MXPA00008335A - Process for preparing a protected 4-aminomethyl-pyrrolidin-3-one - Google Patents

Abstract

A process for preparing a compound of formula (1) in which P1 and P2 are protecting groups;comprising a) reaction of a compound of formula (5) wherein P1 is as defined for formula (1);with a Raney-nickel catalyst in a solvent under hydrogen to produce a compound of formula (6) wherein P1 is as defined for formula (1);b) protecting the amino group to produce a compound of formula (7) wherein P1 and P2 are as defined for formula (1);and c) selective reduction of the double bond to produce the compound of formula (1).

Description

PROCESS FOR PREPARATIONS. A 4-AMINOM? TSL-PXRROLSDIH-5-OH5. PROTECTED D? SCRS PION? THE INVENTION The present invention relates to a novel process for preparing a 4-aminomethyl-pyrrolidin-3-one, novel intermediates produced during this process, and its use in the preparation of quinolone antibiotics: compounds of the formulas (1 ): O) in which Px and P2 are protective groups qua which are useful as intermediates for preparing compounds of the formula (2). wherein R is C4-4 alkyl or haloalkyl of C? _j and salts thereof, for example, the hydrochloride salts, which in turn are useful as intermediates for preparing quinolone antibiotics, such as those described in USP5 5,633,262 and EP 688772 Al. The intermediate of the formula (2) in which R is methyl, is of particular use in the production of the compound of (R, S) -7- (3-aminomethyl-4-methoxyimino-pyrrolidine) -l-yl) -l-cyclopropyl-6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid and salts thereof, especially (R, S) -7 metaisulfonate acid - (3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid and hydrates of the including the sesquihydrate described in WO 98/42705. EP 688772A1 describes a process for the production of a compound of the formula (2) as illustrated in Scheme 1: Esquerros 1 (l) in scheme 1 Boc represents t-butoxycarbonyl, and has the same meaning throughout the present specification. There are, however, several disadvantages with the process of scheme 1, particularly if it is going to be used on a scale of tens to hundreds of kilograms for commercial production, these include: a) The process is inefficient in any way since the use of reducing agents, such as, hydrogen atmospheres under platinum, palladium metal, lithium aluminum hydride (LAH), lithium borohydride (LiBH), sodium borohydride (NaBH4), or NaBH4-trifluoroacetic acid complex, etc .; reduces both acetone and cyano groups, requiring the reoxidation of the acetone alcohol. b) Reductive agents other than NaBH4-trifluoroacetic acid complex do not completely reduce the cyano group resulting in the production of various side products and thus a reduction in yield and purity. Although the use of the NaBH-trifluoroacetic acid complex as a reducing agent can improve the yield and purity of the product, its use results in the discontinuous generation of the hydrogen gas. Therefore, the risk of explosion can not be adequately prevented by simple incinerator-exhaust equipment, and it is not easy to apply this reduction process to large-scale production. In addition, since the process for preparing the complex itself has many problems, such as formation of secondary products, etc., it is inappropriate for large-scale use. c) Secondary reactions that are not observed in small-scale production, occur more frequently in a larger scale production that leads to a reduction in yield. The unwanted by-products, some of which are not clearly identified, make separation and / or purification of the desired difficult product. The secondary products that have been identified include the compound of formulas (3) and (4): It is assumed that by-products (3) and (4) are produced by the starting reactions 4-cyano-l- (N-t-butoxy-carbonyl) pyrrolidin-3-one with sodium borohydride and trifluoroacetic acid. The by-product of formula (3) is particularly problematic when it is not easily removed by recrystallization. • d) The pyridine-sulfur trioxide complex used during the oxidation of the hydroxy group is expensive, improperly making it for use on a commercial or industrial scale. In addition, the dimethyl sulfide formed as a by-product during oxidation is not environmentally acceptable. e) When a transition metal catalyst such as platinum is used in the hydrogenation reaction, the reaction does not proceed properly using a catalytic amount of platinum and a low hydrogen pressure and thus can not be used commercially. . Thus, it is desired to find an alternative process for the production of the compounds of the formulas (1) and (2), particularly one in which an a-cyanoketone derivative can be selectively reduced in such a way that the subsequent reoxidation of the hydroxy group is not requires The present invention is based on the discovery that the cyano group of an a-cyanoketone derivative can be selectively reduced to effectively produce the compound of the formula (1) using low nickel-Raney hydrogen as a reducing agent. The reaction conditions used in this process are very mild and in this way can be used for industrial production. The use of a Raney nickel catalyst gives various advantages over the prior art process described above, for example it does not require the additional oxidation reaction, nor the formation of markedly decreasing side products, compared to the process using NaBH 4 as an agent reducer, which leads to a stoichiometric reaction and good performance. The present invention provides a process for preparing a compound of the formula (1): (Wherein P and P are protective groups, which comprise a) the reaction of a compound of the formula (5): wherein P1 is defined by formula (1); with a Raney nickel catalyst in a hydrogen under solvent to produce a compound of the formula (6): wherein P is defined by formula (1); b) protecting the amino group to produce a compound of the formula (7): wherein P1 and P2 are defined by the formula (1); and c) selecting the reduction of the double bond to produce the compound of the formula (1). The present invention also provides the novel intermediates of formulas (6) and (7). The process of the invention is summarized in Scheme 2: Scheme 2 (5) (6) (7) 0) The above process is explained more specifically in the following. In step a) - the reduction of the cyano group, the solvent is preferably an alcohol or ether, for example methanol or isopropanol, which has been found to improve the reaction rate. However, suitable solvents are not restricted to alcohols and ethers, and various inert solvents that do not adversely affect the reaction can be used to provide the hydrogen pressure that is controlled. The solvent can be used in an amount of 2 to 20 times by volume, preferably 2 to 5 times by volume with respect to the compound of the formula (5). The reaction is advantageously conducted in the presence of one or more additives selected from the group consisting of ammonia water, gaseous ammonia and acetic acid, etc. These additives can be used in an amount of 2 molar equivalents or more, preferably 2 to 4 molar equivalents, with respect to the compound of the formula (5). The use of these additives has been shown to improve the purity of the resulting compounds of the formula (6). Step a) the reaction is suitably carried out under hydrogen pressures ranging from atmospheric to about 50 atms, preferably from 4 to 10 atms, and at suitable temperatures ranging from room temperature to 60 ° C. Various types of Raney nickel can be used as the catalyst in this reduction reaction, however, Raney nickel-type W-2 or a similar type thereof is preferably used. In step b) - the protection of the amino group, any. Adequate amino protection group can be used. The protecting group is preferably removed under acidic conditions. Examples of protecting groups include formyl, acetyl, trifluoacetyl, benzoyl, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, bensilocarbonyl, para-methoxybenzyl, trifly, tetrahydropyranyl, and pivaloyl. Particular protection groups that may be mentioned include acetyl, t-butoxycarbonyl, and pivaloyl. The preferred protecting group ^ for P1 and P2 is t-butoxyarbonyl. The protection of the amino group can be achieved using conditions familiar to those skilled in the art. For example by reacting the formula (6) with a suitable base, for example selected from the group consisting of lithium t-butoxide, lithium isopropoxide, potassium t-butoxide, sodium t-butoxide, lithium chloride, sodium hydroxide and potassium hydroxide. The base is suitably used in an amount of 2.0 molar equivalents or more, preferably 2.0 to 4.0 molar equivalents with respect to the compound of the formula (6). Any solvent conventionally used in organic reactions, such as, for example, tetrahydrofuran, toluene, dioxane, dimethoxyethane, etc., may suitably be used in an amount of 5 to 20 times by volume with respect to the compound of the formula (6). If you want to carry out the reaction at temperatures ranging from -40 to 10 ° C. The reagent for introducing an amino-protecting group can be selected from the group consisting of, for example, di (t-butoxy) dicarbonate, pivaloyl chloride and acetyl chloride, preferably in an amount of 0.9 to 1.5 molar equivalents with respect to composed of the formula (6). The resulting compound of the formula (7) can be purified by recrystallization, for example, from a mixture of alcohol solvent and water ie from 1: 1 to 3: 1 by volume. In step c) - the reduction of the double bond, the selective reduction is preferably carried out using a metal catalyst, such as Raney nickel, palladium-carbon or Lindlar catalyst, for example in an amount of 0.5 to 20% by weight, preferably from 0.5 to 5% by weight, with respect to the compound of the formula, under hydrogen ie at a pressure of 1 to 3 atms. It is desired to maintain the pH of the reaction solution in 3 to 5 or 8a to 10 using an organic amine or a buffer solution in order to selectively reduce the double bond in the -4 position of the pyrrolidine ring without reducing the oxo group in the -3 position with respect to the hydroxy group. Organic amines that can be used include tertiary alkylamines such as triethylamine, tri (n-butyl) amine, diisopropylethylamine, etc.; Aromatic amines such as pyridine, 4-dimethylaminopyridine, 4- (4-methylpiperidin-1-yl) -pyridine, imidazole, quinoline, isoquinoline, etc .; anilines such as dimethylaniline, etc .; and chiral amines such as triethanolamine, quinine, quinidine, etc. The amine is suitably used in an amount of 0.01 to 10 molar equivalents, preferably 1 to 10 molar equivalents, with respect to the starting compound of the formula (7). The amines can be used alone or as mixtures in various portions. Any tertiary amine conventionally used in organic reactions can be used for the present reaction, although they are not specifically listed in the foregoing. Any solvent, preferably one or more organic solvents selected from the group consisting of alcohols such as methanol, ethanol, n-propanol, isopropanol, etc .; ethers such as tetrahydrofuran, dioxane, etc .; ketones such as acetone, methylethyl ketone, etc .; esters such as ethyl acetate, butyl acetate, etc. The auxiliary agents, including the organic amine, etc., are appropriately selected depending on the solvent used. The solvent is suitably used in an amount of 5 to 100 times by volume, preferably 5 to 20 times by volume, with respect to the compound of the formula (7).) When a buffer solution is used in place of the organic amines to adjust the pH of the reaction solution, only solvents that do not precipitate the inorganic salt suddenly during the mixing step can be used, examples of which are: tetrahydrofuran, dioxane, acetone, methanol, ethanol, etc. The most preferred is tetrahydrofuran. Solvents that are not miscible with aqueous solutions, such as ethyl acetate, diethyl ether, can also be used in this reaction. Any buffer solution that can adjust the pH of the reaction solution in 3 to 5 or 8 to 10 can be used, examples of which are phosphates, acetates, borates, etc. Most preferred are borate and acetate buffer solutions. Step c) the reaction is suitably carried out at temperatures ranging from 0 to 50 ° C, preferably from 5 to 40 ° C. The compounds of the formula (1) produced according to the process of the invention can be converted into a compound of the formula (2) or a salt thereof. Thus according to a further aspect of the invention there is provided a process for the production of a compound of the formula (2).

Where R is C? -4 alkyl or C? _ Haloalkyl, or a salt thereof; comprising the reaction of a compound of the formula (1), produced by the process of the invention as described in the following, by a compound of the formula (8). R-ONH2 (8) Where R is as defined by formula (2), preferably methyl; Followed by the deprotection of the amino groups, and, optionally, salt formation. The reaction of the compounds of the formulas (1) and (8) are preferably conducted in a solvent such as ethyl acetate or tetrahydrofuran. The deprotection reaction is preferably conducted under acidic conditions; such as acid, hydrochloric acid gas, sulfuric acid, trifluoacetic acid, etc. Suitable salts of the compounds of the formula (2) include hydrochloride salts, trifluoroacetate salts or sulfate salts. The compounds of formula (2) thus prepared according to this additional aspect of the invention are useful as intermediates for preparing quinolone antibiotics particularly those described in USP 5,633, 362 and EP 688772A1. Thus according to a further aspect of the invention there is provided a process for the production of a compound of the formula (9), or a pharmaceutically acceptable salt thereof: wherein R is as defined by formula (2), which comprises the reaction of a compound of formula (2), or a salt thereof, produced by the process of the invention as described above, by a compound of the formula (10): wherein X is a leaving group, for example, an allogen atom, preferably chlorine; and optionally forming a pharmaceutically acceptable salt. The reaction of the compounds of formulas (2) and (10) is preferably conducted in the presence of a base.

Further details regarding the reaction of the compounds of the formulas (2) and (10) can be found in US 5,633,262 and EP 688772A1. The compound of the formula (9) produced in accordance with this aspect of the invention is preferably (R, S) -7- (3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl) -l- methanesulfbonate. cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid or a hydrate thereof, preferably the sesquihydrate as described in WO 98/42705. The compounds of the formulas (6) and (7) which are intermediates in the process for preparing the compound of the formula (1) are in themselves novel. Therefore, the present invention also provides such novel intermediate compounds. All publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as being fully established. . The present invention will be explained more specifically in the following examples. However, it should be understood that the following examples are intended to illustrate the present invention, but in no way limit the scope of the present invention. Comparative Example 1: Synthesis of 4- (Nt-butoxycarbonyl) amx-no-methyl-1- (Nt-butoxycarbonyl) -pyrrolidin-3-ol 3.78 kg (0.1 Kmol) of NaBH4 and 32 kg of tetrahydrofuran in a reactor and the mixture was cooled to 10 ° C or less. 7.0 kg (0.034 Kmol) of 4-cyano-1- (N-t-butoxycarbonyl) -pyrrolidin-3-one suspended in 20 kg of tetrahydrofuran was slowly added thereto. After the addition was completed, 11.4 kg (0.1 Kmol) of trifluoroacetic acid diluted in 10 kg of tetrahydrofuran was added thereto at a temperature of 20 ° C or less during which the reaction temperature and the gas generation of Hydrogen was controlled carefully. The reaction solution was stirred for about 4 hours at room temperature, cooled to 5 ° C or less then adjusted to pH 1 to 3 by slowly adding aqueous N 3 hydrochloric acid solution with stirring. Again, the reaction solution was stirred for about 3 to 4 hours, and 7.63 kg (0.035 Kmol) of di-t-butyldicarbonate was added thereto during which the solution was monitored at pH 9 to 10 using 25% of a solution of hydroxide. of aqueous sodium. After the reaction was complete, tetrahydrofuran was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate and then dried under reduced pressure while the solvent was removed. The residue obtained in this way was crystallized from 7"1" methylethylacetone and 21"I" n-hexane and filtered to give 4.74 kg (45% Yield) of the title compound. Comparative Example 2: Synthesis of 4- (N-t-butoxycarbanyl) amy-methyl-1- (N-t-butoxycarbanyl) -pyrrolidin-3-ol 160 kg (4.23 Kmol) of NaBH 4 were introduced. and 1,000 1 tetrahydrofuran in a reactor and the mixture was cooled to 10 ° C or less. 295 kg (1.4 Kmol) of 4-cyano-1- (N-t-butoxycarbonyl) -pyrrolidin-3-one suspended in 1000 1 of tetrahydrofuran was slowly added thereto. After the addition was complete, 479 kg (4.2 Kmol) of trifluoacetic acid diluted in 800 1 of tetrahydrofuran was added thereto at a temperature of 20 ° C or less during which the reaction temperature and generation of hydrogen gas It was carefully controlled. The reaction solution was stirred for about 4 hours at room temperature, cooled to 5 ° C or less then adjusted to pH 1 to 3 by slowly adding aqueous N 3 hydrochloric acid solution with stirring. Again, the reaction solution was stirred for about 3 to 4 hours, and 321 kg (1.47 Kmol) of di-t-butyldicarbonate was added thereto during which the solution was monitored at pH 9 to 10 using 25% of a aqueous sodium hydroxide solution. After the reaction was complete, tetrahydrofuran was removed by distillation under reduced pressure. The residue was extracted with ethyl acetate and then dried under reduced pressure while the solvent was removed. The residue obtained in this way was crystallized from 300"2" methylethylacetone and 900"1" n-hexane and filtered to give 131 kg (30% Yield) of the title compound. Example 1: Synthesis of 1- (N-t-butoxycarbanyl) -4-aminomethylene-pyrrolidin-3-on (6) kg (95 moles) of 1- (N-t-butoxycarbonyl) -4-cyano-pyrrolidin-3-one were suspended in 150 ml of methanol and then completely dissolved by adding about 30 1 of ammonia water. 100 g of Raney nickel of the W-2 type was added to the above solution, and the mixture was reacted at room temperature under 4 atms of hydrogen pressure. The reaction was completed when the hydrogen uptake stopped. The catalyst was removed by filtration and the solvent was distilled under reduced pressure to give 20 kg of the title compound (quantitative yield). 'H-NMR (CDC13, d, ppm): 4.95 (m, 0.7H), 4.70 (m, 0.3H), 4. 25 (d, 2H), 3.90 (m, 2H), 1.50 (m, 9H) MS (FAB, m / e): 213 (M + H) GC purity (FID): 99.8% Example 2: Synthesis of 1- (Nt-butoxycarbonyl) -4-aminomethylene-pyrrolidin-3-on (6) 20 kg (95 moles) of 1- (Nt-butoxycarbanyl) -4-cyano-pyrrolidin-3-one were suspended in 150 1 of tetrahydrofuran. 100 g of Raney nickel of the W-2 type was added to the above solution, and the mixture was reacted at room temperature under 4 atms of hydrogen pressure. The reaction was completed when the hydrogen uptake ceased. The catalyst was removed by filtration and the solvent was distilled under reduced pressure to give 20 kg of the title compound (quantitative yield). Example 3: Synthesis of 1- (Nt-butoxisarbonyl) -4-aminomethylene-pyrrolidin-3-one (6) 20 kg (95 mol) of 1- (Nt-butoxycarbanyl) -4-cyano-pyrrolidin-3 were suspended ona in 150 1 of isopropanol. 100 g of Raney nickel of the W-2 type was added to the above solution, and the mixture was reacted at room temperature under 4 atms of hydrogen pressure. The reaction was completed when the hydrogen uptake ceased. The catalyst was removed by filtration and the solvent was distilled under reduced pressure to give 20 kg of the title compound (quantitative yield). Example 4: Synthesis of 1- (N-t-butoxycarbonyl) -4- (t-b-oxycarbonyl) aminomethylene-pyrrolidin-3-one (7) 500 g (2.36 moles) of 1- (N-t-butoxycarbonyl) -4-aminomethylene-pyrrolidin-3-one prepared in Example 1 were suspended in 5 l of toluene and the resulting suspension was cooled to -20 ° C. 380 g (4.72 moles) of lithium t-butoxide was added thereto while the temperature was maintained at -10 ° C or less. 570 g (2.6 moles) of di-t-butyldicarbonate dissolved in 500 ml of tetrahydrofuran was added to the above solution at -10 ° C or less to complete the reaction. The solution was neutralized by IN hydrochloric acid solution 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 solvent mixture of ethanol and water (2/1, v / v) to give 650 g (90% yield) of the title compound. 'H-NMR (CDC13, d, ppm): 10.10 (s, 1H), 7.30 (s, 1H), 4.40 (d, 2H), 3.95 (d, 2H), 1.55 (m, 18H) MS (FAB, m / e): 313 (M + H) purity HPLC: 98% Example 5: Synthesis of 1- (Nt-butoxycarbonyl) -4- (t-butoxycarbonyl) aminomethylene-pyrrolidin-3-on (7) 500 g (2.36 g. moles) of 1- (Nt-butoxycarbonyl) -4-aminomethylene-pyrrolidin-3-one prepared in Example 2 in 51 of tetrahydrofuran and the resulting suspension was cooled to -20 ° C. 570 g (2.6 moles) of di-t-butyldicarbonate dissolved in 500 ml of tetrahydrofuran was added to the above solution at 0 ° C or less. 380 g of sodium hydroxide in water (700 ml) was added thereto while the temperature was maintained at 0 ° C or less to complete the reaction. This solution was neutralized by 1 N hydrochloric acid solution 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 solvent mixture of ethanol and water (2/1, v / v) to give 650 g (90% yield) of the title compound. Example 6: Synthesis of 1- (N-t-butoxycarbonyl) -4- (t-butoxycarbonyl) aminomethylene-pyrrolidin-3-one (7) 500 g (2.36 moles) of 1- (N-t-butoxycarbonyl) were suspended 4-aminomethylene pyrrolidin-3-one prepared in Example 2 in 51 of tetrahydrofuran and the resulting suspension was cooled to -20 ° C. 570 g (2.6 moles) of di-t-butyldicarbonate dissolved in 500 ml of isopropanol was added to the above solution at 0 ° C or less. 380 g of sodium hydroxide in water (700 ml) was added thereto while the temperature was maintained at 0 ° C or less to complete the reaction. This solution was neutralized by IN hydrochloric acid solution 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 solvent mixture of ethanol and water (2/1, v / v) to give 650 g (90% yield) of the title compound. Example 7: Synthesis of 1- (N-t-butoxycarbonyl) -4- (t-butoxycarbonyl) aminomethylpyrrolidin-3-one (1) 500 g (1.6 mmmoless) of 1- (Nt-butoxycarbonyl) -4- (t-butoxycarbonyl) aminomethylene pyrrolidin-3-one (7) prepared in Example 2 was dissolved in 10 ml of n-propanol, and 1.2 ml was added (4.8 mmoles) of tri-n-butylamine thereto. 20 mg of palladium catalyst was added to the above solution and then the mixture was reacted for 24 hours at room temperature under 1 atm of hydrogen pressure. The palladium catalyst was removed by filtration, and the filtrate was diluted with 30 ml of ethyl acetate. The resulting solution was washed with IN hydrochloric acid solution, and washed again with an aqueous solution of sodium chloride, and then, distilled under reduced pressure to give 480 mg of the title compound quantitatively.

'H-NMR (CDC13, d, ppm): 4.95 (s, 1H), 4, 05 (t, 1H), 3.95 (s, 1H) 3.63 (d, 1H), 3.32 (m, 1H), 3.34 ( m, 2H), 2.76 (m, 1H), 1.44 (, 18H) MS (FAB): 315 (M + H) purity HPLC: 97.2% Example 8: Synthesis of 1- (Nt-butoxycarbonyl) -4- (t -butoxycarbonyl) amino ethyl pyrrolidin-3-one (1) 500 g (1.6 moles) of 1- (Nt-butoxycarbonyl) -4- (t-butoxycarbonyl) aminomethylene-pyrrolidin-3-one (7) prepared in Example 2 were dissolved in 5 1 of tetrahydrofuran, and 500 ml of the borate buffer solution (pH = 9.0 ± 1) to it. 20 g of palladium catalyst was added to the above solution and then the mixture was reacted for 6 hours at room temperature under 1 atm of hydrogen pressure. The palladium catalyst was removed by filtration, it was distilled. tetrahydrpurane under reduced pressure, the residue was diluted with 500 ml of ethyl acetate. The resulting solution was washed sequentially with IN hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, and aqueous sodium chloride solution. Then, the organic layer was distilled under reduced pressure to give 500 g of the title compound quantitatively. Reference example 1: Synthesis of 3-aminomethyl-4-methyxyiminopyrrolidine hydrochloride (2) 2HC g (0.09 mol) of 1- (N-t-butoxycarbonyl) -4- (t-butoxycarbonyl) aminomethylene-pyrrolidin-3-one (l) prepared in Example 3 were dissolved in 150 ml of ethyl acetate. 9.06 g (0.11 mol) of methoxylamine were added thereto at room temperature and the resulting solution was cooled to 0 ° C, to which 4.3 g (0.11 mol) of sodium hydroxide dissolved in 17 ml of water was added dropwise. been cold. 5 ml of acetic acid was added thereto and the resulting solution was stirred for about 3 hours at room temperature. After the formation of the layer, the aqueous layer was discarded, and the organic layer was washed once with a saturated saline solution and then distilled under reduced pressure to give a yellow liquid. 120 ml of methanol was added to the liquid and the resulting solution was cooled to 0 ° C. 21.2 g (0.27 mol) of acetyl chloride was slowly added dropwise to the cooled solution, which was then warmed to room temperature, stirred for about 3 hours and filtered. The white crystal obtained in this way was washed with 40 ml of ethyl acetate to give 15.6 g (80% yield) of the title compound. Reference Example 2: Synthesis of 7- (3-aminomethyl-4-methoxyiminopyrrolidin-1-yl) -l-cyclopropyl-6-fluoro-4-oxo-l, 4-dihydro [1, 8] -naphthyridine-carboxylic acid (9) 141 mg (0.5 mmol) of 1-cyclopropy1-7-chloro-6-fluoro-4-oxo-l, 4-dihydro [1,8] naphthyridine-3-carboxylic acid and 108 mg (0.5 mg) were added. mmol) of 3-aminomethylpyrrolidin-4-one di-hydrochloride O-methyloxime to 2.5 ml of dry acetonitrile. Then 230 mg (1.5 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ena was slowly added dropwise thereto and the mixture was heated for 5.0 hours and then cooled to room temperature. Be added 1 ml of distilled water to the reaction solution. The solid precipitate was separated and dried to obtain 167 mg (Yield: 85%) of the title compound.

Claims (20)

1. KESVSNDSCACSONS A process for preparing a compound of the formula (I ' wherein P1 and P2 are protective groups; characterized in that it comprises. a) is the reaction of the compound of a formula (V): (5) wherein P1 is as defined for formula (I); with a Raney nickel catalyst in a solvent under hydrogen to produce a compound of the formula (VI): wherein P1 is as defined for formula (I); b) protection of the amino group to produce a compound of the formula (VII): where P1 and P2 are as defined for the formula (i); and c) the selective reduction of the double bond to produce the compound of the formula (I).
2. 2. The process in accordance with the claim 1, characterized in that P and P2 are independently selected from acetyl, t-butoxycarbonyl and pivaloyl.
3. 3. The process in accordance with the claim 2, characterized in that P1 and P2 are both t-butoxycarbonyl. .
4. The process according to any of the preceding claims, characterized in that the solvent in step a) is an alcohol or an ether.
5. 5. The process according to any of the preceding claims, characterized in that in step a) the solvent is used in an amount of 2 to 20 times by volume with respect to the compound of the formula (V), the hydrogen pressure is from atmospheric pressure at 50 atms, and the reaction temperature is from room temperature to 60 ° C.
6. 6. The process according to any of the preceding claims, characterized in that the nickel-Raney catalyst in step a ) is of type W-2
7. 7. The process according to any of the preceding claims, characterized in that one or more additives selected from the group consisting of ammonia water, gaseous ammonia and acetic acid is used in an amount of 2 to 4 molar equivalents with respect to the compound of the formula (V) in step a)
8. 8. The process according to any of the preceding claims, characterized in that the compound of to formula (VI) is reacted with di (t-butoxy) dicarbonate, pivaloyl chloride or acetyl chloride in step b).
9. 9. The process according to any of the preceding claims, characterized in that one or more bases selected from the group consisting of lithium t-butoxide, lithium isopropoxide, potassium t-butoxide, sodium t-butoxide, lithium chloride , sodium hydroxide and potassium hydroxide are used in an amount of 2.0 to 4.0 molar equivalents with respect to the compound of the formula (VI), one or more solvents selected from the group consisting of tetrahydrofuran, toluene and dioxane, are used in a amount from 5 to 20 times in volume with respect to the compound of the formula (VI), and the temperature ranges from -40 ° C to 10 ° C in step b).
10. The process according to any of the preceding claims, characterized in that the compound of the formula (VII) prepared in step b), is recrystallized from a mixture of ether or alcohol solvent and water in a volume ratio of 1. : 1 to 3: 1 before use in stage c).
11. 11. The process according to any of the preceding claims, characterized in that one or more metal catalysts selected from the group consisting of Raney nickel, palladium carbon and Lindlar catalyst, are used in an amount of 0.5% to 20% by weight with respect to the compound of the formula (VII), one or more solvents selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate and butyl acetate , they are used in an amount of 5 to 100 times in volume with respect to the compound of the formula (VII), and the reaction temperature varies from 0 to 50 ° C in step c).
12. 12. The process according to any of the preceding claims, characterized in that in step c) the pH of the reaction solution is adjusted from 8 to 10 using one or more organic amines selected from the group consisting of triethylamine, tri (n-butyl) amine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine , 4- (4-methyl-piperidin-1-yl) -pyridine, imidazole, quinoline, isoquinoline, dimethylaniline, triethanolamine, quinine and quinidine in an amount of 0.01 to 10 molar equivalents with respect to the compound of the formula (VII) or in 3 to 5 or 8 to 10 using one or more buffer solutions selected from the group consisting of phosphates, acetates and borates.
13. 13. A compound of the formula (VI): (6) characterized in that P1 represents a protective group.
14. 14. A compound of the formula (VII) characterized in that P1 and P2 represent protecting groups.
15. 15. The compound according to claim 13 or 14, characterized in that P1 and P2 independently represent acetyl, t-butoxycarbonyl or pivaloyl.
16. 16. A process for the production of a compound of the formula (II): characterized in that R is C? _4 alkyl or C? - haloalkyl or a salt thereof; comprising the reaction of a compound of the formula (I), produced by the process of the invention as described in the following, by a compound of the formula (VIII). R-ONH2 (8) wherein R is as defined by formula (II), preferably methyl; followed by deprotection of amino groups, and, optionally, salt formation.
17. 17. The process according to claim 16, characterized in that the compound of the formula (II) 3-aminomethyl-4-methoxyiminopyrrolidine hydrochloride.
18. 18. A process for the production of a compound the formula (IX) or a pharmaceutically acceptable salt thereof: (9) wherein R is as defined for the formula (II) according to claim 16, characterized in that it comprises the reaction of a compound of the formula (II), a salt thereof, produced according to the process d Claim 16 or 17, with a compound of the formula (X): wherein X is a leaving group and optionally forms a pharmaceutically acceptable salt.
19. The process according to claim 18, characterized in that the compound of the formula (IX) is (R, S) -7- (3-aminomethyl-4-sy-methoxyimino-pyrrolidin-1-yl) - l-cyclopropyl-6-fluoro-4-oxo-l, 4-dihydro-l, 8-naphthyridine-3-carboxylic acid or a pharmaceutically acceptable salt thereof.
20. 20. The process in accordance with the claim 19, characterized in that the compound of the formula (IX) is (R, S) -7- (3-aminomethyl-4-sy.n-methoxyimino-pyrrolidin-1-yl) -l-cyclopropyl-6- (3-aminomethyl-4-sy.-n-methoxyimino-pyrrolidin-1-yl) -methansulphonate. fluoro-4-oxo-1,4-dihydro-l, 8-naphthyridine-3-carboxylic acid.