阅读说明：本技术 一种制备2-氨基噻唑化合物的方法 (Method for preparing 2-aminothiazole compound ) 是由 吴杰非 周卫 崔冬梅 于 2019-11-13 设计创作，主要内容包括：本发明公开了一种制备2-氨基噻唑化合物的方法,所述的方法为：在有机溶剂中,式(Ⅱ)所示的硫脲和式(Ⅲ)所示的酮类化合物在碘单质的催化下,在50～120℃下进行缩合反应6～24小时,反应结束后,反应液经过后处理得到式(Ⅰ)所示的2-氨基噻唑化合物。本发明反应原料廉价易得,反应条件温和,制备方法简单,无需使用过渡金属催化剂和化学计量的卤化试剂,降低了成本。本发明可用于合成一系列2-氨基噻唑衍生物,制备得到的产品,可作为合成含噻唑结构的药物或生物活性化合物的重要中间体。<Image he="103" wi="700" file="DDA0002271634120000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(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.)

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.

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.