JPS637197B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, R ₁ represents a halogen atom, and R ₂ represents a hydroxyl group or an alkanoyloxy group.) As the halogen atom for R ₁ above, fluorine atom,
Examples of the alkanoyloxy group for _R2 include acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, isovaleryloxy, pivaloyloxy, and valeryloxy groups. Can be done. The object compound of the present invention [ ] has a structural feature in that it has substituents represented by R ₁ and R ₂ above at the 23rd and 3rd positions of mycaminosyl tylonolide, and is a compound that has excellent antibacterial activity. . The antibacterial activity of the object compound of the present invention [] is compared with that of tylosin as shown in the table below, and is characterized by its improved antibacterial activity, especially against Gram-negative bacteria.

[Table] According to the present invention, the target compound [] is produced by the following method. (In the formula, R ₁ is a halogen atom, R ₂ is a hydroxyl group or an alkanoyloxy group, R ₃ is an aldehyde group or a protected aldehyde group, and X is
It means a hydroxyl group, an arylsulfonyloxy group, or an alkylsulfonyloxy group. ) To carry out this method, the mycaminosyl tylonolide represented by the compound [] (including derivatives in which the aldehyde group and the 2'-position hydroxyl group are protected as necessary) is halogenated to produce the corresponding compound [] in which the 23-position is halogenated. ], and if the aldehyde group or hydroxyl group at the 2' position of this compound is protected, the protecting group is removed. In the raw material compound [], the aldehyde group is protected in the form of acetal or thioacetal, specifically,
Dimethyl acetal, diethylacetal, diethylthioacetal, ethylene acetal, ethylenethioacetal, propylene acetal, or those having a substituent such as a methyl group. Furthermore, as the protecting group for the 2'-position hydroxyl group, a lower acyl group such as an acetyl group is preferably used. Furthermore, as the allylsulfonyloxy group,
Examples of the alkylsulfonyloxy group include lower alkylsulfonyloxy groups such as a methylsulfonyloxy group and an ethylsulfonyloxy group. The halogenation in the first step is carried out using a halogen atom such as chlorine, bromine-iodine, or carbon tetrachloride, carbon tetrabromide, carbon iodide, or the like. Addition of triphenylphosphine and optionally a base such as pyridine is preferred in promoting the reaction. Some of these additives can also serve as a solvent, and if necessary, solvents such as pyridine, acetonitrile, tetrahydrofuran, and dioxane can be used alone or in an appropriate mixture. When the aldehyde group and/or the 2'-position hydroxyl group in the obtained compound [] are protected, these protecting groups are then removed. The protective group for the aldehyde group is usually removed by treatment with a mineral acid such as hydrochloric acid or sulfuric acid or an organic acid such as trifluoroacetic acid or trichloroacetic acid. Further, the hydroxyl protecting group can be easily removed by heating in methanol, hydrous alcohol, or hydrous aprotic solvent. The method for producing the target compound [ ] according to the present invention has been described above, and examples will be given to further explain the method for producing the product and the properties of the product. Note that the method for producing the raw material compounds used in the Examples of the present invention will be explained using Reference Examples. Of the symbols that indicate the physical and chemical properties of the compounds obtained in these examples and reference examples, pmr indicates the nuclear magnetic resonance spectrum, ir indicates the infrared absorption spectrum, UV indicates the ultraviolet absorption spectrum, mp indicates the melting point, and anal indicates the nuclear magnetic resonance spectrum. represents an elemental analysis value, and Rf represents a value indicating the migration rate of the target compound in silica gel thin layer chromatography. Reference Example 1 After dissolving 124 mg of 4'-deoxy mycaminosyl tylonolide in 1.24 ml of absolute ethanol,
55 mg of anhydrous p-toluenesulfonic acid was added under ice-cooling, and the mixture was allowed to react for 30 minutes after returning to room temperature. Cooled on ice again, neutralized by adding 0.05 ml of triethylamine, concentrated under reduced pressure, dissolved in 6.2 ml of chloroform, washed once each with a saturated aqueous sodium bicarbonate solution and once with water, and the chloroform layer was dissolved with anhydrous sodium sulfate. After drying, it was concentrated under reduced pressure. Add this to 12g of silica gel (Kieselgel60, 230-
Pour the sample into a 400 mesh column with the solvent system chloroform-methanol-concentrated ammonia water (30:1:0.1), convert the system to chloroform-methanol-concentrated ammonia water (15:1:0.1), and perform chromatography. 4′-deoxy mycaminosyl tylonolide diethyl acetal was obtained. Yield 128 mg, yield 92%. This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) ~2900 −CH ₃ , −CH ₂ − 1720 −COO− 1690 −CO− 1595 −C=C−C=C− (iii) Shape Colorless plate Crystals (acetone-n-hexane) (iv) mp 176-179℃ (Yanagimoto Seisakusho, micro melting point measuring device; melting point correction not performed) (v) anal (as C ₃₅ H ₆₁ NO ₁₀ ) C(% ) H(%) N(%) Calculated value 64.10 9.38 2.14 Analyzed value 64.20 9.17 2.17 (vi) Specific rotation [α] ²³ _D +8° (c1.0, CHCl ₃ ) (vii) UV λ ^MeOH _nax 282.5nm ( ε=22000) (viii) Rf0.40 Wakogel B-5 Chloroform-methanol (9:1) Reference example 2 3.23-di-O-tetrahydrofuranyl-4'-
182 mg of deoxy mycaminosyl tylonolide diethyl acetal was dissolved in 7.3 ml of absolute ethanol; 69 mg of pyridinium p-toluenesulfonate was added thereto and reacted at 78°C for 3 hours. After returning to room temperature, 0.05 ml of triethylamine was added to neutralize, and the mixture was concentrated under reduced pressure. This was dissolved in 9 ml of chloroform, washed once each with saturated aqueous sodium hydrogen carbonate solution and 4 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 135 mg of crude material was mixed with 13 g of silica gel (Kieselgel
-60, 230-400mesh) Column solvent system chloroform-methanol-concentrated aqueous ammonia (15:1:
0.1), and the resulting product was crystallized from acetone-n-hexane to give 4'-deoxy mycaminosyl tylonolide diethyl.
Obtained acetal. Yield: 89.1 mg of primary crystals This product had the same physical and chemical properties as the compound obtained in Reference Example 1. Example 1 (a) Dissolve 95.8 mg of 4'-deoxy mycaminosyl tylonolide diethyl acetal in 4.8 ml of anhydrous pyridine, add 84.5 mg of triphenylphosphine, cool on ice, and slowly dropwise add 24.8 mg of carbon tetrachloride while stirring. , after returning to room temperature 18
A time reaction was performed. Therefore, 1.0ml of methanol
was added and concentrated, azeotroped well with toluene, dissolved in 5 ml of chloroform, saturated aqueous sodium bicarbonate solution, 0.1M aqueous sodium thiosulfate solution,
After washing once with 1.5 ml of water each, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Add this to 10g of silica gel (Kieselgel60, 230
-400mesh) column, add the sample with chloroform-methanol (50:1), flow 20 ml, convert the system to chloroform-methanol (9:1), develop it, and then 23-chloro-23.4'-dideoxy
Mycaminocil Tyronolide Siethyl
Obtained acetal. Yield 97.6 mg Yield 99% 53.3 mg of this material was recrystallized from acetone-n-hexane to obtain plate crystals. Yield 34.5mg Recrystallization yield 65% This product shows the following physical and chemical properties.

【table】

[Table] (iii) Shape Colorless plate-like crystals (acetone-n-hexane) (iv) mp 164-7℃ melting (v) anal (as C ₃₅ H ₆₀ NO ₉ Cl) C H N Cl (%) Calculated value 62.34 8.97 2.08 5.25 Analysis value 62.19 8.71 2.32 5.16 (vi) [α] ²³ _D +12゜ (c1.0, CHCl ₃ ) (vii) UV λ ^MeOH _nax 280nm (ε=23000) (viii) Rf0.39 Wakogel B- 5 Chloroform-methanol (10:1) (b) After dissolving 61.5 mg of 23-chloro-23・4'-dideoxy mycaminosyl tylonolide diethyl acetal in 1.23 ml of acetonitrile.
Add 1.8ml of 0.1N hydrochloric acid and react for 60 minutes. Therefore, 23 mg of sodium hydrogen carbonate was added. Next, this was extracted three times with 2 ml of chloroform, washed twice with 2 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and extracted with 6 g of silica gel (Kieselgel 60, 230-
400mesh) chromatographed on the column with chloroform-methanol (7:1) to yield 28.5 mg.
The desired compound 23-chloro-23・4'-dideoxy mycaminosyl tylonolide was obtained, and the portion containing the desired compound was further separated on a 4 g silica gel (Kieselgel 60, 230-40 mesh) column with a solvent system of chloroform-methanol-concentrated aqueous ammonia (15:1). : 16.9mg after chromatography with 0.1)
The desired compound was obtained. Yield: 45.4 mg (double column purification), yield: 83%. This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2970 −CH ₃ 2940 −CH ₂ − ~1730 −COO− 1725 −CHO 1680 −CO− 1600 −C=C−C=C− ( iii) Shape Colorless amorphous solid (re-precipitated from acetone-n-hexane) (iv) anal (as C ₃₁ H ₅₀ NO ₈ Cl) C H N Cl (%) Calculated value 62.04 8.40 2.33 5.91 Analytical value 62.22 8.47 2.10 5.82 (v) [α] ²³ _D −8゜ (c1.0, CHCl ₃ ) (iv) UV λ ^MeOH _nax 280nm (ε=21000) (vii) Rf0.36 Wakogel B-5 Chloroform-methanol (7:1) Example 2 (a) 131.6 mg of 4'-deoxy mycaminosyl tylonolide diethyl acetal was dissolved in 6.6 ml of anhydrous pyridine, and 108 mg of triphenylphosphine was added. To this was added 67.4 mg of carbon tetrabromide while stirring on ice, and the mixture was immediately returned to room temperature and allowed to react for 60 minutes. After adding 1.3 ml of methanol, the mixture was concentrated under reduced pressure and well azeotroped with toluene. 7ml of this
Dissolved in chloroform, saturated aqueous sodium bicarbonate solution, 0.1M aqueous sodium thiosulfate solution,
The mixture was washed once with 2 ml of water and concentrated under reduced pressure. Add this to 13g of silica gel (Kieselgel60, 230
-400 mesh) was added onto a column packed with chloroform-methanol (50:1) and 26 ml was flowed through the column.
After conversion to 1) and development, 23-bromo-23,4'-dideoxy mycaminosyl tylonolide
Diethyl acetal was obtained. Yield: 136.2mg Yield: 95% This product shows the following physical and chemical properties.

【table】

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2970 −CH ₃ 2940 −CH ₂ − 1735 −COO− 1690 −CO− 1600 −C=C−C=C− (iii) Shape Colorless Amorphous solid (acetone-n-hexane) (iv) anal (as C ₃₅ H ₆₀ NO ₉ Br) C H N Br(%) Calculated value 58.49 8.41 1.95 11.12 Analyzed value 58.23 8.15 2.04 11.35 (v) [α] ²³ _D +31゜ (c1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 280nm (ε=22000) (vii) Rf0.39 Wakogel B-5 Chloroform-methanol (10:1) (b) 23-Bromo-23 - Dissolve 59.4 mg of 4'-dideoxy mycaminocil tylonolide diethyl acetal in 1.2 ml of acetonitrile, then add 1.7 ml of 0.1N hydrochloric acid and allow to react for 1 hour. Then, 21 mg of sodium hydrogen carbonate was added, this was extracted three times with 1.5 ml of chloroform, the chloroform layers were combined, and a saturated aqueous sodium sulfate solution was added.
After washing twice with 1.5 ml, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Add this to 6g of silica gel (Kieselgel60, 230
26.9
mg of 23-bromo-23.4'-dideoxy mycaminosyl tylonolide was obtained. The portion containing impurities was further chromatographed on 3 g of silica gel (Kieselgel 60, 230-400mesh) column using a solvent system of chloroform-methanol-concentrated aqueous ammonia (17:1:0.1).
18.8 mg of the target compound was obtained. Yield (total): 45.7mg Yield: 86% This product shows the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2970 −CH ₃ 2940 −CH ₂ − ~2935 −COO− 2925 −CHO 1680 −CO− 1600 −C=C−C=C− ( iii) Shape Colorless amorphous solid (acetone-n-hexane) (iv) anal (as C ₃₁ H ₅₀ NO ₈ Br) C H N Br(%) Calculated value 57.76 7.82 2.17 12.40 Analytical value 57.83 7.80 2.00 12.31 (v) [α] ²³ _D +11° (c1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 250nm (ε=21000) (vii) Rf0.36 Wakogel B-5 Chloroform-methanol (7:1) Example 3 (a) Dissolve 111.6 mg of 4'-deoxy mycaminosyl tylonolide diethyl acetal in 5.6 ml of anhydrous pyridine, add triphenylphosphine, add 106 mg of carbon tetraiodide under stirring under ice cooling, and continue the reaction for 1 hour. methanol
After adding 1.1 ml, concentrate under reduced pressure, and azeotrope well with toluene. Add 5.6 ml of chloroform. a saturated aqueous sodium bicarbonate solution,
The mixture was washed once with 1 ml each of 0.1 M sodium thiosulfate aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to 12g of silica gel (kieselgel60, 230
-400mesh) Add the solvent system chloroform-methanol (50:1) onto the column, and after flowing 24 ml, develop the system with chloroform-methanol (10:1).
23.4′-dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal was obtained. Yield: 112.5mg Yield: 87% This product shows the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2970 −CH ₃ 2940 −CH ₂ − 1730 −COO− 1680 −CO− 1600 −C=C−C=C− (iii) Shape Colorless Amorphous solid (acetone-n-hexane) (iv) anal (as C ₃₅ H ₆₀ NO ₉ I) C H N I (%) Calculated value 54.90 7.90 1.83 16.57 Analyzed value 54.88 7.75 1.77 16.28 (v) [α] ²³ _D +78゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _Max 281nm (ε=24.000) (vii) Rf0.39 Wakogel B-5 Chloroform-methanol (10:1) (b) 23・4'- After dissolving 59.7 mg of dideoxy-23-iodo mycaminosyl tylonolide diethyl acetal in 1.2 ml of acetonitrile,
Add 1.6 ml of 0.1N hydrochloric acid aqueous solution and react for 60 minutes.
So, add 20mg of sodium hydrogen carbonate and
Extract 3 times with 1.5 ml of chloroform, combine the chloroform layers, and add 1.5 ml of saturated aqueous sodium sulfate solution.
ml twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add 6g of silica gel (kieselgel60, 230
-400mesh) on the column, solvent system chloroform-
Chromatography with methanol (7:1) yielded 29.0 mg of 23,4'-dideoxy-23-iodo mycaminosyl tylonolide. The product containing impurities was further chromatographed on 3 g of silica gel (kieselgel 60, 230-400 mesh) column using a solvent system of chloroform-methanol-concentrated aqueous ammonia (20:1:0.1) to obtain 14.4 mg of the target compound. Yield (total): 43.4mg Yield: 81% This product shows the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2970 −CH ₃ 2940 −CH ₂ − ~1730 −COO− 1720 −CHO 1680 −CO− 1595 −C=C−C=C− ( iii) Shape Colorless amorphous solid (acetone-n-hexane) (iv) anal (as C ₃₁ H ₅₀ NO ₈ I) C H N I (%) Calculated value 53.83 7.29 2.03 18.35 Analytical value 53.65 7.41 1.90 18.52 (v) [α] ²³ _D +56゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 281nm (ε=24000) (vii) Rf0.36 Wakogel B-5 Chloroform-methanol (7:1)

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ represents a halogen atom, and R ₂ represents a hydroxyl group or an alkanoyloxy group.) A 4'-deoxy mycaminosyl tylonolide derivative represented by the formula: