EP0935600A1

EP0935600A1 - Method or producing naphthyridine compounds and novel intermediate products

Info

Publication number: EP0935600A1
Application number: EP97913157A
Authority: EP
Inventors: Stefan Antons; Reinhold Gehring; Tim Bielfeldt; Bernhard Beitzke
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1996-10-30
Filing date: 1997-10-17
Publication date: 1999-08-18
Also published as: IL129597A0; WO1998018795A1; KR20000052892A; JP2001502715A; PL332941A1; CN1235605A; AU5050898A; CA2269984A1; CZ154999A3

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

Process for the preparation of naphthyridine compounds and new intermediates

The present invention relates first of all to an advantageous process for the preparation of the naphthyridine compounds characterized by formulas (Ia) to (Ic) below and to new intermediates which are key compounds for this process. Naphthyridine compounds of the formulas (Ia) to (Ic) are valuable intermediates for the preparation of active compounds, in particular highly effective bactericides (see, for example, US Pat. No. 5,164,402, US Pat. No. 5,298,629 and EP-OS 413 455).

It is known to prepare naphthyridine compounds of the formula (Ia) by reacting a halogenated nicotinoyl chloride with a malonic ester, then decarboxylating one of the two carboxylate groups, then converting the methylene group between the two carbonyl groups into an using an ortho-ester

^ C = CH-OR group

transferred, the alkoxy group thus introduced with an optionally substituted aniline, thus obtained a halogenated nicotinoylphenylaminoacrylate and from this by ring closure and optionally saponification to give a naphthyridine compound of the formula (Ia) (see, for example, DE-OS 35 14 076 and EP-OS 'en 132 845, 153 580, 160 758, 191 451, 302 372 and 449 445). The disadvantages of this process are the multiple stages and the low overall yield, which is below 40% of theory. Th.

A method has now been found for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic)

(la) (Ib)

(Ic) in which

R represents hydrogen or C _r C ₄ alkyl,

Ar for optionally substituted phenyl,

Shark independently for fluorine, chlorine or bromine and

n stands for 1, 2 or 3, found

which is characterized in that a halogenated acid chloride of the formulas (Ha) to (IIc)

(Ha) (Ilb)

(IIc)

in which

Shark and n have the meaning given in the formulas (la) to (c) and

Shark represents fluorine or chlorine, with an aminoacrylic acid ester of the formula (III)

in the

R ^{1 represents} C _r C ₄ alkyl and

1 *

R and R independently of one another represent C _j -C ₆ alkyl, where the alkyl chain can in each case optionally be interrupted by O, S or NH,

thus receives intermediate compounds of the formulas (IVa) to (IVc)

(IVa) (IVb)

(IVc) in which

Hai and n the given in formulas (la) to (Ic),

Shark 'the given in formulas (Ha) to (IIc) and

R ', R ¹ and R ^{2 have} the meaning given for formula (III),

this with an optionally substituted aniline of the formula

H ₂ N-Ar (V), in the

Ar has the meaning given in the formulas (la) to (Ic)

to form interconnections of the formulas (Via) to (VIc)

(Via), (VIb)

(VIc) in which

Ar, n and shark are those given in formulas (la) to (Ic),

Shark 'the specified in the formulas (Ha) to (IIc) and

R 'have the meaning given for formula (III),

this is cyclized by adding an acid scavenger to a compound of the formulas (Ia) to (Ic) with R = CC ₄ -alkyl and, in the case of the preparation of compounds of the formulas (Ia) to (Ic) with R = H, the compounds of the formula (la) to (Ic) saponified with R = CC ₄ alkyl.

R and to the extent that R is C 1 -C ₄ -alkyl can each be straight-chain or branched and can be, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. R preferably represents hydrogen, methyl or ethyl. R preferably represents methyl or ethyl. Insofar as Ar is substituted phenyl, the substituents can be, for example

1 to 4 the same or different from the group of fluorine, chlorine, bromine, cyano, C, - C ₆ alkyl and C exist _j -C ₈ alkoxy. Preferred substituents are 1 or

2 fluorine, chlorine and / or bromine atoms. Ar is preferably phenyl, 2,4-difluorophenyl, 2-fluorophenyl or 4-fluorophenyl.

Shark is preferably fluorine or chlorine. When there are two sharks, one is preferably fluorine and the other is chlorine. When there are three sharks, 1 to 2 are preferably fluorine and the rest are chlorine. It is further preferred that a fluorine substituent is located on the carbon atom in the meta position to the carbonyl group (this is the 6 position in formula (Ia) and the corresponding position in the other formulas).

Hai 'is preferably chlorine, n is preferably 2.

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

The reaction of compounds of the formulas (Ha) to (IIc) with a compound of the formula (III) can be carried out, for example, by initially introducing the compound of the formula (III), a solvent and a base and a compound of the formulas (Ha ) to (IIc). In principle, the reactants can be used in any ratio to one another. For economic reasons, the molar ratio of the compound of the formulas (Ha) to (IIc) to the compound of the formula (III) is preferably 0.8 to 1.2: 1, in particular 0.9 to 1.1: 1.

In principle, a wide variety of inorganic and organic bases can be used as bases. In the case of bases which are sparingly soluble in the reaction mixture, for example inorganic bases, it is advantageous to add a phase transfer catalyst. Organic bases, for example amines, are preferred. Tertiary amines which contain, for example, three identical or different C ₁ -C ₆ -alkyl groups such as triethylamine are particularly preferred. The amount of base should be at least the stoichiometrically required amount, a small excess is preferred, for example up to 120% by weight of the stoichiometrically required amount. For example, chlorinated hydrocarbons and aromatics are suitable as solvents. 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 advantageous to stir at the reaction temperature for a while after the reactants have been combined.

The overall process for the preparation of naphthyridine compounds of the formulas (Ic) to Ic) can be carried out in the reactor in which the fully reacted reaction mixture of reacting a compound of the formulas (Ila) to (IIc) with a compound of the formula (III) is present. Isolation of the compound of the formulas (IVa) to (IVc) produced is not necessary for this.

If you still want to isolate the compound of formulas (IVa) to (IVc), e.g. in order to characterize them and / or to use them for purposes other than for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic), e.g. Proceed as follows: water is added to the fully reacted reaction mixture, for example 30 to 300% by volume (based on the reaction mixture), the mixture is stirred well, then the aqueous phase is separated from the organic phase and the organic phase is freed from the solvent. Compounds of the formulas (IVa) to (IVc) can thus be obtained in purities of over 95%, which can optionally be further purified using conventional methods.

The reaction of a compound of the formulas (IVa) to (IVc) with a compound of the formula (V) to a compound of the formulas (Via) to (VIc) can be carried out e.g. carry out such that a compound of the formulas (IVa) to (IVc), preferably in the form of the fully reacted reaction mixture obtained in its preparation, is acidified and at temperatures of, for example, below

50 ° C, preferably below 40 ° C, optionally with cooling, metered in a compound of formula (V). The compounds of the formulas (IVa) to (IVc) on the one hand and of the formula (V) on the other hand can in principle be used in any ratio to one another. For economic reasons, the molar ratio of the compound of the formulas (IVa) to (IVc) to the compound of the formula is

(V) preferably 0.8 to 1.2: 1, in particular 0.9 to 1.1: 1.

In principle, a wide variety of inorganic and organic acids can be used for acidification. Preferred are C ₂ -C ₆ alkyl and C ₇ -C ₁₃ - Aryl carboxylic acids, especially acetic acid. The amount of acid can be chosen, for example, so that there is a slight excess with respect to the base used. The amount of acid can thus be, for example, up to 125 equivalent%, based on the base used.

Here, too, it is advantageous to stir at the reaction temperature for a while after the reactants have been combined. After the reaction has ended, it is advantageous to e.g. Wash 1 to 3 times with water. The laundry can e.g. at temperatures from room temperature to 95 ° C.

The overall process for the preparation of naphthyridine compounds of the formulas

(la) to (Ic) can then be carried on with the solution then present which essentially contains the compound of the formulas (Via) to (VIc) and the solvent used. It is not necessary to isolate the connection of the formulas (Via) to (VIc).

If you still want to isolate the connection of formulas (Via) to (VIc), e.g. In order to characterize them and / or to use them for purposes other than for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic), the solvent can be removed from the solution after washing with water. In this way, compounds of the formulas (Via) to (VIc) of over 93% purity can be obtained, which can optionally be further purified using conventional methods.

The cyclization of a compound of the formulas (Via) to (VIc) to a compound of the formulas (Ia) to (Ic) with R = C, -C ₄ -alkyl can be carried out, for example, in such a way that a compound of the formulas (Via) bis (VIc), preferably in the form of the solution obtained in their preparation, in the presence of a dipolar aprotic solvent to an acid scavenger. The dipolar aprotic solvent can be, for example, dimethylformamide, dimethyl sulfoxide, tetramethylene sulfone or N-methylpyrrolidone. Examples of suitable acid scavengers are alkali metal salts such as alkali metal fluorides, carbonates, bicarbonates and hydrides. The following may be mentioned as individual examples: sodium fluoride, sodium hydride, sodium carbonate, sodium bicarbonate, potassium fluoride and potassium bicarbonate. It is advantageous to use the acid scavenger in an excess, for example in an excess of 10 to 50% by weight, based on the theoretical required amount. It is also advantageous to carry out the cyclization under as anhydrous conditions as possible.

If you have worked with an excess of acid scavenger, it is advantageous to neutralize it immediately after the cyclization has ended. For this purpose, for example, an aqueous acid can be added until a pH e.g. in the

4 to 6 and temperatures in the range of e.g. Maintain 20 to 70 ° C.

The isolation of the naphthyridine compounds of the formulas (Ia) to (Ic) with R = C, -C ₄ -alkyl can be carried out from the reaction mixture, for example by adding water, stirring the mixture obtained and filtering off the suspension which forms and washes the residue in turn with water and alcohol.

If naphthyridine compounds of the formulas (Ia) to (Ic) with R = H are to be prepared, then an ester hydrolysis must be added. This saponification can be e.g. Carry out with glacial acetic acid, water and mineral acid and remove the resulting acetic acid ester from the reaction mixture by distillation.

One can thus naphthyridine compounds of the formulas (la) to (Ic) in purities of over 99%, often over 99.8%, and in yields (based on halogenated acid chloride of the formulas (IΙa) to (IIc)) of over 80% d. Th. Received.

The process according to the invention is advantageous not only because of these good results in terms of yield and purity, but also because it is particularly simple, requires only two reaction vessels and delivers highly pure products without the isolation of intermediate stages. In view of the prior art described at the outset, this is extremely surprising.

The connections of the formulas (Via) to (VIc) are new. The present invention therefore also relates to compounds of the formulas (Via), (Vlb)

(VIc)

in which

R for C _r C ₄ alkyl,

Shark independently for fluorine, chlorine or bromine,

n for 1, 2 or 3,

Shark for fluorine or chlorine and

Ar represents optionally substituted phenyl.

The preferred meaning of the symbols R, Hai, n, Hai 'and Ar is as stated above.

A production process for the compounds of the formulas (Via) to (VIc) and their use for the advantageous production of naphthyridine compounds of the formulas (Ia) to (Ic) is also described above. The new

Compounds of the formulas (Via) to (VIc) are key compounds in the process according to the invention for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic). Examples

example 1

Preparation of a compound of formula (IVa) with R = ethyl, shark in 5-position = fluorine, shark in 6-position = chlorine, Hai '= chlorine and R ¹ = R ² = methyl.

47.2 g of ethyl β-dimethylaminoacrylic acid and 35 g of triethylamine were placed in 250 ml of methylene chloride. 76 g of 97% 2,6-dichloro-5-fluoronicotinic acid chloride were added dropwise in the course of 3 hours. The temperature rose up to 55 ° C. At this temperature, stirring was continued for 1 hour and then cooled to room temperature. Now 250 g of water were added and stirred well. The organic phase was then separated off and the methylene chloride was distilled off. In this way, 110 g of 97% product with a melting point of 94 ° C. were obtained.

H ^J -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

Preparation of a compound of the formula (Via) with R '= ethyl, shark in 5-position = fluorine, shark in 6-position = chlorine, Hai' = chlorine, R ¹ = R ² = methyl and Ar = 2,4-difluorophenyl .

The procedure was initially as given in Example 1, but toluene was used as the solvent instead of methylene chloride. After cooling down

Room temperature (= before washing with water), 22.5 g of glacial acetic acid were added and then 43 g of 2,4-difluoroaniline were metered in over the course of 30 minutes. After stirring at 25 to 30 ° C. for 1 hour, 250 ml of water were added and the mixture was heated to 80 ° C. The aqueous phase was then separated off and the organic phase was washed again with 100 ml of water. The toluene was then removed in vacuo from the organic phase. It remained 138.5 g of a 95% product with a melting point of 138 to 139 ° C.

H ^] -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 (per m, total 3H, Ar-H); 8.2 ppm (d, 1H nicotinoyl-H); 8.6 and 8.7 ppm (each d, IH in HC = C, ice, trans), 11.6 and 12.6 ppm (each d, IH in NH, ice, trans).

Example 3

Preparation of 7-chloro-6-fluoro-1 - (2,4-difluorophenyl) - 1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid ethyl ester (formula (la) with R = ethyl , Ar = 2,4-difluorophenyl, shark in 6-position = fluorine and shark in 7-position = chlorine).

The procedure was first as in Example 2. The washed toluene solution obtained there was metered in over 3 hours onto a template heated to 60 ° C. from 250 ml of N-methylpyrrolidone and 28 g of anhydrous potassium carbonate. At the same time, toluene was continuously distilled off in vacuo. To

The end of the metering was stirred at 60 ° C. for 1 hour, then cooled to 18 ° C. 12 g of concentrated aqueous hydrochloric acid and then 200 g of water were added to this reaction mixture, and the resulting mixture was stirred for 30 minutes. A suspension was obtained, which was filtered off and the residue was washed successively with 120 g of water and 200 g of methanol.

After drying, 105 g of 99.9% product with a melting point of 215 ° C. were obtained. This corresponds to an overall yield (based on halogenated nicotinic acid chloride used) of 84% of theory. Th.

H ^! -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, total 3H, Ar-H); 8.55 ppm (d, IH, nicotinoyl-H); 8.8 ppm (s, IH, -CH =).

Example 4

85 g of the product from Example 3 were added to a mixture of 200 ml of glacial acetic acid and 50 ml of water. For this, 50 ml of conc. Sulfuric acid metered in, the mixture heated to 60 ° C. In order to complete the saponification, the mixture was heated at 105 to 110 ° C. for 4 hours and the ethyl acetate formed was distilled off. Then 250 ml of water were added to 80 ° C., the precipitated product was filtered off at 22 ° C., washed with water and dried. This gave 75 g of 99.9% product in the form of an inner salt. H * -NMR (DMSO): 7.4, 7.65 and 7.9 ppm em, each IH, Ar-H); 8.85 ppm (d, IH Nictoninoyl-H); 9.05 ppm (s, IH, -CH =).

Claims

claims

1. Process for the preparation of naphthyridine compounds of the formulas (Ia) to (Ic)

(la) (Ib)

(Ic)

in which

R represents hydrogen or C _r C ₄ alkyl,

Ar for optionally substituted phenyl

Shark independently for fluorine, chlorine or bromine and

n stands for 1, 2 or 3,

characterized in that a halogenated acid chloride of the formulas (Ila) to (IIc)

(Ila) (Ilb)

(IIc) in which

Shark and n have the meaning given in the formulas (la) to (c) and

Hai 'represents fluorine or chlorine.

with an aminoacrylic acid ester of the formula (III)

in the

R represents C _r C ₄ alkyl and

R ¹ and R ² independently of one another are C ₁ -C ₆ -alkyl, where the alkyl chain can in each case optionally be interrupted by O, S or NH.

an intermediate compound of the formulas (IVa) to (IVc) is obtained

(IVa) (IVb)

(IVc)

in which

Hai and n the given in formulas (la) to (Ic),

Hai 'the given in formulas (Ila) to (IIc) and

R, R ¹ and R ^{2 have} the meaning given for formula (III),

this with an optionally substituted aniline of the formula

H ₂ N-Ar (V),

in the

Ar has the meaning given in the formulas (la) to (Ic)

to form interconnections of the formulas (Via) to (VIc)

(Via), (VIb)

(VIc) in which

Ar, n and shark are those given in formulas (la) to (Ic),

Hai 'the specified in the formulas (Ila) to (IIc) and

R have the meaning given for formula (III),

this cyclized by adding an acid scavenger to a compound of the formulas (la) to (Ic) with R = C _j -C ₄ alkyl and, in the case of the preparation of compounds of the formulas (la) to (Ic) with R = H the Saponified compounds of formula (Ia) to (Ic) with R = CC ₄ alkyl.

Connections of the formulas

(Via), (Vlb)

(VIc)

in which

Ar, Hai, Hai 'and R have the meaning given in claim 1.

A method according to claim 1, characterized in that in the formulas

R represents hydrogen, methyl or ethyl, R represents methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl,

Ar is optionally substituted with 1 to 4 same or different substituents from the group fluorine, chlorine, bromine, cyano, C _j -C ₆ - alkyl and C ^ Cg-alkoxy substituted phenyl,

R ¹ and R ^{2 are the} same and represent methyl or ethyl and

if there are two sharks, one for fluorine and the other for chlorine, and if there are three sharks, 1 to 2 for fluorine and the rest for chlorine and

Hai 'stands for chlorine.

4. Process according to claims 1 and 3, characterized in that the

Compound of the formula (III), a solvent and a base, the compounds of the formulas (Ila) to (IIc) are metered in in a molar ratio to (III) of 0.8 to 1.2: 1 and up to 120% by weight % of the stoichiometrically required amount of base is used.

5. Process according to Claims 1, 3 and 4, characterized in that the compound of the formulas (IVa) to (IVc) is acidified in the form of the reaction mixture which is produced in the course of its preparation and the compound of the formula (V ) in a molar ratio (IVa) to (IVc): (V) from 0.8 to 1.2: 1.

6. Process according to Claims 1 and 3 to 5, characterized in that the compound of the formulas (Via) to (VIc) is metered in the form of the solution obtained in its preparation in the presence of a dipolar, aprotic solvent to form an acid scavenger which is in excess is used and neutralizes the excess acid scavenger after completion of the cyclization by adjusting a pH in the range 4 to 6 at 20 to 70 ° C by adding an aqueous acid.

7. Process according to Claims 1 and 3 to 6, characterized in that alkali metal fluorides, carbonates, bicarbonates or -hydrides in an excess of 10 to 50 wt .-%, based on the amount theoretically required.

8. A process for the preparation of naphthyridine compounds of the formulas (la) to (Ic) with R = H according to claims 1 and 3 to 7, characterized in that a compound of the formulas (la) to (Ic) with

R = C _j -C ₄ alkyl saponified with glacial acetic acid, water and mineral acid and the resulting acetic acid ester is removed from the reaction mixture by distillation.

9. Compounds of claim 2, characterized in that in the formulas (Via) to (VIc)

R represents methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl,

Ar for phenyl optionally substituted with 1 to 4 identical or different substituents from the group fluorine, chlorine, bromine, cyano, C _j -C ₆ alkyl and C _j -C ₈ alkoxy, if two sharks are present, one of them for fluorine and the other is chlorine, and if there are three sharks, 1 to 2 is fluorine and the rest is chlorine, and

Hai ^* stands for chlorine.