A preparation method of Piaonin

Abstract

The present invention relates to the field of organic synthesis, and more specifically to a method for preparing pionin. This method first synthesizes a dithiocarbamate using ammonium dithiocarbamate as a raw material, and then uses the dithiocarbamate as a raw material to synthesize 2-alkylthio-4-methyl-thiazole. The dithiocarbamate is a solid, making it easy to separate the halogenated hydrocarbons involved in the reaction, thereby avoiding contamination caused by the difficulty in recovering excess halogenated hydrocarbons and reducing the generation of pollutants. This method solves the technical problem of the existing pionin synthesis route, which produces a large number of pollutants.

Description

Technical Field

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

[0002] Pionein, also known as quaternary ammonium salt-73, possesses strong antimicrobial activity. It can disrupt bacterial and fungal cell membranes, and is particularly effective against Propionibacterium acnes. It also inhibits melanin formation. It has important applications in cosmetics, serving as a conditioning agent, antiseptic, and whitening agent in shampoos, facial products, moisturizers, and other personal care products. As a pharmaceutical ingredient, it is used in the medical industry to treat acne, pimples, and dermatitis.

[0003] There are many existing synthesis methods. For example, the prior art: derived from patent CN107840831A, discloses a synthesis route for piaonin using 4-methylthiazolethiol as the raw material. 4-Methylthiazolethiol is prepared by reacting ammonium dithiocarbamate with chloroacetone. This synthesis process generally requires two equivalents of ammonium dithiocarbamate to ensure an excess of ammonium dithiocarbamate. Unreacted ammonium dithiocarbamate is difficult to recycle, and foul-smelling gaseous bodies are generated during the synthesis process, which can easily cause pollution and affect subsequent separation, resulting in low product purity. Due to the high price of the 4-methylthiazolethiol reagent, directly purchasing the 4-methylthiazolethiol reagent increases the preparation cost.

[0004] Therefore, the existing synthesis route of pionin produces more pollutants, causing environmental pollution and high costs. Summary of the Invention

[0005] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for preparing pionin, which cleverly solves the technical problem that the existing pionin synthesis route produces a large amount of pollutants.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] The present invention provides a method for preparing piaoning, comprising the following steps:

[0008] The dithiocarbamate amine and a halogenated hydrocarbon are subjected to a nucleophilic substitution reaction in a first solvent system to obtain a dithiocarbamate; the dithiocarbamate and chloroacetone are subjected to a condensation ring reaction in a second solvent system to obtain 2-alkylthio-4-methylthiazole; 2-alkylthio-4-methylthiazole is mixed with iodoheptane to undergo a nucleophilic substitution reaction to obtain 2-alkylthio-N-heptyl-4-methylthiazolium salt; 2,4-dimethylthiazole is mixed with iodoheptane to undergo a nucleophilic substitution reaction to obtain N-heptyl-2,4-dimethylthiazolium salt; 2-alkylthio-N-heptyl-4-methylthiazolium salt and N-heptyl-2,4-dimethylthiazolium salt are mixed with an organic base and subjected to a nucleophilic substitution reaction in a third solvent system to obtain pionin.

[0009] The halogenated hydrocarbon includes any one of a brominated alkane having 1 to 5 carbon atoms, an iodinated alkane having 1 to 5 carbon atoms, and a chloroalkane having 3 to 5 carbon atoms. The molar ratio of the halogenated hydrocarbon to the dithiocarbamate is 1 to 1.5. The molar ratio of the chloroacetone to the dithiocarbamate is 0.9 to 1.2. The molar ratio of the iodide heptane to the 2,4-dimethylthiazole iodide heptane is 1 to 4, and the molar ratio of the iodide heptane to the 2,4-dimethylthiazole is 1 to 4.

[0010] This application first uses ammonium dithiocarbamate as a raw material to synthesize a dithiocarbamate, which is then used as a raw material to synthesize 2-alkylthio-4-methyl-thiazole. The dithiocarbamate is a solid, making it easy to separate the halogenated hydrocarbons involved in the reaction, avoiding the contamination caused by the difficulty in recovering excess halogenated hydrocarbons and reducing the generation of pollutants. This solves the technical problem of the existing pionin synthesis route that produces a large number of pollutants.

[0011] Optionally, in the step of subjecting the dithiocarbamate amine to a nucleophilic substitution reaction with a halogenated hydrocarbon in the first solvent system to produce the dithiocarbamate, the catalyst for the nucleophilic substitution reaction is at least one of sodium iodide or ammonium iodide. The reaction temperature for the nucleophilic substitution reaction is 0° C. to 80° C., and the reaction time is 12 h to 48 h.

[0012] Optionally, the step of subjecting the dithiocarbamate and chloroacetone to a condensation ring reaction in a second solvent system to obtain 2-alkylthio-4-methylthiazole comprises the following steps: mixing the dithiocarbamate, chloroacetone and the second solvent for reaction, adjusting the pH to pH>8, adding ethyl acetate, extracting multiple times, drying and filtering, and performing reduced pressure distillation to obtain 2-alkylthio-4-methylthiazole.

[0013] Optionally, the reaction temperature of the condensation ring reaction is 25° C. to 100° C., and the reaction time is 18 h to 48 h.

[0014] Optionally, when the 2-alkylthio-4-methylthiazole is mixed with iodoheptane for the nucleophilic substitution reaction, the reaction temperature is 120° C. to 155° C., and the reaction time is 18 h to 48 h.

[0015] Optionally, when the 2,4-dimethylthiazole and iodoheptane are mixed to carry out the nucleophilic substitution reaction, the reaction temperature is 120 to 150° C., and the reaction time is 18 to 48 hours.

[0016] Optionally, when the 2-alkylthio-N-heptyl-4-methylthiazolium salt and N-heptyl-2,4-dimethylthiazolium salt are mixed with an organic base and subjected to a nucleophilic substitution reaction in a third solvent system, the reaction temperature is 30-100° C. and the reaction time is 18-48 h.

[0017] Optionally, the organic base is at least one of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0018] Optionally, the first solvent is at least one of ethanol, methanol, and acetonitrile, the second solvent is at least one of water, ethanol, methanol, and acetonitrile, and the third solvent is at least one of water, ethanol, methanol, and acetonitrile.

[0019] The present application also provides a piaoning prepared by the above-mentioned preparation method.

[0020] The present invention has the beneficial effect of first synthesizing a dithiocarbamate using ammonium dithiocarbamate as a raw material, and then synthesizing 2-alkylthio-4-methyl-thiazole using the dithiocarbamate as a raw material. The dithiocarbamate is a solid and easily separated from the halogenated hydrocarbons involved in the reaction. Therefore, it can be obtained using inexpensive bromohydrocarbons and chlorohydrocarbons. Furthermore, the bromoaryl and chloroaryl hydrocarbons are easily separated and recycled, without affecting subsequent reactions or the purity of the product. This avoids contamination caused by the difficulty in recycling excess halogenated hydrocarbons, thereby reducing the generation of pollutants. This solves the technical problem of the existing pionin synthesis route generating a large number of pollutants, while also reducing production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The present invention provides a schematic diagram of a synthetic route of pionin. DETAILED DESCRIPTION

[0022] In order to solve the above technical problems, the present invention provides a method for preparing pionin. The technical solutions and embodiments of the present invention are now described in detail with reference to the accompanying drawings.

[0023] See Figure 1 , Figure 1A schematic diagram of a synthetic route of Pionin provided by the present invention, a specific synthetic route diagram, is shown below:

[0024]

[0025] The present invention is described in detail below through specific examples. The examples are exemplary and intended to be used to explain the present invention, but should not be understood as limiting the present invention.

[0026] Comparative Example 1

[0027] This comparative example provides a kind of Piao Ning, and its preparation method is as follows:

[0028] Step 1, synthesis of 4-methylthiazolethiol.

[0029]

[0030] 4.00 mol of ammonium dithiocarbamate was weighed and dissolved in 1500 mL of a mixed solvent of ethanol and water in a volume ratio of 2:1. The ice-water mixture was cooled to obtain an ammonium dithiocarbamate solution. 2.00 mol of chloroacetone was slowly added dropwise to the ammonium dithiocarbamate solution. After completion of the dropwise addition, the mixture was heated to reflux for 12 hours. The ethanol in the solvent was removed by distillation under reduced pressure. 200 mL of ethyl acetate was added and extracted three times. The organic phases were combined, dried over sodium sulfate, and the solvent was filtered and spin-dried to obtain 223.5 g of 4-methylthiazole mercaptan in a yield of 85.3%.

[0031] Step 2, synthesis of 2-heptylthio-4-methylthiazole.

[0032]

[0033] 1.67 mol of sodium hydroxide was dissolved in 1200 mL of ethanol, cooled with ice water, and stirred until dissolved. 1.52 mol of 4-methylthiazole thiol was slowly added. After complete dissolution, 2.28 mol of iodine heptane was slowly added dropwise. The temperature was warmed to room temperature and stirring was continued for 24 hours. The ethanol was recovered by distillation under reduced pressure. 300 mL of water was added, and then extracted three times with 200 mL of ethyl acetate. The organic phases were combined, 200 g of anhydrous sodium sulfate was added, and dried for 5 hours. The solvent ethyl acetate was recovered by distillation under reduced pressure. The remaining liquid was a mixture of 2-heptylthio-4-methylthiazole and unreacted iodine heptane, which was set aside without treatment.

[0034] Step 3, synthesis of 2-heptylthio-N-heptyl-4-methylthiazolium salt.

[0035]

[0036] 6.87 mol of iodoheptane was added to the 2-heptylthio-4-methylthiazole obtained in step 2, and the mixture was heated to 140° C. and stirred for reaction for 24 hours. The mixture was cooled to room temperature and set aside without further treatment.

[0037] Step 4: Synthesis of N-heptyl-4-methylthiazolium salt.

[0038]

[0039] 4.42 mol of 2,4-dimethylthiazole was weighed and added with 6.64 mol of iodoheptane. The mixture was heated to 140°C and reacted for 24 hours. The mixture was cooled to room temperature to remove unreacted iodoheptane to obtain a solid, namely N-heptyl-4-methylthiazolium salt. The solid was vacuum dried for later use. The yield was 95%.

[0040] Step 5: Synthesis of Pionein.

[0041]

[0042] To the product obtained in step 2, 1.53 mol of N-heptyl-4-methylthiazolium salt, 3.05 mol of diisopropylethylamine, and 1000 mL of ethanol were added, heated to 80° C., stirred and reacted for 24 hours, cooled to room temperature, and filtered to obtain a crude product. After recrystallization from ethanol, 288 g of pure product was obtained. The total yield calculated based on chloroacetone was 30.7%, and the product purity was greater than 99.5%.

[0043] Example 1

[0044] This embodiment provides a kind of Piao Ning, and the preparation method is as follows:

[0045] Step 1: Synthesis of dithioamino acid esters.

[0046]

[0047] 3.00 mol of ammonium dithiocarbamate, 3.15 mol of bromobutane and 0.30 mol of sodium iodide were placed in a three-necked flask, 1500 mL of ethanol was added, and the mixture was heated to 40°C and stirred for 24 hours. The mixture was cooled to room temperature, the solvent was dried, and recrystallized from ethanol and water to obtain 407.31 g of butyl dithiocarbamate with a yield of 91%.

[0048] Step 2, synthesis of 2-alkylthio-4-methylthiazole.

[0049]

[0050] Weigh 2.00 mol of butyl dithiocarbamate and dissolve it in 800 mL of ethanol. Slowly add 2.00 mol of chloroacetone dropwise. After the addition is complete, heat to 80°C and react for 24 hours. Cool to room temperature, spin dry the solvent, add 200 mL of water, and adjust the pH to >8 with a saturated sodium bicarbonate solution. Extract three times with 200 mL of ethyl acetate, add 200 g of anhydrous sodium sulfate, dry, filter, and remove the solvent from the filtrate to obtain a crude 2-alkylthio-4-methylthiazole, which can be directly used for the next step without further purification.

[0051] Step 3, synthesis of 2-butylthio-N-heptyl-4-methylthiazolium salt.

[0052]

[0053] The crude product of 2-alkylthio-4-methylthiazole synthesized in step 2 was placed in a three-necked flask, and 6.00 mol of iodoheptane was added. The mixture was heated to 145° C. for reaction for 36 hours, and then cooled to room temperature for use.

[0054] Step 4: Synthesis of N-heptyl-2,4-dimethylthiazolium salt.

[0055]

[0056] 5.00 mol of 2,4-dimethylthiazole was weighed, 7.50 mol of iodoheptane was added, and the mixture was heated to 140°C for reaction for 24 hours. The mixture was cooled to room temperature, ethyl acetate was added, and the mixture was crushed and filtered to obtain 1525 g of a white solid with a yield of 90%.

[0057] Step 5: Synthesis of Pionin.

[0058]

[0059] To the product obtained in step 3, 2.0 mol of N-heptyl-2,4-dimethylthiazolium salt, 6.00 mol of diisopropylethylamine, and 600 mL of ethanol were added, heated to 80 ° C, stirred and reacted for 24 hours, cooled to room temperature, filtered to obtain a crude product, and recrystallized from ethanol to obtain 741 g of the product. The total yield calculated based on ammonium dithiocarbamate was 56.9%, and the purity was greater than 99.8%.

[0060] Example 2

[0061] This embodiment provides a kind of Piao Ning, and the preparation method is as follows:

[0062] Step 1: Synthesis of dithioamino acid esters.

[0063]

[0064] 3.00 mol of ammonium dithiocarbamate, 3.15 mol of heptane bromide, and 0.45 mol of sodium iodide were placed in a three-necked flask, 1500 mL of ethanol was added, and the mixture was heated to 40°C and stirred for 24 hours. The mixture was cooled to room temperature, the solvent was dried, and recrystallized from ethanol and water to obtain 407.31 g of heptyl dithiocarbamate with a yield of 85%.

[0065] Step 2: Synthesis of 2-alkylthio-4-methylthiazole.

[0066]

[0067] Weigh 2.00 mol of heptyl dithiocarbamate, add 800 mL of water, slowly add chloroacetone dropwise, heat to reflux after the addition is complete, react for 24 hours, cool to room temperature, and adjust the pH to >8 with a saturated sodium bicarbonate solution. Extract three times with 200 mL of ethyl acetate, add 200 g of anhydrous sodium sulfate, dry, filter, and remove the solvent from the filtrate to obtain a crude 2-alkylthio-4-methylthiazole, which can be directly used for the next step without further purification.

[0068] Step 3, synthesis of 2-heptylthio-N-heptyl-4-methylthiazolium salt.

[0069]

[0070] The crude product of 2-alkylthio-4-methylthiazole synthesized in step 2 was placed in a three-necked flask, and 8.36 mol of iodoheptane was added. The mixture was heated to 145° C. for reaction for 36 hours, and then cooled to room temperature for use.

[0071] Step 4: Synthesis of N-heptyl-2,4-dimethylthiazolium salt.

[0072]

[0073] Weigh 5.00 mol of 2,4-dimethylthiazole, add 7.50 mol of iodoheptane, heat to 140°C for reaction for 24 hours, cool to room temperature, add ethyl acetate, crush and filter to obtain 1525 g of white solid with a yield of 90%.

[0074] Step 5: Synthesis of Pionein.

[0075]

[0076] To the product obtained in step 3, 1.8 mol of N-heptyl-2,4-dimethylthiazolium salt, 6.00 mol of diisopropylethylamine, and 800 mL of ethanol were added, heated to 60 ° C, stirred and reacted for 24 hours, cooled to room temperature, filtered to obtain a crude product, and recrystallized from ethanol to obtain 690 g of the product. The total yield calculated based on ammonium dithiocarbamate was 49.5%, and the purity was greater than 99.8%.

[0077] The statistical results of the yield and purity of the piaoning prepared in Comparative Example 1 and Examples 1-2 are shown in Table 1:

[0078]

[0079] Referring to Table 1, compared with Comparative Example 1, the purity and yield of Examples 1 and 2 are better, among which the purity and yield of Example 1 are significantly better, indicating that the preparation method of the present application can improve the purity and yield of piaoning, especially the yield of piaoning is significantly improved.

[0080] In Comparative Example 1, ammonium carbamate and chloroacetone were used as raw materials to first synthesize 4-methylthiazolethiol, followed by the synthesis of alkylthiothiazoles. This method produced a large amount of waste and was expensive. The present invention uses inexpensive ammonium carbamate and an inexpensive halogenated hydrocarbon to first synthesize a carbamate, and then uses chloroacetone as a raw material to construct the thiazole ring to obtain alkylthiothiazoles. Therefore, compared with existing technologies, the preparation method of the present invention can reduce the production cost of pionin.

[0081] The comparative example uses a large amount of expensive iodoheptane. The present invention partially replaces iodoheptane with bromoalkanes and chloroalkanes in step one, reducing production costs. Furthermore, since the dithiocarbamate is a solid, it is easily separated from the halogenated hydrocarbon involved in the reaction. Unreacted halogenated hydrocarbon in step one can be easily recycled, reducing costs while also reducing the generation of "three wastes" without compromising product purity.

[0082] In summary, the preparation method of the present application can reduce the generation of pollutants and the cost of preparing raw materials, thereby solving the technical problem that the existing synthesis route of pionin produces a large number of pollutants, while reducing production costs.

[0083] The above description is merely a preferred embodiment of the present invention, and the above specific embodiment is not intended to limit the present invention. Various variations and modifications are possible within the technical scope of the present invention. Any modifications, alterations, or equivalent substitutions made by a person skilled in the art based on the above description are within the scope of protection of the present invention.

Claims

1. A method for preparing piaoning, characterized in that: The following steps are involved: dithiocarbamate amine and halogenated hydrocarbon are reacted in a first solvent system through a nucleophilic substitution reaction to prepare dithiocarbamate; The dithiocarbamate and chloroacetone are reacted in a second solvent system to undergo a condensation ring reaction to prepare 2-alkylthio-4-methylthiazole; 2-alkylthio-4-methylthiazole and iodoheptane are mixed to carry out a nucleophilic substitution reaction to prepare a 2-alkylthio-N-heptyl-4-methylthiazolium salt; 2,4-dimethylthiazole and iodoheptane are mixed to undergo a nucleophilic substitution reaction to prepare N-heptyl-2,4-dimethylthiazolium salt; Mixing 2-alkylthio-N-heptyl-4-methylthiazolium salt and N-heptyl-2,4-dimethylthiazolium salt with an organic base, and performing a nucleophilic substitution reaction in a third solvent system to prepare piaoning; The halogenated hydrocarbon includes any one of a brominated alkane having 1 to 5 carbon atoms, an iodinated alkane having 1 to 5 carbon atoms, and a chloroalkane having 3 to 5 carbon atoms, and the molar ratio of the halogenated hydrocarbon to the dithiocarbamate amine is 1 to 1.5; The molar ratio of the chloroacetone to the dithiocarbamate is 0.9-1.2, the molar ratio of the iodine heptane to the 2,4-dimethylthiazole iodine heptane is 1-4, and the molar ratio of the iodine heptane to the 2,4-dimethylthiazole is 1-4.

2. The method for preparing piaoning according to claim 1, characterized in that: In the step of subjecting dithiocarbamate amine to a nucleophilic substitution reaction with a halogenated hydrocarbon in a first solvent system to prepare a dithiocarbamate, the catalyst for the nucleophilic substitution reaction is at least one of sodium iodide or ammonium iodide; The reaction temperature of the nucleophilic substitution reaction is 0° C. to 80° C., and the reaction time is 12 h to 48 h.

3. The method for preparing piaoning according to claim 1, characterized in that: The step of subjecting a dithiocarbamate and chloroacetone to a condensation ring reaction in a second solvent system to prepare 2-alkylthio-4-methylthiazole comprises the following steps: The dithiocarbamate, chloroacetone and the second solvent are mixed for reaction, the pH is adjusted to pH>8, ethyl acetate is added, extraction is performed multiple times, drying and filtering are performed, and 2-alkylthio-4-methylthiazole is prepared after distillation under reduced pressure.

4. The method for preparing piaoning according to claim 3, characterized in that: The reaction temperature of the condensation ring reaction is 25° C. to 100° C., and the reaction time is 18 h to 48 h.

5. The method for preparing piaoning according to claim 1, characterized in that: When the 2-alkylthio-4-methylthiazole and iodoheptane are mixed to carry out the nucleophilic substitution reaction, the reaction temperature is 120° C. to 155° C., and the reaction time is 18 h to 48 h.

6. The method for preparing piaoning according to claim 1, characterized in that: When the 2,4-dimethylthiazole and iodoheptane are mixed to carry out the nucleophilic substitution reaction, the reaction temperature is 120-150° C. and the reaction time is 18-48 hours.

7. The method for preparing piaoning according to claim 1, characterized in that: The 2-alkylthio-N-heptyl-4-methylthiazolium salt and N-heptyl-2,4-dimethylthiazolium salt are mixed with an organic base and subjected to a nucleophilic substitution reaction in a third solvent system at a reaction temperature of 30 to 100° C. and a reaction time of 18 to 48 hours.

8. The method for preparing piaoning according to claim 1, characterized in that: The organic base is at least one of triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

9. The method for preparing piaoning according to claim 1, characterized in that: The first solvent is at least one of ethanol, methanol, and acetonitrile; the second solvent is at least one of water, ethanol, methanol, and acetonitrile; and the third solvent is at least one of water, ethanol, methanol, and acetonitrile.

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