KR20000052892A - Method of producing naphthyridine compounds and novel intermediate products - Google Patents

Abstract

PURPOSE: A method or producing naphthyridine compounds and novel intermediate products are provided. CONSTITUTION: An advantageous method of producing naphthyridine compounds is in 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

METHOD OF PRODUCING NAPHTHYRIDINE COMPOUNDS AND NOVEL INTERMEDIATE PRODUCTS}

The present invention first relates to advantageous processes for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic), and to novel polymers which are important compounds for such processes. The naphthyridine compounds of formulas (Ia) to (Ic) may be used to prepare the active ingredient, particularly highly effective fungicides (see, eg, US Pat. No. 5,164,402, 5,298 629 and EP-OS 413 455). It is an important intermediate for.

After reacting halogenated nicotinyl chloride with malonate, one of the two carboxylate groups is decarboxylated and then a methylene group located between the two carbonyl groups using an ortho ester. And alkoxy groups introduced in this process are reacted with an optionally substituted aniline to obtain halogenated nicotinoyl phenylaminoacrylate, which is subjected to ring closure and optional hydrolysis to obtain a naphthyridine compound of formula (Ia). Processes for preparing the naphthyridine compounds of (la) are known (for example DE-OS 35 14 076 and EP-OS 132 845, 153 580, 160 758, copper). 191 451, 302 372 and 449 445). A disadvantage of this method is the low total yield, which is less than 40% of the number of steps and theories.

The present inventors react the halogenated acid chlorides of the following formulas (IIa) to (IIc) with aminoacrylates of the formula (III) to obtain intermediates of the formulas (IVa) to (IVc), which are optionally Reaction with substituted anilines gives intermediates of the formulas (VIa) to (VIc), which are added to the compounds of formulas (Ia) to (Ic) wherein R is C ₁ -C ₄ -alkyl by addition of an acid scavenger To cyclize and to prepare compounds of formulas (Ia) to (Ic) wherein R is H, characterized in that the compounds of formulas (Ia) to (Ic) wherein R is C ₁ -C ₄ -alkyl are hydrolyzed It was learned how to prepare a naphthyridine compound of formula (Ia) to (Ic).

H ₂ N-Ar

Wherein R is hydrogen or C ₁ -C ₄ -alkyl,

Ar is optionally substituted phenyl,

Hal is independently of each other fluorine, chlorine or bromine,

n is 1, 2 or 3,

Hal 'is fluorine or chlorine,

R 'is C ₁ -C ₄ -alkyl,

R ¹ and R ² are independently of each other C ₁ -C ₆ -alkyl and each alkyl chain may be optionally interrupted by O, S or NH.

Where R ′ and R are C ₁ -C ₄ -alkyl they may be straight or branched chains, for example methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl . R is preferably hydrogen, methyl or ethyl. R 'is preferably methyl or ethyl.

When Ar is substituted phenyl, the substituent is 1 to 4 identical or different substituents selected from the group consisting of, for example, fluorine, chlorine, bromine, cyano, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy Can be. Preferred substituents are one or two fluorine, chlorine and / or bromine atoms. Ar is preferably phenyl, 2,4-difluorophenyl, 2-fluorophenyl or 4-fluorophenyl.

Hal is preferably fluorine or chlorine. If two Hal are present, one is preferably fluorine and the other is chlorine. When three Hals are present, preferably 1-2 are fluorine and the rest are chlorine. It is also preferred for the carbonyl group to have a fluorine substituent on the carbon atom at the meta site (i.e. at position 6 of formula (Ia) and at the corresponding position of the other formula).

Hal 'is preferably chlorine,

n is preferably 2.

R ¹ and R ² are preferably the same and each is methyl or ethyl, in particular ethyl.

The reaction of a compound of formula (IIa) to (IIc) with a compound of formula (III), for example, first introduces a compound of formula (III), a solvent and a base, and then weighs the compound of formula (IIa) to (IIc) Can be carried out by addition. In general, the reactants can be used in any ratio with respect to each other. The molar ratio of the compounds of the formulas (IIa) to (IIc) to the compounds of the formula (III) in terms of cost is preferably 0.8 to 1.2: 1, in particular 0.9 to 1.1: 1.

Suitable bases are generally many different inorganic and organic bases. It is advantageous to add a phase transfer catalyst for bases which are poorly soluble in the reaction mixture, for example inorganic bases. Organic bases such as amines are preferred. Particular preference is given, for example, to tertiary amines containing three identical or different C ₁ -C ₆ -alkyl groups, for example triethylamine. The amount of base should be more than stoichiometrically required, but some excess, for example 120 wt% or less of the stoichiometrically required amount, is preferred.

Examples of suitable solvents are chlorinated hydrocarbons and aromatics. Methylene chloride, dichloromethane, toluene and xylene are preferred. The reaction temperature may be, for example, -10 to +80 ° C. It is generally advantageous to continue stirring for several hours at the reaction temperature after the reactants have been thoroughly mixed with each other.

The entire process for preparing the naphthyridine compounds of formulas (Ia) to (Ic) can be carried out in a reactor containing a reaction mixture in which the reaction of the compounds of formulas (IIa) to (IIc) with the compound of formula (III) is fully reacted. have. Isolation of the compounds of formulas (IVa) to (IVc) prepared is not necessary for this purpose.

Formulas (IVa) prepared, for example, to characterize the compounds of formulas (IVa) to (IVc) prepared and / or to use them for purposes other than the preparation of naphthyridine compounds of formulas (Ia) to (Ic) If it is desired to isolate the compounds of (i) to (IVc), for example 30 to 300% by volume of water (based on the reaction mixture) is added to the fully reacted reaction mixture, the mixture is stirred well and then the aqueous The phase can be separated from the organic phase and the solvent can be removed from the organic phase. In this way, compounds of formulas (IVa) to (IVc) with a purity greater than 95% can be obtained, which can optionally be further purified using conventional methods.

The reaction of the compounds of the formulas (IVa) to (IVc) with the compounds of the formula (V) for obtaining the compounds of the formulas (VIa) to (VIc) is preferably carried out, for example, of the compounds of the formulas (IVa) to (IVc) It can be carried out by optionally cooling in the form of a fully reacted reaction mixture obtained in the preparation method thereof, for example at a temperature below 50 ° C., preferably below 40 ° C., and metering in and acidifying the compound of formula (V). The compounds of the formulas (IVa) to (IVc) and the compounds of the formula (V) can generally be used in any ratio with respect to each other. In terms of cost, the molar ratio of the compounds of the formulas (IVa) to (IVc) to the compounds of the formula (V) is preferably 0.8 to 1.2: 1, in particular 0.9 to 1.1: 1.

A wide variety of inorganic and organic acids can generally be used for acidification. Preference is given to C ₂ -C ₆ -alkyl- and C ₇ -C ₁₃ -arylcarboxylic acids, in particular acetic acid. The amount of acid can be chosen, for example, in slightly excess relative to the base used. Thus, the amount of acid may, for example, be up to 125 equivalent percent based on the base used.

It is also advantageous to continue stirring for several hours at the reaction temperature after the reactants are mixed with each other. When the reaction is complete, it is advantageous to wash the reaction mixture with water, for example 1 to 3 times. For example, the washing can be carried out at a temperature from room temperature to 95 ° C.

The entire process for the preparation of the naphthyridine compounds of the formulas (Ia) to (Ic) may continue with the resulting solution comprising essentially the compounds of the formulas (VIa) to (VIc) prepared and the solvent used. Isolation of the compounds of formulas (VIa) to (VIc) prepared is not required for this purpose.

Formulas (VIa) prepared, for example, to characterize the prepared compounds of formulas (VIa) to (VIc) and / or to use them for purposes other than the preparation of naphthyridine compounds of formulas (Ia) to (Ic) If it is desired to isolate the compounds of (VIc) to (VIc), the solvent can be removed from the solution obtained after washing with water. In this way, compounds of formulas (VIa) to (VIc) with a purity above 93% can be obtained, which can optionally be further purified using conventional methods.

Cyclization reactions of compounds of formulas (VIa) to (VIc) with compounds of formulas (Ia) to (Ic) wherein R is C ₁ -C ₄ -alkyl are for example compounds of formulas (VIa) to (VIc) Can preferably be carried out by metered addition to an acid scavenger in the presence of a bipolar aprotic solvent in the form of a solution obtained in its preparation. Examples of aprotic aprotic solvents are dimethylformamide, dimethyl sulfoxide, tetramethylene sulfone or N'-methylpyrrolidone. Examples of suitable acid scavengers are alkali metal salts such as alkali metal fluorides, carbonates, hydrogen carbonates and hydrides. Individual examples are sodium fluoride, sodium hydride, sodium carbonate, sodium bicarbonate, potassium fluoride and potassium bicarbonate. It is advantageous to use the acid scavenger in excess, for example from 10 to 50% by weight, based on the theoretically required amount. It is also advantageous to carry out the cyclization reaction under conditions such as anhydrides as far as possible.

If the process is carried out using an excess acid scavenger, it is advantageous to neutralize immediately after the cyclization reaction is complete. For this purpose, for example, an aqueous acid can be added while maintaining the temperature at, for example, 20 to 70 ° C. until the pH becomes 4 to 6, for example.

The naphthyridine compounds of formulas (Ia) to (Ic) wherein R prepared are C ₁ -C ₄ -alkyl are added, for example, from the reaction mixture, water is stirred and the resulting mixture is stirred and the suspension formed is filtered off and water and alcohol The residue can be isolated by continuously washing the residue.

If it is desired to prepare the naphthyridine compounds of the formulas (la) to (lc) in which R is H, further ester hydrolysis should be performed. Such hydrolysis can be carried out using, for example, glacial acetic acid, water and mineral acid, and the acetate obtained can be removed from the reaction mixture by distillation.

In this way, the formulas (Ia) to (Ic) are more than 99% pure, often more than 99.8% and the yield [based on the halogenated acid chlorides of formulas (IIa) to (IIC) used] is more than 80% of theory. The naphthyridine compound of can be obtained.

The process according to the invention is advantageous as well as good results in yield and purity, as it requires only two reaction vessels and produces high purity products without isolation of intermediates. This is particularly surprising in view of the prior art described at the outset.

The compounds of the formulas (VIa) to (VIc) are novel. The present invention therefore also relates to compounds of the formulas (VIa) to (VIc).

<Formula VIa>

<Formula VIb>

<Formula VIc>

Wherein R 'is C ₁ -C ₄ -alkyl,

Hal is independently of each other fluorine, chlorine or bromine,

n is 1, 2 or 3,

Hal 'is fluorine or chlorine,

Ar is optionally substituted phenyl.

Preferred meanings of R, Hal, n, Hal 'and Ar are as described above.

Also described above are methods for the preparation of compounds of formula (VIa) to (VIc) and their use for advantageous processes for the preparation of formulas (Ia) to (Ic) naphthyridine compounds. Novel compounds of the formulas (VIa) to (VIc) are important compounds in the novel process for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic).

<Example 1>

R 'is ethyl, Hal in 5 position is fluorine, Hal in 6 position is chlorine, Hal' is chlorine, and R ¹ and R ² are methyl.

47.2 g of ethyl β-dimethylaminoacrylate and 35 g of triethylamine were mixed in 250 ml of methylene chloride. 76 g of 97% pure 2,6-dichloro-5-fluoronicotinoyl chloride was added dropwise over 3 hours. The temperature was raised to 55 ° C. Stirring was continued at this temperature for 1 hour before the mixture was cooled to room temperature. 250 g of water were then added and the mixture was well stirred. The organic phase was then separated off and methylene chloride was distilled off to give 110 g of 97% pure product having a melting point of 94 ° C.

H ¹ -NMR (DMSO): 0.95 ppm (t, CH ₂ CH ₃ ); 2.9 and 3.4 ppm (2 xs, N-CH ₃ ); 3.9 ppm (q, CH ₂ CH ₃ ); 7.95 ppm (br, S .; HC =); 8.04 ppm (d, Ar-H).

<Example 2>

R 'is ethyl, Hal in position 5 is fluorine, Hal in position 6 is chlorine, Hal' is chlorine, R ¹ and R ² are methyl, Ar is 2,4-difluoro A process for preparing a compound of formula (VIa), which is phenyl.

First, the method is as provided in Example 1, except that toluene is used instead of methylene chloride as a solvent. After the mixture was cooled to room temperature (ie, before washing with water), 22.5 g of glacial acetic acid was added and then 43 g of 2,4-difluoroaniline was metered in over 30 minutes. The mixture was stirred for 1 hour at 25-30 ° C, then 250 mL of water was added and the mixture was heated to 80 ° C. The aqueous phase was then separated off and the organic phase washed again with 100 ml of water. Toluene was then removed from the organic phase under reduced pressure to give 138.5 g of 95% pure product having a melting point of from 138 to 139 ° C.

H ¹ -NMR (DMSO): 1 ppm (t, 3H, CH ₂ CH ₃ ); 4 (q, 2H, CH ₂ CH ₃ ); 7.2, 7.5 and 7.9 ppm (each m, 3H total, 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 cis, trans, NH).

<Example 3>

R is ethyl, Ar is 2,4-difluorophenyl, Hal in position 6 is fluorine, Hal in position 7 is chlorine Ethyl 7-chloro-6-fluoro of formula (Ia) Process for the preparation of -1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate.

First, the method is the same as in Example 2. The washed toluene solution thus obtained was metered into an initial charge of 250 ml of N-methylpyrrolidone and 28 g of anhydrous potassium carbonate heated to 60 ° C. over 3 hours. At the same time toluene was continuously distilled off under reduced pressure. When completing the metered addition, stirring was continued at 60 ° C. for 1 hour and then the mixture was cooled to 18 ° C. 12 g of concentrated aqueous hydrochloric acid and then 200 g of water were added to the reaction mixture and the resulting mixture was stirred for 30 minutes. This gave a suspension, filtered and the residue was washed successively with 120 g of water and 200 g of methanol. Drying gave 105 g of a 99.9% pure product with a melting point of 215 ° C. This corresponds to a total yield of 84% of theory (based on halogenated nicotinyl chloride used).

H ¹ -NMR (DMSO): 1.3 ppm (t, 3H, CH ₂ CH ₃ ); 4.3 ppm (q, 2H, CH ₂ CH ₃ ); 7.35, 7.65 and 7.9 ppm (m, 3H total, Ar-H); 8.55 ppm (d, 1H, nicotinoyl-H); 8.8 ppm (s, 1 H, -CH =).

<Example 4>

85 g of the product from Example 3 were added to a mixture of 200 ml glacial acetic acid and 50 ml water. 50 ml of concentrated sulfuric acid was metered in, and the temperature of the mixture was raised to 60 ° C. The mixture was heated to 105-110 ° C. for 4 hours to complete the hydrolysis and the ethyl acetate formed was filtered off. 250 ml of water were then added below 80 ° C. and the precipitated product was filtered at 22 ° C., washed with water and dried. This gave 75 g of 99.9% pure product in the form of an internal salt.

H ¹ -NMR (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, 1 H, -CH =).

Claims (9)

The halogenated acid chlorides of formulas (IIa) to (IIc) are reacted with aminoacrylates of formula (III) to obtain intermediates of formulas (IVa) to (IVc), which are optionally substituted anilines of formula (v) To an intermediate of the formulas (VIa) to (VIc), which is cyclized to a compound of formulas (Ia) to (Ic) wherein R is C ₁ -C ₄ -alkyl by addition of an acid scavenger And hydrolyzing a compound of formulas (Ia) to (Ic) wherein R is C ₁ -C ₄ -alkyl when preparing a compound of formulas (Ia) to (Ic) wherein R is H The method for producing the naphthyridine compound of (la) to (lc). <Formula Ia> <Formula Ib> <Formula Ic> <Formula IIa> <Formula IIb> <Formula IIc> <Formula III> <Formula IVa> <Formula IVb> <Formula IVc> <Formula V> H ₂ N-Ar <Formula VIa> <Formula VIb> <Formula VIc> Wherein R is hydrogen or C ₁ -C ₄ -alkyl, Ar is optionally substituted phenyl, Hal is independently of each other fluorine, chlorine or bromine, n is 1, 2 or 3, Hal 'is fluorine or chlorine, R 'is C ₁ -C ₄ -alkyl, R ¹ and R ² are independently of each other C ₁ -C ₆ -alkyl and each alkyl chain may be optionally interrupted by O, S or NH. Compounds of Formulas VIa, VIb and VIc <Formula VIa> <Formula VIb> <Formula VIc> In said formula, Ar, Hal, Hal ', and R' are as having described in Claim 1. The compound of claim 1 wherein R in formula is hydrogen, methyl or ethyl, R 'is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, Ar is phenyl optionally substituted by 1 to 4 identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, cyano, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy, R ¹ and R ² are the same, methyl or ethyl, If two Hals are present, one is fluorine and the other is chlorine, if three Hals are present, 1-2 are fluorine and the other is chlorine, Hal's characterized by being chlorine. 4. A compound according to claim 1 or 3, wherein the compound of formula (III), a solvent and a base are introduced first, and the compound of formulas (IIa) to (IIc) is molar ratio 0.8 to 1.2: 1 relative to the compound of formula (III). Metering in, and using the base at 120% by weight or less of the stoichiometrically required amount. 5. The compound according to claim 1, wherein the compounds of formulas (IVa) to (IVc) are acidified in the form of a fully reacted reaction mixture obtained in their preparation and at a temperature of less than 50 ° C. 6. A method according to claim 1, wherein the compound of formula (V) is metered in at a molar ratio of (IVa) to (IVc) :( V) of 0.8 to 1.2: 1. The acid according to any one of claims 1 and 3 to 5, wherein the compound of formula (VIa) to (VIc) is used in excess in the presence of a bipolar aprotic solvent in the form of a solution obtained in the preparation thereof. And metering in the scavenger and neutralizing the excess acid scavenger by adjusting the pH to 4-6 by addition of aqueous acid at 20-70 ° C. after the cyclization reaction is complete. 7. The acid scavenger used according to any one of claims 1 and 3 to 6, wherein the acid scavenger used is in an amount of from 10 to 50% by weight of an alkali metal fluoride, carbonate, hydrogencarbonate or A hydride. 8. Compounds of formulas (Ia) to (Ic) according to any one of claims 1 and 3 to 7 wherein R is C ₁ -C ₄ -alkyl are hydrolyzed using glacial acetic acid, water and mineral acid A method for producing a naphthyridine compound of formula (Ia) to (Ic), wherein R is H, wherein the obtained acetate is removed from the reaction mixture by distillation. The compound according to claim 2, wherein in formulas (VIa) to (VIc), R 'is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, Ar is phenyl optionally substituted with 1 to 4 identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, cyano, C ₁ -C ₆ -alkyl and C ₁ -C ₆ -alkoxy, two Hal If present, one is fluorine, the other is chlorine, if three Hals are present, 1-2 are fluorine and the other is chlorine, Hal 'is a compound characterized in that chlorine.