SU680647A3 - Method of obtaining derivatives of n-(benzthiazolyl-2)-oxamine acids or esters of same or salts thereof - Google Patents

Description

in which R, R, 2, RjH R; have the values indicated above, are reacted with an oxalic acid derivative of the general formula (H

Oh oh

where X has the above values

Y is a lower alkoxy residue or a halogen atom, and the resulting desired product is isolated in the form of the free acid, its ester or salt.

The 2-aminobenzthiazoles used as starting materials, corresponding to general formula II, are partially New compounds, and these new compounds can be obtained:

a) by the reaction of Hughershoff tourea of the general formula .1У

Rt

Rz

NH-C-NH

(Iv)

Rj

R4

wherein R, Rg, R.J and R have the foregoing meanings are subjected to dehydrating cyclization with bromine in a suitable solvent, for example in chloroform, to form a compound of formula II, or

b) by the reaction of Kaufman

aniline derivative corresponding to formula Y

RI

- Ji 5

H-v)

R ,, Rj, Kg, and R have the above values, are robanted in the orthoposition and, in this case, without isolating the thiocane compound of the formula D1

Ri

where R, Rj, Rj and R have the indicated meanings, cyclization is carried out to form 2-aminobenzthiazole, corresponding to the formula P.

The reaction of a compound of general formula P with an oxalic acid derivative of formula 111 is carried out using oxalic acid ester halide, preferably oxalic acid ethyl ester chloride, in an aprotic solvent, which can be used as methylene chloride, pyridine, chloroform, and carbon tetrachloride, and temperature (method A). Interaction of 2-aminosoedienien formul. T1 with alkyl ester of oxalic acid 4, such as distilled and methyl-tert-butyl ether, is produced predominantly without a solvent at the boiling point of the reaction mixture or at sec / 150 s (method B). In the case of oxalic acid ethyl t-butyl ester, a free derivative of oxamic acid is directly formed, since 2-methylpropen-1, when this method is used, is thermolytically cleaved under the reaction conditions.

The compound of general formula I, in which R is, for example, a hydroxyl group, can be converted by a suitable alkylating agent into a compound with an alkoxy group. Conversely, the alkoxy group can be converted into a hydroxyl group by known methods. The carboxylic ester of the general formula 1 (the alkyl radical) can be hydrolyzed to the corresponding carboxylic, acid (X hydrogen atom) mineral acid or alkali metal hydroxide in a polar solvent (for example, water, methyl alcohol, ethyl alcohol, dioxane or acetone). The hydrolysis is preferably carried out with a strong base (sodium hydroxide or potassium hydroxide) in a mixture consisting of methyl alcohol and water, at room temperature or at a moderately elevated temperature. In addition, carboxylic acids can be esterified, or an ester with a specific residue X can be converted by esterification into an ester with another residue X. Esterification of carboxylic acids is most expediently carried out in the presence of an acid catalyst, such as hydrogen chloride, sulfuric acid, para-toluenesulfonic acid or strongly acidic ion exchange resin. The transesterification is required when a small amount of a substance with basic properties is added, for example, an alkali hydroxide or alkaline earth metal hydroxide or an alkali metal alcoholate.

For the preparation of salts with organic or inorganic bases, 5 for example, sodium hydroxide, potassium, calcium, ammonium, methyl glucamine morpholine or ethanolamine, carbono. The acidic acids can be reacted with the appropriate Q bases. Mixtures of carboxylic acids with carbon dioxide or acid carbonate salts of alkali metals can also be used.

The structure of the obtained compounds 5 was confirmed by CUN-analya data, IR, UV, and NMR spectra data. In the general analysis, characteristic determinations of physical constants were made in some examples. Example. N-4- (4-methoxybenzthiazolyl-2 -) - oxoic acid ethyl ester. Method A. 18.02 g of 2-amino-4-methoxybenzene ash (0.1 mol) is dissolved in 250 methylene chloride with the addition of 16.1 ml of pyridine, and within 15 m at. The prepared solution is mixed with a solution containing m 15.01 g of oxalic acid ethyl ester chloride (12.3 ml / 0.11 mol) in 30 ml of methylene chloride. Thereafter, the reaction mass is stirred for a further 20 minutes at, the precipitate is filtered off, and the filtrate is evaporated in vacuo. The resulting evaporation was stirred with diluted with hydrochloric acid (5 N) and the solid was isolated by filtration. The product is washed with dilute hydrochloric acid and water, dried (crude product yield 27.8 g, mp 173-174c) and then recrystallized from nitromethane. The result is 24.8 g of the product with so pl. 174-175c. Exit 88.7% (from theoretical). The structure was confirmed by CHN-analysis, IR, UV, NMR and mass spectra (mol. Weight 280). Method B. 18.02 g of 2-amino-4-methoxybenzthiazole (0.1 mol) in 135 ml of oxalic acid (1 mol), heated for 4 hours; at the boiling point of the reaction mixture under reflux the reaction mixture is then filtered in the heated state and after cooling, the precipitate formed is filtered off, which is washed with cold ethyl alcohol and immediately thereafter recrystallized from nitromethane. As a result, 18.1 g (64.6% of the theoretic of the {1 hectare) of product with m.p. 175 C. As the IR spectra show, the obtained substance is identical with the compound obtained in accordance with method A, carbonyl bands are about 17jg5 cm (5.87 microns) and 1740 cm (5.75 microns). 2. N- (4-Methoxybenz thiazolyl-2) -oxamic acid (sodium salt). i Method A. a) 5 g of ethyl ether described in Example 1 (0.01778 mol) are suspended in 150 ml of water and mixed with 17.8 ml of 1N sodium hydroxide solution for 45 minutes at room temperature. After stirring the reaction mixture for a further 2 hours, filtration is carried out and the sodium salt of oxamic acid as a crude product is isolated by freeze drying. After that, the substance is dissolved in 100 ml of water, filtered again and, with the addition of a 2N hydrochloric acid solution, the desired acid is isolated in the free state. After drying, 3.05 g (68% of theory) of product is obtained, mp. which is 223-225 s. b) 1.2 g of the acid is suspended in 100 ml of water and the prepared suspension is neutralized by the addition of 4.75 ml of 1N sodium hydroxide solution. Immediately thereafter, the clear solution was freeze dried, and 1.21 g of the sodium salt of N-14-methoxy-benzothiazolyl-2) -oxamic acid (8% water content) were obtained, mp. which is 25525 bs (with decomposition). Method B. 5 g of 2-amino-4-methoxybenzthiazole (0.0277 mol) is heated with 24.13 g of ethyl tert-butyl oxalic acid ester for 2 hours at 150 C. After cooling, the contents of the flask are diluted with diethyl ether and filtered . The product is washed with ether to give 6.17 g of the compound with so pl. 221-223 ° C, which, according to the IR spectrum, is identical to the N- (4-methoxybenzothiazolyl-2) -oxamic acid obtained in example 2 by method A. The yield is 88.3% (from the theoretical). The mass spectrum shows mol.ves.252. PRI me R 3. N- (6-methoxybenethiazolyl-2-α-oxamic acid ethyl ester. By analogy with the procedure described in Example 1, A, 18.02 g of 2-amino-6-methoxybenzthiazole (0.1 mol ) injected with 15.01 g of oxalic acid ethyl ester chloride (0.11 mol) in 280 ml of methylene chloride in the presence of 16 ml of pyridine. The precipitate formed is separated by filtration and washed with a dilute hydrochloric acid solution and water. 9.1 g of substance are obtained from ethyl acetate and 193194 C. The first filtrate is evaporated. m in vacuo, the residue is stirred with diethyl ether and the solid was separated by filtration. This product was washed with dilute hydrochloric acid and water, after which perekristallizovshayut from ethyl acetate by the addition of activated carbon. The resulting additional prepared th

11.7g substances with so pl. 192 ° C. Shared; the yield of the desired oxamic acid ethyl ester is

20.8g (74.20% of theoretical). IR spectrum: 1730 cm (5.78 microns) 1710 cm (5.84 microns) for carbonyl STRIPS 4 3270 cm (3.06 microns) for the H-band. Mass spectrum: mol.

Example 4. N- (b-Methoxybenethiazolyl-2) -oxamic acid.

In accordance with Example 2, Method A, 5 g of oxamic acid ester as specified in Example 3 (0.0178 molG) is suspended in 150 m of water and, after adding 17.8 ml of 1N sodium hydroxide solution to the prepared suspension, wash the reaction mixture with stirring the mixture for 2 hours at room temperature. The reaction mixture is then filtered and the sodium salt of the corresponding oxamic acid is separated by freeze drying. (mp product 300 ° C.) Yield 4.1 g (84.01% of the theoretically calculated value).

2 g of sodium salt is dissolved in 50 ml of water and the clear solution is acidified by adding 2N hydrochloric acid solution to pH 2. The yellow colored precipitate is filtered, washed with water and then dried under vacuum at 50 ° C. The result is 1.4 g of free oxamic acid with so pl. 227-228 s. The structure is proved analytically using the nuclear resonance spectrum. Mass spectrum mol. Weight .. 252.

PRI me R 5. N- (b-ethoxybenzthiazolyl-2) -oxamic acid ethyl ester.

In accordance with Example 1, Method A, 5.8 g of 2-amino-6-ethoxybenziazole (0.03 mol) and 4.5 g of oxalic acid ethyl ester chloride (0.033 mol) are reacted in 85 ml of methylene chloride with addition of 4.83 ml of pyridine, the reaction being carried out for 1 hour. 6.7 g of the desired oxamic acid ester (76% of the theoretical value), mp. which is 183-184 seconds (from, -nitromethane).

Mass spectrum: mol. Weight. 294. Chromatography in a thin layer: chloroform: methanol - 9: 1.

EXAMPLE 6 LH5-methoxybenzthiazolyl-2) -oxamic acid ethyl ester.

By analogy with the method described in example 1, method A, 18.02 g of 2-amino-5-methoxybenzthiazole (0.1 mol) - is reacted with 15.01 g of oxalic acid ethyl ester chloride (0.11 mol) adding 1 (i, J ml of pyridine in

280 ml of methylene chloride, the reaction is carried out for 35 minutes at 10 ° C. Directly after this, the product is filtered, washed with a solution of hydrochloric acid (2N) and water, after which the crude product (26.4 g, 94.2% yield; mp. 165-166 C) is recrystallized from nitromethane.

The result is 22.9 g of the product (yield 81.7% of the theoretically calculated value), for which it is 168-169 seconds, in mol. Weight. 280. IR spectrum: 1738 (5.77 microns), 1698 (5.89 microns) for the carbonyl band; 3265 (3.06 microns) for the H-band.

Example7. N - (5-Methoxybenzthiazolyl-2) -oxamic acid (sodium salt).

5 g of ester described in Example 6 (0.01778 mol) in accordance with Example 2 a, b. Method A is suspended in 150 ml of water and by adding 17.8 ml of sodium hydroxide to the prepared suspension, saponification is carried out for 2 hours at room temperature. After filtration, the aqueous solution is freeze dried. 3.4 g of the desired sodium salt are obtained (69.7% of the theoretically calculated value), m.p. Z29s, the water content of 5%.

A sample of the sodium salt is dissolved in water and the solution is mixed with an IN solution of hydrochloric acid. The acid produced by this method was analytically pure and has so pl. 228-229 ° C.

PRI me R 8. N- (7-isopropyl-4-methoxybenzthiazolyl-2) -oxamic acid ethyl ester.

a) 7.03 g of benzoyl chloride (0.05 mol) is dissolved in 25 ml of acetone and at 15–20 seconds the prepared solution is mixed with a solution containing 3.8 g (0.05 mol) of ammonium rhodanide in 25 ml of acetone. A solution containing 8.26 g of 2-amino-4-isopropylanisole (0.05 mol) in 25 ml of acetone is added dropwise to the solution for 10 minutes to form a solution.

for 4.5 hours at its reflux temperature. Immediately after this, the reaction mass is poured onto ice and after separation by filtration, 1- (5-isopropyl-2-methoxyphenyl-3-benzoylthiomyochevine) is obtained as an intermediate product, which according to the chromatography in a thin layer turned out to be sufficiently pure for further transformation.

Claims (1)

1. Petyunin P.A., Zakapyuzhny M.V. Amides and oxalic hydrazides, 0 1U Hydrazides of N-substituted oxamic acids. JOH, 1, 1964. 34, p.28.