阅读说明：本技术 一种哌嗪基四氢苯并噻唑肟醚类衍生物及应用 (Piperazinyl tetrahydrobenzothiazole oxime ether derivative and application thereof ) 是由 赵卫光 边强 彭星洁 赵瑞琪 于 2020-07-17 设计创作，主要内容包括：本发明涉及如通式(I)所示的哌嗪基四氢苯并噻唑肟醚类衍生物及其作为杀菌剂的应用。该类化合物代表一种新颖的杀菌剂结构类型,具有优异的杀菌活性的化合物,能用于防治卵菌纲病原菌产生的病害,如霜霉病、晚疫病、霜疫病等,具体的如黄瓜霜霉病、葡萄霜霉病、白菜霜霉病、番茄晚疫病、马铃薯晚疫病、辣椒晚疫病、荔枝霜疫霉病、大豆疫霉根腐病等。本发明化合物也能适用于菌核病、轮纹病、灰霉病、纹枯病等。本发明化合物可以直接使用,也可以加上农业上接受的载体使用,也可以和其它杀菌剂复配使用。<Image he="259" wi="700" file="DDA0002588790410000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to piperazinyl tetrahydrobenzothiazole oxime ether derivatives shown as a general formula (I) and application thereof as bactericides. The compound represents a novel bactericide structure type, has excellent bactericidal activity, and can be used for preventing and treating diseases caused by oomycete pathogenic bacteria, such as downy mildew, late blight, downy blight and the like, and specifically comprises cucumber downy mildew, grape downy mildew, Chinese cabbage downy mildew, tomato late blight, potato late blight, pepper late blight, peronophythora litchi, phytophthora sojae and the like. The compounds of the present invention are also suitable for sclerotinia rot, ring spot, gray mold, sheath blight, etc. The compounds of the invention may be used as such or in combination with an agriculturally acceptable carrierIt can also be used in combination with other bactericides.)

1. A compound having the following general formula (I) or a pharmaceutically acceptable salt thereof:

wherein X and Y are respectively N, S or S, N or N, O or O, N;

z is CH₂，CO，CHCH₃；

R is optionally 1-5 substituents selected from hydrogen, hydroxy, cyano, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_1-6Alkyl, halo C_1-6Alkoxy, halo C_2-6Alkenyl, halo C_2-6Alkynyl, benzyloxy, phenyl, said benzyloxy and phenyl ring optionally substituted with 1-5 hydrogens selected from halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_1-6Alkyl, halo C_1-6Alkoxy, halo C_2-6Alkenyl, halo C_2-6And substituent of alkynyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein:

x and Y are preferably N and S;

z is preferably CH₂；

R is preferably hydrogen, methyl, halogen, methoxy or trifluoromethyl.

3. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-methyl-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-chloro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-bromo-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (3-methyl-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (3-chloro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (3-fluoro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (3-bromo-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (4-methyl-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (4-bromo-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (4-chloro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-fluoro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (4-fluoro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-fluoro-3-bromo-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-bromo-5-fluoro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-chloro-6-chloro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-chloro-6-fluoro-benzyl) -oxime

2- {4- [2- (5-methyl-3-trifluoromethyl-pyrazol-1-yl) -acetyl ] -piperazin-1-yl } -5, 6-dihydro-4H-benzothiazol-7-one-O- (2-chloro-4-chloro-benzyl) -oxime.

4. A process for the preparation of a compound as claimed in any one of claims 1 to 3, which process comprises the steps of:

dissolving 2-bromo-1, 3-cyclohexanedione in an organic solvent, adding thiourea and pyridine, heating to reflux until the reaction is finished, desolventizing to be viscous, pouring into water, stirring, filtering, and drying to obtain a yellow solid compound 2, wherein the organic solvent is ethyl acetate, acetonitrile, tetrahydrofuran, toluene, methanol or ethanol.

Dissolving 2-amino-5, 6-dihydro-4H-benzothiazole-7-ketone 2 in an organic solvent, adding copper bromide and tert-butyl nitrite, refluxing and stirring until the reaction is finished, desolventizing, adding the organic solvent for redissolving, washing an organic layer by using dilute hydrochloric acid solution and water in sequence, drying the organic layer by anhydrous magnesium sulfate, and desolventizing to obtain a black-red compound 3.

Dissolving 2-bromo-5, 6-dihydro-4H-benzothiazole-7-ketone 3 in an organic solvent, adding 1- (tert-butyloxycarbonyl) piperazine 4 at room temperature, heating and stirring until the reaction is finished, filtering, desolventizing, adding an organic solvent for redissolving, washing an organic layer with saturated sodium bicarbonate and water, drying the organic layer with anhydrous magnesium sulfate, and desolventizing to obtain a compound 5.

Adding hydrochloric acid and an organic solvent with proper concentration into the compound 5, heating and refluxing until the reaction is finished, cooling the reaction solution, adding alkali to adjust the water layer to be alkalescent, separating out an organic layer, extracting the water layer, combining the organic layers, drying and desolventizing to obtain a compound 6.

Dissolving the compound 6 in an organic solvent, adding alkali, stirring at 0 ℃, adding the compound 7, reacting at room temperature until the reaction is finished, adding an organic solvent for dilution, washing an organic layer by using dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and saline water respectively, drying and desolventizing to obtain a white solid 8. The alkali refers to sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, N-methylmorpholine or pyridine.

Dissolving the compound 8 in an organic solvent, adding hydroxylamine hydrochloride and alkali, heating and refluxing until the reaction is finished, cooling the reaction solution, filtering, desolventizing, adding the organic solvent for redissolving, washing with water, drying, and desolventizing to obtain the compound 9.

Adding alkali and a compound 9 into an organic solvent, dropwise adding benzyl bromide 10 after stirring, stirring until the reaction is finished, adding water, extracting with the organic solvent, drying, filtering, and desolventizing to obtain a compound 11.

X, Y, Z, R in each of the above steps are as defined in any one of claims 1 to 3.

5. Intermediate 5

6. Intermediate 6

7. Intermediate 8

8. Intermediate 9

Intermediates 5,6, 8 and 9 are specific intermediates for the preparation of compounds of formula (I).

9. A pesticidal composition comprising a compound according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof and a carrier.

10. Use of a compound of any one of claims 1 to 3 and pharmaceutically acceptable salts thereof as fungicides for the control of plant diseases.

Technical Field

The invention belongs to the field of pesticides, and particularly relates to piperazinyl tetrahydrobenzothiazole oxime ether derivatives and application thereof as a bactericide.

Background

In agricultural production, the crop is often damaged by pests such as insects, grass, bacteria and the like to cause the yield reduction of the food and even the failure of the production. The oomycete pathogenic bacteria are important pathogenic bacteria in agriculture, have wide host range and comprise various crops such as vegetables, fruits, flowers, woods, cotton, hemp, oil and the like. The pathogenic bacteria of oomycete plants have strong destructiveness, great harmfulness, short incubation period and frequent re-infection on host plants, so that the pathogenic bacteria can be spread and infected everywhere in one growing season of the plants and are difficult to control, thereby causing serious loss in agriculture and forestry.

The piperidyl thiazole bactericide is a bactericide with a novel structure for preventing and treating plant oomycetes diseases, and the action mechanism of the bactericide is different from that of the original carboxamide bactericide for treating oomycetes. The DuPont company conducts high-throughput activity screening on thiazolyl piperidine derivatives used for inhibiting MTP (microsomal triglyceride transfer protein) in a database of Tripos of Germany, and finds that the compound 1-1 has weak prevention effect on tomato late blight and cucumber downy mildew, so that piperidine-thiazole-carbonyl is used as an active fragment, the structure is optimized from the left and right aspects, and the first piperidyl thiazole isoxazoline bactericide oxathiapirolin (fluorothiazole pyriethanone) is developed in 2007.

Oxathiapiprolin is a novel fungicide developed by dupont and belongs to the inhibitor of the oxysterol binding protein homolog (OSPPI), trade name: zorvec, Orobdis et al, published 2012, marketed 2016, and over 14 years from discovery to marketing. It exhibits excellent activity against pathogenic oomycetes, including Phytophthora capsici (Phytophthora infestans), Phytophthora infestans (Phytophthora infestans), Phytophthora sojae (Phytophthora sojae), Phytophthora melonis (Phytophthora melonis), grapevine downy mildew (Phytophthora viticola), peronospora cucumerinum (Pseudoperonospora cubensis) and the like. At 10mg L^-1Can effectively inhibit the release and movement of phytophthora capsici zoospores. Oxathiapiprolin is effective in treatment and defense of leaf surfaces and root systems of plants, and has the characteristic of conduction from suction to top. Therefore, the piperidyl thiazole derivatives have attracted high attention of various agricultural chemical companies in the world in recent years, and have been invested with huge resources for the research and development of the bactericides.

Compounds 1-2(WO 2010065579A 2) reported by DuPont in the introduction of oxime into oxazaprolin at 10mg L^-1The treatment control rate of the compound reaches 100 percent under the concentration of the compound. Compound 1-3(WO 2009094407A 2) at 40mg L^-1The treatment control rate effect on the grape downy mildew and the tomato late blight reaches more than 99 percent under the concentration of the tomato late blight.

Bayer and Zhanghengda take the lead compounds of Bayer as a lead compound to carry out derivation, and some patents are filed. Bayer introduces oxime ether structure into thiazole ring to obtain compound 1-4(WO 2010037479A 1) at 100mg L^-1The effect on the downy mildew and the late blight of grapes and the treatment control rate of the grape can reach more than 80 percent under the concentration of the active ingredients; introduction of the enone structure on the thiazole ring gave compounds 1-5(US 20110312999 Al), 500mg L^-1The control effect on the tomato epidemic disease reaches 100 percent under the concentration of (3). In 2011, another piperidinyl thiazole isoxazoline bactericide, fluxaprirolin (CN 103180317a), was developed by bayer corporation, which is the second bactericide to obtain the common name of ISO (international organization for standardization) and is about to come into the market.

Cyclopropyl was introduced into an isoxazole ring in a mother nucleus of the fluorothiazole pyrithylone by Ningda company in 2014 to obtain the compounds 1-6(WO 2014118142A 1) and 200mg L^-1The prevention and treatment effect on tomato late blight, potato late blight and grape downy mildew can reach more than 80%. Compounds 1-7(WO 2014154530A 1), 200mg L, were also reported in the same year^-1The prevention and treatment effect on tomato late blight, potato late blight and downy glucose mildew can reach more than 80%.

The invention optimizes the compound of the fluorothiazole pyrithylone, designs and synthesizes a brand-new compound of piperazinyl tetrahydrobenzothiazole oxime ether, and the result of the bactericidal activity test of phytophthora capsici pathogenic bacteria shows that the compound of the invention has excellent bactericidal activity.

Disclosure of Invention

The invention aims to provide a piperazinyl tetrahydrobenzothiazole oxime ether derivative. The compounds have excellent bactericidal activity and wide medicine preparing foreground.

The piperazinyl tetrahydrobenzothiazole oxime ether derivative provided by the invention is a compound with the following general formula (I) or a pharmaceutically acceptable salt thereof:

wherein X and Y are respectively N, S or S, N or N, O or O, N;

z is CH₂，CO，CHCH₃；

R is optionally 1-5 substituents selected from hydrogen, hydroxy, cyano, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_1-6Alkyl, halo C_1-6Alkoxy, halo C_2-6Alkenyl, halo C_2-6Alkynyl, benzyloxy, phenyl, said benzyloxy and phenyl ring optionally substituted with 1-5 hydrogens selected from halogen, hydroxy, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_1-6Alkyl, halo C_1-6Alkoxy, halo C_2-6Alkenyl, halo C_2-6Substituent substitution of alkynyl;

x and Y are preferably N and S;

z is preferably CH₂；

R is preferably hydrogen, methyl, halogen, methoxy or trifluoromethyl.

In addition, the invention relates to the use of a compound as defined in formula (I) as a plant fungicide.

In the present invention, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon. Examples of such substituents include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl.

Likewise, the term "alkoxy" refers to a straight or branched chain saturated alkoxy group. Examples of such substituents include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy.

The term "alkenyl" refers to straight or branched chain alkenyl groups, and examples of such substituents include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl.

The term "alkynyl" refers to straight or branched chain alkynyl groups, and examples of such substituents include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 1-hexynyl.

The term "haloalkyl" is a straight-chain or branched alkyl group, on which the hydrogen atoms may be partially or totally substituted by halogen atoms; the terms "haloalkoxy", "haloalkenyl", "haloalkynyl" are defined analogously to the term "haloalkyl".

The term "halogen" refers to fluorine, chlorine, bromine, iodine.

The invention further provides a pesticidal composition comprising an effective amount of a compound of formula (I) and a carrier. The present invention also provides a pesticidal composition comprising an effective amount of one of the specific compounds disclosed in the examples section and a carrier.

The compound (I) of the present invention is prepared by the following route, and all starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or are commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry.

The compounds of the general formula (I) according to the invention, X and Y, Z, R being as defined in the description.

When X and Y are N and S, respectively, Z is CH₂The synthetic route of compound 11 of the general formula is:

in the synthetic route, carrying out a thionation reaction on a compound 1 to obtain a compound 2; carrying out bromination reaction on the compound 2 to obtain a compound 3; reacting the compound 3 with 1- (tert-butyloxycarbonyl) piperazine 4 to obtain a compound 5; hydrolyzing the compound 5 to obtain a compound 6; reacting the compound 6 with the compound 7 to obtain a compound 8; the compound 8 reacts with hydroxylamine hydrochloride to obtain a compound 9, and then reacts with benzyl bromide to obtain a compound shown in a general formula 11.

The present invention also provides a process for the preparation of said compound of formula 11, which comprises the steps of:

1) dissolving 2-bromo-1, 3-cyclohexanedione in an organic solvent, adding thiourea and pyridine, heating to reflux until the reaction is finished, desolventizing to be viscous, pouring into water, stirring, filtering, and drying to obtain a yellow solid compound 2, wherein the organic solvent is methanol or ethanol.

2) Dissolving 2-amino-5, 6-dihydro-4H-benzothiazole-7-ketone 2 in an organic solvent, adding copper bromide and tert-butyl nitrite, refluxing and stirring until the reaction is finished, desolventizing, adding the organic solvent for redissolving, washing an organic layer by using dilute hydrochloric acid solution and water in sequence, drying the organic layer by anhydrous magnesium sulfate, and desolventizing to obtain a black-red compound 3.

3) Dissolving 2-bromo-5, 6-dihydro-4H-benzothiazole-7-ketone 3 in an organic solvent, adding 1- (tert-butyloxycarbonyl) piperazine 4 at room temperature, heating and stirring until the reaction is finished, filtering, desolventizing, adding an organic solvent for redissolving, washing an organic layer with saturated sodium bicarbonate and water, drying the organic layer with anhydrous magnesium sulfate, and desolventizing to obtain a compound 5.

4) Adding hydrochloric acid and an organic solvent with proper concentration into the compound 5, heating and refluxing until the reaction is finished, cooling the reaction solution, adding alkali to adjust the water layer to be alkalescent, separating out an organic layer, extracting the water layer, combining the organic layers, drying and desolventizing to obtain a compound 6.

5) Dissolving the compound 6 in an organic solvent, adding alkali, stirring at 0 ℃, adding the compound 7, reacting at room temperature until the reaction is finished, adding an organic solvent for dilution, washing an organic layer by using dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and saline water respectively, drying and desolventizing to obtain a white solid 8. The alkali refers to sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, N-methylmorpholine or pyridine.

6) Dissolving the compound 8 in an organic solvent, adding hydroxylamine hydrochloride and alkali, heating and refluxing until the reaction is finished, cooling the reaction solution, filtering, desolventizing, adding the organic solvent for redissolving, washing with water, drying, and desolventizing to obtain the compound 9.

7) Adding alkali and a compound 9 into an organic solvent, dropwise adding benzyl bromide 10, stirring until the reaction is finished, adding water, extracting with the organic solvent, drying, filtering, and desolventizing to obtain a compound 11.

Intermediates 5,6, 8 and 9

Intermediates 5,6, 8 and 9 are specific intermediates for the preparation of compounds of formula (I).

The compound with the structural formula (I) provided by the invention has excellent bactericidal activity, and can be used for preventing and treating diseases caused by oomycete pathogenic bacteria such as downy mildew, late blight, downy blight and the like, specifically cucumber downy mildew, grape downy mildew, Chinese cabbage downy mildew, tomato late blight, potato late blight, pepper late blight, peronophythora litchi, phytophthora sojae and the like. The compounds of the present invention are also suitable for sclerotinia rot, ring spot, gray mold, sheath blight, etc. The compound of the invention can be directly used, can be added with an agriculturally acceptable carrier for use, and can also be compounded with other bactericides for use.

Detailed Description

The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.