KR100236818B1 - Process and intermediates for preparing naphthyridonecarboxylic acid salts - Google Patents

Abstract

The present invention provides naphthyridone antibiotics 7- (1α, 5α, 6α)-(6-amino-3-azabicyclo [3.1.0] hex-3-yl) -1- (2,4-difluorophenyl) A novel process for preparing a compound of formula (I) which is a salt of -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid with a pharmaceutically acceptable acid:

Where

R ¹ H is as defined below.

This salt and antibiotic have antimicrobial activity. The present invention also relates to novel intermediates of the formulas 3, 8 or 9 and methods for their preparation:

The compounds of formulas (9), (8) and (3) are useful as intermediates in the synthesis of azabicyclo naphthyridone carboxylic acid alkanesulfonic acid salts of formula (1).

Description

Intermediates of naphthyridonecarboxylic acid salts and a method for preparing the same {PROCESS AND INTERMEDIATES FOR PREPARING NAPHTHYRIDONECARBOXYLIC ACID SALTS}

The present invention relates to naphthyridone antibiotic 7- (1α, 5α, 6α)-(6-amino-3-azabicyclo [3.1.0] hex-3-yl) -1- (2,4- A method for preparing a pharmaceutically acceptable acid salt of difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridone-3-carboxylic acid and intermediates for preparation:

Formula 1

Where

R ¹ H is a pharmaceutically acceptable acid selected from the group consisting of R ⁴ SO ₃ H, R ⁴ PO ₃ H and YH;

R ⁴ is selected from (C ₁ C ₆ ) alkyl and optionally substituted phenyl or naphthyl wherein the substituent is (C ₁ C ₆ ) alkyl;

Y is selected from Cl, SO ₄ , HSO ₄ , NO ₃ , HPO ₃ H and PO ₄ .

The antimicrobial activity of the above naphthyridone antibiotics is described in US Pat. Nos. 5,164,402 and 5,229,396, issued November 17, 1992 and July 20, 1993, which are incorporated herein by reference. The above patents have been assigned in the same way as the present application.

The present invention seeks to provide novel intermediates useful for the synthesis of azabicyclo naphthyridone carboxylic acid alkanesulfonic acid salts having antimicrobial activity and methods for their preparation.

According to a first aspect of the present invention, when (a) R ³ is NH ₂ , the compound of Formula 2 is treated with a compound of Formula R ¹ H as defined below, or (b) when R ³ is NO ₂ , A process for the preparation of a compound of formula (I) comprising treating with a reducing agent in the presence of a compound of formula (R ¹ H) as defined below:

Formula 1

Where

R ¹ H is a pharmaceutically acceptable acid selected from the group consisting of R ⁴ SO ₃ H, R ⁴ PO ₃ H and YH;

R ⁴ is selected from (C ₁ C ₆ ) alkyl and optionally substituted phenyl or naphthyl wherein the substituent is (C ₁ C ₆ ) alkyl;

Y is selected from Cl, SO ₄ , HSO ₄ , NO ₃ , HPO ₃ H and PO ₄ ;

R ² is (C ₁ -C ₆ ) alkyl, aryl (C ₁ -C ₆ ) alkyl or hydrogen;

R ³ is NO ₂ or NH ₂ .

The present invention is also prepared by treating a compound of formula 2 wherein R ³ is NO ₂ with a reducing agent in the presence of a compound of formula R ¹ H as defined above to produce a compound of formula 2 wherein R ³ is NH ₂ and R ² is as defined above. It is about how to.

In another aspect, the present invention relates to a process for preparing a compound of formula 2 wherein R ³ is NO ₂ by reacting a compound of formula 3 with a compound of formula 4:

Formula 3

Wherein R ² is as defined above and J is a suitable leaving group.

According to another aspect of the invention, a compound of formula 3 is prepared by treating a compound of formula 5 with an N-dealkylating agent:

Wherein R is (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, wherein the aryl group is optionally halo, nitro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, May be substituted with one or more substituents independently selected from amino and trifluoromethyl.

Preferably R is phenyl. Compounds of Formula 5 may be prepared by treating compounds of Formula 6 with a reducing agent:

Wherein R is as defined above.

The compound of formula 6 is prepared by treating the compound of formula 7 with the compound of formula X-CH ₂ -NO ₂ , wherein X is a suitable leaving group, in the presence of a base:

Wherein R is as defined above.

Preferred bases are 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine.

Another aspect of the invention

(a) treating a compound of formula 7 with a compound of formula X—CH ₂ —NO ₂ , wherein X is a suitable leaving group, to form a compound of formula 6 in the presence of a base, followed by treatment with a reducing agent Forming a compound of 5;

(b) treating the compound of formula 5 with a dealkylating agent to form the compound of formula 3;

(c) treating the compound of Formula 3 with a compound of Formula 4 to form R ³ NO ₂ forming a compound of Formula 2;

(d) treating a compound of formula 2 wherein R ³ is NO ₂ with a reducing agent comprising hydrogen in the presence of a catalyst or a metal and an acid of formula R ¹ H as defined above, and (i) an acid R as defined above. Hydrogenation proceeds in the presence of ¹ H, or when R ¹ H is a compound of formula YH or R ⁴ SO ₃ H, wherein Y and R ⁴ are as defined above, form a compound of formula 1; Or (ii) after forming a compound of formula 2 wherein R ³ is NH ₂ , the compound is represented by the compound of formula R ¹ H (which may be the same as or different from R ¹ H in the reduction step), or formula R ⁴ CO Treating with ₂ H a compound wherein R ⁴ is as defined above to form a compound of Formula 1,

A method for preparing a compound of Formula 1:

Formula 4

Wherein R ² is as defined above and J is a suitable leaving group.

Another aspect of the invention relates to a compound of formula

Formula 3

Another aspect of the invention relates to a compound of formula

Formula 8

Wherein R ² is as defined above.

Another aspect of the invention relates to a compound of formula

Formula 9

Wherein R ² is as defined above.

The term halo, as used herein, means fluoro, chloro, bromo or iodo.

As used herein, 'alkyl' includes straight chain, branched chain hydrocarbons and hydrocarbon rings and combinations of hydrocarbon rings and straight or branched chain hydrocarbons when the carbon number is 2 or more.

The process of the present invention and the preparation of the compounds of the present invention are illustrated in Scheme 1 below. Unless otherwise stated, in the Scheme 1 and the discussion below the substituents R, R ¹ H, R ² , R ³ and X are as defined above.

Scheme 1 relates to a process for the preparation of naphthyridone antibiotic salts of formula (1), novel intermediates useful for this preparation, and methods for preparing such intermediates.

Referring to Scheme 1 above, the corresponding compound 2 is prepared by the reaction of compound 1 in the presence of a base with a compound of formula X—CH ₂ —NO ₂ , wherein X is a suitable leaving group such as chloro and bromo. This reaction is generally an inert, polar, aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) or dimethylacetamide (DMAC); Ethereal solvents such as ethyl ether, glyme, diglyme, dioxane or tetrahydrofuran (THF); Or optionally in an aromatic solvent such as 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 preferred to add the base last. Examples of suitable bases are carbonate bases such as potassium carbonate or sodium carbonate, phos such as 2-t-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-phosphorin Porin Amide Base and Triethylamine, Guanidine, Diisopropylethylamine, Tetramethylguanidine, 1,8-diazabicyclo- [5.4.0] undec-7-ene (DBU), 1,5-diazabi Amine bases such as cyclo- [4.3.0] non-5-ene (DBN) and 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine. It is advantageous to use amine bases. Preference is given to 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine.

Reduction of compound 2 in an inert ethereal solvent affords the corresponding compound 3. Suitable reducing agents include boranes, sodium borohydride and boron trifluoride etherate complexes. Inert ethereal solvents useful for reduction include glim, diglyme, diisopropyl ether, dimethyl sulfide, DMSO, diethyl ether and THF. Preferred reducing agent is borane and preferred solvents are THF or diethyl ether. The reduction is typically performed at a temperature of about 25 ° C to about 90 ° C. Preferably at about 25 to about 65 ° C., most preferably at about 25 to about 45 ° C. in THF. This method is described in US Pat. No. 5,256,791, which is incorporated herein by reference.

Compound 3 (wherein R is (C ₁ -C ₅ ) alkyl or (C ₆ -C ₁₀ ) aryl) is hydrogen or α-chloroethyl chloro when (a) R is (C ₆ -C ₁₀ ) aryl Treatment with formate; (b) When R is (C ₁ -C ₆ ) alkyl, it is converted to compound 4 by treatment with α-chloroethyl chloroformate.

When R is (C ₆ -C ₁₀ ) aryl, removal by hydrocracking of the RCH ₂ group from compound 3 generally results in the compound being about 10 in the presence of a noble metal catalyst such as palladium, platinum, or rhodium, or a salt thereof. by reaction with hydrogen gas at a pressure of from about psi to about 2000 psi, preferably from about 14 to about 60 psi. Palladium on carbon, or palladium hydroxide is preferred. The temperature may be about 20 ° C to about 80 ° C, preferably about 25 ° C. The solvent is usually a (C ₁ -C ₆ ) alkyl alcohol, preferably methanol.

Compound 4 is converted to Compound 5 by treatment with a compound of Formula 4:

Formula 4

Wherein R ² is as defined above and J is a suitable leaving group such as chloro and bromo.

Preferred leaving group is chloro or bromo and the most preferred leaving group is chloro.

The reaction can be carried out with or without a solvent. If a solvent is used, the solvent must be inert under the reaction conditions. Suitable solvents are acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, dimethylformamide, pyridine, water or mixtures thereof.

The reaction temperature is typically in the range of about 20 ° C to about 150 ° C.

The reaction can advantageously be carried out in the presence of an inorganic or organic base such as an acid acceptor, for example an alkali or alkaline earth metal carbonate or bicarbonate, or a tertiary amine such as triethylamine, pyridine or picoline.

Compound 5 is converted to compound 6 by treatment with an acid and a metal of the general formula R ¹ H as defined above in the presence of an aqueous aprotic solvent such as acetonitrile or DMF. Preferred metal is zinc. Suitable acids include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as sulfonic acids such as, for example, methane-, trifluoromethane- and p-toluenesulfonic acid. Methanesulfonic acid or hydrochloric acid is preferred. This reaction is generally carried out at about 0 ° C. to about 80 ° C., preferably at about 25 ° C. in an aqueous (C ₁ -C ₆ ) alkyl alcohol solvent such as ethanol, methanol, 1-propanol and 2-propanol, preferably ethanol. Perform.

Optionally, compound 5 may be converted to compound 6 by treatment with hydrogen in the presence of Raney nickel or a noble metal catalyst. Raney nickel is the preferred catalyst.

The hydrogenation reaction is generally carried out in an aqueous solvent mixture. Suitable solvents include (C ₁ -C ₆ ) alkyl alcohols such as ethanol, methanol, 1-propanol and 2-propanol; And water miscible aprotic solvents such as DMF, THF, dimethylacetamide, dioxane, and (C ₁ -C ₆ ) alkyl ethers. The hydrogen pressure used is in the range of about 14 to about 100 psi, preferably about 40 to about 60 psi, and the temperature is in the range of about 15 ° C to about 80 ° C, preferably about 20 to about 30 ° C.

Compound 6 is converted to compound 7 by treating with an compound of formula R ¹ H as defined above in an aqueous medium.

Alternatively, compound 5 can be converted directly to compound 7 by treating with an acid and a metal of formula R ¹ H as described above in an aqueous medium. Preferred metals are zinc and preferred acids are methanesulfonic acid.

Suspensions or solutions in the free base form of the compound of formula 1 are treated with about 1 chemical equivalent of a pharmaceutically acceptable acid to form a pharmaceutically acceptable acid addition salt, wherein the acid is of formula R ⁴ CO ₂ H or R ¹ H (wherein R ⁴ and R ¹ H are as defined above) is prepared. Conventional concentration and recrystallization techniques are used to isolate the salt. Examples of suitable acids are acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid, hydrochloric acid, hydrobromic acid, iodide Hydrogen acid, sulfamic acid, and sulfonic acid.

Antimicrobial compounds of formula (1) and related azabicyclo naphthyridone carboxylic acid antibiotics that can be synthesized using the methods and intermediates of the present invention are useful in the treatment of animals and humans with bacterial infections. They are useful for the treatment of a wide range of bacterial infections, in particular for the treatment of Gram-positive bacterial strains.

The compound of formula 1 may be administered alone, but will generally be administered in a mixture with a pharmaceutical carrier selected for the intended route of administration and standard pharmaceutical practice. For example, it may be administered in the form of a tablet containing an excipient such as starch or lactose, or alone or in a capsule of a mixture with an excipient, or in the form of a suspension or elixir containing a flavoring or coloring agent or orally. . For animals, it is advantageously contained in animal feed or drinking water at a concentration of about 5 to about 5000 ppm, preferably about 25 to about 500 ppm. For example, it can be injected parenterally, such as intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions which may contain, for example, enough salt to make the solution isotonic or other solutes such as glucose. For animals, the compound of formula 1 may be administered intramuscularly or at a dosage level of about 0.1 to about 50 mg / kg / day, advantageously about 0.2 to about 10 mg / kg / day, in a single dose or up to three doses per day May be administered subcutaneously.

The present invention also provides a pharmaceutical composition containing a pharmaceutically acceptable diluent or carrier with an antimicrobial effective amount of the compound of formula (1).

The compounds of the present invention can be administered to humans for the treatment of bacterial diseases by oral or parenteral routes and are administered in about 0.1 to 500 mg / kg / day, advantageously from 0.5 to 1, or up to 3 divided doses. Oral administration at a dosage level of 50 mg / kg / day. For intramuscular or intravenous administration, the dosage level is about 0.1 to 200 mg / kg / day, advantageously 0.5 to 50 mg / kg / day. Intramuscular administration may be a single dose or divided doses of up to 3 times, while intravenous administration may involve continuous dropping. As will be appreciated by those skilled in the art, the weight and conditions of the subject to be treated and the specific route of administration chosen should be varied.

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

The following examples illustrate the methods and compounds of the present invention. However, it should be understood that the present invention is not limited to the specific details of these embodiments.

Example 1

(1α, 5α, 6α) -3-benzyl-6-nitro-2,4-dioxo-3-azabicyclo [3.1.0] -hexane

The 22 L vessel, equipped with an overhead stirrer, thermometer, dropping funnel, cooling bath, condenser, outlet bubbler and nitrogen inlet, was purged with nitrogen. In a vessel purged with nitrogen, N-benzylmaleimide (500gm, 2.67mol), toluene (12L), bromoniromethane (751gm, 90%, 4.83mol) and powdered molecular sieve (2020gm) were added. To about 15 ° C. The slurry was dropwise treated with 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine (DMTHP) (616 gm, 5.49 mol) over 3 hours. The addition of DMTHP causes the formation of large amounts of tar that collect on the molecular sieve. The reaction mixture was warmed to about 25 ° C. and stirred for 60 to 90 minutes. Molecular sieves were collected on a large Buchner funnel and washed twice with 2 liters of toluene. The filtrate was washed three times with 750 ml 2M HCl. Into a refluxed 22 L vessel was placed filtrate and Darco ™ KBB (50 gm). The mixture was heated to 60-70 ° C. and stirred for 1 hour. The mixture was cooled to about 25 ° C., then filtered through a Celite (TM) precoated Buchner funnel and the residue was washed twice with 500 ml of toluene. The carbonized filtrate was stripped under vacuum in a 12 liter round bottom flask equipped with an overhead stirrer, thermometer, vacuum addition port, distillation head, condenser and 22 liter receiver. Vacuum stripping was terminated when about 2 to about 3 liter of concentrate remained. The concentrated solution was slowly treated with 4 liters of 2-propanol. Azeotropic vacuum distillation (25 ° C.) was continued until toluene was absent (as evidenced by a 10 ° C. temperature rise). The orange solid was collected on a frit funnel, washed twice with 500 mL 2-propanol and dried at 40 ° C. under vacuum. Yield 175.38 gm (26.7%), melting point 108-112 degreeC. Purity (89-96%) measured by HPLC on reference sample. ¹ H NMR (CDCl ₃ ) δ 7.3 (s, 5H), 4.55 (s, 2H), 4.45 (s, 1H), 3.36 (s, 2H).

Example 2

(1α, 5α, 6α) -6-nitro-3-azabicyclo [3.1.0] hexane hydrochloride

In a 250 ml three neck round bottom flask equipped with a condenser, an overhead stirrer, and a dropping funnel, 1,2-dichloroethane (115 ml), (1α, 5α, 6α) -3-benzyl-6-nitro-3-azabicyclo [ 3.1.0] -hexane (prepared from the title compound of Example 1 according to the method of Example 2 of US Pat. No. 5,256,791, incorporated herein by reference) (25.1 g, 115 mmol) was added. The solution was cooled to about 0 to about 5 ° C. and α-chloroethyl chloroformate (ACE-C1) (25.3 g, 177 mmol) was added dropwise over 20 minutes. The reaction mixture was warmed to about 50 to about 55 [deg.] C. and held for about 2 to 3 hours (the reaction termination was determined by TLC). Solvent and excess ACE-Cl 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 resulting slurry was cooled to room temperature and granulated for 18 hours. The slurry was treated with concentrated hydrochloric acid (10 ml, 115 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%), melting point 170 to 180 ° C. (decomposition). ¹ H NMR (d ₆ -DMSO) δ9.8 (br s, 2H), 4.9 (s, 1H), 3.5 (m, 4H), 2.9 (s, 2H).

Example 3

7-([1α, 5α, 6α] -6-nitro-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester

Acetonitrile (190 ml), 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-di in a 500 ml three-neck round bottom container equipped with an overhead stirrer, condenser and thermometer Hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (19.07 g, 50 mmol), the title compound of Example 2 (9.88 g, 60 mmol) and triethylamine (15.3 g, 151 mmol) were added. The mixture was heated to reflux (82 ° C.), stirred for 6.5 h and the end of the reaction was tested by TLC (3: 2 ethyl acetate: hexane, UV). The resulting 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 collected on a frit funnel as a white solid and washed with 1: 1 CH ₃ CN: water (50 ml). The product was dried at 40 ° C. under vacuum. Yield: 21.17 g, 44.6 mmol (89.2%). Melting point 245-250 ° C. ¹ H NMR (CDCl ₃ ) δ8.4 (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-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester

A. A 250 ml three necked round bottom flask equipped with a condenser, thermometer, and overhead stirrer, the title compound of Example 3 (10.0 g, 21.1 mmol), acetonitrile (50 ml), water (50 ml), and zinc powder (6.9 g, 105.5 mmol). The gray slurry was treated with methanesulfonic acid (70%, 25.5 ml, 241 mmol) to exothermic to 40 ° C. The orange-yellow reaction mixture was warmed to 50-55 ° C. and maintained for 3 hours (determination of reaction termination by HPLC). The mixture was cooled to room temperature and treated with water (100 ml) and Celite (1 g) and stirred for 15 minutes. The slurry was filtered through a celite precoated funnel to give a dark pale yellow solution. The solution was basified to pH 10.1 with 50% aqueous NaOH. The orange-pale yellow slurry was treated with dichloromethane (250 ml) and filtered to remove insoluble matters. The organic layer was stripped and dried to give crude product (2.57 g, 27.4 wt%). A sample of the crude product (0.55 g) was chromatographed using a silica gel column. Eluted 7 times with 50 ml ethyl acetate and 13 times with 50 ml methanol. The final five fractions were combined and concentrated to give the pure title compound (0.14 g, 27.2% column recovery). Overall yield (5.73%). The product was characterized by HPLC (relative to reference sample) and FAB MS [M + H]⁺Is 445.^OneH NMR (CDCl₃) δ 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. The title compound of Example 3 (2.04 g, 4.3 mmol), Raney Nickel, in a 600 ml Parr brand reactor equipped with a Pressflow (trade name; manufactured by Peteric Ltd.) gas regulator (model 1502) [ A-4000, Activated Metals and Chemicals Inc. of Sevioril, Tennessee. Preparation] (1.44 g wet weight), N, N-dimethylformamide (70 ml) and water (20 ml) were added. The reactor was sealed, purged twice with nitrogen (35 psi), charged with hydrogen (50 psi) and warmed to about 40-45 ° C. over 45 minutes. The pressure was then increased to about 57 psi and maintained for 24 hours. The reaction mixture was cooled to room temperature, purged with nitrogen and tested for termination by TLC (89 CHCl ₃ : 10 methanol: 1 NH ₄ OH). The catalyst was collected through a celite precoated funnel and washed with water (25 ml). Water (40 ml) was added to the filtrate, and extracted three times with 100 ml of ethyl acetate. The ethyl acetate layer was 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 product weight. Yield: 1.36 g (71.1%). HPLC purity analysis (76.5%). Pure yield (54%). The product was characterized by HPLC (relative to reference sample). ¹ NMR data were the same as for the product of Part A above.

C. The method of part B was repeated for the reaction consisting of the title product of Example 3 (10.0 g, 21.1 mmol), Raney Nickel (4.3 g wet weight), tetrahydrofuran (THF) (180 ml) and water (40 ml). . The reactor was sealed and purged twice with nitrogen (35 psi). Hydrogen was then added to the reactor (50 psi) and stirred at 25 to 29 ° C. for 2.5 hours (until hydrogen consumption ceased). The reactor was purged with nitrogen and the end of the reaction was tested by TLC (89 CHCl ₃ : 10 methanol: 1 NH ₄ OH). The catalyst was filtered through a celite precoated funnel. The cake was washed twice with THF (20 ml). THF was removed by rotary evaporation to give a pale yellow slurry. Ethanol (25 ml) was added to the slurry and then granulated at about 20 to about 25 ° C. for 30 minutes. The product was isolated in Buchner funnel. Yield (weight): 7.56 g (80.6%). HPLC purity analysis (97.1%). Pure yield (78.3%). The product was characterized by HPLC (relative to reference sample). ¹ H NMR data corresponded to data in Part A. 0.7 g (7.5 wt% yield) of the second fraction was recovered, but the purity was lower as measured by ¹ H NMR.

Example 5

7-([1α, 5α, 6α] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1- (2,4-difluorophenyl) -1 , 4-dihydro-4-oxo-1,8-naphthyridone-3-carboxylic acid, methanesulfonate

A. The title compound of Example 4 (1.54 g, 3.46 mmol) and water (25 ml) were placed in a 200 ml three necked round bottom flask equipped with a condenser, thermometer and overhead stirrer. The white slurry was treated with 70% aqueous methanesulfonic acid (5.25, 38.4 mmol) and heated to about 45 to about 50 ° C. The starting material slowly became a solution. The mixture was stirred for 18 h (TLC reaction ended). The mixture was cooled to rt and the product was isolated by suction filtration. Yield: 1.48 g (83.5%). HPLC% purity 96.1% for the reference sample. ¹ H NMR (d ₆ -DMSO) δ 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).

B. In a 100 ml three neck round bottom flask equipped with a condenser, an overhead stirrer and a dropping funnel, 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) was added. The gray slurry was warmed to about 50 ° C. and treated with 5 ml of a solution of 70% aqueous methanesulfonic acid (3.3 g, 24 mmol). The reaction was periodically observed by HPLC to confirm the end of the reaction (23 hours). The reaction was heated to about 80 to about 85 ° C. and then further treated with 70% aqueous methanesulfonic acid (2.6 g, 19 mmol) to fully hydrolyze the ester (HPLC). The reaction mixture was cooled to room temperature and treated with water (250 ml) to give a tan slurry. The slurry was filtered and 500 ml of water was added to the filtrate. The resulting solution was concentrated by rotary evaporation to remove acetonitrile. 2-propanol (50 ml) was added to the concentrate, followed by evaporation 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 insoluble components. The filtrate was cooled to 0 to about 5 ° C. to crystallize the product. Yellow crystals of the title compound were obtained (105 mg, 10.5% yield). HPLC on a standard sample of the title compound (20% CH ₃ CN: 80% pH 2, 50 mM H ₃ PO ₄ ; 270 nm, 1.00 ml / min; Zorbax: trade name, RX C ₁₈ 5μ 4.6 mm x 15 cm) supported the structure do. HPLC standard experiments using reference samples of the title compound indicate that the product of this example is the title compound. ¹ H NMR data for the product were the same as for the product of Part A above.

According to the present invention, novel intermediates useful for the synthesis of azabicyclo naphthyridone carboxylic acid alkanesulfonic acid salts having antibacterial activity and methods for preparing the same are provided.

Claims (15)

A compound of formula Formula 3 A process for preparing a compound of Formula 3, comprising treating a compound of Formula 5 with an N-dealkylating agent: Formula 3 Formula 5 Wherein R is (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, wherein the aryl group is optionally halo, nitro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, May be substituted with one or more substituents independently selected from amino and trifluoromethyl. The method of claim 2, R is benzyl. The method of claim 2, R is methyl. The method of claim 2, The dealkylating agent is α-chloroethyl chloroformate when R is benzyl or (C ₁ -C ₆ ) alkyl, or hydrogen when R is benzyl. The method of claim 5, R is benzyl and the dealkylating agent is α-chloroethyl chloroformate. The method of claim 2, A compound of formula 5 is prepared by treating a compound of formula 6 with a reducing agent: Formula 6 Wherein R is (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, wherein the aryl group is optionally halo, nitro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, May be substituted with one or more substituents independently selected from amino and trifluoromethyl. The method of claim 2, The compound of formula 6 is represented by the following formula 7 in the presence of 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine in formula X-CH ₂ -NO ₂ , wherein X is a leaving group. Process prepared by treatment with a compound of: Formula 7 Wherein R is (C ₁ -C ₆ ) alkyl or (C ₆ -C ₁₀ ) aryl, wherein the aryl group is optionally halo, nitro, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, May be substituted with one or more substituents independently selected from amino and trifluoromethyl. The method of claim 8, R is benzyl. The method of claim 8, R is methyl. The method of claim 8, X is chloro or bromo. The method of claim 11, X is bromo. The method of claim 8, The process is carried out at about -78 ℃ to about 80 ℃. The method of claim 8, The process is carried out in a solvent selected from benzene, toluene, dimethylformamide or tetrahydrofuran. The method of claim 14, The solvent is toluene.