CN108358901B - Deuterated pent-4-enyl-N-furfuryl-NPreparation of (E) -imidazole-1-carbonyl-DL-homoalanine ester and bactericidal activity - Google Patents

Deuterated pent-4-enyl-N-furfuryl-NPreparation of (E) -imidazole-1-carbonyl-DL-homoalanine ester and bactericidal activity Download PDF

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CN108358901B
CN108358901B CN201810360623.8A CN201810360623A CN108358901B CN 108358901 B CN108358901 B CN 108358901B CN 201810360623 A CN201810360623 A CN 201810360623A CN 108358901 B CN108358901 B CN 108358901B
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安杰
李恒朝
韩敏晖
张学博
丁宇轩
严子涵
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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Abstract

本发明属于农药创制、病原菌控制技术领域，具体涉及氘代戊4‑烯基‑N‑糠基‑N‑咪唑‑1‑基羰基‑DL‑高丙氨酸酯类化合物的制备方法和杀菌活性应用。本发明利用经济成本低廉的方法首次实现了氘标记的戊4‑烯基‑N‑糠基‑N‑咪唑‑1‑基羰基‑DL‑高丙氨酸酯的合成。四种氘标记的戊4‑烯基‑N‑糠基‑N‑咪唑‑1‑基羰基‑DL‑高丙氨酸酯结构新颖，且具有良好的离体杀菌活性，尤其对水稻恶苗病菌、水稻稻瘟菌具有明显的抑制效果。在动力学上，C‑D键相比C‑H键更为稳定。因此，相比未被氘标记的化合物，氘代戊4‑烯基‑N‑糠基‑N‑咪唑‑1‑基羰基‑DL‑高丙氨酸酯有望具有更长的持效期和对环境更小的压力。氘代戊4‑烯基‑N‑糠基‑N‑咪唑‑1‑基羰基‑DL‑高丙氨酸酯还可作为探针研究这一化合物的代谢及毒理特性。并可作为农药残留分析中的内参。The invention belongs to the technical field of pesticide creation and pathogen control, and in particular relates to a preparation method and bactericidal activity of deuterated 4-enyl-N-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalanine ester compounds application. The invention realizes the synthesis of deuterium-labeled pent-4-enyl-N-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalanine ester for the first time by means of an economical and low-cost method. Four deuterium-labeled pent-4-enyl-N-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalanine esters have novel structures and have good in vitro bactericidal activity, especially against rice baica , Rice blast fungus has obvious inhibitory effect. Dynamically, C‑D bonds are more stable than C‑H bonds. Therefore, deuterated 4-enyl-N-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalanine esters are expected to have a longer duration of potency and greater resistance to less stressful environment. Deuterated 4-enyl-N-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalanine ester can also be used as a probe to study the metabolic and toxicological properties of this compound. It can be used as an internal reference in pesticide residue analysis.

Description

Deuterated pent-4-enyl-N-furfuryl-NPreparation of (E) -imidazole-1-carbonyl-DL-homoalanine ester and bactericidal activity
Technical Field
The invention belongs to the technical field of pesticide creation and pathogen control, and particularly relates to deuterated pent-4-enyl-N-furfuryl-NA preparation method and bactericidal activity application of the (E) -imidazole-1-ylcarbonyl-DL-homoalanine ester compound.
Background
Grain yield is the basis for ensuring global grain safety. At present, the most effective measure for controlling the yield reduction of food caused by diseases, insects and weeds is still to apply chemical pesticides. However, the use of chemical pesticides in large quantities inevitably causes a series of problems such as drug resistance and ecological environment pollution. Therefore, the development of novel efficient green pesticides and the realization of the reduction and the improvement of the pesticide have important practical significance.
In the pharmaceutical industry, introduction of deuterium is increasingly used to improve the metabolic stability and pharmacokinetic properties of drugs (J. Med. Chem., 2011, 54 , 2529; Annu Rep Med Chem. 2011, 46,403). In 2017, the first example of deuterated drugs (deuterabenazine) was officially approved by the U.S. Food and Drug Administration (FDA). However, the economic cost of synthesizing deuterated compounds using conventional methods is often high, which limits the use of deuterated compounds in more price-sensitive pesticide applications. The current development of deuterated pesticides is in the initial stage, and the deuterated pesticides may have longer half-life (smaller application amount) and weaker toxicity to non-target organisms due to kinetic isotope effect: (J. Mass Spectrom. Soc. Jpn.1998, 46, 157). In addition, the deuterated pesticide can also be used as a probe for researching the metabolism and toxicology of the pesticide and can be used as an internal reference in pesticide residue analysis.
The invention aims to utilize an economic and low-cost synthesis method to prepare deuterium-labeled 4-pentenyl-ketone-N-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalaninate in order to obtain deuterated pesticides with improved properties. In the previous work of the inventors, a series of reductive deuteration reactions based on a novel sodium mediated single electron transfer reaction were established (J. Org. Chem.2017, 82, 1285；Tetrahedron Lett.2017, 582757), the method has good selectivity, high deuteration rate and low economic cost. Using the above synthetic strategy, the inventors synthesized 4 types of E-4-alkenyl-substituted compounds labeled with deuterium at different positionsN-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalaninate. The in vitro activity test shows that the compound has good inhibitory activity on both bakanae disease and pyricularia oryzae. No deuterium labeled pent-4-enyl-N-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalaninate, to which end the present invention discloses novel deuterium-labelled pent 4-enyl-N-furfuryl-N-imidazole-1-carbonyl-DL-homoalanine ester, preparation method and bactericidal activity application thereof.
Disclosure of Invention
The object of the present invention is to provide deuterium-labeled pent-4-enyl-N-furfuryl-NA preparation method and bactericidal activity application of the (E) -imidazole-1-ylcarbonyl-DL-homoalanine ester compound.
Deuterium-labeled pent-4-enyl-N-furfuryl-Nthe-imidazole-1-ylcarbonyl-DL-homoalanine ester compound is a compound with a structure shown in a formula 1:
Figure DEST_PATH_IMAGE001
wherein: r1~R8At least one of them being deuterium and the remainder being hydrogen
The compound of formula 1 is prepared as follows:
Figure DEST_PATH_IMAGE002
ti cat. compounds were prepared as follows:
Figure DEST_PATH_IMAGE003
Figure DEST_PATH_IMAGE004
the preparation method is used for R of the compound of the formula 11~R8At least one is deuterium and the remainder is hydrogen
The compound of formula 1 is synthesized from the compound of formula 2 or the compound of formula 3 by one-step reaction
The compound of formula 2 is synthesized from formula 4 through one-step reaction
The compound of formula 3 is synthesized from the compounds of formula 4 and formula 6 through one-step reaction
The compound of formula 4 is synthesized from the compounds of formula 7 and formula 8 through one-step reaction
The compound of formula 5 is synthesized from the compound of formula 9 by one-step reaction
The compound of formula 6 is synthesized from the compound of formula 10 by one-step reaction
In the preparation method, the Ti cat compound is synthesized by the compounds of the formulas 5 and 6 through two-step reaction
The preparation method has the advantages of simple operation, easily obtained raw materials and no generation of harmful byproducts.
The invention also provides application of the compound in bactericidal activity in plant protection.
Preferably, the plant pathogenic bacteria are rice bakanae disease and rice blast disease.
The invention has the beneficial effects that: the invention realizes deuterium-labeled pent-4-enyl-N-furfuryl-N-synthesis of imidazol-1-ylcarbonyl-DL-homoalaninate. Four deuterium-labeled pent-4-enyl-N-furfuryl-NThe (E) -imidazole-1-ylcarbonyl-DL-homoalanine ester has a novel structure, has good in vitro bactericidal activity, and especially has an obvious inhibiting effect on rice bakanae disease and rice blast fungus. The C-D bond is kinetically more stable than the C-H bond. Thus, deuterated pent-4-enyl-N-furfuryl-N-imidazol-1-ylcarbonyl-DL-homoalaninate is expected to have a longer duration and less stress on the environment. Deuterated pent-4-enyl-N-furfuryl-Nthe-imidazole-1-carbonyl-DL-homoalanine ester can also be used as a probe to research the metabolism and the toxicological property of the compound. And can be used as an internal reference in pesticide residue analysis.
Detailed Description
The present invention is further illustrated by the following specific examples. The methods are conventional methods unless otherwise specified. The materials, unless otherwise specified, are commercially available from the open literature.
Deuterated pent-4-enyl-N-furfuryl-NPreparation of (E) -imidazol-1-ylcarbonyl-DL-homoalaninate
Example 1
Preparation of the Compound of formula 4
Figure DEST_PATH_IMAGE005
Furfurylamine (50.00 mmol, 4.85 g) which is a compound of formula 8 and methyl 2-bromobutyrate (50.00 mmol, 9.05 g) which is a compound of formula 7 were added dropwise to anhydrous potassium carbonate (150.00 mmol, 20.70 g)N,N-a suspension of dimethylformamide (35 mL). The reaction was carried out at 80 ℃ for 26 hours with stirring. The potassium carbonate was removed by filtration and the reaction mixture was diluted with ethyl acetate (40 mL). The organic layer was washed with saturated brine (3X 10 mL), and the aqueous layers were combined and extracted with ethyl acetate (3X 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 7.26g of product mass, 74% yield.
1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 1.8, 0.8 Hz, 1H), 6.30 (dd, J= 3.2, 1.8 Hz, 1H), 6.17 (dd, J = 3.2, 0.8 Hz, 1H), 3.80 (d, J = 14.3 Hz, 1H), 3.72 - 3.66 (m, 4H), 3.24 (t, J = 6.4 Hz, 1H), 1.85 (s, 1H), 1.68 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.5, 153.4, 142.0, 110.1, 107.3, 61.8, 51.8, 44.8, 26.6, 10.1.
Preparation of the Compound of formula 6
Figure DEST_PATH_IMAGE006
A solution of the compound of formula 10 (12.20 mmol, 1.39 g) in anhydrous n-hexane (30 mL) was added to anhydrous deuterated ethanol (55.00 mmol, 2.60 g) under nitrogen protection at 0 deg.C with vigorous stirring, followed by a suspension of sodium mineral oil (34.1 wt%, 55.00 mmol, 3.71 g). The reaction was allowed to proceed at 0 ℃ for 5 minutes, and warmed to room temperature and quenched with water (10 mL). To the reaction mixture was added a saturated sodium hydroxide solution (10 mL) and refluxed at 100 ℃ for 2 hours. After cooling to room temperature, the organic layer was washed with saturated brine (3X 10 mL), dried over anhydrous magnesium sulfate, filtered, and stored under nitrogen-sealed atmosphere for further use.
1H NMR (300 MHz, CDCl3) δ 5.79 (m, 1H), 5.06 – 4.87 (m, 2H), 2.88 (br, 1H), 2.08 (m, 2H), 1.60 (t, J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 138.2, 114.7, 61.2 (m), 31.5, 29.9.
Preparation of Ti cat
Figure DEST_PATH_IMAGE007
Figure DEST_PATH_IMAGE008
A solution of the compound of formula 6 (0.40 mmol, 0.035 g) dissolved in anhydrous n-hexane (2.5 mL) was added dropwise to a suspension of sodium hydride (60.0 wt%, 0.50 mmol, 0.020 g) in anhydrous n-hexane (1 mL) with stirring at 0 ℃ for reaction for 30 minutes, titanium tetrachloride (0.10 mmol, 0.019 g) was added dropwise to the reaction system with stirring at 0 ℃ for reaction for 30 minutes, the reaction mixture was subjected to solvent removal using a rotary evaporator, and vacuum was applied. The solid residue was dissolved in toluene (10 mL) and stored under nitrogen-gas seal until needed.
Preparation of the Compound of formula 3
Figure DEST_PATH_IMAGE009
The compound of formula 4 (3.00 mmol, 0.59 g), the compound of formula 6 (9.00 mmol, 0.79 g) and Ti cat (0.15 mmol,0.059 g) were added to toluene (10 mL) and reacted at 150 ℃ for 24 hours. The reaction was quenched with water (5 mL), washed with saturated brine (3X 10 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a product mass of 0.20g, yield 79%.
1H NMR (300 MHz, CDCl3) δ 7.34 (dd, J = 1.8, 0.7 Hz, 1H), 6.29 (dd, J= 3.1, 1.9 Hz, 1H), 6.16 (d, J = 3.1 Hz, 1H), 5.80 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.03 (ddd, J = 23.0, 5.4, 3.8 Hz, 2H), 3.73 (dd, J = 37.7, 14.2 Hz, 2H), 3.21 (dd, J = 8.1, 4.7 Hz, 1H), 2.20 – 2.05 (m, 2H), 1.88 (s, 1H), 1.69 (dt, J = 14.3, 7.5 Hz, 4H), 0.92 (t, J = 7.5 Hz, 3H);13C NMR (75 MHz, CDCl3) δ 175.0, 153.4, 141.8, 137.3, 115.3, 110.0, 107.0, 61.7 (m), 44.7, 29.9, 27.6, 26.5.
Preparation of Compound a of formula 1
Figure DEST_PATH_IMAGE010
A solution of imidazole (1.50 mmol,0.10 g) and triethylamine (1.00 mmol,0.10 g) in dry tetrahydrofuran (5 mL) was slowly added dropwise with stirring at 0 deg.C into dry tetrahydrofuran (10 mL) of solid phosgene (0.35 mmol,0.10 g) and reacted for 1 hour. A solution of the compound of formula 3 (0.50 mmol,0.13 g) in anhydrous tetrahydrofuran (1 mL) was added to the reaction system at 5-10 ℃ and refluxed at 71 ℃ for 1.5 hours. After cooling to room temperature, water (10 mL) was added and extracted with ethyl acetate (3X 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain a product mass of 0.10g, yield of 60%, deuteration > 90%.
1H NMR (300 MHz, CDCl3) δ8.13 (m, 1H), 7.51-7.43 (m, 2H), 7.11 (m, 1H), 6.36 (m, 2H), 5.78 (m, 1H), 5.08 – 4.92 (m, 2H), 4.72 (d, J = 16.3 Hz, 1H), 4.47 (d, J = 16.3 Hz, 1H), 3.99 (dd, J = 9.4, 5.7 Hz, 1H), 2.19 – 1.89 (m, 4H), 1.72 (t, J = 7.4 Hz, 2H), 0.74 (t, J = 7.5 Hz, 3H); 13C NMR (75MHz, CDCl3)δ170.1, 151.4, 148.4, 143.4, 137.2×2,129.3, 118.4, 115.7, 110.7×2, 65.1 (m), 62.5, 46.6, 30.0, 27.5, 21.6, 10.8.
Example 2
Preparation of the Compound of formula 4
Figure DEST_PATH_IMAGE011
Furfurylamine (50.00 mmol, 4.85 g) which is a compound of formula 8 and methyl 2-bromobutyrate (50.00 mmol, 9.05 g) which is a compound of formula 7 were added dropwise to anhydrous potassium carbonate (150.00 mmol, 20.70 g)N,N-a suspension of dimethylformamide (35 mL). The reaction was carried out at 80 ℃ for 26 hours with stirring. The potassium carbonate was removed by filtration and the reaction mixture was diluted with ethyl acetate (40 mL). The organic layer was washed with saturated brine (3X 10 mL), and the aqueous layers were combined and extracted with ethyl acetate (3X 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 7.26g of product mass, 74% yield.
1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 1.8, 0.8 Hz, 1H), 6.30 (dd, J= 3.2, 1.8 Hz, 1H), 6.17 (dd, J = 3.2, 0.8 Hz, 1H), 3.80 (d, J = 14.3 Hz, 1H), 3.72 – 3.66 (m, 4H), 3.24 (t, J = 6.4 Hz, 1H), 1.85 (s, 1H), 1.68 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.5, 153.4, 142.0, 110.1, 107.3, 61.8, 51.8, 44.8, 26.6, 10.1.
Preparation of the Compound of formula 6
Figure DEST_PATH_IMAGE012
A solution of the compound of formula 10 (12.20 mmol, 1.39 g) in anhydrous n-hexane (30 mL) was added to anhydrous ethanol (55.00 mmol, 2.50 g) under nitrogen protection at 0 deg.C with vigorous stirring, followed by a suspension of sodium mineral oil (34.1 wt%, 55.00 mmol, 3.71 g). The reaction was allowed to proceed at 0 ℃ for 5 minutes, and warmed to room temperature and quenched with water (10 mL). To the reaction mixture was added a saturated sodium hydroxide solution (10 mL) and refluxed at 100 ℃ for 2 hours. After cooling to room temperature, the organic layer was washed with saturated brine (3X 10 mL), dried over anhydrous magnesium sulfate, filtered, and stored under nitrogen-sealed atmosphere for further use.
Preparation of Ti cat
Figure DEST_PATH_IMAGE013
Figure DEST_PATH_IMAGE014
A solution of the compound of formula 6 (0.40 mmol, 0.034 g) dissolved in anhydrous n-hexane (2.5 mL) was added dropwise to a suspension of sodium hydride (60.0 wt%, 0.50 mmol, 0.020 g) in anhydrous n-hexane (1 mL) with stirring at 0 ℃ for 30 minutes, titanium tetrachloride (0.10 mmol, 0.019 g) was added dropwise to the reaction system with stirring at 0 ℃ for 30 minutes, the reaction mixture was removed of the solvent using a rotary evaporator, and vacuum was applied. The solid residue was dissolved in toluene (10 mL) and stored under nitrogen-gas seal until needed.
Preparation of the Compound of formula 3
Figure DEST_PATH_IMAGE016
The compound of formula 4 (3.00 mmol, 0.59 g), the compound of formula 6 (9.00 mmol, 0.79 g) and the Ti cat compound (0.15 mmol,0.059 g) were added to toluene (10 mL) and reacted at 150 ℃ for 24 hours. The reaction was quenched with water (5 mL), washed with saturated brine (3X 10 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a product mass of 0.20g, yield 79%.
1H NMR (300 MHz, CDCl3) δ 7.33 (d, J = 1.1 Hz, 1H), 6.31 - 6.10 (m, 2H), 5.78 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.01 (dd, J = 20.9, 5.5 Hz, 2H), 4.10 (t, J = 6.6 Hz, 2H), 3.72 (dd, J = 37.1, 14.2 Hz, 2H), 3.20 (t, J = 6.4 Hz, 1H), 2.11 (dd, J = 14.2, 7.3 Hz, 2H), 1.92 (s, 1H), 1.69 (ddt, J = 21.5, 14.2, 7.0 Hz, 4H), 0.90 (t, J = 7.5 Hz, 3H);13C NMR (75 MHz, CDCl3) δ 174.8, 153.2, 141.7, 137.2, 115.2, 109.9, 107.0, 74.0, 63.9, 61.6, 44.5, 29.9, 27.7, 26.4.
Preparation of Compounds b of formula 1
Figure DEST_PATH_IMAGE017
Stirring at 0 deg.Cd 4 A solution of (1.50 mmol,0.11 g) and triethylamine (1.00 mmol,0.10 g) in dry tetrahydrofuran (5 mL) was slowly added dropwise to solid phosgene (0.35 mmol,0.10 g) in dry tetrahydrofuran (10 mL) and reacted for 1 hour. A solution of the compound of formula 3 (0.50 mmol,0.13 g) in anhydrous tetrahydrofuran (1 mL) was added to the reaction system at 5-10 ℃ and refluxed at 71 ℃ for 1.5 hours. After cooling to room temperature, water (10 mL) was added and extracted with ethyl acetate (3 in 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain a product mass of 0.061g, a yield of 35%, deuteration rate>90%。
1H NMR (300 MHz, CDCl3) δ 7.47 (d, J = 1.2 Hz, 1H), 6.38 (d, J = 1.2 Hz, 2H), 5.80 (m, 1H), 5.08 – 4.97 (m, 2H), 4.74 (d, J = 16.3 Hz, 1H), 4.49 (d, J = 16.3 Hz, 1H), 4.16 (t, J = 6.6 Hz, 2H), 4.01 (dd, J = 9.4, 5.7 Hz, 1H), 2.18 – 1.97 (m, 4H), 1.81 – 1.70 (m, 2H), 0.77 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.1, 151.7, 148.6, 143.2, 137.1, 137.0(m), 129.6(m), 117.8(m), 115.6, 110.6, 110.5, 65.0, 62.4, 46.3, 29.9, 27.7, 21.6, 10.7.
Example 3
Preparation of the Compound of formula 4
Figure DEST_PATH_IMAGE018
Furfurylamine (50.00 mmol, 4.85 g) as a compound of formula 8 and methyl 2-bromobutyrate (50.00 mmol, 9.05 g) as a compound of formula 7 were added dropwise to anhydrous potassium carbonate (150.00 mmol, 20.70 g) in a flaskN,N-suspension in dimethylformamide (35 mL). The reaction was carried out at 80 ℃ for 26 hours with stirring. The potassium carbonate was removed by filtration and the reaction mixture was diluted with ethyl acetate (40 mL). The organic layer was washed with saturated brine (3X 10 mL), and the aqueous layers were combined and extracted with ethyl acetate (3X 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 7.26g of product mass, 74% yield.
1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 1.8, 0.8 Hz, 1H), 6.30 (dd, J= 3.2, 1.8 Hz, 1H), 6.17 (dd, J = 3.2, 0.8 Hz, 1H), 3.80 (d, J = 14.3 Hz, 1H), 3.72 – 3.66 (m, 4H), 3.24 (t, J = 6.4 Hz, 1H), 1.85 (s, 1H), 1.68 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.5, 153.4, 142.0, 110.1, 107.3, 61.8, 51.8, 44.8, 26.6, 10.1.
Preparation of Compounds of formula 5
Figure DEST_PATH_IMAGE019
The substrate of formula 9 (2.13 mmol, 0.24 g) dissolved in anhydrous hexane (16 mL) was added with anhydrous deuterated ethanol EtOD-d 1 (21.30 mmol, 1.00 g) followed by the addition of sodium reagent (34.50 wt%, 21.30mmol, 1.40 g) and vigorous stirring of the reaction solution. After reaction at 0 ℃ for 20 minutes, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (2.0 mL), diluted with ether (10 mL) and washed with saturated brine (20 mL). The aqueous layer was extracted with diethyl ether (2 × 10 mL), all organic layers were combined, dried over anhydrous magnesium sulfate, filtered, the solvent was removed using a rotary evaporator, and stored under nitrogen-sealed atmosphere for further use.
Preparation of Ti cat
Figure DEST_PATH_IMAGE020
Figure DEST_PATH_IMAGE021
A solution of the compound of formula 5 (0.40 mmol, 0.036 g) dissolved in anhydrous n-hexane (2.5 mL) was added dropwise to a suspension of sodium hydride (60.0 wt%, 0.50 mmol, 0.020 g) in anhydrous n-hexane (1 mL) with stirring at 0 ℃ for 30 minutes, titanium tetrachloride (0.10 mmol, 0.019 g) was added dropwise to the reaction system with stirring at 0 ℃ for 30 minutes, the reaction mixture was removed of the solvent using a rotary evaporator, and vacuum was applied. The solid residue was dissolved in toluene (10 mL) and stored under nitrogen-gas seal until needed.
Preparation of the Compound of formula 2
Figure DEST_PATH_IMAGE022
Imidazole (4.00 mmol, 0.27 g), trimethylamine (2.00 mmol, 0.20 g) were mixed into tetrahydrofuran (10 mL), added to a solution of triphosgene in tetrahydrofuran (10 mL), reacted at 0 ℃ for 1 hour with stirring, a solution of the compound of formula 4 in tetrahydrofuran (10 mL) was added, refluxed for 3 hours, cooled to room temperature, the reaction was quenched with water (5 mL), washed with saturated brine (3 × 10 mL), the aqueous phase was extracted with ethyl acetate (3 × 10 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate =1: 1) to obtain a product mass of 0.24g, yield 84%.
1H NMR (300 MHz, CDCl3) δ8.17 (m, 1H), 7.53 (m, 1H), 7.48 (m, 1H), 7.13 (s, 1H), 6.38 (m, 2H), 4.76 (d, J = 16.3 Hz, 1H), 4.47 (d, J = 16.3 Hz, 1H), 4.03 (dd, J = 9.5, 5.7 Hz, 1H), 3.75 (s, 3H), 2.04 (m, 2H), 0.75 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ170.6, 151.7, 148.5, 143.3, 137.3, 130.1, 118.2, 110.6, 110.6, 62.1, 52.6, 46.3, 21.5, 10.6.
Preparation of Compound c of formula 1
Figure DEST_PATH_IMAGE023
The compound of formula 2 (1.00 mmol, 0.29 g), the compound of formula 5 (3.00 mmol, 0.27 g), Ti cat. (0.030 mmol, 0.012 g) were added to the reaction and refluxed for 24 hours, the reaction was cooled to room temperature, stirring was continued for 12 hours, the reaction was quenched with water (5 mL), washed with saturated brine (3 × 10 mL), dried over anhydrous magnesium sulfate, the organic phases were combined and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate =3: 1) to yield 0.22g of product mass, 62% yield, and >90% deuteration.
1H NMR (300 MHz, CDCl3) δ 8.16 (m, 1H), 7.51 (m, 1H), 7.47 (m, 1H), 7.13 (m, 1H), 6.40-6.36 (m, 2H), 4.74 (d, J = 16.2 Hz, 1H), 4.49 (d, J = 16.2 Hz, 1H), 4.01 (dd, J = 9.5, 5.7 Hz, 1H), 2.15 - 1.98 (m, 4H), 1.74 (t, J = 7.4 Hz, 2H), 0.77 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.2, 151.8, 148.7, 143.3, 137.3, 137.0 (m), 130.2, 118.2, 115.2 (m), 110.7, 110.6, 64.8 (m), 62.4, 46.4, 29.8, 27.6, 21.7, 10.8.
Preparation of the Compound of formula 4
Example 4
Figure DEST_PATH_IMAGE024
Furfurylamine (50.00 mmol, 4.85 g) which is a compound of formula 8 and methyl 2-bromobutyrate (50.00 mmol, 9.05 g) which is a compound of formula 7 were added dropwise to anhydrous potassium carbonate (150.00 mmol, 20.70 g)N,N-twoMethylformamide (35 mL) suspension. The reaction was carried out at 80 ℃ for 26 hours with stirring. The potassium carbonate was removed by filtration and the reaction mixture was diluted with ethyl acetate (40 mL). The organic layer was washed with saturated brine (3X 10 mL), and the aqueous layers were combined and extracted with ethyl acetate (3X 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain 7.26g of product mass, 74% yield.
1H NMR (500 MHz, CDCl3) δ 7.36 (dd, J = 1.8, 0.8 Hz, 1H), 6.30 (dd, J= 3.2, 1.8 Hz, 1H), 6.17 (dd, J = 3.2, 0.8 Hz, 1H), 3.80 (d, J = 14.3 Hz, 1H), 3.72 – 3.66 (m, 4H), 3.24 (t, J = 6.4 Hz, 1H), 1.85 (s, 1H), 1.68 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.5, 153.4, 142.0, 110.1, 107.3, 61.8, 51.8, 44.8, 26.6, 10.1.
Preparation of the Compound of formula 6
Figure DEST_PATH_IMAGE025
A solution of the compound of formula 10 (12.20 mmol, 1.39 g) in anhydrous n-hexane (30 mL) was added to anhydrous deuterated ethanol (55.00 mmol, 2.60 g) under nitrogen protection at 0 deg.C with vigorous stirring, followed by a suspension of sodium mineral oil (34.1 wt%, 55.00 mmol, 3.71 g). The reaction was allowed to proceed at 0 ℃ for 5 minutes, and warmed to room temperature and quenched with water (10 mL). To the reaction mixture was added a saturated sodium hydroxide solution (10 mL) and refluxed at 100 ℃ for 2 hours. After cooling to room temperature, the organic layer was washed with saturated brine (3X 10 mL), dried over anhydrous magnesium sulfate, filtered, and stored under nitrogen-sealed atmosphere for further use.
1H NMR (300 MHz, CDCl3) δ 5.79 (m, 1H), 5.06 – 4.87 (m, 2H), 2.88 (br, 1H), 2.08 (m, 2H), 1.60 (t, J = 7.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 138.2, 114.7, 61.2 (m), 31.5, 29.9.
Preparation of Ti cat
Figure DEST_PATH_IMAGE026
Figure 499035DEST_PATH_IMAGE008
A solution of the compound of formula 6 (0.40 mmol, 0.035 g) dissolved in anhydrous n-hexane (2.5 mL) was added dropwise to a suspension of sodium hydride (60.0 wt%, 0.50 mmol, 0.020 g) in anhydrous n-hexane (1 mL) with stirring at 0 ℃ for reaction for 30 minutes, titanium tetrachloride (0.10 mmol, 0.019 g) was added dropwise to the reaction system with stirring at 0 ℃ for reaction for 30 minutes, the reaction mixture was subjected to solvent removal using a rotary evaporator, and vacuum was applied. The solid residue was dissolved in toluene (10 mL) and stored under nitrogen-gas seal until needed.
Preparation of the Compound of formula 3
Figure DEST_PATH_IMAGE027
The compound of formula 4 (3.00 mmol, 0.59 g), the compound of formula 6 (9.00 mmol, 0.79 g) and Ti cat (0.15 mmol,0.059 g) were added to toluene (10 mL) and reacted at 150 ℃ for 24 hours. The reaction was quenched with water (5 mL), washed with saturated brine (3X 10 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a product mass of 0.20g, yield 79%.
1H NMR (300 MHz, CDCl3) δ 7.34 (dd, J = 1.8, 0.7 Hz, 1H), 6.29 (dd, J= 3.1, 1.9 Hz, 1H), 6.16 (d, J = 3.1 Hz, 1H), 5.80 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.03 (ddd, J = 23.0, 5.4, 3.8 Hz, 2H), 3.73 (dd, J = 37.7, 14.2 Hz, 2H), 3.21 (dd, J = 8.1, 4.7 Hz, 1H), 2.20 – 2.05 (m, 2H), 1.88 (s, 1H), 1.69 (dt, J = 14.3, 7.5 Hz, 4H), 0.92 (t, J = 7.5 Hz, 3H);13C NMR (75 MHz, CDCl3) δ 175.0, 153.4, 141.8, 137.3, 115.3, 110.0, 107.0, 61.7 (m), 44.7, 29.9, 27.6, 26.5.
Preparation of Compound d of formula 1
Figure DEST_PATH_IMAGE028
Stirring at 0 deg.Cd 4 A solution of (1.50 mmol,0.11 g) and triethylamine (1.00 mmol,0.10 g) in dry tetrahydrofuran (5 mL) was slowly added dropwise to solid phosgene (0.35 mmol,0.10 g) in dry tetrahydrofuran (10 mL) and reacted for 1 hour. A solution of the compound of formula 3 (0.50 mmol,0.13 g) in anhydrous tetrahydrofuran (1 mL) was added to the reaction system at 5-10 ℃ and refluxed at 71 ℃ for 1.5 hours. After cooling to room temperature, water (10 mL) was added and extracted with ethyl acetate (3 in 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed using a rotary evaporator. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain 0.075g of product mass, 43% yield, deuteration rate>90%。
1H NMR (300 MHz, CDCl3) δ 7.47 (t, J = 1.3 Hz, 1H), 6.38 (d, J = 1.3 Hz, 2H), 5.80 (m, 1H), 5.09 – 4.97 (m, 2H), 4.74 (d, J = 16.3 Hz, 1H), 4.49 (d, J = 16.3 Hz, 1H), 4.01 (dd, J = 9.4, 5.7 Hz, 1H), 2.19 – 1.99 (m, 4H), 1.74 (t, J = 7.4 Hz, 2H), 0.77 (t, J = 7.4 Hz, 3H)；13C NMR (75 MHz, CDCl3) δ 170.0, 151.7, 148.6, 143.2, 137.1, 136.8(m), 129.4(m), 117.6(m), 115.5, 110.6, 110.5, 64.59(m), 62.3, 46.3, 29.9, 27.5, 21.6, 10.7.
Example 5: inhibitory Activity of Compounds of formula 1 against 2 plant pathogens
The bactericidal activity of the compound of formula 1 is measured by a hyphal growth rate method. The tested strains are rice blast germs and rice bakanae germs.
Weighing the compound shown in formula 1 or the pyrifenoxate raw pesticide respectively, preparing a mother solution with the concentration of 10000mg/L by using dimethyl sulfoxide, absorbing the prepared mother solution with the concentration of 10000mg/L by using a gun, adding the mother solution into a sterilized and cooled potato glucose agar (PDA) culture medium, uniformly mixing, preparing into a 50mg/L culture medium with the pesticide, pouring into a culture dish with the diameter of 9cm, wherein each dish is 15mL, and each medicament is repeated for 4 times. After the medicated culture medium in the dish is condensed, a medicated PDA flat plate is prepared. Dimethyl sulfoxide was used as a solvent blank control. Preparing the cultured pathogenic bacteria plate into bacterial cakes with the diameter of 0.7cm along the edges of bacterial colonies by using a puncher, respectively inoculating the bacterial cakes into PDA plates with medicines and blank controls, and placing the plates in an incubator at 25 ℃ for dark culture. After the colonies in the blank PDA plates were sufficiently grown, the diameter of each treated colony was measured by the cross method and the average value was taken.
The hyphal growth inhibition rate was calculated using the following formula:
Figure DEST_PATH_IMAGE029
the in vitro bactericidal activity data of the compounds are shown in table 3.
TABLE 3 in vitro bactericidal Activity results for Compounds of formula 1 (% inhibition)
Numbering Bakanae rice seedlings Blast of rice
a 100 100
b 100 100
c 100 100
d 100 100
As can be seen from Table 3, the compounds of formula 1 provided by the present invention all have very good inhibitory activity against the 2 plant pathogens tested.
The data in Table 3 show that the compound in the formula 1 has a good inhibition effect on rice bakanae disease and rice blast and can be used as a bactericide for preventing and treating the plant pathogenic bacteria.

Claims (4)

1. A method for synthesizing a compound shown as a formula a is characterized by comprising the following steps:
Figure FDA0003152140170000011
adding 2.60g of anhydrous deuterated ethanol EtOD-d into 1.39g of anhydrous n-hexane solution of the compound of the formula 10 under the conditions of nitrogen protection at 0 ℃ and vigorous stirring1Adding 3.71g of 34.1 mass percent sodium mineral oil suspension, reacting at 0 ℃ for 5 minutes, heating to room temperature, quenching with 10mL of water, adding 10mL of saturated sodium hydroxide solution into the reaction mixture, refluxing at 100 ℃ for 2 hours, cooling to room temperature, separating liquid, washing an organic layer with saturated saline solution, drying with anhydrous magnesium sulfate, filtering, introducing nitrogen, and hermetically sealing for later use;
Figure FDA0003152140170000012
dissolving 0.035g of the compound shown in the formula 6 in 2.5mL of anhydrous n-hexane under the condition of stirring at 0 ℃, dropwise adding 0.02g of anhydrous n-hexane suspension with the mass fraction of 60.0% of sodium hydride into the formed solution, reacting for 30 minutes, dropwise adding 0.019g of titanium tetrachloride into a reaction system under the condition of stirring at 0 ℃, continuing to react for 30 minutes, removing the solvent from the reaction mixture by using a rotary evaporator, vacuumizing, dissolving the solid residue by using 10mL of toluene, introducing nitrogen, sealing and storing for later use;
Figure FDA0003152140170000013
adding 0.59g of the compound of formula 4, 0.79g of the compound of formula 6 and 0.059g of Ti catalyst to 10mL of toluene, reacting at 150 ℃ for 24 hours, adding 5mL of water to quench the reaction, followed by washing with saturated brine, drying over anhydrous magnesium sulfate, filtering, removing the solvent using a rotary evaporator, and purifying the crude product by column chromatography to obtain 0.2g of the compound of formula 3;
Figure FDA0003152140170000014
adding a solution of solid phosgene in anhydrous tetrahydrofuran slowly dropwise into a solution of 0.1g of imidazole and 0.1g of triethylamine under stirring at 0 ℃, reacting for 1 hour, adding 0.13g of a solution of a compound of formula 3 in anhydrous tetrahydrofuran into the reaction system at 5-10 ℃, refluxing for 1.5 hours at 71 ℃, cooling to room temperature, adding 10mL of water, extracting with 10mL of ethyl acetate for 3 times, combining organic layers, drying over anhydrous magnesium sulfate, filtering, removing the solvent by using a rotary evaporator, and purifying the crude product by column chromatography to obtain 0.1g of a compound of formula a.
2. A method for synthesizing a compound shown as a formula b is characterized by comprising the following steps:
Figure FDA0003152140170000021
adding 2.50g of absolute ethyl alcohol into 1.39g of an anhydrous n-hexane solution of the compound of the formula 10 under the conditions of nitrogen protection at 0 ℃ and vigorous stirring, then adding 3.71g of a sodium mineral oil suspension with the mass fraction of 34.1%, reacting for 5 minutes at 0 ℃, heating to room temperature, quenching the reaction with 10mL of water, adding 10mL of a saturated sodium hydroxide solution into the reaction mixture, refluxing for 2 hours at 100 ℃, cooling to room temperature, separating liquid, washing an organic layer with saturated common salt, drying with anhydrous magnesium sulfate, filtering, introducing nitrogen, and hermetically sealing for storage for later use;
Figure FDA0003152140170000022
dissolving 0.034g of the compound shown in the formula 6 in 2.5mL of anhydrous n-hexane under the condition of stirring at 0 ℃, dropwise adding 0.02g of anhydrous n-hexane suspension with the mass fraction of 60.0% of sodium hydride into the formed solution, reacting for 30 minutes, dropwise adding 0.019g of titanium tetrachloride into a reaction system under the condition of stirring at 0 ℃, continuing to react for 30 minutes, removing the solvent from the reaction mixture by using a rotary evaporator, vacuumizing, dissolving the solid residue by using 10mL of toluene, introducing nitrogen and sealing for storage for later use;
Figure FDA0003152140170000023
adding 0.59g of the compound of formula 4, 0.79g of the compound of formula 6 and 0.059g of Ti catalyst to 10mL of toluene, reacting at 150 ℃ for 24 hours, adding 5mL of water to quench the reaction, followed by washing with saturated brine, drying over anhydrous magnesium sulfate, filtering, removing the solvent using a rotary evaporator, and purifying the crude product by column chromatography to obtain 0.2g of the compound of formula 3;
Figure FDA0003152140170000031
stirring at 0 deg.CTo 0.11g of deuterated imidazole-d4And 0.1g of triethylamine, slowly dropwise adding an anhydrous tetrahydrofuran solution of solid phosgene into the anhydrous tetrahydrofuran solution, reacting for 1 hour, adding 0.13g of the anhydrous tetrahydrofuran solution of the compound shown in the formula 3 into the reaction system at the temperature of 5-10 ℃, refluxing for 1.5 hours at the temperature of 71 ℃, cooling to room temperature, adding 10mL of water, extracting for 3 times by using 10mL of ethyl acetate, combining organic layers, drying by using anhydrous magnesium sulfate, filtering, removing the solvent by using a rotary evaporator, and purifying a crude product by using column chromatography to obtain 0.061g of the compound shown in the formula b.
3. A method for synthesizing a compound shown as a formula c is characterized by comprising the following steps:
Figure FDA0003152140170000032
adding 1g of anhydrous deuterated ethanol EtOD-d into 0.24g of anhydrous n-hexane solution of the compound of the formula 9 at the temperature of 0 ℃ under the protection of nitrogen and under the condition of vigorous stirring1Adding 1.4g of 34.5 mass percent sodium mineral oil suspension, reacting at 0 ℃ for 20 minutes, then quenching the reaction by using 2.0mL of saturated sodium bicarbonate aqueous solution, then diluting with 10mL of diethyl ether, washing with 20mL of saturated saline solution, extracting the water layer for 2 times by using 10mL of diethyl ether, combining all organic layers, drying by anhydrous magnesium sulfate, filtering, removing the solvent by using a rotary evaporator, introducing nitrogen, and sealing for storage;
Figure FDA0003152140170000033
dissolving 0.036g of the compound shown in the formula 5 in 2.5mL of anhydrous n-hexane under the condition of stirring at 0 ℃, dropwise adding 0.02g of anhydrous n-hexane suspension with the mass fraction of 60.0% of sodium hydride into the formed solution, reacting for 30 minutes, dropwise adding 0.019g of titanium tetrachloride into a reaction system under the condition of stirring at 0 ℃, continuing to react for 30 minutes, removing the solvent from the reaction mixture by using a rotary evaporator, vacuumizing, dissolving the solid residue by using 10mL of toluene, introducing nitrogen and sealing for storage for later use;
Figure FDA0003152140170000041
adding 0.27g of imidazole and 0.2g of trimethylamine into 10mL of tetrahydrofuran, then adding the mixture into a triphosgene tetrahydrofuran solution, reacting for 1 hour under stirring at 0 ℃, adding the tetrahydrofuran solution of the compound of formula 4, refluxing for 3 hours, cooling to room temperature, quenching the reaction with 5mL of water, then washing with saturated saline, extracting the aqueous phase with ethyl acetate, drying over anhydrous magnesium sulfate, filtering, removing the solvent by using a rotary evaporator, and purifying the crude product by column chromatography to obtain 0.24g of the compound of formula 2;
Figure FDA0003152140170000042
0.29g of the compound of formula 2, 0.27g of the compound of formula 5 and 12.30g of Ti catalyst are added to toluene and refluxed for 24 hours, after the reaction is cooled to room temperature, the mixture is stirred for 12 hours, quenched with 5mL of water, washed with saturated brine, dried over anhydrous magnesium sulfate, the organic phases are combined, the solvent is removed using a rotary evaporator, and the crude product is purified by column chromatography to obtain 0.22g of the compound of formula c.
4. A method for synthesizing a compound shown as a formula d is characterized by comprising the following steps:
Figure FDA0003152140170000043
adding 2.60g of anhydrous deuterated ethanol EtOD-d into 1.39g of anhydrous n-hexane solution of the compound of the formula 10 under the conditions of nitrogen protection at 0 ℃ and vigorous stirring1Then, 3.71g of a 34.1% sodium mineral oil suspension was added thereto, the mixture was reacted at 0 ℃ for 5 minutes, the temperature was raised to room temperature, the reaction mixture was quenched with 10mL of water, and 10mL of saturated oxyhydrogen was added to the reaction mixtureDissolving sodium solution, refluxing at 100 deg.C for 2 hr, cooling to room temperature, separating, washing organic layer with saturated saline solution, drying with anhydrous magnesium sulfate, filtering, introducing nitrogen, and storing in sealed condition;
Figure FDA0003152140170000051
dissolving 0.035g of the compound shown in the formula 6 in 2.5mL of anhydrous n-hexane under the condition of stirring at 0 ℃, dropwise adding 0.02g of anhydrous n-hexane suspension with the mass fraction of 60.0% of sodium hydride into the formed solution, reacting for 30 minutes, dropwise adding 0.019g of titanium tetrachloride into a reaction system under the condition of stirring at 0 ℃, continuing to react for 30 minutes, removing the solvent from the reaction mixture by using a rotary evaporator, vacuumizing, dissolving the solid residue by using 10mL of toluene, introducing nitrogen, sealing and storing for later use;
Figure FDA0003152140170000052
adding 0.59g of the compound of formula 4, 0.79g of the compound of formula 6 and 0.059g of Ti catalyst to 10mL of toluene, reacting at 150 ℃ for 24 hours, adding 5mL of water to quench the reaction, followed by washing with saturated brine, drying over anhydrous magnesium sulfate, filtering, removing the solvent using a rotary evaporator, and purifying the crude product by column chromatography to obtain 0.2g of the compound of formula 3;
Figure FDA0003152140170000053
to 0.11g of deuterated imidazole-d, stirring at 0 deg.C4And 0.1g of triethylamine, adding 0.13g of the anhydrous tetrahydrofuran solution of the compound of formula 3 into the reaction system at 5-10 ℃, refluxing for 1.5 hours at 71 ℃, cooling to room temperature, adding 10mL of water, extracting for 3 times with 10mL of ethyl acetate, combining the organic layers, drying over anhydrous magnesium sulfate,filtration, removal of the solvent using a rotary evaporator and purification of the crude product by column chromatography gave 0.075g of the compound of formula d.
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Application of Deuterium Isotope Effects to the Xenobiotic Metabolism Sthdy;Norio Kurihara;《J.Mass Spectrom.Soc.Jpn.》;19881231;第46卷(第3期);第157-172页 *
Synopsis of Some Recent Tactical Application of Bioisoteres in Drug Design;Nicholas A. Meanwell;《J.Med.Chem.》;20110317;第54卷;第2529-2591页 *
新的水稻种子杀菌剂pefurazoate;Mitsuaki Takenaka et al.;《农药译丛》;19911231;第13卷(第6期);第57-60页 *

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