JPH053866B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention provides a general formula useful as an intermediate for pharmaceuticals. (wherein, R represents hydrogen or a nitro group, and Z represents hydrogen or a lower acyl group) and a method for producing the same. [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 new antibacterial agent 8-chloro, which was developed by the present inventors. −
1-Cyclopropyl-6-fluoro-1,4-dihydro-7-(4 or 3-methyl-1-piperazinyl or unsubstituted 1-piperazinyl)-4-
It is used as an intermediate in the production of oxo-3-quinolinecarboxylic acid, etc. [Means for solving the problem] The compound represented by the general formula [ ] is produced as described below. That is, first, 3-chloro-2,4,5-trifluoronitrobenzene [] is reacted with cyclopropylamine to produce 3-chloro-2-cyclopropylamino-4,5-difluoronitrobenzene []. The reaction is carried out using at least an equimolar amount of cyclopropylamine with respect to the compound [], in a suitable solvent such as benzene, toluene, methylene chloride, chloroform, etc., at a temperature between 0°C and the boiling point of the solvent used. I can do it. At this time, it is also preferable to use a deoxidizing agent such as triethylamine or diazabicyclo bases. Furthermore, the compound [] can be reacted with lower fatty acids or reactive derivatives thereof, such as formic acid and acid anhydrides such as acetic anhydride, acetic anhydride, and propionic anhydride, or acid halides such as acetyl chloride, acetyl bromide, and propionic acid chloride. The general formula is (In the formula, R ₁ represents a lower alkyl group.) It can be an N-cyclopropylaniline derivative represented by the following formula. The reaction is carried out without a solvent or in a suitable solvent such as pyridine, benzene, toluene, methylene chloride, chloroform, etc. at a temperature of 0°C to 60°C using an excess of acylating agent. At this time, generally well-known deoxidizing agents may be used. Next, the compound [] is reduced according to a conventional method to obtain an amino derivative represented by the general formula [']. Such reduction can be carried out by a method using a metal or its salt, but hydrogen catalytic reduction is also preferred. For example, the compound [] can be dissolved in a solvent such as methanol or ethanol, and reduced at room temperature from 0° C. under a hydrogen stream at normal pressure using a catalyst such as palladium. (In the formula, R ¹ is the same as above.) The compound ['] thus obtained is used in the next deamination step without any particular purification. That is, by dissolving the compound ['] in a suitable solvent such as acetonitrile, dimethylformamide, etc., and reacting with at least equimolar amount of nitrite gas or nitrite ester at a temperature of 0 to 100°C, the general formula [] (In the formula, R ¹ is the same as above.) It is possible to produce an N-cyclopropylaniline derivative represented by N-cyclopropyl-2-chloro-3,4 by heating method
- induced by difluoroaniline [ ]. [Example] The present invention will be explained below with reference to Examples. Example 1 Synthesis of N-(3-chloro-4-fluorophenyl)acetamide 3-chloro-4-fluoroaniline 100g
When 200ml of acetic anhydride is added to (0.687mol), heat is generated. After standing for 30 minutes, the reaction solution was poured into water from step 1, the precipitate was collected by filtration, and dissolved in 400 ml of ethanol.
600 ml of hot water was added, and the mixture was allowed to cool with occasional stirring, and the precipitated crystals were collected by filtration to obtain 119.4 g of the desired product. Melting point 118~
119℃ elemental analysis value (%): C ₈ H ₇ ClFNO Calculated value C: 51.22, H: 3.76, N: 7.47 Actual value C: 51.04, H: 3.72, N: 7.43 Example 2 N-3-chloro-4 - Synthesis of fluoro-6-nitrophenyl) acetamide Dissolve 55 g (0.293 mol) of N-(3-chloro-4-fluorophenyl) acetamide in 165 ml of concentrated sulfuric acid, add concentrated nitric acid while stirring in a ice-d) salt bath, and (d 1.42) 154 ml was added dropwise at 5 to 10°C over 1 hour. After stirring at the same temperature for 1 hour, the reaction solution was poured into ice water, and the precipitate was collected by filtration, thoroughly washed with water, and recrystallized from acetonitrile, yielding 48.9 g of the desired product as yellow needle-shaped crystals.
I got it. Melting point 114-115℃ Elemental analysis value (%): C ₈ H ₆ CLFN ₂ O ₃ Calculated value C: 41.31, H: 2.60, N: 12.04 Actual value C: 41.48, H: 2.52, N: 12.13 Example 3 3 -Synthesis of chloro-4-fluoro-6-nitroaniline Add 30 g (0.129 mol) of N-(3-chloro-4-fluoro-6-nitrophenyl)acetamide to a mixed solution of 50 ml of concentrated hydrochloric acid and 200 ml of ethanol.
Refluxed for 2.5 hours. 300 ml of ice water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 24.9 g of the target product in the form of yellow needle-like crystals. Melting point 149.5-150℃ Elemental analysis value (%): C ₆ H ₄ ClFN ₂ O ₂ Calculated value C: 37.82, H: 2.11, N: 14.70 Actual value C: 37.85, H: 2.03, N: 14.80 Example 4 2 , 3-dichloro-4-fluoro-6-nitroaniline Dissolve 14.3 g (0.075 mol) of 3-chloro-4-fluoro-6-nitroaniline in 150 ml of acetic acid,
Chlorine gas was bubbled for 70 min at ~20°C. The reaction solution was poured into 300 ml of ice water, the precipitate was collected by filtration, washed with water, and recrystallized from ethanol to obtain the desired product as yellow needle-shaped crystals.
14.33g was obtained. Melting point 161℃ Elemental analysis value (%): C ₆ H ₃ Cl ₂ FN ₂ O ₂ Calculated value C: 32.03, H: 1.34, N: 12.45 Actual value C: 32.17, H: 1.26, N: 12.65 Example 5 2 Synthesis of ,3,4-trichloro-5-fluoronitrobenzene 2,3-dichloro-4 -Fluoro-6-nitroaniline 18.05g
(0.08 mol) was added little by little at 60-62°C over 30 minutes. After stirring at 60-65℃ for 30 minutes, the reaction solution was poured into ice water-dilute hydrochloric acid (100 ml of concentrated hydrochloric acid, 200 ml of ice water), extracted three times with 100 ml of benzene, and the organic layer was sequentially washed with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. The residue was distilled to obtain 17.26 g of the desired product. Boiling point 137-142°C/27 mmHg NMR (δ in CDCl ₃ ), 7.65 (d, J = 7.5 Hz) Example 6 Synthesis of 3-chloro-2,4,5-trifluoronitrobenzene Anhydrous solution containing 64.9 g of potassium fluoride Add 54.4 g of 2,3,4-trichloro-5-fluoronitrobenzene to 230 ml of dimethyl sulfoxide suspension at 140°C.
and stirred at the same temperature for 10 minutes. Pour the reaction mixture into ice water.
The organic layer was washed with water, an aqueous potassium carbonate solution, and water in sequence, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by distillation to obtain 9.7 g of the desired product. I got it. Boiling point 95-108℃/30mmHg NMR (δ in CDCl ₃ ), 7.94 (ddd, J=6.7,
7.6 9.0Hz) Example 7 3-chloro-2-cyclopropylamino-4,
Synthesis of 5-difluoronitrobenzene Dissolve 2.8 g of cyclopropylamine and 5.1 g of triethylamine in 20 ml of anhydrous toluene,
Into a stirred solution of 9.7 g of chloro-2,4,5-trifluoronitrobenzene in 30 ml of anhydrous toluene,
The mixture was added dropwise at 3 to 5°C for 40 minutes. After stirring at the same temperature for 3 hours, the reaction solution was poured into 150 ml of ice water, extracted with methylene chloride, and the organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by a silica gel column (solvent: n-hexane-methylene chloride) to obtain 4.4 g of the target product as an orange-red oil. NMR (δ in CDCl ₃ ), 0.5-1.0 (4H, m,

[Formula]), 3.0 to 3.2 (1H, m,

[Formula]), 7.19 (1H, s, NH), 7.85 (1H, dd, J=8.2,
9.9Hz, 5-H) Example 8 N-(2-chloro-3,4-difluoro-6-
Synthesis of (nitrophenyl)-N-cyclopropylacetamide 3-chloro-2-cyclopropylamino-4,
Acetic anhydride to 4.4 g of 5-difluoronitrobenzene
15 ml was added and stirred at room temperature for 30 minutes. The reaction solution was poured into 100 ml of ice water, potassium carbonate powder was added to decompose excess acetic anhydride, and after standing at 5°C for 12 hours, the precipitate was collected by filtration and recrystallized from ethyl acetate-n-hexane to obtain the desired product. 2.7g of product was obtained. Melting point 98-99.5℃ Elemental analysis value (%): C ₁₁ H ₉ ClF ₂ N ₂ O ₃ Calculated value C: 45.46, H: 3.12, N: 9.64 Actual value C: 45.56, H: 3.00, N: 9.69 Example 9 Synthesis of N-(2-chloro-3,4-difluorophenyl)-N-cyclopropylacetamide N-(2-chloro-3,4-difluoro-6-
Nitrophenyl) N-cyclopropylacetamide
Dissolve 2.7g in 50ml of ethanol, add 0.5g of 10% palladium on carbon, and heat at 2-3℃ in a normal pressure hydrogen stream.
The mixture was stirred for 40 minutes. After filtering and concentrating the reaction solution, a crystalline residue (N-(6-amino-2-chloro-3,
(4-difluorophenyl)-N-cyclopropylacetamide) was vacuum dried at room temperature for 10 hours. This was dissolved in 15 ml of anhydrous dimethylformamide, and added dropwise to 10 ml of anhydrous dimethylformamide containing 1.72 g of tert-butyl nitrite at 50 to 52°C for 13 minutes. The reaction solution was stirred at the same temperature for 5 minutes, then poured into ice water and extracted with ether. The organic layer was washed with water, diluted hydrochloric acid, and water in sequence, dried over anhydrous sodium sulfate, concentrated, and the resulting residue was applied to a silica gel column. (Solvent: n-hexane-ethyl acetate) and recrystallized from petroleum ether to obtain 0.44 g of the desired product. Melting point 60.5~
61.5℃ Elemental analysis value (%): C ₁₁ H ₁₀ ClF ₂ NO Calculated value C: 53.78, H: 4.10, N: 5.70 Actual value C: 53.87, H: 4.02, N: 5.78 Example 10 N-Cyclopropyl- Synthesis of 2-chloro-3,4-difluoroaniline Add N-(2-chloro-3,4-difluoroaniline) to 7 ml of 20% dilute hydrochloric acid.
-difluorophenyl)-N-cyclopropylacetamide (0.44 g) was added, and the mixture was stirred at 80 to 100°C for 6 hours. The reaction solution was poured into ice water, made weakly alkaline with an aqueous sodium hydroxide solution, and extracted with ether.
The organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration,
The obtained residue was isolated and purified by preparative silica gel thin film chromatography (solvent: petroleum ether-ether) to obtain 100 mg of the target product as an orange oil. NMR (δ in CDCl ₃ ), 0.5-0.9 (4H, m,

[Formula]), 2.2 to 2.5 (1H, m,

[Formula]), 4.3-4.7 (1H, s, NH), 6.73 (1H, ddd, J=
2.0, 4.6, 9.2Hz), 6.99 (1H, ddd, J=7.9, 9.2,
9.5Hz)

Claims (1)

[Claims] 1. General formula (In the formula, R represents hydrogen or a nitro group, and Z represents hydrogen or a lower acyl group.) An N-cyclopropylaniline derivative represented by the following. 2 General formula A formula characterized by the action of cyclopropylamine on the compound represented by A method for producing an N-cyclopropylaniline derivative represented by: 3 formulas A general formula characterized by the action of a lower fatty acid or its reactive derivative on the compound represented by (In the formula, R ¹ represents a lower alkyl group.) A method for producing an N-cyclopropylaniline derivative represented by the following formula. 4 General formula (In the formula, R ¹ represents a lower alkyl group.) A general formula characterized by reducing a compound represented by (In the formula, R ¹ is the same as above.) A method for producing an N-cyclopropylaniline derivative represented by the following. 5 General formula (In the formula, R ¹ represents a lower alkyl group) A formula characterized by hydrolyzing an N-cyclopropylaniline derivative represented by A method for producing an N-cyclopropylaniline derivative represented by: