MXPA99004020A - Method or producing naphthyridine compounds and novel intermediate products - Google Patents

Abstract

An advantageous method of producing naphthyridine compounds of formulae (Ia) to (1c) wherein R means hydrogen or C1-C4 alkyl, Ar means possibly substituted phenyl, Hal means independently fluorine, chlorine or bromine, and n stands for 1, 2 or 3, whereby a halogenated nicotinic, isonicotinic or picolinic acid is made to react with an amino acrylic acid ester to obtain a halogenated 2-nicotinoyl-, isonicotinoyl- or picolinoyl-3-aminoacrylate which is made to react with an optionally substituted aniline to obtain a halogenated 2-nicotinoyl-, isonicotinoyl- or picolinoyl-3-aminoacrylate which contains an amino group corresponding to the optionally substituted aniline. The second halogenated 2-nicotinoyl-, isonicotinoyl- or picolinoyl-3-aminoacrylate is cyclized by adding an acid scavenger to a compound of formulae (Ia) to (Ic) with R=C1-C4 alkyl and, in the case of production of a compound of formulae (Ia) to (Ic) with R=H, the compound of the formulae (Ia) to (Ic) with R=C1-C4 alkyl is saponified.

Description

PROCEDURE FOR T.A. OBTAINING COMPOUNDS FROM NAFTIRIDINA AND NEW INTERMEDIATE PRODUCTS.

DESCRIPTION OF THE INVENTION The present invention relates in the first place to an advantageous process for the preparation of naphthyridine compounds characterized below by means of the formulas (a) to (le) and to new intermediates, which are key compounds for this process. The naphyridine compounds of the formulas (a) to (le) are valuable intermediate products for the preparation of active products, especially highly active bactericides (see, for example, US-PS 5 164 402, US-PS 5 298 629 and EP -OS 413 455). It is known to obtain the naphthyridine derivatives of the formula (Ia) by the reaction of halogenated nicotiyl chloride with a malonic ester, followed by a decarboxylation of both carboxylate groups, and then transformation of the methylene group, which lies between both carbonyl groups, by means of an ortho-ester, in a group : C = CH-OR- reaction of the alcoxx group introduced in this way, with REF: 29999 an optionally substituted aniline, so that a halogenated acrylate of nicotinoylphenylamino is obtained and from this it is carried, by means of closing the saponified ring if necessary, still composed of naphtha iridine of the formula (la) (see, for example, DE-OS 35 14 076 and EP-OS 132 845, 153 580, 160 758, 191 451, 302 372 and 449 445). The drawback in this procedure is the large number of stages and the low total yield, which is less than 40% of the theory. A process for obtaining naphthyridine compounds of the formulas (la) up to (le) has now been found (the) (Ib) in which R is hydrogen or alkyl having 1 to 4 carbon atoms, Ar is phenyl, optionally substituted, Hal, independently of one another, means fluorine, chlorine or bromine and n means 1, 2 or 3, characterized in that a halogenated acyl chloride of the formulas (lia) to (lie) (lie) in which Hal and n have the meaning indicated in the case of the formulas (la) to (c) and Hal 'means chlorine or bromine, with an ester of the amino acrylic acid of the formula (III) wherein R 'means alkyl having 1 to 4 carbon atoms and R1 and R2, independently of one another, mean alkyl having 1 to 6 carbon atoms, the alkyl chains being interrupted respectively, optionally by O, S or NH, obtaining the intermediate compounds of the formulas (IVa) to (IVc) (IVc) in which Hal and n have the meaning indicated in the formulas (la) to (le), Hal 'has the meaning indicated in the case of the formulas (lia) to (líe) and R', R1 and R2 have the meaning indicated in the case of the formula (III), these are they react with an aniline, if substituted, of the formula H2N-Ar (V) in which Ar has the meaning indicated in the case of the formulas (la) to (le), to give the intermediate compounds of the formulas (Track) to (VIc) " (Via), (VIb) ? 'Ic) in which Ar, n and Hal have the meaning indicated in the case of the formulas (la) to (le), Hal' has the meaning indicated in the case of the formulas (lia) to (lie) R ' has the meaning indicated in the case of the formula (III), these are cyclized, by the addition of an acid acceptor, to give a compound of the formulas (la) to (le), with R = alkyl having 1 to 4 carbon atoms and, in the case of obtaining the compounds of the formulas (la) to (le) with R = H the compounds of the formulas (la) to (le) are saponified with R = alkyl with 1 to 4 carbon atoms. R 'and as long as R means alkyl having 1 to 4 carbon atoms, they can be straight-chain or branched chain and represent, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, -butyl or t-butyl. Preferably R means hydrogen, methyl or ethyl. Preferably R 'means methyl or ethyl. As long as Ar means substituted phenyl, the same or different substituents of the group consisting of fluorine, chlorine, bromine, cyano, alkyl having 1 to 6 carbon atoms and alkoxy with 1 to 6 may be present as substituents, for example 1 to 4. carbon atoms. Preferred substituents are 1 or 2 fluorine, chlorine and / or bromine atoms. Preferably Ar means phenyl, 2,4-difluorophenyl, 2-fluorophenyl or 4-fluorophenyl. Preferably Hal means fluorine or chlorine. When Hal is present twice, it will preferably mean one of the same fluorine and the other chlorine. When 3 Hal are present, preferably 1 to 2 fluorine and the remainder chlorine. In addition, it is preferred that a substituent formed by fluorine is located on the carbon atom in the meta position with respect to the carbonyl group (ie position 6 in the formula (la) and the corresponding position in the other formulas). Preferably Hal 'means chlorine. Preferably n means 2. Preferably R.sub.1 and R.sub.2 are identical and respectively represent methyl or ethyl, especially ethyl. The reaction of the compounds of the formulas (lia) to (lie) with a compound of the formula (III) can be carried out for example in such a way that the compound of the formula (III), a solvent and a base are disposed and a compound of the formulas is metered in. (lia) to (líe). The reactants can be used in principle in any arbitrary ratio to each other.

For economic reasons, the molar ratio between the compound of the formula (Ha) to (He) with respect to the compound of the formula (III) is preferably 0.8 to 1.2: 1, especially at 0.9 to 1.1: 1. As bases, the most diverse inorganic and organic bases are considered in principle. In the case where the bases are hardly soluble in the reaction mixture, for example inorganic bases, it is convenient to add a phase transfer catalyst. Preferred organic bases are, for example, amines. Especially preferred are tertiary amines, which contain, for example, 3 identical or different alkyl groups with 1 to 6 carbon atoms, such as triethylamine. The amount of the base should be at least the stoichiometrically necessary amount, a small excess, for example up to 120% by weight of the stoichiometrically necessary amount, is preferable. Suitable solvents are, for example, chlorinated hydrocarbons and aromatic hydrocarbons. Methylene chloride, dichloromethane, toluene and xylene are preferred. The reaction temperature can be, for example, in the range from -10 to + 80 ° C. In general, it is convenient to continue stirring the reaction temperature for some time after the combination of the reactants. The whole process for the preparation of the naphthyridine compounds of the formulas (le) to le), can be carried out in the reactor in which the reaction mixture of the reaction of a compound of the formulas (Ha) is present. to (He) with a compound of the formula (III). For this, isolation of the compounds of formulas (IVa) to (IVc) prepared is not required. When, in spite of everything, it is desired to isolate the compound prepared from the formulas (IVa) to (IVc), for example for its characterization and / or for its use in other purposes other than obtaining the naphthyridine compounds of the formulas (a) to (I), for example, the following can be used: the reaction mixture is combined with water, for example 30 to 300% by volume (based on the reaction mixture), is stirred thoroughly , the aqueous phase is separated from the organic phase and the organic phase of the solvent is released. In this way, the compounds of the formulas (IVa) to (IVc) can be obtained with a purity above 95%, which can be further purified, if appropriate, by conventional methods. The reaction of a compound of the formulas (IVa) to (IVc) with a compound of the formula (V) to give a compound of the formulas (Via) to (VIc) can be carried out for example in such a way that it is acidified. - a compound of the formulas (IVa) to (IVc), preferably in the form of the spent reaction mixture which is formed during its preparation and is dosed at temperatures, for example, below 50 ° C, preferably below 50 ° C. 40 ° C, if appropriate under refrigeration, a compound of the formulas (V). The compounds of the formulas (IVa) to (IVc) on the one hand and of the formula (V) on the other hand, can be used with each other in arbitrary proportions in principle. For economic reasons, the molar ratio between the compound of the formulas (IVa) to (IVc) with respect to the compound of the formula (V) is preferably 0.8 to 1.2: 1, especially at 0.9 to 1.1: 1. For acidification, the most diverse inorganic and organic acids can be used in principle. Preferred are alkylcarboxylic acids with 2 to 6 carbon atoms and arylcarboxylic acids with 7 to 13 carbon atoms, especially acetic acid. The amount of the acid can be chosen, for example, in such a way that a slight excess is present relative to the base used. The amount of the acid can therefore be, for example, up to 125% equivalents, based on the base used. In this case too, it is advantageous to continue stirring the reaction temperature for some time after the combination of the reactants. Once the reaction is complete, it is advantageous to wash the reaction mixture, for example one to three times with water. The washing can be carried out for example at temperatures ranging from room temperature to 95 ° C. The whole process for the preparation of the naphthyridine compounds of the formulas (la) to (I) can be carried out with the solution then present, which contains essentially the compound obtained from the formulas (Via) to (VIc) and the Solvent used. For this purpose, isolation of the compound prepared from the formulas (Via) is not required (Vlc). When, in spite of everything, it is desired to isolate the compound prepared from the formulas (Via) to (VIc), for example for its characterization and / or for its use in other purposes other than obtaining the naphthyridine compounds of the formulas ( ) until (le), the solvent could be removed from the solution present after washing with water. In this way, compounds of the formulas (Via) to (VIc) can be obtained with a purity above 93% which can be further purified, if appropriate, by conventional methods. Cyclization of the compound of the formulas (Vía) to (VIc) to give a compound of the formulas (la) up to (le) with R = alkyl having 1 to 4 carbon atoms can be carried out for example in such a way that dose a compound of the formulas (Via) to (VIc), preferably in the form of the solution formed during the preparation, in the presence of a dipolar aprotic solvent, even an acid acceptor. The dipolar aprotic solvent can be constituted for example by dimethylformamide, dimethyl sulfoxide, tetramethylene sulfone or N-methylpyrrolidone. Suitable acid acceptors are, for example, alkali metal salts such as fluorides, carbonates, bicarbonates and alkali hydrides. As individual examples may be mentioned: sodium fluoride, sodium hydride, sodium carbonate, sodium bicarbonate, potassium fluoride and potassium bicarbonate. It is advantageous to use the acid acceptor in an excess, for example in an excess of 10 to 50% by weight, based on the theoretically necessary amount. Furthermore, it is advantageous to carry out the cyclization under as anhydrous conditions as possible. When working with an acid acceptor excess it will be advantageous to carry out its neutralization immediately after the conclusion of the cyclization. For this purpose, for example, an aqueous acid can be added until a pH value is present, for example in the range of 4 to 6, and temperatures in the range of, for example, 20 to 70 [deg.] C. are maintained. of naphthyridine obtained from formulas (la) to (I) with R = C 1 -C 4 alkyl can be carried out from the reaction mixture for example in such a way that it is combined with water, the mixture obtained The suspension is separated by filtration and the residue is washed successively with water and alcohol.When there is a desire to prepare naphthyridine compounds of the formulas (a) to (I) with R = H, a saponification must also be carried out. the esters.

This saponification can be carried out, for example, with acetic acid, water and mineral acids and the acetic ester formed in this case is distilled off from the reaction mixture. In this way, naphthyridine compounds of formulas (la) to (le) can be obtained with a purity above 99%, frequently above 99.8%, and in yields (based on the halogenated acyl chloride used in the formulas (lia) to (lie)) above 80% of the theory. The process according to the invention is not only advantageous because of these good results in terms of yield and purity, but also because it is particularly simple, it only requires two reaction vessels and provides, depending on the isolation of the intermediate products, highly pure products. As regards the state of the art cited at the beginning this is extraordinarily surprising. The compounds of the formulas (Via) up (VIc) are new. The present invention therefore also relates to the compounds of the formulas (Via), (VIb) R 'means alkyl having 1 to 4 carbon atoms, Hal independently of one another, means fluorine, chlorine or bromine, n means 1, 2 or 3, Hal' means fluorine or chlorine and Ar means phenyl, optionally substituted. The preferred meaning of the symbol R, Hal, n, Hal 'and Ar is the one that has already been indicated above. A process for obtaining the compounds of the formulas (Via) to (VIc) and their use for the advantageous preparation of the naphthyridine compounds of the formulas (la) to (le) has also been described above. The novel compounds of the formulas (Via) to (Vlc) are key compounds in the process according to the invention for the preparation of naphyridine compounds of the formulas (la) to (le).

Examples Example 1. Obtaining a compound of formula (IVa) with R '= ethyl, Hal at position 5 = fluorine, Hal at position 6 = chlorine, Hal' = chlorine and R1 = R2 = methyl. 47.2 g of ethyl β-dimethylaminoacrylate and 35 g of triethylamine were placed in 250 ml of methylene chloride. In the course of 3 hours, 76 g of 97% 2, 6-dichloro-5-fluorni-cotinyl chloride were added dropwise. The temperature increased to 55 ° C. This temperature was continued stirring for 1 hour and then cooled to room temperature. Then 250 g of water were added and stirred well. The organic phase was then separated and the methylene chloride was distilled off. In this way, 110 g of 97% product were obtained with a melting point of 94 ° C. H1-NMR (DMSO): 0.95 ppm (t, CH CH3); 2.9 and 3.4 ppm (2 X s, N-CH3); 3.9 ppm (q, CH2CH3); 7.95 ppm (br, S.; HC =); 8.04 ppm (d, Ar-H). Example 2. Obtaining a compound of the formula (Via) with R '= ethyl, Hal at the 5-position = fluorine, Hal at the 6-position = chlorine, Hal' = chlorine, R1 = R2 = methyl and Ar = 2, 4-di-fluorophenyl.

First, the procedure was as indicated in Example 1, however toluene was used as the solvent instead of methylene chloride. After cooling to room temperature (= before washing with water), 22.5 g of glacial acetic acid were added dropwise and then 43 g of 2,4-difluoroaniline were metered in over the course of 30 minutes. After one hour of stirring at 25 to 30 ° C, 250 ml of water were added and the mixture was heated to 80 ° C. The aqueous phase was then dried and the organic phase was washed again with 100 ml of water. The toluene was then removed in vacuo from the organic phase. Remaining 138.5 g of a 95% product with a melting point of 138 to 139 ° C remained. H1-NMR (DMSO): 1 ppm (t, 2H, -CH2CH3); 4 (q, 2H, CH2CH3); 7.2, 7.5 and 7.9 ppm (each m, in total 3H, Ar-H); 8.2 ppm (d, 1H nicotinoyl-H); 8.6 and 8.7 ppm (each d, 1H in HC = C, cis, trans), 11.6 and 12.6 ppm (each d, 1H in NH, cis, trans). Example 3. Preparation of 7-chloro-6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-l, 8-naphidin-3-carboxylic acid ethyl ester (formula) with R = ethyl, Ar = 2,4-difluorophenyl, Hal in the 6-position = fluorine and Hal in the 7-position = chlorine). First, the procedure was as in Example 2. The toluene solution washed there was dosed, over the course of 3 hours, to a mixture, heated at 60 ° C, consisting of 250 ml of N-methylpyrrolidone and 28 g of potassium carbonate. anhydrous. At the same time, toluene under vacuum was eliminated by continuous distillation. Once the dosing was finished, stirring was continued for 1 hour at 60 °, then it was refrigerated at 18 ° C. 12 g of concentrated aqueous hydrochloric acid and then 200 g of water were added to this reaction mixture and the mixture obtained was stirred for 30 minutes. A suspension was obtained which was separated by filtration and the residue was washed successively with 120 g of water and 200 g of methanol. After drying, 105 g of 99.9% product were obtained with a melting point of 215 ° C. This corresponds to a total yield (based on the halogenated nicotinoyl chloride used) of 84% of the theory. H NMR (DMSO): 1.3 ppm (t, 3H, CH2CH3); 4.3 ppm (q, 2H, CH2CH3); 7.35, 7.65 and 7.9 ppm (m, in total 3H, Ar-H); 8.55 ppm (d, 1H, nicotinoyl-H); 8.8 ppm (s, 1H, -CH =). Example 4. 85 g of the product from Example 3 were added to a mixture constituted by 200 ml of glacial acetic acid and 50 ml of water. 250 ml of concentrated sulfuric acid were metered in, whereupon the mixture was heated to 60 ° C, in order to complete the saponification it was heated for 4 hours at 105 to 110 ° C and the ethyl acetate formed was distilled off . Then 250 ml of water were added at 80 ° C, the precipitated product was separated by filtration at 22 ° C, washed with water and dried. In this way 75 g of 99.9% product were obtained in the form of an internal salt. H ^ N-R (DMSO): 7.4, 7.65 and 7.9 ppm (each m, each 1H, Ar-H); 8.85 ppm (d, 1H nicotinoyl-H); 9.05 ppm (s, 1H, -CH =).

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

1. REVITALIZATIONS Having described the invention as above, the content of the following claims is claimed as property: ~ 1.- Procedure for obtaining naphthyridine compounds of the formulas (la) to (le) (the) (Ib) of) wherein R represents hydrogen or alkyl having 1 to 4 carbon atoms, Ar means substituted phenyl, if appropriate, Hal, independently of one another, means fluorine, chlorine or bromine and n means 1, 2 or 3, characterized in that a halogenated acyl chloride of the formulas (Ha) to (He) (Ha) (Ilb) in which Hal and n have the meaning indicated in the case of the formulas (la) to (c) and Hal 'means chlorine or bromine, with an ester of the amino acrylic acid of the formula (III) wherein R 'means alkyl with 1 to 4 carbon atoms and R1 and R2, independently of one another, mean alkyl having 1 to 6 carbon atoms, the alkyl chains may be interrupted respectively, optionally by O, S or NH, obtaining the intermediate compounds of the formulas (IVa) to (IVc) ( IVc) in which Hal and n have the meaning indicated in the formulas (la) to (le), Hal 'has the meaning indicated in the case of the formulas (lia) to (He) and R', R1 and R2 have the meaning indicated in the case of formula (III), these are reacted with an aniline, if substituted, of the formula H2N-Ar (V) in which Ar has the meaning indicated in the case of the formulas ( ) to (le), to give the intermediate compounds of the formulas (Via) to (VIc) (Vía), (VIb) in which Ar, n and Hal have the meaning indicated in the case of the formulas (la) up to (le), Hal 'has the meaning indicated in the case of the formulas (Ha) up to (He) ) R 'has the meaning indicated in the case of the formula (IH), these are cyclized, by the addition of an acid acceptor, to give a compound of the formulas (la) up to (le), with R = alkyl having 1 to 4 carbon atoms and, in the case of the obtaining the compounds of the formulas (la) to (le) with R = H the compounds of the formulas (la) to (le) are saponified with R = alkyl having 1 to 4 carbon atoms. 2.- Compounds of the formulas (Vía), (VIb) (VIc) in which Ar, Hal, Hal 'and R' have the meaning indicated in claim 1. 3. Process according to claim 1, characterized in that in the formulas R means hydrogen, methyl or ethyl, R 'means methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, Ar means phenyl optionally substituted by 1 to 4 substituents which are the same or different from the group formed by fluorine, chlorine, bromine, cyano, alkyl with 1 to 6 carbon atoms and alkoxy with 1 to 6 carbon atoms, R1 and R2 are the same and mean methyl or ethyl and when two Hal are present, one of them means fluorine and the other means chlorine, and when three Hal are present, 1 to 2 means fluorine and the rest means chlorine and Hal 'means chlorine. 4. Method according to claims 1 and 3, characterized in that the compound of the formula (III), a solvent and a base are arranged, the compounds of the formulas (Ha) up to (He) are dosed in a molar proportion with respect to to (III) from 0.8 to 1.2: 1 and up to 120% by weight of the stoichiometrically necessary amount of base is employed. 5. - Procedure according to claims 1, 3 and 4, characterized in that the compound of the formulas (IVa) is acidified to (IVc) in the form of the spent reaction mixture formed during its preparation and is metered, at temperatures below 50 ° C, the compound of the formula (V) in a molar ratio (IVa) to (IVc): (V) from 0.8 to 1.2: 1. Method according to claims 1 and 3 to 5, characterized in that the compound of the formulas (Vía) is dosed to (VIc) in the form of the solution formed during its preparation in the presence of a dipolar aprotic solvent, to an acid acceptor, which is used in excess and once the cyclization is over, the excess acid acceptor is neutralized, adjusting a pH value in the range of 4 to 6, at 20 to 70 ° C, addition of an aqueous acid. 7. Process according to claims 1 and 3 to 6, characterized in that fluorides, carbonates, bicarbonates or hydrides of alkali metals are used as an acid acceptor in an excess of 10 to 50% by weight, based on the theoretically necessary amount. 8. - Process for obtaining naphthyridine compounds of formulas (la) to (le) with R = H according to claims 1 and 3 to 7, characterized in that a compound of the formulas (la) to (le) is saponified, with R = alkyl with 1 to 4 carbon atoms, with acetic acid, water and mineral acids and the acetic acid ester formed in this case is removed from the reaction mixture by distillation. 9. Compounds of claim 2, characterized in that in the formulas (Via) to (VIc) R 'means methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, Ar means phenyl substituted, if appropriate, with 1 to 4 substituents which are the same or different from the group consisting of fluorine, chlorine, bromine, cyano, alkyl having 1 to 6 carbon atoms and alkoxy with 1 to 6 carbon atoms, when two halides are present , one of them means fluorine and the other means chlorine and, when three Hal are present, 1 to 2 means fluorine and the other means chlorine, and Hal 'means chlorine. SUMMARY OF THE INVENTION Advantageous process for obtaining naphthyridine compounds of the formulas (la) to (le) (the) (Ib) in which R is hydrogen or alkyl having 1 to 4 carbon atoms, Ar is phenyl, optionally substituted, Hal independently of one another, means fluorine, chlorine or bromine, n means 1, 2 or 3 in which a halogenated nicotine, isonicotine or picolinyl chloride with an ester of the amino acrylic acid, thereby obtaining a 3-amino-2-nicotinoyl acrylate, isonicotinoyl or halogenated picolinoyl acrylate, this is reacted with an aniline , optionally substituted, to give a 2-nicotinoyl 3-amino-acrylate, isonicotinoyl m or halogenated pico-linoyl, containing an amino group corresponding to the substituted aniline if appropriate, this second halogenated 3-aminoacrilate of 2-nicotinoyl, isonicotinoyl or picolinoyl is cyclized by addition of an acid acceptor to give a compound of the formulas (la) up to (le) with R = alkyl having 1 to 4 carbon atoms, in the case of obtaining of a co In the formula (a) to (le), R = H, the compound of the formulas (la) is saponified to (I) with R = alkyl having 1 to 4 carbon atoms.