JP3066286B2 - Method for producing pyridonecarboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing a pyridonecarboxylic acid derivative useful as an antibacterial agent. More specifically, the invention relates to pyridobenzoxazines, pyridobenzothiazines or pyridoquinoxalines.
The present invention relates to a novel method for producing pyridonecarboxylic acid derivatives represented by the following general formula (I) having an amino-substituted cycloalkyl group at the 0-position, and salts thereof.

[0002]

Embedded image [In the formula, R ₁ represents a hydrogen atom or a carboxyl protecting group; R ₂ represents a hydrogen atom, a halogen atom, an alkoxy group, a hydroxyl group optionally having a protecting group, an amino group optionally having a protecting group. R ₄ represents a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, or a protective group; Represents a good hydroxy-lower alkyl or lower alkylidene group, or R ₄
X forms a cycloalkane ring together with the carbon atom to which it is attached; X denotes a halogen atom; A denotes an oxygen or sulfur atom or NB (where B denotes a hydrogen atom or a lower alkyl group) N represents an integer of 1 to 4. The present invention also relates to an intermediate used in the above production method.

[0003]

2. Description of the Related Art The compound of the formula (I) or a salt thereof has already been disclosed in Korean Patent Publication No. 91-5833 (1991.
8.5), JP-A-2-28187 (1990.1.3)
0), U.S. Pat. No. 4,990,508 (1991.
Known compounds described in 2.5). Since these compounds have strong antibacterial activity not only against gram-positive bacteria but also against gram-negative bacteria including Pseudomonas aeruginosa, they are excellent as antibacterial agents. It is a stable compound with a blood concentration.

The method for producing such a compound of the general formula (I) is described in detail in the above-mentioned known patent documents,
The conventional production methods described in these documents are shown, for example, by the following reaction scheme.

[0005]

Embedded image [In the above reaction scheme, R ₁ , R ₄ , A and X are as defined above, and R ₃ has a hydrogen atom, a lower alkyl group, an amino group which may have a protecting group, and a protecting group. Optionally a lower alkylamino group, a di-lower alkylamino group, a carboxyl group optionally having a protecting group,
An amino-lower alkyl group optionally having a protecting group, a lower alkylamino-lower alkyl group optionally having a protecting group, a di-lower alkylamino-lower alkyl group, or a group having a protecting group; A hydroxy-lower alkyl group; R _1a represents a carboxyl protecting group; R _2a represents a hydrogen atom or a halogen atom; R _2b represents an alkoxy group or a hydroxyl group optionally having a protecting group; R
_2c is a protective amino group which may have a group which may have a protecting group lower alkylamino group or a di - a lower alkyl amino group, R ₅ represents a hydrogen atom or an amino protecting group. As shown in the above reaction scheme, according to the prior art method, the compound of the general formula (I) is first keto-esterified with a compound of the general formula (II) or a salt thereof to obtain a compound of the general formula (III)
Or a salt thereof; the resulting general formula (III)
Is reacted with methyl or ethyl orthoformate in acetic anhydride, and the product is reacted with a compound of the general formula (I
V) with a compound of the formula (I)
Reacting the compound of the formula II) or a salt thereof with an acetal such as N, N-dimethylformamide-dimethylacetal or diethylacetal, and reacting the product with the compound of the general formula (IV) or a salt thereof to obtain a compound of the general formula (IV) V) The compound of the general formula (VI) or a salt thereof is produced, and the resulting compound of the general formula (V) or a salt thereof is ring-closed in the presence or absence of a metal fluoride or a base to give a compound of the general formula (VI) or a salt thereof. After the compound is obtained; the compound of the general formula (VI) or a salt thereof is subjected to ring closure in the presence or absence of a metal fluoride or a base to obtain the compound of the general formula (Ia) or a salt thereof; or R _2a is a halogen atom Reacting a compound of general formula (Ia) or a salt thereof with an alcohol of general formula (VII) or a salt thereof in the presence or absence of a base to obtain a compound of general formula (Ib) or a salt thereof;
Reacting a compound of the formula (Ia) wherein _2a is a halogen atom or a salt thereof with an amine of the formula (VIII) or a salt thereof in the presence or absence of a base to obtain a compound of the formula (Ic) or a salt thereof Manufactured by the method.

On the other hand, the compound of the general formula (II) or a salt thereof used as a starting material for producing the compound of the general formula (I) or a salt thereof in the above-mentioned prior art method is as follows. Can be synthesized.

[0007]

Embedded image [In the above reaction scheme, R ₁ , R _1a , R _2a and X are as defined above, R _1b represents a carboxyl group, and R _3a
Is a hydrogen atom or an amino group optionally having a protecting group, a lower alkylamino group optionally having a protecting group, a di-lower alkylamino group, an amino lower alkyl group optionally having a protecting group A lower alkylamino-lower alkyl group optionally having a protecting group, a di-lower alkylamino-
It represents a lower alkyl group or a hydroxy-lower alkyl group which may have a protecting group, R _3b represents a lower alkyl group, and R _3c represents a hydrogen atom or a lower alkyl group. ]

[0008]

As can be seen from the above reaction scheme, the prior art methods for preparing compounds of general formula (I) involve complex multi-step steps which require a large amount of time and production costs. In addition, the compound of the general formula (II) used as a starting material in the prior art method is not industrially preferable since it is produced by a very complicated process, and there is room for improvement.

Accordingly, the present inventors have developed a method which can produce the compounds of the general formula (I) in a simple and economical manner without going through complicated steps as in the prior art methods. After extensive research, they have found that the above objects can be achieved by a new and simple method described later, and have completed the present invention.

[0010]

Accordingly, an object of the present invention is to oxidize a compound of the following general formula (XXV) or a salt thereof when Z is cyano, and then to carry out a Hoffmann rearrangement reaction, wherein Z is nitro. An object of the present invention is to provide a novel method for producing a pyridonecarboxylic acid derivative of the general formula (I) and a salt thereof, which is characterized by reduction in some cases.

[0011]

Embedded image [In the formula, R ₁ represents a hydrogen atom or a carboxyl protecting group; R ₂ represents a hydrogen atom, a halogen atom, an alkoxy group, a hydroxyl group optionally having a protecting group, an amino group optionally having a protecting group. R ₄ represents a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, or a protective group; Represents a good hydroxy-lower alkyl or lower alkylidene group, or R ₄
X forms a cycloalkane ring together with the carbon atom to which it is attached; X denotes a halogen atom; A denotes an oxygen or sulfur atom or NB (where B denotes a hydrogen atom or a lower alkyl group) N represents an integer of 1 to 4. Unless otherwise stated herein, the term “halogen” includes fluorine, chlorine, bromide and iodine; the term “alkyl” includes methyl, ethyl,
a C _1-10 alkyl group such as n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl and the like; the term “lower alkyl group” means any of the above alkyl groups And C _1-5
The term "alkoxy group" means an O-alkyl group (where the alkyl group is a _C1-10 alkyl group); the term "lower alkylamino group" means methylamino, ethylamino Means a C _1-5 alkylamino group such as, propylamino; the term “di-lower alkyl group”
Means a di-C _1-5 alkylamino group such as dimethylamino; the term “amino-lower alkyl group” means amino-C 1 such as aminomethyl, aminoethyl, aminopropyl and the like.
_1-5 alkyl group; the term "lower alkylamino-
Methylaminomethyl The lower alkyl group ", methylaminoethyl, ethylaminomethyl, methylaminopropyl, C _1-5 alkylamino such as propyl aminoethyl -
Refers to C _1-5 alkyl group; the term dimethylaminomethyl the "di - - lower alkylamino-lower alkyl group", diethylaminomethyl, diethylaminoethyl, di -C _1-5 alkylamino -C ₁ such as dimethylaminopropyl _The term "hydroxy-lower alkyl group" means a hydroxy-C _1-5 alkyl group such as hydroxymethyl, hydroxyethyl, hydroxypropyl; the term "halogeno-lower alkyl group" A halogeno-C _1-5 alkyl group such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, chloroethyl, trichloroethyl, chloropropyl and the like; the term “lower alkylidene group” means methylene, ethylene, propylidene, isopropylidene and the like means C _1-5 alkylidene; term "cycloalkane ring" Cyclopropane, cyclobutane, cyclopentane, C and cyclohexane
_3-7 means a cycloalkane ring.

In the definition for R _{1 in} substituted compounds of the compounds of the general formula (I) or their salts, the carboxyl-protecting group is, for example, by catalytic reduction, chemical reduction or other treatment under mild conditions. Ester-forming groups that can be removed; ester-forming groups that can be easily removed in vivo; organic silyl-containing groups, organic phosphorus-containing groups that can be easily removed by treatment with water or alcohol; Tartaric acid-containing groups; and JP-A-59-80665
And various well-known ester-forming groups.

In the definition of R ₂ , protecting groups for amino groups and lower alkylamino groups are commonly used in the art such as formyl, acetyl, benzyl and other known amino protecting groups described in JP-A-59-80665. It is used for

Protecting groups for hydroxyl and hydroxy-lower alkyl groups in the definition of R ₂ and R ₄ are those commonly used in the art, for example, organic silyl groups which can be easily removed with water or alcohol, Formyl group,
JP-A-59-806, such as acetyl group and benzyl group;
Includes the known hydroxyl-protecting groups described in No. 65.

The salts of the compounds represented by the general formula (I) include conventional salts formed at basic groups such as amino groups and acidic groups such as hydroxy groups and carboxyl groups. . The salt formed at the basic group site is a conventional acid addition salt, for example, an inorganic acid addition salt such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid Organic carboxylic acid addition salts such as, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid,
Includes sulfonic acid addition salts such as naphthalenesulfonic acid. Salts formed at acidic sites are conventional base addition salts,
For example, alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methyl Nitrogen-containing organic base addition salts such as morpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-pentylamine, 1-epenamine, N, N′-dibenzylethylenediamine and the like can be included. .

The compounds of the general formula (I) and salts thereof can exist in the form of isomers, for example, optical isomers, geometric isomers, tautomers and the like. Therefore, it is understood that the target compound produced by the present invention includes not only the compound of the general formula (I) and a salt thereof but also all isomers, crystal forms, solvates and hydrates thereof. Should be.

More specifically, the present invention relates to a compound of the formula (XX)
Is reacted with a metal salt of the compound of the general formula (XXI) to produce a compound of the general formula (XXII) or a salt thereof; and the resulting compound of the general formula (XXII) or a salt thereof is hydrolyzed and dehydrated. A compound of the general formula (XXIII) or a salt thereof is produced by carboxylation; the resulting compound of the general formula (XXIII) or a salt thereof is converted to a compound of the general formula (XXI)
Reacting with a compound of formula V) or a salt thereof to effect ring closure to produce a compound of formula (XXV) or a salt thereof; Z
Reducing the compound of the general formula (XXV) or a salt thereof to produce a compound of the general formula (I) or a salt thereof, or oxidizing the compound of the general formula (XXV) or a salt thereof wherein Z is cyano After preparing the compound of the general formula (XXVI) or a salt thereof, a well-known Hoffmann rearrangement reaction (Hofmann) is performed.
The present invention relates to a method for producing a compound of the general formula (I) or a salt thereof, which comprises converting the compound to a compound of the general formula (I) or a salt thereof by rearrangement. The above-described method of the present invention can be represented by the following reaction scheme.

[0018]

Embedded image [In the reaction scheme, R ₁ , R ₂ , R ₄ , A, X and n are as defined above, and W is easily removable by a metal salt (or anion) such as halogen or active methylene. Y represents a hydrogen atom, a lower alkyl group or a carboxyl-protecting group; Z represents a cyano group or a nitro group. The production method of the present invention will be described in more detail as follows.

The compound of the general formula (XX) or a salt thereof, which is a starting material used in the production method of the present invention, is described in the literature [J. M
ed. Chem. 1987, Vo1.30, 2283-.
2286], and this document further describes the production method thereof in detail.

In the first step of the process of the present invention, the compound of the general formula (XXII) or a salt thereof is reacted with a metal salt of the compound of the general formula (XXI) to produce a compound of the general formula (XXII) or a salt thereof. I do.

The reaction of the first stage can be carried out preferably in the presence of a solvent, and the solvent that can be used for such a purpose can include all solvents that do not directly participate in the reaction. Examples of desirable solvents include benzene, toluene, aromatic hydrocarbon solvents such as xylene, dioxane,
Ethers such as tetrahydrofuran, halogen hydrocarbon solvents such as methylene chloride, chloroform, dichloroethane, and N, N-dimethylformamide, N, N-
Amide solvents such as dimethylacetamide can be mentioned, and any one of these solvents can be used alone or as a mixture of two or more solvents. The metal salt of the compound of the general formula (XXI) used in the reaction of the first step may be used as such, but the free compound (XXI)
Is reacted with a metal compound to produce and use the metal salt in the same reaction system. In this reaction, the compound represented by the general formula (XX)
The metal salt of the compound (I) is used in an amount of at least 1 mole, preferably 1 to 4 moles, per mole of the compound of the formula (XX) or a salt thereof. This reaction is generally performed at a temperature of -10 ° C to 100 ° C for 30 minutes to 20 hours.

The compounds of the general formula (XXII) or the salts thereof obtained from the first-stage reaction of the process according to the invention are novel compounds and are therefore also covered by the invention.

In the second stage of the method according to the invention, the first
The compound of the general formula (XXIII) or a salt thereof is produced by subjecting the compound of the general formula (XXII) or the salt thereof obtained from the step to hydrolysis and decarboxylation.

For such purpose, an acid hydrolysis method is generally used. Acids that can be used when performing acid hydrolysis are conventional organic acids or inorganic acids.For example, as the organic acid, formic acid, acetic acid, p-toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, or the like can be used. Can,
As the inorganic acid, sulfuric acid or hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid and the like can be used.

The acid used in the reaction is mixed with water and used at a ratio of at least 1 mol, preferably 1 to 10 mol, per mol of the compound of the formula (XXII) or a salt thereof. The reaction is usually performed at room temperature to reflux temperature for 5 minutes to 72 minutes.
This is performed for a time, preferably 3 to 70 hours.

The compounds of the general formula (XXIII) or the salts thereof obtained from the second stage reaction of the process according to the invention are also novel compounds. Therefore, this compound (XXIII) is also included in the subject of the present invention.

In the third step of the process according to the present invention, the compound of the general formula (XXV) or a salt thereof is prepared by cyclizing the compound of the general formula (XXIII) or a salt thereof obtained above. In the ring closure reaction, the compound represented by the general formula (XXIII)
Is reacted with a compound of the general formula (XXIV) or a salt thereof in an aqueous alkaline solution using a phase transfer catalyst (PTC) to obtain a compound of the general formula (XXV) or a salt thereof. The alkaline aqueous solution that can be used for the reaction includes, for example, NaOH, KOH, Ca (O
_{H) 2, Na 2 CO 3} , NaHCO 3, K 2 CO 3 alkali metal or alkaline earth metal hydroxides, such as, an aqueous solution such as a carbonate or bicarbonate and the like.

The reactant used in this reaction is represented by the general formula (X)
As the compound of XIV), a commercially available product can be easily used as a known compound. Examples of compounds (XXIV) that can be used include dihalogenoalkane compounds such as dibromoethane, dichloroethane or diiodoethane or the corresponding alkoxyalkane or sulfoxyalkane compounds.

Examples of usable phase transfer catalysts (PTC) include triethylbenzylammonium bromide, triethylbenzylammonium chloride and the like.

In the ring closure reaction, the compound of the general formula (XXIV) or a salt thereof is generally used in a ratio of 1 to 5 mol, preferably 1 to 3 mol, per mol of the compound of the general formula (XXIII) or a salt thereof, The PTC catalyst is used in a ratio of 1 mol to 5 mol, preferably 1 mol to 3 mol.

The reaction is generally carried out at a temperature of 0 to 100 ° C., preferably 0 to 50 ° C., for 1 to 24 hours, preferably 5 to 50 hours.
For 12 to 12 hours.

The compounds of the general formula (XXV) or the salts thereof obtained from the third step reaction of the process according to the invention are further novel compounds which are not known before the present invention and are therefore included in the scope of the present invention It is.

In the fourth step of the process according to the present invention, the desired compound of the general formula (I) is produced from the compound of the general formula (XXV) or a salt thereof by the following method. i) When Z is a cyano group: When Z is a cyano group in the general formula (XXV), firstly, when Z is a cyano group, the general formula (XXV)
By oxidation of a compound of formula (I) or a salt thereof by a conventional method using an inorganic acid such as concentrated sulfuric acid.
After synthesizing a compound having an amide group, such as the compound of the formula XVI) or a salt thereof, the compound can be converted to the compound of the general formula (I) or a salt thereof by a known Hoffman rearrangement reaction.

The oxidation reaction of the compound of the formula (XXV) or a salt thereof is preferably carried out using an inorganic acid such as sulfuric acid or hydrochloric acid.
C. to 100.degree. C., preferably room temperature to 70.degree. C., for 1 to 24 hours, preferably 1 to 12 hours. In this reaction, the acid is generally 1 to the compound of the general formula (XXV).
To 5 mol, preferably 1 to 3 mol.

The general formula (XXV) formed by the oxidation reaction
The compound of the formula (I) or a salt thereof is subjected to a Hoffman rearrangement reaction to obtain the desired pyridonecarboxylic acid derivative of the general formula (I) or a salt thereof. The Hoffman rearrangement reaction can be carried out using fluorine or chlorine in an aqueous alkali solution, or using an aqueous sodium hypochlorite or sodium hypobromite solution or sodium methoxide-fluorine. Thus, the target compound of the general formula (I) wherein R ₃ represents an amino group (—NH ₂ ) and a salt thereof can be obtained. Such Hoffmann rearrangement reaction is generally performed at a temperature of 0 to 100 ° C, preferably room temperature to 70 ° C for 24 hours, preferably 1 to 1 hour.
Perform for 2 hours.

Ii) When Z is a nitro group: The nitro group substituted by a cycloalkyl ring at the C-10 position is a direct reduction method using a chemical reducing agent or indirect reduction by reducing with hydrogen in the presence of a catalyst. It can be easily reduced using any of the methods or in the electrical reduction method.

Examples of the reducing agent that can be used in the direct reduction method include aluminum amalgam, iron, chromic chloride, sodium sulfate, titanium trichloride, sodium borohydride, lithium aluminum hydride, Zn, and SnC.
l ₂ , Cu, Na ₂ S and the like, and the solvent may be an alcoholic solvent such as methanol, ethanol, n-propyl alcohol or isopropyl alcohol, or a solvent such as dimethylformamide or diethylacetamide alone. Alternatively, a mixture of two or more solvents may be used.

The indirect reduction method uses Pd, Pt as a catalyst in the presence of the same solvent as used in the direct reduction.
This is performed using O ₂ , PtO ₂ ReS ₇ , CuCr ₂ O ₄ , Raney nickel or the like. Reaction pressure is from normal pressure to 2000 psi
(13790 kPa), desirably from normal pressure to 1000p
si (6895 kPa). Reaction temperature is from room temperature to 2
The temperature is 00 ° C, preferably room temperature to 100 ° C.

The amount of the catalyst to be used is a catalytic amount to 2 molar equivalents, preferably a catalytic amount to 1 molar equivalent, relative to the compound of the general formula (XXV) or a salt thereof.

The compound of the general formula (I) and the salt thereof produced by the above-mentioned method according to the present invention may be used, if necessary, by a conventional purification method such as recrystallization, fractional crystallization, chromatography and the like. It can be further purified.

According to the process of the present invention, the desired compound of general formula (I) or a salt thereof can be obtained by a method which is much simpler and more convenient than the complicated multi-stage process of the prior art. Is a new and useful method that has obvious advantages in terms of economy.

[0042]

The present invention will be further described by the following examples, which should not be construed as limiting the invention thereto.

Example 1 (S) -10- (cyanoethoxycarbonylmethyl)-
9-fluoro-3-methyl-7-oxo-2,3-dihi
Dro-7H-pyrido [1,2,3-d, e] [1,4]
Preparation of benzoxazine-6-carboxylic acid ethyl ester
60% granulated dimethylformamide 125 ml NaH6.4
g and cooled at 0 ° C. in an ice bath. 32 ml of 93% ethyl cyanoacetate was added thereto, and the mixture was stirred at the same temperature for 30 minutes. (S) -9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H was added to the reaction mixture.
12.4 g of -pyrido [1,2,3-d, e] [1,4] benzoxazine-6-carboxylic acid ethyl ester was added, and the mixture was gradually heated. After stirring at 50 ° C. overnight, the mixture was cooled at room temperature. 500 ml of cold water was added, and the pH was adjusted to 4 with acetic acid. Ethyl acetate (300 ml) was added for extraction, and the organic layer was washed with water and saturated saline. Dry the organic layer over MgSO ₄ and filter. The solvent was removed by distillation under reduced pressure, and the residue was crystallized by adding 300 ml of diethyl ether. The crystals obtained by filtration were dried to give the title compound 13.7.
g (85%).

Melting point: 119-121 ° C.¹ H-NMR (CDCl_Three): Δ 1.37 (d, 3H),
1.42 (t, 3H), 1.61 (t, 3H), 4.2
8 (q, 2H), 4.36 (q, 2H), 4.40
(D, 1H), 4.49 (d, 1H), 5.29 (s,
1H), 7.82 (d, 1H), 8.41 (s, 1H) IR (KBr) cm^-1: ΥC≡N 2230 MS m / e: 403 (M⁺)Example 2 (S) -10-cyanomethyl-9-fluoro-3-methyl
Ru-7-oxo-2,3-dihydro-7H-pyrido
[1,2,3-d, e] [1,4] benzoxazine-
Production of 6-carboxylic acid (S) -10- in 110 ml of dioxane and 20 ml of water
(Cyanoethoxycarbonylmethyl) -9-fluoro-
3-methyl-7-oxo-2,3-dihydro-7H-pi
Lido [1,2,3-d, e] [1,4] benzoxazi
And 13.6 g of ethyl 6-carboxylate
Stirred at room temperature for 30 minutes. Add p-toluene to the reaction mixture
7.3 g of sulfonic acid was added, and 70
After stirring for an hour, the mixture was cooled at room temperature to precipitate crystals. Raw
Filter the formed crystals and thoroughly with water and diethyl ether
8.8 g (86.3) of the title compound.
%).

Melting point: 231-232 ° C.¹ H-NMR (acetone-d₆): Δ 1.72 (d, 3
H), 4.12 (s, 2H), 4.82 (d, 1H),
4.76 (d, 1H), 5.15 (m, 1H), 7.8
7 (d, 1H), 8.94 (s, 1H) IR (KBr) cm^-1: {C} N 2230 MS m / e: 302 (M⁺)Example 3 (S) -10- (1-cyanocyclopropyl) -9-fu
Fluoro-3-methyl-7-oxo-2,3-dihydro-
7H-pyrido [1,2,3-d, e] [1,4] benzo
Oxazine-6-carboxylic acid 13.2 g of sodium hydroxide is added to 30 ml of water and stirred.
Then, the mixture was cooled at 0 ° C. The resulting alkaline water
3. Add triethylbenzylammonium bromide to the solution.
4 g was added, the temperature was raised at room temperature, and the mixture was stirred for 30 minutes.
This is followed by (S) -10-cyanomethyl-9-fluoro-3
-Methyl-7-oxo-2,3-dihydro-7H-pyri
De [1,2,3-d, e] [1,4] benzoxazine
4.9 g of 6-carboxylic acid is gradually added, and the mixture is added at room temperature for 30 minutes.
After stirring, 8.2 g of dibromoethane was added. reaction
The mixture was gradually warmed and stirred at 45 ° C. for 2-5 hours
Thereafter, the mixture was cooled again at room temperature and stirred at this temperature overnight. Reaction mixture
130 ml of water was added to the mixture, and the pH was adjusted to 5 with acetic acid.
Was. The formed crystals are filtered and chloroform, water, ether
After washing thoroughly in the same order as above, drying and drying of the title compound 4.6.
g (86%). Melting point: 277-279 ° C¹ H-NMR (CDCl_Three): Δ 1.42 (m, 1H),
1.55 (s, 2H), 1.73 (d, 3H), 1.8
5 (m, 1H), 4.45-4.56 (m, 2H),
4.61 (m, 1H), 7.80 (d, 1H), 8.7
4 (s, 1H), 14.45 (bs, 1H) IR (KBr) cm^-1: ΥC≡N 2230 MS m / e: 328 (M⁺)Example 4 (S) -10- (1-aminocarbonylcyclopropyl
L) -9-Fluoro-3-methyl-7-oxo-2,3
-Dihydro-7H-pyrido [1,2,3-d, e]
Production of [1,4] benzoxazine-6-carboxylic acid 15 ml of concentrated sulfuric acid was cooled to 0 ° C, and (S) -10- (1-
Cyanocyclopropyl) -9-fluoro-3-methyl-
7-oxo-2,3-dihydro-7H-pyrido [1,
2,3-d, e] [1,4] benzoxazine-6-ca
3.4 g of rubonic acid was gradually added dropwise. Stir at room temperature overnight
After cooling at 0 ° C., 100 ml of water was gradually added to the reaction mixture.
Was dropped. Filter the resulting crystals with water and ether.
Thoroughly wash and dry 3.4 g (93%) of the title compound
I got

Melting point: 277 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ): δ1.06 (m, 2
H), 1.47 (d, 3H), 1.58 (m, 2H),
4.40 (d, 1H), 4.61 (d, 1H), 4.9
7 (m, 1H), 6.85 (bs, 1H), 6.91
(Bs, 1H), 7.60 (d, 1H), 9.08
(S, 1H) IR (KBr) cm ^-1 : ΔC = O 1600, 166
0.1720 MS m / e: 346 (M ⁺ ) Example 5 (S) -10- (1-aminocyclopropyl) -9-f
Fluoro-3-methyl-7-oxo-2,3-dihydro-
7H-pyrido [1,2,3-d, e] [1,4] benzo
Preparation of oxazine-6-carboxylate hydrochloride 5 g of sodium hydroxide was added to and dissolved in 34 ml of water, and then cooled to 0 ° C. to obtain a 12% sodium chlorite solution 19 m
1 was added. (S) -10- (1-Aminocarbonylcyclopropyl) -9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-d, e ] [1,4] benzoxazine-
3.3 g of 6-carboxylic acid was added, and the mixture was gradually heated and stirred at room temperature overnight. The reaction mixture was gradually warmed again to 70 ° C.
And then cooled at room temperature. 29 ml of ice water was added to the reaction mixture, and the pH was adjusted to 6 with concentrated hydrochloric acid while stirring vigorously. The formed crystals were filtered and washed with water. The obtained residue was added to 100 ml of 10% hydrochloric acid and concentrated under reduced pressure to obtain 2.0 g (67%) of the title compound. The product was recrystallized with a mixed solvent of ethyl acetate-ethanol-hexane.

Melting point: 268 ° C. ¹ H-NMR (DMSO-d ₆ ): δ 1.06 (m, 2
H), 1.47 (d, 3H), 1.58 (m, 2H),
4.40 (d, 1H), 4.61 (d, 1H), 4.9
7 (m, 1H), 7.60 (d, 1H), 9.08
(S, 1H) IR (KBr) cm ^-1 : υC = O 1600, 1720 MS m / e: 319 (M ⁺ ) Example 6 (S) -10- (1-aminocyclopropyl) -9-f
Fluoro-3-methyl-7-oxo-2,3-dihydro-
7H-pyrido [1,2,3-d, e] [1,4] benzo
Preparation of oxazine-6-carboxylate hydrochloride (S) -10- (1-nitrocyclopropyl) -9-fluoro-3-methyl-7-oxo- was added to 15 ml of a mixed solution of anhydrous ethanol-dimethylformamide (4: 1). 2,
3-dihydro-7H-pyrido [1,2,3-d, e]
[1,4] benzoxazine-6-carboxylic acid 0.74
g was added and dissolved. 10% Pd-C in the resulting solution
0.15 g of the catalyst was added, and the mixture was reacted with stirring at room temperature overnight while maintaining the hydrogen pressure at 50 psi (345 kPa) using a pressure reactor. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was dissolved in 20 ml of 10% hydrochloric acid, evaporated under reduced pressure, and the residue was recrystallized with a mixed solvent of ethanol-ethyl acetate-hexane to obtain 0.67 g (85%) of the title compound. The physicochemical properties of the product are as described in Example 5.

[0048]

According to the method of the present invention, the pyridone carboxylic acid derivative represented by the general formula (I) can be easily produced by far fewer steps than in the conventional method. This is an excellent method.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/542 A61K 31/542 A61P 31/04 A61P 31/04 (72) Inventor Jo Jae Chong South Korea Gyeonggied Suwonsi Kwonsongkwondong 462 ( 72) Inventor Bae Hyun Sob Seoul, Republic of Korea, Songbuk, Samseong-dong, 4ga, 374 Bondi 21/1 (72) Inventor Park Yang-gi, Seoul, Republic of Korea, Songpak, Jamsil 1-dong 19 Dugong Apartment 107-105 (72) Inventor Te Hyun Seob South Korea Gyeonggied Suwonsi Gwangseong Gwangseong Seryu 2dong 1139-3 (72) Inventor Im Hyun Seok South Korea Gyeonggied Suwonsi Paltaluk Methane 2 Dong Samson 1 Chaa Apartment 3-1305 (5 8) Fields surveyed (Int. Cl. ⁷ , DB name) C07D 498/06 C07D 471/06 C07D 513/06 A61K 31/4985 A61K 31/5365 A61K 31/542 A61K 31/04 CAPLUS (STN) REGISTRY (STN )

Claims (10)

(57) [Claims] 1) The following general formula (XX) wherein Z represents cyano
V) or a salt thereof is oxidized to give the following general formula (XXV)
After forming the compound of the formula (I) or a salt thereof, the compound is converted into a compound of the following general formula (I) or a salt thereof by a Huffman rearrangement reaction, or 2) a compound of the following general formula (XXV) wherein Z represents nitro A method for producing a pyridonecarboxylic acid derivative of the following general formula (I) or a salt thereof, comprising reducing a compound or a salt thereof to produce a compound of the following general formula (I) or a salt thereof. Embedded image Embedded image Embedded image [In the formula, R ₁ represents a hydrogen atom or a carboxyl protecting group; R ₂ represents a hydrogen atom, a halogen atom, an alkoxy group, a hydroxyl group optionally having a protecting group, an amino group optionally having a protecting group. And R ₄ represents a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, or a protective group. Represents a good hydroxy-lower alkyl or lower alkylidene group, or R ₄ forms a cycloalkane ring with the carbon atom to which it is attached; X represents a halogen atom; A is an oxygen or sulfur atom or NB ( Here, B represents a hydrogen atom or a lower alkyl group); n represents an integer of 1 to 4; and Z represents a cyano group or a nitro group. ] 2. The method according to claim 1, wherein the oxidation reaction in the method 1) is carried out using an inorganic acid. 3. The method according to claim 2, wherein the inorganic acid is sulfuric acid or hydrochloric acid. 4. The method according to claim 1, wherein the Hoffmann rearrangement reaction in the method 1) is carried out in the presence of sodium hypochlorite or sodium hypobromite. 5. A compound of the formula (XXV) or a salt thereof is reacted with a compound of the following formula (XXIV) or a salt thereof in the presence of a phase transfer catalyst to react the compound of the formula (XXIII) or a salt thereof. 2. The method of claim 1, wherein the method comprises: Embedded image Embedded image Wherein R ₁ , R ₂ , R ₄ , A, X, Z and n are as defined in the first item, and W is easily removed by halogen or a metal salt (or anion) of active methylene. Indicate groups that can be ] 6. The method according to claim 5, wherein the compound of the general formula (XXIII) or a salt thereof is produced by hydrolyzing and decarboxylating the compound of the following general formula (XXII) or a salt thereof. . Embedded image [Wherein, R ₁ , R ₂ , R ₄ , A, X and Z are as defined in the first item, and Y represents a hydrogen atom, a lower alkyl group or a carboxyl-protecting group. ] 7. A method for producing a compound of the general formula (XXII) or a salt thereof by reacting a compound of the following general formula (XX) or a salt thereof with a metal salt of a compound of the following general formula (XXI): 7. The method of claim 6, wherein Embedded image Embedded image [Wherein R ₁ , R ₂ , R ₄ , A, X and Z are as defined in the first item, and Y is as defined in the sixth item. ] 8. A compound of the general formula (XXV) or a salt thereof. Embedded image [In the formula, R ₁ represents a hydrogen atom or a carboxyl protecting group; R ₂ represents a hydrogen atom, a halogen atom, an alkoxy group, a hydroxyl group optionally having a protecting group, an amino group optionally having a protecting group. Group, which may have a protecting group
A lower alkylamino group or a di-lower alkylamino group; R ₄ represents a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, or an optionally substituted hydroxy-
Represents a lower alkyl group or a lower alkylidene group, or R ₄ forms a cycloalkane ring with the carbon atom to which it is attached; X represents a halogen atom; A represents an oxygen or sulfur atom or NB (where B Represents a hydrogen atom or a lower alkyl group); n represents an integer of 1 to 4;
Represents a cyano group or a nitro group. ] 9. A compound of the general formula (XXIII) or a salt thereof. Embedded image [In the formula, R ₁ represents a hydrogen atom or a carboxyl protecting group; R ₂ represents a hydrogen atom, a halogen atom, an alkoxy group, a hydroxyl group optionally having a protecting group, an amino group optionally having a protecting group. R ₄ represents a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, or a protective group; Represents a good hydroxy-lower alkyl or lower alkylidene group;
₄ represents a cycloalkane ring together with the carbon atom to which it is bonded; X represents a halogen atom; A represents an oxygen or sulfur atom or NB (where B represents a hydrogen atom or a lower alkyl group). Z represents a cyano group or a nitro group. ] 10. A compound of the general formula (XXII) or a salt thereof. Embedded image [In the formula, R ₁ represents a hydrogen atom or a carboxyl protecting group; R ₂ represents a hydrogen atom, a halogen atom, an alkoxy group, a hydroxyl group optionally having a protecting group, an amino group optionally having a protecting group. R ₄ represents a hydrogen atom, a lower alkyl group, a halogeno-lower alkyl group, or a protective group; Represents a good hydroxy-lower alkyl or lower alkylidene group;
₄ represents a cycloalkane ring together with the carbon atom to which it is bonded; X represents a halogen atom; A represents an oxygen or sulfur atom or NB (where B represents a hydrogen atom or a lower alkyl group). Y represents a hydrogen atom, a lower alkyl group or a carboxyl-protecting group. Z represents a cyano group or a nitro group. ]