SK92396A3 - Process for the preparation of naphtyridinecarboxylic acids and their salts - Google Patents

Abstract

The present invention relates to a process for obtaining naphthyridines of general formula (

Description

While the tosufloxacin compound is generically claimed in EP 153580, D.V.Ch. Cftbbott Lab.), The preparation of this compound is specifically described in GB 2158825, H. Narita et al. CToyama Chemical Co.) and the corresponding Spanish patents ES 542584 and ES 551538.

In addition, the preparation of trovafloxacin is described in U.S. Patent No. 5,164,402 to K. E. Brighty (Pfizer Inc.).

The present invention describes a new and improved process for the preparation of the aforementioned compounds tosufloxacin and trovafoxoxin.

Methods of fluoroquinones such as ofloxacin, tin have been described in the literature (Spanish Patent Nos. 5,160,60, 2006882 and

2006994), the reaction between certain boron chelates derived from the corresponding 4-oxo-3-quinolinecarboxylic amines.

SUMMARY OF THE INVENTION Formula (I) and their invention include a (2,4-difluorophenyl) carboxylate of the formula

Process for the preparation of 6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-riaphthyridine-3-carboxylic acid general salt which is the object of the present invention. C 1 -C 7 -alkyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 2 with boric acid in the presence of acetic anhydride and catalytic amounts of zinc salt to give [7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylato-0 ³ 0, ^4- bis-aceto-0-boron of formula 3, followed by treatment of the product with CRS) -3-acetylaminopyrrolidine or alternatively with (1α, 5α, 6α) -6-tert-butoxycarbonylamino-3-azabicyclo-3.1.0 hexane or an acid addition salt of these compounds, optionally in the presence of an acid scavenger base, to yield the intermediate of formula 4 wherein R is 3-acetyl-amino-1-pyrrolidinyl or (1α, 5α, 6α) -6-tert-butoxycarbonylamino -3 azabicyclo [3.1.0] hex-3-yl, and final h by hydrolysis to obtain the desired products of formula (1) which are isolated from the reaction medium by conventional methods.

The chemical reaction taking place in the process can be illustrated as follows:

r ¹ = C 1 -C 6 alkyl

F

This process is novel and has not been previously described for the preparation of 1,8-naphthyridines substituted in the 1-position with 2,4-difluorophenyl and in the 7-position with (RS) -3-amino-1-pyrrolidine-type 1 or ( Ia.

5a, 6a) -6-amino-3-azabicyclo [3.1.0] -hex-3-yl In addition, this method allows the desired compounds of formula (1) to be obtained efficiently, in high yield and purity in a manner that is easy to carry out.

The preparation of the starting compound C 1 -C 8 alkyl-7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-1,8-naphthyridine-3-carboxylate of formula 2 has been described in Spanish patents No. 542584 and no. 557,077th

The process according to the invention is preferably carried out with isolation, in particular between the product [7-chloro-6-fluoro-1-C2,4-difluorophenyl] -1,4-dihydro-4-oxo-1,8-naphthylcarbonyl n-3 - car boxes 1 t. oO ^3, O ^4] Bis (acetato-yne of formula Oibór third This product is reacted with (R) -3-acety1am s nopyrro1 s nominal ID, and because of its acid addition salt, optionally in the presence of a base, with a yield of the product L CRS) -7- (3-Acetylamino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl-1,5-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate-O) ³ , O ⁴ ] bis Cacetato-O) boronine of formula 4a, which hydrolysis affords the desired product tosufloxacin or (RS) -7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4- difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid of the formula Ia, which can optionally be converted into an acid addition salt.

When the compound of formula 3 is reacted with (1α, 5α, aa) -G-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane or an acid addition salt thereof, optionally in the presence of a base, the product [7-C ( 1α, 5α, 6α) -6-tert-butoxycarbonylamino-3-azabicyclo-3-O-hexyl-3-yl) -6-fluoro-1- (2,4-difluorophenyl) - 1,4-dihydro-4-oxo-l, ^{8-naphthyridine-3-carboxylato-3} 0, θ ^'4] bis (acetáto0) Boriny of formula 4b, which by hydrolysis gives the desired product trovafloxacin, or 7 - ((Ia, 5a, OA) 6-amino-3-azabicyclo [3.1.0] hex-3-y1> 6-f1uór-1-C2,4-dif1uórfeny1) -l, 4-dihydro-4-oxo-8-naftyr.idín -3-carboxylic acid of formula 1b, which may be. optionally converted to the desired acid addition salt.

Preferably the process is carried out such that the boron derivative [7-chloro-6-fluoro-l-C2,4-difluorophenyl) -l, 4-dihydro-4-oxo-8naftyridín-3-carboxylato-O ^3, Cl ⁴ 1 converts the bis (acetate o-O) boron in formula 3 to the desired products of formula 1 without prior isolation between the products of formula 4.

Boron derivative [7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylate-O ³ O ^-4] bisCacetáto0) bó.rin of formula 3 and RS) -3-acetyl-1-pyrrolidin nopyr.ro llama or

The [alpha], 5a, 6a) -6-tert-butoxycarbonyl amino-3-azabicyclo [3.1.0] hexane or acid addition salts of these compounds may react if they are heated together for an average time in the presence of a suitable inert organic solvent and optionally in the presence an acid scavenger base.

As organic solvents which are inert to the reaction medium, N-methyl-2-pyrrolidone, dimethylacetamide, dimethylformamide, dimethylsulfoxide, sulfolane or pyridine can be advantageously used.

Salts of CRS) -3-acetylaminopyrrolidine or (1α, 5α, 6α) 6-tert-butoxycarbonylamino-3-azabicyclo [3.1.1] hexane include salts with hydrohalic acids such as dihydrochloride or dihydrobromide.

Zinc salts include zinc chloride and zinc acetate.

Acid-absorbing compounds include either an excess of (RS) -3-acetylaminopyrrolidine alone or Cla, 5 (6,6,6) -6-tert-butoxycarbonyl-amino-3-azabicyclo [3. 1.0] hexane and, alternatively, an organic or inorganic base, for example, more or less sterically protected tertiary amines Ctriethylamine, tributylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN),

1,4-diazabicyclo [2.2.2] octane (CTDE), 1,8-diazabicyclo [5.4.0] undec-7-ene CDBU) or carbonates or hydrogen carbonates of alkaline earth metals or alkali metals.

The temperature of the reaction between the [7-chloro-6-fluoro-1- (2,4-dif1uórfenyl) -l, 4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylato-O ^3, O ^4] bisCacetáto- O) boron of formula 3 and CRS) -3-acetylaminopyrrolidine or Cl 2, 5a, 6 '- 6-tert-butoxycarbonylamino-3-azabicyclo [3.1.0] hexane or acid addition salts of these compounds may be varied between 20 ° C and 200 ° C, depending on the solvent used and the like, the reaction time may vary, from 30 minutes to 24 hours depending on the reaction temperature and dissolution employed. ad 1 a.

Process for the conversion of boron derivatives [CRS] -7-C3-acetylamino-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1 8-naphthyridine-3-carboxylate-0, ³ , ⁴ ] bisacetate-O) boron of formula 4a to (RS) -7-C3-amino-1-pyrrolidinyl) -6-fluoro-1- (2) 1,4-Fluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid of formula Ia or alternatively [7 - ((1α, 5cr, 6 <z) -6-tert-butoxycarbonylamino-3-azabicyclo) [3.1.0] hex-3-y11-6fluór-1-C2,4-difluoro 1uórfeny1) -1,4-dihydro-4-oxo-l, 8-naphthyridin-IN3 lát.o carboxy-0 ^3, O ⁴ ] bis (acetato-O) boron of formula 4b to 7 - <(1ct, 6a, 6a) -6-amino-3-azabicyclo [3.1.0] hex-3-yl} -6-fluoro-1 - (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridin-3-carboxylic acid of formula 1b is preferably carried out by acid hydrolysis or basic conditions.

The basic hydrolysis may preferably be carried out by heating in the presence of an aqueous solution of an alkali metal or alkaline earth metal carbonate or hydroxide.

Conversely, the acid hydrolysis is carried out using an aqueous solution of an inorganic acid such as hydrochloric, sulfuric or phosphoric acid.

Advantageously, the hydrolysis step may be carried out in an aqueous medium in the presence of a water-miscible organic solvent. The degree of alkaline or acid hydrolysis can thus be carried out with mixtures of water and N-methyl-2-pyrrolidine, dimethylacetamide. dimethylformamide, dimethylsulfoxide, or sulfonate.

When the hydrolysis reaction is complete, the desired product of formula 1 is isolated using conventional means and recrystallized from an organic solvent or a mixture of such solvents.

If desired, they may be. (RS) -7- (3-Amino-1-pyrrolidinyl) -6-fluoro-1-C2,4-difluorophenyl) -1,4-dihydro-4-oxo-

1,8-naphthyrid-3-carboxylic acid of the formula Ia and 7 - <(1a, 5 <x, d a) -6-amino-3-azabicyclo [3.1.0] hex- 3-yl-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid of formula 1b converted into the addition salts with organic or inorganic acids according to standard treatment of the free base with a stoichiometric amount of the corresponding acid in a suitable solvent. and d 1 e.

In the following, examples of manufacture according to the present description are given for illustrative purposes and without limitation.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 [7-ch1ór-6-f1uór-1- (2,4-difluoro 1uórfeny1) -1,4-dihydro-4-oxo-8naftyridín-3-carboxylato-O ^3, O ^4] bis ( acetic acid-O) borin (Formula 3) g (1.5 mol) boric acid is added portionwise to a mixture of 480 g (440 ml, 4.7 ml) acetic anhydride and 1.4 g <0.01 mol) anhydrous zinc chloride. The reaction mixture is heated to 110 ° C and cooled, and then 261 g (0.72 mol) of methyl 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4 is added with stirring. dihydro-4-oxo-

The reaction mixture is maintained at 105 ° C for 2 hours and allowed to cool to room temperature. The precipitated solids are filtered off, washed with cold water. The dry product decomposes at 248-249 ° C.

E 1 em entary 11 and analysis for C 19 H 18 E 1 C ₃ F ₃ Ον N2 ^: calculated

5.81% N found

47.37% C,

2.25% H,

5.80% N.

Example 2

Hydrochloride acid salt

(RS) -7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyr id í n

3-carboxylic acid (formula Ia)

The mixture, the content jucat [7-chloro-6-f1uór-1- (2,4-difluórfenyΟΙ, 4-dihydro-4-oxo-1,8-naphthyridine-3-tyridíη of carboxylate 0 ^3, O ⁴ Ibis (acetato -O) boron of formula 3 (48.3 g, 0.1 mol) and (RS) -3-acetyl-1-aminopyrrolidine (15.4 g, 0.12 mol) in 300 ml of anhydrous N-methyl- Of 2-pyrrolidone was treated with 1,8-diazabicyclo [5.4.01 undec-7-ene (36.4 g, 0.24 mol). The mixture was heated at 85 ° C for 4 hours and cooled to 10 ° C. The precipitated solids are filtered off and suspended in concentrated hydrochloric acid. The suspension is heated under reflux for 2 hours, cooled and neutralized. The solids thus obtained are filtered off, washed with water and dried. They are then dissolved in concentrated hydrochloric acid and precipitation is induced by the addition of ethyl alcohol. The obtained crystals were filtered off, washed with ethyl alcohol and dried to give 37.5 g (<85% yield) of (RS) -7 (3-amino-1-pyrrolidinyl) -6-fluoro-1- <2-hydrochloride salt. (4-Difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, m.p. 247-250 ° C.

Example 3

7 - (1α, 5a, 6a) -6-Amino-3-azabicyclo [3.1.1] hex-3-yl-6-fluoro-1-C2,4-difluorophenyl) -1,4-dihydro-4 hydrochloride salt -oxo-1,8-naphthyridene-3-carboxylate (Formula 1b)

Mixture containing [7-chloro-6-fluoro-1- (2,4-difluorophenyl) -

1,4-dihydro-4-oxo-1,8-naphthyridine-3-pyridine of carboxylate 0 ^3, O ^4] bisCacetáto-CDbórin of formula 3 (48.3 g, 0.1 mol) and (?, 5?, 6? 1-tert-butoxycarbonyl-amine-3-azabicyclo [13.1.01] hexane (23.7 g, 0.12 mol) in 300 ml of anhydrous N-methyl-2-pyrrolidone is treated with 1,8-diazybicyclo [5.4.01. -7-ene (36.4 g, 0.24 mol). The mixture was heated at 85 ° C for 4 hours and cooled to 10 ° C. The precipitated solid is filtered off and suspended in concentrated hydrochloric acid. The suspension was heated to reflux for 24 hours, cooled and neutralized. The solid thus obtained was filtered off, washed with water and dried. It is then dissolved in concentrated hydrochloric acid and precipitation is induced by the addition of ethyl alcohol. The obtained crystals were filtered, washed with ethyl alcohol and dried to give 37 g (82% yield) of the title compound, mp 244-246 ° C.

Claims (7)

A process for the preparation of naphthyridines of the general formula 1 wherein: R is 3-amino-1-pyrrolidinyl or (1α, 5α, 6α) -6-amino-3-azabicyclo [3.1.0] -hex-3-yl and their corresponding hydrates or salts, characterized in that: 1 to 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8- naphthyridine-3-carboxylate of formula 2 with boric acid in the presence of acetic anhydride and catalytic amounts of zinc to give [7-chloro-6-fluoro-1- (2,4-difluorophenyl) - 1,4-dihydro-4-oxo-l, 8-naphthyridine-3-tyr.idín of carboxylate O ^3, O ^4] bisíace the O) -bórinu of formula 3, the product is treated with (R) -3-acetyl ylaminopyrrolidine or alternatively with (1α, 5α, 6α) -6-tert-butoxycarbonylamino-3-azabicyclo [3.1.1] hexane or acid addition salts of these compounds, optionally in the presence of a base, to yield intermediate [6-fluoro-1] - (2,4-difluorophenyl) - 1,4-dihydro-4-oxo-l, 8-naphthyridine-3-carboxylic lát.o-0 ^3, O ^4] bis (acetato-O) boron of formula 4 and a final hydrolysis of the desired products of Formula 1, which are isolated from the reaction medium by conventional methods. The process according to claim 1, wherein R is 3-amino-1-pyrrolidinyl, characterized in that C 1 -C 7 -alkyl-7-chloro-6-fluoro-1-C2 is reacted, 4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate of formula 2 with boric acid in the presence of acetic anhydride and catalytic amounts of zinc to give [7-chloro-6-fluoro-1- (2,4-dif1uórfeny1) - 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (C, ³ , ⁴ ) bis (acetato-O) -borin of formula 3, followed by treatment of the product with (RS) -3-acetyl -amino-pyrrolidine or with an acid addition salt of these compounds, optionally in the presence of an acid-scavenging base, yielding between products Γ. CRS) -7-C3-acetylamino-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine 3-carboxylato-0, ³ , ⁴ ] bis (acetato-O) borin of formula 4a and final hydrolysis is performed to obtain the desired product of formula Ia, which is isolated from the reaction medium by conventional methods. The method of claim 1, wherein 3-Azabicyclo [3-1-O] -hex-3-yl, which is reacted C1-7-Chloro-7-chloro-6-fluoro-C2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8 naphthyridine-3-carboxylate of formula 2 with boric acid in the presence of acetan-6-fluoro-1- (2,4-difluorophenyl) -1,4-chloro-4-oxo-1 Of 8-naphthyridine-3-carboxylate-0, ³ , ⁴ ] bis (acetato-O) -borin of formula 3, with the following treatment of the product with (1α, 5α, 6α) -6-tert. butoxycarbonyl amine-3-azabicyclo [3.1.1] hexane or an acid addition salt of this compound, optionally in the presence of a base, yielding the intermediate product [7- (Cla, 5a, 6a) -6-tert. butoxycarbonylamino-3-azabicyclo [3.1.0] hex-3-yl) -6-fluoro-1-C2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine 3-carboxylate o-O, ³ , ⁴ ] bis (aceto-O) boron of formula 4b and final hydrolysis to give the desired product of formula 1b, which is isolated from the reaction medium by conventional methods. The process according to claim 1, wherein the reaction is between [7-chloro-G-fluoro-1- (2,4-difluoro-phenyl) -1,4-dihydro-4-oxo-1. 3-naphthyridine-3-carboxylate-0, ³ , ⁴ ] bis-aceto-CDborin of formula 3 and CRS) -3-acetylaminopyrrolidine or (1α, 5α, 6α) -6-tert-butoxycarbonylamino-3-azabicyclot 3. 1.0] with hexane or an acid addition salt of these compounds in an organic solvent inert to the reaction medium such as N-methyl-2-pyrrolidone, dimethyl acetamide, dimethylformamide, dimethylsulfoxide, sulfolane or pyridine. The process according to claim 1, wherein an acid-absorbing base selected from three ethylamine, three butylamine, pyridine, 1,5-di azabicyclo [4.3.0] non- 5-ene (DEM), 1,4-diazabicyclo [2.2.21 octane CTDE], 1,8-diazabicyclo [5.4.0] undecen-7-ene (CDBU) and alkaline earth metal or alkali metal carbonates or bicarbonates. 6. The method of claim 1, comprising carrying out the hydrolysis in an acidic medium. 7. The method of claim 1, wherein the hydrolysis is performed in a basic medium.