CN114057666B - Synthesis method of 4, 5-disubstituted-2-aminothiazole compound - Google Patents

Synthesis method of 4, 5-disubstituted-2-aminothiazole compound Download PDF

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CN114057666B
CN114057666B CN202010771036.5A CN202010771036A CN114057666B CN 114057666 B CN114057666 B CN 114057666B CN 202010771036 A CN202010771036 A CN 202010771036A CN 114057666 B CN114057666 B CN 114057666B
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thiourea
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ethyl
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CN114057666A (en
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张为革
洪一郎
关奇
张博闻
赵英霖
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Shenyang Pharmaceutical University
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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
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Abstract

The invention belongs to the field of organic synthesis and pharmaceutical synthesis, and particularly relates to a synthesis method of a 4, 5-disubstituted-2-aminothiazole compound. The invention provides the following technical scheme: in organic solvent or water, under the atmosphere of oxygen (or air), a ketone compound with a structure shown as a formula (I) and thiourea or thiourea derivative with a structure shown as a formula (II) are used as reaction raw materials, under the co-catalysis action of activated carbon and metal salt, a condensation/oxidation coupling reaction is carried out to obtain a 4, 5-disubstituted-2-aminothiazole compound with a structure shown as a formula (III), and the reaction process can be expressed by the following reaction equation.

Description

Synthesis method of 4, 5-disubstituted-2-aminothiazole compound
Technical Field
The invention belongs to the field of organic synthesis and pharmaceutical synthesis, and particularly relates to a synthesis method of a 4, 5-disubstituted-2-aminothiazole compound.
Background
The 2-aminothiazole ring is an important five-membered aromatic heterocycle containing nitrogen and sulfur heteroatoms. The 4, 5-disubstituted-2-aminothiazole compound has various effects of resisting convulsion, resisting virus, resisting bacteria, killing pests and the like, and is widely applied in various fields of chemistry, pharmacy, biology, material science and the like.
The development of a novel, efficient and environment-friendly method for synthesizing the 4, 5-disubstituted-2-aminothiazole compound has important value for the development and utilization of the 2-aminothiazole compound.
The synthesis method of the 4, 5-disubstituted-2-aminothiazole compound reported in the literature is summarized as follows:
1. using alpha-halogenated ketone or its analogue as initial raw material
1. Using alpha-halogenated ketone as starting material
In 1887, hantzsch et al (Hantzsch, A.and Weber, H., J.chem.Ber.,20,3118 (1887)) reported synthetic methods for synthesizing 4, 5-disubstituted-2-aminothiazoles from alpha-haloketones and thiourea.
Figure BDA0002616614610000011
2. Alpha-halogenated ketimine as initial raw material
In 1996, kimpe et al (Kimpe, N.De.and Cock, W.De., J.heterocyclic. Chem.,33,1179 (1996)) reported a synthetic method for condensing α -haloketimine with thiourea in methanol to give 4, 5-disubstituted-2-aminothiazoles.
Figure BDA0002616614610000012
2. Starting from ketones
1. Using iodine and thiourea
In 1945, dodson et al (Dodson, R.M. and King, L.C., J.Am.chem.Soc.,67,2242 (1945)) reported a synthesis method in which a ketone is reacted with an iodine simple substance and thiourea to obtain a 4, 5-disubstituted-2-aminothiazole compound in a good yield.
Figure BDA0002616614610000021
2. Using N-bromosuccinimide (NBS) and thiourea
In 1997, dahiya et al (Dahiya, R.and Pujari, H.K., indian J.Chem.,25B,966 (1986)) reported a synthesis of 4, 5-disubstituted-2-aminothiazoles from ketones and thiourea in the presence of N-bromosuccinimide (NBS) and benzoyl peroxide.
Figure BDA0002616614610000022
3. Using sulfuryl chloride or other oxidant and thiourea
In 1946, dodson et al (Dodson, R.M. and King, L.C., J.Am.chem.Soc.,1946,68, 871) reported that a mixture of a ketone and thiourea was treated with an oxidizing agent such as sulfuryl chloride, chlorosulfonic acid or thionyl chloride to obtain a 4, 5-disubstituted-2-aminothiazole compound.
Figure BDA0002616614610000023
3. Other methods for synthesizing 4, 5-disubstituted-2-aminothiazoles
In 1949, king et al (King, l.c. and Miller, f.m., j.am.chem.soc.,1949,71, 367) reported synthetic methods for preparing 4, 5-disubstituted-2-aminothiazoles by reacting alpha-diazo-substituted ketones with thiourea.
Figure BDA0002616614610000024
Among the above methods, the method using α -haloketone or its analogues as raw material has the disadvantages of high toxicity of raw material, complicated preparation process, etc. although the reaction conditions are mild; the method using ketone as raw material has the advantages of simple and easily obtained raw material, excessive oxidant, high price and certain harm to the environment.
Therefore, the research and development of a synthetic method which has cheap and easily obtained raw materials, easily controlled reaction conditions, simple and convenient operation and environmental protection has important theoretical significance and practical value.
Disclosure of Invention
In view of the above, in order to solve the above-mentioned defects of the prior art such as high toxicity of raw materials, complicated preparation process, expensive reagents, environmental pollution, etc., the present inventors have conducted intensive studies on a chemical synthesis method of 4, 5-disubstituted-2-aminothiazole compounds, and have completed the present invention after paying a lot of creative efforts.
The invention solves the technical problem of providing a synthesis method of 4, 5-disubstituted-2-aminothiazole compounds, the synthesis method synthesizes the 4, 5-disubstituted-2-aminothiazole compounds through condensation/oxidation coupling reaction between ketone compounds and thiourea or thiourea derivatives, and the synthesis method has the advantages of cheap and easily obtained raw materials, simple and convenient operation, mild conditions, environmental protection and the like, and has potential industrial application prospects.
In order to solve the technical problems, the invention provides the following technical scheme: in organic solvent or water, in oxygen (or air) atmosphere, using ketone compound with structure shown in formula (I) and thiourea or thiourea derivative with structure shown in formula (II) as reaction raw materials, under the co-catalysis of active carbon and metal salt, obtaining 4, 5-disubstituted-2-aminothiazole compound with structure shown in formula (III) through condensation/oxidation coupling reaction, wherein the reaction process can be expressed by the following reaction equation
Figure BDA0002616614610000031
(1) Ketone compounds
The ketone compounds represented by the formula (I) in the invention are various.
R 1 Can be independently C 1-6 Alkyl, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentane, cyclohexane, most preferably methyl, ethyl, n-propyl, isopropyl;
R 1 and may independently be substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, wherein "substituted" means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C 1-6 Alkyl radical, C 1-6 Alkoxy, N-C 1-6 Alkylamino, N-di-C 1-6 Alkylamino, cyano, C 1-6 Amide group, C 1-6 Ester group, sulfonic acid group, halogenated C 1-6 Alkyl, preferably fluorine, chlorine, bromine, C 1-3 Alkyl radical, C 1-3 Alkoxy, cyano, C 1-6 Ester group, halo C 1-3 Alkyl, most preferably fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, cyano, trifluoromethyl;
R 2 can be independently C 1-6 Ester group, C 1-6 Alkylamide, morpholinylamide, cyano, preferably methyl, ethyl, propyl, N-methylamide, N-ethylamide, N-propylamide, N-dimethylamide, N-diethylamide, N-dipropylamide, morpholinylamideAmides, cyano, most preferably methyl ester, ethyl ester, N-methyl amide, N-ethyl amide, N-dimethyl amide, N-diethyl amide, morpholinyl amide, cyano.
The present invention includes, but is not limited to, the following ketone compounds:
Figure BDA0002616614610000041
(2) Thiourea and thiourea derivatives
The structures of formula (II) in the present invention include thiourea and N-C 1-6 Alkyl-substituted thioureas, i.e. R 3 、R 4 Can be independently selected from H and C 1-6 An alkyl group; preferred are thiourea and N-C 1-3 Alkyl substituted thioureas, most preferably thiourea, N-methyl thiourea, N-ethyl thiourea.
(3) Oxygen (or air)
The oxygen in the present invention may be pure oxygen, or a mixture of oxygen and other gases such as nitrogen (e.g. air).
(4) Activated carbon
In the synthesis method of the invention, the types of the active carbon can be divided into different shapes, different pore diameters and different sources. The shapes include powder, granule, amorphous shape, cylinder and sphere; the pore diameter comprises macropores, transition pores and micropores; the sources include wood activated carbon, coal activated carbon and mineral raw material activated carbon. The raw material of the activated carbon is preferably powder, particles, amorphous shapes, macropores, micropores, wood activated carbon and mineral activated carbon, and the raw material of the activated carbon is most preferably powder, particles, macropores, micropores, wood activated carbon and mineral activated carbon.
(5) Metal salt
The metal salt is prepared from a ketone compound with a structure shown in a formula (I) and thiourea or thiourea derivative with a structure shown in a formula (II) through condensation/oxidation coupling reaction to obtain the metal salt of the 4, 5-disubstituted-2-aminothiazole compound with the structure shown in the formula (III). The metal salt in the invention is a variable valence metal salt such as iron, copper, cobalt, nickel and the like. Iron salts include iron bromide (FeBr) 3 ) Iron chloride (FeCl) 3 ) Sulfuric acid, sulfuric acidIron (Fe) 2 (SO 4 ) 3 ) Iron nitrate (Fe (NO) 3 ) 3 ) Iron (III) bromide (FeBr) 2 ) Ferrous chloride (FeCl) 2 ) Ferrous sulfate (FeSO) 4 ) Ferrous nitrate (Fe (NO) 3 ) 2 ) (ii) a The copper salt comprises copper bromide (CuBr) 2 ) Copper chloride (CuCl) 2 ) Copper iodide (CuI) 2 ) Copper nitrate (Cu (NO) 3 ) 2 ) Copper bromide (CuBr), copper chloride (CuCl), copper iodide (CuI), copper nitrate (CuNO) 3 ) (ii) a Cobalt fluoride (CoF) 2 ) Cobalt chloride (CoCl) 2 ) Cobalt bromide (CoBr) 2 ) Cobalt iodide (CoI) 2 ) Cobalt nitrate (Co (NO) 3 ) 2 ) (ii) a Nickel fluoride (NiF) 2 ) Nickel chloride (NiCl) 2 ) Nickel bromide (NiBr) 2 ) Nickel iodide (NiI) 2 ) Nickel sulfate (NiSO) 4 ) (ii) a Preferably iron bromide (FeBr) 3 ) Iron chloride (FeCl) 3 ) Iron (III) bromide (FeBr) 2 ) Ferrous chloride (FeCl) 2 ) Iron nitrate (Fe (NO) 3 ) 3 ) Ferrous nitrate (Fe (NO) 3 ) 2 ) Copper bromide (CuBr) 2 ) Copper chloride (CuCl) 2 ) Copper bromide (CuBr), copper chloride (CuCl), copper nitrate (Cu (NO) 3 ) 2 ) And cuprous nitrate (CuNO) 3 )。
(6) Material proportioning
The material proportion involved in the preparation method of the invention comprises the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II), the mass ratio of the ketone compound with the structure shown in the formula (I) to the activated carbon and the molar ratio of the ketone compound with the structure shown in the formula (I) to the metal salt.
The molar ratio of the ketone compound having the structure represented by formula (I) to the thiourea or the thiourea derivative having the structure represented by formula (II) may be 1 to 1, preferably 1 to 1.
The mass ratio of the ketone compound having the structure represented by the above formula (I) to the activated carbon may be 1.
The molar ratio of the ketone compound having the structure represented by the above formula (I) to the metal salt may be 1.
(7) Solvent(s)
The solvent used in the production method of the present invention includes an organic solvent and water. The organic solvent may be C 1-8 Alcohol, C 1-8 Ether, C 4-8 Cyclic ether of (5), chloro C 1-8 Alkane, C 1-8 Alkane, C 3-8 Cycloalkanes, C 6-12 Aromatic hydrocarbons or other kinds of solvents. C 1-8 The alcohol comprises C 1-8 Linear or branched alkyl alcohol of (C) 1-8 The ether comprises C 1-8 Linear or branched ethers of (C) 4-8 Cyclic ethers of (C), chloro 1-8 The alkane includes dichloromethane and chloroform, C 3-8 Cycloalkanes include cyclohexane, C 1-8 The alkane includes n-hexane, C 6-12 The aromatic hydrocarbon includes benzene, toluene, xylene, and other organic solvents include acetonitrile, ethyl acetate, and acetone. Preferred are methanol, ethanol, n-propanol, butanol, t-butanol, ethylene glycol, propylene glycol, octanol, polyethylene glycol, diethyl ether, tetrahydrofuran, dichloromethane, benzene, toluene, acetonitrile, ethyl acetate, acetone, and most preferred are methanol, ethanol, n-propanol, diethyl ether, tetrahydrofuran, dichloromethane, toluene, acetonitrile, ethyl acetate.
(7) Reaction temperature
In the preparation method of the invention, the reaction temperature is-10-150 ℃, preferably 20-80 ℃, and most preferably 40-80 ℃.
(8) Reaction time
In the production method of the present invention, the reaction time is not particularly limited, and an appropriate reaction time can be determined by detecting the residual percentage of the target product or the raw material by, for example, a liquid chromatograph, and the reaction can be completed by stirring for 0.2 to 8.0 hours in an oxygen atmosphere and for 1.0 to 72.0 hours in air.
(9) Post-treatment and separation purification
The mixture obtained after the reaction can be subjected to post-treatment and separation and purification, so that a purer final product is obtained. The separation and purification can be carried out by post-treatment and separation and purification methods well known to those skilled in the art, such as filtration, extraction, column chromatography, recrystallization, centrifugation, washing and adsorption, or various combinations thereof.
In a preferred embodiment, the post-treatment step after the reaction is completed may be as follows: after the reaction is finished, cooling the reaction liquid and filtering; decompressing and concentrating the filtrate to recover the solvent to obtain a crude product of the target product; separating the crude product by column chromatography (wherein the silica gel is 200-300 mesh silica gel), collecting eluate with mixed solution of petroleum ether and ethyl acetate as eluent, and concentrating to obtain pure product. The volume ratio of the petroleum ether to the ethyl acetate is as follows: 1.
The catalyst system of the preparation method of the present invention can be recycled, and in a preferred embodiment, the post-treatment step after the reaction is completed can be as follows: after the reaction is finished, recovering the reaction solvent under reduced pressure; adding solvents such as cyclohexane, normal hexane or toluene and the like into the obtained solid, stirring and dissolving the product, and filtering to obtain a mixture of active carbon and metal salt, wherein the filtrate is a target product solution; repeating the process for 2-4 times; mixing the filtrates, and recovering solvent under reduced pressure to obtain crude product; the mixture of the active carbon and the metal salt can be recycled.
The synthesis method of the 4, 5-disubstituted-2-aminothiazole compound provided by the invention has the following beneficial effects:
a) Compared with the prior art, the method takes 'green chemistry' as a characteristic, utilizes a catalytic system consisting of active carbon and metal salt, and prepares different types of 4, 5-disubstituted-2-aminothiazole compounds under the action of air or oxygen;
b) The raw materials are cheap and easy to obtain, the reaction condition is mild, the environment is friendly, and the method has the potential of large-scale industrial production;
c) The post-treatment is simple, and the catalytic system can be recycled.
Detailed Description
The present invention will be described in detail with reference to specific examples, but the use and purpose of these exemplary embodiments are only to exemplify the present invention, and do not limit the actual scope of the present invention in any way, and the scope of the present invention is not limited thereto.
EXAMPLE 1 Synthesis of ethyl 2-amino-4-phenylthiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), copper bromide (23.23mg, 0.104mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; 50mL of water was added and extracted with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 113.1mg of a white solid in 87.5% yield.
Synthesis method 2
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), cuprous bromide (22.38mg, 0.156mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and evaporating the solvent under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 112.3mg of a white solid in 86.9% yield.
Synthesis method 3
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), copper chloride (13.98mg, 0.104mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 115.9mg of a white solid in 89.7% yield.
Synthesis method 4
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), cuprous chloride (15.44mg, 0.156mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and evaporating the solvent under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 111.5mg of a white solid in 86.3% yield.
Synthesis method 5
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), copper nitrate (29.26mg, 0.156mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; separation and purification gave 107.8mg of a white solid with a yield of 83.4%.
Synthesis method 6
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), cuprous nitrate (19.59mg, 0.156mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and evaporating the solvent under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the separation and purification gave 112.7mg of a white solid with a yield of 87.2%.
Synthesis method 7
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), iron bromide (23.1mg, 0.078mmol) and activated carbon (200 mg) were charged into a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and evaporating the solvent under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was purified by column chromatography to give 122.4mg of a white solid in 94.7% yield.
Synthesis method 8
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), ferric chloride (16.87mg, 0.104mmol) and activated carbon (150 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 119.3mg of a white solid in 92.3% yield.
Synthesis method 9
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), ferrous bromide (33.64mg, 0.156mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; 50mL of water was added and extracted with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 114.4mg of a white solid in 88.5% yield.
Synthesis method 10
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), ferrous chloride (19.77mg, 0.156mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 112.3mg of a white solid in 86.9% yield.
Synthesis method 11
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), ferric nitrate (25.15mg, 0.104mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 105.3mg of a white solid in 81.5% yield.
Synthesis method 12
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), ferrous nitrate (28.06mg, 0.156mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the crude product was isolated and purified to give 104.1mg of a white solid in 80.5% yield.
Synthesis method 13
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), copper nitrate (29.26mg, 0.156mmol) and activated carbon (200 mg) were added to a reaction flask, followed by addition of 30mL of anhydrous ethanol as a solvent and stirring under an air atmosphere for 8 hours. After the reaction is finished, filtering, and removing the solvent by evaporation under reduced pressure; adding 50mL of water, and extracting with ethyl acetate; the organic phases were combined and washed with saturated brine; drying the anhydrous sodium sulfate, and then decompressing and steaming to remove the organic solvent to obtain a crude product; the white solid is obtained by separation and purification, and the yield is 85.7 percent.
Synthesis method 14
Ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4 mg, 0.78mmol), ferric chloride (16.87mg, 0.104mmol) and activated carbon (150 mg) were added to a reaction flask, followed by addition of 30mL of absolute ethanol as a solvent and stirring under an oxygen atmosphere for 1 hour. After the reaction was complete, 119.3mg of a white solid was obtained after workup, yield 92.3%. In addition, the yield of the target product obtained by recycling the activated carbon and the metal catalyst in the reaction system once was 90.3%, the yield of the target product obtained by recycling twice was 86.3%, the yield of the target product obtained by recycling three times was 84.7%, the yield of the target product obtained by recycling four times was 82.6%, and the yield of the target product obtained by recycling five times was 81.2%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.76(s,2H),7.58(m,2H),7.35(m,3H),4.05(q,2H),1.10(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝170.3,161.6,159.1,134.8,129.9(2C),129.1,127.7(2C),108.9,60.6,14.3ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 12 H 13 N 2 O 2 S + [M+H] + :249.0698；
Found 249.0686.
example 2 Synthesis of ethyl 2-amino-4- (2-methoxyphenyl) thiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 2-amino-4- (2-methoxyphenyl) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 4 in example 1, except that ethyl 3- (2-methoxyphenyl) -3-oxopropanoate (100mg, 0.45mmol) was used instead of ethyl 3-oxo-3-phenylpropionate in example 1, and 102.5mg of a white solid was obtained in a yield of 81.4%.
Synthesis method 2
Ethyl 2-amino-4- (2-methoxyphenyl) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 5 in example 1, except that ethyl 3- (2-methoxyphenyl) -3-oxopropanoate (100mg, 0.45mmol) was used instead of ethyl 3-oxo-3-phenylpropionate in example 1, and 99.2mg of a white solid was obtained in a yield of 78.7%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.72(s,2H),7.33(m,1H),7.20(dd,1H),7.00(d,1H),6.93(t,1H),3.97(q,2H),3.68(s,3H),1.01(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝170.1,161.5,157.2,155.7,130.5,129.9,129.1,125.3,119.9,111.3,110.7,60.1,55.6,14.3ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 13 H 15 N 2 O 2 S + [M+H] + :279.0803；
Found 279.0800.
EXAMPLE 3 Synthesis of ethyl 2-amino-4- (4-bromophenyl) thiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 2-amino-4- (4-bromophenyl) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 9 in example 1, except that ethyl 3- (4-bromophenyl) -3-oxopropanoate (100mg, 0.37mmol) was used in place of ethyl 3-oxo-3-phenylpropionate in example 1, to give 102.58mg of a white solid in a yield of 85%.
Synthesis method 2
Ethyl 2-amino-4- (4-bromophenyl) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 12 in example 1, except that ethyl 3- (4-bromophenyl) -3-oxopropanoate (100mg, 0.37mmol) was used instead of ethyl 3-oxo-3-phenylpropionate in example 1, and 104.6mg of a white solid was obtained in a yield of 86.7%.
Synthesis method 3
Ethyl 2-amino-4- (4-bromophenyl) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 2 in example 1, except that ethyl 3- (4-bromophenyl) -3-oxopropanoate (100mg, 0.37mmol) was used instead of ethyl 3-oxo-3-phenylpropionate in example 1, and 104.4mg of a white solid was obtained in 83.5% yield.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.88(s,2H),7.58(dd,4H),4.09(dd,2H),1.53(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝170.4,161.4,157.7,134.1,132.1(2C),130.7(2C),122.4,109.0,60.6,14.5ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 12 H 12 BrN 2 O 2 S + [M+H] + :328.9782；
Found 328.9779.
example 4.2 Synthesis of ethyl-amino-4- (4-methoxyphenyl) thiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 3- (4-methoxyphenyl) -3-oxopropanoate (100mg, 0.45mmol) was used in place of ethyl 3-oxo-3-phenylpropionate in example 1 to synthesize ethyl 2-amino-4- (4-methoxyphenyl) thiazole-5-carboxylate in the same manner as in Synthesis method 7 in example 1, and 105.9mg of a white solid was obtained in 84.6% yield.
Synthesis method 2
Ethyl 2-amino-4- (4-methoxyphenyl) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 12 in example 1, except that ethyl 3- (4-methoxyphenyl) -3-oxopropanoate (100mg, 0.45mmol) was used in place of ethyl 3-oxo-3-phenylpropionate in example 1, and 101.8mg of a white solid was obtained in a yield of 81.3%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.80(s,2H),7.66(dd,2H),6.93(m,2H),4.10(q,2H),1.17(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝169.9,161.7,160.0,158.9,131.6(2C),127.2,113.0(2C),107.5,60.3,55.5,14.5ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 13 H 15 N 2 O 2 S + [M+H] + :279.0803；
Found 279.0807.
example 5 Synthesis of ethyl 2-amino-4- (3, 4, 5-trimethoxyphenyl) thiazole-5-carboxylate
The present embodiment includes the following operations:
ethyl 2-amino-4- (3, 4, 5-trimethoxyphenyl) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 7 in example 1, except that ethyl 3-oxo-3- (3, 4, 5-trimethoxyphenyl) propionate (100mg, 0.35mmol) was used instead of ethyl 3-oxo-3-phenyl propionate in example 1, and 103.3mg of a white solid was obtained in a yield of 86.2%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.85(s,2H),7.03(s,2H),4.10(q,2H),3.77(s,6H),3.70(s,3H),1.15(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝170.0,161.6,158.6,152.2(2C),138.5,130.2,108.6,107.8,60.5,60.4,56.2(2C),14.4ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 15 H 19 N 2 O 5 S + [M+H] + :339.1015；
Found 339.1028.
example 6.2 Synthesis of amino-N-methyl-4-phenylthiazole-5-carboxamide
The present embodiment includes the following operations:
synthesis method 1
2-amino-N-methyl-4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 8 of example 1, using N-methyl-3-oxo-3-phenylpropanamide (100mg, 0.56mmol) in place of ethyl 3-oxo-3-phenylpropionate of example 1, and yielded 105.8mg of a white solid with a yield of 80.4%.
Synthesis method 2
2-amino-N-methyl-4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 12 of example 1, using N-methyl-3-oxo-3-phenylpropanamide (100mg, 0.56mmol) in place of ethyl 3-oxo-3-phenylpropionate of example 1, and yielded 105.1mg of a white solid in a yield of 79.8%.
Synthesis method 3
2-amino-N-methyl-4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 5 in example 1, using N-methyl-3-oxo-3-phenylpropionamide (100mg, 0.56mmol) in place of ethyl 3-oxo-3-phenylpropionate in example 1, and yielded 109.4mg of a white solid in a yield of 83.1%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.60(s,1H),7.58(m,2H),7.42(s,2H),7.35(m,3H),2.62(d,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝167.3,162.6,150.9,135.2,129.1(2C),128.4,128.2(2C),114.7,26.6ppm；
theoretical calculations and experimental results for high resolution mass spectrometry analysis of the product are as follows:
HRMS(ESI-TOF)Calcd for C 11 H 12 N 3 OS + [M+H] + :234.0701；
Found 234.0693.
EXAMPLE 7 Synthesis of 2-amino-N, N-dimethyl-4-phenylthiazole-5-carboxamide
The present embodiment includes the following operations:
synthesis method 1
2-amino-N, N-dimethyl-4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 3 of example 1 using N, N-dimethyl-3-oxo-3-phenylpropanamide (100mg, 0.52mmol) in place of ethyl 3-oxo-3-phenylpropionate of example 1, to give 101.4mg of a white solid in a yield of 78.4%.
Synthesis method 2
2-amino-N, N-dimethyl-4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 4 of example 1 using N, N-dimethyl-3-oxo-3-phenylpropanamide (100mg, 0.52mmol) in place of ethyl 3-oxo-3-phenylpropionate of example 1, and was obtained as a white solid in a yield of 99.4mg (76.9%).
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.51(d,2H),7.37(m,3H),7.31(s,2H),2.75(s,6H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝167.6,163.9,147.9,135.1,128.8(2C),128.5,127.5(2C),112.7,37.5(2C)ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 12 H 14 N 3 OS + [M+H] + :248.0858；
Found 248.0852.
EXAMPLE 8 Synthesis of 2-amino-N, N-diethyl-4-phenylthiazole-5-carboxamide
The present embodiment includes the following operations:
synthesis method 1
2-amino-N, N-diethyl-4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 7 in example 1 except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with N, N-diethyl-3-oxo-3-phenylpropionamide (100mg, 0.46mmol), to give 111.4mg of a white solid in a yield of 88.7%.
Synthesis method 2
2-amino-N, N-diethyl-4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 1 in example 1 except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with N, N-diethyl-3-oxo-3-phenylpropionamide (100mg, 0.46mmol), and 106.1mg of a white solid was obtained in a yield of 84.5%.
Synthesis method 3
2-amino-N, N-diethyl-4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 5 in example 1 except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with N, N-diethyl-3-oxo-3-phenylpropionamide (100mg, 0.46mmol), and 106.9mg of a white solid was obtained in a yield of 85.1%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.59(s,2H),7.33(m,5H),3.27(s,4H),0.96(s,6H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝167.0,163.4,146.8,134.9,128.6(2C),128.3,127.5(2C),112.7,42.8(2C),12.8(2C)ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 14 H 18 N 3 OS + [M+H] + :276.1171；
Found 276.1174.
EXAMPLE 9 Synthesis of (2-amino-4-phenylthiazol-5-yl) (morpholino) methanone
The present embodiment includes the following operations:
synthesis method 1
(2-amino-4-phenylthiazol-5-yl) (morpholino) methanone was synthesized in the same manner as in Synthesis method 1 in example 1, except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with 1-morpholino-3-phenylpropane-1, 3-dione (100mg, 0.43mmol), and 118.2mg of a white solid was obtained in a yield of 95.3%.
Synthesis method 2
(2-amino-4-phenylthiazol-5-yl) (morpholino) methanone was synthesized in the same manner as in Synthesis method 2 in example 1, except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with 1-morpholino-3-phenylpropane-1, 3-dione (100mg, 0.43mmol), whereby 116.2mg of a white solid was obtained in a yield of 93.7%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.50(d,2H),7.41(m,2H),7.38(s,2H),7.37(m,1H),3.33(m,4H),3.17(m,4H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝167.9,162.8,148.9,134.9,128.9(2C),128.7,128.0(2C),111.7,65.7(2C),48.9(2C)ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 14 H 16 N 3 O 2 S + [M+H] + :290.0963；
Found 290.0960.
EXAMPLE 10 Synthesis of 2-amino-4-phenylthiazole-5-carbonitrile
The present embodiment includes the following operations:
2-amino-4-phenylthiazole-5-carbonitrile was synthesized in the same manner as in Synthesis method 7 in example 1, using 3-oxo-3-phenylpropanenitrile (100mg, 0.69mmol) in place of ethyl 3-oxo-3-phenylpropionate in example 1, to give 134.9mg of white solid in a yield of 97.3%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝8.24(s,2H),7.92(m,2H),7.50(m,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝171.0,161.4,132.9,130.4,129.2(2C),127.8(2C),115.7,84.0ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 10 H 6 N 2 S - [M-H] - :200.0282；
Found 200.0290.
EXAMPLE 11 Synthesis of 2-amino-4- (4-bromophenyl) thiazole-5-carbonitrile
The present embodiment includes the following operations:
synthesis method 1
2-amino-4- (4-bromophenyl) thiazole-5-carbonitrile was synthesized in the same manner as in Synthesis method 7 in example 1, except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with 3- (4-bromophenyl) -3-oxopropanenitrile (100mg, 0.45mmol), to give 119.0mg of a white solid in yield of 95.2%.
Synthesis method 2
2-amino-4- (4-bromophenyl) thiazole-5-carbonitrile was synthesized in the same manner as in Synthesis method 6 of example 1, except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with 3- (4-bromophenyl) -3-oxopropanenitrile (100mg, 0.45mmol), to give 116.4mg of a white solid in a yield of 93.1%.
Synthesis method 3
2-amino-4- (4-bromophenyl) thiazole-5-carbonitrile was synthesized in the same manner as in Synthesis method 12 in example 1, except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with 3- (4-bromophenyl) -3-oxopropanenitrile (100mg, 0.45mmol), to give 117.8mg of a white solid in 94.2% yield.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝8.28(s,2H),7.86(dd,2H),7.73(dd,2H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝171.1,161.0,132.3(2C),132.0,129.7(2C),123.8,115.4,84.5ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 10 H 5 BrN 3 S - [M-H] - :279.9367；
Found 279.9376.
example 12.2 Synthesis of amino-4- (3, 4, 5-trimethoxyphenyl) thiazole-5-carbonitrile
The present embodiment includes the following operations:
synthesis method 1
2-amino-4- (3, 4, 5-trimethoxyphenyl) thiazole-5-carbonitrile was synthesized in the same manner as in Synthesis method 4 of example 1, except that ethyl 3-oxo-3-phenylpropionate (100mg, 0.43mmol) in example 1 was replaced with 3-oxo-3- (3, 4, 5-trimethoxyphenyl) propionitrile, to give 94.5mg of a white solid in a yield of 76.3%.
Synthesis method 2
2-amino-4- (3, 4, 5-trimethoxyphenyl) thiazole-5-carbonitrile was synthesized in the same manner as in Synthesis method 5 in example 1, except that ethyl 3-oxo-3-phenylpropionate in example 1 was replaced with 3-oxo-3- (3, 4, 5-trimethoxyphenyl) propionitrile (100mg, 0.43mmol), to give 92.5mg of a white solid in a yield of 74.7%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝8.26(s,2H),7.25(s,2H),3.82(s,6H),3.73(s,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝170.8,161.2,153.2(2C),139.3,128.2,115.9,105.3(2C),83.5,60.5,56.2(2C)ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 13 H 12 N 3 O 3 S - [M-H] - :290.0599；
Found 290.0606.
example 13 Synthesis of ethyl 2- (methylamino) -4-phenylthiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 2- (methylamino) -4-phenylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 8 of example 1, except that ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol) and 1-methylthiourea (70.35mg, 0.78mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 97.3mg of a white solid in a yield of 71.3%.
Synthesis method 2
Ethyl 2- (methylamino) -4-phenylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 9 in example 1, using ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol) and 1-methylthiourea (70.35mg, 0.78mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 96.7mg of a white solid in a yield of 70.9%.
Synthesis method 3
Ethyl 2- (methylamino) -4-phenylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 5 in example 1, using ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol) and 1-methylthiourea (70.35mg, 0.78mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 95.1mg of a white solid in a yield of 69.7%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝8.38(q,1H),7.66(dd,2H),7.38(m,3H),4.09(q,2H),2.88(d,3H),1.15(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝170.7,161.5,159.4,135.1,130.0(2C),129.0,127.7(2C),108.4,60.4,31.3,14.4ppm；
theoretical calculations and experimental results for high resolution mass spectrometry analysis of the product are as follows:
HRMS(ESI-TOF)Calcd for C 13 H 15 N 2 O 2 S + [M+H] + :263.0854；
Found 263.0852.
example 14 Synthesis of N, N-dimethyl-2- (methylamino) -4-phenylthiazole-5-carboxamide
The present embodiment includes the following operations:
synthesis method 1
N, N-dimethyl-2- (methylamino) -4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 7 of example 1, using N, N-dimethyl-3-oxo-3-phenylpropanamide (100mg, 0.52mmol), 1-methylthiourea (70.71mg, 0.78mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to obtain 121.1mg of a white solid in a yield of 88.6%.
Synthesis method 2
N, N-dimethyl-2- (methylamino) -4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 12 of example 1, using N, N-dimethyl-3-oxo-3-phenylpropanamide (100mg, 0.52mmol), 1-methylthiourea (70.71mg, 0.78mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 117.1mg of a white solid in a yield of 85.7%.
Synthesis method 3
N, N-dimethyl-2- (methylamino) -4-phenylthiazole-5-carboxamide was synthesized in the same manner as in Synthesis method 4 of example 1, except for using N, N-dimethyl-3-oxo-3-phenylpropionamide (100mg, 0.52mmol) and 1-methylthiourea (70.71mg, 0.78mmol) instead of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to obtain 112.6mg of a white solid in a yield of 82.4%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.87(q,1H),7.54(d,2H),7.40(m,2H),7.35(m,1H),2.88(d,3H),2.73(s,6H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝168.3,163.9,148.5,135.2,128.8(2C),128.5,127.6(2C),112.3,37.5(2C),31.3ppm；
theoretical calculations and experimental results for high resolution mass spectrometry analysis of the product are as follows:
HRMS(ESI-TOF)Calcd for C 13 H 15 N 3 OSNa + [M+Na] + :284.0834；
Found 284.0832.
example 15 Synthesis of 2- (methylamino) -4-phenylthiazole-5-carbonitrile
The present embodiment includes the following operations:
synthesis method 1
2- (methylamino) -4-phenylthiazole-5-carbonitrile was synthesized in the same manner as in Synthesis method 12 of example 1, substituting 3-oxo-3-phenylpropanenitrile (100mg, 0.69mmol) and 1-methylthiourea (93.15mg, 1.03mmol) for ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 118.1mg of a white solid in a yield of 79.6%.
Synthesis method 2
2- (methylamino) -4-phenylthiazole-5-carbonitrile was synthesized in the same manner as in Synthesis method 1 in example 1, using 3-oxo-3-phenylpropanenitrile (100mg, 0.69mmol) and 1-methylthiourea (93.15mg, 1.03mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 120.0mg of a white solid in a yield of 80.9%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝8.74(s,1H),7.97(d,2H),7.51(m,3H),2.95(d,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝171.1,161.5,132.9,130.4,129.2(2C),127.9(2C),115.7,83.7,31.5ppm；
theoretical calculations and experimental results for high resolution mass spectrometry analysis of the product are as follows:
HRMS(ESI-TOF)Calcd for C 11 H 8 N 3 S - [M-H] - :214.0439；
Found 214.0517.
example 16.Synthesis of ethyl 2-amino-4-methylthiazole-5-carboxylate
The present embodiment includes the following operations:
ethyl 2-amino-4-methylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 3 in example 1, except that ethyl 3-oxobutyrate (100mg, 0.77mmol) was used in place of ethyl 3-oxo-3-phenylpropionate in example 1, to give 102.1mg of a white solid with a yield of 71.3%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.70(s,2H),4.15(q,2H),2.37(s,3H),1.22(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝170.7,162.4,159.9,107.8,60.2,17.6,14.8ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 7 H 11 N 2 O 2 S + [M+H] + :187.0541；
Found 187.0538.
example 17 Synthesis of ethyl 4-methyl-2- (methylamino) thiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 4-methyl-2- (methylamino) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 9 in example 1, using ethyl 3-oxobutyrate (100mg, 0.77mmol), 1-methylthiourea (103.90mg, 1.15mmol) instead of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to obtain 90.3mg of a white solid in a yield of 58.7%.
Synthesis method 2
Ethyl 4-methyl-2- (methylamino) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 12 in example 1, except for using ethyl 3-oxo-3-phenylpropionate (100mg, 0.77mmol) and 1-methylthiourea (103.90mg, 1.15mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to obtain 89.4mg of a white solid in a yield of 58.1%.
Synthesis method 3
Ethyl 4-methyl-2- (methylamino) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 3 in example 1, except for ethyl 3-oxo-3-phenylpropionate (100mg, 0.77mmol) and 1-methylthiourea (103.90mg, 1.15mmol) in example 1 and then substituting ethyl 3-oxo-3-phenylpropionate and thiourea to obtain 91.7mg of a white solid in a yield of 59.6%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝8.26(q,1H),4.15(q,2H),2.83(d,3H),2.42(s,3H),1.23(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝167.4,162.4,160.1,107.4,60.3,31.3,17.8,14.8ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 8 H 13 N 2 O 2 S + [M+H] + :201.0698；
Found 201.0695.
example 18.2 Synthesis of ethyl 2-amino-4-isopropylthiazole-5-carboxylate
The present embodiment includes the following operations:
ethyl 2-amino-4-isopropylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 9 in example 1, except that ethyl 4-methyl-3-oxopentanoate (100mg, 0.63mmol) was used in place of ethyl 3-oxo-3-phenylpropionate in example 1, to give 108.1mg of a white solid in yield of 79.8%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.75(s,2H),4.14(q,2H),3.77(sep,1H),1.21(t,3H),1.12(d,6H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝171.2,169.4,162.1,106.4,60.2,28.6,22.3(2C),14.8ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 9 H 15 N 2 O 2 S + [M+H] + :215.0854；
Found 215.0851.
example 19.4 Synthesis of Ethyl 4-isopropyl-2- (methylamino) thiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 4-isopropyl-2- (methylamino) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 10 in example 1, except for using ethyl 4-methyl-3-oxopentanoate (100mg, 0.63mmol) and 1-methylthiourea (85.47mg, 0.95mmol) instead of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 85.4mg of a white solid in a yield of 59.2%.
Synthesis method 2
Ethyl 4-isopropyl-2- (methylamino) thiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 6 in example 1, using ethyl 4-methyl-3-oxopentanoate (100mg, 0.63mmol) and 1-methylthiourea (85.47mg, 0.95mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 84.7mg of a white solid in 58.7% yield.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝8.32(q,1H),4.14(q,2H),3.79(sep,1H),2.81(d,3H),1.22(t,3H),1.13(d,6H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝172.0,169.8,162.1,106.1,60.2,31.5,28.7,22.3(2C),14.8ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 10 H 17 N 2 O 2 S + [M+H] + :229.1011；
Found 229.1007.
example 20 Synthesis of ethyl 2-amino-4-propylthiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 2-amino-4-propylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 9 in example 1, except that ethyl 3-oxohexanoate (100mg, 0.63mmol) was used instead of ethyl 3-oxo-3-phenylpropionate in example 1, whereby 66.5mg of a white solid was obtained in a yield of 49.1%.
Synthesis method 2
Ethyl 2-amino-4-propylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 12 in example 1, except that ethyl 3-oxohexanoate (100mg, 0.63mmol) was used instead of ethyl 3-oxo-3-phenylpropionate in example 1, to obtain 65.9mg of a white solid with a yield of 48.7%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝7.71(s,2H),4.13(q,2H),2.79(t,2H),1.58(six,2H),1.22(t,3H),0.87(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝170.8,164.1,162.3,107.9,60.2,32.5,22.3,14.8,14.2ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 9 H 14 N 2 O 2 S + [M+H] + :215.0854；
Found 215.0852.
example 21 Synthesis of ethyl 2- (methylamino) -4-propylthiazole-5-carboxylate
The present embodiment includes the following operations:
synthesis method 1
Ethyl 2- (methylamino) -4-propylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 7 in example 1, using ethyl 3-oxohexanoate (100mg, 0.63mmol), 1-methylthiourea (85.47mg, 0.95mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 72.2mg of a white solid in a yield of 50%.
Synthesis method 2
Ethyl 2- (methylamino) -4-propylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 1 in example 1, using ethyl 3-oxohexanoate (100mg, 0.63mmol), 1-methylthiourea (85.47mg, 0.95mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 70.3mg of a white solid in a yield of 48.7%.
Synthesis method 3
Ethyl 2- (methylamino) -4-propylthiazole-5-carboxylate was synthesized in the same manner as in Synthesis method 3 in example 1, using ethyl 3-oxohexanoate (100mg, 0.63mmol), 1-methylthiourea (85.47mg, 0.95mmol) in place of ethyl 3-oxo-3-phenylpropionate and thiourea in example 1, to give 71.2mg of a white solid in a yield of 49.3%.
The data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows:
1 H-NMR(600MHz,DMSO-d 6 ):δ＝8.26(q,1H),4.14(q,2H),2.82(t,2H),2.81(d,3H),1.59(six,2H),1.22(t,3H),0.88(t,3H)ppm；
the data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows:
13 C-NMR(600MHz,DMSO-d 6 ):δ＝164.4,162.2(2C),107.5,60.2,32.7,22.4,14.8,14.3(2C)ppm；
theoretical calculations and experimental results for high resolution mass spectrometry of the product are as follows:
HRMS(ESI-TOF)Calcd for C 10 H 17 N 2 O 2 S + [M+H] + :229.1011；
Found 229.1007.
as can be seen from the above examples 1 to 21, when the method of the present invention is employed, 4, 5-disubstituted-2-aminothiazole compounds can be obtained in higher yield.
In summary, it is clear from all the above embodiments that, when the method of the present invention is adopted, in a solvent, in an oxygen or air atmosphere, a ketone compound having a structure shown in formula (I) and thiourea or a thiourea derivative having a structure shown in formula (II) are used as reaction raw materials, and under the co-catalysis of activated carbon and a metal salt, a 4, 5-disubstituted-2-aminothiazole compound having a structure shown in formula (III) is obtained through an oxidative coupling reaction, so as to provide a brand new synthetic route for efficient, rapid and green synthesis of the compound.
Finally, it should be noted that: the use of these examples is merely to illustrate the invention and is not intended to limit the scope of the invention. While the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: as the present invention may be modified in several different ways without departing from the spirit and principle of the invention, the scope of protection is only limited by the claims and not by the specific embodiments described above, and each implementation within its scope is to be considered as the invention.

Claims (24)

1. A synthesis method of 4, 5-disubstituted-2-aminothiazole compounds is characterized in that ketone compounds with a structure shown as a formula (I) and thiourea or thiourea derivatives with a structure shown as a formula (II) are used as reaction raw materials in an oxygen or air atmosphere, and under the co-catalysis action of activated carbon and metal salt, the 4, 5-disubstituted-2-aminothiazole compounds with a structure shown as a formula (III) are obtained through condensation/oxidation coupling reaction:
Figure 165203DEST_PATH_IMAGE001
wherein,
R 1 independently is C 1 - 6 Alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, wherein substituted means that one or more H in the group is substituted with a substituent selected from the group consisting of: halogen, C 1 - 6 Alkyl radical, C 1 - 6 Alkoxy, N-C 1 - 6 Alkylamino, N-di-C 1 - 6 Alkylamino, cyano, amido, ester, sulfonic, haloC 1 - 6 An alkyl group;
R 2 independently is C 1 - 6 Ester group, C 1 - 6 Alkylamido, morpholinylamide, cyano;
R 3 、R 4 independently selected from H, C 1 - 6 An alkyl group;
the metal salt is selected from ferric bromide, ferric chloride, ferric sulfate, ferric nitrate, ferrous bromide, ferrous chloride, ferrous sulfate, ferrous nitrate, cupric bromide, cupric chloride, cupric iodide, cupric nitrate, cuprous bromide, cuprous chloride, cuprous iodide, cuprous nitrate, cobalt fluoride, cobalt chloride, cobalt bromide, cobalt iodide, cobalt nitrate, nickel fluoride, nickel chloride, nickel bromide, nickel iodide and nickel sulfate.
2. The method of synthesis according to claim 1,
R 1 independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopentane, cyclohexane, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, the substituent is fluorine, chlorine, bromine, C 1 - 3 Alkyl radical, C 1 - 3 Alkoxy, cyano, C 1 - 6 Ester group, C 1 - 3 A haloalkyl group.
3. The method of synthesis according to claim 2,
the substituent is fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, cyano or trifluoromethyl.
4. A synthesis process according to any one of claims 1 to 3,
R 2 methyl ester, ethyl ester, propyl ester, N-methyl amide, N-ethyl amide, N-propyl amide, N-dimethyl amide, N-diethyl amide, N-dipropyl amide, morpholinyl amide and cyano.
5. The synthetic method according to any one of claims 1 to 3,
the ketone compound is selected from:
Figure 879081DEST_PATH_IMAGE002
。
6. the method of synthesis according to claim 4,
the ketone compound is selected from:
Figure 393239DEST_PATH_IMAGE003
。
7. the synthetic method according to any one of claims 1 to 3 and 6,
the thiourea or the thiourea derivative is thiourea or N-C 1 - 3 Alkyl substituted thiourea.
8. The method of synthesis according to claim 4,
the thiourea or thiourea derivative is thiourea or N-C 1 - 3 Alkyl substituted thiourea.
9. The method of synthesis according to claim 7,
the thiourea or thiourea derivatives are thiourea, N-methylthiourea and N-ethylthiourea.
10. The method of synthesis according to claim 8,
the thiourea or thiourea derivatives are thiourea, N-methyl thiourea and N-ethyl thiourea.
11. The synthesis method according to any one of claims 1, 2, 3, 6, 8 to 10, wherein the mass ratio of the ketone compound having the structure represented by formula (I) to the activated carbon is 1:0.2 to 1:30; the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II) is 1:1 to 1:5.
12. the synthesis method according to claim 4, wherein the mass ratio of the ketone compound having the structure represented by formula (I) to the activated carbon is 1:0.2 to 1:30, of a nitrogen-containing gas; the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II) is 1:1 to 1:5.
13. the synthesis method according to claim 5, wherein the mass ratio of the ketone compound having the structure represented by formula (I) to the activated carbon is 1:0.2 to 1:30, of a nitrogen-containing gas; the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II) is 1:1 to 1:5.
14. the synthesis method according to claim 7, wherein the mass ratio of the ketone compound having the structure represented by formula (I) to the activated carbon is 1:0.2 to 1:30; the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II) is 1:1 to 1:5.
15. the synthesis method according to claim 11, wherein the mass ratio of the ketone compound having the structure represented by formula (I) to the activated carbon is 1:1 to 1:5; the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II) is 1: 1-1.
16. The synthesis method according to any one of claims 12 to 14, wherein the mass ratio of the ketone compound having the structure represented by formula (I) to the activated carbon is 1:1 to 1:5; the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II) is 1:1 to 1.
17. The synthesis method according to claim 11, wherein the mass ratio of the ketone compound having the structure represented by formula (I) to the activated carbon is 1:1 to 1:2: the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II) is 1:1 to 1:1.5.
18. the synthesis method according to any one of claims 12 to 14, wherein the mass ratio of the ketone compound having the structure represented by formula (I) to the activated carbon is 1:1 to 1:2: the molar ratio of the ketone compound with the structure shown in the formula (I) to the thiourea or the thiourea derivative with the structure shown in the formula (II) is 1:1 to 1:1.5.
19. the synthesis method according to claim 1, wherein the molar ratio of the ketone compound having the structure represented by formula (I) to the metal salt is 1:0.01 to 1:5.
20. the synthesis method according to claim 1, wherein the molar ratio of the ketone compound having the structure represented by formula (I) to the metal salt is 1:0.05 to 1:0.2.
21. the synthesis method according to claim 1, wherein the molar ratio of the ketone compound having the structure represented by formula (I) to the metal salt is 1:0.1 to 1:0.15.
22. the method of claim 1, wherein the solvent comprises C 1 - 8 Alcohol, C 1 - 8 Ether, chloro C 1 - 8 Alkane, C 1 - 8 Alkane, C 3-8 Cycloalkanes, C 6-12 Aromatic hydrocarbons or other kinds of solvents.
23. The synthesis process according to claim 1, characterized in that the reaction temperature is from-10 ℃ to 150 ℃: stirring for 0.2-8.0 hours in oxygen atmosphere to finish the reaction, and stirring for 1.0-72.0 hours in air to finish the reaction.
24. The method for synthesizing 4, 5-disubstituted-2-aminothiazole compounds according to claim 1, wherein said steps comprise: adding a ketone compound with a structure shown in a formula (I), thiourea or a thiourea derivative with a structure shown in a formula (II), metal salt and activated carbon into a reaction bottle, then adding a solvent, stirring in an oxygen or air atmosphere, and after the reaction is finished, separating and purifying a crude product obtained by post-treatment by silica gel column chromatography to obtain a target product.
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