JPH0141149B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a fluoroheterocyclic compound having a nitrogen atom in the ring, and more particularly to an improved method for producing the fluoroheterocyclic compound by halogen exchange. be. A halogen atom on the carbon α-position to the nitrogen atom of a heterocyclic compound having a nitrogen atom in the ring, such as 2-chloropyridine, 2,6-dichloropyridine or 2,4,6-trichloropyrimidine,
There is already a method for producing fluoroheterocyclic compounds corresponding to each starting compound by carrying out a halogen exchange reaction with an alkali metal fluoride salt in an aprotic polar solvent such as dimethylsulfoxide, dimethylsulfone, tetramethylenesulfone, or dimethylformamide. known, and several reports have been made. [For example, GCFinger, Lawrence D. Starr,
et.al., J.Org.Chem. 28 , 1666 (1963), U.S. Patent No. 4031100, U.S. Patent No. 4071521, British Patent No.
No. 1256082, Okano, Goya, Matsumoto, Pharmaceutical Journal 87 ,
1315 (1967) etc. ] However, conventional methods have industrial disadvantages such as requiring high reaction temperatures and long reaction times, and causing decomposition of the solvent and side reactions with the solvent.
have one or more. In addition, in order to avoid disadvantages caused by solvents, methods of carrying out the halogen exchange reaction without a solvent are being considered;
Extremely high temperatures of 350 to 500°C are required, and the results are not necessarily satisfactory in terms of yield. [For example, Max M. Boudakian, J.
Heterocycl.Chem. 5 , 683 (1968), REBanks,
DSField and RNHaszeldine, J.Chem.Soc.(C)
1967, 1822, J.Hinzke, J.Fluorine Chem. 17 ,
385 (1981), etc. ] As a result of intensive research into the fluorination reaction by halogen exchange of the above-mentioned heterocyclic compound having a nitrogen atom in the ring and in which the α-position carbon atom is substituted with halogen, the present inventor discovered that crown The halogen exchange reaction is significantly accelerated by using potassium fluoride or a mixture of potassium fluoride and a fluoride salt of an alkali metal or alkaline earth metal other than potassium fluoride in the presence of the compound. The present invention was completed based on the discovery that a special high temperature is not required and the generation of by-products is also suppressed. That is, the present invention has the general formula (wherein, X is Cl or Br, P is C- ^R3 or N, Q is C- ^R4 or N, and ^R1 , ^R2 , ^R3 and ^R4 are H, alkyl group, alkoxy group, keto group, phenyl group, cyano group, nitro group, perfluoroalkyl group, F, Cl or
It is Br. ) A halogenated heterocyclic compound represented by the general formula (wherein, Y is C- ^R7 or N, Z is C- ^R8 or N, ^R5 , ^R6 , ^R7 and ^R8 are H, alkyl group, alkoxy group, keto group, phenyl group, cyano group, nitro group, perfluoroalkyl group, F, Cl or
It is Br. ) In the reaction to produce the fluoroheterocyclic compound represented by It is characterized by promoting reactivity at relatively low temperatures, and especially when potassium fluoride is used in combination with certain other fluoride salts, its action becomes even more pronounced, and the selectivity of the target product is significantly increased. It was made possible to
The method is summarized as a method for producing a fluoroheterocyclic compound having a nitrogen atom in the ring. The present invention will be described in detail below, focusing on the case where a particularly characteristic fluoride salt is used in combination. The halogenated heterocyclic compound represented by the general formula [], which is the raw material compound of the present invention, has one or more nitrogen atoms in the ring, and at least one carbon atom adjacent to the nitrogen atom. is Cl or
Pyridine, pyrimidine or S substituted with Br
-triazine derivatives are used. Such halogenated heterocyclic compounds represented by the general formula [ ] are well known and can be obtained commercially or can be produced by known methods. Specific examples of these compounds are as follows. 2-Chlorpyridine, 2,6-dichloropyridine, 2,4,6-trichloropyridine, 2-chloro-6-methylpyridine, 2,6-dichloropyridine
-cyanopyridine, 2,6-dichloro-4-nitropyridine, 2-chloro-4-trifluoromethylpyridine, 2,4,6-trichloropyrimidine, 2,4,5,6-tetrachloropyridine,
2,4,6-trichloro-S-triazine, etc., or compounds having a bromine atom instead of chlorine in these compounds. The fluoride salts of alkali metals or alkaline earth metals used as a mixture with potassium fluoride include lithium fluoride, sodium fluoride, rubidium fluoride, cesium fluoride, beryllium fluoride, magnesium fluoride, calcium fluoride, These include strontium fluoride and barium fluoride. Among these, sodium fluoride is particularly preferred. In addition, water contained in these potassium fluoride and other alkali metal or alkaline earth metal fluoride salts is preferably 0.5% by weight or less, as it delays the reaction and facilitates the formation of by-products. is desirably 0.1% by weight or less. The amount of potassium fluoride and fluoride salts of alkali metals or alkaline earth metals other than potassium fluoride to be used is such that the total amount of these fluoride salts is replaced by fluorine atoms in the raw material halogenated heterocyclic compound. It is necessary to use at least an equivalent amount of the halogen atom, and the upper limit is limited by problems such as stirring of the reaction system, but it is more preferable to use 1 to 3 equivalents. The mixing ratio (mole ratio) of potassium fluoride and the fluoride salt of an alkali metal or alkaline earth metal other than potassium fluoride is 1:3 to 3:1, preferably 1:
1-2:1 is good. Crown compounds used as catalysts include 1,4,7,10,13,16-hexaoxacyclooctadecane, commonly called 18-crown-6, 15-crown-5, dibenzo-18-crown, and -6, dicyclohexyl-18-crown-6, dibenzo-24-crown-8, dicyclohexyl-24-crown-8
and the like, and crown compounds containing sulfur or nitrogen atoms in place of the oxygen atoms of these crown compounds are also included, but 18-crown-6 is particularly preferred. The amount of the crown compound to be used is preferably 0.005 equivalent or more, more preferably 0.01 equivalent or more relative to the halogen atom substituted by the fluorine atom in the halogenated heterocyclic compound as the raw material. The reaction temperature is preferably in the range of 120 to 230°C,
A range of 150 to 200°C is more desirable. The reaction time varies depending on the type of halogenated heterocyclic compound as the raw material and other reaction conditions, but
It is desirable to heat and stir for 30 hours. In addition, aprotic polar solvents such as dimethyl sulfoxide, tetramethylene sulfone, and N,N-dimethylformamide can be used as solvents, but when these solvents are used, the solvent may decompose or the solvent may mix with the raw material or product. Since this reaction may occur, it is preferable to carry out the halogen exchange reaction without a solvent. In the case of no solvent, after the reaction is completed, a solvent that dissolves the product and the crown compound of the catalyst and is easily separated from the product, such as toluene or methylene chloride, is added to the reaction mixture to remove insoluble components (unreacted fluoride). chlorinated or bromated alkali metal salts, etc.) can be separated by filtration, and the desired product can be isolated by distillation. The unreacted raw material halogenated heterocyclic compound and the crown compound of the catalyst remain in the distillation residue, but these can be used repeatedly in the next reaction as they are. In the present invention, a crown compound is used as a catalyst,
It is not always clear why the halogen exchange reaction is promoted by using a mixture consisting of potassium fluoride and a fluoride salt of an alkali metal or alkaline earth metal other than potassium fluoride as a fluorinating agent. However, it can be inferred as follows. Potassium chloride or bromide produced by the halogen exchange reaction undergoes halogen exchange with a coexisting alkali metal or alkaline earth metal fluoride salt other than potassium fluoride due to the presence of a crown compound as a catalyst, regenerating potassium fluoride. At the same time, chloride or bromide salts of alkali metals or alkaline earth metals other than potassium are produced. Since the complex formation constant of the metal cation moiety of this chloride or bromide salt with the crown compound is smaller than that of potassium, it is excluded from the halogen exchange reaction system using fluorine ions of the halogenated heterocyclic compound. is expected to be promoted. In other words, the gist of the present invention is to prevent a decrease in the catalytic activity of the crown compound by suppressing the complex formation between the crown compound and potassium chloride or potassium bromide produced by the halogen exchange reaction. It is thought that then. Therefore, by using the other fluoride salts mentioned above, it is also possible to save on crown compounds. Incidentally, the literature (J.
J. Christensen, DJ Eatough, RMIzatt,
Chem.Revs., 74 , 351 (1974)), the log K (K is the complexation equilibrium constant) of 18-crown-6 in methanol at 25°C is K ⁺ : 6.10, Na ⁺ : 4.32,
Cs ⁺ : 4.62. However, it goes without saying that the present invention is not limited in any way by the above estimation. Examples of the fluoroheterocyclic compound obtained by the present invention include 2-fluoropyridine, 2,6-difluoropyridine, 2,6-difluoro-4-chloropyridine, 2-fluoro-6-methylpyridine, and 2,6-difluoropyridine. difluoro-4-cyanopyridine,
2,6-difluoro-4-nitropyridine, 2-
fluoro-4-trifluoromethylpyridine,
2,4,6-trifluoropyrimidine, 2,4,
6-trifluoro-5-chlorpyrimidine, 2,
Examples include compounds useful as synthetic intermediates for agricultural chemicals, medicines, dyes, etc., such as 4,6-trifluoro-S-triazine. According to the method of the present invention, by using a crown compound as a catalyst and a mixture of potassium fluoride and a fluoride salt of an alkali metal or alkaline earth metal other than potassium fluoride as a fluorination agent,
There is a concern that it may decompose itself or react with raw materials or products. The target substance can be produced with high purity and high yield at relatively low temperatures and in a short time without using relatively expensive aprotic polar solvents.
Few or only small amounts of by-products are produced. Furthermore, the crown compound used is quite thermally stable and can be used repeatedly in the next reaction without purification, making the method of the present invention widely used as an industrial method for producing fluoroheterocyclic compounds. Has excellent advantages. Next, the present invention will be specifically explained with reference to Examples. Example 1 In a 500 ml Monel autoclave equipped with a stirring device, 74 g (0.5 mol) of 2,6-dichloropyridine, 6.6 g (0.025 mol) of 18-crown-6,
Potassium fluoride 58g (1 mol) and sodium fluoride 42g dried under reduced pressure at 150°C and 1mmHg for 10 hours
(1 mol). After purging the inside of the autoclave with nitrogen, the autoclave was heated and stirred at 195°C for 15 hours. After the reaction was completed, 200 ml of ethyl ether was added, the insoluble portion was filtered off, the ether was distilled off, and the mixture was distilled using a Wittmer distillation tube. As the main fraction, 47.2 g of 2,6-difluoropyridine (yield 82%, boiling point 125.0-125.5
°C) was obtained. When 12.8 g of the residue was analyzed by GLC, it had the following composition (peak area ratio). 2,6-difluoropyridine 5.8% 2-chloro-6-fluoropyridine 93.0% 2,6-dichloropyridine 1.2% Example 2 Using the same equipment as in Example 1, 74 g (0.5 mole), 18-crown-6
6.6 g (0.025 mol) and 116 g (2.0 mol) of potassium fluoride dried in the same manner as in Example 1 were charged.
After purging the inside of the autoclave with nitrogen, the autoclave was heated and stirred at 200°C for 15 hours. After the reaction is complete, add ethyl ether 200
ml was added, the insoluble portion was filtered off, and analyzed by GLC, which revealed the following composition. 2,6-difluoropyridine 55.3% 2-chloro-6-fluoropyridine 41.9% 2,6-dichloropyridine 2.8% Example 3 3.7% of 2,5-dichloropyridine was placed in a Pyrex glass ampoule tube with an internal volume of 30ml. g (0.025 mol), 18-crown-6 0.33 g (0.00125 mol),
2.9 g of potassium fluoride dried in the same manner as in Example 1
(0.05 mol) and 2.1 g (0.05 mol) of sodium fluoride
mol) was charged, and after purging with nitrogen, it was melt-sealed. Add this to bath temperature
After shaking and stirring in an oil bath at 180°C for 20 hours, the ampoule was opened, the contents were extracted with 50 ml of ethyl ether, and analyzed by GLC.
Chlorpyridine was produced at a conversion rate of 78%. Example 4 4.6 g of 2,4,6-trichloropyridine was placed in a Pyrex glass ampoule tube with an internal volume of 30 ml.
(0.025 mol), 18-crown-6 0.5g (0.0019
mol), 5.2 g (0.09 mol) of potassium fluoride and 3.15 sodium fluoride dried as in Example 1.
g (0.075 mol) was charged, and after purging with nitrogen, the mixture was melt-sealed.
After shaking and stirring for 15 hours in an oil bath with a bath temperature of 185°C, the mixture was extracted with 20 ml of ethyl ether and subjected to GLC analysis. The composition ratio calculated from the peak area ratio was as follows. 2,4,6-trifluoropyrimidine 71% 2,4-difluoro-6-chloropyrimidine
27% 2-fluoro-4,6-dichloropyrimidine
2%

Claims (1)

[Claims] 1. General formula (wherein, X is Cl or Br, P is C- ^R3 or N, Q is C- ^R4 or N, and ^R1 , ^R2 , ^R3 and ^R4 are H, alkyl group, alkoxy group, keto group, phenyl group, cyano group, nitro group, perfluoroalkyl group, F, Cl or
It is Br. ) A halogenated heterocyclic compound represented by the general formula (wherein, Y is C- ^R7 or N, Z is C- ^R8 or N, ^R5 , ^R6 , ^R7 and ^R8 are H, alkyl group, alkoxy group, keto group, phenyl group, cyano group, nitro group, perfluoroalkyl group, F, Cl or
It is Br. ) In the reaction to produce the fluoroheterocyclic compound represented by Characteristic method for producing fluoroheterocyclic compounds. 2. The manufacturing method according to claim 1, wherein a mixture of potassium fluoride and sodium fluoride is used as the fluorinating agent. 3 As a crown compound 1, 4, 7, 10, 13,
3. The method according to claim 1 or 2, using 16-hexaoxacyclooctadecane. 4. The manufacturing method according to claim 1, 2 or 3, wherein the reaction is carried out in the absence of a solvent.