MXPA99009002A - Method for the production of 2,6-dichloro-5-fluoronicotinonitrile and the chemical compound 3-cyano-2-hydroxy-5-fluoropyride-6-one-monosodium salt and its tautomers - Google Patents

Abstract

The invention relates to 2,6-dichloro-5-fluoronicotinitrile which can be advantageously obtained by reacting 3-cyano-2-hydroxy-5-fluoropyride-6-one and/or its tautomers and/or its salts and/or their tautomers with phosphorus trichloride and chloric gas in a solvent with addition of a basic catalyst at temperatures between 30 and 300°C, and then by hydrolysis. The 3-cyano-2-hydroxy-5-fluoropyride-6-one-monosodium salt which can be used is a new chemical compound that is easy to obtain from 3-cyano-2-hydroxy-5-fluoropyride-6-one and/or its tautomers by reaction with alcoholate and precipitation with a moderately weak acid.

Description

Process for the preparation of 2, 6-dialoro-5-fluoronicotinonitrile, chemical compound monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one and the tautomers thereof Description 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-idroxy-5-fluoropyrid-6-one and / or its tautomers and / or its salts and / or the tautomers thereof, and the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one and the tautomers thereof (so-called monosodium salt of 3-cyano-2-hydroxy -5-fluoropyrid-6-one hereafter). 2,6-dichloro-5-fluoronicotinonitrile is the initial compound for the synthesis of important units for antibiotics of the class of the so-called analogous quinolones' aza "(see for example, description open to the German public 35 14 076). Such use also requires the preparation processes for intermediary products that give the intermediate products with high purity, high yield and high economic efficiency. REF .: 31441 Some preparation processes for 2,6-dichloro-5-fluoronicotinonitrile are already known. In this way, 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.degree. 190 ° C (see for example WO 95 26 340). However, the large amount of hydrochloric acid formed and the large quantities of solid that are handled are a great disadvantage for industrial embodiments. The 2,6-dichloro-5-fluoronicotinonitrile can also be obtained from 2,6-dihydroxy-5-fluoronicotinonitrile by reaction with phosphorus pentachloride in phosphorus oxychloride (see, for example, European patent EP-A 333 020). If the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one, which is not yet known in the literature, is reacted under the conditions described in European Patent EP-A 333 020, the The desired product is obtained with a yield of only 67% at a purity of 72.6% (see example 2). Reworking the process described in the European patent EP-A 333 020 further shows a decisive disadvantage that if 2.25 equivalents of phosphorus pentachloride are used, based on the hydroxyl functional groups that are to be chlorinated, relatively large amounts are formed large of more highly chlorinated by-products, in addition to the desired product 2,6-dichloro-5-fluoronicotinonitrile. The use of phosphorus pentachloride, which as a solid, in large quantities, can only be handled with great difficulty and with a very high safety expense, it also presents extreme problems, and the hydrolysis necessary to work with it becomes difficult because the high residual content of phosphorus pentachloride and the production of relatively large amounts of phosphorus-containing wastewater. For the chlorination of analogous dihydroxinicotinonitriles, the single use of phosphorus pentachloride (see for example, Chem. Pharm. Bull. 3_5, 2280-2285 (1987)) is described, which presents great problems industrially for the reasons mentioned above. For this purpose, the exclusive use of the phosphorus oxychloride as a solvent and the chlorinating agent is also described (see for example, German publication open to the public 23 07 444) as well as an addition of large quantities (163 mol%) of triethylamine (see for example, Angew, Chem. 92, 390 (1980)). The reaction of the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one exclusively with phosphorus oxychloride (as a solvent and chlorinating agent) leads to a lack of reaction. Even at elevated temperature, phosphorus oxychloride is not sufficiently reactive. The 2,6-dichloro-5-fluoronicotinonitrile has to be detected in the product isolated only in trace amounts, and the addition of triethylamine also does not lead to a perceptible reaction. In the phosphorus oxychloride / triethylamine / reduced amounts of phosphorus pentachloride system (1.15 equivalents per functional group to be chlorinated), low yields and a higher proportion of undesirable byproducts are again observed (see Example 3). There is therefore still a need for a process for the preparation of 2,6-dichloro-5-fluoronicotinonitrile which can be easily carried out industrially, and gives the product in good yields and in good purities, and is economically advantageous.

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 the tautomers thereof with phosphorus trichloride and chlorine gas in a solvent, with the addition of a basic catalyst at 30-300 ° C and then hydrolyzing the product. The process according to the invention can be illustrated by way of example by the following equation: 0) (») The monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one (see formula (I)) and / or the tautomers thereof are preferably used in the process according to the invention. The use of a basic catalyst makes it possible to employ significantly lower amounts of the chlorinating agent in the chlorination according to the invention, than what is necessary, for example, for the chlorination of the free dihydroxy compound according to the European patent EP -A 333 020. In addition, the product 2,6-dichloro-5-fluoronicotinonitrile is obtained with high purity and high yields after hydrolysis, which is not the case if the conditions are applied according to the European patent EP -A 333 020. The basic catalysts which can be used by 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 nitrogen and phosphorus compounds and you come out of them. Preferred basic catalysts are: pyridine, pyridines alkylated with 1 to 3 alkyl groups of 1 to 6 carbon atoms, piperidine, piperidines, imidazoles and alkylated with 1 to 3 alkyl groups of 1 to 6 carbon atoms, N- (alkylaminopyridines) from 1 to 6 carbon atoms), N-di- (alkylated alkanes of 1 to 6 carbon atoms), N- (alkylamines of 1 to 6 carbon atoms) tertiary, urea and urea derivatives. Particularly preferred basic catalysts are triethylamine, urea and ethylpiperidine.

A particular advantage here is that the catalyst can be used in small amounts for example from 0.1 to 20 mol%, based on the substance to be chlorinated. This amount is preferably from 1 to 15 mol%, particularly and preferably from 10 to 15 mol%. A stoichiometric addition of triethylamine, as in the preparation of the dichloro-nicotinonitrile of the dihydroxy-nicotinonitrile according to the aforementioned literature reference from Angew. Chem., Is not necessary according to the invention. It is advantageous to use the phosphorus trichloride in excess with respect to the chlorine gas, and to carry out the reaction such that at least one small excess of phosphorus trichloride is always present in the reaction mixture. For example, chlorine gas in molar proportions can be used to phosphorus trichloride from 0.1: 1 to 0.99: 1. This ratio is preferably 0.5: 1 to 0.99: 1, particularly and preferably 0.9: 1 to 0.99: 1. A particular advantage of the process according to the invention is that the chlorine gas can be used merely in an amount of 1 to 2 equivalents, based on each functional group that is to be chlorinated, instead of 2.25 equivalents of the phosphorus pentachloride in the procedure analogously to EP-A 333 020. Preferably, 1.5 to 2 equivalents of chlorine gas are used, based on each functional group that is to be chlorinated. The solvents that can be used to carry out the process according to the invention are, for example, phosphorus oxychloride and very 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 of the same. The preferred solvents are phosphorus oxychloride, chloroform, methyl butyl ether N-methylpyrrolidone and any desired mixtures thereof. Phosphorus oxychloride is preferably the only solvent. The solvent can be used, 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. The chlorination is preferably carried out at temperatures of between 20 and 200 ° C, particularly and preferably between 70 and 120 ° C. In a preferred embodiment of the process according to the invention, a process is followed in which the substance which is going to be chlorinated is initially introduced in a stirred vessel in a solvent or mixture of solvents, the catalyst and phosphorus trichloride are added, the mixture is then heated to the desired reaction temperature, the chlorine gas is subsequently dosed and finally , the mixture is maintained at temperatures in the range established for the reaction temperature, for some time. The time for dosing the chlorine gas can be, for example, from 1 to 10 hours, and the time for the subsequent reaction can be, for example, from 1 to 20 hours. It may also be possible to follow a process in which the chlorine gas is already dosed during the entire heating period up to the desired reaction temperature, or during a part thereof. A process may also be followed in which the substance to be chlorinated is dosed as the last component, or together with the catalyst. The simultaneous dosing of all the components is also possible. When the reaction is finished, the solvent can be distilled, together with the phosphorus oxychloride formed and the excess chlorination agent, and if appropriate, it is used again. In the subsequent hydrolysis, for example, the present residue after the distillation of the solvent, the phosphorus oxychloride and the excess chlorinating agent can be used as such. It is also possible for the first residue that it be collected in a solvent. Solvents that are immiscible in water or only slightly miscible in water, for example, are used for this, for example aromatic or aliphatic hydrocarbons, which can also be halogenated, such as benzene, toluene, xylenes, tetralin, ligroin, ether of petroleum, chlorobenzenes, methylene chloride or chloroform, and ethers, such as diethyl ether, dibutyl ether, methyl butyl ether, or tetrahydrofuran, or any desired mixtures thereof. The residue is preferably taken up in toluene, xylenes, petroleum ether, methylene chloride, chloroform, diethyl ether, methyl butyl ether or mixtures thereof, and methylene chloride is particularly and preferably used as the sole solvent in which the waste is collected. The hydrolysis is generally carried out with excess water. For example, 0.5 to 2 parts by volume of water may be used per part by volume of substance to be hydrolyzed or a solution thereof. The temperature during the hydrolysis can be, for example, in the range of 0 to 100 ° C. If the solvents which boil below 100 ° C under normal pressure are present, the hydrolysis is carried out, for example, at temperatures between 0 ° C and the boiling point of the solvent (under normal pressure). The hydrolysis is preferably carried out at temperatures in the range of 0 to 70 ° C. It is advantageous, for example, to subsequently aerate the mixture at the set temperatures for 1 to 2 additional hours. If the hydrolysis has been carried out in the absence of a solvent, it is advantageous to add a solvent of the type mentioned after the hydrolysis. A solution of 2,6-dichloro-5-fluoronicotinonitrile which can also be processed directly can be obtained by phase separation. If desired, 2,6-dichloro-5-fluoronicotinonitrile can be isolated from the solution, for example, by evaporation, with a high yield and high purity. In summary, the process according to the invention has a number of advantages. This gives 2, 6-dichloro-5-fluoronicotinonitrile with high purities and good yields, is handled without solid chlorinating agents, and requires smaller amounts of chlorinating agent than processes according to the prior art, and bases only in catalytic amounts. In addition, more highly chlorinated products are practically not formed, and the amount obtained from waste water containing phosphorus is reduced. The monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one, which is preferred as the starting substance, and its tautomers, has not been previously described in the literature. The present invention therefore also relates to these.

The monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one and its tautomers can be obtained, for example, by the reaction of 3-cyano-2-hydroxy-5-fluoropyrid-6-one , which is known, and / or its tautomers with an alkyl alcoholate of 1 to 6 carbon atoms, preferably a (C 1 -C 6 alkyl) -alkaline metal alcoholate, particularly and preferably sodium methylate , in a mixture of an aromatic solvent, preferably toluene, and an alkyl alcohol of 1 to 6 carbon atoms, preferably methanol, precipitating the salt formed in this way, and / or its tautomers using a medium strength acid, preferably acid acetic and filtering with suction and drying the product.

Eg emplos The 3-cyano-2-hydroxy-5-fluoropyrid-6-one was in each case employed in the form of a mixture of tautomers predominantly comprising this tautomer.

Example 1 240 g of the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one (see example 8) were initially introduced in 2400 g of phosphorus oxychloride. Then 15.8 g of triethylamine and subsequently 648 g of phosphorus trichloride were added while the evolution of heat was observed. The mixture was heated to reflux temperature (74 ° C, evolution of hydrogen chloride) and 312 g of chlorine were passed over a period of 2 hours, slowly raising the reflux temperature to 106 ° C and a vigorous evolution was observed. of hydrogen chloride. To bring the reaction to completion, after the chlorine had passed in, the mixture was heated to reflux for an additional 8 hours. After this, 2794 g of phosphorus oxychloride (comprising excess phosphorus trichloride) was distilled at a bottom temperature of about 70 ° C, the pressure being slowly reduced to 120 millibars. The mixture was allowed to cool and the residue was taken up in methylene chloride. The suspension formed was slowly added to the water, while the evolution of heat was observed, during which the temperature was raised to 40 ° C (reflux of methylene chloride). The mixture was then stirred subsequently at 40 ° C for 1 hour and allowed to cool, the organic phase was separated and the aqueous phase was extracted with fresh methylene chloride. The combined phases of methylene chloride were dried and evaporated on a rotary evaporator. The residue that remained was dried under vacuum at 60 ° C. 232.5 g of 2,6-dichloro-5-fluoronicotinonitrile (purity 94.7%, yield 85% of theory) were obtained as a brown-yellow solid.

Example 2 (For comparison, rework the European Patent EP-A 333 020). 182 g of phosphorus pentachloride were initially introduced slowly into 300 g of phosphorus oxychloride. 30 g of the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one were then added. The mixture was heated to reflux temperature (114 ° C, evolution of hydrogen chloride), and stirred at that temperature for an additional 20 hours. After this, the phosphorus oxychloride was distilled in vacuo. The residue was allowed to cool and was then taken up in methylene chloride. The formed suspension was then added slowly to ice water. After separation of the phases, the organic phase was separated, dried and evaporated in a rotary evaporator. The residue that remained was dried under vacuum at 60 ° C. We obtained 30.3 g of a brown solid consisting of 2,6-dichloro-5-fluoronicotinonitrile to the degree of 72.6% by weight (yield 67% of theory), a nicotinonitrile containing three chlorine atoms (GC / MS) to the degree of 19.2% by weight and four others, in some cases highly chlorinated compounds to the extent of approximately 8% by weight in total.

Example 3 (For comparison, phosphorus oxychloride is used with / without triethylamine and a reduced amount of phosphorus pentachloride). g of the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one were initially slowly introduced into 300 g of phosphorus oxychloride and the mixture was heated to reflux temperature (106 ° C) and it was stirred at that temperature for 2 hours. Up to this point of time, the evolution of hydrogen chloride (negative conversion control) had not been fully observed. After cooling, 2.0 g of triethylamine (exothermic) was carefully added. The mixture was again heated to reflux temperature (106 ° C) and stirred at this temperature for an additional 2 hours. Up to this point in time also, the evolution of hydrogen chloride (negative conversion control) had not been fully observed. Then 81.2 g of phosphorus pentachloride were added at room temperature and the mixture was then heated to reflux (112 ° C) for 20 hours. Within the first hours, moderate evolution of hydrogen chloride was observed there. After this, the phosphorus oxychloride was distilled in vacuo. The mixture was allowed to cool and the residue was taken up in methylene chloride. The suspension that had formed was then slowly poured into ice water. The organic phase was separated and the aqueous phase was extracted once more with fresh methylene chloride. The combined phases of methylene chloride were dried and evaporated on a rotary evaporator. The residue that remained was dried under vacuum at 60 ° C. 27.0 g of a brown solid was obtained which consisted of 2,6-dichloro-5-fluoronicotinonitrile to the degree of 83.1% by weight (yield 60% of theoretical) and additional unknown compounds to the degree of approximately 15% by weight in total. Traces of the unreacted adduct (0.02% by weight) were also found.

Example 4 240 g of the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one were reacted analogously to Example 1, but the hydrolysis was carried out at room temperature. 227.6 g of 2,6-dichloro-5-fluoronicotinonitrile (purity 84.7% by weight, yield 74% of theory) were obtained as a brown-yellow solid.

Example 5 48 g of the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one was reacted analogously to Example 1, but with 1.9 g of urea as the catalyst instead of triethylamine. 48 g of 2,6-dichloro-5-fluoronicotinonitrile (purity 88.5% by weight, yield 81.5% of theory) were obtained as a brown-yellow solid.

Example 6 48 g of the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one was reacted analogously to Example 1, but with 3.5 g of ethyl piperidine as the catalyst, instead of triethylamine. 46 g of 2,6-dichloro-5-fluoronicotinonitrile (purity 92.2% by weight, yield 81.5% of theory) were obtained as a brown-yellow solid.

Example 7 168 g of the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one were reacted analogously to Example 1, but the chlorine gas dosage was carried out in parallel with the heating from room temperature up to 73 ° C in a period of 2 hours. After an additional period of 4 hours, the reflux temperature was reached and the mixture was then stirred at this temperature for an additional 6 hours. 176.5 g of 2,6-dichloro-5-fluoronicotinonitrile (purity 93.9% by weight, yield 90.9% of theory) were obtained as a brown-yellow solid.

Example 8 (Synthesis of the monosodium salt of 3-cyan-2-hydroxy-5-fluoropyrid-6-one) 154. 1 g of the 3-cyano-2-hydroxy __-5-fluoropyrid-6-one dissolved in 300 ml of toluene was added dropwise to 77 g of sodium methylate in 250 ml of methanol, while cooling to 5 ° C. The reaction mixture was then allowed to warm to room temperature and stirred at this temperature for an additional hour. Subsequently, 200 g of glacial acetic acid and then 200 ml of water were added, while cooling to 5 ° C.

The solid that had precipitated was filtered with suction and washed with little cold toluene. After drying, 165.5 g of the monosodium salt of amorphous solid color coffee-beige were obtained The spectroscopic data show that the mixture of tautomers obtained comprises predominantly the monosodium salt of 3-cyano-hydroxy-5-fluoropyrid-6-one.

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

Claims (10)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for the preparation of 2,6-dichloro-5-fluoronicotinonitrile, characterized in that it comprises reacting 3-cyano-2-hydroxy-5-fluoropyrid-6-one and / or its tautomers and / or its salts and / or the tautomers thereof with phosphorus trichloride and chlorine gas in a solvent, with the addition of a basic catalyst at 30-300 ° C and then hydrolyzing the product.

2. The chemical compound, characterized in that it is the monosodium salt of 3-cyano-2-hydroxy-5-fluoropyrid-6-one and its tautomers.

3. The process according to claim 1, characterized in that an aliphatic or aromatic amine or amide, or a basic compound of nitrogen or phosphorus or a salt thereof is used as the basic catalyst.

4. The process according to claim 1, characterized in that the catalyst is used in an amount of 0.1 to 20 mol%, based on the substance to be chlorinated.

5. The process according to claim 1, characterized in that the chlorine gas is used in a molar ratio to phosphorus trichloride from 0.1: 1 to 0.99: 1.

6. The process according to claim 1, characterized in that the chlorine gas is used in an amount of 1 to 2 equivalents, based on each functional group that is going to be chlorinated.

7. The process according to claim 1, characterized in that the phosphorus oxychloride, an aromatic or aliphatic hydrocarbon, which may also be halogenated, an ether or a polar aprotic solvent or any desired mixture thereof, is employed as the solvent.

8. The process according to claim 1, characterized in that the chlorination is carried out at 20-200 ° C.

9. The process according to claim 1, characterized in that when the reaction has finished, the solvent is distilled together with the phosphorus oxychloride formed, and the excess chlorination agent, a solvent is added to the residue which remains, if appropriate, and the hydrolysis is carried out at 0-100 ° C with excess water.

10. The process according to claim 1, characterized in that after hydrolysis, the mixture is subsequently stirred at 0-100 ° C for an additional period of 1 to 2 hours.