JP2782793B2 - Erythromycin A derivative and method for producing the same - Google Patents

Description

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-
Compared to erythromycin A, methylerythromycin A is not only more stable under acidic conditions, but also has a stronger antibacterial activity. In particular, this compound is a useful antibacterial agent because it shows a remarkable effect in the treatment of infectious diseases by oral administration.

Conventionally, for example, the following method is known as a method for producing 6-O-methylerythromycin A. (1) After replacing the hydrogen atom of the 2′-hydroxyl group and the methyl group of the dimethylamino group at the 3′-position of erythromycin A with a benzyloxycarbonyl group, the 6-hydroxyl group is methylated, and then the benzyloxycarbonyl group is removed. A method for obtaining 6-O-methylerythromycin A by methylating the methylamino group at the 3'-position (U.S. Pat. No. 4,331,803).
(2) As a method for improving the selectivity of methylation of the erythromycin A derivative to the 6-position hydroxyl group, erythromycin A in which one or both of the 2′-hydroxyl group and the 3′-position dimethylamino group of the erythromycin A derivative is protected
After converting the derivatives into various substituted oxime derivatives, 6
Methylation of the hydroxyl group, followed by removal of the protecting group, deoximation at the 9-position, and regeneration of the dimethylamino group at the 3'-position.
A method for obtaining -O-methylerythromycin A (EP-A-158,467).

However, in the method (1), since erythromycin A has a large number of hydroxyl groups, many by-products in which the hydroxyl group other than the 6-position is methylated are obtained, and 6-O-methylerythromycin is obtained. There is a disadvantage that the purification of the A derivative requires a complicated operation, and thus the yield is low. In the method (2), selective methylation of the hydroxyl group at the 6-position becomes possible, but deprotection after methylation requires a complicated operation such as catalytic reduction.

Means for Solving the Problems The present inventors have made various studies to solve the drawbacks of the above-mentioned known methods. As a result, the hydroxyl group at the 6-position of erythromycin A is selectively methylated, and the introduction and removal of each protecting group can be reduced. The present inventors have found an easy method for producing an erythromycin A derivative and completed the present invention.

The object of the present invention is to use the general formula [Wherein, R represents a hydrogen atom or a methyl group, and X represents a trimethylsilyl group (hereinafter may be abbreviated as TMS). ] An erythromycin A derivative represented by the formula:

Another object of the present invention is to prepare a compound of formula I
Reacting erythromycin A 9-oxime with any one of 1,1-diisopropoxycyclohexane or 1-isopropoxycyclohexene and a trimethylsilylating agent in any order, or further reacting with a methylating agent. An object of the present invention is to provide a method for producing an erythromycin A derivative.

 Hereinafter, the present invention will be described in detail sequentially.

First, erythromycin A 9-oxime is reacted with 1,1-diisopropoxycyclohexane or 1-isopropoxycyclohexene to protect the hydroxyl group at the 9-oxime position, Erythromycin A 9- {O- [1-
(1-Methylethoxy) cyclohexyl] oxime} is obtained.

This reaction may be a method usually used for introducing an acetal-type protecting group to a hydroxyl group.For example, erythromycin A 9-oxime may be reacted with 1,1-diisopropoxycyclohexane or 1-isopropoxycyclohexene in a solvent in the presence of a catalyst. This is performed by stirring. In this reaction, 1,1-diisopropoxycyclohexane or 1-diisopropoxycyclohexane
-Isopropoxycyclohexene is used in an amount of 2 to 20 equivalents, preferably 2 to 10 equivalents, based on erythromycin A 9-oxime.

As the solvent used in the above reaction, dichloromethane,
Examples thereof include 1,2-dichloroethane, chloroform, tetrahydrofuran, N, N-dimethylformamide, acetone, acetonitrile, nitroethane, and toluene. In addition, as a catalyst to be used, hydrochloric acid, sulfuric acid,
Examples include salts of paratoluenesulfonic acid and the like with tertiary amines (eg, pyridine, α-picoline, β-picoline, γ-picoline, N, N-dimethylaniline, triethylamine, etc.), and pyridine hydrochloride, Pyridinium paratoluenesulfonate and the like are preferred.
These are 1: 1 for erythromycin A 9-oxime.
5 to 5 equivalents are used, preferably 1.5 to 3 equivalents. The reaction temperature is from 0 ° C. to the reflux temperature of the solvent, but room temperature is usually sufficient.

Next, the compound of formula II is reacted with the trimethylsilylating agent in a solvent at 0 ° C. to the reflux temperature of the solvent, preferably at 0 ° C. to room temperature, to obtain a compound of formula I wherein R is a hydrogen atom.

Examples of the trimethylsilylating agent include silylamines such as trimethylsilylimidazole, 1,1,1,3,3,3-hexamethyldisilazane, silylamides such as bis (trimethylsilyl) acetamide, trimethylsilyldiphenylurea, and bis (trimethylsilyl) urea; Trimethylchlorosilane or a mixture thereof can be used. When using trimethylchlorosilane alone, it is preferable to use a base. The amount of the trimethylsilylating agent to be used is 1 to 10 equivalents, preferably 1 to the compound of the formula II.
~ 5 equivalents.

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

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

Alternatively, compounds of formula I wherein R is a hydrogen atom can be obtained by trimethylsilylation of erythromycin A 9-oxime followed by acetalization. That is, erythromycin A 9-oxime is reacted with a silylating agent under the same conditions as the above-mentioned trimethylsilylation, and then the compound obtained is reacted with a compound of the formula II under the same conditions as the above-mentioned acetalization, whereby R is a hydrogen atom. A compound of formula I can be obtained.

The methylation of the hydroxyl group at the 6-position is carried out by subjecting a compound of the formula I wherein R is a hydrogen atom to -15
C. to room temperature, preferably 0.degree. C. to room temperature with stirring. As the methylating agent, methyl bromide, methyl iodide, dimethyl sulfate, methyl p-toluenesulfonate, methyl methanesulfonate, methanesulfonic acid and the like are used. 1 to 3 equivalents is sufficient for the compound of formula (1). Solvents that can be used include aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, N-methyl-2.
-Pyrrolidone, hexamethylphosphoric triamide or mixtures thereof, or tetrahydrofuran,
A mixture with acetone, 1,2-dimethoxyethane, acetonitrile or ethyl acetate. As the base, sodium hydroxide, potassium hydroxide, sodium hydride,
Potassium hydride, potassium tert-butoxide, or the like can be used. The amount of the base to be used is generally 1-2 equivalents relative to the compound of the formula I wherein R is a hydrogen atom.

In the present invention, the erythromycin A 9-oxime derivative has two isomers (syn-form and anti-form). In the present invention, the isomer may be a syn-form or an anti-form. It may be a mixture.

Effects of the Invention In the method of the present invention, the quaternization of the dimethylamino group is prevented during the methylation of the 6-position hydroxyl group by the trimethylsilylation of the 2'- and 4'-position hydroxyl groups. The protection of the dimethylamino group is not required, and the methylation of the hydroxyl group at the 6-position allows the oxime group at the 9-position to be 1-
The selectivity is extremely good due to the protection with a (methylethoxy) cyclohexyl group.

The protecting groups for the respective oxime, 2 'and 4 "hydroxyl groups of the compounds of the formula I according to the invention can be easily removed under acidic conditions.

Further, the regeneration of the ketone by deoximation proceeds in good yield under acidic conditions, and thus can be performed simultaneously with the removal of the protecting group, which is more convenient.

Therefore, the method of the present invention is a method in which the reaction operation is remarkably simplified and 6-O-methylerythromycin A can be obtained in a high yield and economically. That is, R
Is a methyl group, for example, can be converted to 6-O-methylerythromycin A as follows.

First, the protecting groups for the 9-oxime hydroxyl group, the 2′-hydroxyl group and the 4 ″ -hydroxyl group of the compound of the formula I can be prepared by stirring at room temperature to the reflux temperature of the solvent in a suitable organic solvent in the presence of water and an acid. Here, the acid is formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, etc. The organic solvent is methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, N, N A hydrophilic solvent such as dimethylformamide is used.

The obtained 6-O-methylerythromycin A 9-oxime can be easily converted to 6-O-methylerythromycin A by reacting with a deoximation agent. Deoximation agents include sodium bisulfite, sodium pyrosulfate, sodium thiosulfate, sodium sulfite, sodium hydrosulfite, sodium metabisulfite, sodium dithionate, potassium bisulfite, potassium thiosulfate, potassium metabisulfite, etc. Is a salt of an inorganic sulfur oxide. In this reaction, the solvent may be the hydrophilic solvent used for the removal of the silyl group, and the reaction proceeds rapidly when carried out in the presence of an acid. Further, the compound of the formula I is more suitable in the present invention, since it can be deoximeated at the same time as the removal of the protecting group by reacting with a deoximation agent in the presence of an acid. That is, for example, a compound of formula I wherein R is a methyl group, in aqueous ethanol, 1.5 to 10 equivalents, preferably 2 to 5 equivalents of formic acid with respect to the compound of formula I, sodium hydrogen sulfite 1 to
6-O-methylerythromycin A can be obtained by adding 10 equivalents, preferably 4-7 equivalents, and stirring at 50 ° C to reflux temperature. As described above, the intermediate in each step is isolated from the reaction solution by a method such as extraction. Further, it can be purified by crystallization, column chromatography or the like. However, their isolation and purification are not essential.

The progress of the reaction can be monitored by thin-layer chromatography, high-performance liquid chromatography, or the like, and the reaction may be stopped after the disappearance of the raw materials.

EXAMPLES Next, the present invention will be specifically described with reference to examples.

Example 1 (1) 5 g of erythromycin A 9-oxime was dissolved in 35 ml of dichloromethane, and 1.16 g of pyridine hydrochloride was added under ice cooling.
Next, a solution of 6.69 g of 1,1-diisopropoxycyclohexane dissolved in 15 ml of dichloromethane was added, and at room temperature, 42.5 g was added.
Stirred for hours. After the reaction, the reaction mixture was added to a 2N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to remove erythromycin A 9- {O- [1-
(1-Methylethoxy) cyclohexyl] oxime {5.
1 g was obtained.

114-116 ° C (recrystallized from dichloromethane-isopropyl ether) ¹ H-NMR (CDCl ₃ ); δ (ppm) = 2.32 [3′-N (CH ₃ ) ₂ ], 3.32 (3 ″ -OCH ₃ ), 4.05 _{[-O-C H (CH 3} ) 2] Mass (SIMS); m / z = 889 (MH ⁺ ) (2) Dissolve 4.45 g of the compound obtained above in 15 ml of N, N-dimethylformamide, add 0.58 g of pyridine hydrochloride,
Then, under ice cooling, 1,1,1,3,3,3-hexamethyldisilazane
1.76 ml was added. Stir at room temperature for 5 hours and 40 minutes.
50 ml of an aqueous sodium hydroxide solution and 50 ml of water were added, and the mixture was extracted with ethyl acetate (100 ml and 50 ml).

The organic layer was washed with water (50 ml × 2) and saturated saline (50 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.78 g of 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- {O- [1- (1-methylethoxy) cyclohexyl] oxime}.

¹ H-NMR (CDCl ₃ ); δ (ppm) = 0.08 (2′-O-TMS), 0.12 (4 ″ -O-TMS), 2.20 [3′-N (CH ₃ ) ₂ ], 3.28 (3 _{"-OCH 3), 4.05 [-O} -C H (CH 3) 2] Mass (CI); m / z = 1032 (M ⁺ ) Example 2 (1) Erythromycin A 9-oxime (10 g) was dissolved in N, N-dimethylformamide (50 ml), and pyridine hydrochloride (2.31) was dissolved.
g, and 5.6 ml of 1,1,1,3,3,3-hexamethyldisilazane were added under ice-cooling, and stirring was continued at room temperature for 5 hours. After the reaction, 50 ml of a 2N aqueous sodium hydroxide solution and 50 ml of water were added, and the mixture was extracted with ethyl acetate (100 ml and 50 ml).

The organic layer was washed with water (50 ml × 2) and saturated saline (50 ml) and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 11.9 g of 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9-oxime, which was purified by recrystallization from aqueous acetone.

¹ H-NMR (CDCl ₃ ); δ (ppm) = 0.11 (2′-O-TMS) 0.15 (4 ″ -O-TMS) 2.21 [3′-N (CH ₃ ) ₂ ] 3.30 (3 ″ -OCH) ₃ ) 8.05 (= N-OH) ¹³ C-NMR (CDCl ₃ ) δ (ppm) = 0.9 (4 ″ -O-TMS) 1.0 (2′-O-TMS) 41.0 [3′-N (CH ₃ )] ₂ ] 49.8 (3 ″ -OCH ₃ ) Mass (EI); m / z = 892 (M ⁺ ) (2) 2 ′, 4 ″ -O-bis (trimethylsilyl) erythromycin A 9-oxime 9.8 obtained above g in 45 ml of dichloromethane and pyridine hydrochloride 1.73 under ice cooling.
g, then 1,1-- dissolved in 15 ml of dichloromethane.
Add 5.0 g of diisopropoxycyclohexane, and add
The mixture was stirred for 40 minutes. Thereafter, the same treatment as in Example 1 (1) was carried out to obtain 10.7 g of 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- {O- [1- (1-methylethoxy) cyclohexyl] oxime}. Obtained.

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

(3) Dissolve 5.86 g of the compound obtained above in 53 ml of a mixed solvent of dimethyl sulfoxide / tetrahydrofuran (1/1), and add 0.915 g of methyl iodide and then 0.38 g of 95% potassium hydroxide powder under ice-cooling. And stirred for 5 hours. 5 in the reaction solution
1 ml of a 0% dimethylamine aqueous solution was added, and the mixture was stirred as it was for 1 hour. 100 ml of water was added to the reaction solution, and extracted with ethyl acetate (100 ml and 50 ml). After washing the organic layer with saturated saline,
It was dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and 2 ', 4 "-O-bis (trimethylsilyl) -6-O
-Methylerythromycin A 9- {O- [1- (1-
Methylethoxy) cyclohexyl] oxime (5.64 g) was obtained.

¹ H-NMR (CDCl ₃ ); δ (ppm) = 0.09 (2′-O-TMS), 0.15 (4 ″ -O-TMS), 2.21 [3′-N (CH ₃ ) ₂ ], 3.10 (6 _{-OCH 3), 3.30 (3 "} -OCH 3), 4.10 [-O-C H (CH 3) 2] Example 3 5 g of erythromycin A 9-oxime was dissolved in 20 ml of acetonitrile, 1.16 g of pyridine hydrochloride and then 3.35 g of 1,1-diisopropoxycyclohexane dissolved in 5 ml of acetonitrile were added, and the mixture was stirred at room temperature for 14.5 hours. To the reaction solution were added 1.16 g of pyridine hydrochloride and 5.6 ml of 1,1,1,3,3,3-hexamethyldisilazane under ice-cooling, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 1 hour and 30 minutes. 60 ml of n-hexane was added to the reaction solution.
5 ml of a 2N aqueous sodium hydroxide solution and 50 ml of water were added, the organic layer was separated, washed sufficiently with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to remove 2 ', 4 "-O-bis (trimethylsilyl) erythromycin A 9- {O-
6.5 g of [1- (1-methylethoxy) cyclohexyl] oxime A was obtained.

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

Example 4 23.4 g of erythromycin A 9-oxime was dissolved in 160 ml of dichloromethane, and 5.4 g of pyridine hydrochloride was added under ice cooling.
Then 15.3 g of 1-isopropoxy-1-cyclohexene dissolved in 40 ml of dichloromethane were added. Stirred overnight at room temperature. Thereafter, the same treatment as in Example 1 (1) was carried out, and erythromycin A 9- {O- [1- (1-methylethoxy)) was used.
[Cyclohexyl] oxime｝ 20.5 g was obtained.

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

Reference Example 1 2 ', 4 "-O-bis (trimethylsilyl) -6-O-methylerythromycin A obtained in Example 2 (3)
9.63 g of 9- {O- [1- (1-methylethoxy) cyclohexyl] oxime} is dissolved in 100 ml of ethanol / water (1/1), 6.7 g of sodium bisulfite and 1.6 m of 99% formic acid are dissolved.
l was added and the mixture was stirred under reflux for 60 minutes. 150 ml of water was added to the reaction solution, and a 2N aqueous sodium hydroxide solution was further added dropwise to adjust the pH to about 10
The mixture was stirred for 1 hour under ice cooling. The resulting precipitate was collected, washed with water, and recrystallized from ethanol to obtain 6.15 g of 6-O-methylerythromycin A.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Masato Kashimura 3- 24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Toshifumi Asaga 3- 24-1, Takada, Toshima-ku, Tokyo Taisho Inside Pharmaceutical Co., Ltd. (72) Inventor Yoshiaki Watanabe 3- 24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Kaoru 3--24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Kazuto Kannai 7-20 Shuttlemart 501 No.7-20 Otemachi, Tatebayashi-shi, Gunma (58) Field surveyed (Int.Cl. ⁶ , DB name) C07H 17/08 A61K 31/70 CA (STN) REGISTRY (STN) WPIDS (STN)

Claims (2)

(57) [Claims] (1) General formula (Wherein, R represents a hydrogen atom or a methyl group, and X represents a trimethylsilyl group). 2. The general formula (Wherein, R represents a hydrogen atom or a methyl group, and X represents a trimethylsilyl group). In producing the erythromycin A derivative represented by
The oxime is converted to any one of 1,1-diisopropoxycyclohexane or 1-isopropoxycyclohexene
A method for producing an erythromycin A derivative, which comprises reacting a seed and a trimethylsilylating agent in any order, or further reacting with a methylating agent.