AU703541B2 - An intermediate for preparing naphthyridonecarboxylic acid salts - Google Patents

Description

An Intermediate for Preparing Naphthyridonecarboxylic Acid Salts Background of the Invention This invention relates to a novel intermediate for pharmaceutically acceptable acid salts, of the formula the preparation

S

H

H

2 N H

R

1 H F wherein 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 wherein

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; and 1o Y is selected from Cl, SO 4 HS04, NO 3

HPO

3 H, and P0 4 of the naphthyridone antibiotic 7-(la,5a,6c)-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-l-(2,4-difluorophenyl)-6fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.

The antibacterial activity of the aforementioned naphthyridone antibiotic is 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.

Summary of the Invention The invention relates to the compound of the formula The term "halo", as used herein, refers to fluoro, chloro, bromo or iodo, as applicable.

[N:\LIBH]0149:RRB The term "alkyl", as used herein, includes straight, and when comprised or 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 preparation of the compound of the present invention is illustrated in the following reaction scheme which shows an overall scheme for the preparation of naphthyridone antibiotics. The compound of the invention is Compound 4.

SCHEME

0 X NON 0 NO H H R ON N

RHH

1 CH a

CH,

0 C022 0 2

H

H I! H Ii F H 4

F

H F ia i F consisting of R 4

SO

3 H, R 4

PO

3 H and YH wherein R 4 is selected from (C 1

-C

6 )alkyl and optionally substituted phenyl or naphthyl wherein the substituent is (C1-C 6 )alkyl; and Y is selected from CI, SO 4 HS0 4

NO

3

HPO

3 H and P0 4

R

2 is (Cl-C 6 )alkyl, aryl (Cl-C 6 )alkyl or hydrogen and X is a leaving group.

[N:\LIBH]0149:RRB Referring to the above scheme, reaction of a compound I with a compound of the formula X-CH 2 -N0 2 wherein X is a suitable leaving group, such as chloro and bromo, in the presence of a base yields the corresponding compound 2. This reaction is generally conducted in an inert, polar, aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) or dimethylacetamide (DMAC), an ethereal solvent such as ethyl ether, glyme, diglyme, dioxane or tetrahydrofuran (THF) or an aromatic solvent such as optionally chlorinated benzene or toluene. Toluene is preferred. Suitable reaction temperatures range from about -78°C to about 80 0 C, with about 0°C to about 0 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-dimethylperhydro-1,3,2-diazaphosphorine, and amine bases such as triethylamine, guanidine, diisopropylethylamine, tetramethylguanidine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), [4.3.0]non-5-ene (DBN) and 1,2-dimethyl-1,4,5,6-tetrayhydropyrimidine. 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 ehtereal 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 diethyl ether.

The reduction is typically carried out at temperatures ranging from about 25 0 C to about 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 0 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 1 -Cs)alkyl or (C 6 -Clo)aryl, is converted into compound 4, by treating compound 3, a) when R is (C 6

-C

10 )aryl with hydrogen or a-chloroethyl chloroformate; or b) when R is (C 1

-C

6 )alkyl with a-chloroethyl chloroformate.

When R is (C 6

-C

10 )aryl hydrogenolytic removal of the RCH 2 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 rhodium, or salts thereof. Palladium, or palladium hydroxide, on carbon is preferred. The temperature may range from about 20°C to about 80 0 C, and is preferably about 25 0 C. The solvent is usually a (C 1

-C

6 )alkyl alcohol and is preferably methanol.

Compound 4 is converted to compound 5 by treating it with a compound of the formula [N:\LIBH]O149:RRB S*_I OR2 J N N

F

F

wherein R 2 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.

5 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, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, dimethylformamide, pyridine, S. water, or mixtures thereof.

The reaction temperature usually ranges from about 20'C to about 150 0

C.

10 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 metal carbonate or bicarbonate, or a tertiary amine, e.g. triethylamine, pyridine or picoline.

Compound 5 is converted to compound 6 by treatment with a metal and acid, of the formula R 1 H, wherein R 1 H is defined as above, in the presence of an aqueousaprotic 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, methane-, trifluoromethane- and p-toluenesulfonic acids.

Methanesulfonic acid or hydrochloric acid is preferred. This reaction is generally conducted in an aqueous (C 1

-C

6 )alkyl alcohol solvent, such as ethanol, methanol, 1-propanol and 2-propanol, preferably ethanol, at a temperature from about 0°C to about preferably at about Alternatively, compound 5 can be converted to 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 conducted 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. Hydrogen pressures used are in 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 0 C to about 80 0 C, preferably the from about 20 to about 30 0

C.

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

[N:\LIBH]0149:RRB Alternatively, compound 5, may be converted directly into compound 7 by treatment with a metal and an acid of the formula R 1 H, 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 compound of the formula R 4

CO

2 H or R 1 H, wherein R 4 and R 1 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, 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 intermediate of this invention 15 are useful in the treatment of animals, and humans having bacterial infections. They are useful in treating bacterial infections of broad spectrum, particularly in treating grampositive bacterial strains.

The following examples illustrate the preparation of the compound of the present invention. It will be understood, however, that the invention is not limited to the specific 20 details of these examples.

EXAMPLE 1 (la.5a,.6a)-3-Benzyl-6-nitro-2.4-dioxo-3-azabicyclo[3.1.0]hexane A 22 L vessel equipped with overhead stirrer, thermometer, dropping funnel, cooling bath, condenser, exit bubbler and nitrogen inlet was purged with nitrogen. The 25 nitrogen purged vessel was charged with N-benzylmaleimide (500 gm, 2.67 moles), toluene (12L), bromonitromethane (751 gm, 90%, 4.83 moles) and powdered molecular sieves (2020 gm) and stirred at about 10 to about 15 0 C. The slurry was treated dropwise with 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine (DMTHP) (616 gm, 5.49 moles) 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 0 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 HC1. A 22 L vessel equipped for reflux was charged with the filtrate and Darco (Trademark) KBB gm). The mixture was heated to 60-70 0 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, 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.

[N:\LIBHO0149:RRB Azeotropic vacuum distillation (25°C) was continued until toluene was no longer present (as evidenced 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 vacuum at 40 0 C. Yield 175.38 gm mp 108-112 0 C. HPLC determined purity against an authentic sample 1H NMR (CDC1 3 )67.3 5H), 4.55 2H), 4.45 1H), 3.36 (s, 2H).

EXAMPLE 2 (la.5ca.6a)-6-Nitro-3-azabicyclo[3.1.0lhexane 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), (la,5a,6a)-3benzyl-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 reference) (25.1 g, 115 mmol). The solution was cooled to about 0 to about 5 0 C and treated dropwise with a-chloroethyl chloroformate (ACE-C1) (25.3 g, 177 mmol) over 15 minutes. The reaction mixture was warmed to about 50 to about 55°C and held for about 2 to 3 hours (reaction completion determined by TLC). The 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 resultant slurry was cooled to room temperature and granulated for 18 hours. The slurry was then treated win conc. 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 m.p. 170-180°C (Dec).

1 H NMR (d 6 -DMSO)6 9.8 (br s, 2H), 4.9 1H), 3.5 4H), 2.9 2H).

[N:\LIBH]O149:RRB The claims defining the invention are as follows: 1. A compound of the formula

O

2

N,'

H

AT

or a salt thereof.

2. 5aL, 6c)-6-Nitro-3-azabicyclo[3.1 .O]hexane hydrochloride substantially as hereinbefore described with reference to the Examples.

Dated 23 June, 1998 Pfizer Inc.

Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON

I

0 0 0s a.

S

S

S

0 0

S

IN:\LIBH]O1 49:RRB