CN106810497A - Quinoline amide compound and preparation method and application - Google Patents
Quinoline amide compound and preparation method and application Download PDFInfo
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- CN106810497A CN106810497A CN201710047153.5A CN201710047153A CN106810497A CN 106810497 A CN106810497 A CN 106810497A CN 201710047153 A CN201710047153 A CN 201710047153A CN 106810497 A CN106810497 A CN 106810497A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- -1 Quinoline amide compound Chemical class 0.000 title claims abstract description 12
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 230000000694 effects Effects 0.000 claims abstract description 36
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- 235000002017 Zea mays subsp mays Nutrition 0.000 claims abstract description 9
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- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 8
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 claims abstract description 8
- 235000005822 corn Nutrition 0.000 claims abstract description 8
- 235000009566 rice Nutrition 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 244000025254 Cannabis sativa Species 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 239000000376 reactant Substances 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 14
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- 238000003756 stirring Methods 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
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- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
- 239000004563 wettable powder Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/40—Nitrogen atoms attached in position 8
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
- A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of quinoline amide compound and preparation method and application.The general structure of the quinoline amide compound is shown in formula I.Bioactivity checking finds that there is some of which compound special brassinosteroid to react, and such as promotes the hypocotyl elongations of Arabidopsis Mutants det2 1 in dark, and rice leaf inclination increase strengthens ability of the resistance to salt stress of corn etc..Individual compound just has response very high in low concentration, and in addition in the case of high concentration, moreover it is possible to suppress the plant height of wheat, retarding of growing improves its ability resistant to lodging.There is good prevention effect on the grassy weeds such as control of wild oats, Triticum tauschii, barnyard grass, herba setariae viridis grass, goatweed simultaneously.Prepared by the series compound easy, and with low cost, agriculture application and popularization value is high, is worth follow-up further investigation exploitation.
Description
Technical Field
The invention belongs to the field of plant growth regulators, and relates to a quinoline amide compound, and a preparation method and application thereof.
Background
Brassinolide, also known as Brassinolide (BRs), is an endogenous plant growth regulator synthesized in plants. It can regulate several enzymes and hormones required by plant itself, fully utilize its self-potential and growth advantage of plant, and can raise life vigor and drought-resisting and waterlogging-resisting capacity. In view of the fact that the content of brassinolide and the like in plants is extremely low (less than 10)-6ppm) and its excellent physiological activity as a plant hormone in agricultural crops, its synthesis and modification studies have been favored by scientists of various countries. However, the synthesis cost of brassinolide is high, the in vivo metabolic sites are many, and the problem of easy metabolic inactivation is unsound, so the search for searching a new target receptor for analog development is attracting more and more attention.
US6667278(2003) reports that the first class of non-steroidal analogs were modeled on the structure and units of BL and screened for high activity BM1(pM scale), but high concentrations (above nM) were shown to be physiologically inactive and had to work in concert with IAA (5 μ M).
Disclosure of Invention
The invention aims to provide a quinoline amide compound and a preparation method and application thereof.
The structural general formula of the quinoline amide compound provided by the invention is shown in formula I,
in the formula I, R is butyrate, methyl butyrate, Boc-glutamate, Boc-aspartate, p-methoxyphenyl, p-methoxybenzyl ethyl or methyl benzoate.
Specifically, the compound shown in the formula I is any one of the following compounds:
4- (quinoline-8-amino) -4-oxobutanoic acid,
4- (quinoline-8-amino) -4-oxobutanoic acid methyl ester,
4- (quinoline-8-amino) -4-oxobutanoic acid ethyl ester,
N2- (tert-butyloxycarbonyl) -N5- (quinoline-8-amino) glutamine,
N2- (tert-butyloxycarbonyl) -N4- (quinoline-8-amino) asparagine,
4-methoxy-N- (quinoline-8-amino) benzoic acid,
4-methoxy-N- (quinolin-8-amino) phenylacetic acid or 4-methoxycarbonyl-N- (quinolin-8-amino) benzoic acid.
The invention provides a method for preparing a compound shown as a formula I, which comprises the following steps:
carrying out acylation reaction on the compound shown in the formula II and a reactant III to obtain the compound shown in the formula I after the reaction is finished;
in the formula II, R1Are as defined in formula I above;
the reactant III is reactant III1, reactant III2 or
The reactant III1 is
The reactant III2 is
In the method, the molar ratio of the reactant II to the reactant III is 1 (0.9-1.2), specifically 1: 1.1;
the reaction is carried out in a solvent; the solvent is specifically selected from at least one of tetrahydrofuran, dichloromethane, ethyl acetate, acetone and acetonitrile;
when the reactant III is a reactant III1, the acylation reaction is carried out at-5 ℃ or room temperature; the reaction time is 2-12h, and can be 6h specifically;
the reactant III isWhen the reaction temperature of the acylation reaction is the reflux temperature of the solvent; the reaction time is 1-6h, and specifically 2-3 h;
when the reactant III is a reactant III2, the reaction temperature of the acylation reaction is room temperature; the reaction time is 6-24h, and can be 12 h.
The method further comprises the steps of: after the reaction is finished, purifying the reaction system;
the purification method specifically comprises recrystallization or solvent pulping;
in the step of recrystallization, the solvent is ethanol or ethyl acetate;
in the solvent pulping step, the solvent is specifically ethanol or mixed solution consisting of ethyl acetate and petroleum ether in a volume ratio of 2: 1;
the solvent pulping step specifically comprises: adding a solvent for pulping into the reaction system, stirring until a product is separated out, and performing suction filtration; the dosage ratio of the reaction system to the solvent used in the solvent pulping step is specifically 1 g: 5 mL.
In addition, the application of the compound shown in the formula I in regulating the plant growth activity and the plant growth activity regulator containing the compound shown in the formula I also belong to the protection scope of the invention.
Specifically, the plant growth regulating activity is any one of the following:
1) promoting the growth of plants;
2) promoting stem elongation and/or thickening;
3) the germination rate of the seeds is improved;
4) the yield is improved;
5) the quality is improved;
6) enhancing the lodging resistance of the plants;
7) the stress resistance of the plant is enhanced;
the plant growth activity regulator is at least one regulator with the following functions:
1) promoting plant growth
2) Promoting stem elongation and/or thickening;
3) the germination rate of the seeds is improved;
4) the yield is improved;
5) the quality is improved;
6) enhancing the lodging resistance of the plants;
7) the stress resistance of the plant is enhanced;
the stress resistance of the plant is enhanced, specifically, the salt stress resistance of the plant is enhanced;
the plant is rice, corn or wheat.
In addition, the application of the compound shown in the formula I in weeding and the herbicide containing the compound shown in the formula I also belong to the protection scope of the invention.
Specifically, the grass is a grass weed; specifically herba Avenae Fatuae, herba Pileae Scriptae, Echinochloa crusgalli, herba Setariae viridis or herba Caryopteridis Incanae; the plant growth activity regulator or the herbicide is in the form of water dispersible granules, suspending agents, aqueous emulsion, tablets or microcapsules. The carrier in the above dosage forms can be any common carrier as long as it is ensured that the carrier is convenient to apply to the site to be treated after being prepared with the compound represented by formula I of the invention, and can be, for example, plants, seeds or soil; or to facilitate storage, transport or handling. The carrier may be a solid or liquid, or a substance which is normally a gas but which has been compressed to a liquid.
The compounds designed and synthesized by the invention are quinoline amide brassinolide analogues with specific structures, and related biological activity verification shows that some compounds have specific brassinolide reaction, such as promotion of hypocotyl elongation of an arabidopsis thaliana mutant det2-1 in the dark, increase of rice leaf inclination, enhancement of salt stress tolerance of corn and the like. The individual compound has very high response value at low concentration, and can inhibit the plant height of wheat, delay growth and improve the lodging resistance of wheat at high concentration. Meanwhile, the composition has good control effect on gramineous weeds such as wild oat, arthroncus, barnyard grass, green bristlegrass, aegilops tauschii and the like. The series of compounds are easy to prepare, low in cost and high in agricultural application and popularization value, and are worthy of subsequent deep research and development.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Example 1, preparation of compound 1 a:
adding 8-aminoquinoline (10mmol) and succinic anhydride (12mmol) into a 100mL round-bottom flask, stirring and dissolving 15mL tetrahydrofuran (solvent A), heating and refluxing for 2 hours to carry out acylation reaction, cooling to precipitate a solid after the reaction is finished, filtering to obtain the solid, and recrystallizing and purifying by ethanol. The specific recrystallization method comprises the following steps: and (3) dropwise adding 3mL of ethanol into 1g of initial product to be recrystallized, heating and refluxing until the initial product is completely dissolved, continuously refluxing for 10min, slowly cooling to precipitate a solid, and performing suction filtration to obtain a pure product.
Example 2, preparation of compound 1 b:
adding 8-aminoquinoline (10mmol), succinic anhydride (12mmol) and 15mL tetrahydrofuran into a 100mL round-bottom flask, stirring for dissolving, carrying out reflux reaction for 3h for acylation reaction, cooling to precipitate a solid, filtering to obtain a solid, and recrystallizing and purifying with ethanol to obtain an intermediate product. Dissolving intermediate (10mmol) in 3ml methanol, cooling to 0 deg.C in ice salt bath, and adding dropwise the obtained product at constant temperature5ml of tetrahydrofuran solution of thionyl chloride is obtained, and the dropwise addition is finished within 30 min; the reaction was continued for 5 hours, the reaction mixture was poured into 150mL of ice water, extracted with ethyl acetate (3X100mL), washed with brine (3X100mL), anhydrous Na2SO4Drying, filtering and concentrating, and recrystallizing the crude product by ethanol or ethyl acetate to purify. The specific recrystallization method comprises the following steps: and (3) dropwise adding 3mL of ethyl acetate into 1g of the initial product to be recrystallized, heating and refluxing until the initial product is completely dissolved, continuously refluxing for 10min, slowly cooling to precipitate a solid, and performing suction filtration to obtain a pure product.
Example 3, preparation of compound 1 d:
compound 1d was prepared as follows:
in a 100mL round bottom flask, 8-aminoquinoline (10mmol), 3mL (20mmol) triethylamine, 15mL tetrahydrofuran were added and dissolved with stirring, and TBTU (3.531g,11mmol) and Boc-amino acid (10mmol) were added. The reaction mixture was stirred at room temperature for 12h of acylation reaction, and the progress of the reaction was checked by TLC. After completion of the reaction, the reaction mixture was concentrated and dissolved in dichloromethane (50mL), the pH was adjusted to 10 with 1M NaOH, the system was separated into layers, the aqueous phase was taken, acidified to pH 3 with 1M HCl, extracted with ethyl acetate (3 × 100mL), washed with saturated brine (3 × 100mL), and dried over Na2SO4Drying, filtering and concentrating, and purifying the crude product by ethanol recrystallization. The specific recrystallization method comprises the following steps: and (3) dropwise adding 3mL of ethanol into 1g of initial product to be recrystallized, heating and refluxing until the initial product is completely dissolved, continuously refluxing for 10min, slowly cooling to precipitate a solid, and performing suction filtration to obtain a pure product.
The remaining compounds of formula I listed in Table 1 can be prepared according to the same method as above.
The structures and yields of compounds 1a-1h are shown in table 1 below:
TABLE 1 Structure and yield of the synthetic compounds (1a-1h)
Example 4 Arabidopsis thaliana mutant det2-1 hypocotyl elongation Activity assay
Seeds of the Arabidopsis thaliana mutant det2-1 were sterilized with 70% ethanol for 1min, while 1% sodium hypochlorite for 15min, washed with sterile water, and sown in 1/2 MS (0.8% agar, 1% sucrose and compounds of the indicated concentration); the plants were vernalized in a refrigerator at 4 ℃ for 3 days, then transferred to dark conditions and cultured at 22 ℃ for 7 days, and after photographing the whole plant, the length of hypocotyls was measured by ImageJ software.
The results of all compound tests are shown in table 2.
TABLE 2 control agent Arabidopsis thaliana hypocotyl elongation assay results
In Table 2, compound 24-epiBL is 24-epibrassinolide and CAS is 78821-43-9; the CAS of Bikinin is 188011-69-0.
TABLE 3 elongation of hypocotyl of Arabidopsis thaliana
As can be seen from tables 2 and 3, 24-epiBL has very high activity, the hypocotyl length reaches 0.9413 +/-0.0748 cm at the concentration of 1 mu M, and the reported elongation activity of the non-steroidal brassinolide analogue Bikinin is better than 24-epiBL at 40 mu M and reaches 1.1086 +/-0.0684 cm; in all the designed and synthesized compounds, 1d and 1e have certain elongation activity on arabidopsis thaliana mutants, and the maximum value reaches 0.6366 +/-0.0611 cm; while 1g inhibited the elongation of hypocotyl, at high concentration, the length was reduced to 0.1559. + -. 0.0227cm, and the germination rate was not affected.
Example 5 Rice leaf Pitch test
The rice (Nipponbare) seeds are sterilized by 10 percent H2O2 for 20min, washed by sterile water, germinated in an incubator at 30 ℃ for 3 days, the sprouts are cultured for 5-6 days by illumination, when the sprouts grow to 1 leaf and 1 heart, the positions with the leaf inclination angles are cut under the dark condition at 28 ℃ and placed in liquid medicines with different concentrations for 48H, the leaf inclination angles are measured by a protractor, and the test results of all compounds are shown in tables 3 and 4.
TABLE 4 Effect of control Agents on Rice leaf inclination angles
TABLE 5 Effect of synthetic Compounds on Rice leaf inclination angles
As can be seen from the above tables 4 and 5, 24-epiBL has very high activity, the blade inclination angle reaches 125 +/-9 degrees at the concentration of 10 MuM, while the activity of Bikinin is not as good as 24-epiBL but only reaches 75 +/-8 degrees at the maximum concentration of 100 MuM; in all the designed and synthesized compounds, 1g of the compounds has high inhibitory activity on the inclination angle of the leaves, the minimum value reaches 10 +/-2 degrees, and the expression of the compounds is consistent with that of an elongation experiment of an Arabidopsis hypocotyl, which shows that the compounds have the effect of inhibiting the activity related to brassinolide and can be used as a brassinolide antagonist or used as a lead compound for continuous development and research.
Example 6 test of the growth control of wheat seedlings with Compounds
Sterilizing wheat seeds with 10% hydrogen peroxide for 15-20min, cleaning with sterile water, sowing in 0.8% agar and compound with specified concentration), germinating in dark at 25 deg.C for 2 days, culturing at 26 deg.C under 100% illumination and 65% humidity for 6 days, measuring wheat plant height, and performing statistical analysis.
The statistical experimental results are shown in table 6:
TABLE 6 Effect of control Agents on wheat plant height
TABLE 7 Effect of synthetic Compounds on wheat plant height
As can be known from the data in tables 6 and 7, the compound prepared by the invention has good effect on delaying the growth of wheat seedlings, and the plant heights of 1b, 1c, 1d and 1g can be controlled, the minimum value reaches 3.10 +/-0.44 cm, is similar to Bikinin, and does not inhibit the normal growth and development of plants. Under severe conditions, the effects help to prevent wheat lodging and ensure stable yield and normal economic benefit of wheat.
Example 7 Effect of Compounds on corn seedling Biomass under salt stress
Selecting corn seeds (Zhengdan 958) with full seeds, consistent sizes, no mildew and no plant diseases and insect pests, soaking seeds for 24 hours at normal temperature by using a contrast 24-epiBL (1.0mg/L), a Bikinin (40mg/L) and a medicament to be detected (40mg/L), and after the seed soaking is finished, sucking water by using sterilized filter paper for standby. The seeds treated by soaking are placed in germination boxes paved with quartz sand, 10mL of 150mM NaCl solution is added in each box, germination is accelerated at 28 ℃ in an incubator, 25 seeds in each box are arranged 3 times, and the seeds are treated by clear water (CK) as a control and are incubated in the incubator by illumination (day: 18h, 26 ℃, 100% illumination, night: 6h, 20 ℃). The treatment solution was changed every day, and when the seedlings germinated to the 8 th day, the biomass of 10 seedlings was randomly measured (fresh weight of seedlings was weighed, and then dried in an oven at 80 ℃ for 48 hours, and the dry weight was weighed).
The results of the experiment are shown in table 8:
TABLE 8 Effect of control Agents and Compounds on maize seedling Biomass
From the data in table 8, it can be seen that some compounds prepared by the present invention have certain effects on biomass accumulation of corn seedlings under salt stress, wherein 1b, 1c and 1g show certain activities, which exceed those of the clear water control, are actually similar to Bikinin, and promote germination of the stressed seeds. Under severe conditions, the effects are helpful for normal growth and development of the corn under mild salt stress, and economic benefits of the wheat are guaranteed.
Example 8 test of germination inhibition of weed seeds by Compounds
Soaking weed seeds in 80mg/L liquid medicine prepared in the steps of 1b, 1c, 1d and 1g for 24 hours, washing with sterile water, sowing the seeds in a 6cm disposable culture dish with two layers of filter paper on the bottom, uniformly placing a proper amount of plump seeds and 20 seeds with uniform sizes in each dish, culturing in the dark in an incubator (day: 18 hours, 25 ℃, night: 6 hours and 20 ℃), counting the germination vigor for 3 days and the germination rate for 7 days, processing data and analyzing results.
TABLE 9 Germination-inhibiting Activity of Compounds on weed seeds
The results of the experiment are shown in table 9:
as can be seen from the results in Table 9, at a high drug concentration of 80mg/L, the germination of the seeds of Setaria viridis, Leymus chinensis and Avena sativa was inhibited to some extent. In the setaria viridis, the best inhibition is 1g, and the inhibition rate reaches 43.7%; secondly 1c, up to 22.2%. In the aegilops tauschii, the inhibition is 1g, and the inhibition rate reaches 47.5%; secondly 1c, up to 21.1%. 1g of wild oat is also best, and reaches 33.2%; secondly, 1b, reaching 17.7 percent; 1c also had an inhibition of 12.7%. With the increase of the concentration, the drug effect is probably better, wherein 1g has high application value and is worthy of subsequent development and research.
Example 9 preparation of Compound 1b Water dispersible granule (10%)
Weighing 10g of 1b, 6g of wetting dispersant fatty alcohol sulfate, 3g of disintegrant ammonium sulfate and 100g of carrier kaolin, fully and uniformly mixing, crushing into wettable powder by a jet mill, adding into a fluidized bed drying granulator, granulating by using an aqueous solution containing 2g of adhesive polyethylene glycol in a fluidized bed at 50-70 ℃, drying in the dryer, and screening to obtain a 10% 1b water dispersible granule product.
Water-dispersible granules of compounds of the other formulae can be prepared by the process described above.
EXAMPLE 10 preparation of Compound 1c aqueous suspension (25%)
Weigh 1c 25g, emulsifier NPEPO44.8g, desugared lignosulfonate 1.2g, together with total water addition 70g, adding the obtained product into a sand grinding kettle for grinding, and after 1 hour, adding 0.15g of xanthan gum serving as a thickening agent, 4g of ethylene glycol serving as an antifreezing agent and the rest water to the system to complement 100%, and modulating to obtain 1c (25%) white homogeneous phase water suspending agent.
Aqueous suspensions of other compounds of the general formula may be prepared by the methods described above.
Example 11 preparation of Compound 1d aqueous emulsion (5%)
Weigh 1d 5g and emulsifier agricultural milk 501#2.8g of co-emulsifier agricultural milk 601#7.2g were added together to dissolve into a homogeneous oil phase. Water and 5g of antifreeze glycol are mixed together to form a uniform water phase. And adding the water phase into the oil phase under the stirring of a high-shear emulsifying machine at normal temperature to form the well-dispersed aqueous emulsion.
The aqueous emulsion of the compounds of other general formulas can be prepared by the method.
EXAMPLE 12 preparation of Compound 1g effervescent tablet (1%)
Weighing 1g of 1g, drying for 24 hours at 80 ℃, sealing and packaging, mechanically crushing 30g of oxalic acid and 30g of sodium bicarbonate to 100 meshes, uniformly mixing and stirring 0.1g of diatomite, 3g of lactose, 31g of white carbon black and 5g of talcum powder, crushing to 800 meshes, stirring with 1g of the mixture in a mixing and stirring machine for 10 minutes, pressing into effervescent tablets, sealing and packaging to obtain the product.
Tablets of other compounds of the general formula may be prepared by the process described above.
Example 13 preparation of Compound 1h particle size 20 μm microcapsule (3%)
2.0g of chitosan and 1.0g of gelatin were weighed into 100ml of 2% acetic acid solution, 2ml of potassium sorbitan monolaurate was slowly added to the above solution with stirring at 800rpm, and stirring was continued for 20 min. Then 1.0ml of fatty alcohol-polyoxyethylene ether is mixed with 2.0ml of 7.5% ethanol solution for 1 hour, and the mixture is stirred and emulsified for 10min at 1000 rpm. Then, slowly adding the emulsified liquid for 1h into the emulsified acetic acid solution of chitosan and gelatin under the stirring of 1200rpm, and continuing stirring for 45min until the mixed liquid is uniformly dispersed. And finally, curing and drying the prepared mixed solution in a spray dryer with the inlet temperature of 135 ℃ and the outlet temperature of 85 ℃ to obtain powder, namely the 1-hour sustained-release microcapsule. The determination shows that the medicine has 83 percent of capsule forming rate, 3.0 percent of medicine loading rate and 20.5 mu m of average grain diameter.
Microcapsules of compounds of other general formulae can be prepared by the above process.
EXAMPLE 14 Effect of different 1g Compound formulations on drug efficacy (Arabidopsis thaliana hypocotyl elongation test)
Seeds of the Arabidopsis thaliana mutant det2-1 are sterilized by 70% ethanol for 1min, and simultaneously, 1% sodium hypochlorite is used for 15min, and the seeds are washed by sterile water and sown in 1/2 MS (0.8% agar, 1% sucrose and 1g compound preparation with certain concentration); the plants were vernalized in a refrigerator at 4 ℃ for 3 days, then transferred to dark conditions and cultured at 22 ℃ for 7 days, and after photographing the whole plant, the length of hypocotyls was measured by ImageJ software. The concentration of the preparation is 0.025mg/g (25mg/L), and the preparation method comprises the steps of diluting the preparation with various concentrations according to the indicated concentration by adding water or DMSO to the required concentration.
Test results
The results of all compound tests are shown in table 10.
TABLE 10 Arabidopsis thaliana hypocotyl elongation measurement results
As can be seen from the data in Table 10, 1g of the compound preparations prepared by the present invention all had better effect on the hypocotyl of Arabidopsis than the pure drug treatment. The water dispersible granule, the water suspending agent, the water emulsion and the microcapsule show higher activity, are better than tablets and 1g at the concentration of 25mg/L, and show the effect of the preparation on improving the drug effect. Provides a certain guiding significance for later application research.
Characterization profile data for all compounds
4- (quinoline-8-amino) -4-oxobutanoic acid (1a)
1H NMR(300MHz,DMSO-d6)12.17(s,1H),10.14(s,1H),8.94(dd,J＝4.2,1.7Hz,1H),8.61(dd,J＝7.6,1.5Hz,1H),8.40(dd,J＝8.3,1.7Hz,1H),7.71–7.51(m,3H),2.83(dd,J＝7.5,5.8Hz,2H),2.59(dd,J＝7.3,5.9Hz,2H).13C NMR(75MHz,DMSO-d6)174.00,173.77,148.96,138.20,136.72,134.78,128.02,127.14,122.25,121.87,116.69,31.81,29.17.HRMS m/z:245.0919(M+H+,calcd for C13H13N2O3,245.0921)mp:140.0-141.7℃
4- (quinoline-8-amino) -4-oxobutanoic acid methyl ester (1b)
1H NMR(300MHz,DMSO-d6)10.18(s,1H),8.94(dd,J＝4.2,1.7Hz,1H),8.59(dd,J＝7.6,1.4Hz,1H),8.41(dd,J＝8.3,1.7Hz,1H),7.71–7.51(m,3H),3.61(s,3H),2.89(dd,J＝7.5,5.6Hz,2H),2.66(dd,J＝7.5,5.6Hz,2H).13C NMR(75MHz,DMSO-d6)172.95,170.51,148.85,138.17,136.62,134.67,127.95,127.03,122.14,121.84,116.72,51.50,31.55,28.79.
HRMS m/z:259.1080(M+H+,calcd for C14H15N2O3,259.1077)mp:88.3-90.4℃
4- (quinoline-8-amino) -4-oxobutanoic acid ethyl ester (1c)
1H NMR(300MHz,DMSO-d6)10.17(s,1H),8.94(dd,J＝4.2,1.7Hz,1H),8.60(dd,J＝7.6,1.4Hz,1H),8.40(dd,J＝8.3,1.7Hz,1H),7.71–7.50(m,3H),4.13–4.00(m,2H),2.88(dd,J＝7.5,5.6Hz,2H),2.64(dd,J＝7.5,5.7Hz,2H),1.17(t,J＝7.1Hz,3H).13C NMR(75MHz,DMSO-d6)172.41,170.51,148.81,138.16,136.59,134.68,127.93,127.01,122.11,121.79,116.67,60.04,31.59,29.03,14.16.HRMS m/z:273.1236 (M+H+,calcdfor C15H17N2O3,273.1234)mp:90.6-91.8℃
N2- (tert-butyloxycarbonyl) -N5- (quinoline-8-amino) Glutamine (1d)
1H NMR(300MHz,DMSO-d6)12.15(s,1H),10.50(s,1H),8.89(dd,J＝4.2,1.7Hz,1H),8.66(dd,J＝7.6,1.4Hz,1H),8.43(dd,J＝8.3,1.7Hz,1H),7.77–7.54(m,4H),4.24–4.10(m,1H),2.38(t,J＝7.5Hz,2H),2.13(s,1H),1.85(ddt,J＝14.1,9.8,7.4Hz,1H),1.44(s,9H).13C NMR(75MHz,DMSO-d6)174.03,171.07,155.91,148.97,138.08,136.77,134.06,127.93,127.16,122.38,122.08,115.97,78.95,55.28,30.52,28.32,26.39.HRMSm/z:374.1709(M+H+,calcd for C19H24N3O5,374.1710)mp:216.5-218.2℃
N2- (tert-butyloxycarbonyl) -N4- (quinoline-8-amino) asparagine (1e)
1H NMR(300MHz,DMSO-d6)12.68(s,1H),10.18(s,1H),8.94(dd,J＝4.2,1.7Hz,1H),8.65(dd,J＝7.6,1.4Hz,1H),8.42(dd,J＝8.3,1.7Hz,1H),7.74–7.59(m,3H),7.16(d,J＝8.3Hz,1H),4.48–4.34(m,1H),3.03–2.91(m,2H),1.35(s,9H).13C NMR(75MHz,DMSO-d6)173.38,168.85,155.51,148.95,138.18,136.71,134.60,127.98,127.09,122.26,122.13,116.78,78.41,50.85,39.00,28.29.HRMS m/z:360.1553(M+H+,calcd forC18H22N3O5,360.1554)mp:167.1-169.0℃
4-methoxy-N- (quinoline-8-amino) benzoic acid (3f)
1H NMR(300MHz,DMSO-d6)10.72(s,1H),8.97(dd,J＝4.2,1.7Hz,1H),8.71(dd,J＝7.6,1.4Hz,1H),8.46(dd,J＝8.3,1.7Hz,1H),8.16(s,4H),7.77(dd,J＝8.3,1.4Hz,1H),7.73–7.60(m,2H),3.90(s,3H).13C NMR(75MHz,DMSO-d6)164.03,162.37,149.11,138.29,136.80,134.30,129.01,127.91,127.12,126.70,122.34,122.00,116.29,114.33,55.58.HRMSm/z:279.1132(M+H+,calcd for C17H15N2O2,279.1128)mp:119.1-119.8℃
4-methoxy-N- (quinolin-8-amino) phenylacetic acid (3g)
1H NMR(300MHz,DMSO-d6)10.18(s,1H),8.89(dd,J＝4.2,1.7Hz,1H),8.61(dd,J＝7.6,1.4Hz,1H),8.39(dd,J＝8.3,1.7Hz,1H),7.70–7.50(m,3H),7.40–7.28(m,2H),6.98–6.87(m,2H),3.87(s,2H),3.74(s,3H).
13C NMR(75MHz,DMSO-d6)170.09,158.35,148.88,136.61,134.64,130.57,127.90,127.71,127.02,122.13,121.93,116.48,114.06,55.14,43.02.HRMS m/z:293.1282(M+H+,calcd for C18H17N2O2,293.1285)mp:72.7-73.5℃
4-methoxycarbonyl-N- (quinoline-8-amino) benzoic acid (3h)
1H NMR(300MHz,DMSO-d6)10.73(s,1H),8.98(dd,J＝4.2,1.7Hz,1H),8.72(dd,J＝7.6,1.4Hz,1H),8.47(dd,J＝8.3,1.7Hz,1H),8.17(s,4H),7.78(dd,J＝8.3,1.4Hz,1H),7.74–7.61(m,2H),3.92(s,3H).13C NMR(75MHz,DMSO-d6)165.72,163.77,149.33,138.50,136.88,133.97,132.62,129.85,128.00,127.59,127.12,122.81,122.49,117.06,52.61.HRMS m/z:307.1081(M+H+,calcd for C18H15N2O3,307.1077)mp:133.7-134.9℃。
Claims (10)
1. A compound of the formula I, wherein,
in the formula I, R is butyrate, methyl butyrate, Boc-glutamate, Boc-aspartate, p-methoxyphenyl, p-methoxybenzyl ethyl or methyl benzoate.
2. The compound of claim 1, wherein: the compound shown in the formula I is any one of the following compounds:
4- (quinoline-8-amino) -4-oxobutanoic acid,
4- (quinoline-8-amino) -4-oxobutanoic acid methyl ester,
4- (quinoline-8-amino) -4-oxobutanoic acid ethyl ester,
N2- (tert-butyloxycarbonyl) -N5- (quinoline-8-amino) glutamine,
N2- (tert-butyloxycarbonyl) -N4- (quinoline-8-amino) asparagine,
4-methoxy-N- (quinoline-8-amino) benzoic acid,
4-methoxy-N- (quinolin-8-amino) phenylacetic acid or 4-methoxycarbonyl-N- (quinolin-8-amino) benzoic acid.
3. A process for the preparation of a compound of formula I according to claim 1 or 2, comprising the steps of:
carrying out acylation reaction on the compound shown in the formula II and a reactant III to obtain the compound shown in the formula I after the reaction is finished;
in the formula II, R1Is as defined in claim 1;
the reactant III is reactant III1, reactant III2 or
The reactant III1 is
The reactant III2 is
4. The method of claim 3, wherein: the molar ratio of the reactant II to the reactant III is 1 (0.9-1.2) or 1: 1.1;
the reaction is carried out in a solvent; the solvent is specifically selected from at least one of tetrahydrofuran, dichloromethane, ethyl acetate, acetone and acetonitrile;
when the reactant III is a reactant III1, the acylation reaction is carried out at-5 ℃ or room temperature; the reaction time is 2-12h or 6 h;
the reactant III isWhen the reaction temperature of the acylation reaction is the reflux temperature of the solvent; the reaction time is 1-6h or 2-3 h;
when the reactant III is a reactant III2, the reaction temperature of the acylation reaction is room temperature; the reaction time is 6-24h or 12 h.
5. The method according to claim 3 or 4, characterized in that: the method further comprises the steps of: after the reaction is finished, purifying the reaction system;
the purification method specifically comprises recrystallization or solvent pulping;
in the step of recrystallization, the solvent is ethanol or ethyl acetate;
in the solvent pulping step, the solvent is specifically ethanol or mixed solution consisting of ethyl acetate and petroleum ether in a volume ratio of 2: 1;
the solvent pulping step specifically comprises: adding a solvent for pulping into the reaction system, stirring until a product is separated out, and performing suction filtration; the dosage ratio of the reaction system to the solvent used in the solvent pulping step is specifically 1 g: 5 mL.
6. Use of a compound of formula I according to claim 1 or 2 for modulating plant growth activity;
a plant growth activity regulator comprising a compound of formula I as claimed in claim 1 or 2.
7. Use or plant growth activity regulator according to claim 6, characterized in that: the plant growth regulating activity is any one of the following:
1) promoting the growth of plants;
2) promoting stem elongation and/or thickening;
3) the germination rate of the seeds is improved;
4) the yield is improved;
5) the quality is improved;
6) enhancing the lodging resistance of the plants;
7) the stress resistance of the plant is enhanced;
the plant growth activity regulator is at least one regulator with the following functions:
1) promoting the growth of plants;
2) promoting stem elongation and/or thickening;
3) the germination rate of the seeds is improved;
4) the yield is improved;
5) the quality is improved;
6) enhancing the lodging resistance of the plants;
7) the stress resistance of the plant is enhanced;
the stress resistance of the plant is enhanced, specifically, the salt stress resistance of the plant is enhanced;
the plant is rice, corn or wheat.
8. The use of a compound of formula I according to claim 1 or 2 for the control of herbicides; or,
a herbicide comprising a compound of formula i as claimed in claim 1 or 2.
9. Use or herbicide as claimed in claim 8, characterized in that: the grass is a grass weed; specifically herba Avenae Fatuae, herba Pileae Scriptae, Echinochloa crusgalli, herba Setariae viridis or herba Caryopteridis Incanae.
10. Use or plant growth activity regulator or herbicide according to any of claims 6 to 8, characterized in that: the plant growth activity regulator or the herbicide is in the form of water dispersible granules, suspending agents, aqueous emulsion, tablets or microcapsules.
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| CN109320507A (en) * | 2018-09-14 | 2019-02-12 | 北京师范大学 | Chiral fluorescent chemicals and the preparation method and application thereof based on quinoline amides folded formation |
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|---|---|---|---|---|
| GB921315A (en) * | 1958-03-31 | 1963-03-20 | Wellcome Found | The manufacture of 8-aminoalkylamino quinoline derivatives |
| CN103524486A (en) * | 2013-09-18 | 2014-01-22 | 中国科学院昆明植物研究所 | N-quinolyl substituted beta-lactam compound, as well as pharmaceutical composition, synthetic method and application of compound |
| CN105188375A (en) * | 2013-03-05 | 2015-12-23 | 拜耳作物科学股份公司 | Use of quinoline derivatives for improving plant yield |
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| GB921315A (en) * | 1958-03-31 | 1963-03-20 | Wellcome Found | The manufacture of 8-aminoalkylamino quinoline derivatives |
| CN105188375A (en) * | 2013-03-05 | 2015-12-23 | 拜耳作物科学股份公司 | Use of quinoline derivatives for improving plant yield |
| CN103524486A (en) * | 2013-09-18 | 2014-01-22 | 中国科学院昆明植物研究所 | N-quinolyl substituted beta-lactam compound, as well as pharmaceutical composition, synthetic method and application of compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109320507A (en) * | 2018-09-14 | 2019-02-12 | 北京师范大学 | Chiral fluorescent chemicals and the preparation method and application thereof based on quinoline amides folded formation |
| CN109320507B (en) * | 2018-09-14 | 2020-05-22 | 北京师范大学 | Chiral fluorescent compound based on quinoline amide folder and preparation method and application thereof |
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