RU2275362C2 - 3-hydroxy-2-thioxo-4(3h)-quinazolinone possessing fungicide and growth-regulating property and method for it preparing - Google Patents

Abstract

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new chemical compound 3-hydroxy-2-thioxo-4(3H)-quinazolinone of the formula (I):

This compound possesses fungicide and growth-regulating activity. Also, invention relates to a method for preparing the indicated compound that involves the successive interaction of antharanilic acid ester with thiophosgene, sodium acetate followed by reaction with hydroxylamine.

EFFECT: improved preparing method, valuable properties of compound.

3 cl, 4 tbl, 3 ex

Description

The invention relates to organic chemistry and agriculture and for a new derivative of quinazoline, namely 3-hydroxy-2-thioxo-4 (3H) quinazolinone (I), of the following formula:

and having fungicidal and growth regulating properties, and a method for its preparation.

It is known that 2-thioxo-4 (3H) quinazolinones showed a wide range of biological activity. Numerous examples of activity and suggestions for the use of compounds of this class as biologically active compounds in various fields are known, for example, in pharmacology and in agriculture:

1. M.A.E. Shaban et al., Adv. In Heterocyclic Chem., 1991, Vol. 52, p. 1.

2. P.S. Reddy, P.P. Reddy, T. Vasanta, Heterocycles, 2003, Vol.60, No. 1, p. 183.

Derivatives of 3-hydroxy-2-thioxo-4 (3H) quinazolinones with substituents on the hydroxyl group also have different types of activity. So 3-tert-butyloxy and 3-benzoxy-2-thioxo-4 (3H) quinazolinones, which are intermediates in the preparation of anti-asthma and anti-allergic compounds, were synthesized by cyclization of the corresponding anthranilic acid amides with carbon disulfide in an alkaline medium.

4. WO 01/70737 A1 (Sepracor Inc., US) 09/27/2001.

4-Oxo-2-thioxosinazolin-3-yloxyacetic acid having fungicidal properties was obtained by reacting the corresponding anthranilic acid amide with thiophosgene:

5. DD 249910 A (A.Shahs, S. Johne, M. Sube) 09/23/1987.

Known is the synthesis of an oxygen analogue of the claimed compound I - 3-hydroxy-2,4-dioxotetrahydroquinazoline, based on the interaction of N- (alkyl- or arylsulfonyloxy) phthalimides with hydroxylamine.

6. Aly N.F., El-Komy M., Aly N.J., Orabi M. O. Indian J. Chem. 1983, B 22, N 5, p. 471.

7. DM 1068263 A (Bayer AG) 11/05/1959.

However, the synthesis and properties of unsubstituted 3-hydroxy-2-thioxo-4 (3H) quinazolinone are not described in the literature, and the above methods are not suitable for obtaining the claimed compound.

Thus, a new chemical compound 3-hydroxy-2-thioxo-4 (3H) quinazolinone of the following structure is described:

possessing fungicidal and growth regulating activity.

The described 3-hydroxy-2-thioxo-4 (3H) quinazolinone may be present in

two tautomeric forms, which is characteristic of all 2-thioxo-4 (3H) quinazolinones.

The inventive compound can be used in agriculture to protect plants from fungal diseases and to increase plant productivity.

The inventive compound has a high fungicidal activity and is effective both in seed treatment and in spraying vegetative plants.

Also described is a method for producing 3-hydroxy-2-thioxo-4 (3H) quinazolinone by sequential interaction of anthranilic acid ester with thiophosgene, sodium acetate and then with hydroxylamine according to the presented scheme:

An inert aprotic solvent immiscible with water is used as an organic solvent in the reaction, for example: methylene chloride, chloroform, dichloroethane, benzene, toluene, xylene, ethyl acetate, etc. (preferably methylene chloride or chloroform). The addition of a solution of thiophosgene to a mixture of methylanthranilate 1, an organic solvent and water is carried out with vigorous stirring and cooling to 0-10 ° C. The mixture was altered for another 2 hours at this temperature, the aqueous layer was separated and an aqueous solution of sodium acetate was added to the resulting solution of compound 2 in an organic solvent. Stirred for 1 hour at room temperature. After separation of the aqueous phase, a solution of methyl 2-isothiocyanatobenzoate 3 in an organic solvent is obtained, which is added to a solution of hydroxylamine hydrochloride and sodium hydroxide in a significant amount of water (about 500-600 ml per 0.2) while cooling to 0-10 ° C and intensive stirring praying download). The precipitate of 3-hydroxy-2-thioxo-4 (3H) quinazolinone I resulting from the reaction is filtered off, washed with water and the solvent used in the reaction, and dried at 80-90 ° C.

Methyl-2-isothiocyanatobenzoate 3, as described above, was introduced into the next step without isolation. You can also isolate methyl 2-isothiocyanatobenzoate 3 from the reaction mass or use a commercially available methyl 2-isothiocyanatobenzoate product (for example, Acros Organics, Kat. No. 23530), as well as use methyl 2-isothiocyanatobenzoate obtained in any other way. In this embodiment, 3-hydroxy-2-thioxo-4 (3H) quinazolinone is obtained in one step: a solution of methyl 2-isothiocyanatobenzoate 3 in an organic solvent is cooled to 0-10 ° C and vigorously mixed with a solution of hydroxylamine hydrochloride and sodium hydroxide in a significant amount of water (approximately 500-600 ml per 0.2 mole load). The precipitate of 3-hydroxy-2-thioxo-4 (3H) quinazolinone I resulting from the reaction is filtered off, washed with water and the solvent used in the reaction, and dried at 80-90 ° C.

Examples of carrying out the invention

Example 1

To a mixture of 30 g (0.2 mol) of methylanthranilate, 150 ml of methylene chloride and 100 ml of water 0-10 ° C and with vigorous stirring, a solution of 24 g (0.21 mol) of thiophosgene in 50 ml of methylene chloride is added. After addition, it is stirred for another 2 hours at 10 ° C, the aqueous layer is separated, the organic layer is washed with 50 ml of water. A solution of 30 g of sodium acetate in 50 ml of water is added to the organic layer at 20 ° C with stirring. Stirred for 1 hour at this temperature. The organic layer is separated, washed with 50 ml of water, and then 13.9 g (0.2 mol) of hydroxylamine hydrochloride and 8 g (0.2 mol) of sodium hydroxide in 500 ml of water are pinned to a solution at 5-10 ° C with vigorous stirring. After addition, the temperature was brought to room temperature and stirred for 2 hours. The precipitate is filtered off, washed on the filter with 100 ml of methylene chloride and 2 × 100 ml of water. Dried at 80-90 ° C. Compound I was obtained as a white powder. Yield 31 g (80%). T. pl. 252-254 ° C (ethanol). ¹ H NMR Spectrum (DMSO-d ₆ , δ): 12.75 (s, 1H), 10.80 (s, 1H), 8.0 (d, 1H, J = 9 Hz), 7.65 (t , 1H, J = 9 Hz), 7.40 (d, 1H, J = 9 Hz), 7.22 (t, 1H, J = 9 Hz). Mass spectrum [M ⁺ , m / z]: 194. Elemental analysis: Found,%: C 48.56; H 3.10; N, 14.49. Calculated,%: C 48.45; H 3.12; N, 14.43.

Example 2

A solution of 38.4 g (0.2 mol) of methyl 2-isothiocyanato benzoate 3 in 50 ml of ethyl acetate is pinned to a solution of 13.9 g (0.2 mol) of hydroxylamine hydrochloride and 8 g (0.2 mol) of sodium hydroxide in 500 ml water at 5-10 ° C and vigorous stirring. After addition, the temperature was brought to room temperature and stirred for 2 hours. The precipitate is filtered off, washed on the filter with 100 ml of ethyl acetate and 2 × 100 ml of water. Dried at 80-90 ° C. A white powder of compound I is obtained. Yield 35 g (90%). T. pl. 252-254 ° C (ethanol). Elemental analysis: Found,%: C 48.54; H 3.11; N, 14.47. Calculated,%: C 48.45; H 3.12; N, 14.43. The spectral data of compound I are similar to those shown in example 1.

Example 3

Results of biological tests of 3-hydroxy-2-thioxo-4 (3H) quinazolinone.

1. In vitro test results

In the formulation of the experiment, the activity of drugs against pathogenic microorganisms was determined on a pure pathogen culture under cultivation conditions on an agarose medium containing starch. Activity was defined as the percentage of inhibition of the development of the microorganism in relation to the control sample.

Table 1. Diameters of colonies of pathogenic fungi. Mushroom Connection I THE CONTROL Bryansk. 20 (anthracnose) fourteen 37.7 Fusarium Sp. (mono) 0 46 Fusarium Solany (Potato) 14.0 34.0 Fusarium Oxysporum (34) 17.3 36 Table 2. Suppression of the development of colonies of pathogenic fungi. The percentage of suppression. Mushroom Connection I Bryansk. 20 (anthracnose) 86.2% Fusarium Sp. (mono) one hundred% Fusarium solanty (potato) 83.0% Fusarium Oxysporum (34) 76.9%

4.2 In vivo test results.

Evaluation of the biological effectiveness of compound I, against helminthosporosis (Bipolaris sor.). To establish fungicidal activity, seeds of spring barley of the Zazersky 85 variety were etched on a HEGE-11 plant (Germany) with a consumption rate of 10 l / t of seeds of 1% K.s. preparation of compound I. As a reference, we used Premix C Dvesti, Vitavaks 200 FF, V .SK., Kulfugo super color, K.S.

Pickled seeds were sown in the field on experimental plots. Accounting was carried out at the beginning of heading phase (Zadox phase 51) (artificial infectious background). The results are shown in table 3.

Table 3. Fungicidal activity of compound I against helminthosporous rot. a drug The consumption rate of the drug, l / t of seeds prevalence,% The decrease in the prevalence,% The development of the disease,% decrease in the development of the disease,% etching control - 91.3 - 26.4 - Connection I, 1% K.S. 7.5 53.2 42 15.7 41 PremixS Two hundred, K.S. 0.19 59.8 36 18.6 thirty Vitavax 200 FF, V.S.K 3.0 68.3 25 22.2 16 Kolfugo super color, K.S. 2.0 71.1 22 23.0 13

4.3 Assessment of growth-regulating and fungicidal activity.

Evaluation of the growth-regulating activity of compound I. The tests were carried out in the greenhouse complex SKHPK agricultural company "Pavlovskaya" by the effect of the drug on photosynthesis. The test results are shown in table 4.

Table 4. The effect of compound I on the photosynthesis of cucumber plants. A drug Biological activity, μm Reference: 22 Connection I 28 The control twenty

Compound I showed not only fungicidal activity against anthracnose, ascochitosis, fusariosis; but also stimulated the growth and development of plants. So, cucumber plants under the influence of compound I began fruiting before the control plants for 4 days. The spread of the disease was removed by a single treatment at 0.2% concentration, while using industrial fungicides, 2-3 times treatment is required. With a single treatment of cucumber plants, the claimed compound at a concentration of 0.2% protected the plants from anthracnose.

Claims (2)

1. 3-Hydroxy-2-thioxo-4 (3H) quinazolinone of formula I

possessing fungicidal and growth-regulating activity. 2. The method of obtaining 3-hydroxy-2-thioxo-4 (3H) quinazolinone of the formula I according to claim 1, characterized in that the reaction of anthranilic acid ester of the formula 1

with thiophosgene to obtain the compounds of formula 2

, which is subjected to subsequent interaction with sodium acetate and the resulting compound of formula 3

then reacted with hydroxyamine to give a compound of formula I.