Preparation method of piaonine

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of picolinin. The preparation method comprises the following steps: firstly, synthesizing dithiocarbamate by taking ammonium dithiocarbamate as a raw material, and then synthesizing the 2-alkylthio-4-methyl-thiazole by taking the dithiocarbamate as a raw material. The dithiocarbamate is solid and is easy to separate halogenated hydrocarbon participating in the reaction, so that the pollution caused by difficult recovery of excessive halogenated hydrocarbon is avoided, and the generation of pollutants is reduced, thereby solving the technical problem that more pollutants are generated in the existing Pinoxonin synthesis route.

Description

Technical Field

[0001] The 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, has strong antibacterial activity. It can destroy bacterial and fungal cell membranes and has excellent effects on Propionibacterium acnes; it can also inhibit the formation of melanin. It has important applications in the field of cosmetics. As a conditioner, bactericide, whitening agent, etc., it is widely used in shampoo, facial products, moisturizers and other personal care products; as a pharmaceutical ingredient, this product is used in the pharmaceutical industry to treat acne and dermatitis.

[0003] There are many existing synthesis methods, for example, the prior art: derived from patent CN107840831A, discloses a synthesis route of pionin using 4-methylthiazolethiol as raw material. 4-Methylthiazolethiol is prepared by reacting ammonium dithiocarbamate with chloroacetone. In the synthesis process, two equivalents of ammonium dithiocarbamate are generally required to ensure that the ammonium dithiocarbamate is excessive. Unreacted ammonium dithiocarbamate is difficult to recycle, and malodorous gas color bodies will be generated during the synthesis process, which is easy to cause pollution and affect subsequent separation, resulting in low product purity. Due to the high price of 4-methylthiazolethiol reagent, directly purchasing 4-methylthiazolethiol reagent will increase the preparation cost.

[0004] Therefore, the existing synthesis route of pionin will produce 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 ingeniously 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 halogenated hydrocarbon are subjected to nucleophilic substitution reaction in a first solvent system to obtain a dithiocarbamate; the dithiocarbamate and chloroacetone are subjected to condensation ring reaction in a second solvent system to obtain 2-alkylthio-4-methylthiazole; 2-alkylthio-4-methylthiazole is mixed with iodoheptane for nucleophilic substitution reaction to obtain 2-alkylthio-N-heptyl-4-methylthiazolium salt; 2,4-dimethylthiazole is mixed with iodoheptane for 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 nucleophilic substitution reaction in a third solvent system to obtain pionin.

[0009] Wherein, the halogenated hydrocarbon includes any one of a brominated alkane with a carbon number of 1 to 5, an iodinated alkane with a carbon number of 1 to 5, and a chloroalkane with a carbon number of 3 to 5, and 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] The present application first uses ammonium dithiocarbamate as a raw material to synthesize dithiocarbamate, and then uses dithiocarbamate as a raw material to synthesize 2-alkylthio-4-methyl-thiazole. Dithiocarbamate is solid, and it is easy to separate the halogenated hydrocarbons participating in the reaction, avoiding the pollution caused by the difficulty in recycling the excessive halogenated hydrocarbons, so as to reduce the generation of pollutants, thereby solving the technical problem that the existing picolinine synthesis route will produce more 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 obtain 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.

[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: after 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 for multiple times, drying and filtering, and reduced pressure distillation is performed 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 18h to 48h.

[0014] Optionally, when the 2-alkylthio-4-methylthiazole is mixed with iodoheptane for 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 2,4-dimethylthiazole and iodoheptane are mixed for 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, N-heptyl-2,4-dimethylthiazolium salt and an organic base are mixed and subjected to a nucleophilic substitution reaction in a third solvent system, the reaction temperature is 30 to 100° C. and the reaction time is 18 to 48 hours.

[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 kind of piaoning, which is prepared by the above-mentioned preparation method.

[0020] The beneficial effect of the present invention is that, compared with the prior art, the present application first uses ammonium dithiocarbamate as a raw material to synthesize dithiocarbamate, and then uses dithiocarbamate as a raw material to synthesize 2-alkylthio-4-methyl-thiazole. Dithiocarbamate is solid and easy to separate from the halogenated hydrocarbons involved in the reaction, so it can be obtained by reacting with inexpensive bromohydrocarbons and chlorohydrocarbons, and bromoaromatic hydrocarbons and chloroaromatic hydrocarbons are easy to separate and recycle, which will not affect subsequent reactions and will not affect the purity of the product. It is avoided that excessive halogenated hydrocarbons are difficult to recycle and cause pollution, so as to reduce the generation of pollutants, thereby solving the technical problem that the existing picolinine synthesis route will produce more pollutants, and reducing production costs at the same time. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

[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 piaoning, and the 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 a mixed solvent of 1500 mL of ethanol and water in a volume ratio of 2:1, and 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, and after the dropwise addition was completed, the mixture was heated to reflux for 12 hours, and the ethanol in the solvent was removed by vacuum distillation, and 200 mL of ethyl acetate was added for extraction three times, the organic phase was combined, the sewage was dried over sodium sulfate, and the solvent was filtered and spin-dried to obtain 223.5 g of 4-methylthiazole mercaptan, with 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, stirred until dissolved, 1.52 mol of 4-methylthiazolethiol was slowly added, and 2.28 mol of iodoheptane was slowly added dropwise after complete dissolution, and the mixture was warmed to room temperature and stirred for 24 hours. The ethanol was recovered by distillation under reduced pressure, 300 mL of water was added, and then extracted with 200 mL of ethyl acetate for 3 times. 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 iodoheptane, which was set aside without treatment.

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

[0035]

[0036] Add 6.87 mol of iodoheptane to the 2-heptylthio-4-methylthiazole obtained in step 2, heat to 140° C., stir and react for 24 hours, and cool to room temperature without treatment for later use.

[0037] Step 4, synthesis of N-heptyl-4-methylthiazolium salt.

[0038]

[0039] Weigh 4.42 mol of 2,4-dimethylthiazole and add 6.64 mol of iodoheptane, heat to 140°C, react for 24 hours, cool to room temperature to remove unreacted iodoheptane, and obtain a solid, namely N-heptyl-4-methylthiazolium salt, which is vacuum dried for later use, with a yield of 95%.

[0040] Step 5: Synthesis of piaoning.

[0041]

[0042] Add 1.53 mol of N-heptyl-4-methylthiazolium salt, 3.05 mol of diisopropylethylamine, and 1000 mL of ethanol to the product obtained in step 2, heat to 80°C, stir and react for 24 hours, cool to room temperature, filter to obtain a crude product, and obtain 288 g of a pure product after recrystallization from ethanol. The total yield calculated based on chloroacetone is 30.7%, and the product purity is 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 bromobutyl and 0.30 mol of sodium iodide were placed in a three-necked flask, 1500 mL of ethanol was added, the mixture was heated to 40°C, stirred for reaction for 24 hours, 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, dissolve it in 800 mL of ethanol, slowly add 2.00 mol of chloroacetone, heat to 80 ° C after the addition is complete, 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 to dry, filter, remove the solvent from the filtrate to obtain a crude 2-alkylthio-4-methylthiazole, and directly proceed to 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 later use.

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

[0055]

[0056] 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, break and filter to obtain 1525 g of white solid with a yield of 90%.

[0057] Step 5: Synthesis of pionin.

[0058]

[0059] To the product obtained in step 3, add 2.0 mol of N-heptyl-2,4-dimethylthiazolium salt, 6.00 mol of diisopropylethylamine, and 600 mL of ethanol, heat to 80 ° C, stir and react for 24 hours, cool to room temperature, filter to obtain a crude product, and recrystallize from ethanol to obtain 741 g of the product. The total yield calculated based on ammonium dithiocarbamate is 56.9%, and the purity is 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, the mixture was heated to 40° C., stirred for reaction for 24 hours, cooled to room temperature, the solvent was dried, and recrystallized with 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 reaction for 24 hours after the addition is complete, cool to room temperature, and adjust pH>8 with saturated sodium bicarbonate solution, extract three times with 200 mL of ethyl acetate, add 200 g of anhydrous sodium sulfate to dry, filter, remove the solvent from the filtrate to obtain a crude 2-alkylthio-4-methylthiazole, which can be directly reacted in 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, break and filter to obtain 1525 g of white solid with a yield of 90%.

[0074] Step 5: Synthesis of piaoning.

[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 for reaction 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 picolinamide 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 are used as raw materials to first synthesize 4-methylthiazolethiol, and then synthesize alkylthiothiazole, which produces a lot of three wastes and is expensive. In the present invention, inexpensive ammonium carbamate is firstly used to synthesize carbamate with inexpensive halogenated hydrocarbons, and then chloroacetone is used as a raw material to construct a thiazole ring to obtain alkylthiothiazole. Therefore, compared with the prior art, the preparation method of the present invention can reduce the preparation cost of pionin.

[0081] In the comparative example, a large amount of iodoheptane is used, which is expensive and has a high cost. In the present invention, iodoheptane is partially replaced by bromoalkane and chloroalkane in step 1, thereby reducing the preparation cost. Moreover, since dithiocarbamate is solid, it is easy to separate from the halogenated hydrocarbon involved in the reaction, and the unreacted halogenated hydrocarbon in step 1 can be easily recycled, thereby reducing the cost and the generation of "three wastes", and the purity of the product is not affected.

[0082] In summary, the preparation method of the present application can reduce the generation of pollutants and the cost of preparing raw materials, so as to solve the technical problem that the existing synthesis route of pionin produces more pollutants, while reducing production costs.

[0083] The above description is only a preferred embodiment of the present invention, and the above specific embodiment is not intended to limit the present invention. Various deformations and modifications may occur within the scope of the technical concept of the present invention, and any modification, modification or equivalent replacement made by a person of ordinary skill in the art based on the above description shall fall within the scope of protection of the present invention.

Claims

1. A method for preparing piaoning, characterized in that: The following steps are involved: The dithiocarbamate amine and the halogenated hydrocarbon are subjected to a nucleophilic substitution reaction in a first solvent system to prepare a dithiocarbamate; The dithiocarbamate and chloroacetone are subjected to a condensation ring reaction in a second solvent system to prepare 2-alkylthio-4-methylthiazole; Mixing 2-alkylthio-4-methylthiazole and iodoheptane to carry out a nucleophilic substitution reaction to prepare 2-alkylthio-N-heptyl-4-methylthiazolium salt; 2,4-dimethylthiazole and iodoheptane are mixed to carry out 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 obtain pionin; 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 the dithiocarbamate amine to a nucleophilic substitution reaction with a halogenated hydrocarbon in a first solvent system to obtain a dithiocarbamate, the catalyst for the nucleophilic substitution reaction is at least one of sodium iodide and 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 the dithiocarbamate and chloroacetone to a condensation ring reaction in a second solvent system to obtain 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 for multiple times, drying and filtering are performed, and 2-alkylthio-4-methylthiazole is obtained 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 for 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 2,4-dimethylthiazole and iodoheptane are mixed for 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: 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 to 100° C. and the reaction time is 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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