NZ224150A

NZ224150A - Preparation of piperazinyl-substituted quinoline derivatives

Info

Publication number: NZ224150A
Application number: NZ224150A
Authority: NZ
Inventors: Istvan Hermecz; Geza Kereszturi; Lelle Vasvari; Agnes Horvath; Maria Balogh; Peter Ritli; Judit Sipos; Aniko Pajor; Katalin Marmarosi
Original assignee: Chinoin Gyogyszer Es Vegyeszet
Priority date: 1987-04-08
Filing date: 1988-04-06
Publication date: 1990-11-27
Also published as: KR970005910B1; NO885446D0; NO175859C; CA1324137C; FI885523A; FI89710B; NO175859B; GR1000469B; KR890700576A; FI885523A0; ES2006882A6; GR880100231A; HK1003996A1; FI89710C; NO885446L

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £24150 Priority Oate(s): .. . Complete Specification Filed: Class: Publication Date: P.O. Journal, Mo: . ...A3SS • • « • * 1990' 22 4 1 5 0 Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION PROCESS FOR THE PREPARATION OF QUINOLINE CARBOXYLIC ACIDS <n vr X/UZ, CHINOIN GYOGYSZER ES VEGYESZETI TXERMEKEK GYARA RT., a body corporate organized under the laws of Hungary, of 1-5/ To utca, Budapest IV., Hungary hereby declare the invention, for which <r7we pray that a patent may be granted to^frf^/us, and the method by which it is to be--g>erformed, to be particularly described in and by pllowing statement: - 1 - (followed by page la) 2241 10 15 20 25 This invention relates to a process for the preparation of l-cyclopropyl-7-substituted-6-fluoro-4- oxo-1,4-dihydro-quinoline-3-carboxylic acid derivatives # and phariTjaceutically acceptable salts thereof. It is known that l-cyclopropyl-7-subs-tituted-6-fluoro-4-oxo-l, 4-dihydro-quinoline-J-carboxylic acid derivatives of the general Formula I 0 R ^ Jl JCOOH YYV i xn which R represents hydrogen, methyl or ethyl, : 1 — possess high antibacterial activity /Bur. J. Clin. Microbiol. 1983, 2, page 111; J. Clin. Pharmacol. 1985, 25, page 82; Drugs Exptl. Clin, Res. 1985, 5, page 311J The quinoline carboxylic acids of the general Formula I can be prepared by reacting l-cyclopropyl-6-fluoro-7-chloro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid and a cyclic amine in the presence of a solvent at a temperature of 135-140°C for 2 hours [U.S. patent'^4^20 007 and NZ patent specification 202 278] /y 14 $, % %o (followed by pege^2) 5^5 / v p 'O.. / According to the present invention there is provided a process for the preparation of 1-cyclopropyl-7-substituted-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid derivatives of the general Formula I /wherein R has the .same meaning as stated above7 which comprises reacting a compound of the general Formula II II 1 0 /wherein R and R are the same or different and stand for halogen, for an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted by halogen, or for an aromatic acyloxy group containing 7 to 11 carbon atoms7 with a cyclic amine of the general Formula tffQH 111 /wherein R^ stands for hydrogen, methyl or ethyl7 or a salt thereof and subjecting the compound of the general Formula IV "3" 2241 IV o i 2 [wherein Rj R and R are the same as stated above] thus obtained to hydrolysis after or without isolation. If desired, the compound of the formula I may be converted into a salt thereof or the acid may be liberated from its salt. The advantage of -the process of the present invention is that it makes the desired compound of the general Formula I available in a simple manner with high yields and in a short reaction time. According to a preferred form of embodiment of the process of the present invention the borate derivative of the general Formula IV /wherein R, R and R are as stated above7 is converted into the desired quinoline*-^ carboxylic acid of the general Formula I without isolj The "borate derivatives of the general Formul/ are new compounds. \\ The borate derivatives of the general Formula ^I * > \i r. O and the cyclic amine of the general Fornmla' III can be reacted optionally in the presence of an inert organic solvent and an acid binding agent. As inert organic solvents preferably acid amides /e.g. dimethyl formamide, dimethyl acetaaide7, ketones /e.g. acetone, methyl ethyl ketone7, ethers ^e.g. dioxane, tetrahydrofuran, diethyl ether7, esters /e.g. ethyl acetate, - 4 - 224150 methyl acetate, ethyl propionate7, sulfoxides /e.g. dimethyl sulfoxide/, alcohols /e.g. methanol, ethanol, 1-decanol, butanollj may be used. As acid binding agent an organic or inorganic base may be used. From the group of organic bases trialkyl amines /e.g. triethyl amine, tributyl amine/, cyclic amines /e.g. pyridine, l,5-diazabicyclo/5.4.o/undec-5-ene, 1,5-diazabicyclo/4.3. o/non-5-ene, 1,4-aiazabicyclo-[2.2.2/octane/ can be mentioned, while as inorganic base preferably hydroxides or carbonates of alkali or alkaline earth metals can be appli'ed. Thus as acid binding agent preferably potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, calcium hydroxide, etc, or an excess of the amine of the general Formula III can be used. The boron derivative of the general Formula II and the cyclic amine of the general Formula III can be reacted at a temperature ranging from 0 to 200 °C, depending on the solvent used. The reaction time may vary between half an hour and 10 hours depending on the reaction temperature. If the reaction is carried out at an elevated temperature, the reaction time can be shortened. The above reaction conditions are but preferable values and other conditions may be used as well. The borates of the general Formula IV /wherein R, n o R and R are as stated above/ can be hydrolysed to the desired quinoline-3-carboxylic acids of the general Formula I, after or without isolation, under acidic - 5 - 224150 or basic conditions. The compound of the general Formula IV /wherein R is as stated above/ precipitates from the reaction mixture e.g. on cooling and can be separated e.g. by filtration or centrifuging, if desired. Basic hydrolysis may preferably be carried out by heating an aqueous solution of hydroxydes or carbonates of alkali metals or hydroxides of alkaline earth metals, One may preferably use an aqueous solution of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, calcium hydroxide, potassium hydrogen, carbonate. Organic amines /e.g. triethyl amine/ may also be applied in the hydrolysis step. Acidic hydrolysis may preferably be accomplished by using an aqueous mineral acid. One may preferably proceed by hydrolysing a "borate of the general Formula IV by heating same with an aqueous solution of hydrochloric acid, hydrogen bromide, sulfuric acid or phosphoric acid. Hydrolysis may also be accomplished by using organic acids /e.g. acetic acid, propionic acid, etc/. Hydrolysis of the compounds of the general Formula IV may also be carried out in aqueous medium in the presence of a water-miscible organic solvent. For this purpose e.g. alcohols /e.g. methanol, ethanol/, ketones /e.g. acetone/, ethers /e.g. dioxane/, acid amides /e.g. formamide, dimethyl formamide/, sulfoxides /e.g. dimethyl sulfoxide/^or pyridine may be used. 224150 The quinoline-3-carboxylic acid of the general Formula I thus obtained may be isolated e.g. by adjusting the pH value of the aqueous solution to a suitable value and separating the precipitated crystals e.g. by filtration or centrifuging or by liophylization of the aqueous reaction mixture. The compounds of the general Formula I can be converted into pharmaceutically acceptable salts thereof by methods known per se. Thus preferably acid addition salts formed with hydrogen halides, sulfonic acids, sulfuric acid or organic acids. One may preferably form chlorides, bromides, 4-methyl-phenyl-sulfonates, methane sulfonates, maleates, fumarates, benzoates, etc. The compounds of the general Formula I form salts with alkali or alkaline earth metals or other metal ions as well. Accordingly sodium, potassium, magnesium, silver, copper salts, etc, may be prepared. The compounds of the general Formula I and pharmaceutically acceptable salts thereof can be converted into hydrates /"e.g. hemihydrates, trihydrates, etc.J by methods known per se. According to a further aspect of the present invention there are provided new compounds of the general Formula IV /wherein R, R1 and R2 are as stated above/. The starting materials of the general Formula II can be prepared e.g. by reacting l-cyclopropyl-6-fluoro-7-chloro-4-oxo-l, 4-dihydro-quinoline-3-carboxylic acid [NZ patent specification 202278] with a boron derivative [such 22415 - 7 - as a compound of the general Formula V B-R2 V nr5 /wherein r\ R^ and R** stand for halogen, for an aliphatic acyloxy group containing 2 to 6 carton atoms optionally substituted "by halogen, or for an aromatic acyloxy group containing 7 to 11 carbon atoms/ or with fluoroborate in an aqueous or an organic medium. Further details or the present invention are to be • found in the following Examples without limiting the scope of protection to the said Examples. Example 1 4.1 g of /i-cyclopropyl-6-fluoro-7-chloro-l,4-di-hydro-4-oxo-quinoline-3-carboxylate-Cp,C)^/-bis/aceto-o7-boron and 2.8 g of piperazine anhydride are heated in 16 fll of dimethyl sulfoxide to 110 °C under stirring. 40 ml of a 3 w/v % aqueous sodium hydroxide solution are added to the brownish-red solution and the reaction mixture is boiled under reflux for an hour. The hot pale-yellow solution is filtered and the pH value is adjusted to 7 by adding 1.8 ml of 96 % acetic acid. The reaction mixture is cooled to room temperature, the precipitated white crystals are filtered, washed with water and methanol and dried. The crude product is purified by boiling in 10 ml water. Thus 2,99 g of l-cyclopropyl-6-fluoro-7- l-piperazinyl/~l» 4*~dihydro-4-oxo-quinoline-3"~carboxylic 224150 - 8 - acid are obtained. The product decomposes at 255 °C. Analysis for the Formula C^yH^gFN^O^: Calculated: 0=61.62 % H=5.48 % N=12.68 % Found: 0=61.58 % H=5.50 % N=12.6l %. Example 2 By reacting /l-cyclopropyl-6~fluoro-4-chloro-l,4-dihydro-4-oxo-quinoline-3-carboxylate-0^,0^^-Dis/acetato-2/ borone and N-methyl-piperazine according to Example 1. l-cyclopropyl-6-f luoro-7-/4-methyl-piperazinq7-l, 4-di-hydro-4-oxo-quinoline-3-c'arboxylic acid is prepared. The product decomposes at 248-250 °e. Example 3 4.1 g of /l -cyclopropyl-6-fluoro-7-chloro-l,4-di-hydro-4~oxo-quinoline-3-carboxylate-0^,0^/-bis/acetato-^7-borone and 3.7 g of N-ethyl-piperazine are heated in 16 ml of dimethyl sulfoxide to 90 °C under stirring. After 10 minutes 40 ml of a 3 W/w % aqueous sodium hydroxide solution are added and the reaction mixture is boiled for an hour under reflux. The hot solution is filtered and the pH value is adjusted to 7 with 96 % acetic acid. The reaction mixture is cooled, the precipitated crystals are filtered and -washed with water. Thus 3.3 g of 1-cyclo-propyl-7- Z4- ethyl-piperazinyl7-6-f luoro-1,4-dihydro-4~ oxo-q.uinoline-3-carboxylic acid are obtained. M.p.: 183-185 °C. </div>

Claims

<div id="claims" class="application article clearfix printTableText"> H © • - 9 - ' " - I i i Q /—V /—v. 224150 Analysis for -the Formula Calculated; C=63.35 H=6.17 N=11.69 Found: C=63.31 H=6.21 N=11.70 5 Example 4 3.3 g of /i-cyclopropyl-6-fluoro-7-chloro-l,4-di-hydro-4-oxo-quinoline-3-carboxylate-0^,0^/-dif luoro-borone are reacted with. 3.7 g of N-ethyl-piperazine according to Example 3.
Thus 3.4 g of l-cyclopropyl-7-^4-ethyl-l-10 piperazinyl7-6-fluoro-l,4-dihydro-4-oxo-quinoline-3- carboxylic acid are obtained which in admixture at any ratio with the product of Example 3 no depression of the melting point occurs. 22415 - 10 - WHAT V/E CLAIM IS: !• A process for the preparation of compounds of the general Fornrula I COOH in which R^-' represents hydrogen, roethyl or ethyl, — and pharmaceutically acceptable salts thereof, vhich comprises reacting a compound of the general Formula II II 12* in which R and R independently represent halogen, an aliphatic acyloxy group containing 2 to 6 carbon atoms optionally substituted "by halogen, or an aromatic acy1lo3^--group containing 7 to 11 carbon atoms, with a piperaz^L^jg^^j^ derivative of the general Formula III -I 224150 - n - O V.t.«rr _3 R N NH 111 c o 20 15 20 25 in which R represents hydrogen, methyl or ethyl, or a salt "thereof and subjecting the compound of the general Formula IV IV thus obtained, in which R? R1 and R2 are as defined above, to hydrolysis after or without isolation ana if desired converting the compound of the general Fornula I thus-obtained into a salt thereof or setting free th< from its salt. 2. \<& '/ A process according to Claim 1 which comj^^go.^ t i reacting a compound of the general Formula II with a piperazine derivative of the general Formula III in the presence of an organic solvent..
3. A process according to claim 2 in which the solvent is an acid amide, a sulfoxide, a ketone, an alcohol, an ether or an ester. .} . i 224150 - 12 -
4. A process according -to Claim 3 which comprises using dimethyl sulfoxide as organic solvent.
5. A process according to Claim 1 which comprises carrying out the reaction of the compounds of the general Formulae II and III in the presence of an acid "binding agent.
6. A process according to Claim 5 which comprises using an amine or an excess of the compound of the general Formula III as acid "binding agent.
7. A process according to Claim 1 which comprises carrying out the hydrolysis in acidic medium. 15
8. A process according to Claim 7 which comprises U carrying out the reaction "by using as acid an organic or inorganic acid. . ■ o 10 < > 20
9. A process according to claim 8 in which the acid is hydrochloric acid, sulfuric acid or acetic acid.,.'
10. A process according to claim 1 which comprises carrying out the hydrolysis in a basic medium.
11. A process according to claim 10 which comprises using as a base an alkali metal hydroxide, an alkaline earth metal hydroxide or an organic base. v fj 'i 224150 - 13 -
13. A process according claim 1 and substantially as described in this specification with reference to any one of the examples. r\
14. A compound of the formula I whenever produced by a process according to any one of claims 1 to 13 CHIKOIN GYOGYSZER ES VEGYESZETI T^ERMKKEK GYARA RT. </div>