NORFLOXACIN INTERMEDIATE

Abstract: A process for the preparation of compounds of general formula (I), (wherein R and R<1> stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally substituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms), which comprises reacting a compound of general formula (II), (wherein R<2> stands for hydrogen or alkyl comprising 1-4 carbon atoms) with a borone derivative of general formula (III), (wherein R<3>, R<4> and R<5> stand for an alkyl group comprising 1-4 carbon atoms and optionally substituted by halogen or for an aryl group comprising 6-10 carbon atoms). The new compounds of general formula (I) are useful pharmaceutical intermediates.

Description: -TORFLOXACI-T INTERMEDIATE This invention relates to new intermediates useful in the preparation of Norfloxacin . More particularly it is concerned with new anhydrides of l-ethyl-6-f luoro- -7-chloro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid and boric acida and a proceas for the preparation thereof. It ia known that ethyl-l-ethyl-6-fluoro-7-chloro-4- -oxo-l,4-dihydro-quinoline-3-carboxylate /Journal of Medicinal Chemistry 23, 1358 (1980); Japanese patent specification No. 8033,453/ ia an intermediate uaeful in the preparation of l-ethyl-6-fluoro-7-aubatituted- -4-oxo-l, 4-dihydro-quinoline-3-carboxylic acida having antibacerial effect (Ann. Microbiol /Paria/ 1981, Ϊ32A, 267; Journal of Medicinal Ghe iatry 1980, 23, 1358; Pathol. Biol. 1982, 30, 394; Cyo Yakuri, 1983, 25, 475; Fa hoi. Biol. 1983, 31, 501; Antimicrob. Agents Che o- ther. 1980, 17, 103; 1981, 19, 188; 1981, 20, 265; CR. Seances Acad. Sci. , Ser. 3, 1981, 92, 37/. The latter compounds can be prepared in two steps by reacting ethyl-l-ethyl-6-f luoro-7-chloro-4-oxo-l,4- -dihydro-quinoline-3-carboxylate with a cyclic a ine at a temperature above loo °C in the presence of a sol¬ vent for aeveral hours and subjecting the ethyl-1- -ethyl-6-fluoro-7-aubstituted-4-oxo-l,4- ihydro-quino- line-3-carbo ylate thus obtained to hydrolysis; -the order of aucceaaion of the aaid two steps can be changed if desired (Japanese .patent specifications Noa. 79,138,5 and 80,33,453; Belgian patent apecificationa ΪToa. 863,42 870,917; 879,106 and 890,223; DOS _To. 2,840,910 and French patent publication No. 2,424,919). The above proceaaea are accompanied by aeveral drawbacka. The reaction time uaed is long. Moreover the halogeqaminβ group replacement reaction is not se¬ lective and in addition to the desired chlorq&mine reaction in position 7 also a f luoro/amine exchange in position 6 takes place to a considerable extent. It haa been found that the selectivity of the desired halogen/amine replacement reaction in position 7 can be Increased significantly by reacting a cyclic amine with an anhydride of the general Formula I (wherein R and R stand for an aliphatic acyloxy group comprising 2-5 car¬ bon atoms and optionally aubatituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms). A further advantage of this process is that the reaction time is aignificantly ahorter. According to the preaent invention there is provided a process for the preparation of compounds of the general Formula I (wherein R and R stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally aubatituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms), which comprises reacting a compound of the general Formula II /II/ 2 (wherein R stands for hydrogen or alkyl comprising 1-4 carbon atoms) with a borone derivative of the ge¬ neral Formula III (wherein R , R and R stand for an alkyl group compri¬ sing 1-4 carbon atoms and optionally substituted by ha¬ logen or for an aryl group compriaing 6-10 carbon atoms). The reaction of the quinoline-3-carboxylic acid of the general Formula II and the borone derivative of the general Formula III can preferably be carried out in an optionally halogenated organic carboxylic acid - which may also contain the corresponding acid janhyd- ride - at a temperature between 0 and 200 oC. Th•e com¬ pound of the general Formula I thus formed precipitates from the reaction mixture either spontaneously or under cooling and can be separated e.g. by filtration. The reaction may however also be carried out in an other solvent (e.g. aulfoxide, amidea, pyridine, aromatic hydrocarbona) , if de.aired. The borone derivatives of the general Formula III can be used in a molar ratio of 1-50 molea related to 1 mole of the quinoline-3-carboxylie acid derivative of the general Formula II. Further detaila of the preaent invention are to be found in the following Examples without limiting the scope of protection to the aaid Examplea. Example 1 A mixture of 9.3 g of boric acid and 70 g of propionic anhydride is stirred at 100 °C for 15 minutes whereupon the reaction nixture ia heated to the boiling point. After half an hour the temperature is lowered to 110 °C and 29.8 g of e thyl-l-ethyl-6-f luoro-7-chloro- -4-oxo-l, 4-dihydro-quinoline-3-carboxylate are added. The reaction mixture , which turna to a thick auapenaion within aome minutea , is stirred at 110 C for 2 hours , then cooled to room temperature and diluted with 300 ml of water. The reaction nixture is cooled and the pre¬ cipitated crystals are filtered. Thus 41.5 g of 1-ethyl- -6-fluoro -7-chlorc-4-oxo-l,4-dihydro-quinoline-3-carbo- xylic acid-borone-di( propionyloxy) -anhydride are obtaine yie ld: 97.7 ; Mp . : 252 °C (decomposition) . Analysis for the Formula O^gH^gBFCl Oγ calculated C = 50.79 , H = 4.26 %, N = 3.29 found C = 50.94 %, H = 4.15 %, N = 3.41 Example 2 A mixture of 46.3 g of boric acid and 345 g of propi nic anhydride is stirred at 100 °C for 15 minutes where¬ upon the reaction mixture is heated to boiling. After half an hour the reaction temperature is lowered to 110 °C and 134.5 g of l-ethyl-6-fluoro-7-chloro-4-oxo- -l,4-dihydro-quinoline-3-carboxylic acid are added. The reaction mixture is stirred at 110 °C for 2 hours and cooled under 10 C. The reaction mixture ia diluted with 150 ml of water and allowed to crystallize in a refrigerator overnight. Next morning the precipitated crystals are filtered, washed with water and dried in vacuo. Thua 208.6 g of l-ethyl-6-fluoro-7-chloro-4-oxo- -l,4-dihydro-quinoline-3-carboxylic acid——borone-di(pro pionyloxy)-anhydride are obtained, yields 98 %. The product melta at 269 °C (decomposition). A mixture of the product-formed with any amount of the compound prepared according to Example 1 shows no melting point depression. r- Example 3 A mixture of 9.3 g of boric acid and 54.1 g of acetic anhydride is heated at 110 °C for 30 minutes. The reaction mixture is cooled to 80 °G and 29.8 g of eth 1-1-ethy 1-6-f luoro-7-chloro-4-oxo-l, 4-dihydro- -quinoline-3-carboxylate are added. The reaction mix¬ ture is stirred at 110 °G for 2 houra, cooled below 10 °G and diluted with 100 ml of water. The cooled reac¬ tion mixture is allowed to crystallize in a refrigera¬ tor overnight. Next morning the precipitated crystals are filtered, washed with water and dried. Thus 33.5 g of 1-ethy 1-6-f luoro-7-chloro-4-oxo-l,4-dihydro-quinoline -3-carboxylic acid-borone-di( ace toxy) -anhydride are obtained. Yield: 84.4 . The product decompoaes at 274 °C. λnalyaia for the Formula C gH- j aFGlB O-γ calculated C = 48.34 %, H = 3.54 %, N = 3-52 % found C = 48.48 %, H = 3.43 %, N = 3.57 %. Example 4 2.74 g of boric acid and 22.6 g. of acetic acid anyhdride are reacted in the presence of 2 mg of zinc chloride. The boric acid is gradually added to the acetic acid anhydride while the reaction temperature raises to 88 °C. The temperature of the reaction mixture is then slowly raised to 110 °C and 8.79 g. of ethyl- -l-ethyl- ' 6-fluoro-l,4-dihydro-7-chloro-4-oxα-3-quinoliπe- -carboxylate are added, which had been previously dis¬ solved in 18 ml. of hot 96 % by W/V acetic acid. The orange-red clear solution is stirred for 2 hours at 110 °C and then allowed to cool. The precipitated crystals are filtered and washed several times with water and once with methaπol and dried. 10.8 g (92.1 % off- -white (l-ethyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo- -3-quinoliπe-carboxylate- ,fj )-bis(acetate-0)-boron are obtained, decomposing at 273 °C. Analysis for the formula C, ,H, 4 BC1F 0 7 calculated: C= 48.35 H = 3.55 % N = 3.52 % found: C =48.2 % H = 3.5 % N = 3.2 % .

Claims: WHAT WE CLAIMS IS : 1. Compounds of the general Formula I (wherein R and R stand for an aliphatic acyloxy group compriaing 2-5 carbon atoma and optionally aubatituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms ) . 2. Process for the pre paration of compounds of the general Formula I C 2 H 5 (wherein R and R stand for an aliphatic acyloxy group comprising 2-5 carbon atoms and optionally substituted by halogen or for an aromatic acyloxy group comprising 7-11 carbon atoms), which comprises reacting a compound of the general Formula II (wherein R atanda for hydrogen or alkyl compriaing 1-4 carbon ato a) with a borone derivative of the gene¬ ral Formula III (wherein R 3, and atand for an alkyl group compriain 1-4 carbon atoma and optionally aubatituted by halogen or for an aryl group comprising 6-10 carbon εfcoms). 3. Proceaa according to Claim 2 which comprises carrying out the reaction of the compounds of the ge¬ neral Formulae II and III in the presence of a solvent. 4. Proceaa according to Claim 2 which comprises carrying out the reaction of the Compounds of the ge¬ neral Formulae II and III at a temperature between 0 and 150 o σ# 5. Compounds of the general Formula I whenever prepared by the process according to any of Claims 2-4. 6. A proceaa as aubatantially described herein with particular references to the Exacplea.

Inventors: BALOGH MARIA, HERMECZ ISTVAN, HORVATH AGNES, KERESZTURI GEZA, KOVACS GABOR, MESZAROS ZOLTAN, PAJOR ANIKO, RITLI PETER, SIPOS JUDIT, VASVARI LELLE, BALOGH, MARIA, HERMECZ, ISTVAN, HORVATH, AGNES, KERESZTURI, GEZA, KOVACS, GABOR, MESZAROS, ZOLTAN (DECEASED), PAJOR, ANIKO, RITLI, PETER, SIPOS, JUDIT, VASVARI, LELLE
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, MESZAROS MARTA LEGAL HEIR AND, MESZAROS ZOLTANNE LEGAL HEIR A, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT., MESZAROS, MARTA (LEGAL HEIR AND REPRESENTATIVE OF, MESZAROS, ZOLTANNE (LEGAL HEIR AND REPRESENTATIVE
Application year: 1986
Main classification: C07F5
IPC codes: C07D215, C07F5