PL154525B1 - Method of obtaining n-alkyl derivatives of 3-carboethoxyquinolone-4 - Google Patents

Description

REPUBLIC

POLAND

PATENT DESCRIPTION

154 525

OFFICE

PATENT

RP

Additional patent to patent no. - Pending: 87 11 25 / P. 269023 /

Precedence Int. Cl. ⁵ C07D 401/04 msia uhm

Application announced: ⁸ ° 5 30

Patent description published: 1991 12 31

Creators of wmlazku: Jerzy Kazimierczak, Teresa Ryzrnir, Krystyna Bisialska, Romana Jaworska, Magdalena MooSrąg

Entitled by the patent: Institute of Pharmaceutical Industry,

Warsaw / ^p olska /

METHOD OF PREPARATION OF 3-CARBETOXYQUINOLOIFLU-4 N-ALKYL DERIVATIVES

The object of the production is a process for the preparation of N-alkyl 3-carboethoxy-4-olone derivatives of the formula wherein R is ethyl or cyclopropyl, R-j is c12 or piperazinyl or 4-methylpiperazinyl. These compounds are intermediates in the synthesis of norfloxacin, pefloxacin, ciprofloxacin, known third-generation quinolone chemotherapeutic agents with strong antibacterial properties.

It is known from Japanese patent 56,128,765 and the publication of Kogi et al. /j.Med. Chem. 23, 1362/1980 / J a method for the preparation of compounds represented by the formula by N-alkylation of the corresponding 3-carboethoxy-4-hydroxyzhinoine derivatives. The reaction was carried out with an alkyl halide to potassium carbonate in a medium of dimethylformamide at a temperature of 8O-9O ⁰ C. With the reaction mixture oaaesty0 iano ^of dimethylformamide, and the residue was isolated the product by O ^^ ywai® aichlolometanem and then stripping off the solvent. The disadvantage of the known process is the use of the aimetzlo: for □ amide which, due to its properties, i.e. the high boiling point (153 ° C), is difficult to remove from the reaction medium. Distilling it both under normal pressure and under reduced pressure consumes a considerable amount of energy. Moreover, the relatively high reaction temperature causes losses of the low-boiling alkali halides. However, the use of dimethylformamide as the reaction medium is necessary in the known process because it is a good solvent for the reaction substrates and also partially but sufficiently dissolves inorganic salts, which ensures the course of the reaction. As our own research has shown, the N-alkylation reaction does not take place if non-polar solvents such as acetone, dichloromethane, ethyl acetate are used. This is due to the insufficient solubility of inorganic salts in these solvents.

Surprisingly, it turned out that this reaction can be carried out in the above-mentioned solvents if additionally thymeamine is used. It fulfills a function under the reaction conditions

154 525

A phase transfer catalyst by forming a quaternary ammonium salt with an alkyl halide. This reaction can also be carried out using conventional phase transfer catalysts such as: quaternary ammonium salts or crown ethers or cryptand

In the process according to the invention, the N-alkylation reaction of 3-carboethoxy-4-hydroxyquinoline derivatives is carried out with an alkyl halide, in the presence of alkali metal carbonate, in a medium of non-polar organic solvents, with the addition of trieyl ammonium or quaternary ammonium salts or crown ethers or cryptand, in temperature 40-70 ° C. Acetone, dichloromethane, preferably ethyl acetate are used as nonpolar organic solvents, and in particular tetaabutylammonium bisulfate or bromide is used as quaternary ammonium salts.

The advantageous effect of the invention is the reduction of the amount of the alkyl halogenates and alkali metal carbonates used due to the lower losses of the low-boiling alkali halogen halides, the reduction of the energy consumption of the process from the reel to the use of low-boiling solvents in organic and easy stripping, as well as a significant simplification of the extraction the reaction product.

The following examples illustrate wfnlazek.

Example I. To 3.0 g / 0.011 moo / 7-ihtrro-6-flroro-3katbreeckts ~ 4-hydroxyquinoline in 40 ml of ethyl acetate are added 3.0 g (0.022 mooo / potassium carbonate, 3.3 ml / 0.044 moo / bromide) ethyl acetate and 0.5 ml of titanium amine, and heated to reflux for 8 hours with stirring. After the precipitate was filtered off, the solvent of the filtrate was distilled off and the dry residue obtained was triturated with gasoline, filtered and dried. 3.0 g of N-ethyl [beta] -chloro-5-fluoro-3iίcaίboethoxyLinrlon-4 are obtained.

Example II. To 3.0 g / 0.011 moles / 7-chlorrr-6-fluoro-3-carbreto-4-hydroxyquinoline in 40 ml of acetone, 3.0 g (0.022 mole) of potassium carbonate, 3.3 m (0.044 mole) of ethyl bromide are added and 0 , 4 g of tetrabutylaronrovegr hydrodesulfate or 0.4 g of tetrabutylammonium bromide or 0.3 g of (le-crown-e) crown ether or 0.3 g of cryptand and then proceed as in Example 1.

Example III. To 0.3 g / 0.011 moles / 7-chloro-6-fluOΓO-3kBbboethoxy-4-hydroxyquinolint in 40 ml of dichloromethane, 3.0 g / 0.022 moles / potassium carbonate, 3.5 ml / 0.044 moles / cyclopropyl bromide are added and The procedure is then followed as in Example 1. 2.7 g / 85% v / v N-cycloporite Os7-chloro-6-flurro-3-carboethoxyquinolone-4 are obtained.

Claims (3)

Pateno Claims ^ e 1. Boiling process of N-alkil 3-catbretoxquinrlon-4 derivatives of the formula, where R is ethyl or cyclopropyl, and R5 is chlorine or piperazinyl or 4-aethyl-pipetazinyl, by N-alkylation of the corresponding 3-catbottoxetin derivatives A 4-htracchioline carried out with an alkyl halide in the presence of alkali metal carbonate, characterized in that the reaction is carried out in a medium of non-harsh solvents in organic triethoamine or quaternary ammonium salts or crown ether or cryptand at a temperature of 40-70 ° C. The method according to claim 1, characterized in that acetone, dichloromethane, in particular ethyl acetate are used as non-volatile organic solvents. 3. A method according to claim 1, characterized in that vorootsiaΓizan or tetrabutylammonium bromide is used as the quaternary ammonium salts.