CA2269984A1 - Method or producing naphthyridine compounds and novel intermediate products - Google Patents
Method or producing naphthyridine compounds and novel intermediate products Download PDFInfo
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- CA2269984A1 CA2269984A1 CA002269984A CA2269984A CA2269984A1 CA 2269984 A1 CA2269984 A1 CA 2269984A1 CA 002269984 A CA002269984 A CA 002269984A CA 2269984 A CA2269984 A CA 2269984A CA 2269984 A1 CA2269984 A1 CA 2269984A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/26—Radicals substituted by halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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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 2nicotinoyl-, isonicotinoyl- or picolinoyl-3-aminoacrylate which is made to react with an optionally substituted aniline to obtain a halogenated 2nicotinoyl-, 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 = C1C4 alkyl is saponified.
Description
r.. .- __ .~ ..
Process for the preparation of naphthyridine compounds and novel intermediates S The present invention relates firstly to an advantageous process for the preparation of the naphthyridine compounds characterized below by formulae (Ia) to (Ic), and novel intermediates which are key compounds for this process. Naphthyridine compounds of the formulae (Ia) to (Ic) are valuable intermediates for the preparation of active ingredients, in particular highly effective bactericides (see, for example, US
Patent Specification S 164 402, US Patent Specification S 298 629 and EP-OS (European Published Specification) 4l3 4SS).
It is known to prepare naphthyridine compounds of the formula (Ia) by reacting a halogenated nicotinoyl chloride with a malonate, then decarboxylating one of the two 1 S carboxylate groups, then converting the methylene group situated between the two carbonyl groups using an ortho-ester into a ~= CH-OR - Group) reacting the alkoxy group introduced in the process with an optionally substituted aniline to give a halogenated nicotinoyl phenylaminoacrylate, which is subjected to ring closure and optional hydrolysis to give a naphthyridine compound of the formula (Ia) (see, for example, DE-OS (German Published Specification) 3S 14 076 and EP-OS (European Published Specifications) 132 84S, 1 S3 S80, 160 7S8, 19l 4S
1, 2S 302 372 and 449 44S). Disadvantages of this process are the large number of steps and the low overall yield, which is below 40% of theory.
A process for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic) O (Hel)~ O
Hal ~5 4 COOR COOR
~a ~ N ~
~J
Hal N N N
i i Ar Ar (Ia) (lb) O
N COOR
i (H81) I
N
I
Ar (Ic) in which R is hydrogen or C,-C4-alkyl, Ar is optionally substituted phenyl, Hal independently of one another are fluorine, chlorine or bromine, and n is 1,2 or 3, has now been found which is characterized in that a halogenated acid chloride of the formulae (IIa) to (IIc) (Hal) Hal COCI ~ COCI
' N~ I ' Hal N Hal' Hal' (IIa) (IIb) N COCI
i (Hel)~ I , Hal' (IIc) in which Hal and n are as defined for the formulae (Ia) to (c), and Hal' is fluorine or chlorine, is reacted with an aminoacrylate of the formula (III) COOR' (III), NR'Rz in which R' is C,-C4-alkyl and R1 and R2 independently of one another are C~-C6-alkyl, it being possible for each alkyl chain to be optionally interrupted by O, S or NH, to give an intermediate of the formulae (IVa) to (IVc) O (Hal)~ O
Hai COOK' COOR' zl ~ , z ~ N ~ I I~ ~, z Hal N Hal' NR R Hal NR R
(IVa) (IVb) O
N COOK' (Hal)~ \ I
Hal' NR'Rz (IVc) in which Hal and n are as defined for the formulae (Ia) to (Ic), Haf is as defined for the formulae (IIa) to (IIc), and R', R' and RZ are as defined for formula (III), which is reacted with an optionally substituted aniline of the formula H2N-Ar (V), in which Ar is as defined for the formulae (Ia) to (Ic), to give intermediates of the formulae (VIa) to (VIc) O (H21) O
Hal COOR' COOK' N
Hal N Hal NHAr Hal' NR'R2 (VIa) (VIb) O
N COOR' (H21) \ ~ ~ , Hai' NHAr (VIc) in which Ar, n and Hal are as defined for the formulae (Ia) to (Ic), Haf is as defined for the formula (IIa) to (IIc), and R' is as defined for formula (III), which is cyclized by addition of an acid scavenger to a compound of the formulae (Ia) to (Ic) where R = C,-C4-alkyl, and, in the case of the preparation of compounds of the formulae (Ia) to (Ic) where R = H, the compounds of the formula (Ia) to (Ic) where R = C~-C4-alkyl are hydrolysed.
Process for the preparation of naphthyridine compounds and novel intermediates S The present invention relates firstly to an advantageous process for the preparation of the naphthyridine compounds characterized below by formulae (Ia) to (Ic), and novel intermediates which are key compounds for this process. Naphthyridine compounds of the formulae (Ia) to (Ic) are valuable intermediates for the preparation of active ingredients, in particular highly effective bactericides (see, for example, US
Patent Specification S 164 402, US Patent Specification S 298 629 and EP-OS (European Published Specification) 4l3 4SS).
It is known to prepare naphthyridine compounds of the formula (Ia) by reacting a halogenated nicotinoyl chloride with a malonate, then decarboxylating one of the two 1 S carboxylate groups, then converting the methylene group situated between the two carbonyl groups using an ortho-ester into a ~= CH-OR - Group) reacting the alkoxy group introduced in the process with an optionally substituted aniline to give a halogenated nicotinoyl phenylaminoacrylate, which is subjected to ring closure and optional hydrolysis to give a naphthyridine compound of the formula (Ia) (see, for example, DE-OS (German Published Specification) 3S 14 076 and EP-OS (European Published Specifications) 132 84S, 1 S3 S80, 160 7S8, 19l 4S
1, 2S 302 372 and 449 44S). Disadvantages of this process are the large number of steps and the low overall yield, which is below 40% of theory.
A process for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic) O (Hel)~ O
Hal ~5 4 COOR COOR
~a ~ N ~
~J
Hal N N N
i i Ar Ar (Ia) (lb) O
N COOR
i (H81) I
N
I
Ar (Ic) in which R is hydrogen or C,-C4-alkyl, Ar is optionally substituted phenyl, Hal independently of one another are fluorine, chlorine or bromine, and n is 1,2 or 3, has now been found which is characterized in that a halogenated acid chloride of the formulae (IIa) to (IIc) (Hal) Hal COCI ~ COCI
' N~ I ' Hal N Hal' Hal' (IIa) (IIb) N COCI
i (Hel)~ I , Hal' (IIc) in which Hal and n are as defined for the formulae (Ia) to (c), and Hal' is fluorine or chlorine, is reacted with an aminoacrylate of the formula (III) COOR' (III), NR'Rz in which R' is C,-C4-alkyl and R1 and R2 independently of one another are C~-C6-alkyl, it being possible for each alkyl chain to be optionally interrupted by O, S or NH, to give an intermediate of the formulae (IVa) to (IVc) O (Hal)~ O
Hai COOK' COOR' zl ~ , z ~ N ~ I I~ ~, z Hal N Hal' NR R Hal NR R
(IVa) (IVb) O
N COOK' (Hal)~ \ I
Hal' NR'Rz (IVc) in which Hal and n are as defined for the formulae (Ia) to (Ic), Haf is as defined for the formulae (IIa) to (IIc), and R', R' and RZ are as defined for formula (III), which is reacted with an optionally substituted aniline of the formula H2N-Ar (V), in which Ar is as defined for the formulae (Ia) to (Ic), to give intermediates of the formulae (VIa) to (VIc) O (H21) O
Hal COOR' COOK' N
Hal N Hal NHAr Hal' NR'R2 (VIa) (VIb) O
N COOR' (H21) \ ~ ~ , Hai' NHAr (VIc) in which Ar, n and Hal are as defined for the formulae (Ia) to (Ic), Haf is as defined for the formula (IIa) to (IIc), and R' is as defined for formula (III), which is cyclized by addition of an acid scavenger to a compound of the formulae (Ia) to (Ic) where R = C,-C4-alkyl, and, in the case of the preparation of compounds of the formulae (Ia) to (Ic) where R = H, the compounds of the formula (Ia) to (Ic) where R = C~-C4-alkyl are hydrolysed.
R' and R where it is C 1-C4-alkyl can in each case be straight-chain or branched and are, 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.
S Where Ar is substituted phenyl, the substituents may, for example, be from 1 to 4 identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, C ~-C6-alkyl and C 1-C6-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.
Hal is preferably fluorine or chlorine. If two Hal are present, one is preferably fluorine and the other is chlorine. If three Hal are present, preferably from 1 to 2 are fluorine and the remainder is chlorine. It is further preferable that there is a fluorine substituent on the carbon atom in the meta-position relative to the carbonyl group 1 S (i.e. the 6-position in formula (Ia) and the corresponding position in the other formulae).
Hal' is preferably chlorine, n is preferably 2.
R' and R2 are preferably identical and are each methyl or ethyl, in particular ethyl.
The reaction of compounds of the formulae (IIa) to (IIc) with a compound of the formula (III) can be carried out, for example, by introducing initially the compound of the formula (III), a solvent and a base, and metering in a compound of the formulae (IIa) to (IIc). In principle, the reactants can be used in any ratios to one another. For cost considerations, the molar ratio of the compound of the formulae (IIa) to (IIc) to the compound of the formula (III) is preferably from 0.8 to 1.2:1, in particular from 0.9 to 1.1:I .
Suitable bases are in principle many different inorganic and organic bases. In the case of bases which are sparingly soluble in the reaction mixture, e.g. inorganic bases, it is advantageous to add a phase transfer catalyst. Preference is given to organic bases, e.g. amines. Particular preference is given to tertiary amines which contain, for example, three identical or different CI-C6-alkyl groups, such as triethylamine. The amount of base should be at least the stoichiometrically required amount, but a small excess, e.g. up to 120% by weight of the stoichiometrically required amount, is preferable.
Examples of suitable solvents are chlorinated hydrocarbons and aromatics.
Preference is given to methylene chloride, dichloromethane, toluene and xylene. The reaction temperature can, for example, be in the range from -10 to +80~C. It is generally advantageous to continue stirnng for some time at the reaction temperature after the reactants have been mixed together.
The entire process of the preparation of naphthyridine compounds of the formulae (Ic) to Ic) can be carried out in the reactor which contains the fully reacted reaction mixture of the reaction of a compound of the formulae (IIa) to (IIc) with a compound of the formula (III). Isolation of the prepared compound of the formulae (Na) to (IVc) is not necessary for this purpose.
If it is nevertheless desired to isolate the prepared compound of the formulae (Na) to (Nc), for example in order to characterize it and/or to use it for purposes other than for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic), the following procedure may be followed, for example: water, for example from 30 to 300 vol% (based on the reaction mixture) is added to the fully reacted reaction mixture, the mixture is stirred well, and then the aqueous phase is separated from the organic phase and the organic phase is freed from solvent. In this way, it is possible to obtain compounds of the formulae (Na) to (Nc) in purities greater than 95%, which can optionally be further purified using conventional methods.
The reaction of a compound of the formulae (Na) to (Nc) with a compound of the formula (V) to give a compound of the formulae (VIa) to (VIc) can be carried out, for example, by acidifying a compound of the formulae (Na) to (Nc), preferably in the form of the fully reacted reaction mixture obtained in its preparation, and, at temperatures of for example below 50~C, preferably below 40~C, optionally with cooling, metering in a compound of the formula (V). The compounds of the formulae (Na) to (Nc) on the one hand and of the formula (V) on the other can in principle be used in any ratios to one another. For cost considerations, the molar ratio of the compound of the formulae (Na) to (Nc) to the compound of the formula (V) is preferably from 0.8 to l.2:1, in particular from 0.9 to 1.1:1.
For the acidification, it is in principle possible to use a wide variety of inorganic and organic acids. Preference is given to C2-C6-alkyl- and C~-C ~ 3-arylcarboxylic acids, in particular acetic acid. The amount of acid can be chosen, for example, such that there is a slight excess relative to the base used. The amount of acid can thus be, for example, up to 125 equivalent %, in relation to the base used.
Here too, it is advantageous to continue stirring for some time at the reaction temperature after the reactants have been mixed together. When the reaction is complete, it is advantageous to wash the reaction mixture with water for, for example, from 1 to 3 times. The washing can, for example, be carried out at temperatures from room temperature to 95~C.
The entire process of the preparation of naphthyridine compounds of the formulae (Ia) to (Ic) can be continued with the resulting solution which essentially comprises the prepared compound of the formulae (VIa) to (VIc) and the solvent used.
Isolation of the prepared compound of the formulae (VIa) to (VIc) is not required for this purpose.
If it is nevertheless desired to isolate the prepared compound of the formulae (VIa) to (VIc), for example in order to characterize it and/or to use it for purposes other than for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic), it is possible to remove the solvent from the solution resulting following the washing with water. In this way, it is possible to obtain compounds of the formulae (VIa) to (VIc) having above 93% purity, which can optionally be further purified using conventional methods.
The cyclization of a compound of the formulae (VIa) to (VIc) to a compound of the formulae (Ia) to (Ic) where R = C~-C4-alkyl can be carned out, for example, by metering a compound of the formulae (VIa) to (VIc), preferably in the form of the solution obtained in its preparation, in the presence of a dipolar aprotic solvent, into an acid scavenger. The dipolar aprotic solvent can be, for example, dimethylformamide, dimethyl sulphoxide, tetramethylene sulphone or N'-methylpyrrolidone. Examples of suitable acid scavengers are alkali metal salts such as alkali metal fluorides, carbonates, hydrogencarbonates and hydrides.
Individual examples which may be mentioned are: 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 _g_ from 10 to SO% by weight, based on the theoretically required amount. It is also advantageous to carry out the cyclization under conditions which are as anhydrous as possible.
S If the process has been carried out using an excess of acid scavenger, it is advantageous to neutralize it immediately after cyclization is complete. For this purpose, it is possible, for example, to add an aqueous acid until the pH is, for example, in the range from 4 to 6 while maintaining the temperatures in the range from, for example, 20 to 70~C.
The prepared naphthyridine compounds of the formulae (Ia) to (Ic) where R = C,-alkyl can be isolated from the reaction mixture by, for example, adding water, stirring the resulting mixture, filtering off the suspension which forms and washing the residue successively with water and alcohol.
If it is desired to prepare naphthylridine compounds of the formulae (Ia) to (Ic) where R = H, then an ester hydrolysis must also be carried out. This hydrolysis can be carried out, for example, using glacial acetic acid, water and mineral acid, and the resulting acetate can be removed from the reaction mixture by distillation.
In this way, it is possible to obtain naphthyridine compounds of the formulae (Ia) to (Ic) in purities greater than 99%, but frequently greater than 99.8%, and in yields (based on halogenated acid chloride of the formulae (IIa) to (IIc) used) of more than 80% of theory.
The process according to the invention is not only advantageous because of these good results as regards yield and purity, but also because it is particularly straightforward, only requires two reaction vessels and produces high-purity products without isolation of intermediates. In view of the prior art described at the outset, this is extraordinarily surprising.
The compounds of the formulae (VIa) to (VIc) are novel. The present invention thus also relates to compounds of the formulae O (H81) O
Hal COOR' COOR' , Hal N Hal' NHAr Hal' NR'R2 (VIa) (VIb) O
N COOR' i (Hal)~ \ ~ ' Had, NHAr (VIc) in which R' is C,-C4-alkyl, Hal independently of one another are fluorine, chlorine or bromine, n is 1, 2 or 3, Hal' is fluorine or chlorine, and Ar is optionally substituted phenyl.
The preferred meaning of the symbols R, Hal, n, Hal' and Ar is as given above.
Also described above is a process for the preparation of the compounds of the formulae (VIa) to (VIc) and their use for the advantageous preparation of naphthyridine compounds of the formulae (Ia) to (Ic). The novel compounds of the formulae (VIa) to (VIc) are key compounds in the novel process for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic).
Examples Example 1 Preparation of a compound of the formula (IVa) where R' = ethyl, Hal in 5-position =
fluorine, Hal in 6-position = chlorine, Hal' = chlorine and Rl = R2 = methyl.
47.2 g of ethyl f3-dimethylaminoacrylate and 35 g of triethylamine were mixed into 250 ml of methylene chloride. Over the course of 3 hours, 76 g of 97% pure 2,6-dichloro-5-fluoronicotinoyl chloride were added dropwise. The temperature rose to 55~C. At this temperature, stirring was continued for 1 hour and then the mixture was cooled to room temperature. 250 g of water were then added and the mixture was stirred well. The organic phase was then separated off, and the methylene chloride was distilled off to give 110 g of 97% pure product having a melting point of 94~C.
H1-NMR (DMSO): 0.95 ppm (t, CHZCH~); 2.9 and 3.4 ppm (2 x s, N-CHI); 3.9 ppm (q, CHzCH3); 7.95 ppm (br, S.; HC=); 8.04 ppm (d, Ar-H).
Example 2 Preparation of a compound of the formula (VIa) where R' = ethyl, Hal in S-position fluorine, Hal in 6-position = chlorine, Haf = chlorine, Rl = R2 = methyl and Ar =
2,4-difluorophenyl.
Initially, the procedure was as given in Example 1, but using toluene as solvent instead of methylene chloride. After the mixture had been cooled to room temperature (= prior to the washing with water), 22.5 g of glacial acetic acid were added, and then, over the course of 30 minutes, 43 g of 2,4-difluoroaniline were metered in. After the mixture had been stirred for 1 hour at from 25 to 30~C, 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 from the organic phase under reduced pressure to leave 138.5 g of a 95% pure product having a melting point of from l38 to 139~C.
H1-NMR (DMSO): 1 ppm (t, 3H, CH?CHI); 4 (q, 2H, CH~CH3); 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, 1 H in HC = C, cis, trans), 11.6 and 12.6 ppm (each d, 1 H in NH, cis, trans).
_ CA 02269984 1999-04-27 Examine 3 Preparation of ethyl 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (formula (Ia) where R = ethyl, Ar = 2,4-difluorophenyl, S Hal in 6-position = fluorine and Hal in 7-position= chlorine).
Initially, the procedure was as in Example 2. The washed toluenic solution obtained therein was metered over the course of 3 hours into an initial charge of 250 ml of N-methylpyrrolidone and 28 g of anhydrous potassium carbonate which had been heated to 60~C. At the same time, toluene was continuously distilled off under reduced pressure. When the metered addition was complete, stirring was continued for 1 hour at 60~C, 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 this reaction mixture, and the resulting mixture was stirred for 30 minutes. This gave a suspension, which was filtered, and the residue was washed successively with 120 g of water and 200 g of methanol. Drying gave 105 g of 99.9% pure product having a melting point of 2l5~C. This corresponds to an overall yield (based on halogenated nicotinoyl chloride used) of 84% of theory.
H'-NMR (DMSO): 1.3 ppm (t, 3H, CH2CH ); 4.3 ppm (q, 2H, CH~CH3); 7.35, 7.6S
and 7:9 ppm (m, in total 3H, Ar-H); 8.55 ppm (d, 1H, nicotinoyl-H); 8.8 ppm (s, 1H, -CH=).
Exam,Ple 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. SO ml of conc. sulphuric acid were metered in, and the temperature of the mixture increased to 60~C. In order to complete hydrolysis, the mixture was heated for 4 h hours at from l05 to 110~C and the ethyl acetate which formed was filtered off. 250 ml of water were then added up to 80~C, and the product which precipitated out was filtered off at 22~C, washed with water and dried.
This gave 75 g of a 99.9% pure product in the form of an internal salt.
H'-NMR (DMSO): 7.4, 7.65 and 7.9 ppm (each m, each 1 H, Ar-H); 8.85 ppm (d, 1 H
nictoninoyl-H); 9.05 ppm (s, 1H, -CH=).
S Where Ar is substituted phenyl, the substituents may, for example, be from 1 to 4 identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, C ~-C6-alkyl and C 1-C6-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.
Hal is preferably fluorine or chlorine. If two Hal are present, one is preferably fluorine and the other is chlorine. If three Hal are present, preferably from 1 to 2 are fluorine and the remainder is chlorine. It is further preferable that there is a fluorine substituent on the carbon atom in the meta-position relative to the carbonyl group 1 S (i.e. the 6-position in formula (Ia) and the corresponding position in the other formulae).
Hal' is preferably chlorine, n is preferably 2.
R' and R2 are preferably identical and are each methyl or ethyl, in particular ethyl.
The reaction of compounds of the formulae (IIa) to (IIc) with a compound of the formula (III) can be carried out, for example, by introducing initially the compound of the formula (III), a solvent and a base, and metering in a compound of the formulae (IIa) to (IIc). In principle, the reactants can be used in any ratios to one another. For cost considerations, the molar ratio of the compound of the formulae (IIa) to (IIc) to the compound of the formula (III) is preferably from 0.8 to 1.2:1, in particular from 0.9 to 1.1:I .
Suitable bases are in principle many different inorganic and organic bases. In the case of bases which are sparingly soluble in the reaction mixture, e.g. inorganic bases, it is advantageous to add a phase transfer catalyst. Preference is given to organic bases, e.g. amines. Particular preference is given to tertiary amines which contain, for example, three identical or different CI-C6-alkyl groups, such as triethylamine. The amount of base should be at least the stoichiometrically required amount, but a small excess, e.g. up to 120% by weight of the stoichiometrically required amount, is preferable.
Examples of suitable solvents are chlorinated hydrocarbons and aromatics.
Preference is given to methylene chloride, dichloromethane, toluene and xylene. The reaction temperature can, for example, be in the range from -10 to +80~C. It is generally advantageous to continue stirnng for some time at the reaction temperature after the reactants have been mixed together.
The entire process of the preparation of naphthyridine compounds of the formulae (Ic) to Ic) can be carried out in the reactor which contains the fully reacted reaction mixture of the reaction of a compound of the formulae (IIa) to (IIc) with a compound of the formula (III). Isolation of the prepared compound of the formulae (Na) to (IVc) is not necessary for this purpose.
If it is nevertheless desired to isolate the prepared compound of the formulae (Na) to (Nc), for example in order to characterize it and/or to use it for purposes other than for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic), the following procedure may be followed, for example: water, for example from 30 to 300 vol% (based on the reaction mixture) is added to the fully reacted reaction mixture, the mixture is stirred well, and then the aqueous phase is separated from the organic phase and the organic phase is freed from solvent. In this way, it is possible to obtain compounds of the formulae (Na) to (Nc) in purities greater than 95%, which can optionally be further purified using conventional methods.
The reaction of a compound of the formulae (Na) to (Nc) with a compound of the formula (V) to give a compound of the formulae (VIa) to (VIc) can be carried out, for example, by acidifying a compound of the formulae (Na) to (Nc), preferably in the form of the fully reacted reaction mixture obtained in its preparation, and, at temperatures of for example below 50~C, preferably below 40~C, optionally with cooling, metering in a compound of the formula (V). The compounds of the formulae (Na) to (Nc) on the one hand and of the formula (V) on the other can in principle be used in any ratios to one another. For cost considerations, the molar ratio of the compound of the formulae (Na) to (Nc) to the compound of the formula (V) is preferably from 0.8 to l.2:1, in particular from 0.9 to 1.1:1.
For the acidification, it is in principle possible to use a wide variety of inorganic and organic acids. Preference is given to C2-C6-alkyl- and C~-C ~ 3-arylcarboxylic acids, in particular acetic acid. The amount of acid can be chosen, for example, such that there is a slight excess relative to the base used. The amount of acid can thus be, for example, up to 125 equivalent %, in relation to the base used.
Here too, it is advantageous to continue stirring for some time at the reaction temperature after the reactants have been mixed together. When the reaction is complete, it is advantageous to wash the reaction mixture with water for, for example, from 1 to 3 times. The washing can, for example, be carried out at temperatures from room temperature to 95~C.
The entire process of the preparation of naphthyridine compounds of the formulae (Ia) to (Ic) can be continued with the resulting solution which essentially comprises the prepared compound of the formulae (VIa) to (VIc) and the solvent used.
Isolation of the prepared compound of the formulae (VIa) to (VIc) is not required for this purpose.
If it is nevertheless desired to isolate the prepared compound of the formulae (VIa) to (VIc), for example in order to characterize it and/or to use it for purposes other than for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic), it is possible to remove the solvent from the solution resulting following the washing with water. In this way, it is possible to obtain compounds of the formulae (VIa) to (VIc) having above 93% purity, which can optionally be further purified using conventional methods.
The cyclization of a compound of the formulae (VIa) to (VIc) to a compound of the formulae (Ia) to (Ic) where R = C~-C4-alkyl can be carned out, for example, by metering a compound of the formulae (VIa) to (VIc), preferably in the form of the solution obtained in its preparation, in the presence of a dipolar aprotic solvent, into an acid scavenger. The dipolar aprotic solvent can be, for example, dimethylformamide, dimethyl sulphoxide, tetramethylene sulphone or N'-methylpyrrolidone. Examples of suitable acid scavengers are alkali metal salts such as alkali metal fluorides, carbonates, hydrogencarbonates and hydrides.
Individual examples which may be mentioned are: 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 _g_ from 10 to SO% by weight, based on the theoretically required amount. It is also advantageous to carry out the cyclization under conditions which are as anhydrous as possible.
S If the process has been carried out using an excess of acid scavenger, it is advantageous to neutralize it immediately after cyclization is complete. For this purpose, it is possible, for example, to add an aqueous acid until the pH is, for example, in the range from 4 to 6 while maintaining the temperatures in the range from, for example, 20 to 70~C.
The prepared naphthyridine compounds of the formulae (Ia) to (Ic) where R = C,-alkyl can be isolated from the reaction mixture by, for example, adding water, stirring the resulting mixture, filtering off the suspension which forms and washing the residue successively with water and alcohol.
If it is desired to prepare naphthylridine compounds of the formulae (Ia) to (Ic) where R = H, then an ester hydrolysis must also be carried out. This hydrolysis can be carried out, for example, using glacial acetic acid, water and mineral acid, and the resulting acetate can be removed from the reaction mixture by distillation.
In this way, it is possible to obtain naphthyridine compounds of the formulae (Ia) to (Ic) in purities greater than 99%, but frequently greater than 99.8%, and in yields (based on halogenated acid chloride of the formulae (IIa) to (IIc) used) of more than 80% of theory.
The process according to the invention is not only advantageous because of these good results as regards yield and purity, but also because it is particularly straightforward, only requires two reaction vessels and produces high-purity products without isolation of intermediates. In view of the prior art described at the outset, this is extraordinarily surprising.
The compounds of the formulae (VIa) to (VIc) are novel. The present invention thus also relates to compounds of the formulae O (H81) O
Hal COOR' COOR' , Hal N Hal' NHAr Hal' NR'R2 (VIa) (VIb) O
N COOR' i (Hal)~ \ ~ ' Had, NHAr (VIc) in which R' is C,-C4-alkyl, Hal independently of one another are fluorine, chlorine or bromine, n is 1, 2 or 3, Hal' is fluorine or chlorine, and Ar is optionally substituted phenyl.
The preferred meaning of the symbols R, Hal, n, Hal' and Ar is as given above.
Also described above is a process for the preparation of the compounds of the formulae (VIa) to (VIc) and their use for the advantageous preparation of naphthyridine compounds of the formulae (Ia) to (Ic). The novel compounds of the formulae (VIa) to (VIc) are key compounds in the novel process for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic).
Examples Example 1 Preparation of a compound of the formula (IVa) where R' = ethyl, Hal in 5-position =
fluorine, Hal in 6-position = chlorine, Hal' = chlorine and Rl = R2 = methyl.
47.2 g of ethyl f3-dimethylaminoacrylate and 35 g of triethylamine were mixed into 250 ml of methylene chloride. Over the course of 3 hours, 76 g of 97% pure 2,6-dichloro-5-fluoronicotinoyl chloride were added dropwise. The temperature rose to 55~C. At this temperature, stirring was continued for 1 hour and then the mixture was cooled to room temperature. 250 g of water were then added and the mixture was stirred well. The organic phase was then separated off, and the methylene chloride was distilled off to give 110 g of 97% pure product having a melting point of 94~C.
H1-NMR (DMSO): 0.95 ppm (t, CHZCH~); 2.9 and 3.4 ppm (2 x s, N-CHI); 3.9 ppm (q, CHzCH3); 7.95 ppm (br, S.; HC=); 8.04 ppm (d, Ar-H).
Example 2 Preparation of a compound of the formula (VIa) where R' = ethyl, Hal in S-position fluorine, Hal in 6-position = chlorine, Haf = chlorine, Rl = R2 = methyl and Ar =
2,4-difluorophenyl.
Initially, the procedure was as given in Example 1, but using toluene as solvent instead of methylene chloride. After the mixture had been cooled to room temperature (= prior to the washing with water), 22.5 g of glacial acetic acid were added, and then, over the course of 30 minutes, 43 g of 2,4-difluoroaniline were metered in. After the mixture had been stirred for 1 hour at from 25 to 30~C, 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 from the organic phase under reduced pressure to leave 138.5 g of a 95% pure product having a melting point of from l38 to 139~C.
H1-NMR (DMSO): 1 ppm (t, 3H, CH?CHI); 4 (q, 2H, CH~CH3); 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, 1 H in HC = C, cis, trans), 11.6 and 12.6 ppm (each d, 1 H in NH, cis, trans).
_ CA 02269984 1999-04-27 Examine 3 Preparation of ethyl 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (formula (Ia) where R = ethyl, Ar = 2,4-difluorophenyl, S Hal in 6-position = fluorine and Hal in 7-position= chlorine).
Initially, the procedure was as in Example 2. The washed toluenic solution obtained therein was metered over the course of 3 hours into an initial charge of 250 ml of N-methylpyrrolidone and 28 g of anhydrous potassium carbonate which had been heated to 60~C. At the same time, toluene was continuously distilled off under reduced pressure. When the metered addition was complete, stirring was continued for 1 hour at 60~C, 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 this reaction mixture, and the resulting mixture was stirred for 30 minutes. This gave a suspension, which was filtered, and the residue was washed successively with 120 g of water and 200 g of methanol. Drying gave 105 g of 99.9% pure product having a melting point of 2l5~C. This corresponds to an overall yield (based on halogenated nicotinoyl chloride used) of 84% of theory.
H'-NMR (DMSO): 1.3 ppm (t, 3H, CH2CH ); 4.3 ppm (q, 2H, CH~CH3); 7.35, 7.6S
and 7:9 ppm (m, in total 3H, Ar-H); 8.55 ppm (d, 1H, nicotinoyl-H); 8.8 ppm (s, 1H, -CH=).
Exam,Ple 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. SO ml of conc. sulphuric acid were metered in, and the temperature of the mixture increased to 60~C. In order to complete hydrolysis, the mixture was heated for 4 h hours at from l05 to 110~C and the ethyl acetate which formed was filtered off. 250 ml of water were then added up to 80~C, and the product which precipitated out was filtered off at 22~C, washed with water and dried.
This gave 75 g of a 99.9% pure product in the form of an internal salt.
H'-NMR (DMSO): 7.4, 7.65 and 7.9 ppm (each m, each 1 H, Ar-H); 8.85 ppm (d, 1 H
nictoninoyl-H); 9.05 ppm (s, 1H, -CH=).
Claims (9)
1. Process for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic) ,~~, in which R is hydrogen or C1-C4-alkyl, Ar is optionally substituted phenyl, Hal independently of one another are fluorine, chlorine or bromine, and n is 1,2 or 3, characterized in that a halogenated acid chloride of the formulae (IIa) to (IIc) , , , in which Hal and n are as defined for the formulae (Ia) to (c), and Hal' is fluorine or chlorine, is reacted with an aminoacrylate of the formula (III) , in which R' is C1-C4-alkyl, and R1 and R2 independently of one another are C1-C6-alkyl, it being possible for each alkyl chain to be optionally interrupted by O, S or NH, to give an intermediate of the formulae (IVa) to (IVc) ~~ in which Hal and n are as defined for the formulae (Ia) to (Ic), Hal' is as defined for the formulae (IIa) to (IIc), and R', R1 and R2 are as defined for formula (III), which is reacted with an optionally substituted aniline of the formula H2N-Ar (V), in which Ar is as defined for the formulae (Ia) to (Ic), to give intermediates of the formulae (VIa) to (VIc) , in which Ar, n and Hal are as defined for the formulae (Ia) to (Ic), Hal' is as defined for the formula (IIa) to (IIc), and R' is as defined for formula (III), which is cyclized by addition of an acid scavenger to a compound of the formulae (Ia) to (Ic) where R = C1-C4-alkyl, and, in the case of the preparation of compounds of the formulae (Ia) to (Ic) where R = H, the compounds of the formula (Ia) to (Ic) where R = C1-C4-alkyl are hydrolysed.
2. Compounds of the formulae in which Ar, Hal, Hal' and R1 are as defined in Claim 1.
3. Process according to Claim 1, characterized in that, in the formulae, R 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 from 1 to 4 identical or different substituents ftom the group consisting of fluorine, chlorine, bromine, cyano, C1-C6-alkyl and C1-C6-alkoxy, R1 and R2 are identical and are methyl or ethyl, and if two Hal are present, one is fluorine and the other is chlorine, and if three Hal are present, from 1 to 2 are fluorine and the remainder is chlorine, and Hal' is chlorine.
4. Process according to Claims 1 and 3, characterized in that the compound of the formula (III), a solvent and a base are introduced initially, the compounds of the formulae (IIa) to (IIc) are metered in in a molar ratio to (III) of from 0.8 to 1.2 : 1, and up to 120% by weight of the stoichiometrically required amount of base are used.
5. Process according to Claims 1, 3 and 4, characterized in that the compound of the formulae (IVa) to (IVc) is acidified in the form of the fully reacted reaction mixture obtained in its preparation, and, at temperatures below 50°C, the compound of the formula (V) is metered in in a (IVa) to (IVc) : (V) molar ratio of from 0.8 to 1.2 : 1.
6. Process according to Claims 1 and 3 to 5, characterized in that the compound of the formulae (VIa) to (VIc) is metered in the form of the solution obtained in its preparation, in the presence of a dipolar, aprotic solvent, into an acid scavenger which is used in excess, and, after cyclization is complete, the excess acid scavenger is neutralized by, at from 20 to 70°C, adjusting the pH
to be in the range from 4 to 6 by addition of an aqueous acid.
to be in the range from 4 to 6 by addition of an aqueous acid.
7. Process according to Claims 1 and 3 to 6, characterized in that the acid scavenger used is an alkali metal fluoride, carbonate, hydrogencarbonate or hydride in an excess of from 10 to 50% by weight, based on the theoretically required amount.
8. Process for the preparation of naphthyridine compounds of the formulae (Ia) to (Ic) where R = H according to Claims 1 and 3 to 7, characterized in that a compound of the formulae (Ia) to (Ic) where R = C1-C4-alkyl is hydrolysed using glacial acetic acid, water and mineral acid, and the resulting acetate is removed from the reaction mixture by distillation.
9. Compounds of Claim 2, characterized in that, in the formulae (VIa) to (VIc) R' is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, Ar is phenyl optionally substituted by from 1 to 4 identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, C1-C6-alkyl and C1-C6-alkoxy, if two Hal are present, one is fluorine and the other is chlorine, and if three Hal are present, from 1 to 2 are fluorine and the remainder is chlorine, and Hal' is chlorine.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1996143826 DE19643826A1 (en) | 1996-10-30 | 1996-10-30 | Preparation of halo-N-aryl-pyrido:pyridone carboxylic acid compounds |
| DE19643826.8 | 1996-10-30 | ||
| DE19648214.3 | 1996-11-21 | ||
| DE19648214A DE19648214A1 (en) | 1996-11-21 | 1996-11-21 | Naphthyridine-3-carboxylic acid derivative preparation in high yield |
| PCT/EP1997/005743 WO1998018795A1 (en) | 1996-10-30 | 1997-10-17 | Method or producing naphthyridine compounds and novel intermediate products |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2269984A1 true CA2269984A1 (en) | 1998-05-07 |
Family
ID=26030644
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002269984A Abandoned CA2269984A1 (en) | 1996-10-30 | 1997-10-17 | Method or producing naphthyridine compounds and novel intermediate products |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0935600A1 (en) |
| JP (1) | JP2001502715A (en) |
| KR (1) | KR20000052892A (en) |
| CN (1) | CN1235605A (en) |
| AU (1) | AU5050898A (en) |
| CA (1) | CA2269984A1 (en) |
| CZ (1) | CZ154999A3 (en) |
| IL (1) | IL129597A0 (en) |
| PL (1) | PL332941A1 (en) |
| WO (1) | WO1998018795A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0001054A3 (en) | 1997-08-06 | 2001-01-29 | Daiichi Asubio Pharma Co Ltd | 1-aryl-1,8-naphthyridin-4-one derivative as type iv phosphodiesterase inhibitor |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CS274601B2 (en) * | 1983-07-27 | 1991-09-15 | Dainippon Pharmaceutical Co | Method of 1,8-naphthyridine derivative production |
| JPS60228479A (en) * | 1984-04-26 | 1985-11-13 | Toyama Chem Co Ltd | 1,4-dihydro-4-oxonaphthyridine derivative and salt thereof |
| DE4425647A1 (en) * | 1994-07-20 | 1996-01-25 | Bayer Ag | Heterocyclyl-1-phenyl substituted quinolonecarboxylic acids |
-
1997
- 1997-10-17 CZ CZ991549A patent/CZ154999A3/en unknown
- 1997-10-17 EP EP97913157A patent/EP0935600A1/en not_active Withdrawn
- 1997-10-17 JP JP10519989A patent/JP2001502715A/en active Pending
- 1997-10-17 PL PL97332941A patent/PL332941A1/en unknown
- 1997-10-17 CN CN97199280A patent/CN1235605A/en active Pending
- 1997-10-17 CA CA002269984A patent/CA2269984A1/en not_active Abandoned
- 1997-10-17 KR KR1019990703756A patent/KR20000052892A/en not_active Application Discontinuation
- 1997-10-17 AU AU50508/98A patent/AU5050898A/en not_active Abandoned
- 1997-10-17 WO PCT/EP1997/005743 patent/WO1998018795A1/en not_active Application Discontinuation
- 1997-10-17 IL IL12959797A patent/IL129597A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL332941A1 (en) | 1999-10-25 |
| KR20000052892A (en) | 2000-08-25 |
| CZ154999A3 (en) | 1999-08-11 |
| IL129597A0 (en) | 2000-02-29 |
| CN1235605A (en) | 1999-11-17 |
| EP0935600A1 (en) | 1999-08-18 |
| JP2001502715A (en) | 2001-02-27 |
| WO1998018795A1 (en) | 1998-05-07 |
| AU5050898A (en) | 1998-05-22 |
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