NZ231404A - Various intermediate compounds in the preparation of 8-trifluoromethylquinolones - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £31404 2314 Under the provisions of Regulation ; ') ine —■ Specification has been ante-dated to 19 J&u initials Patents Form No. 5 NO DRAWINGS A, Priority Date(s): Complete Specification Filed: J. hS Class: r. ,V. .IC. vV./iC.''. £ A.ci;.^u;j.C,b3.|./.(n, Publication Date: P.O. Journal. No: This is a divisional out of application 225626 dated 29 July 1988 NEV? ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "INTERMEDIATES IN THE PREPARATION dF-8-TRIFLUOROMETHYL QUINOLONES" We, WARNER-LAMBERT COMPANY, 201 Tabor Read, Morris Plains New Jersey 07950, U.S.A./ organised under the laws of the State of Delaware, U.S.A., hereby declare the invention, for which we pray that a patent may be granted to us, and_the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page la) • 23140 la This invention relates to certain intermediates in the preparation of 8-trifluoromethyl quinolones.

US Patent 4,341,784 discloses certain substituted 7-(3-amino-l-pyrrolidinyl)-l-ethyl-6-fluoro-l,4-£3) 5 dihydro-4-oxo-l,8-naphthyridine-3-carboxvlic acids having the general formula: NHR o The Journal of Medicinal Chemistry, 23, 1358 (1980) discloses certain substituted 3-quinoline-10 carboxylic acids having the structural formula wherein O- may be pyrrolidinyl. See also US Patent 4,146,719.

Certain 7-heterocyclic substituted 1,8-napbthyridines are disclosed in Eur. J. Med. Chem. 15 - Chimica Therapeutica, 29, 27 (1977). US (fcilcwec by pace 2; ?31404 Patents 3,753,993, 3,907,608, and US 4,604,401 disclose certain 7-pyridylquinolines.

European Application 184,384 discloses certain substituted dihycroquinoline derivatives having the 5 formula wherein in part R^ is hydrogen, 1-6C alkyl, benzyl, or ] a pharmaceutical^ acceptable cation; R£ may be hydrogen or fluorine; an optionally substituted phenyl; and Y optionally substituted 1-3C alkyl, hydroxyethyl, cyclopropyl, vinyl, allyl or phenyl.

The references teach that these compounds possess antibacterial activity.

This invention provides a compound selected from 3-bromo-2,5,6-trifluorobenzoic acid; l-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene; 2,4,5-trifluoro-3- (trifluoromethyl)benzoic acid; ethyl 2,4, 5-trif luoro-jj -oxo-3-(trifluoromethyl) benzenepropanoate; ethyl l-cyclopropyl-6,7-di f1uoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylate; and l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinoline carboxylic acid.

These compounds are intermediates in the preparation of m 231404 wherein is hydrogen, an alkyl of from cr.e to six carbon atoms or a cation; R„ is alkyl cf from one to four csrbcr. atoms, W 2 vinyl, haloalkyl (in which the halogen is substituted on a 5 straight or branched alkyl of from two to four carbon atoms but not on the alpha carbon atom) or hydroxyalkyl of from one to four carbon atoms or cycloalkyl of from three to six O carbon atoms; 1tW Y is hydrogen, fluoro or amino; Z is -N Y li-R3 , V-(CH2)n.-' ^CIi2)n„ o 231404 R7-N N- w rr\ r7-n V k/ ,ee""\ R, \ N / 7\ N — iW- ' 231404 o c wherein n is 1, 2, 3, or 4; n' is 1, 2, 3, or 4; n + n' is a total of 2, 3, 4, or 5; n" is 0, 1, or 2; n'" is 0, 1, or 2; Iv n is 1, 2, or 3; nv is 0 or 1; R3 is hydrogen, alkyl of from one to four carbon atoms or a cycloalkyl of from three to six carbon atoms; 231 40 R, is hydrogen, alkyl of from one to four carbon atoms, hydroxyalkyl of from two to four carbon atoms, trifluorcethyl, or R\CO wherein R^ is alkyl of from one to four carbon atoms, or aikoxy of from one to 5 four carbon atoms; Re- and R^ are each independently hydrogen or alkyl of from one to three carbon atoms; R7 is hydrogen, alkyl of from one to three carbon atoms, hydroxyalkyl of two or three carbon atoms, benzyl, or p-aminobenzyl; Rg and Rg are each independently hydrogen, alkanoyl of which the alkyl portion has from one to three carbon atoms, alkyl or from one to three carbon atoms, or cyclopropyl; R^q and R^ are each independently hydrogen, methyl, ethyl, or benzyl; R12' R13' anci ^">4 £re e£C'° independently hydrogen or methyl; R15 is methyl, ethyl, or isopropyl; 2 0 R16 is CH2ORn8, CH2NR18R^q, or wherein R.. Q and R. n are hvdroaen, alkvi of from one to three 18 ±9 - carbon atoms, or acyl of from one to three carbon atoms; 2 5 R. _ is absent, hvcrocen cr alkvl of from one to 1 / - three carbon atoms; wherein the dotted line means a single or double bond; and R2q and R^^ each independently hydrogen, halogen, NR0-R-_, 0Ro„, SR..,,, alkvl of from cne to 22 23 2z 2^ three carbon atoms, wherein R„~ and R23 are each independently hydrogen, alkyl of from one to three carbon atoms, or acyl of from one to three carbon atoms; or a pharmaceutically acceptable acid addition or base salt thereof. 23 1 4 0 4 The preferred compounds are those wherein R2 is ethyl, vinyl, 2-fluoroethyl, 2,2-difluoroethyl, or cyclopropyl.

Also preferred compounds are those wherein 2 is Other preferred compounds are those wherein R^ is hydrogen or a pharmaceutically acceptable base salt such as a metal or an amine salt. 10 Other preferred compounds are those wherein n" is one, R„, R^, and R^ are hydrogen, methyl, ethyl, or n-propyl, and Ra is hydrogen.

The most preferred compounds are those wherein 2 is 2314 wherein R^ is hydrogen, R2 is ethyl, vinyl, 2-fluoroethyl, or cyclopropyl, and R3 is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, Rs and Rg are 5 hydrogen or methyl, or a pharmaceutical^ acceptable acid addition or base salt thereof.

Additionally the most preferred compounds include w those wherein R2 is cyclopropyl, Z is v • 231404 o in which n" is 0 or 1 and R3 is hydrogen, methyl, j ethyl, 1-Dropvl, 2-prooyl, and R, are hydrogen or ; ""DO- ^ methyl, and R is hydrogen or a pharmaceutical^ • acceptable base salt thereof. j Particularly preferred are those compounds having the names: • 7-(3-(aminomethyl)pyrrolicin-l-vl)-l-ethyl-6-fluoro-8-(trifluoromethy3)-l, 4-aihydro-4-oxo-quinoline-3-carboxylic acid, 7-[3-(1-aminoethyl )-l-pyrroliainyl]-l-cyclo- propyl-6-fluoro-l,4-dihydro-4-oxo-8-(trifluoromethyl)-3-guinolinecarboxylic acid, l-cyclopropyl-7-[3-[1-(ethyl amino)ethyl]-1-pyrrolidinvl]-6-fluoro-l,4-dihyaro-4-oxo-8- • (trifluoromethyl)-3-quinolinec£rboxvlic acic, l-cvclopropyl-6-fluoro-l,4-dihydro-7-[3 —[1 — methyl-1-(methylamino)ethyl]-1-pyrrolidinyl]-4-oxo- > 8-(trifluoromethyl)-3-quinolinecarboxylic acid, 7-[3-(aminoraethvl)-l-pyrrolidinyl]-l-cyclopropvl-20 6-fluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid, l-ethyl-6-fluoro-l,4-dihvdro-7-[3-[(methylamino)-methyl]-1-pyrrolidinyl]-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid, 2314 0 4 l-cvclopropyl-6-fluoro-l,4-dihydro-7-[3-[ (methylamino Jmethyl]-1-pyrrolidinyl)-4-oxc-8-(trifluoromethyl)-3-quinolinecarboxylic acid, l-ethyl-7- [3- [ (ethyl ammo )methyl ]-1-pyrroli-5 dinyl]-6-fluoro-l,4-dihydro-4-oxo-8-(trifluoromethyl )■ 3-quinolinecarboxylic acid, 1-cyclopropyl-7-[3-[(ethylamino)methyl]-l-(O, pyrrolidinyl]-6-fluoro-l,4-dihyaro-4-oxo-8- (trifluoromethyl)-3-quinolinecarboxylic acid, . 10 l-ethvl-6-fluoro-l,4-dihydro-4-oxo-7-(1-piper- azinyl)-8-(trifluoromethyl)-3-quinolinecarboxylic acid, l-cyclopropyl-6-fluoro-l,4-aihydro-4-oxo-7-(1-piperazinyl)-8-(trifluoromethyl)-3-quinoline-15 carboxylic acid, l-ethyl-6-fluoro-l,4-dihyaro-7-(4-methyl-l-piperazinyl)-4-oxo-8-(trifluoromethyl)-3-guinoline-carboxylic acid, l-cyclopropyl-6-fluoro-l,4-dihvdro-7-(4-methyl-i-20 piperazinvl)-4-oxo-8-(trifluoromethyl)-3-quinoline-.carboxylic acid, l-cyclopropyl-6-fluoro-l, 4-dihydro-7- (3-methyl-l-piperazinyl)-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid, 25 7-{3-amino-l-pyrroliainyl)-l-ethyl-6-fluoro-l,4- dihydro-4-oxo-8-(trifluoromethyl)-3-quinoline-carboxylic acid, 7-(3-amino-1-pyrrolidinyl)-l-cyclopropvl-6-fluoro-1,4-aihydro-4-oxo-8-(trifluoromethyl)-3-30 guinolinecarboxylic acid, and 7-[3-(1-amino-1-methylethyl)-l-pyrrolidinyl]-l-cyclopropvl-6-fluoro-l,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid.

The process for preparing compounds of formula I 3SW* 23 1 4 04 The compounds having the formula Y 0 Z F COOR 1 I wherein the substituents are as defined above are capable of forming both pharmaceutically acceptable acid addition and/or base salts. Base salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Also included are heavy metal salts such as for example silver, zinc, cobalt, and cerium. Such heavy metal salts are effective in the treatment of burns especially.when applied to the affected surface of a burn victim either directly or in combination with a physiologically acceptable carrier such as a water dispersible, hydrophilic carrier. Examples of suitable amines are N/N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethyleneaiamine, N-methylglucamine, and procaine.

Pharmaceutically acceptable acid addition salts are formed with organic and inorganic acids.

Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, lactic, citric, oxalic., malonic, salicylic, malic, gluconic, fumaric, succinic, ascorbic, maleic, methanesulfonic, 2314 04 and the like. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce either a mono or di, etc salt in the conventional manner. The free base forms may 5 be regenerated by treating the salt form with a base. For example, dilute solutions of aqueous base may be utilized. Dilute aqueous sodium hydroxide, potassium ^ carbonate, ammonia, and sodium bicarbonate solutions i v-"" are suitable for this purpose. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention. Use of excess base where R' is 15 hydrogen gives the corresponding basic salt.

The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms and the like are equivalent 20 to the unsolvated forms for purposes of the invention.

The alkyl groups contemplated by the invention comprise both straight and branched carbon chains of Vw' from one to about four carbon atoms except when specifically stated to be greater than four carbon 25 atoms. Representative of such groups are methyl, ethyl, propyl, isopropyl, and the like.

The cycloalkyl groups contemplated by the invention comprise those having three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, 30 and cyclohexyl. 0 1 " The term alkanoyl is intended to include R -C-groups wherein R"*" is an alkyl of from one to three carbon atoms.

The hydroxyalkyl groups contemplated by the invention comprise those having two to four carbon 23140 atoms such as 2-hvdroxyethyl, 2- or 3-hydroxvpropyl, ■ or 2-, 3-, or 4-hydroxybutyl.

The alkoxy croups contemplated by the invention comprise both straight and branched carbon chains of from one to about six carbon atoms unless otherwise specified. Representative of such groups are methoxy, ethoxy, propoxy, i-propoxy, t-butoxy, hexoxy, and the like.

The term, halcalkyl, is intended to include halogen substituted straight and branched carbon chains of from two to four carbon atoms . Those skilled in the art will recognize that the halogen substituent may not be present on the a-carbon atom of the chain. Representative of such groups are p-fluoroethyl, p-chloroethyl, p,p-dichloroethyl, p-chloropropvl, p-chloro-2-propvl, -iodobutyl, and the like.

The term halogen is intended to include fluorine, chlorine, bromine, and iodine unless otherwise specified.

Certain compounds may exist in optically active forms. The pure D isomer, pure L isomer as well as mixtures thereof; including the racemic mixtures, are contemplated.

Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. Certain side chains may contain more than one chiral center. In these cases the diastereoisomers may be separated and utilized individually.

The compounds of formula I m o r>, y 0 CF3 R2 231404 N' o are prepared by a process which comprises (a) carboxylati.ng l-bromo-2,4, 5-trifluorobenzene forming 3-bromo-2,5,6-trifluorobenzoic acid, 5 (b) fluorinating the carboxvlic acid group of the above compound forcing l-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene, (c) carboxylating the bromine position on the above compound forming 2,4,5-trifluoro-3-(trifluoro- methyl)benzoic acid, (d) reacting the above benzoic acid compound with a chlorinating ager.t, an alkyl hydrogen malcnate, and n-butyl lithium forming an alkyl 2,4,5-trifluoro-p-oxo-3-(trifluoromethyl) benzenepropanoate product, (e) reacting the above prccuct with alkyl orthoformate and acetic anhydride and then with a primary alkyl amine forming alkyl a-(N-alkylamino-methylene) -2 , 4,5-trifluoro-p-oxo-3-(trifluoromethyl)-benz enepropanoate, (f) cyclizing the above compound by reacting it with a base in a solvent forming alkyl l-aikyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-cpuinolinecarboxylate, (g) deesterifying the above carboxvlate forming 25 the corresponding carboxylic acid, and (h) reacting the above carboxylic acid with a secondary amine to form a compound of formula I and 231404 convert, if desired, to a pharmaceutically acceptable acid addition or base salt thereof.

The following secondary amines may be used in step h above to form a compound of formula I which may be converted, if desired, to a pharmaceutically acceptable acid addition or base salt thereof.

H2N.

\ NH , 231404 ch. nh.

NH , o ch. ch3nh nh o ch. c2h5nh nh ch3nh ch3 or h2N ch- ch. nh , 231404 The process is illustrated but not limited by Scheme I below.

Scheme I Br F 13 1eq LDA -7 8 THF 2] C02/Et20 -78C ^X.

C02H Br SF./HF 4 120°8h f t f cf 83* bp 147-50' 760mm.

Br 1) 1 eq BuLi Et-0 p pn H i i crici a -78° 2 F\r^Y^C02H U socl2 Aj 2( C02/Et20 -78° 0 0 CF3 77? 92-93°C OEt HC(OEt)3 F ► Ac20 Ax F [>-nh2 O 0 OEt NaH THF F 231 40 The process comprises lithiating and subsequently carboxylating 2, 4,5-trifluorobromobenzene (Alarich) to form the compound 3-bromo-2,5,6-trifluorobenzoic acid. Various lithiating agents such as a lithium dialkylamide, for example lithium diisopropylamide, and carbon dioxide in diethyl ether may be used. The reaction proceeds at temperatures from about -40 to -100°C, preferably from about -60° to -80°C. Possible solvents include but are not limited to ether, aimethoxy ethane and tetrahyarofuran. The preferred solvent is tetrahydro-furan.

The carboxylic acid group of the 3-bromo-2,5,6-trifluorobenzoic acid is treated with a fluorinating agent such as, for example, selenium tetrafluoride or sulphur tetrafluoride and hydrogen fluoride forming the compound l-bromo-2,4,5-trifluoro-3-(trifluoromethyl )benzene . The reaction proceeds for from about one to forty-eight hours at temperatures of about 80 to 1S0°C. Preferably the reaction time is from about six to eight hours at temperatures from about 12 0 to 140°C.

Subsequently the bromine group of the above compound is treated with a carboxylating agent forming the compound 2,4, 5-trifluoro-3-(trifluoromethyl)-benzoic acid. Possible carboxylating agents include but are not limited by n-butyl lithium and carbon dioxide, Mg and either CC>2 or a chloroformate followed by ester hydrolysis, or other organolithium such as MeLi or t-butyl followed by an anhydrous halide salt of a less electropositive metal, then followed either by CO2 or a chloroformate derivative, which would be subsequently hydrolvsed; preferably n-butyl lithium and carbon dioxide are used. This portion of the process proceeds at temperatures from about -40 to -100°C in ether or tetrahydrofuran. Temperatures from 23 1 4 04' about -70 to -80° are preferred. Alternatively, displacement of bromine by CuCN/DMF at 60-140°C, followed by hydrolysis in strong acid.

The benzoic acid formed above is then treated with a chlorinating agent, an alkyl hydrogen malonate and n-butyl lithium forming the desired alkyl 2,4,5-trifluoro-0-oxo-3-(trifluoromethyl) benzenepropanoate. Various chlorinating agents will be useful such as, for example thionyl chloride, POClg, PC-3' an^ Brominating agents are also possible such as, for example, S0Br2. Thionyl chloride is the preferred agent used with a dianion of a malonate, such as ethyl hydrogen malonate. The reaction proceeds at temperatures of from about -40 to -100°C; preferably from about -70 to -85°C.

The above propanoate is reacted with an alkyl orthoformate and acetic anhydride and subsequently with a primary alkvlamino forming an ethyl (N-(cyclo)-alkylaminomethylene)-3-oxo-3-aryl propanoate derivative (5b). The reactants are preferably ethyl orthoformate and cyclopropvlamine or ethylamine. The reaction proceeds for about one to six hours at reflux.

The above product was reacted with a base in an organic solvent to cyclize the compound forming alkyl N-alkyl-6,7-difluoro-8-trifluorcmethyl-quinol-4-one-3-carboxylate. A preferred base is an alkali hydride such as sodium hydride or tertiary amine such as triethylamine ana solvents includes but are not limited to t-butanol, DMSO, tetrahyarofuran. The reaction occurs at temperatures from about -20° to 100°C.

The quinoline is then deesterified forming the corresponding carboxylic acid. Useful reactants are chlorotrimethylsilane and sodium iodide in acetonitrile. Hydrogen chloride in acetic acid is 231404 n also useful. The deesterification occurs at reflux which in the case of acetonitrile would be at about 80°C. The reaction time is from two to six hours. The resulting auinolone is reacted with a 5 secondary amine forming a desired compound of the present invention and converting it, if desired, to a pharmaceutically acceptable acid addition or base salt thereof. Possible reaction solvents include """ acetonitrile, DMSO, or DMF. The reaction proceeds at between 0 and 100° for from about two to ten hours. Secondary amines reacted with the compound may be protected as necessary. Possible secondary amines include but are not limited to all the secondary amines described herein by Z.

The compounds can be prepared ana administered in a wide variety of oral, parenteral and topical dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of 20 formula I or a corresponding pharmaceutically acceptable salt of a compound of formula I.

For preparing pharmaceutical compositions from the compounds, inert, pharmaceutically acceptable carriers can be either 25 solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, 30 lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active compound. In the tablet the active compound is 3 5 mixed with carrier having the necessary binding properties in suitable proportions and compacted in 23 14 04 the shape and size desired. The powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, 5 lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation w of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid 15 dosage forms suitable for oral administration.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared 20 so as to be acceptable to biological systems (isotonicity, pH, etc). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component 25 in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired.

Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or 30 synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.

Ointment preparations contain heavy metal salts of a compound of formula I with a physiologically 35 'acceptable carrier. The carrier is desirably a conventional water-dispersible hydrophilic or 2314 0 4 oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion which may be applied to an affected burn surface or infected surface with a 5 minimum of discomfort. Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.

Preferably, the pharmaceutical preparation is in 10 unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for 15 example, packeted tablets, capsules, powders in vials or ampules, and ointments in tubes or jars. The unit dosage form can also be a capsule, cachet, tablet, gel or cream itself or it can be the appropriate number of any of these packaged forms.

The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 100 mg according to the particular application and the potency of the active ingredient.

In therapeutic use as agents for treating bacterial infections the compounds — are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily. A daily dose range of about 6 mg to about 14 mg per kilogram is preferred. 30 The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. 35 Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. 231404 Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

The following nonlimiting examples illustrate methods for preparing the compounds of the invention.

EXAMPLE 1 3-Bromo-2,5,6-trifluorobenzoic acid. n-Butyl lithium (2.6 M in hexanes, 32 mL, 84 mmol) was added over 10 minutes to a solution of diisopropylamine (8.89 g, 88 mmol) in THF (80 mL) stirred under N2 at 0°C. After a further 10 minutes at 0°, the solution was transferred by catheter over 40 minutes to a solution of 2,4,5-trifluorobromo-benzene (16.88 g, 80 mmol) in THF (200 mL) stirred under N2 at -78°. After a further 15 minutes the solution was blown through a catheter over ~2 minutes onto a slurry of C02 (-200 mL) in ether (400 mL) with vigorous stirring. When the C02 evaporated the slurry was washed with dilute HC1 (1 M, 200 mL) and water (100 mL). The organic phase was extracted with dilute NaOH (0.5 M, 2x100 mL). The aqueous phase was washed with ether (100 mL) and made acidic (12 N HCl, 9 mL). The aqueous phase was extracted with ether (2x100 mL), and the combined organic phases were washed with water (100 mL), saturated brine (100 mL) and dried (MgSO^). The solvent was removed under reduced pressure to give 3-bromo-2,5,6-trifluorobenzoic acid (17.25 g, 84.5%) as white microcrystalline needles; mp 114-6° (sublimation).

Nmr (CDC13) 6 10.73 (1H, s, OH), 7.54 (1H, d of t, Jd = 6 Hz, Jt = 9 Hz aromatic). o 231404 EXAMPLE 2 l-Bromo-2 ,4, 5-trifluoro-3-(trifluoromethyl )benzene. 3-Bromo-2,5,6-trifluorobenzoic acid (16.92 g, 66 mmol) was heated with SF^ (60 g) and HF (30 g) in a 5 stainless steel bomb at 120° for 8 hours. When the reaction cooled to 25° the volatiles were vented through KOH traps, and when gas evolution ceased the y-v vessel was extracted with CH2C12 (150 mL). This <x~" solution was washed with diluted NaEC03 solution (saturated/2, 50 mL), saturated brine (50 mL), and dried (MgSO^). The solvent was removed by distillation through a 15 cm Vigreux column, and the residue was distilled under N2 through a shortpath stillhead at 147-150° to give l-bromo-2,4,5-trifluoro-15 3-(trifluoromethyl)benzene (15.79 g, 83%) as a pale yellow oil.

Nmr (CDC13) 6 7.67 (1H, d of t, Jd = 6 Hz, J = 8.1 Hz, aromatic). Ir (film) 1495, 1315, 1211, 1165, 1149, 919. M.S. 280 (97 81BrM®), 278 (100, 79BrM0). 2 0 EXAMPLE 3 2,4,5-Trifluoro-3-(trifluoromethyl)benzoic acid.

A solution of n-butyl lithium (2.6 M in hexanes, 9.6 mL, 25 mmol) was added dropwise through an addition funnel over 15 minutes to a solution of 25 l-bromo-2 , 4, 5-trifluoro-3-(trifluoromethyl)benzene (7.00 g, 25 mmol) in ether (100 mL) stirred under at -78°. After 5 minutes the mixture was rapidly blown by catheter onto a suspension of dry ice (100 g) in ether (100 mL). After 5 minutes TFA (2 mL) was 30 added to this. When the solution had warmed up to °C, it was washed with diluted HCl (0.5 M, 20 mL), and extracted with dilute base (0.5 N, 2x50 mL). The combined basic extracts were washed with ether (25 mL), made acidic with concentrated HCl (~4 mL) and 35 extracted with ether (3x50 mL). The combined ethereal II 23 1 4 04 extracts were washed with water (50 mL), saturated brine (50 mL) and dried (MgS04). The solvent was removed under reduced pressure to give 2,4,5-trifluoro-3-(trifluoromethyl) benzoic acid 5 (4.21 g, 69%) as white microscopic needles; mp 87-90°C.

Nmr (CDC13) 6 11.80 (1H, br s, OH), 8.05 (1H, d of t, O. Jd = 6 Hz, Jt = 9 Hz, aromatic). IR (KBr) 1721, 1636, 1511, 1464, 1424, 1328, 1256, 1154, 928 cm"1. 10 M® 244 (56).

EXAMPLE 4 Ethyl 2,4,5-trifluoro-g-oxo-3-(trifluoromethyl) benzenepropanoate. 2,4,5-Trifluoro-3-(trifluoromethyl)benzoic acid 15 (0.49 g, 2 mmol) was refluxed in S0Cl2 (1 mL) under N2 for 2% hours. The volatiles were removed under reduced pressure, and azeotroped further with toluene (5 mL). The residual light yellow-brown oil was dissolved in THF (5 mL), and cooled to -78° under N2 20 with stirring. n-Butyl lithium (3.1 mL, 8 mmol, 2.6 M in hexanes) was added dropwise to a solution of ethyl hydrogen malonate (0.53 g, 4 mmol) and bipyriayl (1 mg) in THF (5 mL) stirred at -78° under N„, until 25 pink coloration (~1.5 mL). The reaction mixture was stirred on an ice salt bath and the remainder of the butyl lithium was added, giving a pink color. This suspension was then added dropwise via syringe over 10 minutes to the -78° solution of the acid chloride, to 30 form a nearly clear bright yellow solution. After 2 hours at -78° the mixture was quenched by rapid addition of dilute HCl (1 M, 8 mL). When the mixture had melted, it was poured onto water (25 mL), and extracted with ether (3x10 mL). The combined organic 35 extracts were washed with water (10 mL), saturated NaHC03 (10 mL), saturated brine (10 mL) and dried 23 1 4 04 /"-N (MgSO^). The solvent was removed under reduced pressure to give ethyl-3-oxo-3-(2,4,5-trifluoro-3-(trifluoromethyl)phenyl)propanoate (0.52 g, 83%) as a golden-brown oil.

Nmr (CDClg) <5 7.91 (1H, si br, d of t, = 6 Hz, = 9 Hz, aromatic), 5.74 (~l/3 H, br s, vinyl of enol), 4.15 (2H, q, J = 7 Hz, OCH2) , 3.90 1 1/3 H, d, J = ^ 4 Hz, methylene a to CO), 1.1-1.5 (~ 4H, 2 overlapping ' t + broad m, CH3g), 0.7-1.0 (~1 H, m, Bu n related).

EXAMPLE 5 Ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylate.

Ethyl 2,4,5-trifluoro-p-oxo-3-(trifluoromethyl)-benzenepropanoate (0.52 g, 1.67 mmol) ethyl 15 orthoformate (0.45 g, 3 mmol) and acetic anhydride (0.41 g, 4 mmol) were refluxed under for 90 minutes. The volatiles were removed under reduced pressure, and the residual brown oil (0.59 g) was mixed with eyelopropylamine (0.12 g, 2 mmol) in THF 20 (5 mL) stirred under N2 at 20°C. After 90 minutes the ^ volatiles were removed under reduced pressure to give a waxy brown solid. This was dissolved in THF (5 mL) under N2 at 20° with stirring, and sodium hydride (60% oil suspension, 0.10 g, 2.5 mmol) was added. After 25 15 minutes the reaction was quenched by addition of acetic acid (1 mL). The reaction mixture was diluted 'w with CHClg (25 mL) and washed with water (2x25 mL) and dried (MgSO^). The solvent was removed under reduced pressure to give a reddish-brown solid, which was 30 purified by preparative tic on silica (2x20 cm) eluting with 5% MeOH in CHCl3. The major band (r^ = 0.66) was extracted with CHCl3/MeOH( and the solvent was removed under reduced pressure to give ethyl N-cyclopropyl-6,7-difluoro-8-trifluoromethyl-quinol-35 4-one-3-carboxylate (0.14 g, 23%) as an ochre solid; mp 174-9°C.

Claims (3)

23 1 4 0 4 o -28- Nmr (CDC13) 6 8.68 (1H, s, H2), 8.42 (1H, t, J = 9 Hz, H5), 4.40 (2H, q, J = 6.1 Hz, OCH2), 3.92-4.07 (1H, m, NCH), 1.41 (3H, t, J = 6.1 Hz, CH3), 1.15-1.25 (2H, ra, cyclopropyl), 0.67-0.75 (2H, m, cyclopropvl). ir 5 (KBr) 1738, 1638, 1612, 1470, 1311, 1297, 1269, 1190, 1180, 1162, 1151, 1074, 897, 805. vP 361 (10). EXAMPLE 6 l-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylic acid. 10 Chlorotrimethylsilane (0.54 g, 5 mmol) ethyl l-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-8-(trifluorophenyl)-3-quinolinecarboxylate (0.76 g, 2.1 mmol) and Nal (0.75 g, 5 mmol) were stirred in refluxing CH^CN (10 mL) under N2 for 8 hours. On 15 cooling water (30 mL) was added and the mixture was extracted with EtOAc (2x20 mL). The combined extracts were washed with water (2x10 mL), saturated brine (12 mL), and dried (MgSO^). The solvent was removed under reduced pressure, and the residual brown solid 20 (0.74 g) was dissolved in hot CHC13, and precipitated with ether at 0°C to give l-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-8-(tri f luoromethyl) -3 -quinoline-carboxylic acid (0.43 g, 62%) as yellow needles; mp 243.5-244.5°C. 25 C14HgF5N03 requires C, 50.45; H, 2.40 N, 4.20 F, 28.53%. Found C, 50.10; H, 2.27; N, 4.03 F, 28.08%. Nmr (DMSO) 6 13.5-14.5 (1H, br s, OH), 8.98 (1H, s, H2), 8.53 (1H, t, J = 9.2 Hz, H5), 4.15-4.25 (1H, m, NCH), 1.05-1.15 (2H, m, CH2), 0.80-0.88 (2H, m, CH2). 30 Ir (KBr) 1724, 1630, 1618, 1565, 1505, 1467, 1429, 1398, 1337, 1324, 1283, 1269, 1199, 1180, 1172, 1161, 1130, 1093, 1051, 1023, 922, 910, 808, 743 cm-1. MS 334 (5 MH+) 333 (13, M+). 231404 - 29 - what we claim is;

1. An intermediate in the preparation of a compound of the formula I (as defined in this specification) and selected from 3-bromo-2,5,6-trifluorobenzoic acid; l-bromo-2,4,5-trifluoro-3-(trifluoromethyl)benzene; 2,4,5-trifluoro-3-(trifluoromethyl)benzoic acid; ethyl 2,4,5-trifluoro-^-oxo-3-(trifluoromethyl) benzenepropanoate; ethyl 1-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-8-(trifluoromethyl)-3-quinolinecarboxylate; and 1-cyclopropyl-6,7-difluoro-l,4-dihydro-4-oxo-8-(trifluoromethyl) -3-quinoline carboxylic acid.

2• A process for preparing an intermediate according to claim 1 and substantially as described in this specification with reference to any one of examples 1 to 6.

3. An intermediate whenever prepared by a process according to claim 2.