CN102796111B - Carboxylate (sulfonate) ester compounds of oxazepine spirocyclic amide group, preparation method and use - Google Patents

Abstract

The invention discloses a class of carboxy(sulfonate) ester compounds of oxygen and aza spirocyclic amide groups, a synthesis method and application. Its compound structure is represented by the following general formula (I). The present invention uses piperidone hydrochloride, glycerin, aromatic acid and substituted aromatic acid, nitrogen-containing heterocyclic acid, substituted pyrazole acid, acid chloride and sulfuryl chloride as raw materials, and obtains the intermediate 1,4-di Oxy-8-azaspiro[4,5]decane-2-alkylmethanol is then condensed with different acids to obtain spirocyclic alcohols containing amide structures, and then reacted with acid chlorides and sulfonyl chlorides to obtain the target product. Such compounds exhibit better activity against plant pathogenic bacteria. (I)

Description

Carboxylate (sulfonate) ester compounds of oxazepine spirocyclic amide group, preparation method and use

technical field

The invention relates to carboxy(sulfonate) ester compounds of oxazepine spirocyclic amide group with anti-plant pathogenic bacteria and a preparation method.

Background technique

Heterospiro compounds have broad-spectrum biological activities and can be used in the research of pesticides and medicines. Because organic heterospiro compounds have structures that general organic compounds do not possess, such as spiro conjugated, spiro hyperconjugated or anomeric effects The research on the synthesis and biological activity of heterospirocyclic compounds has aroused great interest, and a variety of heterospirocyclic pesticide varieties have been successfully developed. At the same time, the research on heterospirocyclic compounds in medicine has attracted more and more interest of chemists. Oxygen- and nitrogen-containing heterospirocyclic compounds, as a member of the organic heterospirocyclic ring system, are a class of substances with a wide range of biological activities. In terms of agriculture, it has anti-agricultural fungus, insecticidal and other activities; in 2010, Deshpande et al. synthesized a series of substituted 1,4-dioxa-8-azaspiro[4,5]decane compounds. It has certain activity against rice sheath blight ( R.solani ), Fusarium wilt ( F.oxysporum ), Pythium ( P.aphanidermatum ), rice blast ( D.oryzae ), etc. (Deshpande M V, Deshpande S R, Shirazi F , et al. Substituted 1,4-dioxa-8-azaspiro[4,5] decanes useful as fungicides and a process for the preparation thereof [P]. WO2010/109299A2, 2010-09-30.). In addition, in medicine, heterospirocycles and their derivatives have anti-inflammatory, analgesic, anti-tumor, anti-convulsant activities (Jacques, R., Didler, P., Francois, B., et al. Dissym-metric acid 1 ,4-dihydropyridine-3,5-dicarboxylic,precedes preparation, utilization and therapeutic use[P]. EP0240398A1, 1991-05-15.). Some of the bacteria Streptococcus faecalis , Bacillus subtilis , Escherichia coli, Pseudomonas aeruginosa and Klebsiella pneumoniae ) has better activity, and it has been found that some natural products containing organic spiral structure also have better insecticidal activity. There have been a large number of research reports on active organic heterospirocyclic compounds, which can be used as insecticides, fungicides, herbicides, and plant growth regulators. As a heterospirocyclic derivative for pesticides, it has become a research hotspot in the field of pesticides and medicine because of its low toxicity, high efficiency and pollution-free, easy to be fully degraded and utilized by organisms, and wide source of raw materials.

In 2000, Thinagar et al. cultivated the compound 1 spiro[2-benzoyl-cyclo-cyclohexyl-4,5-diphenylpyrrolidinyl-3,3'-chroman-4-one] Crystal structure, indicating that 3-phenyl-chroman-4-one is the building block of isoflavones. However, isoflavones are abundant in leguminous plants, and their bactericidal activity was tested, and the results showed that bacteria and fungi were resistant (Thinagar S, Velmurugan A, Amalrai R, et al. Crystal Structure of spiro[2- benzoyl-cyclohexyl-4,5-diphenylpyrrolidine-3,3'-chroman-4-one][J]. Cryst. Res. Technol. 2000, 35(8): 979-986).

In 2004, Balasubramanian et al. synthesized a new spiropiperidine thiadiazole compound and tested its antibacterial activity. The results showed that this type of compound was not effective against Streptococcus faecalis , Bacillus subtilis , Escherichia coli Escherichia coli , Pseudomonas aeruginosa and Klebsiella pneumoniae had good activity (Balasubramanian S, Ramalingan C, Aridoss G, et al. Synthesis and Microbiological Evaluation of Novel [N-Acetyl-2,6-Diarylpiperidin-4-yl]-5-Spiro-4-Acetyl-2-(Acetylamino)-Δ ² -1,3,4-Thiadiazolines[J].Med.Chem . Res. 2004, 13(5): 297-311.).

In 2008, Srinivas et al. synthesized a new type of nitrogen- and sulfur-containing spirocyclic compound, and tested it for antibacterial and antifungal biological activities. The results showed that some compounds were found to be highly antibacterial against Klebsiella pneumoniae ( K. pneumoniae ) and Shigella dysentriae ( Shigella dysentriae ); , Aspergillus flavus and Rhizopus oryzae had significant activity (Srinivas A, Nagaraj A, Sanjeeva C R, Synthesis of Some Novel Methylene-bis-pyrimidinyl-spiro-4-thiazolidinones as Biologically Potent Agents[J] . J. Heterocyclic Chem., 2008, 42 (2): 221-225.).

In 2008, Mulwad, VV and others synthesized a series of coumarin-based spiroindolone compounds, and tested the antibacterial activity of these compounds, and found that under the condition of 100ppm, the antibacterial activity of the compound with the spiro ring structure was superior. For compounds without a spiral ring structure unit, the inhibition rate against Staphylococcus aureus and Bacillus subtilis can reach more than 80% (Mulwad V V, Mir A A, Synthesis and antibacterial screening of N-[coumarin - 6-yl] spiro-indoloazetidin-2-ones/thiazolidin-4-ones[J]. J. Korean Chem. Soc., 2008, 52(6):649-656.).

In 2011, Rachid. B et al. used 1,3-dipolar cycloaddition to synthesize a series of nitrogen- and sulfur-containing spiro compounds with anti-inflammatory, anti-bacterial and anti-convulsant activities. These compounds use indole as the core to introduce isoxane Azole, triazole, dioxazole heterocycle (Rachid B, Nicolas J, El M E, et al. Synthesis of NewSpiro[1,4,2-dioxazole-5,3′-indolin]-2′-one by 1 , 3-Dipolar Cycloaddition[J]. Synthetic Commun., 2011, 41(14): 2096-2102.).

In 2004, a class of heteroatom spiro compounds synthesized by Bayer, Germany, had a lethality rate of 100% against green peach aphid at a concentration of 500 g/ha, and had good protection against horseradish beetle and Spodoptera frugiperda. Effect (Mazen, E. S.; Jeschke, P., Loesel. P. et al. Preparation of N-nitro-4,6-

diazaspiro[2.4]hept-4-en-5-amines and related compounds as pesticides [P]. DE102004013528 . 2004-3-19.).

In 1998, Wu Yulin et al. synthesized some derivatives of insect repellents. This type of compound belongs to the heterospiro ring structure, and its typical representative is the chrysanthemum chrysanthemum analogue, most of which have antifeedant activity. Among them, the antifeedant rate of P. Up to 100%.

It can be seen from the background technology that compounds with oxygen-containing and aza-spiro ring structures have a wide range of biological activities, and can be developed as lead compounds in the field of anti-phytopathogenic bacteria and have obtained a certain theoretical basis. At the same time, no one has synthesized carboxy(sulfonate) ester compounds of oxygen and azaspirocyclic amide groups.

Invention content

The purpose of the present invention is to design and synthesize a series of carboxy (sulfonate) ester compounds containing oxygen and azaspirocyclic amide groups with novel structures. This type of compound is based on oxygen and azaspirocyclic alcohols and synthesized by structural modification. A series of oxygen and azaspiro ring derivatives, through the anti-phytopathogenic activity test, shows that the derivatives have better inhibitory activity on cucumber Botrytis cinerea. Oxygen, the carboxyl (sulfonate) ester compound structure of azaspirocyclic amide group is represented by following general formula ( I ):

 

( I )

Wherein R ₁ is (1) phenyl or substituted phenyl; (2) pyridine or substituted pyridyl; (3) substituted pyrazolyl; R ₂ is (1) benzoyl; (2) phenylacetyl; (3) ) ortho, meta, para mono-substituted or multi-substituted benzenesulfonyl; (4) methylsulfonyl;

In the context of the present invention, the substituted phenyl group in _R1 can contain one or more methyl groups, ethyl groups, methoxy groups, ethoxy groups, n-propyl groups, isopropyl groups, trifluoromethyl groups, and nitro groups on the benzene ring. , amino and halogen atoms, halogen atoms can be fluorine, chlorine, bromine, iodine; substituted pyridyl can contain one or more methyl, ethyl, methoxy, ethoxy, n-propyl, Isopropyl, nitro, amino and halogen atoms, halogen atoms can be fluorine, chlorine, bromine, iodine; Substituted pyrazolyl can be 1, 3, 4 mono-substituted or poly-substituted pyrazolyl; R ₂ can be substituted The benzenesulfonyl group may contain one or more methyl groups, ethyl groups, methoxy groups, ethoxy groups, n-propyl groups, isopropyl groups, and trifluoromethyl groups on the benzene ring.

In the content of the present invention, the compound has anti-phytopathogenic activity, especially has good inhibitory activity on cucumber Botrytis cinerea, and is used in the preparation of anti-phytopathogenic medicaments. The preparation method of the compound of general formula (I) of the present invention is to take piperidone hydrochloride, glycerin, aromatic acid and substituted aromatic acid, nitrogen-containing heterocyclic acid, substituted pyrazole acid, acid chloride and sulfonyl chloride as raw materials, through two One-step condensation reaction and one-step substitution reaction to synthesize target product in three steps, and its synthetic route is as follows:

In the reaction formula, R ₁ , the definition of R ₂ is the same as the definition in claim 1 formula (I); Tolune is toluene; EDC HCl is 1-(3-dimethylaminopropyl)-3-ethyl carbon di Imine hydrochloride; HOBt is 1-hydroxy-benzo-triazole; Acyl Chloride is acid chloride; Sulfuryl Chloride is sulfonyl chloride; _Et3N is triethylamine;

The first step: 1,4-dioxo-8-azaspiro[4,5]decane-2-alkylmethanol

Weigh piperidone hydrochloride and place it in a three-neck round bottom flask, add toluene, then add glycerin, add slowly while the temperature rises from 25°C to 75°C, then weigh p-toluenesulfonic acid Add the above system, raise the temperature to 115°C and let it reflux, (note that the device must be equipped with a water dispenser), react for 24 hours, wash the system with secondary water, saturated sodium bicarbonate, and saturated brine successively, discard the organic layer, and depressurize Evaporate the water, then wash the oil with ethanol, spin out the ethanol to obtain a light yellow oil; add 30 mL of toluene, 1.10 g of glycerol, and 0.17 g of p-toluenesulfonic acid for every 1.35 g of piperidone hydrochloride ;

The second step: spirocyclol with amide structure

Add the acid compound into the reaction bottle, dissolve it with dichloromethane and mix it evenly, then add 1.2 times the corresponding acid molar amount of EDC·HCl and HOBt under the condition of ice bath, stir for 2 h, add the dichloromethane dissolved 1,4-Dioxo-8-azaspiro[4,5]decane-2-alkylmethanol, 1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl The amount of methanol used is equal to the molar amount of the corresponding acid feed, and the reaction was reacted at room temperature until the TLC plate detected that the reaction was complete (developing agent V _{petroleum ether} : V _{ethyl acetate} = 1:1), and stopped the reaction after 10~12 h, followed by Wash with 20 mL×2 secondary water, 20 mL×2 saturated brine, discard the water layer, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure to obtain a light yellow oil.

The third step: preparation of carboxy(sulfonate) ester derivatives containing oxygen and azaspirocyclic amide groups

Add the second-step product in the reaction flask, dissolve dichloromethane and stir to mix, add 2 times the molar amount of triethylamine and stir for 15 min, then slowly add 1.2 times the corresponding first-step product molar amount of Substitute sulfuryl chloride and acid chloride, react at room temperature until the reaction is complete as detected by TLC plate (developing agent V _{petroleum ether} : V _{ethyl acetate} = 1:2), stop the reaction after 3~5 h, and use 20 mL×2 Wash with saturated sodium bicarbonate, 20 mL×2 secondary water, 20 mL×2 saturated brine, discard the water layer, dry over anhydrous magnesium sulfate, and separate by thin-layer chromatography to obtain the target product.

This step is applicable to the synthesis of carboxy(sulfonate) esters of all the above-mentioned target compounds oxygen and azaspirocyclic amide groups.

The compound that has been synthesized according to route of invention and preparation method is as follows:

Compound a :

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzenesulfonate

Compound b:

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate

Compound c:

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate

Compound d:

(8-(4-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzenesulfonate

Compound e:

(8-(4-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate

Compound f:

(8-(4-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-benzoate

Compound g:

(8-(2-Chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzoate

Compound h:

(8-(2-Chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate

Compound i:

(8-(2-Methoxybenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate

Compound j:

(8-(3-Chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate

Compound k:

(8-(6-Chloro-nicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate

Compound 1 :

(8-(3-Chloro-1-(3-chloropyridine-2-alkyl)-1H-pyrazole-5-carbonyl)-1,4-dioxo-8-azaspiro[4,5]decane Alk-2-alkyl)methyl 4-(trifluoromethyl)benzenesulfonate

Compound m :

(8-(3-Chloro-1-(3-chloropyridine-2-alkyl)-1H-pyrazole-5-carbonyl)-1,4-dioxo-8-azaspiro[4,5]decane Alk-2-alkyl)methylbenzenesulfonate

Compound n :

(8-(2,6-Dichlorobenzoyl-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzoate

Compound o :

(8-Benzoyl-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl methanesulfonate

Detailed ways

Embodiment one

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzenesulfonate (compound number is a ) synthesis:

Step 1: Synthesis of 1,4-dioxo-8-azaspiro[4,5]decane-2-alkylmethanol

Weigh 1.35 g of piperidone hydrochloride and place it in a 50 mL three-neck round bottom flask, add 30 mL of toluene, then weigh 1.10 g of glycerol, and slowly add , and then weighed 0.17 g of p-toluenesulfonic acid into the above system, raised the temperature to 115 ° C to reflux, (note that the device must be a water dispenser), and reacted for 24 hours, followed by secondary water, saturated sodium bicarbonate, The system was washed with saturated brine, the organic layer was discarded, the water was evaporated under reduced pressure, and the oily substance was washed with ethanol, and the ethanol was spun off to obtain a light yellow oily substance.

Step 2: Synthesis of (3-chlorophenyl)(2-hydroxymethyl)-1,4-dioxo-8-azaspiro[4,5]decane-8-alkyl)methanone

Add 0.16 g of 3-chlorobenzoic acid into a 50 mL three-necked flask, dissolve it with 25 mL of dichloromethane and mix well, then add 0.23 g of EDC·HCl and 0.16 g of HOBt in an ice bath, and stir for 2 h , add 1,4-dioxo-8-azaspiro[4,5]decane-2-alkylmethanol dissolved in dichloromethane, and react at room temperature until the TLC plate detects that the reaction is complete (developing solvent V _{petroleum ether} : V _{ethyl acetate} = 1 : 1), stop the reaction after 10~12 h, wash with 20 mL×2 secondary water, 20 mL×2 saturated brine, discard the water layer, and dry over anhydrous magnesium sulfate , The solvent was distilled off under reduced pressure to obtain (3-chlorophenyl)(2-hydroxymethyl)-1,4-dioxo-8-azaspiro[4,5]decane-8-alkyl)methanone.

The third step: Synthesis of (8-(3-chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzenesulfonate

Add 0.31 g (3-chlorophenyl)(2-hydroxymethyl)-1,4-dioxo-8-azaspiro[4,5]decane-8-alkyl) into a 50 mL three-neck flask Dissolve methanone in 30 mL of dichloromethane and mix well, add 0.20 g of triethylamine and stir for 15 min, then slowly add 0.21 g of benzenesulfonyl chloride in an ice bath and react at room temperature until the TLC plate detects the reaction complete (developing agent V _{petroleum ether} : V _{ethyl acetate} = 1 : 2), stop the reaction after 3~5 h, and then use 20 mL×2 saturated sodium bicarbonate, 20 mL×2 secondary water, 20 mL×2 saturated Wash with brine, discard the aqueous layer, dry over anhydrous magnesium sulfate, and separate and purify by thin-layer chromatography to obtain the target compound with a yield of 78%.

Embodiment two

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate (Compound No. For the preparation of b ):

Prepared according to the method and conditions of Example 1. The first step and the second step are the same as in Example one, except that the third step adds 0.23 g of p-toluenesulfonyl chloride, and the target product yield is 76%.

Embodiment three

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate (compound number is c ) preparation:

Prepared according to the method and conditions of Example 1. The first step and the second step are the same as in Example one, except that the third step adds 0.19 g of phenylacetyl chloride, and the target product yield is 79%.

Embodiment four

(8-(4-chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzenesulfonate (compound number d ) preparation:

Prepared according to the method and conditions of Example 1. The first step and the third step are the same as in Example one, except that the second step adds 0.16 g of 4-chlorobenzoic acid, and the target product yield is 72%.

Embodiment five

(8-(4-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate (Compound No. For the preparation of e ):

Prepared according to the method and conditions of Example 1. The first step is the same as Example 1, except that the second step adds 0.16 g of 4-chlorobenzoic acid and the third step adds 0.23 g of p-toluenesulfonyl chloride, and the target product yield is 76%.

Embodiment six

(8-(4-chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-benzoate (compound number is f ) preparation:

Prepared according to the method and conditions of Example 1. The first step is the same as Example 1, except that the second step adds 0.16 g of 4-chlorobenzoic acid and the third step adds 0.17 g of benzoyl chloride, and the target product yield is 80%.

Embodiment Seven

Preparation of (8-(2-chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzoate (compound number g ) :

Prepared according to the method and conditions of Example 1. The first step is the same as in Example 1, except that the second step adds 0.16 g of 2-chloronicotinic acid and the third step adds 0.17 g of benzoyl chloride, and the yield of the target product is 78%.

Embodiment Eight

(8-(2-Chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate, pale yellow oil ( Compound number is the preparation of h ):

Prepared according to the method and conditions of Example 1. The first step is the same as in Example 1, except that the second step adds 0.16 g of 2-chloronicotinic acid and the third step adds 0.19 g of phenylacetyl chloride, and the yield of the target product is 76%.

Embodiment Nine

(8-(2-methoxybenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate ( Compound number is the preparation of i ):

Prepared according to the method and conditions of Example 1. The first step is the same as in Example 1, except that the second step adds 0.15 g of 2-methoxybenzoic acid and the third step adds 0.23 g of p-toluenesulfonyl chloride, and the target product yield is 80%.

Embodiment ten

(8-(3-chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate (compound number is j ) Preparation:

Prepared according to the method and conditions of Example 1. The first step is the same as in Example 1, except that 0.16 g of 3-chloronicotinic acid is added in the second step and 0.23 g of p-toluenesulfonyl chloride is added in the third step, and the yield of the target product is 79%.

Embodiment Eleven

(8-(6-Chloro-nicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate (compound number is k ) preparation:

Prepared according to the method and conditions of Example 1. The first step is the same as in Example 1, except that the second step adds 0.16 g of 6-chloronicotinic acid and the third step adds 0.19 g of phenylacetyl chloride, and the yield of the target product is 74%.

Example 12

(8-(3-Chloro-1-(3-chloropyridine-2-alkyl)-1H-pyrazole-5-carbonyl)-1,4-dioxo-8-azaspiro[4,5]decane The preparation of alkane-2-alkyl)methyl 4-(trifluoromethyl)benzenesulfonate (compound number is 1 ):

Prepared according to the method and conditions of Example 1. The first step is the same as Example 1, except that the second step adds 0.26 g of 3-chloro-1-(3-chloropyridine-2-alkyl)-1 H -pyrazole-5-carbonyl acid and the third step adds 0.29 g of p-trifluoromethylbenzenesulfonyl chloride, the target product yield is 70%.

Embodiment Thirteen

(8-(3-Chloro-1-(3-chloropyridine-2-alkyl)-1H-pyrazole-5-carbonyl)-1,4-dioxo-8-azaspiro[4,5]decane The preparation of alkane-2-alkyl) toluenesulfonate (compound number is m ):

Prepared according to the method and conditions of Example 1. The first step is the same as Example 1, except that the second step adds 0.26 g of 3-chloro-1-(3-chloropyridine-2-alkyl)-1 H -pyrazole-5-carbonyl acid and the third step adds The benzenesulfonyl chloride of 0.21 g, target product productive rate is 74%.

Embodiment Fourteen

(8-(2,6-dichlorobenzoyl-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzoate (compound number is n ) preparation:

Prepared according to the method and conditions of Example 1. The first step is the same as Example 1, the difference is that 0.19 g of 2,6-dichlorobenzoic acid is added in the second step and 0.17 g of benzoyl chloride is added in the third step, and the yield of the target product is 75%.

Example 15

Preparation of (8-benzoyl-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl methanesulfonate (compound number is o ):

Prepared according to the method and conditions of Example 1. The first step is the same as in Example 1, except that the second step adds 0.12 g of benzoic acid and the third step adds 0.14 g of methanesulfonyl chloride, and the target product yield is 79%.

Other compounds can also be prepared by similar methods as described above.

The structures of the compounds obtained are shown in the table below:

( I )

The spectral data of the synthesized partial oxygen-containing and nitrogen amide derivatives are as follows:

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzenesulfonate

(compound a ) :

Molecular formula: C ₂₁ H ₂₂ ClNO ₆ S; Yield: 78 %; Yellow oil; ESI-MS: 452[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3447, 2934, 2371, 1773, 1734 , 1653, 1578, 1458, 1364, 1188, 1094, 980, 758, 669, 588; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard):7.88 (s, 2H), 7.75 ( s, 1H), 7.65 (s, 2H), 7.43-7.47 (br, m, 3H), 7.31 (d, 1H, J =7.0Hz,Ph-H), 4.30 (s, 1H), 4.14 (d, 1H, J =8.0 Hz), 3.97-3.99 (br, m, 2H), 3.67 (s, 1H), 3.54 (s, 2H), 3.21 (s, 2H), 1.50-1.63 (br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 167.9, 138.6, 135.6, 134.9, 133.7, 130.9, 130.4, 129.8, 128.1, 127.1, 125.7, 108.3, 73.3, 5.1 , 45.6, 35.6.

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate (compound b ):

Molecular formula: C ₂₂ H ₂₄ ClNO ₆ S; Yield: 76 %; Yellow oil; ESI-MS: 466[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3447, 2392, 2369, 1699, 1636 , 1558, 1437, 1362, 1250, 1177, 1088, 978, 814, 741, 669, 554; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 7.74 (s, 2H), 7.30-7.37 (m, 5H), 7.22 (d, 1H, J =7.5 Hz), 4.31 (s, 1H), 3.99-4.03 (m, 3H), 3.74-3.81 (m, 3H), 3.38 (s, 2H), 2.42 (s, 3H, CH ₃ -H), 1.72-1.85 (br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 168.8, 145.2, 137.7, 134.5, 132.5, 129.9, 127.9, 126.9, 124.8, 108.2, 72.9, 69.0, 65.6, 45.1, 40.0, 21.5.

(8-(3-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate (compound c ) :

Molecular formula: C ₂₃ H ₂₄ ClNO ₅ ; Yield: 79 %; pale yellow oil; ESI-MS: 430[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3449, 2957, 2371, 1734, 1636 , 1437, 1248, 1130, 1066, 930, 741, 696; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 7.92-7.94 (br, m, 2H), 7.57-7.63 ( br, m, 1H), 7.51-7.53 (br, m, 2H), 7.47 (d, 2H, J =8.2 Hz, Ph-H), 7.40 (m, 2H,Ph-H), 4.36 (s, 2H ), 4.32 (s, 1H), 4.16 (s, 1H), 4.04 (s, 1H), 3.64-3.68 (br, m, 5H), 3.38-3.40 (br, m, 2H), 1.54-1.74 (br , m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 171.2, 168.6, 137.7, 134.5, 133.7,129.8, 128.7, 127.3, 127.1, 126.7, 125.0, 108.0, 73.9, 71.3, 65.3, 45.5, 33.8.

(8-(4-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzenesulfonate (compound d ) :

Molecular formula: C ₂₁ H ₂₂ ClNO ₆ S; Yield: 72 %; Pale yellow oil; ESI-MS: 452[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3445, 2932, 2369, 1734, 1636, 1558, 1506, 1437, 1362, 1269, 1188, 1070, 978, 833, 756, 689, 588; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 7.88 (d, 2H, J =7.0Hz), 7.76 (s, 1H), 7.66 (s, 2H), 7.45 (d, 2H, J =8.0Hz, Ph-H), 7.38-7.40 (m, 2H, Ph-H) , 4.29 (s, 1H), 4.12-4.15 (dd, 1H, J ₁ =11.0 Hz, J ₂ =9.5 Hz), 3.94-3.97 (br, m, 2H), 3.66 (s, 1H), 3.52-3.54 (br, m, 2H), 3.23 (s, 2H), 1.49-1.61 (br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 168.7, 139.1, 136.3, 134.2, 133.9, 130.9, 130.3, 129.9, 128.2, 127.1, 125.8, 108.4, 73.3, 71.2, 65.2, 45.6, 34.8.

(8-(4-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate (compound e ) :

Molecular formula: C ₂₂ H ₂₄ ClNO ₆ S; Yield: 76 %; Pale yellow oil; ESI-MS: 466[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3445, 2959, 2367, 1636, 1437, 1362, 1250, 1177, 1092, 978, 837, 664, 556; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 7.76 (s, 2H), 7.38-7.47 (m , 6H), 4.28 (s, 1H), 4.09-4.11 (m, 1H), 3.92-3.97 (m, 2H), 3.53-3.65 (br, m, 3H), 3.19-3.25 (m, 2H), 2.36 (br, s, 3H), 1.54-1.61 (br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 168.1, 145.9, 134.5, 132.1, 130.7, 129.3 , 129.0, 128.3, 107.7, 73.1, 70.7, 65.3, 44.3, 35.6, 21.5.

(8-(4-Chlorobenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-benzoate (compound f ):

Molecular formula: C ₂₂ H ₂₂ ClNO ₅ ; Yield: 80 %; Pale yellow oil; ESI-MS: 416[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3447, 2932, 2371, 1719, 1653 , 1558, 1506, 1271, 1092, 920, 714, 669; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 7.90-7.94(br, m, 2H), 7.45 (d, 2H, J =8.0Hz, Ph-H), 7.57-7.63 (br, m, 1H), 7.50-7.52 (br, m, 2H), 7.39 (d, 2H, J =8.5Hz Ph-H), 4.45 (s, 1H), 4.36 (s, 1H), 4.26-4.29 (br, m, 1H), 4.11 (s, 1H), 3.84-3.87 (t, 1H), 3.52-3.69 (br, m, 4H) , 1.63-1.69 (br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 169.8, 166.4, 139.1, 133.5, 132.2, 130.9, 129.7, 128.6, 127.2, 126.9, 125.0, 108.1, 73.9, 71.3, 65.3, 45.5, 33.8.

(8-(2-Chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzoate (compound g ):

Molecular formula: C ₂₁ H ₂₁ ClN ₂ O ₅ ; Yield: 78 %; Pale yellow oil; ESI-MS: 417[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3450, 2392, 2369, 1717 , 1652, 1558, 1506, 1456, 1271, 1098, 1025, 922, 712, 669; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 8.42-8.44 (m, 1H, Pyridine -H), 7.86-7.97 (br, m, 3H), 7.44-7.65 (br, m, 4H), 4.29-4.49 (br, m, 3H), 4.09-4.15 (m, 1H), 3.83-3.88 ( m, 3H), 3.15-3.19 (m, 2H), 1.61-1.78 (br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 166.1, 164.5, 150.7 , 137.9, 134.0, 129.8, 129.7, 129.7, 129.4, 129.3, 129.1, 124.0, 107.9, 73.9, 65.9, 65.3, 65.1, 44.9, 36.1, 33.4.

(8-(2-Chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate (compound h ):

Molecular formula: C ₂₂ H ₂₃ ClN ₂ O ₅ ; Yield: 76 %; Pale yellow oil; ESI-MS: 431[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3445, 2932, 2367, 1734 , 1635, 1558, 1456, 1396, 1269, 1130, 1067, 922, 702; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 8.42-8.47 (m, 1H, Pyridine-H ), 7.87-7.91 (m, 1H), 7.08-7.52 (br, m, 6H), 3.98-4.32 (br, m, 4H), 3.60-3.75 (br, m, 5H), 3.05-3.15 (m, 2H),1.48-1.70(br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 171.5, 164.9, 150.7, 137.9, 132.7, 129.9, 129.2, 129.1 , 128.9, 128.8, 127.3, 124.1, 108.4, 73.8, 65.3, 64.1, 45.4, 34.4.

(8-(2-methoxybenzoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate ( Compound i ) :

Molecular formula: C ₂₃ H ₂₇ NO ₇ S; Yield: 80 %; Pale yellow oil; ESI-MS: 462[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3445, 2932, 2367, 1628, 1558, 1437, 1362, 1244, 1177, 1066, 978, 831, 758, 669, 554; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard):7.71-7.91 (m, 2H) , 7.32-7.49 (m, 3H), 6.91-7.16 (m, 3H), 4.23-4.32 (m, 1H), 3.88-4.12 (m, 3H), 3.49-3.79 (br, m, 6H), 2.94- 3.11 (m, 2H), 2.28-2.34 (d, 3H, CH ₃ -H, J =7.5 Hz), 1.36-1.60 (br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) Δ (PPM): 166.8, 155.4, 145.5, 132.6, 130.8, 130.7, 130.6, 128.2, 126.2, 121.2, 111.8, 108.3, 71.1, 65.2, 55.9, 44.7, 36.2, 21.6, 14.6.

(8-(3-Chloronicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 4-methylbenzenesulfonate (compound j ) :

Molecular formula: C ₂₁ H ₂₃ ClN ₂ O ₆ S; Yield: 79 %; Pale yellow oil; ESI-MS: 467[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3422, 2959, 2367, 1707, 1638, 1541, 1439, 1364, 1264, 1177, 1094, 978, 816, 664, 554; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 8.45 (q, 1H, Pyridine-H), 7.76 (q, 2H), 7.55(d, 1H, J =6.5 Hz), 7.41-7.48 (m, 3H), 4.28-4.30 (m, 1H), 4.09-4.12 (m, 1H) , 3.89-4.02 (m, 2H), 3.55-3.68 (m, 3H), 3.16-3.17 (m, 2H), 2.35 (d, 3H, CH ₃ -H, J =10.0 Hz), 1.56-1.64 (br , m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 165.7, 151.2, 151.0, 147.8, 145.4, 132.6, 130.7, 128.2, 122.1, 121.0, 108.3, 73.4, 71.0, 65.3, 45.3, 34.1, 21.6.

(8-(6-Chloro-nicotinoyl)-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl 2-phenylacetate (compound k):

Molecular formula: C ₂₂ H ₂₃ ClN ₂ O ₅ ; Yield: 74 %; Pale yellow oil; ESI-MS: 431[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3445, 2932, 2369, 1734 , 1636, 1506, 1437, 1362, 1252, 1105, 1026, 920, 841, 756, 702; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 8.43(s, 1H), 7.88(d, 1H, J =7.5 Hz), 7.55-7.61(m, 1H), 7.24-7.32(m, 5H, Ph-H), 4.29(s, 1H), 4.13-4.15(m, 2H), 4.03(br, s, 1H), 3.52-3.67(m, 5H), 3.19-3.23(m, 2H), 1.55-1.67(br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz , DMSO) δ (ppm): 171.4, 166.5, 151.6, 148.5, 138.8, 134.8, 131.9, 129.8, 128.8, 124.8, 107.9, 73.8, 65.3, 64.4, 56.3, 45.6, 34.4.

(8-(3-Chloro-1-(3-chloropyridine-2-alkyl)-1H-pyrazole-5-carbonyl)-1,4-dioxo-8-azaspiro[4,5]decane Alk-2-alkyl)methyl 4-(trifluoromethyl)benzenesulfonate (compound 1):

Molecular formula: C ₂₄ H ₂₁ Cl ₂ F ₃ N ₄ O ₆ S; Yield: 70 %; Pale yellow oil; ESI-MS: 622[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3445, 2932, 2365, 1734, 1653, 1636, 1558, 1456, 1342, 1124, 1063, 889, 669; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 8.41(d, J = 4.0Hz, 1H, pyridine-H), 8.20(d, J =8.1Hz, 2H, Ph-H), 8.05(s, 2H, Ph-H), 7.90(d, J =8.0Hz, 2H, Ph- H), 7.56-7.58(q, 1H, Ph-H), 6.92(s, 1H, paraazole-H), 4.33(s, 1H), 4.24-4.26(m,1H), 4.09(q,2H), 3.69(q, 1H), 3.41-3.50(br, m, 3H), 1.52-1.60(br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 158.8 , 147.6, 147.4, 138.9, 139.5, 134.5, 129.2, 127.5, 126.9, 125.3, 124.4, 115.5, 108.2, 107.3, 73.4, 72.1, 65.2, 60.3, 45.5, 34.

(8-(3-Chloro-1-(3-chloropyridine-2-alkyl)-1H-pyrazole-5-carbonyl)-1,4-dioxo-8-azaspiro[4,5]decane Alk-2-alkyl) toluenesulfonate (compound m):

Molecular formula: C ₂₃ H ₂₂ Cl ₂ N ₄ O ₆ S; Yield: 74 %; Pale yellow oil; ESI-MS: 554[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3447, 2916, 2372, 1734, 1653, 1558, 1548, 1458, 1188, 1086, 889, 669; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 8.41(d, J =4.0Hz, 1H , pyridine-H), 8.20(s, 1H, Ph-H), 7.90(d, J =8.0Hz, 2H, Ph-H), 7.68-7.80(m, 4H, Ph-H), 6.95(d, 1H, J =5.0Hz paraazole-H), 4.33(s, 1H), 4.14-4.20(m, 1H), 3.97(q,2H), 3.69(s, 1H), 3.41-3.50 (br, m, 4H ), 1.45-1.62 (br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 158.7, 147.6, 147.4, 141.1, 140.1, 134.9, 130.3, 127.5, 126.9 , 126.6, 125.3, 115.5, 108.1, 107.5, 73.4, 71.3, 65.3, 45.5, 34.7.

(8-(2,6-dichlorobenzoyl-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methylbenzoate (compound n):

Molecular formula: C ₂₂ H ₂₁ Cl ₂ NO ₅ ; Yield: 75 %; Pale yellow oil; ESI-MS: 450[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3447, 2937, 2367, 1765 , 1635, 1420, 1362, 1234, 1070, 1015, 976, 787, 710; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 7.91-7.95(m, 2H), 7.60- 7.64(m, 1H), 7.39-7.50(m, 5H), 4.31-4.48(m, 2H), 4.26-4.29(m, 1H), 4.11-4.16(m, 1H), 3.85-3.88(m, 1H ), 3.74-3.78(m, 1H), 3.56-3.63(m, 1H), 3.15(s, 1H), 1.64-1.73(br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz , DMSO) δ (ppm): 166.1, 162.8, 135.2, 134.0, 133.3, 131.8, 131.1, 130.0, 129.8, 129.1, 128.9, 107.4, 74.0, 66.0, 65.1, 44.4, 35.7.

(8-Benzoyl-1,4-dioxo-8-azaspiro[4,5]decane-2-alkyl)methyl methanesulfonate (compound o):

Molecular formula: C ₁₆ H ₂₁ NO ₆ S; Yield: 79 %; Pale yellow oil; ESI-MS: 356[M+H] ⁺ ; IR (KBr, cm ^-1 ) v : 3446, 2932, 2369, 1734, 1645, 1506, 1423, 1354, 1269, 1175, 1090, 964, 833, 710, 669, 527; ¹ H NMR (500 MHz, DMSO) δ (ppm) (TMS as internal standard): 7.39-7.41(m, 5H, Ph-H), 4.39(s, 1H), 4.25-4.27(m, 1H), 4.04(d, 3H, J =8.0 Hz), 3.30(s, 2H), 3.16(s, 3H, _CH3 -H), 1.54-1.67(br, m, 4H, N-Spiro-H); ¹³ C NMR (125 MHz, DMSO) δ (ppm): 169.7, 136.5, 130.0, 128.9, 127.2, 108.5, 73.6, 70.5 , 65.4, 45.3, 37.8, 34.3.

Embodiment 16 : medicine supply is to the inhibitory activity test test method of cucumber gray mold pathogenic bacteria and Pinellia solani blight pathogenic bacteria

(1) Test method

The antibacterial activity of the compounds was determined by the in vitro growth rate method (Tarun, K. C.; et al., 2006). Heat potato dextrose agar medium (PDA medium: 200 g potato, 20 g agar, 20 g glucose, 1000 mL distilled water) to a molten state (40~60?С), and 10 mL of liquid medicine (10 times the final concentration liquid) into 90 mL of PDA medium, shake well, pour evenly into a petri dish with a diameter of 9 cm, place it horizontally, and wait for it to cool and solidify. Use a puncher to punch out a 4 mm diameter bacterial disk at the edge of the fresh pathogen colony that has been cultured for 4 days, place the bacterial disk upside down in the center of the PDA plate containing the drug, and then place it in a 27??С constant temperature and humidity incubator for upside-down cultivation , when the blank control colony grew to nearly two-thirds of the plate, the observation was started, and the diameter of the colony was measured by the cross method, and the average value was taken (Song Suqin, et al., 2004). The blank control was not treated with drugs, but contained the same concentration of solvent and 0.1% Tween 20, and each treatment was repeated three times. The inhibitory rate of agents to mycelial growth was calculated by the following formula (Fang Zhongda. 1987; Pandey D. K. et, al . 1982):

Calculation of inhibition rate: I(%)=(C-T)/(C-0.4)×100%

Wherein I is the inhibition rate, C is the diameter of the blank control (cm), and T is the diameter of the treatment (cm).

(2) Test results

After testing, the inhibitory rates of compounds b, e, h, j and k to cucumber pathogenic bacteria at a concentration of 50 ? Inhibition of Cucumber Botrytis Pathogen Activity

Table 1 Inhibitory activity of compounds a - o against Botrytis cinerea and Pinellia solani

The embodiment of the present invention is supplemented to illustrate the technical solution of the present invention, but the content of the embodiment is not limited thereto.

Claims (3)

1. Specific compounds a to o, as follows: (I) . 2. the application of the compound described in claim 1 in the preparation of anti-phytopathogenic bacterium medicine, and described phytopathogenic bacterium is Botrytis cinerea and Pinellia solani. 3. The preparation method of the described compound of claim 1, is characterized in that: take piperidone hydrochloride, glycerol as raw material, obtain intermediate 1,4-dioxo-8-azaspiro through hydroxyketone condensation reaction [4,5] decane-2-alkylmethanol, and then condense with different acids to obtain spirocyclic alcohols containing amide structures, and then react with acid chlorides or sulfonyl chlorides to obtain the target product. The synthetic route is: In the reaction formula, the definitions of R ₁ and R ₂ are the same as those in formula (I) in claim 1.