Process for preparing a protected 4-aminomethyl-pyrrolidin-3-one and intermediates

Description

Process for the preparation of protected 4'aminomethopyr?&tidin-3~one. habi The present invention relates to a new process for the preparation of 4-aminomethylpyrrolidin-3-one, to novel intermediates of the process and to their use in the preparation of quinolone antibiotics. Compounds of formula (1), in which P and Pz are protecting groups, compounds of formula (2), in which R is a C1-4 alkyl or C1-4 haloalkyl group, and their salts, e.g. dihydrochloride salts, can be used in the preparation of which, in turn, they can be used as intermediates in the synthesis of quinolone antibiotics, e.g., as described in U.S. Patent No. 6,333,262 and European Publication No. 6,887,721. The intermediate of formula {2}, in which R is a methyl group, is described in more detail in International Patent Application WO 38 / 42705. (R,S>~7-(3~-aminomethyl-1-methylaminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro~ -4-oxo-l,4-dihydro-l,8-naphthyridine-3-carboxylic acid and its salts, especially (R, S) -7- í3-aminomethyl-l-syn~methoxyiminopyrrolidin~l“ - i 1) -1 - c 1 k 1 opo op í 1 - 6 ~ £ 1 uor - 4 - ο χ ο -1,4 - d 1 bidr ο -1,8 ~ na £ t í r 1 din - 3 carboxylic acid methanesulfonate and its hydrates, including its sesquihydrate, can be used for the preparation. * φ φφ « » »<· φ * * * ΦΦΜ φ · φ φ « φ φ φ φφφ φ *·λ > φφ European Publication No. Α €88 772 Al! describes the process shown in Scheme 1 for the preparation of compounds of the general formula (2i), in which Boo represents tert-butoxycarbonyl, and this abbreviation is used in this sense throughout the specification. However, the process according to reaction scheme 1 has some disadvantages, especially when carried out on an industrial scale, using quantities of 10-100 kg; these disadvantages are as follows. The process is not efficient enough because it uses platinum in a hydrogen atmosphere, palladium metal, lithium aluminum hydride (LAh), lithium hydride (L18H4), sodium hydride CdaBRp or sodium hydride / trifluoroacetic acid complex as reducing agents, which reduce both the ketone and the ethanesophore, and thus reoxidation of the alcohol becomes necessary in order to regenerate the ketone. b) Reducing agents other than sodium borohydride / trifluoroacetic acid complex do not completely reduce the cyano group, which leads to the formation of many by-products and thus reduces the yield and purity, while sodium borohydride / trifluoroacetic acid complex as a reducing agent can increase the yield and purity of the product, its use results in intermittent evolution of hydrogen gas. Therefore, the risk of explosion cannot be adequately prevented with a simple exhaust-burning apparatus, so this reduction process is not easy to apply on an industrial scale. In addition, since. There are also many problems with the complex production process itself. X * · » « * φ ♦ ♦ A « » Λ * ♦ · » Λ ··* « Λ ♦ * φ «ΦΦ* « « * «Φ X Φ ««* * ♦ today, for example, the formation of by-products, the complex is not suitable for industrial scale application. c) Side reactions, which are not observed in small-scale production, often appear during large-scale production and lead to reduced yields. Undesirable side products, some of which have not been clearly identified, complicate the separation and / or purification of the desired product. The identified side products include compounds of general formula (3) and (4). It is assumed that the by-products (3) and (e) are formed in the reaction of the starting material 1-cyano-1-N-tert-butoxykettbonyl)pyrrolidin-3-one, sodium borohydride and trifluoroacetic acid. The by-product (3) is particularly problematic because it is not easy to remove by recrystallization. The pyrene / ketene trioxide complex used for the oxidation of the hydroxyl group is expensive, making it unsuitable for use on an industrial or commercial scale. In addition, the dimethyl sulfide formed as a by-product during the oxidation is environmentally unacceptable. e) When a transition metal catalyst, such as platinum, is used in the hydrogenation reaction, the reaction does not proceed satisfactorily in the presence of a catalytic amount of platinum and at low hydrogen pressure, and is therefore not industrially applicable. It is therefore desirable to find an alternative process for the preparation of compounds of general formula (1) and {2}, in particular one in which an a-cyanoketone derivative selectively reduces4 « ♦ *♦ < * ♦«# ♦ * * * «« « # ♦ φ a. χ « « «♦» ♦ »« λ ♦ ♦* acts in such a way that the hydroxyl group does not have to be reoxidized afterwards. The present invention is based on the discovery that the cyano group of a ~ cyanoketone derivative can be selectively and efficiently reduced by hydrogen as a reducing agent in the presence of a Raney nickel catalyst. The reaction conditions used in the process are very mild and thus can be used in industrial production. The use of a Raney nickel catalyst has several advantages over the prior art process described above, including that it does not require an additional oxidation reaction and the formation of by-products is significantly reduced compared to the use of sodium borohydride as a reducing agent, leading to a stoichiometric reaction and good yield, The present invention provides a process for preparing compounds of general formula (1), wherein P1 and P4 are protecting groups; the process is characterized in that a) a compound of general formula (5), in which ?£ is as defined for the compound of general formula 1;, is reacted with a Raney nickel catalyst in a solvent; under hydrogen, thereby obtaining a compound of general formula (6), in which ü: is as defined for the compound of general formula (1); b) protecting the amino group, thereby forming a compound of formula (7) wherein P1 and P2 are as defined for the compound of formula (11); and o) the double bond is selectively reduced to obtain a compound of general formula (1). « « * X « X * «*« Λ φ Λ ν Χ«* β *« ♦ * »♦ The present invention also provides novel intermediates of general formula (6) and (?). The process of the invention is summarized in Reaction Scheme 2. The procedure is described in more detail below. In step a) in which the clano group is reduced, the solvent is preferably an alcohol or ether, such as methanol or isopropanol, which have been found to improve the reaction rate. However, suitable solvents are not limited to alcohols and ethers, and various inert solvents can be used for the reaction which do not adversely affect the reaction and which allow the hydrogen pressure to be controlled. The solvent can be used in a volume of 2 to 20 times, preferably 2 to 5 times, based on the compound of general formula (5). The reaction is preferably carried out in the presence of one or more additives, such as aqueous ammonia solution, gaseous ammonia and acetic acid. These additives can be used in an amount of 2 or more molar equivalents, preferably 2 to 4 molar equivalents, based on the compound of general formula (5).We have shown that the use of these additives improves the purity of the formed compounds of new general formula. The reaction step a) is suitably carried out under a hydrogen pressure of between ambient and 5065 kPa, preferably between 105.2 and 1013 kPa, and at a temperature of between room temperature and 60° C. Various types of Raney nickels can be used as catalysts in the reduction reaction, however, Raney nickel of the W-2 type or similar type is preferred. fi fiX In step b) the amino group is protected, for which any suitable amino protecting group can be used. The protecting group can be preferably removed under acidic conditions. Examples of protecting groups include fornyl, acetyl, trifluoroacetyl, benzene, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, terebutoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyl, triethyl, tetrahydropyranyl and pivaloyl. Particular protecting groups include acetyl, terebutoxycarbonyl and pivaloyl. The tert-butoxycarbonyl protecting group is also preferred as the P* and P2 protecting groups. The protection of the amino group is carried out using conditions known to the person skilled in the art. For example, the compound of formula (6) is reacted with a suitable base, such as lithium tert-butoxide, lithium isopropoxide, potassium tert-butoxide, sodium tert-butoxide and a base selected from lithium chloride, sodium hydroxide and calcium hydroxide.The base is suitably used in an amount of 2.6 molar equivalents or more, preferably 2.0 to 4.0 molar equivalents, based on the compound of the general formula (β). Any solvent conventionally used in organic reactions, such as tetrahydrofuran, toluene, dioxane and dimethoxyethane, can be used, suitably in a volume of 5 to 20 times that of the compound of the general formula {0}. The reaction is desirably carried out at a temperature of -40 to 10'° C. For introducing the amino-protecting group, the reagent is selected from, for example, ditert-butoxy) dicarbonate, pivaloyl chloride and acetyl chloride, which are used in a ratio of 0.9 to. It is used in an amount of between 1.5 mole equivalents based on the compound of general formula (6). The compound of general formula (7) formed can be purified by recrystallization, for example from a mixture of alcohol and water in a volume ratio of between 1:1 and 3:1. In step c1, the double bond is reduced, the selective reduction is preferably carried out using a metal catalyst, for example a transition metal catalyst, such as Raney™ palladium-on-carbon catalyst or Lindlar catalyst in an amount of 0.5-20% by weight, preferably 0.5-5% by weight, based on the compound of general formula (7), for example under a hydrogen pressure of 101.3-304.2 kPa, it is desirable to maintain the pH of the reaction solution between 3-5 or 8-10 with an organic amine or buffer solution for the selective reduction of the double bond at the 4-position of the pyrrolidine ring without reducing the oxo group at the 3-position. Organic amines that can be used are, for example, tertiary amines, such as triethylamine, triethylamine and diisopropylethylamine; the aromatic amines, such as pyridine, 4-dimethylaminopyridine, 4-(4-methylpiperidin-1-yl)pyridine, imidazole, quinoline and isoquinoline; anilines, such as methylaniline; and chiral amines, such as triethanolamine, quinine and quinidine.The amine is suitably used in an amount of between 0.01 and 10, preferably 1 and 10, molar equivalents based on the starting compound of formula (7). The amines can be used individually or in the form of mixtures in various proportions. Any tertiary amine conventionally used in organic reactions can be used in the present reaction, although they are not specifically listed above. ♦ #*» « ««« < « » Ji Any organic solvent can be used, preferably alcohols such as methanol, ethanol, n-propanol and isopropanol; ethers such as tetrahydrofuran and dioxane; ketones such as acetone and methyl ethyl ketone; esters such as ethyl acetate and phenol acetate. The auxiliary agents, such as the organic amine, are selected depending on the solvent used. The solvent is suitably used in a volume of 5 to 100 times, preferably in a volume of 5 to 20 times, based on the compound of the general formula (?). When a buffer solution is used instead of an organic amine to adjust the pH of the reaction solution, only solvents in which the inorganic salt formed during the mixing step does not precipitate suddenly can be used, such as tetrahydrofuran, acetone, methanol and ethanol. Tetrahydrofuran is most preferred. Solvents that are immiscible with aqueous solutions, such as ethyl acetate and diethyl ether, can also be used in this reaction. Any buffer solution that is suitable for adjusting the pH of the reaction solution to a value between 3 and 5, or 8 and 10, such as phosphates, acetates and borates, can be used. Acetate and borate buffer solutions are most preferred, The reaction of step c) is suitably carried out at a temperature between 0 and 50°C, preferably between 5 and 40°C. The compounds of general formula (1) prepared by the process according to the invention can be converted into a compound of general formula {2} or a salt thereof. Thus, a further subject of the invention is a process for preparing a compound of general formula (2) or a salt thereof, in which R is an alkyl group having 1-4 carbon atoms or a haloalkyl group having 1-4 carbon atoms, the process being characterized in that a compound of general formula (1), which is prepared by the process according to the invention described above, is reacted with a compound of general formula (8), in which R is the same as that given for the compound of general formula (2>, preferably methyl bromide, then the protecting group is removed from the amino group, and optionally the product is converted into a salt. The compound of general formula {!) and the compound of general formula (8; are preferably reacted in a solvent such as ethyl acetate or tetrahydrofuran. The removal of the protecting group is preferably carried out under acidic conditions, for which hydrogen chloride gas, sulfuric acid or trifluoroacetic acid is used as the acid. Suitable salts of the compounds of general formula {2} are the hydrochloride, trifluoroacetate and sulfate salts, The invention further relates to the compounds of general formula (2) thus prepared as quinolone antibiotics, in particular 5-63 3' It also relates to the use as an intermediate in the preparation of quinolone antibiotics as described in U.S. Patent No. 262 and European Publication No. 688 772 Al. Thus, a further subject of the invention is a process for the preparation of a compound of formula (9) or a pharmaceutically acceptable salt thereof, wherein R is as defined for a compound of formula (2), the process comprising reacting a compound of formula {2} or a salt thereof, prepared by the process of the invention as described above, with a compound of formula {10}, wherein X is a leaving group, for example halo. Come. •Λ * gene atom, preferably chlorine atom; and optionally the product is converted into a pharmaceutically acceptable salt, The reaction of compounds of general formula (2) and (10) is preferably carried out in the presence of a base. Further details regarding the reaction of compounds of general formula (2) and (10) can be found in U.S. Patent No. 5,633,262 and European Publication No. 688,772 A1. The compound of general formula (8) in this aspect of the invention is preferably (R, S)-7-[3-aminomethyl-4-syn-ethoxyiminopyrrolidin-1-yl]-1-yl-6-fluoropropyl-4-oxo-1,4-dihydro-1,8-naphthyridine-4-carboxylic acid methanesulfonate or its hydrate, preferably its sesquihydrate, as described in the international patent application published under number WO 98 / 42205. The compounds of general formula (6j) and (7), which are intermediates in the preparation of the compound of general formula (1), are novel. Therefore, the present invention also relates to such intermediates. All publications mentioned in this specification, including, but not limited to, patent specifications and applications, are incorporated by reference into this specification as if each publication were specifically stated to be incorporated by reference into this specification. The present invention is described in more detail in the following examples. Of course, the following examples are for the purpose of illustrating the present invention and do not limit the scope of the present invention in any way. Who Γ*·Α < Comparative example 1 Preparation of 4- (-N~tert-Butylcarbonyl)pyrrole 1-1 - f / v-tert-butoxycarbonyl. 3.78 g (0.1 kmol) of sodium borohydride and 32 kg of tetrahydrofuran are weighed into a reactor, and the mixture is cooled to a temperature of 10°C or lower. To this mixture was slowly added 7.0 kg (0.034 kmol) of 4-cyano-1-(E-tert-fluorocarbonyl)pyrrolidin-3-one in 20 kg of tetrahydrofuran. After the addition was complete, 11.4 kg (0.1 mol) of a solution of trifluoroacetic acid in 10 kg of tetrahydrofuran was added at 20°C or below, while carefully monitoring the reaction temperature and the evolution of hydrogen gas. The reaction solution was stirred at room temperature for about 4 hours, then cooled to 5°C or below, and the pH was adjusted to between 1 and 3 by slow addition of 3N hydrochloric acid with stirring. The reaction solution was then stirred again for about 3-4 hours, and then 7.03 kg (0.035 kmol) ditert-butyl)-dicarbonate is added, while the pn of the solution is maintained between 9 and 10 by the addition of 25% aqueous sodium hydroxide solution.After the reaction was completed, tetrahydrofuran was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate and then dried under reduced pressure while removing the solvent. The residue thus obtained was crystallized from a mixture of 7 liters of methyl ethyl ketone and 21 liters of n-hexane and then filtered to obtain 4.74 kg (45%) of the title compound, a comparative example. 4-(N-tert-Butosicarbyl)aminomethyl ···! - (N-tert-butoxybarbonyl / ρ í rr ο 1 i dí n - 3 -ο 1 350 kg (4.23 km) of sodium borohydride and 1000 liters of tetrahydrofuran are weighed into a reactor and the mixture is cooled to 10°C or lower. To this mixture, a suspension of 29.5 kg (3.4 kcal) of 4-O'lan-ol~ (h~tert-butoxycarbonyl} pyrrolidine-3-one in 100(5 liters of tetrahydrofuran was slowly added, followed by a solution of 479 kg (4.2 kmol) of trifluoroacetic acid in 300 liters of tetrahydrofuran after the addition was complete at a temperature of 20°-C or below, while carefully monitoring the reaction temperature and the evolution of hydrogen gas. The reaction solution was stirred at room temperature for about 4 hours, then cooled to 5°C or lower, and the pH was adjusted to between 1 and 3 by slow addition of 3N hydrochloric acid. Then, the reaction solution was stirred again for about 3-4 hours, and then 321 kg (1.47 kmol) of di(tert-butyl)dicarbonate is added while maintaining the pH of the solution between 9 and 10 with 25% aqueous sodium hydroxide solution.After completion of the reaction, tetrahydrofuran was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate and then dried under reduced pressure while removing the solvent. The residue thus obtained was crystallized from a mixture of 3(50 liters of methyl ethyl ketone and 900(5 liters of n-hexane, filtered, and 131 kg (30%) of the title compound was obtained. * » -X :.-. : , w ♦ XX « *♦* * 1- (tert-butoxycarbonyl)-4-adinomethylenepyrrolidin-d-one is blown out (3. Reaction Example) kg (95 mol) of 1- (N-tert-butoxycarbonyl)-cyano-pyrrolidin-3-one is suspended in 150 liters of methanol and dissolved carefully by adding about 30 liters of aqueous ammonia solution. To the above solution is added a small amount of W-2 type Paney-nickel catalyst and the reaction is allowed to proceed at room temperature under a hydrogen pressure of 4-05.2 kPa. The reaction is completed when the hydrogen uptake ceases. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure, thus obtaining 20 kg (quantitative yield) of the title compound, H-NMR (CDCl 2, s, ppm): 4.95 (m, 0.7H)? 4.70 (m, 0.3H); 4.25 Ia, 2H); 3.90 (m, 2.8); 1.50 (m, 9H) MS(FA8, m / 'e): 213 (rt+K) GC (FID) purity: 99.8%. Example 2 2-Phosphoryl-Sulfoxycarbonyl)-4-aminoethylpyrrolidinone (6) was prepared by suspending 1 kg (95 mol) of 1-(b-tert-butoxycarbonyl)-1-cyanopyrrolidine-3'-one in 150 liters of tetrahydrofuran. 100 g of W-2 type Raney nickel were added to the suspension and the components were reacted at room temperature under a hydrogen pressure of 405.2 kPa. The reaction was completed when hydrogen uptake ceased. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure, yielding 20 kg (quantitative yield) of the title compound. Example 3. Preparation of 1-(tert-butylcarbonyl; ~4-aminos!ethylenpyrrolidin-j-one kg (SS- mol) 1-(N-tert-butylcarbonyl)-1-cyanopyrrolidine•••3-one is suspended in 150 liters of isopropanol. 100 g of W-2 type Raney nickel is added to the suspension, and the components are reacted under a hydrogen pressure of 105.2 kPa. The reaction is completed when hydrogen uptake ceases, the catalyst is removed by filtration, and the solvent is evaporated under reduced pressure, thus obtaining 20 kg (quantitative yield) of the title compound. - (4-tert-butyl-4-butoxybutyrate) amuromethylene-5-one {7} preparation (4. reaction scheme} 500 g (2.36 mol) of 1-(b-tert-fluorooxycarbonyl)-4-aminomethylpyrrolidin-3-yl) prepared in Example 1 was suspended in 5 liters of water, and the resulting suspension was cooled to ~210°C. Then, 330 g (4.72 mol) of lithium tert-butoxide was added to the mixture while maintaining the temperature at or below -10°C. Immediately, a solution of 570 g (2.6 mol) of di(tert-butyl)-dicarbonate in 500 ml of tetrahydrofuran was added to the solution at or below -10°C to complete the reaction. This solution was neutralized with 1N hydrochloric acid, and the aqueous layer was discarded. The organic layer was washed with aqueous sodium chloride solution and then distilled under reduced pressure. The residue was recrystallized from a 2:1 mixture of ethanol and water to give 50 g (90%) of the title compound. (CDCl, δ, ppm) : 10.10 (s, 1H); 7.30 (s, 1H); 4.40 times 2H); 3.95 (d, 2u) ; 1.55 (ra, 15H) MS1FAB, m / e): 313 (MeH; HPLC purity: 93.0%, Example 5 - / 3- tert - .8 ut ο xi ka rbon 11) - 4 - / tere ~bu tor fka rbon z 1 / amin oae tf 1 én pyrrolidin-3-one / 7) production 500 g (2.36 mol) of the 1-b-tert-butoxycarbonyl (11)-4-aminomethylenepyrroline-3-one prepared in Example 2 was suspended in 5 liters of tetrahydrofuran and the suspension was cooled to -20°C. At 0°C or below, a solution of 570 g of (2.6 k-ol) di(tert-butyl)-dicarbonate in 500 ml of tetrahydrofuran was added, followed by a solution of 350 g of sodium hydroxide in 700 ml of water while maintaining the temperature at 0°C or below. After the reaction was complete, the solution was neutralized with 1 N hydrochloric acid and the aqueous layer was separated. The organic layer was washed with aqueous sodium chloride solution and distilled under reduced pressure. The residue was recrystallized from a 2:1 mixture of ethanol and water to give 650 g (901) of the title compound. - (λ?··· ter c -3utoxycarbonyl-ϊ - (tere-bu t oxika rhaaá I.) aminoset i 1 en parrolidin-3-one (7) preparation 500 g (2.36 mol) of 1-(b-tert-butoxycarbonyl)-4-aminomethylenepyrrolidin-3-one prepared in Example 3 was suspended in 5 liters of isopropanol, and the suspension was cooled to -2.00°C. At a temperature of 0°C or below. A solution of 530 g (2.6 mol) of dl (tert-but 11) -dicarbonate in 500 ml of isopropanol was added. Subsequently, a solution of 330 g of sodium hydroxide in 700 ml of water was added to the mixture while maintaining the temperature at 0°C or below. After the reaction, the solution was neutralized with 1N hydrochloric acid and the aqueous layer was discarded. The organic layer was washed with aqueous sodium chloride solution and distilled under reduced pressure. The residue was recrystallized from a 2:1 mixture of ethanol and water to give 650 g (90%) of the title compound. á - (Af~tert-butyl-arb <xná 1 / -4- (terc-hntoxikarboni 1 / ámenemetil~ píirx'oládin-J-on (1) eldarálássa (5. rsíikcid'zázáatj 500 mg (1.6 mmol) of 1-(N-tert-butoxycarbonitrile)-3-one (7) prepared in Example 2 was dissolved in 10 ml of n-propanol, and 1.2 ml (4.8 mmol) of tri(n-butyl)amine and 20 mg of palladium catalyst were added to the solution, and the components were then reacted for 23 hours at room temperature under a hydrogen pressure of 101.3 kPa. The palladium catalyst was then removed by filtration, and the filtrate was washed with 30 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid and aqueous sodium chloride solution, and then distilled under reduced pressure to obtain 430 mg (quantitative yield) of the title compound. dt-NMR (CDCl 3 , δ, ppm): 495 (s, 1H); 4.05 (t, IH) ; 3.95 (s, IH) ; 3.63 (d, IH); 3.32 (m, IH); 3.34 (m, 2H> ; 2.76 (m, 1H) ; 1.44 ISBj MS(EAB): 315 (MeH) HPLC purity: 97.2%, Example 8 7. - Preparation of {li-tert-Butoxycarbonyl -4- (tszc-bvt&xíkazbottíi j aminomethylpyrrolidin-3-one (1) 500 g (1.6 mol) of 1-(tert-butoxycarbonyl)-4-tert-butoxycarbonyl) aminomethylenepyrrolidin-3-one (7) prepared in Example 2 is dissolved in 5 liters of tetrahydrofuran, and 500 ml of borate buffer solution (pH ~ 9.0+1) and then 20 g of palladium catalyst are added to the solution, and the components are reacted for 6 hours at room temperature under a hydrogen pressure of 101.3 kPa. The palladium catalyst is removed by filtration, the tetrahydrofuran is evaporated under reduced pressure, and the. The residue was dissolved in 500 ml of ethyl acetate. The resulting solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution. Then, the organic layer was evaporated under reduced pressure to obtain 500 g (quantitative yield) of the title compound. . / . 1.. reference example - a m ί ή cm e t. i 2 - 4 -metex i. i sj 1. n op irro lidin-hydzechloria f 2) preparation of 30 g (0.03 mol) of 1-(N-tert-butoxycarbonyl) ~4-(tert~butoxycarbonyl 1) aminomethylpyrroline-1-one (1) prepared in example 3 Dissolve in 150 ml of ethyl acetate. To the solution at room temperature, 3.00 g (0.11 mol) of methoxylamine are added. The resulting mixture is cooled to 0°C and a solution of 4.3 g (0.11 mol) of sodium hydroxide in 17 ml of water is added dropwise. Then, 5 ml of acetic acid are added dropwise to the mixture and the resulting solution is stirred at room temperature for about 3 hours. After the formation of phases, the aqueous layer is discarded and the organic layer is washed once with saturated aqueous sodium chloride solution and then under reduced pressure. distilled. To the remaining yellow liquid, 120 ml of methanol was added, and the solution was cooled to 0°C, and then 21.2 g (0.27 mol) of acetyl chloride was slowly added dropwise to the cooled solution. After the addition was complete, the mixture was warmed to room temperature, stirred for about 3 hours, and then filtered. The collected white crystals were washed with 40 ml of ethyl acetate, thus obtaining 15.6 g (30%; yield) of the title compound. Reference example 2 - (3 - Am in om eti 1 - 4 -mef ox 1 im 1 n cp i rro 1 Id i η -1 -17 ) -1 - ci Ad op romi 2-6fi uor-4-οχο-ΐ,, 4 -difiidre fi, ti rí dinka rbensa v (37 eibai 1. i fasa 141 mg (0.5 mmol) of 1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid and 103 mg (0.5 mmol) of O-aminomethylpyrrolidin-a-one-O-methyloxime dihydrochloride were added to 2.5 ml of sterile acetonitrile, followed by 230 mg (1.5 mmol) of 1,8-diazabicyclo[19 4* »« X [S. 4 . Ο j undec-7-ene was added dropwise. The mixture was then heated for 0.5 hours, cooled to room temperature and diluted with '1 ml of distilled water. The precipitated solid was collected and dried to give 167 mg (85%) of the title compound,

Claims

1. A process for the preparation of a compound of general formula (1), in which Px and P are protecting groups, characterized in that a) a compound of general formula (1), in which P1 is as defined for the compound of general formula (1), is reacted with a Paney-nickel catalyst in a solvent under hydrogen to prepare a compound of general formula (6), in which P'1 is as defined for the compound of general formula (1); b) the amino group is protected, thereby obtaining a compound of general formula (7; in which P1 and P4 are as defined for the compound of general formula (1); and e) the double bond is selectively reduced, thus obtaining a compound of general formula (U).

2. The process according to claim 1, characterized in that P: and are independently acetyl, tert-butoxycarbonyl or pivaloyl.

3. The process according to claim 2, wherein P: and P'· are both tert-butyl carbonyl.

4. A process according to any one of the preceding claims, characterized in that the solvent in step a) is an alcohol or an ether.

5. The process according to any one of the preceding claims, characterized in that in step a) the solvent is used in a volume ratio of 2-20 times with respect to the compound of general formula {5}, the hydrogen pressure is between ambient pressure and 50-5 kPa, and the reaction temperature is between room temperature and 60°C.

6. The process according to any one of the preceding claims, characterized in that in step aj the Raney nickel catalyst is of the W-2 type.

7. The process according to any one of the preceding claims, characterized in that in step aj, one or more additives from aqueous ammonia solution, gaseous ammonia and acetic acid are used in an amount of 2-4 molar equivalents based on the compound of general formula (5·).

8. The process according to any one of the preceding claims, characterized in that in step bj the compound of general formula <6J is reacted with di(tert-butoxydicarbonate, pivaloyl chloride or acetyl chloride.

2. The process according to any one of the preceding claims, characterized in that in step foj one or more bases selected from lithium tert-butoxide, lithium isopropoxide, potassium tert-butside, sodium tert-butoxide, lithium chloride, sodium hydroxide and potassium hydroxide are used in an amount of 2.0-4.0 molar equivalents based on the compound of general formula (6'J), one or more solvents selected from tetrahydrofuran, toluene and dioxane are used in an amount of 5-20 times the volume based on the compound of general formula (6), and the reaction temperature is ~40°C and It varies between 10cC.

10. The process according to any one of the preceding claims, characterized in that the compound of general formula {7} prepared in step b) is crystallized from a mixture of ether or alcohol in a volume ratio between 1:1 and 3:1.! tj uk, 11. The process according to any one of the preceding claims, wherein in step c, a metal catalyst selected from Raney nickel, palladium on carbon and Lindlar catalyst is used in an amount of 0.5-20% by weight based on the compounds of the general formula (?), one or more solvents selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, ethoxyl, acetone, methyl ethyl ketone, ethyl acetate and fluoroacetate are used in an amount of 5-100 times the volume, and the reaction temperature varies between 0 and 50°C.

12. The method according to any one of the preceding claims, characterized in that in step c) to adjust the pH of the reaction solution to a value between 8 and 10, one or more organic amines selected from triethylamine, tri(n-butyl)amine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 4-(4-methylpiperidin-1-1.1}pyridine, imidazole, quinoline, isoquinoline, dimethylaniline, trilatan 1 amine, quinine, and quinidine are used in an amount of 0.01-10 molar equivalents based on the compound of general formula (?), or to adjust the pH to a value between 3 and 5 or 8 and 10, one or more buffer solutions selected from phosphates, acetates, and borates are used.

13. Compounds of general formula (1) wherein P1 is a protecting group.

14. Compounds of general formula (7) in which and Pz represent a protecting group, 15. Compounds according to claim 13 or 14, wherein p1 and pα independently represent acetyl, tert-butoxycarbenyl or pivalyl groups.

18. A process for preparing a compound of general formula (2) or a salt thereof, wherein R represents a C1-4 alkyl or C1-4 haloalkyl group, characterized in that I) a compound of general formula (1) is prepared by a process according to any one of claims 1-12, 11} the compound of general formula (1) thus obtained is reacted with a compound of general formula (8), wherein R represents the same as that given for the compound of general formula (2), and the protecting group is removed from the amino group and, if desired, even formed.

17. The process according to claim 18, characterized in that the compound of general formula (2) is 3-aminomethyl-4-methoxyiminopyrrolidine hydrochloride.

18. A process for preparing a compound of formula (9) or a pharmaceutically acceptable salt thereof, wherein R is as defined in claim 16 for compound of formula (2), comprising: i) preparing a compound of formula (2) or a salt thereof by a process according to claim 18 or 17, reacting the compound of formula (2) or a salt thereof thus obtained with a compound of formula (10), wherein X is a leaving group; and optionally forming a pharmaceutically acceptable salt.

19. The process according to Claim 18, characterized in that the compound of general formula (9) (R <S}-7-(3-amlnometil~4-szin-metoxiiminopirröiidin~1 ~lí)~1 -oikloproplí~8~fbor-4-oxo-1,4-dlhldro-l ,8-naftirídln-3~karbonsav vagy gyógyászatilag elfogadható sója * Jí » X A * ·' 5Χ « 20. The subprocess according to claim 19, wherein the compound of general formula (9) is ÍR, S? -7~ (3-aminomethyl-1-sin-methoxyimitropyrro~ 1 iái η -1 ~ i 1} ~ 1 ~ cic Lop ropi 1 - 6~ f 1 uor ~ 4 ~ οxo~ 1,4 - dih ídro- í, 8 -naph t.í ri ~ din ~3-carbon s av-methanes sufοna ts ss sz kvihydrate.