JPS6114157B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing novel macrolide antibiotic derivatives. More specifically, the present invention relates to the general formula [] [In the formula, R ₂ is a methoxy group or a methyl group, R ₃ is -
_CH2CHO , _{-CH2CH2OH ,}

[Formula] (R ₃ represents an alkyl group), R ₄ is hydrogen or

[Formula] (R ₁₁ represents hydrogen or acyl group), R ₅ is methyl group or ethyl group, R ₆ is hydrogen or acyl group, R ₇ is

[Formula] (R ₁₂ is an acyl group, R ₁₃ is hydrogen or an acyl group, respectively), X is

【formula】

【formula】

【formula】

[expression] or

[Formula] (R ₁₄ is hydrogen, acyl group, or

[Formula]) are respectively represented. However, if R ₄

[Formula] When R ₁₄ is hydrogen or an acyl group. The present invention relates to a method for producing a novel macrolide antibiotic derivative shown in the following. The present invention is based on the general formula [] (In the formula, R ₁ represents an acyloxy group, R ₂ , R ₃ ,
R ₄ , R ₅ , R ₆ , R ₇ and X have the same meanings as above) is treated with an alkali under mild conditions in a polar solvent. This is a method for producing an antibiotic derivative represented by the general formula []. That is, the present invention treats the compound represented by the general formula [] with an alkali under mild conditions to remove the 3-position of the aglycon without opening or decomposing the lactone ring, epoxide group, glycoside bond, or acyl group. The purpose of this is to remove the acyloxy group of the compound as the corresponding fatty acid to form a double bond at the 2nd and 3rd positions. The resulting compound represented by the general formula [] not only has strong antibacterial activity against Gram-positive bacteria, but also has
It also shows antibacterial activity against Gram-negative bacteria such as P. pneumoniae. Furthermore, the compound represented by the general formula [] is a useful compound that can also serve as an intermediate for synthesizing various derivatives using it as a starting material. Until now, there are only a few known examples of treatment with a 16-membered ring basic macrolide antibiotic and alkali, but all of the products obtained by known methods are bound to the 4'' position of the neutral sugar micarose. The acyl group undergoes hydrolysis and becomes a hydroxyl group.The antibacterial activity of these 4″-deacyl bodies decreases and decreases, and in the known method, side reactions occur in other parts, resulting in compounds that have lost their antibacterial activity. known to be obtained. In the present invention, since the reaction conditions are mild, the target compound represented by the general formula [] is derived from the neutral sugar micarose.
The acyl group at the 4″ position remains intact, and antibacterial activity is observed. A 16-membered ring basic macrolide represented by the general formula [ ] that can be used as a starting material in carrying out the present invention. Examples of antibiotics include, for example, leucomycin A ₁ , A ₃ , A ₄ , A ₅ , A ₆ , A ₇ , A ₈ , A ₉
(The Journal of Antibiotics Vol.21, No. 532
Pages - No. 538 (1968), Special Publication No. 1973-27393-27397, Publication No. 45-27798-27799), B-
5050-A, -B, -C, -D, -E, -F (Tokuko Showa 47
−7351 Publication, Special Publication No. 49-48518), SF−
837, SF-837A ₂ , A ₃ , A ₄ (Special Publication No. 47-3158, Publication No. 28834 of 1972), YL-704A ₁ , B ₁
(=SF-837) (Special Publication No. 46-28836), YL-
704C ₂ (JP 47-20394), carbomycin A, B (US Patent 2960438) and their mono-, di- or tri-esters (e.g.
B-5050-C-9-propionate) and mono-, di-, tri- or tetra-esters (e.g. triacetylspiramycin) of spiramycin (Japanese Patent Publication No. 36-4599), tylosin (Japanese Patent Publication No. 36-4599), 36-22649) mono-, di-, tri-, tetra- or penta-esters (for example, tylosin-3, 2', 4'',
4.tetraacetate), and their 18-dihydro form (e.g., 18-dihydro-B-5050-C), acetal form (e.g.,
SF-837A ₃ -dimethylacetal), oximes (eg, B-5050-C-oxime), and hydrazones (eg, B-5050-C-dimethylhydrazone). In addition, the ester of the compound represented by the general formula [] can be obtained by reacting tylosin with an esterifying agent such as acetic anhydride in a solvent such as pyridine, for example, according to the same method as in Japanese Patent Publication No. 49-16878. be able to. In the general formula []
Compounds in which R ₃ is -CH ₂ CH ₂ OH can be obtained by using a method similar to Experientia 28 , 878 (1972), in which R ₃ in the general formula [] is -CH 2 CH 2 OH.
It can also be obtained by treating a compound exhibiting CH ₂ CHO with a reducing agent such as sodium borohydride in a solvent such as aqueous methanol. R ₃ is −CH ₂ CH〓〓〓
Compounds showing 〓 are those in which R ₃ is -CH ₂ -CHO, for example, as described in The Journal of Antibiotics.
27 , 221 (1974) by treatment with methanol-hydrochloric acid. Examples of the acyloxy group represented by R ₁ in the general formula [] include acetyloxy, propionyloxy, butyryloxy, etc.
The acyl group represented by R ₆ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ means a straight chain or branched acyl group having 1 to 7 carbon atoms, such as acetyl, propionyl, n-butyryl. , isobutyryl, pentanoyl, isopentanoyl, hexanoyl, heptanoyl, and the like. Furthermore, in the above formula
The alkyl group represented by R ₈ means a straight chain or branched group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, n-butyl, isobutyl, pentyl, and hexyl groups. In the present invention, a compound represented by the general formula [] is dissolved in a polar solvent. Examples of polar solvents used for this include methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, N-methylacetamide, hexamethylphosphoramide, tetramethylurea, acetonitrile, water, or a mixed solvent thereof. Can be mentioned. Next, an alkali is added to this under mild conditions, and the alkalis used in the present invention include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, and alkaline earth metals such as barium hydroxide. hydroxide, alkali metal carbonate or bicarbonate such as sodium carbonate or sodium carbonate, alkaline earth metal carbonate or bicarbonate such as barium carbonate or barium bicarbonate, organic tertiary base such as triethylamine. , Amberlyte IRA-400, Amberlyst A-26 and A-27, Dowex-1
Anion exchange resins such as, sodium borohydride, etc. are used. The amount of alkali added is usually about 1 to 5 mol, preferably about 1 to 2 mol, based on the compound represented by the general formula []. In this reaction, when the alkali used has a reducing effect, a compound represented by the general formula [] may be obtained as a compound in which the carbonyl group at the 9-position and the aldehyde group at the 18-position are cyclically converted to an alcohol. Mild conditions in the present invention mean that the reaction temperature is as low as possible, and can vary appropriately from -80° to 40°C depending on the combination of alkali and solvent used, but is preferably less than 10°C, more preferably less than 10°C. is 0
~5°C. The reaction time varies depending on the raw materials and alkali used, the reaction temperature, etc., and the progress of the reaction can be determined by thin layer chromatography, ultraviolet absorption spectra, etc. The compound represented by the general formula [] thus obtained can be obtained almost as a single substance depending on the raw materials and reaction conditions, and may require almost no purification, but if it is obtained as a mixture, it is usually obtained using a method known per se. Solvent fractionation, fractional precipitation, countercurrent distribution method, or adsorbents such as silica gel, alumina, ion exchange resin, Amberlite XAD-2 (manufactured by Rohm and Haas), HP-10 (manufactured by Mitsubishi Kasei), and activated carbon. It can be separated and purified by adsorption chromatography using as a carrier. The target compound [ ] produced by the present invention is a new compound that has not been described in any literature, and has antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, and mycoplasma. For example, tablets, granules, capsules,
It can be administered in an appropriate dosage form such as an injection. The dosage varies depending on the subject to be administered (e.g., humans and other animals), symptoms, properties of the compound, etc., but for example, in the case of oral administration, the daily dose is approximately 10 to 500 mg/Kg. can be selected. The present invention will be specifically described below with reference to Reference Examples and Examples, but the present invention is not limited thereto. Reference example 1 1.7g of antibiotic B-5050-C in water-containing methanol
Dissolve in 40ml and add sodium borohydride to this.
75.6 mg was added and stirred at room temperature for 1 hour. The reaction solution was diluted with water, extracted with ethyl acetate, and the extract was washed with water, dehydrated, and concentrated to yield 18-dihydro-B.
-5050-C1.61g was obtained. Melting point: 133° to 134°C Specific rotation: [α] ²³ _D -77.2° (C = 1.0, ethanol) Elemental analysis value C ₄₁ H ₆₉ NO ₁₆・1/2H ₂ O Calculated value: C, 58.55; H , 8.39; N, 1.67 Experimental value: C, 58.57; H, 8.49; N, 1.67 Nuclear magnetic resonance spectrum: The signal of the aldehyde group disappeared. Reference example 2 1.8g of antibiotic B-5050-C was mixed with chromium trioxide.
After reacting with pyridine complex (prepared from 1.2 g of chromium trioxide and 12 ml of pyridine) at 15° to 20° C. for 1 hour, the reaction solution was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to obtain 1.4 g of a crude substance. This was subjected to column chromatography on silica gel (70 g) and developed with ethyl acetate-benzene (1:1) to obtain 290 g of 9-dehydro-B-5050-C. Melting point: 204° to 205°C Specific optical rotation: [α] ²⁵ _D -60.1° (C = 1.0, CHCl ₃ ) Elemental analysis value C ₄₁ H ₆₅ NO ₁₆ Calculated value: C, 59.48; H, 7.91; N, 1.69 Experimental value: C, 59.56; H, 8.24; N, 1.69 Ultraviolet absorption spectrum: λ ^C2H5OH _nax 240.5nm
(ε:
14400) Infrared absorption spectrum: ν ^KBr _nax 1690cm ^-1 (conjugated C
= 0) Reference example 3 Dissolve 3.6 g of antibiotic B-5050-C in 24 ml of acetone, add 4.8 g of Jones reagent (chromium trioxide-sulfuric acid) while stirring under ice cooling, and keep on ice for another 1 hour. Stirring was continued under cooling. After the reaction was completed, the mixture was diluted with diluted sodium bicarbonate water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to obtain 2.76 g of a crude substance. 2.7 g of this was adsorbed on a column of silica gel (70 g) and developed with benzene-acetone (3:1) to obtain 1.45 g of purified 9-dehydro-B-5050-C. When this was crystallized from acetone-n-hexane, colorless needle crystals were obtained. This product completely matched those obtained in Reference Example 2 in terms of melting point, infrared absorption spectrum, ultraviolet absorption spectrum, specific optical rotation, etc. Reference example 4 9-dehydro-12・13-deepoxy-B-5050
-C (=SF-837A ₃ ) 160mg in 0.3% methanol -
It was dissolved in 8 ml of hydrochloric acid and left at room temperature. After 1 hour, the mixture was diluted with diluted sodium bicarbonate water, extracted with ethyl acetate, and the extract was washed with water, dried, and concentrated to obtain 135 mg of a crude substance. Add this to silica gel (10
When subjected to column chromatography in g) and developed with benzene-acetone (4:1), white amorphous 9-dehydro-12,13-deepoxy-B-5050 was obtained.
101 mg of -C dimethyl acetal was obtained. Elemental analysis value C ₄₃ H ₇₁ NO ₁₆ Calculated value: C, 60.19; H, 8.34; N, 1.63 Experimental value: C, 59.95; H, 8.56; N, 1.61 Mass spectrum: m/e 857 (M ⁺ ) Nucleus Magnetic resonance spectrum: Aldehyde proton signal disappeared. Reference example 5 865 mg of antibiotic B-5050-C in 10 ml of ethanol
Dissolve in, add 2mM dimethylhydrazine,
After being left at room temperature for 6 hours, this was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, dried, and concentrated to yield 840 mg of B-5050-C-dimethylhydrazone.
was gotten. Elemental analysis value C ₄₃ H ₇₃ N ₃ O ₁₅ Calculated value: C, 59.22; H, 8.44; N, 4.82 Experimental value: C, 59.03; H, 8.45; N, 4.25 Specific optical rotation: [α] ²³ _D − 92.8゜(C=1.0, ethanol) Example 1 860mg of antibiotic B-5050-B in 15ml of methanol
3 ml of 0.5N potassium hydroxide-methanol was added dropwise while cold, and the mixture was kept at 5°C overnight. The reaction solution was poured into ice water, neutralized with acetic acid, and methanol was distilled off under reduced pressure. Extracted with ethyl acetate. The acetic acid ethyl ester extract was washed with water, dried, and concentrated to obtain 677 mg of ^Δ2 -B-5050-B as a white amorphous substance. Specific optical rotation: [α] ²² _D -81.2° (C = 1.0,
C ₂ H ₅ OH) Elemental analysis value C ₄₀ H ₆₅ NO ₁₄・H ₂ O Calculated value: C, 59.90; H, 8.42; N, 1.75 Experimental value: C, 60.41; H, 8.26; N, 1.82 Mass spectrum : m/e783 (M ⁺ ) Infrared absorption spectrum: ν ^KBr _nax cm ^-1 : 1725 (α
・
β-unsaturated lactone) Nuclear magnetic resonance spectrum (CDCl ₃ ): Signal disappearance of acetoxy group This product contains Staphylococcus aureus 209P, Bacillus subtilis, Sarcina lutea The minimum inhibitory concentrations (mcg/ml) for Klebsiella pneumoniae, Klebsiella pneumoniae, and Mycobacterium 607 are 0.5, 0.5, and 0.1, respectively.
They were 20 and 50. Furthermore, 200 mg of the obtained △ ² -B-5050-B was dissolved in 1.5 ml of pyridine, 0.3 ml of acetic anhydride was added thereto, and the mixture was reacted overnight at room temperature, resulting in △ ² -B-5050B.
189 mg of 9,2'-diacetate was obtained. When this was crystallized from ethyl ether-n-hexane, colorless needle crystals were obtained. Melting point: 142° to 143°C Specific optical rotation: [α] ²² _D -78.5° (C = 1.0, CHCl ₃ ) Elemental analysis value C ₄₄ H ₆₉ NO As ₁₆ Calculated value: C, 60.88; H, 8.01; N, 1.61 Experimental value: C, 60.61; H, 8.15; N, 1.59 Mass spectrum: m/e 867 (M ⁺ ) Example 2 2.7 g of antibiotic B-5050-A in 45 ml of methanol
5.4 ml of 1N potassium hydroxide-methanol was added to the mixture while it was cold, and the mixture was left in an ice room. After 19 hours, the reaction solution was poured into ice water and treated in the same manner as in Example 1 to obtain 2.23 g of ^Δ2 -B-5050-A. In order to remove trace impurities, 2.1 g of △ ² -B-5050-A was subjected to silica gel column chromatography.
When the mixture was developed and eluted with benzene-acetone (5:1), 1.7 g of pure ^Δ2 -B-5050-A was obtained. This product is the △ ² -B-5050- obtained in Example 1.
The infrared absorption spectrum, ultraviolet absorption spectrum, mass spectrum, specific optical rotation, etc. completely matched with B. Example 3 8.5g of antibiotic B-5050-C in 150ml of methanol
Dissolve in 1N potassium hydroxide-methanol 20ml
was added dropwise under ice cooling and then left in an ice room. After overnight, the reaction solution was poured into ice, extracted with ethyl acetate, washed with water, dried, and concentrated under reduced pressure to obtain a crude product.
6.55g was obtained. When this was subjected to silica gel column chromatography and developed with benzene-acetone (3:1), Δ ² -B-5050-C was separated and eluted. Yield: 2.48g. Specific optical rotation: [α] ²⁵ _D -80.9° (C = 1.0,
C ₂ H ₅ OH) Elemental analysis value C ₃₈ H ₆₁ NO ₁₄・H ₂ O Calculated value: C, 58.97; H, 8.14; N, 1.84 Experimental value: C, 59.28; H, 8.14; N, 1.84 Mass spectrum : m/e755 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ ): New olefin proton signals were observed at δ5.99 and 6.64. This product Staphylococcus aureus
209P, minimum inhibitory concentration (mcg/
ml) were 0.2, 1, 0.05, 20 and 50, respectively. Example 4 850mg of antibiotic B-5050-E in 15ml of methanol
2 ml of 1N potassium hydroxide was added to the solution under ice cooling, and the mixture was left in an ice room overnight and then poured into ice water. This is PH
The temperature was adjusted to 8 to 9, and methanol was distilled off under reduced pressure.
The obtained concentrate was diluted with water and then extracted with ethyl acetate. The extract was washed with water, dried, and concentrated, and the resulting residue was subjected to silica gel column chromatography and benzene-acetone (3:1).
Upon development, ^Δ2 -B-5050-E was eluted.
Yield 102mg. Specific optical rotation: [α] ²⁷ _D -81.2° (C=0.5,
C ₂ H ₅ OH) Elemental analysis value C ₃₇ H ₅₉ NO ₁₄・H ₂ O Calculated value: C, 58.48; H, 8.09; N, 1.84 Experimental value: C, 58.86; H, 7.90; N, 1.65 Mass spectrum : m/e741 (M ⁺ ) Infrared absorption spectrum: ν ^KBr _nax 1720cm ^-1 (α・
β
-Unsaturated lactone) Nuclear magnetic resonance spectrum: One acetyloxy group signal was observed at δ2.12. This product Staphylococcus aureus
209P, minimum inhibitory concentration (mcg/
ml) were 5, 5, 0.2, 100 and >100, respectively. Example 5 3 g of antibiotic B-5050-C was dissolved in 300 ml of methanol, 300 ml of 2% sodium bicarbonate water was added, and the mixture was reacted at 10° C. for 10 days. After the reaction was completed, methanol was distilled off, the concentrated liquid was extracted with ethyl acetate, the extracted liquid was washed with water, dried, and concentrated again to obtain 2.75 g of a crude substance. 2.35 g of the crude material was adsorbed onto a column of silica gel (100 g) and developed with benzene-acetone (4:1) to elute Δ ² -B-5050-C. yield
104mg. Example 6 12.7 g of antibiotic 18-dihydro-B-5050C was dissolved in 225 ml of methanol, 27 ml of 1N potassium hydroxide-methanol was added under ice cooling, and the mixture was left in an ice room overnight. After the reaction was completed, the same treatment as in Example 1 was carried out to obtain 8.52 g of crude material. This was subjected to column chromatography on silica gel (440 g) and developed with benzene-acetone (2:1) to elute ^Δ2-18 -dihydro-B-5050-C. Yield: 1.24g. Specific optical rotation: [α] ²³ _D -80.7° (C = 1.0,
C ₂ H ₅ OH) Elemental analysis value C ₃₈ H ₆₃ NO ₁₄ Calculated value: C, 60.22; H, 8.38; N, 1.85 Experimental value: C, 59.90; H, 8.41; N, 1.55 Mass spectrum: m/e757 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ ): New olefin proton signals were observed at δ5.98 and 6.54. In addition, this product is △ ² -B-5050- obtained in Example 3.
The result was consistent with a compound obtained by reducing C with sodium borohydride. Example 7 886 mg of antibiotic 9-propionyl-B-5050-C (Japanese Patent Publication No. 16878/1978) was dissolved in 15 ml of methanol, 3 ml of 1N potassium hydroxide-methanol was added dropwise to the ice-cooled solution, and the mixture was left in an ice room overnight. , poured into ice water. This was concentrated under reduced pressure, extracted with ethyl acetate, and the extract was washed with water, dried, and concentrated to obtain 667 mg of a crude substance. This was subjected to column chromatography on silica gel (30 g) and developed with benzene-acetone (5:1) to obtain 110 mg of 9-propionyl- ^Δ2 -B-5050-C. Elemental analysis value C ₄₁ H ₆₅ NO As ₁₅ Calculated value: C, 60.65; H, 8.07; N, 1.73 Experimental value: C, 60.52; H, 7.93; N, 1.68 Mass spectrum: m/e811 (C ₄₁ H ₆₅ NO ₁₅ ,
M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ ): Two olefin protons increased. Example 8 Antibiotic 9-dehydro-B-5050-C 1.245g
was dissolved in 30 ml of methanol, 9 ml of 0.5N potassium hydroxide-methanol was added dropwise under ice cooling, and the mixture was left in an ice room overnight. Pour the reaction solution into 40ml of ice water and adjust the pH to 8.
methanol was distilled off under reduced pressure, corrected to ~9,
The concentrated solution was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to obtain 831 mg of a crude substance. 500 mg of the crude material was subjected to column chromatography on silica gel (25 g) and developed with benzene-acetone (5:1) to obtain 17 mg of 9-dehydro-11-methoxy- ^Δ2 -B-5050-C. Elemental analysis value C ₃₉ H ₆₃ NO ₁₅ Calculated value: C, 59.60; H, 8.08; N, 1.78 Experimental value: C, 59.63; H, 8.03; N, 1.80 Ultraviolet absorption spectrum (in methanol): Only terminal absorption is infrared Absorption spectrum: ν ^KBr _nax 1725cm ^-1 (α・
β
-Unsaturated lactone) Nuclear magnetic resonance spectrum (CDCl ₃ ): In addition to δ3.28, a methoxy group signal was newly observed at δ3.38. In addition, this product's Staphylococcus aureus
209P, minimum inhibitory concentration (mcg/
ml) were 2.0, 2.0, 0.5, >100 and 100, respectively. Example 9 Leucomycin A ₃ (=diyosamycin) 1.65g
Dissolve in 30ml of methanol and add 1N potassium hydroxide.
When 3.6ml was added and treated in the same manner as in Example 1, △ ²
- 1.43 g of crude product of leucomycin A ₃ was obtained.
When this was subjected to silica gel column chromatography to remove a small amount of impurities, △ ² -leucomycin
A purified product of _A3 was obtained as a white powder. Specific optical rotation: [α] ²⁵ _D -65.8° (C = 1.0,
C ₂ H ₅ OH) Elemental analysis value C ₄₀ H ₆₅ NO ₁₃ Calculated value: C, 62.56; H, 8.53; N, 1.82 Experimental value: C, 62.05; H, 8.36; N, 1.90 Mass spectrum m/e: 767 (M ⁺ ) Ultraviolet absorption spectrum: showed shoulders at 215 nm and 230 nm, and its E ¹ % ₁ cm was 345.3 and 318.7. Nuclear magnetic resonance spectrum (CDCl ₃ ): The acetyloxy group signal observed in the raw material leucomycin A ₃ disappeared. This product Staphylococcus aureus
209P, minimum inhibitory concentration (mcg/
ml) were 1.0, 1.0, 0.1, 20.0 and 20.0, respectively. This product is clearly different from leucomycin A ₁ , which is the deacetylated form of leucomycin A ₃ , in the Rf value of thin layer chromatography, ultraviolet absorption spectrum, infrared absorption spectrum, nuclear magnetic resonance spectrum, and mass spectrum. was. Example 10 Leucomycin A ₇ -3-propionate (=
814 mg of SF837, YL-704B ₁ ) was dissolved in 22 ml of methanol, and while stirring under ice cooling, 4 ml of 0.5N potassium hydroxide-methanol was added dropwise, and the mixture was left in an ice chamber. After 17 hours, this was poured into ice water, the pH was corrected to 8.8, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to obtain 590 mg of crude material. This was subjected to column chromatography on silica gel (30 g) and benzene-acetone (5:
When expanded in 1), △ ² -leucomycin A ₇ -3
- 166 mg of propionate were obtained. Elemental analysis value C ₃₈ H ₆₁ NO ₁₃ Calculated value: C, 61.69; H, 8.31; N, 1.89 Experimental value: C, 61.81; H, 8.42; N, 1.67 Ultraviolet absorption spectrum: λ ^CH3OH _nax 241 nm (E
¹ % _1cm
381), 228nm (shoulder) Infrared absorption spectrum: ν ^KBr _nax 1725cm ^-1 (α・
β
-unsaturated lactone) Mass spectrum: m/e739 (C ₃₈ H ₆₁ NO ₁₃ ,
M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ ): 2 olefin protons increased. Example 11 Tylosin-3·2′·4″· obtained by reacting Tylosin with acetic anhydride in pyridine for 5 days at room temperature
110mg of 4-tetraacetate and 1.5ml of methanol
0.8 ml of 0.5N potassium hydroxide-methanol solution was added to the mixture while it was cold, and the mixture was allowed to stand at 0°C. After 24 hours, the reaction solution was poured into ice water and extracted twice with ethyl acetate. The extract was washed with water, dried, and concentrated to obtain 88 mg of a crude reaction product. This was subjected to silica gel thin layer chromatography, and benzene-
By developing with acetone (1:1), △ ²
-Tylosin-4'' 4-diacetate 16 mg was obtained as a colorless amorphous powder. Elemental analysis value C ₅₀ H ₇₉ NO ₁₈ Calculated value: C, 61.14; H, 8.11; N, 1.43 Experimental value: C, 60.92; H, 8.25; N, 1.28 Mass spectrum: m/e981 (M ⁺ ) Ultraviolet absorption spectrum: λ ^CH3OH _nax 213 nm, 28
4nm infrared absorption spectrum: ν ^KBr _nax 1725cm ^-1 (α・
β
-unsaturated lactone) Example 12 Acetylspiramycin (manufactured by Kyowa Hakko Co., Ltd.) 945
mg was dissolved in 15 ml of methanol, and 3.9 ml of 0.5N potassium hydroxide-methanol solution was added dropwise while stirring under ice-cooling, and the mixture was left at 0° C. for 16 hours. After the reaction was completed, the mixture was poured into ice water, the pH was adjusted to 8.5 to 9.5, methanol was distilled off under reduced pressure, and the concentrated solution was extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to obtain 752 mg of a crude reaction product. 200 mg of crude substance was subjected to thin layer chromatography on silica gel (solvent: benzene-acetone (1:1))
The two categories with high Rf and strong antibacterial activity were extracted with ethyl acetate, and the extracts were washed with water, dried, and concentrated to yield 3″/4″-diacetyl-△ ^2.
- Spiramycin 17mg and 4″-monoacetyl-
38 mg of ^Δ2 -spiramycin was obtained respectively. (1) 3″・4″-Diacetyl-△ ² -spiramycin Elemental analysis value C ₄₇ H ₇₆ N ₂ O ₁₅ Calculated value: C, 62.09; H, 8.43; N, 3.08 Experimental value: C, 61.88; H , 8.54; N, 3.01 Infrared absorption spectrum: ν ^KBr _nax 1720cm ^-1 (α
・
β-unsaturated lactone) Mass _spectrum : m/ _e908 ( _{C47H76N2O15 ;}
M ⁺ ) (2) 4″-Monoacetyl- ^Δ2 -Spiramycin Elemental analysis value C ₄₅ H ₇₄ N ₂ O ₁₄ Calculated value: C, 62.33; H, 8.60; N, 3.23 Experimental value: C, 62.06; H, 8.45; N, 3.11 Infrared absorption spectrum: ν ^KBr _nax 1720cm ^-1 (α
・
β-unsaturated lactone) Mass spectrum: m/e866 (C ₄₅ H ₇₄ N ₂ O ₁₄ ,
M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ ): Two olefin proton signals increased. Example 13 9-dehydro-12-13-deepoxy-B-5050
-C-dimethyl acetal 167 mg methanol 4
ml, 0.8 ml of 0.5N potassium hydroxide-methanol was added under ice-cooling, and the mixture was allowed to stand at 0°C. After 18 hours, the mixture was poured into ice water to adjust the pH to 8.8, extracted twice with ethyl acetate, and the extract was washed with water, dried, and concentrated to obtain 133 mg of a crude substance. Of this, 80 mg was subjected to silica gel thin layer chromatography (solvent: benzene-acetone (1:1)), the high Rf fraction was extracted with ethyl acetate, the extract was washed with water, dried, and concentrated. Then, 9-dehydro-12・
16 mg of 13-deepoxy- ^Δ2 -B-5050-C-dimethylacetal was obtained as a white amorphous powder. Elemental analysis value C ₄₀ H ₆₅ NO ₁₄ Calculated value: C, 61.28; H, 8.36; N, 1.79 Experimental value: C, 60.95; H, 8.22; N, 1.80 Ultraviolet absorption spectrum: λ ^CH3OH _nax 211 nm, 28
0nm Infrared absorption spectrum: ν ^KBr _nax 1725cm ^-1 (α・
β
-unsaturated lactone) Mass spectrum: m/e783 (C ₄₀ H ₆₅ NO ₁₄ ,
M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ ): Two olefin protons increased. Example 14 210 mg of 9-dehydro-B-5050C was reduced with 18.9 mg of sodium borohydride in an ethanol-methanol mixture (4:1). After the reaction solution was left at 5°C for 3 days, it was diluted with 1/15M phosphate buffer (PH7.7) and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to obtain 172 mg of crude material. This was subjected to column chromatography on silica gel (25 g) and benzene-acetone (3:
1) and benzene-acetone (2:1), 9-epi-18-dihydro- ^Δ2- B-
114mg of 5050C was obtained. Specific optical rotation: [α] ²⁵ _D -52.9° (C = 1.0, ethanol) Elemental analysis value C ₃₈ H ₆₃ NO ₁₄・1/2H ₂ O Calculated value: C, 59.51; H, 8.41; N, 1.83 Experimental Value: C, 59.32; H, 8.66; N, 1.67 Infrared absorption spectrum: ν ^KBr _nax 1725cm ^-1 (α・
β
-unsaturated lactone)

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ is an acyloxy group, R ₂ is a methoxy group or a methyl group, R ₃ is -CH ₂ CHO, -CH ₂ CH ₂ OH or [Formula] (R ₃ represents an alkyl group), R ₄ is Hydrogen or [formula] (R ₁₁ represents hydrogen or an acyl group), R ₅ is a methyl group or ethyl group, R ₆ is hydrogen or an acyl group, R ₇ is [formula] (R ₁₂ is an acyl group, R ₁₃ is each represents hydrogen or an acyl group), X represents [Formula] [Formula] [Formula] [Formula] or [Formula] (R ₁₄ represents hydrogen, an acyl group, or [Formula]), respectively. However, when R ₄ is [Formula], R ₁₄ is hydrogen or an acyl group] is treated with an alkali under mild conditions in a polar solvent. A method for producing an antibiotic derivative represented by the formula (wherein R ₂ to _{R 7} and X have the same meanings as above). 2 In the general formula, R ₇ is represented by [Formula] (R ₁₂ and R ₁₃ have the same meaning as above) and X is represented by [Formula] (R ₁₄ has the same meaning as above) or [Formula] A method for producing an antibiotic derivative according to claim 1, wherein the compound is treated with an alkali under mild conditions in a polar solvent. 3. The method for producing an antibiotic derivative according to claim 1 or 2, wherein the mild condition is less than 10°C. 4. The method for producing an antibiotic derivative according to claim 3, wherein the temperature below 10°C is 0° to 5°C. 5. The method for producing an antibiotic derivative according to claim 1 or 2, wherein the polar solvent is methanol. 6. The method for producing an antibiotic derivative according to claim 1 or 2, wherein the polar solvent is a water-containing polar solvent. 7. The method for producing an antibiotic derivative according to claim 1 or 2, wherein the alkali is an alkali metal hydroxide. 8 Claim 7, wherein the alkali metal hydroxide is potassium hydroxide or sodium hydroxide
Method for producing antibiotic derivatives as described in Section 1. 9. The method for producing an antibiotic derivative according to claim 1 or 2, wherein the alkali is an alkaline earth metal hydroxide. 10. The method for producing an antibiotic derivative according to claim 9, wherein the alkaline earth metal hydroxide is barium hydroxide. 11 Claim 1 or 2 in which the alkali is an alkali metal carbonate or hydrogen carbonate
Method for producing antibiotic derivatives as described in Section 1. 12. The method for producing an antibiotic derivative according to claim 11, wherein the alkali metal hydrogen carbonate is sodium hydrogen carbonate. 13. The method for producing an antibiotic derivative according to claim 1 or 2, wherein the alkali is sodium borohydride.