JPH06145191A - Production of intermediate for 3,4'-dideoxymycaminosyl tylonolide - Google Patents

Abstract

PURPOSE:To provide a new compound useful as a synthetic intermediate for an antibacterial substance 3,4'-dideoxymycaminosyl tylonolide and effective in producing the antibacterial substance having excellent phylactic action in high efficiency. CONSTITUTION:The compound of formula [A is (protected) carbonyl; B is (protected) aldehyde; W is H or OCOCH3; Y is OH, halogen, etc.; R<4> is (protected) OH; R<2> is lower alkanoyl provided that a part of R<2> is double bond when W is H and is single bond when W is OCOCH3], e.g. 2',3,4'-tri-O- acetyldesmycosin-9,20-bis(ethyleneacetal). The compound can be produced e.g. by treating 3-O-acetyltylosine with an acid anhydride, treating the acylated product with a dehydration agent and an alcohol compound in an inert solvent in the presence of an acid catalyst at 5-80 deg.C and treating the product with a base in an inert solvent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a useful intermediate for producing 3,4'-dideoxymycaminosyl tylonolide, which is an antibacterial substance having an excellent protective effect against infection.

[0002]

2. Description of the Related Art 3,4'-dideoxymycaminosyl tylonolide or a salt thereof is a substance showing antibacterial activity against Gram-positive and -negative microorganisms, and particularly as an antibacterial agent excellent in infection-preventing action. Useful (JP-A-2-
275894). 3,4′-dideoxymycaminosyl tylonolide is a compound in which the functional group of mycaminosyl tylonolide, which is an acid hydrolyzate of tylosin, is appropriately protected, and then the hydroxyl groups at the 3 and 4 ′ positions are deoxygenated. It can be produced by appropriate deprotection. For example, after sulfonylating the hydroxyl groups at the 3 and 4'positions, use the Journal of Antibiotics (J. Antibi
otics 34, pp.1374-1376) or halogenating the hydroxyl group at the 4'position by the method described in JP-A No. 2-191295.
Further, a deoxygenation method is known in which a halogen atom is reductively removed by using tributyltin hydride. JP-A-2-
The method described in Japanese Patent No. 275894 is also a method of deoxidizing the hydroxyl group at the 4'position. Regarding the hydroxyl group at the 3-position, deoxidation can be carried out by eliminating the sulfonic acid under alkaline conditions to form a double bond and then catalytically reducing the double bond.

However, according to the above method, the 3rd and 4'th positions are used.
In performing deoxygenation of the 4-position, both hydroxyl groups are sulfonylated to halogenate the 4'-position, and then three steps (4 '
Step, reduction step with tributyltin hydride at position 3, double bond formation step at position 3, and reduction step),
There was a problem of low yield (about 65-70%). Furthermore, tributyltin hydride used for deoxygenation at the 4'-position has a bad odor, and purification of the product after the reaction becomes difficult, so that there is a problem in industrially applying this reaction.

The present inventor has prepared the above-mentioned preparation of 3,4'-dideoxymycaminosyltylonolide derivative which is a useful intermediate for producing 3,4'-dideoxymycaminosyltylonolide. The research was advanced for the purpose of solving the above problems and providing a new manufacturing method applicable industrially. As a result, a mycaminosyl tylonolide derivative having a hydroxyl group and a halogen atom protected by a sulfonyl group at the 3 and 4'positions, respectively, can be efficiently hydrogen-substituted in one step without using tributyltin hydride. To find a method for producing the desired 3,4′-dideoxymycaminosyl tylonolide derivative,
A patent application for the invention was filed (Japanese Patent Application No. 4-24692).

[0005]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention and Means for Solving the Problems The present invention is useful in the above manufacturing method,
An object of the present invention is to provide an intermediate for producing 3,4'-dideoxymycaminosyl tylonolide. The present invention is
The following general formula:

[0006]

[Chemical 2]

(Wherein A represents a carbonyl group which may be protected, B represents an aldehyde group which may be protected, W represents a hydrogen atom or an —OCOCH ₃ group, Y represents a hydroxyl group or a substituted group). A sulfonyloxy group or a halogen atom, R ¹ represents a hydroxyl group or a protected hydroxyl group, R ² represents a lower alkanoyl group, provided that when the W represents a hydrogen atom, a double bond Indicates that W is -OCOCH ₃
When a group is shown, a single bond is shown)
The present invention provides an intermediate for producing dideoxymycaminosyl tylonolide.

In the compound represented by the formula (I) of the present invention, as the protecting group for the carbonyl group or aldehyde group represented by A or B, any one obvious to those skilled in the art may be used. Dimethyl acetal (dimethyl ketal), diethyl acetal (diethyl ketal), diethyl thioacetal (diethyl thioketal), ethylene acetal (ethylene thioketal),
An acetal (or thioacetal) such as propylene acetal (propylene ketal) or a ketal (or thioketal) can be used.

W represents a hydrogen atom or a --OCOCH ₃ group, and Y
Represents a hydroxyl group, a substituted sulfonyloxy group, or a halogen atom. The substituted sulfonyloxy group is represented by -OSO ₂ R ³ ,
R ³ represents, for example, a lower alkyl group, a trifluoromethyl group, a 2-oxo-10-bornanyl group, a substituted or unsubstituted allyl group, or a substituted or unsubstituted aralkyl group. Examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a 1-methylbutyl group, a 2-methylbutyl group and a neopentyl group. it can. Examples of the substituted or unsubstituted allyl group are phenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-fluorophenyl group, p, o-difluorophenyl group, p-chlorophenyl group, m-chlorophenyl group, o -Chlorophenyl group, o, p-dichlorophenyl group, p-bromophenyl group, p-methylphenyl group, m-methylphenyl group,
Examples thereof include o, p-dimethylphenyl group, m, p-dimethylphenyl group and naphthyl group. The substituted or unsubstituted aralkyl group includes benzyl group, p-nitrobenzyl group, o, p-dinitrobenzyl group, p-chlorobenzyl group, m-
Examples thereof include a chlorobenzyl group, p-methylbenzyl group, m-methylbenzyl group, o-methylbenzyl group, o, p-dimethylbenzyl group, p-methoxybenzyl group and p-fluorobenzyl group. The halogen atom may be, for example, a chlorine atom, a bromine atom, an iodine atom or the like.

R ¹ represents a hydroxyl group or a protected hydroxyl group, and any protective group for the hydroxyl group may be used as long as it is obvious to those skilled in the art. For example, t-butyldimethylsilyl, dimethylthexylsilyl, Alkylsilyl groups such as trimethylsilyl, triethylsilyl, tri (t-butyl) silyl, trityl groups, tetrahydropyranyl groups, tetrahydrofuranyl groups, allyl groups, lower alkanoyl groups such as acetyl groups, benzoyl groups, benzyl groups, A methoxymethyl group, a benzyloxycarbonyl group or the like can be used. R ² represents a hydrogen atom or a lower alkanoyl group, and examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms. Examples of the lower alkanoyl group include formyl group, acetyl group, propionyl group, butyryl group,
An isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a hexanoyl group or the like can be used. In the above formula, the --part represents a single bond or a double bond,
When W represents a hydrogen atom, it represents a double bond and W represents -OCO.
When it represents a CH ₃ group, it represents a single bond.

In the 3,4'-dideoxymycaminosyl tylonolide production intermediate of the present invention, A is a protected carbonyl group, B is a protected aldehyde group, W is a hydrogen atom, Compounds in which Y is a hydroxyl group and R ¹ is a protected hydroxyl group (2 ', 4 "-di-O-acyl-
Δ ² -desmycosine bisacetal form) is, for example,
Easily available 3-O-acetyl tylosin (Journal of Antibiotics 27,542 (1979))
For example, Journal of Antibiotics 3
5, 661 (1982), after treatment with various acid anhydrides to convert to 2 ', 4 "'-di-O-acyl-3-O-acetyltylosin, In the presence of an acid catalyst of about 1.1-1.5 mol, for example, by treating with a dehydrating agent and an alcohol compound at about 5-80 ° C in an inert solvent such as toluene, 2 ', 4 "-di-O-acyl- 3-O-acetyldesmycosin is converted to a 9,20-bisacetal form, and the compound is further converted to the compound in an inert solvent such as toluene.
It can be produced by treating with about 1.0-5.0 mol of a base.

In the above reaction, as the alcohol compound, methanol, ethanol, propanol, butanol, ethylene glycol, propanediol, 2,3-butanediol, etc. can be used. Used in degrees. As the dehydrating agent, ethyl orthoformate, methyl orthoformate, anhydrous calcium chloride, anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieve and the like can be used, and as the acid catalyst, camphorsulfonic acid, benzenesulfonic acid, toluenesulfonic acid, Methanesulfonic acid, sulfuric acid, Amberlyst 15 or the like may be used. As the base used in the deacetic acid step, sodium hydride, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, sodium methoxide, sodium ethoxide, 1,8-diazabicyclo [5.4.0] -7- Undecen, 1,
5-diazabicyclo [4.3.0] -5-nonene or the like may be used.

Further, pyridine, cozine, lutidine,
Organic such as lyethylamine and diisopropylethylamine
The above compound was subjected to R³SO₂
Reactive derivative (R³Is the same as above) and -25 to 25 ° C
By reacting at about temperature, Y is substituted sulfonium
It can be converted to a compound that is a ruoxy group. R³SO
₂Halide or anhydride is used as the reactive derivative.
All you need is the desired R³SO ₂It should be used to introduce an O- group.
R³SO₂The reactive derivative is appropriately selected by those skilled in the art.
It Specifically, methanesulfonyl chloride, methan
Rufonic acid anhydride, ethanesulfonyl chloride, propane
Sulfonyl chloride, butane sulfonyl chloride, pen
Tansulphonyl chloride, trifluormethane sulfo
Nyl chloride, trifluoromethanesulfonic anhydride,
Benzenesulfonyl chloride, p-methoxyphenylsulfate
Honyl chloride, p-nitrophenylsulfonyl chloride
, P-fluorophenylsulfonyl chloride, p, o-diff
Luorophenylsulfonyl chloride, p-chlorophenyl
Sulfonyl chloride, m-chlorophenylsulfonyl chloride
Lido, o-chlorophenylsulfonyl chloride, o, p-di
Lolophenylsulfonyl chloride, p-bromophenyls
Rufonyl chloride, p-methylphenylsulfonyl chloride
, P-methylphenylsulfonic anhydride, m-methylphene
Nylsulfonyl chloride, o, p-dimethylphenylsulfone
Nyl chloride, m, p-dimethylphenylsulfonyl chloride
De, naphthyl sulfonyl chloride, camphor sulphoni
L-chloride, benzylsulfonyl chloride, p-nitrobe
And sulfonyl chloride, o, p-dinitrobenzyl sulphate
Honyl chloride, p-chlorobenzylsulfonyl chloride
, M-chlorobenzylsulfonyl chloride, p-methyl ester
Nylsulfonyl chloride, m-, methylbenzylsulfo
Nyl chloride, orthomethylbenzylsulfonyl chloride
, O, p-dimethylbenzylsulfonyl chloride, p-meth
Xybenzylsulfonyl chloride, p-fluorobenzis
Lesulfonyl chloride and the like can be mentioned.
It is not limited to these.

In a solvent such as acetone, methyl ethyl ketone, dimethoxyethane, acetonitrile, dimethylsulfoxide, dimethylformamide, etc., about 1 to 5 mol of a halogenating agent is added to the above compound in which Y is a substituted sulfonyloxy group. A compound in which Y is a halogen atom can be obtained by acting at a temperature of about 100 ° C. As the halogenating agent, sodium iodide, potassium iodide, sodium bromide, potassium bromide,
Although sodium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, etc. can be used, it is not limited to these.

Although one example of the method for producing the compound of the present invention has been described, the method for producing the compound of the present invention is not limited to these methods, and may be obtained by modifying or altering the above reaction, or by another method. It may be manufactured by a manufacturing method. In the intermediate for producing 3,4′-dideoxymycaminosyl tylonolide of the present invention, A is a protected carbonyl group, B is a protected aldehyde group, and W is
Is a hydrogen atom, Y is a halogen atom, and R ¹ is a protected hydroxyl group, and is converted to 3,4′-dideoxymycaminosyl tylonolide or a salt thereof useful as an antibacterial agent. For example, by reducing the above compound under alkaline conditions to simultaneously replace the 3 and 4'positions with hydrogen to produce a 3,4'-dideoxy derivative, the protecting group can be removed by a conventional method. Good.

The reduction reaction may be carried out, for example, by catalytically reducing the compound as a substrate in an inert solvent in the presence of a catalyst. As the base used to form the alkaline condition, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate or the like can be used. These bases are usually 2 to the substrate.
It may be used in a ratio of 5 mol. Examples of the catalyst used for catalytic reduction include platinum, palladium, Raney nickel and the like, preferably Raney nickel.
The amount of the catalyst used varies depending on the type of the catalyst, but in general, it may be used in a ratio of 1/10 to 1 with respect to the substrate. Examples of the inert solvent include solvents such as methanol, ethanol and tetrahydrofuran. In carrying out the catalytic reduction, the reaction may be carried out, for example, by adding hydrogen at a normal pressure to 5 kg / cm ² and at a reaction temperature under cooling to room temperature, preferably -10 to 30 ° C. These conditions are appropriately selected by those skilled in the art, though they vary depending on the types of raw material compounds and catalysts. The mycinosyl group may be removed by oxidizing the mycinosyl group to give a corresponding ketone body and then treating with an acid or a base. In addition, the removal of the protective group may be carried out usually by treatment with a mineral acid such as hydrochloric acid or sulfuric acid in the presence of water, or with an organic acid such as acetic acid, trifluoroacetic acid or trichloroacetic acid. In some cases, it may be treated with a solvent such as dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile or the like using an arylsulfonic acid such as p-toluenesulfonic acid or an alkylsulfonic acid such as methanesulfonic acid at room temperature to under heating. It can be carried out.

The 3,4'-dideoxymycaminosyl tylonolide obtainable using the method of the present invention has a wide range of gram-positive and negative gram-positive properties as described in JP-A-2-275894. It is a substance that exhibits antibacterial activity against microorganisms, and is particularly useful as an antibacterial agent because it is excellent in infection protection.

[0018]

EXAMPLES The present invention will now be described in more detail with reference to examples, but the present invention is not limited to these examples. Example 1 2 ', 3,4 "-tri-O-acetyldesmycosin
Production of 9,20-bis (ethylene acetal

[0019]

[Chemical 3]

1.00 g (0.922 mmol) of 2 ', 3,4 ", 4"'-tetra-O-acetyltylosin was dissolved in 5 ml of toluene, and 0.61 ml (3.69 mmol) of ethyl orthoformate and 0.51 ml (9.22 ml of ethylene glycol). mmol), dl-camphorsulfonic acid 321 mg
(1.38 mmol) was sequentially added, and the mixture was reacted at 50 ° C for 2 hours. Toluene (10 ml) was added to the reaction mixture, which was washed with 5% aqueous sodium hydrogen carbonate (15 ml) and saturated brine (15 ml), and dried over anhydrous sodium sulfate. The residue obtained by concentrating the organic layer under reduced pressure was subjected to silica gel chromatography (55 g) and eluted with toluene / acetone (5/1) to develop a toluene / acetone (2/1) silica gel TLC.
The fraction showing a positive sulfuric acid coloration with an Rf value of 0.38 was collected to give 525 mg of a colorless amorphous solid of the title compound in a yield of 58%.

UV (MeOH) λmax; 235nm IR (KBr) vmax; 3468, 2976, 2938, 2882, 1742, 1372, 1
236, 1175, 1086, 1049 cm ^-1 NMR (CDCl ₃ ); showing only the main peak δ: 0.84 (3H, br, H-18), 0.90 (3H, t, J = 7.3 Hz, H-
17), 0.99 (3H, d, J = 5.9 Hz, H-21), 1.16 (3H, d, J =
6.6 Hz, H-6 "), 1.31 (3H, d, J = 5.9 Hz, H-6 '), 1.71
(3H, s, H-22), 2.05 (3H, s, OCOCH ₃ ), 2.11 (6H, s, 2
X OCOCH ₃ ), 2.39 (6H, s, N (CH ₃ ) ₂ -3 '), 2.91 (1H, m, H =
14), 3.28 (1H, m, H = 5 '), 3.45 (3H, s, OCH ₃ -2 "), 3.5
2 (3H, s, OCH ₃ -3 "), 4.29 (1H, d, J = 6.6 Hz, H-1 '),
4.43 (1H, dd, J = 2.2 & 10.3 Hz, H-4 "), 4.60 (1H, d,
J = 8.1 Hz, H-1 "), 4.81 (1H, m, H-15), 4.90 (1H, bs,
H-20), 5.42 (1H, d, J = 10.3 Hz, H-13), 5.61 (1H, d,
J = 16.1 Hz, H-10), 6.49 (1H, d, J = 16.1 Hz, H-10) FAB-MS; 986 (M + H) ⁺ Example 2 2 ', 4 "-di-O-acetyl -2,3-dehydro-
Production of 3-deoxydesmycosin 9,20-bis (ethylene acetal)

[0022]

[Chemical 4]

2 ', 3,4 "-tri-O-acetyldesmycosin 9,20-bis (ethylene acetal) 100 mg (0.101 mmo
l) was dissolved in tetrahydrofuran 1 ml, sodium hydride (9.7 mg, 0.404 mmol) was added under ice cooling, and the mixture was reacted at room temperature for 1.5 hours. After adding 20 ml of ethyl acetate to the reaction solution and washing with water,
It was dried over anhydrous sodium sulfate. 110 mg of the residue obtained by concentrating the organic layer under reduced pressure was purified by preparative silica gel TLC developed with toluene / acetone (2/1) to obtain Rf on the same developed TLC.
Sulfuric acid color-positive compound at a value of 0.49 at 80m with a yield of 85%
g got.

UV (MeOH) λmax; 218nm IR (KBr) vmax; 3468, 2975, 2938, 2882, 1746, 1373, 1
235, 1171, 1086, 1051 cm ^-1 NMR (CDCl ₃ ); showing only the main peak δ: 0.95 (3H, t, J = 7.3 Hz, H-17), 1.17 (3H, d, J =
6.6 Hz, H-6 "), 1.33 (3H, d, J = 6.6 Hz, H-6 '), 1.70
(3H, s, H-22), 2.05 (3H, s, OCOCH ₃ ), 2.11 (3H, s, O
COCH ₃ ), 2.40 (6H, s, N (CH ₃ ) ₂ -3 '), 2.57 (1H, t, J = 1
0.3 Hz, H-3 '), 2.91 (1H, m, H = 14), 3.33 (1H, m, H =
5 '), 3.48 (3H, s, OCH ₃ -2 "), 3.52 (3H, s, OCH ₃ -3"),
4.62 (1H, d, J = 8.1 Hz, H-1 "), 4.87 (1H, m, H-15),
4.97 (1H, bs, H-20), 5.05 (1H, dd, J = 7.3 & 10.3 Hz,
H-2 '), 5.33 (1H, d, J = 10.3 Hz, H-13), 5.48 (1H, d,
J = 15.4 Hz, H-10), 5.54 (1H, d, J = 15.4 Hz, H-2), 6.
24 (1H, d, J = 15.4 Hz, H-11), 6.70 (1H, dd, J = 15.4 &
9.5 Hz. H-3) FAB-MS; 926 (M + H) ⁺ Example 3 2 ', 4 "-di-O-acetyl-2,3-dehydro-
3.4 ^'- the production of dideoxy-4'-O-methanesulfonyl-des Mycobacterium Shin 9,20- bis (ethylene acetal)

[0025]

[Chemical 5]

2 ', 4 "-di-O-acetyl-2,3-dehydro-
3-Deoxydesmycosin 9,20-bis (ethylene acetal) 50 mg (0.0539 mmol) was added to methyl ethyl ketone 0.5
Dissolve in 3 ml, add 22.5 μl (0.161 mmol) of triethylamine, and then under ice-cooling 6.3 μl of methanesulfonyl chloride (0.08
A solution of 08 mmol) in methyl ethyl ketone (100 μl) was added, and the mixture was reacted at the same temperature for 15 minutes. Ethyl acetate (10 ml) was added to the reaction mixture, which was washed with 5% aqueous sodium hydrogen carbonate (10 ml) and saturated brine (10 ml), and dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure to give 55 mg of the title compound positive in sulfuric acid coloration at an Rf value of 0.51 on silica gel TLC developed with toluene / acetone (4/1).

NMR (CDCl ₃ ); showing only the main peak δ: 0.95 (3H, t, J = 7.3 Hz, H-17), 1.17 (3H, d, J =
6.6 Hz, H-6 "), 1.38 (3H, d, J = 5.9 Hz, H-6 '), 1.70
(3H, s, H-22), 2.06 (3H, s, OCOCH ₃ ), 2.11 (3H, s, O
COCH ₃ ), 2.40 (6H, s, N (CH ₃ ) ₂ -3 '), 3.05 (1H, dd, J =
8.1 & 2.9 Hz, H-2 "), 3.11 (3H, s, OMs-4 '), 3.48 (3
H, s, OCH ₃ -2 "), 3.52 (3H, s, OCH ₃ -3"), 4.24 (1H, t,
J = 9.5 Hz, H-4 '), 4.62 (1H, d, J = 8.1 Hz, H-1 "), 5.08
(1H, dd, J = 7.3 & 10.3 Hz, H-2 '), 5.33 (1H, d, J = 1
0.3 Hz, H-13), 5.48 (1H, d, J = 15.4 Hz, H-10), 5.55
(1H, d, J = 15.4 Hz, H-2), 6.24 (1H, d, J = 15.4 Hz, H
-11), 6.68 (1H, dd, J = 15.4 & 9.5 Hz, H-3) FAB-MS; 1004 (M + H) ⁺ Example 4 2 ', 4 "-di-O-acetyl-2,3 -Dehydro
-3,4'-dideoxy-4'-iododesmycosin 9,20
-Manufacture of bis (ethylene acetal)

[0028]

[Chemical 6]

2 ', 4 "-di-O-acetyl-2,3-dehydro
-3,4'-deoxydesmycosin 9,20-bis (ethylene acetal) 1.88 g (2.03 mmol) was added to methyl ethyl ketone 20.
After dissolving it in 0.8 ml of triethylamine and adding 0.85 ml (6.09 mmol) of triethylamine, 0.20 ml of methanesulfonyl chloride (2.64
(1.5 mmol) of methyl ethyl ketone in 1.5 ml was added, and the mixture was reacted at the same temperature for 30 minutes. Furthermore, 907 mg (6.09 mmol) of sodium iodide was added to the reaction solution, and the mixture was heated under reflux for 30 minutes. The reaction mixture was concentrated under reduced pressure, ethyl acetate (50 ml) was added, the mixture was washed with 5% aqueous sodium hydrogen carbonate solution (50 ml) and saturated brine (50 ml), and dried over anhydrous sodium sulfate. The organic layer is concentrated under reduced pressure and dried in vacuo to give a colorless amorphous solid containing the title compound as a main component.
2.10 g were obtained.

UV (MeOH) λmax; 216nm IR (KBr) vmax; 2975, 2936, 2880, 1750, 1717, 1373, 1
233, 1171, 1090, 1049 cm ^-1 NMR (CDCl ₃ ); showing only the main peak δ: 0.95 (3H, t, J = 7.3 Hz, H-17), 1.17 (3H, d, J =
6.6 Hz, H-6 "), 1.53 (3H, d, J = 5.1 Hz, H-6 '), 1.69
(3H, s, H-22), 2.04 (3H, s, OCOCH ₃ ), 2.11 (3H, s, O
COCH ₃ ), 3.05 (1H, dd, J = 2.9 & 8.1 Hz, H-2 "), 3.48
(3H, s, OCH ₃ -2 "), 3.52 (3H, s, OCH ₃ -3"), 4.62 (1H,
d, J = 8.1 Hz, H-1 "), 5.33 (1H, d, J = 10.3 Hz, H-13),
5.47 (1H, d, J = 15.4 Hz, H-10), 5.55 (1H, d, J = 15.4
Hz, H-2), 6.24 (1H, d, J = 15.4 Hz, H-11), 6.69 (1H,
dd, J = 15.4 & 9.5 Hz. H-3) FAB-MS; 1036 (M + H) ⁺ Example 5 3,4'-dideoxydesmycosin 9,20-bis
Production of (ethylene acetal)

[0031]

[Chemical 7]

2 ', 4 "-di-O-acetyl-2,3-dehydro-3,4'-dideoxy-4'-iododesmycocin 9,20-bis (ethylene acetal obtained in Example 4 ) 470 mg (
0.454 mmol) is dissolved in 6 ml of methanol and potassium carbonate 20
0 mg (1.45 mmol), followed by Raney Nickel (Kawaken Fine Chemicals NDT-65) wet weight 400 mg (0.3 ml) in 1 ml of methanol was added, and catalytic reduction was carried out at hydrogen pressure of 3.5 Kg / cm ^{2 for} 2 hours. I did. The catalyst was filtered off with Celite and the mother liquor was washed with 1
After leaving it overnight, it was concentrated under reduced pressure. 20 ml of ethyl acetate and water to the residue
20 ml was added and the layers were separated. The organic layer was washed with 20 ml of saturated saline and then dried over anhydrous sodium sulfate. 423 mg of the residue obtained by concentrating the organic layer under reduced pressure was eluted with chloroform / methanol (25/1) by silica gel chromatography (40 g), and Rf was applied by silica gel TLC developed with chloroform / methanol (10/1). Fractions showing a positive sulfuric acid coloration at a value of 0.45 were collected to give 285 mg of a colorless amorphous solid of the title compound in a yield of 76%.

UV (MeOH) λmax; 234nm IR (KBr) vmax; 3466, 2971, 2936, 2880, 1730, 1379, 1
167, 1082 cm ^-1 NMR (CDCl ₃ ); representing only the main peak δ: 0.93 (3H, t, J = 7.3 Hz, H-17), 1.23 (3H, d, J =
6.2 Hz, H-6 '), 1.26 (3H, d, J = 6.6 Hz, H-6 "), 1.72
(3H, s, H-22 ), 2.28 (6H, s, N (CH 3) 2 - 3 '), 2.86 (1H,
m, H-14), 3.48 (3H, s, OCH ₃ -2 "), 3.61 (3H, s, OCH ₃
-3 "), 4.28 (1H, d, J = 7.3 Hz, H-1 '), 4.54 (1H, d, J =
7.7 Hz, H-1 "), 4.91 (1H, m, H-15), 5.01 (1H, br, H-
20), 5.42 (1H, d, J = 10.6 Hz, H-13), 5.60 (1H, d, J = 1
5.8 Hz, H-10), 6.39 (1H, d, J = 15.8 Hz, H-11) FAB-MS; 828 (M + H) ⁺ Example 6 2'-O-acetyl-3,4'-dideoxy Manufacture of desmycosin 9,20-bis (ethylene acetal)

[0034]

[Chemical 8]

After 285 mg of 3,4'-dideoxydesmycosin 9,20-bis (ethylene acetal) was dissolved in 3.0 ml of ethyl acetate, 51.4 μl of acetic anhydride was added and reacted at room temperature for 3 hours, and then 10 ml of ethyl acetate was added. Was added, and the mixture was washed with 10 ml of 5% sodium hydrogen carbonate solution and 10 ml of 20% saline solution. The organic layer was dried over anhydrous sodium sulfate and dried under reduced pressure to give chloroform / methanol (10 /
1) 300 mg of the title compound positive for sulfuric acid coloration was obtained by developing silica gel TLC with an Rf value of 0.44.

UV (MeOH) λmax; 235nm IR (KBr) vmax; 3476, 2973, 2938, 2882, 1744, 1373, 1
238, 1167, 1061, 961 cm ^-1 NMR (CDCl ₃ ); showing only the main peak δ: 0.82 (3H, bd, J = 5.5 Hz, H-18), 0.92 (3H, t, J =
7.3 Hz, H-17), 1.00 (3H, d, J = 6.6 Hz, H-21), 1.23
(3H, d, J = 6.2 Hz, H-6 '), 1.26 (3H, d, J = 6.2 Hz, H-
6 "), 1.35 (1H, m, H-4'a), 1.71 (1H, m, H-4'b), 1.73
(3H, d, J = 1.1 Hz, H-22), 2.04 (3H, s, OCOCH ₃ -2 '),
2.26 [6H, s, N ( CH 3) 2 - 3 '], 2.68 (1H, ddd, J = 12.3 &
10.4 & 4.4 Hz, H-3 '), 3.18 (1H, br, H-4 "), 3.48 (3
H, s, OCH ₃ -2 "), 3.61 (3H, s, OCH ₃ -3"), 4.31 (1H, d,
J = 7.7 Hz, H-1 '), 4.55 (1H, d, J = 7.7 Hz, H-1 "), 4.8
0 (1H, dd, J = 10.4 & 7.7 Hz, H-2 '), 4.90 (1H, m, H
-15), 4.95 (1H, bt J = 5.1 Hz, H-20), 5.42 (1H, d, J =
10.6 Hz, H-13), 5.62 (1H, d, J = 15.8 Hz, H-10), 6.36
(1H, d, J = 15.8 Hz, H-11) FAB-MS; 870 (M + H) ⁺ Example 7 2'-O-acetyl-3,4'-dideoxy-4 "-oxodesmycosin 9 Of 20-bis (ethylene acetal)

[0037]

[Chemical 9]

491 mg (3.68 mmol) of N-chlorosuccinimide was suspended in 8 ml of toluene, cooled to 0 ° C., 0.4 ml (5.5 mmol) of dimethyl sulfide was added, and the mixture was stirred at the same temperature for 20 minutes. After cooling the solution to -20 ° C, 2 '
-O-Acetyl-3,4'-dideoxydesmycosin 9,20-bis (ethylene acetal) 800 mg (0.
(92 mmol) of toluene solution (4 ml) was added, and the mixture was reacted at the same temperature for 1.5 hours. 0.64 ml of triethylamine was added to this reaction solution.
(4.6 mmol) was added and the reaction was further continued for 20 minutes. The reaction solution is 1
After washing twice with 15 ml of 0% saline solution, drying over anhydrous sodium sulfate, and drying under reduced pressure, chloroform / methanol (5 /
1) By developing silica gel TLC, 755 mg of the title compound having a sulfuric acid coloration positive value was obtained with an Rf value of 0.65.

UV (MeOH) λmax; 235nm IR (KBr) νmax; 3441,2971,2938,2882,1744,1373,1240,1
169,1117,1057,974 cm ^-1 NMR (CDCl ₃ ); showing only the main peak δ; 0.83 (3H, d, J = 5.9Hz, H-18), 0.94 (3H, t, J = 7.3Hz, H-1
7), 1.00 (3H, d, J = 6.6Hz, H-21), 1.24 (3H, d, J = 5.9Hz, H-
6 ′), 1.35 (3H, d, J = 7.0Hz, H-6 ″), 1.38 (1H, m, H-4′a),
1.73 (1H, m, H-4′b), 1.76 (3H, d, J = 1.1Hz, H-22), 2.04
(3H, s, OCOCH ₃ -2 '), 2.26 [6H, s, N (CH ₃ ) ₂ -3'], 3.46 (3
H, s, OCH ₃ -2 ″), 3.50 (3H, s, OCH ₃ -3 ″), 3.74 (1H, t, J = 3.3H
z, H-2 ″), 4.17 (1H, q, J = 7.0Hz, H-5 ″), 4.26 (1H, d, J = 3.
7Hz, H-3 ″), 4.32 (1H, d, J = 7.7Hz, H-1 ″), 4.81 (1H, dd, J
= 10.6 & 7.7Hz, H-2 ′), 4.83 (1H, d, J = 2.9Hz, H-1 ″), 4.92
(1H, m, H-15), 4.95 (1H, bt, J = 5.1Hz, H-20), 5.39 (1H, d, J =
10.3Hz, H-13), 5.67 (1H, d, J = 15.8Hz, H-10), 6.37 (1H, d, J
= 15.8 Hz, H-11) FAB-MS; 868 (M + H) ⁺ Example 8 Preparation of 3,4'-dideoxymycaminosyl tylonolide 9,20-bis (ethylene acetal)

[0040]

[Chemical 10]

100 mg (0.115 mmol) of 2'-O-acetyl-3,4'-dideoxy-4 "-oxodemycocin 9,20-bis (ethylene acetal) was dissolved in 1 ml of methanol and then 1N was added at 0 ° C. -0.115 ml of NaOH was added and the reaction was carried out at the same temperature for 1 hour.
l was added and the temperature was raised, and the mixture was reacted at 60 ° C. for 2 hours. Chloroform (5 ml) was added to the reaction solution, and the organic layer was washed 4 times with 10% saline (5 ml). The organic layer was evaporated to dryness under reduced pressure to give 74 mg of a sulfuric acid color-positive title compound having an Rf value of 0.31 by silica gel TLC developed with chloroform / methanol (5/1).

UV (MeOH) λmax; 235 nm IR (KBr) νmax; 3449,2938,2880,1730,1642,1458,1381,1
169,1111,1049,974 cm ^-1 NMR (CDCl ₃ ); represents only the main peak δ; 0.93 (3H, t, J = 7.3Hz, H-17), 0.99 (3H, d, J = 6.6Hz, H-1
8), 1.02 (3H, d, J = 7.0Hz, H-21), 1.24 (3H, d, J = 5.9Hz, H-
6 ′), 1.78 (3H, d, J = 1.1Hz, H-22), 2.35 [6H, s, N (CH ₃ ) _2-
3 ′], 3.30 (1H, dd, J = 10.3 & 7.3Hz, H-2 ′), 4.29 (1H, d, J =
7.0Hz, H-1 ′), 4.84 (1H, m, H-15), 5.01 (1H, bt, J = 5.1Hz, H
-20), 5.34 (1H, d, J = 9.9Hz, H-13), 5.66 (1H, d, J = 15.8Hz, H
-10), 6.42 (1H, d, J = 15.8Hz, H-11) FAB-MS; 654 (M + H) ⁺ , 676 (M + Na) ⁺ Example 9 Preparation of 3,4'-dideoxymycaminosyl tylonolide

[0043]

[Chemical 11]

3,4'-dideoxymycaminosyl tylonolide 9,20-bis (ethylene acetal)
26 mg (0.05 mmol) was dissolved in 0.2 ml of tetrahydrofuran, 0.2 ml of 1N hydrochloric acid was added, and the mixture was reacted at room temperature for 1.5 hours. After the reaction solution was diluted with water, 3 ml of chloroform was added. The organic layer was washed with 2 ml of 5% sodium hydrogen carbonate solution and 2 ml of 10% saline solution and dried over anhydrous sodium sulfate. The organic layer was evaporated to dryness under reduced pressure to give 20 mg of the sulfuric acid color-positive title compound having an Rf value of 0.25 by silica gel TLC developed with chloroform / methanol (5/1).

UV (MeOH) λmax; 283nm IR (KBr) νmax; 3436,2967,2878,1725,1676,1591,1458,1
383,1316,1167,1071,984 cm ^-1 NMR (CDCl ₃ ); represents only the main peak δ; 0.94 (3H, t, J = 7.3Hz, H-17), 1.04 (3H, d, J = 6.6 Hz, H-1
8), 1.20 (3H, d, J = 6.2Hz, H-6 ′), 1.21 (3H, d, J = 6.6Hz, H-
21), 1.85 (3H, d, J = 1.1Hz, H-22), 2.29 (6H, s, N (CH ₃ ) ₂ -3
′), 2.90 (1H, m, H-14), 3.20 (1H, dd, J = 7.3 & 10.3Hz, H-2
′), 4.19 (1H, d, J = 7.3Hz, H-1 ′), 4.88 (1H, m, H-15), 5.8
4 (1H, d, J = 10.6Hz, H-13), 6.35 (1H, d, J = 15.6Hz, H-10), 7.3
0 (1H, d, J = 15.6Hz, H-11), 9.69 (1H, s, H-20) FAB-MS; 566 (M + H) ⁺

[0046]

According to the present invention, 3, which is useful as an antibacterial agent,
Provided is a useful intermediate for efficiently producing 4'-dideoxymycaminosyl tylonolide or a salt thereof.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Shunji Kageyama 2-35-2 Kasuga, Tsukuba, Ibaraki Prefecture Etoile Kasuga 306 (72) Inventor, Toshiaki Miyake 3-5-1, Shimoda-cho, Kohoku-ku, Yokohama-shi, Kanagawa Hiyoshi Heights 207 (72) Inventor Naoki Matsumoto 4-52-11, Higashiyama, Konan-ku, Yokohama-shi, Kanagawa Prefecture (52) Inventor Kaichiro Kominato 6-4-30 Minami-Rinkan, Yamato-shi, Kanagawa Prefecture (72) Hiroshi Tanaka 3 Owada, Chigasaki-shi, Kanagawa Prefecture −16−26−306 (72) Inventor Takeo Yoshioka 3959

Claims (1)

[Claims] 1. The following general formula: (In the formula, A represents an optionally protected carbonyl group, B represents an optionally protected aldehyde group, and W
Represents a hydrogen atom or a —OCOCH ₃ group, Y represents a hydroxyl group, a substituted sulfonyloxy group, or a halogen atom, R ¹ represents a hydroxyl group or a protected hydroxyl group, and R ² represents a lower alkanoyl group. However, the ── moiety represents a double bond when W represents a hydrogen atom, and represents a single bond when W represents a —OCOCH ₃ group). 3,4′-dideoxymycaminosyl Tylonolide production intermediate.