CS248630B1 - Process for producing aryloxyalkanhydroxamic acids - Google Patents

Abstract

A method for producing aryloxyalkanehydroxamic acids of the general formula 1 Ar - 0 - /CH/ - CO - HH - OH /1/ ) n R where Ar represents 1-naphthyl or 2-naphthyl, R represents hydrogen if n » 2 to 10, or represents alkyl with 2 to 10 carbon atoms in the case that η = 1, by reacting the corresponding alkali metal naphtholate with a haloalkanoic acid ester of the general formula 11 X - /CH/ - COOR* 1 /11/ i n R where n and R have the above meanings, X represents halogen, such as chlorine or bromine and R1 is alkyl containing 1 to 3 carbon atoms, in a solvent environment and subsequent reaction of the isolated esters correspondingly! naphthyloxyalkanoic acid with a hydroxylamine salt in the presence of bases, consists in the reaction of an alkali metal naphtholate with a haloalkanoic acid ester of the general formula II being carried out in an inert aprotic polar solvent, for example dimethyl sulfoxide, with a maximum water content of 0.1%, at a temperature of 10 to 35 °C. The substances mentioned have fungicidal and bactericidal effects, which is

Description

248630 2

The present invention relates to a novel process for the preparation of aryloxyalkanhydroxamic acids of the general formula I

Ar - O - (CH) - - CO - NH - OH / 1 /

I nH in which

Ar denotes 1-naphthyl or 2-naphthyl R denotes hydrogen when n = 2 to 10, or denotes alkyl having 2 to 10 carbon atoms in the case of women 1.

Compounds from the group of hydroxy acid derivatives are known and exhibit various valuable biological effects.

For example, trypanocidal effects of salicylhydroxamic acid are described. Furthermore, the use of some (2- (naphthoxy) alkanohydroxamic acid as fungicidal and bactericidal active substances useful in agriculture and forestry (DD Patent No. 141,293) is known. In the literature, I have further described the favorable pharmacological properties of the compounds of the aforementioned general formula which enable their use in human and veterinary medicine to treat the most deleterious diseases, such as, in particular, various forms of bronchial asthma, allergic diseases, thrombosis, and purulent inflammation. and rheumatic diseases. The beneficial pharmacological effects of the compounds of the above general formula are exemplified by the fact that these compounds act as effective inhibitors of arachidonate lipozygenase. In particular, 2- (2-naphthoxy) acethydroxamic acid is particularly preferred from the compounds of the above formula. 2- (2-naphthoxy) -2-n-nonylacetydroxamic acid.

These compounds have a remarkable effect over, for example, the known lipoxygenase-3-amino-N- (3-trifluoromethyl-phenyl) -pyrazoline-2 antiasthmatic.

The compounds of the above formula can be prepared, for example, by reaction of naphthalates of alkali metals with esters of halocarboxylic acids in an environment of lower alcohols or aromatic hydrocarbons, followed by reaction of the resulting carboxylic esters with hydroxylamine.

Another method for preparing compounds of the above formula is, for example, the process (DDpatent No. 141,253) wherein the corresponding carboxylic acid esters are reacted with excess free hydroxylamine or its salts in the presence of an alkali metal alcoholate and an excess alcohol.

The drawbacks of these methods are the relatively low reaction yields, high reaction temperatures, long reaction times and thus considerable time and energy consumption. In a classical embodiment, this is a two-step reaction sequence of the phenolate-hydroxamic acid ester, in which a high-boiling ester (b.p. 200 ° C and separated at 1.3 kPa) is isolated. 86,419 (1974), Przem. Chem. 35, 640 (1956), Chem. Abstr. 1953, 2740, Roczniki Chem.30, 633 (1956) yields naphthoxyalkanhydroxamic acids at about 60%. However, yields are substantially reduced when reproduced on an outdoor scale.

The known two-stage process in a positive sense is followed by the process of the invention wherein the aryloxyalkanhydroxamic acids of the above general formula (1s) are prepared in a reaction corresponding to the above. alkali metal naphthalates with a haloalkanoic acid ester of the formula II X - (CH) n - COOR 'A / 11/246630 wherein H is as defined above X is halo, such as chloro or bromo and r' is alkyl containing t to 3 carbon atoms, in a solvent environment followed by the isolation of the corresponding naphthyloxyalkanoic acid esters with the hydroxylamine salt in the presence of a base,

The present invention relates to the reaction of an alkali metal naphtholate with a haloalkanoic acid ester of formula II in an inert solvent having a maximum water content of 0% at a temperature of 10 to 35 ° C. An inert solvent is an aprotic dipolar solvent such as dimethyl sulfoxide. The process according to the invention is carried out by preparing from 2-naphthol by treatment with sodium methanolate or sodium ethanolate 2-naphtholate, to which is added an aprotic dipolar solvent, and preferably dimethyl sulfoxide is distilled off under reduced pressure in an inert atmosphere of the reaction mixture. so that its content is reduced below 0.1%, preferably below 0.05

Thereafter, the reaction mixture is cooled to 10 to 35 ° C, preferably to 20 to 30 ° C, and 1.1 to 1.3 moles of the ester of the formula II are added to 1 mol of sodium 2-naphtholate followed by chromatography on a thin layer of silica gel. After completion of the reaction, the reaction mixture is poured into water and the product is extracted with ether, benzene, or toluene.

The combined organics were washed with aqueous sodium bicarbonate solution, anhydrous sodium sulfate or magnesium sulfate, and the corresponding naphthyloxyalkanoic acid ester was obtained after distillation, which can be converted without isolation with hydroxylamine salts in the presence of the compounds of formula I. with the known method are the high yields of the reaction products and the saving of the expensive haloalkamate esters, as well as the energy savings and the working Sas. According to the process of the invention, yields of 60 to 85% are achieved, while the workload is also reduced, as exemplified. Přikladl

The reaction is carried out in a three-necked flask equipped with a separating funnel, a stirrer, a 20 to 25 cm long needle column. The flasks were charged with 16.6 g (0.1 mol) of anhydrous naphthol sodium (prepared from sodium methanolate and 2-naphthol) and 100 ml of dimethyl sulfoxide with a maximum content of 0.5% of water by distillation under reduced pressure (1 to 1). , 1 kP (in an inert atmosphere / nitrogen or argon), 30 to 50 g of dimethyl sulfoxide are distilled off with water.

The distillation is carried out at a reflux ratio of 1: 5 to 20. The final water content of the reaction mixture is 0.2 to 0.3%. The mixture was then cooled to 30 ° C and 2-bromo-dacanoic acid ethyl ester (30.7 g, 0.11 mol) was added over a period of 10 to 20 minutes (nitrogen atmosphere) at the temperature of the reaction mixture. The progress of the reaction was monitored by thin layer chromatography of silica gel.

After 3 to 5 hours, the resulting reaction mixture was treated with water and extracted with ether, the combined ether solutions were washed with aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, and after evaporation of the solvent 32.3 g of pale yellow ethyl ester of 2- (2-naphthoxy) were obtained 2-n-octyl acetic acid, 96.5% by gas chromatographic analysis, added dropwise to a mixture of 250 mL of sodium methanolate methanolic solution prepared from 10 g of sodium and 250 mL of absolute methanol and 30.1 g Hydroxylamine hydrochloride and the mixture is stirred at 30-40 ° C for 10-12 hours and finally boiled for 2-3 hours. 248630 4

After evaporation of the solvents in vacuo and after cooling, the precipitated product is filtered off with suction, washed and crystallized to give 27.3 g of 2- (2-naphthyloxy) -2-n-octylacetydroxamic acid, m.p. EXAMPLE 2 21.6 g of 2-naphtol and 150 ml of dimethyl sulfoxide were added to 50 ml of ethanolic sodium ethanol ethanol containing 0.15 mol of C8H4O4a (prepared from sodium hydroxide and ethanol by azeotropic distillation), followed by excess alcohol distilled off under atmospheric pressure (nitrogen atmosphere) to a bath temperature of 155-160 ° C. The remaining alcohol and water residue were removed by vacuum distillation at a bath temperature of 60-70 ° C and a pressure of 13.3 kPa as in Example 1.

The dimethyl sulfoxide solution thus obtained contains 0.025% water. After cooling to 35 ° C, 27.2 g of 2-chloropentanoate ethyl was added dropwise, the reaction mixture was stirred for 5 hours, poured into water, the product extracted with toluene and after analogous treatment as in Example 1, 35.1 g of a product containing gas chromatographic analysis of 97.5% of 2- (2-naphthoxy) -2-n-propyl acetic acid ethyl ester, which was added dropwise to 215 ml of ethanolic 1.211 of sodium ethanolate and 17.8 g of hydroxylamine hydrochloride at room temperature.

After stirring for 10 hours at this temperature, the reaction was heated to boiling for 4 hours, left overnight at room temperature, and after analogous treatment as in Example 1, 26.2 g of 2- (2-naphthyloxy) -2-n-propylacetydroxamic acid was obtained. amorphous crystals. EXAMPLE 3 From a solution of 6.6 g of sodium 2-naphtholate in 10 ml of dimethyl sulfoxide, water was distilled off as in Example 1. To react a mixture containing 0.032% of water, 13.4% of chloroacetic acid ethyl ester was added at 20 DEG to 25 DEG. after stirring for 3 hours, the reaction mixture was worked up as in Example 1.

19.4 g of a 97.6% product (determined by gas chromatography) of 2- (2-naphthoxy) acetic acid ethyl ester were added to the ethanolic hydroxylamine solution (prepared from 2.91 g of sodium). dissolved in 50 ml of ethanol and 8.7 g of hydroxylamine hydrochloride) and after analogous treatment in Example 2, 13.6 g of 2- (2-naphthoxy) acethydroxamic acid tt were obtained. Mp 62- 163 ° C. EXAMPLE 4 A solution of 33.2 g of sodium 2-naphtholate in 200 ml of dimethyl sulfoxide was distilled off under reduced pressure (ca. 50 ml of dimethylsulfoxide at 70 DEG C.) as in Example 1.

After cooling the reaction mixture containing 0.045 X of water to 20 ° C, 64.5 g of ethyl 2-bromundecanoate was added and treated as in Example 2 after stirring for 6 hours.

31.5 g of a pale yellow oil were obtained with 97.4% (determined by gas chromatography) of 2- (2-naphthyloxy) -2-n-nonylacetic acid ethyl ester. The obtained ester was added at room temperature to 280 ml of an ethanolic solution of hydroxylamine prepared from 270 ml of ethanol, 35.74 of triethylamine and 24.4 g of hydroxylamine hydrochloride at 35-40 ° C.

After stirring for 10 hours, the reaction was heated to reflux for 5 hours, allowed to stand overnight, and after working up as in Example 2, 22.6 g of 2- (2-naphthoxy) -2-n-nonylacethydroxamic acid were obtained. 149-51 ° C (ethene-water).

Claims (1)

EXAMPLE 5 Water was removed by distillation under reduced pressure as in Example 1, from a solution of 8.3 g of sodium 2-naphthoate in 75 ml of dimethyl sulfoxide. After cooling the reaction mixture (water content 0.037 ° C) to 20-25 ° C, 15.7 g of ethyl 8-bromoacetate were added to the reaction mixture and stirred for 15 hours. Thereafter, the reaction mixture was worked up as in Example 1 to obtain 12.3 g of a yellowish oil, which, according to gas chromatography, contained 96.9% of 8- (2-naphthoxy) octanoic acid ethyl ester. The crude ester obtained was added to an ethanolic solution of hydroxylane (prepared from 3.6 g of sodium, 280 ml of ethanol, 10.8 g of hydroxylamine hydrochloride) at 30 to 35 ° C. After analogous treatment of the mixture as in Example 1, 8.46 g of 8- (2-naphthoxy) ocanhydroxamic acid m.p. 126 DEG-128 DEG C. (decomposition). Example 6 From a solution of 6.6 g of sodium 1-naphtholate in 1.0 ml of dimethyl sulfoxide, the water was distilled off as in Example 1. 13.1 g of methyl ester was added to the reaction mixture containing 0.029% water at 25-30 ° C chloroacetic acid dissolved in 15 ml of dimethyl sulfoxide and after 3 hours of stirring, the reaction mixture was worked up as in Example 1 and 20.2 g of product 3 was obtained containing 96.4 g of 2- (1-naphthoxy) acetic acid methyl ester which was dissolved after 30 minutes. ml abs. methanol was added to a methanolic solution of hydroxylamine (prepared from 2.96 g of brine, 60 ml of methanol and 8.9 g of hydroxylamine hydrochloride), and after analogous treatment of the reaction mixture as in Example 1, 13.2 g of 2- (n-oxo) acethydroxamic acid mp 139-140 ° C (decomposition). OBJECT OF THE INVENTION A process for the preparation of aryloxyalkanohydroxamic acids of the formula 1 wherein Ar is 1-naphthyl or 2-naphthyl, R is hydrogen when n is from 2 to 10, wherein Ar is 1-naphthyl or 2-naphthyl; or a C 2 -C 10 alkyl group, when n = 1, by reacting the corresponding alkali metal naphthalate with a haloalkanoic acid ester of formula 11, X - (CH) - COOR 1/11 / I n R where R is as defined above X is halogen such as chlorine or bromine and R 1 is an alkyl of from 1 to 3 carbon atoms, in a solvent environment followed by the reaction of isolated naphthyloxyalkanoic acid esters with a hydroxylamine salt in the presence of a base, characterized in that the alkali metal naphthalate reaction is with a haloalkanoic acid ester of the formula II is carried out in an inert aprotic polar solvent, for example dimethylsulfoxide, with a maximum water content of 0.1%, at a temperature of 10 to 35 ° C.