JPH10287669A - Substituted aminomethylpyrrolidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having a wide excellent antibacterial power against gram negative and gram positive bacteria, and in particular, exhibiting a strong antibacterial activity against quinolone-resistant bacteria and further having both good pharmacokinetics and good safety. SOLUTION: This compound is expressed by formula I R<1> is OH, a halogenated 1-6C alkyl; R<2> , R<3> are each H, a (substituted) 1-6C alkyl; R<4> -R<6> are each H, OH, a halogen, etc.; R<7> , R<8> are each H, a 1-6C alkyl; Q is a group of formula II [R<9> is a 1-6C alkyl, a 2-6C alkenyl, etc.; R<10> is H, a 1-6C alkylthio; X<1> is H, a halogen; A<1> is N, a group of formula III (X<2> is H, amino, etc.,); A<2> , A<3> are each N, C, etc.]}, e.g. 5-amino-7-[(3R)-(1-amino-2-fluoroethyl)-1- pyrrolidinyl]-6-fluoro-1-[(2S)-fluoro-(1R)-cyclopropyl]-1,4-dihydro-8- methoxy-4- oxoquinoline-3-carboxylic acid. For example, an optically active cis-2- fluorocyclopropylamine derivative is preferably used as a production raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an antibacterial compound useful as a medicament, an animal drug, a marine drug, or an antibacterial preservative, and further relates to an antibacterial drug and an antibacterial preparation containing this compound.

[0002]

2. Description of the Related Art Since the discovery of norfloxacin, quinolone synthetic antibacterial agents have been improved in antibacterial activity and pharmacokinetics, and many compounds have been put into clinical practice as chemotherapeutic agents effective for almost systemic infections. .

[0003]

In recent years, in the clinical setting, bacteria that are insensitive to quinolone synthetic antibacterial drugs are increasing. For example, in bacteria that are resistant to drugs other than quinolone-based synthetic antibacterials, such as Staphylococcus aureus (MRSA) that is insensitive to β-lactam antibiotics, the number of bacteria that have become insensitive to quinolone-based synthetic antibacterials also increases. ing. Therefore, there is a need for more effective drugs in clinical settings. On the other hand, it has been clarified that convulsions are induced by taking a nonsteroidal anti-inflammatory drug or side effects such as phototoxicity, and the development of a safer quinolone-based synthetic antibacterial agent is also required. .

[0004]

In view of such circumstances, the present inventors have made intensive studies to provide excellent compounds satisfying the above requirements. As a result, the substituted aminomethylpyrrolidine derivatives represented by the following formula (I) and their salts and hydrates thereof have a wide range of excellent antibacterial activity against Gram-negative bacteria and Gram-positive bacteria, The present inventors have found that they have a strong antibacterial activity against quinolone-resistant bacteria including MRSA and also have good pharmacokinetics and safety, and completed the present invention.

That is, the present invention relates to a compound represented by the following formula (I), a salt thereof, and a hydrate thereof.

[0006]

Embedded image In the formula, R ¹ has, as a substituent, at least one group selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms, Represents an alkyl group of 1 to 6;
² and R ³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
It may have, as a substituent, one or more groups selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms, and R ⁴ , R ⁵ And R ⁶ are each independently a hydrogen atom,
A hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms, wherein the alkyl group is a hydroxyl group, a halogen atom And at least one group selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms as a substituent, and R ⁷ and R ⁸ each independently represent a hydrogen atom or a carbon atom having 1 to 6 carbon atoms. And Q represents a partial structure represented by the following formula.

[0007]

Embedded image [In the formula, R ⁹ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or a carbon atom having 3 to 6 carbon atoms which may have a substituent. A cyclic alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms. And R ¹⁰ represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms.
¹⁰ and R ⁹ may be integrated so as to form a cyclic structure including a part of the mother nucleus, and the ring thus formed may include a sulfur atom as a constituent atom of the ring. This ring may further have an alkyl group having 1 to 6 carbon atoms as a substituent.

R ¹¹ represents a hydrogen atom, an amino group, a hydroxyl group,
Represents a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms. The amino group may have, as a substituent, at least one group selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms.

X ¹ represents a halogen atom or a hydrogen atom, and A ¹ represents a nitrogen atom or a compound of the formula (II)

[0010]

Embedded image (Wherein, X ² represents a hydrogen atom, an amino group, a halogen atom,
Cyano group, halogenomethyl group, halogenomethoxyl group,
Represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, of which an amino group is a formyl group, may have one or more groups selected from the group the group consisting of alkyl and acyl group having 2 to 5 carbon atoms from 1 to 6 carbon atoms as a substituent, further this X ² and the above R ⁹ May be integrated so as to form a ring structure including a part of the mother nucleus, but the ring thus formed contains an oxygen atom, a nitrogen atom, or a sulfur atom as a ring constituent atom. But this ring also
It may have an alkyl group having 1 to 6 carbon atoms as a substituent. ) Represents a partial structure.

[0011] ^{A 2} and ^{A 3} are each, represents a nitrogen atom or a carbon atom, a carbon atom bonded These and ^{A 2} and ^{A 3,} the partial structure

[0012]

Embedded image> C ＝ C (A ¹ =) — N (R ⁹ ) — or a partial structure

[0013]

To form: NC (A ¹ =) = C (R ⁹ )-.

Y is hydrogen, phenyl, acetoxymethyl, pivaloyloxymethyl, ethoxycarbonyl, choline, dimethylaminoethyl, 5-indanyl, phthalidinyl, 5-alkyl-2-oxo -1,3-dioxol-4-ylmethyl group, 3-acetoxy-2-oxobutyl group, alkyl group having 1 to 6 carbon atoms, alkoxymethyl group having 2 to 7 carbon atoms, or alkylene group having 1 to 6 carbon atoms And a phenylalkyl group composed of a phenyl group. The present invention further provides a compound represented by the formula (I) wherein Q is

[0015]

Embedded image Or the formula,

[0016]

Embedded image (Wherein R ⁹ , R ¹⁰ , R ¹¹ , A ¹ , X ¹ and Y are the same as defined above), and the above-mentioned compound having a structure represented by the following formula: Hydrates thereof; in the formula (I), Q is a group represented by the formula

[0017]

Embedded image (Wherein, R ⁹ , R ¹⁰ , R ¹¹ , A ¹ , X ¹ and Y are the same as defined above), and the salts thereof, and the salts thereof. In formula (I), Q is 9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-de] [1 .4] the above compound which is benzoxazine-6-carboxylic acid, a salt thereof, and a hydrate thereof; in the formula (I),
Q is 5-amino-6-fluoro-1- [2- (S)-
Fluoro-1- (R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid and salts thereof, and hydrates thereof; ) Wherein Q is 5-amino-6-
Fluoro-1- [2- (S) -fluoro-1- (R)-
Cyclopropyl] -1,4-dihydro-8-methyl-4
The above-mentioned compounds, which are -oxoquinoline-3-carboxylic acids, and salts thereof, and hydrates thereof; the above-mentioned compounds, wherein the compound of the formula (I) is a stereochemically single (pure) compound; R < ¹ > is a methoxymethyl group, a fluoromethyl group, or a 2-fluoroethyl group, a salt thereof, and a hydrate thereof; Wherein ⁹ is a halogenocyclopropyl group, or a salt thereof;
And a hydrate thereof; a compound of the formula (I) wherein the halogenocyclopropyl group is a 1,2-cis-halogenocyclopropyl group and a salt thereof, and a hydrate thereof; Wherein the halogenocyclopropyl group is a stereochemically single (pure) substituent and a salt or hydrate thereof; in the formula (I), the halogenocyclopropyl group is represented by (1R, 2S )-
The above compound which is a 2-halogenocyclopropyl group and a salt thereof, and a hydrate thereof;
The above compound and a salt thereof, wherein the halogen atom of the halogenocyclopropyl group is a fluorine atom, and a hydrate thereof; wherein the compound of the formula (I) is a stereochemically single (pure) compound. And a salt thereof, and a hydrate thereof; a compound comprising the compound of the formula (I) or a salt thereof, or a hydrate thereof (of the compound and salt) as an active ingredient; a compound of the formula (I) or a hydrate thereof Antimicrobial agents comprising salts or hydrates thereof (of compounds and salts) as active ingredients; and the like.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The substituents of the compound represented by formula (I) of the present invention will be described.

The substituent R ¹ is an alkyl group having 1 to 6 carbon atoms, and this alkyl group comprises a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. It has one or more groups selected from the group of groups as a substituent. The compound of the present invention is characterized in that this alkyl group is a substituted alkyl group. This alkyl group has 1 to 6 carbon atoms and may be linear or branched, but is preferably a methyl group, an ethyl group, a normal propyl group or an isopropyl group.

When the alkyl group has a hydroxyl group as a substituent, the hydroxyl group is more preferably substituted on the terminal carbon atom of the alkyl group. The alkyl group having a hydroxyl group preferably has up to 3 carbon atoms, such as a hydroxymethyl group,
2-hydroxyethyl group, 2-hydroxyethyl group, 2
-Hydroxypropyl, 3-hydroxypropyl and the like are preferred. When the alkyl group has a halogen atom as a substituent, the halogen atom is preferably a fluorine atom. In this case, the number of fluorine atoms may be any from mono-substitution to perfluoro-substitution. Examples thereof include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2,2-difluoroethyl group, and a 2,2,2-trifluoroethyl group. Of these, a monofluoromethyl group and a 2-fluoroethyl group are more preferred. When the alkyl group has an alkylthio group as a substituent, the alkylthio group may be linear or branched having 1 to 6 carbon atoms. The alkyl group having an alkylthio group is preferably an alkylthiomethyl group, an alkylthioethyl group, or an alkylthiopropyl group, and more preferably an alkylthio group having 1 to 3 carbon atoms. The alkylthio group is preferably on the terminal carbon atom of the alkyl group. Preferred examples of the alkyl group having an alkylthio group include a methylthiomethyl group, an ethylthiomethyl group, and a methylthioethyl group. When the alkyl group has an alkoxyl group as a substituent, the alkoxyl group may be linear or branched having 1 to 6 carbon atoms. As the alkyl group having an alkoxyl group, an alkoxymethyl group, an alkoxyethyl group, and an alkoxypropyl group are preferable, and the alkoxyl group is also preferably one having up to 3 carbon atoms. The alkoxyl group is preferably on the terminal carbon atom of the alkyl group. Preferred examples of the alkyl group having an alkoxyl group include a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group.

Particularly preferred among the above substituents are a fluoroalkyl group and a methoxyalkyl group, and a fluoromethyl group or a 2-fluoroethyl group is preferred for a fluoroalkyl group, and a methoxymethyl group is preferred for a methoxyalkyl group. The carbon atom to which R ¹ is bonded becomes an asymmetric carbon to produce an isomer, and the present invention includes any of them.

The substituents R ² and R ³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, which is a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms. And at least one group selected from the group consisting of and an alkyloxy group as a substituent. Here, the alkyl group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group.

When the alkyl group has a hydroxyl group as a substituent, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the hydroxyl group may be substituted on the terminal carbon atom of the alkyl group. The ones obtained are more preferable. The alkyl group having a hydroxyl group is preferably an alkyl group having up to 3 carbon atoms, such as a hydroxymethyl group, a 2-hydroxyethyl group,
-Hydroxyethyl group, 2-hydroxypropyl group, 3
-Hydroxypropyl and the like are preferred. When the alkyl group has a halogen atom as a substituent, the alkyl group may be linear or branched having 1 to 6 carbon atoms,
As the halogen atom, a fluorine atom is preferable. Further, the number of fluorine atoms may be any from mono-substitution to perfluoro-substitution. Examples thereof include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a 2,2,2-trifluoroethyl group. When the alkyl group has an alkylthio group as a substituent, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkylthio group may be linear or branched having 1 to 6 carbon atoms. Either may be used. The alkyl group having an alkylthio group is preferably an alkylthiomethyl group, an alkylthioethyl group, or an alkylthiopropyl group, and more preferably an alkylthio group having 1 to 3 carbon atoms.
More preferably, the alkylthio group is on the terminal carbon atom of the alkyl group. Preferred examples of the alkyl group having an alkylthio group include a methylthiomethyl group, an ethylthiomethyl group, and a methylthioethyl group. When the alkyl group has an alkoxyl group as a substituent, the alkyl group may be linear or branched having 1 to 6 carbon atoms, and the alkoxyl group may be linear or branched having 1 to 6 carbon atoms. Either may be used. As an alkyl group having an alkoxyl group, an alkoxymethyl group,
An alkoxyethyl group and an alkoxypropyl group are preferred, and an alkoxyl group having up to 3 carbon atoms is also preferred. The alkoxyl group is preferably substituted on the terminal carbon atom of the alkyl group. Preferred as an alkyl group having an alkoxyl group is a methoxymethyl group,
An ethoxymethyl group and a methoxyethyl group can be exemplified.

R ⁴ , R ⁵ and R ⁶ each independently represent a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, Represents an alkylthio group of 6, wherein the alkyl group may have, as a substituent, at least one group selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms. . Further, R ⁵ and R ⁶ may be integrated to form a methylene chain having 3 to 6 carbon atoms (forming a pyrrolidine ring and a spiro ring system), a hydroxyimino group, or an alkyloxyimino group having 1 to 6 carbon atoms. Good. As the halogen atom, a fluorine atom or a chlorine atom is preferable. The alkyl group may be linear or branched having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group. The alkoxyl group may be linear or branched having 1 to 6 carbon atoms, and is preferably a methoxyl group or an ethoxyl group. The alkylthio group may be linear or branched having 1 to 6 carbon atoms, but is preferably a methylthio group or an ethylthio group.

When a hydroxyl group is present as a substituent on an alkyl group having 1 to 6 carbon atoms, the alkyl group may be linear or branched, and the hydroxyl group may be substituted at the terminal position of the alkyl group. Those substituted on carbon atoms are more preferred. Preferred examples of the alkyl group having 1 to 6 carbon atoms substituted with a hydroxyl group include a hydroxymethyl group, a 2-hydroxyethyl group and a 3-hydroxypropyl group. When a halogen atom is present as a substituent on the alkyl group, the halogen atom is preferably a fluorine or chlorine atom, and particularly preferably a fluorine atom. The alkyl group may be linear or branched.
When an alkoxyl group is present as a substituent on an alkyl group, any alkyl group portion may be linear or branched, and is preferably an alkoxymethyl group or an alkoxyethyl group. More preferred are a methoxymethyl group, an ethoxymethyl group and a 2-methoxyethyl group.

When the substituents R ⁵ and R ⁶ are integrated to form a methylene chain, a new 3 is added to the pyrrolidine ring.
And a 6-membered ring is added to form a spirocyclic structure. The size of the newly formed ring is preferably a cyclopropyl ring or cyclobutyl ring having 2 or 3 carbon atoms.
Further, R ⁵ and R ⁶ are integrated to form an alkyloxyimino group.

[0027]

When ＝ N—O-Alkyl, the alkyl group may be linear or branched. Preferred as the alkyloxyimino group are a methoxyimino group and an ethoxyimino group.

The substituents R ⁷ and R ⁸ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
The alkyl group may be a linear or branched one having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group,
A normal propyl group and an isopropyl group. Among these, the case where each is a hydrogen atom is preferable.

Q represents a partial structure represented by the following formula.

[0030]

Embedded image

In the formula, A ² and A ³ are
Each represents a nitrogen atom or a carbon atom, and A ² and A ³ and the carbon atom to which they are bonded each have a partial structure

[0032]

Embedded image> C ＝ C (A ¹ =) — N (R ⁹ ) — or a partial structure

[0033]

> N—C (A ¹ =) = C (R ⁹ ) —

A preferable structure for Q is represented by the formula

[0035]

Embedded image Or the formula,

[0036]

Embedded image Is a partial structure of the fused heterocyclic ring system represented by

The substituent R ⁹ includes an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, and a carbon atom having 3 to 6 carbon atoms which may have a substituent. A cyclic alkyl group of 6; an aryl group which may have a substituent; a heteroaryl group which may have a substituent; an alkoxyl group having 1 to 6 carbon atoms;
To 6 alkylamino groups. Here, the alkyl group having 1 to 6 carbon atoms is particularly preferably an ethyl group.
As the alkenyl group having 2 to 6 carbon atoms, a vinyl group or a 1-isopropenyl group is preferable. 1 to 6 carbon atoms
Is preferably a 2-fluoroethyl group. As the cyclic alkyl group, a cyclopropyl group is particularly preferred. As a substituent of the cyclic alkyl group, a halogen atom is preferred, and a fluorine atom is particularly preferred as the halogen atom. Examples of the aryl group which may have a substituent include a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom, a hydroxyl group, an amino group, a nitro group, and a group having 1 carbon atom.
A phenyl group which may be substituted with 1 to 3 groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, and the like.
2-fluorophenyl group, 4-fluorophenyl group,
Preferred are a 2,4-difluorophenyl group, a 2-fluoro-4-hydroxyphenyl group, a 3-amino-4,6-difluorophenyl group and a 4,6-difluoro-3-methylaminophenyl group. The heteroaryl group is a compound derived from a 5- or 6-membered aromatic heterocyclic compound containing at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom. For example, a pyridyl group, a pyrimidyl group, etc. can be mentioned. As the substituent on these rings, an alkyl group, a halogen atom and the like are preferable. As the alkoxyl group having 1 to 6 carbon atoms, a methoxyl group is preferable. The alkylamino group having 1 to 6 carbon atoms is preferably a methylamino group. The substituent R ^9, preferably a cyclic alkyl group or a halogenocyclopropyl group. Among these, a cyclopropyl group or a 2-halogenocyclopropyl group is preferred. The halogen atom is preferably a fluorine atom.

The substituent R ¹⁰ represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, or R ⁹ and R ¹⁰ include a part of the mother nucleus (that is, when R ⁹ is bonded to (To include the nitrogen atom present and the carbon atom to which R ¹⁰ is attached) to form a hydrocarbon-based cyclic structure. The ring thus formed may contain a sulfur atom as a constituent atom, and the ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. The ring formed here may be of the size of a 4- to 6-membered ring, and this ring may be saturated, partially saturated or unsaturated.

The substituent X ¹ is a halogen atom or a hydrogen atom, in the case of the halogen atom is preferably a fluorine atom. Among these, a fluorine atom or a hydrogen atom is preferred as a substituent.

The substituent R ¹¹ is a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, a C 1-6
Represents an alkyl group, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, of which an amino group is a formyl group or a 1 to 6 carbon atoms. 1 or 2 selected from the group consisting of an alkyl group and an acyl group having 2 to 6 carbon atoms
May be included as a substituent. The alkyl group may be linear or branched having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group. The alkenyl group may be a straight or branched one having 2 to 6 carbon atoms, and is preferably a vinyl group. The alkynyl group may be linear or branched having 2 to 6 carbon atoms, and is preferably an ethynyl group. The halogen of the halogenomethyl group is particularly preferably a fluorine atom, and the number thereof may be 1 to 3. The alkoxyl group has 1 carbon atom
To 6 but is preferably a methoxyl group. The substituent R ¹¹ is preferably a hydrogen atom, an alkyl group, or an amino group, and among them, a methyl group or an unsubstituted amino group is preferable.

When the substituent R ¹¹ is an amino group, a hydroxyl group or a thiol group, these may be protected by commonly used protecting groups. Examples of such protecting groups include, for example, a tertiary butoxycarbonyl group,
Alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group,
Aralkyloxycarbonyl groups such as paramethoxybenzyloxycarbonyl group and paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group,
Acyl groups such as formyl group, benzoyl group, tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, alkyl groups such as triphenylmethyl group or aralkyl groups, methoxymethyl group, tertiary Ethers such as tert-butoxymethyl group, tethydropyranyl group, 2,2,2-trichloroethoxymethyl group, and substituted silyl groups such as trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group and tribenzylsilyl group Groups. Compounds having a group protected by these protecting groups are particularly preferred as production intermediates.

A ¹ has the formula (II)

[0043]

Embedded image X ² is a hydrogen atom, an amino group,
Halogen atom, cyano group, halogenomethyl group, halogenomethoxyl group, alkyl group having 1 to 6 carbon atoms, 2 carbon atoms
Represents an alkenyl group having from 6 to 6, an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms,
Among them, the amino group may have, as a substituent, one or two groups selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms. Good. The alkyl group may be linear or branched having 1 to 6 carbon atoms, and is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group. The alkenyl group has 2 to 6 carbon atoms.
May be linear or branched, but is preferably a vinyl group. The alkynyl group includes 2 to 6 carbon atoms.
May be linear or branched, but is preferably an ethynyl group. As the halogen of the halogenomethyl group,
Particularly, a fluorine atom is preferable, and the number may be 1 to 3.
The alkoxyl group may have 1 to 6 carbon atoms, but is preferably a methoxyl group. As the halogen of the halogenomethoxyl group, a fluorine atom is particularly preferable,
The number may be from one to three. Among these substituents,
An alkyl group or an alkoxyl group is preferred. More preferred are a methyl group, an ethyl group, and a methoxyl group. These are preferable substituents particularly when Q is a partial structure shown in Chemical formula 21.

Further, X ² and R ⁹ described above include a part of the mother nucleus (ie, include the carbon atom to which X ³ is bonded and the nitrogen atom to which R ⁹ is bonded). In this manner, a hydrocarbon-based cyclic structure (ring size is from 4 to 7-membered and may be saturated, partially saturated, or unsaturated) is formed. The ring thus formed may contain an oxygen atom, a nitrogen atom or a sulfur atom as a constituent atom, and this ring is substituted with an alkyl group having 1 to 6 carbon atoms. It may have as a group.

As Q, a partial structure shown in Chemical formula 21 is preferable. Further, in this case, it is preferable that A ¹ is a partial structure of the formula (II).

When Q is a partial structure of the formula (21) and A ¹ is a partial structure of the formula (II), the combination of R ¹¹ and X ² is preferably such that R ¹¹ is an amino group, a hydrogen atom , A hydroxyl group, or an alkyl group having 1 to 6 carbon atoms,
X ² is an alkyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
In the case of an alkoxyl group, a halogenomethoxyl group, or a hydrogen atom. A more preferable combination is a case where R ¹¹ is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group, and X ² is a methyl group, a methoxyl group, a difluoromethoxyl group, or a hydrogen atom. A particularly preferable combination is a case where R ¹¹ is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group, and X ² is a methyl group or a methoxyl group. These R ¹¹ and X ²
X ¹ is preferably a fluorine atom.

When each of the substituents X ¹ and X ² is a halogen atom, X ¹ is particularly preferably a fluorine atom, and X ² is preferably a fluorine atom or a chlorine atom.

Q is a partial structure represented by the following formula:
When A ¹ is a partial structure of the formula (II), R ¹¹ and X ²
Preferably, R ¹¹ is an amino group, a hydrogen atom, a hydroxyl group, or an alkyl group having 1 to 6 carbon atoms, and X ² is an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms. Group, a halogenomethoxyl group, or a hydrogen atom. A more preferable combination is a case where R ¹¹ is an amino group, a hydrogen atom, a hydroxyl group, or a methyl group, and X ² is a methyl group, a methoxyl group, a difluoromethoxyl group, or a hydrogen atom. As a particularly preferred combination, R ¹¹ is an amino group,
This is a case where X ² is a hydrogen atom, a hydroxyl group, or a methyl group, and a methyl group or a methoxyl group. Substituents X ¹ and X
^{When 2} is a halogen atom, X ¹ is particularly preferably a fluorine atom, and X ² is preferably a fluorine atom or a chlorine atom.

Next, the halogenocyclopropyl group for R ⁹ will be described. Examples of the halogen atom to be substituted include a fluorine atom and a chlorine atom, and a fluorine atom is particularly preferable. The steric environment at this moiety is particularly preferably that the halogen atom and the pyridonecarboxylic acid moiety are in a cis configuration with respect to the cyclopropane ring. Although only the cis-2-halogenocyclopropyl moiety of R ^{9 has} a so-called enantiomer-related isomer, strong antibacterial activity and high safety were observed in any of these isomers.

When the compound of the formula (I) of the present invention has a structure in which a diastereomer exists, the compound of the present invention comprises a single (pure) diastereomer when administered to a human or animal. It is preferred to administer one. The term "consisting of a single diastereomer" is understood to include not only a case where no other diastereomer is contained but also a case where it is chemically pure. In other words, it is interpreted that other diastereomers may be included as long as they have no effect on physical constants and physiological activities. The term "stereochemically single" means that when a compound or the like contains an asymmetric carbon atom, and there are a plurality of types that are in an isomer relationship, only one of them is used. Means something. In this case, the “unity” is also considered in the same manner as described above.

The pyridonecarboxylic acid derivative of the present invention may be in a free form, but may be in the form of an acid addition salt or a salt of a carboxyl group. Examples of acid addition salts include inorganic salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, and phosphate, or acetate,
Organic acid salts such as methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate and lactate can be mentioned. Examples of the salt of a carboxyl group include, for example, alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N-methylglucamine salt, Any of inorganic salts and organic salts such as tris- (hydroxylmethyl) aminomethane salt may be used. The free form, acid addition salt and carboxyl group salt of these pyridobenzoxazinecarboxylic acid derivatives may exist as hydrates.

On the other hand, quinolone derivatives in which the carboxylic acid moiety is an ester are useful as synthetic intermediates and prodrugs. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters are useful as synthetic intermediates. Further, the ester used as a prodrug is an ester that is easily cleaved in a living body to generate a free form of a carboxylic acid, and includes, for example, acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, Choline esters,
Oxoalkyl esters such as dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester and 3-acetoxy-2-oxobutyl ester Can be mentioned.

The compound of the present invention represented by the formula (I) can be produced by various methods. One preferred example is a compound represented by the formula (III)

[0054]

Embedded image [In the formula, X ³ is a group that functions as a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms. Wherein Y ¹ is Y as defined in formula (I) or in formula (IV)

[0055]

Embedded image A boron-containing substituent represented by —B (Y ¹¹ ) Y ¹² IV (wherein Y ¹¹ and Y ¹² represent a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms), ^{9, R} 10, R
¹¹ , A ¹ and X ¹ are the same as defined in formula (I). Or a compound represented by the formula (V)

[0056]

Embedded image [In the formula, X ³ is a group that functions as a leaving group such as a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms. R ⁹ ,
R ¹⁰ , R ¹¹ , A ¹ , X ¹ and Y are the same as defined in the formula (I). With a compound of formula (VI)

[0057]

Embedded image [Wherein R ²¹ is the same as R ² defined in formula (I) or represents an amino-protecting group, and R ¹ , R ³ , R
⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are the same as defined in formula (I). ] Or an addition salt thereof.

The reaction can be carried out with or without a solvent. The solvent used in the reaction may be inert under the reaction conditions, for example, dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water,
Mention may be made of 3-methoxybutanol, or mixtures thereof. The reaction may be carried out with an acid acceptor such as an inorganic or organic base, for example, an alkali metal or alkaline earth metal carbonate or bicarbonate, or an organic basic such as triethylamine, pyridine, 1,8-diazabicycloundecene and the like. It is preferred to work in the presence of the compound. The reaction can be carried out usually at a temperature in the range of room temperature to 200 ° C, and preferably in the range of 25 to 150 ° C. The reaction time may range from 30 minutes to 48 hours, and is usually completed in about 30 minutes to 2 hours.

The protecting group for the amino group may be any protecting group commonly used in this field, for example, an alkoxycarbonyl group such as a tertiary butoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group. , Benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, aralkyloxycarbonyl groups such as paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, Acyl groups such as benzoyl group, tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxybenzyl group, alkyl groups such as triphenylmethyl group, or aralkyl groups, methoxymethyl group, tertiary butoxy Methyl group, tethydropyranyl group, 2,2 Examples include ethers such as 2-trichloroethoxymethyl group, and substituted silyl groups such as trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethylsilyl group, tribenzylsilyl group, and tertiary butyldiphenylsilyl group. .

When Y and Y ¹ are an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, In general, the carboxylic acid ester can be converted to the corresponding carboxylic acid by treating under acidic or basic conditions used for hydrolysis. When Y ¹ has the structure of the formula (IV), the compound (II)
After reacting compound (VI) with I) or compound (V), the compound can be converted to the corresponding carboxylic acid by treating under acidic or basic conditions. When deprotection is required, the desired compound of formula (I) can be obtained by removing the protecting group under appropriate conditions corresponding to the protecting group.

The compound of the formula (VI) can be produced by various methods. As a preferred example, the compound is synthesized by the method shown in Reference Examples, but is not limited thereto.

Formula (I) consisting of a single (pure) isomer
The cis-2-fluorocyclopropylamine composed of a single isomer, which is preferable for the synthesis of the compound (1), can be synthesized by, for example, the method described in JP-A-2-231475. The synthesis of the compound of the formula (I) consisting of a single isomer from the optically active cis-2-fluorocyclopropylamine derivative thus obtained is described in, for example, JP-A-2-23.
It can be carried out by the method described in No. 1475.

Since the compound of the present invention has a strong antibacterial activity, it can be used as a medicament or pesticide for humans, animals and fish,
It can be used as a food preservative. When the compound of the present invention is used as a medicine for the human body, the dose is in the range of 50 mg to 1 g, preferably 100 mg to 300 mg per adult per day. The dosage for animals may vary depending on the purpose of administration (treatment or prevention), the type and size of the animal to be treated, the type and extent of the infected pathogen, but is generally used as a daily dose. 1 mg to 200 mg, preferably 5 mg to 100 m per kg of body weight
g. This daily dose is administered once a day or divided into 2 to 4 times. The daily dose may exceed the above-mentioned amount if necessary.

The compounds of the present invention are active against a wide range of microorganisms that cause various infectious diseases and can treat, prevent or reduce the diseases caused by these pathogens. Staphylococci, S. pyogenes, hemolytic streptococci, enterococci, pneumococci, peptostreptococci, gonococci, Escherichia coli, Citrobacter, Shigella, Klebsiella , Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae,
Acinetobacter, Campylobacter, Chlamydia trachomatis and the like can be exemplified. Diseases caused by these pathogens include folliculitis, cough, syphilis, erysipelas, cellulitis, lymphatic (node) inflammation, glanders, subcutaneous abscess, sweat glanditis, acne conglomerate, infectious nodules, anus Peripheral abscess, mastitis, superficial secondary infection such as trauma / burn / surgical wound, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, chronic respiratory disease Secondary infection, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, nongonococcal urethritis, cholecystitis, cholangitis, bacterial dysentery, enteritis, uterine appendixitis, in utero infection,
Bartholin's glanditis, blepharitis, stye, lacrimal cystitis, blepharitis,
Examples include corneal ulcer, otitis media, sinusitis, periodontitis, pericoronitis, jaw inflammation, peritonitis, endocarditis, sepsis, meningitis, skin infection and the like.

The present invention is also effective against various microorganisms that cause infectious diseases in animals, for example, Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, Mycoplasma and the like.

Illustrative examples of disease names include, in birds, colibacillosis, chick dysentery, chicken paratyphoidosis, poultry cholera, infectious coryza, staphylococci, mycoplasma infection and the like.
Escherichia coli, salmonellosis, pasteurellosis, hemophilus infection, atrophic rhinitis, exudative epidermitis, mycoplasma infection, etc. in pigs, and Escherichia coli, salmonellosis, hemorrhagic sepsis, mycoplasma infection, bovine lung disease, breast in cattle Inflammation, dogs with E. coli sepsis, Salmonella infection, hemorrhagic sepsis, pyometra, cystitis, etc., and cats with exudative pleurisy, cystitis, chronic rhinitis, hemophilus infection, kitten diarrhea, mycoplasma infection, etc. Can be mentioned.

The antibacterial preparation comprising the compound of the present invention can be prepared by selecting an appropriate preparation according to the method of administration and preparing various preparations which are generally used. Examples of the dosage form of the antimicrobial preparation containing the compound of the present invention as a main component include, for example, tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like. .
Injectables may contain stabilizers, preservatives, and solubilizers in the formulation.They may contain these adjuvants in a container, and then be prepared as a solid formulation by freeze-drying etc. May be prepared as a preparation. One dose may be stored in a container, or multiple doses may be stored in the same container. Examples of the external preparation include solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays and the like. Solid dosage forms may contain pharmaceutically acceptable additives together with the active compound, for example, fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricating agents Agents and the like can be selected and mixed as needed to form a formulation. Examples of the liquid preparation include a solution, a suspension, an emulsion and the like, and sometimes include a suspending agent, an emulsifier, and the like as an additive. The method of administering the compound of the present invention to an animal may be a method of orally administering it directly or by mixing it in a feed, or a method of orally administering a solution, and then directly or by adding it to drinking water or a feed, or injection. Can be exemplified. As a preparation for administering the compound of the present invention to an animal, a powder, a fine granule, a soluble powder, a syrup, a solution, or an injection may be appropriately prepared by a technique usually used in this field. be able to. Next, formulation examples are shown.

[0068]

Table 1 Formulation Example 1 (Capsule): Compound of Example 2 100.0 mg Corn starch 23.0 mg CMC Calcium 22.5 mg Hydroxymethylcellulose 3.0 mg Magnesium stearate 1.5 mg Total 150.0 mg Formulation Example 2. (Solution): Compound of Example 2 1 to 10 g Acetic acid or sodium hydroxide 0.5 to 2 g Ethyl parahydroxybenzoate 0.1 g Purified water 87.9 to 98.4 g Total 100 g Formulation Example 3. (Powder for mixing feed): Compound of Example 2 1 to 10 g Corn starch 98.5 to 89.5 g Light anhydrous silicic acid 0.5 g Total 100 g

[0069]

Next, the present invention will be described with reference to examples and reference examples, but the present invention is not limited to these examples.

Reference Example 1 (4S) -hydroxymethyl-N-[(1R) -phenyl
Ruethyl] -2-pyrrolidone (3R) -methoxycarbonyl -N-[(1R) -phenylethyl] -2-pyrrolidone (30.58 g, 0.1
To a solution of 24 mol) in ethanol (200 ml) was added sodium borohydride (10 g) under ice-cooling, followed by stirring at room temperature for 16 hours. Under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution (100 ml) was added to the reaction solution, and chloroform (200 ml ×
Extracted in 2). After the extract was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. 26.28 g (97%) of the title compound was obtained from a 5% methanol-chloroform eluate. ¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, d,
J = 6.83 Hz), 2.22-2.28 (1H,
m), 2.42-2.56 (2H, m), 3.07-
3.11 (1H, m), 3.16-3.20 (1H,
m), 3.55-3.70 (2H, m), 5.48 (1
H, q, J = 6.83 Hz), 7.15-7.37 (5
H, m).

Reference Example 2 (4S) -Cyanomethyl-N-[(1R) -phenyle
Tyl] -2-pyrrolidone (4S) -hydroxymethyl-N-[(1R) -phenylethyl] -2-pyrrolidone (26.28 g, 0.12
methanesulfonyl chloride (16.5 g, 0.144 mol) in a dichloromethane (200 ml) solution of
And then triethylamine (24.24) under ice-cooling.
g, 0.24 mol) was added dropwise. After stirring at room temperature for 15 minutes, the reaction solution was washed with saturated saline (50 ml × 2), dried over sodium sulfate, and the solvent was distilled off. The residue was dissolved in dimethyl sulfoxide (100 ml), and potassium cyanide (10 g, 0.15 mol) was added.
Stirred at 0 ° C. for 16 hours. After cooling, water (100 ml) was added, and the mixture was extracted with ethyl acetate (300 ml × 2). The ethyl acetate layer was washed with water (400 ml x 2) and saturated saline (300 m
1 × 2), dried over sodium sulfate, and then the solvent was distilled off to obtain 22.18 g (81%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.52 (3H, d,
J = 7.33 Hz), 2.25-2.31 (1H,
m), 2.47-2.50 (2H, m), 2.57-
2.71 (2H, m), 3.10-3.14 (1H,
m), 3.19-3.23 (1H, m), 5.51 (1
H, q, J = 7.33 Hz), 7.27-7.37 (5
H, m).

Reference Example 3 (4S) -Carboxymethyl-N-[(1R) -Fe
Nylethyl] -2-pyrrolidone (4S) -cyanomethyl- N-[(1R) -phenylethyl] -2-pyrrolidone (22.18 g, 97.3 mm
ol) in ethanol (130 ml) was added with a 5N aqueous sodium hydroxide solution (130 ml), and the mixture was heated under reflux for 2.5 hours. After cooling, ethanol was distilled off, and the residue was washed with dichloromethane (50 ml × 2), and concentrated hydrochloric acid was added to obtain an acidic aqueous solution. Ethyl acetate (200 ml)
× 2) and dried over sodium sulfate, and then the solvent was distilled off to obtain 20.87 g (87%) of the crude title compound.
%)Obtained. It was used in subsequent reactions without purification.

Reference Example 4 (4S) -tert-butoxycarbonylmethyl-N-
[(1R) -Phenylethyl ] -2-pyrrolidone (4S) -carboxylmethyl-N-[(1R) -phenylethyl] -2-pyrrolidone (23.14 g, 93.
7 mmol) in dichloromethane (500 ml) solution,
N, N'-dicyclohexylcarbodiimide (21.3
g, 103 mmol), tertiary butyl alcohol (9.
After adding 1 g, 122 mmol) and 4- (dimethylamino) pyridine (1.15 g, 9.4 mmol), the mixture was stirred at room temperature for 64 hours. The reaction solution was filtered, the solvent of the filtrate was distilled off, and the residue was subjected to silica gel column chromatography. From the eluted portion of n-hexane: ethyl acetate = 3: 2, 20 g (70%) of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H,
s), 1.51 (3H, d, J = 7.33 Hz), 2.
12-2.20 (1H, m), 2.34-2.39 (2
H, m), 2.56-2.65 (2H, m), 2.99
-3.02 (1H, m), 3.17-3.21 (1H,
m), 5.51 (1H, q, J = 7.33 Hz), 7.
28-7.36 (5H, m).

Reference Example 5 (4S)-[1- (tert-butoxycarbonyl) etheni
] -N-[(1R) -phenylethyl] -2-pyrroli
Don (4S) -tert-butoxycarbonylmethyl-N-
[(1R) -phenylethyl] -2-pyrrolidone (10
g, 33 mmol) in tetrahydrofuran (50 ml)
To the solution was added dropwise a 1 mol solution of sodium (bistrimethylsilyl) amide in tetrahydrofuran (36.5 ml) at −78 ° C. under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 10 minutes. Then, ethyl formate (3.17 g, 42.8 m
mol) in tetrahydrofuran (10 ml), and a 1 mol solution of sodium (bistrimethylsilyl) amide in tetrahydrofuran (36.5 ml) was again added dropwise. After the reaction solution was stirred for 30 minutes under ice cooling, ether (400 ml) was added, and the mixture was stirred at room temperature for 20 minutes.
The precipitated crystals were collected by washing with ether and collected, and this was made into a suspension of tetrahydrofuran (300 ml), which was heated under reflux for 30 minutes in the presence of paraformaldehyde (10 g). After cooling, the solvent was distilled off and chloroform (300 m
l) was added, insolubles were removed by filtration, and the solvent in the filtrate was distilled off. The residue was subjected to silica gel column chromatography, and 7.5 g (72%) of the title compound was obtained from an eluate of n-hexane: ethyl acetate = 2: 1. ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H,
s), 1.51 (3H, d, J = 7.33 Hz), 2.
41-2.51 (1H, m), 2.61-2.67 (1
H, m), 3.13-3.32 (3H, m), 5.48
-5.53 (2H, m), 6.18 (1H, s), 7.
27-7.36 (5H, m).

Reference Example 6 (4S)-(1-tert-butoxycarbonyl-2-fe
Nylthioethyl) -N-[(1R) -phenylethyl]
Solution of -2-pyrrolidone (4S)-[1- (tert-butoxycarbonyl) ethenyl] -N-[(1R) -phenylethyl] -2-pyrrolidone (11.44 g, 36.3 mmol) in chloroform (100 ml) In addition, thiophenol (4.8 g,
After adding 37.4 mmol) and triethylamine (12 ml), the mixture was stirred at room temperature for 15 hours under a nitrogen atmosphere. After evaporating the solvent, the residue was subjected to silica gel column chromatography, and 15.17 g (9: 9) of the title compound was eluted from n-hexane: ethyl acetate = 2: 1, and then eluted with 1: 2.
8%).

Reference Example 7 (4S)-(1-carbamoyl-2-phenylthioethyl)
) -N-[(1R) -phenylethyl] -2-pyrroli
Don (4S)-(1-tert-butoxycarbonyl-2-phenylthioethyl) -N-[(1R) -phenylethyl]
-2-Pyrrolidone (4.84 g, 11.37 mmol)
Was added to a dichloromethane (5 ml) solution and stirred at room temperature for 30 minutes. The solvent was distilled off, and the residue was dissolved in acetonitrile (80 ml) to give 1,1′-carbonyldiimidazole (2.21).
g, 13.6 mmol) and stirred at 60 ° C. for 20 minutes. After cooling the reaction solution to room temperature, ammonia gas was supplied for 15 minutes and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent, chloroform (100 ml) was added to the residue, washed with water, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography to obtain 1.63 g (39%) of a low-polarity title compound (F1) from a 2.5% methanol-chloroform eluate.
Subsequently, 1.21 g of the title compound (F2) having high polarity (2
9%). At this time, the mixture (F1 and F2) is also 1.
3 g (31%) were obtained. F1; ¹ H-NMR (CDCl ₃ ) δ: 1.47 (3H, d,
J = 7.32 Hz), 2.14 to 2.22 (1H,
m), 2.30-2.40 (1H, m), 2.53-
2.63 (2H, m), 3.07-3.14 (4H,
m), 5.43 (1H, q, J = 7.32 Hz), 5.
54 (1H, brs), 5.68 (1H, brs),
7.22-7.36 (10H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, d,
J = 6.83 Hz), 2.25-2.36 (2H,
m), 2.49-2.60 (2H, m), 2.95-
3.12 (4H, m), 5.44 (1H, q, J = 6.
83Hz), 5.66 (1H, brs), 5.84 (1
H, brs), 7.21-7.36 (10H, m).

Reference Example 8 (4S)-(1-tert-butoxycarbonylamino-2)
-Phenylthioethyl) -N-[(1R) -phenyle
Tyl] -2-pyrrolidone (F1) (4S)-(1-carbamoyl-2-phenylthioethyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (F1; 1.62 g, 4.38 mmol) Tert-butyl alcohol (40 ml) solution was heated to 70 ° C.
Lead tetraacetate (purity 90% or more, 3.24 g) was added, and the mixture was stirred at the same temperature for 20 minutes. After cooling, add sodium bicarbonate (4
g), diluted with ethyl acetate (80 ml) and filtered. The filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (50 ml × 2), and the organic layer was dried over sodium sulfate. The solvent was distilled off to obtain 1.63 g (84%) of the title compound. The same reaction was performed for F2 (85%). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.40 (9H,
s), 1.50 (3H, d, J = 6.84 Hz), 1.
62 (1H, brs), 2.12-2.22 (1H,
m), 2.35-2.50 (1H, m), 2.94-
3.05 (2H, m), 3.08-3.20 (2H,
m), 3.84 (1H, brs), 4.62 (1H, b
rs), 5.46 (1H, q, J = 6.84 Hz),
7.21-7.38 (10H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H,
s), 1.46 (3H, d, J = 6.83 Hz), 2.
28-2.65 (3H, m), 2.90-3.16 (4
H, m), 3.85 (1H, brs), 4.76 (1
H, brs), 5.45 (1H, q, J = 6.83H)
z), 7.19-7.36 (10H, m).

Reference Example 9 (4S)-(1-tert-butoxycarbonylamino-2)
-Fluoro-2-phenylthioethyl) -N-[(1
R) -Phenylethyl] -2-pyrrolidone (F1) (4S)-(1-tert-butoxycarbonylamino-2
-Phenylthioethyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (F1; 1.62 g, 3.68)
m) -chloroperbenzoic acid (purity 70% or more, 793 mg) was added to a dichloromethane (50 ml) solution of (mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate (20
ml × 2), the organic layer was dried over sodium sulfate, and the solvent was distilled off. The residue was dissolved in 1,2-dichloroethane (30 ml), and diethylaminosulfur trifluoride (1.48 g, 9.2 mmol) was added thereto.
Stirred at 0 ° C. for 2.5 hours. The reaction solution was poured into ice-cooled saturated aqueous sodium hydrogen carbonate (30 ml), the organic layer was separated, dried over sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and the title compound was eluted with 503 m of n-hexane: ethyl acetate = 7: 3.
g (30%). The same reaction was performed for F2 (31%). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.40-1.60
(12H, m), 2.31-2.71 (3H, m),
3.03-3.29 (2H, m), 4.18-4.30
(1H, m), 4.75-4.90 (1H, m), 5.
45-5.57 (1H, m), 5.68-5.90 (1
H, m), 7.20-7.56 (10H, m). ^{· F2; 1 H-NMR (} CDCl 3) δ: 1.42-1.66
(12H, m), 2.36-2.81 (3H, m),
3.06-3.20 (2H, m), 4.18-4.35
(1H, m), 4.87-4.96 (1H, m), 5.
44-5.55 (1H, m), 5.61-5.82 (1
H, m), 7.22-7.51 (10H, m).

Reference Example 10 (4S)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) -N-[(1R) -phenylethyl
2-pyrrolidone (F1) (4S)-(1-tert-butoxycarbonylamino-2
-Fluoro-2-phenylthioethyl) -N-[(1
R) -Phenylethyl] -2-pyrrolidone (F1;
73 g, 3.77 mmol) of dichloromethane (50 m
l) Add m-chloroperbenzoic acid (purity of 70% or more,
814 mg), and the mixture was stirred at room temperature for 30 minutes. Then, the same amount of m-chloroperbenzoic acid was added again, and the mixture was further stirred for 64 hours. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate (20 ml × 2), the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was dissolved in a mixed solvent of methanol-tetrahydrofuran (1: 1) (80 ml). To this was added sodium amalgam (sodium: 5%; 6 g) and anhydrous disodium hydrogen phosphate (3.7 g), and after stirring at room temperature for 4 hours, the reaction solution was filtered and the solvent of the filtrate was distilled off. Chloroform (30 ml) was added to the residue, and a saturated saline solution (20 m
l) Then, the mixture was washed with saturated aqueous sodium hydrogen carbonate (20 ml), the organic layer was dried over sodium sulfate, and then the solvent was distilled off to obtain the crude title compound quantitatively (1.32 g). It was used in subsequent reactions without purification. The same reaction was performed for F2.

Reference Example 11 (3R)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) -N-[(1R) -phenylethyl
] Pyrrolidine (F1) (4S)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (F1; 928 mg, 2.65 m)
of a borane-tetrahydrofuran complex was added dropwise to a solution of borane-tetrahydrofuran (8 ml) under ice-cooling, and the mixture was stirred at room temperature for 24 hours. The solvent was distilled off, and a mixed solvent (30 ml) of ethanol-water (4: 1) was added to the residue, and the mixture was heated under reflux for 1 hour in the presence of triethylamine (5 ml). After cooling,
The solvent was distilled off, chloroform (30 ml) was added to the residue, and the mixture was washed with saturated saline (20 ml). The organic layer was dried over sodium sulfate, and then the solvent was distilled off to quantitatively elute the crude title compound (891 mg). ). It was used in subsequent reactions without purification. The same reaction was performed for F2.

Reference Example 12 (3R)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) -N- (benzyloxycarbonyl)
Ru) pyrrolidine (F1) (3R)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) -N-[(1R) -phenylethyl] pyrrolidine (F1; 1.27 g, 3.77 mmol)
Carbobenzyloxychloride (1.29 g, 7.57 mmol) was added to a solution of 1) in dichloromethane (30 ml), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography to obtain 576 mg (42%) of the title compound from an eluate of n-hexane: ethyl acetate = 3: 2. The same reaction was performed for F2 (24%). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H,
s), 1.60-1.75 (1H, m), 1.94-
2.11 (1H, m), 2.38-2.51 (1H,
m), 3.16 (1H, t, J = 10.25 Hz),
3.32-3.44 (1H, m), 3.59-3.88
(2H, m), 4.41 (1H, brs), 4.53
(1H, brs), 4.76-4.83 (1H, m),
5.13 (2H, s), 7.28-7.36 (5H,
m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H,
s), 1.66-1.85 (1H, m), 2.00-
2.11 (1H, m), 2.34-2.50 (1H,
m), 3.05-3.17 (1H, m), 3.30-
3.85 (4H, m), 4.30-4.58 (2H,
m), 4.77-4.86 (1H, m), 5.13 (2
H, s), 7.27-7.37 (5H, m).

Reference Example 13 (3R)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) pyrrolidine (F1) (3R)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) -N- (benzyloxycarbonyl) pyrrolidine (F1; 385 mg, 1.05 mmol)
10% palladium on carbon (400 mg) was added to a solution of 1) in ethanol (20 ml), and the mixture was subjected to catalytic hydrogenation for 1 hour. After removing the catalyst by filtration, the solvent of the liquid was distilled off to obtain the title compound as a crude product quantitatively (244 mg). It was used in subsequent reactions without purification. The same reaction was performed for F2.

Example 1 5-amino-7-[(3R)-(1-amino-2-fur
Oroethyl) -1-pyrrolidinyl] -6-fluoro-1
-[(2S) -fluoro- (1R) -cyclopropyl]
-1,4-dihydro-8-methoxy-4-oxoquinolini
3-Carboxylic acid (F1) 5-amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline To a solution of -3-carboxylic acid (288 mg, 0.88 mmol) in dimethyl sulfoxide (8 ml), (3R)-(1-tert-butoxycarbonylamino-2-fluoroethyl) pyrrolidine (F1; 245 mg, 1.01 mmol) , Triethylamine (1 ml) was added, and the mixture was stirred at 110 ° C. for 15 hours under a nitrogen atmosphere. The solvent was distilled off, chloroform (50 ml) was added to the residue, and 10% citric acid (30 ml ×
After washing in 2) and drying with sodium sulfate, the solvent was distilled off. Concentrated hydrochloric acid (3 ml) was added to the residue, and after stirring at room temperature for 5 minutes, the aqueous layer was washed with chloroform (20 ml × 3), and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (50 ml × 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. Chloroform:
It was developed and separated and purified in a lower layer of methanol: water = 20: 3: 1 to obtain 231 mg (60%) of the crude title compound. This was recrystallized from a mixed solvent of methanol-ethanol-ether to obtain 208 mg as a first crystal. ¹ H-NMR (0.1N-NaOD) δ: 1.10-
1.23 (1H, m), 1.37-1.50 (1H,
m), 1.55-1.71 (1H, m), 1.98-
2.11 (1H, m), 2.15.2.32 (1H,
m), 2.92-3.09 (1H, m), 3.42 (3
H, s), 3.40-3.78 (4H, m), 3.83.
-3.90 (1H, m), 4.32-4.68 (2H,
m), 4.98-5.08 (0.5H, m), 8.19
(1H, s). Elemental _{analysis: C 20 H 23 F 3 N} 4 O 4 · 0.25H 2 O
Calculated: C, 53.99; H, 5.32; N, 12.5
9. Analytical values: C, 54.16; H, 5.57; N, 12.2
1. Melting point: 213-216 ° C

Example 2 5-Amino-7-[(3R)-(1-amino-2-fur
Oroethyl) -1-pyrrolidinyl] -6-fluoro-1
-[(2S) -fluoro- (1R) -cyclopropyl]
-1,4-dihydro-8-methoxy-4-oxoquinolini
3-Carboxylic acid (F2) 5-amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline (3R)-(1-tert-butoxycarbonylamino-2-fluoroethyl) pyrrolidine (F1; 150 mg, 0.65 mmol) was added to a solution of -3-carboxylic acid (177 mg, 0.54 mmol) in dimethyl sulfoxide (8 ml). , Triethylamine (1 ml) was added, and the mixture was stirred at 110 ° C. for 15 hours under a nitrogen atmosphere. The solvent was distilled off, chloroform (50 ml) was added to the residue, and 10% citric acid (30 ml ×
After washing in 2) and drying with sodium sulfate, the solvent was distilled off. Concentrated hydrochloric acid (3 ml) was added to the residue, and after stirring at room temperature for 5 minutes, the aqueous layer was washed with chloroform (20 ml × 3), and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (50 ml × 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. Chloroform:
It was developed and separated and purified in a lower layer of methanol: water = 20: 3: 1 to obtain 118 mg (50%) of the crude title compound. This was recrystallized from a mixed solvent of methanol-ethanol-ether to obtain 90 mg as a first crystal. ¹ H-NMR (0.1N-NaOD) δ: 1.08-
1.21 (1H, m), 1.35-1.50 (1H,
m), 1.60-1.75 (1H, m), 2.10-
2.25 (2H, m), 2.90-3.06 (1H,
m), 3.39 (3H, s), 3.40-3.52 (3
H, m), 3.65-3.77 (1H, m), 3.82
-3.88 (1H, m), 4.25-4.61 (2H,
m), 5.02-5.10 (0.5H, m), 8.19
(1H, s). Elemental _{analysis: C 20 H 23 F 3 N} 4 O 4 · 0.25H 2 O
Calculated: C, 53.99; H, 5.32; N, 12.5
9. Analytical values: C, 54.21; H, 5.29; N, 12.5
5. Melting point: 181-184C

Example 3 5-amino-7-[(3R)-(1-amino-2-fur
Oroethyl) -1-pyrrolidinyl] -6-fluoro-1
-[(2S) -fluoro- (1R) -cyclopropyl]
-1,4-dihydro-8-methyl-4-oxoquinoline
-3-carboxylic acid (F1) 5-amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline- (3R)-(1-tert-butoxycarbonylamino-2-fluoroethyl) pyrrolidine (F1; 370 mg, 1.57 mmol) was added to a solution of 3-carboxylic acid (330 mg, 1.06 mmol) in dimethyl sulfoxide (6 ml). Triethylamine (5 ml) was added, and the mixture was added at 140 ° C. under a nitrogen atmosphere.
Stir for 8 hours. The solvent was distilled off, chloroform (50 ml) was added to the residue, and 10% citric acid (30 ml × 2).
After drying with sodium sulfate, the solvent was distilled off. Concentrated hydrochloric acid (3 ml) was added to the residue, and after stirring at room temperature for 5 minutes, the aqueous layer was washed with chloroform (20 ml × 3), and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (50 ml × 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. Chloroform:
It was developed and separated and purified in a lower layer of methanol: water = 20: 3: 1 to obtain 135 mg (30%) of the crude title compound. This was recrystallized from a mixed solvent of methanol-ethanol-chloroform-ether to obtain 130 m as the first crystal.
g was obtained. ¹ H-NMR (0.1 N-NaOD) δ: 0.95-
1.11 (1H, m), 1.44-1.65 (2H,
m), 1.92-2.28 (2H, m), 2.18 (3
H, s), 2.90-3.05 (1H, m), 3.13.
-3.20 (1H, m), 3.33-3.39 (1H,
m), 3.48-3.58 (1H, m), 3.65-
3.77 (1H, m), 3.86-3.95 (1H,
m), 4.33-4.67 (2H, m), 4.98-
5.09 (0.5H, m), 8.26 (1H, s). Elemental _{analysis: C 20 H 23 F 3 N} 4 O 4 · 0.5H as ₂ O, Calculated: C, 55.42; H, 5.58 ; N, 12.9
3. Analytical values: C, 54.32; H, 5.12; N, 12.3.
9. Melting point: 210-216 ° C

Reference Example 14 (4S)-(1-N-tert-butoxycarbonyl-N '
-Methylamino-2-phenylthioethyl) -N-
[(1R) -phenylethyl] -2-pyrrolidone (F
1) (4S)-(1-tert-butoxycarbonylamino-2)
-Phenylthioethyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (F1; 476 mg, 1.08
mmol) N, N-dimethylformamide (5 ml)
The solution was added with 60% sodium hydride (52 mg,
After adding 1.3 mmol), the mixture was stirred at room temperature for 5 minutes, and iodomethane (921 mg, 6.49 mmol) was added, and the mixture was stirred for 45 minutes. A 10% aqueous citric acid solution (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml × 3). The organic layer was washed with saturated saline (50 ml × 2), dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography. From the eluted portion of n-hexane: ethyl acetate = 2: 3, 402 mg (82%) of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.25 to 1.60
(13H, m), 2.11-2, 28 (1H, m),
2.45-2.74 (4H, m), 2.88-3.17
(5H, m), 4.07-4.18 (1H, m), 5.
40-5.43 (1H, m), 7.19-7.41 (1
0H, m).

Reference Example 15 (4S)-(1-N-tert-butoxycarbonyl-N '
-Methylamino-2-fluoro-2-phenylthioethyl
) -N-[(1R) -phenylethyl] -2-pyrroli
Don (F1) (4S)-(1-N-tert-butoxycarbonyl-N ′
-Methylamino-2-phenylthioethyl) -N-
[(1R) -phenylethyl] -2-pyrrolidone (F
1; 11.76 g, 25.87 mmol) in dichloromethane (50 ml) was added with m-chloroperbenzoic acid (purity 70% or higher, 5.58 g) and stirred at room temperature for 10 minutes. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate (20 ml × 2), the organic layer was dried over sodium sulfate, and the solvent was distilled off.
The residue was dissolved in 1,2-dichloroethane (100 ml), and diethylaminosulfur trifluoride (10.5) was added thereto.
g, 65.14 mmol) and stirred at 60 ° C. for 1.5 hours. Ice-cooled saturated aqueous sodium bicarbonate solution (100 ml)
, The organic layer was separated, dried over sodium sulfate, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography, and n-hexane: ethyl acetate =
6.15 g (50 parts) of the title compound was eluted from the 1: 1 eluate.
%)Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.40-1.65
(12H, m), 2.25-3.13 (8H, m),
4.32-4.48 (1H, m), 5.43-5.58
(1H, m), 5.80-5.84 (0.5H, m),
5.93-5.98 (0.5H, m), 7.23-7.
57 (10H, m).

Reference Example 16 (4S)-(1-N-tert-butoxycarbonyl-N '
-Methylamino-2-fluoroethyl) -N-[(1
R) -Phenylethyl] -2-pyrrolidone (F1) (4S)-(1-N-tert-butoxycarbonyl-N '
-Methylamino-2-fluoro-2-phenylthioethyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (F1; 6.3 g, 13.3 mmol) in dichloromethane (100 ml) solution was m-chloro. Perbenzoic acid (purity 70% or more, 2.89 g) was added, and after stirring at room temperature for 10 minutes, the same amount of m-chloroperbenzoic acid was added again, and the mixture was further stirred for 19 hours. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate (50 ml ×
After washing in 2), the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was dissolved in a mixed solvent (200 ml) of methanol-tetrahydrofuran (1: 1). Sodium amalgam (sodium: 5%; 20g)
And anhydrous disodium hydrogen phosphate (13 g) were added, and the mixture was stirred at room temperature for 23 hours. The reaction solution was filtered, the solvent of the filtrate was distilled off, chloroform (100 ml) was added to the residue, and a saturated saline solution (40 ml) and then a saturated aqueous sodium hydrogen carbonate solution (40 ml) were used.
Washed in l). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and 4.73 g (98%) of the crude title compound was removed.
%)Obtained. It was used in subsequent reactions without purification.

Reference Example 17 (3R)-(1-N-tert-butoxycarbonyl-N '
-Methylamino-2-fluoroethyl) -N-[(1
R) -phenylethyl] pyrrolidine (F1) (4S)-(1-N-tert-butoxycarbonyl-N ′
-Methylamino-2-fluoroethyl) -N-[(1
R) -Phenylethyl] -2-pyrrolidone (F1;
A solution of a borane-tetrahydrofuran complex in 1 mol tetrahydrofuran (40 ml) was added dropwise to a solution of 73 g (12.98 mmol) in tetrahydrofuran (60 ml) under ice cooling, followed by stirring at room temperature for 18 hours. The solvent was distilled off and the residue was mixed with a mixed solvent of ethanol-water (4: 1) (100
ml) in the presence of triethylamine (10 ml).
Heated to reflux for an hour. After cooling, the solvent was distilled off, and chloroform (100 ml) was added to the residue.
1), and the organic layer was dried over sodium sulfate. The solvent was distilled off, and 4.37 g (96%) of the crude title compound was obtained.
Obtained. It was used in subsequent reactions without purification.

Reference Example 18 (3R)-(1-N-tert-butoxycarbonyl-N '
-Methylamino-2-fluoroethyl) -N- (benzyl
Ruoxycarbonyl) pyrrolidine (F1) (3R)-(1-N-tert-butoxycarbonyl-N ′
-Methylamino-2-fluoroethyl) -N-[(1
R) -phenylethyl] pyrrolidine (F1; 4.37
g, 12.47 mmol) in dichloromethane (80 m
l) Add carbobenzyloxy chloride (6.38) to the solution.
g, 37.42 mmol) and stirred at room temperature for 1 hour. The solvent was distilled off, and the residue was subjected to silica gel column chromatography, and n-hexane: ethyl acetate = 2: 1.
2.91 g (61%) of the title compound was obtained from the eluted part. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H,
s), 1.60-1.77 (1H, m), 1.98-
2.12 (1H, m), 2.49-2.73 (1H,
m), 2.84 (3H, s), 3.09-3.20 (1
H, m), 3.36-3.75 (3H, m), 3.94
-4.24 (1H, m), 4.42-4.70 (2H,
m), 5.13 (2H, s), 7.27-7.37 (5
H, m).

Reference Example 19 (3R)-(1-N-tert-butoxycarbonyl-N '
-Methylamino-2-fluoroethyl) pyrrolidine (F
1) (3R)-(1-N-tert-butoxycarbonyl-N '
-Methylamino-2-fluoroethyl) -N- (benzyloxycarbonyl) pyrrolidine (F1; 585 mg,
1.54 mmol) in ethanol (30 ml) solution.
0% palladium carbon (700 mg) was added, and catalytic hydrogenation was performed for 15 hours. After the catalyst was separated by filtration, the solvent in the liquid was distilled off to obtain 370 mg (98%) of the crude title compound.
It was used in subsequent reactions without purification.

Example 4 5-amino-6-fluoro-1-[(2S) -fluoro
-(1R) -cyclopropyl] -7-[(3R)-(2
-Fluoro-1-methylaminoethyl) -1-pyrrolidine
Nil] -1,4-dihydro-8-methyl-4-oxo
Norin-3-carboxylic acid (F1) 5-amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline To a solution of -3-carboxylic acid (444 mg, 1.42 mmol) in dimethyl sulfoxide (6 ml) was added (3R)-(1-N-tert-butoxycarbonyl-N'-methylamino-2-fluoroethyl) pyrrolidine (F1 ; 500 mg, 2.03 mm
ol) and triethylamine (7 ml), and the mixture was stirred at 140 ° C for 24 hours under a nitrogen atmosphere. The solvent was distilled off, chloroform (60 ml) was added to the residue, the mixture was washed with 10% citric acid (40 ml × 2), dried over sodium sulfate, and then the solvent was distilled off. Concentrated hydrochloric acid (3 ml) was added to the residue, and the mixture was stirred at room temperature for 5 minutes.
0 ml x 3), and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. Add concentrated hydrochloric acid and p
H7.2, and the aqueous layer was chloroform (60 ml ×
Extracted in 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. It was developed and separated and purified in the lower layer of chloroform: methanol: water = 20: 3: 1 to obtain 225 of the crude title compound.
mg (36%). This is methanol-ethanol-
Recrystallization from a mixed solvent of chloroform-ether gave 172 mg as the first crystal. ¹ H-NMR (0.1N-NaOD) δ: 0.98-
1.13 (1H, m), 1.32-1.69 (2H,
m), 1.92-2.10 (1H, m), 2.18-
2.38 (1H, m), 2.20 (3H, s), 2.3
5 (3H, s), 2.48-2.72 (1H, m),
3.06-3.23 (1H, m), 3.30-3.41
(1H, m), 3.42-3.56 (1H, m), 3.
62-3.75 (1H, m), 3.81-3.93 (1
H, m), 4.38-4.79 (2H, m), 4.83
-4.92 (0.5H, m), 4.99-5.08
(0.5H, m), 8.26 (1H, s). Elemental analysis: As C ₂₁ H ₂₅ F ₃ N ₄ O ₃ Calculated: C, 57.53; H, 5.75; N, 12.7
8. Found: C, 57.40; H, 5.73; N, 12.5.
8. Melting point: 156-179 ° C

Example 5 6-Fluoro-7-[(3R)-(2-fluoro-1-
Methylaminoethyl) -1-pyrrolidinyl] -1-
[(2S) -fluoro- (1R) -cyclopropyl]-
1,4-dihydro-8-methoxy-4-oxoquinoline
-3-carboxylic acid (F1) 6,7-difluoro-1-[(2S) -fluoro- (1
R) -Cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid.BF ₂ Chelate (432 mg, 1.2 mmol) in dimethyl sulfoxide (5 ml) was treated with (3R)- (1-N-tert-butoxycarbonyl-N'-methylamino-2-fluoroethyl) pyrrolidine (F1; 386 mg, 1.57
mmol) and triethylamine (0.5 ml),
Stirred at room temperature for 64 hours. Triethylamine is distilled off,
After adding water (20 ml) to the residue and stirring for 15 minutes, the precipitated crystals were washed with water and collected by filtration. This was dissolved in a mixed solvent of methanol: water = 4: 1 (150 ml), and heated under reflux for 4 hours in the presence of triethylamine (10 ml). After cooling, the solvent was distilled off and chloroform (60 ml) was added to the residue.
Was added, washed with 10% citric acid (20 ml × 2), dried over sodium sulfate, and the solvent was distilled off. Concentrated hydrochloric acid (5 ml) was added to the residue, and after stirring at room temperature for 5 minutes, the aqueous layer was washed with chloroform (20 ml × 3), and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling.
Concentrated hydrochloric acid was added to adjust the pH to 7.2, the aqueous layer was extracted with chloroform (60 ml × 3), the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. Chloroform: methanol: water = 2
Developed in the lower layer of 0: 3: 1 and separated and purified to obtain 404 mg (77%) of the crude title compound. This was recrystallized from a mixed solvent of methanol-ethanol-chloroform,
250 mg was obtained as the first crystal. ¹ H-NMR (0.1N-NaOD) δ: 1.30-
1.47 (1H, m), 1.48-1.60 (1H,
m), 1.65-1.78 (1H, m), 2.06-
2.18 (1H, m), 2.35-2.48 (1H,
m), 2.38 (3H, s), 2.64-2.79 (1
H, m), 3.47-3.55 (2H, m), 3.54
(3H, s), 3.60-3.76 (2H, m), 3.
95-4.06 (1H, m), 4.48-4.90 (2
H, m), 4.90-4.98 (0.5H, m), 5.
07-5.14 (0.5H, m), 7.64 (1H,
d, J = 14.16 Hz), 8.40 (1H, s). Elemental analysis: As C ₂₁ H ₂₄ F ₃ N ₃ O ₄ Calculated: C, 57.40; H, 5.50; N, 9.5
6. Found: C, 57.37; H, 5.40; N, 9.4.
4. Melting point: 194-197 ° C

Example 6 9-Fluoro-2,3-dihydro-10-[(3R)-
(2-fluoro-1-methylaminoethyl) -1-pyro
Lysinyl]-(3S) -methyl-7-oxo-7H-py
Lido [1,2,3-de] [1,4] benzoxazine
-6-carboxylic acid (F1) 9,10-difluoro-2,3-dihydro- (3S)-
Methyl-7-oxo-7H-pyrido [1,2,3-d
e] [1,4] benzoxazine-6-carboxylic acid B
F ₂ chelate (380 mg, 1.15 mmol) in dimethyl sulfoxide (4 ml) solution of (3R) - (1-N
-Tert-butoxycarbonyl-N'-methylamino-2
-Fluoroethyl) pyrrolidine (F1; 370 mg,
1.5 mmol) and triethylamine (0.3 ml), and the mixture was stirred at room temperature for 60 hours. Triethylamine was distilled off, water (20 ml) was added to the residue, and the mixture was stirred for 15 minutes. The precipitated crystals were washed with water and collected by filtration. This was dissolved in a mixed solvent of methanol: water = 4: 1 (150 ml), and heated under reflux for 5 hours in the presence of triethylamine (10 ml). After cooling, the solvent was distilled off, and chloroform (50 m
1) and wash with 10% citric acid (20 ml × 2)
After drying over sodium sulfate, the solvent was distilled off. Concentrated hydrochloric acid (3 ml) was added to the residue, and after stirring at room temperature for 5 minutes, the aqueous layer was washed with chloroform (30 ml × 3), and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (60 ml × 3) to obtain 367 mg (78%) of the crude title compound. This was recrystallized from a mixed solvent of methanol-ethanol-chloroform to obtain 270 mg as a first crystal. ¹ H-NMR (0.1 N-NaOD) δ: 1.49 (3
H, d, J = 6.83 Hz), 1.59-1.73 (1
H, m), 2.05-2.14 (1H, m), 2.37.
-2.47 (1H, m), 2.38 (3H, s), 2.
62-2.76 (1H, m), 3.38-3.62 (3
H, m), 3.65-3.76 (1H, m), 4.29
(1H, d, J = 9.28 Hz), 4.46 (1H,
d, J = 9.28 Hz), 4.53-4.90 (3H,
m), 7.48 (1H, d, J = 14.16 Hz),
8.33 (1H, s). Elemental _{analysis: C 20 H 23 F 2 N} 3 O 4 · 0.25H 2 O
Calculated: C, 58.32; H, 5.75; N, 10.2
0. Found: C, 58.20; H, 5.63; N, 9.9.
6. Melting point: 218-221 ° C

Reference Example 20 N- (tert-butoxycarbonyl) -O-methyl-L-
Serine N- (tert-butoxycarbonyl) -L-serine (4.
1 g, 20 mmol) was dissolved in N, N-dimethylformamide (20 ml), 60% oily sodium hydride (1.76 g, 44 mmol) was added under ice cooling, and the mixture was stirred for 5 minutes. At the same temperature, methyl iodide (1.36 ml, 22 mm
ol) was added dropwise and stirred at room temperature for 1 hour. After the reaction,
A 10% aqueous citric acid solution was added, and ethyl acetate (100 ml
× 4), the combined organic layer was dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography, and the title compound was quantitatively obtained from the eluted portion of 10% methanol / chloroform. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H,
s), 3.38 (3H, s), 3.62 (1H, dd,
J = 3.9, 9.2 Hz), 3.84-3.87 (1
H, m), 4.43-4.45 (1H, m), 5.36
-5.38 (1H, m).

Reference Example 21 N- (tert-butoxycarbonyl) -O-methyl-L-
Serine N-methoxy-N-methylamide N- (tert-butoxycarbonyl) -O-methyl-L-
Serine (4.94 g, 22.5 mmol) was dissolved in N, N-dimethylformamide (80 ml), and 98% N,
O-dimethylhydroxylamine hydrochloride (2.42 g,
24.3 mmol), then diphenylphosphate azide (6.82 g, 24.8 mmol) was added under ice-cooling, and triethylamine (6.9 ml, 4
9.5 mmol) of N, N-dimethylformamide (1
0 ml) solution was added dropwise. After stirring at room temperature overnight, ethyl acetate / toluene (4 / 1,500 ml) was added to the reaction solution, a 10% aqueous citric acid solution (100 ml × 2), a saturated aqueous sodium hydrogen carbonate solution (100 ml × 2), and a saturated saline solution. Washing was performed in the order of (100 ml × 2). After drying over sodium sulfate, the solvent was distilled off, and the title compound (5.31 g) was obtained.
(90%). ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H,
s), 3.23 (3H, s), 3.34 (3H, s),
3.54-3.58 (1H, m), 3.63-3.66
(1H, m), 3.77 (3H, s), 4.84 (1
H, brs), 5.41 (1H, brs).

Reference Example 22 N- (tert-butoxycarbonyl) -O-methyl-L-
Seinal N- (tert-butoxycarbonyl) -O-methyl-L-
Serine N-methoxy-N-methylamide (5.95
g, 22.7 mmol) in diethyl ether (200 m
l), lithium aluminum hydride (1.07 g, 28.4 mmol) was added little by little under ice-cooling, and the mixture was stirred at room temperature for 20 minutes. Potassium hydrogen sulfate (5.40
g, 39.70 mmol) (100 ml) was added dropwise in this order under ice cooling, and diethyl ether (200 ml ×
Extracted in 2). The combined organic layer was washed with 1N hydrochloric acid (100
ml), saturated aqueous sodium hydrogen carbonate solution (100 m
1) and then washed with saturated saline (100 ml) in that order. After drying over sodium sulfate, the solvent was distilled off to obtain 4.00 g (87%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H,
s), 3.34 (3H, s), 3.60-3.64 (1
H, m), 3.90-3.92 (1H, m), 4.27
-4.32 (1H, m), 5.37-5.41 (1H,
m).

Reference Example 23 Ethyl 3-[(1S) -tert-butoxycarbonyla
Mino-2-methoxyethyl] acrylate N- (tert-butoxycarbonyl) -O-methyl-L-
Serinal (1.77 g, 8.7 mmol) was dissolved in tetrahydrofuran (100 ml) and 95% (carbethoxymethylene) triphenylphosphorane (3.64).
g, 9.9 mmol), and the mixture was stirred under reflux with heating for 16 hours. After evaporating the solvent, the obtained residue was subjected to silica gel chromatography, and ethyl acetate: hexane = 1: 1.
2.16 g (91%) of the title compound was obtained from the eluate of 2. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t,
J = 7.3 Hz), 1.45 (9H, s), 3.35
(3H, s), 3.49-3.50 (2H, m), 4.
19 (1H, q, J = 7.3 Hz), 4.46 (1H,
brs), 4.99 (1H, brs), 5.97 (1
H, dd, J = 1.5, 15.6 Hz).

Reference Example 24 Ethyl 3-[(1S) -tert-butoxycarbonyla
Mino-2-methoxyethyl] -4-nitrobutanoateethyl 3-[(1S) -tert-butoxycarbonylamino-2-methoxyethyl] acrylate (4.04
g, 14.8 mmol) with nitromethane (4 ml, 7
3.9 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2.21 m) at room temperature.
1,14.8 mmol) and stirred at the same temperature for 5 hours. A 10% aqueous citric acid solution was added to the reaction solution, extracted with methylene chloride, dried over sodium sulfate, and then the solvent was distilled off to obtain 4.99 g (97%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t,
J = 6.8 Hz), 1.44 (9H, s), 2.42
(1H, dd, J = 6.4, 17.1 Hz), 2.58
(1H, dd, J = 6.3, 17.1 Hz), 2.94
-2.97 (1H, m), 3.32 (3H, s), 3.
41-3.49 (1H, m), 3.52-3.56 (1
H, m), 3.83-3.94 (1H, m), 4.15
(1H, q, J = 7.3 Hz), 4.47 (1H, d
d, J = 7.3, 13.7 Hz), 4.63-4.67
(1H, m), 4.93-4.94 (1H, m).

Reference Example 25 4-[(1S) -tert-butoxycarbonylamino-2
-Methoxyethyl] -2-pyrrolidoneethyl 3-[(1S) -tert-butoxycarbonylamino-2-methoxyethyl] -4-nitrobutanoate (4.99 g, 14.3 mmol) in ethanol (15
0 ml) and Raney nickel (R-100; 10
ml; washed with ethanol) and subjected to catalytic hydrogenation at room temperature for 2 days. After the catalyst was filtered off and the solvent was distilled off, toluene (100 ml) was added to the residue, and the mixture was heated under reflux for 1 hour. The solvent was distilled off and 3.67 g of the title compound (99
%). ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H,
s), 2.12-2.38 (2H, m), 2.72-
2.78 (1H, m), 3.17-3.48 (7H,
m), 3.75-3.88 (1H, m), 4.97 (1
H, brs), 5.96 (1H, brs).

Reference Example 26 1-benzyl-4-[(1S) -tert-butoxycarbo
Nylamino-2-methoxyethyl] -2-pyrrolidone 4-[(1S) -tert-butoxycarbonylamino-2
-Methoxyethyl] -2-pyrrolidone (737 mg,
2.9 mmol) with N, N-dimethylformamide (1
0 ml), 60% oily sodium hydride (137 mg, 3.4 mmol) was added under ice cooling, and the mixture was stirred for 10 minutes. At the same temperature, benzyl chloride (394 μl, 3.4 mm
ol) was added dropwise and stirred at room temperature for 24 hours. Then, further under ice-cooling, 60% sodium hydride (oil-based; 137 m
g, 3.4 mmol) and stirred for 10 minutes. At the same temperature, benzyl chloride (394 μl, 3.4 mmol) was added dropwise, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, methanol was added to the reaction solution to distill off the solvent, water was added to the residue, the mixture was extracted with ethyl acetate, the combined organic layer was dried over sodium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel chromatography, and 652 mg (65%) of the title compound was obtained from a fraction eluted with ethyl acetate. Furthermore, this product was separated and purified by HPLC under the following conditions,
Optical isomer F1 derived from the asymmetric carbon at the 4-position of the pyrrolidine ring
213 mg (21%), and 30% of optical isomer F2
8 mg (31%) were obtained. -HPLC condition column; YMC D-Silica 7-06 S-7
60A; 20 × 250 mm Moving layer: ethyl acetate Flow rate: 20 ml / min Temperature: room temperature Detection: UV (254 nm) The retention time of each optical isomer is shown below. Isomer F1: 8 min Isomer F2: 10 minF1; ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H,
s), 2.37-2.64 (3H, m), 3.03-
3.06 (1H, m), 3.23-3.34 (6H,
m), 3.72-3.74 (1H, m), 4.43 (2
H, AB-q, J = 14.8 Hz), 4.84-4.8.
7 (1H, m), 7.20-7.37 (5H, m). [Α] _D = 5.08 (c = 0.905, chloroform) F2; ¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H,
s), 2.28-2.63 (3H, m), 3.12-
3.16 (1H, m), 3.24-3.37 (6H,
m), 3.67-3.74 (1H, m), 4.43 (2
H, AB-q, J = 14.7 Hz), 4.83 (1H,
d, J = 1.4 Hz), 7.27-7.35 (5H,
m). [Α] _D = −5.61 (c = 0.605, chloroform)

Reference Example 27 4-[(1S) -amino-2-methoxyethyl] -1-
Benzyl-2-pyrrolidone (F1) 1-benzyl-4-[(1S) -tert-butoxycarbonylamino-2-methoxyethyl] -2-pyrrolidone (721 mg, 2.1 mmol) was treated with methylene chloride (5 m).
l), trifluoroacetic acid (7 ml) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The solvent was distilled off, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The combined organic layer was dried over sodium sulfate, and the solvent was distilled off to quantitatively obtain the title compound. The same reaction was performed for F2 (88%). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.42 (2H, br)
s), 2.34-2.40 (2H, m), 2.50-
2.58 (1H, m), 2.86-2.90 (1H,
m), 3.05-3.13 (2H, m), 3.25-
3.30 (5H, m), 4.44 (2H, AB-q, J
= 14.7 Hz), 7.22-7.35 (5H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.34 (2H, br)
s), 2.26-2.35 (2H, m), 2.46-
2.50 (1H, m), 2.80-2.84 (1H,
m), 3.13-3.18 (2H, m), 3.31-
3.36 (5H, m), 4.44 (2H, AB-q, J
= 14.6 Hz), 7.22-7.32 (5H, m).

Reference Example 28 4-[(1S) -amino-2-methoxyethyl] -1-
Benzyl-2-pyrrolidine (F1) 4-[(1S) -amino-2-methoxyethyl] -1-
Benzyl-2-pyrrolidone (F1; 571 mg; 2.3
mmol) was dissolved in tetrahydrofuran (20 ml), and lithium aluminum hydride (436 m
g, 11.5 mmol) was added little by little, and the mixture was heated under reflux for 4 hours. After the reaction was completed, the mixture was cooled on ice, and water (436 μl), 15
% Aqueous sodium hydroxide solution (436 μl), water (436
μl) was added dropwise in this order, and the mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, the solvent was distilled off, and 404 mg of the title compound was obtained.
(75%). The same reaction was carried out for F2 (92%). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.45 (2H, br)
s), 1.63-1.71 (1H, m), 1.94-
2.00 (1H, m), 2.09-2.27 (2H,
m), 2.44-2.50 (1H, m), 2.63-
2.70 (2H, m), 2.83-2.88 (1H,
m), 3.07-3.12 (1H, m), 3.30-
3.35 (5H, m), 3.58 (2H, AB-q, J
= 12.7 Hz), 7.23-7.31 (5H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.56
(3H, m), 1.86-1.95 (1H, m), 2.
08-2.16 (1H, m), 2.27-1.33 (1
H, m), 2.43-2.49 (1H, m), 2.64
-2.70 (1H, m), 2.77-2.85 (2H,
m), 3.10-3.14 (1H, m), 3.34 (3
H, s), 3.39-3.42 (1H, m), 3.60.
(2H, s), 7.22-7.31 (5H, m).

Reference Example 29 4-[(1S) -amino-2-methoxyethyl] -2-
Pyrrolidine (F1) 4-[(1S) -amino-2-methoxyethyl] -1-
404 mg (1.7) of benzyl-2-pyrrolidine (F1)
2 mmol) was dissolved in 20 ml of ethanol, 400 mg of 10% palladium carbon was added, and the mixture was stirred for 5 hours while heating the reaction solution by irradiating the reaction vessel with an infrared lamp under hydrogen pressure (4.5 atm). After the catalyst was removed by filtration, the solvent was distilled off to obtain 218 mg (88%) of the title compound as a crude product.
It was used in subsequent reactions without purification. The same reaction was performed for F2 (95%).

Example 7 (+)-5-Amino-7- [3-[(1S) -amino-
2-methoxyethyl] pyrrolidin-1-yl] -6,8
-Difluoro-1-[(2S) -fluoro- (1R)-
Cyclopropyl] -1,4-dihydro-4-oxoquino
Phosphorus-3-carboxylic acid (F1) 5-amino-6,7,8-trifluoro-1-[(2
S) -Fluoro- (1R) -cyclopropyl] -1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid (2
19 mg, 0.69 mmol) of acetonitrile (10
ml) solution, 4-[(1S) -amino-2-methoxyethyl] -2-pyrrolidine (F1; 129 mg, 0.9
mmol) and triethylamine (1.45 ml), and the mixture was heated under reflux for 16 hours. The solvent is distilled off and the residue
Normal hydrochloric acid was added, the mixture was washed with chloroform, and then made alkaline with a 50% aqueous sodium hydroxide solution under ice cooling.
The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (100 ml × 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. Chloroform: methanol: water =
It was developed and separated and purified in the lower layer of 7: 3: 1, and this was recrystallized from aqueous ammonia-ethanol to give the title compound 137
mg (45%). ¹ H-NMR (0.1 N-NaOD) δ: 1.43-
1.59 (3H, m), 1.82-1.93 (1H,
m), 2.02-2.11 (1H, m), 2.73-
2.81 (1H, m), 3.15-3.68 (10H,
m), 4.78-4.82 (0.5H, m), 4.99
-5.08 (0.5H, m), 8.23 (1H, s). Elemental _{analysis: C 20 H 23 F 3 N} 4 O 4 · 0.25H 2 O
Calculated: C, 53.99; H, 5.32; N, 12.5
9. Found: C, 54.04; H, 5.46; N, 12.3.
0. Melting point: 189-190 ° C [α] _D = 227.46 (c = 0.568, 1N aqueous sodium hydroxide solution)

Example 8 (-)-5-amino-7- [3-[(1S) -amino-
2-methoxyethyl] pyrrolidin-1-yl] -6,8
-Difluoro-1-[(2S) -fluoro- (1R)-
Cyclopropyl] -1,4-dihydro-4-oxoquino
Phosphorus-3-carboxylic acid (F2) 5-amino-6,7,8-trifluoro-1-[(2
S) -Fluoro- (1R) -cyclopropyl] -1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid (2
00 mg, 0.63 mmol) of acetonitrile (10
ml) solution, 4-[(1S) -amino-2-methoxyethyl] -2-pyrrolidine (F2) 118 mg (0.82
mmol) and 1.33 ml of triethylamine.
The mixture was refluxed for 6 hours. The solvent was distilled off, 1N hydrochloric acid was added to the residue, and the mixture was washed with chloroform and then cooled under ice-cooling.
Basified with a 1% aqueous sodium hydroxide solution. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was subjected to chloroform (1).
00 ml × 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off.
Attached to LC. Chloroform: methanol: water = 7:
It was developed and separated and purified in the lower layer of 3: 1, and this was recrystallized from aqueous ammonia-ethanol to give 200 mg of the title compound.
(72%). ¹ H-NMR (0.1 N-NaOD) δ: 1.44-
1.60 (3H, m), 1.93-2.05 (2H,
m), 2.80-2.83 (1H, m), 3.32-
3.69 (10H, m), 4.85-4.94 (0.5
H, m), 8.23 (1H, s). Elemental _{analysis: C 20 H 23 F 3 N} 4 O 4 · 0.5H as ₂ O, Calculated: C, 53.45; H, 5.38 ; N, 12.4
7. Found: C, 53.58; H, 5.25; N, 12.2.
8. Melting point: 152-153 ° C. [α] _D = −165.56 (c = 0.877, 1N aqueous sodium hydroxide solution)

Example 9 (+)-7- [3-[(1S) -amino-2-methoxy]
Ethyl) pyrrolidin-1-yl] -6-fluoro-1-
[(2S) -fluoro- (1R) -cyclopropyl]-
1,4-dihydro-8-methoxy-4-oxoquinoline
-3-carboxylic acid (F1) 6,7-difluoro-1-[(2S) -fluoro- (1
R) -Cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid.BF ₂ Chelate (214 mg, 0.60 mmol) in dimethyl sulfoxide (2 ml) was treated with 4-[( 1S) -Amino-2-methoxyethyl] -2-pyrrolidine (F1; 11
1 mg, 0.77 mmol), triethylamine (1.
25 ml) and stirred at room temperature for 4 hours. The solvent was distilled off, and the mixture was heated under reflux with 80% aqueous methanol overnight. The solvent was distilled off, 1N hydrochloric acid was added to the residue, the mixture was washed with chloroform, and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (100 ml × 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. Chloroform:
It was developed and separated and purified in a lower layer of methanol: water = 7: 3: 1, and recrystallized from aqueous ammonia-ethanol to obtain 110 mg (42%) of the title compound. ¹ H-NMR (0.1N-NaOD) δ: 1.60-
1.75 (3H, m), 2.16-2.24 (2H,
m), 2.96-3.01 (1H, m), 3.34-
3.59 (11H, m), 3.82-3.84 (1H,
m), 4.08-4.11 (1H, m), 5.00-
5.02 (0.5H, m), 7.68 (1H, d, J =
14.6 Hz), 8.51 (1H, s). Elemental analysis: As C ₂₁ H ₂₅ F ₂ N ₃ O ₅ .0.5H ₂ O, Calculated: C, 56.50; H, 5.87; N, 9.4
1. Found: C, 56.40; H, 5.82; N, 9.1.
6. Melting point: 88-89 ° C [α] _D = 146.69 (c = 0.424, 1N aqueous sodium hydroxide solution)

Example 10 (-)-7- [3-[(1S) -amino-2-methoxy]
Ethyl) pyrrolidin-1-yl] -6-fluoro-1-
[(2S) -fluoro- (1R) -cyclopropyl]-
1,4-dihydro-8-methoxy-4-oxoquinoline
-3-carboxylic acid (F2) 6,7-difluoro-1-[(2S) -fluoro- (1
R) -Cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid.BF ₂ Chelate (193 mg, 0.54 mmol) in dimethyl sulfoxide (2 ml) was treated with 4-[( 1S) -Amino-2-methoxyethyl] -2-pyrrolidine (F2; 10
0 mg, 0.70 mmol), triethylamine (1.
12 ml) and stirred at room temperature for 4 hours. The solvent was distilled off, and the residue was dissolved by adding 80% aqueous methanol and heated under reflux overnight. The solvent was distilled off, 1N hydrochloric acid was added to the residue, the mixture was washed with chloroform, and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. Concentrated hydrochloric acid was added to adjust the pH to 7.2.
ml × 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was purified by preparative TLC.
Attached. Chloroform: methanol: water = 7: 3: 1
Was developed and separated and purified in the lower layer, and recrystallized from aqueous ammonia-ethanol to obtain 30 mg of the title compound (13 mg).
%). ¹ H-NMR (0.1 N-NaOD) δ: 1.37-
1.45 (1H, m), 1.52-1.62 (1H,
m), 1.69-1.74 (1H, m), 2.01-
2.11 (1H, m), 2.21-2.32 (1H,
m), 2.97-3.01 (1H, m), 3.40-
3.44 (4H, m), 3.55-3.84 (12H,
m), 4.01-4.06 (1H, m), 4.91-
4.97 (0.5H, m), 5.10-5.14 (0.
5H, m), 7.68 (1H, d, J = 14.2H)
z), 8.42 (1H, s). Elemental _{analysis: C 21 H 25 F 2 N} 3 O 5 · 1.0H as ₂ O, Calculated: C, 55.38; H, 5.97 ; N, 9.2
3. Found: C, 55.51; H, 5.78; N, 9.0.
9. Melting point: 108-109 ° C. [α] _D = −88.05 (c = 0.159, 1N aqueous sodium hydroxide solution)

Reference Example 30 4-[(1S) -tert-butoxycarbonylamino-2
-Methoxyethyl] -1-benzyl-2-pyrrolidine
(F2) 4-[(1S) -amino-2-methoxyethyl] -1-
Benzyl-2-pyrrolidone (F2; 1.33 g, 5.3
6 mmol) was dissolved in tetrahydrofuran (70 ml), and lithium aluminum hydride (813 m
g, 21.4 mmol) was added little by little, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the mixture was cooled on ice, and water (813 μl), 15
% Aqueous sodium hydroxide solution (813 μl), water (813
μl) was added dropwise in this order, and the mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble matter, acetonitrile (50 ml) was added, and then di-tert-butyl dicarbonate (1.85 ml, 8.05 m) was added.
mol), and the mixture was stirred at room temperature overnight. Evaporate the solvent,
The obtained residue was subjected to silica gel chromatography, and 1.53 g (89%) of the title compound was obtained from a 5% methanol-chloroform eluate. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H,
s), 1.56-1.67 (2H, m), 1.94-
2.03 (1H, m), 2.30-2.72 (4H,
m), 3.24-3.66 (8H, m), 5.73-
5.78 (1H, m), 7.22-7.31 (5H,
m).

Reference Example 31 4-[(1S) -tert-butoxycarbonylamino-2
-Methoxyethyl] -2-pyrrolidine (F2) 4-[(1S) -tert-butoxycarbonylamino-2
-Methoxyethyl] -1-benzyl-2-pyrrolidine (F2; 1.53 g, 4.79 mmol) was dissolved in ethanol (70 ml), and 10% palladium on carbon (1.5
g) was added and the mixture was stirred overnight under hydrogen pressure (8 atm). After the catalyst was separated by filtration, the solvent was distilled off to obtain a crude title compound quantitatively. It was used in subsequent reactions without purification.

Example 11 5-Amino-7- [3-[(1S) -amino-2-methoate]
Xylethyl] -1-pyrrolidinyl] -6-fluoro-1
-[(2S) -fluoro- (1R) -cyclopropyl]
-1,4-dihydro-8-methyl-4-oxoquinoline
-3-carboxylic acid (F2) 5-amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline- To a solution of 3-carboxylic acid (747 mg, 2.40 mmol) in dimethyl sulfoxide (6 ml) was added 4-[(1S) -tert-butoxycarbonylamino-2-methoxyethyl] -2-pyrrolidine (F2; 1.01 g, 4.79 mmol) and triethylamine (9 ml) were added under a nitrogen atmosphere.
Stirred at C for 2 days. The solvent was distilled off, 10% citric acid was added to the residue, the precipitate was filtered, and concentrated hydrochloric acid (3 m
After 1) was added and the mixture was stirred at room temperature for 5 minutes, the aqueous layer was washed with chloroform (20 ml × 3), and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was subjected to chloroform (200
ml × 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was purified by preparative TLC.
Attached. Chloroform: methanol: water = 7: 3: 1
The residue was recrystallized from a mixed solvent of methanol-ethanol-chloroform-ether to obtain 484 mg (46%) of the title compound. ¹ H-NMR (0.1 N-NaOD) δ: 1.04-
1.18 (1H, m), 1.47-1.60 (2H,
m), 1.96-2.05 (1H, m), 2.12
2.25 (4H, m), 2.87-2.93 (1H,
m), 3.18-3.93 (10H, m), 8.26
(1H, s). Elemental analysis: As C ₂₁ H ₂₆ F ₂ N ₄ O ₄ .0.5H ₂ O, Calculated: C, 56.62; H, 6.11; N, 12.5
8. Found: C, 56.72; H, 6.08; N, 12.4.
2. Melting point: 181-184C

[Reference Example 32] (4S) -ethoxycarbonylmethyl-N-[(1R)
-Phenylethyl ] -2-pyrrolidone (4S) -carboxylmethyl-N-[(1R) -phenylethyl] -2-pyrrolidone (5.34 g, 21.6)
After adding p-toluenesulfonic acid monohydrate (6.00 g) to a solution of 2 mmol) in ethanol (200 ml),
The mixture was heated under reflux for 2.5 hours. The solvent was distilled off, chloroform was added to the residue, and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline in this order, dried over sodium sulfate, and then evaporated to remove the solvent to give 5.75 g of the title compound (97% ) Got. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t,
J = 7.32 Hz), 1.54 (3H, d, J = 7.3)
3Hz), 2.13-2.25 (1H, m), 2.37
−2.53 (2H, m), 2.60-2.71 (2H,
m), 2.98-3.06 (1H, m), 3.17-
3.25 (1H, m), 4.11 (2H, q, J = 7.
32Hz), 5.52 (1H, q, J = 7.33H)
z), 7.25-7.38 (5H, m).

[Reference Example 33] (4S)-(1-ethoxycarbonyl-3-fluoropropyl)
Ropyl) -N-[(1R) -phenylethyl] -2-pi
Lolidone (4S) -ethoxycarbonylmethyl-N-[(1R)
-Phenylethyl] -2-pyrrolidone (3.82 g, 1
To a solution of 3.9 mmol) in tetrahydrofuran (30 ml) was added tris (dimethylamino) phosphine (5 ml), and a solution of 1 mol of lithium (bistrimethylsilyl) amide in tetrahydrofuran (16.65 ml) was added at -78 ° C under a nitrogen atmosphere. After dropwise addition and stirring at the same temperature for 30 minutes, 1-bromo-3-fluoroethane (5.17) was added.
ml, 69.4 mmol) of tetrahydrofuran (5 m
l) The solution was added and stirred at room temperature for 20 minutes. After completion of the reaction, a 10% aqueous citric acid solution was added, and tetrahydrofuran was distilled off, followed by extraction with chloroform (100 ml × 4).
After the combined organic layers were dried over sodium sulfate, the solvent was distilled off. The obtained residue was subjected to silica gel chromatography, and the title compound was obtained from the eluted portion of ethyl acetate: hexane = 2: 1. Further, this product was separated and purified by HPLC under the following conditions, and the optical isomer F1 derived from the asymmetric carbon at the α-position of the ethoxycarbonyl group was converted into 810.
mg (18%), and 481 mg of optical isomer F2
(11%). -HPLC condition column; YMC D-Silica 7-06 S-7
60A; 20 × 250 mm Moving layer; ethyl acetate: hexane = 2: 1 Flow rate: 15 ml / min Temperature: room temperature Detection: UV (254 nm) ・ The retention time of each optical isomer is shown below. Isomer (F1): 8 min Isomer (F2): 10 min

F1; ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t,
J = 6.8 Hz), 1.51 (3H, d, J = 7.4H)
z), 1.72-2.05 (2H, m), 2.30-
2.38 (1H, m), 2.46-2.57 (3H,
m), 3.05-3.10 (2H, m), 4.17 (2
H, q, J = 7.3 Hz), 4.43-4.54 (2
H, m), 5.49 (1H, q, J = 6.8 Hz),
7.20-7.36 (5H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t,
J = 6.8 Hz), 1.50 (3H, d, J = 7.3H)
z), 1.84-2.06 (2H, m), 2.24-
2.30 (1H, m), 2.46-2.61 (3H,
m), 3.04-3.15 (2H, m), 4.14 (2
H, q, J = 7.4 Hz), 4.32-4.58 (2
H, m), 5.47 (1H, q, J = 6.8 Hz),
7.26-7.35 (5H, m).

Reference Example 34 (4S)-(1-carboxy-3-fluoropropyl)
-N-[(1R) -phenylethyl] -2-pyrrolidone
(F1) 1N water was added to a solution of (4S)-(1-ethoxycarbonyl-3-fluoropropyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (810 mg, 2.52 mmol) in ethanol (6 ml). Sodium oxide (6 ml)
Was added and stirred at room temperature overnight. After completion of the reaction, a 10% aqueous citric acid solution was added, extracted with chloroform (100 ml × 2), the combined organic layer was dried over sodium sulfate, and the solvent was distilled off to obtain the title compound quantitatively. F2
Was also reacted (90%). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.53 (3H, d,
J = 6.8 Hz), 1.75-2.08 (2H, m),
2.37-2.64 (4H, m), 3.10-3.19
(2H, m), 4.37-4.58 (2H, m), 5.
49 (1H, q, J = 6.8 Hz), 7.26-7.3
7 (5H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, d,
J = 6.8 Hz), 1.84-2.10 (2H, m),
2.32-2.38 (1H, m), 2.48-2.68
(3H, m), 3.11-3.21 (2H, m), 4.
38-4.62 (2H, m), 4.58 (1H, q, J
= 4.9 Hz), 7.26-7.35 (5H, m).

Reference Example 35 (4S)-(1-tert-butoxycarbonyl-3-pro
Phenyl) -N-[(1R) -phenylethyl] -2-pi
Lorydone (4S) -tert -butoxycarbonylmethyl-N-
[(1R) -phenylethyl] -2-pyrrolidone (5.
17 g, 17.04 mmol) in a tetrahydrofuran (50 ml) solution at −78 ° C. under a nitrogen atmosphere was added dropwise a 1 mol solution of lithium (bistrimethylsilyl) amide in tetrahydrofuran (20.45 ml), and the mixture was stirred at the same temperature for 15 minutes. After that, allyl bromide (7.37 m
1,85.2 mmol) in tetrahydrofuran (10 m
l) The solution was added and stirred at room temperature for 1 hour. After the reaction,
A 10% aqueous citric acid solution was added, tetrahydrofuran was distilled off, and the mixture was extracted with ethyl acetate (200 ml × 3). The combined organic layer was dried over sodium sulfate, and the solvent was distilled off.
The obtained residue was subjected to silica gel chromatography, and 3.30 g (56%) of the title compound was obtained from an eluate of ethyl acetate: hexane = 2: 3. ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H,
s), 1.48-1.52 (3H, m), 2.14
2.65 (6H, m), 2.93-3.24 (2H,
m), 5.00-5.05 (2H, m), 5.46-
5.49 (1H, m), 5.63-5.71 (1H,
m), 7.26-7.36 (5H, m).

[Reference Example 36] (4S)-(1-tert-butoxycarbonyl-3-hydrido)
Roxypropyl) -N-[(1R) -phenylethyl]
2-Pyrrolidone (4S)-(1-tert-butoxycarbonyl-3-propenyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (3.30 g, 9.61 mmol) in methylene chloride (100 ml) ) The ozone-oxygen mixed gas is added to the solution,
At −78 ° C., the reaction was introduced until it became blue (30 minutes) and at room temperature nitrogen was introduced until the reaction became clear.
Thereafter, dimethyl sulfide (7 ml) was added, and the solvent was distilled off. Then, ethanol (100 ml) was added, and sodium borohydride (727 mg, 19.2) was added under ice cooling.
mmol) and stirred overnight at room temperature. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added, ethanol was distilled off, and then extracted with chloroform (100 ml × 4).
After the combined organic layers were dried over sodium sulfate, the solvent was distilled off. The obtained residue was subjected to silica gel chromatography, and 2.80 g (84%) of the title compound was obtained from a 5% methanol-chloroform eluate. ¹ H-NMR (CDCl ₃ ) δ: 1.41-1.87
(13H, m), 2.25-2.55 (3H, m),
3.06-3.09 (2H, m), 3.63-3.65
(2H, m), 5.46-5.50 (1H, m), 7.
26-7.34 (5H, m).

Reference Example 37 (4S)-(1-tert-butoxycarbonyl-3-fur)
(Oropropyl) -N-[(1R) -phenylethyl]-
2-pyrrolidone (4S)-(1-tert-butoxycarbonyl-3-hydroxypropyl) -N-[(1R) -phenylethyl]
To a solution of -2-pyrrolidone (2.80 g, 8.06 mmol) in methylene chloride (100 ml) was added triethylamine (4.48 ml, 32.1 mmol), and the mixture was cooled with ice.
Methanesulfonyl chloride (1.25 ml, 16.1 m
mol) was added dropwise and stirred at the same temperature for 30 minutes. After completion of the reaction, a 10% aqueous citric acid solution was added, and methylene chloride (10%) was added.
0 ml × 3), and the combined organic layer was dried over sodium sulfate. The obtained residue was dissolved in tetrahydrofuran (60 ml), a 1 mol solution of tetrabutylammonium fluoride in tetrahydrofuran (40 ml) was added, and the mixture was heated under reflux for 1 hour. After the solvent was distilled off, a 10% aqueous citric acid solution was added, and the mixture was extracted with methylene chloride (100 ml × 3). The combined organic layer was dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel chromatography, and the title compound was obtained from the eluted portion of ethyl acetate: hexane = 2: 1. Further, this product was separated and purified by HPLC under the following conditions, and 900 mg (32%) of the optical isomer F1 and 370 mg (13%) of the optical isomer F2 derived from the asymmetric carbon at the α-position of the ethoxycarbonyl group. %)Obtained.・ HPLC conditions Column: YMC D-Silica 7-06 S-7
60A; 20 × 250 mm Moving layer; ethyl acetate: hexane = 1: 1 flow rate: 15 ml / min temperature: room temperature detection: UV (254 nm) ・ The retention time of each optical isomer is shown below. Isomer (F1): 10 min Isomer (F2): 18 min F1; ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H,
s), 1.51 (3H, d, J = 7.3 Hz), 1.7
0-1.99 (2H, m), 2.33-2.55 (4
H, m), 3.03-3.12 (2H, m), 4.29
-4.55 (2H, m), 5.49 (1H, q, J =
7.3 Hz), 7.26-7.36 (5H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.41 (9H,
s), 1.51 (3H, d, J = 6.8 Hz), 1.8
2-2.04 (2H, m), 2.23-2.29 (1
H, m), 2.44-2.59 (3H, m), 3.04.
-3.08 (1H, m), 3.13-3.16 (1H,
m), 4.35-4.57 (2H, m), 5.47 (1
H, q, J = 7.3 Hz), 7.26-7.35 (5
H, m).

Reference Example 38 (4S)-(1-carboxy-3-fluoropropyl)
-N-[(1R) -phenylethyl] -2-pyrrolidone
(F1, F2) (4S)-(1-tert-butoxycarbonyl-3-fluoropropyl) -N-[(1R) -phenylethyl]-
2-pyrrolidone (F1; 790 mg, 2.26 mmol
To a solution of 1) in methylene chloride (10 ml) was added trifluoroacetic acid (10 ml) at room temperature, and the mixture was stirred overnight. The solvent was distilled off, and the residue was azeotropically distilled with toluene (50 ml × 3) to quantitatively obtain the title compound. The same reaction was performed for F2 (quantitative). The ¹ H-NMR spectra of F1 and F2 were obtained by analyzing the products (F1 and F2) described in Reference Example 34.
2).

[Reference Example 39] (4S)-(1-carbamoyl-3-fluoropropyl)
) -N-[(1R) -phenylethyl] -2-pyrroli
Don (F1) (4S)-(1-carboxy-3-fluoropropyl)
-N-[(1R) -Phenylethyl] -2-pyrrolidone (F1; 739 mg, 2.52 mmol) was dissolved in acetonitrile (30 ml) and 1,1′-carbonyldiimidazole (531 mg, 3.3 mmol) was dissolved at room temperature. Was added and stirred for 2 hours. Thereafter, ammonia gas was supplied for 15 minutes, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent, chloroform (100 ml) was added to the residue, washed with water, dried over sodium sulfate, and then the solvent was distilled off.
4 mg (87%) were obtained. The same reaction was performed for F2 (quantitative). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.52 (3H, d,
J = 6.8 Hz), 1.81-2.01 (2H, m),
2.21-2.63 (4H, m), 3.08-3.15
(2H, m), 4.35-4.61 (2H, m), 5.
45-5.65 (3H, m), 7.26-7.36 (5
H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.50 (3H, d,
J = 7.3 Hz), 1.85-2.97 (2H, m),
2.20-2.68 (4H, m), 3.10-3.14
(2H, m), 4.38-4.62 (2H, m), 5.
42-5.64 (3H, m), 7.23-7.35 (5
H, m).

Reference Example 40 (4S)-(1-tert-butoxycarbonylamino-3)
-Fluoropropyl) -N-[(1R) -phenylethyl
] -2-pyrrolidone (F1) (4S)-(1-carbamoyl-3-fluoropropyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (F1; 644 mg, 2.20 mmol) A solution of tert-butyl alcohol (20 ml) is heated to 80 ° C.
Lead tetraacetate (purity 90% or more, 1.95 g) was added, and the mixture was stirred at the same temperature for 20 minutes. After cooling, add sodium bicarbonate (2
g) was added, diluted with ethyl acetate (50 ml) and filtered. The filtrate was washed with saturated aqueous sodium hydrogen carbonate (50 ml × 2), the organic layer was dried over sodium sulfate, and the solvent was distilled off to obtain 706 mg (88%) of the title compound. The same reaction was performed for F2 (85%). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H,
s), 1.50 (3H, t, J = 8.4 Hz), 1.7
0-1.91 (2H, m), 2.20-2.54 (3
H, m), 3.04-3.12 (2H, m), 3.73.
-3.85 (1H, m), 4.37-4.55 (3H,
m), 5.48 (1H, q, J = 6.8 Hz), 7.2
6-7.34 (5H, m). F2; ¹ H-NMR (CDCl ₃ ) δ: 1.42 (9H,
s), 1.51 (3H, t, J = 6.8 Hz), 1.7
1-1.95 (2H, m), 2.20-2.53 (3
H, m), 3.02-3.15 (2H, m), 3.70
-3.82 (1H, m), 4.46-4.58 (3H,
m), 5.48 (1H, q, J = 6.8 Hz), 7.2
6-7.34 (5H, m).

Reference Example 41 (3R)-(1-tert-butoxycarbonylamino-3)
-Fluoropropyl) -N-[(1R) -phenylethyl
Ru] pyrrolidine (F1) (4S)-(1-tert-butoxycarbonylamino-3
-Fluoropropyl) -N-[(1R) -phenylethyl] -2-pyrrolidone (F1; 706 mg, 1.94 m)
mol) of a borane-tetrahydrofuran complex (1 mol) in tetrahydrofuran (5.8 ml) under ice cooling.
Stirred for days. The solvent was distilled off, and to the residue was added a mixed solvent (20 ml) of ethanol-water (4: 1), and the mixture was heated under reflux for 1 hour in the presence of triethylamine (5 ml). After cooling, the solvent was distilled off, chloroform (30 ml) was added to the residue, and the mixture was washed with saturated saline (20 ml). After the organic layer was dried over sodium sulfate, the solvent was distilled off. The obtained residue was subjected to silica gel chromatography, and the title compound (415 m) was eluted from a 5% methanol-chloroform eluate.
g (61%). The same reaction was performed for F2 (57%). F1; ¹ H-NMR (CDCl ₃ ) δ: 1.30-1.97
(17H, m), 2.20-2.40 (3H, m),
2.70-3.70 (3H, m), 4.35-4.50
(2H, m), 5.40-5.60 (1H, m), 7.
26-7.34 (5H, m). ^{· F2; 1 H-NMR (} CDCl 3) δ: 1.36-1.95
(17H, m), 2.23-2.52 (3H, m),
2.75-3.57 (3H, m), 4.41-4.54
(2H, m), 5.43-5.57 (1H, m), 7.
26-7.31 (5H, m).

Reference Example 42 (3R)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) pyrrolidine (F1) (3R)-(1-tert-butoxycarbonylamino-2)
-Fluoroethyl) -N- (benzyloxycarbonyl) pyrrolidine (F1; 415 mg, 1.18 mmol)
10% palladium on carbon (400 mg) was added to a solution of 1) in ethanol (10 ml) and subjected to catalytic hydrogenation at 50 ° C. overnight. After the catalyst was separated by filtration, the solvent of the liquid was distilled off to obtain a crude title compound quantitatively. It was used in subsequent reactions without purification. The same reaction was performed for F2.

Example 12 5-Amino-7-[(3R)-(1-amino-3-fur
Oropropyl) -1-pyrrolidinyl] -6-fluoro-
1-[(2S) -fluoro- (1R) -cyclopropyl
1] -1,4-dihydro-8-methoxy-4-oxo
Norin-3-carboxylic acid (F1) 5-amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline (3R)-(1-tert-butoxycarbonylamino-2-fluoroethyl) pyrrolidine (F1; 291 mg, 1.18 mmol) was added to a solution of -3-carboxylic acid (328 mg, 1.00 mmol) in dimethyl sulfoxide (8 ml). , Triethylamine (1 ml) was added, and the mixture was stirred at 120 ° C for 1 day under a nitrogen atmosphere. The solvent was distilled off, 10% citric acid was added to the residue, the precipitate was collected by filtration, concentrated hydrochloric acid (5 ml) was added, and the mixture was stirred at room temperature for 10 minutes, and the aqueous layer was washed with chloroform (20 ml × 3). Then, the mixture was made alkaline with a 50% aqueous sodium hydroxide solution under ice cooling. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was subjected to chloroform (50 ml).
× 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. It was developed and separated and purified in the lower layer of chloroform: methanol: water = 7: 3: 1, and recrystallized from a mixed solvent of ethanol and ether to obtain 300 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.19-1.72
(5H, m), 2.00-2.20 (2H, m), 2.
94-2.99 (1H, m), 3.43 (3H, s),
3.34-3.58 (1H, m), 3.65-3.68
(2H.m), 3.70-3.75 (1H, m), 3.
85-3.89 (1H, m), 4.59-4.77
(2.5H.m), 4.92-4.94 (0.5H,
m), 8.51 (1H, d, J = 3.4 Hz). Elemental _{analysis: C 21 H 25 F 3 N} 4 O 4 · 0.25H 2 O
Calculated: C, 54.96; H, 5.60; N, 12.2
1. Found: C, 54.71; H, 5.29; N, 12.4.
9. Melting point: 148-153 ° C

Example 13 5-amino-7-[(3R)-(1-amino-3-fur
Oropropyl) -1-pyrrolidinyl] -6-fluoro-
1-[(2S) -fluoro- (1R) -cyclopropyl
1] -1,4-dihydro-8-methoxy-4-oxo
Norin-3-carboxylic acid (F2) 5-amino-6,7-difluoro-1-[(2S) -fluoro- (1R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline To a solution of -3-carboxylic acid (328 mg, 1.00 mmol) in dimethyl sulfoxide (8 ml), (3R)-(1-tert-butoxycarbonylamino-2-fluoroethyl) pyrrolidine (F2; 236 mg, 0.96 mmol) And triethylamine (3 ml) were added, and the mixture was stirred at 120 ° C. for 1 day under a nitrogen atmosphere. The solvent was distilled off, 10% citric acid was added to the residue, the precipitate was collected by filtration, concentrated hydrochloric acid (5 ml) was added, and the mixture was stirred at room temperature for 10 minutes. The aqueous layer was washed with chloroform (20 ml × 3), and then made alkaline with a 50% aqueous sodium hydroxide solution under ice-cooling. The pH was adjusted to 7.2 by adding concentrated hydrochloric acid, and the aqueous layer was subjected to chloroform (50 ml).
× 3). After the organic layer was dried over sodium sulfate, the solvent was distilled off, and the residue was subjected to preparative TLC. It was developed and separated and purified in a lower layer of chloroform: methanol: water = 7: 3: 1, and recrystallized from a mixed solvent of ethanol and ether to obtain 102 mg of the title compound (23%). ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.73
(5H, m), 2.14 to 2.21 (2H, m), 2.
94-2.98 (1H, m), 3.42 (3H, s),
3.54-3.60 (3H, m), 3.71-3.76
(1H, m), 3.81-3.87 (1H, m), 4.
55-4.77 (2.5 Hm), 4.91-4.95
(0.5H, m), 8.50 (1H, d, J = 3.9H)
z). Elemental _{analysis: C 21 H 25 F 3 N} 4 O 4 · 0.25H 2 O
Calculated: C, 54.96; H, 5.60; N, 12.2
1. Found: C, 54.86; H, 5.42; N, 11.8.
9. Melting point: 192-194 ° C

The antibacterial activity of the compound of the present invention was measured according to the standard method specified by the Japanese Society of Chemotherapy, and the results are shown in the following table by MIC (μg / ml).

[0127]

[Table 2]

[0128]

[Table 3]

[0129]

Industrial Applicability The compound of the present invention has a wide range of excellent antibacterial activity against both gram-negative bacteria and gram-positive bacteria, and shows a strong antibacterial activity especially against quinolone-resistant bacteria. It has both pharmacokinetics and safety, and is useful as an antibacterial compound.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Jin Oki 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo Inside the Tokyo Research and Development Center, Daiichi Pharmaceutical Co., Ltd.

Claims (17)

[Claims] A compound represented by the following formula (I), a salt thereof, and a hydrate thereof: In the formula, R ¹ has, as a substituent, at least one group selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms, R ² and R ³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, wherein the alkyl group is a hydroxyl group, a halogen atom, a carbon atom having 1 to 6 carbon atoms; R ⁴ , R ⁵ and R ⁶ may each independently have one or more groups selected from the group consisting of an alkylthio group of 6 and an alkoxyl group having 1 to 6 carbon atoms, Represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms. Alkyl group, a hydroxyl group, may have one or more groups selected from the group the group consisting of an alkoxyl group having from 1 halogen atom and having a carbon number 6 as the substituent, R ⁷ and R ⁸ are each independently , A hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and Q represents a partial structure represented by the following formula. Embedded image [Wherein, R ⁹ represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or a carbon atom having 3 to 6 carbon atoms which may have a substituent. A cyclic alkyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms. R ¹⁰ represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, and R ¹⁰ and R ⁹ are integrated to form a cyclic structure including a part of the mother nucleus. Alternatively, the ring thus formed may contain a sulfur atom as a ring constituent atom, and the ring may have an alkyl group having 1 to 6 carbon atoms as a substituent. R ¹¹ represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or 1 carbon atom. Represents an alkoxyl group having from 6 to 6, wherein an amino group is substituted with at least one group selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms. It may have as a group. X ¹ represents a halogen atom or a hydrogen atom; A ¹ represents a nitrogen atom or a compound of the formula (II) (Wherein, X ² represents a hydrogen atom, an amino group, a halogen atom,
Cyano group, halogenomethyl group, halogenomethoxyl group,
Represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, of which an amino group is a formyl group, may have one or more groups selected from the group the group consisting of alkyl and acyl group having 2 to 5 carbon atoms from 1 to 6 carbon atoms as a substituent, further this X ² and the above R ⁹ May be integrated so as to form a ring structure including a part of the mother nucleus, but the ring thus formed contains an oxygen atom, a nitrogen atom, or a sulfur atom as a ring constituent atom. This ring may further have an alkyl group having 1 to 6 carbon atoms as a substituent. ) Represents a partial structure. A
² and A ³ each represent a nitrogen atom or a carbon atom, and A ² and A ³ and the carbon atom to which they are bonded have a partial structure ## STR4 ##> C ＝ C (A ¹ ）) —N (R ⁹ ) — or a partial structure is formed: NC (A ¹ =) = C (R ⁹ ) —. Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1, A 3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or an alkylene group having 1 to 6 carbon atoms and a phenyl group; Represents a phenylalkyl group composed of ]｝ 2. In the formula (I), Q is a compound represented by the formula: Or the formula: (Wherein R ⁹ , R ¹⁰ , R ¹¹ , A ¹ , X ¹ and Y are the same as defined above). The compound according to claim 1, which is a compound having a structure represented by the following formula: Its salts, and their hydrates 3. In the formula (I), Q is a compound represented by the formula: (Wherein R ⁹ , R ¹⁰ , R ¹¹ , A ¹ , X ¹ and Y are the same as defined above). The compound according to claim 1, which has a structure represented by the following formula: Salts and their hydrates 4. In the formula (I), Q is 9-fluoro-2,3-dihydro-3- (S) -methyl-7-oxo-7H-pyrido [1.2.3-de] [1 .4] benzoxazine-6-carboxylic acid.
And the salts thereof, and hydrates thereof. 5. In the formula (I), Q is 5-amino-
6-fluoro-1- [2- (S) -fluoro-1-
(R) -cyclopropyl] -1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, the compound according to claim 1, 2, or 3, a salt thereof, and a hydration thereof. Stuff 6. In the formula (I), Q is 5-amino-
6-fluoro-1- [2- (S) -fluoro-1-
(R) -cyclopropyl] -1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, the compound according to claim 1, 2, or 3, a salt thereof, and hydration thereof. Stuff 7. The compound according to claim 1, 2, 3, 4, 5, or 6, wherein the compound of the formula (I) is a stereochemically single compound, and salts thereof, and hydration thereof. Stuff 8. The method according to claim 1, wherein, in the formula (I), R ¹ is a methoxymethyl group, a fluoromethyl group, or a 2-fluoroethyl group. Compounds and salts thereof, and hydrates thereof 9. The compound according to claim 1, 2 or 3, wherein R ⁹ is a halogenocyclopropyl group, and a salt thereof.
And their hydrates 10. The compound according to claim 9, wherein the halogenocyclopropyl group in the formula (I) is a 1,2-cis-halogenocyclopropyl group, a salt thereof, and a hydrate thereof. 11. In the formula (I), the halogenocyclopropyl group is a stereochemically single substituent.
The compound according to 0, a salt thereof or a hydrate thereof 12. The compound according to claim 11, wherein in the formula (I), the halogenocyclopropyl group is a (1R, 2S) -2-halogenocyclopropyl group, and a salt thereof.
And their hydrates 13. In the formula (I), the halogen atom of the halogenocyclopropyl group is a fluorine atom.
And the salts thereof, and hydrates thereof. 14. The compound according to claim 13, wherein the compound of the formula (I) is a stereochemically single compound, a salt thereof, and a hydrate thereof. 15. The compound according to claim 14, wherein in formula (I), R ¹ is a methoxymethyl group, a fluoromethyl group, or a 2-fluoroethyl group, a salt thereof, and a hydrate thereof. 16. A pharmaceutical comprising the compound according to any one of claims 1 to 15, a salt thereof, or a hydrate thereof as an active ingredient. 17. An antibacterial agent comprising the compound according to any one of claims 1 to 15, a salt thereof, or a hydrate thereof as an active ingredient.