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

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

A kind of synthetic method of 4,5-disubstituted-2-aminothiazole compound

technical field

The invention belongs to the fields of organic synthesis and drug synthesis, in particular to a synthesis method of 4,5-disubstituted-2-aminothiazole compounds.

Background technique

The 2-aminothiazole ring is an important five-membered aromatic heterocycle containing nitrogen and sulfur heteroatoms. 4,5-disubstituted-2-aminothiazole compounds have various functions such as anticonvulsant, antiviral, antibacterial and insecticidal, and are widely used in many fields such as chemistry, pharmacy, biology and materials science.

The development of novel, efficient and environmentally friendly synthetic methods for 4,5-disubstituted-2-aminothiazoles is of great value for the development and utilization of 2-aminothiazoles.

The synthesis method of 4,5-disubstituted-2-aminothiazole compounds reported in the literature is summarized as follows:

1. Using α-halogenated ketones or their analogues as starting materials

1. Using α-haloketone as the starting material

In 1887, Hantzsch et al. (Hantzsch, A. and Weber, H., J. Chem. Ber., 20, 3118 (1887).) reported the synthesis of 4,5-disubstituted- Synthetic method of 2-aminothiazole compounds.

2. Using α-haloketimine as the starting material

In 1996, Kimpe et al. (Kimpe, N.De.and Cock, W.De., J.Heterocycl.Chem., 33, 1179 (1996).) reported that α-halogenated ketimine and thiourea in methanol Condensation in medium to obtain the synthetic method of 4,5-disubstituted-2-aminothiazole compounds.

2. Using ketones as starting materials

1. Use iodine element and thiourea

In 1945, Dodson et al. (Dodson, R.M.and King, L.C., J.Am.Chem.Soc., 67, 2242 (1945).) reported the reaction of ketone with iodine element and thiourea, and obtained Synthetic method of 4,5-disubstituted-2-aminothiazole compounds.

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 that ketone and thiourea reacted in N-bromosuccinimide (NBS) and A synthetic method for synthesizing 4,5-disubstituted-2-aminothiazole compounds in the presence of benzoyl oxide.

3. Using oxidants such as sulfuryl chloride and thiourea

In 1946, Dodson et al. (Dodson, R.M. and King, L.C., J.Am.Chem.Soc., 1946,68,871.) reported that the mixture of ketone and thiourea was treated with oxidants such as sulfuryl chloride, chlorosulfonic acid or thionyl chloride. The synthetic method of obtaining 4,5-disubstituted-2-aminothiazole compounds after treatment.

Three. 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 the preparation of 4,5-di Synthetic method of substituted-2-aminothiazole compounds.

Among the above-mentioned several types of methods, the method using α-haloketone or its analogues as raw materials, although the reaction conditions are relatively mild, has the disadvantages of high toxicity of raw materials and complicated preparation process; the method using ketones as raw materials uses simple raw materials. It is easy to get, but it needs to use an excessive amount of oxidant, which is expensive and has certain harm to the environment.

Therefore, it is of great theoretical significance and practical value to study and develop a synthetic method with cheap and easy-to-obtain raw materials, easy-to-control reaction conditions, simple operation, and environmental friendliness.

Contents of the invention

In view of this, in order to solve the defects in the above-mentioned prior art such as high toxicity of raw materials, complicated preparation process, expensive reagents, environmental pollution, etc., the inventors have developed a chemical synthesis method for 4,5-disubstituted-2-aminothiazole compounds The present invention has been accomplished after intensive research and a lot of creative work.

The technical problem solved by the present invention is to provide a synthetic method of 4,5-disubstituted-2-aminothiazole compounds, which is achieved by condensation/oxidative coupling between ketone compounds and thiourea or thiourea derivatives. Synthesis of 4,5-disubstituted-2-aminothiazole compounds by joint reaction has the advantages of cheap and easy-to-obtain raw materials, simple operation, mild conditions, and environmental friendliness, and has potential industrial application prospects.

In order to solve the above technical problems, the present invention provides the following technical solutions: in organic solvent or water, under oxygen (or air) atmosphere, with the ketone compound having the structure shown in formula (I) and the structure shown in formula (II) thiourea or thiourea derivatives as reaction raw materials, under the co-catalysis of activated carbon and metal salts, the 4,5-disubstituted-2-aminothiazoles of the structure shown in formula (III) are obtained by condensation/oxidative coupling reaction Compound, the above reaction process can be represented by the following reaction equation

(1) Ketones

In the present invention, there are various types of ketone compounds represented by formula (I).

_R 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 can be independently substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, wherein the "substitution" means that one or more H in the group is replaced by a substituent selected from the following group: Halogen, C _1-6 alkyl, C _1-6 alkoxy, NC _1-6 alkylamino, N,N-bis C _1-6 alkylamino, cyano, C _1-6 amido, C _{1 -6} ester group, sulfonic acid group, halogenated C _1-6 alkyl group, preferably fluorine, chlorine, bromine, C _1-3 alkyl group, C _1-3 alkoxy group, cyano group, C _1-6 ester group , Halogenated C _1-3 alkyl, most preferably fluorine, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, cyano, trifluoromethyl;

_R can be independently C _1-6 ester group, C _1-6 alkyl amido group, morpholino amide, cyano group, preferably methyl ester, ethyl ester, propyl ester, N-methylamide, N-ethyl amide, N-propylamide, N,N-dimethylamide, N,N-diethylamide, N,N-dipropylamide, morpholinoamide, cyano, most preferably methyl ester, Ethyl ester, N-methylamide, N-ethylamide, N,N-dimethylamide, N,N-diethylamide, morpholinoamide, cyano.

The present invention includes but not limited to ketone compounds as shown below:

(2) Thiourea and Thiourea Derivatives

In the present invention, the structure of formula (II) includes thiourea and NC _1-6 alkyl substituted thiourea, that is, R ₃ and R ₄ can be independently selected from H, C _1-6 alkyl; preferably thiourea and NC _{1 -3} alkyl substituted thiourea, most preferably thiourea, N-methylthiourea, N-ethylthiourea.

(3) Oxygen (or air)

The oxygen in the present invention can be pure oxygen, or a mixture of oxygen and nitrogen and other gases (such as air).

(4) Activated carbon

In the synthesis method in the present invention, the types of activated carbon can be divided into different shapes, different pore sizes and different sources. Shapes include powder, granular, amorphous, cylindrical and spherical; pore sizes include macropores, transition pores and micropores; sources include wood activated carbon, coal-based activated carbon and mineral raw material activated carbon. Preferable powdery, granule, amorphous, macroporous, microporous, woody activated carbon, mineral raw material activated carbon, most preferably powdery, granular, macroporous, microporous, woody activated carbon, mineral raw material activated carbon.

(5) metal salt

The metal salt in the present invention is prepared by condensation/oxidative coupling reaction of the ketone compound of the structure shown in the formula (I), the thiourea or the thiourea derivative shown in the formula (II) shown in the formula (III) Metal salts of 4,5-disubstituted-2-aminothiazoles of the structure. The metal salts in the present invention are variable-valence metal salts such as iron, copper, cobalt, and nickel. Iron salts include ferric bromide (FeBr ₃ ), ferric chloride (FeCl ₃ ), ferric sulfate (Fe ₂ (SO ₄ ) ₃ ), ferric nitrate (Fe(NO ₃ ) ₃ ), ferrous bromide (FeBr ₂ ) , ferrous chloride (FeCl ₂ ), ferrous sulfate (FeSO ₄ ), ferrous nitrate (Fe(NO ₃ ) ₂ ); copper salts include copper bromide (CuBr ₂ ), copper chloride (CuCl ₂ ), iodine Copper chloride (CuI ₂ ), copper nitrate (Cu(NO ₃ ) ₂ ), cuprous bromide (CuBr), cuprous chloride (CuCl), cuprous iodide (CuI), cuprous nitrate (CuNO ₃ ); Cobalt fluoride (CoF ₂ ), cobalt chloride (CoCl ₂ ), cobalt bromide (CoBr ₂ ), cobalt iodide (CoI ₂ ), cobalt nitrate (Co(NO ₃ ) ₂ ); nickel fluoride (NiF ₂ ) , nickel chloride (NiCl ₂ ), nickel bromide (NiBr ₂ ), nickel iodide (NiI ₂ ), nickel sulfate (NiSO ₄ ); preferably iron bromide (FeBr ₃ ), iron chloride (FeCl ₃ ), bromine Ferrous chloride (FeBr ₂ ), ferrous chloride (FeCl ₂ ), ferric nitrate (Fe(NO ₃ ) ₃ ), ferrous nitrate (Fe(NO ₃ ) ₂ ), copper bromide (CuBr ₂ ), chloride Copper (CuCl ₂ ), cuprous bromide (CuBr), cuprous chloride (CuCl), copper nitrate (Cu(NO ₃ ) ₂ ), and cuprous nitrate (CuNO ₃ ).

(6) Ratio of materials

The material ratio involved in the preparation method of the present invention includes the molar ratio of the ketone compound with the structure shown in the above formula (I) to the thiourea or thiourea derivative with the structure shown in the formula (II), the formula (I) The mol ratio of the ketone compound of structure shown in structure and the mass ratio of gac and the ketone compound of structure shown in formula (I) and metal salt.

The molar ratio of the ketone compound with the structure shown in the above formula (I) to the thiourea or thiourea derivative with the structure shown in the formula (II) can be 1:1 to 1:5, preferably 1:1 to 1:3, Most preferably 1:1 to 1:1.5.

The mass ratio of the ketone compound with the structure represented by the above formula (I) to the activated carbon may be 1:0.2-1:30, preferably 1:1-1:5, most preferably 1:1-1:2.

The molar ratio of the ketone compound with the structure represented by the above formula (I) to the metal salt may be 1:0.01-1:5, preferably 1:0.05-1:0.2, most preferably 1:0.1-1:0.15.

(7) Solvent

Solvents used in the preparation method of the present invention include organic solvents and water. Organic solvents can be C _1-8 alcohols, C _1-8 ethers, C _4-8 cyclic ethers, chlorinated C _1-8 alkanes, C _1-8 alkanes, C _3-8 cycloalkanes, C _6-12 aromatic At least one of hydrocarbons or other types of solvents. C _1-8 alcohols include C _1-8 straight or branched chain alkyl alcohols, C _1-8 ethers include C _1-8 straight or branched ethers, C _4-8 cyclic ethers, chlorinated C _1-8 alkanes include dichloromethane and chloroform, C _3-8 cycloalkanes include cyclohexane, C _1-8 alkanes include n-hexane, C _6-12 aromatics include benzene, toluene, xylene, and other organic solvents Including acetonitrile, ethyl acetate, acetone. Preferred are methanol, ethanol, n-propanol, butanol, tert-butanol, ethylene glycol, propylene glycol, octanol, polyethylene glycol, diethyl ether, tetrahydrofuran, dichloromethane, benzene, toluene, acetonitrile, ethyl acetate, acetone , most preferably methanol, ethanol, n-propanol, diethyl ether, tetrahydrofuran, dichloromethane, toluene, acetonitrile, ethyl acetate.

(7) Reaction temperature

In the preparation method of the present invention, the reaction temperature is -10°C to 150°C, preferably 20°C to 80°C, most preferably 40°C to 80°C.

(8) Response time

In the preparation method of the present invention, the reaction time is not particularly limited. For example, the appropriate reaction time can be determined by detecting the residual percentage of the target product or raw material by liquid chromatography. Usually, it can be reacted by stirring for 0.2 to 8.0 hours under an oxygen atmosphere. After completion, the reaction can be completed by stirring in the air for 1.0 to 72.0 hours.

(9) Post-treatment and separation and purification

The mixture obtained after the reaction can be post-treated and separated and purified to obtain a relatively pure final product. 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 combined methods for separation and purification.

In a preferred embodiment, the post-processing step after the reaction can be as follows: after the reaction, the reaction solution is cooled and then filtered; the filtrate is concentrated under reduced pressure to recover the solvent to obtain the crude product of the target product; the crude product is separated by column chromatography (wherein the silica gel is 200-300 mesh silica gel), using petroleum ether and ethyl acetate mixture as the eluent, collecting the eluate, and concentrating to obtain the pure product of the target product. The volume ratio of petroleum ether and ethyl acetate is: 1:50～50:1.

The catalytic system of the preparation method of the present invention can be recycled and used repeatedly. In a preferred embodiment, the post-processing step after the reaction can be as follows: after the reaction, the reaction solvent is recovered under reduced pressure; Add solvents such as cyclohexane, n-hexane or toluene to the product, stir the dissolved product, filter to obtain a mixture of activated carbon and metal salt, and the filtrate is the target product solution; repeat this process 2 to 4 times; combine the filtrate, recover the solvent under reduced pressure, and obtain the target product The crude product; the mixture of activated carbon and metal salt can be recycled and reused.

The synthesis method of 4,5-disubstituted-2-aminothiazole compounds provided by the present invention has the following beneficial effects:

a) Compared with the prior art, the present invention is characterized by "green chemistry", using a catalytic system composed of activated carbon and metal salts, under the action of air or oxygen, to prepare different types of 4,5-disubstituted-2-amino Thiazole compounds;

b) The raw materials are cheap and easy to obtain, the reaction conditions are mild, the environment is friendly, and it has the potential for large-scale industrial production;

c) The aftertreatment is simple, and the catalytic system can be recycled and reused.

Detailed ways

The present invention will be described in detail below through specific examples, but the use and purpose of these exemplary embodiments are only used to illustrate the present invention, and do not constitute any form of any limitation to the actual protection scope of the present invention, nor will the present invention The scope of protection is limited to this.

Embodiment 1. Synthesis of ethyl 2-amino-4-phenylthiazole-5-carboxylate

This embodiment includes the following operations:

Synthetic method 1

Add ethyl 3-oxo-3-phenylpropanoate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), copper bromide (23.23 mg, 0.104 mmol) and activated carbon (200 mg) into the reaction flask , followed by adding 30 mL of absolute ethanol as a solvent and stirring for 1 hour under an oxygen atmosphere. After the reaction was completed, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 113.1 mg of white solid was obtained, with a yield of 87.5%.

Synthetic method 2

Add ethyl 3-oxo-3-phenylpropionate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), cuprous bromide (22.38 mg, 0.156 mmol) and activated carbon (200 mg) into the reaction flask , then added 30 mL of absolute ethanol as a solvent, and stirred for 1 hour under an oxygen atmosphere. After the reaction was completed, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 112.3 mg of white solid was obtained, with a yield of 86.9%.

Synthetic method 3

Add ethyl 3-oxo-3-phenylpropanoate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), copper chloride (13.98 mg, 0.104 mmol) and activated carbon (200 mg) into the reaction flask , followed by adding 30 mL of absolute ethanol as a solvent and stirring for 1 hour under an oxygen atmosphere. After the reaction is complete, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 115.9 mg of white solid was obtained with a yield of 89.7%.

Synthetic method 4

Add ethyl 3-oxo-3-phenylpropanoate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), cuprous chloride (15.44 mg, 0.156 mmol) and activated carbon (200 mg) into the reaction flask , then added 30 mL of absolute ethanol as a solvent, and stirred for 1 hour under an oxygen atmosphere. After the reaction was completed, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 111.5 mg of white solid was obtained, with a yield of 86.3%.

Synthetic method 5

Add ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), copper nitrate (29.26mg, 0.156mmol) and activated carbon (200mg) into the reaction flask, Subsequently, 30 mL of absolute ethanol was added as a solvent, and stirred for 1 hour under an oxygen atmosphere. After the reaction is complete, filter and evaporate the solvent under reduced pressure; add 50 mL of water and extract with ethyl acetate; combine the organic phases and wash with saturated brine; dry over anhydrous sodium sulfate and evaporate the organic solvent under reduced pressure to obtain a crude product; Purification gave 107.8 mg of white solid, yield 83.4%.

Synthetic method 6

Add ethyl 3-oxo-3-phenylpropanoate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), cuprous nitrate (19.59 mg, 0.156 mmol) and activated carbon (200 mg) into the reaction flask , followed by adding 30 mL of absolute ethanol as a solvent and stirring for 1 hour under an oxygen atmosphere. After the reaction is complete, filter and evaporate the solvent under reduced pressure; add 50 mL of water and extract with ethyl acetate; combine the organic phases and wash with saturated brine; dry over anhydrous sodium sulfate and evaporate the organic solvent under reduced pressure to obtain a crude product; Purification gave 112.7mg of white solid, yield 87.2%.

Synthetic method 7

Add ethyl 3-oxo-3-phenylpropanoate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), ferric bromide (23.1 mg, 0.078 mmol) and activated carbon (200 mg) into the reaction flask , followed by adding 30 mL of absolute ethanol as a solvent and stirring for 1 hour under an oxygen atmosphere. After the reaction was completed, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification by column chromatography, 122.4 mg of white solid was obtained with a yield of 94.7%.

Synthetic method 8

Add ethyl 3-oxo-3-phenylpropanoate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), ferric chloride (16.87 mg, 0.104 mmol) and activated carbon (150 mg) into the reaction flask , followed by adding 30 mL of absolute ethanol as a solvent and stirring for 1 hour under an oxygen atmosphere. After the reaction was completed, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 119.3 mg of white solid was obtained, with a yield of 92.3%.

Synthetic method 9

Add ethyl 3-oxo-3-phenylpropionate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), ferrous bromide (33.64 mg, 0.156 mmol) and activated carbon (200 mg) into the reaction flask , then added 30 mL of absolute ethanol as a solvent, and stirred for 1 hour under an oxygen atmosphere. After the reaction was completed, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 114.4 mg of white solid was obtained with a yield of 88.5%.

Synthetic method 10

Add ethyl 3-oxo-3-phenylpropanoate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), ferrous chloride (19.77mg, 0.156mmol) and activated carbon (200mg) into the reaction flask , then added 30 mL of absolute ethanol as a solvent, and stirred for 1 hour under an oxygen atmosphere. After the reaction was completed, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 112.3 mg of white solid was obtained, with a yield of 86.9%.

Synthetic method 11

Add ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), ferric nitrate (25.15mg, 0.104mmol) and activated carbon (200mg) into the reaction flask, Subsequently, 30 mL of absolute ethanol was added as a solvent, and stirred for 1 hour under an oxygen atmosphere. After the reaction is complete, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 105.3 mg of white solid was obtained, with a yield of 81.5%.

Synthetic method 12

Add ethyl 3-oxo-3-phenylpropionate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), ferrous nitrate (28.06 mg, 0.156 mmol) and activated carbon (200 mg) into the reaction flask , followed by adding 30 mL of absolute ethanol as a solvent and stirring for 1 hour under an oxygen atmosphere. After the reaction was completed, filter, and evaporate the solvent under reduced pressure; add 50 mL of water, and extract with ethyl acetate; combine the organic phases, wash with saturated brine; dry over anhydrous sodium sulfate, and evaporate the organic solvent under reduced pressure to obtain a crude product; After separation and purification, 104.1 mg of white solid was obtained with a yield of 80.5%.

Synthetic method 13

Add ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol), thiourea (59.4mg, 0.78mmol), copper nitrate (29.26mg, 0.156mmol) and activated carbon (200mg) into the reaction flask, Subsequently, 30 mL of absolute ethanol was added as a solvent, and stirred for 8 hours under an air atmosphere. After the reaction is complete, filter and evaporate the solvent under reduced pressure; add 50 mL of water and extract with ethyl acetate; combine the organic phases and wash with saturated brine; dry over anhydrous sodium sulfate and evaporate the organic solvent under reduced pressure to obtain a crude product; Purification gave 110.8 mg of white solid, yield 85.7%.

Synthetic method 14

Add ethyl 3-oxo-3-phenylpropanoate (100 mg, 0.52 mmol), thiourea (59.4 mg, 0.78 mmol), ferric chloride (16.87 mg, 0.104 mmol) and activated carbon (150 mg) into the reaction flask , followed by adding 30 mL of absolute ethanol as a solvent and stirring for 1 hour under an oxygen atmosphere. After the reaction was completed, 119.3 mg of white solid was obtained after treatment, with a yield of 92.3%. In addition, the yield of the target product obtained by reusing the activated carbon and the metal catalyst in the recovery reaction system once was 90.3%, the yield of the target product obtained by repeated use twice was 86.3%, and the yield of the target product obtained by repeated use three times was 84.7%. , the yield of the target product obtained by repeated use four times was 82.6%, and the yield of the target product obtained by repeated use five times was 81.2%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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

This embodiment includes the following operations:

Synthetic method 1

Replace the ethyl 3-oxo-3-phenylpropionate in Example 1 with 3-(2-methoxyphenyl)-3-oxopropionic acid ethyl ester (100mg, 0.45mmol), and Example The same method as Synthetic Method 4 in 1 was used to synthesize ethyl 2-amino-4-(2-methoxyphenyl)thiazole-5-carboxylate to obtain 102.5 mg of white solid with a yield of 81.4%.

Synthetic method 2

Replace the ethyl 3-oxo-3-phenylpropionate in Example 1 with 3-(2-methoxyphenyl)-3-oxopropionic acid ethyl ester (100mg, 0.45mmol), and Example Synthetic method 5 in 1 was the same method to synthesize ethyl 2-amino-4-(2-methoxyphenyl)thiazole-5-carboxylate to obtain 99.2 mg of white solid with a yield of 78.7%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of 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] ⁺ : 279.0803;

Found 279.0800.

Example 3. Synthesis of ethyl 2-amino-4-(4-bromophenyl)thiazole-5-carboxylate

This embodiment includes the following operations:

Synthetic method 1

Replace the ethyl 3-oxo-3-phenylpropionate in Example 1 with 3-(4-bromophenyl)-3-oxopropionic acid ethyl ester (100mg, 0.37mmol), and in Example 1 The same method as Synthetic Method 9 was used to synthesize ethyl 2-amino-4-(4-bromophenyl)thiazole-5-carboxylate to obtain 102.58 mg of white solid with a yield of 85%.

Synthetic method 2

Replace the ethyl 3-oxo-3-phenylpropionate in Example 1 with 3-(4-bromophenyl)-3-oxopropionic acid ethyl ester (100mg, 0.37mmol), and in Example 1 2-Amino-4-(4-bromophenyl)thiazole-5-carboxylic acid ethyl ester was synthesized by the same method as Synthetic Method 12 to obtain 104.6 mg of white solid with a yield of 86.7%.

Synthetic method 3

Replace the ethyl 3-oxo-3-phenylpropionate in Example 1 with 3-(4-bromophenyl)-3-oxopropionic acid ethyl ester (100mg, 0.37mmol), and in Example 1 The same method as Synthetic Method 2 was used to synthesize ethyl 2-amino-4-(4-bromophenyl)thiazole-5-carboxylate to obtain 104.4 mg of white solid with a yield of 83.5%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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. Synthesis of ethyl 2-amino-4-(4-methoxyphenyl)thiazole-5-carboxylate

This embodiment includes the following operations:

Synthetic method 1

3-(4-methoxyphenyl)-3-oxopropionic acid ethyl ester (100mg, 0.45mmol) was substituted for the 3-oxo-3-phenylpropionic acid ethyl ester in Example 1, and Example The same method as Synthetic Method 7 in 1 was used to synthesize ethyl 2-amino-4-(4-methoxyphenyl)thiazole-5-carboxylate to obtain 105.9 mg of white solid with a yield of 84.6%.

Synthetic method 2

3-(4-methoxyphenyl)-3-oxopropionic acid ethyl ester (100mg, 0.45mmol) was substituted for the 3-oxo-3-phenylpropionic acid ethyl ester in Example 1, and Example Synthetic method 12 in 1 was the same method to synthesize ethyl 2-amino-4-(4-methoxyphenyl)thiazole-5-carboxylate to obtain 101.8 mg of white solid with a yield of 81.3%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of 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] ⁺ : 279.0803;

Found 279.0807.

Example 5. Synthesis of ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)thiazole-5-carboxylate

This embodiment includes the following operations:

Replace ethyl 3-oxo-3-phenylpropionate in Example 1 with ethyl 3-oxo-3-(3,4,5-trimethoxyphenyl)propionate (100mg, 0.35mmol) , synthesized 2-amino-4-(3,4,5-trimethoxyphenyl)thiazole-5-carboxylic acid ethyl ester by the same method as Synthetic Method 7 in Example 1, and obtained 103.3 mg of white solid with a yield of 86.2 %.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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. Synthesis of 2-amino-N-methyl-4-phenylthiazole-5-carboxamide

This embodiment includes the following operations:

Synthetic method 1

Replace ethyl 3-oxo-3-phenylpropionate in Example 1 with N-methyl-3-oxo-3-phenylpropanamide (100mg, 0.56mmol), and the synthetic method in Example 1 8 The same method was used to synthesize 2-amino-N-methyl-4-phenylthiazole-5-carboxamide to obtain 105.8 mg of white solid with a yield of 80.4%.

Synthetic method 2

Replace ethyl 3-oxo-3-phenylpropionate in Example 1 with N-methyl-3-oxo-3-phenylpropanamide (100mg, 0.56mmol), and the synthetic method in Example 1 12 The same method was used to synthesize 2-amino-N-methyl-4-phenylthiazole-5-carboxamide to obtain 105.1 mg of white solid with a yield of 79.8%.

Synthetic method 3

Replace ethyl 3-oxo-3-phenylpropionate in Example 1 with N-methyl-3-oxo-3-phenylpropanamide (100mg, 0.56mmol), and the synthetic method in Example 1 5 The same method was used to synthesize 2-amino-N-methyl-4-phenylthiazole-5-carboxamide to obtain 109.4 mg of white solid with a yield of 83.1%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of 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

This embodiment includes the following operations:

Synthetic method 1

N,N-dimethyl-3-oxo-3-phenylpropionamide (100mg, 0.52mmol) was used to replace ethyl 3-oxo-3-phenylpropionate in Example 1, and Example 2-Amino-N,N-dimethyl-4-phenylthiazole-5-carboxamide was synthesized by the same method as Synthetic Method 3 in 1 to obtain 101.4 mg of white solid with a yield of 78.4%.

Synthetic method 2

N,N-dimethyl-3-oxo-3-phenylpropionamide (100mg, 0.52mmol) was used to replace ethyl 3-oxo-3-phenylpropionate in Example 1, and Example 2-Amino-N,N-dimethyl-4-phenylthiazole-5-carboxamide was synthesized by the same method as Synthetic Method 4 in 1, and 99.4 mg of white solid was obtained with a yield of 76.9%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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

This embodiment includes the following operations:

Synthetic method 1

With N,N-diethyl-3-oxo-3-phenylpropionamide (100mg, 0.46mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, and Example 1 2-Amino-N,N-diethyl-4-phenylthiazole-5-carboxamide was synthesized by the same method as Synthetic Method 7, and 111.4 mg of white solid was obtained with a yield of 88.7%.

Synthetic method 2

With N,N-diethyl-3-oxo-3-phenylpropionamide (100mg, 0.46mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, and Example 1 2-Amino-N,N-diethyl-4-phenylthiazole-5-carboxamide was synthesized by the same method as Synthetic Method 1, and 106.1 mg of white solid was obtained with a yield of 84.5%.

Synthetic method 3

With N,N-diethyl-3-oxo-3-phenylpropionamide (100mg, 0.46mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, and Example 1 2-Amino-N,N-diethyl-4-phenylthiazole-5-carboxamide was synthesized by the same method as Synthetic Method 5, and 106.9 mg of white solid was obtained with a yield of 85.1%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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) ketone

This embodiment includes the following operations:

Synthetic method 1

With 1-morpholino-3-phenylpropane-1,3-dione (100mg, 0.43mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, and in Example 1 (2-Amino-4-phenylthiazol-5-yl)(morpholino)methanone was synthesized by the same method as Synthetic Method 1 to obtain 118.2 mg of white solid with a yield of 95.3%.

Synthetic method 2

With 1-morpholino-3-phenylpropane-1,3-dione (100mg, 0.43mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, and in Example 1 (2-Amino-4-phenylthiazol-5-yl)(morpholino)methanone was synthesized by the same method as Synthetic Method 2 to obtain 116.2 mg of white solid with a yield of 93.7%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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

This embodiment includes the following operations:

With 3-oxo-3-phenylpropionitrile (100mg, 0.69mmol), replace the 3-oxo-3-phenylpropionate ethyl ester in Example 1, the same method as Synthetic Method 7 in Example 1 2-Amino-4-phenylthiazole-5-carbonitrile was synthesized to obtain 134.9 mg of white solid with a yield of 97.3%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis of the product are as follows:

HRMS (ESI-TOF) Calcd for C ₁₀ H ₆ N ₂ S ^- [MH] ^- : 200.0282;

Found 200.0290.

Example 11. Synthesis of 2-amino-4-(4-bromophenyl)thiazole-5-carbonitrile

This embodiment includes the following operations:

Synthetic method 1

With 3-(4-bromophenyl)-3-oxopropionitrile (100mg, 0.45mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, the synthetic method in Example 1 7. Synthesize 2-amino-4-(4-bromophenyl)thiazole-5-carbonitrile by the same method to obtain 119.0 mg of white solid with a yield of 95.2%.

Synthetic method 2

With 3-(4-bromophenyl)-3-oxopropionitrile (100mg, 0.45mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, the synthetic method in Example 1 6. Synthesize 2-amino-4-(4-bromophenyl)thiazole-5-carbonitrile by the same method to obtain 116.4 mg of white solid with a yield of 93.1%.

Synthetic method 3

With 3-(4-bromophenyl)-3-oxopropionitrile (100mg, 0.45mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, the synthetic method in Example 1 12 The same method was used to synthesize 2-amino-4-(4-bromophenyl)thiazole-5-carbonitrile to obtain 117.8 mg of white solid with a yield of 94.2%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis of the product are as follows:

HRMS (ESI-TOF) Calcd for C ₁₀ H ₅ BrN ₃ S ^- [MH] ^- : 279.9367;

Found 279.9376.

Example 12. Synthesis of 2-amino-4-(3,4,5-trimethoxyphenyl)thiazole-5-carbonitrile

This embodiment includes the following operations:

Synthetic method 1

With 3-oxo-3-(3,4,5-trimethoxyphenyl)propionitrile (100mg, 0.43mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, and 2-Amino-4-(3,4,5-trimethoxyphenyl)thiazole-5-carbonitrile was synthesized by the same method as Synthetic Method 4 in Example 1 to obtain 94.5 mg of white solid with a yield of 76.3%.

Synthetic method 2

With 3-oxo-3-(3,4,5-trimethoxyphenyl)propionitrile (100mg, 0.43mmol) instead of ethyl 3-oxo-3-phenylpropionate in Example 1, and 2-Amino-4-(3,4,5-trimethoxyphenyl)thiazole-5-carbonitrile was synthesized by the same method as Synthetic Method 5 in Example 1 to obtain 92.5 mg of white solid with a yield of 74.7%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis of the product are as follows:

HRMS (ESI-TOF) Calcd for C ₁₃ H ₁₂ N ₃ O ₃ S ^- [MH] ^- : 290.0599;

Found 290.0606.

Example 13. Synthesis of ethyl 2-(methylamino)-4-phenylthiazole-5-carboxylate

This embodiment includes the following operations:

Synthetic method 1

Replace 3-oxo-3-phenylpropane in Example 1 with ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol) and 1-methylthiourea (70.35mg, 0.78mmol) Acetate ethyl ester and thiourea, synthesize 2-(methylamino)-4-phenylthiazole-5-carboxylic acid ethyl ester by the same method as Synthetic Method 8 in Example 1 to obtain 97.3 mg of white solid, yield 71.3%.

Synthetic method 2

Replace 3-oxo-3-phenylpropane in Example 1 with ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol) and 1-methylthiourea (70.35mg, 0.78mmol) Acetyl ethyl ester and thiourea, synthesized 2-(methylamino)-4-phenylthiazole-5-carboxylic acid ethyl ester by the same method as Synthetic Method 9 in Example 1, and obtained 96.7 mg of white solid with a yield of 70.9%.

Synthetic method 3

Replace 3-oxo-3-phenylpropane in Example 1 with ethyl 3-oxo-3-phenylpropionate (100mg, 0.52mmol) and 1-methylthiourea (70.35mg, 0.78mmol) Acetate ethyl ester and thiourea, synthesized 2-(methylamino)-4-phenylthiazole-5-carboxylic acid ethyl ester by the same method as Synthetic Method 5 in Example 1, and obtained 95.1 mg of white solid with a yield of 69.7%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of 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

This embodiment includes the following operations:

Synthetic method 1

Replace 3-oxo in Example 1 with N,N-dimethyl-3-oxo-3-phenylpropanamide (100mg, 0.52mmol), 1-methylthiourea (70.71mg, 0.78mmol) -Ethyl 3-phenylpropionate and thiourea, synthesize N,N-dimethyl-2-(methylamino)-4-phenylthiazole-5-methan in the same method as synthetic method 7 in Example 1 Amide, 121.1 mg of white solid was obtained, the yield was 88.6%.

Synthetic method 2

Replace 3-oxo in Example 1 with N,N-dimethyl-3-oxo-3-phenylpropanamide (100mg, 0.52mmol), 1-methylthiourea (70.71mg, 0.78mmol) -Ethyl 3-phenylpropionate and thiourea, synthesize N,N-dimethyl-2-(methylamino)-4-phenylthiazole-5-methan in the same way as synthetic method 12 in Example 1 Amide, 117.1 mg of white solid was obtained, the yield was 85.7%.

Synthetic method 3

Replace 3-oxo in Example 1 with N,N-dimethyl-3-oxo-3-phenylpropanamide (100mg, 0.52mmol), 1-methylthiourea (70.71mg, 0.78mmol) -Ethyl 3-phenylpropionate and thiourea, synthesize N,N-dimethyl-2-(methylamino)-4-phenylthiazole-5-methan in the same way as synthetic method 4 in Example 1 Amide, 112.6mg of white solid was obtained, the yield was 82.4%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of 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

This embodiment includes the following operations:

Synthetic method 1

With 3-oxo-3-phenylpropionitrile (100mg, 0.69mmol) and 1-methylthiourea (93.15mg, 1.03mmol) to replace 3-oxo-3-phenylpropanoic acid ethyl in Example 1 Ester and thiourea, 2-(methylamino)-4-phenylthiazole-5-carbonitrile was synthesized by the same method as Synthetic Method 12 in Example 1 to obtain 118.1 mg of white solid with a yield of 79.6%.

Synthetic method 2

With 3-oxo-3-phenylpropionitrile (100mg, 0.69mmol) and 1-methylthiourea (93.15mg, 1.03mmol) to replace the ethyl 3-oxo-3-phenylpropanoate in Example 1 Ester and thiourea, 2-(methylamino)-4-phenylthiazole-5-carbonitrile was synthesized by the same method as Synthetic Method 1 in Example 1 to obtain 120.0 mg of white solid with a yield of 80.9%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis of the product are as follows:

HRMS (ESI-TOF) Calcd for C ₁₁ H ₈ N ₃ S ^- [MH] ^- : 214.0439;

Found 214.0517.

Example 16. Synthesis of ethyl 2-amino-4-methylthiazole-5-carboxylate

This embodiment includes the following operations:

Substitute ethyl 3-oxo-3-phenylpropionate in Example 1 with ethyl 3-oxobutanoate (100mg, 0.77mmol), and synthesize 2-amino in the same method as Synthetic Method 3 in Example 1 - Ethyl 4-methylthiazole-5-carboxylate to obtain 102.1 mg of white solid, yield 71.3%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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

This embodiment includes the following operations:

Synthetic method 1

Ethyl 3-oxobutanoate (100mg, 0.77mmol), 1-methylthiourea (103.90mg, 1.15mmol) replaced ethyl 3-oxo-3-phenylpropionate and sulfur in Example 1 For urea, ethyl 4-methyl-2-(methylamino)thiazole-5-carboxylate was synthesized by the same method as Synthetic Method 9 in Example 1 to obtain 90.3 mg of white solid with a yield of 58.7%.

Synthetic method 2

Ethyl 3-oxobutanoate (100mg, 0.77mmol), 1-methylthiourea (103.90mg, 1.15mmol) replaced ethyl 3-oxo-3-phenylpropionate and sulfur in Example 1 For urea, ethyl 4-methyl-2-(methylamino)thiazole-5-carboxylate was synthesized by the same method as Synthetic Method 12 in Example 1 to obtain 89.4 mg of white solid with a yield of 58.1%.

Synthetic method 3

Ethyl 3-oxobutanoate (100mg, 0.77mmol), 1-methylthiourea (103.90mg, 1.15mmol) replaced ethyl 3-oxo-3-phenylpropionate and sulfur in Example 1 For urea, ethyl 4-methyl-2-(methylamino)thiazole-5-carboxylate was synthesized by the same method as Synthetic Method 3 in Example 1 to obtain 91.7 mg of white solid with a yield of 59.6%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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. Synthesis of ethyl 2-amino-4-isopropylthiazole-5-carboxylate

This embodiment includes the following operations:

Replace ethyl 3-oxo-3-phenylpropionate in Example 1 with ethyl 4-methyl-3-oxopentanoate (100mg, 0.63mmol), the same as synthetic method 9 in Example 1 Methods 2-Amino-4-isopropylthiazole-5-carboxylic acid ethyl ester was synthesized to obtain 108.1 mg of white solid with a yield of 79.8%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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. Synthesis of ethyl 4-isopropyl-2-(methylamino)thiazole-5-carboxylate

This embodiment includes the following operations:

Synthetic method 1

Ethyl 4-methyl-3-oxopentanoate (100mg, 0.63mmol), 1-methylthiourea (85.47mg, 0.95mmol) replaced 3-oxo-3-phenylpropane in Example 1 Acetate ethyl ester and thiourea, synthesize 4-isopropyl-2-(methylamino)thiazole-5-carboxylate ethyl ester with the same method as synthetic method 10 in embodiment 1, obtain white solid 85.4mg, yield 59.2 %.

Synthetic method 2

Ethyl 4-methyl-3-oxopentanoate (100mg, 0.63mmol), 1-methylthiourea (85.47mg, 0.95mmol) replaced 3-oxo-3-phenylpropane in Example 1 Acetate ethyl ester and thiourea, synthesize 4-isopropyl-2-(methylamino)thiazole-5-carboxylic acid ethyl ester with the same method as synthetic method 6 in embodiment 1, obtain white solid 84.7mg, yield 58.7 %.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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

This embodiment includes the following operations:

Synthetic method 1

Substitute ethyl 3-oxo-3-phenylpropionate in Example 1 with ethyl 3-oxohexanoate (100mg, 0.63mmol), and synthesize 2-amino in the same method as Synthetic Method 9 in Example 1 - Ethyl 4-propylthiazole-5-carboxylate to obtain 66.5 mg of white solid, yield 49.1%.

Synthetic method 2

3-oxo-3-phenylpropionate ethyl ester (100mg, 0.63mmol) was substituted for ethyl 3-oxo-3-phenylpropionate in Example 1, and 2-amino was synthesized in the same way as Synthetic Method 12 in Example 1 - Ethyl 4-propylthiazole-5-carboxylate to obtain 65.9 mg of white solid, yield 48.7%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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

This embodiment includes the following operations:

Synthetic method 1

Ethyl 3-oxohexanoate (100mg, 0.63mmol), 1-methylthiourea (85.47mg, 0.95mmol) was substituted for ethyl 3-oxo-3-phenylpropionate and sulfur in Example 1 For urea, ethyl 2-(methylamino)-4-propylthiazole-5-carboxylate was synthesized by the same method as Synthetic Method 7 in Example 1 to obtain 72.2 mg of a white solid with a yield of 50%.

Synthetic method 2

Ethyl 3-oxohexanoate (100mg, 0.63mmol), 1-methylthiourea (85.47mg, 0.95mmol) was substituted for ethyl 3-oxo-3-phenylpropionate and sulfur in Example 1 For urea, ethyl 2-(methylamino)-4-propylthiazole-5-carboxylate was synthesized by the same method as Synthetic Method 1 in Example 1 to obtain 70.3 mg of white solid with a yield of 48.7%.

Synthetic method 3

Ethyl 3-oxohexanoate (100mg, 0.63mmol), 1-methylthiourea (85.47mg, 0.95mmol) was substituted for ethyl 3-oxo-3-phenylpropionate and sulfur in Example 1 For urea, ethyl 2-(methylamino)-4-propylthiazole-5-carboxylate was synthesized by the same method as Synthetic Method 3 in Example 1 to obtain 71.2 mg of white solid with a yield of 49.3%.

The data of the proton nuclear magnetic resonance spectrum of gained 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 carbon nuclear magnetic resonance spectrum of gained 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;

The theoretical calculation and experimental results of high-resolution mass spectrometry analysis 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.

It can be seen from the above Examples 1-21 that when the method of the present invention is adopted, 4,5-disubstituted-2-aminothiazole compounds can be obtained in a relatively high yield.

In summary, it can be clearly seen from all the above-mentioned examples that when the method of the present invention is adopted, that is, in a solvent, under oxygen or air atmosphere, to have a ketone compound having a structure as shown in formula (I) and formula (II ) of the structure shown in thiourea or thiourea derivatives as reaction raw materials, under the joint catalysis of activated carbon and metal salts, by oxidative coupling reaction to obtain the structure shown in formula (III) 4,5-disubstituted-2-amino Thiazole compounds provide a new synthetic route for the efficient, fast and green synthesis of such compounds.

Finally, it should be noted that the use of these examples is only for illustrating the present invention and is not intended to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that it can be partially adjusted in different ways without departing from the principle and purpose of the present invention, and the protection scope of the present invention is defined in the claims. The book shall prevail and not be limited by the above specific implementation, and each implementation scheme within its scope shall be restricted by the present 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:

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:

。

6. the method of synthesis according to claim 4,

the ketone compound is selected from:

。

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.