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CN102453036B - A kind of camptothecine compounds and preparation method thereof and the purposes in agricultural chemicals - Google Patents

A kind of camptothecine compounds and preparation method thereof and the purposes in agricultural chemicals Download PDF

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CN102453036B
CN102453036B CN201010520770.0A CN201010520770A CN102453036B CN 102453036 B CN102453036 B CN 102453036B CN 201010520770 A CN201010520770 A CN 201010520770A CN 102453036 B CN102453036 B CN 102453036B
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camptothecine
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agricultural chemicals
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CN102453036A (en
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李红玉
代伟
刘映前
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Abstract

The present invention relates to the camptothecine compounds that a class is new, and the preparation method of this compound and the purposes in agricultural chemicals.The preparation method of this compound is by <i>N</iGreatT.Gr eaT.GT-(1 ˊ-oxygen base-2 ˊ, 2 ˊ, 5 ˊ, 5 ˊ-tetramethyl-pyrroles-acid amides)-3 ˊ-<i>L</iGreatT.Gr eaT.GT-amino acid and 5-hydroxyethyl oxygen camptothecine react under proper catalyst and dewatering agent effect, purified separation and get final product.By the desinsection to this compounds, bacteriostasis and herbicides active testing, prove that such Compound Phase has good cytotoxicity for camptothecine and DRF-1042 to Agricultural pests (as Brontispa longissima, prodenia litura), to phytopathogen (as mango anthracnose and mango blossom-end rot) and farmland weed (as lady's-grass, leaf mustard and three-coloured amaranth), there is good restraining effect.

Description

A kind of camptothecine compounds and preparation method thereof and the purposes in agricultural chemicals
Technical field
The present invention relates to a kind of new camptothecine compounds, and the preparation method of this compound and preparing the purposes in agricultural chemicals.Belong to pesticide field.
Background technology
Camptothecine (Camptothecin) be Wall equal 1966 first from the distinctive Nyssaceae plant camptotheca acuminata of China ( camptothecaacuminata) in be separated a kind of quinoline alkaloid of obtaining, its have anticancer, antiviral, desinsection and the multiple biological activity such as antibacterial ( j.Nat.Prod. 2004, 67,129-135).Mainly anti-tumor aspect is laid particular emphasis on both at home and abroad to the research of camptothecine, conduct in-depth research in its chemosynthesis and structural modification, anticancer structure activity relationship, the mechanism of action etc., wherein multiple active compound such as irinotecan, topotecan, 9-aminocamptothecin, 9-nitrocamptothecin, DX-8951f, GG-211 and CKD-602 etc. are gone on the market by FDA approval or are in clinical investigation phase (1. bioorg.Med.Chem. 2004, 12, 1585 – 1604; 2. phytochem. 2004, 65, 2735 – 2749).
In recent years, camptothecine crude extract and simple derivatives be used to prepare sterilant or fungistat ( j.Agric.FoodChem. 2005, 53, 32-37, US20020018762(2002), CN100384329(2005), CN101518250(2009), CN1843128(2006), CN100579372(2006)).But exist when camptothecine crude extract and simple derivatives are used for preparing sterilant or fungistat and be easy to decompose, the lasting period of losing efficacy is short, poorly water-soluble and not easily make the shortcomings such as preparation.
The present invention utilizes principle of hybridization nitroxyl free radical to be passed through l-amino acid connects 5 formation camptothecin esters in camptothecine, the a series of structure of design and synthesis is not easily decomposed, the inefficacy lasting period extends, the new camptothecine compounds of water-soluble raising, also improve medicine agricultural (comprising desinsection, bacteriostasis and herbicides) active simultaneously, and facilitate the preparation of this compounds on pesticide preparation.
Summary of the invention
The invention provides the camptothecine compounds that a class is new.Another object of the present invention provides the preparation method of this kind of new compound and the purposes at pesticide field thereof simultaneously.
Technical scheme of the present invention is that to have agricultural (comprising desinsection, bacteriostasis and herbicides) preferably according to camptothecine active, but it has moderate toxicity, and nitroxyl free radical and l-amino acid has the advantage such as biological activity widely, significantly improving bioactive while, can greatly reduce its toxicity.Therefore, nitroxyl free radical is passed through by the present invention l-amino acid connects 5 formation camptothecin esters in camptothecine, synthesize and a series ofly not easily to decompose, the inefficacy lasting period extends, the camptothecine compounds of water-soluble raising, agricultural (the comprising desinsection, bacteriostasis and herbicides) of improving this compounds active simultaneously, facilitates the preparation of this compounds on pesticide preparation simultaneously.
The object of the invention is to be realized by following measures:
Camptothecine compounds of the present invention refers to have the compound shown in following general formula (I):
（I）
(I) in formula, R is hydrogen, methyl, first sulphur methylene radical, sec.-propyl, butyl, isobutyl-, β-indole methyl or benzyl.
The preparation method of compound of the present invention be by 5-hydroxyethyl oxygen camptothecine with n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-amino acid is dissolved in dry methylene dichloride; stir under nitrogen protection; then dicyclohexylcarbodiimide (DCC) is added; stirring reaction under nitrogen protection; removing white precipitate is refiltered after question response completes, after removing solvent under reduced pressure, crude by column chromatography purifying; with the chloroform-methanol wash-out that volume ratio is 40:1, obtain product.
5-hydroxyethyl oxygen camptothecine 1mmol is dissolved in 50mL methylene dichloride by the best preparation method of compound of the present invention, adds 1mmol's n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-amino-acid compound, under nitrogen protection with N, N-lutidine as catalyzer, and the dicyclohexylcarbodiimide (DCC) adding equivalent is dewatering agent, reacts and carries out at room temperature condition.
Desinsection, bacteriostasis and herbicides Activity determination show, the compound of formula (I) has desinsection, bacteriostasis and herbicides is active, therefore the invention provides the purposes of camptothecine compounds in preparation control plant disease pest and weed medicine.
beneficial effect of the present invention:
Camptothecine compounds novel structure of the present invention, be easy to synthesis, have and not easily decompose, the inefficacy lasting period extends, the feature of water-soluble raising, relative to camptothecine and DRF-1042, good restraining effect is all shown to phytopathogen, Agricultural pests and farmland weed, is easy to make all kinds of pesticide preparation, the environment friendly agricultural that its exploitation is stable, efficient, nontoxic can be utilized.Have broad application prospects.
Below by way of embodiment, foregoing of the present invention is described in further detail.But this should be interpreted as limitation of the present invention.
Embodiment
embodiment 1
Camptothecine compounds preparation process
Preparation method of the present invention be by 5-hydroxyethyl oxygen camptothecine (compound 2) with n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-amino acid (3a-3h) is dissolved in dry methylene dichloride, adds catalytic amount n,N-lutidine; stir 5 minutes under nitrogen protection; then dicyclohexylcarbodiimide (DCC) is added; stirring reaction 2 hours under nitrogen protection; cross and filter white precipitate, after removing solvent under reduced pressure, crude by column chromatography purifying; with the chloroform-methanol wash-out that volume ratio is 40:1, obtain formula I (4a-4h).
Relevant reaction is see reaction formula 1.
reaction formula 1
R in formula 1 is hydrogen, methyl, first sulphur methylene radical, sec.-propyl, butyl, isobutyl-, β-indole methyl or benzyl.
Intermediate therefor raw material 5-hydroxyethyl oxygen camptothecine (compound 2) of the present invention is for raw material is at FeCl by camptothecine (compound 1) 3/ H 2sO 4/ OHCH 2cH 2oH reaction system obtains, and its method therefor is see (Subrahmanyam, D.etal, US6177439 (2001)), and correlated response is shown in formula 1.
embodiment 2
The present invention is used n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-amino acid ( 3a-3h) obtained by following method:
3-carboxyl-2,2,5,5-tetramethyl-pyrroles-nitroxyl free radical (compound 5,9.2g, 0.05mol) and triethylamine (5.05g, 0.05mol) are dissolved in 100mL anhydrous diethyl ether, under agitation mixture are cooled to 0 DEG C.Slow dropping Vinyl chloroformate (5.42g, 0.05mol), at room temperature stirs 3h by mixture after dropwising, and filters, by filtrate evaporate to dryness, uses sherwood oil recrystallization, obtain glassy yellow needle-like crystal 6, productive rate 90%.By gained compound 6(10.25g, what 0.04mol) join stirring immediately is dissolved with sodiumazide (3.88g, in 75mL acetone 0.06mol) and the mixing solutions of water, 30min is stirred under ice bath, then n-hexane extraction is used, extraction liquid anhydrous sodium sulfate drying, removal of solvent under reduced pressure, debris is cooled to-20 DEG C, obtains yellow crystals 7, productive rate 93%.Triazo-compound is prepared into by above-mentioned 7(2.09g, 0.01mol) is dissolved in 20mL diox, is joined and is dissolved with in 0.01mol amino acid and the magnesian 10mL aqueous solution of 0.8g, temperature controls at 40 DEG C, stir 24h, then also use anhydrous sodium sulfate drying with chloroform extraction, steaming desolventizes purifying and obtains n-(1-oxygen base-2,2,5,5-tetramethyl-pyrroles-acid amides)- l-amino acid ( 3a-3h), productive rate: 50 ~ 60%.Method therefor see literature method (Hideg, K.etal, synthesis, 1978, 914-916).
Its reaction is see following formula (reaction formula 2)
Reaction formula 2
R in its reaction formula is hydrogen, methyl, first sulphur methylene radical, sec.-propyl, butyl, isobutyl-, β-indole methyl or benzyl.
5-hydroxyethyl oxygen camptothecine 1mmol is dissolved in 20mL methylene dichloride by best preparation method of the present invention, adds 1mmol's n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-amino-acid compound, under nitrogen protection with n,N-lutidine is as catalyzer, and the dicyclohexylcarbodiimide (DCC) adding equivalent is dewatering agent, reacts and carries out at room temperature condition.
Below provide the embodiment of the present invention
embodiment 3
5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-glycine] camptothecin ester ( 4a) synthesis
By 3-carboxyl-2,2,5,5-tetramethyl-pyrroles-nitroxyl free radical (compound 5)(9.2g, 0.05mol) and triethylamine (5.05g, 0.05mol) are dissolved in 100mL anhydrous diethyl ether, under agitation mixture are cooled to 0 DEG C.Slow dropping Vinyl chloroformate (5.42g, 0.05mol), at room temperature stirs 3h by mixture after dropwising, and filters, by filtrate evaporate to dryness, uses sherwood oil recrystallization, compound 6, forglassy yellow needle-like crystal, 11.6g, productive rate 90%, fusing point: 63-65 DEG C.
By compound 6(10.25g, what 0.04mol) join stirring immediately is dissolved with sodiumazide (3.88g, in 75mL acetone 0.06mol) and the mixing solutions of water, 30min is stirred under ice bath, then n-hexane extraction is used, extraction liquid anhydrous sodium sulfate drying, removal of solvent under reduced pressure, debris is cooled to-20 DEG C, obtains compound 7, foryellow crystals, 7.8g, productive rate 93%, fusing point: 62-63 DEG C.
By the above-mentioned compound 7(2.09g be prepared into, 0.01mol) be dissolved in 20mL diox, joined and be dissolved with in 0.01mol amino acid and the magnesian 10mL aqueous solution of 0.8g, temperature controls at 40 DEG C, stir 24h, then also use anhydrous sodium sulfate drying with chloroform extraction, steaming desolventizes purifying and obtains n-(1-oxygen base-2,2,5,5-tetramethyl-pyrroles-acid amides)- l-amino acid (compound 3a-3h), productive rate: 50 ~ 60%.This reactions steps is with reference to Hideg, K.etal, synthesis, 1978, the method that 914-916 reports.
Intermediate therefor raw material 5-hydroxyethyl oxygen camptothecine of the present invention is that raw material is at FeCl by camptothecine 3/ H 2sO 4/ OHCH 2cH 2oH reaction system obtains, and its method therefor is see (Subrahmanyam, D.etal, US6177439 (2001).
By 1mmol5-hydroxyethyl oxygen camptothecine and 1mmol n-(1-oxygen base-2,2,5,5-tetramethyl-pyrroles-acid amides)- l-glycine is dissolved in the methylene dichloride of 20mL drying; add 0.1 gram of N of catalytic amount; N-lutidine, stirs 5 minutes under nitrogen protection, then adds 0.21 gram of dicyclohexylcarbodiimide (DCC); stirring reaction 2 hours under nitrogen protection; cross and filter white precipitate, after removing solvent under reduced pressure, crude by column chromatography purifying; with the chloroform-methanol wash-out that volume ratio is 40:1, obtain 5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-glycine] camptothecin ester (compound 4a).
The detection data of product (compound 4a) are as follows:
Productive rate: 90%; M.p.115-117; IR (KBr) υ cm -1: 3346 (NH), 1715 (NHCO), 3062,1626,1490 (ArH), 1662 (C=O), 1242,1155,1090 (C-O), 1364 (NO . ); MS (EI) m/z:632 (M+1); HRMSC 33h 35n 4o 9: theoretical value (M+H): 632.2477, measured value: 632.2481; ESR:g 0=2.0055, A n=14.62Gs (tripletpeakin1 × 10 -4m, DMF).
embodiment 4
5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-l-Ala] camptothecin ester (compound 4b) synthesis:
Experimental procedure and embodiment 1 together, only replace glycine with L-Ala.Reaction products therefrom is compound 4b,detection data are as follows:
Productive rate: 86%; M.p.120-122 DEG C; IR (KBr) υ cm -1: 3429 (NH), 1743 (NHCO), 3056,1624,1552 (ArH), 1662 (C=O), 1087,1156,1231 (C-O), 1362 (NO . ); MS (EI) m/z:646 (M+1); HRMSC 34h 37n 4o 9: theoretical value (M+H): 646.2633, measured value: 646.2625; ESR:g 0=2.0058, A n=14.62Gs (tripletpeakin1 × 10 -4m, DMF).
embodiment 5
5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-methionine(Met)] camptothecin ester (compound 4c) synthesis
Experimental procedure and embodiment 1 together, only replace the glycine of embodiment 1 with methionine(Met).Reaction products therefrom (compound 4c) detect data as follows:
Productive rate: 82%; M.p.155-157; IR (KBr) υ cm -1: 3423 (NH), 1711 (NHCO), 3060,1625,1563 (ArH), 1663 (C=O), 1088,1153,1236 (C-O), 1362 (NO . ); MS (EI) m/z:706 (M+1); HRMSC 36h 41n 4o 9s: theoretical value (M+H): 706.2267, measured value: 706.2656; ESR:g 0=2.0055, A n=14.62Gs (tripletpeakin1 × 10 -4m, DMF).
embodiment 6
5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-isoleucine] synthesis of camptothecin ester (compound 4d)
Experimental procedure and embodiment 1 together, only replace the glycine of embodiment 1 with Isoleucine.It is as follows that reaction products therefrom (compound 4d) detects data:
Productive rate: 75%; M.p.160-162; IR (KBr) υ cm -1: 3423 (NH), 1746 (NHCO), 3091,1621,1562 (ArH), 1664 (C=O), 1114,1155,1228 (C-O), 1359 (NO . ); MS (EI) m/z:688 (M+1); HRMSC 37h 43n 4o 9: theoretical value (M+H): 688.3103, measured value: 688.3098; ESR:g 0=2.0055, A n=14.62Gs (tripletpeakin1 × 10 -4m, DMF).
embodiment 7
5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-phenylalanine] camptothecin ester (compound 4e) synthesis
Experimental procedure and embodiment 1 together, only replace the glycine of embodiment 1 with phenylalanine.Reaction products therefrom (compound 4e) detect data as follows:
Productive rate: 87%; 142-144 DEG C; IR (KBr) υ cm -1: 3425 (NH), 1744 (NHCO), 3093,1623,1564 (ArH), 1664 (C=O), 1113,1153,1234 (C-O), 1361 (NO . ); MS (EI) m/z:722 (M+1); HRMSC 40h 41n 4o 9: theoretical value (M+H): 722.2946, measured value: 722.2944; ESR:g 0=2.0055, A n=14.62Gs (tripletpeakin1 × 10 -4m, DMF).
embodiment 8
5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-leucine] camptothecin ester (compound 4f) synthesis
Experimental procedure and embodiment 1 together, only replace the glycine of embodiment 1 with leucine.Reaction products therefrom (compound 4f) detect data as follows:
Productive rate: 68%; M.p.117-119; IR (KBr) υ cm -1: 3418 (NH), 1747 (NHCO), 3065,1621,1562 (ArH), 1664 (C=O), 1114,1157,1227 (C-O), 1359 (NO . ); MS (EI) m/z:688 (M+1); HRMSC 37h 43n 4o 9: theoretical value (M+H): 688.3103, measured value: 688.3110; ESR:g 0=2.0055, A n=14.62Gs (tripletpeakin1 × 10 -4m, DMF).
embodiment 9
5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-α-amino-isovaleric acid] camptothecin ester (compound 4g) synthesis
Experimental procedure and embodiment 1 together, only replace the glycine of embodiment 1 with α-amino-isovaleric acid.Reaction products therefrom (compound 4g) detect data as follows:
Productive rate: 76%; M.p.120-122; IR (KBr) υ cm -1: 3416 (NH), 1750 (NHCO), 3092,1620,1538 (ArH), 1665 (C=O), 1106,1157,1231 (C-O), 1359 (NO . ); MS (EI) m/z:674 (M+1); HRMSC 36h 41n 4o 9 :theoretical value (M+H): 674.2946, measured value: 674.2956; ESR:g 0=2.0055, A n=14.62Gs (tripletpeakin1 × 10 -4m, DMF).
embodiment 10
5-O-second hydroxyl-[ n-(1'-oxygen base-2', 2', 5', 5'-tetramethyl-pyrroles-acid amides)-3'- l-tryptophane] camptothecin ester (compound 4h) synthesis
Experimental procedure and embodiment 1 together, only replace the glycine of embodiment 1 with tryptophane.Reaction products therefrom (compound 4h) detect data as follows:
Productive rate: 54%; M.p.127-129; IR (KBr) υ cm -1: 3413 (NH), 1745 (NHCO), 3061,1619,1522 (ArH), 1663 (C=O), 1086,1158,1229 (C-O), 1356 (NO . ); MS (EI) m/z:761 (M+1); HRMSC 42h 42n 5o 9 :theoretical value (M+H): 761.3055, measured value: 761.3040; ESR:g 0=2.0055, A n=14.62Gs (tripletpeakin1 × 10 -4m, DMF).
embodiment 11
camptothecine compounds 4a-4h is to the inhibit activities of phytopathogen
for examination bacterial classification:mango Stem-rot isolate botryodiplodiatheobromaepat., Colletotrichum gloeosporioides Penz in Mango colletotrichumgloeosporioidespenz, Glorosprium musarum Cookeet Mass colletotrichummusae(Berk.etCurt.) Arx provides by Research Institute of Environment and Plant Protection, Chinese Academy of Tropi.
reagent agent:medicine is compound 4a-4h(preparing according to embodiment 1), camptothecine and 5-hydroxyethyl oxygen camptothecine product in contrast.
test method: test employing growth rate method (Mu Liyi. chemical protection of plant research method. Chinese agriculture press .1987:79-81).Concrete operations are as follows:
1. bacterial classification prepares: in culture dish, pour 10mLPDA substratum (or capsicum epidemic disease Radix Dauci Sativae substratum) into, under aseptic condition, a mycelia block is got from for examination germ inclined-plane, be placed in the middle of culture dish, cultured continuously several generations, test and inoculate once in first 3 days, under thermophilic, darkroom is cultivated for subsequent use, ensures the vigor of bacterial classification.
2. supply reagent liquid: the acetone that test compound is dissolved in, be mixed with the acetone soln of 1mg/mL for examination.
3. make bacterium cake: under aseptic condition, appropriate bacterium cake will be got for examination bacterial classification 0.4cm punch tool for subsequent use.
4. the preparation of medicine substratum is with: after a series of gradient concentration being diluted to for reagent liquid, prepare to draw a certain amount of (1mL) liquid and inject correspondence markings tool plug scale test tube, pour the PDA dissolved or other substratum (9mL) more while hot into, (now liquor strength is diluted 10 times and is not affected solidifying of substratum), firmly shake up rapidly, pour in correspondence markings culture dish immediately, make thin and thick evenly dull and stereotyped, three repetitions are done in each process, two classes are established in contrast, one class is respectively poured in three culture dish with pure culture base 10mL and is connect bacterium, observes after three days, only for referencial use; Another kind ofly add 9ml substratum with 1mL acetone and respectively pour in three culture dish, within after connecing bacterium three days, check statistics.
5. will be placed on plate culture medium for examination bacterium cake carefully with inoculating needle, mycelia faces down, three pieces, every ware or one piece, is equidistantly triangular in shapely put in central authorities, then adds a cover mark, and under putting thermophilic, darkroom is cultivated.
6. result inspection: cultivate in dark after 72 hours (or being determined on a case-by-case basis), take out, use kind of calliper colony diameter, twice statistical average is got in right-angled intersection.Note, above-mentioned sequence of operations must be carried out under stringent asepsis requirements.
Colony growth diameter (mm)=twice diameter mean value-4.0(bacterium cake diameter)
Table 1 embodiment camptothecine compounds is at the bacteriostatic activity of 50mg/L to 3 kinds of germs
Note: third-compound 4b, different bright-compound 4d, bright-compound 4f, egg-compound 4c, figured silk fabrics-compound 4g, look-compound 4h, sweet-compound 4a, phenylpropyl alcohol-compound 4e, DRF-1042 compound 2, camptothecine-compound 1.
Conclusion: as shown in Table 1, camptothecine compounds has good restraining effect to mango Stem-rot isolate, Colletotrichum gloeosporioides Penz in Mango, Glorosprium musarum Cookeet Mass, especially comparatively obvious to mango Stem-rot isolate restraining effect.
embodiment 12
the insecticidal activity of camptothecine compounds 4a-4h
for examination insect:prodenia litura 4 instar larvae is that the Folium Ricini of non-dispenser from Chinese Academy of Tropical Agricultural Sciences's environment and Plant Protection Institute test base is adopted back, in indoor feeding breeding many generations, and the larva confession examination in 4 mid-terms in age of picking Individual Size, solid colour during test.Brontispa longissima 5 instar larvae is adopt back from Danzhou, Hainan coconut palm, in indoor feeding breeding many generations, and the larva confession examination in 5 mid-terms in age of picking Individual Size, solid colour during test.
reagent agent:medicine is compound 4a-4h(preparing according to embodiment 1), camptothecine and 5-hydroxyethyl camptothecine product in contrast.
prodenia litura sod cultivation:test employing leaf dipping method (Mu Liyi. chemical protection of plant research method. Chinese agriculture press .1987:56).First above sample acetone is settled to 2mg/mL, tests using 1mg/mL as screening concentration.Folium Ricini is put into respectively after each confession reagent liquid floods 3s and take out, put on thieving paper and dry, then prodenia litura 4 instar larvae consistent for Individual Size is put into the culture dish that process blade is housed, at the bottom of culture dish, be covered with filter paper moisturizing.Culture dish is placed in incubator (T:25 ± 1 DEG C, RH=70 ~ 80%) to cultivate.Compare with acetone, every concentration repeats 3 times, often repeats 10 cephalonts.Examination worm turns hello normal blade after feeding and being with malicious blade 2d, and worm takes food and death condition in quantitative check examination, touches polypide, be considered as death with complete motionless person with writing brush.Add up dead borer population respectively at 3d, 6d and 9d, calculate mortality ratio and corrected mortality, its test result is in table 2
Table 2 embodiment camptothecine compounds at 1mg/mL to the cytotoxicity to Spodoptera litura larvae
Note: third-compound 4b, different bright-compound 4d, bright-compound 4f, egg-compound 4c, figured silk fabrics-compound 4g, look-compound 4h, sweet-compound 4a, phenylpropyl alcohol-compound 4e, DRF-1042 compound 2, camptothecine-compound 1.
brontispa longissima sod cultivation:test employing leaf dipping method (Mu Liyi. chemical protection of plant research method. Chinese agriculture press .1987:56).First above sample acetone is settled to 1mg/mL, tests using 0.1mg/mL as screening concentration.Coconut leaf is put into respectively after each confession reagent liquid floods 3s and take out, put on thieving paper and dry, then Brontispa longissima larva consistent for Individual Size is put into the culture dish that process blade is housed, at the bottom of culture dish, be covered with filter paper moisturizing.Culture dish is placed in incubator (T:25 ± 1 DEG C, RH=70 ~ 80%) to cultivate.Compare with acetone, every concentration repeats 3 times, often repeats 10 cephalonts.Examination worm turns hello normal blade after feeding and being with malicious blade 2d, and quantitative check examination worm death condition, touches polypide with writing brush, be considered as death with complete motionless person.Add up dead borer population respectively at 3d, 6d and 9d, calculate mortality ratio and corrected mortality, its test result is in table 3.
Table 3 embodiment camptothecine compounds is at the cytotoxicity of 0.1mg/mL to Brontispa longissima 5 instar larvae
Note: third-compound 4b, different bright-compound 4d, bright-compound 4f, egg-compound 4c, figured silk fabrics-compound 4g, look-compound 4h, sweet-compound 4a, phenylpropyl alcohol-compound 4e, DRF-1042 compound 2, camptothecine-compound 1.
Conclusion: from table 2 and table 3, camptothecine compounds all has cytotoxicity in various degree to Brontispa longissima, prodenia litura, and wherein part of compounds has significant cytotoxicity to this two class examination worm.
embodiment 13
the weeding activity of camptothecine compounds 4a-4h
for examination weeds:leaf mustard brassicajuncea(being purchased from Danzhou City seeds company), three-coloured amaranth amaranthusmangostanusl.(is purchased from Danzhou City seeds company), lady's-grass digitariasanguinalis(L.) Scop.(picks up from ring and plants tested base).After measured, seed nature germination rate is all more than 95% for all seeds.
reagent agent:medicine is compound 4a-4h(preparing according to embodiment 1), camptothecine and 5-hydroxyethyl camptothecine product in contrast.
test method: reference farm-chemical indoor determination test rule (People's Republic of China's agricultural industry criteria. farm-chemical indoor determination test rule. weedicide), compound is mixed with the acetone soln that mass concentration is 1000mg/L, draw 1mL liquid to add and be covered with in the 90mm culture dish of filter paper, after acetone volatilization is dry, add the 2mL0.1% tween-80 aqueous solution, dilution obtains the aqueous solution of 500mg/L (0.5mg/mL), then 10, the seed just sprouted fitly is arranged in culture dish, build preservative film, often process and repeat for 3 times, then be placed in growth cabinet and cultivate (daytime 28 DEG C ± 2 DEG C, evening 24 DEG C ± 2 DEG C, relative humidity 75% ± 5%), with the 0.1% tween-80 aqueous solution for blank.Root length and the bud of measuring lady's-grass after 3-6d are respectively long, and the root length of leaf mustard and three-coloured amaranth and plumular axis length, press formulae discovery weeding activity below, it the results are shown in Table 4.
Inhibiting rate (%)=
Table 4 embodiment camptothecine compounds is at the weeding activity of 0.5mg/mL
Note: third-compound 4b, different bright-compound 4d, bright-compound 4f, egg-compound 4c, figured silk fabrics-compound 4g, look-compound 4h, sweet-compound 4a, phenylpropyl alcohol-compound 4e, DRF-1042 compound 2, camptothecine-compound 1.
Conclusion: as shown in Table 4, camptothecine compounds all has weeding activity in various degree to 3 kinds of farmland weeds.。

Claims (9)

1. a camptothecine compounds, is characterized in that its chemical general formula is for the compounds shown in (I) formula:
（I）
Wherein in (I) formula, R is hydrogen, methyl, first sulphur methylene radical, sec.-propyl, butyl, isobutyl-, β-indole methyl or benzyl.
2. the preparation method of a camptothecine compounds as claimed in claim 1; it is characterized in that 5-hydroxyethyl oxygen camptothecine and N-(1-oxygen base-2; 2; 6; 6-tetramethyl piperidine-oxygen-carbonyl)-L-amino acid is dissolved in dry methylene dichloride; stir under nitrogen protection; then dicyclohexylcarbodiimide (DCC) is added; stirring reaction under nitrogen protection; removing white precipitate is refiltered after question response completes, after removing solvent under reduced pressure, crude by column chromatography purifying; with the chloroform-methanol wash-out that volume ratio is 40:1, obtain product.
3. the preparation method of a camptothecine compounds as claimed in claim 1; 5-hydroxyethyl oxygen camptothecine 1mmol is it is characterized in that to be dissolved in 50mL methylene dichloride; add N-(the 1-oxygen base-2 of 1mmol; 2,6,6-tetramethyl piperidine-oxygen-carbonyl)-L-amino-acid compound; under nitrogen protection with N; N-lutidine is as catalyzer, and the dicyclohexylcarbodiimide (DCC) adding equivalent is dewatering agent, reacts and carries out at room temperature condition.
4. the purposes of camptothecine compounds as claimed in claim 1 in agricultural chemicals, is characterized in that it can apply in the agricultural chemicals of preparation control fungal diseases of plants.
5. the purposes of a kind of camptothecine compounds according to claim 4 in agricultural chemicals, is characterized in that described fungal diseases of plants is Colletotrichum gloeosporioides Penz in Mango, mango Stem-rot isolate and Glorosprium musarum Cookeet Mass.
6. the purposes of camptothecine compounds as claimed in claim 1 in agricultural chemicals, is characterized in that it can apply in the agricultural chemicals of preparation control Agricultural pests.
7. the purposes of a kind of camptothecine compounds according to claim 6 in agricultural chemicals, is characterized in that described Agricultural pests are Brontispa longissima, prodenia litura.
8. the purposes of camptothecine compounds as claimed in claim 1 in agricultural chemicals, is characterized in that it can apply in the agricultural chemicals of preparation control farmland weed.
9. the purposes of a kind of camptothecine compounds according to claim 8 in agricultural chemicals, is characterized in that described farmland weed is lady's-grass, leaf mustard and three-coloured amaranth.
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CN103275095B (en) * 2013-05-08 2015-07-22 中国农业科学院植物保护研究所 10-hydroxycamptothecine derivatives and applications thereof
CN103275094B (en) * 2013-05-08 2015-07-08 中国农业科学院植物保护研究所 (20S)-camptothecin derivatives and application thereof
CN104725390B (en) * 2013-12-20 2017-04-05 兰州大学 A kind of camptothecine compounds and preparation method thereof and the purposes in pesticide
CN105295016B (en) * 2014-07-16 2017-12-12 兰州大学 It is a kind of to be used to kill medicine of agricultural pests and its production and use
CN104387401A (en) * 2014-11-28 2015-03-04 中国农业科学院植物保护研究所 Camptothecin derivative and preparation method thereof
CN105767018A (en) * 2016-04-29 2016-07-20 山东胜伟园林科技有限公司 Microbial pesticide for orange pest and disease control and preparation method thereof

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