JPS62246541A - Benzoylacetic acid ester derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R is lower alkyl; X is halogen; Y is Cl, Br or I). EXAMPLE:Ethyl 2-(2,3-dichloro-4,5-difluorobenzoyl)acetate. USE:A synthetic intermediate for antimicrobial agents 8-halogeno-1-substituted-6- fluoro-1,4-dihydro-7-substituted-4-oxo-3-quinolinecarboxylic acids, etc. PREPARATION:An acid chloride expressed by formula II is condensed with a malonic acid ester in the presence of a magnesium alcoholate in an inert solvent, e.g. ether, etc., at -50-+50 deg.C to afford the aimed benzoylmalonic acid ester expressed by formula III (R and R' are lower alkyl), which is then decarboxylated in an aqueous solution of an acid to provide the aimed compound expressed by formula I.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a general formula (wherein R is a lower alkyl group, X is a halogen, and Y is a chlorine, bromine or iodine atom) useful as an intermediate for pharmaceuticals. ).

(Problems to be Solved by the Invention) The compound of the present invention is a novel compound synthesized for the first time by the present inventors, and is an extremely useful novel antibacterial agent 8-halogeno-1- Substituted-6-fluoro-1,4-dihydro-7-substituted-4-oxo-3
-Used as an intermediate in the production of quinoline carboxylic acid, etc.

[Means for solving problems]

The compound represented by the general formula [I] is produced according to the following steps.

[I] (In the formula, R and R' are the same or different lower alkyl groups, X is a halogen, and Y is a chlorine, bromine or iodine atom.) That is, acid chloride [I[] and malonic acid dialkyl ester is condensed in the presence of magnesium alcoholade to produce a benzoyl malonic ester represented by the general formula [■], which is decarboxylated in an acid aqueous solution without purification to produce a benzoyl acetate [I]. be able to. The above condensation reaction is carried out in an inert solvent such as ether or toluene at a temperature of -50 to 50°C, preferably -0°C to room temperature, and is completed in 10 minutes to 20 hours. On the other hand, in the decarboxylation reaction, for example, [I[[] is converted into a catalytic amount of p-
This can be easily carried out by refluxing in an aqueous solution containing toluenesulfonic acid for 30 minutes to 20 hours.

The benzoyl acetate derivative represented by the general formula [I] can be converted into an antibacterial compound, for example, as shown in the following formula.

Y Y [Example] Next, the method for producing the compound of the present invention will be explained in detail with reference to Examples.

Example 1 Synthesis of diethyl 2-(2,3-dichloro-4,5-difluorobenzoyl)malonate 0.77 g of magnesium was added to 5.3 d of absolute ethanol, and while stirring, 0.4-d of carbon tetrachloride was added to the mixture. added. When the reaction started, a mixture of 4.899 ml of diethyl malonate, 5 d of absolute ethanol, and 21.3 rd of anhydrous toluene was added dropwise to the reaction solution at 20 to 40'C over 40 minutes. After stirring at 50-60°C for 2 hours, 2,3-dichloro-4,5-difluorobenzoyl chloride6.
A mixture of 00g and 7.1ml of anhydrous toluene was added dropwise over 10 minutes at -18 to -13°C with stirring. Next, stirring was continued for 2 hours while gradually raising the temperature to room temperature, and then a mixture of 1,1IIIl of concentrated sulfuric acid and 17 d of ice water was added to the reaction solution, and the mixture was extracted three times with 20 rni of toluene. The toluene layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain the desired product 9.689 as a yellow oil.

Example 2 Synthesis of ethyl 2-(2,3-dichloro-4,5-difluorobenzoyl)acetate 9.71'j of diethyl 2-(2,3-dichloro-4,5-difluorobenzoyl)malonate was added to 11 of water. .2rI
Suspended in Ji, P-toluenesulfone 111.2#I9
was added and refluxed for 3 hours with vigorous stirring. Cold welding, extraction three times with 20 d of methylene chloride, and the methylene chloride layer was reduced to 7%
The mixture was washed with an aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off. The remaining pale red oil was dissolved in n-hexane, then cooled and the precipitated crystals were counted to obtain 2.68 g of the desired product as a white powder. The furnace liquid was concentrated to obtain 1.58 g of No. 2 product.

Melting point: 52-53°C Elemental analysis value (%): C11Ha Cj! z FN2
03 calculated value: C; 44.47, H: 2.71
Actual values: C: 44.59, H: 2.65 Reference example 2. Synthesis of 3-dichloro-4,5-difluorobenzoyl chloride 2.3-Cyclo4.5-Schiff) I, tt benzoyl
fi9.33, dimethylformamide 0.013 mi
A mixture of 40 ml of thionyl chloride and thionyl chloride was refluxed for 2.5 hours. Excess thionyl chloride was distilled off under reduced pressure, and the residue was purified by distillation under reduced pressure to obtain 1 q of 8.7 g of the desired product as a pale yellow oil.

Boiling point: 123-126°C (40! MIH (J) Example 3 Synthesis of N-(3,4-difluorophenyl)acetamide 3. 28.2 g of 4-difluoroaniline and 3 acetic anhydride
0d was added under stirring while controlling the heat generation, and further added at the same temperature for 3.
0 minutes @ stirring continued. The reaction solution was poured into 1001d of ice water to separate the precipitated crystals, which were thoroughly washed with cold water to obtain 34.79 of the desired product as colorless needle crystals.

Melting point = 127-127.5℃ Elemental analysis value (%): Ce H7F2 N.

Calculated value: Q; 56.14, t(:4.12.
N; a, ia actual measurement: C: 56.15, H:
4.06. N: 8.00 Example 4 Synthesis of 4.5-difluoro-2-nitroaniline N-(
Add 48 g of 3,4-difluorophenyl)acetamide to 1140 rRIt and stir this in a salt-ice bath while diluting 56 d of concentrated nitric acid (d = 1.42) from -1 to 2
．． The mixture was added dropwise at 5° C. over 50 minutes. Next, stirring was continued for 1.5 hours at 2.5-16°C, and the precipitate was poured into 560 m of ice water, washed thoroughly with cold water, and N-(4,5-difluoro-2-nitrophenyl) was obtained. 55.3 g of acetamide was obtained.

Concentrated hydrochloric acid-ethanol (1:4 V/V) to 70 g of N-(4,5-difluoro-2-nitrophenyl)acetamide
550 d of the mixture was added and refluxed for 2 hours. The reaction solution was poured into 1.51 g of ice water, and the precipitate was collected and thoroughly washed with cold water to obtain the target product of 53.2 tj in the form of yellow prism crystals.

Melting point: 109-109.5℃ Elemental analysis value (%): C684F2 N202 calculated value:
C: 41.39, H: 2.32. N:
16.09 Actual value: C: 41.29, H: 2
．． 31. N: 15.96 Example 5 Synthesis of 2-bromo-3,4-difluoro-6-nitroaniline 4. Dissolve 3.79 of 5-difluoro-2-nitroaniline in 27me of acetic acid and stir at 50-56°C Bottom, bromine 6
68 g was added dropwise, and stirring was continued for an additional 2.5 hours.

The reaction solution was poured into 60 d of ice water, and the precipitated crystals were thoroughly washed with cold water to obtain 4.7 g of the desired product as yellow prism crystals.

Melting point: 105℃ Elemental analysis value (%): C6t-bBr'Fz N202
Calculated value: C: 28.48. l-(:1゜20.N
: 11.07 Actual value: C: 28.62, To1
: 1.15. N: 11.00 Example 6 Synthesis of 3-bromo-2-chloro-4,5-difluoro-1-nitrobenzene 4.6 g of 2-bromo-3,4-difluoro-6-nitroaniline was dissolved in 30 d of anhydrous acetonitrile. After dissolving in the solution, 3.1 g of anhydrous cupric chloride was added. 51% of this mixture
While stirring at ~56°C, 2.8 g of tert-butyl nitrite was added dropwise over 5 minutes, and stirring was continued for an additional 8 minutes. The reaction solution was a water-cooled dilute hydrochloric acid aqueous solution (21 sulfuric acid: water/1:2 V/V) 30
Pour rIJ1, Hensen extraction (70°70IrIl)
Shita. The benzene layer was prepared using a water-cooled dilute hydrochloric acid aqueous solution (m-hydrochloric acid: water/1
: 4 V/V) After washing for 50 days, and further washing with 50 m of saturated saline and 50 m of water, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (silica gel 150 g, developing solvent: n-hexane:methylene chloride 15:1) to obtain the desired product 4.09 as a pale yellow oil.

*H-NMR (δ in CDC13) 7.79 (
11-1, dd, J = 8.79.7.03H2) Example 7 Synthesis of 3-bromo-2-chloro-4,5-difluoroaniline, adding 38.6 g of iron powder to 40 rIIIl of water and adding 50 to 6
While stirring vigorously at 0'C, make salt rM! M was slowly added dropwise. Once the foaming has subsided, use hot ethanol 100Id!
was added, and while stirring at 60-75°C, 3-bromo-2-chloro-4,5-difluoro-1-nitrobenzene 58.8
g was added dropwise over 30 minutes, and stirring was continued for an additional 10 minutes. 300 ml of benzene was added to the hot reaction solution, the insoluble matter was removed in the oven, and the mixture was washed with ethanol 3 (7 d) and benzene 100 d.

The organic layer was washed with saturated saline (250, 250).

250 d) L, dried with anhydrous mirabilite. The solvent was distilled off under reduced pressure, and silica gel column chromatography (800 g of silica gel, developing solvent: n-hexane: methylene chloride/
1:1) to obtain target object 34 as pale brown prism crystals.
．． 5g was obtained.

Melting point = 83-86°C @ 'H-NMR (δ in CDCJ!3) 6.58
(1H, d d, J=11.43, 7.03
H2).

4.4~3.4 (2H,br,NHz>・IR(K
Br, cm-1 > 3370, 3470. 1610. 1590. 14
75. 1420. 12B0゜1220, 1170
．． 850, 835 Example 8 Synthesis of 3-bromo-2-chloro-4,5-difluorobenzenediazonium tetrafluoroborate 3-bromo-2-chloro-4,5-difluoroaniline 30.1
After adding tj to 180 d of 42%-fluoroboric acid and thoroughly grinding, stir vigorously while keeping the temperature at -9 to -1°C in a salt water bath, and add 30 d of sodium nitrite 129.
d aqueous solution was added dropwise over 40 minutes, and stirring was continued for an additional 1.5 hours. The precipitate was 42% - hydrogen borofluoride! fi
The mixture was washed with 100 d of water and then washed with ether 3501 d to obtain 35.6 g of the desired product in the form of pale yellow needles.

Decomposition point: >300℃ @ IR (KBr, cm”) 2940, 2870.22B0.1600. 1570
．． 1460.1310°1250-930,870 Example 9 Synthesis of 3-furomo-2-chloro-4,5-difluorobenzonitrile Cupric cyanide 18.67g, potassium cyanide 27.
A 200 rd aqueous solution of 14 g and 5.52 g of sodium carbonate was mixed with 3-bromo-2-chloro-4,5- under stirring at room temperature.
35.6 g of difluorobenzenediazonium tetrafluoroborate was added over 40 minutes, followed by stirring for 4.5 hours. Add 250 parts of benzene to the reaction solution and
After stirring for a minute, insoluble matter was removed and washed with benzene. Separate the organic layer and wash with saturated saline (200, 200rIJi)
After that, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and separated by silica gel column chromatography (silica gel 1NL developing solvent; n-hexane:methylene chloride/3:1), and then recrystallized from methylene chloride-n-hexane to give pale yellow prism crystals. 10.99 of the desired product was obtained.

Melting point near 1~72.5℃ Elemental analysis value (%): C7HBrCIFz N calculated value:
C: 33.31, H: 0.40. N; 5
．． 55 actual measured value: C: 33.22, H: 0.3
1. N: 5.4B Example 10 Synthesis of 3-bromo-2-chloro-4,5-difluorobenzoic acid 9.8 g of 3-bromo-2-chloro-4,5-difluorobenzonitrile was dissolved in 10 m of sulfuric acid. , outside temperature 100℃
The mixture was stirred for 35 minutes. After cooling, add 50% of 18N sulfuric acid aqueous solution.
4. Add rfdl and 10 d of water at 1 ioo°C.
Stirred for 25 hours. The reaction solution was poured into ice water at 300 rpm to remove the precipitate, which was then thoroughly washed with cold water. This precipitate was recrystallized from methylene chloride-n-hexane to obtain the desired product (9.249 q) as colorless prism crystals.

Melting point: 137.5-139.5°C Elemental analysis value (%): C7HzBrCJ! Fz Oz calculated value: C: 30.97, H: 0.74 Actual value: C; 30.9B, H: 0.71 Example 11 Synthesis of 3-bromo-2-chloro-4,5-difluorobenzoyl chloride 3-bromo-2-chloro-4,5-difluorobenzoic 1
33 ml of thionyl chloride was added to 9.0 g, and the mixture was refluxed for 2.5 hours. After cooling, the mixture was concentrated under reduced pressure using a 10 cm Widmer rectifying column to remove excess thionyl chloride, and purified by distillation to obtain 8.89 q of the desired product as a colorless oil.

Boiling point: 109℃/22mHIJ @'H-NMR<δ in CDCl2:+)7
．． 93 (11-1, dd, J=9.67, 7.47H
2)・IR(crx-') 3090, 1775.1600.1570.1460.
1380.1290°1150, 1040.870,
850, 715 Example 12 Synthesis of diethyl 2-(3-bromo-2-chloro-4,5-difluorobenzoyl)malonate ioo, g Magnesium ethoxide 3 in a three-bore flask
．． 93 g was weighed out, and while stirring at 20 to 25° C., a solution of 4.65 g of diethyl malonate dissolved in 30 d of anhydrous toluene was added dropwise over 25 minutes. Thereafter, the temperature was raised to 50-60°C and stirring was continued for 3 hours. The reaction mixture was cooled in a salt-ice bath, and a solution of 65 g of 3-bromo-2-chloro-4,5-difluorobenzoyl chloride in 15d of anhydrous toluene was added dropwise over 25 minutes while stirring while keeping the temperature between -16 and 0°C. After that, the mixture was continuously stirred for 2.5 hours. Return to maximum temperature and add 4
After stirring for 0 minutes, ice water 15rI11 and concentrated sulfuric acid 1H1
A mixed solution was added to dissolve the contents and the phases were separated. The aqueous phase was further extracted with toluene (25, 25, 25 rn1), and the organic layers were combined, washed with 40 mj of saturated brine, and concentrated under reduced pressure to obtain 11.44 g of the target product as an orange oil.

・I R (cm”) 2975, 1710.1620.1570.1460.
1400.1370°1340, 1300.1235.
1195.1150.1080.1040゜Example 13 Synthesis of ethyl 2-(3-bromo-2-chloro-4,5-difluorobenzoyl)acetate 2-(3-bromo-2-chloro-4,5-difluorobenzoyl) >Add 167! of water to 11.49 diethyl malonate and emulsify it to make 15fItg of P-toluenesulfonic acid.
was added and refluxed for 3 hours with vigorous stirring.

After cooling, methylene chloride extraction (30, 30, 30, 30 m
After washing with saturated brine, it was dried with anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure and subjected to silica gel column chromatography (developing solvent: methylene chloride-n-hexane/1:1)
The product was separated and purified to obtain 4.56 g of the target product.

Melting point: 41-51℃ Elemental analysis value (%): C1t Ha Br'CIFz
03 calculated value: C: 38.68, l-1: 2.
36 actual measurement value: C: 37.94, H: 2.19@
'H-NMR (δ in CDCl5) 7.42 (1f
-f, m, Ar-H>, 4.24 (2H.

m, J=7.36H2, CH2CH3),
1.30 (3t 1゜m, J -7,33HZ
), 12.46 - 5.50 - 4.
00-2.64(2H, -CCH2COO-)・IR(
KBr, an-' ) 3000, 1650.1 & 30.1595.1575.
1470.1420°1380. 1310. 124
0. 1205. 11B5. 1120. 1040
゜860, 800

Claims (2)

[Claims] (1) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] (In the formula, R is a lower alkyl group, X is a halogen, and Y is a chlorine, bromine, or iodine atom.) benzoyl acetic acid derivative. (2) General formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, X is a halogen, and Y is a chlorine, bromine, or iodine atom.) Acid chloride and malonic acid represented by By condensing esters, the general formula [III] ▲Mathematical formulas, chemical formulas, tables, etc. are available▼[III] (In the formula, R and R' represent the same or different lower alkyl groups, and X and Y are the same as above.) General formula [I] ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ [I] (In the formula, R, X and Y are the same as above.) A method for producing a benzoyl acetic acid derivative represented by