Preparation method of isobutyramido thiazolyl resorcinol

Abstract

The invention provides a preparation method of isobutyramido thiazolyl resorcinol, and belongs to the technical field of organic synthesis. The method provided by the invention comprises the following steps: carrying out amidation reaction on 2-aminothiazole and isobutyryl chloride under the action of inorganic alkali to obtain an intermediate 1; obtaining an intermediate 2 from resorcinol and a halogenating reagent under the action of a catalyst; and carrying out a coupling reaction on the intermediate 1 and the intermediate 2 in the presence of a zero-valent palladium catalyst and an organic solvent III to obtain isobutyramido thiazolyl resorcinol. The method provided by the invention has the advantages that the route is short, the cost of the used raw materials and catalyst is low, the environmental protection property is good, the high-purity isobutyramido thiazolyl resorcinol can be obtained through filtration and recrystallization after the coupling reaction, a complicated post-treatment process is not needed, and the operation is simple and convenient. The result of the embodiment shows that the overall yield of the method provided by the invention reaches 70% or above, and the HPLC purity is greater than 99%.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing isobutylamide thiazolyl resorcinol. Background Art

[0002] Thiamidol is a resorcinol derivative containing a thiazolyl group, and its chemical name is isobutylaminothiazolylresorcinol. Experimental data show that isobutylaminothiazolylresorcinol has a strong inhibitory effect on tyrosinase activity, has almost no cytotoxicity and low irritation, and is used in cosmetics for whitening and lightening spots.

[0003] At present, the preparation methods of peptide amine mitrol reported in the literature include the following types: For example, the relevant patents disclose the following preparation methods:

[0004]

[0005] The preparation method uses 2,4-dihydroxyacetophenone as a raw material, first uses methyl chloroacetate to protect the hydroxyl group, then uses bromine to replace the hydrogen on the ortho-methyl group of the carbonyl group to generate intermediate I; thiourea and isobutyryl chloride are used in toluene as a solvent to generate intermediate II, and finally intermediates I and II are cyclized and then deprotected to obtain the final product. The disadvantages of this preparation method are: 1. 2,4-dihydroxyacetophenone is expensive; 2. Methyl chloroacetate is used in large amounts and is a highly toxic substance; 3. When thiourea and isobutyryl chloride react in toluene, it is a two-phase reaction, the yield is low and the post-processing is extremely inconvenient; 4. When bromine is brominated, it is highly toxic, corrosive, and has many side reactions; 5. The overall process route is long, there is a lot of wastewater, and it is not environmentally friendly.

[0006] For example, the relevant patent discloses the following preparation method:

[0007]

[0008] The preparation method is to carry out Friedel-Crafts reaction of resorcinol and bromoacetic acid under the action of a catalyst to obtain intermediate I; thiourea and isobutyryl chloride react to obtain intermediate II; intermediate I and intermediate II are subjected to cyclization reaction under the action of a base to generate a final product. The disadvantages of this preparation method are: 1. Boron trifluoride ether is used as a solvent and catalyst for the Friedel-Crafts reaction, which is relatively expensive and has a strong exothermic reaction during post-processing and is very easy to spray; 2. The synthesis of intermediate II has the problems of difficult post-processing, low yield, and heavy pollution; 3. Resorcinol directly reacts with bromoacetic acid in Friedel-Crafts reaction, which has many side reactions and is difficult to purify and separate; 4. Intermediate I in this method is unstable and is easy to cyclize to generate impurities, resulting in low yield and purity of the product.

[0009] Therefore, there is an urgent need to provide a method for preparing isobutylamide thiazolyl resorcinol with a short route, low cost, environmental protection, simple post-treatment method, high yield and purity. Summary of the invention

[0010] The object of the present invention is to provide a method for preparing isobutylamide thiazolyl resorcinol with short route, low cost, environmental protection, simple post-treatment method, high yield and purity.

[0011] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0012] The present invention provides a method for preparing isobutylamide thiazolyl resorcinol, comprising the following steps:

[0013] (1) mixing 2-aminothiazole, isobutyryl chloride, an inorganic base and a first organic solvent, and performing an amidation reaction to obtain an intermediate 1;

[0014] (2) mixing resorcinol, a halogenation agent, a catalyst and a second organic solvent to carry out a halogenation reaction to obtain an intermediate 2;

[0015] (3) mixing the intermediate 1 obtained in step (1), the intermediate 2 obtained in step (2), a zero-valent palladium catalyst, an alkaline reagent and an organic solvent, performing a coupling reaction, and then filtering and recrystallizing in sequence to obtain isobutylaminothiazolylresorcinol;

[0016] There is no chronological order between step (1) and step (2).

[0017] Preferably, the inorganic base in step (1) comprises one or more of sodium hydroxide, sodium carbonate and potassium carbonate.

[0018] Preferably, in step (1), the molar ratio of 2-aminothiazole, isobutyryl chloride and inorganic base is 1:(1.1-1.5):(1.1-1.8).

[0019] Preferably, the temperature of the amidation reaction in step (1) is -5 to 30°C, and the time of the amidation reaction is 1 to 10 hours.

[0020] Preferably, the halogenating agent in step (2) comprises one or more of I2, N-chlorosuccinimide, N-bromosuccinimide and bromine.

[0021] Preferably, the catalyst in step (2) comprises one or more of aluminum chloride, sulfuric acid, zinc chloride and p-toluenesulfonic acid.

[0022] Preferably, the mass ratio of resorcinol to the halogenating agent in step (2) is 1:(0.95-1.3); the mass percentage of the catalyst to resorcinol is 1-10%.

[0023] Preferably, the temperature of the halogenation reaction in step (2) is 30 to 80° C., and the time of the halogenation reaction is 5 to 24 hours.

[0024] Preferably, in the step (3), the mass ratio of intermediate 1, intermediate 2 and alkaline reagent is 1:(0.95-1.2):(1.1-1.5); the mass percentage of the 0-valent palladium catalyst in intermediate 2 is 1-10%; and the mass ratio of the organic solvent 3 to intermediate 2 is (2-5):1.

[0025] Preferably, the coupling reaction temperature in step (3) is 50-100° C., and the coupling reaction time is 10-48 h.

[0026] The present invention provides a method for preparing isobutylaminothiazolylresorcinol, comprising the following steps: mixing 2-aminothiazole, isobutyryl chloride, an inorganic base and a first organic solvent, performing an amidation reaction, and obtaining an intermediate 1; mixing resorcinol, a halogenating agent, a catalyst and a second organic solvent, performing a halogenation reaction, and obtaining an intermediate 2; mixing the intermediate 1, the intermediate 2, a 0-valent palladium catalyst and an organic solvent, performing a coupling reaction, and then filtering and recrystallizing in sequence to obtain isobutylaminothiazolylresorcinol. The method provided by the present invention uses 2-aminothiazole and isobutyryl chloride to perform an amidation reaction under the action of an inorganic base to obtain an intermediate 1; uses resorcinol and a halogenating agent under the action of a catalyst to obtain an intermediate 2; then uses intermediate 1 and intermediate 2 to perform a coupling reaction under a 0-valent palladium catalyst and an organic solvent, and the isobutylaminothiazolylresorcinol can be obtained by simple filtration and recrystallization. The method provided by the present invention has a short route, uses low-cost raw materials and catalysts, is environmentally friendly, and can obtain high-purity isobutylamide thiazolyl resorcinol by simple filtration and recrystallization after the coupling reaction, without the need for a complex post-processing process, and is easy to operate. The results of the embodiment show that the overall yield of the method provided by the present invention reaches more than 70%, and the HPLC purity is greater than 99%. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The HNMR diagram of the intermediate 1 prepared in Example 1 of the present invention;

[0028] Figure 2 The HNMR diagram of the intermediate 2 prepared in Example 1 of the present invention;

[0029] Figure 3This is the HNMR graph of the isobutylaminothiazolylresorcinol prepared in Example 1 of the present invention;

[0030] Figure 4 This is the chromatogram of isobutylaminothiazolylresorcinol prepared in Example 4 of the present invention. DETAILED DESCRIPTION

[0031] The present invention provides a method for preparing isobutylamide thiazolyl resorcinol, comprising the following steps:

[0032] (1) mixing 2-aminothiazole, isobutyryl chloride, an inorganic base and a first organic solvent, and performing an amidation reaction to obtain an intermediate 1;

[0033] (2) mixing resorcinol, a halogenation agent, a catalyst and a second organic solvent to carry out a halogenation reaction to obtain an intermediate 2;

[0034] (3) mixing the intermediate 1 obtained in step (1), the intermediate 2 obtained in step (2), a zero-valent palladium catalyst, an alkaline reagent and an organic solvent, performing a coupling reaction, and then filtering and recrystallizing in sequence to obtain isobutylaminothiazolylresorcinol;

[0035] There is no chronological order between step (1) and step (2).

[0036] In the present invention, 2-aminothiazole, isobutyryl chloride, an inorganic base and a first organic solvent are mixed and subjected to an amidation reaction to obtain an intermediate 1.

[0037] In the present invention, the inorganic base preferably includes one or more of sodium hydroxide, sodium carbonate and potassium carbonate, and more preferably potassium carbonate. The present invention can promote the activation of the acyl chloride by adding the inorganic base, making it easier to react with 2-aminothiazole; and the inorganic base can also neutralize the HCl generated by the amidation reaction, thereby increasing the reaction rate of the amidation reaction.

[0038] In the present invention, the molar ratio of the 2-aminothiazole, isobutyryl chloride and inorganic base is preferably 1:(1.1-1.5):(1.1-1.8), more preferably 1:(1.2-1.3):(1.2-1.5). The present invention controls the amount of each component within the above range, so that each component can react fully and improve the yield of intermediate 1.

[0039] In the present invention, the first organic solvent preferably includes acetonitrile, tetrahydrofuran or dichloromethane, and more preferably tetrahydrofuran. The present invention uses the above organic solvent to fully dissolve each component and promote the smooth progress of the amidation reaction.

[0040] In the present invention, the mass ratio of the 2-aminothiazole to the mass ratio of the first organic solvent is preferably 1:(1-5), more preferably 1:(2-4). By controlling the amount of the first solvent within the above range, the reaction system can have good fluidity, facilitate stirring, and promote the reaction.

[0041] In the present invention, the method of mixing 2-aminothiazole, isobutyryl chloride, an inorganic base and a first organic solvent preferably comprises: mixing 2-aminothiazole, an inorganic base and a first organic solvent to obtain a mixed solution; and dropping isobutyryl chloride into the mixed solution.

[0042] In the present invention, the temperature at which the 2-aminothiazole, the inorganic base and the first organic solvent are mixed is preferably below 0°C.

[0043] The present invention has no particular limitation on the dripping rate of isobutyryl chloride, which can be adjusted as needed so that the temperature of the mixed system does not exceed 10°C.

[0044] In the present invention, the temperature of the amidation reaction is preferably -5 to 30°C, more preferably 20 to 25°C; the time of the amidation reaction is preferably 1 to 10 hours, more preferably 3 to 6 hours. The present invention can promote a more complete amidation reaction at the above temperature and time.

[0045] In the present invention, water is preferably added to the system obtained after the amidation reaction, and then filtration and column chromatography purification are performed in sequence to obtain intermediate 1.

[0046] In the present invention, the volume ratio of the 2-aminothiazole to the water is preferably 1:(5-25), more preferably 1:(10-20). The present invention can cool the system to 4-5°C, preferably 5°C, by adding water, so as to promote the precipitation of the intermediate 1 from the system.

[0047] The present invention has no particular limitation on the operation method of the filtration and column chromatography purification, and conventional filtration and column chromatography purification operation methods can be used. The present invention can remove impurities in the intermediate 1 by filtration and column chromatography purification. In an embodiment of the present invention, the column chromatography purification is preferably PE / EA column chromatography purification.

[0048] In the present invention, the structural formula of the intermediate 1 is preferably:

[0049] In the present invention, the synthetic route of the intermediate 1 is preferably as shown in formula (1):

[0050]

[0051] In the present invention, resorcinol, a halogenating agent, a catalyst and a second organic solvent are mixed to carry out a halogenating reaction to obtain an intermediate 2.

[0052] In the present invention, the halogenating agent preferably includes one or more of I2, N-chlorosuccinimide, N-bromosuccinimide and bromine, and more preferably N-bromosuccinimide.

[0053] In the present invention, the catalyst preferably includes one or more of aluminum chloride, sulfuric acid, zinc chloride and p-toluenesulfonic acid, and p-toluenesulfonic acid is more preferred. The present invention uses the above catalyst to promote the smooth progress of the halogenation reaction.

[0054] In the present invention, the second organic solvent preferably includes tetrahydrofuran, acetonitrile, dichloromethane or chloroform, and more preferably acetonitrile. The use of the above solvents in the present invention is more conducive to promoting the halogenation reaction more fully.

[0055] In the present invention, the mass ratio of the resorcinol to the halogenating agent is preferably 1:(0.95-1.3), more preferably 1:(0.99-1.2). In the present invention, the mass percentage of the catalyst to the resorcinol is preferably 1-10%, more preferably 2-5%. In the present invention, the amount of the resorcinol, the halogenating agent and the catalyst is controlled within the above range, which is more conducive to improving the yield of the intermediate 2.

[0056] The present invention has no particular limitation on the method for mixing the resorcinol, the halogenating agent, the catalyst and the second organic solvent, as long as the components can be mixed uniformly.

[0057] In the present invention, the temperature of the halogenation reaction is preferably 30 to 80° C., more preferably 50 to 60° C.; the time of the halogenation reaction is preferably 5 to 24 hours, more preferably 6 to 12 hours. The present invention controls the temperature and time of the halogenation reaction within the above ranges, which can promote a more complete halogenation reaction and improve the yield of intermediate 2.

[0058] In the present invention, the system obtained after the halogenation reaction is preferably concentrated, extracted and purified by column chromatography in sequence to obtain intermediate 2.

[0059] The present invention has no special limitation on the operation methods of concentration, extraction and column chromatography purification, and conventional concentration, extraction and column chromatography purification methods can be used. The present invention recovers organic solvent 2 by concentration; obtains crude intermediate 2 by extraction; and further purifies by column chromatography purification.

[0060] In an embodiment of the present invention, the concentration method may be reduced-pressure concentration.

[0061] In the present invention, the extraction method is preferably: adding water and dichloromethane to the concentrated system for extraction, washing the organic phase obtained by the extraction with water, and obtaining an organic phase as a solution of a crude intermediate 2. The volume ratio of the water and dichloromethane is not particularly limited in the present invention, and can be adjusted according to a conventional extraction method.

[0062] In an embodiment of the present invention, the washing may be performed twice. The present invention further removes water-soluble impurities in the organic phase by washing.

[0063] In an embodiment of the present invention, the column chromatography purification method can be PE / EA column chromatography purification. The present invention has no special limitation on the operation method of the PE / EA column chromatography purification, and the conventional PE / EA column chromatography purification method can be used for operation. In the present invention, the volume ratio of PE and EA in the PE / EA column chromatography purification is preferably (2-5):1, more preferably (3-4):1. The present invention controls the volume ratio of PE and EA within the above range, which is more conducive to improving the purification effect.

[0064] In the present invention, the structural formula of the intermediate 2 is preferably: X is preferably Cl, Br or I.

[0065] In the present invention, the synthetic route of the intermediate 2 is preferably as shown in formula (2):

[0066]

[0067] In the formula (2), X is preferably Cl, Br or I.

[0068] After obtaining intermediate 1 and intermediate 2, the present invention mixes the intermediate 1, intermediate 2, a 0-valent palladium catalyst, an alkaline reagent and an organic solvent to carry out a coupling reaction, and then sequentially filters and recrystallizes to obtain isobutylamide thiazolyl resorcinol.

[0069] In the present invention, the zero-valent palladium catalyst is preferably supported tetrakis(triphenylphosphine)palladium(0). The present invention adopts supported tetrakis(triphenylphosphine)palladium(0) as a catalyst, which is not only highly active, low in cost, but also recyclable. In an embodiment of the present invention, the supported tetrakis(triphenylphosphine)palladium(0) can be reused after being used 8 times.

[0070] In the present invention, the preparation method of the supported tetrakis(triphenylphosphine)(0)palladium preferably comprises: subjecting activated carbon to acid treatment, alkali treatment, oxidation treatment and drying in sequence to obtain pretreated activated carbon;

[0071] The pretreated activated carbon is soaked in a soluble palladium salt solution until there is no palladium ion in the mixed solution, and then hydrogen is introduced into the mixed solution to perform a reduction reaction to obtain supported tetrakis(triphenylphosphine)palladium(0).

[0072] In the present invention, the activated carbon is preferably subjected to acid treatment, alkali treatment, oxidation treatment and drying in sequence to obtain pretreated activated carbon.

[0073] The present invention has no special limitation on the source of the activated carbon, and conventional commercially available products are used.

[0074] In the present invention, the acid treatment method preferably comprises: mixing the activated carbon and the hydrochloric acid solution and then boiling the mixture, followed by filtering, washing and drying in sequence to obtain the acid-treated activated carbon.

[0075] In the present invention, the mass fraction of the hydrochloric acid solution is preferably 0.5-3%, more preferably 1-2%; the mass ratio of the activated carbon to the hydrochloric acid solution is preferably 1:(2-5), more preferably 1:3.

[0076] In the present invention, the boiling treatment time is preferably 2 to 3 hours, more preferably 2 to 2.5 hours.

[0077] The present invention has no special limitation on the filtering, washing and drying operations, and the filtering, washing and drying operations known to those skilled in the art can be used. In an embodiment of the present invention, the washing agent can be deionized water, the washing times can be 2 times, and the drying temperature can be 100°C.

[0078] In the present invention, the alkali treatment method preferably comprises: mixing the acid-treated activated carbon and sodium hydroxide solution and boiling the mixture, followed by filtering, washing and drying in sequence to obtain alkali-treated activated carbon.

[0079] In the present invention, the mass fraction of the sodium hydroxide solution is preferably 1-5%, more preferably 2-4%; the mass ratio of the activated carbon to the sodium hydroxide solution is preferably 1:(1-10), more preferably 1:5.

[0080] In the present invention, the boiling treatment time is preferably 1 to 3 hours, more preferably 1 to 2 hours.

[0081] In an embodiment of the present invention, the washing agent may be deionized water, the washing times may be 2 times, and the drying temperature may be 100°C.

[0082] In the present invention, the oxidation treatment method preferably comprises: mixing the activated carbon treated with alkali and a nitric acid solution and then boiling the mixture, followed by filtering, washing and drying in sequence to obtain pretreated activated carbon.

[0083] In the present invention, the mass fraction of the nitric acid solution is preferably 1-10%, more preferably 5-6%; the mass ratio of the activated carbon to the nitric acid solution is preferably 1:(2-10), more preferably 1:(5-6).

[0084] In the present invention, the boiling treatment time is preferably 1 to 3 hours, more preferably 2 to 3 hours.

[0085] In an embodiment of the present invention, the washing agent may be deionized water, the washing times may be 2 times, and the drying temperature may be 100°C.

[0086] The present invention can activate the activated carbon through acid treatment, alkali treatment, oxidation treatment and drying in sequence, thereby improving the adsorption capacity of palladium ions.

[0087] After obtaining the pretreated activated carbon, the present invention preferably soaks the pretreated activated carbon in a soluble palladium salt solution until there are no palladium ions in the mixed solution, and then introduces hydrogen into the mixed solution to perform a reduction reaction to obtain supported tetrakis(triphenylphosphine)palladium(0).

[0088] In the present invention, the soluble palladium salt solution is preferably a palladium chloride solution or a palladium acetate solution. In the present invention, the mass concentration of the soluble palladium salt solution is preferably 1-10%, more preferably 5-8%. The present invention uses a soluble palladium salt solution to provide palladium ions.

[0089] In the present invention, the pH value of the soluble palladium salt solution is preferably 8 to 9. The present invention preferably uses a sodium hydroxide solution to adjust the pH value of the soluble palladium salt solution. The present invention has no special limitation on the concentration of the sodium hydroxide solution. A sodium hydroxide solution of conventional concentration is used to adjust the pH value of the soluble palladium salt solution to 8 to 9. The present invention adjusts the pH value of the soluble palladium salt solution to the above range, which is more conducive to the adsorption of palladium into the pretreated activated carbon.

[0090] In the present invention, the impregnation temperature is preferably 55-60° C., more preferably 58-60° C. The present invention has no particular limitation on the impregnation time, as long as the palladium ions in the soluble palladium salt solution can be fully adsorbed into the pretreated activated carbon.

[0091] The present invention preferably ultrasonicates the infiltrated system every 2 hours. In the present invention, the ultrasonication time may be 15 minutes. The present invention can promote the adsorption of palladium ions by pretreated activated carbon through ultrasound.

[0092] The present invention has no particular limitation on the rate of introduction of hydrogen, as long as continuous bubbles can be formed below the liquid surface of the infiltration system.

[0093] In the present invention, the temperature of the reduction reaction is preferably 30-70°C, more preferably 50-60°C; the pressure of the reduction reaction is preferably 0.5-5MPa, more preferably 1-3MPa; the reduction reaction is preferably carried out under stirring; the present invention has no special limitation on the stirring speed, and can be adjusted to promote uniform mixing of gas and liquid. The present invention can convert the pretreated activated carbon impregnated with palladium ions into a zero-valent palladium catalyst through a reduction reaction.

[0094] In the present invention, the alkaline agent is preferably potassium carbonate. The present invention can provide an alkaline environment for the coupling reaction through the alkaline agent.

[0095] In the present invention, the organic solvent three is preferably DMF. The present invention uses the above organic solvent to provide a suitable reaction environment for the coupling reaction.

[0096] In the present invention, the mass ratio of intermediate 1, intermediate 2 and alkaline reagent in step (3) is preferably 1: (0.95-1.2): (1.1-1.5), more preferably 1: (0.99-1.1): (1.2-1.3); the mass percentage of the 0-valent palladium catalyst to intermediate 2 is preferably 1-10%, more preferably 3-6%; the mass ratio of the organic solvent 3 to intermediate 2 is preferably (2-5): 1, more preferably (3-4): 1. The present invention controls the amount of each component within the above range, so that each component can react fully and improve the yield of the product.

[0097] The present invention preferably has no special limitation on the mixing method of the intermediate 1, the intermediate 2, the zero-valent palladium catalyst, the alkaline reagent and the organic solvent, and the components can be mixed evenly.

[0098] The present invention preferably performs the coupling reaction in an inert atmosphere. In the present invention, the inert atmosphere is preferably helium or argon. The present invention preferably places the coupling reaction system in an inert atmosphere by inert gas replacement. The present invention does not specifically limit the replacement method of the inert gas, and conventional gas replacement methods can be used.

[0099] In the present invention, the coupling reaction temperature is preferably 50-100°C, more preferably 70-80°C; the coupling reaction time is preferably 10-48h, more preferably 20h. The present invention can make the coupling reaction more complete at the above temperature and time.

[0100] The present invention preferably adds water to the system obtained by the coupling reaction. In the present invention, the method of adding water to the system obtained by the coupling reaction preferably comprises: adding water once to the system obtained by the coupling reaction, filtering, and then adding water twice to the filtrate obtained by the filtration. The present invention completely dissolves the inorganic salt in the system by adding water once, and removes the palladium catalyst by filtering; the present invention can promote the precipitation of isobutylamide thiazolyl resorcinol from the reaction system by adding water twice.

[0101] In the present invention, the mass ratio of water to organic solvent three in the first water addition is preferably (0.5-1):1, more preferably (0.8-1):1. In the present invention, the mass ratio of water to organic solvent three in the second water addition is preferably (2-5):1, preferably (3-5):1.

[0102] The present invention has no special limitation on the operation method of the filtration and recrystallization, and the conventional operation method of filtration and recrystallization can be adopted. In the present invention, the reagent for the recrystallization is preferably a mixed solution of ethanol and water, and the volume ratio of the ethanol and water is preferably (1-5):1, more preferably (2-3):1. The present invention can purify isobutylamidothiazolylresorcinol by recrystallization. In the present invention, the recrystallization is preferably carried out under stirring, and the present invention can increase the speed of crystal precipitation by stirring.

[0103] In the present invention, the structural formula of the isobutylaminothiazolylresorcinol is preferably as shown in formula (3):

[0104]

[0105] The method provided by the present invention is to carry out an amidation reaction of 2-aminothiazole and isobutyryl chloride under the action of an inorganic base to obtain an intermediate 1; to carry out an intermediate 2 under the action of a catalyst using resorcinol and a halogenating agent; and then to carry out a coupling reaction of intermediate 1 and intermediate 2 under a 0-valent palladium catalyst and an organic solvent to obtain isobutyramide thiazolyl resorcinol. The method provided by the present invention can significantly reduce the impurity content of isobutyramide thiazolyl resorcinol isomers, and the structure of the isobutyramide thiazolyl resorcinol isomers is as shown in formula (4):

[0106]

[0107] The preparation method provided by the present invention has a short route, uses low-cost raw materials and catalysts, is environmentally friendly, and can obtain high-purity isobutylamide thiazolyl resorcinol through drying and recrystallization after a coupling reaction. The content of isobutylamide thiazolyl resorcinol isomers is low, does not require a complicated post-processing process, and is easy to operate.

[0108] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0109] The preparation method of the catalyst-supported tetrakis(triphenylphosphine)palladium(0) used in the embodiment of the present invention is:

[0110] The activated carbon is mixed with a 1% hydrochloric acid solution in a mass ratio of 1:3, and then boiled for 2 hours for acid treatment, and filtered, washed and dried to obtain acid-treated activated carbon; the acid-treated activated carbon is mixed with a 2% sodium hydroxide solution in a mass ratio of 1:5, and then boiled for 1 hour for alkali treatment, and filtered, washed and dried to obtain alkali-treated activated carbon, and the alkali-treated activated carbon is mixed with a 5% nitric acid solution in a mass ratio of 1:5, and then boiled for 3 hours for oxidation treatment, washed, filtered and dried at 100°C for 6 hours to obtain pretreated activated carbon;

[0111] The pretreated activated carbon (the weight of the activated carbon is calculated based on 5% Pd content) is immersed in a palladium chloride solution at 60°C, and ultrasonicated for 15 minutes every 2 hours until no palladium ions are detected in the solution. Hydrogen is introduced into the mixed solution, and the pressure is maintained at 1MPa. The solution is stirred and reduced at 60°C for 6 hours, then cooled to room temperature, filtered, and washed with water until it is neutral and no chloride ions remain, to obtain supported tetrakis(triphenylphosphine)palladium(0).

[0112] Example 1

[0113] A method for preparing isobutylamide thiazolyl resorcinol, comprising the following steps:

[0114] (1) In a dry 1L three-necked flask, 2-aminothiazole (100 g, 1.0 eq), tetrahydrofuran (150 mL, 1.5 V), and potassium carbonate (152 g, 1.1 eq) were added. The internal temperature was cooled to below 0°C and controlled not to exceed 10°C. Isobutyryl chloride (116 g, 1.1 eq) was added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred for 3 h. The reaction was monitored by HPLC. Water (750 g, 7.5 V) was slowly added. The temperature was lowered to 5°C to precipitate an off-white solid. The solid was filtered and purified by PE / EA column chromatography to obtain intermediate 1 (152 g, yield 89.5%). The HNMR characterization results were as follows: Figure 1 As shown;

[0115] (2) In a dry 500 mL three-necked flask, resorcinol (55 g, 1.0 eq), acetonitrile (200 mL, 3.6 V), N-bromosuccinimide (NBS, 86 g, 0.97 eq), and p-toluenesulfonic acid (2.75 g, 0.05X) were added. The mixture was kept at 60° C. for 6 h. The reaction was completed after TLC monitoring. About 150 mL of acetonitrile was concentrated under reduced pressure, and then 200 g of water was added. The mixture was extracted with dichloromethane. The organic phase was washed with water twice and purified by PE / EA column chromatography to obtain intermediate 2 (85 g, yield of about 90%). The HNMR characterization results are shown as follows: Figure 2 As shown, the HPLC purity is greater than 97%;

[0116] (3) In a dry 100 mL three-necked flask, add intermediate 2 (10 g, 1.0 eq) prepared in step (2), intermediate 1 (9 g, 1.0 eq) prepared in step (1), DMF (25 mL, 2.5 V), potassium carbonate (8.8 g, 1.2 eq), replace with inert gas three times, add catalyst-supported tetrakis(triphenylphosphine)palladium(0) (0.5 g, 0.05X), replace with inert gas three times, and heat to 70° C. for reaction for 2 hours. 0h, HPLC reaction no longer progressed (conversion rate 96%), 20mL of water was added while hot, and the inorganic salts in the system were dissolved at 50℃, then the catalyst was removed by hot filtration, the filtrate was cooled to room temperature, and 60mL of water was slowly added, a large amount of gray solid precipitated in the filtrate, the filter cake was filtered out and recrystallized with a mixed solution of ethanol / water in a ratio of 2:1 to obtain an off-white solid, which was isobutylamidothiazolylresorcinol (13g, yield 88%), characterized by HNMR. The results are as follows Figure 3 shown.

[0117] Example 2

[0118] A method for preparing isobutylamide thiazolyl resorcinol, comprising the following steps:

[0119] (1) In a dry 3L three-necked flask, 2-aminothiazole (200 g, 1.0 eq), tetrahydrofuran (320 mL, 1.5 V), potassium carbonate (305 g, 1.1 eq) were added, the internal temperature was cooled to below 0°C, and the temperature was controlled not to exceed 10°C, isobutyryl chloride (230 g, 1.1 eq) was added dropwise, and after the addition was completed, the temperature was raised to room temperature and stirred for 4 h. The reaction was monitored by HPLC to complete, and water (1500 g, 7.5 V) was slowly added, and the temperature was lowered to 5°C to precipitate an off-white solid, which was filtered, washed with water, and dried to obtain intermediate 1 (305 g, yield 89.7%), characterized by HNMR;

[0120] (2) In a dry 1L three-necked flask, resorcinol (110 g, 1.0 eq), acetonitrile (400 mL, 3.6 V), N-bromosuccinimide (NBS, 175 g, 0.98 eq), p-toluenesulfonic acid (5.5 g, 0.05X) were added, and the mixture was kept at 60°C for 7 h. The reaction was completed after TLC monitoring. About 300 mL of acetonitrile was concentrated under reduced pressure, and then 400 g of water was added. The mixture was extracted with dichloromethane, and the organic phase was washed with water twice. The intermediate 2 (170 g, yield of about 90%) was purified by PE / EA column chromatography, and the HPLC purity was greater than 97%;

[0121] (3) In a dry 250 mL three-necked flask, intermediate 2 (20 g, 1.0 eq), intermediate 1 (18 g, 1.0 eq), DMF (50 mL, 2.5 V), potassium carbonate (17.6 g, 1.2 eq) were added, the inert gas was replaced three times, catalyst-supported tetrakis(triphenylphosphine)palladium(0) (1 g, 5%, 0.05X) was added, and the inert gas was replaced three times again. The temperature was raised to 80°C for reaction for 15 h. The HPLC reaction was completed (product purity 97.3%). 40 mL of water was added while hot to dissolve the inorganic salts in the system at 50°C, and then the catalyst was removed by hot filtration. The filtrate was cooled to room temperature, and 120 mL of water was slowly added. A large amount of gray solid precipitated in the filtrate. The filter cake was filtered out and recrystallized with a mixed solution of ethanol / water in a ratio of 2:1 to obtain an off-white solid (26.1 g, yield of about 88%) with a melting point of 242.6-243.7°C (capillary measurement).

[0122] Example 3

[0123] The catalyst-supported tetrakis(triphenylphosphine)palladium(0) filtered out in Example 2 was used directly as a new catalyst without drying. The operation of Example 2 was repeated for eight times. The results are shown in Table 1.

[0124] Table 1 Summary of experimental data of supported Pd catalysts

[0125] Number of applications Reaction time Conversion rate 1 14 96.1％ 2 13 95.3％ 3 15 95.2％ 4 15 94.7％ 5 16 96.2％ 6 14.5 95.4％ 7 17 97.1％ 8 16.5 96.8％

[0126] As can be seen from Table 1, the catalyst-supported tetrakis(triphenylphosphine)palladium(0) used in the method provided by the present invention can be used 8 times without obvious catalyst failure, indicating that the catalyst used in the present invention has good stability.

[0127] Example 4

[0128] A pilot preparation method of isobutylamide thiazolyl resorcinol, comprising the following steps:

[0129] (1) Prepare intermediates 1 and 2 by the method of Example 1;

[0130] (2) In a dry 100L reactor, 2-aminothiazole (6kg, 1.0eq), tetrahydrofuran (9.6L, 1.5V), potassium carbonate (9.15kg, 1.1eq) were added, the internal temperature was cooled to below 0°C, the temperature was controlled not to exceed 10°C, isobutyryl chloride (6.9kg, 1.1eq) was added dropwise, after the addition was complete, the temperature was raised to room temperature and stirred for 5h, HPLC was used to monitor the completion of the reaction, water (45kg, 7.5V) was slowly added, the temperature was lowered to 10°C to precipitate an off-white solid, centrifuged, washed with water, and dried to obtain the product intermediate 1 (9kg, yield 88%), characterized by HNMR;

[0131] In a dry 100L reactor, resorcinol (11kg, 1.0eq), acetonitrile (40kg, 3.6X), NBS (17.2kg, 0.97eq), p-toluenesulfonic acid (550g, 0.05X) were added, and the mixture was kept at 50-60°C for 6h. After the reaction was completed by TLC monitoring, about 30L of acetonitrile was concentrated under reduced pressure, and then 40kg of water was added to the reaction bottle, extracted with 30L of dichloromethane, and the organic phase was washed with water twice. The organic phase was concentrated to dryness, and the obtained oil was distilled by molecular distillation equipment to obtain intermediate 2 (17.5kg, yield 93%), with HPLC purity of 98.5%;

[0132] (3) In a dry 100L reactor, add intermediate 2 (10kg, 1.0eq), intermediate 1 (9kg, 1.0eq), DMF (25kg, 2.5X), potassium carbonate (8.8kg, 1.2eq), replace with inert gas three times, add supported catalyst (500g, 5%, 0.05X), replace with inert gas three times, heat to 80°C for reaction for 16h, HPLC reaction is complete (product purity 96.4%), add 20kg of water while hot, dissolve inorganic salt at 50°C for 1h, filter and remove the catalyst while hot, cool the filtrate to room temperature, transfer to a 200L reactor and continue to slowly add 60kg of water, a large amount of gray solid precipitates in the filtrate, centrifuge and dry to obtain a crude product;

[0133] The crude product was recrystallized from a mixed solution of ethanol / water in a ratio of 2:1, decolorized with activated carbon, and the crystallization stirring speed was controlled to obtain off-white crystals, namely isobutylamidothiazolylresorcinol (13 kg, yield 88%), with a melting point of 243.6-243.9°C (capillary measurement), and an HPLC purity of more than 99%. Its high performance liquid chromatogram is shown in FIG. Figure 4 shown.

[0134] It can be seen from the above results that the method provided by the present invention has a short route, uses raw materials and catalysts at low cost, is environmentally friendly, and can obtain high-purity isobutylamide thiazolyl resorcinol by drying and recrystallization after the coupling reaction, does not require a complicated post-treatment process, is easy to operate, and can solve the problems of long route, high cost, high toxicity, complicated post-treatment method, low yield and purity existing in the synthesis method of isobutylamide thiazolyl resorcinol.

[0135] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing isobutylamide thiazolyl resorcinol, comprising the following steps: (1) mixing 2-aminothiazole, isobutyryl chloride, an inorganic base and a first organic solvent, and performing an amidation reaction to obtain an intermediate 1; (2) mixing resorcinol, a halogenation agent, a catalyst and a second organic solvent to carry out a halogenation reaction to obtain an intermediate 2; (3) mixing the intermediate 1 obtained in step (1), the intermediate 2 obtained in step (2), a zero-valent palladium catalyst, an alkaline reagent and an organic solvent, performing a coupling reaction, and then filtering and recrystallizing in sequence to obtain isobutylaminothiazolylresorcinol; There is no chronological order between step (1) and step (2).

2. The preparation method according to claim 1, characterized in that: The inorganic base in step (1) includes one or more of sodium hydroxide, sodium carbonate and potassium carbonate.

3. The preparation method according to claim 1, characterized in that: In the step (1), the molar ratio of 2-aminothiazole, isobutyryl chloride and inorganic base is 1:(1.1-1.5):(1.1-1.8).

4. The preparation method according to claim 1, characterized in that: The temperature of the amidation reaction in step (1) is -5 to 30°C, and the time of the amidation reaction is 1 to 10 hours.

5. The preparation method according to claim 1, characterized in that: The halogenating agent in step (2) includes one or more of I2, N-chlorosuccinimide, N-bromosuccinimide and bromine.

6. The preparation method according to claim 1, characterized in that: The catalyst in step (2) includes one or more of aluminum chloride, sulfuric acid, zinc chloride and p-toluenesulfonic acid.

7. The preparation method according to claim 1, characterized in that: The mass ratio of resorcinol to the halogenating agent in step (2) is 1:(0.95-1.3); the mass percentage of the catalyst to resorcinol is 1-10%.

8. The preparation method according to claim 1, characterized in that: The temperature of the halogenation reaction in step (2) is 30 to 80° C., and the time of the halogenation reaction is 5 to 24 hours.

9. The preparation method according to claim 1, characterized in that: In the step (3), the mass ratio of intermediate 1, intermediate 2 and alkaline reagent is 1:(0.95-1.2):(1.1-1.5); the mass percentage of the zero-valent palladium catalyst in intermediate 2 is 1-10%; the mass ratio of the organic solvent 3 to intermediate 2 is (2-5):

1.

10. The preparation method according to claim 1, characterized in that: The temperature of the coupling reaction in step (3) is 50-100° C., and the time of the coupling reaction is 10-48 hours.

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