CN105541753A - Carboxamide derivative containing thiazole ring and preparation method and application thereof - Google Patents
Carboxamide derivative containing thiazole ring and preparation method and application thereof Download PDFInfo
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- CN105541753A CN105541753A CN201510951636.9A CN201510951636A CN105541753A CN 105541753 A CN105541753 A CN 105541753A CN 201510951636 A CN201510951636 A CN 201510951636A CN 105541753 A CN105541753 A CN 105541753A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- 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
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
Abstract
The invention discloses a carboxamide derivative containing thiazole ring and a preparation method and application thereof. The method is as below: reacting oxalyl chloride, benzoic acid and ammonia water to obtain a compound VI-1; reacting the compound VI-1 with a Lawesson's reagent for synthesis of a compound VI-2; reacting ethyl trifluoroacetoacetate with sulfonyl chloride to obtain a compound VI-3; reacting the compound VI-2 with compound VI-3 to obtain a compound VI-4; reacting the compound VI-4 with methanol and sodium hydroxide to prepare a compound VI-5; reacting compound VI-5 with anthranilamide and an acid binding agent reacting pyridine to obtain a compound with a formula (I). the method has the advantages of simple and easily available raw materials, simple preparation method, convenient post-treatment and high product yield; and the compound has a fungicidal activity and good prevention and treatment effects on cucumber gray mold, cucumber timberrot and cucumber bacterial angular leaf spot, but also has anti-cancer activity, and provides basis for the development of new drugs.
Description
Technical field
The invention belongs to carboxamide derivative preparing technical field, be specifically related to a kind of carboxamide derivative and the preparation and application thereof that contain thiazole ring.
Background technology
Nowadays, no matter be in chemistry of pesticide, iatrochemistry, polymer chemistry, coordination chemistry, or be all an important directions in the synthesis of field of industrial chemistry nitrogen-containing heterocycle compound.Carboxamides containing thiazole ring often shows extensive and various activity.In new drug development, carboxamide derivative also has very important value.Carboxamide derivative shows excellent biological activity, such as, except anti-microbial activity and antitumour activity.
The basis of research before the present invention is based on provides a kind of preparation method and the utilisation technology with the carboxamide derivative containing thiazole ring of fungicidal activity.
Summary of the invention
The object of the invention is to provide a kind of carboxamide derivative and preparation method thereof containing thiazole ring and the application with fungicidal activity.
Described a kind of carboxamide derivative containing thiazole ring, is characterized in that its structural formula is as shown in (I):
（I）
Wherein: X is F or Cl; R
1for methyl, trifluoromethyl or Cl; R
2for Cl or H; R
3for H, Br or Cl.
The preparation method of the described carboxamide derivative containing thiazole ring, is characterized in that comprising the steps:
1) in DMF, oxalyl chloride and phenylformic acid scold compound VI-1 benzamide obtained such as formula shown in VI-1 under ammoniacal liquor exists;
2) in tetrahydrofuran solvent, the compound VI-1 and the lawesson reagent that step 1) are obtained react under the protection of nitrogen, obtain such as formula compound VI-2 thiobenzamide shown in VI-2;
3) in carbon tetrachloride solvent, trifluoroacetic ethyl acetoacetate and SULPHURYL CHLORIDE are reacted, and obtain such as formula compound VI-3 chloro trifluoroacetic ethyl acetoacetate shown in VI-3;
4) in anhydrous ethanol solvent, by step 2) compound VI-3 that obtains with step 3) of the compound VI that obtains-2 reacts, and obtains such as formula compound VI-4 thiazole ethyl ester shown in VI-4;
5) add sodium hydroxide in the compound VI-4 obtained in step 4) and the mixed solution of first alcohol and water to react, add dilute hydrochloric acid after reaction, obtain such as formula compound VI-5 thiazole acid shown in VI-5;
6) compound VI-5 and oxalyl chloride, the DMF that step 5) are obtained are obtained by reacting acyl chlorides, then add substituted aniline and acid binding agent pyridine, obtain the carboxamide derivative of the thiazole ring shown in formula (I).
Preparation process is as follows:
The preparation method of the described carboxamide derivative containing thiazole ring, is characterized in that the oxalyl chloride in step 1), phenylformic acid are 1:0.3 ~ 0.4:1.5 ~ 2.0 with the ratio of the amount of substance of ammoniacal liquor.
The preparation method of the described carboxamide derivative containing thiazole ring, is characterized in that step 2) in compound VI-1 be 1:0.8 ~ 1.2 with the ratio of the amount of the matter of lawesson reagent thing.
The preparation method of the described carboxamide derivative containing thiazole ring, is characterized in that in step 3), trifluoroacetic ethyl acetoacetate is 1:1.1 ~ 1.3 with the ratio of the amount of substance of SULPHURYL CHLORIDE.
The preparation method of the described carboxamide derivative containing thiazole ring, is characterized in that in step 4), compound VI-2 is 1:0.9 ~ 1.1 with the ratio of the amount of substance of compound VI-3.
The preparation method of the described carboxamide derivative containing thiazole ring, it is characterized in that compound VI-4 in step 5), sodium hydroxide is 1:1.1 ~ 1.3:1.3 ~ 1.5 with the ratio of the amount of substance of hydrochloric acid.
The preparation method of the described carboxamide derivative containing thiazole ring, it is characterized in that compound VI-5 in step 6), substituted aniline is 1:1.1 ~ 1.3:0.9 ~ 1.1 with the ratio of the amount of substance of pyridine.
The described carboxamide derivative containing thiazole ring is in the application of control gray mold of cucumber, cucumber timberrot and cucumber bacterial angular leaf spot.
The described carboxamides containing thiazole ring prepares the application of cancer therapy drug.
Compared with prior art, beneficial effect of the present invention is mainly reflected in: the preparation method and the application thereof that the invention provides a kind of carboxamide derivative containing thiazole ring, its raw material is simple and easy to get, preparation method is simple, convenient post-treatment, product yield is high, and this compound is for having fungicidal activity, control for gray mold of cucumber, cucumber timberrot and cucumber bacterial angular leaf spot etc. has good effect, for the research and development of novel pesticide provide the foundation, this this compound is for having antitumour activity simultaneously, for the research and development of PTS provide the foundation.
Embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
Carboxamide derivative (I) containing thiazole ring of the present invention can synthesize in the following manner:
Oxalyl chloride (120mmol) is instilled in the suspension of phenylformic acid (40mmol) and methylene dichloride (50mL), then add two DMF.Reaction mixture room temperature reaction 12h, the raffinate to acyl chlorides of decompression precipitation, under cryosel cooling, slowly instills acyl chlorides raffinate in the ammoniacal liquor of 5 times amount and obtains products benzene acid amides VI-1.By benzamide VI-1(20mmol) and lawesson reagent (20mmol) be dissolved in 100mL tetrahydrofuran solution, back flow reaction 3h under nitrogen protection.React complete, the yellow of sloughing solution glues shape solid, and column chromatography obtains the sterling of thiobenzamide VI-2.By trifluoroacetic ethyl acetoacetate (0.2mol), the reaction mixture refluxed reaction 24h of SULPHURYL CHLORIDE (SO2Cl2,0.24mol) and tetracol phenixin (100mL).Slough solution, residual liquid underpressure distillation, the cut collecting 60 ~ 62/20mmHg obtains chloro trifluoroacetic ethyl acetoacetate VI-3.Thiobenzamide VI-2(35mmol is added in 250mL round-bottomed flask) and 100mL dehydrated alcohol, then drip equimolar chloro trifluoroacetic ethyl acetoacetate VI-3(7.7g, 35mmol), back flow reaction 24h.Vacuum sloughs partial solvent, and leave standstill and separate out white needle-like crystals, suction filtration just can obtain thiazole ethyl ester VI-4.VI-4(10mmol is added) in 100mL round-bottomed bottle, 50mL methyl alcohol and 10mL water, then NaOH(0.48g is added, 12mmol), reaction mixture at room temperature reacts 12h, and solvent is sloughed in decompression, add 50mL water, and adjust pH value of solution to 1.5 with dilute hydrochloric acid, continue to stir 30min, solid is obtained product thiazole acid VI-5 by suction filtration.Finally, in 50mL round-bottomed bottle, add VI-5(1mmol), 20mL methylene dichloride and oxalyl chloride (3mmol), add two DMF subsequently.Reaction mixture is at stirring at room temperature 6h, the crude product to acyl chlorides of solvent is sloughed in decompression, acyl chlorides is dissolved in 20mL methylene dichloride, in methylene dichloride (20mL) solution of slow instillation substituted aniline (1.2mmol), after continuing to stir 20min, add acid binding agent pyridine (1mmol), reaction mixture at room temperature reacts 12h.Question response terminates, and adds methylene dichloride (20mL) in reaction flask, then uses dilute hydrochloric acid (20mL), saturated sodium bicarbonate aqueous solution (20mL) and saturated sodium-chloride water solution (20mL) to wash organic layer respectively, and anhydrous Na 2SO4 is dry, filters.Solvent afforded crude material is sloughed in decompression, then obtains VI-7 sterling through reduced pressure chromatography.
Embodiment 1 ~ 8, concrete compound is as shown in table 1, and other synthesis condition does not change.
Embodiment 1
N-(the chloro-2-tolyl of 4-)-2-(2-fluorophenyl)-4-(trifluoromethyl) thiazole-5-carboxamides, white solid, productive rate 69.2%, m.p.>220 DEG C;
1hNMR (DMSO, 400MHz): 2.24 (s, 3H, CH
3), 7.29-7.32 (m, 1H, Ar-H), 7.39-7.56 (m, 4H, Ar-H), 7.65-7.69 (m, 1H, Ar-H), 8.23-8.27 (m, 1H, Ar-H), 10.55 (br, 1H, NH) .Elementalanal.ForC
18h
11clF
4n
2oS (%), calculated:C, 52.12; H, 2.67; N, 6.75; Found:C, 51.61; H, 3.21; N, 6.79.
Embodiment 2
N-(2,4 dichloro benzene base)-2-(2-fluorophenyl)-4-(trifluoromethyl) thiazole-5-carboxamides, white solid, productive rate 57.6%, m.p.>190 DEG C; 1HNMR (DMSO, 400MHz): 7.43-7.56 (m, 3H, Ar-H), 7.65-7.76 (m, 3H, Ar-H), 8.24-8.28 (m, 1H, Ar-H), 10.87 (br, 1H, NH) .Elementalanal.ForC
17h
8cl
2f
4n
2oS (%), calculated:C, 46,91; H, 1.85; N, 6.44; Found:C, 46.85; H, 2.36; N, 6.21.
Embodiment 3
N-(the chloro-2-tolyl of 4-)-2-(2-chloro-phenyl-)-4-(trifluoromethyl) thiazole-5-carboxamides, yellow solid, productive rate 44.0%, m.p.>220 DEG C; 1HNMR (DMSO, 400MHz): 2.25 (s, 3H, CH
3), 7.30-7.49 (m, 3H, Ar-H), 7.59-7.65 (m, 2H, Ar-H), 7.73-7.75 (m, 1H, Ar-H), 8.25-8.27 (m, 1H, Ar-H), 10.59 (br, 1H, NH) .Elementalanal.ForC
18h
11cl
2f
3n
2oS (%), calculated:C, 50.13; H, 2.57; N, 6.50; Found:C, 49.91; H, 2.87; N, 6.59.
Embodiment 4
2-(2-chloro-phenyl-)-N-(2,4 dichloro benzene base)-4-(trifluoromethyl) thiazole-5-carboxamides, white solid, productive rate 65.3%, m.p.>200 DEG C; 1HNMR (DMSO, 400MHz): 7.493-7.52 (m, 1H, Ar-H), 7.56-7.64 (m, 2H, Ar-H), 7.69-7.76 (m, 3H, Ar-H), 8.25-8.27 (m, 1H, Ar-H), 10.90 (br, 1H, NH) .Elementalanal.ForC
17h
8cl
3f
3n
2oS (%), calculated:C, 45.21; H, 1.79; N, 6.20; Found:C, 45.02; H, 2.09; N, 6.29.
Embodiment 5
2-(2-chloro-phenyl-)-4-(trifluoromethyl)-N-(2-(trifluoromethyl) phenyl) thiazole-5-carboxamides, white solid, productive rate 68.2%, m.p.>155 DEG C; 1HNMR (DMSO, 400MHz): 7.56-7.65 (m, 4H, Ar-H), 7.73-7.83 (m, 4H, Ar-H), 10.92 (br, 1H, NH) .Elementalanal.ForC
18h
9clF
6n
2oS (%), calculated:C, 47.96; H, 2.01; N, 6.21; Found:C, 47.67; H, 2.51; N, 6.39.
Embodiment 6
2-(2-chloro-phenyl-)-N-(2,4,6-trichlorophenyl)-4-(trifluoromethyl) thiazole-5-carboxamides, white solid, productive rate 57.6%, m.p.>115 DEG C; 1HNMR (DMSO, 400MHz): 7.56-7.66 (m, 2H, Ar-H), 7.88 (s, 2H, Ar-H), 7.75-7.77 (m, 1H, Ar-H), 8.29-8.31 (m, 1H, Ar-H), 11.18 (br, 1H, NH) .Elementalanal.ForC
17h
7cl
4f
3n
2oS (%), calculated:C, 42.00; H, 1.45; N, 5.76; Found:C, 42.19; H, 1.78; N, 5.49.
Embodiment 7
N-(bromo-4, the 6-dichlorophenyls of 2-)-2-(2-chloro-phenyl-)-4-(trifluoromethyl) thiazole-5-carboxamides, white solid, productive rate 59.8%, m.p.>245 DEG C; 1HNMR (DMSO, 400MHz): 7.59-7.67 (m, 2H, Ar-H), 7.75-7.77 (m, 1H, Ar-H), 7.91 (d, J=2.4Hz, 1H, Ar-H), 7.98 (d, J=2.4Hz, 1H, Ar-H), (8.29-8.31 m, 1H, Ar-H), 11.17 (br, 1H, NH) .Elementalanal.ForC
17h
7brCl
3f
3n
2oS (%), calculated:C, 38.48; H, 1.33; N, 5.28; Found:C, 38.15; H, 1.81; N, 5.28.
Embodiment 8 fungicidal activity is tested
Subjects: cucumber bacterial angular leaf spot, rice sheath blight disease, gray mold of cucumber, cucumber timberrot, Cucumber Target Leaf Spot.
Test method: adopt pot experiment method.Respectively by cucumber seeds and tomato seeds after 50 DEG C are soaked, be seeded in after vernalization in pot for growing seedlings, wait to grow to 2 true leaves for test.
Medicament prepares: for reagent: get it filled and be made into 100ppm, get 89 kinds of each 5mg of compound, add 10% POLYSORBATE 80 again after adding acetone solution, finally adds water and fully dissolves.Because 100ppm is that 100mg/L is so amount of water=5mg*1000/100mg=50ml, because of final content≤1% of organic solvent so the amount=50ml*1%=0.5ml(adding acetone dissolves), be 0.1% so tween 0.05ml should be had in 50ml water because of the final content of tween, that is: 10% tween 0.05ml. should be added
Application method: the morning reagent agent and contrast medicament are prepared by experimental concentration respectively in fine day, the vaccination ways of cucumber aphid adopts spore suspension spray inoculation, the vaccination ways of gray mold of cucumber and cucumber bacterial angular leaf spot adopts hyphal suspension spray inoculation, and after inoculation, moisturizing is cultivated.The vaccination ways of Rhizoctonia solani Kuhn, cucumber sclerotiorum adopts hyphal suspension foliar spray inoculation method.
After clear water is fully fallen ill, carry out Disease investigation, and calculate disease index and prevention effect.
Fungicidal activity testing experiment result is as shown in table 1
The fungicidal activity (% preventive effect) of each compound of table 1
Show from upper table 1 fungicidal activity result, the obtained carboxamide derivative (I) containing thiazole ring of the present invention has excellent sterilization effect to gray mold of cucumber, cucumber timberrot and cucumber bacterial angular leaf spot, its use range is wider, and drug effect is more obvious, is suitable for applying.
Embodiment 9 antitumour activity is tested
Experimental principle: tetrazole is a kind of dyestuff that can accept hydrogen atom.The MTT of yellow can be changed into insoluble hepatic formazon by desaturase relevant to NADP in viable cell plastosome in cell, and dead cell is then without this function.After dissolving formazon with DMSO, under certain wavelength, measure optical density value by microplate reader, both quantitatively can measure the survival rate of cell.
Test method:
Result evaluation: growth of tumour cell inhibiting rate (%)=(OD contrasts-OD experiment)/(it is blank that OD contrasts-OD) X100%
Positive judgement criteria: inhibiting rate is greater than 50%.
The antitumour activity of each compound of table 2
。
Claims (10)
1. the carboxamide derivative containing thiazole ring, is characterized in that its structural formula is as shown in (I):
（I）
Wherein: X is F or Cl; R
1for methyl, trifluoromethyl or Cl; R
2for Cl or H; R
3for H, Br or Cl.
2. a preparation method for the carboxamide derivative containing thiazole ring as claimed in claim 1, is characterized in that comprising the steps:
1) in DMF, oxalyl chloride and phenylformic acid scold compound VI-1 benzamide obtained such as formula shown in VI-1 under ammoniacal liquor exists;
2) in tetrahydrofuran solvent, the compound VI-1 and the lawesson reagent that step 1) are obtained react under the protection of nitrogen, obtain such as formula compound VI-2 thiobenzamide shown in VI-2;
3) in carbon tetrachloride solvent, trifluoroacetic ethyl acetoacetate and SULPHURYL CHLORIDE are reacted, and obtain such as formula compound VI-3 chloro trifluoroacetic ethyl acetoacetate shown in VI-3;
4) in anhydrous ethanol solvent, by step 2) compound VI-3 that obtains with step 3) of the compound VI that obtains-2 reacts, and obtains such as formula compound VI-4 thiazole ethyl ester shown in VI-4;
5) add sodium hydroxide in the compound VI-4 obtained in step 4) and the mixed solution of first alcohol and water to react, add dilute hydrochloric acid after reaction, obtain such as formula compound VI-5 thiazole acid shown in VI-5;
6) compound VI-5 and oxalyl chloride, the DMF that step 5) are obtained are obtained by reacting acyl chlorides, then add substituted aniline and acid binding agent pyridine, obtain the carboxamide derivative of the thiazole ring shown in formula (I),
Preparation process is as follows:
X is F or Cl; R
1for methyl, trifluoromethyl or Cl; R
2for Cl or H; R
3for H, Br or Cl.
3. the preparation method of the carboxamide derivative containing thiazole ring according to claim 2, is characterized in that the oxalyl chloride in step 1), phenylformic acid are 1:0.3 ~ 0.4:1.5 ~ 2.0 with the ratio of the amount of substance of ammoniacal liquor.
4. the preparation method of carboxamide derivative containing thiazole ring according to Claims 2 or 3, is characterized in that step 2) in compound VI-1 be 1:0.8 ~ 1.2 with the ratio of the amount of the matter of lawesson reagent thing.
5., according to the preparation method of the carboxamide derivative containing thiazole ring described in Claims 2 or 3, it is characterized in that in step 3), trifluoroacetic ethyl acetoacetate is 1:1.1 ~ 1.3 with the ratio of the amount of substance of SULPHURYL CHLORIDE.
6., according to the preparation method of the carboxamide derivative containing thiazole ring described in Claims 2 or 3, it is characterized in that in step 4), compound VI-2 is 1:0.9 ~ 1.1 with the ratio of the amount of substance of compound VI-3.
7., according to the preparation method of the carboxamide derivative containing thiazole ring described in Claims 2 or 3, it is characterized in that compound VI-4 in step 5), sodium hydroxide is 1:1.1 ~ 1.3:1.3 ~ 1.5 with the ratio of the amount of substance of hydrochloric acid.
8., according to the preparation method of the carboxamide derivative containing thiazole ring described in Claims 2 or 3, it is characterized in that compound VI-5 in step 6), substituted aniline is 1:1.1 ~ 1.3:0.9 ~ 1.1 with the ratio of the amount of substance of pyridine.
9. the carboxamide derivative as claimed in claim 1 containing thiazole ring is in the application preventing and treating gray mold of cucumber, cucumber timberrot and cucumber bacterial angular leaf spot.
10. prepare as claimed in claim 1 the application of cancer therapy drug containing the carboxamides of thiazole ring for one kind.
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