CN114957288B - Synthesis method of tetramisole hydrochloride - Google Patents

Synthesis method of tetramisole hydrochloride Download PDF

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CN114957288B
CN114957288B CN202210636155.9A CN202210636155A CN114957288B CN 114957288 B CN114957288 B CN 114957288B CN 202210636155 A CN202210636155 A CN 202210636155A CN 114957288 B CN114957288 B CN 114957288B
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hydrochloride
reaction
synthesizing
tetraimidazole
phenylethanol
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CN114957288A (en
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刘明荣
刘辉
陆军
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Suzhou Huadao Biological Pharmacy Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D513/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention discloses a method for synthesizing tetramisole hydrochloride, which comprises the following steps: carrying out hydrothermal reaction on epoxy phenylethane and 2-aminothiazoline to obtain 2- (2-iminothiazolidine-3-yl) -1-phenylethanol; under the catalysis of a cyclization reagent, 2- (2-iminothiazolidine-3-yl) -1-phenylethanol undergoes a cyclization reaction to obtain tetraimidazole, and then hydrochloric acid is used for preparing salt to obtain the tetraimidazole hydrochloride. The synthesis method is simple and convenient to operate, low in cost, environment-friendly, capable of realizing efficient and stable production of the tetramisole hydrochloride and improving the yield and purity of the tetramisole hydrochloride.

Description

Synthesis method of tetramisole hydrochloride
Technical Field
The invention belongs to the technical field of chemical production, and particularly relates to a synthesis method of tetramisole hydrochloride.
Background
Levamisole hydrochloride is a broad-spectrum anthelmintic and anthelmintic, and can be used for treating ascariasis, fishing insects and enterobiasis infection; levamisole hydrochloride has been found to improve the resistance of patients to bacterial and viral infections, and is currently being tried for adjuvant therapy after lung cancer, breast cancer surgery or acute leukemia, and after exacerbation lymphoma chemotherapy. In addition, the medicine can be used for autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, upper sense, infantile respiratory tract infection, hepatitis, bacillary dysentery, sore furuncles, abscess and the like, and has better curative effect on refractory bronchial asthma through preliminary proof of trial.
The most critical intermediate of levamisole hydrochloride is tetramizole hydrochloride, also known as DL-2,3,5, 6-tetrahydro-6-phenylimidazo [2,1-b ]]Thiazole hydrochloride of formula C 11 H 12 N 2 S.hcl, molecular weight 240.76, melting point: 266-267 ℃, white crystalline powder, bitter and astringent taste, is easy to dissolve in water and methanol, slightly dissolve in ethanol and is insoluble in acetone.
The production process of tetramisole hydrochloride reported or adopted at present is few, and the most important is the following 2 synthetic routes:
(1) The method is characterized in that epoxy phenylethane and ethanolamine are used as starting materials, and eight steps of addition, salification, chlorination, hydrolysis, cyclization, chlorination, cyclization, salification and the like are sequentially carried out to prepare tetramidazole hydrochloride, a large amount of raw materials such as concentrated hydrochloric acid, concentrated sulfuric acid, thionyl chloride and the like are required to be used in the production process, a large amount of acid wastewater is generated, the environmental protection pressure is high, a large amount of resinoid waste is generated in a plurality of links, the operation difficulty is high, the yield is low, and the method is the only production route adopted in domestic mass production at present. The production route is as follows:
(2) Using omega-chloroacetophenone and 2-aminothiazoline as starting materials, and sequentially performing four steps of substitution, reduction, cyclization, salt formation and the like to prepare tetraimidazole hydrochloride; the route uses highly-irritant omega-chloroacetophenone and sodium borohydride, has great operation difficulty in the mass production process, and is only in the research stage at present. The production route is as follows:
along with the development of the application of the levamisole hydrochloride, the demand of the levamisole hydrochloride is continuously increased, so that the demand of the key intermediate of the levamisole hydrochloride is also synchronously increased; the existing production process of tetramisole hydrochloride has a plurality of shortages, and in order to overcome the shortages of the original production process, a novel production process is developed to prepare the tetramisole hydrochloride, so that the method has very important significance.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a synthesis method of tetramisole hydrochloride; the synthesis method is simple and convenient to operate, low in cost, environment-friendly, capable of realizing efficient and stable production of the tetramisole hydrochloride and improving the yield and purity of the tetramisole hydrochloride.
In order to achieve the technical purpose and the technical effect, the invention is realized by the following technical scheme:
a method for synthesizing tetraimidazole hydrochloride comprises the following steps:
step (1), carrying out hydrothermal reaction on the phenylethane shown in the formula (I) and the 2-aminothiazoline shown in the formula (II) to obtain 2- (2-iminothiazolidine-3-yl) -1-phenylethanol shown in the formula (III);
step (2), under the catalysis of a cyclization reagent, carrying out cyclization reaction on 2- (2-iminothiazolidine-3-yl) -1-phenylethanol to obtain tetraimidazole shown in a formula (IV), and acidifying with hydrochloric acid to form salt to obtain tetraimidazole hydrochloride shown in a formula (V);
the synthetic route is as follows:
the reaction temperature in step (1) is 100 to 250℃and preferably 120 to 180 ℃.
In the step (1), the mass ratio of the oxirane to the 2-aminothiazoline is 1-1.2:1.
The reaction in step (2) may be carried out under solvent conditions.
Preferably, the solvent is at least one of dichloromethane, chloroform, toluene, benzene, xylene, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, 1, 4-dioxane and methyl cyclopentyl ether.
Preferably, the cyclization reagent in the step (2) is at least one of thionyl chloride, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, concentrated sulfuric acid, chlorosulfonic acid, acetyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxybromide, phosphorus tribromide, phosphorus pentabromide and triphosgene.
The reaction temperature in step (2) is-20 to 100℃and preferably 0 to 60 ℃.
The ratio of the amount of 2- (2-iminothiazolidin-3-yl) -1-phenylethanol to the amount of the substance of the cyclization agent in the step (2) is 1:1.2-10.
In the step (2), hydrochloric acid used for acidification to form a salt is a hydrochloric acid solution with a concentration of 6N, or is derived from the reaction process of the step (2).
The beneficial effects of the invention are as follows:
the invention adopts a hydrothermal synthesis reaction method, and can lead the epoxy phenylethane and the 2-aminothiazoline to have high selectivity for epoxy ring-opening reaction, thereby synthesizing 2- (2-iminothiazolidine-3-yl) -1-phenylethanol with high yield, then carrying out cyclization reaction by utilizing the 2- (2-iminothiazolidine-3-yl) -1-phenylethanol under the catalysis of a cyclization reagent, obtaining high yield tetraimidazole, and then obtaining a tetraimidazole hydrochloride product through acidification into salt;
the cyclization reaction system adopted by the invention has high catalytic efficiency and mild reaction conditions, and the yield of the obtained tetramisole hydrochloride product is ideal;
the whole synthesis process is a brand new process, is safe and reliable, generates less waste pollution, is green and environment-friendly, has higher yield and purity of the obtained tetramisole hydrochloride product, has fewer reaction steps, is simple and convenient to operate, and has higher market popularization value.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of tetramisole hydrochloride obtained in example 1 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made more apparent and fully by reference to the accompanying drawings, in which it is shown, by way of illustration, only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a method for synthesizing tetramisole hydrochloride, which comprises the following steps:
step (1), carrying out hydrothermal reaction on the phenylethane shown in the formula (I) and the 2-aminothiazoline shown in the formula (II) to obtain 2- (2-iminothiazolidine-3-yl) -1-phenylethanol shown in the formula (III);
step (2), under the catalysis of a cyclization reagent, carrying out cyclization reaction on 2- (2-iminothiazolidine-3-yl) -1-phenylethanol to obtain tetraimidazole shown in a formula (IV), and acidifying with hydrochloric acid to form salt to obtain tetraimidazole hydrochloride shown in a formula (V);
the synthetic route is as follows:
wherein the reaction temperature in the step (1) is 100-250 ℃, preferably 120-180 ℃; in the step (1), the mass ratio of the oxirane to the 2-aminothiazoline is 1-1.2:1.
Wherein the reaction in step (2) may be carried out under solvent conditions. Preferably, the solvent is at least one of dichloromethane, chloroform, toluene, benzene, xylene, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, 1, 4-dioxane and methyl cyclopentyl ether.
The cyclization reagent in the step (2) is preferably at least one of thionyl chloride, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, concentrated sulfuric acid, chlorosulfonic acid, acetyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromoxide, phosphorus tribromide, phosphorus pentabromide, and triphosgene.
The reaction temperature in step (2) is-20 to 100℃and preferably 0 to 60 ℃.
The ratio of the amount of 2- (2-iminothiazolidin-3-yl) -1-phenylethanol to the amount of the substance of the cyclization agent in the step (2) is 1:1.2-10.
In the step (2), hydrochloric acid used for acidification to form salt is 6N hydrochloric acid solution, or HCl generated in the reaction process from the reaction process of the step (2).
Example 1
Adding 12 g of ethylene oxide, 10.2 g of 2-aminothiazoline and 100 ml of distilled water into a polytetrafluoroethylene lining of a hydrothermal reaction kettle, and carrying out heat preservation reaction at 120 ℃ for 2 hours after the installation is completed; naturally cooling to room temperature, opening a hydrothermal reaction kettle, putting a polytetrafluoroethylene lining into ice water, fully cooling, stirring, crystallizing, carrying out suction filtration, washing by using a pre-cooled ethanol-water (1:1, v/v) solution, and drying to obtain 21.8 g of 2- (2-iminothiazolidine-3-yl) -1-phenylethanol;
21.8 g of 2- (2-iminothiazolidin-3-yl) -1-phenylethanol are dissolved in 200 ml of dichloromethane, the ice salt is cooled to 0℃and 18 g of thionyl chloride are slowly added dropwise; after the dripping is finished, dropwise adding 20 milliliters of water under the condition of cooling by ice salt for quenching reaction, then using liquid alkali to adjust the pH to be=9, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating filtrate, adding 6N hydrochloric acid to be acidic, concentrating, recrystallizing residues by using ethanol, and drying to obtain 22.9 grams of tetramidazole hydrochloride; the total yield of the step 2 is 95%; the nuclear magnetic spectrum of the tetraimidazole hydrochloride is shown in figure 1.
The nuclear magnetic data are: 1 H NMR(400MHz,d 6 -DMSO):δ11.31(brs，1H)，7.47-7.41(m，5H)，5.79-5.74(m，1H)，4.25(t，1H)，4.02-398(m，1H)，3.84-3.76(m，2H)，3.69-3.64(m，1H)。
example 2
14.4 g of epoxy phenylethane, 10.2 g of 2-aminothiazoline and 100 ml of distilled water are added into a polytetrafluoroethylene lining of a hydrothermal reaction kettle, and after the installation is finished, the reaction is carried out for 1 hour at 150 ℃; naturally cooling to room temperature, opening the hydrothermal reaction kettle, putting the polytetrafluoroethylene lining into ice water, fully cooling, stirring, crystallizing, carrying out suction filtration, washing by using a pre-cooled ethanol-water (1:1, v/v) solution, and drying to obtain 22 g of 2- (2-iminothiazolidine-3-yl) -1-phenylethanol.
15 g of thionyl chloride is added into a reaction bottle, ice water is used for cooling, 22 g of 2- (2-iminothiazolidine-3-yl) -1-phenylethanol is added in 3 times, and 15 g of acetic anhydride is added dropwise after stirring for 30 minutes; removing the ice water bath, and stirring at room temperature for 1 hour; concentrating to dryness, recrystallizing the residue by using ethanol, and drying to obtain 23.4 g of tetramidazole hydrochloride; the total yield of the 2 steps is 97%. In the reaction process, hydrochloric acid used for salification is HCl generated in the reaction process.
Example 3
2- (2-iminothiazolidin-3-yl) -1-phenylethanol was prepared according to the reaction conditions of example 1; 22.2 g of 2- (2-iminothiazolidin-3-yl) -1-phenylethanol are dissolved in 200 ml of chloroform, 10 g of triphosgene are added, and the mixture is heated and refluxed for 1 hour; cooling ice water to room temperature, and dropwise adding 20 g of trifluoroacetic anhydride; removing the ice water bath, and stirring at room temperature for 1 hour; concentrating to dryness, recrystallizing the residue by using ethanol, and drying to obtain 23.6 g of tetramidazole hydrochloride with a yield of 98%. In the reaction process, hydrochloric acid used for salification is HCl generated in the reaction process.
Example 4
2- (2-iminothiazolidin-3-yl) -1-phenylethanol was prepared according to the reaction conditions of example 1; 22.2 g of 2- (2-iminothiazolidine-3-yl) -1-phenyl ethanol and 250 ml of toluene are added into a reaction bottle, the temperature is controlled to be about 5 ℃ by ice salt bath cooling, and 45 g of phosphorus oxychloride is added dropwise; heating and refluxing for 1 hour after the dripping is finished; cooling with ice water, dropwise adding 15% sodium hydroxide aqueous solution until the pH=10, stirring for 30 min, separating, washing the organic phase with saturated saline water for 2 times, concentrating, adding 6N hydrochloric acid until the organic phase is acidic, concentrating, recrystallizing the residue with ethanol, and drying to obtain 23.1 g of tetramidazole hydrochloride with a yield of 96%.
Example 5
2- (2-iminothiazolidin-3-yl) -1-phenylethanol was prepared according to the reaction conditions of example 1; 22.2 g of 2- (2-iminothiazolidine-3-yl) -1-phenyl ethanol and 100 ml of 1, 4-dioxane are added into a reaction bottle, the temperature is controlled to be about 0-5 ℃ by ice salt bath cooling, and 55 g of methanesulfonic anhydride/150 ml of 1, 4-dioxane solution are added dropwise; after the dripping is finished, stirring at room temperature for reacting for 5 hours; cooling with ice water, dropwise adding 100 ml of water for quenching reaction, concentrating to remove the solvent, adjusting the pH of the system to be 10 by using 15% sodium hydroxide solution, cooling for crystallization, filtering, washing with water, adding 6N hydrochloric acid into the solid to be acidic, concentrating, recrystallizing the residue by using ethanol, and drying to obtain 22.7 g of tetramidazole hydrochloride, wherein the yield is 94%.
The foregoing description is only illustrative of the present invention and is not intended to limit the scope of the invention, and all modifications and equivalents made by the present invention and the accompanying drawings, or direct or indirect application in other related arts, are included in the scope of the present invention.

Claims (7)

1. The synthesis method of the tetraimidazole hydrochloride is characterized by comprising the following steps:
step (1), carrying out hydrothermal reaction on the phenylethane shown in the formula (I) and the 2-aminothiazoline shown in the formula (II) to obtain 2- (2-iminothiazolidine-3-yl) -1-phenylethanol shown in the formula (III); the reaction temperature of the step (1) is 100-250 ℃; the mass ratio of the oxirane to the 2-aminothiazoline is 1-1.2:1;
step (2), under the catalysis of a cyclization reagent, carrying out cyclization reaction on 2- (2-iminothiazolidine-3-yl) -1-phenylethanol to obtain tetraimidazole shown in a formula (IV), and acidifying with hydrochloric acid to form salt to obtain tetraimidazole hydrochloride shown in a formula (V);
the synthetic route is as follows:
2. the method for synthesizing tetramisole hydrochloride according to claim 1, wherein the reaction in step (2) is carried out under solvent conditions.
3. The method for synthesizing tetramidazole hydrochloride according to claim 2, wherein the solvent is at least one of dichloromethane, chloroform, toluene, benzene, xylene, acetonitrile, tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, ethylene glycol dimethyl ether, methyl tertiary butyl ether, 1, 4-dioxane, methyl cyclopentyl ether.
4. The method for synthesizing tetraimidazole hydrochloride according to claim 1, wherein the cyclization reagent in the step (2) is at least one of thionyl chloride, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, concentrated sulfuric acid, chlorosulfonic acid, acetyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide and triphosgene.
5. The method for synthesizing tetramisole hydrochloride according to claim 1, wherein the reaction temperature in the step (2) is-20 to 100 ℃.
6. The method for synthesizing tetramisole hydrochloride according to claim 1, wherein the ratio of the amount of 2- (2-iminothiazolidine-3-yl) -1-phenylethanol to the amount of the substance of the cyclization agent in the step (2) is 1:1.2-10.
7. The method for synthesizing tetramisole hydrochloride according to claim 1, wherein in the step (2), the hydrochloric acid used for acidifying to form a salt is a 6N hydrochloric acid solution or is derived from the reaction process of the step (2).
CN202210636155.9A 2022-06-07 2022-06-07 Synthesis method of tetramisole hydrochloride Active CN114957288B (en)

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CN101445491A (en) * 2008-12-26 2009-06-03 山东师范大学 Thiazolinone derivative and preparation method and application thereof
CN111138457A (en) * 2019-12-19 2020-05-12 山东国邦药业有限公司 Synthesis method of tetramisole hydrochloride
CN112358490A (en) * 2020-12-10 2021-02-12 山东国邦药业有限公司 Preparation method of tetramisole hydrochloride

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000042031A2 (en) * 1999-01-14 2000-07-20 Bayer Corporation Substituted 2-arylimino heterocycles and compositions containing them, for use as progesterone receptor binding agents
CN101445491A (en) * 2008-12-26 2009-06-03 山东师范大学 Thiazolinone derivative and preparation method and application thereof
CN111138457A (en) * 2019-12-19 2020-05-12 山东国邦药业有限公司 Synthesis method of tetramisole hydrochloride
CN112358490A (en) * 2020-12-10 2021-02-12 山东国邦药业有限公司 Preparation method of tetramisole hydrochloride

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