JPH0645601B2 - Quinolonecarboxylic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a quinolonecarboxylic acid derivative (I) having a strong antibacterial activity, and provides a compound useful as a medicament for treating bacterial infections. is there.

The quinolonecarboxylic acid derivative of the present invention has the general formula And a pharmacologically acceptable salt or ester thereof.

In the above formula, R ¹ represents a fluorine-substituted methoxy group, and Y is a formula. (In the formula, R ² is a hydrogen atom, a hydroxyl group, an amino group, a hydroxyl group as a substituent, a lower alkoxy group, a lower aliphatic acyloxy group, a lower aliphatic acyl group, a carboxy group, a lower alkoxycarbonyl group, a sulfo group, an amino group, A lower aliphatic acylamino group or a lower alkyl group which may have a mono- or di-lower alkylamino group, an aralkyl group or a lower aliphatic acyl group, R ³ represents a hydrogen atom or a substituent, a hydroxyl group, a lower alkoxy group, or Represents a lower alkyl group which may have a halogen atom, A
Represents an ethylene group, a trimethylene group or a formula —COCH ₂ — group, and m represents 1 or 2. ), ((W is an expression (In the formula, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aralkyl group, and n ′ represents 0 or 1.), a hydroxyl group or a lower alkoxy group, and R ⁴ represents a hydrogen atom. Represents 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 an alkyl moiety, and B represents a methylene group or an ethylene group. , Trimethylene group or tetramethylene group, and n is 1 or 2. )), Formula (In the formula, R ⁷ represents a hydrogen atom or a lower alkyl group.) (In the formula, Z represents an oxygen atom or a sulfur atom).

In the general formula (I), R ¹ is preferably a monofluoromethoxy group, a difluoromethoxy group or a trifluoromethoxy group, and R ² in Y is a hydrogen atom; a hydroxyl group; an amino group; a hydroxyl group, methoxy as a substituent, Ethoxy, n-propoxy,
A straight or branched chain alkoxy group having 1 to 3 carbon atoms such as isopropoxy, and a fat having 2 to 4 carbon atoms such as acetoxy, propionyloxy, n-butyryloxy, isobutyryloxy. Group acyloxy groups, formyl, acetyl, propionyl, n-butyryl, isobutyryl-containing aliphatic acyl groups having 1 to 4 carbon atoms, carboxy groups, methoxycarbonyl,
Alkoxycarbonyl group having 2 to 4 carbon atoms such as ethoxycarbonyl, n-propoxycarbonyl and isopropoxycarbonyl, sulfo group, amino group, acetamide, propionylamino, n-butyrylamino and isobutyrylamino. Aliphatic acylamino groups having 2 to 4 or methylamino, ethylamino, n-propylamino, isopropylamino,
Methyl, ethyl, n-propyl, which may have a mono- or dialkylamino group having 1 to 4 carbon atoms, such as n-butylamino, isobutylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, A linear or branched alkyl group having 1 to 4 carbon atoms such as isopropyl, n-butyl, isobutyl; benzyl, p-methoxybenzyl, p-aminobenzyl, p-methylaminobenzyl,
Aralkyl group optionally having a lower alkoxy group, amino group, mono- or di-lower alkylamino group as a substituent such as p-dimethylaminobenzyl; or carbon number such as formyl, acetyl, n-butyryl and isobutyryl. R ³ represents an aliphatic acyl group having 1 to 4 R ³
Is a hydrogen atom; or a linear or branched alkoxy group having 1 to 3 carbon atoms such as hydroxyl group, methoxy, ethoxy, n-propoxy, and isopropoxy as a substituent, or halogen such as fluorine or chlorine. An alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl and isopropyl which may have an atom, wherein R ⁵ and R ⁶ are the same or different and each is a hydrogen atom;
An alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl, isopropyl; or benzyl, p-methoxybenzyl, p-aminobenzyl, p-
A lower alkoxy group as a substituent such as methylaminobenzyl and p-dimethylaminobenzyl, an amino group, an aralkyl group which may have a mono- or di-lower alkylamino group is shown, and W is a hydroxyl group; or methoxy, R ⁴ represents an alkoxy group having 1 to 3 carbon atoms such as ethoxy, n-propoxy and isopropoxy.
Is a hydrogen atom; a substituent has a carbon number of 1 such as hydroxyl group, methoxy, ethoxy, n-propoxy and isopropoxy.
A linear or branched alkoxy group having 1 to 3 carbon atoms or 1 to 3 carbon atoms such as methyl, ethyl, n-propyl or isopropyl which may have a halogen atom such as fluorine or chlorine. An alkyl group having: a hydroxyl group; or an alkoxy group having 1 to 3 carbon atoms, such as methoxy, ethoxy, n-propoxy, and isopropoxy optionally having 1 to 3 fluorine atoms, R ⁷ 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, trimethylene group or formula —COCH ₂ — group, and B represents 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.

More preferable compounds in the general formula (I) are as follows: R ¹ represents a difluoromethoxy group or a trifluoromethoxy group, and Y is a formula [In the above formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
A, Z, m, n and n ′ have the same meanings as described above, B ′ represents a methylene group or an ethylene group,
R ⁴ ′, R ⁸ and R ⁹ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. ] The compound which shows these can be mentioned.

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

Examples of such salts include acid addition salts of mineral acids such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, methanesulfonate, ethanesulfonate and benzenesulfone. Acid addition salts of organic acids such as acid salts, p-toluenesulfonates, oxalates, maleates, fumarates, tartrates, citrates or sodium salts, potassium salts,
Examples thereof include metal salts of carboxylic acids such as calcium salt, magnesium salt, manganese salt, iron salt and aluminum salt. Examples of the group forming an ester include lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl, aralkyl groups such as benzyl, 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 Examples thereof include a group that can be easily converted into a carboxy group in vivo, such as a -disubstituted aminocarbonylalkyl group, a phthalidyl group or a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group. The compound (I) of the present invention can also exist as a hydrate.

Examples of the compound having the general formula (I) of the present invention include the compounds exemplified in the following table and pharmaceutically acceptable salts and esters thereof.

The novel compound having the above general formula (I) of the present invention can be produced, for example, according to the following reaction route [A] or [B].

Reaction route [A] Reaction route [B] In the above formula, R ¹ and Y have the same meanings as described above, and R ¹⁰ represents a hydrogen atom or a lower alkyl group such as methyl and ethyl.

That is, the novel compound (I) of the present invention comprises the compound (II) or its boron fluoride chelate compound (V) and 1 to several moles of the amine compound (III) in the presence or absence of a deoxidizing agent. Is produced in the presence or absence of a solvent.

As the solvent used in this reaction, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide, a protic polar solvent such as dimethylacetamide is preferable, but also acetone, ketones such as methyl ethyl ketone, diethyl ether, tetrahydrofuran, It is also possible to use ethers such as dioxane, esters such as ethyl acetate, alcohols such as methanol, ethanol, n-propanol, isopropanol and butanol, and nitriles such as acetonitrile. As the deoxidizing agent, 1,8-diazabicyclo [5.4.0] -7-undecene, 1,5-diazabicyclo [4.3.0] -5-nonene,
Tertiary amines such as triethylamine, tributylamine, pyridine, picoline, lutidine, collidine, sodium methoxide, sodium ethoxide, potassium-t-
Examples thereof include metal alkoxides such as butoxide, and inorganic bases such as sodium carbonate and potassium carbonate. The amount of the deoxidizing agent used is preferably an equimolar to 5-fold molar amount with respect to the compound (II) or (V), but in the case of the amines, a large excess can be used as a solvent. Also, since excess amine (III) acts as a deoxidizer,
The reaction proceeds smoothly even when no other deoxidizing agent is added. The reaction is carried out in the range of 0 ° C to 200 ° C.

After completion of the reaction, the target compound of this reaction is obtained by treating the reaction mixture according to a conventional method, and can be further purified, if necessary, by a conventional purification means such as a recrystallization method or column chromatography. In the case of production according to the route [B], the target chelate compound (VI) is first obtained, which is treated with hydrous alcohol or basic hydrous alcohol to give compound (I) / BF ₃ adduct or Can be induced to (I). The compound (I) · BF ₃ adduct is easily induced to the target compound (I) by treatment with a base.

As the base used in this treatment operation, alkali hydroxide such as sodium hydroxide and potassium hydroxide, alkali carbonate such as sodium carbonate and potassium carbonate, 1,
8-diazabicyclo [5.4.0] -7-undecene, 1,5-
Mention may be made of tertiary amines such as diazabicyclo [4.3.0] -5-nonene, triethylamine, 4-dimethylaminopyridine or metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide.

Compound (I) or (I) · BF thus obtained
_{The 3} adduct is converted into a desired salt by a conventional method, if necessary.

The conversion reaction from the compound (II) or (IV) to the boron fluoride chelate compound (V) is carried out by reacting hydrofluoric acid or boron trifluoride according to the method described in JP-A-59-67290. It is done by letting.

The compound having the general formula (I) thus produced may have optical isomers or geometric (cis, trans) isomers based on the asymmetric carbon atom of the Y moiety in the structure. In such a case, if desired, by carrying out the above reaction using the optically resolved or separated starting compound YH (III), the corresponding optical isomer or geometric isomer of the target compound (I) can be obtained. Alternatively, the stereoisomers of the optical isomers or geometrical isomer mixture of the compound (I) can be obtained by a conventional optical resolution method or separation method.

The compound (II) or (IV), which is the starting material in the above production method, and the chelate compound (V) thereof are novel compounds and are produced by the reaction route [C] shown below.

Reaction route [C] In the above formula, R ¹ has the same meaning as described above, and R ¹⁰
_a ▼ represents a lower alkyl group such as methyl and ethyl,
X represents a halogen atom such as fluorine, chlorine, bromine, and iodine, R ¹¹ and R ¹² represent the same or different alkyl groups, or, together with the nitrogen atom to which they are bonded, and optionally an oxygen atom. Represents a cyclic amino group formed together with a sulfur atom, a sulfinyl group or a sulfonyl group.

Among the compounds (VII) used as starting materials in the above reaction route [C], compounds in which X is a fluorine atom and R ¹ is a monofluoromethoxy group or a difluoromethoxy group can be prepared by the following reaction route [D ], And the compound in which R ¹ is a trifluoromethoxy group is a reaction route [E]
Manufactured by.

Reaction route [D] In the above formula, R ¹³ represents a lower alkoxy group or an amino group, and X ^a represents a halogen atom such as chlorine, bromine or iodine.

Reaction route [E] In the above formula, R ¹³ and X ^a have the same meanings as described above,
^Xb is. A halogen atom such as chlorine, bromine or iodine which is the same as or different from X ^a is shown.

In the reaction routes [D] and [E], 3-hydroxy-2,4,5-trifluorobenzoic acid (XIV) used as a starting material is a known compound as shown in the following reaction route [F]. 4-hydroxy 3,5,6-trifluorophthalic acid
It is prepared by heating and decarboxylating (XX) in water or an aqueous solvent.

Reaction route [F] The reaction conditions of each step and the post-treatment method will be described in detail in Reference Examples.

EFFECTS OF THE INVENTION The object compound of the present invention having the general formula (I) and its pharmacologically acceptable salt show excellent antibacterial action. When its antibacterial activity was measured by the agar plate dilution method, for example, gram-positive bacteria such as Staphylococcus aureus, enterococci and Escherichia coli, Shigella, Klebsiella pneumoniae, mutated bacterium, Serratia, Enterobacter, Salmonella, Pseudomonas aeruginosa, etc. It showed strong antibacterial activity against a wide range of pathogens including Gram-negative bacteria and their resistant bacteria. The test results are shown in Table 4 using norfloxacin as a control compound.

Therefore, the compound (I) of the present invention is useful as an antibacterial agent for treating bacterial infections caused by these pathogenic bacteria. Examples of dosage forms for that purpose include oral administration by tablets, capsules, granules, powders, syrups and the like, or parenteral administration by intravenous injection, intramuscular injection, suppositories and the like. The dose varies depending on the age, body weight, symptom, administration form, number of administrations and the like, but usually about 100 to 1000 mg per day is orally administered to an adult once or in several divided doses.

Next, the present invention will be described more specifically with reference to Reference Examples and Examples.

[Reference Example 1] Synthesis of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid (VIIb) -ester route method 3-hydroxy-2,4,5-trifluorobenzoic acid (XIV) 2
0.0 g (0.104 mol) was dissolved in 500 m of ethanol, 5 m of concentrated sulfuric acid was added, the mixture was heated under reflux for 4 hours, ethanol was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate 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:
16.9 g of R ¹³ = OEt) was obtained as a colorless powder.

MS spectrum (CI): m / e 221 (M ⁺ +1), 175 (M ⁺ -OC ₂ H ₅ ), ethyl 3-hydroxy-2,4,5-trifluorobenzoate obtained as above. ester ^{(XV: R 13 = OEt)} 8.83
g (0.04 mol) was dissolved in 40 m of dimethylformamide, and 60% sodium hydride 1.76 g (0.044
Mol) was added little by little, and after the addition was completed, the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was transferred to a 200 m stainless steel autoclave, and chlordifluoromethane was added to it.
Dimethylformamide 100 containing 28.0 g (0.32 mol)
m was added and the mixture was stirred under pressure at 95-100 ° C. for 5 hours. After completion of the reaction, dimethylformamide was distilled off under reduced pressure,
Water was added to the residue and extracted with toluene. The toluene layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (solvent: toluene) to give 3-difluoromethoxy-2,4,5-trifluorobenzoic acid ethyl ester (XVIb: R ^{13 =} OE
t) 4.85 g was obtained as a colorless liquid.

MS spectrum (CI): m / e 271 (M + +1), 225 (M + -OC 2 H 5) obtained in the above manner 3-difluoromethoxy-2,4,5
-Trifluorobenzoic acid ethyl ester (XVIb: R ¹³
= OEt) 5.79 g (0.021 mol) was dissolved in 40 m of ethanol, 20 m of a 6% aqueous sodium hydroxide solution was added, and the mixture was left overnight at room temperature. The reaction mixture was acidified by adding concentrated hydrochloric acid (3.5 m), concentrated under reduced pressure, extracted with ethyl acetate, the ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 3-difluoromethoxy-2,4,5. -5.22 g of trifluorobenzoic acid (VIIb) was obtained as a colorless powder.

Melting point 68-70 ° C MS spectrum (CI): m / e 243 (M ⁺ +1), 225 (M ⁺ -OH), 223 (M ⁺ -)
F), 192 (M ⁺ -CF ₂ ), 175 (M ⁺ -CF ₂ -OH) NMR spectrum (CDC ₃ , δ): 6.67 (1H, t, J = 72H
_{z, -OCHF 2), 7.83 (} 1H, m, aromH), 10.74 (1H, br, COOH) the synthesis of Reference Example 2 3-difluoromethoxy-2,4,5-trifluorobenzoic acid (VIIb) - Via amide 3-hydroxy-2,4,5-trifluorobenzoic acid (XIV) 10
0.0 g (0.52 mol) was dissolved in 400 m of benzene, 300 m of thionyl chloride was added, and the mixture was heated under reflux for 3 hours, then the solvent and excess thionyl chloride were distilled off under reduced pressure to give 3-hydroxy-2,4,5-trifluorobenzoic acid The acid chloride was obtained.
This was added dropwise to 1500 m of 28% ammonia water under ice-cooling stirring, the stirring was continued for 2 hours, then left overnight at room temperature, 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.
-Hydroxy-2,4,5-trifluorobenzoic acid amide (X
88.2 g of V: R ¹³ = NH ₂ ) was obtained as a colorless powder.

MS spectrum (CI): m / e 192 (M + +1), 175 (M + -NH 2) was obtained as the melting point 153-155 ° C. The above 3-hydroxy-2,4,5-trifluorobenzoic Acid amide (XV: R ¹³ = NH ₂ ) 5.00 g (0.026
Mol) was dissolved in 130 m of dimethylformamide, 4.70 g (0.034 mol) of potassium carbonate and 6.8 g (0.079 mol) of chlorodifluoromethane were added, and 1 in an autoclave was added.
The mixture was stirred at 00 ° C for 3 hours. After the reaction was completed, 500 m of water was added, the mixture was extracted with ethyl acetate, the organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 1: 1 mixture) to give 3
- difluoromethoxy-2,4,5-trifluorobenzoic acid amide: was obtained _{^{(XVIb R 13 = NH 2)}} 5.08g as colorless needles.

Melting point: 102-104 ° C MS spectrum (CI): m / e 242 (M ⁺ +1), 225 (M ⁺ -NH ₂ ) 3-difluoromethoxy-2,4,5 obtained as above.
- trifluorobenzoic acid amide _{^{(XVIb: R 13 = NH 2}} ) 15.
Suspension of 53 g (0.064 mol) in concentrated sulfuric acid 20 m, aqueous solution of sodium nitrite 6.60 g (0.096 mol) 30 with stirring under ice cooling
m was gradually added dropwise, followed by heating and heating under reflux for 30 minutes. After cooling to room temperature, 50 m of water was added, extracted with chloroform, the organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 3-difluoromethoxy-2,4,5-.
15.59 g of trifluorobenzoic acid (VIIb) was obtained as a colorless powder. It was confirmed from the melting point, MS spectrum and NMR spectrum that this product was the same as that obtained by the above-mentioned ester route method.

[Reference Example 3] Synthesis of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid (VIIb) -direct method To 2.18 g (0.052 mol) of sodium hydroxide, 5 m of water was added and dissolved, and then 20 m of dimethylformamide was added. , 3-
Hydroxy-2,4,5-trifluorobenzoic acid (XIV) 4.97 g
(0.026 mol) was added little by little under ice cooling. After the addition is complete
The mixture was stirred under ice cooling for 30 minutes. 200 m of this reaction mixture
Transfer to a stainless steel autoclave, add 100 ml of dimethylformamide containing 24.0 g (0.277 mol) of chlorodifluoromethane, and pressurize at 100-110.
The mixture was stirred at 0 ° C for 5 hours. After completion of the reaction, the mixture was added to water and extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was subjected to silica gel column chromatography (solvent: ethyl acetate-ethanol 9: 1 mixture) to give 3-difluoromethoxy-2,4. ,
2.00 g of 5-trifluorobenzoic acid (VIIb) was obtained as a colorless powder.

It was confirmed from 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] 2,4,5 Synthesis of 3-hydroxy-2,4,5-trifluorobenzoic acid ethyl ester trifluoro-3-trifluoromethoxy-benzoic acid ^{(VIIc) (XV: R 13} = OEt) 5.0 g (0.023 mol) was dissolved in 20 m of dimethylformamide, and 1.0 g (0.025 mol) of 60% sodium hydride was added little by little while stirring with ice cooling,
After the addition was completed, the mixture was stirred under ice cooling for 30 minutes. Next, 130 g of dimethylformamide containing 28.0 g (0.13 mol) of difluorodibromomethane was added, and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, the reaction mixture was poured into 300 m of water and extracted with toluene. The toluene layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: toluene) to give 3-difluoromethyl-bromo-methoxy-2,4,5-trifluorobenzoic acid ethyl ester ^{(XVII: R 13 = OEt,} X a = Br) 5.60g
Was obtained as a colorless liquid.

MS spectrum (CI): m / e 351 (M ⁺ +3), 349 (M ⁺ +1) Then this 3-difluorobromomethoxy-2,4,5-trifluorobenzoic acid ethyl ester (XVII: R ¹³ = OE
t, X ^a = Br) 1.50 g (0.0043 mol) of toluene 10 m
Was dissolved in the solution, 2.50 g (0.013 mol) of silver borofluoride was added, and the mixture was heated and refluxed for 8 hours under light shielding and stirring. The reaction solution was passed, the solution was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (solvent: toluene) to give 2,4,5-trifluoro-3. −
Trifluoromethoxybenzoic acid ethyl ester (XVIII:
R ¹³ = OEt) 1.12 g was obtained as a colorless liquid.

MS spectrum (CI): m / e 289 (M ⁺ +1), 269 (M ⁺ -F) 2,4,5-trifluoro-3-trifluoromethoxybenzoic acid ethyl ester (as obtained above) ( XVIII: R
¹³ = OEt) 5.05 g (0.0175 mol) in 100 m of ethanol
1N sodium hydroxide 19.3m (0.0193mol) was added and the mixture was allowed to stand at room temperature for 2 hours. 1N hydrochloric acid 19.3m
After the addition, the mixture 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-trifluoro-3-trifluoromethoxybenzoic acid. 3.98 g of acid (VIIc) was obtained as a colorless powder.

MS spectrum (CI): m / e 261 (M ⁺ +1), 243 (M ⁺ -OH) NMR spectrum (CDC ₃ , δ): 7.88 (1H, m, aromH) [Reference Example 5] 1-cyclopropyl −6,7-Difluoro-
Ethyl tester of 8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate (IV: R ¹ ═O
Synthesis of CHF ₂ , ▲ R ¹⁰ _a ▼ = Et) 5.22 g (0.0216 mol) of 3-difluoromethoxy-2,4,5-trifluorobenzoic acid (VII: X = F, R ¹ ═OCHF ₂ ) was added to 300 m of benzene. Was dissolved in water, thionyl chloride (15 m) was added, and the mixture was 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 (VIII: X = F, R
¹ = OCHF ₂ ) was obtained.

On the other hand, 2.80 g (0.0238 mol) of magnesium ethoxide and 3.81 g (0.0238 mol) of malonic acid diethyl ester were heated and refluxed in 60 m of anhydrous diethyl ether under stirring for 1 hour to give a suspension of ethoxy magnesium malonic acid diethyl ester in diethyl ether. Got The above acid chloride was mixed with anhydrous diethyl ether 50 while stirring at room temperature.
The liquid dissolved in m was added dropwise, and the mixture was further stirred at room temperature for 2 hours. To the reaction mixture was added 1N hydrochloric acid (35 m), and the mixture was vigorously stirred and then separated. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 3-difluoromethoxy-2,
4,5 trifluoride Robben benzoyl malonic acid diethyl ester (IX: X = F, R 1 = OCHF 2, ▲ R 10 a ▼ = Et) The 7.07g as a brown liquid.

MS spectrum (CI): m / e 385 (M ⁺ +1), 339 (M ⁺ -OC ₂ H ₅ ), which was then dissolved in 200 m dioxane to give p-toluenesulfonic acid monohydrate 4.52 g (0.0238 mol). ) Was added and the mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and 100 m of water and 2.52 g (0.03 mol) of sodium hydrogen carbonate were added to the residue.
Was added and extracted with ethyl acetate. Wash the ethyl acetate layer with water,
After drying over anhydrous sodium sulfate, concentration under reduced pressure, 3-difluoromethoxy-2,4,5-trifluorobenzoyl acetic acid ethyl ester (X: X = F, R ₁ = OCHF ₂ , ▲ R ¹⁰ _a ▼ = Et)
5.66 g was obtained as a reddish brown liquid.

MS spectrum (CI): m / e 313 (M ⁺ +1), Then add 20m of acetic anhydride and 6m of ethyl orthoformate.
Was added and refluxed for 2 hours, and then excess acetic anhydride and ethyl orthoformate were distilled off under reduced pressure. The residue is dichloromethane 20
Dissolve in 0m, cyclopropylamine 1.25g with stirring under ice cooling
(0.022 mol) was added dropwise, and the mixture was stirred for 1 hour under ice cooling. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 9: 1 mixture).
And 3-cyclopropylamino-2- (3-difluoromethoxy-2,4,5-trifluorobenzoyl) acrylic acid ethyl ester (XIII: X = F, R ¹ = OCHF ₂ , ▲)
3.29 g of R ¹⁰ _a ▼ = Et) was obtained as a pink liquid.

MS spectrum (CI): m / e 380 (M ⁺ +1), Then, dissolve it in 150 m of anhydrous diethyl ether,
0.39 g (0.0098 mol) of 60% sodium hydride was added little by little with stirring at room temperature. After the addition is complete, continue at room temperature for 1
The whole reaction solution was made acidic by stirring for 1 hour with 1N hydrochloric acid with vigorous stirring. The reaction mixture was washed with water, washed with water, and then with diethyl ether to give 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4.
-Oxoquinoline-3-carboxylate ethyl tester (I
V: R ¹ = OCHF ₂ , ▲ R ¹⁰ _a ▼ = Et) 1.44 g was obtained as colorless needle crystals.

Melting point 224-226 ° C MS spectrum (CI): m / e 360 (M ⁺ +1) [Reference Example 6] 1-cyclopropyl-6,7-difluoro-
8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid _{^{(II: R 1 = OCHF 2}} ) Synthesis of 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4 -Dihydro-4-oxoquinoline-3
-Carboxylic acid ethyl ester (IV: R ¹ = OCHF ₂ , ▲ R ¹⁰ _a
▼ = Et) 1.40 g (0.0039 mol), acetic acid 9 m, concentrated sulfuric acid 1.2
m and 7 m of water were added, and the mixture was heated under reflux for 1 hour. After allowing to cool to room temperature, the reaction mixture was poured into ice water and the precipitated crystals were collected and washed with water and then diethyl ether.
Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid: was obtained _{^{(II R 1 = OCHF 2)}} 1.09g as colorless needles.

Melting point 202-207 ° C MS spectrum (CI): m / e 332 (M ⁺ +1) Elemental analysis value (%): C ₁₄ H ₉ F ₄ NO ₄ [Reference Example 7] 1-Cyclopropyl-6,7-difluoro-
8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.BF ₂ chelate (V: R ¹ ═O
Synthesis of CHF ₂ ) 1-Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid ethyl ester (IV: R ¹ = OCHF ₂ , ▲ R ¹⁰ _a
▼ = Et) 9.50 g (0.0265 mol) dissolved in 150 m of methyl isobutyl ketone, boron trifluoride-ether complex 5.
63 g was added and the mixture was heated under reflux for 6 hours. The reaction solution was ice-cooled, the precipitated crystals were collected, washed with diethyl ether and then with chloroform, and 1-cyclopropyl-6,7-difluoro-
8-Difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid BF ₂ chelate (V: R ¹ = OCHF
₂ ) 6.15 g was obtained as a colorless powder.

Melting point 225-233 ° C MS spectrum (CI): m / e 380 (M ⁺ +1) Elemental analysis value (%): C ₁₄ H ₈ BF ₆ NO ₄ 1 / 2H ₂ O [Reference Example 8] 1-Cyclopropyl-6,7-difluoro-
8-Trifluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (IV: R ¹
= OCF ₃ , ▲ R ¹⁰ _a ▼ = Et) 2,4,5-trifluoro-3-trifluoromethoxybenzoic acid (VIIIc: X = F, R ¹ ═OCF ₃ ) as a starting material In the same manner as in 5, 1-cyclopropyl-6,7
-Difluoro-8-trifluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester (IV: R ¹ = OCF ₃ , ▲ R ¹⁰ _a ▼ = Et) was obtained as colorless needle crystals. It was

Melting point 160-161 ° C MS spectrum (CI): m / e 378 (M ⁺ +1) [Reference Example 9] 1-cyclopropyl-6,7-difluoro-
8-trifluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid / BF ₂ chelate (V: R ¹
= OCF ₃ ) Synthesis of the compound obtained in Reference Example 8 in the same manner as in Reference Example 7
-Cyclopropyl-6,7-difluoro-8-trifluoromethoxy-1,4-dihydro-4-oxoquinoline-3
-Carboxylic acid / BF ₂ chelate (V: R ¹ = OCF ₃ ) was obtained as a colorless powder.

Melting point 266-271 ° C MS spectrum (CI): m / e 398 (M ⁺ +1) Elemental analysis value (%): C ₁₄ H ₇ BF ₇ NO ₄ 1 / 2H ₂ O [Reference Example 10] Synthesis of 3-hydroxy-2,4,5-trifluorobenzoic acid (XIV) 4-hydroxy-2,5,6-trifluorophthalic acid (XX) 2
700 g of water and 6 of water were put into an autoclave, replaced with nitrogen, and heated at 140 ° C. for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated to precipitate crystals. The crystals were filtered, washed with chloroform and then dried. 3-hydroxy-2,4,5-trifluorobenzoic acid as colorless powder
1623 g of (XIV) was obtained.

Melting point 144-146 ° C MS spectrum (CI): m / e 192 (M ⁺ ) NMR spectrum (CD ₃ OD, δ): 4.94 (1H, bs, -oH), 7.25 (1
H, m, aromH) [Reference Example 11] Synthesis of (2S) -methylpyrazine To 10 g (0.065 mol) of L-alanine ethyl ester hydrochloride was added 10 m of water, and then sodium cyanide 3.
2 g (0.065 mol) was added. While stirring, 5.3 g (0.065 mol) of 37% formaldehyde solution was added dropwise. (The reaction temperature rose to around 40 ° C.) After the dropping, the mixture was stirred at room temperature for 6 hours and left overnight. The reaction solution was extracted with methylene chloride, the organic layer was washed with a saturated sodium hydrogen carbonate solution, and further washed with water. Then, after drying over anhydrous sodium sulfate, the mixture was concentrated and subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 9: 1 mixture) to give 5.6 g of N-cyanomethyl-L-alanine ethyl ester as a colorless oil. Obtained.

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 charged into an autoclave and stirred at a reaction temperature of 90 ° C. and hydrogen pressure of 50 kg / cm ² for 2 hours. The catalyst was separated, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: methanol-chloroform 1:20 mixed solution) to give (3
2.8 g of S) -methyl-2-oxopiperazine was obtained as colorless crystals.

Lithium aluminum hydride (1.53 g, 0.040 mol) was added to tetrahydrofuran (35 m), and the above (3S) -methyl-2-oxopiperazine (2.29 g, 0.02 mol) was added while cooling with ice water.
35 m of a tetrahydrofuran solution of 0 mo) was added dropwise. After the dropping, heating and refluxing were performed for 5 hours. After allowing to cool, a small amount of water was added under ice cooling to decompose the excessive reducing agent, and then passed to obtain a reaction solution. 10m concentrated hydrochloric acid
And concentrated to dryness, crystallized from ether / ethyl alcohol, and (2S) -methylpiperazine dihydrochloride 2.73
g was obtained as a colorless powder.

This was dissolved in 10 m of water, 10% sodium hydroxide solution was added to adjust the pH to 10 or more, and then extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was distilled under reduced pressure (2
1.30 g of S) -methylpiperazine was obtained as colorless needle crystals. This product has an optical purity of 98.5% by HPLC analysis ^{* 1)}
It was confirmed to be the (S) form of ee.

Note 1) HPLC analysis conditions [Pretreatment method] Reaction * 2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate (GITC) operation A liquid: 2-methylpiperazine 0.0288 g (0.288 mmo
) / Acetonitrile 25m solution B solution: GITC 0.20g (0.51mmo) / Acetonitrile 25m solution A solution 0.43m (0.005mmo) B solution 0.24m (0.005m)
Mmm) was added and the mixture was left at room temperature for 10 minutes. 2 μ of this reaction solution was analyzed by HPLC.

[HPLC analysis conditions]

Column: TSK-gel ODS-80TM (4.6 x 250 mm) Mobile phase: Methanol: 0.05M Sodium dihydrogen phosphate =
25:75 Flow rate: 0.70 m / min Detection: UV254 nm [Reference Examples 12 to 15] The following piperazines were synthesized according to the method of Reference Example 11.

[Reference Example 16] Synthesis of (3S) -aminopyrrolidine dihydrochloride L-Aspartic acid ethyl ester hydrochloride 14.88 g (0.0
(66 mol) was dissolved in 200 m of methylene chloride, and 7.33 g (0.072 mol) of triethylamine was added under cooling with ice water.
After stirring for 20 minutes, 14.4 g of di-tert-butyl dicarbonate
(0.066 mol) was added portionwise. After stirring for a further 2 hours, the mixture was concentrated under reduced pressure, toluene was added, and the hydrochloride of triethylamine was removed by filtration. The liquid was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 4: 1 mixture) to give N-tert-
18.61 g of butoxycarbonyl-L-aspartic acid ethyl ester was obtained as a colorless oil.

MS spectrum (CI): m / e 234 (M + + 1-CH 2 = C (CH 3) 2), 190 (M + + 1-CO 2, -CH 2 = C (CH 3) 2) Lithium boro 3.01 g (0.138 mol) of hydride was dissolved in 100 m of tetrahydrofuran. 40 m of a tetrahydrofuran solution containing 10.0 g (0.035 mol) of the above product was added dropwise to this solution. After completion of the dropping (the dropping rate was adjusted so as to maintain the reaction temperature at 40 ° C.), stirring was further carried out at room temperature for 4 hours. After a small amount of water was added to decompose the reducing agent, it was filtered to obtain a reaction solution. This was concentrated to remove tetrahydrofuran, then sodium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate,
Concentration under reduced pressure gave 6.15 g of (2S) -tert-butoxycarbonylamino-1,4-dihydroxybutane as a colorless oil.

MS spectrum (CI): m / e 206 (M ⁺ +1) 150 (M ⁺ + 1-CH ₂ = C (CH ₃ ) ₂ ), 106 (M ⁺ + 1-CO ₂ ,, CH ₂ = C ( CH _{3) 2),} was added (2S)-tert-butoxycarbonylamino-1,4-dihydroxy butane 13.0 g (0.060 mol), triethylamine 14.54 g (0.144 mol) in methylene chloride 250 meters. Methanesulfonyl chloride 1 under cooling with ice water
5.12 g (0.132 mol) was added dropwise. After stirring under ice water cooling for 3 hours, the mixture was left at room temperature overnight. Water and methylene chloride were added, 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 / e 210 (M ⁺ -OSO ₂ CH ₃ ,, -CH ₂ = C (C
_{H 3) 2) (2S)} -tert- butoxycarbonylamino-1,4-di - (the methylsulfonyloxy) butane 20.22 g (0.056 mol) was suspended in methanol 130m, triethylamine 6.0g of (0.059 mol) was added It was After absorbing the ammonia gas until it became saturated, the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure to obtain a residue. This was dissolved in 150 m of methylene chloride, 12.22 g (0.056 mol) of di-tert-butyl dicarbonate was added, and then 23 m of triethylamine was added dropwise. After stirring at room temperature for additional 2 hours, the mixture was washed with water, dried over anhydrous sodium sulfate, and the concentrated residue was subjected to silica gel column chromatography (solvent = toluene-ethyl acetate 9: 1 mixture) (3S). -Tert-butoxycarbonylamino-1-
tert-Butoxycarbonylpyrrolidine was obtained as a colorless oil. Concentrated hydrochloric acid (10 m) was added to the concentrate, and the mixture was concentrated to dryness and crystallized from ethyl alcohol to obtain (3S) -aminopyrrolidine dihydrochloride (2.87 g) as a colorless powder.

MS spectrum (CI): m / e 87 (M ⁺ +1), 70 (M ⁺ -NH ₂ ) [Reference Example 17] 3-amino-4- (2,2,2-trifluoroethoxy) pyrrolidine ・ di Synthesis of Hydrochloride To 15 m of 2,2,2-trifluoroethanol, 1.08 g (0.027 mol) of 60% sodium hydride was added under water cooling. After stirring for 20 minutes, 5.0 g (0.027 mol) of 1-tert-butoxycarbonyl-3,4-epoxypyrrolidine was added, and the mixture was heated under reflux for 3 hours. Saturated saline was added, extraction was performed with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and concentrated. This concentrated solution was dissolved in 50 m of pyridine and 3.23 g of methanesulfonyl chloride was cooled with ice water.
(0.028 mol) was added, the mixture was further stirred at room temperature for 5 hours, and then left overnight. After adding 300 m of water and extracting with toluene, the organic layer was dried over anhydrous sodium sulfate and then concentrated, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 9: 1 mixture) to give 1-tert. −
Butoxycarbonyl-3- (2,2,2-trifluoroethoxy) -4-methylsulfonyloxypyrrolidine 7.07 g
Got 3.95 g (0.011 mol) of this product and 100 m of 20% ammonia methanol solution were charged into an autoclave and stirred at a reaction temperature of 140 ° C. for 10 hours. The solvent was evaporated under reduced pressure, saturated sodium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (solvent: ethanol: ethyl acetate 1: 1: 9 mixed solution)
3-amino-1-tert-butoxycarbonyl-4- (2,
1.62 g of 2,2-trifluoroethoxy) pyrrolidine was obtained as a colorless oil.

MS spectrum (CI): m / e 285 (M + +1), 229 (M + -CH 2 = C (CH 3) 2) ethanol 30m to the product obtained in the above reaction 1.61 g (0.006 mol) After adding concentrated hydrochloric acid (2m) and water (4m) overnight at room temperature, the mixture was concentrated to dryness under reduced pressure to give 3-amino-
1.60 g of 4- (2,2,2-trifluoroethoxy) pyrrolidine dihydrochloride was obtained as colorless crystals.

MS spectrum (CI): m / e 185 (M ⁺ +1) [Reference Example 18] Synthesis of 3-amino-4-methoxymethylpyrrolidine dihydrochloride Hydroxylamine hydrochloride 34.7 g (0.5 mol) was added to water 13
After being dissolved in 5 m, a solution of 14.7-benzyl-3-carbethoxy-4-pyrrolidone (24.7 g, 0.1 mol) in ethanol (135 m) was added dropwise at room temperature, and sodium carbonate (28.1 g) was added.
(0.265 mol) was added, and the mixture was stirred at room temperature for 6.5 hours. The reaction solution was extracted with 300 m of chloroform, the obtained chloroform layer was washed with water and dried, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 2: 1 mixture). , 1-benzyl-3-
Carboethoxy-4-hydroxyiminopyrrolidine 15.8
g was obtained as a brown oil.

MS spectrum (CI): m / e 263 (M ⁺ +1) IR spectrum (capillary, ν _max cm ^-1 ): 3300,1
740 sodium bis (2-methoxyethoxy) aluminum hydride 3.4m toluene solution 28m was added to toluene 3
Dissolved in 0m, 1-benzyl-3-carbethoxy-
4-hydroxyiminopyrrolidine 5.24 g (0.022 mol)
Toluene 10m solution was added dropwise over 1 hour at room temperature.
After stirring for an hour, the mixture was heated under reflux for another 2 hours. The reaction solution was allowed to cool to room temperature, ice water was added, and the formed precipitate was separated. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: methanol) to give 1-benzyl-3.
2.16 g of -amino-4-hydroxymethylpyrrolidine were obtained as a brown oil.

MS spectrum (CI): m / e 207 (M ⁺ +1) IR spectrum (capillary, ν _max cm ^-1 ): 3150 ~
3400 1-benzyl-3-amino-4-hydroxymethylpyrrolidine 5.87 g (0.0285 mol) was added to dichloromethane 100 m.
Dissolved in water, 6.21 g of di-tert-butyl carbonate at room temperature
(0.0285 mol) was added portionwise. 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 give 1-benzyl-3.
6.32 g of-(N-tert-butoxycarbonyl) amino-4-hydroxymethylpyrrolidine was obtained as a light brown oil.

IR spectrum (capillary, ν _max cm ^-1 ): 3350,1
680 to 1720 1-benzyl-3- (N-tert-butoxycarbonyl)
Amino-4-hydroxymethylpyrrolidine 6.32 g (0.02
(07 mol) was dissolved in 100 m of ethanol, 2.0 g of 20% palladium-carbon powder was added, and the mixture was stirred and reacted in a stainless autoclave at room temperature and a hydrogen pressure of 100 kg / cm ² for 27 hours. After removing the catalyst, the solution was concentrated under reduced pressure to give 3- (N-te
rt-Butoxycarbonyl) amino-4-hydroxymethylpyrrolidine (3.99 g) was obtained as a colorless crystalline oil.

MS spectrum (CI): m / e 217 (M ⁺ +1) IR spectrum (KBr, ν _max cm ^-1 ): 3350,3270,1680
.About.1690 3.08 g (0.0143 mol) of 3- (N-tert-butoxycarbonyl) amino-4-hydroxymethylpyrrolidine was dissolved in 50 ml of dichloromethane, and 3.12 g of di-tert-butyl dicarbonate was added portionwise 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: toluene-ethyl acetate 1: 1 mixture) to give 1-tert-butoxycarbonyl-3-.
(N-tert-butoxycarbonyl) amino-4-hydroxymethylpyrrolidine (3.99 g) was obtained as colorless crystals.

MS spectrum (CI): m / e 317 (M ⁺ +1) 1-tert-butoxycarbonyl-3- (N-tert-butoxycarbonyl) amino-4-hydroxymethylpyrrolidine 3.86 g (0.0122 mol) in diethyl ether 190 m
After dissolving in water and cooling with ice, 0.3 m of boron trifluoride / diethyl ether complex was added, 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 hours, the mixture was left at room temperature overnight.
Saturated saline was added for liquid separation, the ether layer was dried, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 2: 1 mixture).
1-tert-butoxycarbonyl-3- (N-te
0.47 g of rt-butoxycarbonyl) amino-4-methoxymethylpyrrolidine was obtained as a colorless oil.

MS spectrum (CI): m / e 331 (M ⁺ +1) IR spectrum (capillary, ν _max cm ^-1 ): 3330,1
670 to 1730 Dissolve 0.58 g (0.0021 mol) of 1-tert-butoxycarbonyl-3- (N-tert-butoxycarbonyl) amino-4-methoxymethylpyrrolidine in 30 m of ethanol,
7N of 6N hydrochloric acid was added, and the mixture was heated under reflux for 2 hours and dried under reduced pressure to give 0.43 g of 3-amino-4-methoxymethylpyrrolidine dihydrochloride as a brown oil.

MS spectrum (CI): m / e 131 (M ⁺ +1) [Reference Example 19] Synthesis of 2-fluoromethylpiperazine dihydrochloride Epifluorohydrin 22.20 (0.3 mol) and N-benzylethanolamine 67.95 g ( 0.45 mol) to ethanol 2
It was dissolved in 100 m and heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (solvent: ethyl acetate), and N-benzyl-N- (3
64.93 g of -fluoro-2-hydroxypropyl) ethanolamine was obtained as a colorless oil.

MS spectrum (CI): m / e 228 (M ⁺ +1) 6.75 g of N-benzyl-N- (3-fluoro-2-hydroxypropyl) ethanolamine obtained as above.
(0.03 mol) was dissolved in 200 m of ethyl acetate, 7.27 g (10.072 mol) of triethylamine was added, and then 8.24 g (0.072 mol) of methanesulfonyl chloride was added dropwise under stirring with ice cooling. Then, stirring was continued for 3 hours under ice cooling, an aqueous solution of sodium hydrogen carbonate was added for liquid separation, the organic layer was washed with water, dried and concentrated under reduced pressure, and N- (2-methylsulfonyloxy) ethyl-N- (3- Obtained 12.49 g of fluoro-2-methylsulfonyloxypropyl) benzylamine as a pale yellow oil.

MS spectrum (CI): m / e 384 (M ⁺ +1) Then, this was dissolved in 200 m of ethanol, and 4.82 g (0.045 mol) of benzylamine and 9.0 of triethylamine were dissolved.
9 g (0.09 mol) was added and the mixture was heated under reflux for 2 hours and concentrated under reduced pressure. Ethanol 100m and 2N caustic soda aqueous solution 40m were added to the residue and concentrated again under reduced pressure, ethyl acetate was added to the residue to remove insoluble matter, and the solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (solvent:
Toluene-ethyl acetate 9: 1), 1,4-
3.60 g of dibenzyl-2-fluoromethylpiperazine was obtained as a yellow oil.

MS spectrum (CI): m / e 299 (M ⁺ +1) 1,4-dibenzyl-2-fluoromethylpiperazine 23.85
g (0.08 mol) was dissolved in 500 m of methanol, 33 m of concentrated hydrochloric acid and 1.0 g of 20% palladium-carbon powder were added,
The mixture was vigorously stirred at room temperature for 1 hour while passing hydrogen gas. After completion of the reaction, the catalyst was removed, the mixture was washed with water, the liquid was concentrated under reduced pressure, the residue was dissolved in 200 m of water, and the mixture was shaken well with ethyl acetate to separate it. The aqueous layer was concentrated under reduced pressure, and 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 (%): C ₅ H ₁₃ C ₂ FN ₂ [Reference Example 20] Synthesis of (2S) -methylhomopiperazine dihydrochloride L-alanine ethyl ester 15.3 g (0.131 mol), acrylonitrile 7.0 g (0.132 mol), sodium methylate 1.0 g (0.018 mol) were added to ethanol 150 m. And was heated to reflux for 7 hours. After allowing to cool, it was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 4: 1 mixture) to obtain 12.5 g of N-cyanoethyl-L-alanine ethyl ester as a colorless oil. .

MS spectrum (CI): m / e 171 (M ⁺ +1) 70 g of 4% ammonia ethanol and 1.79 g of Raney nickel were charged to an autoclave at 9.8 g (0.057 mol) of the above reaction product, reaction temperature 90 ° C, hydrogen pressure 60 kg. 3 / cm ²
Stir for hours. After cooling, the catalyst was separated and the liquid was concentrated to obtain a residue. Xylene (200 m) and di-n oxide were added to the residue.
1.4 g of -butyltin was added and the mixture was heated under reflux for 10 hours. During this period, 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 mixed solution of chloroform-methanol) to obtain 5.3 g of (3S) -methyl-2-oxopiperazine as light brown crystals.

MS spectrum (CI): m / e 129 (M ⁺ +1) Tetrahydrofuran 60 m was added with lithium aluminum hydride 2.91 g (0.077 mol) and cooled with ice water. 4.92 g (0.038 mol) of a tetrahydrofuran solution 60 m (slurry) Form) was added dropwise. After the dropping, heating and refluxing were performed for 5 hours. After allowing to cool, a small amount of water was added under ice cooling to decompose the reducing agent, and then filtered to obtain a reaction solution. 20 m of concentrated hydrochloric acid was added thereto, concentrated to dryness, and crystallized with ethanol to obtain 5.93 g of (2S) -methylhomopiperazine dihydrochloride as colorless crystals.

Melting point: 211-220 ° C. MS spectrum (CI): m / e 115 (M ⁺ +1) [Reference Example 21] Synthesis of 2,6-bis (fluoromethyl) piperazine dihydrochloride Epifluorohydrin 27.28 (0.359) Mol) and 19.20 g (0.1795 mol) of benzylamine were dissolved in 200 m of ethanol and heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, N,
46.6 g of N-bis (3-fluoro-2-hydroxypropyl) benzylamine was obtained as a colorless oil.

MS spectrum (CI): m / e 260 (M ⁺ +1) 33.67 g (0.13 mol) of this compound was dissolved in 300 m of tetrahydrofuran, 28.89 g (0.286 mol) of triethylamine was added, and then methanesulfonyl chloride was stirred with ice cooling.
32.76 g (0.286 mol) was added dropwise. After stirring at room temperature for another 6 hours, 39.40 g (0.39 mol) of triethylamine, 20.87 g (0.195 mol) of benzylamine and 3 parts of ethanol.
00 m was added and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, caustic soda (30 g) and water (300 m) were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent: toluene-ethyl acetate 20: 1 mixture) to give 1,4-dibenzyl-2,6-bis (fluoromethyl). Both the A isomer 6.29 g and the B isomer 6.60 g of piperazine were obtained as colorless crystals.

MS spectrum (CI): m / e 331 (M ⁺ +1) ... Same as both A and B isomers 1,4-dibenzyl-2,6-bis (fluoromethyl) piperazine B isomer 5.03 g (0.015 mol) ) Methanol 130
6 g of concentrated hydrochloric acid and 0.6 g of 2% palladium-carbon powder were added, and hydrogen gas was bubbled through for 1 hour with vigorous stirring at room temperature. The catalyst was removed, the liquid was concentrated under reduced pressure, 50 m of water was added to the residue to remove insoluble matter, the liquid was concentrated under reduced pressure, and the residue was washed with ethanol to prepare 2,6-bis (fluoromethyl) piperazine (B isomer). 3.10 g of the dihydrochloride of was obtained as a colorless powder.

Melting point 207-225 ° C MS spectrum (CI): m / e 151 (M ⁺ +1) Elemental analysis value (%) C ₆ H ₁₄ C ₂ F ₂ N ₂ Similarly, from the 1,4-dibenzyl-2,6-bis (fluoromethyl) piperazine A isomer, the dihydrochloride of 2,6-bis (fluoromethyl) piperazine (A isomer) was obtained as a colorless powder.

MS spectrum (CI): m / e 151 (M ⁺ +1) Elemental analysis value (%): C ₆ H ₁₄ C ₂ F ₂ N ₂ 1 / 2H
_{As 20} Example 1 Synthesis of 1-cyclopropyl-8-difluoromethoxy-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid 1-cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3
-2.58 g (0.0068 mol) of carboxylic acid / BF ₂ chelate was dissolved in 20 m of dimethyl sulfoxide, 1.63 g (0.016 mol) of 2-methylpiperazine was added, and the mixture was left overnight at room temperature. The reaction mixture was poured into 100 m of water, and the precipitated yellow crystals were washed with water. This crystal is triethylamine 1
Dissolve in 500m of 80% methanol containing 5m, and
After heating under reflux for an hour, the solvent was distilled off under reduced pressure, and the residue was washed with ethanol to obtain 2.30 g of a pale yellow powder. This was dissolved in 50 m of water, the insoluble matter was removed, and the solution was adjusted to pH 7.50 with 1N caustic soda solution.
The precipitated crystals were washed with water and then with ethanol to obtain 1.74 g of the desired compound as fine yellow fine needle crystals.

Melting point 223-225 ° C MS spectrum (CI): m / e 412 (M ⁺ +1) Elemental analysis value (%): C ₁₉ H ₂₀ F ₃ N ₃ O ₄ · H ₂ O Example 2 1-Cyclopropyl-8-difluoromethoxy-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride Synthesis Suspension of 1.00 g (0.0024 mol) of the free form of the title compound obtained in Example 1 in 50 m of methanol, 2.40 m of 1N hydrochloric acid
(0.0024 mol) was added to make a clear solution. This was concentrated under reduced pressure, and the residue was washed with ethanol to obtain 0.97 g of the desired compound (hydrochloride salt) as a colorless powder.

Melting point 277-287 ° C. (decomposition) Elemental analysis value (%): as C ₁₉ H ₂₁ CF ₃ N ₃ O _4. Example 3 1-Cyclopropyl-8-difluoromethoxy-6-fluoro-7- (3-methyl-1-piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid / methanesulfonic acid Synthesis of salt 0.40 g (0.00097) of the free form of the title compound obtained in Example 1
Mol) suspended in 50 m of methanol, methanesulfonic acid
A transparent solution was prepared by adding 0.093 g (0.00097 mol). This was concentrated under reduced pressure, and the residue was washed with ethanol to obtain 0.47 g of the target compound (methanesulfone salt) as a colorless powder.

Melting point 289-292 ° C (decomposition) Elemental analysis value (%): C ₂₀ H ₂₄ F ₃ N ₃ O ₇ S · 1 / 2H ₂ O The following compounds were completed by the same method as in Example 1, 2 or 3.

Example 22 1-Cyclopropyl-8-difluoromethoxy-6-fluoro-7-[(3S) -methyl-1-
Synthesis of piperazinyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride 1-Cyclopropyl-6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline- Three
-1.82 g (0.0055 mol) of carboxylic acid and 1.20 g (0.012 mol) of (2S) -methylpiperazine were dissolved in 30 m of pyridine, and after stirring at 105-110 ° C for 3 hours, the solvent was distilled off under reduced pressure and the residue was washed with water. The obtained powder (free form) was dissolved in 400 m of a 1: 1 mixture of chloroform and methanol, 1 m of concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. The residue was washed with a 1: 1 mixture of chloroform and methanol to obtain the title compound. 1.84 g was obtained as a slightly yellow powder.

Melting point 283-286 ° C (decomposition) MS spectrum (CI): m / e 412 (M ⁺ +1) Elemental analysis value (%): C ₁₉ H ₂₁ CF ₃ N ₃ O ₄ The following compounds were synthesized by the same method as in Example 22.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/54 9360-4C 31/55 9360-4C (72) Inventor Teruhito Inoue Ube, Yamaguchi Prefecture 5 Ube Kosan Co., Ltd., Ube Research Institute Co., Ltd., Ube Research Institute, Ube, Ltd. (72) Yoshihara Fujiwara, Ube, Yamaguchi Prefecture, Ube City, Kozagushi Co., Ltd. 5 Ube Kosan Co., Ltd. Ube Research Institute, Ube Research Institute, Ube, Yamaguchi Prefecture 5 Ube Kosan Co., Ltd., Ube Research Center

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ represents a fluorine-substituted methoxy group, and Y is a formula. (In the formula, R ² is a hydrogen atom, a hydroxyl group, an amino group, a hydroxyl group as a substituent, a lower alkoxy group, a lower aliphatic acyloxy group, a lower aliphatic acyl group, a carboxy group, a lower alkoxycarbonyl group, a sulfo group, an amino group, A lower aliphatic acylamino group or a lower alkyl group which may have a mono- or di-lower alkylamino group, an aralkyl group or a lower aliphatic acyl group, R ³ is a hydrogen atom or a substituent, a hydroxyl group, a lower alkoxy group or a halogen atom; Represents a lower alkyl group which may have an atom, A represents an ethylene group, a trimethylene group or a formula —COCH ₂ — group, and m represents 1 or 2.), ((W is an expression (In the formula, R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group or an aralkyl group, and n ′ represents 0 or 1.), a hydroxyl group or a lower alkoxy group, and R ⁴ represents a hydrogen atom. Represents 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 an alkyl moiety, and B represents a methylene group or an ethylene group. , Trimethylene group or tetramethylene group, and n is 1 or 2. )), Formula (In the formula, R ⁷ represents a hydrogen atom or a lower alkyl group.) (In the formula, Z represents an oxygen atom or a sulfur atom). ] The quinolone carboxylic acid derivative which has these, and its pharmacologically acceptable salt or ester.