JPS632275B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (In the formula, R ₁ is an alkanoyloxy group, an aromatic acyloxy group that may have a substituent, a tetrahydropyranyloxy group, a benzenesulfonyloxy group that may have a substituent, a halogen with a molecular weight of 80 or less) atom or azide group, and _R2 means a hydroxyl group, an alkanoyloxy group, an aromatic acyloxy group which may have a substituent, or a tetrahydropyranyloxy group). Furthermore, examples of the alkanoyloxy group include acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, isovaleryloxy group, pivaloyloxy group, valeryloxy group, etc., and aromatic groups that may have substituents. Examples of group acyloxy groups include benzoyloxy group, p-
Examples of benzenesulfonyl groups that may have substituents include methylbenzoyloxy groups, p
-Toluenesulfonyl group, benzenesulfonyl group, etc., and the halogen atom with a molecular weight of 80 or less means a bromine atom, a chloro atom, a fluoro atom. 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 mycaminosyltylonolide, and has excellent antibacterial activity. It is a compound with good stability. Now, when the antibacterial activity of the object compound of the present invention [] is compared with that of tylosin, it is as shown in the table below, and it is clear that the antibacterial activity is particularly improved against Gram-negative bacteria or Gram-positive bacteria.

[Table] According to the present invention, the target compound [] is produced by the following method. (In the formula, R ₁ ' is an alkanoyloxy group, an aromatic acyloxy group that may have a substituent, a tetrahydropyranyloxy group, a benzenesulfonyloxy group that may have a substituent, or a molecular weight of 80
The following halogen atoms, R ₂ ' is a hydroxyl group, an alkanoyloxy group, an aromatic acyloxy group which may have a substituent, a tetrahydropyranyloxy group, R 3 is an aldehyde group or a protected aldehyde group, and R ₃ is an aldehyde group or a protected aldehyde group. R ₄ means a hydroxyl group or a protected hydroxyl group. ) To carry out this method, the mycaminosyl or tylonolide represented by the compound [] (including derivatives in which the aldehyde group and the hydroxyl groups at the 2' and 4' positions are protected as necessary) is (1) acylated, or ( 2) The corresponding compound substituted at position 23 and optionally at position 3 by tetrahydropyranylation, (3) allylsulfonylation, or (4) halogenation []
and the aldehyde group or 2′ position of this compound,
If the 4'-position hydroxyl group is protected, remove the protecting group. 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 an ethyl group. Further, as the protecting group for the hydroxyl group at the 2'-position and the 4'-position, a lower acyl group such as an acetyl group is preferably used. (1) Acylation Acylation refers to mycaminosyl tylonolide (Mycaminosyl tylonolide) shown in the above formula [].
tylonolide (or a compound with a protected aldehyde group and/or hydroxyl group) and an acylating agent under neutral to basic conditions. Acylating agents used are aliphatic or aromatic carboxylic acids, especially lower alkyl carboxylic acids, allyl carboxylic acids, aralkyl carboxylic acids or reactive derivatives of these carboxylic acids. Suitable acylating agents include acetic acid, propionic acid, butyric acid, valeric acid, pivalic acid, isobutyric acid, isovaleric acid, benzoic acid, phenyl acetic acid, and the like.
As reactive derivatives of these carboxylic acids, acid anhydrides, acid halides, acid acids, etc. are usually used. Acylation is usually carried out at room temperature or under cooling in a solvent. As the solvent, alcohols having two or more carbon atoms such as ethanol and propanol, and aprotic solvents such as acetonitrile, acetone, dimethyl sulfoxide, and dimethyl formamide can be used. In this acylation, 23
The hydroxyl group at the 3-position may be acylated at the same time as the hydroxyl group at the 3-position. Furthermore, when the hydroxyl groups at the 2' and 4'-positions are not protected, these hydroxyl groups are also acylated. (2) Tetrahydropyranylation This reaction is usually carried out under anhydrous conditions in the above-mentioned aprotic solvent using mycaminosyl tylonolide [] protected at the 2'- and 4'-positions and dihydropyran as raw materials. Dihydropyran having a hydroxyl group, lower alkyl group, or lower alkoxy group as a substituent can also be used. Hydrochloric acid to accelerate this reaction,
Addition of mineral acids such as sulfuric acid and organic acids such as tosylic acid and fluoroacetic acid is effective. In this reaction, if the proportion of dihydropyran used is increased or the reaction time is increased, mycaminosilyl
In addition to the 23-position of tylonolide, compounds in which a tetrahydropyranyl group is introduced into the hydroxyl group at the 3-position are often produced. Additionally, addition of a salt of a strong acid and a weak base is also effective as a reaction accelerator. For example, when using a salt of an organic acid and an organic base such as pyridinium p-toluenesulfonate (PPTS), a tetrahydropyranyl group can be introduced exclusively at the 23rd position. (3) Allylsulfonylation In this reaction, the compound [] or a derivative thereof is reacted with allylsulfonic acid or a reactive derivative thereof such as a halide by a conventional method. Allylsulfonic acid is benzenesulfonic acid, p
-Toluenesulfonic acid etc. are used. (4) Halogenation Halogenation is carried out using a halogen with a molecular weight of 80 or less, such as chlorine or bromine, or using carbon tetrachloride, carbon tetrabromide, or the like. Addition of triphenylphosphine, triphenylphosphine oxide [(C ₆ H ₅ ) ₃ PO] and, if necessary, a base such as pyridine is preferred in order to promote the reaction. Some of these additives can also serve as solvents, but 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 hydroxyl group at the 2' and 4' positions are protected in the compound [] obtained by the above method, 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. In addition, the removal of the hydroxyl protecting group is
This can be easily carried out by heating in methanol, hydrous alcohol, or hydrous aprotic solvent. Next, as an alternative method, for compounds in which R ₁ of the target compound [ ] is an allylsulfonyloxy group, a method can be adopted in which this group is converted with another group. This method is exclusively
It is applied to the production of target compounds in which R ₁ is a halogen atom or an azide group. (In the formula, R ₁ ″ is a halogen atom or an azide group with a molecular weight of 80 or less, and R ₃ and R ₄ are the same groups as above.) (5) Halogenation The allylsulfonyloxy group of the compound [′] Halogenation can be carried out in the same manner as the halogenation of the hydroxyl group at position 23 of mycaminosyl tylonolide described above. (6) Azidation Azidation is carried out by heating in a solvent using an alkali metal azide compound such as sodium azide. The above-mentioned aprotic solvents other than water and alcohol can be used as the solvent.Heating is usually carried out near the boiling point of the solvent.To perform azidation, the aldehyde group in the starting compound ['] and the 2'
It is preferable to protect the 4' hydroxyl group. When the halide or azide thus obtained has a protecting group, the protecting group is removed by the method described above. 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. respectively mean elemental analysis values. Example 1 (a) Mycaminosyl tylonolide 202mg (0.338m)
mole) in 2 ml of anhydrous pyridine, add 0.5 ml of acetic anhydride under ice-cooling, return to room temperature, and react for 48 hours. After adding a small amount of water to this and leaving it to stand for 2 hours, it was concentrated under reduced pressure. After azeotroping with toluene, it was dissolved in 10 ml of chloroform, washed once each with 3 ml of saturated aqueous sodium bicarbonate solution and water, and anhydrous sodium sulfate was added. After drying, it was concentrated under reduced pressure. In this state, the following reaction was carried out. (b) 3,23,2',4'-tetra obtained in (a) above
0-acetyl mycaminosyl tylonolide was dissolved in 10 ml of methanol and reacted at 50°C overnight. This was concentrated under reduced pressure, dissolved in 10 ml of chloroform, washed once each with 3 ml of saturated sodium bicarbonate water and once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to 20g of silica gel (Kieselgel 60 230
-400 mesh) On the column, perform chromatography using a solvent system of chloroform-methanol (10:1) to produce 3,23-di-0-acetyl mycaminosyl.
Got Tyronolide. Yield 100mg (Yield 44
%). This material exhibits the following physical and chemical properties.

[Table] Example 2 (a) Dissolve 992 mg (1.48 mmole) of mycaminosyl tyloride diethyl acetal in 10 ml of anhydrous pyridine, add 2.5 ml of acetic anhydride while stirring under ice cooling, return to room temperature, react overnight, and then dissolve at 50°C for 2 hours.
The reaction was allowed to proceed for additional time. This was cooled with ice, 1 ml of water was added, and the mixture was left to stand (at room temperature) for 2 hours, and then concentrated under reduced pressure. After dissolving this in 50ml of chloroform, 25ml
After washing once each with a saturated aqueous solution of sodium bicarbonate and water, the mixture was concentrated under reduced pressure to obtain 3.23.2'.4'-tetra-O-acetyl mycaminosyl tylonolide diethyl acetal. This material was subjected to the next reaction without further purification. (b) 3・23・2′・4′-Tetra-O-acetyl mycaminosyl tylonolide diethyl acetal was dissolved in 50ml of methanol and then heated to 50°C.
The reaction was carried out overnight to perform 2' and 4' deacetylation. This was concentrated under reduced pressure, dissolved in 50 ml of chloroform, washed once each with 25 ml of saturated aqueous sodium bicarbonate solution and once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was chromatographed on a 50 g silica gel (kieselgel 60 230-400 mesh) column using a solvent system of chloroform-methanol to obtain 3,23-di-O-acetyl mycaminosyl tylonolide diethyl acetal. Yield: 1.05g (yield 94%). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 CH ₃ 2930 -CH ₂ 1740 -OCO- 1680 C=0 1600 -C=C-C=C- (iii) Colorless amorphous solid (Purified with acetone-n-hexane) (iv) anal (as C ₃₉ H ₆₅ NO ₁₃ ) C H N (%) calc. 61.97 8.64 1.85 found 62.15 8.49 1.88 (v) [α] ²⁵ _D +3゜ (c1. 0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 280 nm (ε=22000) (vii) Rf 0.40 Wakogel B-5 CHCl ₃ -MeOH (7:1) (c) 3,23-di-O-acetyl mycaminosyl tylonolide Diethyl acetal 100
mg (0.132 mmole) was dissolved in 2 ml of acetonitrile, 2 ml of 0.1N hydrochloric acid was added, and the mixture was reacted for 1 hour to obtain the following TLC. here 33.4
mg (0.400 mmole) of sodium bicarbonate was added, followed by an additional 4 ml of water. This was extracted three times with 2 ml of chloroform, and the chloroform layers were combined, washed with 2 ml of saturated sodium chloride water and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add 8g of silica gel (Kieselgel60,
230-400 mesh) was chromatographed on a column packed with chloroform-methanol (10:1) using a solvent system of chloroform-methanol (7:1) to obtain 3,23-di-O-acetyl mycaminosyl tylonolide. . Yield 86.2mg
(95% yield). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1735 −OCO− 1600 −C=C−C=C− (iii) Colorless amorphous solid (acetone -n-hexane) (iv) as anal (C ₃₅ H ₅₅ NO ₁₂ ) C H N (%) calc. 61.66 8.13 2.05 found 61.83 8.35 2.32 (v) [α] ²⁵ _D +19 (c0.72, CHCl ₂ ) (vi) UV λ ^MeOH _nax 281.5 nm (ε=22000) (vii) Rf value 0.30 Wakogel B-5 CHCl ₃ -MeOH (7:1) Note that mycaminocil used in Example 2(a) Tyronolide diethyl acetal was produced by the method of Reference Example 1 below. Reference example 1 (a) Mycaminocil tylonolide 825mg
(1.83 mmole) was dissolved in 8.3 ml of absolute ethanol, and anhydrous p-toluenesulfonic acid was dissolved under ice-cooling and stirring.
After adding 356 mg (2.27 mmole) and returning to room temperature,
Incubate for 20 minutes. Next, this was cooled on ice again, and after adding 0.3 ml (2.2 mmole) of triethylamine, it was concentrated under reduced pressure. Dissolve the concentrate in 41 ml of chloroform, add 10 ml of saturated sodium bicarbonate water,
Wash once each with saturated sodium chloride water and water,
The chloroform layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. This was chromatographed on a 40 g silica gel column (Kieselgel 60 230-400 mesh) using a solvent system of chloroform-methanol (7:1) to obtain mycarminosyl tylonolide diethyl acetal. Yield 852mg
(Yield 92%). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) cm ^-1 Attribution 2960 -CH ₃ 2940 -CH ₂ - 1730 -OCO- 1680 C=O 1600 -C=C-C=C- (iii) Colorless amorphous solid ( (purified with ether-hexane) (iv) anal (as C ₃₅ H ₆₁ NO ₁₁ ) C H N (%) calc. 62.57 9.15 2.08 found 62.29 8.95 2.13 (v) [α] ²⁵ _D +14゜ (c1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 283nm (ε=25000) (vii) Rf 0.48 Wakogel B-5 CHCl ₃ -MeOH (5:1) Example 3 Mycaminocil Tyronolide 61.5mg
(0.103 mmole) was dissolved in 0.62 ml of anhydrous tetrahydrofuran, 12.4 mg (0.113 mmol) of N-acetylimidazole was added under ice cooling, and after 10 minutes, the mixture was returned to room temperature and reacted for 20 minutes. After a further 50 minutes of reaction, 22.7 mg (0.206 m
mole) was added under ice-cooling. After reacting this at room temperature for an additional 12 hours, 57 mg (0.515 mmole) of N-acetylimidazole was further added and the reaction was allowed to proceed overnight at room temperature. Pour this into 3ml of water and
ml of chloroform three times, the chloroform layers were combined, and extracted twice with 3 ml of saturated aqueous sodium bicarbonate, once with 2 ml of saturated aqueous sodium chloride, and 2 times with 2 ml of saturated aqueous sodium chloride.
The mixture was washed once with 1 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. (b) The product obtained in (a) above was dissolved in 3 ml of methanol and reacted overnight at 50°C. This was concentrated under reduced pressure, dissolved in 6 ml of chloroform, and 2 ml of
The mixture was washed once each with saturated aqueous sodium bicarbonate and saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was placed on a 7 g silica gel (Kieselgel60 230-400 mesh) column.
Chromatography was performed using a solvent system of chloroform-methanol (5:1) to obtain 23-O-acetyl mycarminosyl tylonolide. yield
21.0 mg (yield 32%). 18.0 mg of this material was recrystallized from acetone-hexane. Yield: 16.1 mg (yield: 84% (assuming 2 molecules of crystal water are included)). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₂ 2930 −CH ₂ − ~1730 −OCO− 1680 C=O 1595 −C=C−C=C− (iii) Colorless Crystal (iv) MP 115-117℃ (melt) (v) anal (as C ₃₃ H ₅₃ NO ₁₁・2H ₂ O) C H N (%) calc. 58.65 8.50 2.07 found 58.53 8.72 2.30 (vi) [α] ²⁵ _D 12゜ (C1.0, CHCl ₃ ) (vii) UV λ ^MeOH _nax 280 nm (ε=22000) (viii) Rf 0.23 Wakogel B-5 CHCl ₃ -MeOH (10:1) Example 4 (a) 2',4'-di-O-acetyl mycaminosyl tylonolide diethyl acetal
135.7 mg (0.180 mmole) was dissolved in 1.4 ml of anhydrous pyridine, and 28.3 mg (0.36 mmole) was dissolved in 1.4 ml of anhydrous pyridine.
Slowly add acetyl chloride (mole),
After reacting for 15 minutes, the temperature was raised to -20°C over 120 minutes. While stirring at -20℃, add 5 drops of water.
After 5 minutes, the temperature was returned to room temperature, concentrated under reduced pressure, and sufficiently azeotroped with toluene. Dissolve this in 5 ml of chloroform and add 2 ml each of saturated sodium bicarbonate and water.
ml, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to 15g of silica gel (Kieselgel60, 230
-400 mesh) to benzene-acetone (10:
The column packed with 1) was developed with a solvent system of benzene-acetone (10:1), and then switched to benzene-acetone (6:1) for elution. Yield: 134.6 mg (94% yield). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) N (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − ~1740 −OCO− 1680 C=O 1595 −C=C−C=C− (iii) Colorless Amorphous solid (purified from acetone-hexane) (iv) anal (as C ₄₁ H ₆₇ NO ₁₄ ) C H N (%) calc. 61.71 8.46 1.76 found 61.42 8.25 1.91 (v) [α] ²⁵ _D +11° (c1 .0, CHCl ₃ ) (vi) UV λ ^EtOH _nax 279 (ε=20000) * (vii) Rf 0.32 Wakogel B-5 Benzene-acetone (6:1) *Methyl alcohol deacetylates 2' and 4' occurs, so I used EtOH (ethyl alcohol). (b) 73.0 mg (0.0916 mmole) of 23.2'.4'-tri-O-acetyl mycaminosyl tylonolide diethyl acetal was dissolved in 3.7 ml of methanol and reacted overnight at 50°C. This was concentrated under reduced pressure and dissolved in 4 ml of chloroform, washed once each with 2 ml of saturated aqueous sodium bicarbonate and saturated aqueous sodium sulfate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Next, 7g of silica gel (Kieselgel60, 230−
Chromatographed on a 400 mesh column with the solvent system chloroform-methanol (10:1).
-O-acetyl mycarminosyl tylonolide diethyl acetal was obtained. yield
62.4 mg (96% yield). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − ~1740 −OCO− 1680 C=O 1595 −C=C−C=C− (iii) Colorless Amorphous solid (purified from acetone-hexane) (iv) anal (as C ₃₇ H ₆₃ NO ₁₂ ) C H N (%) calc. 62.25 8.90 1.96 found 61.96 8.64 1.85 (v) [α] ²⁵ _D +10° (c .0.8, CHCl ₃ ) (vi) UV λ ^MeOH _nax 280.5 (ε=23000) (vii) Rf 0.38 Wakogel B-5 CHCl ₃ -MeOH (10:1) (b) 23-O-acetyl mycaminosyl tylonolide diethyl acetal 46.6 mg
(0.0654 mmole) was dissolved in 0.93 ml of acetonitrile, 1.3 ml of 0.1N hydrogen chloride water was added, and the mixture was allowed to react at room temperature for 1 hour. Next, add 2 ml of water, extract 3 times with 1.5 ml of chloroform, and combine the chloroform layers for 1.5 mg.
After washing once each with a saturated aqueous solution of sodium sulfate and water, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Yield is quantitative. This was recrystallized from acetone-hexane.
Yield: 39.9 mg (yield: 93% (however, the crystals are monohydrate)). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 2720 −CHO− 〜1735 −OCO− 〜1720 −CHO 1680 C=O 1595 −C=C− C=C- (iii) Colorless crystals (acicular) (recrystallized from acetone-n-hexane) (iv) MP 114-115℃ (v) anal (as C ₃₃ H ₅₃ NO ₁₁・H ₂ O) C H N(%) calc. 60.26 8.43 2.13 found 60.31 8.17 2.23 (vi) [α] ²⁵ _D −12゜ (c1.0, CHCl ₃ ) (vii) UV λ ^MeOH _nax 280nm (ε=23000) (viii) Rf 0.37 Wakogel B-5 CHCl ₃ -MeOH (6:1) The raw material compound 2',4'-di-O-acetyl mycaminosyl tylonolide diethyl acetal used in Example 4(a) was produced by the method of Reference Example 2 below. did. Reference example 2 Mycaminocil tylonolide diethyl
Dissolve 362 mg (0.606 mmole) of acetal in 1.8 ml of anhydrous acetonitrile, then add 0.17 ml of acetic anhydride.
(1.8 mmole) was added and allowed to react for 30 minutes. This was concentrated and azeotroped with toluene until the odor of acetic anhydride disappeared. Dissolved in 18 ml of chloroform, dissolved in 6 ml of saturated sodium bicarbonate solution and 1 portion each of water.
The mixture was washed twice, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Add this to silica gel (Kieselgel60, 230−440
Chromatography was carried out on a column of 2',4'-di-methane using a solvent system of benzene-acetone (3:1).
O-acetyl mycaminosyl tylonolide diethyl acetal was obtained. Yield 447 mg (98% yield). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1680 C=O 1590 −C=C−C=C− (iii) Colorless Regular solid (purified from acetone-hexane) (iv) anal (as C ₃₉ H ₆₅ NO ₁₃ ) C H N (%) calc. 61.97 8.67 1.85 found 62.22 8.64 1.71 (v) [α] ²⁵ _D +34° (c1. 0, CHCl ₃ ) (vi) UV λ ^EtOH _nax 282nm (ε=22000) (vii) Rf 0.45 Wakogel B-5 Benzene-Acetone (3:1) Example 5 (a) 2',4'-di-O-acetyl mycaminosyl tylonolide diethylacetal 98.0mg
(0.130 mmole) was dissolved in 1 ml of anhydrous pyridine and heated to -30℃, followed by 27.4 mg of benzoyl chloride.
(0.195 mmole) was added and reacted for 20 minutes. Next, 2 drops of water were added, and after 5 minutes, the mixture was concentrated under reduced pressure and sufficiently azeotroped with toluene. This was dissolved in 10 ml of chloroform, washed with 5 ml of saturated sodium bicarbonate water and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This material was subjected to the next reaction without further purification. Yield is quantitative. (b) 2',4'-di-O-acetyl-23-O-benzoylmycaminosyl tylonolide 104 mg (0.121 mmole) of diethyl acetal was dissolved in 5 ml of methanol and reacted overnight at 50°C.
Concentrate this under reduced pressure, dissolve it in 5 ml of chloroform, and then add 2 ml of saturated sodium bicarbonate water and water to each solution.
The mixture was washed twice, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. At this stage, the next reaction was carried out without further purification. Yield is quantitative. For analysis, 48 mg of this substance was subjected to column chromatography on a 5 g silica gel column (Kieselgel 60, 230-400 mesh) using a solvent system of chloroform-methanol (10:1). yield
46.1mg Yield 96% (after column purification).

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1725 −OCO− 1590 −C=C−C=C− 710

[Formula] (iii) Colorless amorphous solid (purified from acetone-n-hexane) (iv) anal (as C ₄₂ H ₆₅ NO ₁₂ ) C H N (%) calc. 65.01 8.44 1.81 found 64.89 8.37 1.91 (v) [α] ²⁵ _D +8゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 229nm (ε=13000) λ ^MeOH _nax 281nm (ε=20000) (vii) Rf 0.44 Wakogel B-5 CHCl ₃ −MeOH (10:1) (c) 23-O-benzoyl mycaminosyl tylonolide diethylacetal 48.5mg
(0.0626 mmole) was dissolved in 0.97 ml of acetonitrile, then 1.3 ml of 0.1N hydrochloric acid was added and reacted for 60 minutes. So here is 15.8 mg of sodium bicarbonate powder.
(0.188 mmole) was added, and 1.5 ml of water was added, extracted three times with 1.5 ml of chloroform, the chloroform layers were combined, washed once with 1.5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. did. Add this to 5g of silica gel (Kieselgel6.0 230
23-O-benzoyl mycaminosyl tylonolide was obtained by chromatography on the column using a solvent system of chloroform-methanol (7:1). Yield 42.8 mg (yield
95%). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1590 −C=C−C=C− 710

[Formula] (iii) Colorless amorphous solid (purified from acetone-n-hexane) (vi) anal (as C ₃₇ H ₅₅ NO ₁₁ ) C H N (%) calc. 64.42 8.04 2.03 found 64.23 7.80 1.89 (v) [α] ²⁵ _D −14゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 230nm (ε=13000) λ ^MeOH _nax 282nm (ε=27000) (vii) Rf. 0.28 Wakogel B-5 CHCl ₃ -MeOH (10:1) Example 6 (a) 2',4'-di-O-acetyl mycaminosyl tylonolide diethylacetal 51.0mg
(0.0676 mmole) was dissolved in 0.51 ml of anhydrous pyridine, and after heating to -30℃, propionyl chloride was added.
12.5 mg (0.135 mmole) was added and reacted for 30 minutes. Add one drop of water and concentrate under reduced pressure after 5 minutes.
After further azeotroping with toluene, dissolve in 5 ml of chloroform, and dissolve in 2 ml of saturated sodium bicarbonate water.
ml and water once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This material was subjected to the next reaction without further purification. Yield is quantitative. (b) 54.7 mg (0.0674 mmole) of 2',4'-di-O-acetyl-23-O-propionyl mycaminosyl tylonolide diethyl acetal
It was dissolved in 2.7 ml of methanol and reacted at 50°C overnight. This was concentrated under reduced pressure, dissolved in 2.7 ml of chloroform, washed once each with 1 ml of saturated sodium bicarbonate water and once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was placed on a 5 g silica gel (Kieselgel 60, 230-400 mesh) column.
Chromatography was performed using a solvent system of chloroform-methanol (9:1) to obtain 23-0-propionyl mycaminosyl tylonolide diethyl acetal. Yield: 46.4 mg (93% yield). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1590 −C=C−C=C− (iii) Colorless amorphous solid (acetone -purified from hexane) (iv) anal (as C ₃₈ H ₆₅ NO ₁₂ ) C H N (%) calc. 62.70 9.00 1.92 found 62.93 8.89 1.80 (v) [α] ²⁵ _D +13゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 281nm (ε=25000) (vii) Rf 0.48 Wakogel B-5 CHCl ₃ -MeOH (9:1) (c) 23-O-propionyl mycaminocil tylonolide diethyl acetal 46.0mg
(0.0633 mmole) was dissolved in 0.92 ml of acetonitrile, 1.3 ml of 0.1N hydrochloric acid aqueous solution was added and reacted for 60 minutes, and then 16.8 mg (0.20 mmole) of sodium bicarbonate powder was dissolved.
mmole) was added. Then add 1.5ml of water
The extract was extracted three times with 1.5 ml of chloroform, and the chloroform layers were combined, washed once with 1.5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to 5g of silica gel (Kieselgel60 230
23-O-propionyl mycaminosil
Got Tyronolide. Yield 39.6 mg (yield 96
%). This substance purified from acetone-n-hexane showed the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2925 −CH ₂ − 1730 −OCO− 1675 O=C 1590 −C=C−C=C− (iii) Colorless Regular solid (purified from acetone-n-hexane) (iv) anal (as C ₃₄ H ₅₅ NO ₁₁ ) C H N (%) calc. 62.46 8.47 2.14 found 62.66 8.51 2.30 (v) [α] ²⁵ _D −4゜(C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 281 (ε=20000) (vii) Rf 0.38 Wakogel B-5 CHCl ₃ -MeOH (9:1) In addition, the needle crystals of this substance (acetone- The product (recrystallized from n-hexane) showed the following physical and chemical properties. (i) MP 101~03℃ (melt) (ii) anal (as C ₄₄ H ₅₅ NO ₁₁・1/2H ₂ O) C H N (%) calc. 61.61 8.51 2.11 found 61.74 8.35 2.10 (iii) [α ] ²⁵ _D −4゜ (C1.0, CHCl ₃ ) (iv) UV λ ^MeOH _nax 281 (ε=21000) (v) Rf Consistent with colorless amorphous solid Example 7 (a) 2',4'-di-O-acetyl mycaminosyl tylonolide diethyl acetal
52.2 mg (0.0691 mmole) was dissolved in 0.52 ml of anhydrous pyridine, the mixture was heated to -30°C, 14.7 mg (0.138 mmole) of n-butyryl chloride was added, and the reaction was carried out for 30 minutes. One drop of water was added thereto, and after 5 minutes, the mixture was concentrated under reduced pressure and sufficiently azeotroped with toluene. 5ml of this
The solution was dissolved in chlorophor, washed once with 2 ml of saturated sodium bicarbonate water and once with 2 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. At this stage, the next reaction was carried out without further purification. Yield is quantitative. (b) 2',4'-di-O-acetyl-23-n-butyryl mycaminosyl tylonolide 57 mg of diethyl acetal was dissolved in 2.8 ml of methanol and reacted overnight at 50°C. After concentrating this under reduced pressure
The solution was dissolved in 2.8 ml of chloroform, washed once with 1 ml of saturated sodium bicarbonate water and once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. At this stage, the next reaction was carried out without further purification.
Yield is quantitative. (c) Dissolve 49 mg of 23-n-butyryl mycaminosyl tylonolide diethyl acetal in 0.98 ml of acetonitrile, and add 1.3 mg of 0.1N hydrochloric acid water.
ml, react for 1 hour at room temperature, and then make basic with 16.7 mg (0.20 mmole) of sodium bicarbonate powder. Add 1.5ml of water to this, extract 3 times with 1.5ml of chloroform, and combine the chloroform layers.
After washing once with 1.5 ml of saturated aqueous sodium sulfate solution, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Add this to 5g of silica gel (Kieselgel60 230
Chromatography was performed on a -400 mesh) column using a solvent system of chloroform-methanol 7:1 to obtain 23-n-butyryl mycaminosyl tylonolide. Yield: 43.1 mg (93% yield). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1600 −C=C−C=C− (iii) Colorless amorphous solid (acetone -purified from hexane) (iv) anal (as C ₃₅ H ₅₇ NO ₁₁ ) C H N (%) calc. 62.95 8.60 2.10 found 63.17 8.46 2.12 (v) [α] ²⁵ _D -3゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 281nm (ε=23000) (vii) Rf. 0.37 Wakogel B-5 CHCl ₃ -MeOH (7:1) Example 8 (a) 2',4'-di-O-acetyl mycaminosyl tylonolide diethylacetal 52.6mg
(0.0689 mmole) was dissolved in 0.52 ml of anhydrous pyridine and heated to -30℃, followed by isobutyl chloride.
14.7 mg (0.138 mmole) was added and reacted for 30 minutes.
One drop of water was added thereto, and after 5 minutes, the mixture was concentrated under reduced pressure and well azeotroped with toluene. Next, dissolve in 5 ml of chloroform, 2 each of saturated sodium bicarbonate water and water.
The solution was washed once with ml of sodium sulfate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This material was subjected to the next reaction without further purification. Yield is quantitative. (b) 2',4'-di-O-acetyl isobutyryl
Dissolve 57 mg of mycaminocil tylonolide diethyl acetal in 2.8 ml of methanol,
The reaction was allowed to proceed at 50°C overnight. Concentrate this under reduced pressure,
After dissolving in 2.8 ml of chloroform, the solution was washed once with 1 ml of saturated sodium bicarbonate water and once with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The next reaction was carried out as it was. Yield is quantitative. (c) 23-O-isobutyryl mycaminosyl tylonolide diethylacetate 51mg to 1.02ml
was dissolved in acetonitrile, 1.4 ml of 0.1N hydrochloric acid was added, the mixture was reacted at room temperature for 60 minutes, and then made basic with 17.4 mg (0.204 mmole) of sodium bicarbonate powder. Next, add 1.5 ml of water, extract 3 times with 1.5 ml of chloroform, combine the chloroform layers,
After washing once with 1.5 ml of saturated aqueous sodium sulfate solution, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Add this to 5g of silica gel (Kieselgel60 230
-400 mesh) Perform chromatography on the column using a solvent system of chloroform-methanol (7:1).
23-O-isobutyryl mycaminosyl tylonolide was obtained. Yield: 42.4 mg (92% yield). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1595 −C=C−C=C− (iii) Colorless amorphous solid (acetone -purified from hexane) anal (as C ₃₅ H ₅₇ NO ₁₁ ) C H N (%) calc. 62.95 8.60 2.10 found 63.12 8.60 2.08 (v) [α] ²⁵ _D O゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 281nm (ε=24000) (vii) Rf 0.40 Wakogel B-5 CHCl ₃ -MeOH (7:1) Example 9 (a) Dissolve 74 mg (0.109 mmole) of 2',4'-di-O-acetyl mycaminosyl tylonolide in 0.74 ml of anhydrous dichloromethane, add 45.8 mg (0.545 mmole) of dihydropyran (freshly distilled), and stir under ice cooling. , 24.9 mg of trifluoroacetic acid was added. After 5 minutes, the temperature was returned to room temperature, and the reaction was continued for 1 hour. Cool again on ice and add 44 mg of triethylamine.
(0.436 mmole) was added to make the mixture basic, 5 ml of dichloromethane was added, and the mixture was washed once each with saturated sodium bicarbonate water and 2 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to 7g of silica gel (Kieselgel60, 230
-400 mesh) Chromatography was performed on the column using a solvent system of benzene-acetone (10:1), and the main product was collected for the next reaction. Yield 61.3 mg (yield 72%). (b) 43 mg of 2',4'-di-O-acetyl-23-O-tetrahydropyranyl mycaminosyl tylonolide (containing some impurities) was dissolved in 2.1 ml of methanol and reacted overnight at 50°C. This was concentrated under reduced pressure, dissolved in 5 ml of chloroform, washed once with 2.5 ml of saturated sodium sulfate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Next, 5g of silica gel (Kieselgel60 230−
400 mesh) Column solvent system chloroform
Chromatograph with methanol (10:1)23
-O-tetrahydropyranyl mycaminosyl tylonolide was obtained. Yield 32.5 mg (Yield 87
%). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1590 −C=C−C=C− (iii) Colorless amorphous solid (acetone -n-hexane) (iv) anal (as C ₃₆ H ₅₉ NO ₁₁ ) C H N (%) calc. 63.41 8.72 2.05 found 63.65 8.75 2.25 (v) [α] ²⁵ _D -10゜ (C1.0 , CHCl ₃ ) (vi) UV λ ^MeOH _nax 283 nm (ε=17000) Wakogel B-5 CHCl ₃ -MeOH (10:1) Note that the raw material compound 2' used in Example 9(a)
4'-Di-O-acetyl mycaminosyl tylonolide was produced by the method of Reference Example 3 below. Reference example 3 Mycaminocil tylonolide 562mg (0.941
mmole) in 5.6 ml of anhydrous acetonitrile, and add 0.27 ml of acetic anhydride (distilled) thereto.
(2.9 mmole) was added and reacted for 60 minutes. It was concentrated under reduced pressure and sufficiently azeotroped with toluene. This was dissolved in 15 ml of chloroform, washed once each with 5 ml of saturated sodium bicarbonate water, saturated sodium sulfate water, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was used directly in the next reaction. In addition, benzene-acetone (4:1) was used for analysis.
20x silica gel (Kieselgel 60 230-400 mesh) column chromatography was performed. quantitative. This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1740 −OCO− 1680 C=O 1595 −C=C−C=C− (iii) Colorless Fixed shape (purified with acetone-n-hexane) (iv) anal (as C ₃₅ H ₃₉ NO ₁₄ ) C H N (%) calc. 61.66 8.13 2.05 found 61.84 8.27 2.03 (v) [α] ²⁵ _D −18° (C1.0, CHCl ₃ ) (vi) UV λ ^EeOH _nax 283nm (ε=25000) (vii) Rf 0.40 Wakogale B-5 Benzene-Acetone (3:1) Example 10 (a) 2′,4′-di-O-acetyl mycaminosyl tylonolide 74 mg (0.109 mmole) to 0.74
ml of anhydrous dichloromethane, 45.8 mg (0.545 mmole) of dihydropyran was added, and then 24.9 mg of trifluoroacetic acid was added and reacted overnight. Cool the reaction solution on ice and add 44.1 mg of triethylamine.
After adding (0.436 mmole), 5 ml of dichloromethane was added, and the mixture was washed with 2 ml each of saturated sodium bicarbonate water and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This was used as it was in the next reaction. (b) 2',4'-di-O-acetyl-3,23-di-O
-Tetrahydropyranyl mycaminosyl tylonolide (previous reactant itself) was dissolved in 4 ml of methanol and reacted overnight at 50°C. After concentration under reduced pressure, dissolve in 5 ml of chloroform and 2 ml.
The mixture was washed once each with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to 10g of silica gel (Kieselgel60 230
-400 mesh) Column solvent system chloroform-methanol-concentrated aqueous ammonia (20:1:0.1)
When chromatographic treatment is performed, two di-tetrapyranyl compounds are eluted while being slightly separated. Each mixture was concentrated separately (upper rich (a) and lower rich (b)), and the upper rich was concentrated on a column of 5 g of silica gel (Kieselgel 60 230-400 mesh) solvent system chloroform-methanol-concentrated aqueous ammonia (21:1: 0.1), the lower Rich was chromatographed on a 5 g silica gel (Kieselgel 60 230-400 mesh) column with a solvent system of chloroform-methanol-concentrated ammonia (19:1:0.1) to separate the two components (di-tetrahydropyranyl compound). (a) Rf (top) Yield: 25.7 mg (yield 31%). (B) Rf (bottom) Yield: 29.4 mg (yield 35%).
mg (yield 19%). The di-tetrahydropyranyl compounds of Rich above (a) and Rich below (b) exhibit the following physical and chemical properties. (Upper Rich)

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1590 −C=C−C=C− (iii) Colorless amorphous solid (acetone -purified from hexane) (iv) anal (as C ₄₁ H ₆₇ NO ₁₂ ) C H N (%) calc. 64.29 8.82 1.83 found 64.51 8.74 2.01 (v) [α] ²⁵ _D -35゜ (C1.0 , CHCl ₃ ) (vi) UV λ ^MeOH _nax 282nm (ε=19.000) (vii) Rf 0.39 Wakogel B-5 CHCl ₃ −MeOH−concNH ₄ OH (20:1:0.1) (Lower Rich)

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1735 −OCO− 1720 −CHO 1680 C=O 1590 −C=C−C=C− (iii ) Colorless amorphous solid (purified from acetone-n-hexane) (iv) anal. (as C ₄₁ H ₆₇ NO ₁₂ ) C H N (%) calc. 64.29 8.82 1.83 found 64.42 8.76 1.82 (v) [α] ²⁵ _D −29゜(C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 282nm (ε=21000) (vii) Rf 0.32 Wakogel B-5 Chloroform: Methanol: Concentrated ammonia water (20:1:0.1) Example 11 Mycaminocil Tyronolide 255mg (0.427
mmole) in 12.8 ml of anhydrous pyridine and 224 mg (0.854
mmole) was added. Cool this on ice and use carbon tetrachloride.
66 mg (0.427 mmole) was slowly added under stirring. The mixture was returned to room temperature and reacted for 18 hours. Then, 2.6 ml of methanol was added and stirring was continued for about 30 minutes, then concentrated under reduced pressure and azeotroped with toluene. This was dissolved in 13 ml of chloroform, washed once each with 4 ml of saturated sodium bicarbonate solution, saturated sodium sulfate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to a 25g silica gel column (Kieselgel60
230-400 mesh), chloroform alone produces approx.
After flowing 100 ml (to flush triphenylphosphine and triphenylphosphine oxide), the solvent was changed to chloroform-methanol (7:1) to elute the target product. Yield 182mg, (yield 69
%). Example 12 (a) Dissolve 307 mg (0.458 mmole) of mycaminosyl tylonolide diethylacetal in 15.4 ml of anhydrous pyridine, add 243 mg (0.926 mmole) of triphenylphosphine (MW262), dissolve, and then add 1.01 times the amount of carbon tetrachloride ( 71.3mg)
was slowly added, the temperature was returned to room temperature, and the mixture was allowed to react for 18 hours. Carbon tetrachloride 21mg (0.3 times mole; 0.137m
mole) was added under ice-cooling, the mixture was returned to room temperature, and the reaction was continued for an additional 18 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and sufficiently azeotroped with toluene. Next, this material was dissolved in 15 ml of chloroform, washed once each with 5 ml of saturated aqueous sodium bicarbonate, saturated aqueous sodium sulfate, and water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to 30g of silica gel (Kieselgel60 230
-400 mesh) The column was developed with 200 ml of the solvent system chloroform-methanol 100:1 to flow out triphenylphosphine and triphenylphosphine oxide, and then the solvent system was changed to chloroform-methanol (9:1). -Deoxy-23-chloro mycaminosyl tylonolide diethyl acetal was obtained. Yield is quantitative. The product purified for analysis shows the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1735 −OCO− 1680 C=O 1600 −C=C−C=C− (iii) Colorless Regular solid (purified from acetone-n-hexane) (iv) anal (as C ₃₅ H ₆₀ NO ₁₀ Cl) C H N Cl(%) calc. 60.90 8.76 2.03 5.14 found 60.64 8.56 2.08 5.35 (v) [α] ²⁵ _D +16゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 280nm (ε=22000) (vii) Rf 0.41 Wakogel B-5 CHCl ₃ -MeOH (6:1) (b) 23-deoxy-23 -Chloro mycaminosyl tylonolide diethyl acetal 258.4
After dissolving mg (0.375 mmole) in 5.2 ml of acetonitrile, 7.5 ml (2 times the mole) of a 0.1N aqueous hydrochloric acid solution was added and reacted at room temperature for 60 minutes. Therefore, after neutralizing with 95 mg of sodium bicarbonate powder and adding 5 ml of water,
The extract was extracted three times with 5 ml of chloroform, and the chloroform layers were combined, washed with 5 ml of saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Next, 25g of silica gel (Kieselgel60 230−
400 mesh) and column chromatography using a solvent system of chloroform-methanol (6:1) to obtain 23-deoxy-23-chloro mycaminosyl tylonolide. Yield: 224.5 mg (97% yield). This material exhibits the following physical and chemical properties.

[Table] 〓
(ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − ~1730 −OCO− 1720 CHO 1680 C=O 1595 −C=C−C=C− (iii) Colorless Regular solid (purified from acetone-n-hexane) (iv) anal (as C ₃₁ H ₅₀ NO ₉ Cl) C H N Cl(%) calc. 60.43 8.18 2.27 5.75 found 60.35 8.21 2.27 5.82 (v) [α] ²⁵ _D −4゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 281 nm (ε=19000) (vii) Rf 0.35 Wakogel B-5 CHCl ₃ −MeOH (5:1) Example 13 Mycaminocil Tyronolide 221mg (0.370
mmole) in 11 ml of anhydrous pyridine and 195 mg (0.742 m
mole) and completely dissolved. Cool this on ice,
Carbon tetrabromide (MW331.6) under stirring in a nitrogen stream
123 mg (0.371 mmole) was added, and after 10 minutes, the temperature was returned to room temperature, and the reaction was continued for an additional 3 hours. Add 2.2 ml of methanol to stop the reaction.15
After a few minutes, the mixture was concentrated under reduced pressure and thoroughly azeotroped with toluene. This was dissolved in 11 ml of chloroform, washed once with 3 ml each of saturated sodium bicarbonate solution, saturated sodium sulfate solution, and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. It was then chromatographed on a 25 g silica gel (Kieselgel 60, 230-400 mesh) column with a gradient of chloroform to chloroform-methanol (7:1).
23-deoxy-23-bromo mycaminosyl tylonolide was obtained. Yield 126.8 mg (yield 52%). Example 14 (a) Dissolve 381 mg (0.568 mmole) of mycaminosyl tylonolide diethyl acetal in 19 ml of pyridine, then dissolve triphenylphosphine (MW262.3), cool on ice, replace with nitrogen, and add carbon tetrabromide with stirring. (MW331.6) 302mg
(1.15 mmole) was added. Methanol after 60 minutes 3.8
ml was added thereto, and after another 15 minutes, the mixture was concentrated under reduced pressure and sufficiently azeotroped with toluene. Add this to 35g of silica gel (Kieselgel60, 230
-400 mesh) on the column (packed with chloroform-methanol-concentrated ammonia water 30:1:0.1) Solvent system After developing with 100 ml of chloroform-methanol-concentrated ammonia water (30:1:0.1), chloroform-methanol-concentrated ammonia solution (15:
1:0.1) to obtain 23-deoxy-23-bromo mycaminosyl tylonolide diethyl acetal. Yield 367 mg (yield 88
%). This material exhibits the following physical and chemical properties.

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1680 C=O 1595 −C=C−C=C− (iii) Colorless Regular solid (purified from acetone-n-hexane) (iv) anal. (as C ₃₅ H ₆₀ NO ₁₀ Br) C H N Br(%) calc. 57.21 8.23 1.91 10.87 found 56.98 8.01 1.94 10.57 (v) [α] ²⁵ _D +29゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 280nm (ε=19000) (vii) Rf 0.34 Wakogel B-5 CHCl ₃ -MeOH (6:1) (b) 23-deoxy- 23-bromo mycaminocil tylonolide diethylacetal 70.3mg
After dissolving (0.0958 mmole) in 1.4 ml of acetonitrile, add 1.92 ml (2 times the mole) of 0.1N hydrochloric acid aqueous solution and allow to react at room temperature for 60 minutes. Neutralize by adding 33 mg of sodium bicarbonate powder, add 1.5 ml of water, extract three times with 1.5 ml of chloroform, combine the chloroform layers, wash with 1.5 ml of saturated aqueous sodium sulfate solution, and add anhydrous sodium sulfate. After drying,
It was concentrated under reduced pressure. Add this to 7g of silica gel (Kieselgel60, 230
-400 mesh) was charged on a column packed with the solvent system chloroform-methanol-concentrated aqueous ammonia (30:1:0.1) using the same system, and then the solvent system was changed to chloroform-methanol-concentrated aqueous ammonia (14:1:0.1). 23-deoxy-23-bromo mycaminosyl tylonolide was obtained. Yield: 62.6 mg (99% yield). This material exhibits the following physical and chemical properties.

[Table] 〓
(ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − ~1740 −OCO− 1720 CHO 1680 C=O 1600 −C=C−C=C− (iii) Colorless Regular solid (purified from acetone-n-hexane) (iv) anal. (as C ₃₁ H ₅₀ NO ₉ Br) C H N Br(%) calc. 56.36 7.63 2.12 12.09 found 56.32 7.58 2.02 12.23 (v) [α] ²⁵ _D +10゜ (C1.0, CHCl ₃ ) (vi) UV λ ^MeOH _nax 282nm (ε=24000) (vii) Rf 0.24 Wakogel B-5 Chloroform: Methanol: Concentrated ammonia water (10:1:0.1) Example 15 Mycaminocil Tyronolide 398mg (0.666
mmole) was dissolved in 8 ml of anhydrous pyridine, and 234 mg of p-toluenesulfonyl chloride (1.23 m
After adding mole), the mixture was returned to room temperature and left overnight. After confirming the completion of the reaction by TLC, a small amount of water was added to decompose excess p-toluenesulfonyl chloride, and water was added.
Pour into 40ml. Add 50ml of chloroform to this
Extract twice, combine the chloroform layers, wash once with 50 ml of saturated sodium sulfate water, concentrate under reduced pressure, and thoroughly azeotrope pyridine with toluene. This was applied to a 40 g silica gel (Kieselgel 60, 230-400 mesh) column using a solvent system of chloroform-methanol (4:
Chromatography was performed in step 1) to obtain 23-O-p-toluenesulfonyl mycaminosyl tylonolide. Yield 220 mg (yield 44%). This material exhibits the following physical and chemical properties.

【table】

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO−} CHO 1680 C=O 1600 −C=C−C=C− (iii) Colorless solid (iv) anal. (as C ₃₈ H ₅₇ NO ₁₂ S) C H N S(%) calc. 60.74 7.64 1.68 4.27 found 60.61 7.84 1.75 4.09 (v) [α] ¹⁷ _D +4.0゜ (C1. 0, MeOH) [α] ¹⁷ ₃₆₅ −66.0゜ 〃 [α] ¹⁷ ₄₀₅ −47.5゜ 〃 [α] ¹⁷ ₄₃₆ −12.5゜ 〃 [α] ¹⁷ ₅₄₆ +2.5゜ 〃 (vi) Rf 3.7 Wakogel B-5 Chloroform:methanol (3:1) Example 16 (a) Dissolve 362 mg (0.508 mmole) of mycaminocil tylonolide ethylene acetal in 6.5 ml of anhydrous pyridine, cool on ice, and add 168 mg (0.88 mmole) of p-toluene sulfonic acid chloride with stirring.
mole) and react overnight in the refrigerator.
A small amount of water is added to this to decompose excess p-toluenesulfonic acid chloride, and the mixture is poured into 30 ml of water.
This is extracted three times with 40 ml of chloroform, the chloroform layers are combined, washed with 40 ml of saturated sodium sulfate water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained yellow syrup was mixed with 30 g of silica gel (Kiesegel 60, 230-400
Chromatography was performed on a mesh column using a solvent system of chloroform-methanol (4:1).
Op-toluenesulfonyl mycaminosyl tylonolide ethylene acetal was obtained. Yield 237 mg (yield 57%). This material exhibits the following physical and chemical properties.

【table】

[Table] (ii) ir (KBr) WN (cm ^-1 ) Attribution 2960 −CH ₃ 2930 −CH ₂ − 1730 −OCO− 1680 C=O 1600 −C=C−C=C− (iii) Colorless solid (iv) anal. (as C ₄₀ H ₆₃ NO ₁₄ S) C H N S(%) calc. 60.36 7.72 1.76 4.03 found 60.51 7.74 1.85 3.99 (v) Rf 0.36 Wakogel B-5 Chloroform:methanol (4:1) (b) 43.6 mg (0.6548 mmole) of the compound obtained above
was dissolved in 0.9 ml of anhydrous acetone, 23.8 mg (0.274 mmole) of lithium bromide was added, heated under reflux for 2 hours and 30 minutes, and then concentrated under reduced pressure. This was dissolved in 3 ml of chloroform and washed with 1 ml of water. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This was placed on a 4 g silica gel (Kieselgel 60, 230-400 mesh) column.
Chromatography was performed using a solvent system of chloroform-methanol (4:1) to obtain 23-bromo-23-deoxymycaminosyl tylonolide diethyl acetal. Yield: 35.5 mg (90% yield). (c) Add 0.2 ml of 90% trafluoroacetic acid to the compound obtained in (b) above while stirring on ice, and after reacting for 30 minutes, add 270 mg of sodium hydrogen carbonate powder,
Stop the reaction. This was dissolved in chloroform, washed with water, dried with anhydrous sodium sulfate,
Concentrate under reduced pressure and perform silica gel column chromatography to obtain 23-O-p-toluenesulfonyl.
I got mycaminocil tylonolide. This substance had the same physical and chemical properties and MIC as the substance obtained in Example 15 above. Example 17 (a) 19.0 mg of 23-O-p-toluenesulfonyl mycaminosyl tylonolide ethylene acetal obtained in the same manner as in Example 16(a) was dissolved in 0.1 ml of anhydrous dimethylformamide, and 5.9 mg (10.0908 mmole) of sodium azide was added. In addition, after purging with argon, the reaction is carried out at 110°C for 4 hours. After removing the precipitate, the dimethylformamide was distilled off under reduced pressure using a pump, and then applied to a 1.3 g silica gel (Kieselgel 60, 230-400 mesh) column.
Chromatography was performed using a solvent system of chloroform-methanol (3:1) to obtain 23-azido-23-deoxy mycaminosyl tylonolide ethylene acetal. Yield: 11.5 mg (72% yield). (b) The compound obtained above was treated according to Example 16(c) to obtain 23-azido-23-deoxy mycaminosyl tylonolide. Example 18 (a) After dissolving 63.7 mg of 2',4'-di-O-acetyl mycaminosyl tylonolide in 1.3 ml of anhydrous methylene chloride, 2,3-dihydropyran
31.4 mg of p-toluenesulfonic acid pyridine salt was added thereto, and the mixture was reacted at 40°C for 16 hours. this
Stir vigorously with 1.5 ml of saturated aqueous sodium hydrogen carbonate solution to make it weakly basic, separate the layers, and remove the methylene chloride layer. Furthermore, the aqueous layer was extracted twice with 1.5 ml of methylene chloride, and the methylene chloride layers were combined.
After washing once with 1.5 ml of saturated sodium chloride water and twice with 1.5 ml of water, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. This material was used as a raw material for the next reaction without further purification. (b) 3.2 ml of methanol was added to 23-O-tetrahydropynyl-2',4'-di-O-acetyl mycaminosyl tylonolide obtained in (a) above, and the mixture was reacted at 50°C for 6 hours. This was concentrated under reduced pressure, dissolved in 3.2 ml of chloroform, washed once each with 1 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium sulfate solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Add this to 8g of silica gel (Kieselgel60, 230
-400 mesh) Perform chromatography on the column using a solvent system of chloroform-methanol (7:3).
23-tetrahydropyranyl mycaminosyl
Got Tyronolide. Yield 41.3mg Yield 65% This product shows the following physical and chemical properties.

【table】

[Table] (ii) ir (KBr) W, N (cm ^-1 ) Attribution 2970 −CH ₃ 2940 −CH ₂ ~2800 N (CH ₃ ) ₂ 1725 −CO− 1680 −CO− (α・β・γ - δ unsaturated) 1595 -C=C-C=C- Note that the raw material compound used in Example 18(a) was produced by the method of Reference Example 3 above.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is an alkanoyloxy group, an aromatic acyloxy group that may have a substituent, a tetrahydropyranyloxy group, a benzenesulfonyloxy group that may have a substituent, a halogen with a molecular weight of 80 or less) atom or azide group, and _R2 means a hydroxyl group, an alkanoyloxy group, an aromatic acyloxy group which may have a substituent, or a tetrahydropyranyloxy group.