Preparation method of 4,5-disubstituted-2-substituted aminothiazole compound

Abstract

The invention discloses a preparation method of a 4,5-disubstituted-2-substituted aminothiazole compound. The preparation method comprises steps as follows: 1), nitro epoxy compounds and thiourea compounds react at the room temperature for 4-8 h in the presence of a solvent and a basic catalyst; a mole ratio of the nitro epoxy compounds to the thiourea compounds to the basic catalyst is 1: (1.8-2.2): (1.8-2.2); 2), a reaction liquid obtained in the step 1) is concentrated, subjected to solvent removal and added with water, a mixture is extracted by dichloromethane, an organic layer is obtained and then is washed, dried and concentrated by a rotary evaporator; 3), the concentrate obtained in the step 2) is subjected to silica-gel column chromatography, and the 4,5-disubstituted-2-substituted aminothiazole compound is obtained.

Description

technical field

[0001] The invention belongs to a compound synthesis method, and mainly relates to a preparation method of a 4,5-disubstituted-2-substituted aminothiazole compound. Background technique

[0002] As a class of five-membered heterocyclic compounds with broad-spectrum biological activity, thiazole compounds have important applications in the fields of medicine, pesticides, and materials. Especially in recent years, studies have found that the thiazole ring, as a very important structural unit, widely exists in many natural products and drugs, such as Tiazofurinanddasatinib, Ritonavir, Nizatidine, VitaminB1, Epothilones, Thiostreptonandthiaminepyrophosphate, etc., which are used for tumors, AIDS , Ulcers, allergies, high blood pressure, osteoporosis, asthma and other diseases.

[0003] Due to the important application value of thiazole compounds, their synthetic methods have been widely concerned, among which the thiazole synthesis method proposed by Hantzsch et...

Examples

Embodiment 1

[0056] Embodiment 1, 4-methyl-5-phenyl-2-aminothiazole (m1)

[0057] Add 179.1 mg (1 mmol) of 2-methyl-2-nitro-3-phenyloxirane and 152.2 mg (2 mmol) of thiourea into the reaction flask, and then add K 2 CO 3 212.0mg (2mmol), methanol 5.0ml, after the addition was complete, the reaction was stirred at room temperature (25°C) for 6-8 hours, and the reaction was detected by TLC (petroleum ether: ethyl acetate = 20:1 volume ratio). When the TLC detection reaction result is that 2-methyl-2-nitro-3-phenyloxirane disappears, it means that the reaction has ended.

[0058] After the reaction was finished, the solvent was evaporated by a rotary evaporator, 60ml of water was added, extracted three times with 3×20mL ethyl acetate, the organic layer (located on the upper layer) was combined and washed three times with 3×20mL saturated brine, and then washed with anhydrous sodium sulfate ( 2.0 g) was dried for 30 minutes, and concentrated by a rotary evaporator until there was basically n...

Embodiment 2

[0084] Embodiment 2, 4-ethyl-5-phenyl-2-aminothiazole (m2)

[0085] Replace 2-methyl-2-nitro-3-phenyloxirane with 2-ethyl-2-nitro-3-phenyloxirane, the molar weight is constant, and the rest are equal to Example 1 . 180.9 mg of 4-ethyl-5-phenyl-2-aminothiazole was obtained as a white powder, with a yield of 88.7%.

[0086] Its structural formula is:

[0087]

[0088] Whitepowder; mp: 128.3~129.0℃; 1 HNMR (500MHz, CDCl 3 )δ7.41–7.31(m,4H),7.28(dd,J=10.5,3.9Hz,1H),5.12(s,2H),2.62(q,J=7.5Hz,2H),1.25(t,J =7.5Hz,3H). 13 CNMR (126MHz, CDCl 3 )δ165.51(s),149.39(s),132.68(s),129.05(s),128.58(s),126.99(s),120.93(s),77.29(s),77.04(s),76.78( s),22.94(s),14.19(s).HRMS(ESI):m / zcalcdforC 11 h 13 N 2 S[M+H] + :205.0794,found:205.0797.

Embodiment 3

[0089] Example 3, 4-methyl-5-(4-fluoro-phenyl)-2-aminothiazole (m3)

[0090] Replace 2-methyl-2-nitro-3-phenyloxirane with 2-methyl-2-nitro-3-(4-fluoro-phenyl)-oxirane, the molar weight remains unchanged , all the other are with embodiment 1. 199.1 mg of 4-methyl-5-(4-fluoro-phenyl)-2-aminothiazole was obtained as a white powder product, with a yield of 95.7%.

[0091] Its structural formula is:

[0092]

[0093] Whitepowder; mp: 165.5~167.0℃; 1 HNMR (500MHz, CDCl 3 )δ7.35–7.28(m,2H),7.10–7.02(m,2H),5.18(s,2H),2.27–2.25(m,3H). 13 CNMR (126MHz, CDCl 3 ( s),77.30(s),77.04(s),76.79(s),15.85(s).HRMS(ESI):m / zcalcdforC 10 h 10 FN 2 S[M+H] + :209.0543,found:209.0544.

technical field

[0001] The invention belongs to a compound synthesis method, and mainly relates to a preparation method of a 4,5-disubstituted-2-substituted aminothiazole compound. Background technique

[0002] As a class of five-membered heterocyclic compounds with broad-spectrum biological activity, thiazole compounds have important applications in the fields of medicine, pesticides, and materials. Especially in recent years, studies have found that the thiazole ring, as a very important structural unit, widely exists in many natural products and drugs, such as Tiazofurinanddasatinib, Ritonavir, Nizatidine, VitaminB1, Epothilones, Thiostreptonandthiaminepyrophosphate, etc., which are used for tumors, AIDS , Ulcers, allergies, high blood pressure, osteoporosis, asthma and other diseases.

[0003] Due to the important application value of thiazole compounds, their synthetic methods have been widely concerned, among which the thiazole synthesis method proposed by Hantzsch et...

Examples

Embodiment 1

[0056] Embodiment 1, 4-methyl-5-phenyl-2-aminothiazole (m1)

[0057] Add 179.1 mg (1 mmol) of 2-methyl-2-nitro-3-phenyloxirane and 152.2 mg (2 mmol) of thiourea into the reaction flask, and then add K 2 CO 3 212.0mg (2mmol), methanol 5.0ml, after the addition was complete, the reaction was stirred at room temperature (25°C) for 6-8 hours, and the reaction was detected by TLC (petroleum ether: ethyl acetate = 20:1 volume ratio). When the TLC detection reaction result is that 2-methyl-2-nitro-3-phenyloxirane disappears, it means that the reaction has ended.

[0058] After the reaction was finished, the solvent was evaporated by a rotary evaporator, 60ml of water was added, extracted three times with 3×20mL ethyl acetate, the organic layer (located on the upper layer) was combined and washed three times with 3×20mL saturated brine, and then washed with anhydrous sodium sulfate ( 2.0 g) was dried for 30 minutes, and concentrated by a rotary evaporator until there was basically n...

Embodiment 2

[0084] Embodiment 2, 4-ethyl-5-phenyl-2-aminothiazole (m2)

[0085] Replace 2-methyl-2-nitro-3-phenyloxirane with 2-ethyl-2-nitro-3-phenyloxirane, the molar weight is constant, and the rest are equal to Example 1 . 180.9 mg of 4-ethyl-5-phenyl-2-aminothiazole was obtained as a white powder, with a yield of 88.7%.

[0086] Its structural formula is:

[0087]

[0088] Whitepowder; mp: 128.3~129.0℃; 1 HNMR (500MHz, CDCl 3 )δ7.41–7.31(m,4H),7.28(dd,J=10.5,3.9Hz,1H),5.12(s,2H),2.62(q,J=7.5Hz,2H),1.25(t,J =7.5Hz,3H). 13 CNMR (126MHz, CDCl 3 )δ165.51(s),149.39(s),132.68(s),129.05(s),128.58(s),126.99(s),120.93(s),77.29(s),77.04(s),76.78( s),22.94(s),14.19(s).HRMS(ESI):m / zcalcdforC 11 h 13 N 2 S[M+H] + :205.0794,found:205.0797.

Embodiment 3

[0089] Example 3, 4-methyl-5-(4-fluoro-phenyl)-2-aminothiazole (m3)

[0090] Replace 2-methyl-2-nitro-3-phenyloxirane with 2-methyl-2-nitro-3-(4-fluoro-phenyl)-oxirane, the molar weight remains unchanged , all the other are with embodiment 1. 199.1 mg of 4-methyl-5-(4-fluoro-phenyl)-2-aminothiazole was obtained as a white powder product, with a yield of 95.7%.

[0091] Its structural formula is:

[0092]

[0093] Whitepowder; mp: 165.5~167.0℃; 1 HNMR (500MHz, CDCl 3 )δ7.35–7.28(m,2H),7.10–7.02(m,2H),5.18(s,2H),2.27–2.25(m,3H). 13 CNMR (126MHz, CDCl 3 ( s),77.30(s),77.04(s),76.79(s),15.85(s).HRMS(ESI):m / zcalcdforC 10 h 10 FN 2 S[M+H] + :209.0543,found:209.0544.

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