CN111909110A - Preparation method of 2, 4-disubstituted thiazole compound - Google Patents
Preparation method of 2, 4-disubstituted thiazole compound Download PDFInfo
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- -1 2, 4-disubstituted thiazole compound Chemical class 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical class CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000007787 solid Substances 0.000 claims abstract description 19
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000001408 amides Chemical class 0.000 claims abstract description 15
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000000243 solution Substances 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010992 reflux Methods 0.000 claims abstract description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 10
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 238000002390 rotary evaporation Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000010790 dilution Methods 0.000 claims abstract description 3
- 239000012895 dilution Substances 0.000 claims abstract description 3
- 238000001035 drying Methods 0.000 claims abstract description 3
- 238000000967 suction filtration Methods 0.000 claims abstract description 3
- 238000005406 washing Methods 0.000 claims abstract description 3
- 239000003960 organic solvent Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- CFHGBZLNZZVTAY-UHFFFAOYSA-N lawesson's reagent Chemical compound C1=CC(OC)=CC=C1P1(=S)SP(=S)(C=2C=CC(OC)=CC=2)S1 CFHGBZLNZZVTAY-UHFFFAOYSA-N 0.000 claims description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000003480 eluent Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 230000015572 biosynthetic process Effects 0.000 abstract description 17
- 230000035484 reaction time Effects 0.000 abstract description 7
- 230000007613 environmental effect Effects 0.000 abstract description 5
- 238000001308 synthesis method Methods 0.000 abstract description 4
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 15
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 5
- VQFOHZWOKJQOGO-UHFFFAOYSA-N 4-fluorobenzenecarbothioamide Chemical compound NC(=S)C1=CC=C(F)C=C1 VQFOHZWOKJQOGO-UHFFFAOYSA-N 0.000 description 4
- MIECVJDZXBUVSN-UHFFFAOYSA-N 2,4-diphenyl-1,3-thiazole Chemical compound C=1SC(C=2C=CC=CC=2)=NC=1C1=CC=CC=C1 MIECVJDZXBUVSN-UHFFFAOYSA-N 0.000 description 3
- FKJSFKCZZIXQIP-UHFFFAOYSA-N 2-bromo-1-(4-bromophenyl)ethanone Chemical compound BrCC(=O)C1=CC=C(Br)C=C1 FKJSFKCZZIXQIP-UHFFFAOYSA-N 0.000 description 3
- FLAYZKKEOIAALB-UHFFFAOYSA-N 2-bromo-1-(4-chlorophenyl)ethanone Chemical compound ClC1=CC=C(C(=O)CBr)C=C1 FLAYZKKEOIAALB-UHFFFAOYSA-N 0.000 description 3
- HEMROKPXTCOASZ-UHFFFAOYSA-N 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone Chemical compound FC(F)(F)C1=CC=C(C(=O)CBr)C=C1 HEMROKPXTCOASZ-UHFFFAOYSA-N 0.000 description 3
- LSMAABODKIIJEU-UHFFFAOYSA-N 2-phenyl-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole Chemical compound C1=CC(C(F)(F)F)=CC=C1C1=CSC(C=2C=CC=CC=2)=N1 LSMAABODKIIJEU-UHFFFAOYSA-N 0.000 description 3
- QIOZLISABUUKJY-UHFFFAOYSA-N Thiobenzamide Chemical compound NC(=S)C1=CC=CC=C1 QIOZLISABUUKJY-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- VQMVCNNOCNZWOJ-UHFFFAOYSA-N 2,4-bis(4-chlorophenyl)-1,3-thiazole Chemical compound C1=CC(Cl)=CC=C1C1=CSC(C=2C=CC(Cl)=CC=2)=N1 VQMVCNNOCNZWOJ-UHFFFAOYSA-N 0.000 description 2
- LTCQRGMJXLCPEM-UHFFFAOYSA-N 2-(4-chlorophenyl)-4-phenyl-1,3-thiazole Chemical compound C1=CC(Cl)=CC=C1C1=NC(C=2C=CC=CC=2)=CS1 LTCQRGMJXLCPEM-UHFFFAOYSA-N 0.000 description 2
- GQWINXMZMDBBRS-UHFFFAOYSA-N 2-(4-fluorophenyl)-4-phenyl-1,3-thiazole Chemical compound C1=CC(F)=CC=C1C1=NC(C=2C=CC=CC=2)=CS1 GQWINXMZMDBBRS-UHFFFAOYSA-N 0.000 description 2
- IEMYDFIJEIAQCO-UHFFFAOYSA-N 2-fluorobenzenecarbothioamide Chemical compound NC(=S)C1=CC=CC=C1F IEMYDFIJEIAQCO-UHFFFAOYSA-N 0.000 description 2
- WXCOMGNRDCUQKD-UHFFFAOYSA-N 4-(4-bromophenyl)-2-(4-fluorophenyl)-1,3-thiazole Chemical compound C1=CC(F)=CC=C1C1=NC(C=2C=CC(Br)=CC=2)=CS1 WXCOMGNRDCUQKD-UHFFFAOYSA-N 0.000 description 2
- CCRRTAIYVFVIKB-UHFFFAOYSA-N 4-(4-bromophenyl)-2-phenyl-1,3-thiazole Chemical compound C1=CC(Br)=CC=C1C1=CSC(C=2C=CC=CC=2)=N1 CCRRTAIYVFVIKB-UHFFFAOYSA-N 0.000 description 2
- IZEQQIVJQWJZCQ-UHFFFAOYSA-N 4-(4-chlorophenyl)-2-phenyl-1,3-thiazole Chemical compound C1=CC(Cl)=CC=C1C1=CSC(C=2C=CC=CC=2)=N1 IZEQQIVJQWJZCQ-UHFFFAOYSA-N 0.000 description 2
- OKPUICCJRDBRJT-UHFFFAOYSA-N 4-chlorobenzenecarbothioamide Chemical compound NC(=S)C1=CC=C(Cl)C=C1 OKPUICCJRDBRJT-UHFFFAOYSA-N 0.000 description 2
- NQRFDNJEBWAUBL-UHFFFAOYSA-N N-[cyano(2-thienyl)methyl]-4-ethyl-2-(ethylamino)-1,3-thiazole-5-carboxamide Chemical compound S1C(NCC)=NC(CC)=C1C(=O)NC(C#N)C1=CC=CS1 NQRFDNJEBWAUBL-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
- 238000007144 microwave assisted synthesis reaction Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003557 thiazoles Chemical class 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- FLQYOORLPNYQEV-UHFFFAOYSA-N 2-chlorobenzenecarbothioamide Chemical compound NC(=S)C1=CC=CC=C1Cl FLQYOORLPNYQEV-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- 241000233654 Oomycetes Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- FJWKOPYHCRJVHU-UHFFFAOYSA-N s-(4-chlorophenyl)thiohydroxylamine Chemical compound NSC1=CC=C(Cl)C=C1 FJWKOPYHCRJVHU-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000007979 thiazole derivatives Chemical class 0.000 description 1
- VJQYLJSMBWXGDV-UHFFFAOYSA-N tiadinil Chemical compound N1=NSC(C(=O)NC=2C=C(Cl)C(C)=CC=2)=C1C VJQYLJSMBWXGDV-UHFFFAOYSA-N 0.000 description 1
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- C07D277/22—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Abstract
The invention discloses a preparation method of a 2, 4-disubstituted thiazole compound. It comprises the following steps: heating substituted carboxylic acid in thionyl chloride for reflux reaction to obtain yellow transparent liquid, and adding dichloromethane for dilution for later use; under ice bath, slowly dripping the substituted acyl chloride solution into ammonia water while stirring, stirring at room temperature to separate out a white solid, and performing suction filtration, washing and drying after the reaction to obtain substituted amide; refluxing the substituted amide and Lawesson in tetrahydrofuran, removing the solvent by rotary evaporation after the reaction is finished, and purifying a crude product by a column to obtain substituted sulfamide; the substituted sulfamide, ethanol, triethylamine and alpha-bromocarbonyl compound are put into a pressure reaction tank, and are placed into an annular focusing single-mode microwave synthesizer for irradiation, and compressed air is cooled to obtain the target compound. The microwave-based synthesis of the invention has the following advantages: short reaction time, high yield, rapid heating, environmental protection and the like, and provides a microwave synthesis method of the 2, 4-disubstituted thiazole compound.
Description
Technical Field
The invention relates to a preparation method of a thiazole compound, namely a 2, 4-disubstituted thiazole compound.
Background
Nowadays, thiazole compounds have become a hot spot of green pesticide research due to the characteristics of low toxicity, excellent bioactivity and various structural changes. In recent years, thiazole compounds have attracted much attention for their bactericidal activity. A large number of thiazole derivatives having excellent fungicidal activity have been reported by domestic and foreign research institutes, and a number of commercial varieties such as a succinate dehydrogenase inhibitor thiafluzamide (triflamide) for controlling rice and wheat sheath blight, ethaboxam (ethaboxam), benthiavalicarb-isoproxil (benthiavalicarb-isoproxy) and tiadinil (tiadinal) for controlling oomycetes, and the like have been successfully developed. When the 2, 4-disubstituted thiazole compound is synthesized conventionally, the reaction time is longer, and the yield is lower.
Microwave radiation is a useful synthetic technique in modern organic synthetic chemistry. Compared with the conventional method, the microwave synthesis has the following advantages: short reaction time, high yield, rapid heating, environmental protection, and the like.
In view of the above, the invention explores the conditions for synthesizing the 2, 4-disubstituted thiazole compounds under microwave radiation.
Disclosure of Invention
In view of the above problems in the prior art, the present invention is directed to a method for preparing 2, 4-disubstituted thiazole compounds, which is based on microwave synthesis and has the following advantages: short reaction time, high yield, rapid heating, environmental protection and the like, and provides a microwave synthesis method of the 2, 4-disubstituted thiazole compound.
The preparation method of the 2, 4-disubstituted thiazole compound is characterized by comprising the following steps:
1) heating and refluxing raw material substituted carboxylic acid in thionyl chloride until the raw material substituted carboxylic acid is clear, continuously refluxing until the reaction is finished, removing excessive thionyl chloride by rotary evaporation to obtain yellow transparent liquid, and then adding an organic solvent A for dilution to obtain a substituted acyl chloride solution shown as a formula (II);
2) placing the substituted acyl chloride solution shown in the formula (II) obtained in the step 1) into a constant-pressure dropping funnel under an ice bath condition, slowly dropping the substituted acyl chloride solution into ammonia water while stirring, removing the constant-pressure dropping funnel after dropping, moving the constant-pressure dropping funnel to room temperature, continuously stirring and reacting, wherein a large amount of white solids appear in the solution, and performing suction filtration, washing and drying after the reaction is finished to obtain substituted amide shown in the formula (III);
3) refluxing the substituted amide shown in the formula (III) obtained in the step 2) and a Lawesson reagent in an organic solvent B solution, performing TLC tracking reaction, performing rotary evaporation to remove the solvent after the reaction is finished to obtain a crude product, and performing column chromatography purification with the EA/PE ratio of 4/1 to obtain the substituted sulfamide shown in the formula (IV);
4) filling the substituted sulfamide shown in the formula (IV) obtained in the step 3), ethanol, triethylamine and the alpha-bromocarbonyl compound shown in the formula (V) into a pressure reaction tank, then placing the pressure reaction tank into a CEM DISCOVER 2.0 annular focusing single-mode microwave synthesizer for irradiation reaction, cooling the mixture to room temperature by compressed air through a microwave cavity of the CEM DISCOVER 2.0 annular focusing single-mode microwave synthesizer after the reaction is finished, filtering to obtain a target compound crude product, recrystallizing by using an organic solvent C to obtain the 2, 4-disubstituted thiazole compound shown in the formula (I),
wherein, in formula (I), formula (II), formula (III) and formula (IV): the substituent R1 is hydrogen, amino, alkyl, halogenated phenyl, alkyl phenyl, alkoxy phenyl, trifluoromethyl phenyl, nitro phenyl, halogenated heterocycle, alkoxy heterocycle, nitro heterocycle; in the formulae (I) and (V): the substituent R2 is alkyl, halogenated phenyl, alkyl phenyl, alkoxy phenyl, trifluoromethyl phenyl, nitro phenyl, halogenated heterocycle, alkoxy heterocycle or nitro heterocycle.
The preparation method of the 2, 4-disubstituted thiazole compound is characterized in that the feeding molar ratio of the substituted carboxylic acid and the thionyl chloride in the step 1) is 1:6-8, preferably 1: 7.
The preparation method of the 2, 4-disubstituted thiazole compound is characterized in that the organic solvent A in the step 1) is dichloromethane, and the volume ratio of the volume consumption of the organic solvent A to the volume of the substituted carboxylic acid is 2-4:1, preferably 3: 1.
The preparation method of the 2, 4-disubstituted thiazole compound is characterized in that ammonia water in the step 2) is 80 wt% of ammonia water, and the feeding molar ratio of substituted acyl chloride shown in the formula (II) to the ammonia water is 1:1.0-1.3, preferably 1: 1.2.
The preparation method of the 2, 4-disubstituted thiazole compound is characterized in that the feeding molar ratio of the substituted amide shown as the formula (III) in the step 3) and the Lawesson reagent is 1:0.5-0.7, preferably 1: 0.6.
The preparation method of the 2, 4-disubstituted thiazole compound is characterized in that the feeding molar ratio of the substituted sulfamide shown in the formula (IV) and the substituted alpha-bromocarbonyl compound in the step 4) is 1:1.0-1.2, preferably 1:1.1, the volume usage of ethanol is 3-5mL/mmol, preferably 4mL/mmol, based on the amount of the substituted sulfamide shown in the formula (IV), and the volume usage of triethylamine is 0.1-0.25 drop mL/mmol, preferably 0.2mL/mmol, based on the amount of the substituted sulfamide shown in the formula (IV).
The preparation method of the 2, 4-disubstituted thiazole compound is characterized in that the organic solvent B in the step 3) is tetrahydrofuran, and the volume consumption of the organic solvent B is 2-5mL/mmol, preferably 3mL/mmol based on the amount of the substituted amide shown in the formula (III).
The preparation method of the 2, 4-disubstituted thiazole compound is characterized in that the organic solvent C in the step 4) is absolute ethyl alcohol, and the volume consumption of the organic solvent C is 1.0-1.5mL/mmol, preferably 1.2mL/mmol based on the substance of the substituted sulfamide shown in the formula (IV).
The preparation method of the 2, 4-disubstituted thiazole compound is characterized in that eluant for column chromatography separation in the step 3) adopts mixed solution of ethyl acetate and petroleum ether with the volume ratio of 4: 1.
The reaction process of the 2, 4-disubstituted thiazole compound of the invention is as follows:
by adopting the technology, compared with the prior art, the invention has the following beneficial effects:
the microwave synthesis method of the 2, 4-disubstituted thiazole compound is based on microwave synthesis reaction, has the advantages of short reaction time, high yield, rapid heating, environmental friendliness and the like, and is provided.
Detailed Description
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
the invention discloses a general synthesis method of a 2, 4-disubstituted thiazole compound shown as a formula (I): the method comprises the following steps of carrying out reflux reaction on substituted sulfamide, triethylamine and a substituted alpha-bromocarbonyl compound in an ethanol solution, and optimizing by using benzenethioamide and alpha-bromoacetophenone as model compounds by a microwave radiation convection method in order to optimize reaction conditions, wherein the optimization results are shown in Table 1.
TABLE 1 comparison of the yields of 4a in the processes with and without microwave irradiation
It can be seen from table 1 that the addition of the catalyst TEA in the solvent EtOH brought the yield of the desired product to 90%, whereas in the absence of the catalyst TEA the yield of this product was 69%, which was relatively low. The results show that EtOH/TEA has a higher efficiency than without TEA. In addition, the influence of the feed molar ratio, the reaction temperature and the reaction time on the reaction was investigated. As can be seen from Table 1, the reaction molar ratio (phenylthioamide: α -bromoacetophenone) is preferably 1:1.1, and the yield of 4a increases from 69% to 90% when the reaction time increases from 10 minutes to 20 minutes.
The experimental results in Table 1 show that the reaction yields higher in the ethanol/TEA system, since the condensation of 2, 4-disubstituted thiazoles is an endothermic reaction, perhaps the higher the temperature, the better. Thus, the reaction can be faster and with higher yield under microwave irradiation. Notably, triethylamine acts as a catalyst in the reaction.
EXAMPLE 12 microwave preparation of 4, 4-disubstituted thiazoles
(1) Synthesis of benzoyl chloride (II):
adding thionyl chloride (10mL) and benzoic acid (5mmol) into a reaction bottle at room temperature, heating and refluxing to be clear, then continuously refluxing for 30min, removing excessive thionyl chloride by rotary evaporation after the reaction is finished to obtain a yellow transparent liquid, and then adding dichloromethane (3mL) to dilute for later use. De intermediate body type (II)
(2) Synthesis of benzamide (iii):
the diluted benzoyl chloride (5mmol) was placed in a constant pressure dropping funnel and slowly added dropwise to ammonia water with stirring under ice bath. After 20min, the dropping funnel is removed, the mixture is moved to room temperature for continuous stirring, a large amount of white solid appears in the solution, and after the reaction is finished, the mixture is filtered, washed and dried to obtain the benzamide.
(3) Synthesis of thiophenylamide (IV)
The benzamide (iv) (5mmol) and Lawesson (3mmol) were refluxed in tetrahydrofuran, followed by TLC, and after the reaction was completed, the solvent was removed by rotary evaporation to obtain a crude product, which was then purified by column chromatography EA/PE ═ 4/1(V) to obtain the compound thiophenylamide.
(4) Synthesis of 2, 4-diphenylthiazole (I):
a10 mL pressure pot designed for CEM was charged with the thiophenylamide of formula (IV) (1mmol), absolute ethanol (4mL), α -bromoacetophenone (1.1mmol) and TEA (0.2 mL). The mixture was irradiated (150w, 80 ℃, 200psi, 20 min) in a CEM DISCOVER 2.0 ring focus single mode microwave synthesizer. The mixture was cooled to room temperature by passing compressed air through the microwave cavity for 5 minutes. After cooling, the target compound is filtered. The crude product of the target compound was recrystallized from ethanol to give 2, 4-diphenylthiazole.
2, 4-diphenylthiazole: white solid, microwave preparation yield 90%; conventional synthesis yields: 79 percent.
EXAMPLE 24 preparation of- (4-chlorophenyl) -2-phenylthiazole
The target compound 4- (4-chlorophenyl) -2-phenylthiazole represented by the formula (3b) was obtained in the same manner as in example 1 except that α -bromoacetophenone in step 3) in example 1 was changed to α -bromo-p-chloroacetophenone.
4- (4-chlorophenyl) -2-phenylthiazole: white solid, microwave preparation yield: 87%; conventional synthesis yields: 74 percent.
Example 34 preparation of- (4-bromophenyl) -2-phenylthiazole
The target compound, 4- (4-bromophenyl) -2-phenylthiazole represented by the formula (3c), was obtained in the same manner as in example 1 except that α -bromoacetophenone was changed to α -bromo-p-bromoacetophenone in step 3) in example 1.
4- (4-bromophenyl) -2-phenylthiazole: white solid, microwave preparation yield: 84%; conventional synthesis yields: 75 percent.
EXAMPLE 44 preparation of- (2-bromo-4-methoxyphenyl) -2-phenyloxazole
The target compound, 4- (2-bromo-4-methoxyphenyl) -2-phenylthiazole represented by the formula (3d), was prepared by changing α -bromoacetophenone to α -bromo-2-bromo-4-methoxyacetophenone in step 3) of example 1 and by otherwise performing the same procedure as in example 1.
4- (2-bromo-4-methoxyphenyl) -2-phenylthiazole white solid, microwave preparation yield: 81 percent; conventional synthesis yields: 73 percent
EXAMPLE 52 preparation of phenyl-4- (4- (trifluoromethyl) phenyl) thiazole
The target compound 2-phenyl-4- (4- (trifluoromethyl) phenyl) thiazole shown in the formula (3e) was prepared by changing the α -bromoacetophenone to α -bromo-p-trifluoromethylacetophenone in the step 3) of the example 1 and the other operations were performed in the same manner as in the example 1.
2-phenyl-4- (4- (trifluoromethyl) phenyl) thiazole white solid, microwave prepared yield: 79 percent; conventional synthesis yields: 70 percent;
EXAMPLE 62 preparation of- (4-chlorophenyl) -4-phenylthiazole
The thiophenylamide in step 3) of example 1 was changed to 4-chlorobenzenethioamide, and the other operations were carried out in the same manner as in example 1 to obtain the target compound 2- (4-chlorophenyl) -4-phenylthiazole represented by the formula (4 f).
2- (4-chlorophenyl) -4-phenylthiazole: white solid, microwave preparation yield: 79 percent; conventional synthesis yields: 71 percent.
EXAMPLE 72 preparation of 4, 4-bis (4-chlorophenyl) thiazole
The operation was carried out in the same manner as in example 1 except for changing the phenylthioamide in step 3) of example 1 to 4-chlorophenylthioamide and the α -bromoacetophenone to α -bromo-p-chloroacetophenone to obtain the target compound, 2, 4-bis (4-chlorophenyl) thiazole represented by the formula (4 g).
2, 4-bis (4-chlorophenyl) thiazole: white solid, microwave preparation yield: 82%; conventional preparation yields: and 69 percent.
EXAMPLE 84 preparation of- (4-bromophenyl) -2- (4-chlorophenyl) thiazole
The thiophenylamide in the step 3) of example 1 was changed to 4-chlorobenzenethioamide and α -bromoacetophenone was changed to α -bromo-p-bromoacetophenone, and the other operations were performed in the same manner as in example 1 to obtain the target compound, 4- (4-bromophenyl) -2- (4-chlorophenyl) thiazole represented by the formula (4 h).
4- (4-bromophenyl) -2- (4-chlorophenyl) thiazole: white solid, microwave preparation yield: 84%; conventional preparation yields: 75 percent.
EXAMPLE 94 preparation of- (2-bromo-4-methoxyphenyl) -2- (4-chlorophenyl) thiazole
The thioacid amide in the step 3) of the example 1 was changed to 2-fluorobenzothioamide and the α -bromoacetophenone was changed to α -bromo-2-bromo-4-methoxyacetophenone, and the other operations were performed in the same manner as in the example 1 to obtain the target compound, 4- (2-bromo-4-methoxyphenyl) -2- (4-chlorophenyl) thiazole represented by the formula (4 i).
4- (2-bromo-4-methoxyphenyl) -2- (4-chlorophenyl) thiazole: white solid, microwave preparation yield: 81 percent; conventional preparation yields: 70 percent.
EXAMPLE 102 preparation of 4- (4-chlorophenyl) -4- (4- (trifluoromethyl) phenyl) thiazole
The thiophenylamide in the step 3) of example 1 was changed to 2-chlorobenzenethioamide and α -bromoacetophenone was changed to α -bromo-p-trifluoromethylacetophenone, and the other operations were performed in the same manner as in example 1 to obtain the target compound, 2- (4-chlorophenyl) -4- (4- (trifluoromethyl) phenyl) thiazole represented by the formula (4 j).
2- (4-chlorophenyl) -4- (4- (trifluoromethyl) phenyl) thiazole: white solid, microwave preparation yield: 78%, yield of conventional preparation: 65 percent.
EXAMPLE 112 preparation of 4- (4-fluorophenyl) -4-phenylthiazole
The thiophenylamide in step 3) of example 1 was changed to 2-fluorobenzenethioamide, and the procedure was otherwise the same as in example 1 to give the objective compound 2- (4-fluorophenyl) -4-phenylthiazole represented by the formula (4 k).
2- (4-fluorophenyl) -4-phenylthiazole: white solid, microwave preparation yield: 82%; conventional preparation yields: 70 percent.
EXAMPLE 124 preparation of- (4-chlorophenyl) -2- (4-fluorophenyl) thiazole
The thioacid amide in step 3) of example 1 was changed to 4-fluorobenzothioamide and α -bromoacetophenone was changed to α -bromo-p-chloroacetophenone, and the other operations were performed in the same manner as in example 1 to obtain the objective compound, 4- (4-chlorophenyl) -2- (4-fluorophenyl) thiazole represented by the formula (4 l).
4- (4-chlorophenyl) -2- (4-fluorophenyl) thiazole: white solid, microwave preparation yield: 77%; conventional synthesis yields: 68 percent.
Example preparation of 134- (4-bromophenyl) -2- (4-fluorophenyl) thiazole
The thioacid amide in the step 3) of example 1 was changed to 4-fluorobenzothioamide and α -bromoacetophenone was changed to α -bromo-p-bromoacetophenone, and the other operations were performed in the same manner as in example 1 to obtain the target compound, 4- (4-bromophenyl) -2- (4-fluorophenyl) thiazole represented by the formula (4 m).
4- (4-bromophenyl) -2- (4-fluorophenyl) thiazole: white solid, microwave preparation yield: 79 percent; conventional synthesis yields: 65 percent.
Example 144 preparation of- (2-bromo-4-methoxyphenyl) -2- (4-fluorophenyl) thiazole
The thioacid amide in step 3) of example 1 was changed to 4-fluorobenzothioamide and α -bromoacetophenone was changed to α -bromo-2-bromo-4-methoxyacetophenone, and the other operations were performed in the same manner as in example 1 to obtain the target compound, 4- (2-bromo-4-methoxyphenyl) -2- (4-fluorophenyl) thiazole represented by the formula (4 n).
4- (2-bromo-4-methoxyphenyl) -2- (4-fluorophenyl) thiazole: white solid, microwave preparation yield: 75 percent; conventional synthesis yields: and 69 percent.
EXAMPLE 154 preparation of- (2-bromo-4-methoxyphenyl) -2- (4-fluorophenyl) thiazole
The thioacid amide in step 3) of example 1 was changed to 4-fluorobenzothioamide and α -bromoacetophenone was changed to α -bromo-p-trifluoromethylacetophenone, and the other operations were performed in the same manner as in example 1 to obtain the target compound, 4- (2-bromo-4-methoxyphenyl) -2- (4-fluorophenyl) thiazole represented by the formula (4 o).
4- (2-bromo-4-methoxyphenyl) -2- (4-fluorophenyl) thiazole: white solid, microwave preparation yield: 75 percent; conventional synthesis yields: and 64 percent.
Furthermore, the microwave-assisted synthesis of the 2, 4-disubstituted thiazole compound shown in the formula (I) is realized, and compared with the prior art, the microwave-assisted synthesis method has the following beneficial effects that: the invention provides a 2, 4-disubstituted thiazole compound and a preparation method thereof, and optimizes the compound. The method has high yield, easy post-treatment and environmental friendliness.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (9)
1. A preparation method of a 2, 4-disubstituted thiazole compound is characterized by comprising the following steps:
1) heating and refluxing raw material substituted carboxylic acid in thionyl chloride until the raw material substituted carboxylic acid is clear, continuously refluxing until the reaction is finished, removing excessive thionyl chloride by rotary evaporation to obtain yellow transparent liquid, and then adding an organic solvent A for dilution to obtain a substituted acyl chloride solution shown as a formula (II);
2) placing the substituted acyl chloride solution shown in the formula (II) obtained in the step 1) into a constant-pressure dropping funnel under an ice bath condition, slowly dropping the substituted acyl chloride solution into ammonia water while stirring, removing the constant-pressure dropping funnel after dropping, moving the constant-pressure dropping funnel to room temperature, continuously stirring and reacting, wherein a large amount of white solids appear in the solution, and performing suction filtration, washing and drying after the reaction is finished to obtain substituted amide shown in the formula (III);
3) refluxing the substituted amide shown in the formula (III) obtained in the step 2) and a Lawesson reagent in an organic solvent B solution, performing TLC tracking reaction, performing rotary evaporation to remove the solvent after the reaction is finished to obtain a crude product, and performing column chromatography purification with the EA/PE ratio of 4/1 to obtain the substituted sulfamide shown in the formula (IV);
4) filling the substituted sulfamide shown in the formula (IV) obtained in the step 3), ethanol, triethylamine and the alpha-bromocarbonyl compound shown in the formula (V) into a pressure reaction tank, then placing the pressure reaction tank into a CEM DISCOVER 2.0 annular focusing single-mode microwave synthesizer for irradiation reaction, cooling the mixture to room temperature by compressed air through a microwave cavity of the CEM DISCOVER 2.0 annular focusing single-mode microwave synthesizer after the reaction is finished, filtering to obtain a target compound crude product, recrystallizing by using an organic solvent C to obtain the 2, 4-disubstituted thiazole compound shown in the formula (I),
wherein, in formula (I), formula (II), formula (III) and formula (IV): the substituent R1 is hydrogen, amino, alkyl, halogenated phenyl, alkyl phenyl, alkoxy phenyl, trifluoromethyl phenyl, nitro phenyl, halogenated heterocycle, alkoxy heterocycle, nitro heterocycle; in the formulae (I) and (V): the substituent R2 is alkyl, halogenated phenyl, alkyl phenyl, alkoxy phenyl, trifluoromethyl phenyl, nitro phenyl, halogenated heterocycle, alkoxy heterocycle or nitro heterocycle.
2. The method for preparing 2, 4-disubstituted thiazole compounds according to claim 1, wherein the molar ratio of the substituted carboxylic acid to thionyl chloride in the step 1) is 1:6 to 8, preferably 1: 7.
3. The method for preparing 2, 4-disubstituted thiazole compounds according to claim 1, wherein the organic solvent a in the step 1) is dichloromethane, and the ratio of the volume of the organic solvent a to the volume of the substituted carboxylic acid is 2-4:1, preferably 3: 1.
4. The process for preparing 2, 4-disubstituted thiazole compounds according to claim 1, wherein the aqueous ammonia in the step 2) is 80% by weight aqueous ammonia, and the molar ratio of the substituted acyl chloride represented by the formula (II) to the aqueous ammonia is 1:1.0 to 1.3, preferably 1: 1.2.
5. The process for producing 2, 4-disubstituted thiazole compounds according to claim 1, wherein the molar ratio of the substituted amide represented by the formula (iii) to the Lawesson's reagent in the step 3) is 1:0.5 to 0.7, preferably 1: 0.6.
6. The method for preparing 2, 4-disubstituted thiazole compounds according to claim 1, wherein the molar ratio of the substituted sulfamide represented by the formula (iv) and the substituted α -bromocarbonyl compound charged in the step 4) is 1:1.0 to 1.2, preferably 1:1.1, the volume usage of ethanol is 3 to 5mL/mmol, preferably 4mL/mmol, based on the amount of the substituted sulfamide represented by the formula (iv), and the volume usage of triethylamine is 0.1 to 0.25 drop mL/mmol, preferably 0.2mL/mmol, based on the amount of the substituted sulfamide represented by the formula (iv).
7. The method for preparing 2, 4-disubstituted thiazole compounds according to claim 1, wherein the organic solvent B in the step 3) is tetrahydrofuran, and the volume of the organic solvent B is 2 to 5mL/mmol, preferably 3mL/mmol based on the amount of the substituted amide represented by the formula (III).
8. The method for preparing 2, 4-disubstituted thiazole compounds according to claim 1, wherein the organic solvent C in the step 4) is absolute ethanol, and the volume of the organic solvent C is 1.0 to 1.5mL/mmol, preferably 1.2mL/mmol based on the amount of the substituted sulfamide represented by the formula (IV).
9. A process for preparing 2, 4-disubstituted thiazole compounds according to claim 3, wherein the eluent for column chromatography in step 3) is a mixture of ethyl acetate and petroleum ether in a volume ratio of 4: 1.
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| CN105130923A (en) * | 2015-10-13 | 2015-12-09 | 浙江工业大学 | Preparation method of polysubstituted 2-imino thiazole compound |
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| CN105130923A (en) * | 2015-10-13 | 2015-12-09 | 浙江工业大学 | Preparation method of polysubstituted 2-imino thiazole compound |
| WO2018230528A1 (en) * | 2017-06-13 | 2018-12-20 | 株式会社富士薬品 | Novel nitrocatechol derivative |
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