RU2039048C1 - Trans-4-azido-3,6-dimethylhexahydropyrimidin-2-thione having nematocidal activity - Google Patents

Abstract

FIELD: agriculture. SUBSTANCE: the product is trans-4-azido-3, 6- dimethylhexahydropyridin-2-thione of the formula: C₆H₁₁N₅S. The yield 89.5-97.8% mp 126.5-127.5. Reagent 1: 4 hydroxy-3,6-dimethylhexahydropyridin-2-thione. Reagent 2: sodium azide. Reaction conditions: concentrated hydrochloric acid, 20 C. EFFECT: improved properties of the title compound. 3 tbl

Description

 The invention relates to a new derivative of hexahydropyrimidine, namely to trans-4-azido-3,6-dimethylhexahydropyrimidin-2-thion of formula I, which exhibits nematicidal activity and which can be used in agriculture.

I
Наиболее близким по структуре аналогами предлагаемого соединения являются 2-моно- и 2,4-бифункционально замещенные гексагидропиримидины.

I
The closest in structure to the analogues of the proposed compounds are 2-mono- and 2,4-bifunctionally substituted hexahydropyrimidines.

II Имеются данные о том, что 4-функционально замещенные 3-арил(гетарил)гексагидропиримидин-2-оны (III) проявляют гербицидную активность [2, 3]

III
Более широким спектром пестицидной активности по сравнению с гидрированными аналогами обладают функционально замещенные ароматические пиримидины [4] Вместе с тем, сведений о нематоцидной активности функционально замещенных пиримидинов, как ароматических, так и гидрированных, являющихся структурными аналогами заявляемого соединения, не обнаружено.However, information on the use of these compounds in agriculture is very scarce. So, [1] it was shown that hexahydropyrimidin-2-ones of formula II have a beneficial effect on the growth of algae

II There is evidence that 4-functionally substituted 3-aryl (hetaryl) hexahydropyrimidin-2-ones (III) exhibit herbicidal activity [2, 3]

III
Functionally substituted aromatic pyrimidines possess a broader spectrum of pesticidal activity compared to hydrogenated analogues [4] However, no information was found on the nematicidal activity of functionally substituted pyrimidines, both aromatic and hydrogenated, which are structural analogues of the claimed compound.

 Heterophos, etaphos and carbathion, which are used in agriculture as nematicides, in particular against saprozoy nematodes, rice aphelenchoid, potato stem nematodes, beet cyst-forming nematodes, and the closest in nature to the activity, but very distant in chemical structure to compound (I), are gall nematodes in the soil. These compounds, selected as prototypes, have the following disadvantages.

Heterophos-O-phenyl-O-ethyl-S-propylthiophosphate and ethaphos-O-ethyl-ethylpropyl-O- (2,4-dichlorophenyl) thiophosphate belongs to the class of phosphorus-containing substances, have an odor and high acute toxicity (for example, for heterophos LD -30-60 ₅₀ mg / kg in rats), which significantly reduces their practical value.

Sodium carbide dihydrate N-methyldithiocarbamate is a highly toxic substance (LD ₅₀ = 146 mg / kg in mice), it is inconvenient to handle, because methylisothiocyanate released during its decomposition irritates the mucous membranes of the eyes, it is obtained on the basis of toxic and explosive carbon disulfide.

 Based on the foregoing, it is clear that the search for new effective, low-toxic, affordable nematicides is a very urgent task.

 The aim of the invention is to obtain new derivatives of hexahydro-pyrimidine-2-thione, with a higher nematicidal activity compared with drugs used in agriculture.

 The goal is achieved by synthesizing a previously undescribed compound of trans-4-azido-3,6-dimethylhexahydro-pyrimidin-2-thione (I), which exhibits high nematicidal activity against the saprozoid nematode, rice aphelenchoid, potato stem nematode, beet cyst nematode, and also against gall nematodes in soil.

+ NaN₃+HCl

Способ получения соединения (I) становится ясным из примеров 1-3.Compound (I) was synthesized by the reaction of nucleophilic substitution of a hydroxyl group in readily available trans-4-hydroxy-3,6-dimethylhexahydro-pyrimidin-2-thione (IV) [5] with an azide group in the interaction of compound (IV) with sodium azide and hydrochloric acid in the aquatic environment. To complete the reaction at ²⁰ ° C takes approximately 24 hours, the synthesis yield is 95-98% By increasing the reaction temperature formation speed compound (I) increases, but decreases somewhat with the yield of the reaction product. So, at ⁷⁰ ° C and reaction time 10 min yield compound (I) was 89.5% and at ⁵⁰ ° C and a reaction time of 30 min 91.4%

+ NaN ₃ + HCl

The method of obtaining compound (I) becomes clear from examples 1-3.

PRI me R 1. Synthesis of trans-4-azido-3,6-dimethylhexahydro-pyrimidin-2-thione at 20 ^about C.

To a cooled ^to 0 ° C mixture of 10.10 g (63.1 mmol) of finely divided hydroxypyrimidine (IV), 7,00 g (107.7 mmol) of sodium azide and 20 ml of water was added, cooled to the same temperature a solution of 9.3 ml (108.4 mmol) of concentrated hydrochloric acid in 25 ml of water. The resulting mixture was left in a closed container at 20 ^about C for 92 hours, periodically shaking the contents. Cool to ⁰ ° C, the precipitate was filtered off, washed thoroughly with ice water and dried. 11.42 g (97.8%) of substantially pure compound (I) are obtained.

PRI me R 2. The synthesis of compound (I) at 70 ^about C.

Prepared according to the procedure described in example 1, from 0.548 g (3.42 mmol) of hydroxypyrimidine (IV), 0.379 g (5.84 mmol) of sodium azide, 0.50 ml (5.83 mmol) conc. hydrochloric acid, 2.4 ml of water, however, the reaction is carried out at 70 ^about C for 10 minutes The yield of compound (I) is 0.567 g (89.5%).

PRI me R 3. The synthesis of compound (I) at 50 ^about C.

Obtained according to the procedure described in example 1, from 0.473 g (2.95 mmol) of hydroxypyrimidine (IV), 0.330 g (5.08 mmol) of sodium azide, 0.44 ml (5.13 mmol) conc. hydrochloric acid, 2.1 water, however, the reaction is carried out at 50 ^about C for 30 minutes The yield of compound (I) is 0.499 g (91.4%).

Compound (I) is purified by recrystallization from ethyl acetate. T. pl. 126,5-127,5 ^{° C} (decomposition; from ethyl acetate).

Found, C, 39.44; H 5.75; N, 37.84; S 17.11. C ₆ H ₁₁ N ₅ S. Calculated C 38.90; H 5.99; N, 37.81; S 17.31.

UV spectrum (in acetonitrile), λ _max , nm (log ε): 214 (4.11), 257 (4.27).

IR spectrum (in liquid paraffin), <N> nu <N>, cm ^-1 : 3208 br. (<N> nu <N> NH), 2103 (N ₃ ), 1525 and 1501 (thioamide-II).

PMR spectrum (in DMSO-D ₆ ), δ, ppm 8.52 s. (NH, J _{NH, 6-H} ≈ О Hz, J _{NH, 5-He} ≈1.5 Hz), 5.39 d.d. (4-He, J _{4e, 5e} = 2.3 Hz, J _{4e, 5a} = 3.5 Hz), 3.45 m (6-He, J _{5e, 6a} = 3.8 Hz), 3.35 s (N-CN ₃ ), 2.09 m (5-He, J _{5e, 5a} = 13.9 Hz), 1.70 ddd (5-Na, J _{5a, 6a} = 12.2 Hz), 1.15 d (6-CH ₃ , J _{CH 3, 6-Na} = 6.5 Hz).

 Compound (I) is a white crystalline substance, insoluble in water, ether, hexane, poorly soluble in cold ethyl acetate, soluble in acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide. It is steady during storage.

 The structure of compound (I) is unambiguously proved by IR, UV and PMR spectroscopy.

The thioureid group of compound (I) is manifested in the UV spectrum by the presence of an intense absorption band at 214 and 257 nm, and in the IR spectrum by the thioamide-II bands at 1501 and 1525 cm ^-1 and a wide stretching band of the NH group at 3208 cm ^{- 1} . The presence of an azide group in the molecules of compound (I) determines the presence in the IR spectra of this compound of a very intense absorption band at 2103 cm ^-1 .

By NMR spectroscopy, it was found that compound (I) is formed completely diastereoselectively in the form of an individual transisomer. Based on the spin-spin coupling constants of protons N-H, 4-H, 5-H and 6-H, it was shown that the molecules of this compound exist in a crescent conformation with an axial orientation of the azide group at the C ₍₄₎ atom and an equatorial orientation of the methyl group at carbon atom C ₍₆₎ .

 The methodology for determining the nematicidal activity of compound (I) and the results obtained are reflected in examples 4, 5.

 PRI me R 4. The test of compound (I) for nematicidal activity against saprozoid nematodes, potato stem nematodes, rice aphelenchoid, beet cyst-forming nematodes.

 In the laboratory, the compounds were tested for toxicity to the saprozoid nematode Panagrellus redivivus, the potato stem nematode Ditylenchus destructor, the rice aphelenchoid Aphelenchoides besseyi, and the beet cyst nematode Heterodera schachtii.

The saprozoic, stem nematode of potato and rice aphelenchoid were cultured in laboratory conditions, the larvae of beet cyst-forming nematode were isolated from cysts obtained on plant roots in a greenhouse. A 4% mother liquor was prepared from compound (I), from which a working solution of a given concentration was obtained by the dilution method. The activity of the compound was studied by immersing suspended nematodes in working solutions of the compound. The course of work is as follows: 0.5 ml of distilled water was poured into cups with a capacity of 1.5 ml, nematodes were placed there in an amount of 30-40 pcs. Then, 0.5 ml of a working solution of a given concentration was poured into each cup. 0.5 ml of distilled water was added to the control plates. Then we put the cup in a humid chamber petri dishes with moist filter and placed in an incubator (25-27 ° ^C). The counts in the experiments were carried out after 48, 120 and 168 hours by counting live and dead nematodes under a binocular microscope.

 As can be seen from the table. 2, compound (I) showed high activity against rice aphelenchoid and, according to this indicator, at a concentration of 0.0033% d.p. significantly superior to etaphos (94.8% and 81.8%, respectively). Compound (I) also showed high nematicidal activity against potato stem nematode, and this activity was higher (at a concentration of 0.0011% bp) or at a level of etaphos activity. In addition, compound (I) at a concentration of 0.02% d.p. showed a slightly higher nematicidal activity against beet cyst-forming nematodes compared to heterophos.

 PRI me R 5. Test for nematicidal activity against gall nematodes in the soil. Vegetation tests against gall nematodes were carried out by introducing compound (I) into the soil infested with larvae of gall nematodes Meloidogyne incognita and M.arenaria, uniform mixing 5 days before sowing the cucumber culture. Compound (I) was tested in the form of a sand granulate prepared from 30 g of granulate and a 4% mother liquor of compound (I). Assessment of biological effectiveness was carried out 25 days after sowing to reduce gall formation on the roots in comparison with the control.

· 100 где а общее число нематод, среднее количество галлов в контрольном варианте;
в количество живых нематод, среднее количество галлов в опытном варианте.The percentage reduction in gall formation and death of nematodes was calculated by the formula:
T

· 100 where a is the total number of nematodes, the average number of galls in the control variant;
in the number of live nematodes, the average number of galls in the experimental version.

 Evaluation of the activity of the compounds was carried out according to the percentage reduction in gall formation.

 As can be seen from the table. 3, compound (I) at a consumption rate of 0.032 g / kg of soil reduces gall formation more significantly than heterophos used in agriculture (69.5% and 65.2%, respectively).

 Thus, trans-4-azido-3,6-dimethylhexahydropyrimidin-2-thion (I) showed high biological efficacy against the saprozoid nematode, rice aphelenchoid, potato stem nematode, beet cyst nematode, and gall nematodes in the soil, and the activity of the compound (I ) was comparable, and in some cases exceeded the activity of drugs used in agriculture.

 Considering the need to replace heterophos, etaphos and carbathion nematicides due to their high toxicity and difficulty in handling, the claimed compound (I) exhibiting high nematicidal activity, and also obtained in high yield on the basis of available cheap domestic raw materials, promising for use in agriculture should be considered as a nematicidal drug.

Claims (1)

Trans-4-azido-3,6-dimethylhexahydropyrimidin-2-thion of the formula

showing nematicidal activity.

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