CN114920761B - Synthesis method of tetramisole hydrochloride - Google Patents
Synthesis method of tetramisole hydrochloride Download PDFInfo
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- CN114920761B CN114920761B CN202210850635.5A CN202210850635A CN114920761B CN 114920761 B CN114920761 B CN 114920761B CN 202210850635 A CN202210850635 A CN 202210850635A CN 114920761 B CN114920761 B CN 114920761B
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
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Abstract
The invention discloses a method for synthesizing tetramisole hydrochloride, which relates to the technical field of organic chemical production and comprises a step of synthesizing tetramisole by taking 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and benzene as raw materials and a step of preparing the tetramisole hydrochloride by acidification and salt formation; the step of synthesizing the tetramisole is carried out under the condition of a catalyst; the solvent used in the step of synthesizing the tetramisole is selected from organic solvents; the organic solvent comprises one or more of acetone, cyclohexanone, acetonitrile, DMF, and ethanol. According to the method for synthesizing the tetramisole hydrochloride, the introduction of heteroatoms in a reaction system is avoided, the steps are simple, the waste water is less, the energy is saved, the environment is protected, and the industrial production is facilitated; the yield of the prepared tetramisole hydrochloride product is obviously increased, and the product quality is high.
Description
Technical Field
The invention belongs to the technical field of organic chemical production, and particularly relates to a method for synthesizing tetramisole hydrochloride.
Background
The tetramisole hydrochloride is an important intermediate for synthesizing levamisole. Levamisole is a broad-spectrum anthelmintic which can inhibit the activity of succinate dehydrogenase in muscles of worms and cause the muscles to continuously contract to be paralyzed, is mainly used for expelling roundworms and hookworms and can improve the resistance of patients to bacterial and viral infections. At present, the traditional Chinese medicine composition is used as auxiliary treatment after lung cancer and breast cancer operations or acute leukemia and malignant lymphoma chemotherapy. In addition, it can be used for autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, upper respiratory tract infection, infantile respiratory tract infection, hepatitis, bacillary dysentery, furuncle, abscess, etc. Trial shows that the medicine has obvious curative effect on intractable bronchial asthma.
The existing synthesis of the tetramisole hydrochloride needs to go through long reaction steps, which also causes the difficulty in improving the reaction yield of the process in such a way. The existing tetramisole hydrochloride comprises the following preparation methods: firstly, styrene oxide and ethanolamine are subjected to addition, thiourea cyclization and salification after thionyl chloride chlorination and hydrolysis, the process is complex, and post-treatment and purification are difficult; secondly, the hydroxyl salt 2-imino-alpha-phenyl-3-thiazolidine ethanol hydrochloride is used as a raw material and is prepared by chlorination, neutralization and cyclization, the raw material is expensive, and liquid waste and solid waste are polluted; thirdly, N- (2-chloroethyl) -alpha- (chloromethyl) -benzylamine hydrochloride is used as a raw material, and the price of the raw material is high; fourthly, 1, 2-dibromo ethyl benzene and 2-amino thiazoline hydrochloride react, the steps are simple, but hetero atoms are introduced in the ring forming operation, and the post-treatment purification operation is complicated.
Disclosure of Invention
The invention aims to provide a method for synthesizing tetramisole hydrochloride, which has the advantages that a reaction system avoids introducing heteroatoms, and has simple steps, easy purification, less waste water, energy conservation, environmental protection and convenient industrial production; the yield of the prepared tetramisole hydrochloride product is obviously increased, and the product quality is high.
The technical scheme adopted by the invention for realizing the purpose is as follows:
a method for synthesizing tetramisole hydrochloride comprises the steps of synthesizing tetramisole by taking 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and benzene as raw materials, and preparing the tetramisole hydrochloride by acidification and salt formation.
The synthesis route of the tetramisole hydrochloride provided by the invention is shorter than other process routes, such as taking styrene as an initiator and tetramisole free alkali as a final product, long in reaction route and more in reaction steps, by taking 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and benzene as raw materials to synthesize the tetramisole hydrochloride; the preparation method provided by the invention has higher yield, for example, the yield of the hydroxyl salt process route is about 65%, and the yield can reach more than 77% by using the synthesis route provided by the invention. Meanwhile, the synthetic route provided by the invention avoids the problem of large amount of waste generated by multi-step reactions such as hydrolysis, cyclization and the like, and meets the requirements of green chemical industry; the reaction system avoids introducing heteroatoms, and the steps are simple and easy to purify; and the equipment input cost can be reduced, the reaction avoids using hydroxyl salt or N- (2-chloroethyl) -alpha- (chloromethyl) -benzylamine hydrochloride as the raw material, the raw material cost is reduced to a certain extent, the economic benefit is obvious, and the method has a huge industrialization prospect.
Specifically, the method for synthesizing the tetramisole hydrochloride comprises the following reaction steps:
the first step is as follows: benzene and 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole are used for generating the tetramisole under the action of a catalyst;
the second step is that: and acidifying the tetramizole in hydrochloric acid, and spin-drying the solvent to obtain the tetramizole hydrochloride.
Preferably, the preparation route of the tetramisole hydrochloride comprises the following steps:
preferably, the catalyst is aluminum trichloride or iron trichloride.
Preferably, the 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole is reacted with benzene in an organic solvent in the first step described above.
Preferably, the reaction temperature in the first step is the reflux temperature of the solvent; the reaction time is 2.5 to 6h.
Preferably, the organic solvent comprises one or more of acetone, cyclohexanone, acetonitrile, DMF, and ethanol. Wherein, the organic solvent is a preparation process of mixing at least two substances, has higher product yield which can reach more than 80 percent.
Preferably, the treatment after the reaction in the first step to form crude tetramisole comprises: and (3) placing the reaction system under an ice bath condition, adding alkali liquor into the system to adjust the pH value to 7.5-9.0, and filtering to obtain the tetramisole.
Preferably, the alkali liquor is one or two of sodium carbonate and potassium carbonate.
Preferably, the molar ratio of the 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole to the benzene is 1.
Preferably, the molar ratio of the 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole to the catalyst is 1.
Preferably, the solvent used in the second step is water; wherein the dosage of the water is 2.5 to 4 times of the mass of the tetramisole.
More preferably, the amount of the hydrochloric acid used in the second step is calculated by adjusting the pH value of the reaction system to 4.0-4.5.
Preferably, the yield of the product prepared by the preparation method is more than 72 percent; more preferably, the yield of product is > 77%.
More preferably, the catalyst in the preparation method is an immobilized catalyst, i.e. modified silica gel is used as a carrier to load aluminum trichloride to form the immobilized catalyst. The immobilized catalyst prepared by the method has more excellent catalytic activity; the prepared modified silica gel has higher aluminum trichloride loading capacity and better recycling stability. The method is applied to the preparation process of the tetramisole hydrochloride, the high catalytic efficiency is reflected, the catalytic reaction can be rapidly and efficiently carried out, and the obtained product has higher yield which can reach more than 85%; and the purity is higher and can reach more than 99.5 percent, and the product quality is obviously improved. And the catalyst preparation process is simple to operate, mild in condition and more beneficial to industrial production.
Preferably, the modified silica gel comprises a silane coupling agent, geniposide modified silica gel.
Preferably, the preparation method of the supported catalyst comprises the following steps:
activating silica gel, and soaking the silica gel by hydrochloric acid and hydrogen peroxide;
performing amination treatment on the activated silica gel, and treating the activated silica gel by adopting a silane coupling agent to obtain aminated silica gel;
chemically modifying the aminated silica gel by adopting geniposide to chemically modify the aminated silica gel to obtain modified silica gel;
preparing the immobilized catalyst by taking modified silica gel and anhydrous AlCl 3 The contact forms the solid-supported catalyst.
Specifically, the preparation method of the supported catalyst comprises the following steps:
adding hydrochloric acid with the concentration of 0.8 to 1.5M into silica gel, soaking overnight, then soaking for 10 to 12h by using hydrogen peroxide with the concentration of 28 to 30wt%, then cleaning to be neutral, and drying for 8 to 12h under the temperature of 100 to 120 ℃ to obtain activated silica gel;
adding toluene and a silane coupling agent into activated silica gel, carrying out reflux stirring reaction at 70 to 80 ℃ for 10 to 14h, then washing with toluene, alcohol and ether in sequence, and carrying out vacuum drying at 70 to 80 ℃ for 20 to 24h to obtain silicon amide gel;
adding THF and geniposidic acid into the aminated silica gel, then adding DCC, reacting for 20 to 24h under the condition of 30 to 40 ℃, then washing with hydrochloric acid with the concentration of 4 to 5M and deionized water in sequence, and drying in vacuum at 30 to 35 ℃ to obtain modified silica gel;
adding carbon tetrachloride into the modified silica gel, and refluxing for 2 to 4 hours; then adding anhydrous AlCl 3 Continuously stirring and refluxing for 48 to 32h, detecting that no hydrogen chloride gas is discharged basically, performing suction filtration, and sequentially using anhydrous EtOH and CH 2 Cl 2 And washing and drying to obtain the immobilized catalyst.
Preferably, the solid-liquid ratio of the activated silica gel to the toluene is 0.08 to 0.15g:1mL; the solid-to-liquid ratio of the activated silica gel to the silane coupling agent is 0.8 to 1.2g:1mL.
Preferably, the silane coupling agent structure includes at least one amino group.
Preferably, the solid-to-liquid ratio of the silicon amide glue to THF is 0.08 to 0.15g:1mL; the mass ratio of the geniposide to the silicon amide gel is 0.1 to 0.2; the mass ratio of the DCC to the silicon amide adhesive is 0.1-0.12.
Preferably, the solid-to-liquid ratio of the modified silica gel to the carbon tetrachloride is 0.1 to 0.2g:1mL; alCl 3 The mass ratio of the modified silica gel to the modified silica gel is 0.45 to 0.6:1.
preferably, the solid loading of the aluminum trichloride in the solid-supported catalyst is 4.5 to 5.5mmol/g.
Preferably, the supported catalyst prepared by the invention can be recycled.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method of the tetramisole hydrochloride provided by the invention uses benzene and 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole as raw materials, performs substitution under the action of a catalyst, and obtains the tetramisole hydrochloride through the salt formation of the tetramisole after purification, wherein the product purity is good, and the yield is higher than that of the traditional process; the reaction system avoids introducing heteroatoms, and the method has simple steps and easy purification; the waste water generated in the reaction system is less, and the energy is saved and the environment is protected; the preparation method provided by the invention has the advantages of simple and convenient required equipment, low cost and good economic benefit, and is more beneficial to industrial production. Meanwhile, the immobilized catalyst prepared by the method has more excellent catalytic activity and better recycling stability, can quickly and efficiently catalyze the reaction, further improves the yield of the product, and has higher product purity.
Therefore, the invention provides a method for synthesizing the tetramisole hydrochloride, which has the advantages that a reaction system avoids introducing heteroatoms, and the method is simple in steps, easy to purify, less in waste water, energy-saving, environment-friendly and convenient for industrial production; the yield of the prepared tetramisole hydrochloride product is obviously increased, and the product quality is high.
Drawings
FIG. 1 is an IR spectrum of an activated silica gel and a modified silica gel prepared in example 11 of the present invention.
Detailed Description
The technical solutions of the present invention will be described in further detail below with reference to the detailed description and the accompanying drawings, but it should be understood that these examples are only for illustrating the disclosure of the present invention to assist understanding, and are not intended to limit the scope of the present invention, and the scope of the present invention is not limited to the following examples.
The present invention is not particularly limited with respect to the sources of the raw materials in the following examples, and they may be prepared by a preparation method known to those skilled in the art or commercially available.
It should be noted that the 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole used in the examples of the present invention can be prepared by the following method, which is custom-made from the raw material supplier:
6-Chloroimidazol-thiazoles in Ru/PPh 3 Catalytically hydrogenating under the condition, purifying the product to obtain 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ]]A thiazole; wherein the purification step comprises: and (2) taking a reaction product, performing suction filtration, evaporating the filtrate to dryness, washing a filter cake by using petroleum ether/ethyl acetate (v/v, 2)]And (b) a thiazole. The specific reaction conditions include: the hydrogen pressure is 3.2MPa, the reaction temperature is 96 ℃, and the reaction time is 4h; the molar ratio of 6-chloroimidazole-thiazole to triphenylphosphine was 1; the molar ratio of triphenylphosphine to ruthenium was 1.67, reaction solvent THF.
The product nuclear magnetic data are as follows: 1 H NMR (400 MHz, DMSO), δ ppm ：4.10(t，2H，CH 2 )，3.79、3.58 (m, 2H, CH 2 ), 3.51 (dd, 1H, Cl-CH), 3.62(m，2H，CH 2 )。
example 1:
a method for synthesizing tetramisole hydrochloride comprises the following reaction steps:
the first step is as follows: 50g of 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and 24.25g of benzene are dissolved in 100mL of acetone, 40.99g of aluminum trichloride is added into the system as a catalyst, the reaction temperature is 50 ℃ reflux temperature, and the reaction time is 4h; after the reaction, placing the reaction system in an ice bath, when the temperature is reduced to be below 10 ℃, adding a sodium carbonate saturated solution into the system to adjust the pH value to be 7.5, and filtering to obtain the tetramisole with the yield of 72.4%;
the second step is that: adding 45.47g of tetramisole into 150g of water, and adding hydrochloric acid into the system for acidification until the pH value of the aqueous solution is 4.5; and (3) standing for stabilization, and then spin-drying the solvent to obtain the tetramisole hydrochloride with the yield of 100%.
The product nuclear magnetic data are as follows: 1 H NMR (500 MHz, D 2 O), δ ppm ： 7.22~7.51 (m，5H, Ph-H), 5.64 (dd, 1H, Ph-CH), 4.17 (t, 2H, CH 2 ), 3.92、3.63(m，2H，CH 2 )，3.75(2H，CH 2 )。
example 2:
the synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the method changes the dosage of each raw material and catalyst and solvent, and comprises the following specific reaction processes:
the first step is as follows: 50g of 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and 24.73g of benzene are dissolved in 100mL of acetonitrile, 49.19g of aluminum trichloride is added into the system as a catalyst, the reaction temperature is 75 ℃, the reflux temperature is high, and the reaction time is 2.5 hours; after the reaction, placing the reaction system in an ice bath, adding a sodium carbonate saturated solution into the system to adjust the pH value to 8.5 when the temperature is reduced to be below 10 ℃, and filtering to obtain the tetramisole with the yield of 73.1%;
the second step: adding 45.91g of tetramisole into 115g of water, and adding hydrochloric acid into the system for acidification until the pH value of the aqueous solution is 4.0; and (3) after standing and stabilizing, spin-drying the solvent to obtain the tetramisole hydrochloride with the yield of 100%.
Example 3:
the synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the method changes the dosage of each raw material, catalyst and solvent, and comprises the following specific reaction processes:
the first step is as follows: 50g of 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and 25.21g of benzene are dissolved in 100mL of DMF, 57.39g of aluminum trichloride is added into the system as a catalyst, the reaction temperature is 120 ℃, and the reaction time is 3.5h; after the reaction, placing the reaction system in an ice bath, adding a sodium carbonate saturated solution into the system to adjust the pH value to 7.8 when the temperature is reduced to be below 10 ℃, and filtering to obtain the tetramisole with the yield of 77.6 percent;
the second step is that: adding 48.73g of tetraimidazole into 150g of water, and adding hydrochloric acid into the system for acidification until the pH value of the aqueous solution is 4.3; and (3) after standing and stabilizing, spin-drying the solvent to obtain the tetramisole hydrochloride with the yield of 100%.
Example 4:
the synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the method changes the dosage of each raw material and catalyst, and comprises the following specific reaction processes:
the first step is as follows: 50g of 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and 25.21g of benzene are dissolved in 100mL of DMF solvent, 65.58g of aluminum trichloride is added into the system as a catalyst, the reaction temperature is 120 ℃, and the reaction time is 5h; after the reaction, placing the reaction system in an ice bath, when the temperature is reduced to be below 10 ℃, adding a sodium carbonate saturated solution into the system to adjust the pH value to be 8.5, and filtering to obtain the tetramisole with the yield of 76.2%;
the second step is that: adding 47.85g of tetramisole into 150g of water, and adding hydrochloric acid into the system for acidification until the pH value of the aqueous solution is 4.2; and (3) standing for stabilization, and then spin-drying the solvent to obtain the tetramisole hydrochloride with the yield of 100%.
Example 5:
the synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the method changes the dosage of each raw material, catalyst and solvent, and comprises the following specific reaction processes:
the first step is as follows: 50g of 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and 25.69g of benzene are dissolved in 100mL of ethanol solvent, 73.78g of aluminum trichloride is added into the system as a catalyst, the reaction temperature is 65 ℃ of reflux temperature, and the reaction time is 4.5h; after the reaction, placing the reaction system in an ice bath, adding a potassium carbonate saturated solution into the system to adjust the pH value to 7.8 when the temperature is reduced to below 10 ℃, and filtering to obtain the tetramisole with the yield of 75.4%;
the second step is that: adding 47.35g of tetramisole into 190g of water, and adding hydrochloric acid into the system for acidification until the pH value of the aqueous solution is 4.1; and (3) standing for stabilization, and then spin-drying the solvent to obtain the tetramisole hydrochloride with the yield of 100%.
Example 6:
the synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the method changes the dosage of each raw material, catalyst and solvent, and comprises the following specific reaction processes:
the first step is as follows: 50g of 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and 26.41g of benzene are dissolved in 100mL of cyclohexanone solvent, 81.98g of aluminum trichloride is added into the system as a catalyst, the reaction temperature is 120 ℃, and the reaction time is 2.5h; after the reaction, placing the reaction system in an ice bath, adding a potassium carbonate saturated solution into the system to adjust the pH value to 8.8 when the temperature is reduced to be below 10 ℃, and filtering to obtain the tetramisole with the yield of 74.1%;
the second step is that: adding 46.53g of tetramisole into 120g of water, and adding hydrochloric acid into the system for acidification until the pH value of the aqueous solution is 4.4; and (3) after standing and stabilizing, spin-drying the solvent to obtain the tetramisole hydrochloride with the yield of 100%.
Example 7:
the synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the method changes the dosage of each raw material and catalyst and solvent, and comprises the following specific reaction processes:
the first step is as follows: 50g of 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and 25.21g of benzene are dissolved in 100mL of DMF, 69.80g of ferric trichloride is added into the system as a catalyst, the reaction temperature is 120 ℃, and the reaction time is 3.5h; after the reaction, placing the reaction system in an ice bath, adding a potassium carbonate saturated solution into the system to adjust the pH value to 7.9 when the temperature is reduced to be below 10 ℃, and filtering to obtain the tetramisole with the yield of 77.1%;
the second step is that: adding 48.42g of tetraimidazole into 150g of water, and adding hydrochloric acid into the system for acidification until the pH value of the aqueous solution is 4.0; and (3) standing for stabilization, and then spin-drying the solvent to obtain the tetramisole hydrochloride with the yield of 100%.
Example 8:
the synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the specific reaction process is as follows:
the first step is as follows: 50g of 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and 25.21g of benzene are dissolved in 100mL of DMF solvent, 79.79g of ferric trichloride is added into the system as a catalyst, the reaction temperature is 120 ℃, and the reaction time is 6h; after the reaction, placing the reaction system in an ice bath, adding a potassium carbonate saturated solution into the system to adjust the pH value to 8.5 when the temperature is reduced to be below 10 ℃, and filtering to obtain the tetramisole with the yield of 75.5%;
the second step: adding 47.41g of tetramisole into 150g of water, and adding hydrochloric acid into the system for acidification until the pH value of the aqueous solution is 4.5; and (3) standing for stabilization, and then spin-drying the solvent to obtain the tetramisole hydrochloride with the yield of 100%.
Example 9:
the synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the solvents are acetone and ethanol (v/v, 1;
the yield of the tetramisole obtained in the first step was 76.4%.
Example 10:
a method for synthesizing the tetramisole hydrochloride is different from that of the embodiment 7: solvents were cyclohexanone and DMF (v/v, 1; the yield of the tetramisole prepared in the first step was 81.7%.
Example 11:
preparation of the immobilized catalyst:
adding hydrochloric acid with the concentration of 1.2M into silica gel, soaking overnight, then soaking for 12 hours by using hydrogen peroxide with the concentration of 29wt%, then cleaning to be neutral, and drying for 10 hours at the temperature of 120 ℃ to obtain activated silica gel;
adding toluene and a silane coupling agent (3-aminopropyltriethoxysilane) into activated silica gel, refluxing and stirring at 75 ℃ for reaction for 13h, then washing with toluene, alcohol and ether in sequence, and vacuum drying at 80 ℃ for 24h to obtain silicon amide gel; wherein the solid-to-liquid ratio of the activated silica gel to the toluene is 0.12g:1mL; the solid-to-liquid ratio of the activated silica gel to the silane coupling agent is 1g:1mL;
adding THF and geniposidic acid into the aminated silica gel, adding DCC, reacting at 32 deg.C for 22h, sequentially washing with 4.5M hydrochloric acid and deionized water, and vacuum drying at 32 deg.C to obtain modified silica gel; wherein the solid-to-liquid ratio of the silicon amide gel to THF is 0.12g:1mL; the mass ratio of the geniposide to the amino silica gel is 0.16; the mass ratio of DCC to the aminated silica gel is 0.11;
adding carbon tetrachloride (the solid-liquid ratio is 0.11g; then adding anhydrous AlCl 3 (the mass ratio of the modified silica gel to the modified silica gel is 0.52, 1), stirring and refluxing are continued for 30h, after no hydrogen chloride gas is basically released, suction filtration is carried out, and anhydrous EtOH and CH are sequentially used 2 Cl 2 Washing and drying to obtain the solid supported catalyst (the solid loading of aluminum trichloride is 5.0 mmol/g).
The synthesis method of the tetramisole hydrochloride is different from that of the embodiment 1: the solid-supported catalyst prepared by the method is adopted to replace aluminum trichloride, and the dosage of the solid-supported aluminum trichloride is the same as that of the aluminum trichloride used in the embodiment 1;
the first step of post-reaction treatment comprises the following steps: after the reaction, the reaction system is subjected to rotary evaporation, ethanol/acetone (v/v, 2) mixed solution is added, suction filtration is carried out, the filtrate is placed in ice bath, when the temperature is reduced to be below 10 ℃, sodium carbonate saturated solution is added into the system to adjust the pH value to be 7.5, and then the filtration is carried out to obtain the tetramisole, wherein the yield is 85.7%.
Example 12:
the preparation of the supported catalyst differs from that of example 11: the solid-to-liquid ratio of the activated silica gel to the silane coupling agent is 0.9g:1mL; the mass ratio of the geniposide to the amino silica gel is 0.11; the mass ratio of DCC to the aminated silica gel is 0.12; alCl 3 The mass ratio of the modified silica gel to the modified silica gel is 0.56:1.
a method for synthesizing the tetramisole hydrochloride is different from that of the embodiment 11: the supported catalyst was prepared in this example;
the yield of the tetramisole obtained in the first step was 86.2%.
Comparative example 1:
preparation of the immobilized catalyst:
adding hydrochloric acid with the concentration of 1.2M into silica gel, soaking overnight, then soaking for 12 hours by using hydrogen peroxide with the concentration of 29wt%, then cleaning to be neutral, and drying for 10 hours at the temperature of 120 ℃ to obtain activated silica gel;
adding carbon tetrachloride (solid-liquid ratio is 0.11g; then adding anhydrous AlCl 3 (the mass ratio of the active silica gel to the active silica gel is 0.52), stirring and refluxing are continued for 30h, after no hydrogen chloride gas is basically released, suction filtration is carried out, and anhydrous EtOH and CH are sequentially used 2 Cl 2 Washing and drying to obtain the solid supported catalyst (the solid supported amount of the aluminum trichloride is 3.8 mmol/g).
The synthesis method of a tetramisole hydrochloride is different from that of the embodiment 11: the immobilized catalyst is prepared in the comparative example;
the yield of the tetramisole obtained in the first step was 75.5%.
Comparative example 2:
preparation of the immobilized catalyst:
adding hydrochloric acid with the concentration of 1.2M into silica gel, soaking overnight, then soaking for 12 hours by using hydrogen peroxide with the concentration of 29wt%, then cleaning to be neutral, and drying for 10 hours at the temperature of 120 ℃ to obtain activated silica gel;
adding toluene and a silane coupling agent (3-aminopropyltriethoxysilane) into activated silica gel, refluxing and stirring at 75 ℃ for reaction for 13h, then washing with toluene, alcohol and ether in sequence, and vacuum drying at 80 ℃ for 24h to obtain silicon amide gel; wherein the solid-to-liquid ratio of the activated silica gel to the toluene is 0.12g:1mL; the solid-liquid ratio of the activated silica gel to the silane coupling agent is 1g:1mL;
adding carbon tetrachloride (solid-to-liquid ratio is 0.11mL) into the aminated silica gel, and refluxing for 3.5h; then adding anhydrous AlCl 3 (the mass ratio of the catalyst to the silicon amide gel is 0.52 2 Cl 2 Washing and drying to obtain the solid supported catalyst (a)The solid loading of aluminum trichloride is 4.1 mmol/g).
The synthesis method of a tetramisole hydrochloride is different from that of the embodiment 11: the immobilized catalyst is prepared in the comparative example;
the yield of tetramisole obtained in the first step was 77.7%.
Test example 1:
purity test results
The purity of the tetramisole hydrochloride products prepared in the comparative examples 1 to 12 and the comparative examples 1 to 2 was tested, and the results are shown in table 1:
TABLE 1 purity test results for tetramisole hydrochloride products
As can be seen from the data in Table 1, the purity of the product prepared by the preparation method of the tetramisole hydrochloride provided by the invention is more than 99.00%, the product purity is good, and the product quality is high; in addition, the purity of the products prepared in the examples 11 and 12 can reach more than 99.5%, which is obviously better than that of the products prepared in the comparative examples 1 to 2, and the results show that the purity of the products prepared by catalyzing and preparing the tetramisole by using the immobilized catalyst is higher and the quality of the products is better.
Determination of circulation stability of immobilized catalyst
The procedure of example 11 was followed, in the first post-reaction treatment: and (3) after the reaction, carrying out rotary evaporation on the reaction system, adding an ethanol/acetone (v/v, 2). And then the product is used in the preparation process of the tetramisole hydrochloride for 5 times in a circulating way, and the reduction rate of the tetramisole yield is calculated.
The results of the above tests on the supported catalysts prepared in examples 11 to 12 and comparative examples 1 to 2 are shown in Table 2:
TABLE 2 cycling stability test results
As can be seen from the data in Table 2, the yield of the product prepared by the immobilized catalyst prepared in the example 11 of the invention is obviously reduced less than that of the products prepared in the comparative examples 1 to 2, which shows that the immobilized catalyst prepared by modifying silica gel with geniposide to obtain modified silica gel and loading aluminum trichloride has better recycling stability.
Test example 2:
infrared characterization
And measuring by using a Fourier infrared spectrometer. Wave number range of 4000 to 400cm -1 And scan number 128.
The above tests were carried out on the activated silica gel and the modified silica gel prepared in example 11, and the results are shown in FIG. 1. From the analysis in the figure, 1672cm in the infrared spectrum of the modified silica gel, compared with the infrared test result of the activated silica gel -1 、1540cm -1 A characteristic absorption peak of 1625cm was observed near the amide group -1 Characteristic absorption peak of C = C bond, 1295cm -1 A characteristic absorption peak for the C-N bond appeared nearby, indicating that the modified silica gel of example 11 was successfully prepared.
Conventional techniques in the above embodiments are known to those skilled in the art, and therefore, will not be described in detail herein.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily think of the changes or substitutions within the technical scope of the present invention, and shall cover the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (5)
1. A method for synthesizing tetramisole hydrochloride comprises the steps of synthesizing tetramisole by taking 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole and benzene as raw materials, and preparing the tetramisole hydrochloride by acidification and salt formation;
the step of synthesizing the tetramisole is carried out under the condition of a catalyst;
the solvent used in the step of synthesizing the tetramisole is selected from organic solvents; the organic solvent comprises one or more of acetone, cyclohexanone, acetonitrile, DMF and ethanol;
the molar ratio of the 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole to benzene is 1;
the molar ratio of the 6-chloro-2, 3,5, 6-tetrahydroimidazo [2,1-b ] thiazole to the catalyst is 1;
the catalyst is an immobilized catalyst, and the preparation method of the immobilized catalyst comprises the following steps:
adding hydrochloric acid with the concentration of 0.8-1.5M into silica gel, soaking overnight, then soaking for 10-12h by using hydrogen peroxide with the concentration of 28-30wt%, then cleaning to be neutral, and drying for 8-12h under the condition of 100-120 ℃ to obtain activated silica gel;
adding toluene and a silane coupling agent into activated silica gel, carrying out reflux stirring reaction for 10 to 14h at the temperature of 70 to 80 ℃, then washing with toluene, alcohol and ether in sequence, and carrying out vacuum drying for 20 to 24h at the temperature of 70 to 80 ℃ to obtain silicon amide gel;
adding THF and geniposidic acid into the aminated silica gel, then adding DCC, reacting at 30 to 40 ℃ for 20 to 24h, then washing with hydrochloric acid with the concentration of 4 to 5M and deionized water in sequence, and drying in vacuum at 30 to 35 ℃ to obtain modified silica gel;
adding carbon tetrachloride into the modified silica gel, and refluxing for 2 to 4 hours; then adding anhydrous AlCl 3 Continuously stirring and refluxing for 48 to 32h, detecting that no hydrogen chloride gas is discharged basically, performing suction filtration, and sequentially using anhydrous EtOH and CH 2 Cl 2 Washing and drying to obtain the immobilized catalyst;
wherein the silane coupling agent is 3-aminopropyltriethoxysilane.
2. The method for synthesizing tetramisole hydrochloride according to claim 1, wherein the method comprises the following steps: the acid used in the acidification salt-forming step is hydrochloric acid.
3. The method for synthesizing tetramisole hydrochloride according to claim 2, wherein the method comprises the following steps: the dosage of the hydrochloric acid is calculated by adjusting the pH value of a reaction system for preparing the hydrochloric acid tetramisole from the tetramisole to 4.0 to 4.5.
4. The method for synthesizing tetramisole hydrochloride according to claim 1, wherein the method comprises the following steps: the solvent used in the acidification salt-forming step is water.
5. The method for synthesizing tetramisole hydrochloride according to claim 1, wherein the method comprises the following steps: the yield of the product prepared by the synthesis method is more than 72 percent.
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| stereospecific friedel-crafts alkylation of benzene with 4-mesyloxy-L-prolines. A new synthesis of 4-phenylprolines;D. R. Kronenthal et al.;《Tetrahedron Letters》;19901231;第31卷(第9期);第1241-1244页 * |
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