CZ211196A3 - Process for preparing pharmaceutically acceptable salts of naphthyridonecarboxylic acid - Google Patents

Abstract

This invention relates to novel processes for preparing compounds of formula (I), wherein R<1>H is as defined below, which is a salt of the naphthyridone antibiotic 7-(1 alpha ,5 alpha ,6 alpha )-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbocylic acid and a pharmaceutically acceptable acid. The salt and antibiotics have antibacterial activity. This invention also relates to novel intermediates, and processes for their preparation, of formulae (IV), (IIIB) or (IIIA). The compounds of formulae (IIIA), (IIIB) and (IV) are useful as intermediates in the syntheses of the azabicyclo naphthyridone carboxylic acid alkanesulfonic acid salts of formula (I).

Description

A process for the preparation of pharmaceutically acceptable salts of naphthyridonecarboxylic acid

Technical field

The present invention relates to novel processes for the preparation of a pharmaceutical aqueous formulation. 3 (1c, 10o, -c) - (C 6-amino-3-azabicyclo [3.1.0] hex-3-yl) -1- (2,4-difluorophenyl) -6-fluoro -1,1-dihydric-4-trans-1,8-naphthyridine-3-carboxylic acid and intermediates for the preparation of these salts. The abovementioned salts, hereinafter referred to as the pharmaceutically acceptable salts of naphthyridinecarboxylic acid, have a structure corresponding to the usual

(AND)

R 4 H represents a pharmaceutically acceptable acid selected from the group consisting of R 6 SO-J H, R 6 PO 4 H, and YH, wherein:

R ¹ is C 1 -C 6 alkyl or optionally substituted phenyl or naphthyl, the substituent being C 1 -C 6 alkyl; and after ₄ .

Y is Cl, S0 _4, HSO _4, NQ ₃ = H or HPO-

BACKGROUND OF THE INVENTION

The antibacterial activity of the aforementioned naphthyridone antibiotic is described in U.S. Patent Nos. 5,164,402 issued Nov. 17, 1992 and 5,229,396 issued Nov. 20, 1993. The aforementioned US patents are incorporated herein by reference in their entirety for the disclosure of this invention . These patents are transferred to the same subject as the present invention.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of a pharmaceutically acceptable salt of a naphthyridinecarboxylic acid of the general formula

R 4 H represents a pharmaceutically acceptable acid selected from the group consisting of R ⁴ SO ₃ H, R ⁴ PO-H and YH, wherein

R ⁴ is C 1 -C 6 alkyl or optionally substituted phenyl or naphthyl, the substituent being C 1 -C 6 alkyl; and

Y is Cl, SO ₄ , HSO ₄ , NO ₃ , HPO ₃ H, or a compound of formula II

COOR (II) where

R 1 is C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, or hydrogen; and

R ³ is NO ₂ or NH ₂ ;

a) when R ³ is NH ₂ , it is reacted with a compound of formula R 4 H, wherein R 4 H is as defined above; or

b) when R ³ represents a group of formula NQ ₂ , it is reacted with a reducing agent in the presence of a compound of formula R ¹ H, wherein R 1 H is as defined above.

The present invention also provides a process for the preparation of compounds of formula II wherein R ³ is NH 2 and R ² is as defined above by reacting a compound of formula II wherein R is NO 2 with a reducing agent. in the presence of a compound of formula RH, wherein RH is as defined above.

The invention further provides a method for producing a compound of formula II wherein R ³ represents a NO _2, which is characterized in that the compound of formula IV _H \ H

IV) is reacted with a compound of formula

OR 'wherein R is as defined above and J is a suitable leaving group.

The present invention further provides a process for the preparation of a compound of formula (IV), characterized in that the compound of formula (V) is formed

where C H £

R

R is C 1 -C 6 alkyl or C 6 -C 10 aryl, said aryl optionally substituted with one or more substituents independently selected from halogen, nitro C 1 -C 6 alkyl, C 1 -C 6 alkoxy carbon atoms, amino and trifluoromethyl;

is reacted with an N-dealkylating agent. Preferably, R is phenyl or hydrogen.

Compounds of formula (V) may be prepared by reacting a compound of formula (VT)

AND

Wherein R is as defined above, with a reducing agent.

Compounds of formula (VI) may be prepared by reacting a compound of formula (VII)

R wherein R is as defined above, with a compound of formula x-ch ₂ -no ₂ wherein X represents a suitable leaving group, in the presence of a base. 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine is preferred as the base.

In yet another aspect, the present invention provides a process for the preparation of a compound of formula (I), the process comprising:

a) reacting a compound of formula VII with a compound of formula X-CH ₂ -NO ₂ , wherein X is a leaving group, in the presence of a base to form a compound of formula VI, which is then reacted with a reducing agent to form a compound of formula V;

b) reacting the compound of formula V with a dealkylating agent to form a compound of formula IV;

c) reacting the compound of formula IV with a compound of formula U U

wherein R ² is as defined above and J represents a suitable leaving group; to form a compound of Formula II wherein R is NO ₂ ; and

d) reacting a compound of formula II wherein R ³ is NO ₂ with a hydrogen-containing reducing agent in the presence of a catalyst or metal and an acid of formula R 4 H, wherein R ³ H is as defined above,

i) wherein when the hydrogenation is carried out in the presence of an acid of the formula R 1 H as defined above, or when R 1 H represents a compound of the formula YH, or

R ⁴ SO ₃ H, wherein Y and R ⁴ are as defined above, gives a compound of formula I; or (ii) the obtained compound of formula (II), wherein R ³ is NH _{2, is} then reacted with a compound of formula (R 4) H, which may be the same as or different from the compound of formula (R 4) H used in the reduction step; with a compound of the formula R ⁴ COtH, wherein th

R &lt; ¹ &gt; is as defined above to give a compound of formula (I).

2 ...... H

H ....... \

The invention further provides a compound of formula IV

I \ ......... Ί \ (iv;

The present invention also provides compounds of formula IIIB

cq ₂ r ²

(IIIB) where it is as defined above.

The present invention also provides compounds of formula (IIIA)

where it has the meaning given above.

The term halogen as used herein refers to fluorine, chlorine, bromine or iodine.

The term alkyl as used herein refers to straight hydrocarbon chains and, if they contain more than two carbon atoms, also branched hydrocarbon chains and hydrocarbon rings and combinations of straight or branched hydrocarbon chains with hydrocarbon rings.

A detailed description of the invention follows.

The methods of the invention and the preparation of the compounds of the invention are illustrated in the following reaction scheme. Unless otherwise indicated, R, R 1, H, R ² , R ³ and X in the following reaction scheme and discussion have the meanings given above.

Diagram

The above scheme illustrates methods of making salts of the naphthyridone antibiotic of Formula I, novel intermediates useful in these methods, and methods of making these intermediates.

In the above scheme, a compound of formula 1 is reacted with a compound of formula X-CH ₂ NO ₂ , wherein X represents a suitable leaving group such as chlorine or bromine, in the presence of a base to give the corresponding compound of formula 2. an inert polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), or dimethylacetamide (DMAC); an ether solvent such as diethyl 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 ° C, with temperatures of about 0 ° C to about -20 ° C being preferred. The base is preferably added last. Examples of suitable bases include carbonate bases such as potassium or sodium carbonate, phosphoramide 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-diazabicyclic (5.4.0) undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,2-dimethyl Preferably, an amine base, preferably 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine, is used.

Reduction of the compound of Formula 2 in an inert ether solvent yields the corresponding compound of Formula 3. Suitable reducing agents include borane, sodium borohydride, and boron trifluoride-ethyl ether complexes.

Inert reduction solvents such as glyme, diglyme, diisopropyl ether, dimethylsulfide, dimethylsulfoxide, diethyl ether and tetrahydrofuran are suitable for the reduction reaction. The preferred reducing agent is borane and the preferred solvents are tetrahydrofuran or diethyl ether. The reduction reaction is typically carried out in a temperature range of about 25 to about 90 ° C, preferably about 25 to about 65 ° C, and most preferably about 25 to about 45 ° C, in tetrahydrofuran. This procedure is described in U.S. Patent No. 5,256,791, the disclosure of which is incorporated herein by reference in its entirety.

A compound of formula 3 wherein R is C 1 -C 5 alkyl or C 6 -C 10 aryl is converted to a compound of formula 4 by converting a compound of formula 3

a) when R is C 6 -C 10 aryl, reacted with hydrogen or α-chloroethyl chloroformate; or

b) when R is C 1 -C 6 alkyl, it is reacted with α-chloroethyl chloroformate.

When R is a C 6 -C 10 aryl group, the hydrogenolytic removal of the RCH 2 group from the compound of Formula 3 is usually accomplished by reacting the compound with hydrogen gas at a pressure of from about 10 to about 50 psig. , preferably from about 10 to 10 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 reaction temperature is about 20 to about 80'C, preferably about 25'C. The solvent used is usually an alkanol of 1 to 6 carbon atoms, preferably methanol.

The compound of formula 4 is converted to the compound of formula 5 by reaction with a compound of formula

wherein R ^a is as defined above and J is a suitable leaving group such as chloro or bromo. A preferred leaving group is chlorine or bromine, most preferably chlorine.

The reaction described above is optionally carried out in the presence of a solvent. If a solvent is used, it must be inert under the reaction conditions. Suitable solvents include acetonitrile, tetrahydrofuran, ethanol, chloroform, dimethylsulfoxide, dimethylformamide, pyridine, water, and mixtures thereof.

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

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

The compound of formula 5 is converted to the compound of formula 6 by reaction with a metal and an acid of formula R 1 H, where R 1 H is as defined above, in the presence of an aqueous aprotic solvent such as acetonitrile or DMF. Zinc is preferred as the metal. Suitable acids are inorganic acids such as hydrochloric and sulfuric acid; and organic acids such as sulfonic acids such as methane, trifluoromethane and p-toluenesulfonic acid. Methanesulfonic acid or hydrochloric acid is preferred.

This reaction is generally carried out in aqueous C 1 -C 6 alkanol as solvent. Such a solvent is ethanol, methanol, 1-propanol and 2-propanol, preferably ethanol.

The reaction temperature is about 0 to about 80, preferably about 25 ° C.

or [- ι ι i Λ

Raneyova

Preference

Alternatively, the compound of formula 5 can be converted to formula G by reacting in the presence of nickel or a noble metal catalyst. is given Raney nickel.

The hydrogenation reaction is generally carried out in an aqueous solvent mixture. Suitable solvents include C 1 -C 6 alkanols such as ethanol, methanol, 1-propanol and 2-propanol; and water miscible aprotic solvents such as dimethylformamide, tetrahydrofuran, dimethylacetamide, dioxane, and C1 -C6 alkyl ethers. A hydrogen pressure in the range of about 20 to about 20 psig is used, preferably about 20 to about 20 psig, and the reaction temperature is about 15 to about 80, preferably about 20 to about 30 ° C.

The compound of formula 6 is converted to the compound of formula 7 by reaction with a compound of formula R ^H as defined above in an aqueous medium.

Alternatively, the compound of formula 5 can be converted to compound 7 directly by treatment with a metal and an acid of the formula R - * - H as defined above in an aqueous medium. The preferred metal is zinc and the preferred acid is methanesulfonic acid.

Pharmaceutically acceptable acid addition salts, wherein the acid is a compound of the general formula R ⁴ CO ₂ H or R 4 H wherein

R ⁴ and R ⁴ H as defined above are prepared in a conventional manner by treating a solution or suspension of a compound of formula I in the free base form with about one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration and recrystallization techniques are used to isolate the salts. Illustrative examples of suitable acids include acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid, paratoluenesulfonic acid, cinnamic acid, fumaric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, amidosulfonic acid and sulfonic acid.

The antibacterial compounds of formula I and the like antibiotics based on azabicyclonaphthyridonecarboxylic acid which can be synthesized using the methods and intermediates of the invention are useful in the treatment of animals and humans affected by bacterial infections. They are suitable for the treatment of bacterial infections caused by a wide range of bacteria, particularly gram-positive bacterial strains.

The compounds of Formula I may be administered alone, but will usually be administered in admixture with a pharmaceutical carrier selected in accordance with the intended mode of administration in accordance with standard pharmaceutical practice. For example, the compounds of formula I may be administered orally in the form of tablets containing excipients such as starch or lactose, or in the form of capsules containing the active compound alone or a mixture thereof with excipients. Elixirs or suspensions containing flavoring or coloring agents may also be used. For veterinary applications, the active compounds may be contained in feed or drinking water, in which case a concentration of active compound of from about 5 to about 5,000 ppm, preferably from about 25 to about 500 ppm, is used. The compounds of formula (I) may also be administered by parenteral injection, for example, intramuscularly, intravenously or subcutaneously. For parenteral administration, sterile aqueous solutions, which may also contain other solutes, for example, sufficient salt or glucose to render the solution isotonic, are best suited. In veterinary applications, the compounds of formula I may be administered intramuscularly or subcutaneously at a dose of 1,331 to 50 mg / kg / day. The above dose may be administered in one or three divided doses.

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

The compounds of the invention may be administered to humans for the treatment of bacterial infections by either the oral or parenteral route. The oral dose is usually in the range of about 0.1 to about 500 mg / kg / day, preferably about 0.5 to about 50 mg / kg / day. This dose may be administered at one time or up to three divided doses. A suitable dosage level for intramuscular or intravenous administration is about 0.1 to 200, preferably 0.5 to 50 mg / kg / day. When administered intramuscularly, this dose may be administered at once or in the form of up to three sub-doses, whereas intravenous administration may also be by continuous infusion. The dosage will naturally depend on the weight and condition of the subject being treated and the particular mode of administration chosen. These circumstances are apparent to those skilled in the art.

The antibacterial activity of the compounds of the invention can be documented by testing using the Steer replicator technique. This technique is a standard test method for in vitro detection of antibacterial activity and is described in E. Steers et al., Antibiotics and Chemotherapy 9,

307 (1959).

The invention is illustrated by the following examples. These examples are illustrative only, and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

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

221-liter flask equipped with eviohu triggered by a coolant, a thermometer, a dropping funnel, an ice bath, a reflux condenser, a gas scrubber, and a nitrogen inlet. 12 L), bromonitromethane (751 g, 90%, 4.83 mol) and powdered molecular sieve (2020 g) are added and the mixture is stirred at a temperature of about 10 ° C to about 15 ° C. 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine (DMTHP) (616 g, 5.49 mol) After the addition of DMTHP, a large amount of tar is formed which is collected on a molecular sieve. The molecular sieve was collected in a large Buchner funnel and washed twice with 2 liters of toluene, the filtrate was washed three times with 750 ml of 2M hydrochloric acid, and placed in a 22 liter flask equipped with a reflux condenser. filtrate and Darco® KBB (50 g). The resulting mixture was heated to 60-70 ° C and stirred for 1 hour. It is then cooled to about 25 ° C, filtered through a Celite-coated Buchner funnel and the filter cake is washed twice with 500 ml of toluene. The filtrate was purified by charcoal and then evaporated under reduced pressure in a 121 L round bottom flask equipped with an overhead stirrer, thermometer, reduced pressure inlet, distillation head, reflux condenser, and a 221 L receiver. After evaporation of the volatiles under reduced pressure, about 2-3 liters of concentrate are obtained as a residue. The concentrated solution is slowly mixed with 4 liters of 2-propanol and continued to distil under reduced pressure (at 25 ° C) for so long. until all of the toluene was removed (resulting in a 10-degree temperature rise). The yellow-orange solid was collected in a sinter funnel, washed twice with 500 mL of 2-propanol, and dried under vacuum at 40 ° C. 175.38 g (26.7%) of the desired product with a melting point of 108 DEG-112 DEG C. is obtained. The purity achieved (HPLC against an authentic sample) is 89 to 96%.

^R 1 HNMR (CDCl _3): δ 7.3 (s, 5H), 4.55 (s, 2H), 4.45 (s, IH), 3.36 (s, 2H)

Example 2

(Ια, 5α, 6a) -6-Nitro-3-azabicyclo (3.1.0) hexane hydrochloride

In a 250 ml three-necked round-bottom flask equipped with a reflux condenser, stirrer and dropping funnel above, add 1,2-dichloroethane (115 ml) and (1α, 5α, 6α) 3-benzyl-6-nitro-3-azabicyclo [3.1. O] hexane (made from the title compound of Example 1 as described in Example 2 of US Patent No. 5,256,791) (25.1 g, 115 mmol). The solution was cooled to about 0-5 ° C and α-chloroethyl chloroformate (ACE-Cl) (25.3 g, 177 mmol) was added dropwise over 20 minutes. The reaction mixture is heated to about 50 to about 55 ° C and maintained at this temperature for about 2 to 3 hours (completeness of reaction is monitored by thin layer chromatography). The solvent and excess ACE-Cl were removed in a rotary evaporator. The resulting black residue was dissolved in methanol (100 mL), and the resulting solution was heated to about 55-50

C for 3 hours. The resulting suspension was cooled to room temperature and granulated for 18 hours. Concentrated hydrochloric acid (10 mL, 115 mmol) was then added to the suspension and the mixture was stirred for 1.5 hours. The product was filtered off with suction, the filter cake was washed with chloroform (25 ml) and dried in vacuo. Yield: 9.99 g, 60 mmol (53%); Melting point: 170-180 ° C (dec.) ¹ H NMR (d 6 -DMSO): δ 9.8 (br s, 2H), 4.9 (s, 1H), 3.5 (m,

4H), 2.9 (s, 2H)

Example 3

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

Acetonitrile (190 mL), 7-chloro-6-fluoro- (2,4-difluorophenyl) -1,4-dihydro-4-oxo ethyl ester, was placed in a 500 mL three-necked round bottom flask equipped with a stirrer, reflux condenser and thermometer on top. -1,8-naphthyridine-3-carboxylic acid (19.07 g, 50 mmol), the title compound of Example 2 (9.88 g, 60 mmol) and triethylamine (15.3 g,

151 mmol). The resulting mixture was heated to reflux (82'C) and stirred for 6.5 hours. The completion of the reaction was monitored by thin layer chromatography (3: 2 ethyl acetate / hexanes as eluent, UV detection). The resulting suspension was cooled to room temperature, treated with water (115 mL) and then granulated at about 0 to about 5 ° C for 1 hour. The product was collected in a fritted funnel as a white solid, which was washed with a 1: 1 mixture of acetonitrile and water (50 mL). The product is dried under vacuum at 40'C. Yield:

21.17 g, 44.6 mmol (89.2%), mp 245-250 ° C.

¹ H NMR (CDCl ₃ ): δ 8.4 (s, 1H), 8.1 (d, 1H), 7.4 (m, H), 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- ([Ια, 5α, 6a] -6-amino-3-azabicyclo [3.1.0] hex-3-yl) 6-fluoro-1- (2,4-difluoro-phenyl) -1,4- dihydro-4-oxo-1,8-naphthyridine

3-carboxylic acids

A. Place the title compound of Example 3 (10.0 g, 21.1 mmol), acetonitrile (50 mL), water (50 mL) and zinc dust in a 250 mL three-necked round bottom flask equipped with a reflux condenser, thermometer, and stirred from above. (6.9 g, 105.5 mmol). The gray suspension was treated with methanesulfonic acid (70%, 25.5 mL, 241 mmol) while warming to 40 ° C due to an exothermic reaction. The orange-yellow reaction mixture was heated to 50-55 ° C and maintained at this temperature for 3 hours (completion of the reaction was monitored by HPLC). The mixture was cooled to room temperature and treated with water (100 mL) and Celite ^(R) (1 g). The resulting mixture was stirred for 15 minutes, the resulting suspension was filtered through a Buchner funnel covered by a layer of Celite @ ^R \ to give a dark amber solution. This solution was basified to pH 10.1 using 50% aqueous sodium hydroxide. The orange-amber suspension was treated with dichloromethane (250 mL) and filtered to remove insoluble materials. The organic layer was evaporated to dryness to give the crude product (2.57 g, 27.4%). A sample of the crude product (0.55 g) was chromatographed on a silica gel column which was eluted 7 times with 50 ml of ethyl acetate and 13 times with 50 ml of methanol. The last five fractions were combined and concentrated. Obtained the pure title compound (0.14 g, 27.2% yield from chromatography). Total yield: 5.73%. The product was characterized by high pressure liquid chromatography (against an authentic sample) and FAB MS [M + H] ⁺ = 445.

¹ H NMR (CDCl ₃ ): 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. Up to 600 ml Parrovareactor equipped with Peteric Ltd. gas regulator PressFlower ^R Gas Gas Controller (Model 1502) is placed the title compound of Example 3 (2.04 g, 4.3 mmol), Raney Nickel [A-4000, Activated Metals and Chemicals Inc, Seviorille, TN, USA] (1.44 g wet), Ν, Ν-dimethylformamide (70 mL) and water (20 mL). The reactor was sealed, purged with nitrogen (240.5 kPa), charged with hydrogen (343.5 kPa), and heated to about 40-45 ° C for 45 minutes. The pressure is then increased to 391.5 kPa and held for 24 hours. The reaction mixture was cooled to room temperature and purged with nitrogen. The completion of the reaction was confirmed by thin layer chromatography using a 89:10 mixture of trichloromethane, methanol and ammonium hydroxide; 1 as eluent. The catalyst was collected by filtration through a Celite-coated Buchner funnel and washed with water (25 mL). Water (40 mL) was added to the filtrate and the aqueous mixture was 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 the residual dimethylformamide. The ethyl acetate layer was evaporated to dryness in a rotary evaporator. Crude yield: 1.36 g (71.1%), HPLC purity: 76.5%, pure product yield: 54%. The product was characterized by HPLC (against an authentic sample). The ¹ H NMR data is the same as that obtained for the product obtained in paragraph A.

C. Repeat the procedure of Part B wherein the batch consisted of the product of Example 3 (10.0 g, 21.1 mmol), Raney nickel (4.3 g wet), tetrahydrofuran (180 mL) and water (40 mL). ). The reactor was sealed, purged twice with nitrogen (240.5 kPa), then charged with hydrogen (343.5 kPa) and stirred for 2.5 hours at 25-29 ° C (until the uptake of hydrogen was complete). The reactor was purged with nitrogen and the reaction mixture was subjected to thin layer chromatography using a 89: 10: 1 mixture of trichloromethane, methanol and ammonium hydroxide as the eluent to confirm the completion of the reaction.

The catalyst was collected by filtration through a Buchner funnel covered with Celite. The filter cake was washed twice with tetrahydrofuran (20 mL). Tetrahydrofuran was removed in a rotary evaporator. Ethanol (25 ml) was added to the obtained pale yellow suspension and the suspension was granulated for 30 minutes at about 20 to about 25 ^and C. The product was isolated on a Buchner funnel. Yield: 7.56 g (80.6%), HPLC purity: 97.1%, pure product yield: 78.3%. The product was characterized by HPLC (against an authentic sample). Data ^± H NMR consistent with the product obtained in paragraph A. Also give a second crop (0.7 g, yield 7.5 wt.%), But the purity was lower as determined by 'H NMR ή.

Example 5

Salt 7 - ([1a, 5a, 6a] -6-amino-3-azabicyclo [3.1.0] hex-3-yl] 16-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4- oxo-1,8-naphthyridone

3-carboxylic acids with methanesulfonic acid

A. In a 200 mL three-necked round-bottom flask equipped with a reflux condenser, a thermometer and an overhead stirrer was charged the title compound of Example 4 (1.54 g, 3.46 mmol) and water (25 mL). The resulting white suspension was treated with 70% aqueous methanesulfonic acid (5.25 g, 38.4 mmol) and the resulting mixture was heated to about 45 to about 50 ° C. The starting material slowly goes into solution. The reaction mixture was stirred for 18 hours (completion of the reaction was monitored by thin layer chromatography), cooled to room temperature and the product was filtered off with suction. Yield: 1.48 g (83.5%), HPLC purity (against authentic sample): 96.1%. ³ H NMR: (dg-DMSO): δ 8.85 (s, 1H), 8.17 ( br m, 2H), 8.11 (d,

1H), 7.83 (m, IH), 7.62 (m, IH), 7.37 (m, IH), 3.67 (br S,

3H), 2.45 (s, 1H), 2.37 (s, 4H), 2.08 (s, 2H).

B. In a 100 ml three-necked round bottom flask equipped with a reflux condenser, stirrer and dropping funnel above, was placed 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 gray suspension was warmed to about 50 ° C and treated with 5 mL of a 70% aqueous solution of methanesulfonic acid (3.3 g, mmol). Completeness of the reaction was periodically monitored by high pressure liquid chromatography (23 hours). The reaction mixture is heated to about 80 to about 85 ° C and then treated with an additional amount of 70% aqueous methanesulfonic acid solution (2.6 g, 19 mmol) to complete ester hydrolysis (by HPLC). The reaction mixture was cooled to room temperature and treated with water (250 mL). The resulting golden brown suspension is filtered and 500 ml of water are added to the filtrate. The solution was concentrated in a rotary evaporator to remove acetonitrile. 2-Propanol (50 mL) was added to the residue and the resulting mixture was evaporated to dryness. The residue was treated with water (50 mL) and acetone (50 mL). The brown suspension obtained is filtered to remove insoluble materials. The filtrate is cooled to 0 to about 5 ° C to crystallize the product. The title compound was obtained as yellow crystals (105 mg, 10.5% yield). The structure of the title compound was checked by HPLC versus a standard sample (20% acetonitrile and 80% 50 mM phosphoric acid, pH 2, 270 nm, 1.00 mL / min; Zorbax ^RX-R ύ ₁₈ 5μ 4.6 mm x 15 cm). HPLC experiments with the addition of an authentic sample of the title compound show that the product of this example is indeed the title compound. The NMR data of the product obtained is the same as that of the product of Part A.

Claims (31)

PATENT CLAIMS A process for the preparation of pharmaceutically acceptable salts of naphthyridonecarboxylic acid of the general formula I wherein R ^X 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 C 1 -C 6 alkyl or optionally substituted phenyl or naphthyl wherein the substituent is C 1 -C 6 alkyl ; and Y represents Cl, SO ^, HSO ^, N0 _3, or HPOjH PO, characterized in that the compound of the general formula II COOR F (II) where R ² is C 1 -C 6 alkyl, C 1 -C 6 arylalkyl, or hydrogen; and O R is NO ₂ or NH ₂ ; 'ΐ a) when R is NH ₂ , react with a compound of formula R ³ H, wherein R 1 H is as defined above; or b) when R ³ represents a group of formula NO ₂ , it is reacted with a reducing agent in the presence of a compound of formula R ¹ H, wherein R A is as defined above. A process according to claim 1 wherein the compound of formula II wherein R ^{3 is} NH ₂ and R is as defined above by preparing a compound of formula II wherein R ³ is react the NO ₂ group with a reducing agent, 3. A process according to claim 2 wherein the reducing agent is hydrogen gas. 4. The process according to claim 3, wherein the reducing agent is a metal and an acid of the formula R ¹ H, wherein R 1 H is as defined above. 5. The process of claim 4 wherein the metal is zinc and the acid is hydrochloric acid or methanesulfonic acid. 6. The process of claim 5 wherein the acid is methanesulfonic acid. A process according to claim 2, characterized in that the compound of formula II, wherein R ³ represents NO ₂ , is prepared by producing a compound of formula IV U t \ 5 Hb ...... 7-7 (IV) \ / 1 H is reacted with a compound of formula η "," ¹ . wherein R ⁶ is as defined above and J represents a leaving group. 8. The process of claim 7 wherein J is chloro or bromo. 9. The process of claim 8 wherein J is chlorine. 10. The process of claim 7 wherein the reaction is carried out in the presence of an acid scavenger. 15. The process of claim 14 wherein R is benzyl and α-chloroethyl chloroformate is used as the dealkylating agent. 16. A process according to claim 11, wherein the compound of formula (v) is prepared by reacting a compound of formula (VIi) Wherein R is as defined above, with a reducing agent. 17. A process according to claim 11, wherein the compound of formula VI is prepared by reacting a compound of formula VII R where R is C 1 -C 6 alkyl or C 6 -C 10 aryl, said aryl optionally substituted with one or more substituents independently selected from halogen, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy 6 carbon atoms, amino and trifluoromethyl; * - 28 with a compound of formula _X-CH2-NO2 wherein X is a leaving group, in the presence of 1,2dimethyl-1,4,5,6-tetrahydropyrimidine. 18. The process of claim 17 wherein R is benzyl. 19. The method of claim 17 wherein R is methyl. 20. The method of claim 17 wherein X is chlorine or bromine. 21. The method of claim 20 wherein X is bromo. 22. The method according to claim 17, characterized in that the reaction is performed at a temperature ranging from about -78 to about 80 ³ C. 23. The process of claim 17 wherein the reaction is carried out in a solvent selected from benzene, toluene, dimethylformamide and tetrahydrofuran. 24. The process of claim 23 wherein the solvent is toluene. 25. A process for the preparation of a pharmaceutically acceptable salt of a naphthyridinecarboxylic acid of formula (I), which process comprises: a) reacting a compound of formula VII with a compound of formula X-Cl 1 -NC 4 wherein X is a leaving group in the presence of a base to form a compound of formula VI, which is then reacted with a reducing agent to form a compound of formula V; J__Ί. uea x j \ _y b) the compound of the general formula C is reacted with Τ vzorce Λ b -b- Λ Λ Τ Τ r. ο ιιγ v4.ui.0c xv _f c) reacting the compound of formula IV with a compound of formula o wherein R is as defined above and J is a suitable leaving group; to form a compound of formula II wherein R ³ is NO 2; and d) reacting a compound of formula II wherein R ³ is NO ₂ with a hydrogen-containing reducing agent in the presence of a catalyst or metal 11 and an acid of formula RH, wherein RH is as defined above, i) wherein when hydrogenation is carried out in the presence of an acid of formula 11¼ as defined above, or when R 1 H represents a compound of formula YH or R ⁴ SO ₃ H, wherein Y and R ⁴ are as defined above, a compound of formula I is obtained; or (ii) the obtained compound of formula (II) wherein R ³ is NH 2 is then reacted with a compound of formula (R 1) H, which may be the same as or different from the compound of formula (RH), or of formula R ⁴ CO ² H, wherein R ⁴ is as defined above, to give a compound of formula I. The process according to step a) of claim 24, wherein the base is 1,2-dimethyl-1,4,5,6-tetrahydropyrimidine. A process according to step b) of claim 24, wherein the dealkylating agent is α-chloroethyl chloroformate when R is benzyl or C 1 -C 6 alkyl, or hydrogen is used when R is benzyl . The process according to step d) of claim 24, wherein the acid is an alkanesulfonic acid. 29. The process of claim 28 wherein the alkanesulfonic acid is methanesulfonic acid. 30. The process of claim 28 wherein the metal is zinc. A compound of formula IV 0 ₂ rk. _H Η / V (iv) A compound of formula IIIB (iiib; wherein P. is as defined above. 33. A compound of formula IIIA (IIIA) r I o wherein R is as defined above. 34. The method of claim 2 wherein the reducing agent is selected from the group consisting of a potentiator a) a combination of a metal with an acid of the formula R ¹ H wherein R ¹ H is as defined above; and b) hydrogen in the presence of Raney nickel. 35. The method of step d) ii) of claim 24, wherein the reducing agent is selected from the group consisting of a label