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Halogenating Agent (Or () ?O O/Nann/ O/Y/NN/ (VI) K

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Halogenating Agent (Or () ?O O/Nann/ O/Y/NN/ (VI) K United States Patent (19) (11) 3,761,482 Nakagome et al. (45) Sept. 25, 1973 (54) PROCESS AND INTERMEDIATES FOR THE O PREPARATION OF N-SUBSTITUTED -o-messau-au-3 6,7-METHYLENEDIOXY-4-QUINOLONE COOR1 DERIVATIVES M-NH cio-ch-c / (75) inventors: Takenari Nakagome; Hideo Agui, (IV) COOR." - both of Osaka, Toru Mitani; Mitsuo O COOR." N N acid anhydrous or Nakashita, both of Hyogo, all of g-coor; acidic substance Japan -H-> (73) Assignee: Sumitomo Chemical Co., Ltd., O NMCHN Osaka, Japan (II) R (22 Filed: July 9, 1970 X (2) Appl. No.: 53,706 ON OOR HO or alcohol Y- s (30) Foreign Application Priority Data O July 10, 1969. Japan................................ 44/54890 R Oct. 2, 1969 Japan................................ 44/794.08 (III) O y Oct. 2, 1969. Japan..... ... 44/79409 Oct. 2, 1969 Japan..... ... 44/794.10 O Nov. 12, 1969 Japan................................ 44/90957 July 9, 1969 Japan................................ 44/54661 Feb. 23, 1970 Japan................................ 45/15722 (O N r R (I) k 52) U.S. Cl.... 260/287 R, 260/283 SY, 260/286 O, wherein R and R are as defined above, R is alkyl; X 260/340.5 is halogen; and Y is, for example, halogen. The 1 51 ) Int. Cl....... is essa e s a r s so as a se n e o a r s s r. s r. so a so on sess C07d 33/48 substituted-6,7-methylenedioxy-4-quinolone-3- 58 Field of Search............... .... 260/287 carboxylic acid derivative of the formula (I) can be also produced directly from the compound of the formula 56 References Cited (II) by the reaction with the acid anhydrous or acidic OTHER PUBLICATIONS substance. Gramstad - J. Chem. Soc., 1957, Pt. 3 pp. 4069-4079. The quinolinium salt of the formula (III) can be, alternatively produced by the process as shown below: Primary Examiner-Donald G. Daus OE Attorney-Sughrue, Rothwell, Mion, Zinn and O COOR." O Macpeak N OOR." C-COOR." Or 57) : ABSTRACT ch O NY Novel process for producing antimicrobial 1 O NH substituted-6,7-methylenedioxy-4-quinolone-3- (VII) (VIII) carboxylic acid derivatives of the formula, X O On halogenating agent (Or () ?o o/NaNN/ o/Y/NN/ (VI) k . () wherein R is alkyl or alkenyl, and R is hydrogen or al O kyl. The novel process is shown by the following reac alkylating agent ( OOR Y tion schema: ..-area-mb u O si R O hydrogenation catalyst (LII) - ROH --> wherein R, R', X and Y is as defined above. NH O 1 Claim, No Drawings 3,761,482 1 PROCESS AND INTERMEDIATES FOR THE pH O PREPARATION OF N-SUBSTITUTED O 6,7-METHYLENEDIOXY-4-QUINOLONE O DERIVATIVES ( N OOH 5 O NN/ . () ?on BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the production of 1 N-alkylation N /hydrolysis N / substituted-6,7-methylenedioxy-4-quinolone deriva . tives which have prominent antibacterial activity and to O novel compounds useful as intermediates for the pro duction thereof. More particularly, the invention per substituted-6,7-methylenedioxy-4-quinolone-3-tains to a novel method for the production of 1 carboxylic acid derivatives of the formula, 15 Cor O l-substituted-6,7-methylenedioxy-4-quinolone-3-carboxylic acid. This prior art process includes N-alkylation of either ( ?o R 3-ethoxycarbonyl-6,7-methylenedioxy-4- o/ NN/ hydroxyquinoline or 6,7-methylenedioxy-4-hydroxy-3- k (E) quinoline-carboxylic acid. It has been found, however, wherein R is alkyl or alkenyl and R is hydrogen or al that such N-alkylation is disadvantageous in that the kyl, and to novel compounds useful as intermediates 25 reaction necessitates the use of sodium hydride, which for their production. is very troublesome to handle and further requires the The term "alkyl' as used throughout this specifica use of a large amount of alkylbromide or alkyliodide, tion means straight or branched chain alkyl radicals both of which are very expensive. In addition, the yield having from one to twenty carbon atoms. The term "al obtained in the cyclization of diethyl 3,4- kenyl' refers to alkenyl radicals having from two or 30 methylenedioxy-anilinomethylenemalonate to ethyl 4 four carbon atoms. hydroxy-6,7-methylene-dioxy-3-quinolinecarboxylate Preferred examples of R and R are alkyl radicals of is poor. not more than 4 carbon atoms, for example, methyl, et hyl, n-propyl, n-butyl, isopropyl, isobutyl or secondary sUMMARY OF THE INVENTION butyl radicals, in terms of both the antibacterial activity 35 Applicants, on the other hand, have developed a of the product and the readiness with which the reac novel and advantageous method for the production of tion proceeds. 1 -substituted-6,7-methylenedioxy-4-quinolone-3- 2. Description of the Prior Art carboxylic acid derivatives. According to the present It has been known that the l-substituted-6,7- invention, 1 -substituted-6,7-methylene-dioxy-4- methylenedioxy-4-quinolone-3-carboxylic acids are 40 quinolone-3-carboxylic acid derivatives of formula (I) useful as antimicrobials (see, for example, Japanese can be produced very economically and advanta Pat. Publication 18141/1968). geously by reacting 3,4-methylenedioxyaniline with an Hitherto these 1-substituted-6,7-methylenedioxy-4- alcohol in the presence of a conventional hydrogena quinolone-3-carboxylic acids have been produced by tion catalyst, preferably a Raney nickel catalyst, to the process shown by the following reaction schema: 45 yield an N-substituted-3,4-methylenedioxyaniline, con densing the obtained N-substituted-3,4- methylenedioxyaniline with a dialkyl ethoxyme thylenemalonate to yield a dialkyl N-substituted-3,4- o/ -NH2 methylenedioxyanilinomethylenemalonate, and cycliz (O 50 ing the obtained dialkyl N-substituted-3,4- diethyl ethoxymethylenemalonate methylenedioxyanilinomethyl-lenemalonate in the presence of a condensing agent selected from the group COO CEIs consisting of an acid anhydride, an acidic substance C -COO CHs 55 and a mixture thereof to yield a 1-substituted-6,7- l methylenedioxy-4-quinolone-3-carboxylic acid or its (O N C H ester, either directly or through an intermediate N o/N/Y1 substituted 3-alkoxycarbonyl-6,7-methylenedioxy heating quinolinium salt. All of the above reactions proceed in 60 high yield and require a reagent which is neither expen sive nor troublesome to handle. pH Applicants have further discovered that the - O substituted-3-alkoxy-carbonyl-4-halogeno-6,7- methylenedioxyquinolinium salt can be alternatively ( N o 65 produced by reacting a dialkyl 3,4-methylenediox o/N/NN% yanilinomethylenemalonate or a 3-alkoxycarbonyl-4- hydrolysis/ NN-alkylation hydroxy-6,7-methylenedioxyquinoline with a haloge s N nating agent to yield a 3-alkoxycarbonyl-4-halogeno 3,761,482 3 4 6,7-methylene-dioxyquinoline and reacting the ob duction of 1-substituted 6,7-methylene-dioxy-4- tained 3-alkoxycarbonyl-4-halogeno-6,7- quinolone-3-carboxylic acid derivatives of the formula methylenedioxyquinoline with an alkylating or al (I). Another object of the present invention is to pro kenylating agent. In contrast with the known cycliza vide novel compounds which are useful for the produc tion reaction of diethyl 3,4-methylenedioxyanilino tion of the 1-substituted 6,7-methylenedioxy-4- methylenen alonate where the yield is poor, the novel quinolone-3-carboxylic acid derivatives of the formula method of the present invention, using a halogenating (I). Other objects and merits of the present invention agent, furnishes a high yield of cyclized product under will be apparent from the following descriptions. much milder reaction conditions. The reaction of 3 In order to accomplish these objects, the present in alkoxy-carbonyl-4-halogeno-6,7- 10 vention provides a method for the production of the methylenedioxyquinoline with an alkylating or al formula, kenylating agent results in an almost quantitative yield of the product. DETAILED DESCRIPTION OF THE INVENTION 5 The method of the present invention is briefly shown - ( ?o by the following reaction schema, wherein R and R are as defined above, R is alkyl as defined for R, and Y k (I) is an organic or inorganic acid anion. wherein R is C-Cao alkyl or C-C alkenyl and R is hy O (A) OH O COOR." O N N g-coor N ch O NH ( O OrN% (IV) (VII) (VIII) COOR." / COOR." ^ O COO R' x N O G-coor; CE ( N root O NN/ o/ N% k (II) (VI) (C) O X on M- O ( all. COO R1 (o/ N N? r Y k k (I) (III) The aforesaid organic or inorganic anion may be ex drogen or C-Co alkyl. emplified by chloride, bromide, iodide, sulfate, phos Further detailed descriptions concerning the reaction phate, nitrate, perchlorate, borofluoride, formate, ace 55 steps of the method of the present invention are given tate, propionate, oxalate, succinate, alkylsulfate, alkyl below. sulfonate, arylsulfonate or the like. However, these ex Reaction A-Preparation of N-substituted 3,4- amples are not limitative but only illustrative. methylenedioxyanilines Among the compounds produced by our method, N In the reaction of the present invention, 3,4- Co-alkyl- or N-alkenyl-3,4-methylenedioxyanilines of 60 methylenedioxyaniline is contacted with an equivalent the formula (IV), N-alkyl- or N-alkenyl-3,4- or larger amount of an alcohol of the formula, ROH, methylenedioxyanilinomethylenemalonates of the for wherein R is as defined above, at a temperature of mula (II), 3-alkoxycarbonyl-4-halogeno-6,7- 0-200°C, preferably 50-150°C, in the presence of a methylenedioxyquinolines of the formula (VI) and 65 conventional hydrogenation catalyst, preferably a their N-alkylated or N-alkenylated quaternary ammo Raney nickel catalyst.
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