CN102796111B - Carboxylate (sulfonate) compounds with oxoaza-spiro-amido group, and preparation method and application thereof - Google Patents
Carboxylate (sulfonate) compounds with oxoaza-spiro-amido group, and preparation method and application thereof Download PDFInfo
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- CN102796111B CN102796111B CN201210332306.8A CN201210332306A CN102796111B CN 102796111 B CN102796111 B CN 102796111B CN 201210332306 A CN201210332306 A CN 201210332306A CN 102796111 B CN102796111 B CN 102796111B
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Abstract
The invention discloses carboxylate (sulfonate) compounds with oxoaza-spiro-amido group, and a synthesis method and application thereof. The structure of the compounds is disclosed as the following general formula (I). The method comprises the following steps: by using piperidone hydrochloride, glycerol, aromatic acid, substituted aromatic acid, nitrogenous heterocyclic acid, substituted pyrazole acid, acyl chloride and sulfonyl chloride as raw materials, carrying out hydroxy-ketone condensation reaction to obtain an intermediate 1,4-dioxy-8-azaspiro-[4,5]decane-2-alkylmethanol, condensing with different acids to obtain spiro-alcohols containing amide structure, and reacting with acyl chloride and sulfonyl chloride to obtain the target product. The compounds have favorable anti-phytopathogen activity. The general formula (I) is shown in the specification.
Description
Technical field
The present invention relates to have carboxylic (sulphur) acid esters compound and the preparation method of the oxygen azaspiro amide group of anti-phytopathogen effect.
Background technology
Assorted spirocyclic compound has the biological activity of wide spectrum, can be in agricultural chemicals and medical research, because organic assorted volution compound has that spiral shell is gripped altogether, spiral shell is super grips altogether or the superiority of the structure that the general organic compound such as different effect does not possess, synthetic and the bioactive research of assorted volution compound has caused the great interest of people, and has successfully developed multiple assorted volution class pesticide species.Assorted volution compound also more and more causes chemists' interest in the research aspect medical simultaneously.Containing oxygen, the assorted spirocyclic compound of nitrogen class, as a member in organic assorted volution system, be that a class has extensive bioactive material.Aspect agricultural, there is anti-agricultural fungi, desinsection isoreactivity; 2010, Isosorbide-5-Nitrae-dioxa-8-azaspiro [4,5] decane compound of synthetic a series of replacements such as Deshpande, to this series compound to Rhizoctonia solani Kuhn (
r.solani), blight (
f.oxysporum), rotten mildew (
p.aphanidermatum), rice blast (
d.oryzae) etc. have certain activity (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, aspect medical, assorted volution class and derivative thereof have anti-inflammatory analgesic, antitumor, anticonvulsion isoreactivity (Jacques, R., Didler, P., Francois, B., et al. Dissym-metric acid Isosorbide-5-Nitrae-dihydropyridine-3,5-dicarboxylic, precedes preparation, utilization and therapeutic use[P]. EP0240398A1,1991-05-15.).Wherein to some bacterium streptococcus faecium (
streptococcus faecalis), subtilis (
bacillus subtilis), colon bacillus (
escherichia coli), Pseudomonas aeruginosa (
pseudomonas aeruginosa) and Cray Bai Shi pulmonitis strain (
klebsiella pneumoniae) there is good activity, it is found that in some natural product also to there is good insecticidal activity containing organic spirane structure.Follow-up have in a large number about the research report of the organic assorted spirocyclic compound of activity, and it can be used as sterilant, sterilant, weedicide, plant-growth regulator etc.The assorted Spirocyclic derivatives of using as agricultural chemicals, because it has that toxicity is low, Effictive nuisancelless, easily by the biology features such as utilization, raw material sources are extensive of all degrading, it has become the focus of agricultural chemicals, field of medicaments research.
2000, Thinagar etc. turned out the crystalline structure of compound 1 spiral shell [2-benzoyl-ring-cyclohexyl-4,5-Diphenyl Pyrrole alkyl-3,3 '-chromanone], pointed out that 3-phenyl-chromanone is the base unit of isoflavones.And isoflavonoid is a large amount of existence in leguminous plants, it is carried out to fungicidal activity test, result shows resistance (the Thinagar S of bacterium and fungi, 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).
2004, Balasubramanian etc. synthesized novel spiroperidol thiadiazole compound, and it is carried out to germ resistance active testing, result show and this compounds to streptococcus faecium (
streptococcus faecalis), subtilis (
bacillus subtilis), colon bacillus (
escherichia coli), Pseudomonas aeruginosa (
pseudomonas aeruginosa) and Cray Bai Shi pulmonitis strain (
klebsiella pneumoniae) there is 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.).
2008, Srinivas etc. synthesized the spirane structure compound of a kind of novel nitrogen-containing and sulphur, and it is carried out to antibacterium, antimycotic biological activity test.Result shows, find part of compounds for Klebsiella pneumonia (
k. pneumoniae) and will he formula bacillus (
shigella dysentriae) have height germ resistance; Antimycotic aspect to black-koji mould (
aspergillus niger), Candida albicans (
candida albicans), Aspergillus flavus (
aspergillus flavus) and rhizopus oryzae (
rhizopus oryzae) active significantly (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.).
Mulwad in 2008, V.V. wait synthetic a series of containing tonka bean camphor base spiral shell indole ketone compound, and this compounds is carried out to bacteriostatic activity test, discovery is under the condition of 100ppm, compound bacteriostatic activity with spirane structure is better than the compound without spirane structure unit, to streptococcus aureus (
staphylococcus aureus), subtilis (
bacillus subtilis) inhibiting rate reaches 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.).
2011, Rachid. B etc. is with 1,3-Dipolar Cycloaddition is synthesized a series of anti-inflammatories that have, nitrogenous and the sulphur spirocyclic compound of antibacterial and anti-convulsant activity, this compounds be take indoles as core introducing isoxzzole, 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.).
A synthetic class heteroatoms spirocyclic compound of Bayer Bitterfeld GmbH exploitation in 2004 reaches 100% to the lethality rate of black peach aphid when concentration 500 g/ha, and, meadow greedy noctuid etc. chrysomelid to horseradish ape has good preventive 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?pesticide
s[P].?DE102004013528
.?2004-3-19.)。
1998, Wu Yulin etc. have synthesized some derivatives of antifeedant for insect, this compounds belongs to assorted spirane structure, its typical representative is Spiro Enol Ether Analogues, and the overwhelming majority has antifeedant activity, wherein to the food refusal rate of large white butterfly up to 100% (Wu Yulin, Gaoyang, Xu Hanhong. a kind of preparation method and its usage of Garland chrysanthemum extract compounds. China, CN1178633,1998-04-15.).
From background technology, containing the compound of oxygen, azaspiro structure, there is biological activity widely, and in anti-phytopathogen field, can be used as lead compound and develop and obtained certain theoretical basis.Simultaneously about carboxylic (sulphur) the esters of gallic acid compounds of oxygen, azaspiro amide group, there is no at present people synthesized.
Summary of the invention
The object of the invention is carboxylic (sulphur) acid esters compound containing oxygen, azaspiro amide group of the synthetic a series of novel structures of design, it is parent that this compounds be take oxygen, azaspiro cyclic alcohol, by structural modification, a series of oxygen, azaspiro derivatives have been synthesized, by anti-phytopathogen active testing, show, its derivative suppresses better the activity of botrytis cinerea pers.The carboxylic of oxygen, azaspiro amide group (sulphur) esters of gallic acid compounds structure by following general formula (
i) represent:
(
I)
R wherein
1for (1) phenyl or substituted-phenyl; (2) pyridine or substituted pyridinyl; (3) substituted pyrazolecarboxylic base; R
2for (1) benzoyl; (2) phenylacetyl; (3) neighbour,, the monosubstituted or Multi substituted benzenes alkylsulfonyl of contraposition; (4) methyl sulphonyl;
In content of the present invention, R
1middle substituted-phenyl can be on phenyl ring and contains one or more methyl, ethyl, methoxyl group, oxyethyl group, n-propyl, sec.-propyl, trifluoromethyl, nitro, amido and halogen atom, and halogen atom can be fluorine, chlorine, bromine, iodine; Substituted pyridinyl can be on pyridine ring and contains one or more methyl, ethyl, methoxyl group, oxyethyl group, n-propyl, sec.-propyl, nitro, amido and halogen atom, and halogen atom can be fluorine, chlorine, bromine, iodine; Substituted pyrazolecarboxylic base can be 1,3,4 monosubstituted or multi-substituted pyrazol bases; R
2middle substituted benzene alkylsulfonyl can be and on phenyl ring, contains one or more methyl, ethyl, methoxyl group, oxyethyl group, n-propyl, sec.-propyl, trifluoromethyl.
In content of the present invention, it is active that compound has anti-phytopathogen, particularly to botrytis cinerea pers, has good inhibition active, and purposes is the application in the anti-phytopathogen medicine of preparation.The preparation method of general formula of the present invention (I) compound is take piperidone hydrochloride, glycerine, aromatic acid and substituted aroma acid, nitrogen-containing hetero naphthenic acid, substituted pyrazolecarboxylic acid, acyl chlorides and SULPHURYL CHLORIDE as raw material, through two step condensation reactions and the synthetic target product of step substitution reaction three steps, its synthetic route is as follows:
In reaction formula, R
1, R
2definition identical with the definition in claim 1 formula (I); Tolune is toluene; EDCHCl is 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride; HOBt is 1-hydroxyl-benzo-triazole; Acyl Chloride is acyl chlorides; Sulfuryl Chloride is SULPHURYL CHLORIDE; Et
3n is triethylamine; DCM is methylene dichloride.
The first step: Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl methyl alcohol
Take piperidone hydrochloride and be placed in three neck round-bottomed flasks, add toluene, then add glycerol, in temperature, from 25 ℃, rise to the process of 75 ℃ and slowly add, then take p-methyl benzenesulfonic acid and add above-mentioned system, be warming up to 115 ℃ and make its backflow, (attention device is wanted dutiful hydrophone), react 24 h, use successively intermediate water, saturated sodium bicarbonate, saturated aqueous common salt washing system, discard organic layer, remove moisture under reduced pressure, then use washing with alcohol oily matter, screw out ethanol, obtain faint yellow oily matter; Every 1.35 g piperidone hydrochlorides are put and are added toluene 30 mL, glycerol 1.10 g, p-methyl benzenesulfonic acid 0.17 g;
Second step: the volution alcohol of amide containing structure
In reaction flask, add acid compounds, with methylene dichloride, dissolve stirring and evenly mixing, then under condition of ice bath, add EDCHCl and the HOBt of 1.2 times of corresponding sour molar weights, stir 2 h, add with 1 of methylene dichloride dissolving, 4-dioxy-8-azaspiro [4,5] decane-2-alkyl methyl alcohol, 1,4-dioxy-8-azaspiro [4,5] decane-2-alkyl methanol usage and the corresponding acid molar weight that feeds intake equates, will react at room temperature and react, until complete (the developping agent V of TLC plate detection reaction
sherwood oil: V
ethyl acetate=1:1), stopped reaction after 10 ~ 12 h, uses 20 mL * 2 intermediate waters successively, and 20 mL * 2 saturated common salt washings, discard water layer, anhydrous magnesium sulfate drying, and decompression steams solvent and obtains faint yellow oily matter.
The 3rd step: contain the preparation of carboxylic (sulphur) the esters of gallic acid derivative of oxygen, azaspiro amide group
In reaction flask, add second step product, methylene dichloride dissolves stirring and evenly mixing, add the triethylamine of 2 times of molar weights to stir 15 min, then under condition of ice bath, slowly add replacement SULPHURYL CHLORIDE and the acyl chlorides of 1.2 times of corresponding the first step product molar weights, to react at room temperature reaction, until complete (the developping agent V of TLC plate detection reaction
sherwood oil: V
ethyl acetate=1:2), stopped reaction after 3 ~ 5 h, uses 20 mL * 2 saturated sodium bicarbonates successively, 20 mL * 2 intermediate waters, and 20 mL * 2 saturated common salt washings, discard water layer, and anhydrous magnesium sulfate drying, obtains target product by thin-layer chromatography chromatographic separation.
This step is applicable to carboxylic (sulphur) esters of gallic acid compounds synthetic of all above-mentioned target compound oxygen, azaspiro amide group.
As follows according to invention route and the synthetic compound of preparation method:
Compound
a:
(8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) toluene sulfonic acide ester
Compound
b:
(8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-toluene sulfonic acide ester
Compound
c:
(8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-phenylacetate
Compound
d:
(8-(4-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) toluene sulfonic acide ester
Compound
e:
(8-(4-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-toluene sulfonic acide ester
Compound
f:
(8-(4-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-benzoic ether
Compound
g:
(8-(2-chloronicotinoyl base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl benzoic acid ester
Compound
h:
(8-(2-chloronicotinoyl base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-phenylacetate
Compound
i:
(8-(2-anisoyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-toluene sulfonic acide ester
Compound
j:
(8-(3-chloronicotinoyl base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-toluene sulfonic acide ester
Compound k:
(8-(the chloro-nicotinoyl of 6-)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-phenylacetate
Compound
l:
(8-(the chloro-1-of 3-(3-chloropyridine-2-alkyl)-1H-pyrazoles-5-carbonyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-(trifluoromethyl) benzene sulfonate
Compound
m:
(8-(the chloro-1-of 3-(3-chloropyridine-2-alkyl)-1H-pyrazoles-5-carbonyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) toluene sulfonic acide ester
Compound
n:
(8-(2,6-dichloro-benzoyl base-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl benzoic acid ester
Compound
o:
(8-benzoyl-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methylmethanesulfonate ester
Embodiment
Embodiment mono-
(8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is toluene sulfonic acide ester
a) synthetic:
The first step: synthetic Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl methyl alcohol
Take 1.35 g piperidone hydrochlorides and be placed in 50 mL tri-neck round-bottomed flasks, add 30 mL toluene, then take the glycerol of 1.10 g, in temperature, from 25 ℃, rise to the process of 75 ℃ and slowly add, the p-methyl benzenesulfonic acid that takes again 0.17 g adds above-mentioned system, be warming up to 115 ℃ and make its backflow, (attention device is wanted dutiful hydrophone), react 24 h, use successively intermediate water, saturated sodium bicarbonate, saturated aqueous common salt washing system, discard organic layer, remove moisture under reduced pressure, then use washing with alcohol oily matter, screw out ethanol, obtain faint yellow oily matter.
Second step: synthetic (3-chloro-phenyl-) (2-hydroxymethyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-8-alkyl) ketone
The 3-chloro-benzoic acid that adds 0.16 g in the there-necked flask of 50 mL, with 25 mL methylene dichloride, dissolve stirring and evenly mixing, then under condition of ice bath, add the EDCHCl of 0.23 g and the HOBt of 0.16 g, stir 2 h, add Isosorbide-5-Nitrae-dioxy-8-azaspiro [4, the 5] decane-2-alkyl methyl alcohol dissolving with methylene dichloride, to react at room temperature reaction, until complete (the developping agent V of TLC plate detection reaction
sherwood oil: V
ethyl acetate=1: 1), stopped reaction after 10 ~ 12 h, use successively 20 mL * 2 intermediate waters, 20 mL * 2 saturated common salt washings, discard water layer, anhydrous magnesium sulfate drying, decompression steams solvent and obtains (3-chloro-phenyl-) (2-hydroxymethyl)-1,4-dioxy-8-azaspiro [4,5] decane-8-alkyl) ketone.
The 3rd step: synthetic (8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) toluene sulfonic acide ester
In the there-necked flask of 50 mL, add 0.31 g (3-chloro-phenyl-) (2-hydroxymethyl)-1,4-dioxy-8-azaspiro [4,5] decane-8-alkyl) ketone, with 30 mL methylene dichloride, dissolve stirring and evenly mixing, add the triethylamine of 0.20 g to stir 15 min, under condition of ice bath, slowly add the benzene sulfonyl chloride of 0.21 g will react at room temperature reaction, until complete (the developping agent V of TLC plate detection reaction
sherwood oil: V
ethyl acetate=1: 2), stopped reaction after 3 ~ 5 h, uses 20 mL * 2 saturated sodium bicarbonates successively, 20 mL * 2 intermediate waters, 20 mL * 2 saturated common salt washings, discard water layer, and anhydrous magnesium sulfate drying, obtains target compound by thin-layer chromatography chromatographic purification, productive rate 78 %.
Embodiment bis-
(8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl 4-toluene sulfonic acide ester
b) preparation:
As the method for embodiment mono-and condition preparation.The first step and second step are with embodiment mono-, and difference is that the 3rd step adds the p-methyl benzene sulfonic chloride of 0.23 g, and target product productive rate is 76 %.
Embodiment tri-
(8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl 2-phenylacetate
c) preparation:
As the method for embodiment mono-and condition preparation.The first step and second step are with embodiment mono-, and difference is that the 3rd step adds the phenyllacetyl chloride of 0.19 g, and target product productive rate is 79 %.
Embodiment tetra-
(8-(4-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is toluene sulfonic acide ester
d) preparation:
As the method for embodiment mono-and condition preparation.The first step and the 3rd step are with embodiment mono-, and difference is that second step adds the 4-chloro-benzoic acid of 0.16 g, and target product productive rate is 72 %.
Embodiment five
(8-(4-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl 4-toluene sulfonic acide ester
e) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the 4-chloro-benzoic acid of 0.16 g and the p-methyl benzene sulfonic chloride that the 3rd step adds 0.23 g, and target product productive rate is 76 %.
Embodiment six
(8-(4-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl 2-benzoic ether
f) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the 4-chloro-benzoic acid of 0.16 g and the Benzoyl chloride that the 3rd step adds 0.17 g, and target product productive rate is 80 %.
Embodiment seven
(8-(2-chloronicotinoyl base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl benzoic acid ester
g) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the 2-chlorine apellagrin of 0.16 g and the Benzoyl chloride that the 3rd step adds 0.17 g, and target product productive rate is 78 %.
Embodiment eight
(8-(2-chloronicotinoyl base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-phenylacetate, (compound number is faint yellow oily matter
h) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the 2-chlorine apellagrin of 0.16 g and the phenyllacetyl chloride that the 3rd step adds 0.19 g, and target product productive rate is 76 %.
Embodiment nine
(8-(2-anisoyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl 4-toluene sulfonic acide ester
i) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the O-Anisic Acid of 0.15 g and the p-methyl benzene sulfonic chloride that the 3rd step adds 0.23 g, and target product productive rate is 80 %.
Embodiment ten
(8-(3-chloronicotinoyl base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl 4-toluene sulfonic acide ester
j) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the 3-chlorine apellagrin of 0.16 g and the p-methyl benzene sulfonic chloride that the 3rd step adds 0.23 g, and target product productive rate is 79 %.
Embodiment 11
(8-(the chloro-nicotinoyl of 6-)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl 2-phenylacetate
k) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the 6-chlorine apellagrin of 0.16 g and the phenyllacetyl chloride that the 3rd step adds 0.19 g, and target product productive rate is 74 %.
Embodiment 12
(8-(the chloro-1-of 3-(3-chloropyridine-2-alkyl)-1H-pyrazoles-5-carbonyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methyl 4-(trifluoromethyl) benzene sulfonate
l) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the chloro-1-of 3-(3-chloropyridine-2-alkyl)-1 of 0.26 g
h-pyrazoles-5-carbonylic acid and the 3rd step add 0.29 g to trifluoromethyl benzene sulfonyl chloride, target product productive rate is 70 %.
Embodiment 13
(8-(the chloro-1-of 3-(3-chloropyridine-2-alkyl)-1H-pyrazoles-5-carbonyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is toluene sulfonic acide ester
m) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the chloro-1-of 3-(3-chloropyridine-2-alkyl)-1 of 0.26 g
h-pyrazoles-5-carbonylic acid and the 3rd step add the benzene sulfonyl chloride of 0.21 g, and target product productive rate is 74 %.
Embodiment 14
((compound number is methyl benzoic acid ester 8-(2,6-dichloro-benzoyl base-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl)
n) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds 2 of 0.19 g, and 6-dichlorobenzoic acid and the 3rd step add the Benzoyl chloride of 0.17 g, and target product productive rate is 75%.
Embodiment 15
(8-benzoyl-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) (compound number is methylmethanesulfonate ester
o) preparation:
As the method for embodiment mono-and condition preparation.The first step is with embodiment mono-, and difference is that second step adds the phenylformic acid of 0.12 g and the methylsulfonyl chloride that the 3rd step adds 0.14 g, and target product productive rate is 79%.
Adopt above-mentioned similar approach can prepare other compound equally.
The structure of gained compound is as shown in the table:
(
I)
Under the spectral data institute of synthetic part containing oxygen, nitrogen amide derivatives:
(8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) toluene sulfonic acide ester
(compound
a)
:
Molecular formula: C
21h
22clNO
6s; Productive rate: 78 %; Yellow oily; 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;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c NMR (125 MHz, DMSO)
δ(ppm): 167.9,138.6,135.6,134.9,133.7,130.9,130.4,129.8,128.1,127.1,125.7,108.3,73.3,71.2,65.1,45.6,35.6.
(8-(3-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-toluene sulfonic acide ester (compound
b):
Molecular formula: C
22h
24clNO
6s; Productive rate: 76 %; Yellow oily; 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;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-phenylacetate (compound
c)
:
Molecular formula: C
23h
24clNO
5; Productive rate: 79 %; Faint yellow oily; ESI-MS:430[M+H]
+; IR (KBr, cm
-1)
v: 3449,2957,2371,1734,1636,1437,1248,1130,1066,930,741,696;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) toluene sulfonic acide ester (compound
d)
:
Molecular formula: C
21h
22clNO
6s; Productive rate: 72 %; Faint yellow oily; 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;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-toluene sulfonic acide ester (compound
e)
:
Molecular formula: C
22h
24clNO
6s; Productive rate: 76 %; Faint yellow oily; ESI-MS:466[M+H]
+; IR (KBr, cm
-1)
v: 3445,2959,2367,1636,1437,1362,1250,1177,1092,978,837,664,556;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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-chlorobenzene formacyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-benzoic ether (compound
f):
Molecular formula: C
22h
22clNO
5; Productive rate: 80 %; Faint yellow oily; ESI-MS:416[M+H]
+; IR (KBr, cm
-1)
v: 3447,2932,2371,1719,1653,1558,1506,1271,1092,920,714,669;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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 base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl benzoic acid ester (compound
g):
Molecular formula: C
21h
21clN
2o
5; Productive rate: 78 %; Faint yellow oily; ESI-MS:417[M+H]
+; IR (KBr, cm
-1)
v: 3450,2392,2369,1717,1652,1558,1506,1456,1271,1098,1025,922,712,669;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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 base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-phenylacetate (compound
h):
Molecular formula: C
22h
23clN
2o
5; Productive rate: 76 %; Faint yellow oily; ESI-MS:431[M+H]
+; IR (KBr, cm
-1)
v: 3445,2932,2367,1734,1635,1558,1456,1396,1269,1130,1067,922,702;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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), 1.48-1.7 0 (br, m, 4H, N-Spiro-H);
13c 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-anisoyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-toluene sulfonic acide ester (compound
i)
:
Molecular formula: C
23h
27nO
7s; Productive rate: 80 %; Faint yellow oily; 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;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c NMR (125 MHz, DMSO)
δ(ppm): 166.8,155.4,145.5,132.6,130.8,130.7,130.6,128.2,126.2,121.2,111.8,108.3,73.3,71.1,65.2,60.3,55.9,44.7,36.2,21.6,14.6.
(8-(3-chloronicotinoyl base)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-toluene sulfonic acide ester (compound
j):
Molecular formula: C
21h
23clN
2o
6s; Productive rate: 79 %; Faint yellow oily; 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;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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-(the chloro-nicotinoyl of 6-)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 2-phenylacetate (compound k):
Molecular formula: C
22h
23clN
2o
5; Productive rate: 74 %; Faint yellow oily; 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;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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-(the chloro-1-of 3-(3-chloropyridine-2-alkyl)-1H-pyrazoles-5-carbonyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl 4-(trifluoromethyl) benzene sulfonate (compound l):
Molecular formula: C
24h
21cl
2f
3n
4o
6s; Productive rate: 70 %; Faint yellow oily; ESI-MS:622[M+H]
+; IR (KBr, cm
-1)
v: 3445,2932,2365,1734,1653,1636,1558,1456,1342,1124,1063,889,669;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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, parazole-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);
13c NMR (125 MHz, DMSO)
δ(ppm): 158.8,147.6,147.4,138.9,139.5,134.5,129.2,127.5,126.9,125.3,124.4,115.5,108.2,107.3,73.4,72.1,65.2,60.3,45.5,34.7.
(8-(the chloro-1-of 3-(3-chloropyridine-2-alkyl)-1H-pyrazoles-5-carbonyl)-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) toluene sulfonic acide ester (compound m):
Molecular formula: C
23h
22cl
2n
4o
6s; Productive rate: 74 %; Faint yellow oily; ESI-MS:554[M+H]
+; IR (KBr, cm
-1)
v: 3447,2916,2372,1734,1653,1558,1548,1458,1188,1086,889,669;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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 parazole-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);
13c 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-dichloro-benzoyl base-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methyl benzoic acid ester (compound n):
Molecular formula: C
22h
21cl
2nO
5; Productive rate: 75 %; Faint yellow oily; ESI-MS:450[M+H]
+; IR (KBr, cm
-1)
v: 3447,2937,2367,1765,1635,1420,1362,1234,1070,1015,976,787,710;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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);
13c 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-Isosorbide-5-Nitrae-dioxy-8-azaspiro [4,5] decane-2-alkyl) methylmethanesulfonate ester (compound o):
Molecular formula: C
16h
21nO
6s; Productive rate: 79 %; Faint yellow oily; 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;
1h NMR (500 MHz, DMSO)
δ(ppm) (TMS marks in doing): 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, CH
3-H), 1.54-1.67 (br, m, 4H, N-Spiro-H);
13c 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
:inhibition activity test test method for medicine to the former bacterium of gray mold of cucumber and the former bacterium of tuber of pinellia damping-off
(1) test method
Adopt isolated growth rate method (Tarun, K. C.; Et al., 2006) measure the bacteriostatic activity of compound.Heating potato dextrose agar (PDA substratum: potato 200 g, agar 20 g, glucose 20 g, distilled water 1000 mL) is to dissolving state (40 ~ 60 С), 10 mL liquids (liquids of 10 times of final concentrations) are poured in 90 mL PDA substratum, fully shake up, evenly pour in the culture dish of diameter 9 cm, horizontal positioned, to be cooled solidifying.At the fresh pathogenic bacteria colony edge of cultivating 4 d, with punch tool, play the bacterium dish that cut-off footpath is 4 mm, bacterium dish is inverted in to the dull and stereotyped central authorities containing medicament PDA, then be placed in 27 С fixed temperature and humidity incubators and be inverted cultivation, until blank colony growth, start observation when approaching plate 2/3rds place, right-angled intersection method is measured colony diameter, average (Song Suqin, etc., 2004).Blank is adding medicine not, but the solvent that contains same concentration and 0.1% Tween 20, every processing is in triplicate.By following formula calculate medicament to the inhibiting rate of mycelial growth (Fang Zhongda. 1987; Pandey D. K.
et, al. 1982):
Calculate inhibiting rate: I (%)=(C-T)/(C-0.4) * 100%
Wherein I is inhibiting rate, and C is blank diameter (cm), and T is for processing diameter (cm).
(2) test-results
After tested, compound
b, e, h, j and kin concentration, be 50
?g/mL is respectively 82.16 %, 84.17 %, 92.21 %, 89.98 % and 83.29 % to the inhibiting rate of cucumber pathogenic bacteria, shows the activity of the former bacterium of good inhibition gray mold of cucumber
Table
1compound
a-
oactive to the inhibition of botrytis cinerea pers and tuber of pinellia rhizoctonia solani
The embodiment of the present invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited to this.
Claims (3)
1. particular compound a to o, as follows:
(I)
。
2. the application of compound claimed in claim 1 in the anti-phytopathogen medicine of preparation, described phytopathogen is botrytis cinerea pers and tuber of pinellia rhizoctonia solani.
3. the preparation method of compound described in claim 1, it is characterized in that: take piperidone hydrochloride, glycerol is raw material, through the condensation reaction of hydroxyl ketone, obtain intermediate 1,4-dioxy-8-azaspiro [4,5] decane-2-alkyl methyl alcohol, then carry out from different acid the volution alcohol that condensation obtains amide containing structure, then react and obtain target product with acyl chlorides or SULPHURYL CHLORIDE, its synthetic route is:
In reaction formula, R
1, R
2definition identical with the definition in claim 1 Chinese style (I).
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