JPH07109288A - Novel 16-membered macrolide derivative and novel production process thereof - Google Patents

Abstract

PURPOSE:To obtain a novel compound which is useful as an anti-microbial because it shows powerful antimicrobial activity against gram-positive bacteria and can maintain the activity in blood for hours. CONSTITUTION:A compound of the formula I [R<1>, R<2> are H, COR (R is 1-3C straight-chain alkyl); R<3> is 1-4C straight-chain alkyl, alkenyl) or its salts, for example, 4''-0-isoamyl-3''-0-methyl-9-O-propionylleucomycin V. The compound of the formula I (the case where both of R<1> and R<2> are H is excluded) is obtained by reaction of a compound of the formula II or its salt is allowed to react with pyridine and acetyl chloride. The compound of the formula II is novel, and obtained by using a compound in the leucomycin Fr group of the formula III as a starting substance.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to novel 16-membered ring macrolide derivatives which are effective against Gram-positive bacteria and a novel method for producing them.

[0002]

2. Description of the Related Art The role of antibacterial agents in pharmaceuticals is important, and in consideration of clinical safety, especially in the pediatric field and mainly oral administration forms, Gram-positive bacteria, mycoplasma, chlamydia, etc. Effective macrolide antibiotics are classified as indispensable antibacterial agents. Recently, the causative bacteria of infectious diseases of interest have been gradually specified, and the clinical importance of macrolide antibiotics is increasing. The present inventors consider the quality of life of patients first, and have little influence on the intestinal tract,
A 16-membered macrolide antibiotic with low interaction with other drugs was selected as a research object, and it was effective against various Gram-positive bacteria and was searched for synthetic chemical and biochemical activity of a derivative with long-lasting antibacterial activity in vivo . I have been carrying out research.

[0003] First, the inventors of the present invention said, "Myokamycin (MOM) (Journal of
Antibiotics, 29 (5), 536 (1976), Japanese Journal of Antibiotics, 35 (6), 146
2 (1982)), the in vitro metabolism cleaves the acyl group of the mycarose moiety, reducing the in vitro antibacterial activity ”(Pharmaceutical Journal, 102 (8), 781 (1982)). We fed back to the drug design and designed the derivative based on a new idea. That is, it is more stable in vivo, and its antibacterial activity is less likely to decrease even if it is metabolized.
6-membered macrolide derivatives directed to a result of repeated synthetic chemical studies and succeeded in two hydroxyl groups of mycarose portion of 16-membered macrolide derivative together newly synthesized ether linked derivatives with alkyl groups, in vitro Has proved that the antibacterial activity lasts remarkably, and applied for a patent (Japanese Patent Application No. 4-39013).

Then, by microbial conversion of the carbonyl group at the 9-position of these derivatives into hydroxyl groups having a natural configuration, a novel 16-membered ring macrolide derivative exhibiting excellent pharmacokinetics was created and applied for a patent. (Japanese Patent Application No. 4-29143
8). Furthermore, the present inventors have the most excellent class of in vitro antibacterial activity among leucomycin derivatives by cleaving the acyl group bonded to the 3-position hydroxyl group of the lactone ring of these derivatives using microbial conversion. , Succeeded in creating a novel 16-membered ring macrolide derivative in which the mycalose moiety is not easily metabolized, and filed a patent application (Japanese Patent Application No. 5-1162).
31).

[0005]

A novel 16-membered ring macrolide derivative having two ether bonds in the mycalose moiety and a hydroxyl group having a natural configuration at the 9-position, which was recently prepared by the present inventors, For example 4 "-O-depropionyl-4" -O-isoamyl-3 "-O-methylmidecamycin A
₁ (Japanese Patent Application No. 4-291438) is a mouse animal compared with the recently marketed 16-membered macrolide antibiotic because its mycalose part is not easily attacked by esterase and the 9-position is a hydroxyl group. Serum concentration and its persistence in the experiment, and urinary recovery were significantly improved. Derivatives obtained by cleaving the acyl group bonded to the 3-hydroxyl group of those lactone rings, such as 4 "-O-isoamyl-3" -O
-Methylleucomycin V (Japanese Patent Application No. 5-116231) had extremely excellent in vitro antibacterial activity.

However, in order to actually prepare these derivatives, a multi-step chemical reaction including a regio- and stereoselective glycosylation reaction for introducing a neutral sugar (Japanese Patent Application No. 4-39013) and It is necessary to carry out a two-step or continuous two-step microbial conversion, and the costs and the time required to produce these derivatives are not always completely satisfactory. At the same time, in the glycosylation reaction, an activator that is dangerous and requires careful handling needs to be used stoichiometrically, and there is no problem in its scale-up. Further, the tertiary hydroxyl group at the 3-position of the glycosyl donor actually used in the glycosylation reaction is methylated,
No example has been reported of carrying out the glycosylation reaction using a glycosyl donor of a neutral sugar having an alkyl group other than a methyl group introduced.

Therefore, without using the glycosylation reaction, the two hydroxyl groups of the mycarose moiety for which the present inventors applied for a patent were both ether-bonded with an alkyl group.
An invention relating to a method for producing a membered ring macrolide derivative by chemical synthesis is expected. Furthermore, by using this method, the 3-position of the lactone ring is a free hydroxyl group,
Various 16-membered macrolide derivatives in which the position is a free hydroxyl group and the two hydroxyl groups of the mycarose moiety are both ether-bonded with the same or different alkyl groups, especially 3 "
It is expected that a derivative in which an alkyl group other than a methyl group is introduced into the tertiary hydroxyl group at the position will appear. In fact, a 16-membered macrolide derivative in which an alkyl group other than a methyl group has been introduced into the tertiary hydroxyl group at the 3 "-position of the mycalose moiety, including natural products, has not been known so far.

By the way, in the chemical modification of a 16-membered macrolide antibiotic, an example is known in which an alkyl group is introduced into the secondary hydroxyl group at the 4 "-position of the mycarose moiety without going through a glycosylation reaction. Have introduced an alkyl group into the secondary hydroxyl group at the 4 "-position of the mycarose moiety by protecting the hemiacetal hydroxyl group formed at the 3,18-position of spiramycin I with a silyl group. Kaisho 60-5
8998, JP-A-60-239494). On the other hand, Yoshioka et al. Modified the two hydroxyl groups of the 16-membered macrolide derivative of the mycarose moiety with dialkyl tin, and added a benzyl group to the secondary hydroxyl group at the 4 "position, which is one of them. However, up to now, an alkyl group has been introduced to the tertiary hydroxyl group at the 3 "-position of the mycalose portion of the 16-membered ring macrolide derivative without going through the glycosylation reaction. There is no report on the reaction.

[0009]

Means for Solving the Problems The present inventors have repeatedly conducted synthetic chemical research in order to meet the above expectations, put a specific deacylation reaction using a phase transfer catalyst into practical use, and further used silyl using hydrochloric acid or silica gel. A new method for selective deprotection of groups was newly developed. By organically assembling these new technologies, the known naturally occurring 16-membered macrolide antibiotics, the leucomycin Fr group, such as leucomycin A ₇ (Journal of Antibiotics, Ser.
A, 20 (4), 234 (1967)) as a starting material and undergoing a chemical reaction in 5 or 6 steps, the 3-position of the lactone ring is a free hydroxyl group, the 9-position is a free hydroxyl group, and mycarose We succeeded in efficiently synthesizing a 16-membered ring macrolide derivative in which the two hydroxyl groups of both moieties are ether-bonded by the same or different alkyl groups. Moreover, by using the production method of the present invention, a large number of novel derivatives including a derivative in which an alkyl group other than a methyl group has been introduced into the tertiary hydroxyl group at the 3 "-position of the mycalose portion are synthesized, and these are clinically important Gram-positive bacteria. The present invention has been completed by finding that the growth of peaches is strongly inhibited.

The gist of the first aspect of the present invention resides in the following formula (I) as a novel compound.

[Chemical 4]

[Wherein R ¹ is a hydrogen atom or a group of formula COR (where R is a linear alkyl group having 1 to 3 carbon atoms), R ² is a hydrogen atom or a group of formula COR (where R is R ³ is a linear alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R ⁴ is a substituted or unsubstituted carbon group. A linear or branched alkyl group, alkenyl group or aralkyl group of the formulas 1 to 10], or a pharmaceutically acceptable salt thereof. The compound represented by the general formula (I) according to the present invention has the following formula (III) except that R ¹ and R ² are both hydrogen atoms.

[Chemical 5]

[Wherein R ³ is a straight-chain alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R ⁴ is a substituted or unsubstituted C 1 to C 1 1
0 straight chain or branched chain alkyl group, alkenyl group or aralkyl group] or a salt thereof,
It is easily produced by carrying out a known selective or non-selective synthetic chemical reaction (fermentation and industry, 37 (12), 1171 (1979)) for the hydroxyl group at the 9-position and / or the 2'-position of the mycaminose moiety. It

The gist of the second invention is that the following formula (II)

[Chemical 6]

[Wherein R ⁵ is a linear or branched aliphatic acyl group having 2 to ⁵ carbon atoms] or a salt thereof as a starting material, and the following formula (III)

[Chemical 7]

[In the formula, R ³ is a linear alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R ⁴ is a substituted or unsubstituted C 1 to C 1 1
0 straight-chain or branched alkyl group, alkenyl group or aralkyl group], or a salt thereof, can be chemically synthesized efficiently. The compound represented by the general formula (III) according to the present invention is
It is manufactured as follows by the method shown in the process drawing 1.

[0016]

[Chemical 8]

[0017]

[Chemical 9]

First, a brief description will be given of alkylation of hydroxyl groups in macrolide compounds. Several methods are known for introducing an alkyl side chain into a free hydroxyl group to form an ether bond. However, basically, it is only a modified method of the Williamson reaction using a classical and well-known strong base. The formation reaction of ether bond under various reaction conditions is not well known. By the way, in the 14-membered ring macrolide compound, the sites near both sides of the ester bond of the lactone ring are mainly C-methyl group (2-position) and C-ethyl group (13-position). For example, in leucomycins, both adjacent sites are mainly hydrogen atom (2nd position) and C-methyl group (15th position). Therefore, the ester bond of the 14-membered ring lactone under basic conditions is more likely to be compared with the ester bond of the 16-membered ring lactone of the leucomycins, mainly due to their steric hindrance and electronic factors at the 2-position. It is significantly stable. As an example, the methylation of the secondary hydroxyl group of the neutral sugar moiety in the 14-membered ring macrolide compound can be facilitated by protecting the other hydroxyl group (Journal of
Antibiotics, 43 (5), 566 (1990)).

That is, in a 16-membered ring macrolide compound, especially leucomycin, in addition to the ester bond of the lactone ring described above, the vicinity of the 3-position of the lactone ring, and
There are many functional groups that are unstable under strong basic conditions such as aldehyde groups. By the way, the second grade of the micarose part (4 "
Position) and tertiary (3 "position) hydroxyl groups can be efficiently and sequentially introduced by Omura and Sano et al. Protection method using silyl group (JP-A-60-5899)
It was thought that it would be ideal to modify 8 and JP-A-60-239494) progressively and further apply it to leucomycins.

First, the naturally occurring 16-membered macrolide antibiotic Leucomycin Fr group (Journal of Antibiotics, 28 (6), 401 (1975))
The protection of the hydroxyl group and the aldehyde group by the silyl group will be described. For a compound represented by the formula (II) (wherein R ⁵ is an acyl group), that is, a single compound of the leucomycin Fr group or a mixture of a plurality of components, or a salt thereof, a necessary amount in the presence of a base. Of the hemiacetal hydroxyl group formed at the 3,18-position, and the hydroxyl groups at the 9-position and the 2'-position are respectively silylated by reacting with an excess amount of the silylating reagent or the formula (IV) (wherein R ⁵ is an acyl group and R ⁶ is a silyl protecting group) or a salt thereof is obtained. For example, leucomycin A ₇ (in formula (II), R ⁵
Is represented by a propionyl group) in dimethylformamide (DMF) in the presence of imidazole with t-butyldimethylsilyl chloride (TBDMSCl) to give 3,18
A compound (1) (in the formula (IV) in which R ⁵ is R ⁵ is a hemiacetal-type hydroxyl group formed at the position and a total of three hydroxyl groups at the 9-position and the 2′-position are converted to t-butyldimethylsilyl (TBDMS). A compound represented by a propionyl group and R ⁶ represented by a TBDMS group was obtained in high yield (note that the compounds represented by the formulas (IV), (V), (VI) and (VII) shown in the process chart 1). In the structural formula of the compound described below, regarding the spatial relative positional relationship (front-back relationship) between the bond connecting the 3-position hydroxyl group and the 18-position carbon and the bond connecting the 5-position hydroxyl group and the 1'position carbon, Not clear so far).

Regarding the stereochemistry at the 18-position at this time, the production of one diastereoisomer is very preferential, and the other diastereoisomer at the 18-position as observed in the protection with spiramycin I was observed. (Journal of Antibiotics, 37 (7), 750 (1984)) is not prominently produced. On the other hand, it is undeniable that the 18-position diastereoisomer may be by-produced, depending on the type of silyl protecting group used, the silylation conditions, and the difference in the reaction substrate. However, in carrying out the production method of the present invention, the isomers may or may not be separated.

The silyl group used in the protection step is
In addition to the TBDMS group, other silyl groups such as isopropyldimethylsilyl group and ethyldimethylsilyl group are also possible, and particularly isopropyldimethylsilyl group is applicable to the production method of the present invention. By the way, as the silylation reagent when introducing the TBDMS group, in addition to TBDMSCl, TBDMSOClO ₃ , TBDMSOSO ₂ CF
₃ , it is possible to use a reagent such as TBDMSCN, which can be used in the usual TBDMS conversion to a hydroxyl group, but preferably
It is advisable to use 3 equivalents or excess of TBDMSCl. As the base used in the silylation, pyridine, dimethylaminopyridine, lutidine, triethylamine and the like can be used in addition to imidazole, but it is preferable to use 6 equivalents or an excess amount of imidazole. The reaction solvent is DMF,
Although it is possible to use acetonitrile, methylene chloride, tetrahydrofuran (THF), etc., the reaction using DMF often gives good results. This protection step proceeds with good yield in the range of 0 ° C to 80 ° C, and the reaction time is 1 hour to several days.

Secondly, the 4 "-position acyl side chain of the mycarose moiety of the compound represented by the formula (IV) is chemically cleaved. The compound represented by the formula (IV) is 3,18 A silyl group is introduced into the hemiacetal hydroxyl group formed at the position,
In addition to protecting the aldehyde groups, the 7-membered ring portion containing them is condensed to a 16-membered lactone. Therefore, compared with a 16-membered ring macrolide derivative having a free hydroxyl group at the 3-position and a free aldehyde group at the same time, a strong basic condition of the compound itself represented by the formula (IV) is obtained. The stability of the lactone ring in is dramatically improved.
Therefore, it is possible to selectively cleave the acyl group bonded to the 4 "-position hydroxyl group without cleaving the lactone ring by usual alkali treatment. However, the yield is not always satisfactory. Therefore, the present inventor investigated the possibility of 4 "-deacylation by a heterogeneous reaction using a phase transfer catalyst because the compound represented by the formula (IV) is particularly fat-soluble, and as a result, mica 4 "of loin
We succeeded in quantitatively cleaving the acyl group at position.

That is, as an example thereof, in the compound (1) (formula (IV), R ⁵ is represented by a propionyl group and R ⁶ is TB.
Compound represented by DMS group) is dissolved in benzene and vigorously stirred with 25% aqueous sodium hydroxide solution at room temperature in the presence of tetra-n-butylammonium hydrogen sulfate to give compound (2)
(Compound in which R ⁶ is a TBDMS group in formula (V)) was efficiently obtained. In the heterogeneous reaction, generally, a strongly basic aqueous layer and a mixture of an organic solvent in which the compound represented by the formula (IV) is dissolved (not uniformly mixed with water) are vigorously mixed in the presence of a phase transfer catalyst. It is performed with stirring. The strong base that dissolves in the aqueous layer may be either sodium hydroxide or potassium hydroxide, and the concentration is usually preferably concentrated. The organic solvent that is not uniformly mixed with water may be benzene, toluene, xylene, n-pentane, n-hexane, cyclohexane, methylene chloride, 1,2-dichloroethane, etc.,
Preferred is benzene and the like. As a phase transfer catalyst,
Tetra-n-butylammonium bromide, tetra-n-butylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium chloride, tetra-n-butylammonium hydrogensulfate and the like can be used, and the amount thereof is represented by the formula (IV). The amount is a catalytic amount to several equivalents, usually 1 equivalent. Reaction is 5 ℃
The reaction proceeds easily between -40 ° C and the stirring efficiency in the reaction system shortens the reaction time and improves the yield, but the reaction is usually completed in 10 minutes to several hours.

The starting material used in the production method of the present invention may be any compound of the leucomycin Fr group,
The acyl side chain at the 4 "-position of the mycarose moiety is an isovaleryl group (leucomycin) in the heterogeneous reaction.
The reaction time of the propionyl group (leucomycin A ₇ ) is shorter than that of A ₁ ) and the yield is slightly improved. However, the desired deacylation reaction can be achieved by this heterogeneous reaction regardless of which natural acyl group the side chain bonded to the 4 "-position hydroxyl group is.

Thirdly, selective or non-selective alkylation of the compound represented by the formula (V) (wherein R ⁶ is a silyl protecting group) to the 4 "-position hydroxyl group of the mycarose moiety. The compound represented by the formula (V) has two free hydroxyl groups, but the hydroxyl group at the 3 "position is a tertiary alcohol and the hydroxyl group at the 4" position is a secondary alcohol. ,
Also in the ether bond formation reaction (Williamson reaction) due to the introduction of the alkyl group, it is possible to properly use the difference in reactivity between the two hydroxyl groups. That is, the compound represented by the formula (V) is subjected to a Williamson reaction to selectively introduce an alkyl group into the 4 "-position hydroxyl group of the mycarose portion, and the formula (VI) (wherein R ⁴ is an alkyl group) And R ⁶ is a silyl protecting group) can be obtained in good yield.

For example, compound (2) (in formula (V), R
⁶ is a compound represented by TBDMS group) in DMF in the presence of sodium hydride in the presence of an excess amount of isoamyl iodide under heating conditions, and compound (15) (in formula (VI), R ⁴ is an isoamyl group) Compound in which R ⁶ is represented by TBDMS group) was synthesized in good yield. Thus, when the alkyl side chain to be introduced, such as an isoamyl group, is bulky to some extent, the regioselectivity of the reaction is good, but the selectivity gradually decreases as the alkyl side chain becomes smaller. In fact, when compound (2) or its analogue is reacted with methyl iodide in the presence of sodium hydride, a compound in which not only the 4 "-position but also the tertiary hydroxyl group at the 3" -position is methylated is formed. (See Example 23).

In the present alkylation reaction, a metal hydride such as potassium hydride may be used in addition to sodium hydride for extracting a proton from a free hydroxyl group to generate an alkoxide. A reagent for introducing an alkyl group is used. In addition to alkyl iodide, alkyl halide such as alkyl bromide may be used. The alkyl chain in that case is preferably a primary alkyl group or a secondary alkyl group, but is preferably a primary alkyl group. As the reaction solvent, THF, dioxane or the like may be used in addition to DMF or the like. Alkylation reaction is 0 ℃ -100 ℃
Easily progresses at temperatures between, but preferably 40 ℃ ~ 50 ℃
Is. By the way, in order to complete this reaction with a high yield, control of the reaction temperature is particularly important.

Fourthly, the compound of the formula (VI)
Introducing an alkyl group into the tertiary hydroxyl group at the 3 "position of the callose part
And the chain bonded to the 2'-hydroxyl group of the mycaminose moiety.
The selective deprotection of the ryl group will be described. First Expression (VI)
The compound represented by
Introducing an alkyl group into the tertiary hydroxyl group at the 3 "position of the squid
did. Then, one atom of oxygen is added using an organic peroxide.
I gave it. Finally, selection of 2'position with removal of one oxygen atom
(VII) (wherein R ³And R^Four
Is an alkyl group, R⁶Is a silyl protecting group)
To obtain the compound.

For example, the compound (15) (in the formula (VI), R ⁴ is an isoamyl group and R ⁶ is a TBDMS group) is added to DMF in the presence of sodium hydride,
By reacting with an excess amount of ethyl iodide, the tertiary hydroxyl group at the 3 "position was ethylated, and then one atom of oxygen was donated using m-chloroperbenzoic acid. Subsequently, in the coexistence of << A >> organic solvent Alternatively, by selective reaction with silica gel in the absence of coexistence, or by << B >> acid hydrolysis reaction, selective removal of TBDMS at the 2'-position accompanied by removal of one oxygen atom is carried out, and compound (18) (formula (VII ), R ³ represents an ethyl group, R ⁴ represents an isoamyl group, and R ⁶ represents a TBDMS group).

Regarding the Williamson reaction at the time of introducing an alkyl group into a general tertiary hydroxyl group, a method via a copper (I) tertiary alkoxide (Journal of American Chemical Society, 96 (9) , 2829 (1974)) and the like have been established. However, in the alkylation () of the mycarose moiety to the tertiary hydroxyl group at the 3 "position in the present invention, the reaction substrate is protected and stabilized by three silyl groups. Therefore, it was possible to apply the ordinary Williamson reaction without special modification. Therefore, the reaction conditions themselves are the 4 "position of the mycarose moiety of the compound represented by formula (V). It is almost similar to the case where the hydroxyl group is alkylated, but the temperature control during the reaction becomes more important. Also,
Regarding the alkyl side chain to be introduced, a bulky alkyl group may cause a slight decrease in yield.

By the way, a three-step chemical reaction (3 "-O-alkylation, donation of one oxygen atom, for synthesizing the compound represented by the formula (VII) from the compound represented by the formula (VI),
In this step including selective desilylation of 2'position accompanied by removal of one oxygen atom, the above reaction sequence is not always the best depending on the type of alkylating reagent and the type of silyl protecting group. The reaction pathway of donating one oxygen atom of ,, followed by 3 "-O-alkylation of, and then is also useful to complete the process. In fact, Examples 7, 10
Etc., after giving one oxygen atom of
3 "-O-methylation is performed. That is, the donation of one oxygen atom by an organic peroxide is not essential for alkylation of the tertiary hydroxyl group at the 3" position, but is described below. Thus, it exerts its effect on the selective deprotection of the silyl group.

That is, in the 16-membered macrolide derivative in which the two hydroxyl groups of the mycarose moiety are both ether-bonded by an alkyl group, the hemiacetal hydroxyl group formed at the 3,18-position and the hydroxyl groups at the 9-position and the 2'-position, respectively. The three silyl groups introduced into the substrate, eg, three TBDMS groups, can be deprotected by known deprotection methods (Th
eodora W. Greene; Peter GM Wuts. Protective Gro
ups in Organic Synthesis , 2nd ed., Wiley: New Yor
K, 1991), it was extremely difficult to completely deprotect. However, in the derivative in which one oxygen atom is added () to the trisilyl protected body, selective desilylation () of the 2'position accompanied by removal of one oxygen atom, for example,
It was discovered that the selective deprotection of TBDMS at the 2'position proceeded efficiently and that the other two silyl groups were completely deprotected by a further step.

By the way, it is presumed that the donation of one oxygen atom by the organic peroxide () is performed in the vicinity of the mycaminose portion, but the compound to which one oxygen atom is donated is somewhat unstable. In addition, the chemical structures of these compounds have not yet been determined because they are extremely unstable, especially under acidic conditions. On the other hand, as the peroxide for carrying out the oxygen atom donating reaction, other organic peroxides such as m-chloroperbenzoic acid, perbenzoic acid and peracetic acid, hydrogen peroxide may be used, and preferably m-chloro. It is perbenzoic acid. As the reaction solvent, chloroform, methylene chloride,
Ether, t-butanol, etc. may be used, and the reaction is completed in a short time at a temperature of -10 ° C to room temperature or higher.

Therefore, the 16-membered ring macrolide compound, which is protected by three silyl groups, has two hydroxyl groups in the mycarose moiety both ether-bonded by an alkyl group, and has one oxygen atom, is further added. The selective deprotection of the silyl group at the 2'position accompanied by removal of the atom, that is, will be described in detail. It has been confirmed that this reaction proceeds quantitatively by leaving it at room temperature in the presence of << A >> silica gel. The reaction with silica gel may or may not coexist with an organic solvent in the reaction system, and the reaction form may be a batch method or a column method, and a small amount of compound TL for manufacturing
Method C is also useful.

First, the batch method will be described. An organic solvent is added to the reaction substrate to dissolve it, and silica gel is added so as to be uniform. In either case, even if it is left in the coexistence of an organic solvent at room temperature, or after the organic solvent is removed by concentration under reduced pressure or the like, it is left in the absence of an organic solvent, the desired oxygen 1 atom The selective deprotection of the silyl group at the 2'position accompanied by removal proceeds efficiently. Next, the column method will be described. The desired main reaction also proceeded efficiently by attaching a concentrated solution of the reaction substrate to the upper bottom of a silica gel column packed by a wet method and then leaving it at room temperature. After standing, it was possible to efficiently obtain the compound represented by the formula (VII) by successively developing the silica gel column. The organic solvent used in this reaction is not particularly limited, and chloroform, methylene chloride, acetonitrile, methanol and the like can be used alone or as a mixture. Furthermore, regarding the silica gel used at this time, general silica gel used in ordinary experimental operations such as Wakogel C-200, C-300, Merck Kieselgel Art.15101, and Art.9385 can be freely applied. Things are possible.

Finally, a TL suitable for the production of small amounts of compounds
The C method will be described. It was possible to efficiently obtain the compound represented by the formula (VII) by dissolving the reaction substrate in a small amount of an organic solvent, charging it on a TLC plate, allowing it to stand at room temperature, and then developing it normally. . Which of the batch method, the column method, and the TLC method is selected and how long the standing time is set is determined by the structure of the reaction substrate and the scale of the reaction. The time required for completion is usually several hours to several days.

On the other hand, in order to achieve this reaction by << B >> acid hydrolysis, a mixed solution of a dilute aqueous solution of an organic acid or an inorganic acid and an organic solvent which is uniformly mixed with water may be used. This method has an advantage that silica gel is not used as compared with the << A >> method. The aqueous acid solution used in this method may have a hydrochloric acid concentration of 0.001 to 0.5 normal, preferably 0.01 to 0.05 normal. As the type of acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoroacetic acid or the like can be used in addition to hydrochloric acid. As the organic solvent, methanol, ethanol, acetonitrile, THF, dioxane and the like can be used, and preferably methanol or acetonitrile. The dilute aqueous solution of the acid and the organic solvent may be mixed at any ratio as long as the reaction substrate is dissolved, and a mixture ratio of about 1: 1 is usually used. The reaction temperature and the same time largely depend on the type and concentration of the acid used, but the reaction is usually performed at 0 ° C to 60 ° C.
It is completed within a few minutes to a few hours (see Example 17).

By the way, another advantage of selecting the present hydrolysis method (<< B >>) when carrying out the reaction () is:
By further continuing the reaction, two silyl groups other than the 2'position, for example, TBDMS group are sequentially deprotected, and the formula (III)
(In the formula, R ³ and R ⁴ are alkyl groups) to obtain the final target product. For example, compound (15)
(In the formula (VI), R ⁴ is represented by an isoamyl group, and R ⁶ is
The compound represented by the TBDMS group) is methylated at the tertiary hydroxyl group at the 3 "position, and at the same time, a compound to which one oxygen atom is endowed is added to a mixture of 0.025N hydrochloric acid / acetonitrile (1: 1) at 45 ° C.
By acid hydrolysis for 4 hours, the compound (1
7) (in the formula (III), R ³ is represented by a methyl group, and R ⁴
Was found to be a compound represented by an isoamyl group) (see Example 25). In this reaction, the compound (1
In addition to 7), separable allylic rearrangement of compound (17) (Chemical and Pharmaceutical Bretan, 18 (8), 1501 (1970), Annual Report of Meiji Seika, 12 , 85 (19)
72), Journal of Antibiotics, 35 (11),
1521 (1982)) as a by-product in a trace amount, but the number of reaction steps is reduced and the reaction reagents are compared with the production method of the present invention via the compound represented by the formula (VII) shown in the process chart 1. Has been realized, and it can greatly contribute to the reduction of manufacturing cost. Finally 3 silyl groups, eg TB
The reaction time required until the DMS group is deprotected is longer than that in the selective desilylation at the 2'position, but the reaction conditions themselves are the same as those in the << B >> acid hydrolysis method described above. It is the same.

Fifth, the deprotection of the two silyl groups bonded to the hemiacetal hydroxyl group formed at the 3,18-position and the hydroxyl group at the 9-position will be described. These silyl groups, such as the TBDMS group, are well known for their deprotection conditions (Theodora W. Greene ; Peter GM Wuts. Protecti
ve Groups in Organic Synthesis , 2nd ed., Wiley: New
York, 1991) allows complete or incomplete deprotection. Using the compound of formula (VII) as a reaction substrate and observing its usefulness using various desilylation reaction reagents, good results are obtained when the deprotection is carried out using TBAF. There was found. In fact, R ⁶
For a compound of formula (VII) in which is a TBDMS group,
Deprotection using TBAF results in chemical conversion to the final end product of formula (III). For example, compound (18)
(A compound represented by the formula (VII) in which R ³ is an ethyl group, R ⁴ is an isoamyl group, and R ⁶ is a TBDMS group)
Is reacted with an excess amount of TBAF in THF under heating conditions to give a compound (19) (a compound represented by the formula (III) in which R ³ is an ethyl group and R ⁴ is an isoamyl group). Obtained as the product.

Using TBAF, two silyl groups, eg TBDM
When deprotecting the S group, by devising such that water is not mixed in the reaction system, the completion of the reaction is accelerated and side reactions can be completely suppressed. Since TBAF acts as a strong base on the free aldehyde group, in order to carry out this deprotection step in high yield, it is necessary to pay close attention to the post-treatment after the reaction, but details are not provided. Described in the examples. TB
As the reaction solvent in the main deprotection using AF, it is possible to use an ether-based solvent, a halogen-based solvent, a nitrile-based solvent, etc., but a good result is obtained when THF is used. There are many. Furthermore, in order to complete the reaction, the concentration of TBAF itself in the reaction solvent can be an important factor. That is, when the number of TBAF equivalents to the reaction substrate is constant, the concentration of TBAF with respect to the reaction solvent is too dilute (too much reaction solvent) or too high (if there is too little reaction solvent). ) The reaction is difficult to complete,
Usually, the reaction proceeds efficiently at a concentration of 0.5M to 4M, preferably at a concentration of 1M to 2M. TBAF is used in 2 equivalent to excess amount,
Complete deprotection proceeds rapidly by reaction with 10 or more equivalents of TBAF.

By the way, a compound represented by the formula (III),
Alternatively, for the salt thereof, a known method of selectively acylating the hydroxyl group at the 9-position or 2'-position (Fermentation and Industry, 37 (12), 1171
(1979)) or a known method of allylic rearrangement of the 9-position hydroxyl group to the 11-position or 13-position in the presence of a dilute acid (Chemical and Pharmaceutical Bretan, 18 (8), 1501 (19).
70), Annual Report of Meiji Seika, 12 , 85 (1972), Journal ・
Of Antibiotics, 35 (11), 1521 (1982)) or a known method of selectively oxidizing the 9-position hydroxyl group (Journal of Antibiotics, 24 (8), 526 (1971))
It is possible to produce a new useful substance based on the present invention by carrying out the above. As an example, the compound (1
7) (in the formula (III), R ³ is represented by a methyl group, and R ⁴
The present inventors have already filed a patent application for a derivative obtained by selectively acetylating the 9-position hydroxyl group of a compound represented by an isoamyl group) using a known method (JP-A-48-13380) (Japanese Patent Application No. Flat 5-116231).

In the production method of the present invention, mycamino is used.
Silyl group bonded to the 2'-position hydroxyl group of the base moiety, eg
For example, to deprotect the TBDMS group, use an organic peroxide, etc.
Chemistry to give one oxygen atom by m-chloroperbenzoic acid
He said that the reaction was important. As I mentioned earlier, the oxygen source
This reaction, which gives off pups, is a 3 "grade 3rd grade of mycarose.
It is also possible to carry out prior to the alkylation reaction of the hydroxyl groups.
It was. In fact, this oxygen atom donating reaction is
Part of the 4 "-position secondary hydroxyl group
Even (see Example 23), it is further bound to the hydroxyl group at the 4 "position.
Before cleaving the acyl group by heterogeneous reaction
However, it is possible to produce the compound represented by the formula (III).
Is. However, as far as the inventor observes
Is the oxygen atom donation reaction, which is 3 "at the 3" position of the mycalose part.
Immediately (or just before) alkylating the primary hydroxyl group
Is the most effective way to improve the overall yield.
It By the way, in the process diagram 1 relating to the method of the present invention,
The compound represented by (V) is a leucomycin Fr group
It was synthesized as a starting material through two steps. On the other hand, Leucomai
Shin V (Journal of Antibiotics,28
(6), 401 (1975)) as the starting material, one-step selection
Of compound of formula (V) by selective trisilylation
It is added that it is possible to do. Next, the present invention is carried out.
Describe in detail by an example.

[0044]

【Example】

Example 1 Compound (1) (in formula (IV), R ⁵ is a propionyl group
And a compound in which R ⁶ is a TBDMS group) leucomycin A ₇ 1.00 g and anhydrous dimethylformamide
Add 12 ml to dissolve and t-butyldimethylsilyl chloride.
1.18 g and imidazole 1.08 g were added, and it stirred at 50 degreeC all day and night. After returning the reaction solution to room temperature, methanol 50
ml was added, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was concentrated under reduced pressure. The obtained residue was extracted with 500 ml of benzene, and the benzene layer was extracted twice with 500 ml of a saturated aqueous sodium hydrogen carbonate solution,
After successively washing twice with 500 ml of saturated saline, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried to obtain 1.22 g of crude compound (1). Of this, 60 mg was purified by preparative TLC (developing system: chloroform-methanol (50: 1)) to obtain 35 mg of compound (1). Physicochemical properties of compound (1) (1) Color and shape: Colorless solid (2) Molecular formula: C ₅₆ H ₁₀₅ NO ₁₄ Si ₃ (3) Mass spectrum (SIMS): m / z 1100 (M + H)
⁺ (4) Specific rotation: [α] _D ²⁵ -17 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 105 to 107 ° C without showing a clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.61 (dd, 2-H), 4.22 (m, 3-H), 3.14 (br s,
4-H), 3.38 (s, 4-OCH ₃ ), 3.42 (br dd, 5-H), 0.41 (br d
d, 7-H), 4,23 (m, 9-H), 5.75 (dd, 10-H), 6.12 (m, 11-
H), 6.12 (m, 12-H), 5.62 (dt, 13-H), 4.85 (ddq, 15-
H), 1.30 (d, 16-H ₃ ), 1.38 (dt, 17-H), 1.66 (br d, 17-
H), 4.63 (br dd, 18-H), 4.21 (d, 1'-H), 3.52 (dd, 2'-
H), 2.55 (t, 3'-H), 3.35 (t, 4'-H), 1.25 (d, 6'-H ₃ ),
2.53 (s, 3'-N (CH ₃ ) ₂ ), 5.10 (d, 1 "-H), 1.86 (dd, 2" -Ha
x), 2.00 (d, 2 "-Heq), 1.11 (s, 3" -CH ₃ ), 4.62 (d, 4 "-
H), 4.37 (dq, 5 "-H), 1.17 (t, 4" -OCOCH ₂ C H ₃ ).

Example 2Compound (2) (in formula (V), R ⁶ is represented by the TBDMS group
Compound) 130 ml of benzene was added to 1.16 g of crude compound (1) to dissolve it.
65% 25% aqueous sodium hydroxide solution and hydrogen sulfate.
358 mg of tra-n-butylammonium was added, and the mixture was kept at room temperature for 2 hours.
Stir vigorously. After separating the benzene layer, add saturated salt
It was washed twice with 150 ml of water, and the organic layer was dried over anhydrous sodium sulfate.
It was dried over and filtered. Obtained by concentrating the filtrate under reduced pressure
The residue was subjected to silica gel column chromatography (200 g:
The compound was purified by roloform-methanol (30: 1)).
(2) 795 mg was obtained. Physicochemical properties of compound (2) (1) Color and shape: colorless solid (2) molecular formula: C₅₃H₁₀₁NO₁₃Si₃ (3) Mass spectrum (SIMS): m / z 1044 (M + H)
⁺ (4) Specific rotation: [α]_D ^{twenty five} -12 ° (c1.0, CH₃OH) (5) Melting point: No clear melting point at 98-100 ° C
Melting (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.37 (br dd, 2-H), 2.61 (dd, 2-H), 4.21 (m,
 3-H), 3.13 (br s, 4-H), 3.37 (s, 4-OCH₃), 3.42 (br d
d, 5-H), 0.41 (br dd, 7-H), 4,23 (m, 9-H), 5.74 (dd,
10-H), 6.11 (m, 11-H), 6.11 (m, 12-H), 5.62 (dt, 13-
H), 4.85 (ddq, 15-H), 1.30 (d, 16-H₃), 1.38 (dt, 17-
H), 1.66 (br d, 17-H), 4.63 (br dd, 18-H), 4.20 (d,
1'-H), 3.57 (dd, 2'-H), 2.53 (t, 3'-H), 3.32 (t, 4'-
H), 1.25 (d, 6'-H₃), 2.51 (s, 3'-N (CH₃) ₂), 5.08 (d,
1 "-H), 1.77 (dd, 2" -Hax), 2.02 (d, 2 "-Heq), 1.22 (s,
3 "-CH₃), 2.94 (t, 4 "-H), 3.99 (dq, 5" -H), 1.30 (d, 6 "
-H₃)

Example 3 Compound (3) (in formula (VI), R ⁴ represents an ethyl group.
R ⁶ is a compound represented by TBDMS group) (200) Compound (2) anhydrous dimethylformamide 3.0 m
l was added and dissolved, 38% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. Ethyl iodide 899 after the bubbles have weakened
mg was added and the mixture was stirred at 45 ° C for 30 minutes. After returning the reaction solution to room temperature, gradually add 100 ml of water, and add chloroform 100
extracted with ml. Chloroform (100 ml) was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (2: 1)) to obtain 140 mg of compound (3). Physicochemical properties of compound (3) (1) Color and shape: Colorless solid (2) Molecular formula: C ₅₅ H ₁₀₅ NO ₁₃ Si ₃ (3) Mass spectrum (SIMS): m / z 1072 (M + H)
⁺ (4) Specific rotation: [α] _D ²⁶ -17 ° (c1.0, CH ₃ OH) (5) Melting point: 92 ° C (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.37 (br dd, 2-H), 2.60 (dd, 2-H), 4.21 (m,
3-H), 3.37 (s, 4-OCH ₃ ), 3.38 (br dd, 5-H), 0.39 (br
dd, 7-H), 4,21 (m, 9-H), 5.73 (dd, 10-H), 6.10 (m, 11
-H), 6.10 (m, 12-H), 5.60 (dt, 13-H), 4.82 (ddq, 15-
H), 1.38 (dt, 17-H), 1.63 (br d, 17-H), 4.61 (br dd,
18-H), 4.16 (d, 1'-H), 3.44 (dd, 2'-H), 2.52 (t, 3'-
H), 3.34 (t, 4'-H), 2.50 (s, 3'-N (CH ₃ ) ₂ ), 5.02 (d, 1 "
-H), 1.75 (dd, 2 "-Hax), 1.96 (br d, 2" -Heq), 1.23 (s,
3 "-CH ₃ ), 2.70 (d, 4" -H), 4.22 (dq, 5 "-H), 3.66 (dq,
4 "-OC H ₂ CH ₃ ), 3.68 (dq, 4" -OC H ₂ CH ₃ )

Example 4Compound (4) (in formula (VII), R ³ represents a methyl group.
And R ⁴ is represented by an ethyl group and R ⁶ is represented by a TBDMS group.
Compound) manufacturing method To compound (3) 120 mg, chloroform 6.0 ml was added and dissolved.
Then, add 29 mg of m-chloroperbenzoic acid and stir at room temperature for 5 minutes.
I stirred. 30 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture.
It was dripped at and extracted with 60 ml of chloroform. Chloroform
60 ml of saturated aqueous sodium hydrogen carbonate solution and saturated
After washing twice with 60 ml of brine each time, the organic layer was dried over anhydrous sulfuric acid.
It was dried over sodium and filtered. Concentrate the filtrate under reduced pressure
Anhydrous dimethylformamide was added to 127 mg of the obtained solid.
Add 1.3 ml and dissolve, 60% oily sodium hydride 24 mg
Was added and stirred at room temperature. After the bubbles are weakened
(498 mg) was added, and the mixture was stirred at 45 ° C. for 1 hour. Room temperature
Then, add 30 ml of water slowly, and add chloroform 60
extracted with ml. Add 60 ml of chloroform again to the aqueous layer and extract.
I put it out. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. Chloroform layer is anhydrous sodium sulfate
After drying with triumnium, this was filtered and the filtrate was concentrated under reduced pressure. Profit
Charge the resulting residue to a preparative TLC and allow it to stand for 2 days
Development and purification (Development system: chloroform-methanol (2
0: 1)), 68 mg of compound (4) was obtained. Physicochemical properties of compound (4) (1) Color and shape: Colorless solid (2) Molecular formula: C₅₀H₉₃NO₁₃Si₂ (3) Mass spectrum (SIMS): m / z 971 (M)⁺ (4) Specific rotation: [α]_D ^{twenty three} -2 ° (c1.0, CH₃OH) (5) Melting point: No melting point, melting at 72-74 ° C
Melt (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 4.05 (br dt, 3-H), 3.43 (s, 4-OCH₃), 3.45
(br d, 5-H), 0.41 (br dd, 7-H), 4,18 (br d, 9-H), 5.
72 (dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (d
t, 13-H), 4.80 (ddq, 15-H), 1.30 (d, 16-H)₃), 1.43 (dt,
 17-H), 1.66 (br d, 17-H), 4.56 (br dd, 18-H), 4.29
(d, 1'-H), 3.32 (dd, 2'-H), 2.45 (t, 3'-H), 3.36 (t,
4'-H), 2.55 (s, 3'-N (CH₃)₂), 4.87 (d, 1 "-H), 1.52 (dd,
 2 "-Hax), 2.23 (d, 2" -Heq), 1.21 (s, 3 "-CH₃), 3.25 (s,
3 "-OCH₃), 2.76 (d, 4 "-H), 4.45 (dq, 5" -H), 3.64 (dq,
4 "-OCH ₂CH₃), 3.68 (dq, 4 "-OCH ₂CH₃)

Example 5 Compound (5) (in the formula (III), R ³ represents a methyl group.
And R ⁴ is an ethyl group) (4 "-O-ethyl-
Method for producing 3 "-O-methylleucomycin V) To 63 mg of compound (4), 530 µl of 2M tetra-n-butylammonium fluoride tetrahydrofuran solution was added and reacted for 1 hour at 45 ° C. The reaction solution was returned to room temperature. Then, the mixture was added dropwise to 5.2 ml of 5% potassium hydrogen sulfate aqueous solution and extracted twice with 30 ml of chloroform.The chloroform layers were combined and washed twice with 50 ml of saturated aqueous sodium hydrogen carbonate solution and twice with 50 ml of saturated saline solution. After that, the organic layer was dried over anhydrous sodium sulfate and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (10 g: chloroform-methanol (50: 1)). 24 mg of compound (5) was obtained Physicochemical properties of compound (5) (1) Color and shape: colorless solid (2) Molecular formula: C ₃₈ H ₆₅ NO ₁₃ (3) Mass spectrum (SIMS): m / z 744 (M + H) ⁺ (4) Specific rotation: [α] _D ²⁴ -60 ° (c1.0, CH ₃ OH) (5) Melting around 89 to 92 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz , CDCl ₃ ) δ
(ppm): 2.20 (br d, 2-H), 2.68 (dd, 2-H), 3.76 (br
d, 3-H), 3.07 (br d, 4-H), 3.52 (s, 4-OCH ₃ ), 4.08 (br
dd, 5-H), 1.88 (m, 8-H), 4.07 (dd, 9-H), 5.66 (dd, 1
0-H), 6.24 (dd, 11-H), 6.01 (br dd, 12-H), 5.58 (ddd,
13-H), 2.10 (dt, 14-H), 2.48 (br d, 14-H), 5.26 (dd
q, 15-H), 1.28 (d, 16-H ₃ ), 2.31 (br dd, 17-H), 2.85
(br dd, 17-H), 9.80 (br s, 18-H), 0.99 (d, 19-H ₃ ),
4.56 (d, 1'-H), 2.40 (t, 3'-H), 3.45 (t, 4'-H), 3.24
(dq, 5'-H), 1.15 (d, 6'-H ₃ ), 2.57 (s, 3'-N (CH ₃ ) ₂ ),
4.87 (d, 1 "-H), 1.53 (dd, 2" -Hax), 2.22 (d, 2 "-Heq),
1.21 (s, 3 "-CH ₃ ), 2.76 (d, 4" -H), 4.39 (dq, 5 "-H), 1.2
1 (d, 6 "-H ₃ ), 3.22 (s, 3" -OCH ₃ ), 3.63 (dq, 4 "-OC H ₂ C
H ₃ ), 3.67 (dq, 4 "-OC H ₂ CH ₃ )

Example 6 Compound (6) (in formula (VI), R ⁴ represents a propyl group.
A compound in which R ⁶ is a compound represented by TBDMS group) (200) Compound (2) anhydrous dimethylformamide 3.0 m
l was added and dissolved, 38% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. Propyl iodide 97 after the bubbles have weakened
9 mg was added and it stirred at 45 degreeC for 30 minutes. After returning the reaction solution to room temperature, gradually add 100 ml of water, and add chloroform 100
extracted with ml. Chloroform (100 ml) was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (2: 1)) to obtain 187 mg of compound (6). Physicochemical properties of compound (6) (1) Color and shape: Colorless solid (2) Molecular formula: C ₅₆ H ₁₀₇ NO ₁₃ Si ₃ (3) Mass spectrum (FDMS): m / z 1085 (M + H)
⁺ (4) Specific rotation: [α] _D ²⁵ -11 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at around 88 to 90 ° C (6) ¹ H NMR Spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.38 (br dd, 2-H), 2.60 (dd, 2-H), 4.22 (m,
3-H), 3.37 (s, 4-OCH ₃ ), 3.39 (br dd, 5-H), 0.39 (br
dd, 7-H), 4,22 (m, 9-H), 5.75 (dd, 10-H), 6.10 (m, 11
-H), 6.10 (m, 12-H), 5.61 (dt, 13-H), 4.82 (ddq, 15-
H), 1.39 (dt, 17-H), 4.62 (br dd, 18-H), 4.17 (d, 1'-
H), 3.43 (dd, 2'-H), 2.53 (t, 3'-H), 3.35 (t, 4'-H),
2.51 (s, 3'-N (CH ₃ ) ₂ ), 5.03 (d, 1 "-H), 1.76 (dd, 2" -Ha
x), 1.97 (br d, 2 "-Heq), 1.25 (s, 3" -CH ₃ ), 2.71 (d,
4 "-H), 4.23 (dq, 5" -H), 3.56 (t, 4 "-OC H ₂ CH ₂ CH ₃ ), 0.9
2 (t, 4 "-OCH ₂ CH ₂ C H ₃ )

Example 7 Compound (7) (in formula (VII), R ³ represents a methyl group.
R ⁴ is represented by a propyl group and R ⁶ is represented by a TBDMS group.
Compound (6) (187 mg) was added with chloroform (9.0 ml) and dissolved, m-chloroperbenzoic acid (44 mg) was added, and the mixture was stirred at room temperature for 5 minutes. 50 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture.
It was dripped at and extracted with 100 ml of chloroform. The chloroform layer was washed successively with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate and 100 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. To a solid (164 mg) obtained by concentrating the filtrate under reduced pressure, 1.6 ml of anhydrous dimethylformamide was added and dissolved, and 60% oily sodium hydride was added.
30 mg was added and stirred at room temperature. After the bubbles were weakened, 635 mg of methyl iodide was added, and the mixture was stirred at 45 ° C for 1 hour. After the reaction solution was returned to room temperature, 40 ml of water was gradually added and extracted with 80 ml of chloroform. 80 ml of chloroform again in the water layer
Was extracted. The chloroform layers were combined and washed twice with 150 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was charged in a preparative TLC, left standing for 2 days, developed and purified (developing system: chloroform-methanol (20: 1)) to obtain 44 mg of compound (7). Physicochemical properties of compound (7) (1) Color and shape: Colorless solid (2) Molecular formula: C ₅₁ H ₉₅ NO ₁₃ Si ₂ (3) Mass spectrum (SIMS): m / z 986 (M + H) ⁺ ( 4) Specific rotation: [α] _D ²⁴ -3 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 67-69 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz , CDCl ₃ ) δ
(ppm): 4.05 (br dt, 3-H), 3.43 (s, 4-OCH ₃ ), 0.42
(br dd, 7-H), 4,18 (br d, 9-H), 5.73 (dd, 10-H), 6.10
(m, 11-H), 6.10 (m, 12-H), 5.62 (dt, 13-H), 4.80 (dd
q, 15-H), 1.31 (d, 16-H ₃ ), 1.43 (dt, 17-H), 1.65 (br
d, 17-H), 4.57 (br dd, 18-H), 4.30 (d, 1'-H), 3.32 (d
d, 2'-H), 2.47 (t, 3'-H), 3.36 (t, 4'-H), 2.56 (s, 3 '
-N (CH ₃ ) ₂ ), 4.87 (d, 1 "-H), 1.54 (dd, 2" -Hax), 2.22
(d, 2 "-Heq), 1.23 (s, 3" -CH ₃ ), 2.77 (d, 4 "-H), 4.45
(dq, 5 "-H), 3.25 (s, 3" -OCH ₃ ), 3.54 (dt, 4 "-OC H ₂ CH ₂ C
H ₃ ), 3.57 (dt, 4 "-OC H ₂ CH ₂ CH ₃ ), 1.63 (m, 4" -OCH ₂ C H ₂ CH
₃ )

Example 8Compound (8) (in formula (III), R ³ represents a methyl group.
And R ⁴ is a propyl group) (3 "-O-methyl
Method for producing le-4 "-O-propylleucomycin V) Compound (7) 41 mg to 2 M tetra-n-butylammonium
Add 330 μl of mufluoride tetrahydrofuran solution.
Then, the mixture was reacted at 45 ° C. for 1 hour. The reaction solution was returned to room temperature
Then, add dropwise to 3.3 ml of a 5% potassium hydrogen sulfate aqueous solution, and
It was extracted twice with 20 ml of Loform. Combine the chloroform layers
And saturate twice with 40 ml of saturated aqueous sodium hydrogen carbonate solution.
After sequentially washing twice with 40 ml of saline solution, the organic layer was dehydrated with sulfuric acid.
It was dried over sodium and filtered. Concentrate the filtrate under reduced pressure
The residue obtained by silica gel column chromatography
-(10 g: chloroform-methanol (50: 1))
Thus, 30 mg of compound (8) was obtained. Physicochemical properties of compound (8) (1) Color and shape: Colorless solid (2) Molecular formula: C₃₉H₆₇NO₁₃ (3) Mass spectrum (SIMS): m / z 758 (M + H)⁺ (4) Specific rotation: [α]_D ^{twenty five} -55 ° (c1.0, CH₃OH) (5) Melting around 79-81 ℃ without showing clear melting point (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.20 (br d, 2-H), 2.68 (dd, 2-H), 3.77 (br
d, 3-H), 3.07 (br d, 4-H), 3.52 (s, 4-OCH₃), 4.08 (br
 dd, 5-H), 1.88 (m, 8-H), 4.07 (dd, 9-H), 5.66 (dd, 1
0-H), 6.24 (dd, 11-H), 6.01 (br dd, 12-H), 5.58 (ddd,
 13-H), 2.10 (dt, 14-H), 2.48 (br d, 14-H), 5.26 (dd
q, 15-H), 1.28 (d, 16-H₃), 2.31 (br dd, 17-H), 2.85
(br dd, 17-H), 9.80 (br s, 18-H), 0.99 (d, 19-H₃),
4.56 (d, 1'-H), 3.16 (dd, 2'-H), 2.39 (t, 3'-H), 3.45
(t, 4'-H), 3.25 (dq, 5'-H), 1.15 (d, 6'-H)₃), 2.55 (s,
 3'-N (CH ₃)₂), 4.87 (d, 1 "-H), 1.54 (dd, 2" -Hax), 2.2
1 (d, 2 "-Heq), 1.22 (s, 3" -CH₃), 2.76 (d, 4 "-H), 4.40
(dq, 5 "-H), 1.21 (d, 6" -H₃), 3.23 (s, 3 "-OCH₃), 3.52
(dt, 4 "-OCH ₂CH₂CH₃), 3.56 (dt, 4 "-OCH ₂CH₂CH₃), 1.60
(m, 4 "-OCH₂CH ₂ CH₃), 0.90 (t, 4 "-OCH₂CH₂CH ₃ )

Example 9 Compound (9) (in the formula (VI), R ⁴ represents a butyl group.
R ⁶ is a compound represented by TBDMS group) (200) Compound (2) anhydrous dimethylformamide 3.0 m
l was added and dissolved, 38% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. Butyl bromide 788 m after air bubbles weaken
g was added and the mixture was stirred at 45 ° C for 30 minutes. After returning the reaction solution to room temperature, gradually add 100 ml of water and add 100 ml of chloroform.
It was extracted with. Chloroform 100 ml was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (2: 1)) to obtain 140 mg of compound (9). Physicochemical properties of compound (9) (1) Color and shape: colorless solid (2) Molecular formula: C ₅₇ H ₁₀₉ NO ₁₃ Si ₃ (3) Mass spectrum (FDMS): m / z 1099 (M) ⁺ (4) Specific rotation: [α] _D ²⁶ -13 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 82-83 ° C without showing a clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.38 (br dd, 2-H), 2.60 (dd, 2-H), 4.22 (m,
3-H), 3.37 (s, 4-OCH ₃ ), 3.39 (br dd, 5-H), 0.40 (br
dd, 7-H), 4,22 (m, 9-H), 5.74 (dd, 10-H), 6.11 (m, 11
-H), 6.11 (m, 12-H), 5.61 (dt, 13-H), 4.82 (ddq, 15-
H), 1.39 (dt, 17-H), 1.64 (br d, 17-H), 4.62 (br dd,
18-H), 4.17 (d, 1'-H), 3.43 (dd, 2'-H), 2.53 (t, 3'-
H), 3.34 (t, 4'-H), 2.51 (s, 3'-N (CH ₃ ) ₂ ), 5.03 (d, 1 "
-H), 1.75 (dd, 2 "-Hax), 1.97 (br d, 2" -Heq), 1.24 (s,
3 "-CH ₃ ), 2.70 (d, 4" -H), 4.22 (dq, 5 "-H), 3.60 (dt,
4 "-OC H ₂ CH ₂ CH ₂ CH ₃ ), 0.90 (t, 4" -OCH ₂ CH ₂ CH ₂ C H ₃ )

Example 10 Compound (10) (in formula (VII), R ³ is a methyl group.
R ⁴ is represented by a butyl group and R ⁶ is represented by a TBDMS group.
Compound (9) (140 mg) was dissolved in chloroform (7 ml), and m-chloroperbenzoic acid (33 mg) was added. The mixture was stirred at room temperature for 5 minutes. The reaction solution was added dropwise to 35 ml of a 10% sodium thiosulfate aqueous solution and extracted with 70 ml of chloroform. The chloroform layer was washed successively with 70 ml of a saturated aqueous sodium hydrogen carbonate solution and 70 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 141 mg of a solid. 1.3 ml of anhydrous dimethylformamide was added to and dissolved in 129 mg of the obtained solid, 23 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles were weakened, 494 mg of methyl iodide was added, and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, 30 ml of water was gradually added and the mixture was extracted with 60 ml of chloroform. Chloroform (60 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed with 120 ml of saturated saline twice. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was charged in a preparative TLC, allowed to stand for 3 days and developed (development system: chloroform-methanol (20: 1)) to obtain 80 mg of compound (10). Physicochemical properties of compound (10) (1) Color and shape: Colorless solid (2) Molecular formula: C ₅₂ H ₉₇ NO ₁₃ Si ₂ (3) Mass spectrum (SIMS): m / z 999 (M + H) ⁺ ( 4) Specific rotation: [α] _D ²⁴ -4 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 67-68 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz , CDCl ₃ ) δ
(ppm): 4.05 (br dt, 3-H), 3.44 (s, 4-OCH ₃ ), 3.46
(dd, 5-H), 0.42 (br dd, 7-H), 4,18 (br d, 9-H), 5.73
(dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (dt,
13-H), 4.80 (ddq, 15-H), 1.30 (d, 16-H ₃ ), 1.43 (dt,
17-H), 1.66 (br d, 17-H), 4.56 (br dd, 18-H), 4.29
(d, 1'-H), 3.32 (dd, 2'-H), 2.46 (t, 3'-H), 3.36 (t,
4'-H), 2.55 (s, 3'-N (CH ₃ ) ₂ ), 4.87 (d, 1 "-H), 1.53 (d
d, 2 "-Hax), 2.21 (d, 2" -Heq), 1.22 (s, 3 "-CH ₃ ), 2.76
(d, 4 "-H), 4.45 (dq, 5" -H), 3.25 (s, 3 "-OCH ₃ ), 3.57
(dt, 4 "-OC H ₂ CH ₂ CH ₂ CH ₃ ), 3.61 (dt, 4" -OC H ₂ CH ₂ CH ₂ C
H ₃ ), 1.58 (m, 4 "-OCH ₂ C H ₂ CH ₂ CH ₃ ), 1.36 (m, 4" -OCH ₂ CH ₂
C H ₂ CH ₃ ), 0.99 (t, 4 "-OCH ₂ CH ₂ CH ₂ C H ₃ )

Example 11Compound (11) (in formula (III), R ³ is a methyl group
A compound in which R ⁴ is a butyl group) (4 "-O-butyl
Process for the production of le-3 "-O-methylleucomycin V) Compound (10) 75 mg to 2M tetra-n-butylammoni
Add 600 μl of umfluoride tetrahydrofuran solution.
Then, the mixture was reacted at 45 ° C. for 1 hour. The reaction solution was returned to room temperature
Then, add dropwise to 6.0 ml of 5% potassium hydrogensulfate aqueous solution and add black.
It was extracted twice with 40 ml of Loform. Combine the chloroform layers
Let it saturate twice with 80 ml of saturated aqueous sodium hydrogen carbonate solution.
After washing twice with 80 ml of brine, the organic layer was dried over anhydrous sulfuric acid.
It was dried over sodium and filtered. Concentrate the filtrate under reduced pressure
The residue obtained by silica gel column chromatography
-(10 g: chloroform-methanol (50: 1))
Thus, 30 mg of compound (11) was obtained. Physicochemical properties of compound (11) (1) Color and shape: colorless solid (2) molecular formula: C₄₀H₆₉NO₁₃ (3) Mass spectrum (SIMS): m / z 772 (M + H)⁺ (4) Specific rotation: [α]_D ^{twenty five} -54 ° (c1.0, CH₃OH) (5) Melting at around 80-84 ℃ without showing clear melting point (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.20 (br d, 2-H), 2.68 (dd, 2-H), 3.77 (br
d, 3-H), 3.08 (br d, 4-H), 3.53 (s, 4-OCH₃), 4.09 (br
 dd, 5-H), 1.89 (m, 8-H), 4.08 (dd, 9-H), 5.67 (dd, 1
0-H), 6.25 (dd, 11-H), 6.02 (br dd, 12-H), 5.59 (ddd,
 13-H), 2.10 (dt, 14-H), 2.49 (br d, 14-H), 5.27 (dd
q, 15-H), 1.29 (d, 16-H₃), 2.31 (br dd, 17-H), 2.86
(br dd, 17-H), 9.80 (br s, 18-H), 4.57 (d, 1'-H), 3.
16 (dd, 2'-H), 2.39 (t, 3'-H), 3.45 (t, 4'-H), 3.25 (d
q, 5'-H), 1.16 (d, 6'-H₃), 2.55 (s, 3'-N (CH₃)₂), 4.8
7 (d, 1 "-H), 1.54 (dd, 2" -Hax), 2.21 (d, 2 "-Heq), 1.2
2 (s, 3 "-CH₃), 2.76 (d, 4 "-H), 4.40 (dq, 5" -H), 1.21
(d, 6 "-H), 3.23 (s, 3" -OCH₃), 3.55 (dt, 4 "-OCH ₂CH₂C
H ₂CH₃), 3.60 (dt, 4 "-OCH ₂CH₂CH₂CH₃), 1.60 (m, 4 "-OCH
₂CH ₂ CH₂CH₃), 1.36 (m, 4 "-OCH₂CH₂CH ₂ CH₃), 0.89 (t, 4 "
-OCH₂CH₂CH₂CH ₃ )

Example 12 Compound (12) (in the formula (VI), R ⁴ is a pentyl group.
A compound represented by the formula (2) wherein R ⁶ is a TBDMS group) (200) Compound (2) anhydrous dimethylformamide 3.0 m
l was added and dissolved, 38% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles have weakened, pentyl iodide 1.
14 g was added and stirred at 45 ° C. for 30 minutes. After returning the reaction solution to room temperature, gradually add 100 ml of water, and add chloroform 100
extracted with ml. Chloroform (100 ml) was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC (developing system: hexane-ethyl acetate (2: 1)) to obtain 164 mg of compound (12). Physicochemical properties of compound (12) (1) Color and shape: colorless solid (2) Molecular formula: C ₅₈ H ₁₁₁ NO ₁₃ Si ₃ (3) Mass spectrum (FDMS): m / z 1113 (M) ⁺ (4) Specific rotation: [α] _D ²⁶ -13 ° (c1.0, CH ₃ OH) (5) Melting point: No melting point, melting around 77-78 ° C (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.38 (br dd, 2-H), 2.61 (dd, 2-H), 4.22 (m,
3-H), 3.37 (s, 4-OCH ₃ ), 3.39 (br dd, 5-H), 0.40 (br
dd, 7-H), 4,22 (m, 9-H), 5.74 (dd, 10-H), 6.11 (m, 11
-H), 6.11 (m, 12-H), 5.61 (dt, 13-H), 4.83 (ddq, 15-
H), 1.39 (dt, 17-H), 4.62 (br dd, 18-H), 4.17 (d, 1'-
H), 3.43 (dd, 2'-H), 2.53 (t, 3'-H), 3.35 (t, 4'-H),
2.51 (s, 3'-N (CH ₃ ) ₂ ), 5.03 (d, 1 "-H), 1.76 (dd, 2" -Ha
x), 1.97 (br d, 2 "-Heq), 1.24 (s, 3" -CH ₃ ), 2.70 (d,
4 "-H), 4.22 (dq, 5" -H), 3.59 (dt, 4 "-OC H ₂ CH ₂ CH ₂ CH ₂ CH
₃ )

Example 13 Compound (13) (in formula (VII), R ³ is a methyl group.
R ⁴ is represented by a pentyl group and R ⁶ is represented by a TBDMS group.
Compound (12) (148 mg) was added with chloroform (7.5 ml) and dissolved, m-chloroperbenzoic acid (35 mg) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution is a 10% aqueous solution of sodium thiosulfate 35 m
It was added dropwise to l and extracted with 70 ml of chloroform. The chloroform layer was washed successively with 70 ml of a saturated aqueous sodium hydrogen carbonate solution and 70 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. To the solid 145 mg obtained by concentrating the filtrate under reduced pressure, 1.5 ml of anhydrous dimethylformamide was added and dissolved, and 60% oily sodium hydride 26
mg was added and stirred at room temperature. After the bubbles were weakened, 545 mg of methyl iodide was added, and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, gradually add 35 ml of water and add chloroform.
Extracted with 75 ml. Chloroform (75 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed twice with 150 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was charged in a preparative TLC, left standing for 3 days, developed and purified (developing system: chloroform-methanol (20: 1)) to obtain 54 mg of compound (13). Physicochemical properties of compound (13) (1) Color and shape: colorless solid (2) Molecular formula: C ₅₃ H ₉₉ NO ₁₃ Si ₂ (3) Mass spectrum (SIMS): m / z 1014 (M + H)
⁺ (4) Specific rotation: [α] _D ²⁵ -2 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 63-64 ° C without showing a clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 4.06 (br dt, 3-H), 3.44 (s, 4-OCH ₃ ), 3.45
(dd, 5-H), 0.42 (br dd, 7-H), 4,18 (br d, 9-H), 5.73
(dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (dt,
13-H), 4.80 (ddq, 15-H), 1.31 (d, 16-H ₃ ), 1.43 (dt, 17
-H), 1.66 (br d, 17-H), 4.57 (br dd, 18-H), 4.29 (d,
1'-H), 3.32 (dd, 2'-H), 2.47 (t, 3'-H), 3.36 (t, 4'-
H), 2.55 (s, 3'-N (CH ₃ ) ₂ ), 4.87 (d, 1 "-H), 1.54 (dd,
2 "-Hax), 2.22 (d, 2" -Heq), 1.22 (s, 3 "-CH ₃ ), 2.76 (d,
4 "-H), 4.45 (dq, 5" -H), 3.25 (s, 3 "-OCH ₃ ), 3.54 (dt,
4 "-OC H ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 3.60 (dt, 4" -OC H ₂ CH ₂ CH ₂ CH ₂ CH
₃ )

Example 14 Compound (14) (in the formula (III), R ³ is a methyl group.
A compound in which R ⁴ is a pentyl group) (3 "-O-me
Method for producing tyl-4 "-O-pentylleucomycin V) To 50 mg of compound (13), 400 µl of 2M tetra-n-butylammonium fluoride tetrahydrofuran solution was added, and the mixture was reacted at 45 ° C for 1 hour. The mixture was added dropwise to 4.0 ml of 5% potassium hydrogensulfate aqueous solution and extracted twice with 25 ml of chloroform.The chloroform layers were combined and washed twice with 50 ml of saturated aqueous sodium hydrogen carbonate solution and twice with 50 ml of saturated saline solution. After that, the organic layer was dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (10 g: chloroform-methanol (50: 1)). compound (14) 23 mg to give compound (14) physicochemical properties (1) color and shape:. colorless solid (2) molecular _{formula: C 41 H 71 NO 13 (} 3) mass spectrum (SIMS) m / z 786 (M + H ) + (4) Specific ^{_{rotation: [α] D 24 -55 °}} (c1.0, CH 3 OH) (5) showed no clear melting point, at around 76 to 78 ° C. Melt (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.19 (br d, 2-H), 2.68 (dd, 2-H), 3.77 (br
d, 3-H), 3.07 (br d, 4-H), 3.52 (s, 4-OCH ₃ ), 4.08 (br
dd, 5-H), 1.88 (m, 8-H), 4.07 (dd, 9-H), 5.66 (dd, 1
0-H), 6.24 (dd, 11-H), 6.01 (br dd, 12-H), 5.58 (ddd,
13-H), 2.10 (dt, 14-H), 2.48 (br d, 14-H), 5.27 (dd
q, 15-H), 1.28 (d, 16-H ₃ ), 2.31 (br dd, 17-H), 9.80
(br s, 18-H), 0.99 (d, 19-H ₃ ), 4.57 (d, 1'-H), 3.16 (d
d, 2'-H), 2.40 (t, 3'-H), 3.45 (t, 4'-H), 3.25 (dq,
5'-H), 1.15 (d , 6'-H 3), 2.56 (s, 3'-N (CH 3) 2), 4.86
(d, 1 "-H), 1.54 (dd, 2" -Hax), 2.20 (d, 2 "-Heq), 1.22
(s, 3 "-CH ₃ ), 2.75 (d, 4" -H), 4.39 (dq, 5 "-H), 1.20
(d, 6 "-H ₃ ), 3.23 (s, 3" -OCH ₃ ), 3.54 (dt, 4 "-OC H ₂ CH ₂ C
H ₂ CH ₂ CH ₃ ), 3.58 (dt, 4 "-OC H ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 0.87 (br
t, 4 "-OCH ₂ CH ₂ CH ₂ CH ₂ C H ₃ )

Example 15Compound (15) (in formula (VI), R ⁴ is an isoamyl group
And a compound in which R ⁶ is a TBDMS group) Compound (2) 1.00 g and anhydrous dimethylformamide 15 ml
And dissolve, and add 192 mg of 60% oily sodium hydride.
Stir at room temperature. After the bubbles have weakened, isoamyl iodide
 5.70 g was added and stirred at 45 ° C. for 1 hour. Room temperature
Then, add 250 ml of water gradually, and add 25 ml of chloroform.
It was extracted with 0 ml. Add 250 ml of chloroform again to the aqueous layer.
I extracted it. Combine the chloroform layers and add this to saturated sodium chloride.
It was washed twice with 500 ml of water. The chloroform layer was washed with anhydrous sodium sulfate.
After drying with thorium, this was filtered and the filtrate was concentrated under reduced pressure.
The obtained residue is subjected to silica gel column chromatography.
(150 g: hexane-ethyl acetate (2: 1))
Compound (15) 715 mg was obtained. Physicochemical properties of compound (15) (1) Color and shape: colorless solid (2) molecular formula: C₅₈H₁₁₁NO₁₃Si₃ (3) Mass spectrum (FDMS): m / z 1113 (M)⁺ (4) Specific rotation: [α]_D ^{twenty five} -13 ° (c1.0, CH₃OH) (5) Melting point: No clear melting point, around 84-86 ℃
Melting with (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.37 (br dd, 2-H), 2.59 (dd, 2-H), 4.20 (m,
 3-H), 3.36 (s, 4-OCH₃), 3.38 (br dd, 5-H), 0.38 (br
dd, 7-H), 4,20 (m, 9-H), 5.73 (dd, 10-H), 6.10 (m, 11
-H), 6.10 (m, 12-H), 5.60 (dt, 13-H), 4.81 (ddq, 15-
H), 1.38 (dt, 17-H), 1.62 (br d, 17-H), 4.60 (br dd, 1
8-H), 4.16 (d, 1'-H), 3.42 (dd, 2'-H), 2.52 (t, 3'-
H), 3.34 (t, 4'-H), 2.50 (s, 3'-N (CH₃)₂), 5.01 (d, 1 "
-H), 1.74 (dd, 2 "-Hax), 1.95 (br d, 2" -Heq), 1.23 (s,
 3 "-CH₃), 2.69 (d, 4 "-H), 4.20 (dq, 5" -H), 3.59 (dt,
4 "-OCH ₂CH₂CH (CH₃)₂), 3.63 (dt, 4 "-OCH ₂CH₂CH (CH₃)₂),
 1.49 (m, 4 "-OCH₂CH ₂ CH (CH₃)₂), 1.68 (m, 4 "-OCH₂CH₂CH
(CH₃)₂)

Example 16 Compound (16) (in the formula (VII), R ³ is a methyl group.
R ⁴ is an isoamyl group and R ⁶ is a TBDMS group.
The compound) of Preparation Compound (15) in 1.42 g was dissolved by adding 71 ml of chloroform, m- chloroperbenzoic acid 328 mg was added and stirred for 5 minutes at room temperature. The reaction solution is a 10% aqueous solution of sodium thiosulfate 15
The mixture was added dropwise to 0 ml and extracted with 500 ml of chloroform. The chloroform layer was washed successively with 500 ml of a saturated aqueous sodium hydrogen carbonate solution and 500 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. 14 ml of anhydrous dimethylformamide was added to and dissolved in 1.42 g of a solid obtained by concentrating the filtrate under reduced pressure, 251 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles were weakened, 5.39 g of methyl iodide was added and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, 500 ml of water was gradually added, and the mixture was extracted with 500 ml of chloroform. Chloroform (500 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed twice with 500 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.55 g of an oily substance. To 190 mg of the obtained oily substance, 12 ml of methanol was added and dissolved, and after adsorbing on 16.0 g of silica gel, methanol was distilled off under reduced pressure, and the mixture was left overnight. The substance adsorbed on silica gel was extracted with a mixed solvent (chloroform-methanol (5: 1)), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (12 g: chloroform-methanol (50: 1)) to obtain 103 mg of compound (16). Physicochemical properties of compound (16) (1) Color and shape: Colorless solid (2) Molecular formula: C ₅₃ H ₉₉ NO ₁₃ Si ₂ (3) Mass spectrum (SIMS): m / z 1014 (M + H)
⁺ (4) Specific rotation: [α] _D ²⁵ -2 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 68-70 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.42 (dd, 2-H), 4.05 (br dt, 3-H), 3.44 (s,
4-OCH ₃ ), 3.46 (dd, 5-H), 0.42 (br dd, 7-H), 4,18 (br
d, 9-H), 5.73 (dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 1
2-H), 5.62 (dt, 13-H), 4.80 (ddq, 15-H), 1.31 (d, 16-
H ₃ ), 1.43 (dt, 17-H), 1.66 (br d, 17-H), 4.57 (br dd,
18-H), 4.30 (d, 1'-H), 3.32 (dd, 2'-H), 2.46 (t, 3'-
H), 3.36 (t, 4'-H), 2.55 (s, 3'-N (CH ₃ ) ₂ ), 4.87 (d, 1 "-
H), 1.54 (dd, 2 "-Hax), 2.21 (d, 2" -Heq), 1.22 (s, 3 "-
CH ₃ ), 2.76 (d, 4 "-H), 4.45 (dq, 5" -H), 3.25 (s, 3 "-OC
H ₃ ), 3.57 (dt, 4 "-OC H ₂ CH ₂ CH (CH ₃ ) ₂ ), 3.63 (dt, 4" -OC H ₂
CH ₂ CH (CH ₃ ) ₂ )

Example 17 Compound (16) (in the formula (VII), R ³ is a methyl group.
R ⁴ is an isoamyl group and R ⁶ is a TBDMS group.
The compound) of Preparation Compound (15) in 1.42 g was dissolved by adding 71 ml of chloroform, m- chloroperbenzoic acid 328 mg was added and stirred for 5 minutes at room temperature. Add 10% aqueous sodium thiosulfate solution to the reaction mixture 1
The mixture was added dropwise to 50 ml and extracted with 500 ml of chloroform. The chloroform layer was washed successively with 500 ml of a saturated aqueous sodium hydrogen carbonate solution and 500 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. 14 ml of anhydrous dimethylformamide was added to and dissolved in 1.42 g of a solid obtained by concentrating the filtrate under reduced pressure, 251 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles were weakened, 5.39 g of methyl iodide was added and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, gradually add 500 ml of water,
It was extracted with 500 ml of chloroform. Chloroform (500 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed twice with 500 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.55 g of an oily substance. To 190 mg of this oily substance, 19 ml of methanol and 19 ml of 0.025N hydrochloric acid were added.
Were sequentially added and dissolved, and the mixture was reacted at 45 ° C. for 2 hours. After returning the reaction solution to room temperature, a saturated aqueous solution of sodium hydrogencarbonate 150
The mixture was added dropwise to 150 ml and extracted twice with 150 ml of chloroform. The chloroform layers were combined and washed twice with 300 ml of saturated saline, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure is TL for preparative separation.
Purification with C (developing system: chloroform-methanol (30: 1)) yielded 98 mg of compound (16).

Example 18Compound (17) (in the formula (III), R ³ is a methyl group.
Represented by R ⁴ is an isoamyl group) (4 "-O-
Method for producing isoamyl-3 "-O-methylleucomycin V) Compound (16) 1.07 g to 2M tetra-n-butylammoni
Add 8.4 ml of umfluoride tetrahydrofuran solution.
Then, the mixture was reacted at 45 ° C. for 1 hour. The reaction solution was returned to room temperature
Then, add dropwise to 50 ml of 5% potassium hydrogensulfate aqueous solution and add chloro.
It was extracted twice with 300 ml of form. Combine the chloroform layers
And saturate with 600 ml of saturated aqueous sodium hydrogen carbonate solution twice.
After sequentially washing twice with 600 ml of saline solution, the organic layer was dehydrated.
It was dried over sodium acidate and filtered. The filtrate is concentrated under reduced pressure.
Silica gel column chromatograph of the residue obtained by shrinking
(100 g: chloroform-methanol (50: 1))
The compound (17) (380 mg) was obtained. Physicochemical properties of compound (17) (1) Color and shape: colorless solid (2) molecular formula: C₄₁H₇₁NO₁₃ (3) Mass spectrum (EIMS): m / z 785 (M)⁺ (4) Specific rotation: [α]_D ²⁶ -71 ° (c1.0, CH₃OH) (5) Melting at around 101-106 ℃ without showing clear melting point (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.22 (br d, 2-H), 2.71 (dd, 2-H), 3.80 (br
d, 3-H), 3.10 (br d, 4-H), 3.55 (s, 4-OCH₃), 4.12 (br
 dd, 5-H), 1.91 (m, 8-H), 4.11 (dd, 9-H), 5.69 (dd, 1
0-H), 6.27 (dd, 11-H), 6.04 (br dd, 12-H), 5.62 (ddd,
 13-H), 2.13 (dt, 14-H), 2.52 (br d, 14-H), 5.30 (ddq,
 15-H), 1.31 (d, 16-H₃), 2.34 (br dd, 17-H), 2.88 (br
 dd, 17-H), 9.81 (br s, 18-H), 0.99 (d, 19-H)₃), 4.60
(d, 1'-H), 3.18 (dd, 2'-H), 2.41 (t, 3'-H), 3.48 (t,
4'-H), 3.28 (dq, 5'-H), 1.18 (d, 6'-H₃), 2.57 (s, 3'-
N (CH ₃)₂), 4.90 (d, 1 "-H), 1.57 (dd, 2" -Hax), 2.23 (d,
 2 "-Heq), 1.25 (s, 3" -CH₃), 2.79 (d, 4 "-H), 4.43 (dq,
5 "-H), 1.23 (d, 6" -H₃), 3.26 (s, 3 "-OCH₃), 3.60 (dt,
4 "-OCH ₂CH₂CH (CH₃)₂), 3.64 (dt, 4 "-OCH ₂CH₂CH (CH₃)₂),
 1.52 (m, 4 "-OCH₂CH ₂ CH (CH₃)₂), 1.70 (m, 4 "-OCH₂CH₂CH
(CH₃)₂), 0.89 (d, 4 "-OCH₂CH₂CH (CH ₃ ) ₂ )

Example 19 Compound (18) (in formula (VII), R ³ is an ethyl group
R ⁴ is an isoamyl group and R ⁶ is a TBDMS group.
Compounds) of Preparation compound (15) in anhydrous dimethylformamide 1.0 190 mg
ml was added and dissolved, 34% of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles have weakened, ethyl iodide 7
96 mg was added and it stirred at 45 degreeC for 3 hours. After returning the reaction solution to room temperature, gradually add 100 ml of water, and add chloroform 100
extracted with ml. Chloroform (100 ml) was added again to the aqueous layer for extraction. Combine the chloroform layers and add saturated saline solution 1
It was washed twice with 00 ml. The chloroform layer was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure to obtain 114 mg of crude 9,18,2'-tri-O-TBDMS-3 "-O-ethyl-4" -O-isoamylleucomycin V-3,18-acetal. Chloroform (5.7 ml) was added to and dissolved in this, m-chloroperbenzoic acid (26 mg) was added, and the mixture was stirred at room temperature for 5 minutes. The reaction solution
The mixture was added dropwise to 30 ml of a 10% aqueous sodium thiosulfate solution and extracted with 60 ml of chloroform. The chloroform layer was diluted with 60 ml of saturated aqueous sodium hydrogencarbonate solution and 60 ml of saturated saline solution each for 2 times.
After being washed successively, the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure was charged in a preparative TLC, left standing for 3 days and developed (development system: chloroform-methanol (20: 1)) to obtain 56 mg of compound (18). It was Physicochemical properties of compound (18) (1) Color and shape: colorless solid (2) Molecular formula: C ₅₄ H ₁₀₁ NO ₁₃ Si ₂ (3) Mass spectrum (FDMS): m / z 1028 (M + H)
⁺ (4) Specific rotation: [α] _D ²⁶ -11 ° (c1.0, CH ₃ OH) (5) Melting point: 66-67 ° C (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.41 (dd, 2-H), 4.05 (br dt, 3-H), 3.44 (s,
4-OCH ₃ ), 0.42 (br dd, 7-H), 4,19 (br d, 9-H), 5.73 (d
d, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (dt, 1
3-H), 4.80 (ddq, 15-H), 1.31 (d, 16-H ₃ ), 1.44 (dt, 17-
H), 1.66 (br d, 17-H), 4.57 (br dd, 18-H), 4.29 (d,
1'-H), 3.33 (dd, 2'-H), 2.45 (t, 3'-H), 3.31 (t, 4'-
H), 3.24 (dq, 5'-H), 2.55 (s, 3'-N (CH ₃ ) ₂ ), 4.84 (d,
1 "-H), 1.54 (dd, 2" -Hax), 2.21 (d, 2 "-Heq), 1.23 (s,
3 "-CH ₃ ), 2.74 (d, 4" -H), 4.46 (dq, 5 "-H), 3.45 (dq,
3 "-OC H ₂ CH ₃ ), 3.50 (dq, 3" -OC H ₂ CH ₃ ), 1.14 (t, 3 "-OCH ₂
C H ₃ ), 3.54 (dt, 4 "-OC H ₂ CH ₂ CH (CH ₃ ) ₂ ), 3.66 (dt, 4" -OC
H ₂ CH ₂ CH (CH ₃ ) ₂ )

Example 20Compound (19) (in formula (III), R ³ is an ethyl group
Represented by R ⁴ is an isoamyl group) (3 "-O-
Method for producing ethyl-4 "-O-isoamyl leucomycin V) Compound (18) 56 mg to 2M tetra-n-butylammoni
Add 430 μl of um fluoride tetrahydrofuran solution.
Then, the mixture was reacted at 45 ° C. for 1 hour. The reaction solution was returned to room temperature
Then, add dropwise to 4.3 ml of 5% potassium hydrogensulfate aqueous solution and add black.
Extracted twice with 25 ml Loform. Combine the chloroform layers
And saturate with 50 ml of saturated aqueous sodium hydrogen carbonate solution twice.
After sequentially washing twice with 50 ml of brine, the organic layer was dried over anhydrous sulfuric acid.
It was dried over sodium and filtered. Concentrate the filtrate under reduced pressure
The residue obtained by silica gel column chromatography
-(10 g: chloroform-methanol (30: 1))
Thus, 23 mg of compound (19) was obtained. Physicochemical properties of compound (19) (1) Color and shape: Colorless solid (2) Molecular formula: C₄₂H₇₃NO₁₃ (3) Mass spectrum (EIMS): m / z 799 (M)⁺ (4) Specific rotation: [α]_D ²⁶ -70 ° (c1.0, CH₃OH) (5) Melting at around 98-100 ° C without showing clear melting point (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.20 (br d, 2-H), 2.69 (dd, 2-H), 3.77 (br
d, 3-H), 3.08 (br d, 4-H), 3.53 (s, 4-OCH₃), 4.09 (br
 dd, 5-H), 1.88 (m, 8-H), 4.08 (dd, 9-H), 5.66 (dd, 1
0-H), 6.25 (dd, 11-H), 6.01 (br dd, 12-H), 5.59 (ddd,
 13-H), 2.10 (dt, 14-H), 2.49 (br d, 14-H), 5.27 (dd
q, 15-H), 1.29 (d, 16-H₃), 2.31 (br dd, 17-H), 2.86
(br dd, 17-H), 9.80 (br s, 18-H), 0.97 (d, 19-H₃),
4.56 (d, 1'-H), 3.16 (dd, 2'-H), 2.38 (t, 3'-H), 3.40
(t, 4'-H), 3.24 (dq, 5'-H), 1.15 (d, 6'-H₃), 2.55 (s,
 3'-N (CH ₃)₂), 4.83 (d, 1 "-H), 1.55 (dd, 2" -Hax), 2.2
0 (d, 2 "-Heq), 1.22 (s, 3" -CH₃), 2.73 (d, 4 "-H), 4.41
(dq, 5 "-H), 1.21 (d, 6" -H₃), 3.42 (dq, 3 "-OCH ₂CH₃),
3.47 (dq, 3 "-OCH ₂CH₃), 1.11 (t, 3 "-OCH₂CH ₃ ), 3.56 (d
t, 4 "-OCH ₂CH₂CH (CH₃)₂), 3.64 (dt, 4 "-OCH ₂CH₂CH (CH₃)
₂), 1.49 (m, 4 "-OCH₂CH ₂ CH (CH₃)₂), 1.65 (m, 4 "-OCH ₂CH
₂CH(CH₃)₂), 0.87 (d, 4 "-OCH₂CH₂CH (CH ₃ ) ₂ )

Example 21 Compound (20) (in the formula (VII), R ³ is a propyl group)
, R ⁴ is an isoamyl group, and R ⁶ is a TBDMS group.
Preparation compound of the compound represented by) (15) 410 anhydrous mg dimethylformamide 820
μl was added and dissolved, 60% oily sodium hydride (74 mg) was added, and the mixture was stirred at room temperature. Propyl iodide after the bubbles have weakened
1.88 g was added and the mixture was stirred at 45 ° C. for 4 hours. After returning the reaction solution to room temperature, slowly add 200 ml of water and add chloroform 200
extracted with ml. 200 ml of chloroform was added again to the aqueous layer for extraction. Combine the chloroform layers and add this to saturated saline.
It was washed twice with 400 ml. The chloroform layer was dried over anhydrous sodium sulfate and then filtered. 420 mg of a solid obtained by concentrating the filtrate under reduced pressure was purified by preparative TLC (developing system: hexane-ethyl acetate (4: 1)) to obtain 9,18,2'-tri-O-.
TBDMS-4 "-O-isoamyl-3" -O-propylleucomycin V
147 mg of -3,18-acetal was obtained. Chloroform
6.5 ml was added and dissolved, 24 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was added dropwise to 25 ml of 10% aqueous sodium thiosulfate solution and extracted with 100 ml of chloroform. The chloroform layer was washed successively with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate and 100 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure is preparative TLC
And leave it for 3 days before developing and refining (Development system:
Chloroform-methanol (20: 1)), compound (20) 8
1 mg was obtained. Physicochemical properties of compound (20) (1) Color and shape: colorless solid (2) Molecular formula: C ₅₅ H ₁₀₃ NO ₁₃ Si ₂ (3) Mass spectrum (FDMS): m / z 1042 (M + H)
⁺ (4) Specific rotation: [α] _D ²⁴ -17 ° (c1.0, CHC
l ₃ ) (5) Melting around 57-63 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.43 (dd, 2-H), 4.07 (br d, 3-H), 3.27 (br
d, 4-H), 3.46 (s, 4-OCH ₃ ), 3.48 (br dd, 5-H), 4.21 (d
d, 9-H), 5.75 (dd, 10-H), 6.12 (m, 11-H), 6.12 (m, 12
-H), 5.64 (ddd, 13-H), 4.83 (ddq, 15-H), 1.33 (d, 16-
H ₃ ), 1.49 (br dd, 17-H), 4.59 (br s, 18-H), 4.31 (d,
1'-H), 3.36 (dd, 2'-H), 2.48 (t, 3'-H), 3.25 (dq, 5'-
H), 2.58 (s, 3'-N (CH ₃ ) ₂ ), 4.85 (d, 1 "-H), 1.57 (dd, 2"
-Hax), 2.21 (d, 2 "-Heq), 1.24 (s, 3" -CH ₃ ), 2.77 (d, 4 "
-H), 4.46 (dq, 5 "-H), 1.22 (d, 6" -H ₃ ), 3.42 (dt, 3 "-O
C H ₂ CH ₂ CH ₃ ), 0.88 (t, 3 "-OCH ₂ CH ₂ C H ₃ ), 3.59 (dt, 4" -OC
H ₂ CH ₂ CH (CH ₃ ) ₂ ), 3.68 (dt, 4 "-OC H ₂ CH ₂ CH (CH ₃ ) ₂ ), 0.90
(d, 4 "-OCH ₂ CH ₂ CH (C H ₃ ) ₂ )

Example 22 Compound (21) (in the formula (III), R ³ is a propyl group)
And a compound in which R ⁴ is an isoamyl group) (4 "-O
Method for producing -isoamyl- 3 "-O-propylleucomycin V) To 37 mg of compound (20) was added 280 µl of 2M tetra-n-butylammonium fluoride tetrahydrofuran solution, and the mixture was reacted at 45 ° C for 1 hour. After returning to room temperature, the mixture was added dropwise to 3 ml of 5% potassium hydrogen sulfate aqueous solution and extracted twice with 20 ml of chloroform.The chloroform layers were combined, twice with 50 ml of saturated aqueous sodium hydrogen carbonate solution and twice with 50 ml of saturated saline solution. After washing sequentially, the organic layer was dried over anhydrous sodium sulfate and filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (6.0 g: chloroform-methanol (50: 1)). ., compounds (21) to obtain a 9.8 mg physicochemical properties of the compound (21) (1) color and shape: colorless solid (2) molecular _{formula: C 43 H 75 NO 13 (} 3) mass spectrometry (SIMS): m / z 814 (M + H) + (4) Specific ^{_{rotation: [α] D 24 -73 °}} (c1.0, CH 3 O
H) (5) Melting in the vicinity of 88 to 93 ℃ without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.22 (br d, 2-H), 2.70 (dd, 2-H), 3.79 (br
d, 3-H), 3.10 (br d, 4-H), 3.55 (s, 4-OCH ₃ ), 4.10 (br
dd, 5-H), 1.91 (m, 8-H), 4.11 (dd, 9-H), 5.68 (dd, 1
0-H), 6.26 (dd, 11-H), 6.04 (br dd, 12-H), 5.61 (ddd,
13-H), 2.12 (dt, 14-H), 2.51 (br d, 14-H), 5.29 (ddq,
15-H), 1.30 (d, 16-H ₃ ), 2.33 (br dd, 17-H), 2.88 (br
dd, 17-H), 9.80 (br s, 18-H), 0.98 (d, 19-H ₃ ), 4.58
(d, 1'-H), 3.18 (dd, 2'-H), 2.40 (t, 3'-H), 3.41 (t,
4'-H), 3.26 (dq, 5'-H), 1.17 (d, 6'-H ₃ ), 2.56 (s, 3'-
N (CH ₃ ) ₂ ), 4.84 (d, 1 "-H), 1.57 (dd, 2" -Hax), 2.21 (d,
2 "-Heq), 1.23 (s, 3" -CH ₃ ), 2.76 (d, 4 "-H), 4.41 (dq,
5 "-H), 1.22 (d, 6" -H ₃ ), 3.28 (dt, 3 "-OC H ₂ CH ₂ CH ₃ ), 3.3
9 (dt, 3 "-OC H ₂ CH ₂ CH ₃ ), 0.87 (t, 3" -OCH ₂ CH ₂ C H ₃ ), 3.58
(dt, 4 "-OC H ₂ CH ₂ CH (CH ₃ ) ₂ ), 3.66 (dt, 4" -OC H ₂ CH ₂ CH (CH
₃ ) ₂ ), 1.68 (m, 4 "-OCH ₂ CH ₂ C H (CH ₃ ) ₂ ), 0.89 (d, 4" -OCH ₂
CH ₂ CH (C H ₃ ) ₂ )

Example 23 Compound (22) (in the formula (VII), R ³ is a methyl group.
R ⁴ is represented by a methyl group and R ⁶ is represented by a TBDMS group.
Compound (2) (200 mg) was dissolved in chloroform (10 ml), m-chloroperbenzoic acid (50 mg) was added, and the mixture was stirred at room temperature for 5 minutes. 50 ml of 10% aqueous sodium thiosulfate solution was added to the reaction mixture.
It was dripped at and extracted with 100 ml of chloroform. The chloroform layer was washed successively with 100 ml of a saturated aqueous solution of sodium hydrogen carbonate and 100 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. To 200 mg of the solid obtained by concentrating the filtrate under reduced pressure, 2.0 ml of anhydrous dimethylformamide was added and dissolved, and 60% oily sodium hydride was added.
60 mg was added and stirred at room temperature. After the bubbles were weakened, 1.2 g of methyl iodide was added and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, 100 ml of water was gradually added and extracted with 100 ml of chloroform. Chloroform 100m again in the water layer
l was added for extraction. The chloroform layers were combined and washed twice with 100 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Charge the resulting residue to a preparative TLC, 2
After standing for 1 day, it was developed and purified (developing system: chloroform-methanol (20: 1)) to obtain 55 mg of compound (22). Physicochemical properties of compound (22) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₉ H ₉₁ NO ₁₃ Si ₂ (3) Mass spectrum (FDMS): m / z 958 (M + H) ⁺ ( 4) Specific rotation: [α] _D ²⁶ -4 ° (c1.0, CH ₃ OH) (5) Melting point: 76 ° C (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 4.05 (br dt, 3-H), 3.44 (s, 4-OCH ₃ ), 3.46
(br d, 5-H), 0.41 (br dd, 7-H), 4,18 (br d, 9-H), 5.
72 (dd, 10-H), 6.10 (m, 11-H), 6.10 (m, 12-H), 5.62 (d
t, 13-H), 4.80 (ddq, 15-H), 1.30 (d, 16-H ₃ ), 1.43 (dt,
17-H), 1.66 (br d, 17-H), 4.57 (br dd, 18-H), 4.30
(d, 1'-H), 3.33 (dd, 2'-H), 2.46 (t, 3'-H), 3.36 (t,
4'-H), 2.55 (s, 3'-N (CH ₃ ) ₂ ), 4.87 (d, 1 "-H), 1.52 (dd,
2 "-Hax), 2.22 (d, 2" -Heq), 1.23 (s, 3 "-CH ₃ ), 2.56 (d,
4 "-H), 4.44 (dq, 5" -H), 3.24 (s, 3 "-OCH ₃ ), 3.53 (s,
4 "-OCH ₃ )

Example 24 Compound (23) (in the formula (III), R ³ is a methyl group.
Compound in which R ⁴ is a methyl group) (3 ", 4" -di-O
-Methylleucomycin V) Production Method To 55 mg of compound (22), 460 μl of 2M tetra-n-butylammonium fluoride tetrahydrofuran solution was added, and reacted at 45 ° C. for 1 hour. After the reaction solution was returned to room temperature, it was added dropwise to 4.6 ml of 5% potassium hydrogensulfate aqueous solution and extracted twice with 25 ml of chloroform. The chloroform layers were combined, washed with 50 ml of a saturated aqueous solution of sodium hydrogencarbonate twice and 50 ml of a saturated saline solution in this order, dried over anhydrous sodium sulfate, and filtered. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (10 g: chloroform-methanol (50: 1)) to obtain 12 mg of compound (23). Physicochemical properties of compound (23) (1) Color and shape: Colorless solid (2) Molecular formula: C ₃₇ H ₆₃ NO ₁₃ (3) Mass spectrum (SIMS): m / z 730 (M + H) ⁺ (4) Specific rotation: [α] _D ²⁵ -53 ° (c1.0, CH ₃ OH) (5) Melting around 99-101 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.20 (br d, 2-H), 2.68 (dd, 2-H), 3.77 (br
d, 3-H), 3.08 (br d, 4-H), 3.52 (s, 4-OCH ₃ ), 4.09 (br
dd, 5-H), 1.87 (m, 8-H), 4.08 (dd, 9-H), 5.66 (dd, 1
0-H), 6.25 (dd, 11-H), 6.02 (br dd, 12-H), 5.59 (ddd,
13-H), 2.10 (dt, 14-H), 2.49 (br d, 14-H), 5.27 (dd
q, 15-H), 1.29 (d, 16-H ₃ ), 2.31 (br dd, 17-H), 2.85
(br dd, 17-H), 9.80 (br s, 18-H), 4.57 (d, 1'-H), 2.
40 (t, 3'-H), 3.46 (t, 4'-H), 3.24 (dq, 5'-H), 1.16
(d, 6'-H ₃ ), 2.57 (s, 3'-N (CH ₃ ) ₂ ), 4.88 (d, 1 "-H), 1.
53 (dd, 2 "-Hax), 2.22 (d, 2" -Heq), 1.22 (s, 3 "-CH ₃ ),
2.66 (d, 4 "-H), 4.37 (dq, 5" -H), 1.21 (d, 6 "-H ₃ ), 3.2
2 (s, 3 "-OCH ₃ ), 3.52 (s, 4" -OCH ₃ )

Example 25 Compound (17) (in the formula (III), R ³ is a methyl group.
Represented by R ⁴ is an isoamyl group) (4 "-O-
Method for producing isoamyl-3 "-O-methylleucomycin V) To 1.42 g of compound (15), 71 ml of chloroform was added and dissolved, 328 mg of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 5 minutes. 10% sodium thiosulfate solution 15
The mixture was added dropwise to 0 ml and extracted with 500 ml of chloroform. The chloroform layer was washed successively with 500 ml of a saturated aqueous sodium hydrogen carbonate solution and 500 ml of a saturated saline solution twice each, and then the organic layer was dried over anhydrous sodium sulfate and filtered. 14 ml of anhydrous dimethylformamide was added to and dissolved in 1.42 g of a solid obtained by concentrating the filtrate under reduced pressure, 251 mg of 60% oily sodium hydride was added, and the mixture was stirred at room temperature. After the bubbles were weakened, 5.39 g of methyl iodide was added and the mixture was stirred at 45 ° C. for 1 hour. After returning the reaction solution to room temperature, 500 ml of water was gradually added, and the mixture was extracted with 500 ml of chloroform. Chloroform (500 ml) was added again to the aqueous layer for extraction. The chloroform layers were combined and washed twice with 500 ml of saturated saline. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1.55 g of an oily substance. To 38 mg of this oily substance, 2.7 ml of acetonitrile and 0.025N hydrochloric acid 2.7
ml was sequentially added and dissolved, and the mixture was reacted at 45 ° C. for 4 hours. After returning the reaction solution to room temperature, saturated aqueous sodium hydrogen carbonate solution
The mixture was added dropwise to 25 ml and extracted twice with 25 ml of chloroform.
The chloroform layers were combined and washed twice with 50 ml of saturated saline, and then the organic layer was dried over anhydrous sodium sulfate and filtered. The residue obtained by concentrating the filtrate under reduced pressure is used for preparative T
It was purified by LC (developing system: hexane-acetone-chloroform-methanol-concentrated aqueous ammonia (4: 4: 5: 1: 0.1)) to obtain 10 mg of compound (17).

Example 26 Compound (24) (in the formula (I), R ¹ is propionyl
Group, R ² is a hydrogen atom, and R ³ is a methyl group.
And R ⁴ is an isoamyl group) (4 "-O-
Soamyl-3 "-O-methyl-9-O-propionyl leucomyc
V) Production method Compound (17) 100 mg dry toluene
5.0 ml was added and dissolved, 55 μl of pyridine and 44 μl of acetyl chloride were added successively, and the mixture was stirred at room temperature for 45 minutes.
Saturated aqueous sodium hydrogen carbonate solution (10 ml) was gradually added to the reaction mixture, and the mixture was extracted with chloroform (20 ml) and saturated brine (1).
The extract was washed twice with 0 ml, dried over anhydrous sodium sulfate, and filtered. To the residue obtained by concentrating the filtrate under reduced pressure was added 10 ml of methanol to dissolve it, and the mixture was allowed to stand at room temperature for 24 hours. The residue obtained by concentration under reduced pressure was purified by preparative TLC (developing system: chloroform-methanol (10: 1)) to obtain 51 mg of compound (24). Physicochemical properties of compound (24) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₄ H ₇₅ NO ₁₄ (3) Mass spectrum (EIMS): m / z 841 (M) ⁺ (4) Specific rotation Degree: [α] _D ³⁰ -63 ° (c1.0, CH ₃ OH) (5) Melting around 97-100 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.19 (br d, 2-H), 2.68 (dd, 2-H), 3.76 (br
d, 3-H), 3.06 (br d, 4-H), 3.51 (s, 4-OCH ₃ ), 4.11 (br
dd, 5-H), 2.28 (br t, 6-H), 0.94 (br dt, 7-H), 1.58
(br dt, 7-H), 5.15 (dd, 9-H), 2.25 (q, 9-OCOC H ₂ CH ₃ ),
1.07 (t, 9-OCOCH ₂ C H ₃ ), 5.58 (dd, 10-H), 6.36 (dd, 11-
H), 6.00 (br dd, 12-H), 5.62 (ddd, 13-H), 2.09 (dt, 1
4-H), 2.47 (br d, 14-H), 5.26 (ddq, 15-H), 1.27 (d, 1
6-H ₃ ), 2.39 (br dd, 17-H), 2.80 (br dd, 17-H), 9.77
(br s, 18-H), 0.94 (d, 19-H ₃ ), 4.55 (d, 1'-H), 3.13
(br dd, 2'-H), 2.38 (t, 3'-H), 3.44 (t, 4'-H), 3.24
(dq, 5'-H), 1.15 (d, 6'-H ₃ ), 2.54 (s, 3'-N (CH ₃ ) ₂ ),
4.86 (d, 1 "-H), 1.53 (dd, 2" -Hax), 2.20 (d, 2 "-Heq),
1.21 (s, 3 "-CH ₃ ), 2.75 (d, 4" -H), 4.39 (dq, 5 "-H), 1.
19 (d, 6 "-H ₃ ), 3.22 (s, 3" -OCH ₃ ), 3.57 (dt, 4 "-OC H ₂ CH
₂ CH (CH ₃ ) ₂ ), 3.60 (dt, 4 "-OC H ₂ CH ₂ CH (CH ₃ ) ₂ ), 1.49 (m,
4 "-OCH ₂ C H ₂ CH (CH ₃ ) ₂ ), 1.65 (m, 4" -OCH ₂ CH ₂ C H (CH ₃ ) ₂ ),
0.86 (d, 4 "-OCH ₂ CH ₂ CH (C H ₃ ) ₂ )

[0070]

The first effect of the present invention is to create a useful novel 16-membered ring macrolide derivative. That is, the compounds (5), (8), (11), (14), (17), (1) represented by the general formula (I) obtained in the present invention
All of 9), (21), (23) and (24) have strong antibacterial activity against clinically important Gram-positive bacteria.
Tables 1 and 2 show several compounds of the present invention and leucomycin A ₇ (LM-A ₇ ) and myocamycin (MO) for comparison.
M) showed antibacterial activity.

[0071]

[Table 1]

[0072]

[Table 2] As shown in Table 1 and Table 2, in particular, compounds (11) and (1
4) and (17) are clearly superior to MOM in vitro
With natural antibacterial activity and natural leucomycin 16
The member-membered macrolide has the same or more prominent antibacterial activity, except for Haemophilus influenzae , even when compared to LM-A ₇ which belongs to a class having strong antibacterial activity.

Further, the compound represented by the general formula (I) obtained in the present invention is a leucomycin A in which the 3-position of the lactone ring is a free hydroxyl group and the propionyl group is bonded to the 4 "-position of the mycarose moiety. _It has the property that the antibacterial activity lasts longer in rat plasma as compared with _7. This stability is due to the fact that the hydroxyl group of the mycarose moiety in the compound obtained in the present invention is ester-bonded with an acyl group. However, according to the research report on myocamycin, the patterns of metabolism of the mycarose moiety are generally similar in humans and rats. Have been reported (pharmaceutical journal, 10
2 (8), 781 (1982)). Therefore, it is easily suggested that the derivatives according to the present invention, especially the compounds (11), (14), (17) and the like, retain their strong antibacterial activity in human blood for a relatively long time.

The second effect of the present invention is that it is an important synthetic intermediate for producing the novel 16-membered ring macrolide derivative represented by the general formula (I), and at the same time, it is extremely useful as an antibacterial agent. A compound represented by the general formula (III), which is a useful novel 16-membered ring macrolide derivative, can be prepared by
Another object of the present invention is to provide a novel production method for efficiently preparing a naturally occurring known 16-membered macrolide antibiotic represented by I) in 5 to 6 steps as a starting material. Previously, when the present inventors prepared the compound (17) of the present invention using midecamycin A ₃ and erythromycin as starting materials,
Eight-step chemical reaction including glycosylation reaction and two-step microbial conversion were performed, and the total yield from midecamycin A ₃ was less than 1%. However, according to the novel production method of the present invention, it has become possible to synthesize compound (17) using leucomycin A ₇ as a starting material in a total yield of about 10%.

To date, compound (19),
A compound in which an alkyl group other than a methyl group is introduced into the tertiary hydroxyl group at the 3 "-position of the mycalose moiety as in (21) is not known at all regardless of whether it is a natural product or a derivative. Providing new compounds provides important information to elucidate the structure-activity relationship of 16-membered macrolide derivatives and the relationship between their structure and their pharmacokinetics by promoting their biochemical evaluation. .

The third effect of the present invention is that the 16-membered macrolide compound, which has been chemically modified only by relatively mild reaction conditions until now, is provided by providing the novel production method. It was possible to chemically modify under various reaction conditions. That is, this new production method not only provides a methodology for introducing an alkyl group into each of the two hydroxyl groups of the mycarose moiety, but also uses a reaction condition that is more severe than that of acylation or the like to convert the neutral sugar moiety into a neutral sugar moiety. It also provides a methodology that can be radically chemically modified. Therefore, by using this new production method, it is possible to create a novel 16-membered ring macrolide derivative having a completely new structure in which the hydroxyl group of the mycalose moiety is modified.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Osamu Hara 760 Shimooka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Seiji Shibahara 760 Shimohara-cho, Kohoku-ku, Yokohama-shi, Kanagawa Address Meiji Seika Co., Ltd. Pharmaceutical Research Institute

Claims (10)

[Claims] 1. The following formula (I): [In the formula, R ¹ is a hydrogen atom or a group of the formula COR (where R is a carbon number 1
~ 3 straight chain alkyl group), R ² is a hydrogen atom or a formula
A COR group (wherein R has the same meaning as above), R ³ is a straight-chain alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R ⁴ is a substituted group. Or a non-substituted linear or branched alkyl group, alkenyl group or aralkyl group having 1 to 10 carbon atoms], or a pharmaceutically acceptable salt thereof. 2. In the formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a methyl group, and R ⁴ is a methyl group. Or a pharmaceutically acceptable salt thereof. 3. In the formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a methyl group, and R ⁴ is an ethyl group. Or a pharmaceutically acceptable salt thereof. 4. In the formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a methyl group, and R ⁴ is a propyl group. Or a pharmaceutically acceptable salt thereof. 5. In the formula (I) according to claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a methyl group, and R ⁴ is a butyl group. Or a pharmaceutically acceptable salt thereof. 6. In the formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a methyl group, and R ⁴ is a pentyl group. Or a pharmaceutically acceptable salt thereof. 7. In the formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is an ethyl group, and R ⁴ is an isoamyl group. Or a pharmaceutically acceptable salt thereof. 8. In the formula (I) of claim 1, R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³ is a propyl group, and R ⁴ is an isoamyl group. Or a pharmaceutically acceptable salt thereof. 9. In the formula (I) of claim 1, R ¹ is a propionyl group, R ² is a hydrogen atom, R ³ is a methyl group, and R ⁴ is an isoamyl group. Or a pharmaceutically acceptable salt thereof. 10. The following formula (II): [Wherein R ⁵ is a linear or branched aliphatic acyl group having 2 to ⁵ carbon atoms] or a salt thereof as a starting material, and the compound represented by the following formula (III): ] [In the formula, R ³ is a straight-chain alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted allyl group, and R ⁴ is a substituted or unsubstituted C 1 to 10 straight-chain group. Chain or branched alkyl group, alkenyl group or aralkyl group] or a salt thereof.