JPH0436144B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula () This relates to a compound represented by Here, X represents a halogen atom, R represents -CH( _COOR1 ) _COOR2 (Ia), _-CH2 ( _COOR1 )(Ib) or -C( _C00R1 )= _CHOR3 (Ic), Furthermore, R ₁ , R ₂ and R ₃ each have 1 to 3 carbon atoms.
The compounds (Ia, Ib, Ic) of the present invention are produced by the method exemplified by the following reaction formula. That is, 2-halogeno-4,5-difluorobenzoic acid obtained by treating 2-halogeno-4,5-difluorobenzoic acid with thionyl chloride
Halogeno-4,5-difluorobenzoyl chloride () is reacted with a reagent () synthesized from magnesium ethoxide and diethyl malonate to produce 2-halogeno-4,5-difluorobenzoyl malonic acid diethyl ester (Ia). get. This was subjected to a decarboxylation reaction in dioxane containing a catalytic amount of p-toluenesulfonic acid, and 2-halogen-
4,5-difluorobenzoylacetic acid (keto-enol tautomer) (Ib) is obtained. This (Ib),
3- by reacting with ethyl orthoformate in acetic anhydride
Ethoxy-2-(2-halogeno-4,5-difluorobenzoyl)acrylic acid ethyl ester (Ic) is obtained. Compounds obtained using the compounds of the present invention as raw materials (see Reference Examples 6 and 7) are useful not only in medicine but also in animals and fish, food preservatives, and external disinfectants and disinfectants. An example of the method for synthesizing the starting material () will be explained using a reaction formula for the case where X=F. That is, 1-bromo-2,4,5-trifluorobenzene (1) was mixed with a slight excess of cuprous cyanide and N
The reaction is carried out by heating in a polar solvent such as methylpyrrolidone or dimethylformamide for 2 to 5 hours to obtain 2,4,5-trifluorobenzonitrile (2) as a colorless liquid. This is heated and stirred in concentrated sulfuric acid to obtain the amide compound (3), and when this is heat-treated with a concentrated sulfuric acid-sodium nitrite aqueous solution without purification, 2.
4,5-trifluorobenzoic acid (4) is produced. When this material is treated with thionyl chloride, 2,4,
5-trifluorobenzoyl chloride (a) is obtained. Next, the present invention will be explained by reference examples and examples. Reference Example 1 (1) A suspension of 11 g of 1-bromo-2,4,5-trifluorobenzene (1) and 6 g of cuprous cyanide in N-methylpyrrolidone was placed in a sealed tube at a bath temperature of 170 to 190°C.
Let it react for 4 hours. The suspension turns dark brown and becomes a solution. Add 500ml of benzene to the reaction solution, filter off the precipitate, and add benzene to the filtrate.
Add 500 ml and partition with 1 water (300, 300, 400 ml) to remove N-methylpyrrolidone. After drying the benzene layer, the oily residue obtained by distilling off benzene under reduced pressure was subjected to silica gel column chromatography, and 5.8 g of 2,4,5-trifluorobenzonitrile was obtained as a transparent liquid as a benzene eluate.
get. IRν ^CHCl3 _nax cm ^-1 : 2250 (CN) NMRδ ^CDCl3 _ppn : 7.05 to 7.35 (IH, m, C ₃ - H ) 7.40 to 7.66 (IH, m, C ₆ - H ) Elemental analysis amount C ₇ H ₂ F ₃ As N Calculated value C 54.55, H 1.30, N 9.09 Analytical value C 54.41, H 1.34, N 8.91 Reference example 2 Dissolve 5.8g of this in 20ml of 80% sulfuric acid,
Heat to reflux for 1 minute. After cooling, pour the reaction solution into ice water.
Extract with ethyl acetate. After drying the sodium sulfate and distilling off the solvent, 2,4,5-trifluorobenzamide
5.32g (IRν ^CHCl3 _nax (cm ^-1 ): 3540, 3410 (NH ₂ ),
1675 (C-0), melting point 113-115°C).
Dissolve this in 8.1ml of concentrated sulfuric acid without purifying it,
While cooling with ice water, slowly drip 18 ml of an aqueous solution of 3.8 g of sodium nitrite. After dropping, heat in a water bath for 30 minutes, cool, extract with chloroform, dry sodium sulfate, and distill off the solvent to obtain 2,4,5-trifluorobenzoic acid.
5.16 g (melting point 95.5-96.5°C) is obtained. IRν ^CHCl3 _nax (cm ^-1 ): 3450-2500 (OH), 1705 (C-0) NMRδ ^CDCl3 _ppn : 6.90-7.25 (1H, m, C ₃ , -H) 7.71-8.00 (1H, m, C ₆ , -H) 11.05 (1H, s, COOH) Elemental analysis value C ₇ H ₃ F ₃ O ₃ Calculated value C 47.75, H 1.72 Analysis value C 47.70, H 1.64 Reference example 3 2,4,5-trifluorobenzoic Add 3.4 g of acid and 10 ml of thionyl chloride to 20 ml of anhydrous benzene and reflux for 2 hours. After the solvent was distilled off, benzene was added three times and excess thionyl chloride was distilled off azeotropically.
2,4,5-trifluorobenzoyl chloride (a). Example 1 2.2 g of magnesium ethoxide and 3.1 g of diethyl malonate in anhydrous ether
30 ml of the suspension was refluxed for 1 hour, and after cooling, the previously obtained 2,4,5-
15 ml of an anhydrous ether solution of trifluorobenzoyl chloride (a) is added dropwise and stirred at room temperature for 1 hour. After the reaction, acidify with dilute hydrochloric acid and add 15% of ethyl acetate.
ml (50 x 3), dried with Glauber's salt, and distilled off the solvent to obtain an oily product, 2,4,5-trifluorobenzoylmalonic acid diethyl ester (
obtain a). NMRδ ^CDCl3 _ppn : 6.8-7.2 (1H, m, aromatic ring (C ₃ -H)) 7.7-8.1 (1H, m, aromatic ring (C ₆ -H)) Example 2 Residue 2,4 obtained above ,5-trifluorobenzoylmalonic acid diethyl ester (
Dissolve a) in 50 ml of dioxane and add a catalytic amount of p
- Add toluenesulfonic acid and reflux for 24 hours. After cooling, the reaction solution is neutralized with an aqueous sodium bicarbonate solution and extracted with 200 ml of chloroform. After drying the chloroform extract with Glauber's salt, the solvent was distilled off, and the residue was subjected to silica gel column chromatography to obtain 2,4,5-trifluorobenzoylacetic acid ethyl ester (b) as a benzene eluate.
Obtain 2.1 g (melting point 63-64 °C). IRν ^CHCl3 _nax cm ^-1 : 1735and1690 (C-0) NMRδ ^CDCl3 _ppn : 1.27 (1/2×3H, t, J=6.5Hz, 1/2×CHCH ₃ ) 1.36 (1/2×3H, t, J =6.5Hz, 1/2 x CH ₂ CH ₃ ) 3.95 (1/2 x 2H, d, J = 3.2Hz, COCH ₂ CO ₂ Et) 4.22 (1/2 x 2H, q, J = 6.5Hz, 1 /2×-CH ₂ CH ₃ ) 4.28 (1/2×2H, q, J=6.5Hz, 1/2×-CH ₂ CH ₃ ) 5.82 (1/2×1H, s,

[Formula]) 6.83~7.20 (1H, m, C ₃ -H) 7.55~7.90 (1H, m, C ₆ -H) 12.69 (1/2H, s, -OH) Elemental analysis value C ₁₁ H ₁₉ F ₃ As O ₃ Calculated value C 53.67, H 3.69 Analytical value C 53.91, H 3.77 Example 3 Ketoester form (b) obtained in Example 2
A solution of 1.36 g and 1 ml of ethyl orthoformate in 5.1 ml of acetic anhydride is heated under reflux for 1 hour. The solvent is distilled off under reduced pressure to obtain a residue (oil). This thing is
Subjected to silica gel column chromatography,
Purify by developing with chloroform, distill off the solvent of the eluate, and crystallize when left to stand. This was recrystallized from a mixed solvent of n-hexane-isopropyl ether to obtain 3-ethoxy-2-(2,4,5-trifluorobenzoyl) as transparent crystals.
Acrylic acid ethyl ester (c) is obtained. NMRδ ^CDCl3 _ppn : 1.09 (3H, t), 1.25 (3H, t) 4.09 (2H, q), 4.10 (2H, q) 6.88 (1H, ddd) 7.67 (1H, s), 7.1~7.9 (1H, m ) Reference example 4 The steplessly obtained residue (Ic) is dissolved in 10 ml of anhydrous dichloromethane, 0.4 ml of cyclopropylamine is added at room temperature, and the mixture is stirred for 1 hour. After distilling off the solvent,
Dry under reduced pressure, and dissolve the resulting residue, 3-cyclopropylamino-2(2,4,5-trifluorobenzoyl)acrylic acid ethyl ester (5), in 30 ml of anhydrous dioxane, and add 270 mg of 50% sodium hydride. and heated under reflux for 1 hour. After cooling, the reaction solution is acidified with diluted hydrochloric acid and extracted with chloroform. After drying Glauber's salt, chloroform was distilled off and subjected to silica gel column chromatography to obtain 1-chloroform-acetone (2%) eluate.
cyclopropyl-6,7-difluoro-1,4
-Dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester 820mg (melting point 231-233℃)
get. IRν ^CHCl3 _nax cm ^-1 : 1720and1685 (C-0) NMRδ ^CDCl3 _ppn : 1.20 (2H, m

[Formula]) 1.40 (3H, t, J=6.5Hz, -CH ₂ CH ₃ ) 3.45 (1H, m,

[Formula]) 4.36 (2H, q, J = 6.5Hz, -CH ₂ CH ₃ ) 6.70 (1H, dd, J = 5.5and10.5Hz, C ₈ -H) 8.16 (1H, dd.J = 5.5and10. 5Hz, C ₅ -H) 8.51 (1H, s, C ₂ -H) Elemental analysis value C ₁₅ H ₁₃ F ₂ NO ₃ Calculated value C 61.43, H 4.47, N 4.78 Analysis value C 61.66, H 4.31, N 4.72 Reference example 5 Add 3 ml of an aqueous solution of 120 mg of potassium hydroxide to a suspension of 530 mg of this product in 20 ml of ethanol,
Stir for 20 minutes at °C. 170mg of citric acid in solution
When 10ml of an aqueous solution of is added, crystals will precipitate. This was collected by filtration and 400 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (melting point 234-236°C)
get. NMRδ ^DMSO-d6 _ppn : 1.06-1.43 (4H, m,

【formula】) 3.75~(1H, m,

[Formula]) 8.03 ~ 8.36 (2H, m, C ₅ -HandC ₈ -H) 8.66 ~ (1H, a, C ₂ ) -H) 14.53 (1H, s, CO ₂ H) Elemental analysis value C ₁₃ H ₉ As F ₂ NO ₃ Calculated value C 58.87, H 3.42, N 5.28 Analysis value C 58.80, H 3.33, N 5.09 Reference example 6 1-cyclopropyl-6,7-difluoro-
1,4-dihydro-4-oxoquinoline-3-
130 mg of carboxylic acid and 2-methylpiperazine
Dissolve 150mg in 5ml of dimethyl sulfoxide,
Stir for 1 hour at a bath temperature of 100-110°C. After the reaction, the solvent was distilled off under reduced pressure, and the residue was diluted with ether three times, a small amount of water twice, and then ether-ethanol (4:
Wash with the mixture of 1) to obtain a pale yellowish brown powder. Dissolve (partially suspend) in 5 ml of ethanol, add 1 ml of concentrated ammonia water, treat with activated carbon, and concentrate to obtain 1-cyclopropyl-6- as colorless crystals.
95 mg of fluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (melting point 232-233 DEG C.) are obtained. NMRδ ^DMSO-d6 _ppn : 1.09 (3H, d, J=4Hz,

【formula】) 1.13~1.40 (4H, m,

【formula】 3.8~3.9 (1H, m,

[Formula]) 7.58 (1H, d, J = 5.5Hz, C ₆ -H) 7.94 (1H, d, J = 11.5Hz, C ₅ -H) 8.71 (1H, s, C ₂ -H) Elemental analysis value Calculated value as C ₁₈ H ₂₀ FN ₃ O ₃・1/2H ₂ O C 61.01, H 5.97, N
11.86 Analysis value C 60.88, H 5.67, N
11.82 Reference example 7 1-cyclopropyl-6,7-difluoro-
1,4-dihydro-4-oxoquinoline-3-
80mg of carboxylic acid to 1.5ml of dimethyl sulfoxide
and heat this to 110-120℃ (2-3
minute). A solution of 140 mg of 2,2-dimethylpyrabezine dissolved in 1.0 ml of dimethyl sulfoxide is added to this and stirred for 20 minutes. After evaporating the solvent under reduced pressure, ether was added to remove excess 2,2-dimethylpiperazine, and the residue was washed with ethanol and chloroform. Add ethanol to this,
Add a few drops of concentrated ammonia to dissolve and treat with activated carbon. When the liquid is condensed and the precipitated crystals are collected by filtration, 1-
cyclopropyl-6-fluoro-7-(3,3
-dimethyl-1-piperazinyl)1,4-dihydro-4-oxoquinoline-3-carboxylic acid is obtained. Melting point 217℃. NMR (NaOD) ppm 1.10-1.20 (2H, m

[Formula]) 1.25 (6H, s, 2×CH ₃ ) 1.30~1.40 (2H, m,

[Formula]) 3.06 (2H, s-N-CH ₂ -) 3.03-3.15 (2H, m, -N-CH ₂ -) 3.17-3.30 (2H, m, -N-CH ₂ -) 3.60-3.75 ( 1H, m,

[Formula]) 7.60 (1H, d, J = 4.3HZ, C ₈ -H) 7.94 (1H, d, J = 8.8HZ, C ₅ -H) 8.52 (1H, s, C ₂ -H) Elemental analysis C ₁₉ H ₂₂ N ₃ O ₃ Calculated value as F C 63.50, H 6.17, N
11.70 Experimental value C 63.33, H 6.01, N
11.55

Claims (1)

[Claims] 1 General formula () (In the formula, X means a fluorine atom, R represents -CH( _COOR1 ) _COOR2 , _-CH2 ( _COOR1 ) or -C( _C00R1 )= _CHOR3 , where _R1 , R ₂ and R ₃ have 1 to 1 carbon atoms
Compound 2 is 2,4,5-trifluorobenzoyl malonic acid diethyl ester Compound 3 of Claim 1 is 2,4,5-trifluorobenzoyl malonic acid ethyl ester Compound 4 of Claim 1 A compound of Claim 1 which is 3-ethoxy-2-(2,4,5-trifluorobenzoyl)acrylic acid ethyl ester.