KR900006443B1 - Process for the preparation of aniline derivative - Google Patents

Abstract

Anilline deriv. is prepd. by reacting imidoyl chloride of formula (II) which is prepd. from N-cyclopropyl formamide with phenol deriv. of formula (III) to obtain N-cyclopropyl imidate of formula (IV); then position trasfer reacting (IV) by heating. In formulas, R is H or -CHO; X is halogen atom, e.g. Cl or Br. The anilline deriv. is useful as important intermediate for preparing quinolinic antibacterial agent, syproflosuccine having excellent antibaterial property.

Description

Method for preparing aniline derivative

The present invention relates to a novel process for preparing N-cyclopropyl-4-fluoro aniline derivatives represented by the following general formula (I).

(In the formula, R represents a hydrogen atom or a -CHO group, X represents a halogen atom such as chlorine, fluorine, cancellation.)

The compounds of the present invention are very important intermediates for the preparation of quinoline-based antibacterial agents, ciprofloxacin, which show very good antibacterial activity.

The present invention is a novel method for preparing aniline derivatives of general formula (I) from N-cyclopropyl formamide by applying Chapman displacement.

The Chapman shift reaction means that when the aryl amidate is heated, the aryl group of the aryloxy group shifts to become diarylamide. Similarly, it is known that allyl iminoesters also undergo an inversion reaction to become amides (Tetrahedron, 28,5903, (l972), J. Am. Chem. Soc., 82, 1950 (1960). By applying this shifting reaction, N-cyclopropyl formamide is treated with a suitable chlorinated reagent, reacted with a phenol derivative to form N-cyclopropyl iminoester, and then the shifting reaction is induced to induce the desired general formula (I). In more detail, a preferred process for preparing the present invention is prepared from N-cyclopropyl formamide, followed by reaction of imidoyl chloride of formula (II) with a phenol derivative of formula (III) To prepare N-cyclopropylimidate of the following general formula (IV), and then by heating and shifting to prepare the aniline derivative of the general formula (I).

(Wherein R and X are as described above)

The present invention is described in detail by the following reaction scheme.

(X in the scheme is as described above.)

N-cyclopropylformamide is prepared with powerful chlorination reagents such as phosgene, ulsalyl chloride and contamination confirmation to prepare imidoyl chloride, and then react with N-cyclopropylimino without reacting imidoyl chloride directly. It is form esterified. This reaction all takes place in one vessel. The resulting intermediate imidoyl chloride and imino ester are very difficult to handle and have not been separated and do not need to be separated and purified. The imino ester thus prepared is added to a high boiling point solvent such as xylene together with a catalyst such as zinc chloride or copper sulfate to prepare a desired aniline derivative. This reaction proceeds as a reaction in a single container, and the operation is simple. That is, the highly reactive imidoyl chloride does not need to be separated, so that the reaction with phenol in one container, and after all the reaction is completed, only the target product is purified, there is no difficult operation due to the reactivity or stability of the intermediate product. Advantages of the present invention are first, the method of producing the N-cyclopropylanilene derivative is unique. Second, the whole process is carried out in one container.

The present invention will be described in more detail with reference to the following examples.

Example 1

After dissolving 0.56 g of N-cyclopropylformamide in 6 ml of dichloromethane, 1.5 ml of oxalyl chloride was added and stirred at room temperature for 12 hours. The solvent is removed under reduced pressure and 1.9 g of 3-chloro-4-fluorophenol are added together with xylene 3.0 ml. After heating at about 70-80 ° C. for 2 hours, 0.9 g of zinc chloride is added and stirred at 130-140 ° C. for 1 hour. When the reaction is completed, the solution is weakly basicized with an aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The ethyl acetate layer was combined, concentrated and separated by silica gel tube separation to separate 120 mg of N-cyclopropyl-N-formyl-4-fluoro-3-chloroaniline and 85 mg of N-cyclopropyl-4-fluoro-3-chloroaniline. .

N-cyclopropyl-N-formyl-4-fluoro-3-chloroaniline:

IR (KBr): 1660cm ^-1

1 H NMR (CDC1 ₃ , δ): 8.46 (s, 1H), 7.66-6.63 (m, 3H), 2.10-2.43 (m, 1H), 0.66-1.69 (m, 4H).

N-cyclopropyl-4-fluoro-3-chloroaniline:

IR (KBr): 1610, 1500, 1460 cm ^-1

1 H NMR (CDCl ₃ , δ): 6.37-7.1 (m, 3H), 3.9 (1H, br), 2.2 (m, 1H), 0.6-1.2 (m, 4H).

Example 2

After reacting in the same manner as in Example 1, the reaction was terminated and hydrolyzed with aqueous sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, the extract was concentrated and purified by silica gel tube separation to yield 210 mg of N-cyclopropyl-4-fluoro-3-chloroaniline.

Example 3

Except for using copper sulfate instead of zinc chloride, the same procedure as in Example 2 gave 1800 mg of N-cyclopropyl-4-fluoro-3-chloroaniline.

Example 4

208 mg of N-cyclopropyl-4-fluoro-3-bromoaniline was obtained in the same manner as in Example 2 except that 4-fluoro-3-bromophenol was used instead of 4-fluoro-3-chlorophenol. .

Example 5

213 mg of N-cyclopropyl-4-fluoro-3-chloroaniline was prepared by reacting in the same manner as in Example 1 except for using two equivalents of phosgene instead of oxalyl chloride.

Example 6

175 mg of N-cyclopropyl-4-fluoro-3-chloroaniline was prepared in the same manner as in Example 1 except that an equivalent phosphorus pentachloride was used instead of oxalyl chloride.

Example 7

1.02 g of N-cyclopropylformamide was dissolved in 10 ml of dichloromethane, and then 3.8 ml of oxalyl chloride was added and stirred at room temperature for 12 hours. 7.5 ml of xylene is added thereto, and dichloromethane and excess ulsalyl chloride are distilled off. 3.8 g of 0-trimethylsilyl 3-chloro-4-fluorophenolether is added to the residue, and 50 mu l of titanium tetrachloride is added as a catalyst. After heating at about 70-80 ° C. for 2 hours, 1.5 g of zinc chloride are added and stirred at 130-140 ° C. for 1 hour. The reaction mixture is poured into an aqueous sodium bicarbonate solution to weaken base and then hydrolyzed. The aqueous layer was extracted with ethyl acetate, collected, and the organic layer was concentrated and separated by silica gel to obtain 414 mg of N-cyclopropyl-4-fluoro-3-chloroaniline. This compound is added to 395 mg of 5-ethoxymethylene-2,2-dimethyl-1,3-dioxane-4,6-dione, followed by stirring at 110 ° C. for 2 hours and cooling.

The resulting solid is washed with ether, then dissolved in dichloromethane (5 ml) and chlorosulfonic acid (0.12 ml) is added at around 3 ° C. The reaction mixture was stirred at room temperature for 2 hours, and the resulting solid was washed with ethyl ether to give 325 mg of 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-3-quilinine. Carboxylic acid is obtained.

Melting Point 228-230 ℃

1 H NMR (CF ₃ COOD, δ): 9.5 (lH, s), 8.0-9.1 (3H, m), 1.4-1.9 (4H, m).

Claims (1)

N-cyclopropylimidate of formula (IV) is prepared by reacting imidoyl chloride of formula (II) with a phenol derivative of formula (III), which is prepared from N-cyclopropylformamide, and then heated A method for producing an aniline derivative of the general formula (I), characterized in that by the displacement reaction.

(In the general formula, R is a hydrogen atom or a -CHO group, X is a halogen atom such as chlorine, bromine.)