A process for the preparation of a (benz)thiazole amide compound

Abstract

The application provides a preparation method of a (benzo)thiazole amide compound and belongs to the technical field of amide compound preparation. The application mixes a substituted acyl chloride, a compound 1 or a compound 2, samarium powder and a base in a solvent, and carries out a reaction under ultrasonic assistance, so that the (benzo)thiazole amide compound is obtained. In the preparation of the (benzo)thiazole amide compound, the samarium powder and the base are added, and then the target product is successfully synthesized through the ultrasonic assistance method. The preparation method has the advantages of simple operation, low cost, high product yield, wide substrate application range and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of amide compound preparation, and particularly relates to a preparation method of a (benzo)thiazole amide compound. BACKGROUND

[0002] Amide compounds are widely present in various products with practical applications, from drugs, peptides (proteins) to synthetic polymers, etc. [see: Humphrey, J. M. ; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243-2266.]. In the field of organic synthesis, amide bonds often play a key role in the preparation of other compounds such as nitriles, amines, heterocycles and amino acids.

[0003] One of the important classes of amide compounds is the compounds containing (benzo)thiazole structural units in the molecules. Such compounds often exhibit different pharmacological and physiological activities. For example, the following compound I (SAR125844) is a highly selective MET kinase inhibitor; the benzothiazole-2,6-diamine derivative II is an antibacterial drug; compound III shows good tumor growth inhibition on various tumors (U-87MG, A549 and HCT116 cell lines) with different genetic backgrounds; the picomolar inhibitor of Src and Bcr-Abl kinases, dasatinib (compound IV), has been used in clinical treatment; the amide V containing thiazole structural units in the following formula can be used for treating hepatitis C virus infection; and another amide VI containing thiazole ring is reported to have excellent metabolic stability and plasma stability.

[0004]

[0005] The existing preparation process of the (benzo)thiazole amide compound is complex and has a low yield. Therefore, it is of great significance to study a preparation method of the (benzo)thiazole amide compound and improve the yield of the (benzo)thiazole amide compound. SUMMARY

[0006] The present application aims to provide a preparation method of a (benzo)thiazole amide compound to solve the problem of low yield of the (benzo)thiazole amide compound in the prior art.

[0007] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions.

[0008] The present application provides a preparation method of a (benzo)thiazole amide compound, comprising the following steps: mixing a substituted acyl chloride, compound 1 or compound 2, samarium powder and a base in a solvent, and performing a reaction under ultrasonic waves to obtain the (benzo)thiazole amide compound.

[0009] The structural formula of the substituted acyl chloride is wherein R1 is benzyl, alkyl, aryl or heteroaryl;

[0010] The structural formula of the compound 1 is wherein R2 and R3 are independently chlorine, bromine, nitro, methoxy, methyl or hydrogen; and the structural formula of the compound 2 is wherein R4 and R5 are independently methyl, bromine or nitro.

[0011] As a preference, the substituted acyl chloride is phenylacetyl chloride, 2,5-dimethylphenylacetyl chloride, 4-chlorophenylacetyl chloride, 4-methoxyphenylacetyl chloride, thienylacetyl chloride, benzoyl chloride, 2-naphthoyl chloride, 4-tert-butylbenzoyl chloride, furfuryl chloride, 2-thiophenecarbonyl chloride or propionyl chloride.

[0012] As a preference, the compound 1 is 2-aminothiazole, 2-amino-5-methylthiazole, 2-amino-4-methylthiazole, 2-amino-5-nitrothiazole or 2-amino-5-bromothiazole.

[0013] As a preference, the compound 2 is 2-amino-6-chlorobenzothiazole, 2-aminobenzothiazole, 2-amino-6-fluorobenzothiazole, 2-amino-6-bromobenzothiazole, 2-amino-6-nitrobenzothiazole, 2-amino-6-methoxybenzothiazole, 2-amino-6-methylbenzothiazole or 2-amino-4-methylbenzothiazole.

[0014] As a preference, the base comprises one or several of triethylamine, pyridine, potassium hydroxide, sodium carbonate and potassium carbonate.

[0015] As a preference, the solvent comprises one or several of tetrahydrofuran, ethanol, acetonitrile, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide and dimethyl sulfoxide.

[0016] As a preference, the molar volume ratio of the substituted acyl chloride, the compound 1 or the compound 2, the samarium powder, the base and the solvent is 0.4-0.8 mmol: 0.4-0.8 mmol: 0.04-0.48 mmol: 0.4-0.8 mmol: 1-8 mL.

[0017] As a preference, the frequency of the ultrasound is 40-50 kHz.

[0018] As a preference, the temperature of the reaction is 0-40℃ and the time is 15-600 s.

[0019] The beneficial effects of the present application are:

[0020] (1) The present application adds samarium powder and base when preparing (benzo)thiazole amide compounds, and successfully synthesizes the target product through the method of ultrasound assistance.

[0021] (2) The present application has the advantages of simple operation, low cost, high product yield, and wide substrate application range. DETAILED DESCRIPTION

[0022] The present application provides a preparation method of a (benzo)thiazole amide compound, comprising the following steps: mixing a substituted acyl chloride, compound 1 or compound 2, samarium powder and a base in a solvent, and performing a reaction under ultrasonic waves to obtain the (benzo)thiazole amide compound.

[0023] The structural formula of the substituted acyl chloride is , wherein R1 is benzyl, alkyl, aryl or heteroaryl;

[0024] The structural formula of the compound 1 is , wherein R2 and R3 are independently chlorine, bromine, nitro, methoxy, methyl or hydrogen; and the structural formula of the compound 2 is , wherein R4 and R5 are independently methyl, bromine or nitro.

[0025] In the present application, the substituted acyl chloride is phenylacetyl chloride, 2,5-dimethylphenylacetyl chloride, 4-chlorophenylacetyl chloride, 4-methoxyphenylacetyl chloride, thienylacetyl chloride, benzoyl chloride, 2-naphthoyl chloride, 4-tert-butylbenzoyl chloride, furfuryl chloride, 2-thiophenecarboxylate or propionyl chloride, preferably phenylacetyl chloride, 2,5-dimethylphenylacetyl chloride, 4-chlorophenylacetyl chloride, 4-methoxyphenylacetyl chloride, thienylacetyl chloride, furfuryl chloride or propionyl chloride, and further preferably phenylacetyl chloride, 4-chlorophenylacetyl chloride, 4-methoxyphenylacetyl chloride, thienylacetyl chloride or propionyl chloride.

[0026] In the present application, the compound 1 is 2-aminothiazole, 2-amino-5-methylthiazole, 2-amino-4-methylthiazole, 2-amino-5-nitrothiazole or 2-amino-5-bromothiazole, preferably 2-aminothiazole, 2-amino-5-methylthiazole or 2-amino-4-methylthiazole, and further preferably 2-aminothiazole or 2-amino-5-methylthiazole.

[0027] In the present application, the compound 2 is 2-amino-6-chlorobenzothiazole, 2-aminobenzothiazole, 2-amino-6-fluorobenzothiazole, 2-amino-6-bromobenzothiazole, 2-amino-6-nitrobenzothiazole, 2-amino-6-methoxybenzothiazole, 2-amino-6-methylbenzothiazole or 2-amino-4-methylbenzothiazole, preferably 2-amino-6-chlorobenzothiazole, 2-aminobenzothiazole, 2-amino-6-methoxybenzothiazole, 2-amino-6-methylbenzothiazole or 2-amino-4-methylbenzothiazole, and further preferably 2-amino-6-methoxybenzothiazole, 2-amino-6-methylbenzothiazole or 2-amino-4-methylbenzothiazole.

[0028] In the present application, the base comprises one or more of triethylamine, pyridine, potassium hydroxide, sodium carbonate and potassium carbonate, preferably one or more of pyridine, potassium hydroxide and sodium carbonate, further preferably pyridine and / or potassium hydroxide.

[0029] In the present application, the solvent comprises one or more of tetrahydrofuran, ethanol, acetonitrile, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide and dimethyl sulfoxide, preferably one or more of tetrahydrofuran, ethanol, acetonitrile, 1,4-dioxane, ethyl acetate and dichloromethane, further preferably one or more of tetrahydrofuran, ethanol, acetonitrile and 1,4-dioxane.

[0030] In the present application, the molar volume ratio of the substituted acyl chloride, compound 1 or compound 2, samarium powder, base and solvent is 0.4-0.8 mmol: 0.4-0.8 mmol: : 0.04-0.48 mmol: 0.4-0.8 mmol: 1-8 mL, preferably 0.5-0.7 mmol: 0.5-0.7 mmol: 0.10-0.45 mmol: 0.5-0.7 mmol: 2-7 mL, further preferably 0.55-0.65 mmol: 0.55-0.65 mmol: 0.15-0.40 mmol: 0.55-0.65 mmol: 3-6 mL.

[0031] In the present application, the frequency of the ultrasound is 40-50 kHz, preferably 42-48 kHz, further preferably 45 kHz.

[0032] In the present application, the temperature of the reaction is 0-40 °C, preferably 5-35 °C, further preferably 10-20 °C; the time is 15-600 s, preferably 30-550 s, further preferably 50-500 s.

[0033] The technical solutions provided by the present application are described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application.

[0034] Example 1

[0035] 0.5 mmol of phenylacetyl chloride, 0.5 mmol of 2-amino-6-chlorobenzothiazole, 0.25 mmol of samarium powder and 0.5 mmol of pyridine were mixed in 4 mL of tetrahydrofuran, and reacted at 0 °C under ultrasound with a frequency of 45 kHz for 60 s, followed by filtration through diatomite, ethyl acetate washing, removal of the solvent by reduced pressure distillation, and fast column chromatography purification with ethyl acetate and petroleum ether as the mobile phase to obtain the pure product, which was product 3a with the structural formula The yield was 94%.

[0036] 1 H NMR (400 MHz, d6-DMSO) δ 3.85 (s, 2H), 7.27-7.30 (m, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.46 (dd, J = 8.6, 2.2 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 12.70 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 42.3, 120.9, 122.2, 124.0, 126.6, 127.4, 128.9, 129.8, 131.9, 135.2, 148.9, 158.4, 170.2.

[0037] Example 2

[0038] 0.4 mmol of phenylacetyl chloride, 0.4 mmol of 2-aminobenzothiazole, 0.2 mmol of samarium powder and 0.4 mmol of pyridine were mixed in 5 mL of dichloromethane, reacted under ultrasonic frequency of 40 kHz at 25 °C for 100 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, and purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 3b, the structural formula of which is The yield was 95%.

[0039] 1 H NMR (400 MHz, d6-DMSO) δ 3.85 (s, 2H), 7.27-7.30 (m, 1H), 7.35 (d, J = 4.4 Hz, 4H), 7.46 (dd, J = 8.6, 2.2 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 12.70 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 42.3, 120.9, 122.2, 124.0, 126.6, 127.4, 128.9, 129.8, 131.9, 135.2, 148.9, 158.4, 170.2.

[0040] Example 3

[0041] 0.6 mmol of phenylacetyl chloride, 0.6 mmol of 2-amino-6-fluorobenzothiazole, 0.3 mmol of samarium powder, and 0.6 mmol of triethylamine were mixed in 8 mL of ethanol and reacted at 40°C for 200 s under ultrasound at a frequency of 50 kHz. The mixture was then filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was removed by vacuum distillation. The product was purified by flash column chromatography using ethyl acetate and petroleum ether as the mobile phase to obtain the pure product 3c, with the structural formula: The yield was 88%.

[0042] 1 H NMR (400MHz, d6-DMSO) δ3.84(s,2H),7.27–7.32(m,3H),7.35(d,J=4.5Hz,3H),7.76(dd,J=8.9,4.8Hz,1H),7.89(dd,J=8.7,2.6Hz,1H),12.64(s,1H); 13 C NMR(100MHz,d6-DMSO)δ42.3,108.6(d,J CF =26.9Hz),114.7(d,J CF =24.4Hz),122.1(d,J CF =9.1Hz),127.0,127.4,128.9,129.8,133.2(d,J CF =11.1Hz),135.1,145.7,159.1(d,J CF =239.9Hz),170.8.

[0043] Example 4

[0044] 0.8 mmol of phenylacetyl chloride, 0.8 mmol of 2-amino-6-bromobenzothiazole, 0.48 mmol of samarium powder, and 0.8 mmol of sodium carbonate were mixed in 7 mL of ethyl acetate and reacted at 0°C for 400 s under ultrasound at a frequency of 45 kHz. The mixture was then filtered through diatomaceous earth, washed with ethyl acetate, and the solvent was removed by vacuum distillation. The pure product was purified by flash column chromatography using ethyl acetate and petroleum ether as the mobile phase to obtain product 3d, whose structural formula is The yield was 92%.

[0045] 1 H NMR(400MHz,d6-DMSO)δ3.85(s,2H),7.26–7.30(m,1H),7.35(d,J=4.5Hz,4H),7.58 (dd,J=8.6,2.1Hz,1H),7.69(d,J=8.6Hz,1H),8.25(d,J=1.9Hz,1H),12.71(s,1H);13 CNMR (100 MHz, d6-DMSO) δ 42.3, 115.9, 122.6, 124.8, 127.4, 128.9, 129.6, 129.8, 134.1, 135.0, 148.2, 159.2, 170.9. HRMS (ESI) m / z: calcd for C 15 H 11 BrN2OS (M+H) + 346.9848, found 346.9845.

[0046] Example 5

[0047] 0.8 mmol of phenylacetyl chloride, 0.8 mmol of 2-amino-6-nitrobenzothiazole, 0.15 mmol of samarium powder and 0.8 mmol of potassium carbonate were mixed in 6 mL of dimethyl sulfoxide, reacted under ultrasonic frequency of 50 kHz at 25 °C for 100 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 3e, the structural formula of which is The yield was 82%.

[0048] 1 H NMR (400 MHz, d6-DMSO) δ 3.90 (s, 2H), 7.27-7.38 (m, 5H), 7.91 (d, J = 9.0 Hz, 1H), 8.29 (dd, J = 8.9, 2.4 Hz, 1H), 9.06 (d, J = 2.4 Hz, 1H), 13.03 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 42.3, 119.5, 121.1, 122.2, 127.5, 128.9, 129.9, 132.7, 134.8, 143.5, 153.9, 163.9, 171.4.

[0049] Example 6

[0050] 0.5 mmol of phenylacetyl chloride, 0.5 mmol of 2-amino-6-methoxybenzothiazole, 0.30 mmol of samarium powder and 0.5 mmol of pyridine were mixed in 3 mL of N,N-dimethylformamide, reacted under ultrasonic frequency of 45 kHz at 40 °C for 80 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 3f, the structural formula of which is The yield was 97%.

[0051] 1 H NMR (400 MHz, d6-DMSO) δ 3.56 (s, 3H), 3.81 (s, 2H), 7.02 (dd, J = 8.8, 2.5 Hz, 1H), 7.24 - 7.35 (m, 5H), 7.55 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 12.45 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 42 173.2.3, 56.1, 105.2, 115.4, 121.6, 127.3, 128.7, 129.8, 133.2, 135.5, 143.1, 156.2, 170.4.

[0052] Example 7

[0053] Example 7 Yield 94%.

[0054] 1 H NMR (400 MHz, d6-DMSO) δ 2.41 (s, 3H), 3.82 (s, 2H), 7.24 - 7.36 (m, 6H), 7.63 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 12.53 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 21.4, 42.3, 120.6, 121.8, 127.3, 127.9, 128.9, 129.8, 132.0, 133.5, 135.2, 146.9, 157.5, 170.5. HRMS (ESI) m / z: calcd for C 16 H 14 N2OS (M+H) + 283.0900, found 283.0906.

[0055] Example 8

[0056] A mixture of 0.7 mmol of phenylacetyl chloride, 0.7 mmol of 2-amino-4- methylbenzothiazole, 0.45 mmol of samarium powder and 0.7 mmol of triethylamine was mixed in 8 mL of tetrahydrofuran, and reacted under ultrasonic frequency of 45 kHz at 25 °C for 500 s, followed by diatomite filtration, ethyl acetate washing, removal of the solvent by reduced pressure distillation, and fast column chromatography purification with ethyl acetate and petroleum ether as the mobile phase to obtain the pure product, to obtain product 3h, with the structural formula of The yield was 90%.

[0057] 1 H NMR (400 MHz, d6-DMSO) δ 2.58 (s, 3H), 3.83 (s, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.25-7.30 (m, 2H), 7.35-7.38 (m, 4H), 7.78 (d, J = 7.8 Hz, 1H), 12.69 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 18.4, 42.3, 119.6, 123.9, 127.1, 127.4, 128.9, 129.8, 130.3, 131.6, 135.2, 148.1, 157.5, 170.6. HRMS (ESI) m / z: calcd for C 16 H 14 N2OS (M+H) + 283.0900, found 283.0896.

[0058] Example 9

[0059] A mixture of 0.5 mmol of phenylacetyl chloride, 0.5 mmol of 2-aminothiazole, 0.15 mmol of samarium powder and 0.5 mmol of triethylamine was mixed in 6 mL of ethanol, and reacted under ultrasonic frequency of 45 kHz at 40 °C for 600 s, followed by diatomite filtration, ethyl acetate washing, removal of the solvent by reduced pressure distillation, and fast column chromatography purification with ethyl acetate and petroleum ether as the mobile phase to obtain the pure product, to obtain product 3i, with the structural formula of The yield was 95%.

[0060] 1 H NMR (400 MHz, d6-DMSO) δ 3.77 (s, 2H), 7.20 (d, J = 3.6 Hz, 1H), 7.25-7.34 (m, 5H), 7.47 (d, J = 3.6 Hz, 1H), 12.35 (s, 1H); 13C NMR (100 MHz, d6-DMSO) δ 42.1, 113.9, 127.3, 128.9, 129.7, 135.5, 138.1, 158.4, 169.6.

[0061] Example 10

[0062] 0.6 mmol of phenylacetyl chloride, 0.6 mmol of 2-amino-5-methylthiazole, 0.15 mmol of samarium powder and 0.6 mmol of pyridine were mixed in 8 mL of tetrahydrofuran, reacted under ultrasonic frequency of 45 kHz at 25 °C for 300 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 3j, the structural formula is The yield was 96%.

[0063] 1 H NMR (400 MHz, d6-DMSO) δ 2.32 (s, 3H), 3.73 (s, 2H), 7.13 (s, 1H), 7.24-7.35 (m, 5H), 12.14 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 11.5, 42.1, 126.6, 127.2, 128.9, 129.7, 135.2, 135.6, 156.6, 169.3.

[0064] Example 11

[0065] 0.6 mmol of phenylacetyl chloride, 0.6 mmol of 2-amino-5-methylthiazole, 0.15 mmol of samarium powder and 0.6 mmol of pyridine were mixed in 8 mL of tetrahydrofuran, reacted under ultrasonic frequency of 45 kHz at 25 °C for 300 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 3j, the structural formula is The yield was 92%.

[0066] 1 H NMR (400 MHz, d6-DMSO) δ 2.32 (s, 3H), 3.73 (s, 2H), 7.13 (s, 1H), 7.24-7.35 (m, 5H), 12.14 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 17.3, 42.2, 108.1, 127.3, 128.9, 129.7, 135.5, 147.1, 157.7, 169.5.

[0067] Example 12

[0068] 0.5 mmol of phenylacetyl chloride, 0.5 mmol of 2-amino-5-nitrothiazole, 0.15 mmol of samarium powder and 0.5 mmol of potassium carbonate were mixed in 7 mL of acetonitrile, reacted under ultrasonic frequency of 40 kHz at 0 °C for 200 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by distillation under reduced pressure, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 3l, with structural formula The yield was 69%.

[0069] 1 H NMR (400 MHz, d6-DMSO) δ 3.88 (s, 2H), 7.22-7.35 (m, 5H), 8.63 (s, 1H), 12.29 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 41.9, 127.5, 128.7, 129.8, 134.5, 135.5, 143.1, 162.2, 171.6.

[0070] Example 13

[0071] 0.8 mmol of phenylacetyl chloride, 0.8 mmol of 2-amino-5-bromothiazole, 0.45 mmol of samarium powder and 0.8 mmol of potassium hydroxide were mixed in 7 mL of ethyl acetate, reacted under ultrasonic frequency of 45 kHz at 25 °C for 450 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by distillation under reduced pressure, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 3m, with structural formula The yield was 91%.

[0072] 1 H NMR (400 MHz, d6-DMSO) δ 3.78 (s, 2H), 7.25-7.35 (m, 5H), 7.56 (s, 1H), 12.62 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 41.8, 102.1, 127.4, 128.9, 129.7, 135.1, 139.2, 158.8, 170.2.

[0073] Example 14

[0074] A mixture of 0.4 mmol of 2,5-dimethylbenzeneacetyl chloride, 0.4 mmol of 2-aminothiazole, 0.35 mmol of samarium powder and 0.4 mmol of potassium hydroxide was mixed in 3 mL of ethanol, reacted under ultrasonic frequency of 45 kHz at 40 °C for 500 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 4a, the structural formula is The yield was 89%.

[0075] 1 H NMR (400 MHz, d6-DMSO) δ 2.22 (s, 3H), 2.24 (s, 3H), 3.76 (s, 2H), 6.97 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 3.9 Hz, 2H), 7.19 (d, J = 3.5 Hz, 1H), 7.47 (d, J = 3.5 Hz, 1H), 12.31 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 19.3, 20.9, 39.8, 113.9, 127.9, 130.4, 131.2, 133.9, 134.0, 135.1, 138.1, 158.5, 169.6. HRMS (ESI) m / z: calcd for C 13 H 14 N2OS (M+H) + 247.0900, found 247.0892.

[0076] Example 15

[0077] A mixture of 0.6 mmol of 4-chlorobenzeneacetyl chloride, 0.6 mmol of 2-aminothiazole, 0.35 mmol of samarium powder and 0.6 mmol of potassium hydroxide was mixed in 5 mL of tetrahydrofuran, reacted under ultrasonic frequency of 45 kHz at 0 °C for 550 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 4b, the structural formula is The yield was 96%.

[0078] 1 H NMR (400 MHz, d6-DMSO) δ 3.78 (s, 2H), 7.20 (d, J = 3.5 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 3.5 Hz, 1H), 12.35 (s, 1H); 13C NMR (100 MHz, d6-DMSO) δ 41.3, 114.0, 128.8, 131.6, 132.0, 134.4, 138.1, 158.4, 169.3.

[0079] Example 16

[0080] A mixture of 0.8 mmol of 4-methoxybenzeneacetyl chloride, 0.8 mmol of 2- aminothiazole, 0.45 mmol of samarium powder and 0.8 mmol of pyridine was mixed in 8 mL of dichloromethane, reacted under ultrasonic frequency of 45 kHz at 40 °C for 300 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 4c, with the structural formula of The yield was 95%.

[0081] 1 H NMR (400 MHz, d6-DMSO) δ 3.68 (s, 2H), 3.73 (s, 3H), 6.89 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 3.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 3.5 Hz, 1H), 12.27 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 41.2, 55.5, 113.9, 114.3, 127.4, 130.7, 138.1, 158.5, 158.7, 169.9.

[0082] Example 17

[0083] A mixture of 0.4 mmol of thiophene acetyl chloride, 0.4 mmol of 2- aminothiazole, 0.15 mmol of samarium powder and 0.4 mmol of sodium carbonate was mixed in 5 mL of N,N-dimethylformamide, reacted under ultrasonic frequency of 45 kHz at 25 °C for 150 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 4d, with the structural formula of The yield was 92%.

[0084] 1 H NMR (400 MHz, d6-DMSO) δ 4.00 (s, 2H), 6.97 - 6.99 (m, 2H), 7.22 (d, J = 3.5 Hz, 1H), 7.41 (dd, J = 4.8, 1.1 Hz, 1H), 7.48 (d, J = 3.5 Hz, 1H), 12.35 (s, 1H); 13C NMR (100 MHz, d6-DMSO) δ 36.4, 114.1, 125.9, 127.2, 127.3, 136.4, 138.2, 158.4, 168.6. HRMS (ESI) m / z: calcd for C9H8N2OS2 (M+H) 225.0150, found 225.0151. + 225.0151,found 225.0150.

[0085] Example 18

[0086] 0.7 mmol of benzoyl chloride, 0.7 mmol of 2-aminothiazole, 0.45 mmol of samarium powder and 0.7 mmol of triethylamine were mixed in 5 mL of dimethyl sulfoxide, reacted under ultrasonic frequency of 45 kHz at 0 °C for 350 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 4e with the structural formula of The yield was 88%.

[0087] 1 H NMR (400 MHz, d6-DMSO) δ 7.29 (d, J = 3.5 Hz, 1H), 7.48 - 7.57 (m, 3H), 7.64 (t, J = 7.3 Hz, 1H), 8.10 (d, J = 7.9 Hz, 2H), 12.65 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 114.3, 128.6, 129.0, 132.7, 132.9, 138.1, 159.2, 165.6.

[0088] Example 19

[0089] 0.6 mmol of 2-naphthoyl chloride, 0.6 mmol of 2-aminothiazole, 0.25 mmol of samarium powder and 0.6 mmol of potassium hydroxide were mixed in 6 mL of ethanol, reacted under ultrasonic frequency of 45 kHz at 25 °C for 180 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by reduced pressure distillation, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, to obtain product 4f with the structural formula of The yield was 79%.

[0090] 1H NMR (400 MHz, d6-DMSO) δ 7.31 (d, J = 3.5 Hz, 1H), 7.59 (d, J = 3.5 Hz, 1H), 7.62 - 7.70 (m, 2H), 8.01 - 8.09 (m, 3H), 8.13 (d, J = 8.6 Hz, 1H), 8.79 (s, 1H), 12.77 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 114.3, 124.8, 127.5, 128.2, 128.7, 128.8, 129.6, 129.7, 129.9, 132.5, 135.1, 138.1, 159.3, 165.7. HRMS (ESI) m / z: calcd for C 14 H 10 N2OS (M+H) + 255.0587, found 255.0591.

[0091] Example 20

[0092] 0.7 mmol of 4-tert-butylbenzoyl chloride, 0.7 mmol of 2-aminothiazole, 0.35 mmol of samarium powder and 0.7 mmol of potassium hydroxide were mixed in 7 mL of 1,4-dioxane, and reacted under ultrasonic frequency of 45 kHz at 40 °C for 260 s, followed by filtration through diatomite, washing with ethyl acetate, removing the solvent by reduced pressure distillation, and fast column chromatography purification with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, obtaining 4 g of product with the structural formula The yield was 86%.

[0093] 1 H NMR (400 MHz, d6-DMSO) δ 7.31 (d, J = 3.5 Hz, 1H), 7.59 (d, J = 3.5 Hz, 1H), 7.62 - 7.70 (m, 2H), 8.01 - 8.09 (m, 3H), 8.13 (d, J = 8.6 Hz, 1H), 8.79 (s, 1H), 12.77 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 114.3, 124.8, 127.5, 128.2, 128.7, 128.8, 129.6, 129.7, 129.9, 132.5, 135.1, 138.1, 159.3, 165.7. HRMS (ESI) m / z: calcd for C

[0094] Example 21

[0095] Example 1 0.8 mmol of 2-furoyl chloride, 0.8 mmol of 2-aminothiazole, 0.35 mmol of samarium powder and 0.8 mmol of potassium hydroxide were mixed in 8 mL of dichloromethane, reacted under ultrasonic frequency of 45 kHz at 25 °C for 430 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by distillation under reduced pressure, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, and the product 4h had the structural formula The yield was 89%.

[0096] 1 H NMR (400 MHz, d6-DMSO) δ 6.73-6.75 (m, 1H), 7.27 (d, J = 3.5 Hz, 1H), 7.55 (d, J = 3.6 Hz, 1H), 7.65 (d, J = 3.5 Hz, 1H), 8.01 (s, 1H), 12.59 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 112.7, 114.3, 116.8, 137.9, 146.2, 147.6, 156.4, 158.6.

[0097] Example 22

[0098] 0.8 mmol of 2-thiophenecarbonyl chloride, 0.8 mmol of 2-aminothiazole, 0.48 mmol of samarium powder and 0.8 mmol of potassium hydroxide were mixed in 8 mL of tetrahydrofuran, reacted under ultrasonic frequency of 45 kHz at 40 °C for 600 s, then sequentially filtered through diatomite, washed with ethyl acetate, removed the solvent by distillation under reduced pressure, purified by flash column chromatography with ethyl acetate and petroleum ether as mobile phase to obtain the pure product, and the product 4i had the structural formula The yield was 87%.

[0099] 1 H NMR (400 MHz, d6-DMSO) δ 7.24-7.28 (m, 2H), 7.56 (d, J = 3.6 Hz, 1H), 7.96 (d, J = 4.9 Hz, 1H), 8.24 (d, J = 3.0 Hz, 1H), 12.74 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 114.3, 129.0, 131.2, 133.9, 137.7, 137.9, 159.2, 160.3.

[0100] Example 23

[0101] A mixture of 0.6 mmol of propionyl chloride, 0.6 mmol of 2-aminothiazole, 0.24 mmol of samarium powder and 0.6 mmol of pyridine was mixed in 5 mL of tetrahydrofuran, and reacted under ultrasonic wave with a frequency of 45 kHz at 28°C for 340 s, followed by diatomite filtration, ethyl acetate washing, removal of the solvent by reduced pressure distillation, and purification by flash column chromatography using ethyl acetate and petroleum ether as mobile phases to obtain a pure product, to obtain product 4j, which has a structural formula of The yield was 97%.

[0102] 1 H NMR (400 MHz, d6-DMSO) δ 1.09 (t, J = 7.5 Hz, 3H), 2.44 (q, J = 7.5 Hz, 2H), 7.16-7.18 (m, 1H), 7.45 (d, J = 3.5 Hz, 1H), 12.03 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 9.6, 28.6, 113.6, 137.9, 158.6, 172.4.

[0103] Example 24

[0104] A mixture of 20 mmol of 4-chlorobenzeneacetyl chloride, 20 mmol of 2-aminothiazole, 10 mmol of samarium powder and 20 mmol of pyridine was mixed in 60 mL of dichloromethane, and reacted under ultrasonic wave with a frequency of 40 kHz at 25°C for 180 s, followed by diatomite filtration, ethyl acetate washing, removal of the solvent by reduced pressure distillation, and purification by flash column chromatography using ethyl acetate and petroleum ether as mobile phases to obtain a pure product, to obtain product 4b, which has a yield of 92%.

[0105] 1 H NMR (400 MHz, d6-DMSO) δ 3.78 (s, 2H), 7.20 (d, J = 3.5 Hz, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 3.5 Hz, 1H), 12.35 (s, 1H); 13 C NMR (100 MHz, d6-DMSO) δ 41.3, 114.0, 128.8, 131.6, 132.0, 134.4, 138.1, 158.4, 169.3.

[0106] Comparative Example 1

[0107] The difference from Example 1 is that no base was added, and the reaction was carried out under stirring at 25°C for 1.5 h, and the other conditions were the same, to obtain product 3a, which has a yield of 45%.

[0108] Comparative Example 2

[0109] The difference from Example 1 is that the added base is triethylamine, the reaction is carried out at 25°C for 1.5h under stirring, and the other conditions are the same, and the obtained product is 3a with a yield of 73%.

[0110] Comparative Example 3

[0111] The difference from Example 1 is that the reaction is carried out at 25°C for 1.5h under stirring, and the other conditions are the same, and the obtained product is 3a with a yield of 86%.

[0112] Comparative Example 4

[0113] The difference from Example 1 is that the added base is potassium hydroxide, the reaction is carried out at 25°C for 1.5h under stirring, and the other conditions are the same, and the obtained product is 3a with a yield of 65%.

[0114] Comparative Example 5

[0115] The difference from Example 1 is that the added base is sodium carbonate, the reaction is carried out at 25°C for 1.5h under stirring, and the other conditions are the same, and the obtained product is 3a with a yield of 82%.

[0116] Comparative Example 6

[0117] The difference from Example 1 is that the added base is potassium carbonate, the reaction is carried out at 25°C for 1.5h under stirring, and the other conditions are the same, and the obtained product is 3a with a yield of 62%.

[0118] Comparative Example 7

[0119] The difference from Example 1 is that the added base is sodium hydroxide, the reaction is carried out at 25°C for 1.5h under stirring, and the other conditions are the same, and the obtained product is 3a with a yield of 67%.

[0120] Comparative Example 8

[0121] The difference from Example 1 is that the amount of samarium powder is 0.15mmol, the reaction is carried out at 25°C for 1.5h under stirring, and the other conditions are the same, and the obtained product is 3a with a yield of 79%.

[0122] Comparative Example 9

[0123] The difference from Example 1 is that the amount of samarium powder is 0.05mmol, the reaction is carried out at 25°C for 1.5h under stirring, and the other conditions are the same, and the obtained product is 3a with a yield of 68%.

[0124] Comparative Example 10

[0125] The difference from example 1 is that no samarium powder is added, the reaction is carried out at 25℃ for 1.5h under stirring, and other conditions are the same, and the obtained product is 3a, and the yield is 52%.

[0126] Comparative example 11

[0127] The difference from example 1 is that the amount of samarium powder is 0.3mmol, the reaction is carried out at 25℃ for 1.5h under stirring, and other conditions are the same, and the obtained product is 3a, and the yield is 87%.

[0128] By comparing example 1 and the above comparative examples, it can be found that the amount of added samarium powder and different types of bases all affect the yield of the product, and under the combined action of ultrasonic conditions and samarium powder, the yield of the product can be ensured to be the highest.

[0129] Comparative example 12

[0130] The difference from example 14 is that 4-nitrobenzoyl chloride is reacted with 2-aminothiazole, and other conditions are the same, and no corresponding amide compound is obtained.

[0131] Comparative example 13

[0132] The difference from example 14 is that 2,4,6-trimethylbenzoyl chloride is reacted with 2-aminothiazole, and other conditions are the same, and only trace amount of amide compound is obtained.

[0133] From the above examples, it can be seen that the present application provides a preparation method of (benzo)thiazole amide compound, which mixes substituted acyl chloride, compound 1 or compound 2, samarium powder and base in a solvent, and carries out reaction under ultrasonic, so as to obtain (benzo)thiazole amide compound. The present application has the advantages of simple operation, low cost, high product yield, wide substrate application range and the like in the preparation of (benzo)thiazole amide compound.

[0134] The above only describes the preferred embodiments of the present application, and it should be noted that for ordinary skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method for preparing a thiazole amide compound, characterized by, The method comprises the following steps: mixing a substituted acyl chloride, a compound 1 or a compound 2, samarium powder and a base in a solvent, and performing a reaction under ultrasonic waves to obtain a thiazole amide compound. The substituted acyl chloride is phenylacetyl chloride, 2,5-dimethylphenylacetyl chloride, 4-chlorophenylacetyl chloride, 4-methoxyphenylacetyl chloride, thienylacetyl chloride, benzoyl chloride, 2-naphthoyl chloride, 4-tert-butylbenzoyl chloride, furfuryl chloride, 2-thiophenecarboxylic acid chloride or propionyl chloride. The structural formula of the compound 1 is wherein R2and R3are independently chlorine, bromine, nitro, methoxy, methyl or hydrogen; the structural formula of the compound 2 is wherein R4and R5are independently methyl, bromine or nitro; The molar volume ratio of the substituted acyl chloride, the compound 1 or the compound 2, the samarium powder, the base and the solvent is 0.4-0.8 mmol: 0.4-0.8 mmol: 0.04-0.48 mmol: 0.4-0.8 mmol: 1-8 mL. The frequency of the ultrasonic waves is 40-50 kHz. The reaction temperature is 0-40 DEG C, and the reaction time is 15-600 s.

2. The production method according to claim 1, characterized by, The compound 1 is 2-aminothiazole, 2-amino-5-methylthiazole, 2-amino-4-methylthiazole, 2-amino-5-nitrothiazole or 2-amino-5-bromothiazole.

3. The preparation method according to claim 1, characterized in that The compound 2 is 2-amino-6-chlorobenzothiazole, 2-aminobenzothiazole, 2-amino-6-fluorobenzothiazole, 2-amino-6-bromobenzothiazole, 2-amino-6-nitrobenzothiazole, 2-amino-6-methoxybenzothiazole, 2-amino-6-methylbenzothiazole or 2-amino-4-methylbenzothiazole.

4. The method of claim 1, wherein, The base comprises one or more of triethylamine, pyridine, potassium hydroxide, sodium carbonate and potassium carbonate.

5. The preparation method according to claim 4, characterized in that The solvent comprises one or more of tetrahydrofuran, ethanol, acetonitrile, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide and dimethyl sulfoxide.

Images