Method for the production of...

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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C546S288000

Reexamination Certificate

active

06197964

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to an advantageous process for the preparation of 2,6-dichloro-5-fluoronicotinonitrile starting from 3-cyano-2-hydroxy-5-fluoropyrid-6-one and/or its tautomers and/or its salts and/or tautomers thereof, and to 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt and tautomers thereof (called 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt in the following).
2,6-dichloro-5-fluoronicotinonitrile is the starting compound for synthesis of important units for antibiotics from the class of so-called “aza”-analogous quinolones (cf., for example, German Offenlegungsschrift 35 14 076). Such a use also requires preparation processes for the intermediate products which give the intermediate products in a high purity, high yield and high economic efficiency.
Some preparation processes for 2,6-dichloro-5-fluoronicotinonitrile are already known. Thus, 2,6-dichloro-5-fluoronicotinonitrile can be prepared starting from 2,6-dichloro-5-fluoro-3-trichloromethylpyridine by reaction with ammonium chloride and copper oxide in sulfolane at 180 to 190° C. (cf., for example, WO 95 26 340). However, the large amount of hydrochloric acid formed and the large amounts of solid to be handled are a great disadvantage for industrial realizations.
2,6-dichloro-5-fluoronicotinonitrile can furthermore be obtained from 2,6-dihydroxy-5-fluoronicotinonitrile by reaction with phosphorus pentachloride in phosphorus oxychloride (cf., for example, EP-A 333 020). If 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt, which is not yet known in the literature, is reacted under the conditions described in EP-A 333 020, the desired product is obtained in a yield of only 67% at a purity of 72.6% (cf. Example 2).
Reworking of the process described in EP-A 333 020 moreover shows a decisive disadvantage that if 2.25 equivalents of phosphorus pentachloride, based on the hydroxyl functions to be chlorinated, are used, relatively large amounts of more highly chlorinated by-products are formed, in addition to the desired product 2,6-dichloro-5-fluoronicotinonitrile.
The use of phosphorus pentachloride, which, as a solid, in large amounts, can be handled only with great difficulty and with a very high expenditure on safety, furthermore presents extreme problems, and the hydrolysis necessary for working up is made difficult due to the high residual content of phosphorus pentachloride and the production of relatively large amounts of phosphorus-containing waste waters.
For chlorination of analogous dihydroxynicotinonitriles, the sole use of phosphorus pentachloride (cf., for example, Chem. Pharm. Bull. 35 2280-2285 (1987)) is described, which presents great problems industrially for the abovementioned reasons. For this purpose, the sole use of phosphorus oxychloride as a solvent and chlorinating agent is also described (cf., for example, German Offenlegungsschrift 23 07 444) as well as an addition of large amounts (163 mol %) of triethylamine (cf., for example, Angew. Chem. 92, 390 (1980)).
The reaction of 3-cyano-2-hydroxy-5-fluoropyrid-6-one monosodium salt exclusively with phosphorus oxychloride (as a solvent and chlorinating agent) leads to no reaction. Even at elevated temperature, phosphorus oxychloride is not sufficiently reactive. 2,6-dichloro-5-fluoronicotinonitrile is to be detected in the product isolated only in traces, and the addition of triethylamine also does not lead to a noticeable reaction. In the system of phosphorus oxychloride/triethylamine/reduced amounts of phosphorus pentachloride (1.15 equivalents per function to be chlorinated), low yields and a higher proportion of undesirable by-products are again observed (cf. Example 3).
There is therefore still a need for a process for the preparation of 2,6-dichloro-5-fluoronicotinonitrile which can readily be carried out industrially, gives the product with good yields and in good purities and is economically advantageous.
DESCRIPTION OF THE INVENTION
A process has now been found for the preparation of 2,6-dichloro-5-fluoronicotinonitrile, which comprises reacting 3-cyano-2-hydroxy-5-fluoropyrid-6-one and/or its tautomers and/or its salts and/or tautomers thereof with phosphorus trichloride and chlorine gas in a solvent with the addition of a basic catalyst at 30 to 300° C. and then hydrolyzing the product.
The process according to the invention can be illustrated by way of example by the following equation:
The monosodium salt of the 3-cyano-2-hydroxy-5-fluoropyrid-6-one (cf. Formula (I)) and/or tautomers thereof are preferably employed in the process according to the invention.
The use of a basic catalyst enables significantly lower amounts of chlorinating agent to be employed in the chlorination according to the invention than is necessary, for example, for chlorination of the free dihydroxy compound according to EP-A 333 020. Furthermore, the product 2,6-dichloro-5-fluoronicotinonitrile is obtained in a high purity and high yields after hydrolysis, which is not the case if the conditions according to EP-A 333 020 are applied.
Basic catalysts which can be used for the process according to the invention are, for example, organic bases, for example aliphatic and aromatic amines and amides, and also inorganic bases, for example basic compounds of nitrogen and phosphorus and salts thereof. Preferred basic catalysts are: pyridine, pyridines alkylated with 1 to 3 C
1
-C
6
-alkyl groups, piperidine, piperidines, imidazoles and indoles alkylated with 1 to 3 C
1
-C
6
-alkyl groups, N—C
1
-C
6
-alkylaminopyridines, N—di-C
1
-C
6
-alkylated anilines, tertiary N—C
1
-C
6
-alkylamines, urea and urea derivatives. Particularly preferred basic catalysts are triethylamine, urea and ethylpiperidine.
A particular advantage here is that the catalyst can be employed in small amounts of, for example, 0.1 to 20 mol %, based on the substance to be chlorinated. This amount is preferably 1 to 15 mol %, particularly preferably 10 to 15 mol %. A stoichiometric addition of triethylamine, as in the preparation of the dichloro-nicotinonitrile from dihydroxy-nicotinonitrile according to the abovementioned literature reference from Angew. Chem., is not necessary according to the invention.
It is advantageous to employ the phosphorus trichloride in excess with respect to the chlorine gas and to carry out the reaction such that at least a small excess of phosphorus trichloride is always present in the reaction mixture. For example, chlorine gas can be employed in molar ratios to phosphorus trichloride of 0.1:1 to 0.99:1. This ratio is preferably 0.5:1 to 0.99:1, particularly preferably 0.9:1 to 0.99:1.
A particular advantage of the process according to the invention is that chlorine gas can be employed merely in an amount of 1 to 2 equivalents, based on each functional group to be chlorinated, instead of 2.25 equivalents of phosphorus pentachloride in the procedure analogously to EP-A 333 020. Preferably, 1.5 to 2 equivalents of chlorine gas, based on each functional group to be chlorinated, are employed.
Solvents which can be employed for carrying out the process according to the invention are, for example, phosphorus oxychloride and largely inert organic solvents, for example aromatic or aliphatic hydrocarbons, which can also be halogenated, such as tetralin, ligroin, petroleum ether, chlorobenzenes, methylene chloride or chloroform, ethers, such as diethyl ether, dibutyl ether, methyl butyl ether or tetrahydrofuran, polar aprotic solvents, such as sulfolane or N-methylpyrrolidone, or any desired mixtures thereof. Preferred solvents are phosphorus oxychloride, chloroform, methyl butyl ether, N-methylpyrrolidone and any desired mixtures thereof. Phosphorus oxychloride is preferably the sole solvent.
The solvent can be employed, for example, in amounts of 40 to 99% by weight, preferably 60 to 95% by weight, in particular 80 to 95% by weight, based on the substance to be chlorinated employed.
The chlorination is preferably carried out at temperatures between 20 and 200° C., particularly preferably between 70 and 120° C.
In a pref

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