4 1. 0 [3'-N(CHs)t.

49.7 (3-OCHs).

50', 9 (6-OCH8) Example 9 Production of Erythromycin A 9-oxime (10 g) was dissolved in 75 ml of tetrahydrofuran, and 1.25 ml of allylpromide was dissolved in 75 ml of tetrahydrofuran.
Add 970 mg of 1 and 85% potassium hydroxide powder,
The mixture was stirred at room temperature for 2 hours. 1 ml of 50% dimethylamine aqueous solution was added to the reaction solution, and the mixture was stirred for 30 minutes, then poured into ethanol/water (50 ml/200 ynll), and stirred for 30 minutes under water 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 the crude erythromycin A
9.7 g of 9-(0-allyloxime) was obtained.

3.58 mQ of trimethylsilylimidazole and 3.10 mft of trimethylchlorosilane were dissolved in 25 ml of dry dichloromethane, and 9.7 g of the above erythromycin A 9-(0-allyl-27=oxime) dissolved in 125 ml of dichloromethane was added at once at room temperature. 1 at room temperature
Stirred for 0 minutes. 200ml of n-hexane was added to the reaction solution, insoluble materials were filtered off, and the filtrate was concentrated. Add 200 ml of n-hexane to the residue once again to filter out insoluble materials, and concentrate the filtrate to obtain crude 2'',4''-bis(trimethylsilyl)erythromycin A 9-(0-allyloxime).
10g was obtained.

10 g of the above crude 2',4''-〇-bis(trimethylsilyl)erythromycin λ 9-(0-allyloxime)
dimethyl sulfoxide/tetrahydrofuran ('1/
Dissolve in 75 ml of mixed solvent of 1) and add 1 ml of methyl iodide.
, then add 837 mg of 85% potassium hydroxide powder,
The mixture was stirred for 1.5 hours under water cooling. After the reaction was completed, 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 extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 10.3 g of crude 2',4''-〇-bis(trimethylsilyl)-6-0-methylerythromycin A 9-(O-allyloxime).

Purification was performed in the same manner as in Example 8 to obtain the title compound.

The melting point, Mass, :PMR, CMR of this compound is:
This was consistent with the compound obtained in Example 8.

Example 10 3.79 g of erythromycin A 9-oxime and 0.75 yd of benzyl chloride were dissolved in 30 ml of N,N-dimethylformamide, and dissolved in sodium hydride (60%
) 0.24g was added. After stirring for 2 hours 1.1.1゜3
, 2.5 ml of 3,3-hexamethyldisilazane and 0.99 g of pyridine hydrochloride were added, and the mixture was further stirred at room temperature for 6 hours. - After standing overnight, pour the reaction solution into water and extract with ethyl acetate.
After washing with water, drying over anhydrous magnesium sulfate and distilling off the solvent, the resulting crude product was recrystallized from aqueous acetone to obtain 3.0 g of the title compound. This compound matched the compound obtained in Example 2 in m, p, PMR, and Mass.

Example 11 (1) Erythromycin A 9-oxime 90g N.

It was dissolved in 500 ml of N-dimethylformamide, 23.6 g of 0-chlorobenzyl chloride and 9.7 g of 85% potassium hydroxide were added, and the mixture was stirred for 30 minutes under water cooling. 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 to give erythromycin A 9-[0
-(o-chlorobenzyl)oxime] 98 g were obtained.

m, p, 11.4°C to 117°C (recrystallized from n-hexane) (2) Dissolve 8.7 g of the above compound in 80 ml of ethyl acetate, and add 2.53 ml of trimethylchlorosilane and 2.8 g of trimethylsilylimidazole to acetic acid. A solution dissolved in 10 mQ of ethyl was added and stirred at room temperature for 1 hour. After adding n-hexane, the mixture was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give a glassy 2',4''-bis(trimethylsilyl)erythromycin A9-[0-().

9.78 g of (n-lolobenzyl) oxyjimco was obtained.

Ma s s (E I); m/z:
1 0 1 6 (M”) P M R (CDC1) 3
) ; δ (ppm) = 0, 10 (2'-0-IMS>
.

0.15 (4”-0-TMS).

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

3.30 (3"-0CR,) (3) 5.09 g of 2',4"-O-bis(trimethylsilyl)erythromycin A9-[0-(o-chlorobenzyl)oxime] was dissolved in dimethyl sulfoxide/tetrahydrofuran (1/ 1) Dissolved in 100ml of mixed solvent,
0.41 m2 of methyl iodide and then 360 mg of 85% potassium hydroxide powder were added, and the mixture was stirred for 1.5 hours under cooling. Add 2 mQ of 50% dimethylamine aqueous solution to the reaction solution and
After stirring for a minute, 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 under reduced pressure to give the glassy title compound 4.
3g was obtained.

Mas s (E I); m/z: 1030 (
M") P M R (CD (J'3); δ (ppm>= 0, 10 (2'-0-IMS)
.

0.15 (4”-〇-IMS>.

2, 22 [3'-N (CH8)! ].

3.02 (6-OCHa).

3,32 (3'=OCHa) Example 12 Erythromycin A obtained in (1) of Example 11 above
9-[0-(o-chlorobenzyl)oxime]15.2
7 g was dissolved in 150 ml of N,N-dimethylformamide, 7.8 ml of 1.1.1,3.3.3-hexamethyldisilazane and 2.6 g of pyridine hydrochloride were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water and 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 to obtain 14.5 g of the title compound. This compound is the compound (2) of Example 11.
) Mass and PMR were consistent with the compound in section 2.

Example 13 3 g of erythromycin A 9-oxime was dissolved in 15 ml of N,N-dimethylformamide, 0.773 g of 0-chloro, lobenzyl chloride and 0.192 g of 60% sodium hydride were added, and the mixture was stirred for 2 hours under water cooling.

Then, the reaction solution was returned to room temperature, and 1,1.1,3.3.3-
1.69 ml of hexamethyldisilazane and 0.321 g of ammonium chloride were added, and stirring was continued for 20 hours at room temperature. After the reaction, 50 ml of n-hexane and 10 ml of saturated saline
0 ml of water was added, the organic layer was separated, and saturated brine (100 ml of
After washing with QX2), it was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4.2 g of the title compound.

This compound is the compound of Section (2) of Example 11.
, PMR matched.

Reference Example 1 Production of Syn A Crude 2',4''-0-bis(trimethylsilyl)-6-0-methylerythromycin A obtained in Example 9
Dissolve 10.3 g of 9-(0-allyloxime) in 100 ml of methanol, add 6.2 ml of 99% formic acid, and
The mixture was stirred at 0°C for 1 hour. Add 300ml of water to the reaction solution,
The mixture was made alkaline by adding a 2N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off to give crude 6-0-methylerythromycin A 9-(0
-allyl oxime) 8.93 g was obtained.

The obtained crude 6-0-methylerythromycin A9-(0
- Dissolve 8.93 g of allyloxime in a mixed solvent of 50 ml of dioxane and 7.5 ml of water, and dissolve 8.93 g of allyl oxime in a mixed solvent of 50 ml of dioxane and 7.5 ml of water.
9 mg, ) 539 mg of liphenylphosphine and 9.7 g of triethylammonium formate were added, and the mixture was 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 give crude 6-0-methylerythromycin A.
8.5 g of 9-oxime was obtained.

m, p, 223-225°C Reference Example 2 Crude 2',4''-0-bis(trimethylsilyl)'-'6-0-methylerythromycin A ^-['0-ci- chlorobenzyl) oxime]
2.8g was dissolved in methanol 30TIIQ, 10% palladium encyclopedia 4S0mg, formic acid 1.8yd, and ammonium formate 300mg were added, and the mixture was stirred at 60°C for 2 hours. The palladium catalyst was removed by filtration, 200 TrlIII of water was added to the filtrate, and the mixture was made basic with a 2N aqueous sodium hydroxide solution. The deposited precipitate was collected by filtration, washed with water, and dried to obtain 1.7 g of crude 6-0-methylerythromycin A 9-oxime.

The obtained 6-0-methylerythromycin A9-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 crystalline 6-0-methylerythromycin. .

m, 1), 223-225°C

Claims (2)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 is a 2-alkenyl group with 3 to 15 carbon atoms, an arylmethyl group, or a halogen atom, or a halogen atom with 1 to 4 carbon atoms. represents an arylmethyl group substituted with 1 to 3 alkoxy groups, nitro groups, and alkoxycarbonyl groups having 2 to 6 carbon atoms, and R^2 is of the formula -SiR^4
R^5R^6 (in the formula, R^4, R^5 and R^6 are the same or different and each has 1 to 1 carbon atoms substituted with a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, or a phenyl group) Indicates three alkyl groups, phenyl groups, cycloalkyl groups having 5 to 7 carbon atoms, or alkenyl groups having 2 to 5 carbon atoms.However, at least one of R^4, R^5 and R^6 represents a substituted silyl group (not a hydrogen atom), and R^3 represents a hydrogen atom or R^2. ] 6-O-
Methylerythromycin derivative. (2) General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ [In the formula, R^1 is a 2-alkenyl group with 3 to 15 carbon atoms, an arylmethyl group, or a halogen atom, or a halogen atom with 1 to 4 carbon atoms. represents an arylmethyl group substituted with 1 to 3 alkoxy groups, nitro groups, and alkoxycarbonyl groups having 2 to 6 carbon atoms, and R^2 is of the formula -SiR^4
R^5R^6 (in the formula, R^4, R^5 and R^6 are the same or different and each has 1 to 1 carbon atoms substituted with a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, or a phenyl group) Indicates three alkyl groups, phenyl groups, cycloalkyl groups having 5 to 7 carbon atoms, or alkenyl groups having 2 to 5 carbon atoms.However, at least one of R^4, R^5 and R^6 represents a substituted silyl group (not a hydrogen atom), and R^■ represents a hydrogen atom or R^2. ] 6-O-
In preparing methylerythromycin derivatives, erythromycin A9-oxime can be added in any order to the formula R
By reacting with a compound of ^1-X (wherein R^1 has the same meaning as above and X represents a halogen atom) and a silylating agent having R^2, a compound of the general formula ▲ mathematical formula, chemical formula, There are tables, etc. ▼ (In the formula, R^1, R^2 and R^3 have the same meanings as above.) - A method for producing a methylerythromycin A derivative.