A method of obtaining a partially fluorinated benzoic acids

 

(57) Abstract:

The invention relates to a method for partially fluorinated benzoic acids by restorative detonirovanie pentafluorobenzoic acid in the presence of metal-reducing agent zinc or magnesium and a metal complex catalyst such as compounds of Nickel or cobalt with ligands - aryl - and alkylphosphine, nitrogen-containing heterocyclic compounds selected from 2,2-bipyridyl, 1,10-phenanthroline or phthalocyanine, environment dipolar aprotic solvent at a temperature of 35-80°C in the presence of a source of proton - water, acids, ammonium salts in a molar ratio of catalyst/pentafluorobenzoic acid of 0.01/0.05 and the reducing agent/substrate 3/10. The technical result - the creation of a convenient, does not contain highly toxic reagents. 7 table.

The invention relates to methods for producing compounds of General formula 1:

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where X = F (1a) H (1b), which are used as intermediates for obtaining medicines and remedies plants (Organofluorine chemistry: principles and commercial applications / edited by R. E. Banks, B. E. Smart and J. C. Tatlow. New York, Plenum Press, 1994).

Known methods for producing compound (1a) by de is p. patent JP 05025084 A2; CA 118-233664) proposed decarboxylation tetrafluorophthalic acid in an aprotic solvents having a boiling point above 110oC. the Reaction is carried out at temperatures of 110-250VoC for 1.5 hours, the outputs (1a) reaches 90%. The disadvantage of this method is high enough temperature the reaction.

Described (Jap. patent JP 63270640 A2; CA 111: 57295q) obtaining 3,4,5-triterpenoids acid (1b) by heating the acid chloride 3,4,5-trichlorobenzoic acid (4) in an aprotic polar solvents with alkali metal fluorides in the presence of phase transfer catalysts (Quaternary fofanah salts, crown ethers, polyalkylene glycols) (EQ. 2). Thus, the heating of the compound (4) with potassium fluoride in sulfolane in the presence of bromide tetraphenylporphine at a temperature of 230oC for 6 hours allows you to get acid (1b) with the release of 50%.

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The disadvantage of this method are fairly rigid conditions the reaction and relatively low outputs 3,4,5 - tetrafluorobenzoic acid (1b).

The closest analogue to the proposed method of obtaining compounds (1a, b) is the method that is described in the work of G. B. Deacon, C. Forsyth M, Sun J, the m pentafluorobenzoic acid (5). Sequential processing pentafluorobenzoic acid magnesium in the presence of catalytic amounts (20 mol.% relative to the substrate) Yb(cyclopentadienyl)2(1,2-dimethoxyethane) and cyclopentadienyl thallium, and then an aqueous solution of the acid allows you to get 2,3,4,5-tetrafluorobenzoic acid (1a) (EQ. 3):

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The reaction is conducted in tetrahydrofuran at a temperature of 67oC for 6 hours. The output from unity (1a) is 87%.

The main disadvantage of this method is the closest analogue is the necessity of using large quantities (20 mol.% relative to the substrate) is quite expensive catalytic complex. In addition, the use of highly toxic compounds thallium substantially limits the application of this method.

The objective of the invention is to create a safe, containing no toxic reagents method of producing partially fluorinated benzoic acids.

The problem is solved by obtaining the target product (1a, b) by restorative detonirovanie pentafluorobenzoic acid (5) (ur. 4).

Hydrogenolysis of aromatic C-F bonds (EQ. 4) flows under the influence rebuild the body, in which h is the environment dipolar aprotic solvents in the presence of sources of protons at temperatures 35-80oC. after the reaction of the target products are extracted and purified by known methods. 2,3,4,5-Tetrafluorobenzoic acid is obtained in the form of a technical product with the content of the basic substance (1a) 78-85%. 3,4,5-Triptoreline acid (1b) is obtained in the form of individual compounds with a basic substance content not less than 98%.

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Ni(II) and Co(II): compounds of divalent Nickel and cobalt, respectively, ligand: PPh3Ph2P(CH2)2PPh2Ph2P(CH2)3PPh2, 2,2'-bipyridyl, 1,10-phenanthroline, solvent: DMF, DMA, MP, DMSO, HMPA, pyridine, a source of protons: H2O, NH4Cl, C2H5OH, etc.

Catalytic complexes are obtained in situ from the available compounds of Nickel or cobalt and ligand directly before the reaction, or are prepared complexes. As a ligand are bis(diphenylphosphino)ethane, bis(diphenylphosphino)propane, triphenylphosphine, 2,2'-bipyridyl, 1,10-phenanthroline. As prepared complexes are compounds of Nickel and cobalt with these ligands, as well as phthalocyanine complexes of these metals. The amount of catalyst relative to the substrate is from 0.1 to 100 molinate and is determined by the rational consumption of reagents.

As reducing agents are zinc and magnesium. On one mole of the substrate is required from 2.3 to 10 moles of zinc or magnesium. The optimum quantity of reductant from 3 to 10 moles. When smaller quantities of reducing agent significantly reduced the degree of conversion of pentafluorobenzoic acid compounds (1a) and (1b), and at large - unjustified but increases the consumption of the reactants.

The reaction is conducted in the environment of aprotic dipolar solvents: N,N'-dimethylformamide (DMF), N, N'-dimethylacetamide (DMA), N-organic-2 (MP), dimethyl sulfoxide (DMSO), hexamethylphosphorotriamide (GMPA) and pyridine. In addition, the reaction may be carried out in mixtures of the above solvents with an inert hydrocarbon solvents are: benzene, toluene and hexane.

Temperature of the reaction is determined by the following circumstances: when the temperature is below 35oC significantly increases the time required for reaction and if the reaction at temperatures above 80oC unreasonably increase the energy consumption.

The reaction proceeds in the presence of a source of protons. As a source of protons can perform the following compounds: water, alcohol and chloride, shumilkin) of the task is illustrated by the currently available literature data. So that is described only three way catalytic activation of aromatic carbon-fluorine bonds (Kiplinger, J. L. , Richmond T. G. Chem. Commun., 1996, N 10, P 1115-1116; Aizenberg, M., Milstein, D. J. Am. Chem. Soc., 1995, Vol. 117, N 33, P 8674 - 8675: G. B. Deacon, C. M. Forsyth, Sun J. Tetrahedron Lett. 1994, Vol. 35, No. 7, p. 1095-1098) and none of them are means, which are used as catalysts compounds of Nickel or cobalt. In addition, compared with the way the closest analogue was not known a priori, the effect on the reaction of the changing nature of the catalytic complex and the reaction conditions.

The invention is illustrated by the following examples.

Example 1. Getting 2,3,4,5-tetrafluorobenzoic acid.

In a three-neck flask equipped with thermometer, mechanical stirrer and an oil bath with thermostat, put 0,024 g (0.1 mmole) NiCl26H2O, 0.03 g (0.2 mmole) of 2,2'-bipyridyl, 15 ml DMF and 2 ml of H2O. the Mixture is heated with stirring to 60oC and kept at this temperature for 0.5 hours. Pour 3.25 g (50 mmole) of zinc dust and stirred for another 10 minutes. Add a 2.12 g (10 mmole) pentafluorobenzoic acid in 8 ml of DMF. Stirred at a temperature of 60oC for 4 hours. Poured into 50 ml of water, acidified with hydrochloric KIS is t 1.8 g of product, containing 85% 2,3,4,5-tetrafluorobenzoic acid (degree of conversion of 93%).

Examples 2-6. Getting 2,3,4,5-tetrafluorobenzoic acid. The reaction is conducted in the conditions of example 1. Changing nature of the catalytic complex. The results are shown in Table 1.

Example 7. Getting 2,3,4,5-tetrafluorobenzoic acid.

In a three-neck flask equipped with thermometer, mechanical stirrer and an oil bath with thermostat, place of 0.12 g (0.5 mmole) CoCl26H2O, 0.15 g (0.2 mmole) of 2,2'-bipyridyl, 10 ml of DMF and 2 ml of H2O. the Mixture is heated with stirring to 60oC and kept at this temperature for 0.5 hours. Pour 3.25 g (50 mmole) of zinc dust and stirred for another 10 minutes. Add a 2.12 g (10 mmole) pentafluorobenzoic acid in 8 ml of DMF. Stirred at a temperature of 70oC for 3 hours. Poured into 50 ml of water, acidified with hydrochloric acid to pH 5-6 and extracted with 5 x 10 ml diethyl ether. The ether extracts are washed three times with water and dried. Get to 1.79 g of the product, the content of the basic substance of 76.5%

Example 8. Getting 2,3,4,5-tetrafluorobenzoic acid.

In a three-neck flask equipped with thermometer, mechanical stirrer and an oil bath with thermostat, place of 0.16 g (0.25 more at this temperature for 0.5 hours. Pour 6.5 g (100 mmole) of zinc dust and stirred for another 10 minutes. Add a 2.12 g (10 mmole) pentafluorobenzoic acid in 8 ml of DMF. Stirred at a temperature of 70oC for 1 hour. Poured into 50 ml of water, acidified with hydrochloric acid to pH 5-6 and extracted with 5 x 10 ml diethyl ether. The ether extracts are washed three times with water and dried. Obtain 1.5 g of the product (degree of conversion of 86%).

Example 9. Getting 3,4,5-triterpenoids acid.

In a three-neck flask equipped with thermometer, mechanical stirrer and an oil bath with thermostat, place of 0.12 g (0.5 mmole) NiCl26H2O, 0.156 g (1 mmol) of 2,2'-bipyridyl, 15 ml of DMF and 5 ml of H2O. the Mixture is heated with stirring to 60oC and kept at this temperature for 0.5 hours. Pour 6.5 g (100 mmole) of zinc dust and stirred for another 10 minutes. Add a 2.12 g (10 mmole) pentafluorobenzoic acid in 5 ml of DMF. Stirred at a temperature of 60oC for 6 hours. Poured into 50 ml of water, acidified with hydrochloric acid to pH 5-6 and extracted with 5 x 10 ml diethyl ether. The ether extracts are washed three times with water and dried. After distillation of the ether get a 1.75 g of 3,4,5-triterpenoids acid with a basic substance content of 98% (the degree of conversion of 100%).

Prim is icela and cobalt. The results are shown in table 2.

Examples 17-22. Getting 2,3,4,5-tetrafluorobenzoic acid. The reaction is conducted in the conditions of example 1. Changing the molar ratio of catalyst/substrate. The results are shown in table 3.

Example 23. Getting 2,3,4,5-tetrafluorobenzoic acid.

In a three-neck flask equipped with thermometer, mechanical stirrer and an oil bath with thermostat, put 0,024 g (0.1 mmole) NiCl26H2O, 0.03 g (0.2 mmole) of 2,2'-bipyridyl, 15 ml DMF and 2 ml of H2O. the Mixture is heated with stirring to 60oC and maintained at this temperature for 0.5 hours. Add to 0.72 g (30 mmole) magnesium turnings and stirred for another 10 minutes. Add a 2.12 g (10 mmole) pentafluorobenzoic acid in 8 ml of DMF. Stirred at a temperature of 60oC for 4 hours. Poured into 50 ml of water, acidified with hydrochloric acid to pH 5-6 and extracted with 5 x 10 ml diethyl ether. The ether extracts are washed three times with water and dried. Get 1,72 g of product containing 82.5 percent 2,3,4,5-tetrafluorobenzoic acid.

Examples 24-28. Getting 2,3,4,5-tetrafluorobenzoic acid. Conducted under the conditions of example 9. Changing the molar ratio of the reducing agent/substrate. The results are shown in table 4.

Example 38. Getting 3,4,5-triterpenoids acid.

In a three-neck flask equipped with thermometer, mechanical stirrer and an oil bath with thermostat, place of 0.12 g (0.5 mmole) NiCl26H2O, 0.08 g (0.5 mmole) of 2,2'-bipyridyl, 15 ml DMF) and 1.07 g of NH4Cl. The mixture is heated with stirring to 50oC and kept at this temperature for 0.5 hours. Pour 6.5 g (100 mmole) of zinc dust and stirred for another 10 minutes. Add a 2.12 g (10 mmole) pentafluorobenzoic acid in 5 ml of DMF. Stirred at a temperature of 50oC for 1 hour. Poured into 50 ml of water, acidified with hydrochloric acid to pH 5-6 and extracted with 5 x 10 ml diethyl ether. The ether extracts are washed three times with water and dried. Obtain 1.73 g of 3,4,5-triterpenoids acid OWLS 98% (the degree of conversion of 100%).

Examples 39-41. Getting 2,3,4,5-tetrafluorobenzoic acid. The reaction is conducted in the conditions of example 1. Changes the source of protons. The results are shown in table 6.

Examples 42-45. Getting 2,3,4,5-tetrafluorobenzoic acid. The reaction is conducted in the conditions of example 1. Vary the temperature at which the reaction is carried out, the nature of the catalytic complex. The results are shown in the table is the notes with high yields under mild conditions using low-toxic reagents.

A method of obtaining a partially fluorinated acids of the formula I,

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where X = F, H,

through restorative detonirovanie pentafluorobenzoic acid in the presence of metal-reducing agent and a metal complex catalyst in the environment of the solvent by heating, characterized in that metal-reducing agent used zinc or magnesium as a catalyst is a complex compound of Nickel or cobalt with ligands - aryl - and alkylphosphine, nitrogen-containing heterocyclic compounds selected from 2,2'-bipyridyl, 1,10-phenanthroline or phthalocyanine, and the reaction is carried out in an environment dipolar aprotic solvent at a temperature of 35 - 80oC in the presence of a source of proton - water, acids, ammonium salts, at a molar ratio of catalyst/pentafluorobenzoic acid 0.01 to 0.05 and the reducing agent/substrate 3 to 10.

 

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