JP2006306727A - 12-position substituted mutiline derivative having pyridine ring in 14-position substituent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a 12-position substituted derivative of a novel analog of mutiline which exhibits a strong and broad antibacterial action against Gram-positive and Gram-negative bacteria including various resistant bacteria and is promising in the use as an agent for treating infectious diseases. <P>SOLUTION: The agent for treating infectious diseases contains at least one of mutiline derivatives represented by formula (1) and its acid addition salts as an active ingredient. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a 12-position substituted mutilin derivative that is a novel analog of mutilin that exhibits a strong antibacterial action against gram-positive bacteria including various resistant bacteria and gram-negative bacteria, and is expected to be used as a therapeutic agent for infectious diseases. About.

Pleuromutilin was released in 1951 by Pleurotus
from mutilus Sacc. and in 1976 Pleurotus
It is a diterpene compound isolated from passeckerianus Pil. and its structure determined, and its aglycone part is called a mutilin (Non-patent Documents 1 and 2). A structural feature is that it has a tricyclic structure in which a hydroindanone structure is fused to a highly functionalized 8-membered ring and has 9 asymmetric carbon atoms.

  In recent years, the spread of intractable infectious diseases caused by various resistant bacteria has become a global problem. It is clear that preuromutilin exhibits antibacterial activity by acting on bacterial ribosomes to inhibit protein synthesis and is useful as a new lead compound in the search for drugs for intractable infections. Among them, Tiamulin (trademark) has been used as a preuromutilin derivative for a long time as an infectious disease treatment for livestock. However, there are still reports on the application of pleuromutilin or mutilin derivatives to human infections. Absent.

  Thus, a mutilin compound is a compound that attracts worldwide attention from two points of strong antibacterial activity and interesting chemical structure, and in recent years, novel mutilin derivatives have been reported by several groups. That is, in Patent Document 1,

(Wherein R ₁ is vinyl, ethyl,
R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an optionally substituted saturated or unsaturated lower alkyl group, an optionally substituted saturated or unsaturated 3- to 8-membered cyclic group When a lower alkyl group, an optionally substituted heterocyclic ring, an optionally substituted aromatic ring or R ₂ is the above substituent, R ₃ represents the following general formula (I)

(R ₄ represents an optionally substituted chain or cyclic lower alkyl group, an optionally substituted heterocyclic ring, an optionally substituted aromatic ring, an optionally substituted lower alkylamino group, a substituted An aromatic amino group which may be substituted, and R ₅ is a linear or cyclic lower alkyl group which may be substituted, a heterocyclic ring which may be substituted, or an aromatic ring which may be substituted , R ₆ and R ₇ are each a hydrogen atom, an optionally substituted saturated or unsaturated lower alkyl group, an optionally substituted saturated or unsaturated 3- to 8-membered cyclic alkyl group , An optionally substituted heterocycle, an optionally substituted aromatic ring, or may contain one or more heteroatoms such as O, N, S, etc. together with a nitrogen atom, and may be substituted May be carbonized Heterocyclic, heterocyclic, or fused with an aromatic ring, from 3-membered to form a 8-membered ring) or is R ₂ and is R ₃ taken together may be substituted, also O, A 3- to 8-membered cyclic lower alkyl group which may contain one or more heteroatoms such as N and S),

In Patent Document 2,

(In the formula, R ₁ is vinyl or ethyl, R ₂ is the following general formula (I)

(R ₃ and R ₄ are azabicyclo rings, and R ₅ and R ₆ together form an azabicyclo ring)
Represents)

In Patent Document 3,

(In the formula, R ₁ is vinyl or ethyl, and Ra is represented by the following general formula (I)

(X is O, S, NR ′, R and R ′ are different from each other and each represents an aliphatic substituent or an aromatic substituent, and R ₃ and R ₄ are the same or different and are each substituted with a hydrogen atom or substituted. May be a saturated or unsaturated lower alkyl group, an optionally substituted saturated or unsaturated 3- to 8-membered cyclic lower alkyl group, an optionally substituted heterocyclic ring, an optionally substituted When R ₄ is a good aromatic ring or R ₃ is the above substituent, R ₄ is represented by the following general formula (I)

(R ₅ is an optionally substituted chain or cyclic lower alkyl group, an optionally substituted heterocyclic ring, an optionally substituted aromatic ring, an optionally substituted lower alkylamino group, R ₆ is an optionally substituted aromatic amino group, R ₆ is a linear or cyclic lower alkyl group which may be substituted, a heterocyclic ring which may be substituted, an aromatic ring which may be substituted R ₇ and R ₈ are different from each other, a hydrogen atom, an optionally substituted saturated or unsaturated lower alkyl group, an optionally substituted saturated or unsaturated 3- to 8-membered cyclic group A lower alkyl group, an optionally substituted heterocycle, an optionally substituted aromatic ring, or may contain one or more heteroatoms such as O, N, and S together with a nitrogen atom; Even if it is replaced There hydrocarbon ring, a heterocyclic ring may be condensed with an aromatic ring, or a 3- to form a 8-membered ring), or R ₃ and R ₄ together may be substituted And represents a 3- to 8-membered cyclic lower alkyl group which may contain one or more heteroatoms such as O, N and S),

In Patent Document 4,

(In the formula, R ₁ represents the following general formula (I)

(R represents a spiro-linked monocyclic or bicyclic substituent containing 1 to 2 basic nitrogen atoms, and X ₁ and X ₂ are the same or different and each represents a methylene group or a carbonyl group; Or at least one represents a carbonyl group, Y represents a nitrogen atom, a methylene group, or an ethylene group, R ₅ represents an aromatic ring or a heteroaromatic ring which may be substituted via a carbon atom, and m represents (1 represents an integer of 1-3, n represents an integer of 0-2, and p represents an integer of 1-4)
R ₂ is vinyl or ethyl;
R ₃ is a hydrogen atom, a hydroxyl group or a fluorine atom, R ₄ represents a hydrogen atom, or when R ₃ is a hydrogen atom, R ₄ represents a fluorine atom),

In Patent Document 5,

(Wherein R ₁ represents an optionally substituted heteroaromatic ring containing a 5-membered heteroaromatic ring bonded via a nitrogen atom containing at least one nitrogen atom;
R ₂ is vinyl or ethyl;
R ₃ is a hydrogen atom, a hydroxyl group or a fluorine atom,
R ₄ represents a hydrogen atom, or when R ₃ is a hydrogen atom, R ₄ represents a fluorine atom),

In Patent Document 6,

(Wherein R ₁ represents a heterocyclic group containing an optionally substituted phenyl group, an optionally substituted nitrogen atom,
R ₂ is vinyl or ethyl;
R ₃ is a hydrogen atom, a hydroxyl group or a fluorine atom,
R ₄ represents a hydrogen atom, or when R ₃ is a hydrogen atom, R ₄ represents a fluorine atom)
Represents)

In Patent Document 7,

(Wherein R ₁ is vinyl or ethyl;
R ₂ and R ₃ are the same or different and each represents a hydrogen atom, an optionally substituted saturated or unsaturated lower alkyl group, an optionally substituted saturated or unsaturated 3- to 8-membered cyclic lower group; When an alkyl group, an optionally substituted heterocyclic ring, an optionally substituted aromatic ring, or R ₂ is the above substituent, R ₃ represents the following general formula (I)

(R ₄ is an optionally substituted chain or cyclic lower alkyl group, an optionally substituted heterocyclic ring, an optionally substituted aromatic ring, an optionally substituted lower alkylamino group, R ₅ is an optionally substituted aromatic amino group, and R ₅ is an optionally substituted chain or cyclic lower alkyl group, an optionally substituted heterocycle, an optionally substituted aromatic ring. Each of R ₆ and R ₇ is different from a hydrogen atom, an optionally substituted saturated or unsaturated lower alkyl group, an optionally substituted saturated or unsaturated 3- to 8-membered cyclic lower group; An alkyl group, an optionally substituted heterocycle, an optionally substituted aromatic ring, or may contain one or more heteroatoms such as O, N, and S together with a nitrogen atom; May be replaced Hydrocarbon ring, a heterocyclic ring may be condensed with an aromatic ring, and either a 3-membered to form a 8-membered ring), or R ₂ and R ₃ taken together may be substituted, And represents a 3- to 8-membered cyclic lower alkyl group which may contain one or more heteroatoms such as O, N and S),

In Patent Document 8,

(In the formula, R ₁ is a heterocycle containing a nitrogen atom, an optionally substituted aromatic ring, an optionally substituted heteroaromatic ring, or the following general formula (I):

(X represents a halogen atom, and R ₅ represents a lower alkylamino group, a heterocycle containing a nitrogen atom, an optionally substituted aromatic ring, or an optionally substituted heteroaromatic ring)
Represents
R ₂ is vinyl or ethyl;
R ₃ is a hydrogen atom, a hydroxyl group or a fluorine atom,
R ₄ represents a hydrogen atom, or when R ₃ is a hydrogen atom, R ₄ represents a fluorine atom)
Represents)

In Patent Document 9,

(R ₁ is a 5- or 6-membered optionally substituted heteroaromatic ring, R ₂ represents vinyl or ethyl),

In Patent Document 10,

(Wherein R ₁ is a 5- or 6-membered halogen atom, an optionally substituted lower alkoxy group, an optionally substituted lower alkylthioalkoxy group, a hydrogen atom, or an optionally substituted lower atom; An aromatic or heteroaromatic ring substituted by an amino group substituted with an alkyl group, containing a 5-membered or 6-membered one oxygen atom or one or two nitrogen atoms, and condensed with a benzene ring An optionally dihydroheteroaromatic ring, a 5-membered or 6-membered heteroaromatic ring containing 1 to 2 nitrogen atoms, a 5-membered or 6-membered heterocycle optionally containing O, N, S; A 6-membered tetrahydroheteroaromatic ring containing 1 to 2 nitrogen atoms, a 9- to 10-membered bicyclic heteroaromatic ring containing 1-4 nitrogen atoms,
R ₂ is vinyl or ethyl;
R ₃ is a hydrogen atom, a hydroxyl group or a fluorine atom,
R ₄ represents a hydrogen atom, or when R ₃ is a hydrogen atom, R ₄ represents a fluorine atom. At this time, R ₅ and R ₆ together represent an oxygen atom, or R ₃ And when R ₄ is a hydrogen atom, R ₅ is a hydrogen atom or a hydroxyl group, R ₆ is a hydrogen atom, or when R ₅ is a hydrogen atom, R ₆ represents a hydrogen atom or a hydroxyl group. ),

In Patent Document 11,

(Wherein R ₁ is an optionally substituted lower alkyl group, an optionally substituted 3- to 6-membered cyclic lower alkyl group, and an optionally substituted heterocyclic ring;
R ₂ is vinyl or ethyl;
R ₃ is a hydrogen atom, a hydroxyl group or a fluorine atom,
R ₄ represents a hydrogen atom, or when R ₃ is a hydrogen atom, R ₄ represents a fluorine atom, in which case R ₅ and R ₆ together represent an oxygen atom, or R ₃ And when R ₄ is a hydrogen atom, R ₅ is a hydrogen atom or a hydroxyl group, R ₆ is a hydrogen atom, or when R ₅ is a hydrogen atom, R ₆ represents a hydrogen atom or a hydroxyl group) ,

In Patent Document 12,

Wherein R ₁ is an optionally substituted 5-membered or 6-membered heteroaromatic ring,
R ₂ represents vinyl or ethyl),
Such an example has been reported. Each of these patents claims a vinyl group derived from pleuromutilin, which is a natural product of the 12-position substituent, or an ethyl group obtained by reducing the vinyl group, and the 12-position substituent as shown in the present invention A mutilin derivative having a structural feature of being various substituents has not yet been reported, and thus its antibacterial activity is unknown.

Further, in Patent Document 1 and Patent Document 7, a mutilin derivative having a structural feature that a (3-pyridyl) acrylic acid structure is included in the 14-position substituent as shown in the present invention is included in the claims. The 12-position substituent is a vinyl group derived from a natural product, pleuromutilin, or a reduced ethyl group, and the 14-position substituent has a (3-pyridyl) acrylic acid structure. Mutilin derivatives have not been produced and therefore their antibacterial activity is also unknown. Similarly, Patent Document 3 includes a mutilin derivative having a structural feature that a 2-position substituent includes a fluorine atom as shown in the present invention, but actually includes a fluorine atom in the 2-position substituent. In addition, the structural feature is that the 12-position substituent is a vinyl group derived from a natural product, pleuromutilin, or a reduced ethyl group, and the 14-position substituent contains a (3-pyridyl) acrylic acid structure. No mutilin derivative has been produced and therefore its antibacterial activity is also unknown.

The following compounds are known for the 12-position substituted mutilin derivative and the 12-position substituted 4-epimutilin derivative. That is, in Non-Patent Document 3, the following 12-position desethenyl 4-epimutilin derivative is known.

In Non-Patent Document 4, the following 12-position dimethyl-4-epimutilin derivative is known.

Non-Patent Document 5 discloses a preuromutilin derivative and a 12-position cyclopropyl-substituted pleuromutilin derivative in which the stereochemistry of the 12-position substituent is opposite to that of the natural type.

These are compounds in which the substituent at the 12-position described in the present invention is not a natural vinyl group or an ethyl group obtained by reducing it, but through an acylcarbamoyl structure as shown in the present invention. Thus, no compound having a cyclic amine structure has been reported, and therefore the antibacterial activity of these compounds is not known.

Moreover, the following compound is well-known about the mutilin derivative in which the 11-position hydroxyl group is protected. That is,
In Non-Patent Document 6, the following mutilin derivatives are known.

In this paper, the 11-position acetoxy, dichloroacetoxy and trifluoroacetoxymutilins are reported and these compounds are known, but these compounds are not included in the scope of the claims of the present invention, and As shown in the invention, no compound has been produced in which the 12-position is various substituents and the 14-position has a cyclic amine structure via an acylcarbamoyl structure, and thus the antibacterial activity of these compounds is also known. Not.

On the other hand, the production of the following mutilin derivatives directed to antibacterial activity has been reported. That is,
In Non-Patent Document 7, the following mutilin 14-carbamate derivative is known.

Thus, a compound in which the 12th position described in Non-Patent Document 7 is a natural vinyl group or an ethyl group obtained by reducing the natural vinyl group and the 14th position is a carbamoyl derivative is known, but the present invention As shown in the figure, the 12-position is a variety of substituents and the 14-position has a cyclic amine structure via an acylcarbamoyl structure. Therefore, the antibacterial activity of these compounds is also known. Not.

As described above, none of the mutilin derivatives disclosed so far is satisfactory in antibacterial action, toxicity, and pharmacokinetics, and an excellent mutilin derivative is always required.
WO1997 / 25309 pamphlet WO1998 / 05659 pamphlet WO2000 / 07974 pamphlet WO2000 / 27790 pamphlet WO2000 / 37074 pamphlet WO2000 / 73287 pamphlet US6239175 Gazette WO2001 / 14310 pamphlet WO2001 / 74788 pamphlet WO2002 / 12199 pamphlet WO2002 / 30929 pamphlet US2003 / 0114674 Kavanagh, F. et al., Proc. Natl. Acad. Sci. USA 1951, 37,570-574. Knauseder, F. et al., J. Antibiot. 1976, 29, 125-131. Berner, H. et al., Tetrahedron 1981, 37, 915-919. Berner, H. et al., Tetrahedron 1983, 39, 1745-1748. Berner, H. Monatsch. Chem. 1986, 117, 1073-1080. Birch, AJ et al., Tetrahedron 1966, Suppl. 8, Part II, 359-387. Brooks, G. et al., Bioorg. Med. Chem. 2001, 9, 1221-1231.

  The object of the present invention is to replace position 12 which is a novel analog of mutilin that shows a strong and broad antibacterial action against gram-positive and gram-negative bacteria including various resistant bacteria and is expected to be used as a therapeutic agent for infectious diseases. It is to provide a derivative and its production intermediate.

As a result of intensive studies in view of the above problems, the present inventors have found that the following compounds of the present invention have a strong antibacterial action and are extremely useful as production intermediates in the production thereof. It came to be completed.
That is, the present invention

1) The following general formula (1)

(In the formula, R ₁ is a hydrogen atom, a formyl group, an optionally substituted lower alkyl group, an aromatic ring in which an aromatic ring may be substituted, a heteroaralkyl group in which an aromatic ring may be substituted, or a lower alkyl. Represents an oxycarbonyl group, R ₂ represents a hydrogen atom, a lower alkyl group or an aralkyl group optionally substituted with an aromatic ring, R ₃ represents a hydrogen atom or a fluorine atom, and a broken line portion represents a single bond or a double bond A mutilin derivative represented by the above or an acid addition salt thereof,

2) The following general formula (1-1)

Wherein R ₁ ^′ is a hydrogen atom, an optionally substituted lower alkyl group, an aromatic ring optionally substituted with an aromatic ring, a heteroaralkyl group optionally substituted with an aromatic ring or a lower alkyloxycarbonyl. R ₂ represents a hydrogen atom, a lower alkyl group or an aralkyl group which may be substituted with an aromatic ring, R ₄ represents a hydroxyl-protecting group, and the broken line portion represents a single bond or a double bond) A mutilin derivative represented by or an acid addition salt thereof,

3) The following general formula (1-2)

(In the formula, R ₁ is a hydrogen atom, a formyl group, an optionally substituted lower alkyl group, an aromatic ring in which an aromatic ring may be substituted, a heteroaralkyl group in which an aromatic ring may be substituted, or a lower alkyl. Represents an oxycarbonyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₃ represents a hydrogen atom or a fluorine atom, R ₄ represents a hydroxyl protecting group, A mutilin derivative represented by a single bond or a double bond) or an acid addition salt thereof,

4) The following general formula (1)

(In the formula, R ₁ is a hydrogen atom, a formyl group, an optionally substituted lower alkyl group, an aromatic ring in which an aromatic ring may be substituted, a heteroaralkyl group in which an aromatic ring may be substituted, or a lower alkyl. Represents an oxycarbonyl group, R ₂ represents a hydrogen atom, a lower alkyl group or an aralkyl group optionally substituted with an aromatic ring, R ₃ represents a hydrogen atom or a fluorine atom, and a broken line portion represents a single bond or a double bond A therapeutic agent for infectious diseases, comprising as an active ingredient at least one of mutilin derivatives represented by

5) The following general formula (1-1)

Wherein R ₁ ^′ is a hydrogen atom, an optionally substituted lower alkyl group, an aromatic ring optionally substituted with an aromatic ring, a heteroaralkyl group optionally substituted with an aromatic ring or a lower alkyloxycarbonyl. R ₂ represents a hydrogen atom, a lower alkyl group or an aralkyl group which may be substituted with an aromatic ring, R ₄ represents a hydroxyl-protecting group, and the broken line portion represents a single bond or a double bond) A therapeutic agent for infectious diseases, comprising as an active ingredient at least one of mutilin derivatives represented by the above or acid addition salts thereof,

6) The following general formula (1-2)

(In the formula, R ₁ is a hydrogen atom, a formyl group, an optionally substituted lower alkyl group, an aromatic ring in which an aromatic ring may be substituted, a heteroaralkyl group in which an aromatic ring may be substituted, or a lower alkyl. Represents an oxycarbonyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₃ represents a hydrogen atom or a fluorine atom, R ₄ represents a hydroxyl protecting group, A therapeutic agent for infectious diseases, comprising as an active ingredient at least one of a mutilin derivative represented by a single bond or a double bond) or an acid addition salt thereof,
It is about.

  The compound of the present invention is a novel mutilin derivative having an excellent antibacterial action, and is useful as a therapeutic agent for infectious diseases involving gram-positive and gram-negative bacteria including various drug-resistant bacteria.

In the present invention, the position number of the compound in the mutilin chemistry shown below is used as the position number of the compound regardless of the IUPAC nomenclature. That is, according to Non-Patent Document 3, mutilin is expressed as “(1S, 2R, 3S, 4S, 6R, 7R, 8R, 14R) -3,6-dihydroxy-2,4,7,14-tetra methyl-4-vinyl - a tricyclo [5.4.3.0 ^{1, 8]} tetradecane-9-one "

On the other hand, in the following general formula (3), the IUPAC name is “(1R, 2R, 4S, 6R, 7R, 8S, 9R, 14R) -6-hydroxy-9-methoxy-2,4,7,14-tetramethyl” -4-Vinyl-1-tricyclo [5.4.3.01,
8] Tetradecan-3-one ", but in mutilin chemistry it is" (3R) -3-deoxo-11-deoxy-3-methoxy-11-oxo-4-epimutilin ".

  In the present invention, “lower alkyl” includes linear or branched ones having 1 to 6 carbon atoms such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl and the like. As a substituent, a lower alkoxy group, a halogen atom, a cyano group, an amino group, a thiol group, a lower acyloxy group, a lower alkyloxycarbonyl group, a lower alkylcarbonyl group, a lower alkylcarboxamide group, a nitro group, one or more substitutions Optionally having an aliphatic heterocyclic ring or one or more substituents, which may contain one or more hetero atoms such as O, N, S, etc. Examples thereof include aromatic heterocycles which may contain one or more hetero atoms such as O, N and S of 5 to 14 membered rings. Moreover, it does not ask | require chain | strand shape, cyclic | annular form, saturation, and unsaturated.

Examples of the “aralkyl group” include a benzyl group and a 1-phenylethyl group, and examples of the substituent include a lower alkoxy group, a halogen atom, a cyano group, an amino group, a thiol group, a lower acyloxy group, and a lower alkyloxycarbonyl group. , A lower alkylcarbonyl group, a lower alkylcarboxamide group, a nitro group, and the like.

The “lower alkoxy group” is a straight chain or branched one having 1 to 6 carbon atoms such as methoxy group, ethoxy group, 1-methylethoxy group, 1,1-dimethylethoxy group, propoxy group, 2-methylpropoxy group, etc. Regardless of saturation or unsaturation.

Examples of the “aralkyloxy group” include a benzyloxy group and a 1-phenylethoxy group, and examples of the substituent include a lower alkoxy group, a halogen atom, a cyano group, an amino group, a thiol group, a lower acyloxy group, and a lower alkyloxy group. Examples thereof include a carbonyl group, a lower alkylcarbonyl group, a lower alkylcarboxamide group, and a nitro group.

Examples of the “lower acyloxy group” include those having 1 to 5 carbon atoms such as formyl group, acetoxy group, propionyloxy group or 2,2-dimethylpropionyloxy group.

"One or more substituents" in "aliphatic heterocycle optionally having one or more substituents, which may contain one or more 5- to 14-membered ring heteroatoms such as O, N, and S" "" Includes, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a nitro group, an amino group, a cyano group, and the "aliphatic heterocycle" includes, for example, pyrrolidyl, Examples include piperidyl, piperazil, morpholyl and the like. The “amino group” in this case may be substituted with acyl, for example, acetyl or the like, or may be substituted with 1 to 2 lower alkyl groups.

“One or more substituents” in the “aromatic heterocycle optionally having one or more substituents, which may contain one or more hetero atoms such as O, N, S, etc. of 5- to 14-membered rings” "" Includes, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower alkoxycarbonyl group, a nitro group, an amino group, a cyano group, and the "aromatic heterocycle" includes, for example, furanyl, Examples include thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyridazyl, pyratyl and the like, and they may be condensed with a benzene ring at an arbitrary position. The “amino group” in this case may be substituted with acyl, for example, acetyl or the like, or may be substituted with 1 to 2 lower alkyl groups.

Examples of the “optionally substituted hydroxyl group” include a hydroxyl group, a lower alkoxy group, a lower acyloxy group, a hydroxyl group having a protecting group, an arylacyloxy group, or a hydroxyl group formed integrally with an oxygen atom to form a leaving group. It is done. Examples of the “aryl acyl group” herein include a benzoyl group, and examples of the substituent include a lower alkyl group, a lower alkoxy group, a halogen atom, a cyano group, and a nitro group.

In addition, as a protective group for a hydroxyl group, a trialkylsilyl group such as a trimethylsilyl group and a t-butyldimethylsilyl group, an arylmethyl group such as a benzyl group and a diphenylmethyl group, an acyl group such as an acetyl group and a propionyl group, and a methoxymethyl group And lower alkoxymethyl groups such as ethoxymethyl group, aralkyloxymethyl groups such as benzyloxymethyl group, tetrahydropyranyl groups and the like, and introduction and removal thereof can be carried out by appropriately adopting methods described in the literature ( Green, TW; Wuts, PGM “Protective
^{Groups in Organic Synthesis ", 2 nd} Ed., Wiley Interscience
Publication, John-Weiley & Sons, New York, 1991. Hereinafter, "Green
et.al. " ).

Examples of the “leaving group which is integrated with an oxygen atom” include a lower alkylsulfonyloxy group and an arylsulfonyloxy group.

Examples of the “optionally substituted thiol group” include a thiol group, a lower thioalkoxy group, a lower acylthiooxy group, a thiol group having a protecting group, or an arylacylthiooxy group. Examples of the “aryl acyl group” herein include a benzoyl group, and examples of the substituent include a lower alkyl group, a lower alkoxy group, a halogen atom, a cyano group, and a nitro group. In addition, as a protective group for thiol groups, trialkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group, arylmethyl groups such as benzyl group and diphenylmethyl group, acyl groups such as acetyl group and propionyl group, methoxymethyl Group, lower alkoxymethyl group such as ethoxymethyl group, aralkyloxymethyl group such as benzyloxymethyl group, tetrahydropyranyl group and the like, and introduction and removal thereof can be carried out by appropriately adopting methods described in the literature. (Green et.al.).

Examples of the “optionally substituted amino group” include an amino group, a lower alkylamino group, a lower acylamino group, an amino group having a protecting group, and an arylacylamino group.

Examples of the “amino-protecting group” include a lower acyl group such as acetyl and propionyl, a lower alkoxycarbonyl group such as ethoxycarbonyl and t-butoxycarbonyl, a benzyl group, and the introduction and removal thereof are described in the literature. This method can be adopted as appropriate (Green et.al.).

Examples of the “aryl acyl group” include a benzoyl group, and examples of the substituent include a lower alkyl group, a lower alkoxy group, a halogen atom, a cyano group, and a nitro group.

Preferred compounds in the present invention include
14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
14- [2- (pyridin-3-yl) propanoyl] carbamolyl mutilin,
11-O-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
11-O-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propanoyl] carbamoylmutilin,
(2R) -2-fluoro-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
(2S) -2-fluoro-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
(2S) -2-fluoro-14- [2- (pyridin-3-yl) propanoyl] carbamoylmutilin,
14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12-desethenylmutilin,
14- [2- (pyridin-3-yl) propanoyl] carbamoyl-12-desethenylmutilin,
12-desethenyl-12-methyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12- (1-hydroxyethane-2-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12- (1-propen-3-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12-phenylmethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12- (1-propyn-3-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12- (2-propyn-3-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12- (1-fluoroethane-2-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12- (1,1,1-trifluoroethane-2-yl) mutilin,
12-desethenyl-12-fluoromethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-hydroxymethyl-12-desethenyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12- (4-pyridyl) methyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12- [2-propen-3-yl] -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-cyanomethyl-12-desethenyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12- [1- (1,2,3-triazol-1-yl) ethyl] mutilin,
12-desethenyl-12-formyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
12-desethenyl-12-formyl-14- [2- (pyridin-3-yl) propanoyl] carbamoylmutilin,
12-desethenyl-12-methoxycarbonyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin,
14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- [1- (E)-(ethoxycarbonyl) ethen-2-yl] mutilin,
14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethane-2-yl) mutilin,
14- [2- (pyridin-3-yl) propanoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethane-2-yl) mutilin,
14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethanedimethylketal-2-yl) mutilin,
14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,3-dioxolan-2-one-4-yl) mutilin,
14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12-desethenylmutilin 12-N-methylcarboxamide,
14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12-desethenylmutilin 12-N, N-dimethylcarboxamide,
Etc.

  When the compound of the present invention forms a pharmacologically acceptable salt, inorganic salts such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or acetic acid, maleic acid, fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid And addition salts with organic acid salts such as citric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, salicylic acid, stearic acid, palmitic acid or trifluoroacetic acid.

  The compound of the present invention has a plurality of asymmetric carbons, and corresponding optical isomers may exist. However, these optical isomers and a mixture showing any ratio thereof are also included in the present invention. is there.

  The compound of the present invention represented by the above general formula (1) or a salt thereof includes any of intramolecular salts and adducts, solvates or hydrates thereof.

  The compound of the present invention represented by the above general formula (1) or a salt thereof can be used alone or in combination with one or more pharmaceutically acceptable adjuvants as a pharmaceutical composition. Forms (eg starch, lactose, calcium phosphate or calcium carbonate), lubricants (eg magnesium stearate, calcium stearate talc or stearic acid), binders (eg starch, crystalline cellulose, carboxymethylcellulose, gum arabic) , Polyvinylpyrrolidone or alginic acid, etc.), disintegrating agents (eg talc or carboxymethylcellulose calcium etc.), diluents (eg saline, aqueous solutions of glucose, mannitol or lactose etc.) etc. , Capsules, It can be administered orally or parenterally in the form of granules, powders, fine granules, ampoules or injections. The dose varies depending on the type of the compound of the present invention represented by the above general formula (1) or a salt thereof, administration method, patient age, weight, symptoms, etc. The compound of the present invention represented by the formula (1) or a salt thereof is 0.0001 to 1000 mg / kg / day. Administration is, for example, once a day or divided into several times.

  The compound group represented by the general formula (1) of the present invention can be produced, for example, according to the following production steps using the compound represented by the chemical formula (3) as a key intermediate. Here, the compound represented by the chemical formula (3) is a known compound, and its production can be carried out with reference to, for example, a method described in non-patent literature (Tetrahedron 1980, 36, 1807-1811).

(First step)
In this step, a suitable protecting group is introduced into the 14-position hydroxyl group of the 4-epimutilin derivative represented by the above chemical formula (3) produced from pleuromutilin by a known method, and represented by the above general formula (3-1). The 4-epimutilin derivative in which the 14-position hydroxyl group is protected is produced.

  Introduction of a hydroxyl-protecting group in this reaction can be carried out by appropriately adopting methods described in the literature (Green et.al.). Any solvent can be used as the reaction solvent as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, aprotic such as acetonitrile, propionitrile, nitromethane, nitroethane, N, N-dimethylformamide and dimethyl sulfoxide A polar solvent is preferably used. The reaction normally proceeds smoothly at -20 ° C to 200 ° C.

(Second step)
In this step, the 12-position double bond in the 4-epimutilin derivative in which the 14-position hydroxyl group represented by the general formula (3-1) obtained in the first step is protected is converted into a diol, and the general formula (2 1-a), which is a 4-epimutilin 19,20-diol derivative.

  In this reaction, an appropriate osmium derivative is usually used in a catalytic amount, and the reaction is carried out in the presence of an equivalent amount to an excess amount of an oxidizing agent. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl- An alcohol solvent such as 1-propanol or 2-methyl-2-propanol or a mixed solvent of these with water is preferably used. The reaction proceeds smoothly at 0 ° C to 200 ° C.

(Third process)
In this step, the diol portion of the 4-epimutilin 19,20-diol derivative represented by the general formula (2-1a) obtained in the second step is removed by a reverse aldol-type reaction, and the general formula (2 -1b), which is a 12-position desethenyl 4-epimutilin derivative.

  This reaction is usually carried out by using an appropriate reactant such as alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal hydrides such as sodium hydride and potassium hydride, n-butyllithium, lithium bis (trimethylsilyl). ) Amide, alkali metal organic bases such as sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.3. The reaction can be performed in the presence of a tertiary organic base such as 0] non-5-ene and 1,8-diazabicyclo [5.4.0] unde-7-cene, and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. If necessary, it is carried out in the presence of a Lewis acid such as zinc chloride, zinc bromide, zinc iodide, boron trifluoride, aluminum chloride, tin tetrachloride, boron trifluoride-diethyl ether complex, or lithium perchlorate. be able to. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. A halogenated hydrocarbon solvent such as carbon and an ether solvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane are preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C.

(Fourth process)
In this step, a suitable electrophile is reacted in the presence of a base at the 12-position of the 12-position desethenyl 4-epimutilin derivative represented by the general formula (2-1b) obtained in the third step, and the general formula A 12-position R ₁ -substituted 4-epimutilin derivative represented by (2-1c) is produced.

  In this reaction, an appropriate electrophilic agent is usually used in an equivalent amount to an excess amount, and an appropriate reactant such as an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, sodium hydride or potassium hydride is used. Alkali metal hydrides, n-butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, alkali metal organic bases such as potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N -Tertiary organic bases such as methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] unde-7-cene, potassium carbonate , In the presence of an inorganic base such as sodium bicarbonate It can be. If necessary, it is carried out in the presence of a Lewis acid such as zinc chloride, zinc bromide, zinc iodide, boron trifluoride, aluminum chloride, tin tetrachloride, boron trifluoride-diethyl ether complex, lithium perchlorate or the like. be able to. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, aprotic such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide A polar solvent is preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C.

(Fifth process)
In this step, the protecting group for the 14-position hydroxyl group in the 12-position R ₁ -substituted 4-epimutilin derivative represented by the general formula (2-1c) obtained in the fourth step is removed, and the general formula (2 14d-hydroxylated 4-epimutilin derivative represented by -1d). The method for removing the hydroxyl-protecting group can be carried out by appropriately adopting the method described in the literature (Green et.al.). Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2 Alcohol solvents such as -methyl-1-propanol and 2-methyl-2-propanol are preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C.

(Sixth process)
In this step, the 14-position hydroxyl group in the 14-position hydroxylated 4-epimutilin derivative represented by the general formula (2-1d) obtained in the fifth step is represented by the general formula (4) under appropriate reaction conditions. An acylcarbamoylation reaction is carried out by reacting the pyridylacrylic acid chloride derivative represented by the formula to produce a 14-position acylcarbamoylated 4-epimutilin derivative represented by the general formula (1-1a).

This step can usually be performed with reference to the methods described in the literature. That is, (A) in the presence of a suitable base, a pyridylacrylic acid chloride derivative represented by the general formula (4) and silver cyanate are converted to a 14-position hydroxylated 4-hydroxy group represented by the general formula (2-1d). Method of reacting with epimutilin derivative
(J. Org. Chem. 1962, 27, 3317.), a method using tributyltin isocyanate (Chem. Ber. 1986, 119, 83.), or (B) the above general formula under ordinary reaction conditions Carbamoylation reaction is performed on the 14-position hydroxyl group of the 14-position hydroxylated 4-epimutilin derivative represented by (2-1d), and then pyridyl acrylate is represented by the general formula (4) in the presence of a suitable base. Or (C) a 14-position hydroxylated 4-epimutilin derivative represented by the general formula (2-1d) in the presence of a suitable base, trimethylsilyl isocyanate, and the general formula (4) A method using a pyridylacrylic acid chloride derivative represented by the formula (J. Gen. Chem. USSR, 1977, 2061-2067.), Or (D) pyridylacrylic acid represented by the general formula (4), After acid amidation under normal reaction conditions in the presence of a suitable base, the 14-position represented by the general formula (2-1d) A method in which an oxidized 4-epimutilin derivative is reacted with a carbonyl source such as oxalyl chloride, phosgene, or CDI in the presence of a suitable base such as a bis (trimethylsilyl) amide salt (J. Org. Chem. 1962, 27, 3742 .) Etc. can be adopted. The reaction is usually carried out with a suitable base such as alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal hydrides such as sodium hydride and potassium hydride, n-butyllithium, lithium diisopropylamide, lithium bis (Trimethylsilyl) amide, alkali metal organic bases such as sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [ 4.3.0] The reaction is carried out in the presence of a tertiary organic base such as non-5-ene and 1,8-diazabicyclo [5.4.0] unde-7-cene, and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, and ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane are used. The reaction proceeds smoothly at -100 ° C to 100 ° C.

(Seventh step)
In this step, R ₂ (hydrogen atom is added to the nitrogen atom present at the 14-position spacer site in the 14-position acylcarbamoylated 4-epimutilin derivative represented by the general formula (1-1a) obtained in the sixth step. And the 14-position acylcarbamoylated 4-epimutilin derivative represented by the general formula (1-1b) is produced. Examples of the base used include alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal hydrides such as sodium hydride and potassium hydride, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl). ) Amide, alkali metal organic bases such as sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.3. It can be carried out in the presence of a tertiary organic base such as 0] non-5-ene and 1,8-diazabicyclo [5.4.0] unde-7-cene, and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2 Alcohol solvents such as -methyl-1-propanol and 2-methyl-2-propanol, and aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethylsulfoxide are preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C.

(Eighth process)
This step removes the 3-position protecting group in the 14-position acylcarbamoylated 4-epimutilin derivative represented by the general formula (1-1a and 1-1b) obtained in the seventh step, and the general formula The 14-position acylcarbamoylated mutilin derivative represented by (1) is produced. The protecting group can be removed by appropriately adopting methods described in the literature (Green et al.), But preferably hydrochloric acid or zinc chloride-hydrochloric acid (Lucas reagent) is used. Any solvent can be used as the reaction solvent as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, acetonitrile, propionitrile, nitromethane, nitroethane, N, N-dimethylformamide, N, N- The reaction is carried out in the presence or absence of an aprotic polar solvent such as dimethylacetamide or dimethylsulfoxide or a mixed solvent of these with water, and usually proceeds smoothly at -20 ° C to 200 ° C.

Or the compound group represented by General formula (1) of this invention can also be manufactured according to the following manufacturing process, for example by using a preuromutilin as a starting material.

(First step)
In this step, an appropriate protecting group was introduced into both the hydroxyl group at the 14-position glycolic acid ester site and the 11-position hydroxyl group of pleuromutilin, and the two hydroxyl groups represented by the general formula (5-1) were protected. A preuromutilin derivative is produced.

  Introduction of a hydroxyl-protecting group in this reaction can be carried out by appropriately adopting methods described in the literature (Green et.al.). Any solvent can be used as the reaction solvent as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, acetonitrile, propionitrile, nitromethane, nitroethane, N, N-dimethylformamide, N, N- The reaction can be performed with an aprotic polar solvent such as dimethylacetamide or dimethylsulfoxide. The reaction normally proceeds smoothly at -20 ° C to 200 ° C.

(Second step)
This step hydrolyzes the 14-position glycolic acid ester moiety in the pleuromutilin derivative in which the two hydroxyl groups represented by the general formula (5-1) obtained in the first step are protected, and the general formula A mutilin derivative in which only the 11-position hydroxyl group represented by (5-2) is protected is produced.

  This reaction is usually carried out by using a suitable reactant such as an alkali metal alkoxide such as sodium methoxide or sodium ethoxide, an alkali metal hydride such as sodium hydride or potassium hydride, n-butyllithium, lithium diisopropylamide, Alkali metal organic bases such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5- It can be carried out in the presence of a tertiary organic base such as diazabicyclo [4.3.0] non-5-ene and 1,8-diazabicyclo [5.4.0] unde-7-cene, and an inorganic base such as potassium carbonate and sodium bicarbonate. it can. In addition, if necessary, in the presence of a Lewis acid such as zinc chloride, zinc bromide, zinc iodide, boron trifluoride, aluminum chloride, tin tetrachloride, boron trifluoride-diethyl ether complex, lithium perchlorate, or It can be carried out in the presence of hydrochloric acid. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, aprotic such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide The reaction proceeds smoothly in the presence or absence of a polar solvent or a mixed solvent of these with water, and the reaction proceeds smoothly at −110 ° C. to 100 ° C.

(Third process)
In this step, the 19, 20-position double bond site of the mutilin derivative in which the 11-position hydroxyl group represented by the general formula (5-2) obtained in the second step is protected is converted into a diol, and the general formula (2 -2a) is a mutyline 19,20-diol derivative in which the hydroxyl group at position 11 is protected.

  In this reaction, an appropriate osmium derivative is usually used in a catalytic amount, and the reaction is carried out in the presence of an equivalent amount to an excess amount of an oxidizing agent. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2 An alcohol solvent such as -methyl-1-propanol or 2-methyl-2-propanol or a mixed solvent of these with water is preferably used. The reaction proceeds smoothly at 0 ° C to 200 ° C.

(Fourth process)
In this step, a mutilin 19,20-diol derivative in which the hydroxyl group at position 11 represented by the general formula (2-2a) is protected is subjected to a diol cleavage reaction, and represented by the general formula (2-2b). A 12-formylated mutilin derivative in which the 11 hydroxyl group is protected is produced.

  This reaction can usually be performed in the presence of sodium periodate. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, aprotic such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide A polar solvent or a mixed solvent of these with water is preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C.

(Fifth process)
In this step, the 12-formylylated mutilin derivative in which the 11-hydroxyl group represented by the general formula (2-2b) is protected is subjected to various functional group transformations using the 12-position formyl group as a foothold, A 12-position R1-substituted mutilin derivative in which the 11-position hydroxyl group represented by (2-2c) is protected is produced. For example, when the Wittig reaction is taken as an example, examples of the phosphonium salt used in this step include methyltriphenylphosphonium chloride, methyltriphenylphosphonium bromide, methyltriphenylphosphonium iodide, and the base used is For example, alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal hydrides such as sodium hydride and potassium hydride, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (Trimethylsilyl) amide, alkali metal organic bases such as potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidi , Tertiary organic bases such as potassium, piperidine, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] unde-7-cene, potassium carbonate, sodium hydrogen carbonate, etc. It can be carried out in the presence of an inorganic base. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2 Alcohol solvents such as -methyl-1-propanol and 2-methyl-2-propanol are preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C. Alternatively, the formyl group can be oxidized and converted to a carboxylic acid derivative. In that case, the reaction is carried out in the presence of a suitable oxidizing agent. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2 Alcohol solvents such as 2-methyl-1-propanol and 2-methyl-2-propanol, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethylsulfoxide, or a mixture of these with water A solvent is preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C. Alternatively, it is possible to produce an oxime derivative by reacting a hydroxyamine derivative. In that case, hydroxyamine hydrochloride or a derivative thereof is used. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl- Alcohol solvents such as 1-propanol and 2-methyl-2-propanol, aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide, or mixed solvents of these with water are suitable. Used for. The reaction proceeds smoothly at -110 ° C to 100 ° C.

(Sixth process)
In this step, the 14-position hydroxyl group in the 12-position R _1- substituted mutilin derivative in which the 11-position hydroxyl group represented by the general formula (2-2c) obtained in the fifth step is protected is subjected to the reaction conditions described above. An acylcarbamoylation reaction is performed by reacting a pyridylacrylic acid chloride derivative represented by the general formula (4), and the 14-position acylcarbamoylation in which the 11-position hydroxyl group represented by the general formula (1-2a) is protected is performed. A mutilin derivative is produced.

This step can usually be performed with reference to the methods described in the literature. That is, (A) In the presence of a suitable base, the pyridylacrylic acid chloride derivative represented by the general formula (4) and the silver cyanate are protected by the 11-position hydroxyl group represented by the general formula (2-2c). By reacting with the 14-position mutilin hydroxide derivative (J. Org. Chem. 1962, 27, 3317.) or using tributyltin isocyanate
(Chem. Ber. 1986, 119, 83.) or (B) a 14-position hydroxylated mutilin derivative in which the 11-position hydroxyl group represented by the general formula (2-2c) is protected under normal reaction conditions. A method in which a carbamoylation reaction is performed on the hydroxyl group at position 14, and then a pyridyl acrylate chloride derivative represented by the general formula (4) is bonded in the presence of a suitable base, or (C) the general formula (2- A method using the 14-position hydroxylated mutilin derivative in which the 11-position hydroxyl group represented by 2c) is protected using trimethylsilyl isocyanate and the pyridylacrylic acid chloride derivative represented by the general formula (4) in the presence of a suitable base
(J. Gen. Chem. USSR, 1977, 2061-2067.) Or (D) The pyridylacrylic acid represented by the general formula (4) is acidified under normal reaction conditions in the presence of a suitable base. After amidation, the 14-position hydroxylated mutilin derivative in which the 11-position hydroxyl group represented by the general formula (2-2c) is protected is converted into a carbonyl source in the presence of a suitable base such as bis (trimethylsilyl) amide salt, for example, Method of reacting reagents such as oxalyl chloride, phosgene, CDI
(J.Org.Chem.1962,27,3742.) Etc. can be adopted. The reaction is usually carried out with a suitable base such as alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal hydrides such as sodium hydride and potassium hydride, n-butyllithium, lithium diisopropylamide, lithium bis (Trimethylsilyl) amide, alkali metal organic bases such as sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [ 4.3.0] The reaction is carried out in the presence of a tertiary organic base such as non-5-ene and 1,8-diazabicyclo [5.4.0] unde-7-cene, and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, and ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane are used. The reaction proceeds smoothly at -100 ° C to 100 ° C.

(Seventh step)
In this step, the nitrogen atom present at the 14-position spacer site in the 14-position acylcarbamoylated mutilin derivative in which the 11-position hydroxyl group represented by the general formula (1-2a) obtained in the sixth step is protected is bonded to R. ₂ (excluding a hydrogen atom) is introduced to produce a 14-position acylcarbamoylated mutilin derivative in which the 11-position hydroxyl group represented by the general formula (1-2b) is protected. Examples of the base used include alkali metal alkoxides such as sodium methoxide and sodium ethoxide, alkali metal hydrides such as sodium hydride and potassium hydride, n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl). ) Amide, alkali metal organic bases such as sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo [4.3. It can be carried out in the presence of a tertiary organic base such as 0] non-5-ene and 1,8-diazabicyclo [5.4.0] unde-7-cene, and an inorganic base such as potassium carbonate and sodium hydrogen carbonate. Any solvent can be used as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl- Alcohol solvents such as 1-propanol and 2-methyl-2-propanol, and aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and dimethyl sulfoxide are preferably used. The reaction proceeds smoothly at -110 ° C to 100 ° C.

(Eighth process)
This step is a protecting group for the 11-position hydroxyl group in the 14-position acylcarbamoylated mutilin derivative in which the 11-position hydroxyl group represented by the general formula (1-2a and 1-2b) obtained in the seventh step is protected. Is removed to produce a 14-position acylcarbamoylated mutilin derivative represented by the general formula (1). The protecting group can be removed by appropriately adopting methods described in the literature (Green et al.), But preferably hydrochloric acid or zinc chloride-hydrochloric acid (Lucas reagent) is used. Any solvent can be used as the reaction solvent as long as it does not participate in the reaction. For example, hydrocarbon solvents such as pentane, hexane, cyclohexane, benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, chloroform, tetrachloride. Halogenated hydrocarbon solvents such as carbon, ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, acetonitrile, propionitrile, nitromethane, nitroethane, N, N-dimethylformamide, N, N- The reaction is carried out in the presence or absence of an aprotic polar solvent such as dimethylacetamide or dimethylsulfoxide or a mixed solvent of these with water, and usually proceeds smoothly at -20 ° C to 200 ° C.

EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention in detail, it cannot be overemphasized that this invention is not what is limited to these.

(Reference Example 1)
(3R) -3-deoxo-11-deoxy-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin

4-epimutilin 2.00 prepared from pleuromutilin in two steps according to literature method (Tetrahedron 1980, 36, 1807-1811.)
Add 2.08 mL (12.0 mmol) of diisopropylethylamine and 0.91 mL (12.0 mmol) of chloromethyl methyl ether in a methylene chloride solution (50 mL) of g (5.98 mmol) at 0 ° C under argon atmosphere, and stir at room temperature for 60 hours. did. The reaction mixture was poured into a cold dilute aqueous citric acid solution, and the solvent was distilled off under reduced pressure, followed by extraction with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1), 2.30
The title compound was obtained as a colorless oil of g (yield 100%).
MS
(FAB) (m / z): 379 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₃₉ O ₄ (MH ⁺ ):
379.2848. Found, 379.2883.

(Reference example 2)
(3R) -3-deoxo-11-deoxy-19,20-dihydroxy-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin

In a water-containing acetone solution (800 mL) of 130 g (0.34 mol) of the compound of Reference Example 1, 4-methylmorpholine N-oxide 60.3 g (0.52
mol) and a catalytic amount of osmium tetroxide (5% t-butanol solution) were added and heated under reflux for 60 hours. The reaction mixture was evaporated under reduced pressure, diluted aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, then ethyl acetate: methanol = 10: 1).
The title compound was obtained as a yellow oil (yield 95%).
MS
(FAB) (m / z): 413 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₄₁ O ₆ (MH ⁺ ):
413.2903. Found, 413.2933.

(Reference Example 3)
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin

To an acetone solution (1000 mL) of 94.6 g (0.23 mol) of the compound of Reference Example 2, 63.4 g (0.46 mol) of potassium carbonate was added at 0 ° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered through celite, the residue was washed with ethyl acetate, and the filtrate was evaporated under reduced pressure. A dilute aqueous citric acid solution (1000 mL) was added to the resulting residue, and the mixture was extracted with ethyl acetate (500 mL x 3). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1), 70.2
g of the title compound was obtained as a colorless powder (yield 87%).
MS
(FAB) (m / z): 353 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₁ H ₃₇ O ₄
(MH ⁺ ): 353.2692. Found, 353.2720.

(Reference Example 4)
11-O-methoxymethylmutilin

20.0 g (0.13 mol) of pleuromutilin in 2 L Nascol and 138 mL (0.79 mol) of N, N-diisopropylethylamine in methylene chloride solution (500 mL) were added chloromethyl methyl ether 40.1 in an argon atmosphere at 0 ° C.
mL (0.53 mol) was added dropwise and left at room temperature for 21 days. 3- (Dimethylamino) propylamine 33.2 was added to the reaction mixture.
Add mL (0.26 mol) and evaporate under reduced pressure.Add dilute aqueous citric acid solution to the residue and extract with ethyl acetate (200 mL
x 3) The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give a crude compound. This was dissolved in 500 mL of a 2 mol / L potassium hydroxide-methanol solution and heated to reflux for 3 hours. After cooling, the solvent was evaporated under reduced pressure, diluted aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate (300 mL x 3). The combined organic layers were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), 42.0
The title compound was obtained as a colorless powder of g (2 step yield 87%).
MS
(FAB) (m / z): 365 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₇ O ₄ (MH ⁺ ):
365.2692. Found, 365.2665.

(Reference Example 5)
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-4-epimutilin

To a methylene chloride solution (30 mL) of 970 mg (2.75 mmol) of the compound of Reference Example 3, 523 mg (2.75 mmol) of p-toluenesulfonic acid was added and stirred at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), 772
mg of the title compound was obtained as a colorless powder (91% yield).
MS
(FAB) (m / z): 291 (MH ⁺ -H ₂ O).
HRMS
(FAB) (m / z): Calcd. For C ₁₉ H ₃₁ O ₂ (MH ⁺ -H ₂ O):
291.2324. Found, 291.2317.

(Reference Example 6)
12-desethenyl-12-formyl-11-O-methoxymethylmutilin

To a tetrahydrofuran solution (5 mL) of 300 mg (0.82 mmol) of the compound of Reference Example 4, an aqueous solution (5 mL) of a catalytic amount of osmium tetroxide (5% t-butanol solution) and sodium periodate 352 mg (1.65 mmol). ) Was added and stirred at room temperature for 24 hours. The reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. The filtrate was evaporated under reduced pressure, diluted aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1, then hexane: ethyl acetate = 1: 4) to obtain 169 mg of the title compound as a colorless powder (yield). Rate 56%).
MS
(CI) (m / z): 367 (MH ⁺ ).
HRMS
(CI) (m / z): Calcd. For C ₂₁ H ₃₅ O ₅ (MH ⁺ ):
Found, 367.2500.

(Reference Example 7)
14-acetoxy-12-desethenyl-12-formyl-11-O-methoxymethylmutilin

To 1.50 g (4.09 mmol) of the compound of Reference Example 6, acetic anhydride 3.86 mL (41.0 mmol), pyridine 6.62 mL (41.0
mmol) and 4- (dimethylamino) pyridine 460 mg (4.09 mmol) were added, and the mixture was stirred at room temperature for 72 hours. A diluted aqueous citric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1).
The title compound as a yellow powder was obtained (56% yield).
MS
(FAB) (m / z): 409 (MH ⁺ ).
Rf
= 0.20 (hexane: ethyl acetate = 2: 1)

(Example 1)
First step
(3R) -3-deoxo-11-deoxy-3-methoxy-11-oxo-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-4-epimutilin

In a methylene chloride solution (9 mL) of 300 mg (0.90 mmol) of the compound described in the literature (Tetrahedron 1980, 36, 1807-1811.), 202 mg (1.35 mmol) of silver cyanate, trans-3- (3 Acid chloride hydrochloride prepared from (pyridyl) acrylic acid and oxalyl chloride 275 mg (1.35
mmol), triethylamine 0.19 mL (1.35 mmol) and 4- (dimethylamino) pyridine 165
mg (1.35 mmol) was added, and the mixture was stirred at room temperature for about 16 hours under light shielding. The reaction mixture was filtered through celite, and the residue was washed with methylene chloride. The combined organic layers were evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1, hexane: ethyl acetate = 2: 1, then hexane: ethyl acetate
= 1: 1) to give 317 mg of the title compound as a colorless powder (yield 63%).
MS
(FAB) (m / z): 509 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₁ N ₂ O ₅
(MH ⁺ ): 509.3015. Found, 509.3022.

Second step
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoylmutilin

To a dioxane solution (2 mL) of 165 mg (0.32 mmol) of the compound in the first step, 2.00 mL of concentrated hydrochloric acid was added under ice-cooling and stirring, and the mixture was stirred for 2.5 hours while naturally heating. The reaction mixture was made alkaline by adding 10% aqueous sodium hydroxide solution, and the aqueous layer was extracted with ethyl acetate (10%
mL x 3). The combined organic layers were washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2).
mg of the title compound was obtained as a colorless powder (yield 90%).
MS
(FAB) (m / z): 495 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₃₉ N ₂ O ₅
(MH ⁺ ): 495.2859. Found, 495.2878.

(Example 2)
14- [2- (Pyridin-3-yl) propanoyl] carbamolyl mutilin

According to the method of the first step of Example 1, 1.00 g (2.99 mmol) of 4-epimutilin, 924 mg of carboxylic acid chloride hydrochloride (4.48
mmol), 1.34 g (8.97 mmol) of silver cyanate and 625 μL (4.48 mmol) of triethylamine, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, then hexane: ethyl acetate = 1: Purification in 4) gave 159 mg of a colorless powdery compound (yield 10%). Using the obtained compound 159 mg (0.31 mmol), the same reaction as in the second step of Example 1 was performed, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, then ethyl acetate). 94.4 mg of the title compound was obtained as a colorless powder (yield 45%).
MS
(FAB) (m / z): 497 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₁ N ₂ O ₅
(MH ⁺ ): 497.3015. Found, 497.3026.

(Example 3)
11-O-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the first step of Example 1, 120 mg (0.33 mmol) of the compound of Reference Example 4, 101 mg (0.43 of carboxylate chloride hydrochloride)
mmol), silver cyanate 123 mg (0.82 mmol), 4- (dimethylamino) pyridine 40.2
The reaction was performed with mg (0.33 mmol) and triethylamine 69.0 μL (0.49 mmol), and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, then hexane: ethyl acetate = 1: 4) 154 mg of the title compound was obtained as a colorless powder (yield 87%).
MS
(FAB) (m / z): 539 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₃ N ₂ O ₆
(MH ⁺ ): 539.3121. Found, 539.3106.

(Example 4)
11-O-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propanoyl] carbamoylmutilin

According to the method of the first step of Example 1, 120 mg (0.33 mmol) of the compound of Reference Example 4, 102 mg of carboxylic acid chloride hydrochloride (0.49
mmol), silver cyanate 123 mg (0.82 mmol), 4- (dimethylamino) pyridine 40.2
The reaction was conducted with mg (0.33 mmol) and triethylamine 69.0 μL (0.49 mmol), and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, then hexane: ethyl acetate = 1: 4) 116 mg of the title compound was obtained as a colorless powder (yield 65%).
MS
(FAB) (m / z): 541 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₅ N ₂ O ₆
(MH ⁺ ): 541.3278. Found, 541.3284.

(Example 5)
(2R) -2-Fluoro-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

(2R) -2-fluoro-11-O-formylmutilin 733 mg (2.00 mmol), carboxylic acid 447 mg, prepared according to the method of the literature (WO2000 / 07974 pamphlet) according to the method of the first step of Example 1 Carboxylic acid chloride hydrochloride prepared from (3.00 mmol), silver cyanate 749 mg (5.00 mmol), and triethylamine 0.29 mL (2.00
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 25.0 mg of a compound as a colorless powder (yield 2%). This compound was reacted with 25.0 mg (46.2 μmol) according to the method of the second step of Example 1, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), 9.90
The title compound as a colorless powder was obtained (42% yield).
MS
(FAB) (m / z): 513 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₃₈ FN ₂ O ₅
(MH ⁺ ): 513.2765. Found, 513.2772.

(Example 6)
First step
(2S) -2-Fluoro-11-O-formyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

(2S) -2-Fluoro-11-O-formylmutilin 820 mg (4.02 mmol), carboxylic acid chloride prepared according to the method of the literature (WO2000 / 07974 pamphlet) according to the method of the first step of Example 1 1.04 g (2.83
mmol), 1.06 g (7.07 mmol) of silver cyanate and 0.56 mL (4.02 mmol) of triethylamine, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, then hexane: ethyl acetate = 1: Purification in 4) yielded 170 mg of the title compound as a colorless powder (yield 8%).
MS
(FAB) (m / z): 541 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₃₈ FN ₂ O ₆
(MH ⁺ ): 541.2714. Found, 541.2718.

Second step
(2S) -2-Fluoro-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 74.0 mg (0.14 mmol) of the compound of the first step, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 2, hexane: ethyl acetate = 1: 2, then hexane: ethyl acetate
= 1: 2) to give 51.9 mg of the title compound as a colorless powder (yield 74%).
MS
(FAB) (m / z): 513 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₃₈ FN ₂ O ₅
(MH ⁺ ): 513.2765. Found, 513.2738.

(Example 7)
First step
(2S) -2-Fluoro-11-O-formyl-14- [2- (pyridin-3-yl) propanoyl] carbamoylmutilin

(2S) -2-Fluoro-11-O-formylmutilin 100 mg (0.27 mmol) produced according to the method described in the literature (WO2000 / 07974 pamphlet) according to the method of the first step of Example 1, carboxylated Hydrochloride 84.3 mg (0.41
mmol), silver cyanate 102 mg (0.68 mmol), 4- (dimethylamino) pyridine 33.4
The reaction was conducted with 5 mg (0.27 mmol) and 57.0 μL (0.41 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2, then hexane: ethyl acetate = 1: 4) 70.7 mg of the title compound was obtained as a colorless powder (yield 48%).
MS
(FAB) (m / z): 543 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₀ FN ₂ O ₆
(MH ⁺ ): 543.2870. Found, 543.2896.

Second step
(2S) -2-Fluoro-14- [2- (pyridin-3-yl) propanoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 62.7 mg (0.12 mmol) of the compound of the first step, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3: 2, hexane: ethyl acetate = 1: 1, then hexane: ethyl acetate
= 1: 2) to give 21.8 mg of the title compound as a colorless powder (yield 37%).
MS
(FAB) (m / z): 515 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₀ FN ₂ O ₅
(MH ⁺ ): 515.2921. Found, 515.2924.

(Example 8)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-4-epimutilin

According to the method of the first step of Example 1, the compound of Reference Example 5 400 mg (1.30 mmol), carboxylic acid chloride hydrochloride 399 mg (1.95
mmoL), silver cyanate 486 mg (3.24 mmol), 4- (dimethylamino) pyridine 159
The reaction was conducted with mg (1.30 mmol) and triethylamine 0.27 mL (1.95 mmol), and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: ethyl acetate = 1: 2, then hexane: ethyl acetate).
= 1: 4) to give 552 mg of the title compound as a colorless powder (yield 88%).
MS
(EI) (m / z): 482 (M ⁺ ).
HRMS
(EI) (m / z): Calcd. For C ₂₈ H ₃₈ N ₂ O ₅
(M ⁺ ): 482.2781. Found, 482.2773.

Second step
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenylmutilin

According to the method of the second step of Example 1, the reaction was performed using 253 mg (0.52 mmol) of the compound of the first step, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 8), 183
The title compound as a colorless powder was obtained (75% yield).
MS
(FAB) (m / z): 469 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₇ H ₃₇ N ₂ O ₅
(MH ⁺ ): 469.2702. Found, 469.2699.

(Example 9)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-14- [2- (pyridin-3-yl) propanoyl] carbamoyl-4-epimutilin

According to the method of the first step of Example 1, 400 mg (1.30 mmol) of the compound of Reference Example 5, 402 mg of carboxylate chloride hydrochloride (1.95
mmol), 486 mg (3.24 mmol) of silver cyanate and 0.27 mL (1.95 mmol) of triethylamine, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, then hexane: ethyl acetate = 1: Purification in 4) yielded 448 mg of the title compound as a colorless powder (yield 71%).
MS
(EI) (m / z): 484 (MH ⁺ ).
HRMS
(EI) (m / z): Calcd. For C ₂₈ H ₄₀ N ₂ O ₅
(MH ⁺ ): 484.2937. Found, 484.2907.

Second step
14- [2- (Pyridin-3-yl) propanoyl] carbamoyl-12-desethenylmutilin

実施例1の第二工程の方法に従って、第一工程の化合物210 mg (0.43 mmol) を用いて反応を行い、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル = 1:8）にて精製し、155
mgの無色粉末状物である表題化合物を得た（収率76%）。
MS
(FAB) (m/z): 471 (MH⁺).
HRMS
(FAB) (m/z): Calcd. for C₂₇H₃₉N₂O₅
(MH⁺): 471.2859. Found, 471.2859.

According to the method of the second step of Example 1, the reaction was performed using 210 mg (0.43 mmol) of the compound of the first step, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 8), 155
The title compound as a colorless powder was obtained (76% yield).
MS
(FAB) (m / z): 471 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₇ H ₃₉ N ₂ O ₅
(MH ⁺ ): 471.2859. Found, 471.2859.

(Example 10)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-12-methyl-11-oxo-4-epimutilin

To a solution of 5.00 g (14.2 mmol) of the compound of Reference Example 3 in anhydrous tetrahydrofuran (200 mL) was added 34.0 mL (17.0 mmol) of potassium bis (trimethylsilyl) amide (0.5 mol / L toluene solution) at -70 ° C under an argon atmosphere. And stirred for 0.5 hour. Under the same conditions, 1.06 mL (17.0 mmol) of methyl iodide was added, and the mixture was stirred for 4 hours while raising the temperature to -50 ° C. A dilute aqueous citric acid solution was added to the reaction mixture, and the mixture was distilled off under reduced pressure. The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and 5.20
g of the title compound as a yellow oil was obtained (yield 100%).
MS
(FAB) (m / z): 367 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₉ O ₄ (MH ⁺ ):
Found, 367.2884.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-12-methyl-11-oxo-4-epimutilin

According to the method of Reference Example 5, 5.20 g (14.2 mmol) of the first step compound and 2.70 p-toluenesulfonic acid
Reaction was performed using g (14.2 mmol), and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 3.70 g of the title compound as a colorless powder. (Yield 81%).
MS
(FAB) (m / z): 323 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₀ H ₃₅ O ₃ (MH ⁺ ):
323.2586. Found, 323.2609.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-12-methyl-11-oxo-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-4- Epimutilin

According to the method of the first step of Example 1, the compound of the second step 76.2 mg (0.24 mmol), carboxylate chloride hydrochloride 72.3 mg (0.35 mmol), silver cyanate 88.5 mg (0.59
mmol), 4- (dimethylamino) pyridine 28.8 mg (0.24 mmol) and triethylamine 49.0 μL (0.35 mmol), and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, then hexane: acetic acid). Purification with ethyl = 1: 4) gave 83.5 mg of the title compound as a colorless powder (yield 71%).
MS
(FAB) (m / z): 497 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₁ N ₂ O ₅
(MH ⁺ ): 497.3015. Found, 497.3007.

Fourth step
12-desethenyl-12-methyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 78.2 mg (0.16 mmol) of the compound of the third step, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4), 68.8
The title compound as a colorless powder was obtained (91% yield).
MS
(FAB) (m / z): 483 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₈ H ₃₉ N ₂ O ₅
(MH ⁺ ): 483.2859. Found, 483.2902.

(Example 11)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-12,14-O, O-dimethoxymethyl-11-oxo-4-epimutilin

According to the method of the first step of Example 10, 2.00 g (5.67 mmol) of the compound of Reference Example 3, chloromethyl methyl ether 0.52 mL
(6.81 mmol) and 13.6 mL (6.81 mmol) of potassium bis (trimethylsilyl) amide (0.5 mol / L toluene solution), and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1 To 1.80
g of the title compound as a yellow oil was obtained (yield 80%).
MS
(FAB) (m / z): 397 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₄₁ O ₅ (MH ⁺ ):
397.2954. Found, 397.2926.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-12-methoxymethyl-11-oxo-4-epimutilin

According to the method of Reference Example 5, 1.80 g (4.54 mmol) of the first step compound and 0.86 p-toluenesulfonic acid
Reaction was performed using g (4.54 mmol), and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 1.30 g of the title compound as a colorless powder. (Yield 81%).
MS
(FAB) (m / z): 353 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₁ H ₃₇ O ₄ (MH ⁺ ):
353.2692. Found, 353.2656.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-12-methoxymethyl-11-oxo-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-4 -Epimutilin

According to the method of the first step of Example 1, the compound of the second step 654 mg (1.86 mmol), carboxylate chloride hydrochloride 569 mg (2.79 mmol), silver cyanate 418 mg (2.79 mmol), 4- (dimethyl Amino) pyridine 341
The reaction was performed with mg (2.79 mmol) and triethylamine 0.39 mL (2.79 mmol), and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: ethyl acetate = 1: 1, hexane: ethyl acetate =
1: 2 and then hexane: ethyl acetate = 1: 4) to obtain 470 mg of the title compound as a colorless powder (yield 48%).
MS
(FAB) (m / z): 527 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₃ N ₂ O ₆
(MH ⁺ ): 527.3121. Found, 527.3149.

Fourth step
12-desethenyl-12-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was carried out using 470 mg (0.89 mmol) of the compound of the third step, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: ethyl acetate = 1: 1, hexane: ethyl acetate =
1: 2, hexane: ethyl acetate = 1: 4, then ethyl acetate: methanol = 10: 1)
The title compound was obtained in the form of mg colorless powder (yield 63%).
MS
(FAB) (m / z): 513 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₁ N ₂ O ₆
(MH ⁺ ): 513.2965. Found, 513.2968.

(Example 12)
First step
(3R) -12- (1-Acetoxyethan-2-yl) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin

According to the method of the first step of Example 10, the compound of Reference Example 3 5.00 g (14.2 mmol), bromoethyl acetate 1.88 mL (17.0
mmol) and potassium bis (trimethylsilyl) amide (0.5
mol / L toluene solution) 34.0
The reaction was performed using mL (17.0 mmol), and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 5.47 g of the title compound as a pale yellow oil (yield). 88%).
MS
(FAB) (m / z): 377 (MH ⁺ -HOCH ₂ OCH ₃ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₃₇ O ₄ (MH ⁺ -HOCH ₂ OCH ₃ ):
377.2692. Found, 377.2725.

Second step
(3R) -12- (1-Acetoxyethan-2-yl) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-4-epimutilin

According to the method of Reference Example 5, 5.18 g (11.8 mmol) of the first step compound and 2.25 p-toluenesulfonic acid
g (14.2 mmol) was used for the reaction, and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 2, then hexane: ethyl acetate).
= 1: 4) and (3R) -3-deoxo-11-deoxy-12-desethenyl-12- (1-hydroxyethane-2-yl) -3- 3.15 g of a colorless powder Methoxy-11-oxo-4-epimutilin was obtained (76% yield). Of these, 359 mg (1.02 mmol), 1 mL of acetic anhydride and 1 mL of pyridine were reacted, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1).
The title compound as a colorless powder was obtained (yield 80%).
MS
(FAB) (m / z): 377 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₃₇ O ₄ (MH ⁺ ):
377.2692. Found, 377.2701.

Third process
(3R) -12- (1-Acetoxyethan-2-yl) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-14-[(E) -2- (pyridine-3 -Il) propenoyl] carbamoyl-4-epimutilin

According to the method of the first step of Example 1, 210 mg (1.07 mmol) of the second step, 163 mg (0.80 mmol) of carboxylic acid chloride hydrochloride, 120 mg (0.80 mmol) of silver cyanate, 4- (dimethyl Amino) pyridine 97.7
The reaction was carried out with mg (0.80 mmmol) and 0.11 mL (0.80 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, then ethyl acetate: methanol = 40: 1) 173
The title compound as a colorless powder was obtained (57% yield).
MS
(FAB) (m / z): 569 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₂ H ₄₅ N ₂ O ₇
(MH ⁺ ): 569.3227. Found, 569.3240.

Fourth step
12-Desethenyl-12- (1-hydroxyethane-2-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was carried out using 173 mg (0.30 mmol) of the compound of the third step, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, then ethyl acetate: methanol). = 10: 1), 24.7
The title compound as a colorless powder was obtained (yield 16%).
MS
(FAB) (m / z): 513 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₁ N ₂ O ₆
(MH ⁺ ): 513.2965. Found, 513.2955.

(Example 13)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-12- (1-propen-3-yl) -4-epimutilin

According to the method of the first step of Example 10, the compound of Reference Example 3 5.00 g (14.2 mmol), allyl iodide 1.47 mL (17.0
mmol) and potassium bis (trimethylsilyl) amide (0.5
mol / L toluene solution) 34.0
Reaction was performed using mL (17.0 mmol), and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 2.52 g of the title compound as a yellow oil (yield) 45%).
MS
(FAB) (m / z): 393 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₄ H ₄₁ O ₄ (MH ⁺ ):
393.3005. Found, 393.2977.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (1-propen-3-yl) -4-epimutilin

According to the method of Reference Example 5, the reaction was carried out using 2.52 g (6.42 mmol) of the compound in the first step and 1.22 g (6.42 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purify with ethyl = 4: 1), 1.76
The title compound was obtained as a colorless powder of g (yield 79%).
MS
(FAB) (m / z): 349 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₇ O ₃ (MH ⁺ ):
349.2743. Found, 349.2788.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (1-propen-3-yl) -14-[(E) -2- (pyridine-3- Il) propenoyl] carbamoyl-4-epimutilin

According to the method of the first step of Example 1, the compound of the second step 178 mg (0.51 mmol), carboxylate chloride hydrochloride 157 mg (0.77 mmol), silver cyanate 115 mg (0.77 mmol), 4- (dimethyl Amino) pyridine 94.1
The reaction was performed with mg (0.77 mmol) and 0.11 mL (0.77 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, then ethyl acetate: methanol = 40: 1) 189
The title compound as a colorless powder was obtained (71% yield).
MS
(FAB) (m / z): 523 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₃ N ₂ O ₅
(MH ⁺ ): 523.3172. Found, 523.3207.

Fourth step
12-desethenyl-12- (1-propen-3-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

In accordance with the method of the second step of Example 1, the reaction was carried out using 129 mg (0.25 mmol) of the compound of the third step, and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 2, then acetic acid). Purified with ethyl: methanol = 20: 1), 67.6
The title compound as a colorless powder was obtained (53% yield).
MS
(FAB) (m / z): 509 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₁ N ₂ O ₅
(MH ⁺ ): 509.3015. Found, 509.2987.

(Example 14)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-12-phenylmethyl-4-epimutilin

According to the method of the first step of Example 10, 2.00 g (5.67 mmol) of the compound of Reference Example 3, 0.81 mL of benzyl bromide (6.81
mmol) and potassium bis (trimethylsilyl) amide (0.5 mol / L toluene solution) 13.6 mL (6.81 mmol), and the resulting residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1). 2.51
g of the title compound was obtained as a colorless oil (yield 100%).
MS
(FAB) (m / z): 381 (MH ⁺ -HOCH ₂ OCH ₃ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₆ H ₃₇ O ₂ (MH ⁺ -HOCH ₂ OCH ₃ ):
381.2794.Found, 381.2817.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12-phenylmethyl-4-epimutilin

According to the method of Reference Example 5, the reaction was carried out using 2.51 g (5.67 mmol) of the compound in the first step and 1.08 g (5.67 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purify with ethyl = 4: 1), 1.55
The title compound was obtained as a colorless powder of g (69% yield).
MS
(FAB) (m / z): 399 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₆ H ₃₉ O ₃ (MH ⁺ ):
399.2899. Found, 399.2900.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12-phenylmethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-4 -Epimutilin

According to the method of the first step of Example 1, the compound of the second step 517 mg (1.30 mmol), carboxylate chloride hydrochloride 398 mg (1.95 mmol), silver cyanate 292 mg (1.95 mmol), 4- (dimethyl Amino) pyridine 238
The reaction was conducted with mg (1.95 mmol) and 0.27 mL (1.95 mmol) of triethylamine, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: ethyl acetate = 1: 1, hexane: ethyl acetate =
1: 2 and then hexane: ethyl acetate = 1: 4) to obtain 313 mg of the title compound as a colorless powder (yield 42%).
MS
(FAB) (m / z): 573 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₅ H ₄₅ N ₂ O ₅
(MH ⁺ ): 573.3328. Found, 573.3333.

Fourth step
12-desethenyl-12-phenylmethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was carried out using 313 mg (0.55 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: Ethyl acetate = 1: 1, hexane: ethyl acetate =
1: 2 and then hexane: ethyl acetate = 1: 4) to obtain 212 mg of the title compound as a colorless powder (yield 69%).
MS
(FAB) (m / z): 559 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₄ H ₄₃ N ₂ O ₅
(MH ⁺ ): 559.3172. Found, 559.3194.

(Example 15)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-12- (1-propyn-3-yl) -4-epimutilin

According to the method of the first step of Example 10, 2.00 g (5.67 mmol) of the compound of Reference Example 3, 0.51 mL of propargyl bromide (6.81
mmol) and potassium bis (trimethylsilyl) amide (0.5
mol / L toluene solution) 13.6
Reaction was performed using mL (6.81 mmol), and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 2.32 g of the title compound as a yellow oil (yield) 100%).
MS
(FAB) (m / z): 329 (MH ⁺ -HOCH ₂ OCH ₃ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₃ O ₂ (MH ⁺ -HOCH ₂ OCH ₃ ):
329.2481. Found, 329.2467.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (1-propyn-3-yl) -4-epimutilin

According to the method of Reference Example 5, the reaction was performed using 2.32 g (5.67 mmol) of the compound in the first step and 1.08 g (5.67 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purified with ethyl = 2: 1), 1.61
The title compound was obtained as a colorless powder of g (yield 82%).
MS
(FAB) (m / z): 347 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₅ O ₃ (MH ⁺ ):
347.2586. Found, 347.2600.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (1-propyn-3-yl) -14-[(E) -2- (pyridine-3- Il) propenoyl] carbamoyl-4-epimutilin

According to the method of the first step of Example 1, the compound of the second step 300 mg (0.87 mmol), carboxylate chloride hydrochloride 267 mg (1.31 mmol), silver cyanate 196 mg (1.31 mmol), 4- (dimethyl Amino) pyridine 160 mg
(1.31 mmol) and triethylamine 0.18 mL (1.31 mmol), and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: ethyl acetate = 1: 1, hexane: ethyl acetate =
1: 2 and then hexane: ethyl acetate = 1: 4) to obtain 232 mg of the title compound as a colorless powder (yield 51%).
MS
(FAB) (m / z): 521 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₁ N ₂ O ₅
(MH ⁺ ): 521.3015. Found, 521.3022.

Fourth step
12-desethenyl-12- (1-propyn-3-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 232 mg (0.45 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: Ethyl acetate = 1: 1, hexane: ethyl acetate =
1: 2, hexane: ethyl acetate = 1: 4, then ethyl acetate) to give 152 mg of the title compound as a colorless powder (yield 67%).
MS
(FAB) (m / z): 507 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₀ H ₃₉ N ₂ O ₅
(MH ⁺ ): 507.2859. Found, 507.2850.

(Example 16)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-12- (2-propyn-3-yl) -4-epimutilin

To a tetrahydrofuran solution (150 mL) of 13.3 g (34.0 mmol) of the compound of the first step of Example 15, 3.82 g (34.0 mmol) of potassium t-butoxide was added under ice-cooling, and the mixture was stirred for 12 hours while allowing the temperature to rise naturally. The reaction mixture was poured into dilute aqueous citric acid solution and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate (100 mL x 3), and the combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1).
g of the title compound as a yellow oil was obtained (yield 99%).
MS
(FAB) (m / z): 391 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₄ H ₃₉ O ₄ (MH ⁺ ):
391.2848. Found, 391.2871.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (2-propyn-3-yl) -4-epimutilin

According to the method of Reference Example 5, the reaction was performed using 3.09 g (7.91 mmol) of the compound in the first step and 1.50 g (7.91 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purify with ethyl = 4: 1), 2.12
The title compound was obtained as a yellow oil (yield 77%).
MS
(FAB) (m / z): 329 (MH ⁺ -H ₂ O).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₃ O ₂ (MH ⁺ -H ₂ O):
329.2481. Found, 329.2477.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (2-propyn-3-yl) -14-[(E) -2- (pyridine-3- Il) propenoyl] carbamoyl-4-epimutilin

According to the method of the first step of Example 1, the compound of the second step 500 mg (1.44 mmol), carboxylate chloride hydrochloride 441 mg (2.16 mmol), silver cyanate 324 mg (2.16 mmol), 4- (dimethyl Amino) pyridine 264
The reaction was carried out with mg (2.16 mmol) and 0.30 mL (2.16 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, then ethyl acetate) to give 367 mg of colorless powder The title compound was obtained (49% yield).
MS
(FAB) (m / z): 521 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₁ N ₂ O ₅
(MH ⁺ ): 521.3015. Found, 521.3000.

Fourth step
12-desethenyl-12- (2-propyn-3-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 367 mg (0.70 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: The product was purified by ethyl acetate = 1: 2, hexane: ethyl acetate = 1: 4, and then ethyl acetate) to obtain 281 mg of the title compound as a colorless powder (yield 79%).
MS
(FAB) (m / z): 507 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₃₉ N ₂ O ₅
(MH ⁺ ): 507.2859. Found, 507.2889.

(Example 17)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-12- (1-fluoroethane-2-yl) -3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin

According to the method of the first step of Example 10, 5.00 g (14.2 mmol) of the compound of Reference Example 3, 2.16 g (17.0 mmol) of 1-bromo-2-fluoroethane and potassium bis (trimethylsilyl) amide (0.5 mol / L toluene) Solution) The reaction was carried out using 34.0 mL (17.0 mmol), and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1).
g of the title compound as a pale yellow oil was obtained (yield 94%).
MS
(FAB) (m / z): 399 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₄₀ FO ₄ (MH ⁺ ):
399.2911. Found, 399.2916.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-12- (1-fluoroethane-2-yl) -3-methoxy-11-oxo-4-epimutilin

According to the method of Reference Example 5, the reaction was performed using 5.29 g (13.3 mmol) of the compound in the first step and 2.52 g (13.3 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purification with ethyl = 4: 1 and then hexane: ethyl acetate = 2: 1) gave 4.07 g of the title compound as a colorless powder (yield 86%).
MS
(FAB) (m / z): 355 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₁ H ₃₆ FO ₃ (MH ⁺ ):
355.2648. Found, 355.2672.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-12- (1-fluoroethane-2-yl) -3-methoxy-11-oxo-14-[(E) -2- (pyridine-3 -Il) propenoyl] carbamoyl-4-epimutilin

According to the method of the first step of Example 1, the compound of the second step 500 mg (1.41 mmol), carboxylic acid chloride hydrochloride 433 mg (2.12 mmol), silver cyanate 318 mg (2.12 mmol), 4- (dimethyl Amino) pyridine 259
The reaction was performed with mg (2.12 mmol) and 0.28 mL (2.12 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, then ethyl acetate: methanol = 20: 1) 276
The title compound as a colorless powder was obtained (37% yield).
MS
(FAB) (m / z): 529 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₂ FN ₂ O ₅
(MH ⁺ ): 529.3078. Found, 529.3088.

Fourth step
12-desethenyl-12- (1-fluoroethane-2-yl) -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 276 mg (0.52 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 2, hexane: Purification with ethyl acetate = 1: 4, ethyl acetate) gave 92.8 mg of the title compound as a colorless powder (yield 35%).
MS
(FAB) (m / z): 495 (MH ⁺ -HF).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₃₉ FN ₂ O ₅
(MH ⁺ -HF): 495.2859. Found, 495.2897.

(Example 18)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-12- (1,1,1-trifluoroethane-2-yl) -4 -Epimutilin

According to the method of the first step of Example 10, 600 mg (1.70 mmol) of the compound of Reference Example 3, 201 μL (2.04 mmol) of trifluoroethyl iodide and potassium bis (trimethylsilyl) amide (0.5 mol / L toluene solution) 4.08 The reaction was carried out using mL (2.04 mmol), and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1).
mg of the title compound was obtained as a colorless oil (yield 78%).
MS
(FAB) (m / z): 391 (MH ⁺ -MeOH).
HRMS
(FAB) (m / z): Calcd. For C ₂₁ H ₃₄ F ₃ O ₃
(MH ⁺ -MeOH): 391.2460. Found, 391.2459.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (1,1,1-trifluoroethane-2-yl) -4-epimutilin

According to the method of Reference Example 5, the reaction was carried out using 563 mg (1.33 mmol) of the compound in the first step and 253 mg (1.33 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purified with ethyl = 4: 1) and 396
The title compound as a yellow powder was obtained (79% yield).
MS
(CI) (m / z): 391 (MH ⁺ ).
HRMS
(CI) (m / z): Calcd. For C ₂₁ H ₃₄ F ₃ O ₃
(MH ⁺ ): 391.2460. Found, 391.2479.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12- (1,1 , 1-Trifluoroethan-2-yl) -4-epimutilin

According to the method of the first step of Example 1, the compound of the second step 198 mg (0.51 mmol), carboxylate chloride hydrochloride 157 mg (0.77 mmol), silver cyanate 115 mg (0.77 mmol), 4- (dimethyl Amino) pyridine 94.1
The reaction was conducted with mg (0.77 mmol) and triethylamine 0.11 mL (0.77 mmol), and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, then ethyl acetate: methanol = 20: 1) 161
The title compound as a colorless powder was obtained (56% yield).
MS
(FAB) (m / z): 565 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₀ F ₃ N ₂ O ₅
(MH ⁺ ): 565.2889. Found, 565.2916.

Fourth step
12-desethenyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12- (1,1,1-trifluoroethan-2-yl) mutilin

According to the method of the second step of Example 1, the reaction was performed using 161 mg (0.29 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 4). Purify and 135
The title compound as a colorless powder was obtained (85% yield).
MS
(FAB) (m / z): 551 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₃₈ F ₃ N ₂ O ₅
(MH ⁺ ): 551.2733. Found, 551.2718.

(Example 19)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-12-fluoromethyl-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin

According to the method of the first step of Example 2, 5.00 g (14.2 mmol) of the compound of Reference Example 3, 1.67 mL (17.0 mL) of bromomethyl acetate
mmol) and potassium bis (trimethylsilyl) amide (0.5
mol / L toluene solution) 34.0
The reaction was carried out using mL (17.0 mmol), and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 3.93 g of colorless oily (3R) -3-deoxo- 11-deoxy-12-desethenyl-12-acetoxymethyl-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin was obtained (yield 65%).
MS
(FAB) (m / z): 363 (MH ⁺ -HOCH ₂ OCH ₃ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₅ O ₄ (MH ⁺ -HOCH ₂ OCH ₃ ):
363.2535. Found, 363.2552.

Methanol was added to 2.00 g (4.71 mmol) of this compound, 1.30 g (9.42 mmol) of potassium carbonate was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. After distilling off the solvent under reduced pressure, a diluted citric acid aqueous solution was added to the residue, followed by extraction with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL), filtered, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1, then hexane: ethyl acetate = 1: 2) to give 1.13 g of (3R) -3-deoxo as a colorless powder. -11-deoxy-12-desethenyl-12-hydroxymethyl-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin was obtained (yield 63%).
MS
(FAB) (m / z): 383 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₉ O ₅ (MH ⁺ ):
383.2797. Found, 383.2824.

To a toluene solution of 1.13 g (2.95 mmol) of this compound was added 1,8-1 diazabicyclo [5.4.0] unde-7-cene 1.33 in an ice-cooled argon atmosphere.
mL (8.86 mmol), followed by perfluorooctanesulfonyl fluoride 1.22 mL (4.43
mmol) was added dropwise and stirred for 15 hours while allowing the temperature to rise naturally. A diluted aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (10 mL), filtered, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1).
The title compound was obtained as a yellow powder of g (yield 88%).
MS
(FAB) (m / z): 323 (MH ⁺ -H ₂ O).
Rf
= 0.41 (hexane: ethyl acetate = 4: 1).

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-12-fluoromethyl-3-methoxy-11-oxo-4-epimutilin

According to the method of Reference Example 5, the reaction was performed using 1.00 g (2.60 mmol) of the compound in the first step and 0.49 g (2.60 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purification with ethyl = 4: 1, then hexane: ethyl acetate = 2: 1) gave 526 mg of the title compound as a colorless powder (yield 59%).
MS
(FAB) (m / z): 341 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₀ H ₃₄ FO ₃ (MH ⁺ ):
341.2492. Found, 341.2502.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-12-fluoromethyl-3-methoxy-11-oxo-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-4 -Epimutilin

According to the method of the first step of Example 1, the compound of the second step 263 mg (0.77 mmol), carboxylate chloride hydrochloride 237 mg (1.16 mmol), silver cyanate 174 mg (1.16 mmol), 4- (dimethyl Amino) pyridine 142
The reaction was carried out with mg (1.16 mmol) and 0.16 mL (1.16 mmol) of triethylamine, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, hexane: ethyl acetate = 1: 1, hexane: ethyl acetate =
1: 2, then hexane: ethyl acetate = 1: 4, then ethyl acetate) to give 133 mg of the title compound as a colorless powder (yield 34%).
MS
(FAB) (m / z): 515 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₀ FN ₂ O ₅
(MH ⁺ ): 515.2910. Found, 515.2921.

Fourth step
12-Desethenyl-12-fluoromethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 133 mg (0.26 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 4). Purify and 94.3
The title compound as a colorless powder was obtained (72% yield).
MS
(FAB) (m / z): 501 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₈ H ₃₈ FN ₂ O ₅
(MH ⁺ ): 501.2765. Found, 501.2785.

(Example 20)
First step
(3R) -12-acetoxymethyl-3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-4-epimutilin

According to the method of Reference Example 5, (3R) -3-deoxo-11-deoxy-12-desethenyl-12-acetoxymethyl-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin 600
The reaction was performed using 16.9 mg (1.41 mmol) and 26.9 mg (0.14 mmol) of p-toluenesulfonic acid, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1).
The title compound was obtained as a colorless oil (29% yield).
MS
(FAB) (m / z): 381 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₇ O ₅ (MH ⁺ ):
381.2641. Found, 381.2656.

Second step
(3R) -12-acetoxymethyl-3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-4 -Epimutilin

According to the method of the first step of Example 1, the compound of the first step 195 mg (0.51 mmol), carboxylate chloride hydrochloride 157 mg (0.77 mmol), silver cyanate 115 mg (0.77 mmol), 4- (dimethyl Amino) pyridine 94.1
The reaction was conducted with mg (0.77 mmol) and triethylamine 0.11 mL (0.77 mmol), and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1, then ethyl acetate: methanol = 20: 1) 153
The title compound as a colorless powder was obtained (55% yield).
MS
(FAB) (m / z): 555 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₃ N ₂ O ₇
(MH ⁺ ): 555.3070. Found, 555.3074.

Third process
12-Hydroxymethyl-12-desethenyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 153 mg (0.28 mmol) of the compound of the second step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, then acetic acid). Purified with ethyl: methanol = 10: 1), 82.1
The title compound as a colorless powder was obtained (59% yield).
MS
(FAB) (m / z): 499 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₈ H ₃₉ N ₂ O ₆
(MH ⁺ ): 499.2808. Found, 499.2819.

(Example 21)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-12- (4-pyridyl) methyl-4-epimutilin

According to the method of the first step of Example 10, 2.00 g (5.67 mmol) of the compound of Reference Example 3, 1.01 g (6.81 mmol) of 4-chloromethylpyridine hydrochloride and potassium bis (trimethylsilyl) amide (0.5 mol / L toluene solution) ) 13.6 mL (6.81 mmol) was used for the reaction, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1, hexane: ethyl acetate = 1: 4, then ethyl acetate). 2.06 g of the title compound was obtained as a brown powder (yield 82%).
MS
(FAB) (m / z): 444 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₇ H ₄₂ NO ₄ (MH ⁺ ):
444.3114. Found, 444.3122.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (4-pyridyl) methyl-4-epimutilin

According to the method of Reference Example 5, the reaction was performed using 2.06 g (4.64 mmol) of the compound in the first step and 1.77 g (9.29 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (ethyl acetate, Then purified with ethyl acetate: methanol = 10: 1), 1.32
The title compound was obtained as a colorless powder of g (yield 71%).
MS
(FAB) (m / z): 400 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₅ H ₃₈ NO ₃ (MH ⁺ ):
400.2852. Found, 400.2872.

Third process
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- (4-pyridyl) methyl-14-[(E) -2- (pyridin-3-yl) propenoyl ] Carbamoyl-4-epimutilin

According to the method of the first step of Example 1, the compound of the second step 500 mg (1.25 mmol), carboxylic acid chloride hydrochloride 384 mg (1.88 mmol), silver cyanate 282 mg (1.88 mmol), 4- (dimethyl Amino) pyridine 230
The reaction was conducted with mg (1.88 mmol) and triethylamine 0.26 mL (1.88 mmol), and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4, then ethyl acetate: methanol = 10: 1) 294
The title compound as a colorless powder was obtained (41% yield).
MS
(FAB) (m / z): 574 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₄ H ₄₄ N ₃ O ₅
(MH ⁺ ): 574.3281. Found, 574.3268.

Fourth step
12-desethenyl-12- (4-pyridyl) methyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was carried out using 294 mg (0.51 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (NH, ethyl acetate, then ethyl acetate: methanol = 10: 1) to give 229 mg of the title compound as a colorless powder (yield 80%).
MS
(FAB) (m / z): 560 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₃ H ₄₂ N ₃ O ₅
(MH ⁺ ): 560.3124. Found, 560.3099.

(Example 22)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-12- [2-propen-3-yl] -4-epimutilin

Compound 16.2 of the first step of Example 16
Lindlar catalyst 1.30 g (10% by weight) was added to a toluene solution (250 mL) of g (33.8 mmol), and catalytic reduction was performed at 98.1 KPa at room temperature for 5 hours. The reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. The combined filtrates were distilled off under reduced pressure to obtain 13.3 g of the title compound as a colorless oil (yield 100%).
MS
(FAB) (m / z): 393 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₄ H ₄₁ O ₄ (MH ⁺ ):
393.3005. Found, 393.3010.

Second step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- [2-propen-3-yl] -4-epimutilin

In accordance with the method of Reference Example 5, the reaction was carried out using 13.3 g (33.9 mmol) of the compound in the first step and 6.44 g (33.9 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purify with ethyl = 4: 1), 10.1
The title compound was obtained as a colorless powder of g (yield 86%).
MS
(FAB) (m / z): 331 (MH ⁺ -H ₂ O).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₅ O ₂ (MH ⁺ -H ₂ O):
331.2637. Found, 331.2645.

Third process
12-desethenyl-3-methoxy-11-O-methoxymethyl-11-oxo-12- [2-propen-3-yl] -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl -4-epimutilin

According to the method of the first step of Example 1, the compound of the second step 300 mg (0.86 mmol), carboxylate chloride hydrochloride 263 mg (1.29 mmol), silver cyanate 193 mg (1.29 mmol), 4- (dimethyl Amino) pyridine 158
The reaction was performed with mg (1.29 mmmol) and 0.18 mL (1.29 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1, then hexane: ethyl acetate = 2: 1) 442 mg of the title compound was obtained as a colorless powder (yield 83%).
MS
(FAB) (m / z): 523 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₃ N ₂ O ₅
(MH ⁺ ): 523.3172. Found, 523.3215.

Fourth step
12-desethenyl-12- [2-propen-3-yl] -14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was carried out using 185 mg (0.35 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 4). Purify and 164
The title compound as a colorless powder was obtained (82% yield).
MS
(FAB) (m / z): 509 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₁ N ₂ O ₅
(MH ⁺ ): 509.3015. Found, 509.3029.

(Example 23)
First step
(3R) -12-cyanomethyl-3-deoxo-11-deoxy-12-desethenyl-3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin

According to the method of the first step of Example 10, the compound of Reference Example 3 3.00 g (8.51 mmol), 0.65 mL of chloroacetonitrile (10.2
mmol) and potassium bis (trimethylsilyl) amide (0.5
mol / L toluene solution) 20.4
Reaction was performed using mL (10.2 mmol), and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1, then hexane: ethyl acetate).
= 2: 1) to give 2.10 g of the title compound as a yellow oil (yield 63%).
MS
(FAB) (m / z): 330 (MH ⁺ -HOCH ₂ OCH ₃ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₁ H ₃₂ NO ₂ (MH ⁺ -HOCH ₂ OCH ₃ ):
330.2433. Found, 330.2426.

Second step
(3R) -12-cyanomethyl-3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-4-epimutilin

According to the method of Reference Example 5, the reaction was carried out using 2.10 g (5.36 mmol) of the compound in the first step and 1.02 g (5.36 mmol) of p-toluenesulfonic acid, and the resulting residue was subjected to silica gel column chromatography (hexane: acetic acid). Purify with ethyl = 2: 1), 1.31
The title compound was obtained as a colorless powder of g (yield 70%).
MS
(FAB) (m / z): 330 (MH ⁺ -H ₂ O).
Rf
= 0.23 (hexane: ethyl acetate = 2: 1)

Third process
(3R) -12-cyanomethyl-3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-4- Epimutilin

According to the method of the first step of Example 1, the compound of the second step 500 mg (1.44 mmol), carboxylate chloride hydrochloride 441 mg (2.16 mmol), silver cyanate 324 mg (2.16 mmol), 4- (dimethyl Amino) pyridine 264
The reaction was carried out with mg (2.16 mmol) and 0.30 mL (2.16 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1).
The title compound as a colorless powder was obtained (51% yield).
MS
(FAB) (m / z): 522 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₀ N ₃ O ₅
(MH ⁺ ): 522.2968. Found, 522.2968.

Fourth step
12-Cyanomethyl-12-desethenyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 380 mg (0.73 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: Ethyl acetate
= 1: 2, then hexane: ethyl acetate = 1: 4) to obtain 61.8 mg of the title compound as a colorless powder (yield 17%).
MS
(FAB) (m / z): 508 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₃₈ N ₃ O ₅
(MH ⁺ ): 508.2811. Found, 508.2771.

(Example 24)
First step
(3R) -3-deoxo-11-deoxy-12-desethenyl-3-methoxy-11-oxo-12- [1- (1,2,3-triazol-1-yl) ethyl] -4-epimutilin

(3R) -3-deoxo-11-deoxy-12-desethenyl-12- (1-hydroxyethane-2-yl) -3-methoxy-14-O-methoxymethyl-11-oxo-4-epimutilin
Add 4.49 g (11.3 mmol) of methylene chloride solution (100 mL) to triethylamine (4.74 mL, 34.0 mmol) and then methanesulfonyl chloride (1.32 mL) under an ice-cooled argon atmosphere.
(17.0 mmoL) was added and the mixture was stirred for 2 hours while allowing the temperature to rise naturally. The reaction mixture was poured into dilute aqueous citric acid solution, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to obtain 4.35 g of a colorless oil (yield 81%).

Among these, 2.30 g (4.85 mmol) was dissolved in N, N-dimethylformamide (30 mL), 0.47 g (7.27 mmol) of sodium azide was added, and the mixture was heated and stirred at 80 ° C. for 4 hours. After cooling, the reaction mixture was poured into cold water and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated to give a crude azide. Bicyclo [2.2.1] hepta-2,5-diene 5.23
mL (48.5 mmol) was added, and the mixture was heated and stirred at 80 ° C. for 1 hour. After cooling, the reaction mixture was diluted with dioxane (20 mL) and heated to reflux for 1 hour. After cooling, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (hexane: ethyl acetate = 1: 1, hexane: ethyl acetate = 1: 2, then hexane: ethyl acetate = 1: 4), 1.50 g Was obtained (69% yield). This was dissolved in methanol (50 mL) and p-toluenesulfonic acid 1.27
g (6.70 mmol) was added and allowed to stand at room temperature for 24 hours. The reaction mixture was concentrated, diluted aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 1: 2, ethyl acetate, then ethyl acetate: methanol = 10: 1) to obtain 1.03 g of the title compound as a colorless powder. (Yield 76%).
MS
(FAB) (m / z): 386 (MH ⁺ -HOCH ₂ OCH ₃ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₃₆ N ₃ O ₂
(MH ⁺ -HOCH ₂ OCH ₃ ): 386.2808. Found, 386.2859.

Second step
12-desethenyl-3-methoxy-11-oxo-12- [1- (1,2,3-triazol-1-yl) ethyl] -14-[(E) -2- (pyridin-3-yl) propenoyl ] Carbamoyl-4-epimutilin

According to the method of the first step of Example 1, 400 mg (0.99 mmol) of the first step, 304 mg (1.49 mmol) of carboxylic acid chloride hydrochloride, 223 mg (1.49 mmol) of silver cyanate, 4- (dimethyl Amino) pyridine 182
The reaction was performed with mg (1.49 mmol) and triethylamine 0.21 mL (1.49 mmol), and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 4, hexane: ethyl acetate = 1: 8, ethyl acetate, then ethyl acetate). : Methanol = 10: 1) to give 346 mg of the title compound as a colorless powder (yield 60%).
MS
(FAB) (m / z): 578 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₄₄ N ₅ O ₅
(MH ⁺ ): 578.3342. Found, 578.3360.

Third process
12-desethenyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12- [1- (1,2,3-triazol-1-yl) ethyl] mutilin

According to the method of the second step of Example 1, the reaction was performed using 346 mg (0.60 mmol) of the compound of the second step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 4, ethyl acetate). And then purified with ethyl acetate: methanol = 10: 1), 230
The title compound as a colorless powder was obtained (68% yield).
MS
(FAB) (m / z): 564 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₂ N ₅ O ₅
(MH ⁺ ): 564.3186. Found, 564.3199.

(Example 25)
First step
12-desethenyl-12-formyl-11-O-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the first step of Example 1, the compound of Reference Example 6 103 mg (0.28 mmol), carboxylate chloride hydrochloride 86.2 mg (0.42
mmol), silver cyanate 105 mg (0.70 mmol), 4- (dimethylamino) pyridine 34.3
The reaction was conducted with 5 mg (0.28 mmol) and 59.0 μL (0.42 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4, then ethyl acetate) to give 56.0 mg of colorless powder The title compound was obtained (37% yield).
MS
(FAB) (m / z): 541 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₁ N ₂ O ₇
(MH ⁺ ): 541.2914. Found, 541.2928.

Second step
12-desethenyl-12-formyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 50.2 mg (92.8 μmol) of the compound of the first step, and the obtained residue was purified by silica gel column chromatography (ethyl acetate). The title compound was obtained as a colorless powder (yield 76%).
MS
(FAB) (m / z): 497 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₈ H ₃₇ N ₂ O ₆
(MH ⁺ ): 497.2652. Found, 497.2664.

(Example 26)
First step
12-desethenyl-12-formyl-11-O-methoxymethyl-14- [2- (pyridin-3-yl) propanoyl] carbamoylmutilin

According to the method of the first step of Example 1, 103 mg (0.28 mmol) of the compound of Reference Example 6, 87.0 mg (0.42) of carboxylic acid chloride hydrochloride
mmol), silver cyanate 105 mg (0.70 mmol), 4- (dimethylamino) pyridine 34.3
The reaction was performed with 5 mg (0.28 mmol) and 59.0 μL (0.42 mmol) of triethylamine, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4, then ethyl acetate) to give 78.5 mg of colorless powder The title compound was obtained (51% yield).
MS
(FAB) (m / z): 543 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₃ N ₂ O ₇
(MH ⁺ ): 543.3070. Found, 543.3050.

Second step
12-Desethenyl-12-formyl-14- [2- (pyridin-3-yl) propanoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 75.5 mg (0.14 mmol) of the compound of the first step, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 58.7 mg of The title compound was obtained as a colorless powder (yield 85%).
MS
(FAB) (m / z): 499 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₈ H ₃₉ N ₂ O ₆
(MH ⁺ ): 499.2808. Found, 499.2815.

(Example 27)
First step
12-desethenyl-12-methoxycarbonyl-11-O-methoxymethylmutilin

To a hydrous tetrahydrofuran solution (15 mL) of 1.37 g (3.74 mmol) of the compound of Reference Example 6, 1.01 g (11.2 mmol) of sodium chlorate and 1.75 g of sodium dihydrogen phosphate were added and stirred at room temperature for 9 hours. A dilute aqueous sodium hydroxide solution was added to the reaction mixture, followed by extraction with ethyl acetate (10 mL x 3). Dilute aqueous citric acid solution was added to the aqueous layer and extracted with ethyl acetate (10
The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off to obtain 1.16 g of a crude carboxylic acid derivative as a colorless powder. (81% yield) was obtained.
MS
(CI) (m / z): 383 (MH ⁺ ).
HRMS
(CI) (m / z): Calcd. For C ₂₁ H ₃₅ O ₆ (MH ⁺ ):
383.2434. Found, 383.2414.

To an acetonitrile solution (2 mL) of 100 mg (0.26 mmol) of this carboxylic acid derivative, 49.5 μL (0.52 mmol) of dimethyl sulfate and 145 mg (1.05 mmol) of potassium carbonate were added and heated under reflux for 7 hours. The reaction mixture was filtered through celite, and the residue was washed with ethyl acetate. The filtrate was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), 89.3
The title compound was obtained as a colorless oil (yield 86%).
MS
(FAB) (m / z): 397 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₇ O ₆ (MH ⁺ ):
397.2590. Found, 397.2598.

Second step
(3R) -12-desethenyl-12-methoxycarbonyl-11-O-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

実施例1の第一工程の方法に従って、第一工程の化合物83.0 mg (0.21 mmol) 、カルボン酸塩化物塩酸塩64.1 mg (0.31 mmol) 、シアン酸銀78.4 mg (0.52
mmol) 、4-(ジメチルアミノ)ピリジン25.5 mg (0.21 mmol) およびトリエチルアミン44.0 μL (0.31 mmol) にて反応を行い、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン:酢酸エチル = 1:1、ヘキサン:酢酸エチル = 1:2、次いでヘキサン:酢酸エチル
= 1:4）にて精製し、65.5 mgの無色粉末状物である表題化合物を得た（収率55%）。
MS
(FAB) (m/z): 571 (MH⁺).
HRMS
(FAB) (m/z): Calcd. for C₃₁H₄₃N₂O₈
(MH⁺): 571.3019. Found, 571.3066.

According to the method of the first step of Example 1, the compound of the first step 83.0 mg (0.21 mmol), carboxylate chloride hydrochloride 64.1 mg (0.31 mmol), silver cyanate 78.4 mg (0.52
mmol), 4- (dimethylamino) pyridine 25.5 mg (0.21 mmol) and triethylamine 44.0 μL (0.31 mmol), and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1, hexane: ethyl acetate). = 1: 2, then hexane: ethyl acetate
= 1: 4) to obtain 65.5 mg of the title compound as a colorless powder (yield 55%).
MS
(FAB) (m / z): 571 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₁ H ₄₃ N ₂ O ₈
(MH ⁺ ): 571.3019. Found, 571.3066.

Third process
12-desethenyl-12-methoxycarbonyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoylmutilin

According to the method of the second step of Example 1, the reaction was performed using 64.0 mg (0.11 mmol) of the compound of the second step, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 4, then acetic acid). To give 51.9 mg of the title compound as a colorless powder (yield 88%).
MS
(FAB) (m / z): 527 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₃₉ N ₂ O ₇
(MH ⁺ ): 527.2757. Found, 527.2751.

(Example 28)
First step
12-Desethenyl-12- [1- (E)-(ethoxycarbonyl) ethen-2-yl] -11-O-methoxymethylmutilin

To a tetrahydrofuran solution (10 mL) of 288 mg (1.28 mmol) of triethylphosphonoacetate was added 76.9 mg (1.92 mmol) of sodium hydride at room temperature, and the mixture was stirred at room temperature for 0.5 hour. A tetrahydrofuran solution (10 mL) of 470 mg (1.28 mmol) of the compound of Reference Example 6 was added under the same temperature and argon atmosphere, followed by stirring for 1 hour. A diluted aqueous citric acid solution was added to the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1).
The title compound as a colorless powder was obtained (59% yield).
MS
(FAB) (m / z): 437 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₅ H ₄₁ O ₆ (MH ⁺ ):
437.2903. Found, 437.2903.

Second step
12-desethenyl-12- [1- (E)-(ethoxycarbonyl) ethen-2-yl] -11-O-methoxymethyl-14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl Mutilin

According to the method of the first step of Example 1, the compound of the first step 150 mg (0.34 mmol), carboxylate chloride hydrochloride 104 mg (0.51 mmol), silver cyanate 76.4 mg (0.51 mmol)
, 4- (dimethylamino) pyridine 62.3 mg (0.51 mmol) and triethylamine 71.1 μL (0.51 mmol), and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, then ethyl acetate: methanol = 20: 1)
The title compound as a colorless powder was obtained (50% yield).
MS
(CI) (m / z): 611 (MH ⁺ ).
HRMS
(CI) (m / z): Calcd. For C ₃₄ H ₄₇ N ₂ O ₈
(MH ⁺ ): 611.3332. Found, 611.3325.

Third process
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- [1- (E)-(ethoxycarbonyl) ethen-2-yl] mutilin

According to the method of the second step of Example 1, the reaction was performed using 106 mg (0.17 mmol) of the compound of the second step, and the obtained residue was purified by silica gel column chromatography (ethyl acetate). The title compound was obtained as a colorless powder (yield 6%).
MS
(FAB) (m / z): 567 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₂ H ₄₃ N ₂ O ₇
(MH ⁺ ): 567.3070. Found, 567.3072.

(Example 29)
First step
14-acetoxy-11-O-methoxymethylmutilin

According to Reference Example 7, 3.00 g (7.38 mmol) of 11-O-methoxymethylmutilin obtained in Reference Example 4 was subjected to acetylation reaction, and the resulting crude product was subjected to silica gel column chromatography (hexane: acetic acid). Purification with ethyl = 2: 1, then hexane: ethyl acetate = 1: 2) afforded 1.73 g of the title compound as a yellow oil (53% yield).
MS
(FAB) (m / z): 407 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₄ H ₃₉ O ₅ (MH ⁺ ):
407.2797. Found, 407.2804.

Second step
19,20-O, O-isopropylidene-19,20-dihydroxy-12-desethenyl-11-O-methoxymethylmutilin

According to Reference Example 2, 3.00 g (7.38 mmol) of the compound obtained in the first step was subjected to a diolation reaction, and the resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1, then Hexane: ethyl acetate = 1: 2) to obtain 1.73 g of a diol form as a yellow oil (yield 53%). This compound was dissolved in methanol (10 mL), diluted aqueous sodium hydroxide solution (10 mL) was added, and the mixture was heated to reflux for 13 hours. After cooling, the solvent was distilled off under reduced pressure, diluted aqueous citric acid was added to the residue, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated to give a crude triol. This was dissolved in acetone (30 mL) and acetone dimethyl acetal 1.45 mL (11.8 mL
mmol) and a catalytic amount of p-toluenesulfonic acid were added and left at room temperature for 12 hours. The reaction mixture was evaporated under reduced pressure, diluted aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate.
(30 mL x 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained residue was purified by column chromatography (hexane: ethyl acetate = 2: 1) to obtain 1.22 g of the title compound as a pale yellow powder (yield 71%).
MS
(FAB) (m / z): 439 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₅ H ₄₃ O ₆ (MH ⁺ ):
439.3060. Found, 439.3082.

Third process
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethanedimethylketal-2-yl) -11-O-methoxymethylmutilin

According to the method of the first step of Example 1, the compound of the second step 266 mg (0.61 mmol), carboxylic acid chloride hydrochloride 187 mg (0.92 mmol), silver cyanate 229 mg (1.53 mmol), 4- (dimethyl Amino) pyridine 74.6
The reaction was performed with mg (0.61 mmol) and triethylamine 0.11 mL (0.92 mmol), and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1, then hexane: ethyl acetate = 1: 4), 333 mg of the title compound was obtained as a colorless powder (yield 89%).
MS
(FAB) (m / z): 613 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₄ H ₄₉ N ₂ O ₈
(MH ⁺ ): 613.3489. Found, 613.3491.

Fourth step
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethane-2-yl) mutilin

According to the method of the second step of Example 1, the reaction was performed using 131 mg (0.21 mmol) of the compound of the third step, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 10: 1). Purify and 67.0
The title compound as a colorless powder was obtained (59% yield).
MS
(FAB) (m / z): 529 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₁ N ₂ O ₇
(MH ⁺ ): 529.2914. Found, 529.2959.

(Example 30)
First step
14-[(E) -2- (Pyridin-3-yl) propanoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethanedimethylketal-2-yl) -11-O-methoxymethylmutilin

According to the method of the first step of Example 1, 266 mg (0.61 mmol) of the compound obtained in the first step of Example 29, 189 mg (0.92) of carboxylic acid chloride hydrochloride
mmol), silver cyanate 229 mg (1.53 mmol), 4- (dimethylamino) pyridine 74.6
The reaction was carried out with mg (0.61 mmol) and triethylamine 0.11 mL (0.92 mmol), and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1).
The title compound as a colorless powder was obtained (yield 61%).
MS
(FAB) (m / z): 615 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₄ H ₅₁ N ₂ O ₈
(MH ⁺ ): 615.3645. Found, 615.3649.

Second step
14- [2- (Pyridin-3-yl) propanoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethane-2-yl) mutilin

According to the method of the second step of Example 1, the reaction was performed using 205 mg (0.33 mmol) of the compound of the first step, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 10: 1). Purify and 110
The title compound as a colorless powder was obtained (62% yield).
MS
(FAB) (m / z): 531 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₃ N ₂ O ₇
(MH ⁺ ): 531.3070. Found, 531.3101.

(Example 31)
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethanedimethylketal-2-yl) mutilin

14- [2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethane-2-yl) mutilin obtained in Example 29 50.0 mg (94.6 μmol)
Of N, N-dimethylformamide (1.50 mL) in acetone dimethylacetal 11.8 mg (0.11
mmol) and 28.4 mg (0.11 mmol) of pyridinium p-toluenesulfonate were added and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 mL x 2). The combined organic layers were washed with water (3 mL) and then with saturated brine (3 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 4), 51.3
mg of the title compound was obtained (95% yield).
MS
(FAB) (m / z): 569 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₂ H ₄₅ N ₂ O ₇
(MH ⁺ ): 569.3227. Found, 569.3238.

(Example 32)
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,3-dioxolan-2-one-4-yl) mutilin

14- [2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-12- (1,2-dihydroxyethane-2-yl) mutilin obtained in Example 29 50.0 mg (94.6 μmol)
A methylene chloride solution (4 mL) of 1,1′-carbonyldiimidazole 16.9 mg (0.10 mmol) was added to a methylene chloride solution (4 mL), and the mixture was heated to reflux for 8 hours. After cooling, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 8), 50.9
The title compound as a colorless powder was obtained (98% yield).
MS
(FAB) (m / z): 555 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₃₉ N ₂ O ₈
(MH ⁺ ): 555.2706. Found, 555.2701.

(Example 33)
First step
12-desethenyl-11-O-methoxymethylmutilin 12-N-methylcarboxamide

To a solution of 2-carboxy-12-desethenyl-11-O-methoxymethylmutilin 200 mg (0.52 mmol) prepared in the first step of Example 27 in methylene chloride (2 mL) was added 1- (3-dimethylaminohydrochloride hydrochloride. Propyl) -3-ethylcarbodiimide 100 mg (0.52 mmol) and methylamine (2 mol / L
Tetrahydrofuran solution) 0.78 mL (1.57 mmol) was added and stirred at room temperature for 12 hours. Dilute aqueous citric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate (5 mL x
3) The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The obtained residue was subjected to column chromatography (NH, hexane: ethyl acetate =
1: 1) to give 46.7 mg of the title compound as a colorless oil (23% yield).
MS
(FAB) (m / z): 396 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₂ H ₃₈ NO ₅ (MH ⁺ ):
396.2750. Found, 396.2759.

Second step
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenylmutilin 12-N-methylcarboxamide

According to the method of the first step of Example 1, the compound of the first step 43.1 mg (0.11 mmol), carboxylate chloride hydrochloride 33.4 mg (0.16 mmol), silver cyanate 40.8 mg (0.27
mmol), 4- (dimethylamino) pyridine 13.3 mg (0.11 mmol) and triethylamine 23.0 μL (0.16 mmol), and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1). , 29.9
14 mg of colorless powder 14-[(E) -2- (pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-11-O-methoxymethylmutilin 12-N-methylcarboxamide was obtained ( Yield 48%).
According to the method of the second step of Example 1, the reaction was performed using 29.9 mg (52.5 μmol) of the above compound, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1), 22.9
The title compound as a colorless powder was obtained (83% yield).
MS
(FAB) (m / z): 526 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₉ H ₄₀ N ₃ O ₆
(MH ⁺ ): 526.2917. Found, 526.2935.

(Example 34)
First step
12-desethenyl-11-methoxymethyloxymutilin 12-N, N-dimethylcarboxamide

According to the method of Example 33, 12-carboxy-12-desethenyl-11-O-methoxymethylmutilin prepared in the first step of Example 27 200 mg (0.52 mmol), 1- (3-dimethylaminopropyl) hydrochloride -3-Ethylcarbodiimide 100 mg (0.52 mmol) and dimethylamine (2 mol / L
The reaction was carried out using 0.78 mL (1.57 mmol) of tetrahydrofuran solution), and the resulting residue was subjected to column chromatography (NH, hexane: ethyl acetate =
1: 1) to give 46.6 mg of the title compound as a colorless oil (22% yield).
MS
(FAB) (m / z): 410 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₂₃ H ₄₀ NO ₅ (MH ⁺ ):
410.2906.Found, 410.2988.

Second step
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenyl-11-O-methoxymethylmutilin 12-N, N-dimethylcarboxamide

According to the method of the first step of Example 1, the compound of the first step 40.3 mg (98.4 mmol), carboxylate chloride hydrochloride 30.1 mg (0.15 mmol), silver cyanate 36.9 mg (0.25
mmol), 4- (dimethylamino) pyridine 12.0 mg (98.4 μmol) and triethylamine 18.0 μL (0.15 mmol), and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1). , 24.4
The title compound as a colorless powder was obtained (42% yield).
MS
(FAB) (m / z): 584 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₂ H ₄₆ N ₃ O ₇
(MH ⁺ ): 584.3336. Found, 584.3368.

Third process
14-[(E) -2- (Pyridin-3-yl) propenoyl] carbamoyl-12-desethenylmutilin 12-N, N-dimethylcarboxamide

According to the method of the second step of Example 1, the reaction was performed using 23.2 mg (39.7 μmol) of the compound of the second step, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate: methanol = 10: 1). Purify and 19.3
The title compound as a colorless powder was obtained (90% yield).
MS
(FAB) (m / z): 540 (MH ⁺ ).
HRMS
(FAB) (m / z): Calcd. For C ₃₀ H ₄₂ N ₃ O ₆
(MH ⁺ ): 540.3074. Found, 540.3039.

(Test example)
MIC [Minimum inhibitory concentration (MIC,
minimum inhibitory concentration)] is measured using the NCCLS agar plate dilution method.
(Methods for dilution antimicrobial susceptibility tests
for bacteria that grow aerobically; approved standard-sixth edition. NCCLS.
2003, M7-A6, Vol. 23 (No. 2).).
As a result, it was found that the compound of the present invention has excellent antibacterial activity.

The compound of the present invention is a novel mutilin derivative having an excellent antibacterial action, and is useful as a therapeutic agent for infectious diseases involving gram-positive and gram-negative bacteria including various drug-resistant bacteria.

Claims (6)

The following general formula (1)

(Wherein R ₁ represents a hydrogen atom, a formyl group, an optionally substituted lower alkyl group, an aromatic ring optionally substituted with an aromatic ring, an aromatic ring optionally substituted heteroaralkyl group or lower alkyl Represents an oxycarbonyl group, R ₂ represents a hydrogen atom, a lower alkyl group or an aralkyl group optionally substituted with an aromatic ring, R ₃ represents a hydrogen atom or a fluorine atom, and a broken line portion represents a single bond or a double bond Or an acid addition salt thereof. The following general formula (1-1)

Wherein R ₁ ^′ is a hydrogen atom, an optionally substituted lower alkyl group, an aromatic ring optionally substituted with an aromatic ring, a heteroaralkyl group optionally substituted with an aromatic ring or a lower alkyloxycarbonyl. R ₂ represents a hydrogen atom, a lower alkyl group or an aralkyl group which may be substituted with an aromatic ring, R ₄ represents a hydroxyl-protecting group, and the broken line portion represents a single bond or a double bond) Or a acid addition salt thereof. The following general formula (1-2)

(Wherein R ₁ represents a hydrogen atom, a formyl group, an optionally substituted lower alkyl group, an aromatic ring optionally substituted with an aromatic ring, an aromatic ring optionally substituted heteroaralkyl group or lower alkyl Represents an oxycarbonyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₃ represents a hydrogen atom or a fluorine atom, R ₄ represents a hydroxyl protecting group, A single bond or a double bond), or an acid addition salt thereof. The following general formula (1)

(Wherein R ₁ represents a hydrogen atom, a formyl group, an optionally substituted lower alkyl group, an aromatic ring optionally substituted with an aromatic ring, an aromatic ring optionally substituted heteroaralkyl group or lower alkyl Represents an oxycarbonyl group, R ₂ represents a hydrogen atom, a lower alkyl group or an aralkyl group optionally substituted with an aromatic ring, R ₃ represents a hydrogen atom or a fluorine atom, and a broken line portion represents a single bond or a double bond A therapeutic agent for treating infectious diseases, which comprises at least one of mutilin derivatives represented by (2) or acid addition salts thereof as an active ingredient. The following general formula (1-1)

Wherein R ₁ ^′ is a hydrogen atom, an optionally substituted lower alkyl group, an aromatic ring optionally substituted with an aromatic ring, a heteroaralkyl group optionally substituted with an aromatic ring or a lower alkyloxycarbonyl. R ₂ represents a hydrogen atom, a lower alkyl group or an aralkyl group which may be substituted with an aromatic ring, R ₄ represents a hydroxyl-protecting group, and the broken line portion represents a single bond or a double bond) A therapeutic agent for an infectious disease comprising at least one of the mutilin derivatives represented by the above or acid addition salts thereof as an active ingredient. The following general formula (1-2)

(Wherein R ₁ represents a hydrogen atom, a formyl group, an optionally substituted lower alkyl group, an aromatic ring optionally substituted with an aromatic ring, an aromatic ring optionally substituted heteroaralkyl group or lower alkyl Represents an oxycarbonyl group, R ₂ represents a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aralkyl group, R ₃ represents a hydrogen atom or a fluorine atom, R ₄ represents a hydroxyl protecting group, A therapeutic agent for an infectious disease, comprising as an active ingredient at least one of a mutilin derivative represented by a single bond or a double bond) or an acid addition salt thereof.