A preparation method of isobutyramide thiazolyl resorcinol

Abstract

The present invention provides a preparation method of isobutyramide thiazolyl resorcinol, which belongs to the technical field of organic synthesis. The method provided by the present invention is to carry out an amidation reaction with 2-aminothiazole and isobutyryl chloride under the action of an inorganic base to obtain intermediate 1; to obtain intermediate 2 with resorcinol and a halogenating agent under the action of a catalyst; and then to carry out a coupling reaction using 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 has a short route, low cost of raw materials and catalysts used, good environmental protection, and high-purity isobutyramide thiazolyl resorcinol can be obtained by filtration and recrystallization after the coupling reaction, without the need for a complicated post-processing process, and is easy to operate. The results of the examples 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%.

Description

Technical Field

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

[0002] Thiamidol is a resorcinol derivative containing a thiazolyl group, chemically known as isobutylaminothiazolylresorcinol. Experimental data indicates that isobutylaminothiazolylresorcinol has a strong inhibitory effect on tyrosinase activity, exhibits little cytotoxicity, and exhibits minimal irritation, leading to its use in cosmetics for whitening and spot-lightening.

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

[0004]

[0005] This preparation method uses 2,4-dihydroxyacetophenone as the raw material. The hydroxyl group is first protected with methyl chloroacetate. Bromine is then used to replace the hydrogen on the ortho-methyl group of the carbonyl group to produce intermediate I. Thiourea and isobutyryl chloride are reacted in toluene as the solvent to produce intermediate II. Finally, intermediates I and II undergo cyclization and are then deprotected to yield the final product. The disadvantages of this preparation method are: 1. 2,4-dihydroxyacetophenone is relatively expensive; 2. Methyl chloroacetate is used in large quantities and is a highly toxic substance; 3. The reaction of thiourea and isobutyryl chloride in toluene is a two-phase reaction, resulting in low yields and extremely inconvenient post-processing; 4. Bromine is highly toxic, corrosive, and prone to numerous side reactions during bromination; and 5. The overall process is long, produces a large amount of wastewater, and is environmentally unfriendly.

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

[0007]

[0008] This preparation method involves a Friedel-Crafts reaction between resorcinol and bromoacetic acid in the presence of a catalyst to produce intermediate I; thiourea reacts with isobutyryl chloride to produce intermediate II; and intermediates I and II undergo a cyclization reaction in the presence of a base to produce the final product. The disadvantages of this preparation method are: 1. Boron trifluoride etherate, used as a solvent and catalyst for the Friedel-Crafts reaction, is relatively expensive and is highly exothermic during post-processing, making it prone to spraying; 2. The synthesis of intermediate II is difficult to post-process, resulting in low yield and heavy pollution; 3. The direct Friedel-Crafts reaction between resorcinol and bromoacetic acid results in numerous side reactions and makes purification and separation difficult; and 4. Intermediate I in this method is unstable and easily cyclizes to form impurities, resulting in low product yield and purity.

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

[0010] The object of the present invention is to provide a method for preparing isobutyramide thiazolyl resorcinol with a 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 isobutyramide 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 duration of the amidation reaction is 1 to 10 h.

[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 molar ratio of resorcinol to the halogenating agent in step (2) is 1:(0.95-1.3); and the mass percentage of the catalyst to the 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 step (3), the molar 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%; and the mass ratio of the organic solvent 3 to intermediate 2 is (2-5): 1.

[0025] Preferably, the temperature of the coupling reaction 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 isobutyramidothiazolylresorcinol, comprising the following steps: mixing 2-aminothiazole, isobutyryl chloride, an inorganic base, and a first organic solvent to carry out an amidation reaction to obtain an intermediate 1; mixing resorcinol, a halogenating agent, a catalyst, and a second organic solvent to carry out a halogenation reaction to obtain an intermediate 2; mixing the intermediate 1, the intermediate 2, a zero-valent palladium catalyst, and the organic solvent to carry out a coupling reaction, and then filtering and recrystallizing in sequence to obtain isobutyramidothiazolylresorcinol. The method provided by the present invention involves carrying out an amidation reaction of 2-aminothiazole and isobutyryl chloride under the action of an inorganic base to obtain an intermediate 1; using resorcinol and a halogenating agent under the action of a catalyst to obtain an intermediate 2; then using intermediate 1 and intermediate 2 to carry out a coupling reaction under the action of a zero-valent palladium catalyst and an organic solvent, and obtaining isobutyramidothiazolylresorcinol through simple filtration and recrystallization. The method provided by the present invention has a short route, uses low-cost raw materials and catalysts, and is environmentally friendly. After the coupling reaction, high-purity isobutylamidothiazolylresorcinol can be obtained through simple filtration and recrystallization, eliminating the need for complex post-processing and simplifying the operation. The results of the examples show that the overall yield of the method provided by the present invention exceeds 70%, and the HPLC purity exceeds 99%. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

[0030] Figure 4 This is a chromatogram of isobutyramide thiazolyl resorcinol prepared in Example 4 of the present invention. DETAILED DESCRIPTION

[0031] The present invention provides a method for preparing isobutyramide 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, more preferably potassium carbonate. The addition of the inorganic base promotes activation of the acyl chloride, making it more susceptible to reaction with 2-aminothiazole. Furthermore, the inorganic base can neutralize HCl produced during the amidation reaction, thereby increasing the reaction rate of the amidation reaction.

[0038] In the present invention, the molar ratio of 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). By controlling the amount of each component within the above range, the present invention allows for sufficient reaction of each component and improves the yield of intermediate 1.

[0039] In the present invention, the first organic solvent preferably includes acetonitrile, tetrahydrofuran or dichloromethane, more preferably tetrahydrofuran. The use of the above organic solvents in the present invention can fully dissolve the components and promote the smooth progress of the amidation reaction.

[0040] In the present invention, the mass ratio of the 2-aminothiazole to 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 dropwise adding isobutyryl chloride to 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 0° C. or lower.

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

[0044] In the present invention, the amidation reaction temperature is preferably -5 to 30°C, more preferably 20 to 25°C; the amidation reaction time 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 addition of water in the present invention can cool the system to 4-5°C, preferably 5°C, to promote the precipitation of the intermediate 1 from the system.

[0047] The present invention does not particularly limit 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 halogenation agent, a catalyst and a second organic solvent are mixed to carry out a halogenation 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, more preferably N-bromosuccinimide.

[0053] In the present invention, the catalyst preferably comprises one or more of aluminum chloride, sulfuric acid, zinc chloride and p-toluenesulfonic acid, more preferably p-toluenesulfonic acid. 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, 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 molar ratio of 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 resorcinol is preferably 1-10%, more preferably 2-5%. Controlling the amounts of resorcinol, halogenating agent, and catalyst within the above ranges is more conducive to increasing the yield of 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 30-80°C, more preferably 50-60°C; and the time of the halogenation reaction is preferably 5-24 hours, more preferably 6-12 hours. Controlling the temperature and time of the halogenation reaction within the above ranges can promote a more complete halogenation reaction and increase 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 does not specifically limit the operation methods of the concentration, extraction, and column chromatography purification, and conventional concentration, extraction, and column chromatography purification methods can be used. The present invention recovers the organic solvent 2 by concentration; obtains the crude intermediate 2 by extraction; and further purifies the crude intermediate 2 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, and washing the organic phase obtained by the extraction with water to obtain an organic phase as a solution of crude intermediate 2. The volume ratio of water to dichloromethane is not particularly limited in the present invention and can be adjusted according to conventional extraction methods.

[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 does not specifically limit the operation method of the PE / EA column chromatography purification, and conventional PE / EA column chromatography purification methods can be used. In the present invention, the volume ratio of PE to EA in the PE / EA column chromatography purification is preferably (2-5):1, more preferably (3-4):1. Controlling the volume ratio of PE to EA within the above range 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 zero-valent palladium catalyst, an alkaline reagent, and an organic solvent to perform a coupling reaction, and then sequentially filters and recrystallizes to obtain isobutyramide thiazolyl resorcinol.

[0069] In the present invention, the zero-valent palladium catalyst is preferably supported tetrakis(triphenylphosphine)palladium(0). The present invention uses supported tetrakis(triphenylphosphine)palladium(0) as a catalyst, which is not only highly active and low-cost, but also recyclable. In an embodiment of the present invention, the supported tetrakis(triphenylphosphine)palladium(0) can be reused after being used eight 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 no palladium ions are left 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 activated carbon and hydrochloric acid solution and boiling the mixture, followed by filtering, washing and drying in sequence to obtain 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 does not specifically limit the filtering, washing, and drying operations, and any of the filtering, washing, and drying operations known to those skilled in the art may be employed. In an embodiment of the present invention, the washing agent may be deionized water, the washing may be performed twice, and the drying temperature may be 100°C.

[0078] In the present invention, the alkali treatment method preferably comprises: mixing the acid-treated activated carbon with a sodium hydroxide solution and boiling the mixture, followed by filtering, washing and drying in sequence to obtain the 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 may be performed twice, and the drying temperature may be 100°C.

[0082] In the present invention, the oxidation treatment method preferably includes: mixing the activated carbon treated with alkali and a nitric acid solution, boiling the mixture, and then filtering, washing, and drying the mixture 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 may be performed twice, 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 performed 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 to 10%, more preferably 5 to 8%. The present invention utilizes the 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 does not particularly limit the concentration of the sodium hydroxide solution; a sodium hydroxide solution of conventional concentration can be used to adjust the pH value of the soluble palladium salt solution to 8 to 9. Adjusting the pH value of the soluble palladium salt solution to the above range is more conducive to the adsorption of palladium into the pretreated activated carbon.

[0090] In the present invention, the immersion temperature is preferably 55-60° C., more preferably 58-60° C. The present invention has no particular limitation on the immersion time, as long as the palladium ions in the soluble palladium salt solution are 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 can be 15 minutes. The present invention can promote the adsorption of palladium ions by the pretreated activated carbon through ultrasound.

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

[0093] In the present invention, the reduction reaction temperature is preferably 30-70°C, more preferably 50-60°C; the reduction reaction pressure is preferably 0.5-5 MPa, more preferably 1-3 MPa; the reduction reaction is preferably carried out under stirring; the stirring speed is not particularly limited in the present invention, and can be adjusted to promote uniform mixing of the gas and liquid. The present invention can convert pretreated activated carbon impregnated with palladium ions into a zero-valent palladium catalyst through the reduction reaction.

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

[0095] In the present invention, the third organic solvent 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 molar 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 zero-valent palladium catalyst in 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 fully react and improve the yield of the product.

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

[0098] The present invention preferably conducts 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 particularly limit the inert gas replacement method, 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 10-48 hours, more preferably 20 hours. The present invention can make the coupling reaction more complete at the above temperature and time.

[0100] In the present invention, water is preferably added 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 a second time to the filtrate obtained by filtration. In the present invention, the single addition of water completely dissolves the inorganic salts in the system and removes the palladium catalyst by filtration; and the secondary addition of water promotes the precipitation of isobutylamidothiazolylresorcinol from the reaction system.

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

[0102] The present invention does not particularly limit the operation method of the filtration and recrystallization, and conventional filtration and recrystallization operation methods can be used. In the present invention, the recrystallization reagent 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 isobutyramidothiazolylresorcinol through recrystallization. In the present invention, the recrystallization is preferably carried out under stirring, and stirring can increase the speed of crystal precipitation.

[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 involves an amidation reaction between 2-aminothiazole and isobutyryl chloride under the action of an inorganic base to obtain intermediate 1; intermediate 2 is obtained by reacting resorcinol and a halogenating agent under the action of a catalyst; and intermediate 1 and intermediate 2 are then subjected to a coupling reaction under a zero-valent palladium catalyst and an organic solvent to obtain isobutyramidothiazolylresorcinol. The method provided by the present invention can significantly reduce the impurity content of isobutyramidothiazolylresorcinol isomers. The structure of the isobutyramidothiazolylresorcinol isomers is 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 isobutyramide thiazolyl resorcinol through drying and recrystallization after a coupling reaction. The content of isobutyramide thiazolyl resorcinol is low, does not require a complex post-processing process, and is easy to operate.

[0108] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the embodiments described are only some 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 making creative efforts 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 as follows:

[0110] The activated carbon was mixed with a 1% hydrochloric acid solution in a mass ratio of 1:3, and then boiled for 2 hours for acid treatment, and then filtered, washed, and dried to obtain acid-treated activated carbon; the acid-treated activated carbon was mixed with a 2% sodium hydroxide solution in a mass ratio of 1:5, and then boiled for 1 hour for alkali treatment, and then filtered, washed, and dried to obtain alkali-treated activated carbon; the alkali-treated activated carbon was mixed with a 5% nitric acid solution in a mass ratio of 1:5, and then boiled for 3 hours for oxidation treatment, and then 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 then introduced into the mixed solution, and the pressure is maintained at 1 MPa. 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, thereby obtaining supported tetrakis(triphenylphosphine)palladium(0).

[0112] Example 1

[0113] A method for preparing isobutyramide 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, but not exceeding 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 by TLC monitoring. The mixture was concentrated under reduced pressure to obtain about 150 mL of acetonitrile. 200 g of water was then added, and 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 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, the intermediate 2 (10 g, 1.0 eq) prepared in step (2), the 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) were added, the inert gas was replaced three times, and the catalyst-supported tetrakis(triphenylphosphine)palladium (0) (0.5 g, 0.05X) was added, and the inert gas was replaced three times. The temperature was raised to 70° C. for reaction for 2 minutes. 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 and recrystallized from a mixed solution of ethanol / water at a ratio of 2:1 to obtain an off-white solid, which was isobutylamidothiazolylresorcinol (13g, yield 88%). HNMR characterization results were as follows Figure 3 shown.

[0117] Example 2

[0118] A method for preparing isobutyramide 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), and potassium carbonate (305 g, 1.1 eq) were added. The internal temperature was cooled to below 0°C, but not exceeding 10°C. Isobutyryl chloride (230 g, 1.1 eq) was added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred for 4 h. The reaction was monitored by HPLC. Water (1500 g, 7.5 V) was slowly added, and the temperature was lowered to 5°C to precipitate an off-white solid. The solid 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), and p-toluenesulfonic acid (5.5 g, 0.05X) were added. The mixture was kept at 60°C for 7 h. The reaction was monitored by TLC. About 300 mL of acetonitrile was concentrated under reduced pressure, and 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 about 90%) was purified by PE / EA column chromatography. 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. The temperature was raised to 80 ° C for 15 h. The HPLC reaction was completed (product purity 97.3%). 40 mL of water was added while hot, and the inorganic salts in the system were dissolved at 50 ° C. 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 at a ratio of 2:1 to obtain an off-white solid (26.1 g, yield 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 catalyst

[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 reused 8 times without any obvious catalyst failure, indicating that the catalyst used in the present invention has good stability.

[0127] Example 4

[0128] A pilot-scale preparation method for isobutylamidothiazolylresorcinol comprises the following steps:

[0129] (1) Intermediates 1 and 2 were prepared using the method of Example 1;

[0130] (2) In a dry 100L reactor, 2-aminothiazole (6kg, 1.0eq), tetrahydrofuran (9.6L, 1.5V), and potassium carbonate (9.15kg, 1.1eq) were added. The internal temperature was cooled to below 0°C and 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. The reaction was monitored by HPLC to complete. Water (45kg, 7.5V) was slowly added. The temperature was cooled to 10°C to precipitate an off-white solid. The solid was centrifuged, washed with water, and dried to obtain the product intermediate 1 (9kg, yield 88%), which was characterized by HNMR.

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

[0132] (3) In a dry 100L reactor, intermediate 2 (10kg, 1.0eq), intermediate 1 (9kg, 1.0eq), DMF (25kg, 2.5X), potassium carbonate (8.8kg, 1.2eq) were added, the inert gas was replaced three times, a supported catalyst (500g, 5%, 0.05X) was added, and the inert gas was replaced three times again. The temperature was raised to 80°C for 16h. The HPLC reaction was completed (product purity 96.4%). 20kg of water was added while hot, and the inorganic salt was dissolved at 50°C for 1h. The catalyst was removed by hot filtration. The filtrate was cooled to room temperature and transferred to a 200L reactor. 60kg of water was slowly added. A large amount of gray solid was precipitated in the filtrate, and the crude product was obtained by centrifugation and drying.

[0133] The crude product was recrystallized from a 2:1 ethanol / water mixture, 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 greater than 99%. The HPLC chromatogram is shown below. Figure 4 shown.

[0134] From the above results, it can be seen that 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 isobutyramidothiazolylresorcinol by drying and recrystallization after the coupling reaction. No complicated post-processing process is required, and the operation is simple. It can solve the problems of long route, high cost, high toxicity, complicated post-processing method, low yield and purity in the synthesis method of isobutyramidothiazolylresorcinol.

[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 principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing isobutyramide 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 steps (1) and (2); The zero-valent palladium catalyst in the step (3) is supported tetrakis(triphenylphosphine)palladium(0).

2. The preparation method according to claim 1, characterized in that The inorganic base in step (1) is 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 duration 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) is 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) is 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 molar ratio of resorcinol to the halogenating agent in step (2) is 1:(0.95-1.3); the mass percentage of the catalyst to the 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 molar 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%; and 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 coupling reaction time is 10-48 hours.

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