CN113354646B - 8-aryloxy alkoxy substituted xanthine derivative and preparation method and application thereof - Google Patents

8-aryloxy alkoxy substituted xanthine derivative and preparation method and application thereof Download PDF

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CN113354646B
CN113354646B CN202110760621.XA CN202110760621A CN113354646B CN 113354646 B CN113354646 B CN 113354646B CN 202110760621 A CN202110760621 A CN 202110760621A CN 113354646 B CN113354646 B CN 113354646B
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trimethyl
purine
dione
dihydro
propoxy
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CN113354646A (en
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王宝雷
刘航
张舒昀
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Nankai University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/12—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1, 3, and 7, e.g. caffeine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Agronomy & Crop Science (AREA)
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Abstract

The invention discloses an 8-aryloxy alkoxy substituted xanthine derivative and a preparation method and application thereof. The 8-chloro-substituted xanthine derivative is used as an initial raw material, and the derivative is synthesized through multiple steps of reactions such as nucleophilic substitution, reduction and the like. The compound has a structural formula shown as a general formula I. The compound has certain control effect on lepidoptera pests such as diamondback moth, oriental armyworm and the like; meanwhile, the compound has certain in-vitro inhibitory activity on plant pathogenic fungi such as tomato early blight bacteria, phytophthora capsici leonian, sclerotinia sclerotiorum, cucumber gray mold bacteria, apple ring rot bacteria, wheat sheath blight bacteria and the like, and particularly has higher inhibitory activity on apple ring rot bacteria and wheat sheath blight bacteria. The invention is suitable for the comprehensive prevention and control of insect pests and diseases and bacteria on various crops.

Description

8-aryloxy alkoxy substituted xanthine derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of agricultural pesticides and bactericides, and relates to a preparation method and application of an 8-aryloxy alkoxy substituted xanthine derivative.
Background
In the implementation process of various industries such as agriculture, forestry, pasturing, subsidiary, fishing, public health and the like, the prevention and the treatment of insects and plant germs are one of important subjects. With the deepening of the environmental awareness of people, some old and old pesticides which pollute the environment, kill beneficial organisms, generate drug resistance and are difficult to degrade are gradually eliminated, and the direction for creating new pesticides in the future is to research and develop low-toxicity and high-efficiency green pesticides and environment-friendly pesticides. The development of new green pesticide products is a strategy commonly adopted in the pesticide creating process, and the medicines generally have the advantages of high efficiency, easy degradation, low toxicity to warm-blooded animals and safety to birds and fishes, and become a hotspot of current pesticide development.
Xanthine, 1H-purine-2,6 (3h, 7h) -dione, is a natural heterocyclic purine-based alkaloid. Natural xanthine alkaloids such as caffeine, theophylline and theobromine are methylxanthine derivatives which are closely related to the daily life of people, are important components in tea leaves and coffee, have low toxicity to human bodies, and many drugs used by people for treating diseases also contain xanthine structures.
The research of xanthine derivatives in the field of pesticides is rare, and the existing related reports mainly focus on the research of natural caffeine. In the prior art, the preparation method of the 8-aryloxy alkoxy substituted xanthine derivative and the application of the derivative as an agricultural pesticide and a bactericide are not disclosed.
Disclosure of Invention
The invention aims to provide a substitute 8-aryloxy alkoxy substituted xanthine derivative of a traditional pesticide or an agricultural bactericide with a novel structure, a preparation method and application thereof.
The 8-aryloxy alkoxy substituted xanthine derivative provided by the invention has a structural formula shown as a general formula I:
Figure BDA0003148919930000021
in the formula:
R 1 ～R 3 is C1-C6 alkyl or substituted C1-C6 alkyl, the substituent on the substituted C1-C6 alkyl is halogen atom, and the substitution is mono-substitution or multi-substitution;
a is methylene, ethyl-1, 1-diyl (-CH) 2 CH 2 -), ethan-1, 2-diyl (-CH (CH) 3 ) -), prop-1, 3-diyl (-CH) 2 CH 2 CH 2 -), propan-1, 2-diyl (-CH) 2 CH(CH 3 ) -), propan-1, 1-diyl (-CH (CH) 2 CH 3 ) -) or prop-2, 2-diyl (-C (CH) 3 ) 2 -)；
Ar is phenyl, substituted phenyl, pyrimidinyl, substituted pyrimidinyl, pyridyl, substituted pyridyl, thiazolyl, substituted thiazolyl, the substituents on said substituted phenyl, substituted pyrimidinyl, substituted pyridyl and substituted thiazolyl being lower alkyl, lower alkoxy, lower haloalkyl, haloalkenylalkyl, nitro, cyano or halogen atoms, said substitution being mono-or poly-substituted;
the term "lower alkyl" is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl;
the term "lower alkoxy" is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclopropyloxy, cyclopropylmethoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy;
the carbon skeleton of the term "lower haloalkyl" is the same as that of the lower alkyl group as defined above, provided that the hydrogen atoms on the lower alkyl group are partially or totally substituted by halogen atoms;
the term "haloalkenylalkyl" is 1, 1-dichloroallyl, 1-difluoroallyl, 3, 4-trifluorobut-3-en-1-yl and 4, 4-difluorobut-3-en-1-yl;
the halogen atom is fluorine, chlorine, bromine or iodine.
Preferably, R 1 ～R 3 Is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, cyclopropylmethyl, 2-fluoroethyl, 2-difluoroethyl, 2-trifluoroethyl, 3-fluoropropyl, 3-difluoropropyl or 3, 3-trifluoropropyl;
a is methylene, ethyl-1, 1-diyl (-CH) 2 CH 2 -), ethan-1, 2-diyl (-CH (CH) 3 ) -), prop-1, 2-diyl (-CH) 2 CH(CH 3 ) -) or prop-2, 2-diyl (-C (CH) 3 ) 2 -)；
Ar is phenyl, methyl-substituted phenyl, ethyl-substituted phenyl, methoxy-substituted phenyl, ethoxy-substituted phenyl, isopropyl-substituted phenyl, isopropoxy-substituted phenyl, allyl-substituted phenyl, allyloxy-substituted phenyl, phenoxy-substituted phenyl, monohalomethyl-substituted phenyl, dihalomethyl-substituted phenyl, trihalomethyl-substituted phenyl, monohalomethoxy-substituted phenyl, dihalomethoxy-substituted phenyl, trihalomethoxy-substituted phenyl, monohaloethoxy-substituted phenyl, dihaloethoxy-substituted phenyl, trihaloethoxy-substituted phenyl, heptafluoroisopropylphenyl, halo-substituted phenyl, nitro-substituted phenyl, cyano-substituted phenyl, pyridyl, methyl-substituted pyridyl, ethyl-substituted pyridyl, methoxy-substituted pyridyl, ethoxy-substituted pyridyl, monohalomethyl-substituted pyridyl, dihalomethyl-substituted pyridyl, trihalomethyl-substituted pyridyl, monohalomethoxy-substituted pyridyl, dihalomethoxy-substituted pyridyl, trihaloethoxy-substituted pyridyl, heptafluoroisopropyl-substituted pyridyl, halo-substituted pyridyl, nitro-substituted pyridyl, cyano-substituted pyridyl, methyl-substituted pyrimidinyl, ethyl-substituted pyrimidinyl, dihaloethoxy-substituted pyrimidinyl, dihalomethyl-substituted pyrimidinyl, dihalo-substituted pyrimidinyl, trihaloethoxy-substituted pyrimidinyl, trihalomethyl-substituted pyrimidinyl, trihaloethoxy-substituted pyrimidinyl, trihalomethoxy-substituted pyrimidinyl, trihaloethoxy-substituted pyrimidinyl, halogen-substituted pyrimidinyl, or trihaloethoxy-substituted pyrimidinyl, the substitution is mono-or polysubstitution.
The 8-aryloxyalkoxy substituted xanthine derivative can be specifically the following compounds: 1,3, 7-trimethyl-8- (3-phenoxypropoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-1), 8- (3- (2-methoxy-4-methylphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-2), 8- (3- (4-methoxyphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-3) 8- (3- (2-chloro-4-methoxyphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-4), 8- (3- (2-isopropyl-5-methylphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-5), 8- (3- (4-chloro-2-methylphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-6), 8- (3- (2, 4-dichlorophenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro- 1H-purine-2, 6-dione (I-7), 1,3, 7-trimethyl-8- (3- (4- (trifluoromethoxy) phenoxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-8), 8- (3- (3-chloro-4- (trifluoromethoxy) phenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-9), 8- (3- (2, 6-difluorophenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-10) 1,3, 7-trimethyl-8- (3- (4- (trifluoromethyl) phenoxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-11), 8- (3- (4-allyl-2-methoxyphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-12), 8- (3- (benzo [ d ] [1,3] dioxa-5-yloxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I- 13 1,3, 7-trimethyl-8- (3- (3-phenoxyphenoxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-14), 1,3, 7-trimethyl-8- (3- (pyridin-2-yloxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-15), 8- (3- ((3-chloropyridin-2-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-16) 8- (3- (((3, 5-dichloropyridin-2-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-17), 2- (3- ((1, 3, 7-trimethyl-2, 6-dioxo-2, 3,6, 7-tetrahydro-1H-purin-8-yl) oxy) propoxy) nicotinonitrile (I-18), 6- (3- ((1, 3, 7-trimethyl-2, 6-dioxo-2, 3,6, 7-tetrahydro-1H-purin-8-yl) oxy) propoxy) nicotinonitrile (I-19), 1,3, 7-trimethyl-8- (3- ((5- (trifluoromethyl) pyridin-2-yl) oxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-20), 8- (3- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-21), 8- (3- ((5, 6-dichloropyridin-3-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-22) 8- ((1- (2-methoxy-4-methylphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-23), 8- ((1- (4-methoxyphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-24), 8- ((1- (2-chloro-4-methoxyphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-25), 8- ((1- (2-isopropyl-5-methylphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-26), 8- ((1- (4-chloro-2-methylphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-27) 8- ((1- (2, 4-Dichlorophenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-28), 1,3, 7-trimethyl-8- ((1- (4- (trifluoromethoxy) phenoxy) propan-2-yl) oxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-29), 8- ((1- (3-chloro-4- (trifluoromethoxy) phenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-30), 8- ((1- (2, 6-difluorophenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-31), 1,3, 7-trimethyl-8- ((1- (4- (trifluoromethyl) phenoxy) propan-2-yl) oxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-32), 8- ((1- (4-allyl-2-methoxyphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-33), 8- ((1- (benzo [ d ] [1,3] dioxa-5-yloxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-34), or 1,3, 7-trimethyl-8- (3-phenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-1H-purine-2, 6-dione (I-34), or 1,3, 7-trimethyl-8- (1- (3-phenoxy) propan-2-yl) oxy) -2-dihydro-1, 35.
The compounds of the general formula I according to the invention can be prepared by one of the two processes in which the substituents are as defined above, unless otherwise specified.
The method comprises the following steps:
Figure BDA0003148919930000041
and (3) under the protection of nitrogen, fully reacting the compound shown in the formula III with NaH in 1, 4-dioxane at room temperature, then adding the compound shown in the formula II, heating to 80 ℃, and stirring for reacting for 2-6 hours. After the reaction is finished, adding a small amount of ethanol for quenching, concentrating the solution under reduced pressure, and separating by column chromatography to obtain the compound shown in the formula I. The mol ratio of the compound of the formula II, the compound of the formula III and NaH is 1: 1.2: 1.5.
Compounds of formula II may be prepared according to literature procedures (j.agric.food chem.,2000,48, 5312-5315, j.heterocyclic chem.1976, 13-925-926; the compound of the general formula III can be prepared by reacting substituted phenol and halogenated aliphatic alcohol in anhydrous K 2 CO 3 The product can be prepared by refluxing reaction of substituted phenol and halogenated aldehyde/ketone in anhydrous K 2 CO 3 After nucleophilic substitution reaction in an acetone system, reducing by sodium borohydride to obtain the product; when Ar is an uncharged aromatic ring, the compound of formula III can be prepared by reacting an aryl halide with 5-10 times equivalent of a lower aliphatic diol in NaH as a base and 1, 4-dioxane as a solventUnder the condition of (3).
The second method comprises the following steps:
Figure BDA0003148919930000051
under the protection of argon, the compound shown in the formula IV and NaH are fully reacted in 1, 4-dioxane at room temperature, and then the compound shown in the formula V is added, heated to 80 ℃, stirred and reacted for 2 to 6 hours. After the reaction is finished, adding a small amount of ethanol for quenching, and purifying the solution by column chromatography after decompression and concentration to obtain the compound shown in the formula I. The molar ratio of the compound shown in the formula IV to the compound shown in the formula V to NaH is 1: 1.2.
The compound of the general formula IV is prepared by the reaction of the compound of the general formula II and 5-10 times of equivalent of lower aliphatic diol in a NaH/1, 4-dioxane system at 80-101 ℃, and the reaction formula is as follows:
Figure BDA0003148919930000052
the compound of the general formula I has good insecticidal activity on lepidoptera pests such as oriental armyworm, diamondback moth and the like. The compound of the general formula I has certain in vitro inhibitory activity on phytophthora capsici, early blight of tomato, botrytis cinerea, sclerotinia sclerotiorum, ring rot of apple, rhizoctonia cerealis and other plant pathogenic fungi, and particularly has higher in vitro inhibitory activity on ring rot of apple and rhizoctonia cerealis, so the compound of the general formula I can be used for preventing and treating insect pests and harmful bacteria on various crops.
The invention also provides an insecticidal or bactericidal composition which takes the compound shown in the general formula I as an active component and can be used for preparing agricultural insecticides or bactericides. The insecticidal or bactericidal composition also comprises a carrier which is acceptable in agriculture, forestry and sanitation.
The invention has the advantages and beneficial effects that:
the invention provides an 8-aryloxy alkoxy substituted xanthine derivative (a compound shown in a general formula I) with a novel structure, and the derivative has better insecticidal activity and bactericidal activity. The insecticidal composition has good control effect on pests such as diamondback moth, oriental armyworm and the like, and crop pathogenic bacteria such as ring rot of apple, rhizoctonia cerealis and the like, can be used as an active component of an insecticidal or bactericidal composition, is used for preparing agricultural insecticides or bactericides, and can be applied to prevention and control of insect pests or pathogenic bacteria.
Detailed Description
The present invention will be further described with reference to the following examples, which are intended to better understand the contents of the present invention and thus to embody the essential characteristics of the present invention, and therefore, the examples should not be construed as limiting the scope of the present invention. It is also specifically noted herein that the particular experimental procedures and equipment referred to in the examples are, unless otherwise specified, conducted in accordance with conventional procedures or conditions as recommended by the manufacturer's instructions and that the reagents referred to are commercially available without further specification.
Example 1
Process for preparing compound I-11
Step A: preparation of 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (Compound II-1)
Figure BDA0003148919930000061
To a 250mL round bottom flask were added 8-chlorotheophylline (10.73g, 50.0 mmol), anhydrous K 2 CO 3 (11.06g, 80.0 mmol) and 50mL DMF, stirred at room temperature for 30min, methyl iodide (3.3 mL,53.0 mmol) was added, and after the addition was complete, the system was stirred at room temperature overnight. And after the reaction is finished, adding 300mL of water into the system to separate out a large amount of white solid, continuously stirring for 15min, performing suction filtration, washing the solid with cold water, and drying to obtain 10.75g of white solid (compound II-1) with the yield of 94%.
And B: preparation of 3- (4- (trifluoromethyl) phenoxy) propan-1-ol (Compound III-11)
Figure BDA0003148919930000062
To a 50mL round bottom flask was added 4-trifluoromethylPhenylphenol (811mg, 5.0mmol), anhydrous K 2 CO 3 (1.38g, 10.0 mmol) and 15mL of acetonitrile, and stirred at room temperature for 30min, then 3-bromopropan-1-ol (765mg, 5.5 mmol) was added, and the mixture was heated under reflux with stirring overnight. After the reaction, the system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography, eluting with petroleum ether/ethyl acetate (v/v = 3/1) to obtain 837mg of a colorless liquid (compound II-1) with a yield of 76%.
And C: preparation of 1,3, 7-trimethyl-8- (3- (4- (trifluoromethyl) phenoxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (Compound I-11)
Figure BDA0003148919930000071
A50 mL Schlenk bottle was charged with NaH (60%, 60mg,1.5 mmol), surface-coated paraffin was washed with n-hexane, argon was replaced, a solution of 3- (4- (trifluoromethyl) phenoxy) propan-1-ol (III-11) (264mg, 1.2mmol) in 1, 4-dioxane (5 mL) was added, stirring was carried out at room temperature for 15min, and then 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (II-1) (228mg, 1.0mmol) was added and the mixture was reacted at 80 ℃ for 6H. After the reaction was completed, the system was cooled to room temperature, quenched with a small amount of ethanol, and the solution was concentrated under reduced pressure and purified by column chromatography, eluting with ethyl acetate/petroleum ether (v/v = 2/1) to obtain 305mg of a white solid (compound I-11) with a yield of 74%.
Example 2
Process for preparing compound I-17
Step A: preparation of 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (Compound II-1)
Same as example 1
And B, step B: preparation of 3- ((3, 5-dichloropyridin-2-yl) oxy) propan-1-ol (Compound III-17)
Figure BDA0003148919930000072
To a 100mL Schlenk bottle was added NaH (60%, 300mg,7.5 mmol), and the surface-coated paraffin was washed off with n-hexane, and after replacement of argon, a solution of 1, 4-dioxane (25 mL) of 1, 3-propanediol (1.1mL, 25.0 mmol) was added, followed by stirring at room temperature for 15min, followed by addition of 3, 5-dichloro-2-fluoropyridine (830mg, 5.0 mmol), and the mixture was reacted at 80 ℃ for 4h (TLC monitoring). After the reaction was completed, the system was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography using petroleum ether/ethyl acetate (v/v = 3/1) to obtain 822mg of a colorless liquid (compound III-17) in a yield of 74%.
And C: preparation of 1,3, 7-trimethyl-8- (3- ((3, 5-dichloropyridin-2-yl) oxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (Compound I-17)
Figure BDA0003148919930000073
A50 mL Schlenk flask was charged with NaH (60%, 60mg,1.5 mmol), the surface-coated paraffin was washed with n-hexane, a solution of 3- ((3, 5-dichloropyridin-2-yl) oxy) propan-1-ol (III-17), (264mg, 1.2mmol) in 1, 4-dioxane (5 mL) was added after the replacement of argon, stirring was carried out at room temperature for 15min, followed by addition of 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (II-1) (228mg, 1.0 mmol), and the mixture was reacted at 80 ℃ for 2H. The system was cooled to room temperature, quenched with a small amount of ethanol, and the solution was concentrated under reduced pressure and purified by column chromatography eluting with ethyl acetate/petroleum ether (v/v = 2/1) to give 253mg of a white solid (compound I-17) in 61% yield.
Example 3
Process for preparing compound I-19
Step A: preparation of 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (Compound II-1)
Same as example 1
And B, step B: preparation of 8- (3-hydroxypropoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (Compound IV-1)
Figure BDA0003148919930000081
A200 mL Schlenk flask was charged with NaH (60%, 1.80g,45.0 mmol), the surface-coated paraffin was washed away with n-hexane, argon was replaced and a solution of 1, 3-propanediol (6.5 mL,90.0 mmol) in 1, 4-dioxane (100 mL) was added, and the mixture was stirred at room temperature for 15min, followed by addition of 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (II-1) (6.84g, 30.0 mmol), and the mixture was reacted at 80 ℃ for 6H (TLC monitoring). After the reaction was completed, the system was cooled to room temperature, and the mixture was concentrated under reduced pressure and purified by column chromatography eluting with methylene chloride/methanol (v/v = 30/1) to obtain 6.28g of a white solid (compound IV-1) in 78% yield.
And C:6- (3- ((1, 3, 7-trimethyl-2, 6-dioxo-2, 3,6, 7-tetrahydro-1H-purin-8-yl) oxy) propoxy) nicotinonitrile (Compound I-19)
Figure BDA0003148919930000082
A50 mL Schlenk flask was charged with NaH (60%, 60mg,1.2 mmol), and the surface-coated paraffin was washed with n-hexane to displace argon, followed by addition of a solution of 8- (3-hydroxypropoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (IV-1) (268mg, 1.0 mmol) in 1, 4-dioxane (5 mL), stirring at room temperature for 15min, followed by addition of 6-chloronicotinonitrile (166.2mg, 1.2mmol), and the mixture was reacted at 80 ℃ for 2H. After completion of the reaction, the system was cooled to room temperature, quenched with a small amount of ethanol, and the mixture was concentrated under reduced pressure and purified by column chromatography, eluting with ethyl acetate/petroleum ether (v/v = 2/1) to give 252mg of a white solid (compound I-19) in 68% yield.
Example 4
Process for preparing compound I-22
Step A: preparation of 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (Compound II-1)
Same as example 1
And B: preparation of 8- (3-hydroxypropoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (Compound IV-1)
Same as example 3
And C:8- (3- ((5, 6-dichloropyridin-3-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (Compound I-22)
Figure BDA0003148919930000091
A50 mL Schlenk flask was charged with NaH (60%, 60mg, 1.2mmol), and the surface-coated paraffin was washed with n-hexane to displace argon, followed by addition of a solution of 8- (3-hydroxypropoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (IV-1) (268mg, 1.0mmol) in 1, 4-dioxane (5 mL), stirring at room temperature for 15min, followed by addition of 2, 3-dichloro-5-fluoropyridine (166.2mg, 1.2mmol), and the mixture was reacted at 80 ℃ for 6H. After completion of the reaction, the system was cooled to room temperature, quenched with a small amount of ethanol, and the mixture was concentrated under reduced pressure and purified by column chromatography, eluting with ethyl acetate/petroleum ether (v/v = 2/1) to give 252mg of a white solid (compound I-22) with a yield of 72%.
Example 5
A preparation method of the compound I-31.
Step A: preparation of 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (Compound II-1)
Same as example 1
And B: preparation of 1- (2, 6-difluorophenoxy) propan-2-one
Figure BDA0003148919930000092
To a 100mL round bottom flask was added 2, 6-difluorophenol (1.30g, 10.0 mmol), anhydrous K 2 CO 3 (2.07g, 15.0 mmol) and 30mL of acetone, stirred at room temperature for 30min, monochloroacetone (0.81mL, 10.0 mmol) was added, and the mixture was reacted at room temperature for 12h (TLC monitoring). After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography, eluting with petroleum ether/ethyl acetate (v/v = 15/1) to obtain 1.55g of a colorless liquid with a yield of 83%.
And C: preparation of 1- (2, 6-difluorophenoxy) propan-2-ol (Compound III-31)
Figure BDA0003148919930000101
1- (2, 6-Difluorophenoxy) was placed in a 50mL round bottom flask in an ice bathYl) propan-2-one (9.31g, 5.0 mmol) was dissolved in 15mL of methanol, to which was then added sodium borohydride (567mg, 15.0 mmol) in portions, after which the system was slowly warmed to room temperature and stirred for 6h (TLC monitor). After completion of the reaction, the mixture was concentrated under reduced pressure, the residue was dispersed in 20mL of water, extracted with ethyl acetate (20 mL. Times.3), and the organic phases were combined, washed with brine, and washed with anhydrous Na 2 SO 4 The solution was dried, the solvent was removed by evaporation under reduced pressure, and the residue was purified by flash column chromatography to give 875mg of a colorless oil (compound III-31) which was used directly in the next reaction.
Step D:8- ((1- (2, 6-difluorophenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione
Figure BDA0003148919930000102
A50 mL Schlenk flask was charged with NaH (60%, 60mg,1.5 mmol), the surface-coated paraffin was washed with n-hexane, argon was replaced, a solution of 1- (2, 6-difluorophenoxy) propan-2-ol (III-31) (226mg, 1.2 mmol) in 1, 4-dioxane (5 mL) was added, stirring was carried out at room temperature for 15min, and then 8-chloro-1, 3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (II-1) (228mg, 1.0 mmol) was added, and the mixture was reacted at 80 ℃ for 4H. After the reaction was completed, the system was cooled to room temperature, quenched with a small amount of ethanol, and the solution was concentrated under reduced pressure and purified by column chromatography, eluting with ethyl acetate/petroleum ether (v/v = 2/1) to obtain 293mg of a white solid (compound I-31) in 71% yield.
Table 1 lists the structure and physical properties of some of the compounds of formula I.
TABLE 1 Structure and physical Properties of Compounds of formula I
Figure BDA0003148919930000103
Figure BDA0003148919930000111
Figure BDA0003148919930000121
Figure BDA0003148919930000131
Table 2 lists the NMR and HRMS data for the compounds of formula I.
TABLE 2 NMR and HRMS data for compounds of formula I
Figure BDA0003148919930000132
Figure BDA0003148919930000141
Figure BDA0003148919930000151
Figure BDA0003148919930000161
Figure BDA0003148919930000171
Figure BDA0003148919930000181
Figure BDA0003148919930000191
Examples of biological Activity tests
Example 6
Insecticidal Activity test
The insecticidal activity of the diamondback moth is tested by adopting a leaf soaking method: dissolving a test compound in 1mL of DMF, diluting with distilled water to prepare a solution with a corresponding test concentration, soaking cabbage leaves (5 multiplied by 1 cm), throwing away residual liquid after 3-5 s, airing, putting into a test tube with the length of 10cm, inoculating 10 larvae of 2-year-old diamond back moth, making three groups for each sample, and maintaining the room temperature at 25 +/-1 ℃. Blank control cabbage leaves were impregnated with DMF diluted solution only to feed larvae. The test results are obtained at 72h, the contact immobility is taken as the death standard of the larvae, and the lethality of the test compound to the armyworm larvae is evaluated in a range of 0-100%, wherein 0% represents no insecticidal effect, and 100% means complete killing.
The method for testing the insecticidal activity of the oriental armyworms adopts a leaf soaking method: preparing a test compound into a solution with a corresponding test concentration by using acetone, then soaking corn leaves (5 multiplied by 1 cm) in a seedling stage, throwing off residual liquid after 3-5 s, airing, putting into a 7cm culture dish, inoculating 10-head 4-year-old test larvae, making three groups for each sample, and maintaining the room temperature at 25 +/-1 ℃. The blank control was fed larvae by dipping corn leaves with acetone solution only. The test results were obtained at 72h with touch-and-hold as the criteria for larval mortality, and the mortality of the test compounds on armyworm larvae was evaluated at 0-100%, where 0% indicates no insecticidal effect and 100% is complete kill.
Table 3 insecticidal activity (% lethality) of the compounds at various concentrations tested
Figure BDA0003148919930000201
Figure BDA0003148919930000211
Example 7
In vitro plate method for determining bactericidal activity
Test compounds were dissolved in DMSO to a concentration of 3.0X 10 4 mg·L -1 The solution of (1) is diluted to a concentration of 50 mg.L with a Tween solution -1 The test solution of (4). Adding 1.0mL of the culture medium into 9mLPDA under aseptic condition, inoculating the test strain, and adding 1mL of sterilized water into the culture medium as blankAnd (6) comparison. After the medium was cultured in a 25. + -. 1 ℃ incubator for 72 hours, the colony diameter (D) was measured and the inhibition rate was calculated.
Figure BDA0003148919930000212
In vitro bactericidal Activity of the Compounds of Table 4 (50 mg. L) -1 Inhibition ratio%)
Figure BDA0003148919930000213
Figure BDA0003148919930000221

Claims (6)

1. An 8-aryloxyalkoxy-substituted xanthine derivative characterized by having a structural formula shown in formula I:
Figure FDA0003885951380000011
wherein R is 1 ～R 3 Is methyl;
a is ethyl-1, 1-diyl (-CH (CH) 3 ) -) or ethane-1, 2-diyl (-CH) 2 CH 2 -)；
Ar is phenyl, 2-methoxy-4-methylphenyl, 4-methoxyphenyl, 2-chloro-4-methoxyphenyl, 4-chloro-2-methylphenyl, 2, 4-dichlorophenyl, 3-chloro-4-trifluoromethoxyphenyl, 2, 6-difluorophenyl, 4-trifluoromethylphenyl, 4-allyl-2-methoxyphenyl, 3, 4-methylenedioxyphenyl, 4-phenoxyphenyl, pyridin-2-yl, 3-chloropyridin-2-yl, 3, 5-dichloropyridin-2-yl, 3-cyanopyridin-2-yl, 5-cyanopyridin-2-yl, 2-isopropyl-5-methylphenyl, 4-trifluoromethoxyphenyl, 5-trifluoromethylpyridin-2-yl, 3-chloro-5-trifluoromethylpyridin-2-yl or 5, 6-dichloropyridin-3-yl.
2. An 8-aryloxyalkoxy-substituted xanthine derivative according to claim 1, characterized in that it is the following compound: 1,3, 7-trimethyl-8- (3-phenoxypropoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-1), 8- (3- (2-methoxy-4-methylphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-2), 8- (3- (4-methoxyphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-3) 8- (3- (2-chloro-4-methoxyphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-4), 8- (3- (2-isopropyl-5-methylphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-5), 8- (3- (4-chloro-2-methylphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-6), 8- (3- (2, 4-dichlorophenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro- 1H-purine-2, 6-dione (I-7), 1,3, 7-trimethyl-8- (3- (4- (trifluoromethoxy) phenoxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-8), 8- (3- (3-chloro-4- (trifluoromethoxy) phenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-9), 8- (3- (2, 6-difluorophenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-10) 1,3, 7-trimethyl-8- (3- (4- (trifluoromethyl) phenoxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-11), 8- (3- (4-allyl-2-methoxyphenoxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-12), 8- (3- (benzo [ d ] [1,3] dioxa-5-yloxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I- 13 1,3, 7-trimethyl-8- (3- (4-phenoxyphenoxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-14), 1,3, 7-trimethyl-8- (3- (pyridin-2-yloxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-15), 8- (3- ((3-chloropyridin-2-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-16) 8- (3- (((3, 5-dichloropyridin-2-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-17), 2- (3- ((1, 3, 7-trimethyl-2, 6-dioxo-2, 3,6, 7-tetrahydro-1H-purin-8-yl) oxy) propoxy) nicotinonitrile (I-18), 6- (3- ((1, 3, 7-trimethyl-2, 6-dioxo-2, 3,6, 7-tetrahydro-1H-purin-8-yl) oxy) propoxy) nicotinonitrile (I-19), 1,3, 7-trimethyl-8- (3- ((5- (trifluoromethyl) pyridin-2-yl) oxy) propoxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-20), 8- (3- ((3-chloro-5- (trifluoromethyl) pyridin-2-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-21), 8- (3- ((5, 6-dichloropyridin-3-yl) oxy) propoxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-22) 8- ((1- (2-methoxy-4-methylphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-23), 8- ((1- (4-methoxyphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-24), 8- ((1- (2-chloro-4-methoxyphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-25), 8- ((1- (2-isopropyl-5-methylphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-26), 8- ((1- (4-chloro-2-methylphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-27) 8- ((1- (2, 4-dichlorophenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-28), 1,3, 7-trimethyl-8- ((1- (4- (trifluoromethoxy) phenoxy) propan-2-yl) oxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-29), 8- ((1- (3-chloro-4- (trifluoromethoxy) phenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-30), 8- ((1- (2, 6-difluorophenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-31), 1,3, 7-trimethyl-8- ((1- (4- (trifluoromethyl) phenoxy) propan-2-yl) oxy) -3, 7-dihydro-1H-purine-2, 6-dione (I-32), 8- ((1- (4-allyl-2-methoxyphenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-33), 8- ((1- (benzo [ d ] [1,3] dioxa-5-yloxy) propan-2-yl) oxy) -1,3, 7-trimethyl-3, 7-dihydro-1H-purine-2, 6-dione (I-34), or 1,3, 7-trimethyl-8- (4-phenoxy) propan-2-yl) oxy) -1,3, 7-trimethyl-1H-purine-2, 6-dione (I-34).
3. The process for producing an 8-aryloxyalkoxy-substituted xanthine derivative according to claim 1, which comprises one of the following two processes;
in the first method, the first step is to provide,
the reaction route is as follows:
Figure FDA0003885951380000021
in the formula R 1 、R 2 、R 3 A, ar have the same definitions as given in claim 1;
the preparation method comprises the following steps: under the protection of nitrogen, placing the compound of the formula III and NaH in 1, 4-dioxane for reaction at room temperature, then adding the compound of the formula II, heating to 80 ℃, stirring for reaction for 2-6 hours, adding ethanol for quenching after the reaction is finished, concentrating the solution under reduced pressure, and separating by column chromatography to obtain the compound of the formula I; the mol ratio of the compound of the formula II, the compound of the formula III and NaH is 1: 1.2: 1.5;
in the second method, the first step is to perform the first step,
the reaction route is as follows:
Figure FDA0003885951380000031
in the formula R 1 、R 2 、R 3 A, ar have the same meanings as given in claim 1, X is a halogen atom;
the preparation method comprises the following steps:
under the protection of nitrogen, placing the compound shown in the formula IV and NaH in 1, 4-dioxane at room temperature for full reaction, then adding the compound shown in the formula V, heating to 80 ℃, stirring for reaction for 2-6 hours, adding ethanol for quenching after the reaction is finished, and performing column chromatography purification after the solution is subjected to reduced pressure concentration to obtain the compound shown in the formula I; the mol ratio of the compound shown in the formula IV to the compound shown in the formula V to NaH is 1: 1.2.
4. The process for producing an 8-aryloxyalkoxy-substituted xanthine derivative according to claim 3, wherein the intermediate compound of formula IV is produced by reacting a compound of formula II with 5 to 10 equivalents of a lower aliphatic diol in a NaH/1, 4-dioxane system at 80 to 101 ℃ for 2 to 6 hours, wherein the reaction formula is as follows:
Figure FDA0003885951380000032
in the formula R 1 、R 2 、R 3 A has the same definition as given in claim 1.
5. Use of an 8-aryloxyalkoxy-substituted xanthine derivative according to any one of claims 1 to 2 for the control of pests and germs on various crops, characterized in that the use is for the preparation of agricultural insecticides and fungicides, the insecticides being those which kill diamond back moth or oriental armyworm, the fungicides being those which kill ring rot of apple, rhizoctonia cerealis, sclerotinia sclerotiorum, botrytis cinerea, early blight of tomato or phytophthora capsici.
6. The use of an 8-aryloxyalkoxy-substituted xanthine derivative according to claim 5 for the control of insect pests and disease germs on a variety of crops, wherein the use further comprises using the 8-aryloxyalkoxy-substituted xanthine derivative as an active ingredient in a pesticidal or fungicidal composition for the preparation of an agricultural pesticide or fungicide; the insecticidal or bactericidal composition also comprises a carrier which is acceptable in agriculture, forestry and hygiene.
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