JPH0812696A - New 16-membered ring macrolide derivative and its efficient production - Google Patents

Abstract

PURPOSE:To obtain a new compound showing excellent effect in vivo as an antibacterial agent against gram-positive bacteria. CONSTITUTION:This compound is expressed by formula I (R<1> is H 1-3C straight- chain alkyl; R<2> is H or an OH-protecting group; R<3> is H or a 2-5C aliphatic acyl). The compound of formula I is obtained by using a compound of formula II (R<4> is a 2-5C aliphatic acyl) (salt) as a starting raw material. The hydroxyl group at the 3'' position of the compound is methylated and the hydroxyl group at the 3 position of the lactone ring is acylated.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 16-membered ring macrolide derivative effective against Gram-positive bacteria and an efficient method for producing the same.

[0002]

2. Description of the Related Art At present, groups in various countries are actively conducting derivative research on 16-membered macrolide antibiotics for the purpose of improving their clinical utility. Certain of these derivatives were synthesized in an attempt to improve in vitro antibacterial activity and / or pharmacokinetics by acylating a specific hydroxyl group. However, the mainstream of recent research on derivatives has been the introduction of substituted amino groups into 16-membered ring lactones (Journal of Antibiotics, 44 (4), 448 (1991)), or deoxylation of specific hydroxyl groups ( Journal of Antibiotics, 45
(1), 144 (1992)) or focused on alkylation.

The inventors of the present invention conducted derivative research based on the idea of the chemical structure of L-cladinose, which is one of the constituent sugars of erythromycin, and found that the 9-position of the lactone ring was the sp ³ carbon and the neutral sugar moiety. The hydroxyl group at the 3 "position is methylated 1
A 6-membered ring macrolide derivative (the 4 "position may be a free hydroxyl group or an acylated hydroxyl group) is prepared by way of a glycosylation reaction, and they have excellent antibacterial activity. On the other hand, regarding the synthesis and antibacterial activity of the 16-membered ring macrolide derivative in which the 9-position is sp ² carbon and the hydroxyl group at the 3 "-position is methylated, There is already a report prior to the application of the present inventors (Japanese Patent Application No. 5-3545) (Chemistry.
Letters, 769 (1977)).

On the other hand, our company is a 16-member ring
Chloride antibiotic medemycin (midecamycin
A₁) (Journal of Antibiotics,twenty four
(7), 452 (1971))in vivoAim to improve the effect
I continued to study derivatives. In the process of those studies
Have produced several excellent medemycin derivatives,
One of them is the hydroxyl group at the 3 "position, which is the neutral sugar moiety.
Tylthiomethyl (-CH₂SCH₃) Transformed 16-member ring macro
Derivative, that is, the synthesis of the key intermediate in the present application has already been announced.
(Journal of Antibiotics,33
(1), 61 (1980)). On the other hand, in sugar chemistry, secondary hydroxyl groups
The methylthiomethyl group introduced into
The fact that it is chemically converted to a methoxy group has been known since the 1960s.
(Carbo hydrate research,7, 474 (1
968)).

By the way, a 16-membered macrolide antibiotic in which the 3-position hydroxyl group of the lactone ring is free is used as a starting material, and an alkyl group is sequentially added to the neutral sugar moiety 4 "-position hydroxyl group and 3" -position hydroxyl group. Regarding the synthetic method to be introduced, the present inventors have already applied for a patent (Japanese Patent Application No. 5-206731).

[0006]

A 16-membered ring macrolide derivative in which the hydroxyl group at the 3 "position, which is a neutral sugar moiety, is methylated, and the hydroxyl group at the 4" position is free or is acylated, Up to now, no method for preparing it without going through a glycosylation reaction is known regardless of the structure at the 9-position. Therefore, in particular, it is expected to find a method for preparing the compound in which the 9-position of the lactone ring has sp ³ carbon, without going through the glycosylation reaction.

[0007]

Means for Solving the Problems The present inventors have repeatedly conducted synthetic chemical research in order to meet the above-mentioned expectations, using a natural 16-membered macrolide antibiotic having an acyl group at the 3-hydroxy group of the lactone ring as a starting material. A 16-membered ring in which the hydroxyl group at the 3-position of the lactone ring is acylated and the tertiary hydroxyl group at the 3 "-position, which is a neutral sugar moiety, is methylated via a methylthiomethyl ether synthetic intermediate at the 3-position We have succeeded in establishing a method for efficiently producing macrolide derivatives without going through a glycosylation reaction. Furthermore, the inventors have found that the derivative prepared using the production method of the present invention inhibits the growth of clinically important Gram-positive bacteria and has an excellent in vivo effect, and completed the present invention. Further, in the course of research leading to the present invention, an excellent protection / deprotection method for the hydroxyl group at the 9-position of the lactone ring of the 16-membered macrolide derivative was found.

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

[Chemical 4]

[In the formula, R ¹ is a linear alkyl group having 1 to 3 carbon atoms, R ² is a hydrogen atom or a substituent for modifying (or protecting) a hydroxyl group, and R ³ is a hydrogen atom or a carbon atom. Number 2-5
A linear or branched aliphatic acyl group of the above], or a pharmaceutically acceptable salt thereof.

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

Embedded image

A compound represented by the formula: wherein R ¹ is a linear alkyl group having 1 to 3 carbon atoms and R ⁴ is a linear or branched aliphatic acyl group having 2 to 5 carbon atoms. , Or a salt thereof as a starting material and passing through a methylthiomethyl ether synthetic intermediate at the 3 ”position to give the following formula (III):

[Chemical 6]

[In the formula, R ¹ is a linear alkyl group having 1 to 3 carbon atoms, R ² is a hydrogen atom or a substituent for modifying (or protecting) a hydroxyl group, and R ⁴ is 2 to 2 carbon atoms. 5 straight-chain or branched-chain aliphatic acyl group] or a salt thereof, which is capable of efficiently chemically synthesizing a compound. The compound represented by the general formula (III) according to the present invention is produced by the method shown in the process chart 1 as follows (the compound represented by the general formula (III) is represented by the formula in the process chart 1). (VIII) or formula (IX)).

[0013]

[Chemical 7]

[0014]

Embedded image

[0016] Regarding the promising antibacterial agent, a compound in which a methyl group is selectively introduced into the hydroxyl group at the 3 "-position of the neutral sugar moiety in the 16-membered ring macrolide derivative is a prior application (Japanese Patent Application No. 169418). On the other hand, for 16-membered ring macrolide compounds, especially leucomycins, it is known that direct alkylation of the hydroxyl group without going through a special synthetic intermediate causes a difficult problem. (Japanese Patent Application No. 5-206731). The present application relates to a compound in which the hydroxyl group at the 3-position of the lactone ring and the hydroxyl group at the 4 "position, which is the neutral sugar moiety, are both acylated, and the 3" position at the 3 "position, which is the neutral sugar moiety. A synthetic method in which a methyl group is indirectly introduced into a primary hydroxyl group is described, and the antibacterial activity and in vivo effect of the novel derivative prepared by the production method of the present invention are also described.

Prior to describing the synthetic method, the structure of the 16-membered macrolide derivative relating to the hydroxyl group at the 9-position of the lactone ring and the correlation with the in vitro antibacterial activity and pharmacokinetics will be briefly described. In the derivative, a compound in which only the 9-position hydroxyl group is selectively acylated, for example, acetylated, is
The in vitro antibacterial activity is equivalent to or slightly attenuated as compared with that of the drug substance, and there is almost no report that the activity is clearly enhanced. On the other hand, small animals, such as actually using a mouse in
In vivo tests showed that some compounds in which only the 9-position hydroxyl group was acetylated had improved derivative pharmacokinetics or infection treatment effects, while others did not, compared to the drug substance. The impact on in vivo effects is
It is greatly involved in the structure itself of the corresponding 16-membered macrolide derivative.

Therefore, in designing a synthetic method for actually producing a 16-membered ring macrolide derivative efficiently,
It is desired to construct a production route capable of separately producing a compound in which the 9-position hydroxyl group is modified with a substituent and a compound in which the 9-position hydroxyl group is free, by one key reaction.

By the way, an acyl group such as acetyl group
If the manufacturing method is designed by considering it as a protecting group for the hydroxyl group at the position, it is relatively convenient from the viewpoint of reaction conditions in the protecting step.
However, in the chemical synthesis of the 16-membered ring macrolide derivative, a method of completely suppressing other side reactions, removing the acyl group bonded to the hydroxyl group at the 9-position, and regenerating the free hydroxyl group is not well known. On the other hand, in the 16-membered macrolide derivative, an example of removing the acetyl group bonded to the 9-position hydroxyl group of the lactone ring by carrying out microbial conversion using actinomycetes has been reported (Journal of Fermentation. Andbio Engineering, 71 (5), 370 (1991)), but there seems to be room for improvement in the conversion rate.

Through the research, the present inventors have added to the synthetic method of introducing a methyl group into the tertiary hydroxyl group at the 3 "-position, which is the neutral sugar moiety of the 16-membered ring macrolide derivative, under mild conditions. Since a quantitative protection / deprotection method relating to the 9-position hydroxyl group of the lactone ring has been found, the details thereof will be described below with reference to Process Diagram 1. In Process Diagram 1, a lactone ring is shown as an example of the production process. Of 9
A natural 16-membered macrolide antibiotic with position sp ³ carbon is used as a starting material, but when a compound with a carbonyl group at position 9 is used as a starting material, a similar methodology is used to indirectly It is possible to efficiently introduce a methyl group into the tertiary hydroxyl group at the position.

First, among the free hydroxyl groups of the compound represented by the formula (II), two hydroxyl groups other than the 3 "position, that is, the 9 position and
A substituent is introduced into the 2'-position hydroxyl group to obtain a compound represented by the formula (V). First, the formula (II) (in the formula, R ¹ is a carbon number of 1 to
3 is a straight-chain alkyl group, and R ⁴ is a straight-chain or branched-chain aliphatic acyl group having 2 to 5 carbon atoms). Modified (or protected) with formula (IV) (wherein R ¹ is a straight chain alkyl group having 1 to 3 carbon atoms, and R ⁴ is a straight chain or branched chain group having 2 to 5 carbon atoms). A compound represented by an aliphatic acyl group and R ⁵ is a substituent that modifies (or protects) a hydroxyl group is obtained.

As the substituent R ⁵ , not only a lower aliphatic acyl group (Fermentation and Industry, 37 (12), 1171 (1979)) but also a substituent that can be used for ordinary modification of a hydroxyl group, for example, methoxymethyl is used. Groups and ethoxyethyl groups and the like. Further, when the substituent R ^{5 is} to be treated as a protective group for the hydroxyl group of the 16-membered ring macrolide derivative, an acetal-based substituent having an asymmetric carbon, for example, 1-ethoxyethyl group, tetrahydrofuranyl group or tetrahydropyranyl group Etc. are convenient.

As an example thereof, medemycin (formula (II)
In which R ¹ is an ethyl group and R ⁴ is a propionyl group) is reacted with ethyl vinyl ether in the presence of pyridinium p-toluenesulfonate (PPTS) in anhydrous methylene chloride to give compound (7) (formula In (IV), R ¹ is an ethyl group, R ⁴ is a propionyl group,
A compound in which R ⁵ is a 1-ethoxyethyl group was synthesized in good yield. The types of substituents that can be used in the step and the reaction conditions when introducing the substituents are not limited to those described here, and general substituents used as protective groups for hydroxyl groups ( Theodora W. Greene;
Peter GM Wuts. Protective Groups in Organic Synt
Hesis , 2nd ed., Wiley: New York, 1991), as well as the substituents that are difficult to use as a protecting group, and include all types and reaction conditions for introducing them.

By the way, an acetal-based protecting group having an asymmetric carbon, such as a 1-ethoxyethyl group, is attached to the lactone ring 9
When introduced into the hydroxyl group at the position, the derivative exists as a mixture of two diastereoisomers while the substituent is introduced. However, these isomers may or may not be separated. Also, when the substituent is regarded as a modifying group for the 9-position hydroxyl group of the lactone ring, these isomers may or may not be separated.

Next, in the compound represented by the formula (IV), the hydroxyl group at the 2'-position which is the mycaminose (amino sugar) moiety is protected by an acetyl group, and the compound represented by the formula (V) (in the formula, R ¹ has ¹ to 10 carbon atoms
3 is a linear alkyl group, R ⁴ is a linear or branched aliphatic acyl group having 2 to 5 carbon atoms, and R ⁵ is a substituent that modifies (or protects) a hydroxyl group. The compound represented is obtained. For example, compound (7) is reacted with acetic anhydride in anhydrous acetonitrile to give compound (8) (in formula (V), R ¹
Is an ethyl group, R ⁴ is a propionyl group, and R ⁵ is 1-
A compound having an ethoxyethyl group) was quantitatively obtained. At this time, among the compounds represented by the formula (V), the compound in which R ⁵ is an acetyl group can be prepared from the compound represented by the formula (II) in one step. In addition, the compound represented by the formula (V) is a compound represented by the formula (II), in which the 2'-position hydroxyl group of the mycaminose portion is selectively acetylated, and then a substituent is introduced into the hydroxyl group at the 9-position of the lactone ring. However, it can be easily prepared.

Secondly, a method for preparing a key compound, a synthetic intermediate of methylthiomethyl ether, will be described. First, a methylthiomethyl group is introduced into the tertiary hydroxyl group at the 3 "position, which is a neutral sugar. When dimethyl sulfoxide (DMSO) is reacted with acetic anhydride to oxidize the secondary hydroxyl group to a carbonyl group, a by-product is formed. It has been known since the 1960s that methyl thiomethyl ether can be obtained as a product (Journal of American Chemical Society, 89 (10), 2416 (196
7)). In the mid-1970s, it was also reported by the Japanese research group that the methylthiomethyl group was the most suitable as a protective group for the tertiary hydroxyl group in the synthesis of natural organic compounds (Tetrahedron Letters, 65 (1976)). In the late 1970s, the theoretical interpretation of adding acetic acid to the reaction system to promote methylthiomethylation over oxidation was also published (Australian Journal of Chemistry, 31 , 1031 (1978)).

First, according to the method of our research group (Journal of Antibiotics, 33 (1), 61 (1980)), the hydroxyl group at the 3 "position of the compound represented by the formula (V) is methylthiomethylated, With a yield of about 60 to 70%, R ¹ is a linear alkyl group having 1 to 3 carbon atoms, and R ⁴ is a linear or branched chain having 2 to 5 carbon atoms. A compound represented by an aliphatic acyl group and R ⁵ is a substituent that modifies (or protects) a hydroxyl group is synthesized, for example, compound (8)
DMSO is reacted with acetic anhydride to give compound (9) (formula (V
In I), a compound in which R ¹ is an ethyl group, R ⁴ is a propionyl group, and R ⁵ is a 1-ethoxyethyl group) was synthesized. There are many known methods for introducing a methylthiomethyl group into a hydroxyl group (Theodora W. Greene; Peter G.
M. Wuts. ProtectiveGroups in Organic Synthesis , 2n
ed., Wiley: New York, 1991), the production method of the present invention is not limited to the method for introducing a methylthiomethyl group, and includes all known methods related to the introduction method.

Next, the 2'position of the compound represented by the formula (VI)
The acetyl group bonded to the hydroxyl group of
I) (In the formula, R¹Is a linear alkyl group having 1 to 3 carbon atoms
R ^FourIs a linear or branched aliphatic acyl having 2 to 5 carbon atoms
The base and R^FiveIs a substituent that modifies (or protects) the hydroxyl group
Is a key compound represented by
The ether synthetic intermediate is quantitatively obtained. For example, compound (9)
To give compound (10)
(In the formula (VII), R¹Is an ethyl group and R^FourIs a professional
Is a pionyl group, R^FiveIs a 1-ethoxyethyl group
Thing).

Thirdly, the methylthiomethyl group introduced into the tertiary hydroxyl group at the 3 "position, which is the neutral sugar moiety of the key intermediate represented by the formula (VII), is selectively reduced to give the 3" position. The 16-membered ring macrolide derivative in which the tertiary hydroxyl group is methylated is efficiently synthesized. 2 methylthiomethylated in carbohydrate chemistry
Since it was reported that the primary hydroxyl group was reduced by Raney nickel and chemically converted to a methoxy group (Carbohydrate Research, 7 , 474 (1968)), a similar reaction example was introduced (Tetrahedron Letters, 43 (1969), Carbohydrate Research, 15 , 101 (1970)). In addition, relatively recently, it was reported that primary and secondary hydroxyl groups having an arylthiomethyl group introduced as a substituent other than the methylthiomethyl group undergo radical reduction or the like and are chemically converted to a methoxy group (Journal・ Of Organic Chemistry, 54 (25), 5998 (1989)).

As described above, the methodology for reducing a methylthiomethylated hydroxyl group to a methoxy group is by no means new, but most of the reduction reaction was carried out with a secondary hydroxyl group. Further, in most cases, the reaction substrate does not have a functional group showing reactivity to catalytic reduction such as a double bond or a free aldehyde group.

The present inventors have used Raney nickel with moderately controlled activity to methylthiomethylate the double bond and the free aldehyde group of the compound of formula (VII) without undergoing reduction. By chemically converting the tertiary hydroxyl group at the 3 "-position to a methoxy group, formula (VIII) (wherein R ¹ is a linear alkyl group having 1 to 3 carbon atoms, and R ⁴ is 2 to 2 carbon atoms).
5 is a straight-chain or branched-chain aliphatic acyl group, and R ⁵ is a substituent that modifies (or protects) the hydroxyl group. It was For example, the compound (10) is selectively stirred with Raney nickel whose activity is appropriately controlled at room temperature in ethanol to selectively give the compound (11) (in the formula (VIII), R ¹ is an ethyl group, and R ^A compound in which ⁴ is a propionyl group and R ⁵ is a 1-ethoxyethyl group) was synthesized. The selective reduction reaction efficiently proceeds even when R ⁵ is modified (or protected) with a substituent other than acetal, for example, an acetyl group like compound (1) (see Example 1).

In the selective reduction reaction, the methods for controlling the Raney nickel activity, the reaction solvent, the post-treatment method after the reaction, etc. are described in Examples 1, 4, 1 below.
Although described in 0 and 11, the production method of the present invention is not limited to the reaction conditions and the like, and the modification means thereof is also included in the present production method.

That is, in order to control the activity of Raney nickel, it is not necessary to limit to the method using acetone described in Example 1 of the present invention, and the control may be performed using ethyl acetate or hot water. Alternatively, it is possible to improve the selectivity of the reaction by adding a certain organic compound or inorganic compound containing a nitrogen atom, a sulfur atom or the like to the reaction system. On the other hand, the reaction solvent is not limited to lower alcohols such as ethanol,
Using an ether-based organic solvent such as 1,4-dioxane,
It is possible to carry out the reaction. Further, the method of post-treatment after the reaction is not limited as long as the reaction products can be extracted more efficiently than Raney nickel without decomposing the reaction products.

The compound represented by the formula (VIII) prepared as described above, by itself, inhibits the growth of clinically important Gram-positive bacteria and exhibits an excellent in vivo effect. Further, at this time, in the case where R ⁵ is a certain acetal-based substituent such as 1-ethoxyethyl group, tetrahydrofuranyl group or tetrahydropyranyl group, it is possible to further deprotect these substituents in good yield. Is.

That is, the substituent introduced into the 9-position hydroxyl group of the lactone ring of the compound represented by the formula (VIII) is treated under conditions suitable for the substituent (Theodora W. Greene; Peter G.
M. Wuts. Protective Groups in Organic Synthesis , 2
nd ed., Wiley: New York, 1991)
Formula (IX) (in the formula, R ¹ is a linear alkyl group having 1 to 3 carbon atoms, and R ⁴ is a linear or branched aliphatic acyl group having 2 to 5 carbon atoms) The compound obtained is quantitatively obtained. For example, compound (11) is reacted with a mixed solvent of 5% aqueous acetic acid solution: acetonitrile (3: 1) to give compound (12) (in formula (IX), R ¹ is an ethyl group, R ⁴
Was a propionyl group). The compound represented by the formula (IX) produced as described above also strongly inhibits the growth of clinically important Gram-positive bacteria.

In the process diagram 1, when the compound represented by the formula (IX) is synthesized from the compound represented by the formula (VII), first, methylthiomethyl ether at the 3 "-position, which is a neutral sugar moiety, is added. After reduction to the methoxy group, the substituent bonded to the hydroxyl group at the 9-position of the lactone ring was deprotected. On the other hand, when the 3'-position was reduced after deprotecting the 9-position first,
It is possible to produce compounds of formula (IX). However, the yield and selectivity in the selective reduction reaction at the 3 "-position are better when the compound represented by the formula (VII) is used as the substrate.

By the way, for the compound represented by the formula (IX) or a salt thereof, a known method of selectively acylating the hydroxyl group at the 9-position or 2'-position (Fermentation and Industry, 37 (12), 1171 (197
9)) (see Example 23) or a known method for 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 ( 1970), Annual Report of Meiji Seika, 12 , 85 (19)
72), Journal of Antibiotics, 35 (11),
1521 (1982)) or a known method for selectively oxidizing the hydroxyl group at the 9-position (Journal of Antibiotics,
24 (8), 526 (1971)), etc., and a novel useful substance based on the present invention can be produced. The present invention will now be described in detail by way of examples.

[0037]

【Example】

 Example 1Compound (2) (in the formula (VIII), R ¹ represents an ethyl group.
R ⁴ is a propionyl group and R ⁵ is an acetyl group.
Compound represented) (Japanese Patent Application No. 5-169418) First, the activity of Raney nickel was controlled. That is
6 ml of Raney nickel washed twice with 10 ml of water each time
After that, wash with 10 ml of acetone for 3 times while suppressing heat generation.
The sex was adjusted appropriately. Then 2 with each 10 ml ethanol
It was washed twice and used for the reaction. Compound (1) (formula
In (VII), R¹Is represented by an ethyl group, R ^FourIs propi
Represented by an onyl group, R^FiveIs a compound represented by an acetyl group)
(Journal of Antibiotics,33(1), 61
(1980)) After dissolving 227 mg in 20 ml of ethanol,
Of Raney Nickel with controlled
It was added to the reaction solution together with ethanol. 20 at room temperature
After stirring vigorously for 1 minute, the insoluble matter was filtered and concentrated to 1% (v / v).
Wash twice with 20 ml each of ethanol containing ammonia water
Was. The filtrate and washings were combined and concentrated under reduced pressure to obtain a residue 2
90 mg of TLC for separation (Development system: benzene-acetone (3:
The compound (2) 79 mg was obtained by purification with 1)).

Example 2 Compound (4) (in the formula (VI), R ¹ represents a methyl group.
R ⁴ is an isovaleryl group and R ⁵ is an acetyl group.
In the compound) of Preparation Compound (3) (formula (V), R ¹ is represented by a methyl group, R ⁴ is represented by an isovaleryl group, a compound R ⁵ is represented by an acetyl group) (Tetrahedron・ Letters, 609 (196
7)) 2.0 g was dissolved in a mixed solution of 63 ml of DMSO and 6.3 ml of acetic anhydride, and then reacted at 33 ° C for 3 days. After 2.0 L of toluene was added to the reaction solution, it was washed 4 times with 2.0 L of water. The toluene layer was dried over anhydrous sodium sulfate and then filtered,
3.00 g of the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (300 g: hexane-ethyl acetate (3: 1) → (1: 1)) to obtain 1.4 g of compound (4). It was Physicochemical properties of compound (4) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₈ H ₇₇ NO ₁₇ S (3) Mass spectrum (SIMS): m / z 972 (M + H) ⁺ (4) ) Specific rotation: [α] _D ²⁴ -85 ° (c1.0, CHCl ₃ ) (5) Melting point: Melting at 118-122 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.25 (br d, 2-H), 2.72 (dd, 2-H), 5.09 (br
d, 3-H), 3.16 (br d, 4-H), 3.50 (s, 4-OCH ₃ ), 3.94 (br
d, 5-H), 0.85 (br ddd, 7-H), 1.46 (br dt, 7-H), 5.0
5 (dd, 9-H), 5.56 (dd, 10-H), 6.70 (dd, 11-H), 6.05 (b
r dd, 12-H), 5.85 (ddd, 13-H), 2.45 (br dt, 14-H),
4.99 (ddq, 15-H), 1.26 (d, 16-H ₃ ), 2.55 (br dd, 17-
H), 2.81 (br dd, 17-H), 9.63 (br s, 18-H), 0.96 (d, 1
9-H ₃ ), 2.30 (s, 3-OCOCH ₃ ), 2.00 (s, 9-OCOCH ₃ ), 4.59
(d, 1'-H), 4.91 (dd, 2'-H), 2.68 (t, 3'-H), 3.16 (t,
4'-H), 3.26 (dq, 5'-H), 1.14 (d, 6'-H ₃ ), 2.00 (s, 2'-
OCOCH ₃ ), 2.42 (s, 3'-N (CH ₃ ) ₂ ), 4,81 (d, 1 "-H), 1.68
(dd, 2 "-Hax), 1.18 (s, 3" -CH ₃ ), 4.63 (d, 4 "-H), 4.56
(dq, 5 "-H), 1.05 (d, 6" -H ₃ ), 4.50 (d, 3 "-OC H ₂ SCH ₃ ),
4.64 (d, 3 "-OC H ₂ SCH ₃ ), 2.20 (s, 3" -OCH ₂ SC H ₃ ), 0.98
(d, 4 "-OCOCH ₂ CH (C H ₃ ) ₂ )

Example 3Compound (5) (in formula (VII), R ¹ represents a methyl group.
R ⁴ is an isovaleryl group and R ⁵ is an acetyl group.
Represented compound) 1.30 g of compound (4) was dissolved in 39 ml of methanol
Then, the mixture was reacted at 33 ° C for 16 hours. The reaction solution was concentrated under reduced pressure.
1.29 g of the residue obtained by silica gel column chromatography
Purified with Raffy (125 g: hexane-ethyl acetate (1: 1))
Thus, 964 mg of compound (5) was obtained. Physicochemical properties of compound (5) (1) Color and shape: colorless solid (2) molecular formula: C₄₆H₇₅NO₁₆S (3) Mass spectrum (SIMS): m / z 930 (M + H)⁺ (4) Specific rotation: [α]_D ^{twenty four} -77 ° (c1.0, CH₃OH) (5) Melting point: No clear melting point at 115-118 ° C
Melting (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.27 (br d, 2-H), 2.75 (dd, 2-H), 5.00 (br
d, 3-H), 3.25 (br d, 4-H), 3.57 (s, 4-OCH₃), 3.96 (br
 d, 5-H), 0.93 (br ddd, 7-H), 1.57 (br dt, 7-H), 4.9
7 (dd, 9-H), 5.57 (dd, 10-H), 6.71 (dd, 11-H), 6.09 (b
r dd, 12-H), 5.86 (ddd, 13-H), 2.47 (br dt, 14-H),
5.00 (ddq, 15-H), 1.27 (d, 16-H₃), 2.59 (br dd, 17-
H), 2.84 (br dd, 17-H), 9.66 (br s, 18-H), 0.96 (d, 1
9-H₃), 2.29 (s, 3-OCOCH₃), 2.01 (s, 9-OCOCH₃), 4.50
(d, 1'-H), 3.21 (dd, 2'-H), 2.42 (t, 3'-H), 3.42 (t,
4'-H), 3.28 (dq, 5'-H), 1.15 (d, 6'-H₃), 2.58 (s, 3'-
N (CH₃)₂), 4,92 (d, 1 "-H), 1.74 (dd, 2" -Hax), 1.20 (s,
 3 "-CH₃), 4.66 (d, 4 "-H), 4.56 (dq, 5" -H), 1.08 (d,
6 "-H ₃), 4.52 (d, 3 "-OCH ₂SCH₃), 4.65 (d, 3 "-OCH ₂SC
H₃), 2.18 (s, 3 "-OCH₂SCH ₃ ), 0.98 (d, 4 "-OCOCH₂CH (C
H ₃ ) ₂ )

Example 4 Compound (6) (in the formula (VIII), R ¹ represents a methyl group.
R ⁴ is an isovaleryl group and R ⁵ is an acetyl group.
After the preparation the compound (5) 300 mg of the compound) represented in ethanol 7.0 ml, Raney nickel 15ml controlling the activity in the same manner as in Example 1, was added to the solution along with 7.5 ml of ethanol. This was vigorously stirred at room temperature for 20 minutes, the insoluble material was filtered off, and washed twice with 30 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. The filtrate and washings were combined and concentrated under reduced pressure to obtain 297 mg of the residue, which was purified by preparative TLC (developing system: toluene-acetone (3: 1)) to obtain 81 mg of compound (6). Physicochemical properties of compound (6) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₅ H ₇₃ NO ₁₆ (3) Mass spectrum (SIMS): m / z 884 (M + H) ⁺ (4) Specific rotation: [α] _D ²⁶ -74 ° (c1.0, CH ₃ OH) (5) Melting point: No melting point, melting at 115-119 ° C (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.75 (dd, 2-H), 5.12 (br d, 3-H), 3.25 (br
d, 4-H), 3.57 (s, 4-OCH ₃ ), 3.96 (br d, 5-H), 0.92 (br
ddd, 7-H), 1.58 (br dt, 7-H), 5.06 (dd, 9-H), 5.57
(dd, 10-H), 6.71 (dd, 11-H), 6.09 (br dd, 12-H), 5.8
6 (ddd, 13-H), 4.99 (ddq, 15-H), 1.26 (d, 16-H ₃ ), 2.5
9 (br dd, 17-H), 2.84 (br dd, 17-H), 9.66 (br s, 18-
H), 0.96 (d, 19-H ₃ ), 2.29 (s, 3-OCOCH ₃ ), 2.01 (s, 9-O
COCH ₃ ), 4.51 (d, 1'-H), 3.19 (dd, 2'-H), 2.42 (t, 3'-
H), 3.46 (t, 4'-H), 3.29 (dq, 5'-H), 1.16 (d, 6'-H ₃ ),
2.58 (s, 3'-N (CH ₃ ) ₂ ), 4,93 (d, 1 "-H), 1.67 (dd, 2" -H
ax), 1.11 (s, 3 "-CH ₃ ), 4.72 (d, 4" -H), 5.54 (dq, 5 "-
H), 1.08 (d, 6 "-H ₃ ), 3.26 (s, 3" -OCH ₃ ), 0.97 (d, 4 "-O
COCH ₂ CH (C H ₃ ) ₂ )

Example 5 Compound (7) (in the formula (IV), R ¹ represents an ethyl group.
R ⁴ is represented by a propionyl group, and R ⁵ is 1-ethoxyethyl.
The compound represented by the formula (1) is dissolved in a mixed solution of 600 ml of methylene chloride and 22 ml of ethyl vinyl ether, and then 9.4 g of PPTS is added.
Was added, and the mixture was reacted at room temperature for 16 hours. The reaction mixture was gradually added to 2.0 L of saturated aqueous sodium hydrogen carbonate solution, and extracted with 1.8 L of chloroform. Chloroform layer was 5% potassium hydrogen sulfate aqueous solution 2.0 L, saturated sodium hydrogen carbonate aqueous solution 2.0
It was washed successively with L and 2.0 L of a saturated sodium chloride aqueous solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue (23.0 g), which was purified by silica gel column chromatography (1.0 kg: chloroform-methanol (50: 1)) to give a compound. (7)
I got 20 g. Physicochemical properties of compound (7) (1) Color and shape: Colorless solid (2) Molecular formula: C ₄₅ H ₇₅ NO ₁₆ (3) Mass spectrum (EIMS): m / z 885 (M) ⁺ (4) Specific rotation Degree: [α] _D ²¹ -61 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 100 to 103 ° C without showing a clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.28 (br d, 2-H), 2.73 (dd, 2-H), 2.74 (dd,
2-H), 5.13 (br d, 3-H), 3.24 (br d, 4-H), 3.53 (s, 4
-OCH ₃ ), 3.87 (br d, 5-H), 1.44 (br dt, 7-H), 1.90 (m,
8-H), 3.78 (dd, 9-H), 3.92 (dd, 9-H), 5.47 (dd, 10-
H), 5.56 (dd, 10-H), 6.57 (dd, 11-H), 6.61 (dd, 11-
H), 6.09 (br dd, 12-H), 5.78 (br ddd, 13-H), 5.82 (br
ddd, 13-H), 2.15 (br dt, 14-H), 5.02 (ddq, 15-H),
2.82 (br dd, 17-H), 2.83 (br dd, 17-H), 9.64 (br s, 18
-H), 9.65 (br s, 18-H), 0.99 (d, 19-H ₃ ), 1.00 (d, 19-
H ₃ ), 2.63 (br dq, 3-OCOC H ₂ CH ₃ ), 4.64 (q, 9-OC H (OCH ₂ C
H ₃ ) CH ₃ ), 4.66 (q, 9-OC H (OCH ₂ CH ₃ ) CH ₃ ), 3.44 (dq, 9-OC
H (OC H ₂ CH ₃ ) CH ₃ ), 3.63 (dq, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 4.41
(d, 1'-H), 2.51 (s, 3'-N (CH ₃ ) ₂ ), 5.07 (d, 1 "-H), 1.85
(dd, 2 "-Hax), 2.01 (d, 2" -Heq), 1.12 (s, 3 "-CH ₃ ), 4.
62 (d, 4 "-H), 4.46 (dq, 5" -H), 1.13 (d, 6 "-H ₃ ), 2.44
(apparent q, 4 "-OCOC H ₂ CH ₃ ), 2.46 (ap. q, 4" -OCOC H ₂ C
H ₃ ), 1.18 (t, 4 "-OCOCH ₂ C H ₃ )

Example 6 Compound (8) (in the formula (V), R ¹ represents an ethyl group.
R ⁴ is represented by a propionyl group, and R ⁵ is 1-ethoxyethyl.
The compound (7) (12 g) was dissolved in acetonitrile (370 ml), acetic anhydride (2.7 ml) was added, and the mixture was reacted at 40 ° C. for 16 hours. 42 ml of 1N aqueous ammonia solution was added dropwise, and 1 at room temperature
It was left for 0 minutes. The reaction solution was concentrated under reduced pressure, the residue obtained was dissolved in 1.0 L of chloroform, and washed successively with 1.0 L of saturated aqueous sodium hydrogen carbonate solution and 1.2 L of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 13 g of compound (8). Physicochemical properties of compound (8) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₇ H ₇₇ NO ₁₇ (3) Mass spectrum (SIMS): m / z 928 (M + H) ⁺ (4) Specific rotation: [α] _D ²¹ -64 ° (c1.0, CHCl ₃ ) (5) Melting point: Melting at 104-107 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.24 (br d, 2-H), 2.70 (dd, 2-H), 5.11 (br
d, 3-H), 3.17 (br d, 4-H), 3.47 (s, 4-OCH ₃ ), 3.89 (br
d, 5-H), 1.42 (br t, 7-H), 3.75 (dd, 9-H), 3.88 (dd,
9-H), 5.45 (dd, 10-H), 5.54 (dd, 10-H), 6.57 (dd, 11
-H), 6.61 (dd, 11-H), 6.05 (br dd, 12-H), 5.79 (ddd, 1
3-H), 5.83 (ddd, 13-H), 2.15 (br dt, 14-H), 2.26 (br
dd, 17-H), 2.81 (br dd, 17-H), 9.62 (br s, 18-H), 9.6
3 (br s, 18-H), 0.98 (d, 19-H ₃ ), 0.99 (d, 19-H ₃ ), 2.65
(dq, 3-OCOC H ₂ CH ₃ ), 4.64 (q, 9-OC H (OCH ₂ CH ₃ ) CH ₃ ), 4.6
5 (q, 9-OC H (OCH ₂ CH ₃ ) CH ₃ ), 3.35 (dq, 9-OCH (OC H ₂ CH ₃ ) CH
₃ ), 3.43 (dq, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 3.49 (dq, 9-OCH (OC
H ₂ CH ₃ ) CH ₃ ), 3.62 (dq, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 4.61 (d,
1'-H), 4.98 (dd, 2'-H), 2.02 (s, 2'-OCOCH ₃ ), 2.41 (s,
3'-N (CH ₃ ) ₂ ), 5.06 (d, 1 "-H), 1.84 (dd, 2" -Hax), 2.0
0 (d, 2 "-Heq), 1.12 (br s, 3" -CH ₃ ), 4.62 (d, 4 "-H), 4.
37 (dq, 5 "-H), 2.43 (apparent q, 4" -OCOC H ₂ CH ₃ ), 2.44
(apparent q, 4 "-OCOC H ₂ CH ₃ ), 1.18 (t, 4" -OCOCH ₂ C H ₃ )

Example 7Compound (9H) (in formula (VI), R ¹ represents an ethyl group.
R ⁴ is a propionyl group and R ⁵ is 1-ethoxyethyl.
Among the compounds represented by the chill group, in the development system described later
The isomer with the higher Rf value in TLC) and the compound (9
L) (in the formula (VI), R ¹ is an ethyl group and R ⁴ is
It is represented by a propionyl group and R ⁵ is represented by a 1-ethoxyethyl group.
Isomer of the same compound with the smaller Rf value)
Law Compound (8) 305 mg was added to DMSO 9.1 ml and acetic anhydride 0.91 ml.
After being dissolved in the mixed solution of, the reaction was carried out at 30 ° C. for 16 hours.
The reaction solution was gradually added to 60 ml of toluene, and 60 ml of water was added 3 times.
Washed. After drying the toluene layer with anhydrous sodium sulfate,
It was filtered and the filtrate was concentrated under reduced pressure. Residue obtained 300 m
silica gel chromatography (30 g: hexane-vinegar)
Ethyl acetate (1: 1)) to obtain 195 mg of compound (9)
Was. Of this, 106 mg was used for separation TLC (Development system: Hexane-
Repurified with ethyl acetate (1: 1)), compound (9H) 56 mg
And 39 mg of compounds (9L) were obtained. Physicochemical properties of compound (9H) (1) Color and shape: Colorless solid (2) Molecular formula: C₄₉H₈₁NO₁₇S (3) Mass spectrum (FDMS): m / z 988 (M + H)⁺ (4) Rf value in TLC: 0.50 (expansion system: hexa
-Ethyl acetate (1: 1)) (5) Specific rotation: [α]_D ¹⁹ -71 ° (c1.0, CHCl₃(6) Melting at around 94-96 ℃ without showing clear melting point (7)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.24 (br d, 2-H), 2.72 (dd, 2-H), 5.11 (br
d, 3-H), 3.17 (br d, 4-H), 3.49 (s, 4-OCH₃), 3.87 (br
 d, 5-H), 0.85 (br dt, 7-H), 1.41 (br dt, 7-H), 1.87
(m, 8-H), 3.88 (dd, 9-H), 5.45 (dd, 10-H), 6.61 (dd,
11-H), 6.06 (br dd, 12-H), 5.82 (ddd, 13-H), 2.15 (d
t, 14-H), 4.99 (ddq, 15-H), 1.26 (d, 16-H₃), 2.83 (br
 dd, 17-H), 9.62 (br s, 18-H), 0.98 (d, 19-H₃), 2.50
(dq, 3-OCOCH ₂CH₃), 2.65 (dq, 3-OCOCH ₂CH₃), 1.21 (t,
3-OCOCH₂CH ₃ ), 3.42 (dq, 9-OCH (OCH ₂CH₃) CH₃), 3.50 (d
q, 9-OCH (OCH ₂CH₃) CH₃), 1.14 (t, 9-OCH (OCH₂CH ₃ ) CH₃),
 1.22 (d, 9-OCH (OCH₂CH₃) CH ₃ ), 4.60 (d, 1'-H), 4.92 (d
d, 2'-H), 2.68 (t, 3'-H), 3.16 (t, 4'-H), 3.26 (dq,
5'-H), 1.14 (d, 6'-H₃), 2.01 (s, 2'-OCOCH₃), 2.43 (s,
 3'-N (CH₃)₂), 4.81 (d, 1 "-H), 1.68 (dd, 2" -Hax), 2.2
5 (d, 2 "-Heq), 1.17 (s, 3" -CH₃), 4.56 (dq, 5 "-H), 1.05
(d, 6 "-H₃), 4.51 (d, 3 "-OCH ₂SCH₃), 4.64, 4.65 (2 × d,
 4 "-H, 3" -OCH ₂SCH ₃), 2.20 (s, 3 "-OCH₂SCH ₃ ), 2.42 (q,
 4 "-OCOCH ₂ CH₃), 1.18 (t, 4 "-OCOCH₂CH ₃ ) Physicochemical properties of compound (9L) (1) Color and shape: Colorless solid (2) Molecular formula: C₄₉H₈₁NO₁₇S (3) Mass spectrum (FDMS): m / z 988 (M + H)⁺ (4) Rf value in TLC: 0.46 (expansion system: hexa
-Ethyl acetate (1: 1)) (5) Specific rotation: [α]_D ¹⁹ -87 ° (c1.0, CHCl₃) (6) Melting around 90-94 ℃ without showing clear melting point (7)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.25 (br d, 2-H), 2.72 (dd, 2-H), 5.11 (br
d, 3-H), 3.18 (br d, 4-H), 3.49 (s, 4-OCH₃), 3.87 (br
 d, 5-H), 0.87 (br dt, 7-H), 1.43 (br dt, 7-H), 1.86
(m, 8-H), 3.74 (dd, 9-H), 5.54 (dd, 10-H), 6.58 (dd,
 11-H), 6.06 (br dd, 12-H), 5.80 (ddd, 13-H), 2.15 (d
t, 14-H), 5.00 (ddq, 15-H), 1.26 (d, 16-H)₃), 2.84 (br
 dd, 17-H), 9.63 (br s, 18-H), 0.98 (d, 19-H₃), 2.52
(dq, 3-OCOCH ₂CH₃), 2.65 (dq, 3-OCOCH ₂CH₃), 1.23 (t,
3-OCOCH₂CH ₃ ), 4.65 (q, 9-OCH(OCH₂CH₃) CH₃), 3.35 (dq,
 9-OCH (OCH ₂CH₃) CH₃), 3.63 (dq, 9-OCH (OCH ₂CH₃) CH₃),
1.14 (t, 9-OCH (OCH₂CH ₃ ) CH₃), 1.25 (d, 9-OCH (OCH₂CH₃) C
H ₃ ), 4.60 (d, 1'-H), 4.92 (dd, 2'-H), 2.68 (t, 3'-H),
 3.16 (t, 4'-H), 3.26 (dq, 5'-H), 1.14 (d, 6'-H₃), 2.
01 (s, 2'-OCOCH₃), 2.43 (s, 3'-N (CH₃)₂), 4.81 (d, 1 "-
H), 1.69 (dd, 2 "-Hax), 2.26 (d, 2" -Heq), 1.17 (s, 3 "-
CH₃), 4.57 (dq, 5 "-H), 1.05 (d, 6" -H₃), 4.51 (d, 3 "-O
CH ₂SCH₃), 4.64, 4.65 (2 × d, 4 "-H, 3" -OCH ₂SCH₃), 2.2
0 (s, 3 "-OCH₂SCH ₃ ), 2.42 (q, 4 "-OCOCH ₂ CH₃), 1.18 (t,
4 "-OCOCH₂CH ₃ )

Example 8 Compound (10H) (in the formula (VII), R ¹ is an ethyl group
, R ⁴ is a propionyl group, and R ⁵ is 1-ethoxy
From compounds (9H) among compounds represented by cyethyl group
Method for producing derivatized isomer 50 mg of the compound (9H) was dissolved in 1.5 ml of methanol and then reacted at 30 ° C. for 16 hours. The reaction solution is concentrated under reduced pressure,
The obtained residue (47 mg) was used for separation TLC (development system: hexane-
Purified with ethyl acetate (1: 1)), compound (10H) 36 mg
I got Physicochemical properties of compound (10H) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₇ H ₇₉ NO ₁₆ S (3) Mass spectrum (SIMS): m / z 946 (M + H) ⁺ (4 ) Rf value in TLC: 0.24 (Development system: Hexane-ethyl acetate (1: 1)) (5) Specific rotation: [α] _D ¹⁹ -55 ° (c1.0, CH ₃ OH) (6) Melting point: Melts in the vicinity of 95-98 ℃ without showing clear melting point (7) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.26 (br d, 2-H), 2.75 (dd, 2-H), 5.13 (br
d, 3-H), 3.26 (br d, 4-H), 3.57 (s, 4-OCH ₃ ), 3.88 (br
d, 5-H), 0.93 (br ddd, 7-H), 1.53 (br dt, 7-H), 1.8
9 (m, 8-H), 3.90 (dd, 9-H), 5.46 (dd, 10-H), 6.62 (dd,
11-H), 6.10 (br dd, 12-H), 5.83 (ddd, 13-H), 5.01 (d
dq, 15-H), 2.85 (br dd, 17-H), 9.63 (br s, 18-H), 0.
98 (d, 19-H ₃ ), 2.51 (dq, 3-OCOC H ₂ CH ₃ ), 2.64 (dq, 3-OC
OC H ₂ CH ₃ ), 4.64 (q, 9-OC H (OCH ₂ CH ₃ ) CH ₃ ), 3.43 (dq, 9-O
CH (OC H ₂ CH ₃ ) CH ₃ ), 3.50 (dq, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 4.51
(d, 1'-H), 3.41 (t, 4'-H), 3.28 (dq, 5'-H), 2.58 (s,
_{3'-N (CH 3) 2} ), 4.92 (d, 1 "-H), 1.75 (dd, 2" -Hax), 2.28
(d, 2 "-Heq), 4.56 (dq, 5" -H), 1.08 (d, 6 "-H ₃ ), 4.52
(d, 3 "-OC H ₂ SCH ₃ ), 4.65, 4.66 (2 × d, 4" -H, 3 "-OC H ₂ SC
H ₃ ), 2.19 (s, 3 "-OCH ₂ SC H ₃ ), 2.42 (q, 4" -OCOC H ₂ CH ₃ )

Example 9Compound (10 L) (in formula (VII), R ¹ is an ethyl group
, R ⁴ is a propionyl group, and R ⁵ is 1-ethoxy
From compounds (9L) among compounds represented by cyethyl group
Derived isomer) production method 230 mg of the compound (9 L) was dissolved in 6.8 ml of methanol.
Then, the mixture was reacted at 30 ° C. for 16 hours. The reaction solution is concentrated under reduced pressure,
The obtained residue, 204 mg, was used for separation TLC (development system: hexane-
Purified with ethyl acetate (1: 1)), compound (10 L) 150 mg
Got Physicochemical properties of compound (10 L) (1) Color and shape: Colorless solid (2) Molecular formula: C₄₇H₇₉NO₁₆S (3) Mass spectrum (SIMS): m / z 946 (M + H)⁺ (4) Rf value in TLC: 0.16 (expansion system: hexa
-Ethyl acetate (1: 1)) (5) Specific rotation: [α]_D ¹⁹ -73 ° (c1.0, CH₃OH) (6) Melting point: No melting point, melting at 91-93 ° C
Melt (7)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.26 (br d, 2-H), 2.75 (dd, 2-H), 5.13 (br
d, 3-H), 3.26 (br d, 4-H), 3.57 (s, 4-OCH₃), 3.88 (br
 d, 5-H), 0.94 (br ddd, 7-H), 1.53 (br dt, 7-H), 1.8
8 (m, 8-H), 3.76 (dd, 9-H), 5.55 (dd, 10-H), 6.59 (d
d, 11-H), 6.09 (br dd, 12-H), 5.80 (ddd, 13-H), 5.02
(ddq, 15-H), 2.25 (br dd, 17-H), 2.85 (br dd, 17-H),
 9.64 (br s, 18-H), 2.52 (dq, 3-OCOCH ₂CH₃), 2.65 (dq,
3-OCOCH ₂CH₃), 3.36 (dq, 9-OCH (OCH ₂CH₃) CH₃), 3.63 (d
q, 9-OCH (OCH ₂CH₃) CH₃), 4.51 (d, 1'-H), 3.41 (t, 4'-
H), 3.28 (dq, 5'-H), 2.59 (s, 3'-N (CH₃)₂), 4.92 (d,
1 "-H), 1.75 (dd, 2" -Hax), 2.28 (d, 2 "-Heq), 4.56 (dq,
 5 "-H), 1.08 (d, 6" -H₃), 4.52 (d, 3 "-OCH ₂SCH₃), 4.6
5,4.66 (2 × d, 4 "-H, 3" -OCH ₂SCH₃), 2.19 (s, 3 "-OCH₂SC
H ₃ ), 2.42 (q, 4 "-OCOCH ₂ CH ₃)

Example 10 Compound (11H) (in the formula (VIII), R ¹ is an ethyl group
, R ⁴ is a propionyl group, and R ⁵ is 1-ethoxy
Compound (10H) among compounds represented by cyethyl group
After dissolving Ri induced isomer) of preparation the compound (10H) 30 mg of ethanol 0.35 ml, a 0.75 ml of Raney nickel was controlled activity in the same manner as in Example 1, the above solution along with 0.40 ml of ethanol added. This was vigorously stirred for 20 minutes at room temperature, then the insoluble matter was filtered off, and washed twice with 1.5 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. The filtrate and washings were combined and concentrated under reduced pressure.
(Development system: toluene-acetone (2: 1)) to obtain 10 mg of compound (11H). Physicochemical properties of compound (11H) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₆ H ₇₇ NO ₁₆ (3) Mass spectrum (SIMS): m / z 900 (M + H) ⁺ (4) Rf value in TLC: 0.32 (Development system: Toluene-acetone (3: 1)) (5) Specific rotation: [α] _D ¹⁹ -43 ° (c1.0, CH ₃ OH) (6) Clear melting point Melting around 90-93 ℃ (7) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.26 (br d, 2-H), 2.74 (dd, 2-H), 5.13 (br
d, 3-H), 3.26 (br d, 4-H), 3.57 (s, 4-OCH ₃ ), 3.88 (br
d, 5-H), 2.13 (br t, 6-H), 0.93 (br ddd, 7-H), 1.54
(br dt, 7-H), 1.89 (m, 8-H), 3.90 (dd, 9-H), 5.46 (d
d, 10-H), 6.62 (dd, 11-H), 6.10 (br dd, 12-H), 5.83
(ddd, 13-H), 2.17 (dt, 14-H), 5.00 (ddq, 15-H), 1.26
(d, 16-H ₃ ), 2.28 (br dd, 17-H), 2.85 (br dd, 17-H),
9.64 (br s, 18-H), 0.98 (d, 19-H ₃ ), 2.50 (dq, 3-OCOC H ₂
CH ₃ ), 2.64 (dq, 3-OCOC H ₂ CH ₃ ), 1.23 (t, 3-OCOCH ₂ C H ₃ ),
4.64 (q, 9-OC H (OCH ₂ CH ₃ ) CH ₃ ), 3.43 (dq, 9-OCH (OC H ₂ CH
₃ ) CH ₃ ), 3.50 (dq, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 1.14 (t, 9-OCH
(OCH ₂ C H ₃ ) CH ₃ ), 1.22 (d, 9-OCH (OCH ₂ CH ₃ ) C H ₃ ), 4.53 (d,
1'-H), 3.46 (t, 4'-H), 3.29 (dq, 5'-H), 1.16 (d, 6'-
H ₃ ), 2.60 (s, 3'-N (CH ₃ ) ₂ ), 4.93 (d, 1 "-H), 1.67 (dd,
2 "-Hax), 2.29 (d, 2" -Heq), 1.11 (s, 3 "-CH ₃ ), 4.73 (d,
4 "-H), 4.54 (dq, 5" -H), 1.08 (d, 6 "-H ₃ ), 3.26 (s, 3"-
OCH ₃ ), 2.43 (apparent q, 4 "-OCOC H ₂ CH ₃ ), 2.44 (ap. Q,
4 "-OCOC H ₂ CH ₃ ), 1.20 (t, 4" -OCOCH ₂ C H ₃ )

Example 11Compound (11L) (in the formula (VIII), R ¹ is an ethyl group
, R ⁴ is a propionyl group, and R ⁵ is 1-ethoxy
Compound (10 L) among compounds represented by cyethyl group
Isomer) Dissolve 150 mg of compound (10 L) in 2.0 ml of ethanol
Then, 3.8 ml of Raney nickel was treated in the same manner as in Example 1.
Control the activity and mix with 1.8 ml ethanol.
It was added to the above solution. This was stirred vigorously for 20 minutes at room temperature
After that, the insoluble matter is filtered and contains 1% (v / v) concentrated aqueous ammonia.
It was washed twice with 4.0 ml each of ethanol. Combine the filtrate and wash
And concentrate the residue under reduced pressure to obtain 145 mg of the residue, which is then separated by TLC for separation.
(Development system: toluene-acetone (2: 1))
32 mg of the product (11 L) was obtained. Physicochemical properties of compound (11L) (1) Color and shape: Colorless solid (2) Molecular formula: C₄₆H₇₇NO₁₆ (3) Mass spectrum (SIMS): m / z 900 (M + H)⁺ (4) Rf value in TLC: 0.32 (Development system: Torue
-Acetone (3: 1)) (5) Specific rotation: [α]_D ¹⁹ -65 ° (c1.0, CH₃OH) (6) Melting point: No clear melting point, around 87-90 ° C
Melting with (7)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.26 (br d, 2-H), 2.75 (dd, 2-H), 5.13 (br
d, 3-H), 3.26 (br d, 4-H), 3.57 (s, 4-OCH₃), 3.88 (br
 d, 5-H), 2.13 (br t, 6-H), 0.94 (br ddd, 7-H), 1.55
(br dt, 7-H), 1.88 (m, 8-H), 3.75 (dd, 9-H), 5.55 (d
d, 10-H), 6.59 (dd, 11-H), 6.09 (br dd, 12-H), 5.80
(ddd, 13-H), 2.16 (dt, 14-H), 5.01 (ddq, 15-H), 1.26
(d, 16-H₃), 2.25 (br dd, 17-H), 2.86 (br dd, 17-H),
9.64 (br s, 18-H), 2.52 (dq, 3-OCOCH ₂CH₃), 2.64 (dq,
3-OCOCH ₂CH₃), 1.23 (t, 3-OCOCH₂CH ₃ ), 3.36 (dq, 9-OCH
(OCH ₂CH₃) CH₃), 3.63 (dq, 9-OCH (OCH ₂CH₃) CH₃), 1.14
(t, 9-OCH (OCH₂CH ₃ ) CH₃), 1.25 (d, 9-OCH (OCH₂CH₃) C
H ₃ ), 4.52 (d, 1'-H), 3.21 (dd, 2'-H), 2.42 (t, 3'-H),
 3.45 (t, 4'-H), 3.29 (dq, 5'-H), 1.16 (d, 6'-H₃), 2.
57 (s, 3'-N (CH₃)₂), 4.92 (d, 1 "-H), 1.67 (dd, 2" -Hax),
 2.29 (d, 2 "-Heq), 1.10 (s, 3" -CH₃), 4.72 (d, 4 "-H),
4.55 (dq, 5 "-H), 1.08 (d, 6" -H₃), 3.26 (s, 3 "-OCH₃),
2.43 (apparent q, 4 "-OCOCH ₂CH₃), 2.44 (ap. Q, 4 "-OCO
CH ₂CH₃), 1.18 (t, 4 "-OCOCH₂CH ₃ )

Example 12 Compound (12) (in the formula (IX), R ¹ represents an ethyl group.
Compound in which R ⁴ is a propionyl group)
5-169418) Production method 60 mg of compound (11H) was dissolved in a mixed solution of 4.5 ml of 5% aqueous acetic acid solution and 1.5 ml of acetonitrile, and the mixture was mixed with 1
The reaction was performed for 6 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in 10 ml of chloroform, and then the mixture was washed 3 times with 10 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 10 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 56 mg of the residue, which was purified by preparative TLC (developing system: chloroform-methanol (10: 1)) to give the compound (12 ) 50
to obtain mg.

Example 13 Method for producing compound (12) 30 mg of compound (11 L) was dissolved in a mixed solution of 2.4 ml of a 5% aqueous acetic acid solution and 0.8 ml of acetonitrile, and the mixture was allowed to stand at room temperature for 1 hour.
The reaction was performed for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue obtained was dissolved in 5.0 ml of chloroform, and the mixture was washed 3 times with 5.0 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 5.0 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 28 mg of the residue, which was purified by preparative TLC (developing system: chloroform-methanol (10: 1)) to give compound (1
2) 24 mg was obtained.

Example 14 Compound (13) (in formula (IV), R ¹ represents a methyl group.
R ⁴ is an isovaleryl group, and R ⁵ is 1-ethoxyethyl.
Preparation method of compound represented by tyl group) 10.0 g of Josamycin was dissolved in a mixed solution of 300 ml of methylene chloride and 16 ml of ethyl vinyl ether, and then PPTS
5.40 g was added and reacted at room temperature for 4 days. The reaction solution was gradually added to 1.0 L of saturated sodium hydrogen carbonate aqueous solution, and extracted with 0.80 L of chloroform. The chloroform layer was washed successively with 1.0% aqueous 5% potassium hydrogen sulfate solution, 1.0 L saturated aqueous sodium hydrogen carbonate solution and 1.0 L saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue of 12.0.
g was purified by silica gel column chromatography (600 g: chloroform-methanol (50: 1)) to give compound (1
3) Obtained 8.40 g. Physicochemical properties of compound (13) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₆ H ₇₇ NO ₁₆ (3) Mass spectrum (EIMS): m / z 899 (M) ⁺ (4) Specific rotation Degree: [α] _D ¹⁶ -68 ° (c1.0, CH ₃ OH) (5) Melting point: Melting at 105 to 108 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.73 (dd, 2-H), 2.75 (dd, 2-H), 5.12 (br d,
3-H), 3.24 (br d, 4-H), 3.54 (s, 4-OCH ₃ ), 3.90 (br
d, 5-H), 1.45 (br dt, 7-H), 1.90 (m, 8-H), 3.75 (dd,
9-H), 3.89 (dd, 9-H), 5.46 (dd, 10-H), 5.55 (dd, 10-
H), 6.56 (dd, 11-H), 6.58 (dd, 11-H), 6.08 (br dd, 12
-H), 5.76 (ddd, 13-H), 5.81 (ddd, 13-H), 5.04 (ddq, 1
5-H), 1.27 (d, 16-H ₃ ), 2.84 (br dd, 17-H), 2.85 (br d
d, 17-H), 9.64 (s, 18-H), 9.65 (s, 18-H), 0.98 (d, 19
-H ₃ ), 0.99 (d, 19-H ₃ ), 4.63 (q, 9-OC H (OCH ₂ CH ₃ ) CH ₃ ),
4.64 (q, 9-OC H (OCH ₂ CH ₃ ) CH ₃ ), 3.35 (dq, 9-OCH (OC H ₂ CH ₃ )
CH ₃ ), 3.42 (dq, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 3.63 (dq, 9-OCH
(OC H ₂ CH ₃ ) CH ₃ ), 1.14 (t, 9-OCH (OCH ₂ C H ₃ ) CH ₃ ), 1.23 (d,
9-OCH (OCH ₂ CH ₃ ) C H ₃ ), 1.25 (d, 9-OCH (OCH ₂ CH ₃ ) C H ₃ ), 4.
43 (d, 1'-H), 3.28 (t, 4'-H), 1.19 (d, 6'-H ₃ ), 2.52
(s, 3'-N (CH ₃ ) ₂ ), 5.07 (d, 1 "-H), 1.85 (dd, 2" -Hax),
2.02 (d, 2 "-Heq), 1.12 (s, 3" -CH ₃ ), 4.63 (d, 4 "-H),
4.46 (dq, 5 "-H), 1.14 (d, 6" -H ₃ ), 0.98 (d, 4 "-OCOCH ₂ C
H (C H ₃ ) ₂ )

Example 15Compound (14) (in formula (V), R ¹ represents a methyl group.
R ⁴ is an isovaleryl group, and R ⁵ is 1-ethoxyethyl.
Compound represented by tyl group) Dissolve 7.70 g of compound (13) in 231 ml of acetonitrile
After that, add 1.6 ml of acetic anhydride and react at 40 ℃ for 16 hours.
Was. Add 25 ml of 1N aqueous ammonia solution, and add 1 at room temperature.
It was left for 0 minutes. The residue obtained by concentrating the reaction solution under reduced pressure
Dissolved in 800 ml of chloroform and saturated sodium bicarbonate
800 ml aqueous solution and 800 ml saturated aqueous sodium chloride solution
Was sequentially washed. Chloroform layer is anhydrous sodium sulfate
After drying with, this was filtered, and the filtrate was concentrated under reduced pressure. Got
7.90 g of the residue was subjected to silica gel column chromatography (7
00 g: hexane-ethyl acetate (1: 1))
(14) 5.10 g was obtained. Physicochemical properties of compound (14) (1) Color and shape: colorless solid (2) molecular formula: C₄₈H₇₉NO₁₇ (3) Mass spectrum (FDMS): m / z 942 (M + H)⁺ (4) Specific rotation: [α]_D ¹⁹ -70 ° (c1.0, CHCl₃) (5) Melting point: No clear melting point at 110-113 ° C
Melting (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.25 (br d, 2-H), 2.72 (dd, 2-H), 5.10 (br
d, 3-H), 3.18 (br d, 4-H), 3.49 (s, 4-OCH₃), 3.91 (br
 d, 5-H), 0.86 (br ddd, 7-H), 1.43 (br dt, 7-H), 3.7
2 (dd, 9-H), 3.86 (dd, 9-H), 5.46 (dd, 10-H), 5.54 (d
d, 10-H), 6.55 (dd, 11-H), 6.58 (dd, 11-H), 6.05 (br
dd, 12-H), 5.76 (ddd, 13-H), 5.81 (ddd, 13-H), 2.12
(dt, 14-H), 2.45 (br dt, 14-H), 5.01 (ddq, 15-H), 1.
26 (d, 16-H₃), 2.83 (br dd, 17-H), 9.63 (s, 18-H), 9.
64 (s, 18-H), 2.29 (s, 3-OCOCH₃), 3.34 (dq, 9-OCH (OCH
₂CH₃) CH ₃), 3.41 (dq, 9-OCH (OCH ₂CH₃) CH₃), 3.63 (dq, 9
-OCH (OCH ₂CH₃) CH₃), 1.14 (t, 9-OCH (OCH₂CH ₃ ) CH₃), 1.2
2 (d, 9-OCH (OCH₂CH₃) CH ₃ ), 1.24 (d, 9-OCH (OCH₂CH₃) C
H ₃ ), 4.99 (dd, 2'-H), 2.69 (t, 3'-H), 1.18 (d, 6'-
H₃), 2.02 (s, 2'-OCOCH₃), 2.41 (s, 3'-N (CH₃)₂), 5.06
(d, 1 "-H), 1.84 (dd, 2" -Hax), 2.01 (d, 2 "-Heq), 1.12
(s, 3 "-CH₃), 4.38 (dq, 5 "-H), 1.13 (d, 6" -H₃), 0.98
(d, 4 "-OCOCH₂CH (CH ₃ ) ₂ )

Example 16Compound (15) (in formula (VI), R ¹ represents a methyl group.
R ⁴ is an isovaleryl group, and R ⁵ is 1-ethoxyethyl.
Compound represented by tyl group) Compound (14) (5.00 g) in DMSO (150 ml) and acetic anhydride (15 ml)
After being dissolved in the mixed solution of, the reaction was carried out at 30 ° C. for 40 hours.
The reaction solution was gradually added to 1.0 L of toluene, and 1.0 L of water was added 3 times.
Washed. After drying the toluene layer with anhydrous sodium sulfate,
It was filtered and the filtrate was concentrated under reduced pressure. The residue obtained 6.41g
Silica gel column chromatography (500 g: hexa
-Ethyl acetate (1: 1)) to give compound (15) 2.
Got 25 g. Physicochemical properties of compound (15) (1) Color and shape: colorless solid (2) molecular formula: C₅₀H₈₃NO₁₇S (3) Mass spectrum (FDMS): m / z 1002 (M + H)
⁺ (4) Specific rotation: [α]_D ¹⁶ -87 ° (c1.0, CHCl₃) (5) Melting around 102-105 ℃ without showing clear melting point (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.25 (br d, 2-H), 2.72 (dd, 2-H), 2.73 (dd,
 2-H), 5.10 (br d, 3-H), 3.18 (br d, 4-H), 3.50 (s, 4
-OCH₃), 3.51 (s, 4-OCH₃), 3.89 (br d, 5-H), 0.85 (br
ddd, 7-H), 1.43 (br dt, 7-H), 1.87 (m, 8-H), 3.73 (d
d, 9-H), 3.86 (dd, 9-H), 5.45 (dd, 10-H), 5.54 (dd, 10
-H), 6.54 (dd, 11-H), 6.58 (dd, 11-H), 6.05 (br dd, 1
2-H), 5.76 (ddd, 13-H), 5.82 (ddd, 13-H), 2.15 (dt, 1
4-H), 2.45 (br dt, 14-H), 5.01 (ddq, 15-H), 1.26 (d,
16-H₃), 2.85 (br dd, 17-H), 9.63 (s, 18-H), 9.64 (s,
18-H), 0.99 (d, 19-H₃), 3.35 (dq, 9-OCH (OCH ₂CH₃) C
H₃), 3.41 (dq, 9-OCH (OCH ₂CH₃) CH ₃), 3.63 (dq, 9-OCH (O
CH ₂CH₃) CH₃), 1.14 (br t, 9-OCH (OCH₂CH ₃ ) CH₃), 1.22
(d, 9-OCH (OCH₂CH₃) CH ₃ ), 1.24 (d, 9-OCH (OCH₂CH₃) CH ₃ ),
 5.10 (d, 1'-H), 4.93 (dd, 2'-H), 2.68 (t, 3'-H), 3.16
(t, 4'-H), 3.27 (dq, 5'-H), 1.14 (d, 6'-H₃), 2.01 (s,
 2'-OCOCH₃), 2.42 (s, 3'-N (CH₃)₂), 4.81 (d, 1 "-H),
1.68 (dd, 2 "-Hax), 1.18 (s, 3" -CH₃), 4.57 (dq, 5 "-H),
 1.05 (d, 6 "-H₃), 4.50 (d, 3 "-OCH ₂SCH₃), 4.64, 4.65
(2 × d, 4 "-H, 3" -OCH ₂SCH₃), 2.20 (s, 3 "-OCH₂SCH ₃ ),
0.98 (d, 4 "-OCOCH₂CH (CH ₃ ) ₂ )

Embodiment 17Compound (16) (in formula (VII), R ¹ is a methyl group
R ⁴ is an isovaleryl group and R ⁵ is 1-ethoxy.
Method for producing compound represented by ethyl group) 2.20 g of compound (15) was dissolved in 65 ml of methanol.
Then, the mixture was reacted at room temperature for 40 hours. The reaction solution is concentrated under reduced pressure,
2.10 g of compound (16) was obtained. Physicochemical properties of compound (16) (1) Color and shape: colorless solid (2) molecular formula: C₄₈H₈₁NO₁₆S (3) Mass spectrum (FDMS): m / z 959 (M)⁺ (4) Specific rotation: [α]_D ¹⁸ -75 ° (c1.0, CH₃OH) (5) Melting point: No clear melting point, with 105-107 ° C
Melting nearby (6)¹1 H NMR spectrum (400MHz, CDCl₃) δ
(ppm): 2.26 (br d, 2-H), 2.75 (dd, 2-H), 2.76 (dd,
 2-H), 5.11 (br d, 3-H), 3.58 (s, 4-OCH₃), 3.91 (br
d, 5-H), 0.92 (br ddd, 7-H), 1.54 (br dt, 7-H), 1.89
(m, 8-H), 3.73 (dd, 9-H), 3.88 (dd, 9-H), 5.46 (dd, 10
-H), 5.55 (dd, 10-H), 6.56 (dd, 11-H), 6.60 (dd, 11-
H), 6.09 (br dd, 12-H), 5.77 (ddd, 13-H), 5.82 (ddd,
13-H), 2.13 (dt, 14-H), 2.46 (br dt, 14-H), 5.03 (dd
q, 15-H), 1.27 (d, 16-H₃), 2.88 (br dd, 17-H), 9.64
(s, 18-H), 9.65 (s, 18-H), 2.28 (s, 3-OCOCH₃), 3.35
(dq, 9-OCH (OCH ₂CH₃) CH₃), 3.41 (dq, 9-OCH (OCH ₂CH₃) CH
₃), 3.49 (dq, 9-OCH (OCH ₂CH₃) CH₃), 3.63 (dq, 9-OCH (OC
H ₂CH₃) CH₃), 1.14 (br t, 9-OCH (OCH₂CH ₃ ) CH₃), 1.22 (d,
 9-OCH (OCH₂CH₃) CH ₃ ), 1.24 (d, 9-OCH (OCH₂CH₃) CH ₃ ),
4.51 (d, 1'-H), 1.15 (d, 6'-H₃), 2.57 (s, 3'-N (C
H₃)₂), 4.92 (d, 1 "-H), 1.74 (dd, 2" -Hax), 1.20 (s, 3 "
-CH ₃), 4.56 (dq, 5 "-H), 1.08 (d, 6" -H₃), 4.52 (d, 3 "-
OCH ₂SCH₃), 4.65, 4.66 (2 × d, 4 "-H, 3" -OCH ₂SCH₃), 2.
20 (s, 3 "-OCH₂SCH ₃ ), 0.98 (d, 4 "-OCOCH₂CH (CH ₃ ) ₂ )

Example 18 Compound (17) (in formula (VIII), R ¹ is a methyl group
R ⁴ is an isovaleryl group and R ⁵ is 1-ethoxy.
Method for producing compound represented by ethyl group ) 1.00 g of compound (16) was dissolved in 25 ml of ethanol, and 25 ml of Raney nickel was added to the above solution together with 25 ml of ethanol to control the activity in the same manner as in Example 1. added. After stirring it vigorously for 20 minutes at room temperature,
The insoluble material was filtered and washed twice with 50 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. Combine the filtrate and wash,
930 mg of the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (100 g: toluene-acetone (1:
Purification in (1)) gave 614 mg of crude compound (17). This was re-purified by silica gel column chromatography (100 g: hexane: ethyl acetate (1: 1) → (1: 2)) to obtain 360 mg of compound (17). Physicochemical properties of compound (17) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₇ H ₇₉ NO ₁₆ (3) Mass spectrum (SIMS): m / z 914 (M + H) ⁺ (4) Specific rotation: [α] _D ¹⁶ -62 ° (c1.0, CH ₃ OH) (5) No clear melting point, melting around 98-101 ° C (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.75 (dd, 2-H), 2.76 (dd, 2-H), 5.12 (br d,
3-H), 3.58 (s, 4-OCH ₃ ), 3.91 (br d, 5-H), 1.55 (br d
t, 7-H), 1.89 (m, 8-H), 3.73 (dd, 9-H), 3.88 (dd, 9-
H), 5.46 (dd, 10-H), 5.55 (dd, 10-H), 6.57 (dd, 11-
H), 6.59 (dd, 11-H), 6.09 (br dd, 12-H), 5.77 (ddd, 1
3-H), 5.82 (ddd, 13-H), 2.13 (dt, 14-H), 2.46 (br dt,
14-H), 5.03 (ddq, 15-H), 1.26 (d, 16-H ₃ ), 2.88 (br d
d, 17-H), 9.64 (s, 18-H), 9.66 (s, 18-H), 2.28 (s, 3-
OCOCH ₃ ), 4.63 (q, 9-OC H (OCH ₂ CH ₃ ) CH ₃ ), 4.64 (q, 9-OC H
(OCH ₂ CH ₃ ) CH ₃ ), 3.35 (dq, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 3.42 (d
q, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 3.50 (dq, 9-OCH (OC H ₂ CH ₃ ) C
H ₃ ), 3.63 (dq, 9-OCH (OC H ₂ CH ₃ ) CH ₃ ), 1.14 (br t, 9-OCH
(OCH ₂ C H ₃ ) CH ₃ ), 1.22 (d, 9-OCH (OCH ₂ CH ₃ ) C H ₃ ), 1.24 (d,
9-OCH (OCH ₂ CH ₃ ) C H ₃ ), 4.52 (d, 1'-H), 3.46 (t, 4'-H),
_{1.16 (d, 6'-H 3} ), 2.58 (s, 3'-N (CH 3) 2), 4.93 (d, 1 "-
H), 1.10 (s, 3 "-CH ₃ ), 4.73 (d, 4" -H), 4.54 (dq, 5 "-
H), 1.08 (d, 6 "-H ₃ ), 3.26 (s, 3" -OCH ₃ ), 0.97 (d, 4 "-O
COCH ₂ CH (C H ₃ ) ₂ )

Example 19 Compound (18) (in the formula (IX), R ¹ represents a methyl group.
Is, after the R ⁴ is dissolved in a mixed solution of Preparation Compound (17) a 190 mg 5% aqueous acetic acid 15 ml and acetonitrile 5.0 ml of the compound represented by) with isovaleryl group, at room temperature 16
Allowed to react for hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in 20 ml of chloroform, and the mixture was washed 3 times with 20 ml of saturated aqueous sodium hydrogen carbonate solution and successively with 20 ml of saturated aqueous sodium chloride solution. The chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 192 mg of the residue, which was separated by TLC for separation (developing system: chloroform-methanol-concentrated aqueous ammonia (30: 1: 0.1)). Purified,
135 mg of compound (18) was obtained. Physicochemical properties of compound (18) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₃ H ₇₁ NO ₁₅ (3) Mass spectrum (SIMS): m / z 842 (M + H) ⁺ (4) Specific rotation: [α] _D ¹⁷ -65 ° (c1.0, CH ₃ OH) (5) No clear melting point, melting around 115-117 ° C (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.74 (dd, 2-H), 5.12 (br d, 3-H), 3.26 (br
d, 4-H), 3.58 (s, 4-OCH ₃ ), 3.90 (br d, 5-H), 0.92 (br
ddd, 7-H), 1.58 (br dt, 7-H), 1.89 (m, 8-H), 4.05 (d
d, 9-H), 5.62 (dd, 10-H), 6.64 (dd, 11-H), 6.08 (br d
d, 12-H), 5.76 (ddd, 13-H), 2.46 (br dt, 14-H), 5.04
(ddq, 15-H), 1.26 (d, 16-H ₃ ), 2.33 (br dd, 17-H), 2.
88 (br dd, 17-H), 9.64 (s, 18-H), 0.98 (d, 19-H ₃ ), 2.
28 (s, 3-OCOCH ₃ ), 4.52 (d, 1'-H), 3.21 (dd, 2'-H), 2.
41 (t, 3'-H), 3.46 (t, 4'-H), 3.29 (dq, 5'-H), 1.16
(d, 6'-H ₃ ), 2.57 (s, 3'-N (CH ₃ ) ₂ ), 4.93 (br d, 1 "-H),
1.66 (dd, 2 "-Hax), 1.10 (s, 3" -CH ₃ ), 4.72 (d, 4 "-H),
5.54 (dq, 5 "-H), 1.08 (d, 6" -H ₃ ), 3.25 (s, 3 "-OCH ₃ ),
0.97 (d, 4 "-OCOCH ₂ CH (C H ₃ ) ₂ )

Example 20 Compound (20) (in formula (VI), R ¹ represents a methyl group.
R ⁴ is an isovaleryl group and R ⁵ is propionyl
Compound represented by group (19) ( a compound represented by the formula (V), wherein R ¹ is a methyl group, R ⁴ is an isovaleryl group, and R ⁵ is a propionyl group) (JP-A-49-10515) 22.0 g of DMS
After dissolving in a mixed solution of 500 ml O and 50 ml acetic anhydride,
Reaction was performed at 16 ° C. for 16 hours. The reaction solution was gradually added to 5.0 L of toluene and washed with 5.0 L of water three times. The toluene layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 30.0 g of the obtained residue was subjected to silica gel column chromatography (1.0 kg: toluene-acetone (8: 1) → (7:
Purification by 1)) yielded 9.00 g of compound (20). Physicochemical properties of compound (20) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₉ H ₇₉ NO ₁₇ S (3) Mass spectrum (SIMS): m / z 986 (M + H) ⁺ (4) ) Specific rotation: [α] _D ¹⁶ -90 ° (c1.0, CHCl ₃ ) (5) Melting around 114-116 ℃ without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.25 (br d, 2-H), 2.71 (dd, 2-H), 5.09 (br
d, 3-H), 3.16 (br d, 4-H), 3.49 (s, 4-OCH ₃ ), 3.94 (br
d, 5-H), 0.85 (br dt, 7-H), 1.46 (br dt, 7-H), 5.05
(dd, 9-H), 5.57 (dd, 10-H), 6.69 (dd, 11-H), 6.05 (br
dd, 12-H), 5.85 (ddd, 13-H), 2.45 (br dt, 14-H), 4.
98 (ddq, 15-H), 1.26 (d, 16-H ₃ ), 2.58 (br dd, 17-H),
2.82 (br dd, 17-H), 9.64 (s, 18-H), 0.95 (d, 19-H ₃ ),
2.30 (s, 3-OCOCH ₃ ), 1.10 (t, 9-OCOCH ₂ C H ₃ ), 4.59 (d,
1'-H), 4.90 (dd, 2'-H), 2.67 (t, 3'-H), 3.16 (t, 4'-
H), 3.26 (dq, 5'-H), 1.14 (d, 6'-H ₃ ), 2.01 (s, 2'-OCO
CH ₃ ), 2.42 (s, 3'-N (CH ₃ ) ₂ ), 4.81 (d, 1 "-H), 1.68 (dd,
2 "-Hax), 1.18 (s, 3" -CH ₃ ), 4.56 (dq, 5 "-H), 1.05 (d,
6 "-H ₃ ), 4.50 (d, 3" -OC H ₂ SCH ₃ ), 4.63, 4.64 (2 × d, 4 "-
H, 3 "-OC H ₂ SCH ₃ ), 2.20 (s, 3" -OCH ₂ SC H ₃ ), 0.98 (d, 4 "-
OCOCH ₂ CH (C H ₃ ) ₂ )

Example 21 Compound (21) (in the formula (VII), R ¹ is a methyl group.
R ⁴ is an isovaleryl group and R ⁵ is propionyl.
Le compounds represented by groups) of the preparation the compound (20) 8.90 g was dissolved in methanol 445 ml, was allowed to react for 16 hours at 36 ° C.. The reaction solution was concentrated under reduced pressure to obtain 7.80 g of compound (21). Physicochemical properties of compound (21) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₇ H ₇₇ NO ₁₆ S (3) Mass spectrum (SIMS): m / z 944 (M + H) ⁺ (4) ) Specific rotation: [α] _D ¹⁶ -58 ° (c1.0, CH ₃ OH) (5) Melting point: No melting point, melting at around 113-116 ° C (6) ¹ H NMR spectrum (400MHz , CDCl ₃ ) δ
(ppm): 2.26 (br d, 2-H), 2.75 (dd, 2-H), 5.10 (br
d, 3-H), 3.25 (br d, 4-H), 3.57 (s, 4-OCH ₃ ), 3.96 (br
d, 5-H), 0.92 (br dt, 7-H), 1.57 (br dt, 7-H), 2.03
(m, 8-H), 5.07 (dd, 9-H), 5.58 (dd, 10-H), 6.71 (dd,
11-H), 6.09 (br dd, 12-H), 5.86 (ddd, 13-H), 2.46 (br
dt, 14-H), 5.00 (ddq, 15-H), 1.26 (d, 16-H ₃ ), 2.62
(br dd, 17-H), 2.84 (br dd, 17-H), 9.66 (s, 18-H),
0.95 (d, 19-H ₃ ), 2.29 (s, 3-OCOCH ₃ ), 1.10 (t, 9-OCOCH ₂
C H ₃ ), 4.49 (d, 1'-H), 3.21 (dd, 2'-H), 2.42 (t, 3'-
H), 3.42 (t, 4'-H), 3.28 (dq, 5'-H), 1.15 (d, 6'-H ₃ ),
2.57 (s, 3'-N (CH ₃ ) ₂ ), 4.92 (d, 1 "-H), 1.74 (dd, 2" -Ha
x), 1.20 (s, 3 "-CH ₃ ), 4.55 (dq, 5" -H), 1.08 (d, 6 "-
H ₃ ), 4.52 (d, 3 "-OC H ₂ SCH ₃ ), 4.64, 4.66 (2 × d, 4" -H,
3 "-OC H ₂ SCH ₃ ), 2.19 (s, 3" -OCH ₂ SC H ₃ ), 0.98 (d, 4 "-OCO
CH ₂ CH (C H ₃ ) ₂ )

Example 22 Compound (22) (in the formula (VIII), R ¹ is a methyl group.
R ⁴ is an isovaleryl group and R ⁵ is propionyl.
Le compounds represented by groups) of the production method of compound (21) After the 1.50 g were dissolved in ethanol 35 ml, Raney nickel 38ml controlling the activity in the same manner as in Example 1, the above solution with 40 ml of ethanol added. After stirring it vigorously for 20 minutes at room temperature,
The insoluble material was filtered and washed twice with 50 ml of ethanol each containing 1% (v / v) concentrated aqueous ammonia. Combine the filtrate and wash,
1.00 g of the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (100 g: hexane-ethyl acetate (1:
The compound (22) (220 mg) was obtained after purification by 1)). Physicochemical properties of compound (22) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₆ H ₇₅ NO ₁₆ (3) Mass spectrum (SIMS): m / z 898 (M + H) ⁺ (4) Specific rotation: [α] _D ¹⁵ -61 ° (c1.0, CH ₃ OH) (5) No clear melting point, melting around 115-118 ° C (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.26 (br d, 2-H), 2.75 (dd, 2-H), 5.11 (br
d, 3-H), 3.24 (br d, 4-H), 3.58 (s, 4-OCH ₃ ), 3.96 (br
d, 5-H), 0.92 (br dt, 7-H), 1.58 (br dt, 7-H), 2.03
(m, 8-H), 5.07 (dd, 9-H), 5.58 (dd, 10-H), 6.71 (dd,
11-H), 6.09 (br dd, 12-H), 5.86 (ddd, 13-H), 2.17 (d
t, 14-H), 2.46 (br dt, 14-H), 5.00 (ddq, 15-H), 1.26
(d, 16-H ₃ ), 2.62 (br dd, 17-H), 2.85 (br dd, 17-H),
9.66 (s, 18-H), 0.95 (d, 19-H ₃ ), 2.29 (s, 3-OCOCH ₃ ),
1.11 (t, 9-OCOCH ₂ C H ₃ ), 4.51 (d, 1'-H), 3.19 (dd, 2'-
H), 2.41 (t, 3'-H), 3.45 (t, 4'-H), 3.29 (dq, 5'-H),
1.16 (d, 6'-H ₃ ), 2.57 (s, 3'-N (CH ₃ ) ₂ ), 4.93 (d, 1 "-
H), 1.67 (dd, 2 "-Hax), 1.11 (s, 3" -CH ₃ ), 4.73 (d, 4 "-
H), 4.54 (dq, 5 "-H), 1.08 (d, 6" -H ₃ ), 3.26 (s, 3 "-OC
H ₃ ), 0.97 (d, 4 "-OCOCH ₂ CH (C H ₃ ) ₂ )

Example 23 Compound (23) (in formula (VIII), R ¹ is an ethyl group
R ⁴ is a propionyl group and R ⁵ is a propionyl group.
Method for producing compound represented by diol group ) To 20 mg of compound (12), 1.0 ml of anhydrous toluene was added and dissolved, and 8.4 μl of anhydrous pyridine was added, followed by stirring at room temperature for 20 minutes. 10 ml of ethyl acetate and 7.8 μl of triethylamine were added to the reaction mixture for extraction, and the ethyl acetate layer was washed with water.
It was washed twice with ml, dried over anhydrous sodium sulfate, and filtered. 28 mg of residue obtained by concentrating the filtrate under reduced pressure
Was purified by preparative TLC (developing system: chloroform-methanol-concentrated aqueous ammonia (30: 1: 0.1)) to give compound (23) 1
3 mg was obtained. Physicochemical properties of compound (23) (1) Color and shape: colorless solid (2) Molecular formula: C ₄₅ H ₇₃ NO ₁₆ (3) Mass spectrum (EIMS): m / z 883 (M) ⁺ (4) Specific rotation Degree: [α] _D ²² -72 ° (c1.0, CH ₃ OH) (5) Melting around 114 to 117 ° C without showing clear melting point (6) ¹ H NMR spectrum (400MHz, CDCl ₃ ) δ
(ppm): 2.26 (br d, 2-H), 2.74 (dd, 2-H), 5.12 (br
d, 3-H), 3.24 (br d, 4-H), 3.56 (s, 4-OCH ₃ ), 3.94 (br
d, 5-H), 0.90 (br ddd, 7-H), 1.57 (br dt, 7-H), 2.0
2 (m, 8-H), 5.09 (dd, 9-H), 5.58 (dd, 10-H), 6.74 (dd,
11-H), 6.09 (br dd, 12-H), 5.88 (ddd, 13-H), 2.17 (d
t, 14-H), 4.98 (ddq, 15-H), 1.26 (d, 16-H ₃ ), 2.60 (br
dd, 17-H), 2.83 (br dd, 17-H), 9.65 (br s, 18-H), 0.
96 (d, 19-H ₃ ), 2.51 (dq, 3-OCOC H ₂ CH ₃ ), 2.68 (dq, 3-OC
OC H ₂ CH ₃ ), 1.21 (t, 3-OCOCH ₂ C H ₃ ), 2.30 (q, 9-OCOC H ₂ CH
₃ ), 1.11 (t, 9-OCOCH ₂ C H ₃ ), 4.51 (d, 1'-H), 3.21 (dd,
2'-H), 3.45 (t, 4'-H), 3.28 (dq, 5'-H), 1.16 (d, 6'-H)
₃ ), 2.58 (s, 3'-N (CH ₃ ) ₂ ), 4.93 (d, 1 "-H), 1.67 (dd, 2"
-Hax), 2.29 (d, 2 "-Heq), 1.10 (s, 3" -CH ₃ ), 4.72 (d,
4 "-H), 4.53 (dq, 5" -H), 1.08 (d, 6 "-H ₃ ), 3.26 (s, 3"-
OCH ₃ ), 2.43 (apparent q, 3-OCOC H ₂ CH ₃ ), 2.44 (apparen
tq, 3-OCOC H ₂ CH ₃ ), 1.17 (t, 3-OCOCH ₂ C H ₃ )

[0060]

The first effect of the present invention is to create a useful novel 16-membered ring macrolide derivative. That is, the compounds represented by the general formulas (VIII) and (IX) obtained in the present invention have excellent antibacterial activity against clinically important Gram-positive bacteria. First, among the compounds represented by the general formula (VIII), the compounds (2) and (6) in which the 9-position hydroxyl group is acetylated are myocamycin (MOM), which is an excellent 16-membered ring macrolide antibacterial agent.・ Compared to that of Antibiotics, 29 (5), 536 (1976)), it has equivalent or higher in vitro antibacterial activity. Note Compound (6) is compared with the compound (2), Bran
The antibacterial activity against hamella catarrhalis was slightly superior. Incidentally, the compounds (22) and (23) in which the hydroxyl group at the 9-position of the lactone ring is propionylated also have practically sufficient antibacterial activity. On the other hand, the hydroxyl group at the 9-position of the lactone ring
1-ethoxyethylated compound (11H), (1
The antibacterial activities of (1L) and (17) are as follows: Compounds (12) and (1
Although inferior to 8), it had effective antibacterial activity.

The formula (I) synthesized by the production method of the present invention
The compound represented by the formula (6) exhibits a superior in vivo effect in a mouse infection treatment experiment as compared with the existing 16-membered ring macrolide antibacterial agent. As an example, the compound (2) produced by this method is Streptococcus pneumoniae DP-1 Ty.
In a mouse infection treatment experiment with pe1, an equivalent infection treatment was performed with an amount of 1/4 or less of MOM and 1/8 or less of rokitamycin (Journal of Antibiotics, 34 (8), 1001 (1981)). Showed the effect. This excellent effect is directly related to the fact that the tertiary hydroxyl group at the 3 "-position is not ester-bonded by an acyl group but ether-linked by a methyl group. That is, in vivo of compound (2) One of the metabolites, 3 "-O-methyl midecamycin M ₁ (3" -O-methyl
-3-O-propionyl leucomycin V) (Japanese Patent Application No. 5-16941)
8) is the equivalent substance of MOM, midecamycin M ₁ (Journal of Bacteriology, 174 (15), 5141 (1992),
The fact that the antibacterial activity is far superior to that of JP-A-48-10288) is one reason for the excellent in vivo effect.
By the way, it has been reported that the isovaleryl group bonded to the 4 "-position hydroxyl group is less likely to be cleaved in rat plasma than the propionyl group (Pharmaceutical Journal, 102 (8), 781 (19).
82)). Therefore, when the compound (6) of the present invention is actually subjected to a mouse infection treatment experiment, the compound (6) is converted to the compound (2).
The in vivo effect was equal to or higher than that of.

The second effect of the present invention is that the compound represented by the general formula (III) is started from a known naturally-occurring 16-membered macrolide antibiotic represented by the general formula (II). The purpose of the present invention is to provide a novel production method in which a 3 "-methylthiomethyl ether synthetic intermediate is used as a raw material to efficiently prepare in 4 to 6 steps without passing through a glycosylation reaction. When the present inventors prepared the compound (2) of the present invention using midecamycin A ₃ and erythromycin as starting materials, 9 steps of chemical reaction including glycosylation reaction and 1-step microbial conversion were carried out to obtain midecamycin A ₃ The total yield from
It was less than%. However, according to the novel production method of the present invention, it became possible to synthesize compound (2) using medemycin as a starting material in a total yield of about 20%.

The third effect of the present invention is to provide a general method for indirectly introducing a methyl group into a tertiary hydroxyl group present in a compound having poor chemical stability under mild reaction conditions. To do. The reaction itself for converting a methylthiomethyl etherified hydroxyl group into a methoxy group has already been known as described above (Carbohydrate Research, 7 , 474 (1968)), but the chemical conversion is applied to the tertiary hydroxyl group. There are few known examples. Furthermore, there have been few reports of developing this reaction for a compound having a functional group having a high reactivity under a catalytic reduction condition such as a double bond or a free aldehyde group.

The effect of the fourth invention is 16
It is intended to provide an efficient protecting group for the hydroxyl group at the 9-position of the lactone ring in the study of derivatives of a membered ring macrolide antibiotic. When producing an excellent derivative by a chemical reaction using a compound obtained from nature as a starting material, it is often necessary to protect a specific functional group such as an amino group or a hydroxyl group. In the study of synthetic chemical derivatives of 16-membered ring macrolide compounds, few examples of the use of an efficient protecting group for the 9-position hydroxyl group were known. The present inventors have demonstrated that an acetal-based protecting group having an asymmetric carbon atom, particularly a 1-ethoxyethyl group, has sufficient properties as a protecting group.

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

Claims (9)

[Claims] 1. The following formula (I): [In the formula, R ¹ is a linear alkyl group having 1 to 3 carbon atoms,
R ² is a hydrogen atom or a substituent that modifies (or protects) a hydroxyl group, R ³ is a compound represented by a hydrogen atom or a linear or branched aliphatic acyl group having 2 to 5 carbon atoms, or A pharmaceutically acceptable salt thereof. 2. A compound represented by the formula (I) according to claim 1, wherein R ¹ is a methyl group, R ² is an acetyl group and R ³ is an isovaleryl group, or a pharmaceutically acceptable compound thereof. Possible salt. 3. A compound represented by formula (I) according to claim 1, wherein R ¹ is an ethyl group, R ² is a 1-ethoxyethyl group, and R ³ is a propionyl group, or a pharmaceutical thereof. Acceptable salt. 4. A compound represented by the formula (I) of claim 1, wherein R ¹ is a methyl group, R ² is a 1-ethoxyethyl group, and R ³ is an isovaleryl group, or a pharmaceutical thereof. Acceptable salt. 5. A compound represented by formula (I) according to claim 1, wherein R ¹ is a methyl group, R ² is a hydrogen atom and R ³ is an isovaleryl group, or a pharmaceutically acceptable compound thereof. Possible salt. 6. A compound represented by the formula (I) of claim 1, wherein R ¹ is a methyl group, R ² is a propionyl group, and R ³ is an isovaleryl group, or a pharmaceutically acceptable compound thereof. Possible salt. 7. A compound represented by the formula (I) of claim 1, wherein R ¹ is an ethyl group, R ² is a propionyl group, and R ³ is a propionyl group, or a pharmaceutically acceptable compound thereof. Possible salt. 8. The following formula (II): [In the formula, R ¹ is a linear alkyl group having 1 to 3 carbon atoms,
R ⁴ is a linear or branched aliphatic acyl group having 2 to 5 carbon atoms]
Using a compound represented by the following formula or a salt thereof as a starting material, the following formula (III): [In the formula, R ¹ is a linear alkyl group having 1 to 3 carbon atoms,
R ² is a hydrogen atom or a substituent that modifies (or protects) a hydroxyl group, and R ⁴ is a compound represented by a linear or branched aliphatic acyl group having 2 to 5 carbon atoms, or a salt thereof. Efficient manufacturing method to obtain. 9. An acetal-based substituent having an asymmetric carbon atom such as a 1-ethoxyethyl group, a tetrahydrofuranyl group or a tetrahydropyranyl group as a protective group for the 9-position hydroxyl group of the lactone ring in the chemical synthesis of a 16-membered ring macrolide derivative. Method using a group.