RU2512293C1 - Method of obtaining ethyl 1,2,4-oxadiazole-5-carboxylates - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to field of obtaining derivatives of ethyl 1,2,4-oxadiazole-5-carboxylates of general formula VII from respective amidoximes of general formula VI by interaction with diethyl ether of oxalic acid:

Method includes mixing amidoxime of general formula VI with 3-fold excess of diethyl ether of oxalic acid with the following exposure at temperature 120°C for 3-4 hours. Separation of target ethyl 1,2,4-oxadiazole-5-carboxylate VII consists in cooling reaction mass to room temperature, filtering formed suspension and washing with dichloromethane.

EFFECT: method of obtaining derivatives of ethyl 1,2,4-oxadiazole-5-carboxylates with increased output of product without application of sodium ethoxide is elaborated Obtained derivatives of ethyl 1,2,4-oxadiazole-5-carboxylates can be applied in chemical industry as antibacterial medications or half-products in synthesis of antithrombotic, antiplatelet and antiparasitic medications.

1 tbl, 4 ex

Description

The invention relates to the field of production of ethyl 1,2,4-oxadiazole-5-carboxylate derivatives of the general formula:

which can potentially be used in the chemical industry as antibacterial drugs or intermediates in the synthesis of antithrombotic, antiplatelet and antiparasitic agents.

A known method for producing 1,2,4-oxadiazoles from amidoximes I, which includes two stages: acylation with acid chloride of 3- [3,4-bis- (tert-butyl-dimethyl-silanooxy) phenyl] acrylic acid II (Pat. 104680 WO , A61K 31/4295. Oxadiazole compounds, their preparation and use / M. Sivakumar, KS Joshi, VS Aware; Applicant Piramal life sciences limited, IN. - No. 2011104680; filed 02/24/2011; it is published 09/01/2011. - 148 p. - Access mode http://ep.espacenet.com) and further intramolecular cyclization:

Acylation of I is carried out in xylene medium in the presence of pyridine and 3- [3,4-bis- (tert-butyl-dimethyl-silanooxy) phenyl] -acrylic acid chloride at a molar ratio of I: II: xylene: pyridine = 1.5: 1:60:30 and when heated in the range of 130-140 ° C for 4 hours. Isolation of the desired 1,2,4-oxadiazole III consists in the removal of xylene and pyridine with further cooling of the reaction mass and extraction with ethyl acetate. Purification of the product was carried out by column chromatography. The product yield is 33% of theory.

The disadvantages include the low yield of the target product.

Closest to the proposed is a method for producing ethyl 1,2,4-oxadiazole-5-carboxylate V from amidoxime IV by reaction with oxalic acid diethyl ether (diethyl oxalate) (Pat. 03082861 WO, A61K 31/5377. Novel compounds / RA Acliff; CM Cook; CD Eldred; PM Gore; LA Harrison; Applicant Glaxo group LTD, GB. - No. 200303335; filed 03/27/2003; it is published 10/09/2003. - 112 p. - Access mode http://ep.espacenet.com ):

The reaction is carried out in absolute ethanol. The molar ratio of IV: oxalic acid diethyl ether: sodium ethoxide = 1: 4: 15. Oxalic acid diethyl ether was added to a solution of compound IV and sodium ethoxide in ethyl alcohol at a reaction temperature of 25 ° C, then the temperature was raised to 78 ° C and kept under stirring for 3.5 hours. Isolation of the desired ester V consists of filtering the suspension and washing with ethyl alcohol, followed by removal of the solvent. The residue was dissolved in dichloromethane, washed with a saturated solution of sodium hydrogen carbonate (25 mol), hydrochloric acid with a molar concentration of equivalent 2 mol / L (25 mol) and water (25 ml), dried with magnesium sulfate and the dichloromethane was evaporated under reduced pressure. The product yield is 28% of theory.

The method is characterized by a low yield of the target product, as well as the need to use sodium ethoxide, which increases economic costs.

The objective of the invention is to increase the yield of the target product and eliminating the need to use sodium ethoxide.

The problem is solved as follows: a method is claimed for producing ethyl 1,2,4-oxadiazole-5-carboxylates of the general formula VII from the corresponding amidoximes of the general formula VI by reaction with oxalic acid diethyl ester:

The reaction is carried out in an environment of oxalic acid diethyl ether. The molar ratio of VI: oxalic acid diethyl ester = 1: 3. To oxalic acid diethyl ester was added to compound VI at a temperature of the reaction mass of 25 ° C, then the temperature was raised to 120 ° C and kept under stirring for 3-4 hours. Isolation of the desired ester VII consists in cooling the reaction mass to room temperature, filtering the resulting suspension and washing with dichloromethane. The resulting solution was washed with water (25 ml), dried with magnesium sulfate and dichloromethane was evaporated under reduced pressure. The product yield is 65% of theory.

The key factor is the use of oxalic acid diethyl ether as a medium for the reaction, which allows the reaction to be carried out at a temperature sufficient to form a 1,2,4-oxadiazole ring.

As a result of the application of this method, the yield was increased and the use of expensive sodium ethoxide was not required.

The invention is illustrated by the following examples:

Example 1. Obtaining ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate. To 8 ml (0.066 mol) of oxalic acid diethyl ester, 3 g (0.022 mol) of the substrate are added with stirring. Stand for 4 hours at a temperature of 120 ° C. The reaction mixture was cooled to room temperature, the resulting suspension was filtered, washed with dichloromethane. The resulting solution was washed with water (25 ml), dried with magnesium sulfate and dichloromethane was evaporated under reduced pressure. The yield of ethyl 3-phenyl-1,2,4-oxadiazole-5-carboxylate is 65%.

¹ H NMR ([ ² H ₆ ] DMSO) δ, J (Hz): 1.41 (3H, t, J = 7); 4.45-4.52 (2H, m.); 7.57-7.6 (3H, m.); 8.05-8.08.

Mass spectrometry, m / z, I _rel (%): 218 (M ⁺ , 70), 190 (10), 145 (5), 119 (100), 103 (33), 91 (30), 89 (6 ), 77 (22), 64 (11), 51 (19).

Examples 2-4. The preparation of other ethyl 1,2,4-oxadiazole-5-carboxylates of the general formula VII from amidoximes of the general formula VI is carried out analogously to Example 1. The reaction conditions and results are shown in Table 1.

Table 1 Reaction conditions Example Substrate T ₁ , ° C τ ₂ h Product Exit, % 2

120 four

73 3

120 3

85 four

120 four

69

Claims (1)

The method of producing ethyl 1,2,4-oxadiazole-5-carboxylates by the general formula:

where R is C ₆ H ₅ , 4-NO ₂ -C ₆ H ₄ , 4-Cl-C ₆ H ₄ , 4-CH ₃ -C ₆ H _4,
by reacting amidoximes with the general formula:

where R is C ₆ H ₅ , 4-NO ₂ -C ₆ H ₄ , 4-Cl-C ₆ H ₄ , 4-CH ₃ -C ₆ H _4,
with a 3-fold excess of oxalic acid diethyl ester at 25 ° C, followed by heating to 120 ° C and holding for 3-4 hours, isolating the target product by cooling and further filtering with washing and drying with magnesium sulfate, characterized in that the reaction is carried out in an environment of oxalic acid diethyl ether at a temperature of 120 ° C, and dichloromethane is used to wash the precipitate:

.