JPH02124873A - Quinolonecarboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The quinolonecarboxylic acid derivative of formula I {R<1> is fluorine-substituted methoxy; Y is group of formula II (R<2> is H, hydroxyl, amino, lower alkyl, etc.; R<3> is H or lower alkyl; A is ethylene, COCH2, etc.), group of formula III [W is group of formula IV (R<5> and R<6> are H, lower alkyl, etc.; n' is 0 or 1), hydroxyl group, etc.; R<4> is H, hydroxyl group, lower alkyl, etc.; B is (CH2)1-4; n is 1 or 2], group of formula V (R<7> is H, lower alkyl, etc.) or group of formula VI (Z is O or S)}, its salt and ester. EXAMPLE:1-Cycloproplyl-8-difluoromethoxy-6-fluoro-7-(3-methylpiperazin yl)-1,4- dihydro-4-oxoquinoline-3-carboxylic acid. USE:The compound exhibits strong antibacterial activity and is useful as a remedy for microbism. PREPARATION:The compound of formula I can be produced e.g., according to the reaction formula by reacting 1mol of a compound of formula VII with 1-several mol of a compound of formula VIII.

Description

[Detailed Description of the Invention] Object of the Invention The present invention relates to a quinolone carboxylic acid derivative (1) that exhibits strong antibacterial activity, and provides a compound useful as a medicine for treating bacterial infections. be.

Constitution of the Invention The quinolone carboxylic acid derivative of the present invention is a compound represented by the general formula and a pharmacologically acceptable salt or ester thereof.

In the above formula, R' represents a fluorine-substituted methoxy group, and substituents include a hydroxyl group, a hydroxyl group, an amino group, a hydroxyl group, a lower alkoxy group, a lower aliphatic acyloxy group, a lower aliphatic acyl group,
Represents a lower alkyl group, aralkyl group, or lower aliphatic acyl group that may have a carboxy group, lower alkoxycarbonyl group, sulfo group, amino group, lower aliphatic acylamino group, or mono- or di-lower alkylamino group, and R3 is It represents a hydrogen atom or a hydroxyl group, a lower alkoxy group, or a lower alkyl group which may have a halogen atom as a substituent, A represents an ethylene group, a trimethylene group, or a group of the formula -COCHz-, and m represents 1 or 2. show. ), R5 and R6 are the same or different and represent a hydrogen atom, a lower alkyl group or an aralkyl group, and n represents O or 1. ), represents a hydroxyl group or a lower alkoxy group, and R4
represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, or a lower alkyl group which may have a halogen atom as a substituent, a lower alkoxy group which may have a fluorine atom in the hydroxyl group or alkyl moiety, and B represents a methylene group. , ethylene group z represents a trimethylene group or a tetramethylene group, n represents 1 or 2, )), ni' (wherein R? represents a hydrogen atom, a lower alkyl group, or a sulfur atom) .

In the general formula (1), R1 preferably represents a monofluoromethoxy group, a difluoromethoxy group, or a trifluoromethoxy group, and R2 in Y is a hydrogen atom; a hydroxyl group; an amino group; as a substituent a hydroxyl group, methoxy, ethoxy, n-propoxy,
Straight-chain or branched alkoxy groups having 1 to 3 carbon atoms such as isopropoxy; aliphatic groups having 2 to 4 carbon atoms such as acetoxy, propionyloxy, n-butyryloxy, and isobutyryloxy; Acyloxy group, aliphatic acyl group having 1 to 4 carbon atoms such as formyl, acetyl, propionyl, n-butyryl, isobutyryl, carboxyl group, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, etc. Alkoxycarbonyl group having 2 to 4 carbon atoms, sulfo group, amino group, acetamido, propionylamino, n-butyrylamino,
Aliphatic acylamino groups having 2 to 4 carbon atoms such as isobutyrylamino, methylamino, ethylamino, n-propylamino, isopropylamino, n-
Methyl, ethyl, n which may have a mono- or dialkylamino group having 1 to 4 carbon atoms such as butylamino, isobutylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, etc.
- Straight chain or branched alkyl group having 1 to 4 carbon atoms such as propyl, isopropyl, n-butyl, isobutyl; benzyl, p-methoxybenzyl, p
- an aralkyl group which may have a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group as a substituent such as aminobenzyl, p-methylaminobenzyl, p-dimethylaminobenzyl; or formyl;
It represents an aliphatic acyl group having 1 to 4 carbon atoms such as acetyl, n-butyryl, and isobutyryl, and R3 is a hydrogen atom; or a substituent is a hydroxyl group, and a carbon group such as methoxy, ethoxy, n-propoxy, and isopropoxy. Number 1
A linear or branched alkoxy group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, which may contain a halogen atom such as fluorine or chlorine; R5 and R6 are the same or different and represent a hydrogen atom; an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, and isopropyl; or benzyl, p
- an aralkyl group which may have a lower alkoxy group, an amine group, a mono- or di-lower alkylamino group as a substituent, such as methoxybenzyl, p-aminobenzyl, p-methylaminobenzyl, p-dimethylaminobenzyl; Furthermore, W represents a hydroxyl group; or an alkoxy group having 1 to 3 carbon atoms such as methoxy, ethoxy, n-propoxy, and isopropoxy, and R4 represents a hydrogen atom; as a substituent, a hydroxyl group, methoxy, ethoxy, n −
Methyl, ethyl, n-propyl, which may have a linear or branched alkoxy group having 1 to 3 carbon atoms such as propoxy or isopropoxy, or a halogen atom such as fluorine or chlorine; Alkyl group having 1 to 3 carbon atoms such as isopropyl; hydroxyl group; or 1 to 3 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy which may have 1 to 3 fluorine atoms R7 represents a hydrogen atom; or an alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, and isopropyl; A represents an ethylene group, a trimethylene group, or an alkyl group having the formula - C
represents an OCH,- group, B represents a methylene group, ethylene group, trimethylene group or tetramethylene group, Z represents an oxygen atom or a sulfur atom, m and n represent 1 or 2, and n' represents 0 or 1 shows.

In a more preferable compound in the general formula (1), R1 represents a difluoromethoxy group or a trifluoromethoxy group, and Y represents the formula [in the above formula, R'', R', R', R', R'R
', A% 2% m, n and n' have the same meanings as above, B' represents a methylene group or an ethylene group, and R'', R'' and R9 are the same or different and represent a hydrogen atom or carbon number. Represents 1 to 3 alkyl groups. ] Compounds that exhibit the following can be mentioned.

The compound having the general formula (I) can be converted into a pharmacologically acceptable salt or ester, if necessary.

Such salts include acid addition salts of mineral acids such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, methanesulfonates, ethanesulfonates, benzenesulfonates. acid addition salts or sodium salts, potassium salts of organic acids, such as acid salts, p-toluenesulfonates, oxalates, maleates, fumarates, tartrates, citrates;
Examples include metal salts of carboxylic acids such as calcium salts, magnesium salts, manganese salts, iron salts, and aluminum salts. Examples of ester-forming groups include lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl, aralkyl groups such as benzyl, and acetoxymethyl and pivaloyloxymethyl. Lower aliphatic acyloxyalkyl group, lower alkoxycarbonyloxyalkyl group such as 1-(ethoxycarbonyloxy)ethyl, 1-(isopropoxycarbonyloxy)ethyl, N,N such as N,N-dimethylaminocarbonylmethyl group -disubstituted aminocarbonylalkyl group, phthalidyl group or (5-methyl-2-
Examples include groups that can be easily converted into carboxy groups in vivo, such as oxo-1,3-dioxolen-4-yl)methyl groups. Note that the compound (1) of the present invention can also exist as a hydrate.

Examples of the compound having the general formula (1) of the present invention include the compounds shown in the table below, as well as their pharmacologically acceptable salts and esters. N-Omote-o-≦N-Omote (Continued) Chapter 22-Table.

(Continued) Man-≦N-inside (Continued) ]-22-Table (Continued) Man-2-Table (Continued) Man-≦Knee-Table (Continued) Man-2-1 Table Man-Nimi-Table (Continued) Table 1-22 (Continued) Table 1-27 (Continued) Table 1-27 (Continued) Table (Continued) The novel compounds of the present invention having the general formula (1) are as follows, for example: It can be produced according to reaction A or B shown in .

Anti-Chin' = M4 Rakugono J- (II) ([) Reaction route CB) (V) In the above formula, R1 and Y have the same meanings as above, and R111 is a hydrogen atom or a hydrogen atom such as methyl or ethyl. represents a lower alkyl group.

That is, the novel compound (I) of the present invention is the compound (II
) or its boron fluoride chelate compound (V) and one to several moles of the amine compound (I[ Manufactured by.

Suitable solvents used in this reaction include aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, and dimethylacetamide, but also acetone, ketones such as methyl ethyl ketone, diethyl ether, and tetrahydrofuran. , ethers such as dioxane, esters such as ethyl acetate, methanol, ethanol, n-propertool,
Alcohols such as isopropanol and butanol, and nitriles such as acetonitrile can also be used. As a deoxidizer, 1,8-diazabicyclo(5,4,0)
-7-undecene, 1,5-diazabicyclo(4,3
,0)-5-nonene, triethylamine, tributylamine, pyridine, picoline, lutidine, collidine, etc.
Examples include metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium-1-butoxide, and inorganic bases such as sodium carbonate and potassium carbonate. The amount of the deoxidizing agent used is preferably equimolar to 5 times the molar amount of the compound (Il) or (V), but in the case of the above amines, it can be used in large excess as a solvent. Moreover, since the excess amine (I[I) acts as a deoxidizing agent, the reaction proceeds smoothly even when no other deoxidizing agent is added.

The reaction is carried out at a temperature ranging from 0°C to 200°C.

After completion of the reaction, the target compound of this reaction can be obtained by treating the reaction mixture according to a conventional method, and if necessary, it can be further purified using a conventional purification method such as a recrystallization method or column chromatography.

In the case of manufacturing according to the method ``1 method IL process'', the target chelate compound (VI) is first obtained, which can be treated with a hydrous alcohol or a basic hydrous alcohol to form the compound CI) and the compound CI), respectively. It can be derived from BP, adducts or (I). Compound (1) ・
BF, the adduct can be easily converted to the target compound (I) by treatment with a base.
).

The bases used in this treatment operation include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate,
．． Tertiary amines such as 8-diazabicyclo(5,4,0)-7-undecene, 1,5-diazabicyclo(4,3,0)-5-nonene, triethylamine, 4-dimethylaminopyridine or sodium methoxide Mention may be made of metal alkoxides such as , sodium ethoxide, potassium butoxide.

Compound (1) or (1) thus obtained
- BP and adducts are converted into desired salts according to conventional methods, if necessary.

The conversion reaction from compound (n) or (IV) to boron fluoride chelate compound (V) is described, for example, in JP-A-59
The reaction is carried out by reacting hydroborophonic acid or boron trifluoride according to the method described in Japanese Patent No. -67290.

The compound having the general formula (1) produced in this way may have optical isomers or geometric (cis, trans) isomers based on the asymmetric carbon atom of the Y moiety in its production. In such cases, if desired, the corresponding optical isomer or geometric isomer of the target compound (I) can be obtained by carrying out the above reaction using the optically resolved or separated starting compound YH (I[[). Alternatively, each stereoisomer can be obtained from a mixture of optical isomers or geometric isomers of compound (I) according to a conventional optical resolution method or separation method.

Compound (II) or (IV
) and their chelate compound (V) are new compounds and are produced by the following method.

anti-amσL In the above formula, R1 has the same meaning as defined above, R1 represents a lower alkyl group such as methyl or ethyl, X represents a halogen atom such as fluorine, chlorine, bromine, or iodine, and R1 , R12 represent the same or different alkyl groups, or together with the nitrogen atom to which they are bonded,
Furthermore, depending on the case, it indicates a cyclic amino group formed together with an oxygen atom, a sulfur atom, a sulfinyl group, or a sulfonyl group.

Among the compounds (■) used as starting materials in the above-mentioned anti-bottom route process, compounds in which X is a fluorine atom and R1 is a monofluoromethoxy group or a difluoromethoxy group can be obtained by the anti-mX shown below. Further, a compound in which R1 is a trifluoromethoxy group is manufactured by Anti-Hoku, EL.

In the above formula, R13 is lower alkoxy group or amino represents a group; is chlorine, bromine, Ha such as iodine Indicates a rogen atom.

(XIV) (XV) (■C) (X■) In the above formula, R13 and Xl have the same meanings as described above,
) (b is the same as or different from Xa and represents a halogen atom such as chlorine bromine or iodine.

In addition, in D E, 3-hydroxy-2,4,5-)lifluorobenzoic acid (XIV) used as a starting material is a known compound 4-hydroxy-3, It is produced by thermally decarboxylating 5,6-)lifluorophthalic acid (XX) in water or an aqueous solvent.

*, FL (XX) (XIV) The reaction conditions and post-treatment methods for each step are detailed in Reference Examples.

Effects of the Invention The object compound of the present invention having the general formula (1) and its pharmacologically acceptable salts exhibit excellent antibacterial activity. When its antibacterial activity was measured by the agar plate dilution method, it was found that it was effective against Gram-negative bacteria such as Staphylococcus aureus and Enterococcus, as well as Escherichia coli, Shigella, Klebsiella pneumoniae, M. aeruginosa, Serratia, Salmonella Enterobacterella, and Pseudomonas aeruginosa. It showed strong antibacterial activity against a wide range of pathogenic bacteria, including Gram-negative bacteria and their resistant bacteria. The test results are shown in m using norfloxacin as a control compound.

Therefore, the compound (1) of the present invention is useful as an antibacterial agent for treating bacterial infections caused by these pathogens. Examples of dosage forms for this purpose include oral administration in the form of tablets, capsules, granules, powders, syrups, etc., and parenteral administration in the form of intravenous injections, intramuscular injections, halvings, etc. The dosage varies depending on age, body weight, symptoms, dosage form and number of administrations, but usually about 100 to 1000 μl per day is orally administered to adults in one or several divided doses.

Next, the present invention will be explained in more detail with reference to Reference Examples and Examples.

3-Hydroxy-2,4,5-)lifluorobenzoic acid (
X■) Dissolve 20.0 g (0,104 mol) in 500 mff1 of ethanol, 5 mjl of concentrated sulfuric acid! After heating and refluxing for 4 hours, ethanol was distilled off under reduced pressure and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-hydroxy-2,4,5-trifluorobenzoic acid ethyl ester (XV: R''=
16.9 g of oEt) were obtained as a colorless powder.

MS spectrum (CI): m/e 221 (M”+
1).

175 (M”-0CJs) 3-hydroxy-2,4,5-trifluorobenzoic acid ethyl ester (XV:R”=OE
t) 8.83 g (0.04 mol) was dissolved in 40 ral of dimethylformamide, and 1.76 g (0.044 mol) of 60% sodium hydride was added little by little under stirring while cooling with water. Stir for a minute. This reaction mixture was heated to 20On+j! Transfer to a stainless steel autoclave and add 28.0 g of chlordifluoro/tan.
(0,32 mol) of dimethylformamide 100
IIIl was added and stirred under pressure at 95-100°C for 5 hours. After the reaction was completed, dimethylformamide was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with toluene. After washing the toluene layer with water and drying over anhydrous sodium silicate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene) to obtain 3-difluoromethoxy 2.4.
5-1-Lifluorobenzoic acid ethyl ester (XVI
bsR''=OBt) 4.85 g were obtained as a colorless liquid.

MS spectrum (CI): m/e 271 (M”+
1).

225(M”-0CJs) 3-difluoromethoxy-2,4 obtained by the above method
,5-)lifluorobenzoic acid ethyl ester (XVIb
: R13=OEt) 5.79 g (0,02
1 mol) in 40 rgl of ethanol, 6% aqueous sodium hydroxide solution 20n+4! was added and left at room temperature overnight. The reaction mixture was made acidic by adding 3.5 mf of concentrated hydrochloric acid, concentrated under reduced pressure, extracted with ethyl acetate, the ethyl acetate layer was washed with water, and anhydrous sulfuric acid).
5.22 g of difluoromethoxy-2,4,5-1-lifluorobenzoic acid (■b) was obtained as a colorless powder.

Melting point 68-70°C MS spectrum (CI): m/e 243 (M”+
1), 225 (M"-0H), 223 (M"-F
), 192 (M”-cFz).

175 (M” CFz Off) NMR spectrum (CDCj!s, δ): 6.67 (
18,t, J=7211z.

-0C1lFz), 7.83 (IH, m, aromaH)
+ 10.74 (LH, br.

Coo)l) 3-hydroxy-2,4,5-trifluorobenzoic acid (
XIV) Dissolve 100.0 g (0.52 mol) in 400 mf of benzene, 300 mj of thionyl chloride! After heating and refluxing for 3 hours, the solvent and excess thionyl chloride were distilled off under reduced pressure to obtain 3-hydroxy-2,4,5-trifluorobenzoic acid chloride.

This was added dropwise to 1500 m2 of 28% aqueous ammonia while stirring under water cooling, and stirring was continued for 2 hours.The mixture was left at room temperature overnight, acidified with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
88.2 g of hydroxy-2,4,5-trifluorobenzoic acid amide (XV: R''=NH2) was obtained as a colorless powder.

MS spectrum (CI): m/e 192 (M”+
1).

175 (M”-NHK) Melting point 153-155°C 3-Hydroxy-2,4,5-trifluorobenzoic acid amide (XV:R”・N1h) obtained as above 5
．． 00 g (0,026 mol) of dimethylformamide 130III! , dissolved in potassium carbonate 4.70
g (0,034 mol) and 6.8 g (0,079 mol) of chlorodifluoromethane were added thereto, and the mixture was stirred in an autoclave at 100°C for 3 hours. After the reaction, 500 m of water
, e was added, extracted with ethyl acetate, the organic layer was washed with water, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (solvent: 1:1 mixture of toluene and ethyl acetate), and 3-difluoromethoxy-2 ,4,5 trifluorobenzoic acid amide (XVIb: R'3=NHz) 5
．． 08 g were obtained as colorless needle crystals.

Melting point: 102-104°C MS spectrum (CI): m/e 242 (M”+
1).

225(M”-NHK) 3-difluoromethoxy-2,4 obtained as above
, 5-trifluorobenzoic acid amide (XVIb:R”=
Suspend 15.53 g (0,064 mol) of NH2) in 20 m2 of concentrated sulfuric acid, stir with water cooling, and add 6.6 g of sodium nitrite.
30 ml of an aqueous solution of 0 g (0,096 mol) was gradually added dropwise, then heated and refluxed for 30 minutes.

50 mj of condensed water cooled to room temperature! was added, extracted with chloroform, the organic layer was washed with water, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 3-difluoromethoxy-2,4,5
15.59 g of -trifluorobenzoic acid (■b) was obtained as a colorless powder. This item has melting point, MS spectrum, N
The MR spectrum confirmed that the product was the same as that obtained by the ester-mediated method described above.

1 part sodium hydroxide 2.18g (0,052 mol) and water 5
ml and dissolve, then add 20 mjl of dimethylformamide.
! was added thereto, and 4.97 g (0,026 mol) of 3-hydroxy-2,4,5-)lifluorobenzoic acid (XIV) was added little by little while cooling with water. After the addition was completed, the mixture was stirred for 30 minutes under water cooling. 200m/! of this reaction mixture! The volume was transferred to a stainless steel autoclave, and 100 mff1 of dimethylformamide containing 24.0 g (0,277 mol) of chlorodifluoromethane was added thereto, and the mixture was heated at 100 mff1 under pressure.
The mixture was stirred at 110°C for 5 hours. After the reaction was completed, the mixture was added to water and extracted with chloroform. After washing the chloroform layer with water and drying with anhydrous sodium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (solvent: 9=1 mixture of ethyl acetate and ethanol) to obtain 3-difluoromethoxy-2,4 ,5-)lifluorobenzoic acid (■b)2. O
Og was obtained as a colorless powder.

It was confirmed by the melting point, MS spectrum, and NMR spectrum that this product was the same as that obtained by the above-mentioned ester-mediated method and amide-mediated method.

[Reference Example 4] 245-1fluoro-33-hydroxy-2,4,5-)rifluorobenzoic acid ethyl ester (X V : R”=OEt) 5.0 g (0,0
23 mol) dimethylformamide 20n/! dissolved in
60% sodium hydride 1.0g (0,02
5 mol) was added little by little, and after the addition was complete, the mixture was stirred for 30 minutes under water cooling. Then difluorodibromomethane 28.0
dimethylformamide containing g (0,13 mol) 130
m/! was added and stirred at room temperature for 23 hours. After the reaction was completed, the reaction mixture was diluted with 300 mf of water and extracted with toluene, and the toluene layer was washed with water, dried over anhydrous sulfuric acid, and then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent: toluene) to obtain 3-difluorobromomethoxy-2,4,5-)rifluorobenzoic acid ethyl ester (X■: R"=OEt, X"=Br)5
, 60 g was obtained as a colorless liquid.

+IS spectrum (CI): m/e 35HM”+
3).

349 (M”+1) Then this 3-difluorobromomethoxy-2,4,5
-Trifluorobenzoic acid ethyl ester (X■: R”
= OEt, X" = Br) 1.50 g (0,0
043 mol) was dissolved in 10 m2 of toluene, 2.50 g (0,013 mol) of silver borofluoride was added, and the mixture was heated under reflux for 8 hours with stirring while shielding from light. Filter the reaction solution, wash the solution with water,
After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (solvent: toluene) to obtain 2.4.5-trifluoro-3-trifluoromethoxybenzoic acid ethyl ester (X ■：R
1.12 g (=OEt) were obtained as a colorless liquid.

MS spectrum (CI): m/e 289 (M”+
1).

269(M”-F) 2,4.5-)refluoro-3 obtained as above
-Trifluoromethoxybenzoic acid ethyl ester (X■
: RI'=OEt) 5.05 g (0,0175 mol) in ethanol 100m+j! 3 ml (0,0193 mol) of IN caustic soda 19 was added and the mixture was left at room temperature for 2 hours. Add to this 19.3 mf of IN hydrochloric acid.
After adding f1, it was concentrated under reduced pressure, the residue was extracted with ethyl acetate, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and dried under reduced pressure to give 2,4.5-)rifluoro-3-trifluoromethoxy. 3.98 g of benzoic acid (■c) was obtained as a colorless powder.

Old spectrum (CI): ra/e 26HM”+1
).

243(M”-OH) NMR spectrum (CDCf 3+δ) Near, 88(
LH, n, aromaH) 3-difluoromethoxy-2,
4,5-)lifluorobenzoic acid (■: X = F,
R' = OCHFz ) 5.22 g (0,0216 mol) was dissolved in 300 1N benzene, thionyl chloride 1
5mj2 was added and heated under reflux for 3 hours.

After the reaction, benzene and excess thionyl chloride were distilled off under reduced pressure, and 3-difluoromethoxy-2,4,5-trifluorobenzoic acid chloride (■: X=F, R'=OCHF2
) was obtained.

On the other hand, 2.80 g of magnesium ethoxide (0,0
238 mol) and 3.81 g of malonic acid diethyl ester (
0,0238 mol) in anhydrous diethyl ether 60+++
By heating and refluxing the mixture under stirring for 1 hour in 42 ml, a suspension of diethyl ethoxymagnesium malonate in diethyl ether was obtained. A solution of the above acid chloride dissolved in 50 ml of anhydrous diethyl ether was added dropwise to this while stirring at room temperature, and 35 ml of IN hydrochloric acid was added to the reaction mixture, which was further stirred at room temperature for 2 hours, stirred vigorously, and then separated. After washing the organic layer with water and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 3-difluoromethoxy-2,4,5-trifluorobenzoylmalonic acid diethyl ester (IX:X=F).

Rr=OCHFz, R-=Et) 7.07 g were obtained as a brown liquid.

MS spectrum (CI): m/e 385 (M”+
1).

339 (M"-oczHs) Next, this was dissolved in 200mj! of dioxane, and 4.52 g of p-toluenesulfonic acid monohydrate (0,0238
mol) was added and heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was mixed with 100 mf of water and 2.5 mf of sodium hydrogen carbonate.
2 g (0.03 mol) was added and extracted with ethyl acetate.

The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-difluoromethoxy-2,4,5-1-
Lifluorobenzoylacetic acid ethyl ester (X:
=F, R1=OC)lFz, Ra-Et) 5.66
g was obtained as a reddish-brown liquid.

? IS spectrum (CI): m/e 313 (M”
+1).

225 (M'-CH2COC2H5) Then acetic anhydride 20a+4! and 6 rnl of ethyl orthoformate were added, and after heating under reflux for 2 hours, excess acetic anhydride and ethyl orthoformate were distilled off under reduced pressure.

Dichloromethane 200a+f! , cyclopropylamine 1.25 g (0,022
The reaction solution was stirred for 1 hour under water cooling, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (
Solvent: 9=1 mixture of toluene and ethyl acetate),
3-Cyclopropylamino-2-(3-difluoromethoxy-2,4,5-1-lifluorobenzoyl)acrylic acid ethyl ester (XII[: X=F, R'=
3.29 g of OC1 (Pi, R, = Et) was obtained as an amber-colored liquid.

MS spectrum (CI): m/e 380 (M'+
1).

225 (M”-LeIJH-CH=C(Cotε1))
Next, dissolve this in 150 nl of anhydrous diethyl ether,
0.39 g (0,0098 mol) of 60% sodium hydride was added little by little at room temperature with stirring. After the addition was completed, the mixture was further stirred at room temperature for 1 hour, and IN hydrochloric acid was added with vigorous stirring to make the entire reaction solution acidic. Filter the reaction mixture, wash with water,
Then washed with diethyl ether, 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,
4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (IV: R' = OCHF2.R,
= [Et) 1.44 g were obtained as colorless needle crystals.

Melting point 224-226°C MS spectrum (CI): rnle 360 (M”
+1) [Reference Example 6] -cyclolobi-67-di1
-Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid ethyl ester (■: R' = OCH
Fz+Ra=Et) 1.40 g (0,003
9 mol) to acetic acid 9 rnlS concentrated sulfuric acid 1.2 mj! and 7 ml of water were added, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was placed in ice water and the precipitated crystals were washed with water and diethyl ether to give 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4. -dihydro-4-oxoquinoline-3-carboxylic acid (II: R' = OCHFz) 1.09 g
was obtained as colorless needle-like crystals.

Melting point 202-207°C MS spectrum (CI): m/e 332 (M”+
1) Elemental analysis value (%): Theoretical value analysis value as C+4HtFJO4 50, 77 50, 53 2.74 2.79 4.23 4.06 1-Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1 , 4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (■: R1=OCHF
2. R,=Et) 9.50 g (0,0265 mol) to 150 m! of methyl isobutyl ketone! ! , dissolved in
Add 5.63 g of boron trifluoride-ether complex to 6
The mixture was heated to reflux for an hour. The reaction solution was cooled with water, and the precipitated crystals were collected in a furnace and washed with diethyl ether and then chloroform.
-Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-
3-carboxylic acid Bh chelate (V: R'-0CH
h) 6.15 g were obtained as a colorless powder.

Melting point 225-233°C MS spectrum (CI): m/e 380 (M”+
1) Elemental analysis value (%): Cl4HIBF1,804
・CHN as 1/2 uzo Theoretical value 43.33 2.34 3.61 Analysis value 43.06 2.09 3.782.4.5-
Trifluoro-3-trifluoromethoxybenzoic acid (■
c: X=F, R1=OCFi) as a starting material,
By the same method as Reference Example 5, 1cyclopropyl-6,
7-difluoro-8-trifluoromethoxy-1,4-
Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (■:R'=OCF3.R,=Et) was obtained as colorless needle crystals.

Melting point: 160-161°C MS spec Tor (CI): m / e 378 (M++1) Precepts.

From the compound obtained in Reference Example 8, 1 was prepared in the same manner as in Reference Example 7.
-Cyclopropyl-6,7-difluoro-8-trifluoromethoxy-1,4-dihydro-4oxoquinoline-
3-carboxylic acid BF2 chelate (V: R'-0C
Fi) was obtained as a colorless powder.

Melting point 266-271'C MS spectrum (CI): m/e 398 (M''+
1) Elemental analysis value (%) Cl 41 (?BF7NO4
・CHN as 1/2+1□0 Theoretical value 41.42 1.99 3.45 Analytical value 41.26 1.69 3.57 4-Hydroxy-3,5,6-)lifluorophthalic acid (XX) 270
0g and 6j2 of water were placed in an autoclave, the atmosphere was replaced with nitrogen, and the autoclave was heated at 140°C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to precipitate crystals. The crystals were filtered, washed with chloroform, and then dried. 1623 g of 3-hydroxy-2,4,5-)lifluorobenzoic acid (XIV) was obtained as a colorless powder.

Melting point 144-146°C MS spectrum: m/e 192 (M NMR spectrum (CD30D, δ): 4.94 (IH,
bs, -01(), 7.25(IH,m,ar
omH) [Reference Example 11] Gold or L-alanine ethyl ester salt M salt of S-melpipagene 10 g (0,0
65 mol) was added with 10 ml of water, and then 3.2 g (0,065 mol) of sodium cyanide was added. 3 under stirring
5.3 g (0,065 mol) of 7% formaldehyde solution was added dropwise. (The reaction temperature rose to around 40° C.) After the dropwise addition, the mixture was stirred at room temperature for 6 hours, and then left in the apparatus overnight. The reaction solution was extracted with methylene chloride, and the organic layer was washed with saturated sodium bicarbonate solution and further washed with water. After drying over anhydrous sodium sulfate, the residue was subjected to silica gel column chromatography (solvent: 9:1 mixture of toluene and ethyl acetate) to obtain 5.6 g of N-cyanomethyl-L-alanine ethyl ester as a colorless oil. Obtained.

MS spectrum (CI): m/e 157 (M”+
1).

130 (M”-CN) NMR spectrum (CDCj!, δ): 1.28
(3)1. t, J = 6Hz - CHz subres 1.33
(3H, w, J=6Hz, mountain CHri), 2.15 (L
H, s, -NH-), 3.45 (LH, q, J=
6) 1z, CH3CH8).

3.60 (2H, S, -1cN), 4.20 (2H
, q, J=6Hz.

5.0 g (0,321 mol) of the above reaction product, 56 g of 4% ammonia ethanol, and 1.38 g of Raney nickel were placed in an autoclave, and the reaction temperature was 90°C and the hydrogen pressure was 5.
The mixture was stirred at 0 kg/cJ for 2 hours. The catalyst was separated off, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (1-20 mixture of dimethanol and chloroform as solvents) to obtain (3S)-methyl-2-oxopiperazine 2. 8 g was obtained as colorless crystals.

MS spectrum (CI): m/e 115 (M”+
1) NMR spectrum (CDCl: l, δ): 1.4
0(311,w,sub-)1.78(IH,s,-N
H-), 2.9-3.6 (5H, m.

NFLB! 1=jhN-, CHz-CHz)+7.0
0(IH+br.

NHf, -) 1.53 g (0,040 mol) of lithium aluminum hydride was added to 35 mff1 of tetrahydrofuran, and under cooling with ice water, a solution of 2.29 g (0,020 mof) of the above (3S)-methyl-2-oxopiperazine in 35 mj of tetrahydrofuran was added. ! was dripped. After the dropwise addition, the mixture was heated under reflux for 5 hours. After cooling, a small amount of water was added under water cooling to decompose the excess reducing agent, and the mixture was filtered to obtain a reaction liquid. To this was added 10 mff1 of concentrated hydrochloric acid, concentrated to dryness, and crystallized with ether/ethyl alcohol to obtain 2.73 g of (2S)-methylpiperazine dihydrochloride as a colorless powder.

This was dissolved in 10n+j2 of water, 10% sodium hydroxide solution was added to adjust the pH to 10 or higher, and the mixture was extracted with chloroform. After drying the chloroform layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was confirmed to be the (2S)-methylpiperadi(S) form by distillation under reduced pressure.

MS spectrum (CI): m/e 1101(”+
1) NMR spectrum (CDCI, δ): 1.0
0 (3H, w, flea-)! , 85(2H,s, -NH-
0,2,30-2.45 (IH, m.

CH2Cl), 2.6-3.0 (6H, m, -N
Mt. H CHz Mt. NH -) Note 1) HPLC analysis conditions [pretreatment method] * 2.3,416-tetra-0-acetyl-β-glucopyranosyl isothiocyanate (ldTc) 1 Liquid A: 2-methyl Piperazine 0.0288g (0,2
88 mmof)/acetonitrile 25 ml solution B: G
ITCO, 20g (0.51mmof) / Acetonitrile 25n+j! Solution A 0.43 ml (0,005m-mol!,)
0.24 ml (0,005 mmol) of solution B was added to the mixture, and the mixture was left at room temperature for 10 minutes. Transfer 2 μl of this reaction solution to HP
LC analysis was performed.

[HPLC analysis conditions] Column: TSK-gel ODS-80TM (4,
6X250 mm) Mobile phase: Methanol: 0.05
M sodium dihydrogen phosphate = 25 = 75 Flow rate: 0.70 ml/min Detection: U 254 nm [Reference Examples 12 to 15] The following piperazines were synthesized according to the method of Reference Example 11.

[Reference Example 16] S-aminopyrrozine dihydrochloride Danxakitan L-aspartic acid ethyl ester hydrochloride 14.88g
(0,066 mol) was dissolved in 200 ml of methylene chloride, and while cooling with ice water, 7.33 g of triethylamine (0,
072 mol) was added. After stirring for 20 minutes,
Butyl dicarbonate 14.4 g (0,066 mol)
was added in portions. After further stirring for 2 hours, the mixture was concentrated under reduced pressure, toluene was added, and triethylamine hydrochloride was removed by filtration. The furnace liquid was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: 4:1 mixture of toluene and ethyl acetate) to obtain N-tert-butoxycarbonyl-L-aspartic acid ethyl ester (18.6%).
1 g was obtained as a colorless oil.

MS spectrum (CI): m/e 234 (M"+1-CHz=C(C1h)z)+190
(M" +1-Co□, CHz=C(CHs)z)
3.01 g (0,138 mol) of lithium borohydride was dissolved in 100 mI of tetrahydrofuran! , dissolved in. To this solution, 40 ml of a tetrahydrofuran solution containing 10.0 g (0,035 mol) of the above product was added dropwise.

(The dropping rate was adjusted to maintain the reaction temperature at 40°C.) After the dropping was completed, stirring was further performed at room temperature for 4 hours. A small amount of water was added to decompose the reducing agent, and the mixture was filtered to obtain a reaction solution. After concentrating this to remove tetrahydrofuran, common salt was added and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure (2S
6.15 g of )-tertbutoxycarbonylamino-1,4-dihydroxybutane were obtained as a colorless oil.

MS spectrum (CI): m/e 206 (M”+
1).

150(M"+I GHz"'C(C1h)z)11
06(M”+I COX, CHz=C(CH:+
)z).

(2S) -tert-butoxycarbonylamino-1
,4-dihydroxybutane 13.0 g (0,060
mole), 14.54 g (0,144 mole) of triethylamine at 25 On/! of methylene chloride. Under cooling with ice water, 15.12 g of methanesulfonyl chloride (0,
132 mol) was added dropwise. After stirring for 3 hours under cooling with ice water, the mixture was left at room temperature overnight. Add water and methylene chloride,
The methylene chloride layer was separated, dried over anhydrous sodium sulfate, and concentrated to give (2S) -tert- as colorless crystals.
20.22 g of butoxycarbonylamino-1,4-di(methylsulfonyloxy)butane was obtained.

MS spectrum (CI): m/13 210 (M”
0SOzCHs.

C1tz=C(C1h)z) (2S) -tert-butoxycarbonylamino-1
,4-di(methylsulfonyloxy)butane 20.22
g (0,056 mol) was suspended in 130 ml of methanol and 6.0 g (0,059 mol) of triethylamine was added. After absorbing ammonia gas until saturation, the mixture was stirred at room temperature for 2 days. This reaction solution was concentrated under reduced pressure to obtain a residue. Add this to 150n/! of methylene chloride! Dissolved in di-tert-butyl dicarbonate 12.2
2 g (0,056 mol) was added, and then 23 ml of triethylamine was added dropwise. After further stirring at room temperature for 2 hours, the mixture was washed with water, then dried over anhydrous sodium sulfate, and the concentrated residue was subjected to silica gel column chromatography (solvent = 9:1 mixture of toluene and ethyl acetate).
3S)-tert-butoxycarbonylamino-1-t
Ertbutoxycarbonylpyrrolidine was obtained as a colorless oil. Concentrated hydrochloric acid was added to this mixture, concentrated to dryness, and crystallized with ethyl alcohol to obtain 2.87 g of (3S) aminopyrrolidine dihydrochloride as a colorless powder.

MS spectrum (CI): m/e 87 (M”+1
).

70(M"-Nil□) 2.2.2-) Refluoroethanol 15mj!,
Under water cooling, 1.08 g of 60% sodium hydride (0
,027 mol) was added. After stirring for 20 minutes, 1tert
-butoxycarbonyl-3,4-epoxypyrrolidine 5
．． 0 g (0,027 mol) was added and heated under reflux for 3 hours. Saturated brine was added and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated. This concentrated solution was dissolved in 50 mf of pyridine, and 3.23 g (0,028 mol) of methanesulfonyl chloride was added while cooling with ice water. After further stirring at room temperature for 5 hours, the mixture was heated overnight. Add 300 m2 of water, perform toluene extraction, dry the organic layer over anhydrous sodium sulfate, concentrate, and apply the residue to silica gel column chromatography (solvent: 9:1 mixture of toluene and ethyl acetate) to obtain 1-tert- Butoxycarbonyl-3-(2,2,2-1-lifluoroethoxy)-4-methylsulfonyloxypyrrolidine 7,07
I got g. 3.95 g (0,011 mol) of this product and 100 n/! of 20% ammonia methanol solution! was charged into an autoclave and stirred at a reaction temperature of 140°C for 10 hours. The solvent was distilled off under reduced pressure, saturated sodium carbonate solution was added, and ethyl acetate extraction was performed. The organic layer was dried over anhydrous sodium sulfate, concentrated, and the residue was subjected to silica gel column chromatography (solvent: ethanol: ethyl acetate 1: 9
1.61 g of 3-amino-1-tert-butoxycarbonyl-4-(2,2,2-)lifluoroethoxy)pyrrolidine was obtained as a colorless oil.

MS spectrum (CI): mle 285 (M”+
1).

229 (M”+1-CI□=C(C1h)Z) To 1.61 g (0,006 mol) of the product obtained in the above reaction, add 30 ml of ethanol, 2 mf of concentrated hydrochloric acid, 4 ml of water.
ml and left overnight at room temperature, concentrated to dryness under reduced pressure to obtain 1.60 g of 3-amino-4-(2,2,2-)lifluoroethoxy)pyrrolidine dihydrochloride as colorless crystals. Obtained.

MS spectrum (CI): mle 185 (M”+
1) 34.7 g (0.5 mol) of hydroxylamine hydrochloride in 135 mjl of water! 1-benzyl-
24.7 g of 3-carboethoxy-4-pyrrolidone (0
, 1 mole) of ethanol 135 m! ! After dropping the solution, 28.1 g (0,265 mol) of sodium carbonate was added, and the mixture was stirred at room temperature for 6.5 hours. Add 300mj of chloroform to the reaction solution! Extract with , wash the obtained chloroform layer with water,
After drying, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 2:1).
) to obtain 15.8 g of 1-benzyl-3-carboethoxy-4-hydroxyiminopyrrolidine as a brown oil.

MS spectrum (Cf): mle 263 (M”+
1) IR spectrum (capillary, ν□x c, m
-'): 3300, 1740 28 m2 of a 3.4 mol toluene solution of sodium bis(2-methoxyethoxy)aluminum hydride to 30 m2 of toluene? 5.24 g of 1-benzyl-3-carboethoxy-4-hydroxyiminopyrrolidine (0,
A solution of 0.02 mol) in 10 m2 of toluene was added dropwise over 1 hour, and after stirring at room temperature for 1.5 hours, the mixture was further heated under reflux for 2 hours. After the reaction solution was allowed to cool to room temperature, ice water was added to separate the formed precipitate. After concentrating the filtrate under reduced pressure, the residue was subjected to silica gel column chromatography (solvent: methanol).
2.16 g of -benzyl-3-amino-4-hydroxymethylpyrrolidine were obtained as a brown oil.

MS spectrum (CI): mle 20? (M"+
1) IR spectrum (capillary + !'sex
Cm-'): 3150-3400 - 5,87 g (0,0285 mol) of benzy-3-amino-4-hydroxymethylpyrrolidine in 100 mj of dichloromethane! 6.21 g (0.0285 mol) of di-tert-butyl dicarbonate was added in portions at room temperature. After stirring at room temperature for one day, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate) to obtain 1-benzyl-3-(N-te
6.32 g of rt-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine were obtained as a light brown oil.

IR spectrum (capillary r vl&mx C1
m-'): 3350, 1680-1720 1-benzyl-3-(N-tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine 6, 32
g (0,0207 mol) was dissolved in 100 ml of ethanol, 2.0 g of 20% palladium-carbon powder was added,
In a stainless steel autoclave, room temperature, hydrogen pressure 100 k
The reaction was stirred for 27 hours at g/cf. After the catalyst was separated from the furnace, the furnace liquid was concentrated under reduced pressure to obtain 3.99% of 3-(N-tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine.
g was obtained as a colorless crystalline oil.

MS spectrum (CI): mle 217 (M”+
1) IR spectrum (KBr, “IIIK C
l11-'): 3350.3270°1680~16
90 3(N-tert-butoxycarbonyl)amino 4-hydroxymethylpyrrolidine 3.08 g (0,0143
mol) in 50 ml of dichloromethane and diluted at room temperature.
3.12 g of er t-butyl dicarbonate was added in portions. After stirring for one day at room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: 1:1 mixture of toluene and ethyl acetate) to obtain 1-tert-
Butoxycarbonyl-3(N tert-butoxycarbonyl)amino-4hydroxymethylpyrrolidine3.
99 g were obtained as colorless crystals.

MS spectrum (CI): mle 317 (M”+
1) 1 tert-butoxycarbonyl-3-(N-
3.86 g (0,0122 mol) of ter t-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine was dissolved in 90 mffi of diethyl ether L, and after cooling on ice, 0.3 m of boron trifluoride/diethyl ether complex was dissolved.
1 was added thereto, and then a diethyl ether solution of diazomethane (containing 0.126 mol) was added dropwise over 1.5 hours.

After stirring at the same temperature for 0.5 hour, the mixture was left at room temperature overnight. Saturated brine was added to separate the layers, the ether layer was dried, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: 2:1 mixture of toluene and ethyl acetate). -butoxycarbonyl-3-(N-t
0.47 g of ert-butoxycarbonyl)amino-4-methoxymethylpyrrolidine was obtained as a colorless oil.

MS spectrum (CI): mle 33HM”+1
) IR spectrum (capillary, ν11, cm-')
:3330, 1670-1730 1-tert-butoxycarbonyl-3-(Nter
0.58 g (0,0021 mol) of t-butoxycarbonyl)amino-4-methoxymethylpyrrolidine was dissolved in 30 ml of ethanol, 7 ml of 6N hydrochloric acid was added, and after heating under reflux for 2 hours, it was dried under reduced pressure to obtain 3-amino- 0.43 g of 4-methoxymethylpyrrolidine dihydrochloride was obtained as a brown oil.

MS spectrum (CI): mle 13HM”+1
) Epifluorohydrin 22.20 (0.3 mol) N
-benzylethanolamine 67.95 g (0,4
5 mol) in 200 mI of ethanol! , and heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate) to obtain 64.93 g of N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine as a colorless oil. Obtained.

MS spectrum (CI): mle 228 (M”+
1) N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine 6 obtained as above
．． 75 g (0.03 mol) was dissolved in 200 mj2 of ethyl acetate, and after adding 7.27 g (10,072 mol) of triethylamine, 8.8 g of methanesulfonyl chloride was dissolved under stirring under water cooling.
．． 24 g (0,072 mol) was added dropwise. Thereafter, stirring was continued for 3 hours under water cooling, and an aqueous sodium hydrogen carbonate solution was added to separate the layers. The organic layer was washed with water, dried, and concentrated under reduced pressure.
-(2-methylsulfonyloxy)ethyl-N-(3-
12.49 g of fluoro-2-methylsulfonyloxypropyl)benzylamine was obtained as a pale yellow oil.

MS spectrum (CI): mle 384 (M”+
1) Next, dissolve this in 200 mf of ethanol,
Add 4.82 g (0,045 mol) of benzylamine and 9.09 g (0,09 mol) of triethylamine to make 2
After heating under reflux for an hour, the mixture was concentrated under reduced pressure. 100% ethanol to the residue
mjl! and 40 ml of 2N sei soda aqueous solution were added thereto and concentrated again under reduced pressure, ethyl acetate was added to the residue, insoluble materials were removed in an oven, the oven solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 9 :
1) to obtain 3.60 g of 1,4-dibenzyl-2-fluoromethylpiperazine as a yellow oil.

MS spectrum (CI): m/e 299 (M”+
1) 23.85 g (0.08 mol) of 1,4-dibenzyl-2-fluoromethylpiperazine was dissolved in 50 g of methanol.
Dissolved in 0ml, concentrated hydrochloric acid 33ml and 20% palladium-
1.0 g of carbon powder was added, and the mixture was vigorously stirred at room temperature for 1 hour while passing hydrogen gas. After the reaction was completed, the catalyst was removed from the furnace and washed with water, the furnace liquid was concentrated under reduced pressure, and the residue was dissolved in 200 ml of water and thoroughly mixed with ethyl acetate to separate the layers. Concentrate the aqueous layer under reduced pressure,
The residue was washed with ethanol to obtain 13.76 g of 2-fluoromethylpiperazine dihydrochloride as a colorless powder.

Melting point 205-218°C MS spectrum (CI): m/e 119 (M”+
1) Elemental analysis value (%): HN as CsH+3Cf□FNz Theoretical value 31.43 6.86 14.66 Analysis value 31.42 6.81 14.71 [Reference example 20] 23-Methylhomopipage L-alanine 15.3 g (0,131 mol) of ethyl ester, 7.0 g (0,132 mol) of acrylonitrile, and 1.0 g (0,018 mol) of sodium methylate were dissolved in 150 mf of ethanol and heated under reflux for 7 hours. After cooling, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: 4:1 mixture of toluene and ethyl acetate) to obtain 12.5 g of N-cyanoethyl-L-alanine ethyl ester as a colorless oil. Ta.

MS spectrum (CI): m/e 171 (M”+
1) To 9.8 g (0,057 mol) of the above reaction product, 4
% ammonia ethanol 70g, Raney nickel 1.7
9 g was charged into an autoclave and stirred for 3 hours at a reaction temperature of 90° C. and a hydrogen pressure of 60 kg/cffl. After cooling, the catalyst was separated and the furnace liquid was concentrated to obtain a residue.

Add 200n/2. 1.4 g of di-lophthyltin oxide was added and the mixture was heated under reflux for 10 hours. During this time, the produced fraction containing ethanol was discharged from the system. Then, the reaction solution was concentrated and the residue was subjected to silica gel column chromatography (solvent: 9=1 mixture of chloroform and methanol).
(3S)-methyl-2-oxopiperazine 5,
3 g was obtained as pale brown crystals.

MS spectrum (C4): m/e 129 (M”+
1) Add 2.91 g (0,077 mol) of lithium aluminum hydride to 60 ml of tetrahydrofuran,
After cooling with ice water, 4.92 g (0,038
A solution of 60 n/2 (mol) in tetrahydrofuran (slurry) was added dropwise. After the dropwise addition, the mixture was heated under reflux for 5 hours. After cooling, a small amount of water was added under ice cooling to decompose the reducing agent.
The reaction solution was obtained by filtration. Add 20 m2 of concentrated hydrochloric acid to this, concentrate to dryness, crystallize with ethanol, (2S)
-Methylhomopiperazine dihydrochloride (5.93 g) was obtained as colorless crystals.

Melting point = 211-220"C Old spectrum (CI): m/e 115(M"+1
) (Reference"ll+21) 26-bis fluorome
Lupipagene 208 shrimp fluorohydrin 27.28 g (0,359 mol) and benzylamine 19.20 g (0,1795
mol) was dissolved in 200 mff1 of ethanol and heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure to give N,N-bis(3
46.6 g of -fluoro-2-hydroxypropyl)benzylamine were obtained as a colorless oil.

MS spectrum (CI): m/e 260 (M”+
1) Dissolve 33.67 g (0.13 mol) of this compound in 300 mj2 of tetrahydrofuran, and dissolve 2 ml of triethylamine.
After adding 8.89 g (0,286 mol), under water cooling and stirring,
Methanesulfonyl chloride 32.76 g (0,28
6 mol) was added dropwise. After further stirring at room temperature for 6 hours, 39.40 g (0.39 mol) of triethylamine, 20.87 g (0.195 mol) of benzylamine and 300 mj2 of ethanol were added, and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, and 30 g of caustic soda and 300 n of water were added to the residue.
! ! , and extracted with ethyl acetate. Wash the organic layer with water,
After drying, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (vehicle: toluene-ethyl acetate 20:1 mixture) to determine the A isomer of 1,4-dibenzyl-2,6-bis(fluoromethyl)piperazine. Body 6.29 g and B
6.60 g of each isomer was obtained as colorless crystals.

MS spectrum (CI): m/e 331 (M”+
1)...1,4-dibenzyl-2,6-bis(fluoromethyl), which is the same for both A and B isomers
Piperazine B isomer 5.03 g (0,015 mol)
was suspended in 130 nl of methanol, and mixed with 6 ml of concentrated hydrochloric acid and 2
% palladium-carbon powder was added, and hydrogen gas was passed through the mixture for 1 hour while stirring vigorously at room temperature.

The catalyst was removed from the furnace, the liquid was concentrated under reduced pressure, 50 ml of water was added to the residue, the insoluble matter was removed from the furnace, the furnace liquid was concentrated under reduced pressure, the residue was washed with ethanol, and 2,6-bis(fluoromethyl)piperazine ( 3.10 g of dihydrochloride of B isomer) was obtained as a colorless powder.

Melting point 207-225"C MS spectrum (CI): m/e 100M"+
1) Elemental analysis value (%) C611+ 4CI ZFZ
CHN as N2 Theoretical value 32.30 6-32 12.56 Analytical value 32.38 6.26 12.60 1.4-
Similarly, dihydrochloride of 2,6-bis(fluoromethyl)piperazine (A isomer) was obtained as a colorless powder from dibenzyl-2,6-bis(fluoromethyl)piperazine A isomer.

MS spectrum (CI): m/e 100M”+1
) Elemental analysis value (%>: C6HI4CI!, 2P2N2
CHN as -1/2H20 Theoretical value 31.04 6.51 12.07 Analytical value 30.66 6.22 11.78 OxyquinoI-3-carvone 1-Cyclopropyl-6,7-difluoro-8difluoromethoxy -1,4-dihydro-4-oxoquinoline-
3-carboxylic acid BF2 chelate 2.58g (0,0
0.68 mol) was dissolved in 20 mj2 of dimethyl sulfoxide, and 1.63 g of 2-methylpiperazine (0.016 mol) was dissolved in 20 mj2 of dimethyl sulfoxide.
mol) and left at room temperature overnight. Add 1 part of the reaction mixture to 1 part of water.
00mj! The yellow crystals precipitated inside were collected in a furnace and washed with water. 80% of this crystal containing 15ml of triethylamine
It was dissolved in 500 mf of methanol, heated under reflux for 3 hours, the solvent was distilled off under reduced pressure, and the residue was washed with ethanol to obtain 2.30 g of pale yellow powder. Add this to 50mI of water! , remove insoluble matter in a furnace, and reduce the furnace solution to pH 7.50 with IN caustic soda solution.
The precipitated crystals were collected in the center, washed with water, and then washed with ethanol to obtain 1.74 g of the target compound as pale yellow fine needle-like crystals.

Melting point 223-225°C MS spectrum (CI): m/e 412 (M'+
1) Elemental analysis value (%): C+JIzoFJ3On
・CHN as HzO Theoretical value 53.14 5.17 9.79 Analytical value 53.44. 4.93 9.77 Preparation of the title compound obtained in Example 11. OOg(0,0024
mol) methanol 50mI! , suspended in IN hydrochloric acid 2.
40 ml (0,0024 mol) was added to give a clear solution. This was concentrated under reduced pressure, and the residue was washed with ethanol.
0.97 g of the target compound (hydrochloride) was obtained as a colorless powder.

Melting point 277-287°C (decomposition) Elemental analysis value Theoretical value Analysis value (%): C+Jz+CfFJ:+04 CHN 50.95 4.73 9.3850.84
4.44 9.29 0.40 g (0,00097 mol) of the title compound obtained in Example 1 was added to 50 mj of methanol! Methanesulfonic acid suspended in 0.093
g (0,00097 mol) to give a clear solution.

This was concentrated under reduced pressure, and the residue was washed with ethanol to obtain 0.47 g of the target compound (methane sulfonate) as a colorless powder.

Melting point 289-292°C (decomposition) Elemental analysis value (%): C2°Hz<F: +lJ+07S・
CHN as 1/2H,0 Theoretical value 46.51 4.88 8.14 Analytical value 46.44 4.65 7.97 Example 1. The following compound was synthesized by the same method as in 2 or 3.

[Example 22] 1.82 g (0, 0055 mol)
and (2S)-methylpiperazine 1.20 g (0,0
12 mol) in 30 ml of pyridine, 105-11
After stirring at 0°C for 3 hours, the solvent was distilled off under reduced pressure, and the residue was washed with water. The resulting powder (free solid) was dissolved in 400 mf of a 1:1 mixture of chloroform and methanol, and 1 ml of concentrated hydrochloric acid was added and concentrated under reduced pressure. The residue was washed with a 1=1 mixture of chloroform and methanol to obtain 1.84 g of the title compound.
was obtained as a slightly yellow powder.

Melting point 283-286°C (decomposed)? IS spectrum (CI): m/e 412 (M”
+1) Elemental analysis value (%): C,, lI□rc l
CHN as F3N304

Claims (1)

[Claims] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 represents a fluorine-substituted methoxy group, Y is the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Group (in the formula , R^2 is a hydrogen atom, hydroxyl group, amino group, hydroxyl group, lower alkoxy group, lower aliphatic acyloxy group, lower aliphatic acyl group, carboxy group, lower alkoxycarbonyl group, sulfo group, amino group, lower aliphatic group as a substituent A lower alkyl group, an aralkyl group, or a lower aliphatic acyl group that may have a group acylamino group or a mono- or di-lower alkylamino group, and R^3 is a hydrogen atom or a hydroxyl group, lower alkoxy group, or halogen atom as a substituent. represents a lower alkyl group that may have a , A represents an ethylene group, a trimethylene group, or a -COCH_2- group, and m represents 1 or 2.), Formula ▲ Numerical formula, chemical formula, table, etc. ▼ group ((in the formula, w is a formula▲a mathematical formula, a chemical formula, a table, etc.)▼group (in the formula, R^5 and R^6 are the same or different and represent a hydrogen atom, a lower alkyl group, or an aralkyl group, and n' represents 0 or 1), represents a hydroxyl group or a lower alkoxy group, R^4 is a hydrogen atom, a lower alkyl group, a hydroxyl group, or an alkyl moiety which may have a hydroxyl group, a lower alkoxy group, or a halogen atom as a substituent represents a lower alkoxy group which may have a fluorine atom, B represents a methylene group, ethylene group, trimethylene group or tetramethylene group, and n represents 1 or 2.)), Formula ▲ Numerical formula, Chemical formula, There are tables, etc. ▼ Groups (in the formula, R^7 represents a hydrogen atom or a lower alkyl group) or formulas ▲ Numerical formulas, chemical formulas, tables, etc. ▼ Groups (in the formula, Z represents an oxygen atom or a sulfur atom) ). ] A quinolone carboxylic acid derivative and a pharmacologically acceptable salt or ester thereof.