CN117486872A

CN117486872A - Mechanical ball milling synthesis method of aminothiazole compound

Info

Publication number: CN117486872A
Application number: CN202311516723.2A
Authority: CN
Inventors: 姜灵; 韩亚楠; 管萍萍; 范怡廷; 储消和
Original assignee: Zhejiang University of Technology ZJUT
Current assignee: Zhejiang University of Technology ZJUT
Priority date: 2023-11-15
Filing date: 2023-11-15
Publication date: 2024-02-02

Abstract

The invention discloses a mechanical ball milling synthesis method of aminothiazole compounds, which comprises the following specific implementation processes: mixing aromatic ketone compound, brominating reagent and acid catalyst uniformly, adding grinding aid to make mechanical ball milling, scraping out reactant after ball milling, adding solvent, filtering, and making filtrate undergo the process of aftertreatment so as to obtain a-monobromoketone, mixing a-monobromoketone and thiourea compound uniformly, adding grinding aid to make mechanical ball milling, scraping out reactant after ball milling, adding solvent, filtering, and making filtrate undergo the process of aftertreatment so as to obtain the aminothiazole compound. The invention realizes the synthesis of aminothiazole compounds, has short reaction time, simple and convenient operation, less pollution and wide application range.

Description

Mechanical ball milling synthesis method of aminothiazole compound

Technical Field

The invention belongs to the technical field of synthesis of aminothiazole compounds, and particularly relates to a mechanical ball milling synthesis method of aminothiazole compounds.

Background

The aminothiazole compound has wide biological activity and good application prospect in anti-inflammatory, anti-tumor, antibacterial, bactericidal, anti-infection, antioxidant, antiallergic and other medicines. The compounds are generally prepared by a chemical method, the used catalyst is expensive and difficult to recycle, the reaction time is too long, and the environment is polluted.

For example, in 2018, shalma et al passed NiFe ₂ O ₄ Nanoparticle catalyzed one-pot three-component reactions to synthesize pyrimidine-thiazole derivatives in ethanol-water green solvents (Sharma a, et al chem. Select, 2018, 3, 11012-11019); in 2018, dastageer et al used tetraiodofluorescein as a photo-redox catalyst to generate sulfur radicals in situ from thiourea, which was then added to the enol tautomer of the 1, 3-dicarbonyl group to form an aminothiazole backbone in a series of cascading steps (Roslan ii, et al adv. Synth. Catalyst, 2018, 360, 1584-1589); in 2017, netankar et al synthesized 4-aryl-2-aminothiazole (Wagare D S, et al, environ. Chem. Lett, 2017, 15, 475-479) from aromatic ketones, NBS (N-bromosuccinimide) and thiourea in the presence of polyethylene glycol 400 and water (1:2) as green reaction medium under microwave radiation. These chemical methods have the disadvantages of long reaction time, expensive catalyst, difficult separation of products from the catalyst, unfriendly environment, etc.

Disclosure of Invention

The invention provides a mechanical ball milling synthesis method of aminothiazole compounds, which aims to solve the problems of long reaction time, expensive catalyst and difficult separation of products and catalysts in the synthesis of aminothiazole compounds in the prior art.

The specific technical scheme is as follows:

a mechanical ball milling synthesis method of aminothiazole compounds comprises the following steps:

1) Uniformly mixing an aromatic ketone compound, a bromination reagent and an acid catalyst, adding a grinding aid for mechanical ball milling, scraping out reactants after ball milling, adding a solvent, filtering, washing filtrate with water and sodium bicarbonate, concentrating, and performing column chromatography to obtain a-monobromoketone;

2) Uniformly mixing the a-monobromoketone and thiourea compound prepared in the step 1), adding a grinding aid for mechanical ball milling, scraping out reactants after ball milling, adding a solvent, filtering, washing filtrate, concentrating, and performing column chromatography to obtain the aminothiazole compound.

The specific reaction route is as follows:

further, the aromatic ketone compound in the step 1) is 2-acetyl-4-chlorothiophene, 3-acetylthiophene, 3-acetyl-2, 5-dichlorothiophene, 2-acetyl-5-chlorothiophene, 4-bromo-2-acetylthiophene, 2-acetyl-3-bromothiophene, 2-acetyl-5-bromothiophene, 2-acetylbenzofuran, acetophenone, 4-Cl acetophenone, 4-Br acetophenone, 4-NO ₂ Acetophenone or 4-CH ₃ Acetophenone.

Further, the brominating reagent in the step 1) is N-bromosuccinimide and CuBr ₂ One of dibromohydantoin.

Further, the acid catalyst in the step 1) is one of p-toluenesulfonic acid, trifluoroacetic acid, aspartic acid, formic acid, acetic acid and trifluoromethanesulfonic acid.

Further, the molar ratio of the aromatic ketone compound, the brominating reagent and the acid catalyst in the step 1) is 1:0.5-1.2:0.5-1.2.

Further, the thiourea compound in the step 2) is thiourea, N-methyl thiourea or phenylthiourea, and the molar ratio of the a-bromoketone to the thiourea compound is 1:1.

further, the grinding aid in the step 1) and the step 2) is one of sodium sulfate, sodium chloride, potassium chloride, silica gel, neutral alumina and alkaline alumina.

Further, the ball milling frequency in the step 1) and the step 2) is 10-30HZ, and the ball milling time is 10-90min.

Further, the solvent in step 1) and step 2) is ethyl acetate.

Further, the column chromatography eluent in the step 1) is a mixed solution of petroleum ether and toluene, and the volume ratio of petroleum ether to toluene is 1-5: 1, a step of; the column chromatography eluent in the step 2) is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 4-50: 1.

the invention has the beneficial effects that:

Compared with the existing chemical method, the method has the advantages of simple operation, mild reaction condition, short reaction time, less pollution and wide application range, and can effectively realize the synthesis of a series of aminothiazole compounds.

Detailed Description

The present invention will be further described with reference to examples, but the scope of the present invention is not limited thereto.

Example 1 4 Synthesis of- (4-chloro-2-thienyl) -2-thiazolamine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by 0.5 mmol of 2-acetyl-4-chlorothiophene, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid and 150 mg silica gel, followed by ball milling under 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=8:1, v/v as eluent) to give the desired product as a pale yellow solid in 92% yield.

The specific characterization data are as follows: m.p. 162.1-165.3 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.41 (s, 1H, ArH), 7.39 (s, 1H, ArH), 7.21 (s, 2H, NH ₂ ), 6.99 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.94, 143.65, 140.43, 124.34, 122.61, 120.01, 101.68.

example 2 4 Synthesis of- (4-chlorothien-2-yl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=11:1, v/v as eluent) to give the desired product as a pale yellow solid in 49% yield.

The specific characterization data are as follows: m.p. 155.3-158.6 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (q,J= 4.4 Hz, 1H, NH), 7.42 (d,J= 1.4 Hz, 1H, ArH), 7.40 (d,J= 1.4 Hz, 1H, ArH), 7.04 (s, 1H, ArH), 2.83 (d,J= 4.8 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 170.03, 144.11, 140.44, 124.29, 122.84, 120.13, 101.13, 31.52.

example 3 4 Synthesis of- (4-chlorothien-2-yl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=16:1, v/v as eluent) to give the desired product as a yellow solid in 91% yield.

The specific characterization data are as follows: m.p. 133.5-136.2 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H, NH), 7.67 (d,J= 7.8 Hz, 2H, ArH), 7.53 (d,J= 1.4 Hz, 1H, ArH), 7.49 (d,J= 1.4 Hz, 1H, ArH), 7.35 (t,J= 7.9 Hz, 2H, ArH), 7.31 (s, 1H, ArH), 6.98 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.82, 143.90, 141.38, 139.97, 129.51, 124.55, 123.22, 122.00, 120.51, 117.43, 103.04.

example 4 4 Synthesis of- (5-chlorothien-2-yl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by 0.5 mmol of 2-acetyl-5-chlorothiophene, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid and 150 mg silica gel, followed by ball milling under 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=3:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=8:1, v/v as eluent) to give the desired product as a yellow solid in 71% yield.

The specific characterization data are as follows: m.p. 120.2-125.3 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.27 – 7.17 (m, 3H, ArH-NH ₂ ), 7.03 (d,J= 3.9 Hz, 1H, ArH), 6.89 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.95, 143.77, 138.66, 128.04, 127.04, 122.40, 100.81.

example 5 4 Synthesis of- (5-chlorothien-2-yl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=14:1, v/v as eluent) to give the desired product as a pale orange solid in 74% yield.

The specific characterization data are as follows: m.p. 95.1-100.3 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (q,J= 4.8 Hz, 1H, NH), 7.25 (d,J= 3.9 Hz, 1H, ArH), 7.04 (d,J= 3.9 Hz, 1H, ArH), 6.95 (s, 1H, ArH), 2.83 (d,J= 4.5 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 170.04, 144.24, 138.69, 128.01, 127.16, 122.61, 100.24, 31.51.

example 6 4 Synthesis of- (5-chlorothien-2-yl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=30:1, v/v as eluent) to give the desired product as a yellow oil in 75% yield.

The specific characterization data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H, NH), 7.66 (d,J= 7.9 Hz, 2H, ArH), 7.34 (dd,J= 9.9, 6.0 Hz, 3H, ArH), 7.20 (s, 1H, ArH), 7.09 (d,J= 3.9 Hz, 1H, ArH), 6.97 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.80, 144.00, 141.37, 138.21, 129.52, 128.24, 127.60, 123.04, 122.01, 117.42, 102.17.

example 7 4 Synthesis of- (3-bromothiophen-2-yl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by sequential addition of 0.5 mmol 2-acetyl-3-bromothiophene, 0.55 mmol N-bromosuccinimide (NBS), 0.35 mmol trifluoromethanesulfonic acid and 150 mg silica gel, followed by ball milling at 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=4:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=11:1, v/v as eluent) to give the desired product as a white solid in 75% yield.

The specific characterization data are as follows: m.p. 151.9-155.3 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.51 (d,J= 5.3 Hz, 1H, ArH), 7.23 (s, 3H, ArH-NH ₂ ), 7.09 (d,J= 5.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.03, 142.50, 134.16, 132.07, 126.30, 105.58, 102.90.

example 8 4 Synthesis of- (3-bromothiophen-2-yl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=18:1, v/v as eluent) to give the target product as a white solid in 73% yield.

The specific characterization data are as follows: m.p. 112.2-115.2 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.74 (q,J= 5.2, 4.3 Hz, 1H, NH), 7.52 (d,J= 5.3 Hz, 1H, ArH), 7.28 (s, 1H, ArH), 7.09 (d,J= 5.3 Hz, 1H, ArH), 2.84 (d,J= 4.7 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.12, 142.94, 134.24, 132.03, 126.41, 105.74, 102.36, 31.53.

example 9 4 Synthesis of- (3-bromothiophen-2-yl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=30:1, v/v as eluent) to give the desired product as a yellow oil in 82% yield.

The specific characterization data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.40 (s, 1H, NH), 7.70 (d,J= 7.9 Hz, 2H, ArH), 7.58 (d,J= 5.3 Hz, 1H, ArH), 7.49 (s, 1H, ArH), 7.34 (t,J= 7.9 Hz, 2H, ArH), 7.14 (d,J= 5.3 Hz, 1H, ArH), 6.98 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 162.96, 142.70, 141.38, 133.85, 132.24, 129.50, 126.82, 122.03, 117.42, 106.16, 104.23.

EXAMPLE 10 Synthesis of 4- (4-bromothiophen-2-yl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by 0.5 mmol of 4-bromo-2-acetylthiophene, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid, and 150 mg silica gel, followed by ball milling under 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=5:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=10:1, v/v as eluent) to give the desired product as a pale yellow solid in 79% yield.

It is specificallyThe characterization data of (2) are as follows: m.p.155.6-157.2 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.49 (d,J= 1.2 Hz, 1H, ArH), 7.41 (d,J= 1.2 Hz, 1H, ArH), 7.19 (s, 2H, NH ₂ ), 6.98 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.95, 143.46, 141.06, 124.91, 122.66, 109.68, 101.72.

EXAMPLE 11 Synthesis of 4- (4-bromothiophen-2-yl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=18:1, v/v as eluent) to give the desired product as a pale yellow solid in 76% yield.

The specific characterization data are as follows: m.p. 112.8-115.8 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.70 (q,J= 4.4 Hz, 1H, NH), 7.50 (d,J= 1.4 Hz, 1H, ArH), 7.43 (d,J= 1.3 Hz, 1H, ArH), 7.03 (s, 1H, ArH), 2.84 (d,J= 4.8 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 170.05, 143.94, 141.07, 125.14, 122.77, 109.63, 101.15, 31.53.

EXAMPLE 12 Synthesis of 4- (4-bromothiophen-2-yl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=26:1, v/v as eluent) to give the desired product as a yellow solid in 74% yield.

The specific characterization data are as follows: m.p. 122.2-125.5 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H, NH), 7.67 (d,J= 7.7 Hz, 2H, ArH), 7.57 (d,J= 1.4 Hz, 1H, ArH), 7.54 (d,J= 1.4 Hz, 1H, ArH), 7.40 – 7.30 (m, 2H, ArH), 7.28 (s, 1H, ArH), 6.97 (t,J= 7.4 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.82, 143.73, 141.37, 140.61, 129.51, 125.50, 123.16, 122.00, 117.43, 109.86, 103.07.

EXAMPLE 13 Synthesis of 4- (5-bromothiophen-2-yl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by sequential addition of 0.5 mmol 2-acetyl-5-bromothiophene, 0.55 mmol N-bromosuccinimide (NBS), 0.35 mmol trifluoromethanesulfonic acid and 150 mg silica gel, followed by ball milling at 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=8:1, v/v as eluent) to give the target product as an orange solid in 71% yield.

The specific characterization data are as follows: m.p. 133.4-142.2 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.20 (d,J= 3.9 Hz, 3H, ArH-NH ₂ ), 7.13 (d,J= 3.9 Hz, 1H, ArH), 6.89 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.95, 143.81, 141.34, 131.54, 123.41, 110.42, 100.88.

EXAMPLE 14 Synthesis of 4- (5-bromothiophen-2-yl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=14:1, v/v as eluent) to give the desired product as an orange solid in 50% yield.

The specific characterization data are as follows: m.p. 101.0-107.5 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (q,J= 3.6 Hz, 1H, NH), 7.23 (d,J= 3.9 Hz, 1H, ArH), 7.14 (d,J= 3.9 Hz, 1H, ArH), 6.96 (s, 1H, ArH), 2.83 (d,J= 4.4 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 170.04, 144.27, 141.35, 131.51, 123.63, 110.53, 100.32, 31.51.

EXAMPLE 15 Synthesis of 4- (5-bromothiophen-2-yl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=30:1, v/v as eluent) to give the desired product as a yellow oil in 59% yield.

The specific characterization data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H, NH), 7.66 (d,J= 8.0 Hz, 2H, ArH), 7.39 – 7.30 (m, 3H, ArH), 7.24 – 7.17 (m, 2H, ArH), 6.97 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.79, 144.03, 141.36, 140.88, 131.75, 129.52, 124.04, 122.00, 117.41, 110.96, 102.25.

EXAMPLE 16 Synthesis of 4- (thiophen-3-yl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by 0.5 mmol of 3-acetylthiophene, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid, and 150 mg silica gel, followed by ball milling at 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=6:1, v/v as eluent) to give the target product as a white solid in 73% yield.

The specific characterization data are as follows: m.p. 142.7-145.9 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (dd,J= 3.0, 1.2 Hz, 1H, ArH), 7.51 (dd,J= 5.0, 3.0 Hz, 1H, ArH), 7.45 (dd,J= 5.0, 1.3 Hz, 1H, ArH), 7.04 (s, 2H.NH ₂ ), 6.83 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.65, 146.74, 137.73, 126.92, 126.34, 121.26, 101.55.

EXAMPLE 17 Synthesis of N-methyl-4- (thiophen-3-yl) thiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=11:1, v/v as eluent) to give the desired product as a white solid in a yield of 41%.

The specific characterization data are as follows: m.p.111.4-114.5 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.69 – 7.64 (m, 1H, ArH), 7.58 – 7.53 (m, 1H, NH), 7.54 – 7.50 (m, 1H, ArH), 7.47 (dd,J= 5.0, 0.9 Hz, 1H, ArH), 6.89 (s, 1H, ArH), 2.85 (s, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.86, 147.16, 137.77, 126.91, 126.40, 121.51, 100.90, 31.53.

EXAMPLE 18 Synthesis of N-phenyl-4- (thiophen-3-yl) thiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=20:1, v/v as eluent) to give the desired product as a yellow solid in 81% yield.

The specific characterization data are as follows: m.p. 123.8-125.7 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.27 (s, 1H, NH), 7.86 – 7.81 (m, 1H, ArH), 7.74 (d,J= 8.1 Hz, 2H, ArH), 7.56 (d,J= 1.5 Hz, 2H, ArH), 7.34 (t,J= 7.9 Hz, 2H, ArH), 7.13 (s, 1H, ArH), 6.96 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.60, 146.99, 141.60, 137.33, 129.51, 127.25, 126.35, 122.06, 121.77, 117.34, 102.75.

EXAMPLE 19 Synthesis of 4- (2, 5-dichlorothiophen-3-yl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by sequential addition of 0.5 mmol of 3-acetyl-2, 5-dichlorothiophene, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid, and 150 mg silica gel, followed by ball milling at 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=4:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=14:1, v/v as eluent) to give the desired product as a white solid in 80% yield.

The specific characterization data are as follows: m.p.147.1-149.0 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.31 (s, 1H, ArH), 7.12 (s, 2H, NH ₂ ), 7.04 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.18, 142.81, 133.42, 128.27, 125.07, 120.16, 105.91.

EXAMPLE 20 Synthesis of 4- (2, 5-dichlorothiophen-3-yl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=30:1, v/v as eluent) to give the desired product as a white solid in 62% yield.

The specific characterization data are as follows: m.p. 161.3-167.5 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.63 (q,J= 4.3 Hz, 1H, NH), 7.38 (s, 1H, ArH), 7.09 (s, 1H, ArH), 2.85 (d,J= 4.8 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.13, 143.13, 133.50, 128.37, 125.05, 120.30, 105.25, 31.40.

EXAMPLE 21 Synthesis of 4- (2, 5-dichlorothiophen-3-yl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=50:1, v/v as eluent) to give the desired product as a pale yellow oil in 71% yield.

The specific characterization data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H, NH), 7.72 (d,J= 7.7 Hz, 2H, ArH), 7.49 (s, 1H, ArH), 7.38 – 7.25 (m, 3H, ArH), 6.95 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.12, 143.15, 141.45, 132.96, 129.45, 128.13, 125.43, 121.77, 120.80, 117.39, 107.39.

EXAMPLE 22 Synthesis of 4- (benzofuran-2-yl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by 0.5 mmol of 2-acetylbenzofuran, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid, and 150 mg of silica gel, followed by ball milling at 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=1:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=10:1, v/v as eluent) to give the desired product as a yellow solid in 79% yield.

The specific characterization data are as follows: m.p. 241.2-242.5 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.62 (d,J= 7.2 Hz, 1H, ArH), 7.55 (d,J= 8.0 Hz, 1H, ArH), 7.34 – 7.18 (m, 4H, ArH-NH ₂ ), 7.05 (s, 1H, ArH), 6.97 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.34, 154.42, 152.68, 141.70, 129.01, 124.89, 123.61, 121.70, 111.35, 104.62, 102.46.

EXAMPLE 23 Synthesis of 4- (benzofuran-2-yl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=20:1, v/v as eluent) to give the desired product as a pale yellow solid in 88% yield.

The specific characterization data are as follows: m.p. 175.9-178.4 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.75 (q,J= 4.4 Hz, 1H, NH), 7.63 (d,J= 7.3 Hz, 1H, ArH), 7.56 (d,J= 8.1 Hz, 1H, ArH), 7.26 (dt,J= 23.2, 7.1 Hz, 2H, ArH), 7.10 (s, 1H, ArH), 7.04 (s, 1H, ArH), 2.89 (d,J= 4.7 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 170.31, 154.45, 152.72, 142.08, 129.02, 124.91, 123.60, 121.72, 111.36, 104.01, 102.74, 31.48.

EXAMPLE 24 Synthesis of 4- (benzofuran-2-yl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered off with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=40:1, v/v) to give the desired product as a yellow solid in 76% yield.

The specific characterization data are as follows: m.p. 158.9-162.3 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.44 (s, 1H, NH), 7.77 (d,J= 7.9 Hz, 2H, ArH), 7.69 (d,J= 7.2 Hz, 1H, ArH), 7.60 (d,J= 8.1 Hz, 1H, ArH), 7.44 – 7.24 (m, 5H, ArH), 7.22 (s, 1H, ArH), 7.00 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 164.29, 154.62, 152.37, 141.93, 141.44, 129.53, 128.99, 125.10, 123.72, 121.95 (d,J= 13.2 Hz), 117.54, 111.45, 105.76, 103.30.

EXAMPLE 25 Synthesis of 4-phenylthiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot, 3 stainless steel balls with a diameter of 10 mm were added, followed by 0.5 mmol acetophenone, 0.55 mmol N-bromosuccinimide (NBS), 0.35 mmol trifluoromethanesulfonic acid, and 150 mg silica gel in that order, followed by ball milling at 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=4:1, v/v as eluent) to give the desired product as a white solid in 85% yield.

The specific characterization data are as follows: m.p.131.9-144.0 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d,J= 7.7 Hz, 2H, ArH), 7.35 (t,J= 7.3 Hz, 2H, ArH), 7.24 (t,J= 7.1 Hz, 1H, ArH), 7.06 (s, 2H, NH ₂ ), 6.99 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.67, 150.24, 135.32, 128.92, 127.64, 125.98, 101.95.

EXAMPLE 26 Synthesis of N-methyl-4-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=8:1, v/v as eluent) to give the desired product as a white solid in 50% yield.

The specific characterization data are as follows: m.p. 113.9-119.9 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (d,J= 7.4 Hz, 2H, ArH), 7.64 – 7.50 (m, 1H, NH), 7.37 (t,J= 7.2 Hz, 2H, ArH), 7.26 (t,J= 7.2 Hz, 1H, ArH), 7.05 (s, 1H, ArH), 2.88 (d,J= 3.2 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.81, 150.63, 135.37, 128.90, 127.72, 126.08, 101.28, 31.49.

EXAMPLE 27 Synthesis of N, 4-diphenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=14:1, v/v as eluent) to give the desired product as a pale yellow solid in 53% yield.

The specific characterization data are as follows: m.p. 128.5-134.6 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H, NH), 7.94 (d,J= 7.6 Hz, 2H, ArH), 7.76 (d,J= 8.0 Hz, 2H, ArH), 7.44 (t,J= 7.6 Hz, 2H, ArH), 7.35 (dd,J= 15.4, 6.7 Hz, 4H, ArH), 6.97 (t,J= 7.4 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.55, 150.55, 141.68, 134.99, 129.49, 129.12, 128.06, 126.12, 121.68, 117.27, 103.36.

EXAMPLE 28 Synthesis of 4- (4-chlorophenyl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by 0.5 mmol of 4-Cl acetophenone, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid, and 150 mg silica gel, followed by ball milling at 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=6:1, v/v as eluent) to give the target product as a white solid in 71% yield.

The specific characterization data are as follows: m.p. 164.6-169.2 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.80 (d,J= 8.6 Hz, 2H, ArH), 7.41 (d,J= 8.6 Hz, 2H, ArH), 7.10 (s, 2H, NH ₂ ), 7.06 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.80, 149.01, 134.18, 131.98, 128.92, 127.67, 102.76.

EXAMPLE 29 Synthesis of 4- (4-chlorophenyl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=16:1, v/v as eluent) to give the desired product as a white solid in a yield of 56%.

The specific characterization data are as follows: m.p. 138.7-141.8 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.84 (d,J= 8.6 Hz, 2H, ArH), 7.60 (q,J= 4.4 Hz, 1H, NH), 7.41 (d,J= 8.6 Hz, 2H, ArH), 7.11 (s, 1H, ArH), 2.87 (d,J= 4.8 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.86, 149.33, 134.21, 132.07, 128.90, 127.76, 102.10, 31.45.

EXAMPLE 30 Synthesis of 4- (4-chlorophenyl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=20:1, v/v as eluent) to give the desired product as a pale yellow solid in 80% yield.

The specific characterization data are as follows: m.p. 95.2-99.8 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H, NH), 7.94 (d,J= 8.6 Hz, 2H, ArH), 7.74 (d,J= 7.8 Hz, 2H, ArH), 7.48 (d,J= 8.6 Hz, 2H, ArH), 7.42 – 7.29 (m, 3H, ArH), 6.97 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.72, 149.32, 141.59, 133.83, 132.46, 129.49, 129.12, 127.81, 121.77, 117.32, 104.16.

EXAMPLE 31 Synthesis of 4- (4-bromophenyl) thiazol-2-amine

(1) To a 25 mL stainless steel ball mill pot was added 3 stainless steel balls having a diameter of 10 mm, followed by 0.5 mmol 4-Br acetophenone, 0.55 mmol N-bromosuccinimide (NBS), 0.35 mmol trifluoromethanesulfonic acid and 150 mg silica gel, followed by ball milling at 20 Hz for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=4:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=10:1, v/v as eluent) to give the desired product as a white solid in 59% yield.

The specific characterization data are as follows: m.p. 181.0-185.7 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.73 (d,J= 8.5 Hz, 2H, ArH), 7.53 (d,J= 8.5 Hz, 2H, ArH), 7.10 (s, 2H, NH ₂ ), 7.06 (s, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.95, 143.46, 141.06, 124.91, 122.66, 109.68, 101.72.

EXAMPLE 32 Synthesis of 4- (4-bromophenyl) -N-methylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=16:1, v/v as eluent) to give the desired product as a white solid in 62% yield.

The specific characterization data are as follows: m.p.141.2-145.2 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.79 (d,J= 8.5 Hz, 2H, ArH), 7.61 (q,J= 4.5 Hz, 1H, NH), 7.55 (d,J= 8.6 Hz, 2H, ArH), 7.12 (s, 1H, ArH), 2.88 (d,J= 4.8 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 170.05, 143.94, 141.07, 125.14, 122.77, 109.63, 101.15, 31.53.

EXAMPLE 33 Synthesis of 4- (4-bromophenyl) -N-phenylthiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=16:1, v/v as eluent) to give the desired product as a pale yellow solid in 78% yield.

The specific characterization data are as follows: m.p. 137.2-141.6 ℃, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H, NH), 7.88 (d,J= 8.5 Hz, 2H, ArH), 7.74 (d,J= 7.8 Hz, 2H, ArH), 7.61 (d,J= 8.5 Hz, 2H, ArH), 7.42 – 7.31 (m, 3H, ArH), 6.97 (t,J= 7.3 Hz, 1H, ArH); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.82, 143.73, 141.37, 140.61, 129.51, 125.50, 123.16, 122.00, 117.43, 109.86, 103.07.

EXAMPLE 34 Synthesis of 4- (4-nitrophenyl) thiazol-2-amine

(1) 3 stainless steel balls with the diameter of 10 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.5 mmol of 4-NO is added in sequence ₂ Acetophenone, 0.55 mmol N-bromosuccinimide (NBS), 0.35 mmol trifluoromethaneSulfonic acid and 150 mg silica gel, 20: 20 Hz ball milling for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=5:1, v/v as eluent) to give the desired product as a yellow solid in 53% yield.

The specific characterization data are as follows: m.p. 278.5-283.2 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (d,J= 8.9 Hz, 2H, ArH), 8.04 (d,J= 8.9 Hz, 2H), 7.40 (s, 1H, ArH), 7.23 (s, 2H, NH ₂ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.05, 148.27, 146.37, 141.31, 126.73, 124.46, 107.05.

example 35 Synthesis of N-methyl-4- (4-nitrophenyl) thiazol-2-amine

(1) 3 stainless steel balls with the diameter of 10 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.5 mmol of 4-NO is added in sequence ₂ Acetophenone, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid and 150 mg silica gel, 20 Hz were ball milled for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. Organic phase addition Drying anhydrous sodium sulfate, suction filtering, transferring filtrate into a round bottom flask, rotary evaporating and concentrating, and finally purifying by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=10:1, v/v as eluent) to give the desired product as a yellow solid in 45% yield.

The specific characterization data are as follows: m.p. 179.5-183.4 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.23 (d,J= 8.9 Hz, 2H, ArH), 8.07 (d,J= 8.9 Hz, 2H, ArH), 7.73 (q,J= 4.6 Hz, 1H, NH), 7.44 (s, 1H, ArH), 2.90 (d,J= 4.7 Hz, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.98, 148.54, 146.43, 141.33, 126.82, 124.43, 106.39, 31.42.

EXAMPLE 36 Synthesis of 4- (p-tolyl) thiazol-2-amine

(1) 3 stainless steel balls with the diameter of 10 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.5 mmol of 4-CH is added in sequence ₃ Acetophenone, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid and 150 mg silica gel, 20 Hz were ball milled for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=6:1, v/v as eluent) to give the desired product as a white solid in 77% yield.

The specific characterization data are as follows: m.p. 116.6-125.7 deg.C, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.68 (d,J= 8.1 Hz, 2H, ArH), 7.16 (d,J= 8.0 Hz, 2H, ArH), 7.03 (s, 2H, NH ₂ ), 6.90 (s, 1H, ArH), 2.29 (s, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 168.58, 150.28, 136.84, 132.69, 129.49, 125.94, 101.02, 21.25.

EXAMPLE 37 Synthesis of N-methyl-4- (p-tolyl) thiazol-2-amine

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of N-methyl thiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask, concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=10:1, v/v as eluent) to give the target product as a white solid with a yield of 55%.

The specific characterization data are as follows: m.p.117.6-123.2 deg.c, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (d,J= 8.1 Hz, 2H, ArH), 7.53 (q,J= 4.3 Hz, 1H, NH), 7.16 (d,J= 8.0 Hz, 2H, ArH), 6.96 (s, 1H, ArH), 2.86 (d,J= 4.8 Hz, 3H, CH ₃ ), 2.29 (s, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 169.75, 150.67, 136.92, 132.74, 129.46, 126.03, 100.36, 31.50, 21.27.

EXAMPLE 38 Synthesis of N-phenyl-4- (p-tolyl) thiazol-2-amine

(1) Add 3 stainless steel balls with a diameter of 10 mm to a 25 mL stainless steel ball mill pot and then add 0.5 mmol in sequence

-CH ₃ Acetophenone, 0.55 mmol of N-bromosuccinimide (NBS), 0.35 mmol of trifluoromethanesulfonic acid and 150 mg silica gel, 20 Hz were ball milled for 60 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water and sodium bicarbonate respectively (6×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase is added with anhydrous sodium sulfate, dried and filtered, the filtrate is transferred into a round bottom flask to be concentrated by rotary evaporation, and finally, the mixture is purified by column chromatography (the eluent is petroleum ether: toluene=2:1, v/v) to obtain a-monobromoketone;

(2) Then, 2 stainless steel balls with the diameter of 8 mm are added into a 25 mL stainless steel ball grinding tank, and then 0.3 mmole of alpha-monobromoketone, 0.3 mmole of phenylthiourea and 200 mg NaCl,30 Hz are added in turn for ball milling for 30 minutes. After ball milling, the reaction mixture was scraped off, 30 mL ethyl acetate was added, filtered, the filtrate was washed three times with water (3×15 mL), the aqueous phase was extracted three times with ethyl acetate (3×15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was transferred to a round bottom flask and concentrated by rotary evaporation, and finally purified by column chromatography (petroleum ether: ethyl acetate=18:1, v/v as eluent) to give the desired product as a yellow oil in 78% yield.

The specific characterization data are as follows: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H, NH), 7.82 (d,J= 8.0 Hz, 2H, ArH), 7.75 (d,J= 7.9 Hz, 2H, ArH), 7.35 (t,J= 7.9 Hz, 2H, ArH), 7.23 (d,J= 7.0 Hz, 3H, ArH), 6.96 (t,J= 7.3 Hz, 1H, ArH), 2.32 (s, 3H, CH ₃ ); ¹³ C NMR (400 MHz, DMSO-d ₆ ) δ 163.49, 150.62, 141.72, 137.32, 132.36, 129.58 (d,J= 19.0 Hz), 126.08, 121.64, 117.27, 102.40, 21.32.

compared with the prior invention, the invention has the main characteristics that: the invention provides a novel synthesis method of aminothiazole, which can be used for carrying out reaction under mechanical ball milling, and has the advantages of short reaction time, simple and convenient operation, less pollution and wide application range.

Claims

1. The mechanical ball milling synthesis method of the aminothiazole compound is characterized by comprising the following steps of:

2. The mechanical ball milling synthesis method of aminothiazole compound as claimed in claim 1, wherein the aromatic ketone compound in the step 1) is 2-Acetyl-4-chlorothiophene, 3-acetylthiophene, 3-acetyl-2, 5-dichlorothiophene, 2-acetyl-5-chlorothiophene, 4-bromo-2-acetylthiophene, 2-acetyl-3-bromothiophene, 2-acetyl-5-bromothiophene, 2-acetylbenzofuran, acetophenone, 4-Cl acetophenone, 4-Br acetophenone, 4-NO ₂ Acetophenone or 4-CH ₃ Acetophenone.

3. The mechanical ball milling synthesis method of aminothiazole compound as claimed in claim 1, wherein the brominating reagent in the step 1) is N-bromosuccinimide or CuBr ₂ One of dibromohydantoin.

4. The method for mechanical ball milling synthesis of aminothiazole compounds according to claim 1, wherein the acid catalyst in the step 1) is one of p-toluenesulfonic acid, trifluoroacetic acid, aspartic acid, formic acid, acetic acid and trifluoromethanesulfonic acid.

5. The mechanical ball milling synthesis method of aminothiazole compounds as claimed in claim 1, wherein the molar ratio of the aromatic ketone compounds to the brominating reagent to the acid catalyst in the step 1) is 1:0.5-1.2:0.5-1.2.

6. The mechanical ball milling synthesis method of aminothiazole compounds as claimed in claim 1, wherein the thiourea compound in the step 2) is thiourea, N-methyl thiourea or phenylthiourea, and the molar ratio of the a-bromoketone to the thiourea compound is 1:1.

7. the mechanical ball milling synthesis method of aminothiazole compounds according to claim 1, wherein the grinding aid in the step 1) and the step 2) is one of sodium sulfate, sodium chloride, potassium chloride, silica gel, neutral alumina and basic alumina.

8. The mechanical ball milling synthesis method of aminothiazole compounds according to claim 1, wherein the ball milling frequency in the step 1) and the step 2) is 10-30HZ, and the ball milling time is 10-90min.

9. The method for mechanical ball milling synthesis of aminothiazole compounds according to claim 1, wherein the solvent in step 1) and step 2) is ethyl acetate.

10. The mechanical ball milling synthesis method of aminothiazole compounds according to claim 1, wherein the column chromatography eluent in the step 1) is a mixed solution of petroleum ether and toluene, and the volume ratio of petroleum ether to toluene is 1-5: 1, a step of; the column chromatography eluent in the step 2) is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 4-50: 1.