NZ276478A - Azabicyclohexyl-substd. naphthyridine carboxylic acid derivatives and their manufacture; intermediates - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £76478 New Zealand No. International No. 276478 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 18.01.1994; Complete Specification Filed: 12.12.1994 Classification^) C07D471/04; C07D209/02; C07D207/448; A61K31/445.435 Publication date: 27 May 1998 Journal No.: 1428 Title of Invention: Process and intermediates for preparing naphthyridonecarboxylic acid salts Name, address and nationality of applicant(s) as in international application form: PFIZER INC., a Delaware corporation of 235 East 42nd Street, New York, NY 10017, United States of America NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION 276478 PROCESS AND INTERMEDIATES FOR PREPARING NAPHTHYRIDONECARBOXYLIC ACID SALTS Background of the Invention This invention relates to novel processes and intermediates for the preparation 10 of pharmaceutical^ acceptable acid salts, of the formula 0 wherein R1H is a pharmaceutically acceptable acid, selected from the group consisting of R4SOaH, R4P03H and YH wherein R4 is selected from (C1-Cs)aikyi and optionally substituted phenyl or naphthyl 25 wherein the substituent is (C1-Ce)alkyi; and Y is selected from CI, S04, HS04, NO„ HP03H, and P04, of the naphthyridone antibiotic 7-(1a,5ar,6ff)-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1 -(2,4-difluorop^enyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. The antibacterial activity of the aforementioned naphthyridone antibiotic is 30 described in United States Patent No. 5,164,402 and 5,229,396 issued 11/17/92 and 7/20/93, respectively, the disclosures of which are hereby incorporated herein by reference in their entirety. The foregoing patents are assigned in common with the present application.

F Summary of the Invention In a first embodiment the present invention relates to a process for preparing a compound of the formula .V\\* % YVy AA,/1 'M N' ✓ h2h h Vh COOH wherein R'H is a pharmaceuticaiiy acceptable acid selected from the group consisting of FfSOaH, R4PO,H and YH wherein R4 is selected from (C,-Ca)alkyl and optionally substituted phenyl or naphthyl wherein the substituent is (C1-C8)aikyl; and Y is selected from CI, S04, HS04, NO,, HP03H, and P04, which comprises treating a compound of the formula H iair C00R' ** \ H II wherein R2 is (C,-Ce)alkyi, aryl(C,-C8)alkyl or hydrogen and R3 is N02 or NHa; a) when R3 is NH2 with a compound of the formula R1 H is as defined above; 4> or b) when R3 is N02 with a reducing agent in the presence of a compound of the formula R1H wherein R'H is as defined above.

The invention also relates to a process as defined above wherein the compound of the formula II wherein R3 is NHa and R2 is as defined above is prepared by treating a compound of the formula II wherein R3 is N02 with a reducing agent in the presence of a compound of the formula R1H wherein R1H is as defined above.

In another embodiment, the present invention relates to a process as defined above wherein the compound of the fbrmula II wherein R3 is N02 is prepared by reacting the compound of the formula 6 IV with a compound of the formula 0 0 Jt wherein R2 is as defined above and J is a suitable leaving group.

In accordance with another embodiment of the invention, the compound of the formula IV is prepared by treating a compound of the forr.ula I CHp i c R wherein R is selected from (C,-C8) alkyl or (C6-C10)aryl wherein said aryi group may be 10 substituted, optionally, with one or more substituents independently selected from haio, nitro, (C,-C8) alkyl, (C,-Ce) alkoxy, amino and trifiuoromethyl, with an N-dealkylating agent. Preferably R is phenyl or hydrogen. The compound of formula V may be prepared by treating the compound of formula 02l\ VI wherein R is as defined above, with a reducing agent. The compound of formula VI is prepared by treating a compound of the formula 0=^ >=0 VII N I CH, I R wherein R is as defined above, with a compound of the formula X-CH2-N02, wherein X is a suitable leaving group, in the presence of a base. A preferred base is 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine.

PCT/IB940C410 Yet another embodiment of the invention relates to a process for the preparation of a compound of formula I which comprises the steps of a) treating a compound of the formula VII with a compound of the formula X-CH2-N02, wherein X Is a leaving group, in the presence of a base to form a compound of the formula VI which is then treated with a reducing agent to form the compound of the formula V; b) treating the compound of the formula V with a dealkylating agent to form the compound of formula IV; c) treating the compound of formula IV with a compound of the formula F wherein R2 is as defined above and J is a suitable leaving group, to form a compound of the formula II wherein R3 is NO}; and d) treating the compound of formula II, wherein R3 is N02, with a reducing agent comprising hydrogen in the presence of a catalyst or a metal and an ac'd of the formula R'H, as defined above, to form 25 i) when the hydrogenation is effected in the presence of an acid R'H, as defined above, or R'H is a compound of the formula YH or R4SOaH, wherein Y and R4 are as defined above, the compound of the formula I; or ii) the compound of the formula II, wherein R3 is NH2, and then treating said compound with a compound of the formula R1H, which may be the same 30 as or different from the R^ of the reducing step, or a compound of the formula R4C02H, wherein R4 is defined as above, to form the compound of the formula I.

Another embodiment of the invention relates to the compound of the formula 2?6 8 IV Yet another embodiment of the invention relates to a compound of the formula H xxY .COpR' OaN H III B wherein R2 is as defined above.

Also described herein is a carpound of the formula « rxxrc°*" V/^N^N^hr ,nt # H2N 2.

H 1 T *&?* (y • S'VGD wherein R2 is defined above.

The term 'halo*, as used herein, refers to fluoro, chloro, bromo or iodo. as applicable.

The term "alkyl", as used herein, includes straight, and when comprised of more than two carbon atoms, branched hydrocarbon chains and hydrocarbon rings and combinations of the straight or branched hydrocarbon chains with the hydrocarbon rings.

Detailed Description of the Invention The processes of the present Invention and the preparation of the compounds of the present invention are illustrated in the following reaction scheme. Except where otheirwise indicated, in the reaction scheme and discussion that follow substituents R,R1H, R2, R3 and X are defined as above.

The above reaction scheme illustrates the preparation of the naphthyridone antibiotic salts of formula I, novel intermediates useful in said preparations and methods for preparing said Intermediates.

Referring to the above scheme, reaction of a compound 1 with a a compound 5 of the formula X-CH3-NOj, wherein X is a suitable leaving group such as chloro and bromo. in the presence of a base yields the corresponding compound £. This reaction is generally conducted in an inert, polar, aprotic solvent such as dimethylformamide (DMF), dimethyisulfoxide (DMSO) or dimethylacetamlde (DMAC), an ethereal solvent such as ethyl ether, glyme, diglyme, dioxane or tetrahydrofuran (THF) or an aromatic 10 solvent such as optionally chlorinated benzene or toluene. Toluene is preferred. Suitable reaction temperatures range from about -78 °C to about 80°C, with about 0°C to about -20°C being preferred. It is preferable to add the base last. Examples of appropriate bases include carbonate bases such as potassium or sodium carbonate, phosphorine amide bases such as 2-tert-butylimino-2-diethylamino-1,3-15 dimethylperhydro-1,3,2-diaza-phosphorine, and amine bases such as triethylamine, guanidine, diisopropylethylamlne.tetramethyl guanidine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), 1,5-dlazaicyclo-[4.3.0]non-5-ene (DBN) and 1,2-dimethyM ,4,5,6-tetrahydropyrimidine. It is advantageous to use an amine base. 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine is preferred.

Reduction of compound 2 in an inert ethereal solvent yields the corresponding compound 3. Appropriate reducing agents include borane, sodium borohydride and boron trifluoride*etherate complexes. Inert ethereal solvents useful in the reduction include glyme, diglyme, diisopropyl ether, dimethyl sulfide, DMSO, diethyl ether and THF. The preferred reducing agent is borane and the preferred solvents are THF or 25 diethyl ether. The reduction is typically carried out at temperatures ranging from about 25 °C to about 90 °C. It is preferably carried out in the range from about 25 to about 65 °C and most preferably in the range from about 25 to about 45 °C in THF. This method is described In United States Patent No. 5,256,791, incorporated herein by reference.

Compound 3, wherein R is (C,-C6)alkyl or (Ce-C10)aryl, is converted into compound 4, by treating compound 3, a) when R is (C8-C10)aryl with hydrogen or o-chloroethyl chloroformate; or b) when R is (C.,-Ca)eUkyl with a-chloroethyl chloroformate.

When R is (C6-C,0)aryl hydrogenolytlc removal of the RCH2 group from compound 3 is generally accomplished by reacting said compound with hydrogen gas at a pressure from about 10 psi to about 2000 psi, preferably from about 14 to about 60 psi, in the presence of a noble metal catalyst, such as palladium, platinum or 5 rhodium, or salts thereof. Palladium, or palladium hydroxide, on carbon is preferred. The temperature may range from about 20°C to about 80°C, and is preferably about 25°C. The solvent is usually a (C,-Cfl)alkyl alcohol and is preferably methanol.

Compound 4 Is converted to compound 5 by treating it with a compound of the formula wherein R3 is as defined above and J is a suitable leaving group such as chloro and bromo. A preferred leaving group is chloro or bromo and a most preferred leaving group is chloro.

The reaction may be conducted with or without a solvent. The solvent, when used, must be inert under the reaction conditions. Suitable solvents are acetonitrile, 25 tetrahydrofuran, ethanol, chloroform, dimethyisulfoxide, dimethylformamide, pyridine, water, or mixtures thereof.

The reaction temperature usually ranges from about 20°C to about 150°G, The reaction may advantageously be carried out in the presence of an acid acceptor such as an inorganic or organic base, e.g. an alkali metal or alkaline earth 30 metal carbonate or bicarbonate, or a tertiary amine, e.g. triethylamlne, pyridine or plcoline.

Compound 5 is converted to compound 6 by treatment with a metal and acid, of the formula R'H, wherein R1H is defined as above, in the presence of an aqueous 0 0 F aprotic solvent such as acetonitrile or DMF. The preferred metal is zinc. Suitable acids include inorganic acids, such as hydrochloric and sulfuric acids, and organic acids, such as sulfonic acids, e. g., methane-, trifluoromethane- and p-toluenesulfonic acids. Methanesulfonic acid or hydrochloric acid is preferred. This reaction is generally 5 conducted in an aqueous (C,-Ca)alkyl alcohol solvent, such as ethanol, methanol, 1-propanol and 2-propanol, preferably ethanol, at a temperature from about 0°C to about 80°C, preferably at about 25°C.

Alternatively, compound 5 can be converted to § by treatment with hydrogen in the presence of Raney nickel or a noble metal catalyst. Raney nickel Is the preferred 10 catalyst.

The hydrogenatlon reaction is generally conducted in an aqueous solvent mixture. Suitable solvents include (C1-Cs)alkyl alcohols such a ethanol, methanol 1-propanol and 2-propanol; and water miscible aprotic solvents such as DMF, THF, dimethylacetamlde, dioxane, and (C,-C0)alkyl ethers. Hydrogen pressures used are in 15 the range from about 14 to about 100 psi, preferably In the range about 40 to about 60 psi and temperatures are in the range of about 15°C to about 80°C, preferably the from about 20 to about 30 °C.

Compound 6 is converted to compound 7 by treatment with a compound of the formula R1H, as defined as above, in an aqueous medium.

AJternatively, compound 5, may be converted directly into compound 7 by treatment with a metal and an acid of the formula R1H, such as those described above, in an aqueous medium. A preferred metal is zinc and a preferred acid is methanesulfonic acid.

The pharmaceutically acceptable acid addition salts wherein the acid is a 25 compound of the formula R4COaH or R'H, wherein R4 and R'H are defined as above, are prepared in a conventional manner by treating a solution or suspension of the free base form of compound I with about one chemical equivalent of the pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are employed in isolating the salts. Illustrative of suitable acids are acetic, lactic, succinic, 30 maleic, tartaric, citric, gluconic, ascorbic, benzoic, methanesulfonic, p-toluenesulfonic, cinnamic, fumaric, phosphonic, hydrochloric, hydrobromic, hydroidic, sulfamic, and sulfonic acid.

The antibacterial compounds of formula I and the related azabicyclo naphthyridone carboxylic acid antibiotics that can be synthesized using the methods and intermediates of this invention are useful in the treatment of animals, and humans having bacterial infections. They are useful in treating bacterial infections of broad 5 spectrum, particularly in treating gram-positive bacterial strains.

The compounds of formula I may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally or in the form of tablets containing such excipients as 10 starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. In the case of animals, they are advantageously contained in an animal feed or drinking water in a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm. They can be injected parenterally, for example, intramuscularly, intravenously or 15 subcutaneously, For parenteral administration, they are best used in the form of a sterile aqueous solution which can contain other solutes, for example, enough salt or glucose to make the solution isotonic. In the case of animals, the compounds of formula I can be administered intramuscularly or subcutaneously at dosage levels of about 0.1 to about 50 mg/kg/day, advantageously about 0.2 to about 10 mg/kg/day 20 given in a single dally dose or up to 3 divided doses.

The invention also provides pharmaceutical compositions comprising an antibacterially effective amount of a compound of the formula I together with a pharmaceutically acceptable diluent or carrier.

The compounds of the invention can be administered to humans for the 25 treatment of bacterial diseases by either oral or parenteral routes, and may be administered orally at dosage levels of about 0.1 to 500 mg/kg/day, advantageously 0.5-50 mg/kg/day given in a single dosage or up to 3 divided dosages. For intramuscular or intravenous administration, dosage levels are about 0.1-200 mg/kg/day, advantageously 0.5-50 mg/kg/day. While intramuscular administration may 30 be a single dose or up to 3 divided doses, intravenous administration can include a continuous drip. Variations will necessarily occur depending on the weight and condition of the subject being treated and the particular route of administration chosen as will be known to those skilled in the art.

The antibacterial activity of the compounds of the invention is shown by testing according to the Steer's replicator technique which is a standard in vitro bacterial testing method described by E. Steers et al., Antibiotics and Chemotherapy, 9, 307 (1959).

The following examples illustrate the methods and compounds of the present 5 Invention. It will be understood, however, that the invention is not limited to the specific ' details of these examples.

EXAMPLE 1 Ho. 5a. 6o)-3-Benzvl-6-nitro-2.4-dloxo-3-azablcvclof3.1.01-hexane A 22 L vessel equipped with overhead stirrer, thermometer, dropping funnel, 10 cooling bath, condenser, exit bubbler and nitrogen inlet was purged with nitrogen. The nitrogen purged vessel was charged with N-benzylmaleimide (500 gm, 2.67 moles), toluene (12 L), bromonitromethane (751 gm, 90%, 4.83 moles) and powdered molecular sieves (2020 gm) and stirred at about 10 to about 15°C. The slurry was treated dropwlse with 1,2-dimethyl-1,4,5,6-tetrahydropyrimldine (DMTHP) (616 gm, 5.49 moles) 15 over 3 hours. Addition of DMTHP results in a large amount of tar formation, collected on the molecular sieves. The reaction mixture was warmed to about 25°C and stirred for 60-90 minutes. The molecular sieves were collected on a large Buchner funnel and washed twice with 2 L toluene. The filtrate was washed three times with 750 mL 2 M HCI. A 22 L vessel equipped for reflux was charged with the filtrate and Darco 20 (Trademark) KBB (50 gm). The mixture was heated to 60-70°C and stirred for 1 hour. The mixture was then cooled to about 25 °C, filtered through a Celite (Trademark) precoated Buchner funnel, and the residue washed two times with 500 mL toluene. The carbon treated filtrate was stripped under vacuum in a 12 L round bottom flask equipped with overhead stirrer, thermometer, vacuum addition port, distillation head, 25 condenser and 22 L receiver. Vacuum stripping was complete with about 2 to about 3 L concentrate remaining. The concentrated solution was slowly treated with 4 liters of 2-propanol. Azeotropic vacuum distillation (25 °C) was continued until toluene was no longer present ( as evitJanced by a 10°C temp. rise). The yellow orange solid was collected on a fritted funnel, washed twice with 500 mL 2-propanol and dried under 30 vacuum at 40°C. Yield 175.38 gm (26.7%), mp 108-112°C. HPLC determined purity against an authentic sample (89-96%). 'H NMR (CDCI3) 6 7.3(s, 5H), 4.55 (s,2H), 4.45 (s, 1H), 3.36 (s, 2H).

EXAMPLE 2 (1 p.5a.6pV6-Nitro-3-azabicvclof3.1 .Olhexane hydrochloride A 250 mL 3 neck round bottom flask equipped with a condenser, overhead stirrer, and dropping funnel was charged with 1,2-dichloroethane (115 mL), (1 a, 5a, 6a)-5 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane (prepared from the title compound of Example 1 by the method of Example 2 of United States Patent No. 5,256,791 (incorporated herein by referet.se) (25.1 g, 115 mmol). The solution was cooled to about 0 to about 5°C and treated dropwise with a-chloroethyl chloroformate (ACE-CI) (25.3 g, 177 mmol) over 20 minutes. The reaction mixture was warmed to about 50 to 10 about 55 °C and held for about 2 to 3 hours (reaction completion determined by TLC). The solvent and excess ACE-CI were removed by rotary evaporation. The resulting black residue was dissolved in methanol (100 mL) and heated to about 55 to about 60° C for 3 hours. The resultant slurry was cooled to room temperature and granulated for 18 hours. The slurry was then treated with conc. hydrochloric acid (10 mL, 115 15 mmol) and stirred for 1.5 hours. The product was isolated by suction filtration. The cake was washed with chloroform (25 mL) and dried under vacuum. Yield: 9.99 g, 60 mmol (53%), m.p. 170-180°C (Dec). 'H NMR (de-DMSO) 6 9.8 (br s, 2H), 4.9 (s, 1H), 3.5 (m, 4H), 2.9 (s, 2H). examples 7-ff1a.5a.6a1-6-Nitro-3-azablovclof3.1.01hex-3-vn-6-fluoro-1-f2.4-dlfluoroDhenvn-1.4-dihvdro-4-oxo-1.8-naphthvridine-3-carboxvdic acid ethvl ester A 500 mL 3 neck round bottom vessel equipped with an overhead stirrer, condenser and thermometer was charged with acetonitrile (190 mL), 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyrldine-3-carboxyllc acid ethyl ester 25 (19.07g, 50 mmol), the title component of example 2 (9.88 g, 60 mmol), and triethylamine (15.3 g, 151 mmol). The mixture was heated to reflux (82°C), stirred for 6.5 hours and tested for reaction completion by TLC (3:2 ethyl acetate:hexanes, UV). The resultant slurry was cooled to room temperature and treated with water (115 mL). The slurry was then granulated at about 0 to about 5°C for 1 hour. The product was 30 collected on a fritted funnel as a white solid and washed with 1:1 CH3CN: water (50 mL). The product was dried under vacuum at 40°C. Yield: 21.17 g, 44.6 mmol (89.2%). m.p. 245-250°C. nH NMR (CDCI3) 6 8.4(s, 1H), 8.1 (d, 1H), 7.4 (m, 2H), 7.05 (m, 1H), 4.35 (q, 2H), 4.1 (s, 1H), 3.95 (m, 2H), 3,65 (m, 2H), 2.75 (m, 2H), 1.35 (t, 3H).

EXAMPLE 4 7-(Mg.5o.6g1-6-Amino-3-azablcvclof3.1.01hex-3-vn-6-fluoro-1-(2.4-dlfluorophenv0-1.4-dlhvdro-4-oxo-1.8-naphthvridine-3-carboxvclic acid ethvl ester A. A 250 mL 3 neck round bottom flask equipped with a condenser, 5 thermometer, and overhead stirred was charged with the title compound of example 3 (10.0g, 21.1 mmol), acetonitrile (50 mL), water (50 mL), and zinc dust (6.9 g, 105.5 mmol). The grey slurry was treated with methanesulfonic acid (70%, 25.5 mL, 241 mmol) resulting in an exotherm to 40°C. The orange-yellow reaction mixture was warmed to 50-55°C and held for 3 hr (reaction completion by HPLC). The mixture was 10 cooled to room temperature, treated with water (100 mL) and Celite (Trademark) (1 g), and stirred for 15 min. The slurry was filtered through a Celite precoated funnel to give a deep amber solution. The solution was basified to pH 10.1 using 50% aqueous NaOH. The orange amber slurry was treated with dichloromethane (250 mL) and filtered to remove insolubles. The organic layer was stripped to dryness yielding crude 15 product (2.57 g, 27.4 wt%). A sample of the crude product (0.55g) was chromatographed using a silica gel column. It was eluted seven times with 50 mL ethyl acetate and thirteen times with 50 mL methanol. The last five fractions were combined and concentrated to yield pure title compound (0.14 g, 27.2% column recovery). Overall Yield (5.73%). The product was characterized by HPLC (vs. authentic sample) 20 and FAB MS [M+H]*=445. 1H NMR (CDCI,) 6 8.35 (s, 1H), 7.8 (d, 1H), 7.35 (m, 1H), 7.05 (m, 2H), 4.35 (q, 2H), 3.6 (br s, 2H), 3.5 (br s, 2H), 2.05 (s, 1H), 1.57 (s, 2H), 1.51 (s, 2H), 1.39 (t, 3H).

B. A 600 mL Parr (Trademark) Reactor, equipped with a Peteric Ltd. Pressflow (Trademark) Gas Controller (Model 1502), was charged with the title 25 compound cf example 3 (2.04 g, 4.3 mmol), Raney nickel [A-4000, Activated Metals and Chemicals Inc., Seviorille, TN] (1.44 g wet wt.), N,N-dimethylformamide (70 mL) and water (20 mL). The reactor was sealed, purged two times with nitrogen (35 psi), charged with hydrogen (50 psi) and warmed, over 45 minutes, to about 40 to 45 °C. The pressure was then increased to about 57 psi and held for 24 hours. The reaction 30 mixture was cooled to room temperature, purged with nitrogen and tested for completion by TLC (89 CHCIa: 10 methanol: 1 NH40H). The catalyst was collected through a Celite precoated funnel and was washed with water (25 mL). The filtrate to which water (40 mL) was added, extracted three times with 100 mL ethyl acetate . The ethyl acetate layer was then concentrated to 100 mL and extracted with water (100 mL) to remove residual DMF. The ethyl acetate layer was evaporated to dryness by rotary evaporation. Crude Wt. Yield: 1.36g (71.1%). HPLC purity assay (76.5%). Purity Yield (54%). The product was characterized by HPLC (versus an authentic sample). The 5 'NMR data were the same as for the product of section A above.

C. The process of section B was repeated with a charge consisting of the title product of claim 3 (10.0 g, 21.1 mmol), Raney nickel (4.3 g wet wt.), tetrahydrofuran (THF) (180 mL) and water (40 mL). The reactor was sealed and purged two times with nitrogen (36 psi). The reactor was then charged with hydrogen (50 psi) and stirred at 10 25-29°C for 2.5 hours (until hydrogen uptake ceased). Th* reactor was purged with nitrogen and the reaction was tested for completion by TLC (89 CHCI,: 10 methanol: 1 NH4OH). The catalyst was filtered off through a Celite precoated funnel. The cake was washed two times with THF (20 mL). The THF was removed by rotary evaporation to yield a pale yellow slurry. Ethanol (25 mL) was added to the slurry which was then 15 granulated at about 20 to about 25°C for 30 minutes. The product was Isolated on a Buohner funnel. Wt. Yield: 7.56 g (80.6%). HPLC purity assay (97.1%). Purity Yield (78.3%). The product was characterized by HPLC (versus an authentic sample). The 1H NMR data corresponded to that of section A. A second crop 0.7g (7.5 wt% yield) was recovered, but the purity was lower as determined by 1H NMR.

EXAMPLE 5 7-f f 1 o.5ff.6ff'l-6-Amlno-3-azabicvclof3.1.01hex-3-vn-6-fluoro-1 -(2.4-dlfluoroDhenvn-1.4-dihvdro-4-oxo-1.8-naphthvr)done-3-carboxvllc add, methanesulfonic acid salt A. A 200 mL 3 neck round bottom flask equipped with a condenser, thermometer, and overhead stirrer was charged with the title compound of the example 25 4 (1.54 g, 3.46 mmol) and water (25 mL). The white slurry was treated with 70%aq methanesulfonic acid (5.25, 38.4 mmol) and heated to about 45 to about 50°C. The starting material slowly went into solution. The mixture was stirred for 18 hours (tic reaction completion). The mixture was cooled to room temperature and the product isolated by suction filtration. Yield: 1.48 g (83.5%). HPLC % purity (vs. authentic 30 sample) 96.1%. 'H NMR (de-DMSO) 6 8.85 (s, 1H), 8.17 (br m, 2H). 8.11 (d, 1H), 7.83 (m, 1H), 7.62 (m, 1H), 7.37 (m, 1H), 3.67 (br s, 3H), 2.45 (s, 1H), 2.37 (s, 4H), 2.08 (s, 2H).

Claims (39)

WO 95/19361 PCT/IB94/00410 -17- B. A 100 mL 3 neck round bottom flask equipped with a condenser, overhead stirrer and dropping funnel was charged with the title compound of example 3 (1.01 g, 2.13 mmol), zinc (0.70 g, 10.7 mmol), acetonitrile (20 mL), and water (20 mL). The grey slurry was warmed to about 50°C and treated with a 5 mL of a solution of 5 0%aq methanesulfonic acid (3.3 g, 24 mmol). The reaction was monitored periodically, by HPLC, for completion (23 hours). The reaction was heated to about 80 to about 85° C, then treated with additional 70%aq methanesulfonic acid (2.6 g, 19 mmol) to completely hydrolyse the ester (HPLC). The reaction mixture was cooled to room temperature and treated with water (250 mL) to yield a tan slurry. The slurry was 10 filtered and 500 mL water was added to the filtrate. The resultant solution was concentrated by rotary evaporation to remove acetonitrile. 2-Propanol (50 mL) was added to the concentrate which was then evaporated to dryness. The residue was treated with water (50 mL) and acetone (50 mL) to give a brown slurry. The slurry was filtered to remove the insoiubles. The filtrate was cooled to 0 to about 5° C to crystallize 15 the product. Yellow crystals of title compound were obtained (105 mg, 10.5% yield). HPLC (20% CH,CN: 80% pH 2, 50 mM H3P04; 270 nm, 1.00 mL/mln; Zorbax (Trademark) RX C,e5// 4.6 mm x 15cm) vs. standard sample of the title compound supports structure. HPLC spiking experiments with an authentic sample of the title compound demonstrated that the product of this example Is the title compound.The 1H 20 NMR data for the product were the same as for the product of Section A above. WO 95/19361 PCT/IB94/00410 -18- 276478 CLAIMS

1. A process for preparing a compound of the formula 0 yyV HX.

I V COOH 10 ✓ h2n h ' R*H;wherein R'H is a pharmaceutically acceptable acid selected from the group consisting 15 of R4SOaH, R4P03H and YH wherein;R4 is selected from (C,-C6)alkyl and optionally substituted phenyl or naphthyl wherein the substituent is (C,-CB)alkyl; and;Y is selected from CI, S04, HS04, N03, HP03H, and P04,;which comprises treating a compound of the formula;20;C00R2;25;II;30;wherein R2 is (C,-Ce)aikyl, aryl(CrCa)alkyl, or hydrogen and R3 is N02 or NH2;;a) when R3 is NH2 with a compound of the formula R'H wherein R'H is as defined above;;WO 95/19361;PCT/IB94/00410;-19-;or b) when R3 Is N02 with a reducing agent in the presence of a compound of the formula R1H whereinR'H is as defined above.;2.

The process of claim 1 wherein the compound of formula II wherein R2 is as defined above and R3 is NHa is prepared by treating the compound of formula II;5 wherein R3 is NOa with a reducing agent.;3.

The process of claim 2 wherein the reducing agent is hydrogen gas.;4.

The process of claim 3 wherein the reducing agent is the mixture of a metal and an acid of the formula R'H wherein R'H is defined as above.;5.

The process of claim 4 wherein the metal is zinc and the acid is selected 10 from HCI and methanesulfonic acid.;6.

The process of claim 5 wherein the acid is methanesulfonic acid.;7.

The process of claim 2 wherein the compound of formula II, wherein R3 is N02 is prepared by reacting the compound of formula;°aNv;15;Him"");IV;20 with a compound of the formula;F J;25;0 0;OR2;30;wherein R2 is defined as above and J is a leaving group.;8.

The process of claim 7 wherein J is selected from chloro and bromo.;9.

The process of claim 8 wherein J is chloro.;WO 95/19361;PCT/IB94/00410;-20-;10.

The process of claim 7 wherein the process is effected in the presence of an acid scavenger.;11.

The process of claim 7 wherein the compound of formula IV is prepared by treating a compound of the formula;10;wherein R is selected from (C,-C8) alkyl or (C6-C,0)aryl wherein said aryl group may be substituted, optionally, with one or more substituents independently selected from halo, 15 nltro, (C,-Cfl) alkyl, (C,-C8) alkoxy, amino and trifluoromethyl; with an N-dealkylating agent.;12.

The process of claim 11 wherein R is benzyl.;13.

The process of claim 11 wherein R is methyl.;14.

The process of claim 11 wherein the dealkylating agent is a-chloroethyl 20 chloroformate when R is benzyl or (C,-C8)alkyl or hydrogen when R is benzyl.;15.

The process of claim 14 wherein R is benzyl and the dealkylating agent is a-chloroethyl chloroformate.;16.

The process of claim 11 wherein the compound of formula V is prepared by treating a compound of the formula;25 08N^;VI;30;with a reducing agent.;WO'95/19361;PCT/IB94/00410;-21-;irepfjpd;17.

The process of claim 11 wherein a compound of formula VI is prep by treating a compound of the formula;N';I;CH2;I;R;VII;aryl gfoopfi^ I;10 wherein R is selected from (C,-C8) alkyl or (Ca-C,0)aryl whorein said aryl gfoopQ^ be substituted, optionally, with one or more substituents independently selected from halo, nltro, (C,-Ca) elkyl, (C,-C8) alkoxy, amino and trifluoromethyl; with a compound of the formula X-CH2-N02, wherein X is a leaving group, In the presence of 1,2-dlmethyl-1,4,5,6-tetrahydropyrimldine.;15 18.

The process according to claim 17 wherein R is benzyl.;19.

The process according to claim 17 wherein R is methyl.;20.

The process according to claim 17, wherein X is chloro or bromo.;21.

The process according to claim 20 wherein X is bromo.;22.

The process according to claim 17 wherein said process is carried out 20 at a temperature from about -78°C to about 80°C.;23.

The process according to claim 17 wherein said process is carried out in a solvent selected from benzene, toluene, dimethylformamide or tetrahydrofuran.;24.

The process according to claim 23 wherein said solvent is toluene.;25.

A process for the preparation of a compound of the formula I which 25 comprises the steps of a) treating a compound of the formula VII with a compound of the formula X-CH2-N02, wherein X is a leaving group, in the presence of a base to form a compound of the formula VI and treating the resultant compound of formula VI with a reducing agent to form the compound of the formula V; 30 b) treating the compound of the formula V with a dealkylating agent to form the compound of formula IV;;c) treating the compound of formula IV with a compound of;WO 95/19361;PCT/IB94/00410;F;-22-;0 0;OR2;J;5;F;10 wherein R2 is as defined above and J is a leaving group, in the presence of a base to form a compound of the formula II, wherein R3 is N02; and d) treating the compound of formula II, wherein R3 is NOa, with a reducing agent comprising hydrogen in the presence of a catalyst or a metal and an acid of the formula R'H, as defined above, to form 15 i) when the hydrogenation is effected in the presence of an acid;R'H, as defined above, or R'H is a compound of the formula YH or R4S03H, wherein Y and R4 are as defined cbove, the compound of the formula I; or treating said compound with a compound of the formula R'H, which may be the same 20 as or different from the R'H of the reducing step, or a compound of the formula R4C02H, wherein R4 is defined as above, to form the compound of the formula I.;26.

The p. ocess of step a) of claim 25 wherein said base is 1,2-dimethyl-1,4,5.6-tetrahydropyrimidine.;25 a-chloroethyl chloroformate when R is benzyl or (C,-Ce)alkyl or hydrogen when R is;

28. The process of step d) of claim 25 wherein the acid is an alkanesulfonic acid.;

29. The process of claim 28 wherein said acid is methanesulfonic acid.;ii) the compound of the formula II, wherein R3 is NH2, and then;27. The process of step b) of claim 25 wherein said dealkylating agent is benzyl.;30;

30. The process of claim 28 wherein said metal is zinc.;

31. A compound of the formula .;^//ectua/ n;WO 95/19361;PCT/IB94/00410;-23-;h;Hh»;IV;?? 6;4?;8;10;15;

32. A compound of the formuia;H;OpN;XXX;XOpR';V^NT^N^N;H;III B;wherein R2 is defined as above.;30

33. The process of claim 2 wherein the reducing agent is selected from the group consisting of a) the combination of a metal and an acid of the formuia R'H as defined as above, or b) hydrogen over Raney nickel.;'^a, Pmn;,c« of figerty;*eceiveo WO 95/19361 PCT/IB94/Q0410 -24-

34. The process of step d) ii) of claim 25 wherein the reducing agent m selected from the group consisting of a) the combination of a metal and an acid of the formula R'H as defined as above, or b) hydrogen over Raney nickel.

35. A process as defined in claim 1 for preparing a compound of the formula 1 defined therein substantially as herein described with reference to any example thereof.

36. A process as defined in claim 25 for the preparation of a compound of the formula I substantially as herein described with reference to any example thereof.

37. A compound of the formula I which is the product of a process as claimed in any one of claims 1 to 30 and 35.

38. A compound of the formula IV as claimed in claim 31 substantially as herein described with reference to any example thereof.

39. A compound of the formula DIB as claimed in claim 32 substantially as herein described with reference to any example thereof. END OF CLAIMS