JPH0567156B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides a novel tin-containing 16-membered ring macrolide system that is useful as an intermediate in a method for selectively acylating or alkylating the 4''-OH group in the disaccharide residue at the 5-position of a 16-membered ring macrolide system. Regarding compounds. 16-membered ring macrolide antibiotics such as tylosin, leucomycin, and spiramycin have excellent antibacterial activity and are widely used as pharmaceuticals, veterinary drugs, feed additives, etc. However, Macrolide antibiotics produced by fermentation generally have a low ability to be absorbed and excreted in the body, and due to the emergence of resistant bacteria due to general use, macrolide antibiotics produced by fermentation cannot be used chemically or biologically. Derivatives with excellent absorption and excretion ability and/or antibacterial activity against resistant bacteria are being actively researched by conversion methods.For example, in the case of tylosin, the disaccharide residue at the 5-position It has been found that derivatives in which the 4″-OH group is acylated have excellent antibacterial activity against macrolide-resistant bacteria, and also have improved absorption and excretion ability in vivo. However, tylosin has the following formula

As shown in [Chemical formula], it has a total of four reactive hydroxyl groups at each of the 3-, 2'-, 4''-, and 41-positions, and selectively only the 4''-OH group. It is not easy to acylate. Conventionally, this 4"-OH acylation method uses a bacterial cell producing carbomycin, which is a type of 16-membered ring macrolide antibiotic. Biochemical methods for selectively acylating
50-158388). In addition, from the viewpoint that it is difficult to introduce acyl groups other than lower alkanoyl groups by such biochemical methods, it is difficult to introduce acyl groups other than lower alkanoyl groups.
After stepwise protecting the hydroxyl group at the position with an acyl group that can be easily removed, a desired acyl group is introduced into the hydroxyl group at the 4″ position,
A method of partially removing the acyl group, which is difficult to remove and is easy to remove, is known (for example, Japanese Patent Application No. 137982/1982;
(See Publication No. 54-70291). However, as mentioned above, the types of acyl groups that can be introduced are limited in the former method, and on the other hand, the latter method requires multiple hydroxyl group protection steps, making it difficult to obtain the desired product in high yield. The present inventors have discovered that tylosin does not have such drawbacks.
As a result of intensive research on selective acylation of 4″-OH, we found that when the hydroxyl groups at the 3″- and 4″-positions are acetalized with dibutyltin oxide and then acylated,
By simply protecting the 2′-position hydroxyl group, the 3-position and 4-position
It is possible to selectively acylate the 4″-position hydroxyl group in good yield without protecting the −-position hydroxyl group, and this 3″,4″-dibutyltin acetalization method is applicable not only to tylosin but also to tylosin. , that it can be applied to other 16-membered ring macrolide antibiotics that have a disaccharide residue similar to tylosin at the 5-position, and that this 3″,4″-dibutyltin acetalization method can be used only for acylation. First, the present inventors discovered that the present invention can be applied to alkylation of 4''-OH, which could not be done conventionally, and completed the present invention. According to the present invention, the following formula is present at the 5-position:

[Chemical formula] In the formula, R ¹ represents a hydrogen atom or a hydroxyl group protected with an easily removable protecting group. A tin-containing 16-membered ring macrolide compound having a disaccharide residue represented by the formula R ² X In the formula, R ² represents a substituted or unsubstituted alkyl group or acyl group, and X represents a halogen atom.

Provided is a method for producing a 16-membered ring macrolide compound having a disaccharide residue represented by the following formula: wherein R ² has the above meaning. In this specification, "16-membered ring macrolide compound" refers to the following formula:

The basic skeleton is a 16-membered lactone ring represented by the formula,
It means a macrocyclic compound having a substituent on a ring carbon atom depending on the fermentation production source or a chemically or biologically converted substituent thereof. Many such 16-membered ring macrolide compounds have been known for a long time and have been introduced in many academic documents and patent publications. The following are representative examples. Carbomycin, leucomycin, spiramycin, nidamycin, deltamycin, diyosamycin, calcomycin, espinomycin, reromycin, midecamycin, maridomycin,
B-58941, neutramycin, angoramycin, tylosin, silamycin, rosamicin [e.g., Omura et al., Journal of Antibiotics, 28 , 401 (1975)]
and 23-deoxydemycinosyltylosin, demycinosyltylosin (e.g., JP-A-57-
(see Publication No. 31699). In the method of the present invention, in the above-mentioned 16-membered ring macrolide compound, particularly at the 5-position, the following formula is used.

[Chemical formula] In the formula, R ¹ ' represents a hydrogen atom or a hydroxyl group. A 16-membered ring macrolide compound having a disaccharide residue represented by, for example, leucomycin U, spiramycin, angoramycin, deltamycin, maridomycin , tylosin, 23-deoxydemysinosyltylosin, demysinosyltylone, derivatives thereof, and the like. That is, according to the present invention, a 16-membered ring macrolide compound having a disaccharide residue represented by the above formula (B) at the 5-position, when R ¹ ' in the above formula (B) is a hydroxyl group, After protecting the hydroxyl group in advance with a protecting group that can be easily removed, the OH at the 3″- and 4″-positions of the disaccharide residue represented by the above formula (B) is converted to dibutyltin acetalization to obtain the following formula:

[Chemical Formula] ^A 16-membered ring macrolide compound having a 3″,4″-dibutyltin acetalated disaccharide residue at the 5-position, represented by By acylating or alkylating ^this with a halide represented by the following formula R ²
OH at the 4″-position can be converted to OR ² in good yield and selectively. In the disaccharide residue of formula (B), the OH at the 2′-position
When R ¹ ′ is a hydroxyl group, the protecting group is:
Any protecting group that can be removed by hydrolysis or alcoholysis can be used, and specific examples include the following. (1) Acyl group: For example, a linear or cyclic alkanoyl group such as acetyl, propionyl, butyryl, cyclohexanecarbonyl; haloalkanoyl group such as chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, trifluoroacetyl; phenoxy Aryloxy (or thio)alkyl groups such as acetyl, phenylthioacetyl, p-methoxyphenoxyacetyl, p-chlorophenoxyacetyl; arylcarbonyl groups such as benzoyl, p-nitrobenzoyl, natatyl. (2) Silyl group: e.g. trimethylsilyl, tert
- trialkylsilyl groups such as butyldimethylsilyl; triarylsilyl groups such as triphenylsilyl; trialkylsilyl groups such as tribenzylsilyl. Dibutyltin acetalization of the 3″- and 4″-OH of the disaccharide residue of formula (B) in which any 2′-OH that may exist is protected, converts the disaccharide residue of formula (B) into a 5- This can be carried out by treating a macrolide compound having a position with dibutyltin oxide. The treatment is carried out in a suitable solvent, for example, an aromatic hydrocarbon such as benzene, toluene, xylene, etc.; a halogenated hydrocarbon such as carbon tetrachloride, chloroform, etc., at a temperature ranging from about 50°C to the reflux temperature of the solvent, preferably a solvent. This is done by heating to the reflux temperature of . Since the reaction between the macrolide compound and dibutyltin oxide is a dehydration reaction, it is convenient to carry out the reaction using a solvent capable of azeotroping with water while removing water from the reaction system by azeotropy. The amount of dibutyltin oxide to be used is not strictly limited, but it is generally appropriate to use it within the range of 1.0 to 5.0 mol, preferably 1.2 to 3.0 mol, per mol of the macrolide compound. Thus, tin having a 3″,4″-dibutyltin acetalized disaccharide residue at the 5-position represented by the above formula (C)
A 16-membered ring macrolide compound is produced. this tin
The 16-membered ring macrolide compound can be isolated, but generally it can be directly reacted with the halide of formula () without being isolated. The tin-containing 16-membered ring macrolide compound represented by the above formula (C) having a 3″,4″-dibutyltin acetalized disaccharide residue at the 5-position is a novel compound that has not been described in conventional literature. , 4″-position acylation or alkylation 16
It is useful as an intermediate for producing ring-membered macrolide compounds. Therefore, a suitable group of such new tin-containing 16-membered ring macrolide compounds includes the following formula:

[Chemical formula] In the formula, R ¹ represents a hydrogen atom or a hydroxyl group protected with an easily removable protecting group, and R ³ and R ⁴
one represents a hydrogen atom and the other represents a hydroxyl group or a D-fluorosamino group, or R ³ and R ⁴
together represent an oxo group, R ⁵ represents a hydrogen atom or a methyl group, R ⁶ and R ⁷ together represent a single bond or -O-, R ⁸ represents a hydrogen atom, a methyl group, a hydroxy group, Methyl group, lower alkanoyloxymethyl group or formula

[Chemical formula] (Here, R ¹² represents a hydrogen atom or a hydroxyl group which may be appropriately protected with an easily removable protecting group), R ⁹ represents a methyl group or an ethyl group, and R ¹⁰ represents a hydroxyl group or a lower alkanoyloxy group,
Included are tin-containing 16-membered ring macrolide compounds represented by the following, in which R ¹¹ represents a methyl group or a methoxy group. In addition, the term "lower" used in the present invention means that the number of carbon atoms of the atom or compound to which this term is attached is 6 or less, preferably 4 or less. A 16-membered ring macrolide compound having a 3″,4″-dibutyltin acetalized disaccharide residue at the 5-position represented by the above formula (C), such as a compound of the above formula () and a halide of the above formula () The reaction with is generally carried out in a suitable solvent, such as aromatic hydrocarbons such as Γbenzene, toluene, and xylene; halogenated hydrocarbons such as Γmethylene chloride and chloroform; ethereal solvents such as Γdiethyl ether, tetrahydrofuran, and dioxane. ; Aprotic polar solvents such as Γ acetonitrile and dimethylformamide; ester solvents such as Γ ethyl acetate and butyl acetate. can. The amount of halide used in formula () is not strictly limited and can be varied over a wide range depending on the type of halide.
Generally 1 per mole of 16-membered ring macrolide compound
It is convenient to use within the range from 1.1 to 3 mol, preferably from 1.1 to 3 mol. In the compound of formula () used as an acylating agent or alkylating agent in the above reaction, the "alkyl group" represented by R ² is of any type, linear, branched or cyclic. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, etc. Among them, those having up to 6 carbon atoms, especially lower alkyl groups, are preferred. This alkyl group may further have at least one of its hydrogen atoms substituted with another atom or atomic group, and possible substituents include halogen atoms such as chlorine and fluorine; alkoxy groups; acyloxy groups; optionally a furanyl, thiophenyl, phenoxy or phenylthio group; an optionally substituted alkanoyl group;
Aryl group that may be substituted; optionally substituted pyridyl, pyranyl, piperidino, piperazino, morpholino, pyrrolidino, triazolyl, tetrazolyl, indolino, imidazolyl,
Heterocyclic groups such as pyrimidyl, thiazolyl, and phthaloyl are mentioned, and the substituents in the above-mentioned substituents that may be substituted include, for example, chlorine, fluorine, methoxy, ethoxy, phenoxy,
Examples include phenylthio, methoxycarbonyl, nitro, phenyl, lower alkyl, and cycloalkyl. Thus, specific examples of "substituted alkyl groups" include: methoxymethyl, ethoxymethyl, methoxyethoxymethyl,
Phenoxymethyl, benzyl, methoxybenzyl, nitrobenzyl, methylbenzyl, acetylbenzyl, methylthiobenzyl, fluorobenzyl, chlorobenzyl, cyclohexanemethyl, pyridylmethyl, imidazolylmethyl, morpholinomethyl, furanylmethyl, indolinomethyl, thiophenylmethyl, benzoylmethyl , p-methylbenzoylmethyl, p-methoxybenzoylmethyl, p-nitrobenzoylmethyl, cyclohexanecarbonylmethyl, thenoylmethyl, furancarbonylmethyl, benzylcarbonylmethyl,
p-methylbenzylcarbonylmethyl, pyridylmethylcarbonylmethyl, furanylmethylcarbonylmethyl, phenylethyl, pyridylethyl,
Furanylethyl, thiophenylethyl, imidazolylethyl, indolinoethyl groups, etc. On the other hand, the "acyl group" represented by ^R2 includes _a group represented by the formula ^R20CO- or ^R21SO2- . Here, R ²⁰ and R ²¹ are residues of organic carboxylic acid and organic sulfonic acid, respectively, and specifically, methyl, ethyl, propyl, n-propyl, isopropyl, trifluoromethyl, n-butyl, sec-butyl , isobutyl, tert-butyl,
Fluoro-n-butyl, fluoroisobutyl, n
-pentyl, isopentyl, iclopentyl, n
-alkyl or haloalkyl groups such as hexyl, isohexyl; cycloalkyl groups such as phenylsulfonylmethyl; cycloalkyl-alkyl groups such as cyclohexylethyl; Aryl that may be present;
Benzyl, α-methylbenzyl, α-ethylbenzyl, phenylethyl, naphthylethyl, o,p
-dichlorophenylmethyl, α-acetoxybenzyl, α-acetoxyphenethyl, p-nitrobenzyl, o-fluorobenzyl, p-fluorobenzyl, (p-acetylphenyl)methyl, (p-
Optionally substituted aralxy groups such as methylthiophenyl)methyl, (p-methylsulfonylphenyl)methyl, (p-methoxyphenyl)methyl, and (p-benzoylphenyl)methyl; aralkenyl groups such as styryl; phenoxymethyl,
Aryloxyalkyl groups such as 1-phenoxyethyl and naphthoxymethyl; phenylthiomethyl,
Arylthioalkyl groups such as phenylthioethyl; pyridyl, pyridylmethyl, pyridylethyl, pyridylthiomethyl, pyridylthioethyl,
Examples include heterocyclic groups such as furanyl, furanylmethyl, thiophen-2-yl, thiophen-3-yl, imidazolylmethyl, tetrazolylmethyl, and morpholinomethyl. Also, "halogen atom" represented by X
Included are chlorine, bromine and iodine atoms. Therefore, the following can be exemplified as halides of formula () that can be particularly preferably used: acetyl chloride, propionyl chloride, fluoroisobutyryl chloride, benzoyl chloride, cyclohexanecarbonyl chloride, methoxy Methyl chloride, benzyl bromide, phenyl acetate chloride, p-methoxyphenylacetate chloride, p-acetylphenylacetate chloride, p-fluoroacetate chloride, pyridylacetate chloride, phenoxyacetate chloride, nicotinyl bromide, tetrazolylacetate chloride, pyridylpropion Acid chloride, furanyl acetate chloride, p-methoxybenzyl bromide, p-methoxyphenacyl bromide, (p-acetyl)benzyl bromide, (furanylmethylcarbonyl)methyl bromide, thenoylmethyl bromide, (furanylethylcarbonyl)
Methyl bromide, (benzylcarbonyl)methyl bromide, [(p-methoxyphenyl)ethyl]carbonylmethyl bromide, [(p-acetylbenzyl)carbonyl]methyl bromide, trifluoromethanesulfonyl chloride, methanesulfonyl chloride, toluenesulfonyl chloride, p -Fluorophenylsulfonyl chloride, etc. By the method of the present invention described above, the following formula

[Chemical formula] In the formula, R ¹ and R ² have the above-mentioned meanings. A 16-membered ring macrolide compound having a disaccharide residue represented by the following at the 5-position is produced in good yield, and this compound has the same meaning as above. Methods known per se, for example Tsuchiya [Journal of Antibiotics (J.
Antibiotics) 35 , 661 (1982)]. In the above formula (D), when R ¹ represents a protected hydroxyl group, the protecting group can be removed by hydrolysis or alicholysis (for example, methanol lysis) by a conventional method, if necessary. 4″-acylated 16-membered ring macrolide compound produced by the method of the present invention (16-membered ring macrolide having a disaccharide residue of formula (D) in which R ² is an acyl group at the 5-position) Compounds) have excellent antibacterial activity against macrolide-resistant bacteria, and are also characterized by excellent absorption and excretion ability in vivo [for example, Journal of Antibiotics 33 , 1309 (1980)] On the other hand, a 4″-substituted or unsubstituted alkylated 16-membered ring macrolide compound (a disaccharide residue of formula (D) in which R ² is a substituted or unsubstituted alkyl group) -16-membered ring macrolide compound)
is a new compound that has not been described in conventional literature, and is promising as a macrolide antibacterial agent that exhibits antibacterial activity against macrolide-resistant bacteria that is not degraded even by in vivo eslatase (antibacterial activity test data described later). reference). Next, the present invention will be further explained with reference to Examples. Example 1 Production of 2′-O-acetyl-3″,4″-O-dibutylstanylentylosin

[Chemical] 2'-O-acetyltylosin 1.0g (1.05mmol)
and 260 mg (1.05 mmol) of dibutyltin oxide were suspended in 50 ml of toluene and heated under reflux for 3 hours while water produced in a Dean-Stark condenser was azeotropically removed with toluene. After cooling, 1.24 g of 2'-O-acetyl-3'',4''-O-dibutylstanylentylosin was obtained by concentrating to dryness. IR (KBr) cm ^-1 , 2940, 2915, 2720, 1748,
1720, 1680, 1592, 1232, 1165, 1062, 670 NMR (CKCl ₃ ) δ0.89−1.02 (m, CH ₃ ), 1.80
(3H, s, 12−CH ₃ ), 2.06 (S, 2′OCOCH ₃ ),
3.50 (3H, s, 2 OCH ₃ ), 3.63 (3H, s, 3
OCH ₃ ), 4.56 (1H, d, J _{1 ,2} = 7.5HzH−
1), 5.91 (1H, d, J _13,14 = 10.5Hz, H-
13), 6.28 (1H, d, J _10,11 = 15.5Hz, H-10),
7.34 (1H, d, H-11), 9.70 (1H, CHO) Example 2 Production of 2′-O-acetyl-4″-O-(p-methoxyphenylacetyl)tylosin

[Chemical] Add p- to 10ml of a reaction solution of 2'-O-acetyl-3'',4''-O-dibutylstanylenetylosin (1.6g molar ratio: 2'-O-acetyltylosin/dibutyltin oxide = 1/2.5). A solution of 355 mg of methoxyphenylacetyl chloride in 20 ml of toluene (1.88 mmol) was added dropwise at room temperature over 15 minutes, and the mixture was further stirred at the same temperature for 1 hour. The reaction solution was placed in an ice block and stirred for 30 minutes, then 200 ml of ethyl acetate and an aqueous sodium bicarbonate solution were added, and the organic layer was separated, washed with an aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the residue was concentrated to dryness and subjected to column chromatography using 50 g of silica gel (developing solvent: benzene/acetone = 3/1).
The elution fractions showing sulfuric acid coloring at an Rf value of 0.34 were combined and concentrated under reduced pressure by silica gel TLC, and 2′-O-
Acetyl-4″-O-(p-methoxyphenylacetyl)tylosin 912 mg (yield 79%) was obtained. Physics of Γ2′-O-acetyl-4″-O-(p-methoxyphenylacetyl)tylosin Chemical properties NMR (CDCl ₃ )... Shows major peaks (same below) δ9.68 (1H, s, CHO), 7.23 (H, d, J = 9
Hz, aromatic ring), 6.82 (2H, d, J = 9Hz, aromatic ring), 6.27 (1H, d, J = 16Hz, H-10),
5.90 (1H, d, J=10.5Hz, H-13), 3.78
(3H, s, -OCH ₃ ), 3.64 (2H, s, -CH ₂
-), 3.61 (3H, s, 3-OCH ₃ ), 3.49
(3H, s, 2-OCH ₃ ), 2.40 (6H, s, N
( _CH3 ) ₂ ), 2.07(3H,s,2'- _OCOCH3 ),
1.79 (3H, s, 12-CH ₃ ) Example 3

[Chemical] Production of 4″-O-(p-methoxyphenylacetyl)tylosin 912 mg of 2′-O-acetyl-4″-O-(p-methoxyphenylacetyl)tylosin was added to methanol.
The solution was dissolved in 25 ml and heated under reflux for 16 hours. After cooling,
Concentrate to dryness and subject the residue to column chromatography on 40 g of silica gel (developing solvent: benzene acetone =
2/1), silica gel TLC developed with benzene/acetone (2/1), and the elution fractions showing sulfuric acid coloration at an Rf value of 0.25 were combined and concentrated under reduced pressure to obtain 4″-O-(p
-Methoxyphenylacetyl) tylosin crude powder (675 mg) was obtained. Dissolve 675 mg of coarse powder in 0 ml of toluene and adjust the pH
Acid inversion extraction was performed twice with 100 ml of 3.09 (1/50M sodium acetate-1/50N hydrochloric acid) buffer. The aqueous layer was adjusted to pH 5.0 with a 1N aqueous sodium hydroxide solution, extracted with 150 ml of ethyl acetate, and the organic layer was washed with an aqueous sodium carbonate solution and brine, and then dried over anhydrous sodium sulfate. After filtration, it was concentrated to dryness to obtain 631 mg. The obtained powder was dissolved in 6 ml of benzene and added dropwise to 30 ml of hexane while stirring. The resulting white precipitate was filtered by suction, washed with 5 ml of hexane, and then dried to obtain 608 mg (yield 55%) of 4″-O-(p-methoxyphenylacetyl)tylosin. M・W 1065 mp: 110~111℃ [α] ²⁴ _D : −43.6° (c1.0, CH ₃ OH) UV: λ ^CH ₃ ^OH _nax 284nm (ε19000) 227nm (ε 8700) IR: ν ^Kr _nax 1725cm ^-1 (ester, aldehyde ) 1675cm ^-1 (conjugated ketone) 1590cm ^-1 (double bond) NMR (CDCl ₃ ) The main peaks are shown below.

[Table] Example 4 Production of 2',4-di-O-trimethylsilyltyrosine

[Chemical] Tylosin 1.0g (1.09mmol) ethyl acetate 10
0.35 ml of toluethylamine, cooled and dissolved in ml
(2.51 mmol) was added thereto, and further 0.29 ml (2.29 mmol) of trimethylsilane chloride was added dropwise. reaction temperature
The temperature was increased to 10° and stirred for 24 hours. The reaction solution was diluted with ethyl acetate, washed with an aqueous sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate.
After filtration, 1.1 g of 2',4-di-O-trimethylsilyltylosin was obtained by concentrating and drying. NMR (CDCl ₃ ) δ 9.71 (1H, s, CHO), 6.28 (1H, d, 15.5Hz,
H-10), 5.95 (1H, d, 10.5Hz, H-13),
4.59 (1H, d, 8Hz, H-1), 3.60 (3H,
s, 3OCH ₃ ), 3.51 (3H, s, 2OCH ₃ ),
2.49 (6H, s, N(CH ₃ ) ₂ ), 1.80 (3H, s, 12
-CH ₃ ), 0.19 (9H, s, TMS), 0.15 (9H,
s, TMS) Example 5 2′,4-di-O-trimethylsilyl-3″,
Production of 4″-dibutylstanylentylosin

[Chemical formula] 1.1g (1.09mmol) of 2',4-di-O-trimethylsilyltyrosine and 271 dibutyltin oxide
mg (1.09 mmol) suspended in 50 ml of toluene,
The mixture was heated under reflux for 3 hours while water produced in a Dean-Stark condenser was azeotropically removed with toluene. The reaction solution was concentrated to dryness to give 2',4-di-O-
1.35 g of trimethylsilyl-3'',4''-O-dibutylstanylentylosin was obtained. IR (KBr), 2960, 2925, 1680, 1595, 675 NMR (CDCl ₃ ) δ 9.69 (1H, s, CHO), 6.28 (1H, d, 15.5
Hz, H-10), 5.96 (1H, d, 10.5Hz, H-
13), 4.60 (1H, d, 8Hz, H-1), 3.61
(3H, s, 3 OCH ₃ ), 3.51 (3H, s, 2
OCH ₃ ), 2.48 (6H, s, N (CH ₃ )), 1.80
(3H, s, 12・CH ₃ ), 1.05-0.84 (12H, m,
CH ₂ ), 0.18 (9H, s, TMS), 0.15 (9H,
s, TMS) Example 6 2',4-di-O-trimethylsilyl-O-
Production of (p-methoxyphenylacetyl)tylosin

[Chemical formula] 2',4-di-O-trimethylsilyltyrosine 1.1g (1.04mmol) and sibutyltin oxide 645
mg (2.59 mmol) suspended in 50 ml of toluene,
The reaction solution was concentrated to about 15 ml while heating under reflux for 3 hours while removing water produced by a Dean-Stark apparatus azeotropically with toluene. After cooling the reaction solution, p
-Methoxyphenylacetyl chloride 286mg/
A 20 ml toluene solution (1.55 mmol) was added dropwise at room temperature over 15 minutes, and the mixture was further stirred at the same temperature for 1 hour. The reaction solution was placed in an ice block and stirred for 30 minutes, then diluted with ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness.
1.51 g of a mixture of trimethylsilyl-4″-O-(p-methoxyphenylacetyl)tylosin and dibutyltin oxide was obtained. Example 7 Production of 4″-O-(p-methoxyphenylacetyl)tylosin

[Chemical] 2′,4-di-O-trimethylsilyl-4″-O
1.51 g of a mixture of -(p-methoxyphenylacetyl)tylosin and dibutyltin oxide was dissolved in 8 ml of dioxane, 3.1 ml of 1N hydrochloric acid was added dropwise, and the mixture was stirred at 10°C for 2 hours and at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and water, and the organic layer was removed. After washing the aqueous layer with toluene, the pH was adjusted to 6.0 with an aqueous sodium hydrogen carbonate solution and extracted with toluene. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give 4″-O-(p-methoxyphenylacetyl)tylosin 661 mg (yield
57%). The physical and chemical properties were the same as in Example 3. Example 8 Production of 2'-O-acetylleucomycin U

[Chemical] Dissolve 1.0 g (1.35 mmol) of leucomycin U in 3 ml of acetone, and add 0.27 ml of acetic anhydride under ice cooling.
(2.85 mmol) was added dropwise. The reaction temperature was returned to room temperature and stirred for 1.5 hours. Add ice cubes to the reaction solution and incubate for 30 minutes.
After stirring for a minute, the pH was adjusted to 9.40 with 25% aqueous ammonia and extracted with 110 ml of ethyl acetate. The organic layer was washed three times with brine and then dried over anhydrous sodium sulfate. After filtration, the residue was concentrated to dryness to obtain 1.05 g of 2'-O-acetyl leucomassin (yield: 99%). Example 9 Production of 2′-O-acetyl-4″-O-(methoxyphenylacetyl)leucomycin U

[Chemical] 2'-O-acetylleucomycin U1.0g
(1.27mmol) and dibutyltin oxide 793mg
(3.19 mmol) was suspended in 50 ml of toluene and heated under reflux for 3 hours while the water produced was azeotropically removed with the toluene using a Dean-Stark apparatus. The reaction solution was concentrated to about 15 ml. After cooling the reaction solution, a solution of 433 mg of p-methoxyphenylacetyl chloride in 20 ml of toluene (2.29 mmol) was added dropwise at room temperature over 15 minutes, and the mixture was further stirred at the same temperature for 1.5 hours. The reaction solution was placed in an ice block and stirred for 30 minutes, then washed with 200 ml of ethyl acetate, an aqueous sodium bicarbonate solution, and brine, and dried over anhydrous sodium sulfate. After filtration, the residue was concentrated to dryness and subjected to column chromatography using 50 g of silica gel (developing solvent: benzene/acetone = 3/1).
Ethyl acetate/acetone/methanol = (30/25/
20/10/8) Rf value by developed silica gel TLC
The elution fractions showing sulfuric acid coloration at 0.49 were combined and concentrated under reduced pressure to obtain 466 mg of 2′-O-acetyl-4″-O-(p-methoxyphenylacetyl)leucomycin U.
(yield 40%). Physicochemical properties of Γ2′-O-acetyl-4″-O-(p-methoxyphenylacetyl)leucomycin [α] ²⁴ _D −66.7° (C0.855, MeOH) UV λ ^MeOH _nax 230nm, E1% 1cm=319 Rf 0.49 (n-hexane/benzene/ethyl acetate/acetone/methanol=30/25/20/
10/8) NMR (CDCl ₃ ) δ 9・67 (1H, CHO), 7.23 (2H, d, J=10
Hz, aromatic ring), 6.89 (2H, d, J = 10Hz, aromatic ring), 6.02 (1H, dd, H-12), 5.60 (1H, dd,
H-10), 4.61 (1H, d, J=9Hz, H-1'),
4.57 (1H, d, J=10Hz, H-4″), 3.79 (3H,
s, -OCH ₃ ), 3.64 (2H, s, -CH ₂ -), 3.49
(3H, s, 4-OCH ₃ ), 2.41 (6H, s, 3′-N
( _CH3 ) ₂ ), 2.27 (3H,s,3- _OCOCH3 ), 2.02
(3H,s,2′-OCOCH ₃ ) Example 10 Production of 4″-O-(p-methoxyphenylacetyl)leucomycin U

[Chemical] 2′-O-acetyl-4″-O-(p-methoxyphenylacetyl) leucomycin U200mg
(0.21 mmol) was dissolved in 5.2 ml of methanol and heated under reflux for 16 hours. After cooling, the residue was concentrated to dryness and subjected to column chromatography using 9 g of silica gel (developing solvent: n-hexane/benzene/ethyl acetate/acetone/methanol = 30/25/20/10/1.5). / Benzene / Ethyl acetate / Acetone / Methanol = (30/25/20/10/8) silica gel TLC was conducted to combine the elution fractions showing sulfuric acid coloration with an Rf value of 0.41, and concentrated under reduced pressure to obtain 4″-O-
(p-methoxyphenylacetyl)leucomycin U 98.0 mg (yield 53%) was obtained. Physicochemical properties of Γ4″-O-(p-methoxyphenylacetyl)leucomycin U [α] ²⁴ _D −59.2° (C0.813, MeOH) UV λ ^MeOH _nax 230nm, E1% cm=346 Rf 0.41 ( n-hexane/benzene/ethyl acetate/acetone/methanol 30/25/20/10/
8) NMR (CDCl ₃ ) δ 9.68 (1H, s, CHO), 7.26 (2H, d, J=
9Hz, aromatic ring), 6.87 (2H, d, J = 9Hz, aromatic ring), 6.07 (1H, dd, H-12), 5.61 (1H,
dd, H-10), 4.57 (1H, d, J=10Hz, H-
4″), 4.44 (1H, d, J=8Hz, H-1′), 3.80
(3H, s, -OCH ₃ ), 3.65 (2H, s, -CH ₂ ),
3.54 (3H, s, 4-OCH ₃ ), 2.51 (6H, s, N
(CH ₃ ) ₂ ), 2.26 (3H,s,3-OCOCH ₃ ) Example 11 Production of 4″-O-(p-methoxy)benzyltylosin

[Chemical formula] 1.5 g of 2'-O-acetyl 3'',4''-O-dibutylstanylenetylosin (molar ratio: 2'-O-acetyltylosin/dibutyltin oxide = 1/5) and 0.25 g of tetrabutylammonium iodide was suspended in 20 ml of dry benzene, 0.5 ml of p-methoxybenzyl chloride was added thereto, and the mixture was heated under reflux for 23 hours. After cooling, the reaction mixture was diluted with 20 ml of toluene, washed with water, sodium bicarbonate solution and brine, and dried over glass. After filtration, it was concentrated to dryness and precipitated from chloroform-hexane to give 580 mg of 2′-O-acetyl-4″-O.
-(p-methoxy)benzyltylosin crude powder was obtained. This material was dissolved in 30 ml of methanol and heated under reflux for 11 hours. After cooling, it was concentrated to dryness and purified by silica gel column chromatography (developing solvent: toluene/acetone = 7/2) to give 350 mg.
4″-O-(p-methoxy)benzyltylosin was obtained. [α] ²⁴ _D −32.7° (C 2.71, MeOH) UV λ ^MeOH _nax 282 nm, E1% 1 cm = 220 λ ^MeOH _nax 227 nm, E1% 1 cm = 138 Rf 0.22 (benzene/acetone = 2/1) Molecular formula C ₅₄ H ₈₅ NO ₁₈ Mass 1035 (M ⁺ ) NMR (CDCl ₃ ) δ 2.45 and 2.52 (6H, N(CH ₃ ) ₂ ),
2.91 (1H, d, _J4 ″ _,5 ″=10Hz, H-4″), 3.51 (3H
，
OCH ₃ ), 3.63 (3H, s, OCH ₃ ), 3.82 (3H, s,
OCH ₃ ), 6.86 (2H, d, J = 8.5H, aromatic ring),
7.28 (2H, d, aromatic ring), 9.71 (1H, CHO) Example 12 Production of 4″-O-benzyltylosin 2′-O-acetyl-3″,4″-O-dibutylstanylenetylosin is converted into benzyl bromide and examples
The title compound could be obtained by reacting and treating in the same manner as in 11. Physicochemical properties of Γ4″-O-benzyltylosin [α] ²⁴ _D −41.3 (C 1.25, MeOH) UV λ ^MeOH _nax 285nm, E1% 1cm=207 Rf 0.16 (benzene/acetone = 2/1) Molecular formula C ₅₃ H ₈₃ NO ₁₇ Mass 1006 (M+H) ⁺ NMR (CDCl ₃ ) δ1.80 (3H, s, 12−CH ₃ ), 2.53
(6H, s, N(CH ₃ ) ₂ ), 2.94 (1H, d, J ₄ ″ _,5 ″=10
Hz, H-4″), 3.51 (3H, s, OCH ₃ ), 3.63 (3H,
s, OCH ₃ ), 4.23 (1H, d, J ₁ ′ _,2 ′=7.5Hz, H−
1'), 4.57 (1H, d, J _{1 ,2} = 7.5Hz, H-1),
4.69 (2H, s, 4″-O-CH ₂ −), 5.01 (1H, H-
1″), 5.92 (1H, d, H-13), 6.28 (1H, d, H
-10), 7.25-7.41 (6H, m, H-11 and aromatic ring),
9.72 (1H, CHO). Example 13 Production of 4″-O-(p-acetyl)benzyltylosin 2′-O-acetyl-3″,4″-O-dibutylstanylenetylosin was mixed with (p-acetyl)benzyl bromide in the same manner as in Example 11. The title compound was obtained by reaction and treatment. Physicochemical properties of Γ4″-O-(p-acetyl)benzyltylosin [α] ²⁴ _D −41.5° (C 0.53, MeOH) UV λ ^MeOH _nax 282nm, E1% 1cm=190 λ ^MeOH _nax 255nm, E1% 1cm=162 Rf 0.16 (benzene/acetone=2/1) Molecular formula C ₅₅ H ₈₅ NO ₁₈ Mass 1048 (M+H) ⁺ NMR (CDCl ₃ ) δ1.81 (3H, s, 12- _CH3 ), 2.54
(6H, s, N(CH ₃ ) ₂ ), 2.61 (3H, s, COCH ₃ ),
2.95 (1H, d, _J4 ″ _,5 ″=10Hz, H-4″), 3.51 (3H
，
s, OCH ₃ ), 3.64 (3H, s, OCH ₃ ), 5.92 (1H,
d, H-13), 6.28 (1H, d, H-10), 7.49 (2H,
d, aromatic ring), 7.96 (2H, d, aromatic ring), 9.74 (1H,
CHO). Example 14 Preparation of 4″-O-methoxymethyltylosin

[Chemical formula] 1.5 g of 2'-O-acetyl-3'',4''-O-dibutylstanylenetylosin (molar ratio: 2'-O-acetyltylosin/dibutyltin oxide = 1/5) and tetrabutylammonium iodide 0.25 20ml of g
The suspension was suspended in dry benzene, 0.16 ml of chloromethyl ether was added thereto, and the mixture was stirred at room temperature for 15 hours.
The reaction mixture was diluted with toluene, washed with water, aqueous sodium bicarbonate, and brine, and then dried over glass. After filtration, the residue was concentrated to dryness and redissolved in 30 ml of methanol.
The mixture was heated under reflux for 7 hours. After cooling, it was concentrated to dryness and purified by silica gel chromatography (developing solvent: toluene/acetone = 5/2) to give 180 mg.
4″-O-methoxymethyltylosin was obtained. [α] ²⁴ _D −51.1° (C 0.93, MeOH) UV λ ^MeOH _nax 283 nm, E1% 1 cm = 230 Rf 0.45 (chloroform/methanol/25% aqueous ammonia = 15/1/0.1) Molecular formula C ₄₈ H ₈₁ NO ₁₈ Mass 959 (M ⁺ ) NMR (CDCl ₃ ) δ2.57 (6H, sN (CH ₃ ) ₂ ), 3.41 and 3.46 (3H, 4″OCH ₂ OCH= ₃ ), 3.53(3H,s,
OCH ₃ ), 3.66 (3H, s, OCH ₃ ), 4.63 and 4.93
(2H, J=7Hz, 4″O−CH ₂ −), 5.94(1H,
d, H-13), 6.30 (1H, d, H-10), 7.37
(1H, d, H-11), 9.76 (1H, CHO) Example 15 Production of 4″-O-(P-methoxy)phenacyltylosin

[Chemical formula] 1.5 g of 2'-O-acetyl-3'',4''-O-dibutylstanylenetylosin (molar ratio: 2'-O-acetyltylosin/dibutyltin oxide = 1/5) and 1.5 g of sodium iodide. The suspension was suspended in 20 ml of dry benzene, 0.78 g of α-bromo-p-methoxyacetophenone was added thereto, and the mixture was heated under reflux for 17 hours.
While cooling, the mixture was diluted with 30 ml of toluene, washed with water, an aqueous sodium bicarbonate solution, and a saline solution, and then dried on a glass plate. The concentrated residue was purified by silica gel chromatography (developing solvent: toluene/acetone = 4/1) to obtain 63 mg of 2'-O-acetyl-4''-O-
(p-methoxy)phenacyltylosin was obtained.
This material was dissolved in 20 ml of methanol and heated under reflux for 18 hours. After cooling, the residue was concentrated to dryness and subjected to silica gel chromatography (developing solvent: toluene/
Purified with acetone = 7/2) to give 37 mg of 4″-O
-(p-methoxy)phenacyltylosin was obtained. [α] ²⁴ _D −37.5゜(C 0.92, MeOH) UV λ ^MeOH _nax 284nm, E1% 1cm=320 UV λ ^MeOH _nax 221nm, E1% 1cm=116 Rf 0.14 (Benzene/Acetone=2/1) Molecular formula C ₅₅ H ₈₅ NO ₁₉ Mass 1064 (MH ⁺ ) NMR (CDCl ₃ ) δ2.57 (6H, sN (CH ₃ ) ₂ ), 3.51
(3H, s, OCH ₃ ), 3.63 (3H, s, OCH ₃ ),
3.90 (3H, s, OCH ₃ ), 5.91 (1H, d, H-
13), 6.28 (1H, d, H-10), 6.94 (2H, d,
aromatic ring), 7.35 (1H, d, H-11), 8.07 (2H,
d, aromatic ring), 9.72 (1H, CHO) Example 16 Production of 2′-O-acetyl-4″-O-trifluoromethanesulfonyltylosin

[Chemical formula] 1.5 g of 2'-O-acetyl-3'',4''-O-dibutylstanylenetylosin (molar ratio: 2'-O-acetyltylosin/dibutyltin oxide = 1/5) was suspended in 7 ml of dry dichloromethane. It became cloudy and cooled to 0°C. A solution of 0.23 ml of trifluoromethanesulfonic anhydride/5 ml of dichloromethane was added dropwise to this mixture over 10 minutes. After adding ice blocks to the reaction mixture and stirring, the mixture was extracted with 50 ml of toluene. The toluene layer was washed with an aqueous sodium bicarbonate solution and a saline solution, and dried over glass. After filtration and concentration to dryness, 0.85 g of 2′-O-acetyl-4″-O-trifluoromethanesulfonyltylosin was obtained as a crude powder. Note that this material is relatively unstable and can be used immediately in the next reaction. Rf 0.40 (benzene/acetone = 2/1) NMR (CDCl ₃ ) δ1.81 (3H, s, 12-CH ₃ ), 2.07
(3H, s, 2′OCOCH ₃ ), 2.42 (6H, s, N
(CH ₃ ) ₂ ), 3.52 (3H, s, OCH3), 3.65 (3H,
s, OCH ₃ ), 4.42 (1H, d, J ₄ ″ _,5 ″=10Hz, H
−4″), 4.57 (1H, d, J _{1 ,2} = 7.5Hz, H−1
), 5.92 (1H, d, H-13), 6.29 (1H, d,
H-10), 7.34 (1H, d, H-11), 9.71 (1H,
CHO) Example 17 Production of 2′-O-acetyl-4″-deoxy-4″-iodotylosin

[Chemical formula] 0.4 g of 2'-O-acetyl-4''-O-trifluoromethanesulfonyl tylosin crude powder and 0.75 g of tetrabutylammonium iodide were dissolved in 10 ml of acetonitrile and stirred at 60°C for 1 hour. After cooling, toluene was added. After adding 30 ml of acetonitrile, the acetonitrile was distilled off under reduced pressure, and the remaining toluene solution was washed with water, an aqueous sodium bicarbonate solution, and a saline solution, and then dried over Bowel glass. = 5/1),
40 ml of 2'-O-acetyl-4''-deoxy-4''-iodotylosine was obtained. Rf 0.43 (benzene/acetone = 2/1) NMR (CDCl ₃ ) δ1.43 (3H, d, J ₅ ″ _,6 ″=5Hz,
H-6″), 1.80 (3H, s, 12-CH ₃ ), 2.06 (3H,
s.2′OCOCH ₃ ), 2.43(6H,s,N(CH ₃ ) ₂ ),
3.52 (3H, s, OCH ₃ ), 3.65 (3H, s,
OCH ₃ ), 3.87-4.10 (m, H-4″ and H-5″),
5.88 (1H, d, H-13), 6.27 (1H, d, H-
10), 7.32 (1H, d, H-11), 9.71 (1H,
CHO) Example 18 Production of 4″-deoxytylosin

[Chemical formula] 120 mg of 2'-O-acetyl-4''-deoxy-4''-iodotylosine is dissolved in 7 ml of dry benzene, and to this is added 0.1 ml of tributylstannane hydride and a catalytic amount of azobisisobutyronitrile. was added and stirred for 2.5 hours at 75°C under nitrogen atmosphere.
After cooling, the mixture was diluted with 30 ml of toluene, washed with water and saline, and dried over glass. After filtration, the concentrated residue was purified by Sephadex LH-20 column chromatography (developing solvent: methanol),
100 mg of 2'-O-acetyl-4''-deoxytylosin was obtained. This was dissolved in 20 ml of methanol and heated under reflux for 11 hours. After cooling, the residue was concentrated to dryness and subjected to silica gel chromatography (developing solvent:
Chloroform/methanol = 35/1 and 30/1)
45 mg of 4″-deoxytylosin was obtained. [α] ²⁴ _D +0.1° (C 1.18, MeOH) UV λ ^MeOH _nax 283 nm, E1% 1 cm = 224 Rf 0.28 (chloroform/methanol/ 25% ammonium water = 15/1/0.1) Molecular formula C ₄₆ H ₇₇ NO ₁₆ Mass 899 (M ⁺ ) NMR (CDCl ₃ ) δ1.79 (3H, s.12−CH ₃ ), 2.49
(6H, s, N(CH ₃ ) ₂ ), 3.47 (3H, s,
OCH ₃ ), 3.60 (3H, s, OCH ₃ ), 4.22 (1H,
d, J ₁ ′ _,2 ′=7.5Hz, H−1′), 4.55(1H, d,
J _{1 ,2} = 7.5Hz, H-1), 4.84 (1H, dd,
J ₁ ″ _,2 ″ _a = 9Hz, J ₁ ″ _,2 ″ _b = 2.5Hz, H-1″), 5.89
(1H, d, H-13), 6.25 (1H, d, H-10),
7.33 (1H, d, H-11), 9.74 (1H, CHO) Example 19 Production of 2'-O-acetyl-4-O-trifluoromethanesulfonyltylosin

[Chemical formula] 2 g of 2'-O-acetyltylosin was dissolved in 10 ml of dichloromethane, 0.5 ml of pyridine was added, and the mixture was cooled to 0° C. and stirred. Next, 5 ml of a dichloromethane solution of 0.37 ml of trifluoromethanesulfonic anhydride was added dropwise over 30 minutes. The reaction was completed in 1 hour. After adding ice cubes to the reaction mixture and stirring, toluene and water were added for extraction. The toluene layer was washed with NaHCO ₃ water and then with brine, and then dried with sulfur salt. After filtration, the residue was concentrated and dried to obtain 2.36 g of the title compound. This product was used in the next reaction without further purification. Rf 0.37 (benzene/acetone (2/1)) NMR (CDCl ₃ ) δ1.77 (3H, s.12−CH ₃ ), 2.03
(3H, s, 2′0COCH ₃ ), 2.37 (6H, s, N
( _CH3 ) ₂ ), _4.38 (1H, dd, _J3,4 = 2.5Hz,
J _{4 ,5} = 10Hz, H-4), 4.61 (1H, d,
J _{1 ,2} = 7.5Hz, H-1), 5.86 (1H, d,
J _13,14 = 10.5Hz, H-13), 6.26 (1H, d, J _10,11
= 15.5Hz, H-10), 7.29 (1H, d, H-11),
9.67 (1H, CHO), 3.49 (3H, s, 2OCH3),
3.59 (3H,s, _3OCH3 ) Example 20 Production of 2'-O-acetyl-4-deoxy-4-iodotylosine

[Chemical formula] 1.0 g of 2'-O-acetyl-4-O-trifluoromethanesulfonyltylosin and 509 mg of tetrabutylammonium iodide were dissolved in 12 ml of acetonitrile and stirred at 50-60°C for an hour. After cooling, add 50 ml of toluene to the reaction mixture to dilute, add water,
After washing with NaHCO ₃ water and then with saline, it was dried with boron salt. After filtration, the mixture was concentrated and dried to obtain 680 mg of a crude powder of the title compound. This was subjected to silica gel chromatography (benzene/acetone, (6/
1)) to obtain 410 mg of the title compound. [α] ²⁴ _D −59.3° (C ~ 1.04, methanol) Rf 0.37 (benzene/acetone (2/1)) Mass 1067 (M ⁺ ) NMR (CDCl ₃ ) δ1.37 (3H, d, J _{5 ,6} =5
Hzm, H-6), 1.77 (3H, s, 12- _CH3 ),
2.04 (3H, s, 2′OCOCH ₃ ), 2.38 (6H, s, N
( _CH3 ) ₂ ), 3.46 (3H,s,2- _OCH3 ), 3.61
(3H, s, 3-OCH ₃ ), 4.25 (1H, d,
J ₁ ′ _,2 ′=7.5Hz, H−1′), 4.64(1H, d, J _{1 ,2}
= 8Hz, H-1), 5.88 (1H, d, J _13,14 =
10.5Hz, H-13), 6.26 (1H, d, J _10,11 = 15.5
Hz, H-10), 7.29 (1H, d, H-11), 9.68
(1H, CHO) Example 21 Production of 2'-O-acetyl-4-deoxytylosin

[Chemical] 600mg of 2'-O-acetyl-4-deoxy-
4-iodotylosine was dissolved in 15 ml of benzene, 0.45 ml of tributyltin hydride and a catalytic amount of azoisobutyronitrile were added thereto, and the mixture was stirred at 65-75° C. under a nitrogen gas atmosphere for 2 hours. After cooling, the mixture was diluted with 30 ml of toluene, washed with water and saline, and dried with salt water. After filtration, the residue was concentrated to dryness and purified using a Sephadex LH-20 (manufactured by Pharmacia Fine Chemicals) column (methanol) to obtain 528 mg of 2'-O-acetyl 4-deoxytylosin. [α] ²⁴ _D −55.6° (C 3.65, methanol) Rf 0.26 (benzene/acetone, (2/1)) Mass 941 (M ⁺ ) Example 22 4″-O-(p-methoxy)phenylacetyl
Production of 4″-deoxytylosin

[Chemical] Using 2′-O-acetyl-4-deoxytylosine as a starting material, 4″-O-(p-methoxy)phenylacetyltylosin was synthesized from 2′-O-acetyltylosin using the same method. The title compound was obtained. [α] ²⁴ _D −57.6° (c 0.92, MeOH) UV λ ^MeOH _nax 283 nm, E1% 1 cm = 235 λ ^MeOH _nax 226 nm, E1% 1 cm = 110 Rf 0.27 (benzene/acetone = 2/ 1) Molecular formula C ₅₅ H ₈₅ NO ₁₈ Mass 1048 (MH ⁺ ) NMR (CDCl ₃ ) δ1.79 (3H, s, 12−CH ₃ )
2.50 (6H, s, N(CH ₃ ) ₂ ), 3.40 (3H, s,
OCH ₃ ), 3.49 (3H, s, OCH ₃ ), 3.63 (2H,
s,

[Formula]), 3.79 (3H, s,

[Formula]), 4.53 (1H, d, J ₄ ″ _{, 5} ″ = 10Hz, H-4″), 4.63 (1H, d, J ₄ ″ _{, 5} ″ = 8Hz, H-1
), 5.02 (1H, H-1″), 5.91 (1H, d,
J _{1 ,2} = 10.5Hz, H-13), 6.23 (1H, d,
J _10,11 = 15.5Hz, H-10), 6.82 (2H, d, aromatic cyclic proton), 7.22 (2H, d, aromatic cyclic proton), 7.31 (1H, d, H-11), 9.68 ( 1H,
CHO) The 16-membered ring macrolide compound obtained by the method of the present invention exhibits the following antibacterial activity and stability in mouse liver homogenate. Antibacterial activity The antibacterial activity of each compound was measured by the agar dilution method using Mueller-Hint broth (PH7.4) as a medium, and the minimum inhibitory concentrations (μg/ml) against various pathogenic microorganisms were as shown in Table 1. .

[Table] 2 Stability test on mouse liver homogenate The liver of an ICR mouse was homogenized with 5 times the amount of 0.1M phosphate buffer (PH7.2) using a Botter homogenizer (3000 rpm, 10 min). Add 1 ml of analyte 500 μg/ml (10% methanol water) to the supernatant (1 ml), react at 37°C for 1 hour, heat at 100°C for 3 minutes, and then add 0.1M phosphate buffer (PH9.0).
Add 1 ml and extract with 1 ml of ethyl acetate. Silica gel thin layer chromatography (chloroform/methanol/ammonia-15/1.2/
0.1), the production ratio of the unchanged substance and the hydrolyzed product was determined using a chromatoscanner (283 nm), and the production of the hydrolyzate was expressed as a percentage. The result is the second
Shown in the table.

【table】

Claims (1)

[Claims] 1 General formula [Chemical formula] In the formula, R ¹ represents a hydrogen atom or a hydroxyl group protected with an easily removable protecting group, one of R ³ and R ⁴ represents a hydrogen atom, and the other represents a hydroxyl group or a D-fluorosamino group, or R ³ and R ⁴ together represent an oxo group, R ⁵ represents a hydrogen atom or a methyl group, and R ⁶ and R ⁷ together represent a single bond. or -O-, R ⁸ is a hydrogen atom, a methyl group, a hydroxymethyl group, a lower alkanoyloxymethyl group, or [Formula] (where R ¹² is a hydrogen atom or is appropriately protected with an easily removable protecting group R ⁹ represents a methyl group or an ethyl group, R ¹⁰ represents a hydroxyl group or a lower alkanoyloxy group, and R ¹¹ represents a methyl group or a methoxy group. Tin-containing 16-membered ring macrolide compound.