CN110845437A - Method for preparing 2-aminothiazole compound - Google Patents
Method for preparing 2-aminothiazole compound Download PDFInfo
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a method for preparing a 2-aminothiazole compound, which comprises the following steps: in an organic solvent, thiourea shown in a formula (II) and a ketone compound shown in a formula (III) are subjected to condensation reaction for 6-24 hours at 50-120 ℃ under the catalysis of a simple substance of iodine, and after the reaction is finished, a reaction solution is subjected to post-treatment to obtain a 2-aminothiazole compound shown in a formula (I). The invention has the advantages of cheap and easily obtained reaction raw materials, mild reaction conditions, simple preparation method, no need of using a transition metal catalyst and a stoichiometric halogenating reagent and reduced cost. The invention can be used for synthesizing a series of 2-aminothiazole derivatives, and the prepared products can be used as important intermediates for synthesizing medicaments containing thiazole structures or bioactive compounds.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a synthetic method for preparing a 2-aminothiazole compound by condensation reaction of thiourea and a ketone compound in a dimethyl sulfoxide solvent under the catalysis of iodine.
Background
The 2-aminothiazole compound is an important intermediate and is widely applied to the fields of medicines, pesticides, dyes and the like. In the field of medicine, 2-aminothiazole is an important structural part of a plurality of drugs and bioactive molecules, such as anti-cancer drugs of Dasatinib (Dasatinib), fourth-generation injection of cephalosporin of Mashimide (MaxiPime) and cefcapene (Flomox), analgesic and anti-inflammatory drugs of meloxicam (Mobic), and tacrolixole hydrochloride (Talipexole) for treating Parkinson's syndrome.
Although the preparation methods of the 2-aminothiazole compounds reported in the literature are various, most methods have similar reaction mechanisms and can be classified as a Hantzsch method. The method takes ketone compounds as raw materials, carries out halogenation reaction with stoichiometric halogenated reagents to synthesize 2-halogenated ketone in advance (or on site), and then carries out condensation reaction with thiourea to prepare the 2-aminothiazole. Typical examples of such methods are: 1) hitendra task group reports a solid phase reagent (SiO)2-Cl) to react with ketone compounds to synthesize 2-aminothiazole (Catalysis Communications,2007,8(4), 741-746). The method has short reaction time and high yield, but needs equivalent/excessive solid phase reagent (SiO)2-Cl), whereas the preparation/regeneration of the reagent requires the use of an excess of thionyl chloride; 2) the Dhanaji project group reported a method for synthesizing aminothiazoles using polyethylene glycol (PEG-400) as a solvent and thiourea, ketone and NBS as raw materials in a one-pot method (Chinese chemical letters,2010,21(4), 412-. The method uses polyethylene glycol as a green solvent, but needs to use an equivalent amount of a bromization reagent NBS, so that the cost is higher, and the separation difficulty of the product is increased due to the formation of a stoichiometric byproduct; 3) rajendiran topic group reported as H2O2The corresponding 2-aminothiazole product was prepared by reacting α -bromoacetone, which was formed in situ, with thiourea as the oxidizing agent in acetone and HBr aqueous solution (Journal of Chemical and pharmaceutical Research,2016,8(2), 813-820.) this procedure avoids the preparation and isolation of the highly tear-promoting α -bromocarbonyl compound, but requires an excess of aqueous hydrogen bromide.
The Yadav task group reports a synthesis method of 2-aminothiazole of another reaction type, which takes copper transition metal trifluoromethanesulfonate as a catalyst and prepares 2-aminothiazole by reacting α -diazoketone and thiourea (tetrahedron letters,2008,49(15): 2381-2383). The method has high reaction yield and chemical selectivity, almost no byproduct of wolff rearrangement and OTf insertion, but the reaction raw material α -diazoketone and the catalyst copper trifluoromethanesulfonate are difficult to prepare, have high cost and possibly cause the problem of residual metal copper in the medicine, therefore, the method is not suitable for large-scale production of the 2-aminothiazole compound.
Disclosure of Invention
The invention provides a method for preparing a 2-aminothiazole compound by taking thiourea and a ketone compound as raw materials and carrying out condensation reaction in a dimethyl sulfoxide solvent under the action of an iodine simple substance as a catalyst.
A method for preparing a 2-aminothiazole compound comprises the following steps:
in an organic solvent, under the catalysis of a simple substance of iodine, thiourea shown in a formula (II) and a ketone compound shown in a formula (III) are subjected to condensation reaction for 6-24 hours at 50-120 ℃, and after the reaction is finished, the reaction solution is subjected to post-treatment to obtain a 2-aminothiazole compound shown in a formula (I); the ratio of the iodine simple substance to the thiourea shown in the formula (II) and the ketone compound shown in the formula (III) is 0.05-0.2: 1: 1-3;
in formula (I) or formula (III), R1Is tert-butyl, phenyl or substituted phenyl; the substituent on the phenyl is C1-C4Alkyl radical, C1-C4Alkoxy, methanesulfonyl, halogen or hydroxy;
R2is hydrogen, C1-C4Alkyl or phenyl.
The preparation method is expressed by the following equation:
preferably, R is1Selected from tert-butyl, phenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-bromophenyl, 4-methylphenyl, 2-methylphenyl, 3, 4-dimethoxybenzeneA group or a 2-hydroxyphenyl group;
preferably, R is2Is hydrogen, methyl or phenyl.
Preferably, the organic solvent is dimethyl sulfoxide.
Preferably, the amount of the organic solvent added is 2mL/mmol of thiourea represented by the formula (II) based on the amount of the thiourea.
Preferably, the reaction temperature is 70-90 ℃; the reaction time is 12-24 hours.
Further, the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, the reaction solution is saturated NaHCO3Treating the solution, adding water, extracting with ethyl acetate for three times to obtain extractive solution, washing with water and saturated NaCl solution, and removing anhydrous Na2SO4Drying, removing solvent under reduced pressure, separating the residue by silica gel column chromatography, eluting with petroleum ether/ethyl acetate eluent at volume ratio of 5:1, collecting eluate containing target product, and removing solvent under reduced pressure to obtain target product.
Most preferably, the ratio of the iodine to the thiourea shown in the formula (II) and the ketone compound shown in the formula (III) is 0.2: 1: and 2, the reaction temperature is 80 ℃, the reaction time is 12 hours, the reaction yield is highest, the byproducts are few, and more reaction substrates can be adapted.
Compared with the prior art, the invention has the beneficial effects that:
the invention takes thiourea and ketone compounds as raw materials and iodine simple substance as a catalyst to directly carry out condensation reaction in dimethyl sulfoxide solvent to prepare the 2-aminothiazole compound. The reaction raw materials are cheap and easy to obtain, the reaction conditions are mild, the preparation method is simple, a transition metal catalyst and a stoichiometric halogenating reagent are not needed, and the cost is reduced. The invention can be used for synthesizing a series of 2-aminothiazole derivatives, and the prepared products can be used as important intermediates for synthesizing medicaments containing thiazole structures or bioactive compounds.
Detailed Description
The present invention will be described in detail with reference to examples, but the present invention is not limited thereto.
Example 1
To a reaction tube equipped with a stirring magneton were added 0.480g (4mmol) of acetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, the residue was chromatographed on silica gel column eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-phenylthiazole (0.170 g) in 48.1% yield as a white solid with melting point 120-.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)δ7.80–7.77(m,2H),7.39(dd,J＝8.4,6.9Hz,2H),7.33–7.27(m,1H),6.72(s,1H),5.39(s,2H).
example 2
To a reaction tube equipped with a stirring magneton were added 0.553g (4mmol) of p-fluoroacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-p-fluorophenyl thiazole (0.212 g) in 54.5% yield. The product was a white solid with a melting point of 94-96 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)δ7.99–7.54(m,2H),7.18–6.99(m,2H),6.64(s,1H),5.38(s,2H).
example 3
To a reaction tube equipped with a stirring magneton were added 0.553g (4mmol) of o-fluoroacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-o-fluorophenyl thiazole (0.201 g) in 51.7% yield. The product was a red solid with a melting point of 88-90 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)δ8.02(td,J＝7.8,1.9Hz,1H),7.26(m,1H),7.19(td,J＝7.8,1.9Hz,1H),7.12(m,1H),7.02(d,J＝2.2Hz,1H),5.40(s,2H).
example 4
To a reaction tube equipped with a stirring magneton were added 0.618g (4mmol) of p-chloroacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated and 30mL of water was addedExtracted three times with 20mL portions of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-p-chlorophenyl thiazole (0.215 g) in 51.1% yield. The product was a white solid with a melting point of 165-167 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)δ7.71(d,J＝8.5Hz,1H),7.35(d,J＝8.5Hz,1H),6.72(s,1H),5.14(s,2H).
example 5
To a reaction tube equipped with a stirring magneton were added 0.618g (4mmol) of o-chloroacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-o-chlorophenyl thiazole (0.181 g) in 42.9% yield. The product was a red solid with melting point 135-137 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ7.83(dd,J＝7.8,1.5Hz,1H),7.45(d,J＝7.8Hz,1H),7.31(t,J＝7.8Hz,1H),7.24(td,J＝7.8,1.5Hz,1H),7.04(s,1H),5.30(s,2H).
example 6
To a reaction tube equipped with a stirring magneton were added 0.618g (4mmol) of m-chloroacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, and the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-m-chlorophenyl thiazole (0.332 g) in 78.7% yield. The product was a white solid with melting point 126-.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)δ7.78(t,J＝1.8Hz,1H),7.64(dt,J＝7.6,1.8Hz,1H),7.34–7.23(m,2H),6.74(s,1H),5.41(s,2H).
example 7
To a reaction tube equipped with a stirring magneton were added 0.796g (4mmol) of p-bromoacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-p-bromophenylthiazole (0.216 g) in 42.3% yield. The product was a white solid with a melting point of 176-.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3)δ7.66(d,J＝8.5Hz,2H),7.51(d,J＝8.5Hz,2H),6.75(s,1H),5.03(s,2H).
example 8
To a reaction tube equipped with a stirring magneton were added 0.796g (4mmol) of o-bromoacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed under reduced pressure using a rotary evaporator, and the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-o-bromophenylthiazole (0.203 g) in 39.8% yield. The product was a red solid with melting point 135-137 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ7.70(d,J＝7.7Hz,1H),7.65(d,J＝7.7Hz,1H),7.35(t,J＝7.7Hz,1H),7.18(t,J＝7.7Hz,1H),6.94(s,1H),5.32(s,2H).
example 9
To a reaction tube equipped with a stirring magneton were added 0.537g (4mmol) of p-methylacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated and,30mL of water were added thereto, and the mixture was extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-p-methylphenylthiazole (0.169 g) in 44.3% yield. White solid, melting point 119-.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ7.68(d,J＝7.9Hz,1H),7.21(d,J＝7.9Hz,1H),6.67(s,1H),5.42(s,2H),2.39(s,3H).
example 10
To a reaction tube equipped with a stirring magneton were added 0.537g (4mmol) of o-methylacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-o-tolylthiazole (0.124 g) in 32.5% yield. The product was a red solid with a melting point of 90-93 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ7.55(d,J＝6.7Hz,1H),7.35–7.11(m,3H),6.45(s,1H),5.53(s,2H),2.47(s,3H).
example 11
To a reaction tube equipped with a stirring magneton were added 0.537g (4mmol) of m-methylacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-m-methylphenyl thiazole (0.216 g) in 56.8% yield. The product was a white solid with a melting point of 70-72 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ7.63(s,1H),7.58(d,J＝7.8Hz,1H),7.29(t,J＝7.8Hz,1H),7.14(d,J＝7.8Hz,1H),6.72(s,1H),5.37(s,2H),2.41(s,3H).
example 12
To a reaction tube equipped with a stirring magneton were added 0.721g (4mmol) of 3, 4-dimethoxyacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed under reduced pressure using a rotary evaporator, and the residue was subjected to silica gel column chromatography and eluted with petroleum ether/ethyl acetate (volume ratio 1:1) to give 2-amino-4- (3, 4-dimethoxyphenyl) thiazole (0.199 g) in 42.1% yield. The product was a yellow solid with melting point 188-.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ7.36(s,1H),7.34(dd,J＝8.3,1.6Hz,1H),6.89(d,J＝8.3Hz,1H),6.62(s,1H),5.18(s,2H),3.96(s,3H),3.92(s,3H).
example 13
To a reaction tube equipped with a stirring magneton were added p-methanesulfonylacetophenone 0.793g (4mmol), thiourea 0.152g (2mmol), elemental iodine 0.051g (0.4mmol), and DMSO 4 ml. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed under reduced pressure using a rotary evaporator, and the residue was separated by silica gel column chromatography and eluted with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4- (p-methanesulfonylphenyl) thiazole (0.287 g) in 56.4% yield. The product was a white solid with melting point 183-.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ8.14–7.78(m,4H),6.95(s,1H),5.07(s,2H),3.09(s,3H).
example 14
To a reaction tube equipped with a stirring magneton, 0.545g (4mmol) of o-hydroxyacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO were added. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction, the reaction mixture was saturated with NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, the residue was chromatographed on silica gel column, eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-hydroxyphenyl thiazole (0.120 g) in 31.3% yield. The product was a yellow solid with melting point 136-.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ11.59(s,1H),7.56(dd,J＝7.9,1.0Hz,1H),7.22(dd,J＝11.0,4.2Hz,1H),6.98(d,J＝7.9Hz,1H),6.87(dd,J＝11.0,4.2Hz,1H),6.77(s,1H),5.11(s,2H).
example 15
To a reaction tube equipped with a stirring magneton were added 0.401g (4mmol) of t-butyl methyl ketone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure and the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (vol: 5:1) to give 2-amino-4-tert-butylthiazole (0.125 g) in 40.0% yield. The product was a yellow solid with a melting point of 61-62 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ6.07(s,1H),5.64(s,2H),1.26(s,9H).
example 16
To a reaction tube equipped with a stirring magneton were added 0.785g (4mmol) of 2-phenylacetophenone, 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine and 4ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure and the residue was chromatographed on silica gel eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4, 5-diphenylthiazole product (0.378 g) in 74.9% yield. The product was a yellow solid with melting point 179-182 ℃.
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(600MHz,CDCl3)δ7.48(dd,J＝7.5,1.7Hz,2H),7.35–7.17(m,8H),5.23(s,2H).
example 17
To a reaction tube equipped with a stirring magneton, 0.537g (4mmol), 0.152g (2mmol) of thiourea, 0.051g (0.4mmol) of elemental iodine, and 4ml of DMSO were added. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (20mL) was treated, 30mL of water was added, and extracted three times with 20mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed under reduced pressure using a rotary evaporator and the residue was chromatographed on silica gel using petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-phenyl-5-methylthiazole (0.152 g) in 40.0% yield. The product is a yellow solid with a melting point of 108-110℃。
The reaction process is shown as the following formula:
the product obtained in this example was subjected to nmr analysis:
1H NMR(500MHz,CDCl3):δ2.40(s,3H),5.11(s,2H),7.59–7.55(m,2H),7.45–7.38(m,2H),7.32(tt,J＝7.3,1.3Hz,1H).
example 18 (gram-scale amplification experiment)
To a reaction tube equipped with a stirring magneton were added 2.765g (20mmol) of p-fluoroacetophenone, 0.760g (10mmol) of thiourea, 0.255g (2mmol) of elemental iodine and 10ml of DMSO. The reaction tube is put into an oil bath kettle at the temperature of 80 ℃, and stirred for reaction for 12 hours. After the reaction is finished, the reaction solution is saturated NaHCO3The solution (30mL) was treated, 40mL of water was added, and extracted three times with 30mL of ethyl acetate. Washing the extractive solution with water and saturated NaCl solution respectively, and removing anhydrous Na2SO4And (5) drying. The solvent was removed by rotary evaporator under reduced pressure, and the residue was separated by silica gel column chromatography eluting with petroleum ether/ethyl acetate (volume ratio 5:1) to give 2-amino-4-p-fluorophenyl thiazole (1.02 g) in 52.4% yield. The product was a white solid with a melting point of 94-96 ℃.
The reaction process is shown as the following formula:
Claims (9)
1. a process for preparing a 2-aminothiazole compound, which comprises: the method comprises the following steps:
in an organic solvent, under the catalysis of a simple substance of iodine, thiourea shown in a formula (II) and a ketone compound shown in a formula (III) are subjected to condensation reaction for 6-24 hours at 50-120 ℃, and after the reaction is finished, the reaction solution is subjected to post-treatment to obtain a 2-aminothiazole compound shown in a formula (I); the ratio of the iodine simple substance to the thiourea shown in the formula (II) and the ketone compound shown in the formula (III) is 0.05-0.2: 1: 1-3;
in formula (I) or formula (III), R1Is tert-butyl, phenyl or substituted phenyl; the substituent on the phenyl is C1-C4Alkyl radical, C1-C4Alkoxy, methanesulfonyl, halogen or hydroxy;
R2is hydrogen, C1-C4Alkyl or phenyl.
2. The method of claim 1, wherein: said R1Selected from tert-butyl, phenyl, 4-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-bromophenyl, 2-bromophenyl, 4-methylphenyl, 2-methylphenyl, 3, 4-dimethoxyphenyl or 2-hydroxyphenyl.
3. The method of claim 1, wherein: said R2Is hydrogen, methyl or phenyl.
4. The method of claim 1, wherein: the organic solvent is dimethyl sulfoxide.
5. The method of claim 1 or 4, wherein: the amount of the organic solvent added is 2mL/mmol of thiourea represented by the formula (II) based on the amount of the thiourea.
6. The method of claim 1, wherein: the reaction temperature is 70-90 ℃; the reaction time is 12-24 hours.
7. The method of claim 1, wherein: the post-treatment method of the reaction solution comprises the following steps: after the reaction is finished, the reaction solution is saturated NaHCO3Treating the solution, adding water, extracting with ethyl acetate for three times to obtain extractive solution, washing with water and saturated NaCl solution, and removing anhydrous Na2SO4Drying, removing solvent under reduced pressure, separating the residue by silica gel column chromatography, eluting with petroleum ether/ethyl acetate eluent at volume ratio of 5:1, collecting eluate containing target product, and removing solvent under reduced pressure to obtain target product.
8. The method of claim 1, wherein: the ratio of the amount of the iodine simple substance to the amount of the thiourea shown in the formula (II) and the ketone compound shown in the formula (III) is 0.2: 1: 2.
9. the method of claim 1, wherein: the reaction temperature is 80 ℃, and the reaction time is 12 hours.
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