A method for rapidly synthesizing thiocyanato-substituted formanilide

Abstract

The invention provides a method for rapidly synthesizing thiocyanate-substituted formanilide, belonging to the technical field of organic chemical preparation. Alpha-aminoketone and potassium thiocyanate are used as starting raw materials. Under the conditions of a copper catalyst, an oxidant and an organic solvent, the mixture is sealed and placed in an oil bath pot, stirred at 80°C, and heated for reaction for 24 hours. After the reaction is completed, the mixture is purified by column chromatography to obtain a thiocyanate-substituted formanilide compound. The copper catalyst comprises any one of copper chloride, copper acetate, copper sulfate, copper acetylacetonate and copper trifluoromethanesulfonate. The oxidant comprises one of iodophenyldiacetic acid, potassium persulfate, di-tert-butyl peroxide and tert-butyl peroxide. The method overcomes the problems of many reaction steps and low synthesis efficiency in the prior art and has the advantages of easy availability of raw materials, simple operation and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical preparation, and particularly relates to a preparation method for rapidly synthesizing thiocyanate-substituted formanilide compounds. Background Art

[0002] The N-formylation of amines is an important type of reaction in synthetic chemistry because this conversion provides a direct route to synthesize structurally diverse formamide compounds. Formyl groups are widely present in natural products and drug molecules. For example, leucovorin, formoterol and orlistat all have formamide structural units. Moreover, N-formyl derivatives such as methyl formanilide are very useful reagents in Vilsmeier formylation reactions and are often used as precursors for synthesizing compounds such as isocyanides, formamidines, aromatic amides, isocyanates, and nitriles. In addition, organic thiocyanides are also substructures or building blocks of biologically active natural products. Therefore, these two types of functional groups are common structural units in the synthesis of drug molecules. At present, the thiocyanate-substituted formanilide compounds are mainly prepared by multi-step reactions using the corresponding aniline as raw materials, which have the disadvantages of complex operation and low efficiency. Summary of the invention

[0003] In order to solve the above technical problems, the present invention provides a method for rapidly synthesizing thiocyanate-substituted formanilide, which aims to overcome the problems of multiple reaction steps and low synthesis efficiency, and has the advantages of easy raw material availability and simple operation.

[0004] To achieve the above object, the present invention first provides a method for rapidly synthesizing thiocyanate-substituted formanilide, the method comprising the following steps: using α-amino ketone and potassium thiocyanate as reaction substrates, sealing and placing in an oil bath pot under the conditions of a copper catalyst, an oxidant, and an organic solvent, stirring and heating the reaction, and after the reaction is completed, purifying by column chromatography to obtain a thiocyanate-substituted formanilide compound as shown in formula II, the general reaction formula is as follows:

[0005] ;

[0006] Wherein, R is selected from any one of Me, Et, Bu, Bn, and CH2=CHCH2—.

[0007] Preferably, the copper catalyst is selected from any one of copper chloride, copper acetate, copper sulfate, copper acetylacetonate and copper trifluoromethanesulfonate.

[0008] Preferably, the oxidant is one of iodophenyldiacetic acid, potassium persulfate, di-tert-butyl peroxide and tert-butyl peroxide.

[0009] Preferably, the organic solvent is selected from any one of acetonitrile, dioxane, chloroform, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

[0010] Preferably, the heating reaction is carried out at a temperature of 50-80°C and for 24 hours.

[0011] Preferably, the molar ratio of the α-amino ketone to potassium thiocyanate is 1:1-1:5, and the molar ratio of the α-amino ketone to the oxidant is 1:3.

[0012] The synthesis mechanism of this scheme is as follows:

[0013] The α-amino ketone shown in formula I is used as a starting material, potassium cyanide is used as a thiocyanate source, and a copper catalyst, potassium thiocyanate, iodophenyl diacetic acid, and an organic solvent are used. The mixture is sealed and placed in an oil bath pot and stirred for reaction. After the reaction is completed, the mixture is purified by column chromatography to obtain a thiocyanate-substituted formylanilide compound shown in formula II. The compound is synthesized in one step by thiocyanation of the benzene ring and oxidation cleavage of the carbon-carbon bond. The steps are shown in the following formula:

[0014] ;

[0015] Compared with the prior art, the present invention has the following beneficial effects:

[0016] (1) The synthesis of thiocyanate-substituted formanilide compounds is subject to interference from a variety of factors. The present invention provides optimal reaction conditions in the examples, with a yield of up to 75%.

[0017] (2) The reaction conditions are mild, the operation is simple, and the reaction steps are few. The one-pot method avoids the lengthy separation process and purification process of intermediate compounds in the post-treatment process, thereby saving time and resources and improving the yield, which is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0019] Figure 1 This is the H NMR spectrum of the thiocyanate-substituted formanilide compound of Experimental Example 1;

[0020] Figure 2 This is the C NMR spectrum of the thiocyanate-substituted formylanilide compound of Experimental Example 1. DETAILED DESCRIPTION

[0021] In order to make the technical problems, technical solutions and advantages to be solved by the present invention more clear, a detailed description will be given below with reference to the accompanying drawings and specific embodiments.

[0022] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. Without departing from the spirit and substance of the present invention, modifications or substitutions made to the methods, steps or conditions of the present invention are within the scope of the present invention.

[0023] Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art; unless otherwise specified, the reagents used in the examples are commercially available.

[0024] Example 1-23 Synthesis of thiocyanate-substituted formanilide compounds.

[0025] α-Amino ketone and potassium thiocyanate were used as substrates, 20 mol% copper catalyst, oxidant (3 equivalents), and organic solvent were added to the reaction tube, sealed and placed in an oil bath pot under heating conditions and stirred for reaction for 24 h. After the reaction was completed, the thiocyanate-substituted formanilide compound was purified by column chromatography. The following Table 1 shows the specific substrates, catalysts, oxidants, solvents and experimental parameters of Examples 1-23, and only the substituent group of the reaction substrate α-amino ketone was changed:

[0026]

[0027]

[0028]

[0029] From Table 1, we can see that when the reaction substrate is , , , , , or , the catalyst is CuCl2 (20 mol%), PhI(OAc)2 (3 eq), KSCN (3 eq), the solvent is acetonitrile, and the reaction temperature is 80℃, the yield of thiocyanate-substituted carboxanilide compounds is high, ≥60%;

[0030] The type of copper catalyst has a slight effect on the reaction yield, but it is basically above 50%; the oxidant has a greater impact on the reaction. When TBHP and DTBP are used as oxidants, the yield drops to about 30%, while K2S2O8 can be maintained at 56%; the reaction solvent has a significant effect on the yield of the product. When the solvent is changed to dioxane, chloroform, DMF or DMSO, the yield drops to 48%, 21%, 45% or 40%; the reaction temperature has a significant effect on the yield of the product. When the temperature drops to 70℃ and 50℃, the yield also decreases. Maintaining the amount of KSCN at 3 equivalents has a better effect. Increasing or decreasing the amount has a negative effect on the reaction.

[0031] As can be seen from the above, the synthesis of thiocyanate-substituted formanilide compounds is interfered by various factors, so during the synthesis, the present invention provides an efficient and easy-to-operate synthesis method.

[0032] Experimental Examples 1-7

[0033] The reaction products of Examples 1-7 were characterized by nuclear magnetic resonance, and the results are shown in Table 2:

[0034]

[0035]

[0036] The product of Example 1 is Its H NMR spectrum is shown in Figure 1 , NMR carbon spectrum see Figure 2 .

[0037] The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments. For those skilled in the art, improvements and changes obtained without departing from the technical concept of the present invention should also be regarded as the protection scope of the present invention.

Claims

1. A method for rapidly synthesizing thiocyanate-substituted formanilide, characterized in that: The preparation method comprises the following steps: using α-amino ketone and potassium thiocyanate as reaction substrates shown in formula I, placing the mixture in an oil bath in a sealed state under the conditions of a copper catalyst, an oxidant and an organic solvent, stirring and heating the mixture for reaction, and after the reaction is completed, purifying the mixture by column chromatography to obtain a thiocyanate-substituted formylanilide compound shown in formula II. The general reaction formula is as follows: ； Wherein, R is selected from any one of Me, Et, Bu, Bn, CH2=CHCH2—; The copper catalyst is selected from any one of copper chloride, copper acetate, copper sulfate, copper acetylacetonate, and copper trifluoromethanesulfonate; The oxidant is one of iodophenyldiacetic acid, potassium persulfate, di-tert-butyl peroxide, and tert-butyl peroxide; The organic solvent is selected from any one of acetonitrile, dioxane, chloroform, N,N-dimethylformamide and dimethyl sulfoxide.

2. The preparation method according to claim 1, characterized in that: The heating reaction is carried out at a temperature of 50-80°C and for 24 hours.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the α-amino ketone to potassium thiocyanate is 1:1-1:5, and the molar ratio of the α-amino ketone to the oxidant is 1:3.

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