RU2209198C2 - Method for preparing fluoro-containing heterocyclic compounds - Google Patents

Abstract

FIELD: organofluoric chemistry, chemical technology. SUBSTANCE: method is realized by the initial preparing a mixture of the parent reagents from halogen-containing heterocyclic compound comprising from one to three nitrogen atoms and one or more halogen atoms excepting for fluorine atom and alkaline metal fluoride is used as the source of fluorine atom and a catalyst also. Salt of N,N',N''-hexasubstituted guanidinium is used as a catalyst. Mixture is heated in autoclave up to reaction of halide exchange (100- 250 C) and kept at this temperature with simultaneous control of pressure in autoclave up to ceasing its rise. Then the required fluorocontaining heterocyclic compound is isolated from reaction mass formed in autoclave. EFFECT: improved preparing method, reduced cost of end product preparing. 4 cl, 3 ex

Description

 The invention relates to organofluorine chemistry, in particular to halogen exchange reactions involving haloheterocyclic compounds and alkali metal fluorides, and in particular, to a technology for producing fluorine-containing heterocyclic compounds based on halide exchange reactions in the presence of a catalyst.

State of the art
A known method for producing fluorinated heterocyclic compounds by reacting a heterocyclic compound with elemental fluorine in the presence of another non-fluorine halogen (US Patent 5859255, M. Cl. C 07 D 211/72; C 07 D 211/84; C 07 D 213/61, C 07 D 221/12, 1999).

 There are no signs common to the known and claimed methods.

 The reason that prevents obtaining in the known method the required technical result is the use of elemental fluorine.

 The closest analogue (prototype) is a method for producing polyfluoroheterocyclic compounds, in particular 2,3-difluoro-5-chloropyridine, which consists in initially preparing a mixture of the starting reagents from a haloheterocyclic compound, in particular 2-fluoro-3,5-dichloropyridine, potassium fluoride and tetrakis (diethylamino) phosphonium bromide as a catalyst, which is then heated in the reactor to the required temperature and the chlorine is replaced by fluorine for the required time. After completion of the substitution, the reactor is cooled, the reaction mixture is poured into excess water, extracted with methylene chloride, the organic phase is washed with water, dried and the target product is immediately purified by distillation in vacuo (see example 11 in the description of the invention to international application WO 98/05610, M .cl. C 07 B 39/00, 1997).

 Signs that are common to the known and claimed methods consist in using as a reagent a haloheterocyclic compound containing one or more halogen atoms other than fluorine, alkali metal fluoride as a source of substitute fluorine atoms, and also a catalyst.

 The reason that prevents obtaining the required technical result in the known method is the use of N, N ′, N ″, N ″ ″ as octa-substituted tetrakisaminophosphonium salts, which are difficult to access and have a relatively high price on the market for chemical products.

SUMMARY OF THE INVENTION
The problem to which the invention is directed, is to reduce the cost of the target product.

 The technical result, which mediates the solution of this problem, is to use a well-known compound as a catalyst, the methods for which are well developed and therefore have a relatively low price in the market of chemical products.

 The technical result is achieved by the fact that the initially prepared mixture of the starting reagents, consisting of a haloheterocyclic compound containing one or more halogen atoms other than fluorine, alkali metal fluoride as a source of substitute fluorine atoms and salts of N, N ', N' '- hexa-substituted guanidinium as catalyst, then heated to the temperature of the reaction of halide exchange with the formation of the desired fluorine-containing heterocyclic compounds.

The technical result is also achieved by the fact that the aforementioned mixture of starting reagents is heated in an autoclave to a temperature of a halide exchange reaction of 100-250 ^o C, and maintained at this temperature while monitoring the pressure in the autoclave until its growth ceases, after which it is formed in the autoclave the reaction mass emit the desired fluorine-containing heterocyclic compound.

The technical result is also achieved by the fact that the said alkali metal fluoride and the salt of N, N ', N''- hexazubstituted guanidinium are taken in the following molar ratio of these reagents to each substituted halogen atom in the initial haloheterocyclic compound:
Alkali Metal Fluoride - 1-5
Salt N, N ', N''- hexasubstituted guanidinium - 0.001-0.05
The technical result is also achieved by the fact that the said salt of N, N ', N''- hexazubstituted guanidinium has the formula
[(RR ¹ N) ₂ CNR ² R ³ ] ⁺ X ^- ,
where R is R ³ -alkyl, aralkyl; X ^- is a monovalent acid residue or the equivalent of a multivalent acid residue, especially the residues of inorganic acids, organic carboxylic acids and sulfonic acids.

 New (relative to the prototype) features of the claimed method are to use as a catalyst the aforementioned salt of hexazubstituted guanidinium.

Signs are also new regarding:
- control the pressure in the autoclave during the substitution reaction, which lead to the cessation of the increase in this pressure,
- said molar ratio of starting reagents.

 Information confirming the possibility of carrying out the invention.

 The synthesis is carried out in a stirred reactor. Moreover, any heterocyclic compound having at least one replaceable halogen atom in the hetero ring other than fluorine can be used as the main starting material for the exchange reaction. This compound may have a monocyclic heteronucleus or a hetero ring system. A compound may also contain one or more activating groups, such as nitro, cyano, carbonyl, sulfo, etc., or it may not contain such a group. Moreover, this compound contains one or more atoms of chlorine, bromine or iodine or a combination of atoms of these elements in a hetero ring, and may also have one or more halogen atoms on one or more side chains. In addition, the compound may contain one or more fluorine atoms anywhere in the molecule, provided that the compound has at least one hetero ring containing at least one replaceable halogen atom other than fluorine. In this case, the hegerosystem in which it is necessary to make a substitution includes from 1 to 3 nitrogen atoms. Other heteroatoms that may be present in side chains or in additional ring systems of a compound include one or more nitrogen, oxygen, sulfur, phosphorus, boron, or silicon atoms, or a combination of two or more of these elements.

 Alkali metal fluoride, namely potassium, rubidium or cesium fluoride, which are most preferred in view of their high reactivity in halide exchange reactions, is used as another initial reactant of the exchange reaction serving as a source of fluorine. It is also possible to use sodium fluoride, especially when the starting compound has an activating group in the hetero ring, and also in cases where only partial replacement of halogen atoms is necessary. It is also possible to use a combination of any two or more alkali metal fluorides. It is preferable to take potassium fluoride as the cheapest substance as the fluorinating agent.

 Typically, fluorides are added equivalently to substituted halogen in a molar ratio of (1-5): 1, more preferably (1.5-2): 1.

 It must be taken into account that there are cases in which an excess of fluoride leads to undesirable side reactions. In such cases, it is recommended to add fluoride in deficiency.

 An important part of this invention is the use of hexazubstituted guanidinium salts as a catalyst.

 The preparation of such compounds is described in detail in many publications, for example, W. Kantlehner, et al. // Liebigs Ann. Chem. (1984), (1), 108-26; W. Kantlehner, et al. // Synthesis (1983), (11), 904-5; DE 2718275 Al.

 Salts of substituted guanidinium are produced in industry and are widely used, for example, in the preparation of polymers. As an illustration, US 5,229,482 A (Phase transfer catalyzed preparation of aromatic polyether polymers); US 5663275 (Preparation of polyetherimides using bisphenol hydrate as intermediate). Therefore, they are readily available compounds that do not require special preparation methods.

 Another advantage of the salts of hexazubstituted guanidine in comparison with the compounds used as catalysts in the prototype is the lower molecular weight associated with fewer substituents (three instead of four) and the replacement of phosphorus as the central atom by carbon. This allows for the same molar ratio of catalyst to reagents to use a lower weight amount of guanidinium salt.

 Also important is the absence in the molecule of the catalyst used in the described invention of phosphorus, which excludes the formation of harmful organophosphorus compounds during the halide exchange reaction.

As a catalyst in the described invention, it is best to use salts of N, N ', N''- hexazubstituted guanidinium of the General formula
[(RR ¹ N) ₂ CNR ² R ³ ] ⁺ X ^- ,
where RR ³ is alkyl, aralkyl; X ^- is a monovalent acid residue or the equivalent of a multivalent acid residue, especially the residues of inorganic acids, organic carboxylic acids and sulfonic acids.

Most often, X ^- is F ^- , Cl ^- , Br ^- , I ^- , НF ₂ ^- , BF ₄ ^- , C ₆ H ₅ SO ₃ ^- , p-CH ₃ -C ₆ H ₅ SO ₃ ^- , HSO ₄ ^- , CF ₃ SO ₃ ^- , especially C1 ^- , Br ^- , BF ₄ ^- .

 Hexaethylguanidinium bromide or chloride is preferably used.

 The amount of catalyst in the reaction is 0.001-0.05 mol per substitutional halogen atom in the starting haloheterocyclic compound. This corresponds to the mass ratio of the catalyst to the compound containing halogen, changing to fluorine, from 0.15 to 30, preferably 1-15% of its mass.

 The use of small concentrations of the catalyst leads to a slowdown of the reaction and a decrease in the yield of the target products, and an increase in its amount over 30% is not economically feasible.

 The process can be carried out in the presence and absence of a solvent. If solvents are used, then any liquids that do not interfere with the halide exchange reaction, in particular, both polar and non-polar aprotic liquids, are suitable as their solvents.

 The polar aprotic solvents used are DMSO (dimethyl sulfoxide), sulfolane, DMF (dimethylformamide), dimethylacetamide, 1,3-imidazolin-2-one, N-methylpyrrolidone, HMFTA, (hexamethylphosphoric triamide), acetonitrile, benzonitrile, etc. These solvents may be used in a mixture.

 The non-polar aprotic solvents used are aromatic hydrocarbons, for example benzene, toluene, xylenes and their technical mixture, ethylbenzene, mesitylene, chlorotoluenes, chlorobenzene, dichlorobenzenes, etc. Aliphatic and alicyclic hydrocarbons also fall into this category. These solvents can be used in a mixture both with each other and with solvents from the first group.

 Solvents serve to improve mixing of the reaction mass and to reduce the pressure in the reactor by dissolving the gaseous reaction products.

 Aprotic solvents can be used in any amount, for example from 5 to 500 wt.%, Preferably a small amount in the range of 5-30 wt. % with respect to the compound containing halogen, changing to fluorine.

 The following examples illustrate the invention.

 The general part of the examples.

 A 0.25 liter stainless steel autoclave equipped with a thermocouple, pressure gauge and blow-off valve, with a working stirrer, is charged with a mixture of starting reagents. The autoclave is sealed and brought to operating temperature. When entering the mode, excess pressure is released. The process is carried out at a given temperature until the end of the pressure increase.

 After completion of the reaction, the reactor is cooled with cold water, opened, the reaction mass is transferred to a distillation flask, 0.5 L of water is poured, and reaction products are distilled with steam. The organic layer is separated, weighed and analyzed.

 Example 1. Obtaining pentafluoropyridine.

The synthesis is carried out according to the General method. 100 g of potassium fluoride, 50 g of pentachloropyridine and 4.62 g of hexaethylguanidinium bromide are charged into the autoclave. The autoclave is kept for 24 hours at a temperature of 195-200 ^o C. In this case, the pressure rises to 9.2 ati. After separation of the products, 21.65 g of a mixture of the composition are obtained: pentafluoropyridine - 62.5%, chlorotetrafluoropyridines - 30.6%, dichlorotrifluoropyridines - 5.9%. The yield of pentafluoropyridine is 40.2%, of the total substitution products is 61.3%.

 Example 2. Obtaining 1,3,5-trifluoropyrimidine.

The synthesis is carried out according to the General method in an autoclave with a stirrer with a volume of 2.5 DM ³ . Loading: 800 g of potassium fluoride, 612 g of 1,3,5-trichloropyrimidine, 16 g of hexaethylguanidinium bromide.

The autoclave is kept for 6 hours at a temperature of 140-150 ^o C, while the pressure rises to 3.2 ati. After isolation of the products, a mixture of the composition is obtained: 1,3,5-trifluoropyrimidine - 60.2%, chlorodifluoropyrimidines - 34.6%, dichlorofluoropyrimidines - 4.94%. The yield of 1,3,5-trifluoropyrimidine is 51.5%, of the total substitution products is 81.2%.

 Example 3. Obtaining 2,6-difluoro-3,5-dichloropyridine.

The synthesis is carried out according to the General method. 65 g of potassium fluoride, 80 g of pentachloropyridine and 4.2 g of hexaethylguanidinium chloride are charged into the autoclave. The autoclave is kept for 9 hours at a temperature of 185-195 ^o C, while the pressure rises to 1.5 ati. After separation of the products, 52 g of a mixture of the composition are obtained: 2,6-difluoro-3,5-dichloropyridine - 93.4%, trichlorofluoropyridines - 4.3%. The yield of 2,6-difluoro-3,5-dichloropyridine is 70.6%. Total substitution products - 73.6%.

Claims (3)

 1. A method for producing fluorine-containing heterocyclic compounds comprising one to three nitrogen atoms as a heteroatom by initial preparation of a mixture of the starting reagents from a halogen heterocyclic compound comprising one to three nitrogen atoms and containing one or more halogen atoms other than fluorine, alkali metal fluoride as a source of fluorine atoms, as well as a catalyst, the resulting mixture is heated to the temperature of the reaction of halide exchange with the formation of the target fluorine-containing hetero iklicheskogo compound, characterized in that the catalyst is a salt of N, N ', N' '- geksazameschennogo guanidinium. 2. The method for producing fluorine-containing heterocyclic compounds according to claim 1, which consists in the fact that the aforementioned mixture of the starting reagents is heated in an autoclave to 100-250 ^o C and maintained at this temperature while monitoring the pressure in the autoclave until its growth ceases, and then from the resulting in the autoclave of the reaction mass, the desired fluorine-containing heterocyclic compound is isolated. 3. A method for producing fluorine-containing heterocyclic compounds according to one of claims 1 and 2, wherein said alkali metal fluoride and a salt of N, N ′, N ″ -hexazubstituted guanidinium are taken in the following molar ratio of these reagents to each substituted halogen atom in the original halogenocyclic connection:
Alkali Metal Fluoride - 1-5
Salt N, N ', N''- hexasubstituted guanidinium - 0.001-0.05
4. The method of producing fluorine-containing heterocyclic compounds according to one of claims 1 to 3, in which said salt of N, N ', N''- hexazubstituted guanidinium has the general formula
[(RR ¹ N) ₂ CNR ² R ³ ] ⁺ X ^- ,
where RR ^{3 is} alkyl, aralkyl;
X ^- is a monovalent acid residue or the equivalent of a multivalent acid residue, especially the residues of inorganic acids, organic carboxylic acids and sulfonic acids.