JPH06116283A - Production of 3,4'-dideoxymycaminosyltylonolide derivative - Google Patents

Abstract

PURPOSE:To obtain the compound useful as a synthetic intermediate for dideoxymycaminosyltylonolide, an antimicrobial agent, by reducing a specific mycaminosyltylonolide derivative under an alkali condition. CONSTITUTION:A compound of formula I (A is protecting carbonyl; B is protecting aldehyde; R<1> is hydroxyl group which may be protected; R<2> is H or lower alkanoyl; R<3> is sulfonic acid residue; X is halogen) is reduced under an alkali condition to give the objective compound of formula II. To be concrete, the compound of formula II is catalytically reduced in an inert solvent in the presence of a catalyst. In order to make the alkali condition, potassium carbonate is preferably used and Raney nickel is preferable as the catalyst. The raw material compound of formula I is preferably obtained by reacting a mycaminosyltylonolide derivative of formula III prepared from tylosin with a sulfonylating agent such as benzylsulfonic acid and halogenating the reactional product.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 3,4'-dideoxymycaminosyl tylonolide, which is an antibacterial substance having an excellent infection-protecting action, and 3,4'-, which is an intermediate thereof.
The present invention relates to a novel method for producing a dideoxymycaminosyl tylonolide derivative and a production intermediate useful for the method.

[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.

[0004]

The present invention is based on 3,4'-
In producing a 3,4'-dideoxymycaminosyl tylonolide derivative, which is a useful intermediate for producing dideoxymycaminosyl tylonolide, the above-mentioned problems are solved and industrially applicable. It is intended to provide a new manufacturing method. More specifically, the present invention provides a mycaminosyl tylonolide derivative having a hydroxyl group and a halogen atom protected by a sulfonyl group at the 3 and 4'positions, respectively, without using tributyltin hydride. Efficiently replace hydrogen in the process,
It is an object of the present invention to provide a method for producing a 4'-dideoxymycaminosyl tylonolide derivative. Another object of the present invention is to provide a method for simultaneous deoxygenation of 3-position and 4'-position from a mycaminosyl tylonolide derivative by an efficient and industrially applicable method.

[0005]

The present invention provides the following general formula (II):

[0006]

[Chemical 6]

(In the formula, A represents a protected carbonyl group, B represents a protected aldehyde group, R ¹ represents an optionally protected hydroxyl group, and R ² represents a hydrogen atom or a lower alkanoyl group. R ³ represents a sulfonic acid residue,
X represents a halogen atom), and a step of reducing the compound represented by the following general formula (I):

[0008]

[Chemical 7]

The present invention provides a method for producing a 3,4'-dideoxymycaminosyl tylonolide derivative represented by the formula (wherein A, B and R ¹ have the same meanings as described above). According to the present invention, the following general formula (IV):

[0010]

[Chemical 8]

(In the formula, A, B, R ¹ and R ² have the same meanings as the above A, B, R ¹ and R ² , respectively)
By reacting a mycaminosyl tylonolide derivative represented by a sulfonylating agent with the following general formula (III):

[0012]

[Chemical 9]

(Where A, B, R ¹ , R ² and R ³ are
A step of producing a compound represented by the above-mentioned A, B, R ¹ , R ² and R ³ )
A step of reacting a compound represented by II) with a halogenating agent to obtain a compound represented by the general formula (II), and a step of reducing the compound represented by the formula (II) under alkaline conditions, Provided is a method for producing a 3,4'-dideoxymycaminosyl tylonolide derivative represented by the above general formula (I).

According to another aspect of the present invention, the compound represented by the general formula (II) is reduced to the compound represented by the general formula (I), and then the protecting group is removed. A method for producing the compound represented by the formula (VI), and the following general formula (V) useful for the above production method:

[0015]

[Chemical 10]

[Wherein A and B are as described above, and Y
Represents a hydrogen atom, a substituted sulfonyloxy group, or a halogen atom, W represents a hydrogen atom or a substituted sulfonyloxy group, R ⁴ represents a hydrogen atom or a lower alkanoyl group,
Z is CHOH, CHOR ⁵ (wherein R ⁵ represents a hydroxyl-protecting group), or C═O], and 3,4′-dideoxymycaminosyl tai represented by the general formula (I) Intermediates for the production of lonolide derivatives are also provided.

In the compounds represented by the formulas (I) to (IV) of the present invention, as the protective 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. However, for example, acetal (or thioacetal) such as dimethyl acetal (dimethyl ketal), diethyl acetal (diethyl ketal), diethyl thioacetal (diethyl thioketal), ethylene acetal (ethylene thioketal), propylene acetal (propylene ketal), or Ketal (or thioketal) or the like can be used.

In the above formula, R ¹ represents a hydroxyl group which may be protected, 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, Alkylsilyl groups such as dimethylthexylsilyl, trimethylsilyl, triethylsilyl, tri (t-butyl) silyl, trityl group, tetrahydropyranyl group, tetrahydrofuranyl group, allyl
) Group, lower alkanoyl group such as acetyl group, benzoyl group, benzyl group, methoxymethyl group, benzyloxycarbonyl group and the like can be used. Further, a mycinosyl group may be used as the hydroxyl-protecting group, and the hydroxyl group of the mycinosyl group may be protected by the above-mentioned hydroxyl-protecting group R ² represents a hydrogen atom or a lower alkanoyl group, and as a lower alkanoyl group, A straight-chain or branched alkanoyl group having 1 to 6 carbon atoms can be mentioned. The lower alkanoyl group, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group,
An isovaleryl group, a pivaloyl group, a hexanoyl group or the like can be used. R ³ represents a sulfonic acid residue, and for example, a mesyl group, an ethanesulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a benzenesulfonyl group, a tosyl group, a benzylsulfonyl group or the like can be used. X represents a halogen atom, for example, a chlorine atom,
It may be a bromine atom, an iodine atom or the like.

In the compound of the general formula (V), A and B
Is as defined above, and for example, those exemplified above can be used. Y represents a hydrogen atom, a substituted sulfonyloxy group, or a halogen atom. When Y represents a halogen atom, it may be, for example, a chlorine atom, a bromine atom, an iodine atom or the like. W represents a hydrogen atom or a substituted sulfonyloxy group, R ⁴ represents a hydrogen atom or a lower alkanoyl group, and as the lower alkanoyl group,
The ones exemplified above can be used. Z is CH
OH, CHOR ⁵ or C═O is shown, but R ⁵ is a hydroxyl-protecting group, and for example, the above-mentioned hydroxyl-protecting groups other than the mycinosyl group can be used.

In W and Y above, the substituted sulfonyloxy group is represented by -OSO ₂ R ⁶ , and R ⁶ is, for example, a lower alkyl group, a trifluoromethyl group, a 2-oxo-10-bornanyl group, a substituted or unsubstituted group. Represents an allyl group or a substituted or unsubstituted aralkyl group. As the lower alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, 1-methylbutyl group, 2-methylbutyl group,
Examples thereof include neopentyl group. The substituted or unsubstituted allyl group is a phenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-fluorophenyl group, o, p-difluorophenyl group, p-chlorophenyl group,
m-chlorophenyl group, o-chlorophenyl group, o, p-dichlorophenyl group, p-bromophenyl group, p-methylphenyl group, m-methylphenyl group, o, p-dimethylphenyl group, m,
Examples thereof include 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-chlorobenzyl group, p-methylbenzyl group, m-methylbenzyl group. , O-methylbenzyl group, o, p-dimethylbenzyl group, p-methoxybenzyl group,
Mention may be made of p-fluorobenzyl groups.

According to the method of the present invention, 3,4'-dideoxymycaminosyl tylonolide can be efficiently and efficiently produced from easily available tylosin. The mycaminosyl tylonolide derivative represented by the formula (IV) is a hydroxyl group, an aldehyde group, and a carbonyl group of mycaminosyl tylonolide obtained by acid hydrolysis of tylosin, using the above protecting group. It can be produced by appropriate protection according to a conventional method. Alternatively, for example, by the method described in Journal of Antibiotics ( 35 , 661, (1982)),
Tylosin is treated with an acid anhydride to obtain 2'-O-acyl tylosin, and the compound is appropriately protected with a protecting group to produce a mycaminosyl tyronolide derivative of the formula (IV) having a myosyl group. Good.

By reacting the above-mentioned mycaminosyl tylonolide derivative represented by the formula (IV) with a sulfonylating agent such as benzylsulfonic acid or its reactive derivative, the hydroxyl groups at the 3-position and the 4'-position are removed. The compound of formula (III) can be obtained by sulfonylation. As the benzyl sulfonic acid, one having 1 to 3 substituents such as a methyl group and an ethyl group on the benzene ring can be used. As the reactive derivative of benzylsulfonic acid, halides such as chloride and bromide and acid anhydrides may be used. When R ² represents a hydrogen atom, reaction with benzylsulfonyl chloride can selectively sulfonylate the 3-position and the 4′-position. The sulfonylation reaction may be carried out usually in an organic solvent at a temperature of −40 ° C. to + 50 ° C. As the solvent, acetonitrile, acetone, dimethyl sulfoxide, dioxane or the like may be used. Pyridine, 4-dimethylaminopyridine, triethylamine and the like may also be used as the basic catalyst and / or solvent.

The compound of the formula (III) is treated with sodium iodide, potassium iodide, lithium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride in an inert solvent such as acetone, 2-butanone and dimethylformamide. It is possible to obtain the compound represented by the above formula (II) in which the 4'-position is selectively halogenated by reacting with a halogenating agent such as. Normal,
The halogenation reaction is -30 depending on the kind of the sulfonyl residue.
It may be performed at ~ 100 ° C. Depending on the halogenation conditions,
Some compounds may have a double bond at the 2,3 position or the 3,4 position, but these compounds may be used as raw material compounds in the next step.

The 3,4'-dideoxy derivative represented by the formula (I) is obtained by reducing the compound represented by the above formula (II) under alkaline conditions to simultaneously substitute hydrogen at the 3 and 4'positions. It can be manufactured. The reaction is carried out, for example, by catalytically reducing the compound represented by the formula (II) in the presence of a catalyst in a solvent inert to the reaction. As the base used to form the alkaline condition, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, etc., preferably potassium carbonate can be used. These bases are usually used in a proportion of 2 to 5 mol with respect to the compound represented by the formula (II) serving as a substrate. 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 compound represented by the formula (II) serving as a substrate. Examples of the inert solvent include solvents such as benzene, toluene, ether, dimethylformamide, dimethylsulfoxide, methanol, ethanol and tetrahydrofuran. In carrying out the catalytic reduction, the addition pressure of hydrogen may be atmospheric pressure to 5 kg / cm ² , and the reaction temperature may be, for example, under cooling to room temperature, preferably at -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.

According to the above process, the 3-position and the 4'-position of the compound represented by the formula (II) can be simultaneously hydrogen-substituted, whereby the compound of the formula (II) can be produced in one step and in a high yield (approximately). At about 80%),
A 4'-dideoxy derivative can be obtained. The compound of formula (I) thus obtained has the 3,4'-dideoxymycaminosyl represented by the following general formula (VI) useful as an antibacterial agent, by removing the protecting group according to a conventional method. It can be converted to tylonolide or a salt thereof.

[0026]

[Chemical 11]

The removal of the protecting group is usually carried out by treatment with a mineral acid such as hydrochloric acid or sulfuric acid in the presence of water or an organic acid such as acetic acid, trifluoroacetic acid or trichloroacetic acid. Depending on the case, by treatment with arylsulfonic acid such as p-toluenesulfonic acid or alkylsulfonic acid such as methanesulfonic acid in a solvent such as dioxane, dimethylformamide, dimethylsulfoxide or acetonitrile, at room temperature to under heating. Can also be done. On the other hand, when a mycinosyl group is used, the mycinosyl group may be oxidized to a corresponding ketone body and then removed by treatment with an acid or a base.

The 3,4'-dideoxymycaminosyltylonolide of the formula (VI) obtainable by using the method of the present invention is as described in JP-A-2-275894.
It is a substance that exhibits antibacterial activity against a wide range of Gram-positive and -negative microorganisms, and is particularly useful as an antibacterial agent because it has an excellent action of preventing infection.

[0029]

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. a) Synthesis of 23-Ot-butyldimethylsilyl-3,4'-di-O-benzylsulfonyl-mycaminosyltylonolide 9,20-bis (ethylene acetal)

[0030]

[Chemical 12]

23-Ot-Butyldimethylsilyl-mycaminosyltylonolide 9,20-bis (ethylene acetal) 1.00 g (1.25 mmol) was dissolved in 20 ml of anhydrous pyridine and cooled to -40 ° C. , 0.67 g (3.51 mmol) of benzylsulfonyl chloride was added with stirring, and the temperature was -20 ° C.
And reacted for 3 hours. Confirm the reaction by TLC, 0.67 ml of water
Was added to stop the reaction, and the temperature was returned to room temperature. After 1 hour from the addition of water, the reaction solution was concentrated with a pump and extracted with chloroform. The chloroform layer was washed successively with saturated sodium bicarbonate water and saturated saline, dehydrated with magnesium sulfate, filtered, and the filtrate was concentrated. Crude 23-Ot-butyldimethylsilyl-
1.38 g (quantitative) of 3,4'-di-O-benzylsulfonyl-mycaminosyl tylonolide 9,20-bis (ethylene acetal) was obtained as a pale yellow foamy solid. b) Synthesis of 3-O-benzylsulfonyl-23-O-t-butyldimethylsilyl-4'-deoxy-4'-iodo-mycaminosyltylonolide 9,20-bis (ethylene acetal)

[0032]

[Chemical 13]

415 mg (0.1%) of the crude compound obtained in a) above.
375 mmol) was dissolved in 6.2 ml of anhydrous methyl ethyl ketone and, after purging with nitrogen, 84 mg of sodium iodide (0.560 mm)
ol) was added and the mixture was heated and stirred at 80 ° C., and after 30 minutes, the reaction solution was returned to room temperature, filtered, and the filtered material was washed with acetone, and the filtrate and the washing solution were combined and concentrated. The concentrated residue was extracted with chloroform, washed successively with saturated sodium bicarbonate solution, 10% sodium thiosulfate and saturated saline, dried over magnesium sulfate and filtered.
The filtrate was concentrated to give 410 mg of pale yellow syrup. The obtained syrup was purified by silica gel column chromatography to give 3-O-benzylsulfonyl-23-Ot-.
Butyldimethylsilyl-4'-deoxy-4'-iodo-mycaminosyl tylonolide 9,20-bis (ethylene acetal) as a colorless solid 300 mg (yield 7
5%) was obtained. (Physical and chemical properties) Specific light intensity [α] ²⁷ _D −70 ° (cl, CHCl ₃ ) Mass (FAB) m / z 1064 (M + H) ⁺ c) 23-Ot-butyldimethylsilyl-3,4'-dideoxymycaminosyl tylonolide 9,20-Bis (ethylene acetal) synthesis

[0034]

[Chemical 14]

296 mg (0.278 mm) of the compound obtained in b) above
ol) was dissolved in 6 ml of methanol and Raney nickel 0.5 ml was added.
Was added and the atmosphere was replaced with argon, and then 116 mg of potassium carbonate (0.8
35 mmol) was added and hydrogen was bubbled in for 3 hours. HPLC
Confirm the end of the reaction with, filter the reaction solution, then concentrate the filtrate,
Extracted with chloroform, washed successively with 1M aqueous potassium carbonate solution and saturated brine, dried over magnesium sulfate, filtered, and concentrated to give a colorless foamy solid crude compound 204 mg.
(95%) was obtained. The obtained solid was purified by silica gel column chromatography, and 23-O-t-butyldimethylsilyl-3,4'-dideoxymycaminosyltylonolide 9,20-bis (ethylene acetal) was obtained.
Was obtained as a colorless foamy solid (186 mg, yield 87%).

This product was identical with the standard product previously synthesized by another route in ¹ H-nmr and Mass. (Physical and chemical properties) Mass (FAB) m / z = 768 (M + H) ^{+ 1} H-nmr (CDCl ₃ , TMS internal standard) δ 0.88 (t-butyl of 9H, s, t-butyldimethylsilyl), 1.02 (3H, d, CH ₃ −21), 1.24 (3H, d, CH ₃ −6
′), 1.74 (3H, s, CH ₃ −22), 2.29 (6H, s, N (CH ₃ )
_2-3 '), 4.28 (1H, d, H-1'), 5.37 (1H, d, H
-13), 5.61 (1H, d, H-10), 6.39 (1H, d, H-11) d) 2'-O-acetyldesmycosin 9,20-bis (ethylene acetal)

[0037]

[Chemical 15]

23.7 g of 2'-O-acetyltylosin was suspended in 100 ml of toluene, followed by ethyl orthoformate 12.
36 g (83.5 mol), ethylene glycol 12.95 g
(208.8 mmol) and camphorsulfonic acid 6.30 g
(27.1 mmol) was added to form a homogeneous solution. After stirring this solution at 50 ° C. for 2 hours, the reaction solution was added with 5% aqueous sodium hydrogen carbonate (100 m).
l, washed with 100 ml of water and 10% saline. The organic layer was dried over anhydrous sodium sulfate and dried under reduced pressure to give toluene /
Silica gel TLC developed with acetone (1/1) gave an Rf value of 0.
As a result, 20.20 g of the title compound positive for sulfuric acid coloration was obtained in 49.

UV (MeOH) λmax; 235 nm IR (KBr) νmax; 3470,2975,2938,2882,1746,1236,1169,1
084,961 cm ^-1 NMR (CDCl ₃ ); representing only the main peak δ; 0.78 (3H, bs, H-18), 0.93 (3H, t, J = 7.3Hz, H-17), 1.01
(3H, d, J = 6.6Hz, H-21), 1.26 (3H, d, J = 6.2Hz, H-6 ″), 1.32
(3H, d, J = 6.2Hz, H-6 ′), 1.70 (3H, s, H-22), 2.01 (3H, s, O
COCH ₃ -2 '), 2.39 (6H, s, N (CH ₃ ) ₂ -3'), 3.05 (1H, t, J = 9.5
Hz, H-4 ′), 3.18 (1H, bd, J = 7.0Hz, H-4 ″), 3.49 (3H, s, O
CH ₃ -2 ″), 3.62 (3H, s, OCH ₃ -3 ″), 4.55 (1H, d, J = 8.1Hz, H-1
″), 4.64 (1H, br, H-1 ′), 4.96 (1H, m, H-20), 4.96 (1H,
m, H-15), 5.03 (1H, dd, J = 10.6 & 7.7Hz, H-2 '), 5.42 (1H,
d, J = 10.6Hz, H-13), 5.64 (1H, d, J = 15.8Hz, H-10), 6.37 (1
H, d, J = 15.8Hz, H-11) FAB-MS; 902 (M + H) ⁺ 2′-O-acetyl-4 ″ -O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal)

[0040]

[Chemical 16]

2'-O-acetyldesmycosin 9,
20-bis (ethylene acetal) 18.9g (20.9mm
ol) was dissolved in 94 ml of toluene and 2.52 ml of pyridine (31.
2 mmol) was added and the mixture was cooled to -5 ° C. 3.42 ml (27 mmol) of trimethylsilane chloride was added dropwise to this solution, and the mixture was reacted at the same temperature for 80 minutes. 150 ml of 5% sodium hydrogen carbonate solution,
The extract was washed with 150 ml of 10% saline and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure to give 20.64 g of a sulfuric acid color-positive title compound having an Rf value of 0.57 by silica gel TLC developed with toluene / acetone (1/1).

UV (MeOH) λ max; 235 nm IR (KBr) ν max; 3520,2973,2884,1748,1713,1373,1236,1
171,1100,966,882,841cm ^-1 NMR (CDCl ₃ ); showing only the main peak δ; 0.17 (9H, s, Si (CH ₃ ) ₃ ), 0.77 (3H, bs, H-18), 0.91 (3H,
t, J = 7.3Hz, H-17), 1.01 (3H, d, J = 6.6Hz, H-21), 1.18 (3H,
d, J = 6.2Hz, H-6 ″), 1.32 (3H, d, J = 5.9Hz, H-6 ′), 1.69 (3
H, d, J = 0.7Hz, H-22), 2.01 (3H, s, OCOCH ₃ -2 '), 2.38 (6H,
s, N (CH ₃ ) ₂ -3 ′), 2.59 (1H, t, J = 10.3Hz, H-3 ′), 3.05 (1
H, t, J = 9.9Hz, H-4 ′), 3.28 (1H, dd, J = 9.2 & 2.6Hz, H-
4 ″), 3.49 (3H, s, OCH ₃ -2 ″), 3.60 (3H, s, OCH ₃ -3 ″), 4.
59 (1H, d, J = 7.7Hz, H-1 ″), 4.64 (1H, br, H-1 ′), 4.95 (1H,
m, H-20), 4.96 (1H, m, H-15), 5.03 (1H, dd, J = 10.6 & 7.7Hz,
H-2 ′), 5.42 (1H, d, J = 10.6Hz, H-13), 5.62 (1H, d, J = 15.8H
z, H-10), 6.36 (1H, d, J = 15.8Hz, H-11) FAB-MS; 974 (M + H) ⁺ 2 ′, 4 ″ -di-O-acetyl-desmycosin 9,
Production of 20-bis (ethylene acetal)

[0043]

[Chemical 17]

2'-O-acetyl-desmycosin
200 mg (0.2) of 9,20-bis (ethylene acetal)
22 mmol) in 2 ml of methylene chloride and pyridine 35.
7 μl (0.444 mmol) was added, 23.6 μl (0.333 mmol) of acetyl chloride was added under ice cooling, and the mixture was reacted at the same temperature for 1 hour. Methylene chloride (20 ml) was added to the reaction solution, which was washed with 5% aqueous sodium hydrogen carbonate solution (20 ml) and saturated brine (20 ml) and dried over anhydrous sodium sulfate. 244 mg of the residue obtained by concentrating the organic layer under reduced pressure was eluted with toluene / acetone (5/1) by silica gel chromatography (10 g), and Rf value was measured by silica gel TLC developed with toluene / acetone (2/1).
Fractions showing positive sulfuric acid coloration at 0.45 were collected to obtain 133 mg of a colorless amorphous solid of the title compound in a yield of 64%.

UV (MeOH) λmax; 235 nm IR (KBr) ν max; 3524, 1745, 1236, 1088, 1049 cm ^-1 NMR (CDCl ₃ ); showing only the main peak δ; 0.77 (3H, bs, H-18) , 0.92 (3H, t, J = 7.3Hz, H-17), 1.00
(3H, d, J = 6.6Hz, H-21), 1.17 (3H, d, J = 6.6Hz, H-6 ″), 1.32
(3H, d, J = 5.9Hz, H-6 ′), 1.70 (3H, s, H-22), 2.01 (3H, s,
OCOCH ₃ ), 2.11 (3H, s, OCOCH ₃ ), 2.39 (6H, s, N (CH ₃ ) ₂ -3 '),
2.59 (1H, t, J = 10.3Hz, H-3 '), 2.89 (1H, m, H-14), 3.31 (1H,
m, H-5 ′), 3.48 (3H, s, OCH ₃ -2 ″), 3.52 (3H, s, OCH _3-
3 ″), 4.44 (1H, dd, J = 2.9 & 9.5Hz, H-4 ″), 4.61 (1H, d, J =
8.1Hz, H-1 ″), 5.03 (1H, dd, J = 10.3 & 7.3Hz, H-2 ′), 5.40
(1H, d, J = 10.3Hz, H-13), 5.63 (1H, d, J = 15.4Hz, H-10), 6.3
6 (1H, d, J = 15.4Hz, H-11) FAB-MS; 944 (M + H) ⁺ 2'-O-acetyl-3,4'-di-O-methanesulfonyl-4 "-O-trimethylsilyl- Desmycocin
Production of 9,20-bis (ethylene acetal)

[0046]

[Chemical 18]

2'-O-Acetyl-4 "-O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal) 10.07 g (10.3 mmol) was added to 50 ml of toluene.
After being dissolved in the solution, triethylamine (7.20 ml, 51.7 mmol) was added and the mixture was cooled to -15 ° C. To this solution was added methanesulfonyl chloride (2.8 ml, 36.2 mmol), and the mixture was reacted at -10 ° C for 1 hour. Toluene (40 ml) was added to the reaction solution, and the organic layer was washed with water (80 ml), 5% sodium hydrogen carbonate solution (40 ml) and 10% saline solution (40 ml) and dried over anhydrous sodium sulfate. The organic layer was evaporated to dryness under reduced pressure to obtain 12.94 g of the title compound having a sulfuric acid coloration positive with an Rf value of 0.55 by silica gel TLC developed with toluene / acetone (3/1). Since this compound was unstable, it was immediately subjected to the next reaction.

NMR (CDCl ₃ ); representing only the main peak δ; 0.16 [9H, s, Si (CH ₃ ) ₃ ], 0.88 (3H, d, J = 7.3Hz, H-18), 0.
92 (3H, t, J = 7.3Hz, H-17), 1.02 (3H, d, J = 6.6Hz, H-21), 1.1
8 (3H, d, J = 6.2Hz, H-6 ″), 1.35 (3H, d, J = 5.9Hz, H-6 ′),
1.69 (3H, d, J = 0.7Hz, H-22), 2.04 (3H, s, OCOCH ₃ -2 '), 2.
39 (6H, s, N (CH ₃ ) ₂ -3 '), 2.93 (1H, t, J = 10.3Hz, H-3'), 3.
10 (3H, s, OMs), 3.14 (3H, s, OMs), 3.28 (1H, dd, J = 9.5 & 2.6H
z, H-4 ″), 3.47 (3H, s, OCH ₃ -2 ″), 3.59 (3H, s, OCH ₃ -3 ″),
4.22 (1H, t, J = 9.9Hz, H-4 ′), 4.57 (1H, d, J = 7.7Hz, H-1
″), 4.60 (1H, br, H-1 ′), 4.75 (1H, br, H-3), 4.93 (1H,
m, H-15), 4.96 (1H, m, H-20), 5.03 (1H, dd, J = 10.3 & 8.0Hz,
H-2 ′), 5.47 (1H, d, J = 11.0Hz, H-13), 5.54 (1H, d, J = 15.8
Hz, H-10), 6.34 (1H, d, J = 15.8Hz, H-11) FAB-MS; 1130 (M + H) ⁺ 2 ', 4 "-di-O-acetyl-3,4'-di- Production of O-methanesulfonyldesmycosin 9,20-bis (ethylene acetal)

[0049]

[Chemical 19]

2 ', 4 "-di-O-acetyldesmycosin 9,20-bis (ethylene acetal) 109 mg
(0.115 mmol) was dissolved in 0.5 ml of toluene, 80.2 ml (0.575 mmol) of triethylamine was added, and then 31.2 ml (0.403 mmol) of methanesulfonyl chloride was added under ice-cooling, and 1 at the same temperature. Allowed to react for 5 hours. 10 ml of ethyl acetate was added to the reaction solution, 10 ml of 5% sodium hydrogen carbonate solution and 10 ml of saturated saline solution.
After washing with, it was dried over anhydrous sodium sulfate. The organic layer was concentrated to dryness under reduced pressure to give 134 mg of the title compound positive for sulfuric acid coloration with an Rf value of 0.64 on silica gel TLC developed with toluene / acetone (2/1). Since this compound was unstable, it was immediately subjected to the next reaction.

NMR (CDCl ₃ ); showing only main peaks δ; 0.88 (3H, d, J = 7.3Hz, H-18), 0.93 (3H, t, J = 7.3Hz, H-1)
7), 1.03 (3H, d, J = 6.6Hz, H-21), 1.17 (3H, d, J = 6.2Hz, H-6
″), 1.36 (3H, d, J = 5.9Hz, H-6 ′), 1.70 (3H, s, H-22),
2.04 (3H, s, OCOCH ₃ ), 2.11 (3H, s, OCOCH ₃ ), 2.40 [6H, s, N (C
_{H 3) 2 -3 '],} 2.84 (1H, m, H-14), 2.94 (1H, t, J = 10.3Hz, H-3
′), 3.04 (1H, dd, J = 2.9 & 8.1Hz, H-2 ″), 3.10 (3H, s, OM
s), 3.12 (3H, s, OMs), 3.46 (3H, s, OCH ₃ -2 ″), 3.52 (3H, s,
OCH ₃ -3 ″), 4.22 (1H, t, J = 9.9Hz, H-4 ′), 4.45 (1H, dd, J =
2.6 & 9.9Hz, H-4 ″), 4.60 (1H, d, J = 8.1Hz, H-1 ″), 5.03 (1
H, dd, J = 10.3 & 7.7Hz, H-2 ′), 5.46 (1H, d, J = 10.6Hz, H-1
3), 5.55 (1H, d, J = 15.6Hz, H-10), 6.35 (1H, d, J = 15.6Hz, H-
11) FAB-MS; 1100 (M + H) ⁺ 2'-O-acetyl-3,4'-di-O-benzylsulfonyl-4 "-O-trimethylsilyl-desmycosin 9,20-bis (ethylene acetal)

[0052]

[Chemical 20]

1.0 g (1.03 mmol) of 2'-O-acetyl-4 "-O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal) was dissolved in 10 ml of toluene, and then 0.46 ml (3.4 mmol) of triethylamine. ) Is added -1
Cooled to 5 ° C. To this solution was added benzylsulfonyl chloride (430 mg, 2.3 mmol), and the mixture was reacted at -10 ° C for 1.5 hours. Toluene (40 ml) was added to the reaction solution, and the organic layer was washed with water (50 ml), 5% sodium hydrogen carbonate solution (50 ml) and 10% brine (50 ml), and dried over anhydrous sodium sulfate. When the organic layer was evaporated to dryness under reduced pressure, 1.34 g of the title compound positive with sulfuric acid coloration was obtained by silica gel TLC developed with toluene / acetone (4/1) and an Rf value of 0.57. Since this compound was unstable, it was immediately subjected to the next reaction.

NMR (CDCl ₃ ); representing only the main peak δ; 0.16 (9H, s, Si (CH ₃ ) ₃ ), 0.81 (3H, d, J = 7.3Hz, H-18), 0.
94 (3H, t, J = 7.3Hz, H-17), 1.01 (3H, d, J = 6.6Hz, H-21), 1.1
8 (3H, d, J = 6.2Hz, H-6 ″), 1.31 (3H, d, J = 6.2Hz, H-6 ′),
1.69 (3H, d, J = 0.7Hz, H-22), 1.99 (3H, s, OCOCH ₃ -2 '), 2.
47 (6H, s, N ( CH 3) 2 -3 '), 2.94 (1H, t, J = 10.3Hz, H-3'), 3.
29 (1H, dd, J = 9.2 & 2.6Hz, H-4 ″), 3.47 (3H, s, OCH ₃ -2 ″), 3.
59 (3H, s, OCH ₃ -3 ″), 4.33 (1H, t, J = 9.9Hz, H-4 ′), 4.40 (1
H, brd, J = 15.0Hz, OSO ₂ C H Hph), 4.51 (1H, m, H-1 ′), 4.53
(2H, m, OSO ₂ CH ₂ ph), 4.57 (1H, m, SO ₂ CH H ph), 4.58 (1H, d, J
= 8.1Hz, H-1 ″), 4.87 (1H, br, H-3), 4.97 (1H, m, H-15),
5.03 (1H, dd, J = 10.3 & 7.7Hz, H-2 ′), 5.50 (1H, d, J = 10.6Hz,
H-13), 5.55 (1H, d, J = 15.8Hz, H-10), 6.36 (1H, d, J = 15.8H
z, H-11), 7.36-7.42 (10H, m, ph x2) FAB-MS; 1282 (M + H) ⁺ 2'-O-acetyl-4'-deoxy-4'-iodo-
Production of 3-O-methanesulfonyl-4 ″ -O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal)

[0055]

[Chemical 21]

2'-O-acetyl-3,4'-di-O-
Methanesulfonyl-4 ″ -O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal) 12.
94 g (11.5 mmol) was dissolved in 60 ml of methyl ethyl ketone, 2.58 g (17.2 mmol) of sodium iodide was added, and the mixture was reacted in the dark at 85 ° C. for 1 hour. After cooling the reaction solution to room temperature, the precipitate was filtered off. The precipitate was washed with 5 ml of toluene. Wash solution and mother liquor are combined and concentrated under reduced pressure. Toluene 60 ml
And 60 ml of water were added for liquid separation. The organic layer was washed with 40 ml of 10% sodium thiosulfate and 40 ml of water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. 10.73 g of a color-positive title compound was obtained.

UV (MeOH) λmax; 235nm IR (KBr) νmax; 3443,2973,2940,2886,1746,1360,1233,1
173,1101,1049,966,909,882,843 cm ^-1 NMR (CDCl ₃ ); represents only the main peak δ; 0.16 (9H, s, Si (CH ₃ ) ₃ ), 0.89 (3H, d, J = 7.3Hz, H- 18), 0.
92 (3H, t, J = 7.3Hz, H-17), 1.02 (3H, d, J = 7.0Hz, H-21), 1.1
8 (3H, d, J = 6.2Hz, H-6 ″), 1.51 (3H, d, J = 5.9Hz, H-6
′), 1.69 (3H, d, J = 0.7Hz, H-22), 2.02 (3H, s, OCOCH ₃ -2
′), 2.42 (6H, s, N (CH ₃ ) ₂ -3 ′), 3.12 (3H, s, OMs-3), 3.
47 (3H, s, OCH ₃ -2 ″), 3.59 (3H, s, OCH ₃ −3 ″), 4.57 (1H, d,
J = 8.1Hz, H-1 ″), 4.57 (1H, br, H-1 ′), 4.77 (1H, br, H-3),
4.91 (1H, dd, J = 9.9 & 7.3Hz, H-2 ′), 4.93 (1H, m, H-15), 4.
98 (1H, br, H-20), 5.47 (1H, d, J = 10.6Hz, H-13), 5.54 (1H,
d, J = 15.8Hz, H-10), 6.34 (1H, d, J = 15.8Hz, H-11) FAB-MS; 1162 (M + H) ⁺ 2 ', 4 "-di-O-acetyl-4' -Deoxy-4 '
-Iodo-3-O-methanesulfonyl desmycosin
Production of 9,20-bis (ethylene acetal)

[0058]

[Chemical formula 22]

2 ', 4 "-di-O-acetyl-3,4'
-Di-O-methanesulfonyl desmycosin 9,20
-Bis (ethylene acetal) 134mg (0.115mmo
l) was dissolved in 1 ml of methyl ethyl ketone, 25.7 mg (0.173 mmol) of sodium iodide was added, and the mixture was heated under reflux for 30 minutes. Ethyl acetate (10 ml) was added to the reaction mixture, which was washed with 5% aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (10 ml), and dried over anhydrous sodium sulfate. Residue 12 obtained by concentrating the organic layer under reduced pressure
When 8 mg was purified by preparative silica gel TLC developed with toluene / acetone (3/1), the Rf value was 0.6 on the same developed TLC.
Sulfate color-positive title compound was 2 ', 4 "-di-O- in 1
From acetyl-3,4'-di-O-methanesulfonyldesmycosin 9,20-bis (ethylene acetal), 134 mg was obtained in a yield of 72% in 2 steps.

UV (MeOH) λmax; 234nm IR (KBr) νmax; 2975,2938,2884,1740,1377,1233,1171,1
088,1049,963,909cm ^-1 NMR (CDCl ₃ ); showing only the main peak δ; 0.89 (3H, d, J = 7.3Hz, H-18), 0.92 (3H, t, J = 7.3Hz, H- 1
7), 1.02 (3H, d, J = 6.6Hz, H-21), 1.17 (3H, d, J = 5.9Hz, H-
6 ″), 1.51 (3H, d, J = 5.9Hz, H-6 ′), 1.70 (3H, s, H-22), 2.
02 (3H, s, OCOCH ₃ ), 2.11 (3H, s, OCOCH ₃ ), 2.42 (6H, s, N (C
H ₃ ) ₂ -3 ′), 3.04 (1H, dd, J = 2.9 & 8.1Hz, H-2 ″), 3.12 (3
H, s, OMs-3), 3.46 (3H, s, OCH ₃ -2 ″), 3.52 (3H, s, OCH _3-
3 ″), 4.47 (1H, dd, J = 2.9 & 11.7Hz, H-4 ″), 4.60 (1H, d, J =
8.1Hz, H-1 ″), 5.46 (1H, d, J = 11.0Hz, H-13), 5.55 (1H, d,
J = 15.4Hz, H-10), 6.35 (1H, d, J = 15.4Hz, H-11) FAB-MS; 1134 (M + H) ⁺ 2'-O-acetyl-3-O-benzylsulfonyl-
Production of 4'-deoxy-4'-iodo-4 "-O-trimethylsilyl-desmycosin 9,20-bis (ethylene acetal)

[0061]

[Chemical formula 23]

2'-O-acetyl-3,4'-di-O-
Benzylsulfonyl-4 ″ -O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal) 1.
23 g (0.96 mmol) was dissolved in 10 ml of methyl ethyl ketone, 216 mg (1.4 mmol) of sodium iodide was added, and the mixture was reacted at 85 ° C. for 30 minutes in the dark. After cooling the reaction solution to room temperature, the precipitate was filtered off. The precipitate was washed with 5 ml of toluene. Wash solution and mother liquor are combined and concentrated under reduced pressure. Toluene 30 ml
And 30 ml of water were added for liquid separation. The organic layer is saturated sodium bicarbonate water 3
After washing with 0 ml and 10% brine 30 ml, drying over anhydrous sodium sulfate and concentrating to dryness under reduced pressure, silica gel TLC developed with toluene / acetone (4/1) gave an Rf value of 0.51 and the title compound was a sulfuric acid color-positive compound. 1.22 g was obtained.

UV (MeOH) λmax; 235 nm IR (KBr) νmax; 3488,2938,2886,1748,1456,1373,1233,1
171,1101,1049,968,882 cm ^-1 NMR (CDCl ₃ ); represents only the main peak δ; 0.17 (9H, s, Si (CH ₃ ) ₃ ), 0.81 (3H, d, J = 7.3Hz, H- 18), 0.
93 (3H, t, J = 7.3Hz, H-17), 1.01 (3H, d, J = 6.6Hz, H-21), 1.1
8 (3H, d, J = 6.2Hz, H-6 ″), 1.49 (3H, d, J = 5.5Hz, H-6 ′),
1.68 (3H, s, H-22), 1.97 (3H, s, OCOCH ₃ -2 ′), 2.41 (6H,
_{s, N (CH 3) 2} -3 '), 2.78 (1H, t, J = 10.3Hz, H-3'), 3.48 (3H,
s, OCH ₃ -2 ″), 3.59 (3H, s, OCH ₃ -3 ″), 4.40 (1H, m, H-
1 '), 4.40 (1H, m, OSO ₂ C H Hph), 4.58 (1H, d, J = 8.1Hz, H-1
″), 4.58 (1H, m, OSO ₂ CH H ph), 4.87 (1H, dd, J = 9.9 & 7.7H
z, H-2 ′), 4.96 (1H, m, H-15), 5.51 (1H, d, J = 11.4Hz, H-1
3), 5.54 (1H, d, J = 15.8Hz, H-10), 6.36 (1H, d, J = 15.8Hz, H-
11), 7.40 (5z, s, ph) FAB-MS; 1238 (M + H) 2'-O-acetyl-3,4'-dideoxydesmycosin 9,20-bis (ethylene acetal)

[0064]

[Chemical formula 24]

2'-O-acetyl-4'-deoxy-
4'-iodo-3-O-methanesulfonyl-4 "-O-
Trimethylsilyldesmycosin 9,20-bis (ethylene acetal) 10.70 g (9.2 mmol) was dissolved in 50 ml of methanol to obtain potassium carbonate 3.82 g (27.6 mmo).
l), followed by Raney Nickel (Kawaken Fine Chemicals Co. NDT-65) wet weight 6.4 g (5 ml) methanol 8 ml
The suspension was added, and catalytic reduction was carried out at a hydrogen pressure of 3 kg / cm ^{2 for} 2 hours. The catalyst was filtered off through Celite and the mother liquor was concentrated under reduced pressure. 100 ml of ethyl acetate and 100 ml of water were added to the residue and the layers were separated. The organic layer was washed with 100 ml of 20% saline and then concentrated under reduced pressure. 0.86 ml of acetic anhydride was added to the concentrate and reacted at room temperature for 1.5 hours, then 30 ml of 5% sodium hydrogen carbonate solution and 30 ml of 20% saline solution.
Washed with. The organic layer was dried over anhydrous sodium sulfate and then dried under reduced pressure to give 7.46 g of the title compound having a sulfuric acid coloration positive with an Rf value of 0.44 by silica gel TLC developed with chloroform / methanol (10/1).

UV (MeOH) λmax; 235nm IR (KBr) νmax; 3476,2973,2938,2882,1744,1373,1238,1
167,1061,961 cm ^-1 NMR (CDCl ₃ ); represents only the main peak δ; 0.82 (3H, bd, J = 5.5Hz, H-18), 0.92 (3H, t, J = 7.3Hz, H-1
7), 1.00 (3H, d, J = 6.6Hz, H-21), 1.23 (3H, d, J = 6.2Hz, H-
6 ′), 1.26 (3H, d, J = 6.2Hz, H-6 ″), 1.35 (1H, m, H-4′a),
1.71 (1H, m, H-4′b), 1.73 (3H, d, J = 1.1Hz, H-22), 2.04
(3H, s, OCOCH ₃ -2 '), 2.26 (6H, s, N (CH ₃ ) ₂ -3'), 2.68 (1
H, ddd, J = 12.3 & 10.4 & 4.4Hz, H-3 ′), 3.18 (1H, br, H-4 ″),
3.48 (3H, s, OCH ₃ -2 ″), 3.61 (3H, s, OCH ₃ −3 ″), 4.31 (1
H, d, J = 7.7Hz, H-1 ″), 4.55 (1H, d, J = 7.7Hz, H-1 ″), 4.80
(1H, dd, J = 10.4 & 7.7Hz, H-2 ′), 4.90 (1H, m, H-15), 4.95
(1H, bt, J = 5.1Hz, H-20), 5.42 (1H, d, J = 10.6Hz, H-13), 5.6
2 (1H, d, J = 15.8Hz, H-10), 6.36 (1H, d, J = 15.8Hz, H-11) FAB-MS; 870 (M + H) ⁺ 2'-O-acetyl-3,4 Production of ′ -dideoxy-4 ″ -oxodesmycosin 9,20-bis (ethylene acetal)

[0067]

[Chemical 25]

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
= 15.8Hz, H-11) FAB-MS; 868 (M + H) ⁺ 3,4'-dideoxymycaminosyl tylonolide
Production of 9,20-bis (ethylene acetal)

[0070]

[Chemical formula 26]

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; 235nm 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) ⁺ 3,4'-dideoxymycaminosyl tylonolide

[0073]

[Chemical 27]

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. When this organic layer was evaporated to dryness under reduced pressure, 20 mg of sulfuric acid color-positive was found to have an Rf value of 0.25 on silica gel TLC developed with chloroform / methanol (5/1).
Was obtained.

UV (MeOH) λmax; 283 nm 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) ⁺

[0076]

According to the present invention, 3,4 'which is a useful intermediate for producing 3,4'-dideoxymycaminosyl tylonolide or a salt thereof useful as an antibacterial agent.
-A dideoxymycaminosyl tylonolide derivative,
3,4'-dideoxy mye, which can be efficiently produced from easily available tylosin and tylosin analogues (mycaminosyl tylonolide derivative, demycinosyl tylonolide derivative, etc.). It is extremely useful as an industrial method for producing caminosyl tylonolide or a salt thereof. Furthermore, according to the present invention, deoxygenation at the 4'-position can be carried out without using tributyltin hydride, which is industrially useful.

The compounds represented by the above general formula (V) are all novel.

 ─────────────────────────────────────────────────── ─── Continued 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, Kanagawa Hiyoshi Heights 207 (72) Inventor Hiroshi Tanaka 3-16-26-306 Owada, Chigasaki City, Kanagawa Prefecture (72) Inventor Takeo Yoshioka 1959, Kamishitatan, Ayase City, Kanagawa Prefecture 3-3102 Green Heights

Claims (4)

[Claims] 1. The following general formula (II): (In the formula, A represents a protected carbonyl group, B represents a protected aldehyde group, R ¹ represents an optionally protected hydroxyl group, R ² represents a hydrogen atom or a lower alkanoyl group, and R 2 ³ represents a sulfonic acid residue and X represents a halogen atom), and includes a step of reducing the compound represented by the following general formula (I): (Wherein A, B and R ¹ have the same meanings as described above), and a method for producing a 3,4′-dideoxymycaminosyl tylonolide derivative. 2. The following general formula (IV): (Wherein A represents a protected carbonyl group, B represents a protected aldehyde group, R ¹ represents an optionally protected hydroxyl group, and R ² represents a hydrogen atom or a lower alkanoyl group). By reacting the indicated mycaminosyl tylonolide derivative with a sulfonylating agent, the following general formula (III)
: [Chemical 4] (In the formula, A, B, R ¹ and R ² have the same meanings as described above, and R ³ represents a sulfonic acid residue); a process of producing the compound represented by the formula (III) A method comprising reacting a compound with a halogenating agent to obtain a compound represented by the general formula (II) according to claim 1; and reducing the compound represented by the formula (II) under alkaline conditions. 1. A method for producing a 3,4′-dideoxymycaminosyltylonolide derivative represented by the general formula (I) according to 1. 3. A compound represented by the general formula (II) according to claim 1 is reduced to a compound represented by the general formula (I) according to claim 1, and the protecting group is removed. The method for producing the compound represented by the general formula (VI) according to claim 2. 4. A compound represented by the formula: General formula (V): [wherein A represents a protected carbonyl group, B represents a protected aldehyde group, Y represents a hydrogen atom, a substituted sulfonyloxy group, or a halogen atom, and W represents hydrogen. An atom or a substituted sulfonyloxy group, R ⁴ represents a hydrogen atom or a lower alkanoyl group, Z
Is CHOH, CHOR ⁵ (wherein R ⁵ represents a hydroxyl-protecting group), or C═O], and 3,4′-dideoxy represented by the general formula (I) according to claim 1. Production intermediate of mycaminosyl tylonolide derivative.