Preparation method of 3-cyclohexylamino propanesulfonic acid

Abstract

The invention belongs to the technical field of preparation of 3-cyclohexylamino propanesulfonic acid, and particularly relates to a preparation method of 3-cyclohexylamino propanesulfonic acid. The preparation method of the 3-cyclohexylamino propanesulfonic acid comprises the following steps: (1) preparing a sodium hydroxypropanesulfonate aqueous solution; (2) dissolving cyclohexylamine in an organic solvent, adding a phase transfer catalyst, then stirring and heating until reflux, and then dropwise adding a sodium hydroxypropanesulfonate aqueous solution for reaction; (3) acidification reaction; and (4) preparing the 3-cyclohexylamino propanesulfonic acid. According to the preparation method of the 3-cyclohexylaminopropanesulfonic acid, the adopted phase transfer catalyst can be combined with the hydroxy propanesulfonic acid sodium salt in the aqueous solution, transferred into the organic phase and reacted with cyclohexylamine in the organic phase to generate the 3-cyclohexylaminopropanesulfonic acid, and then the solvent is evaporated out instead of layering, so that the 3-cyclohexylaminopropanesulfonic acid is obtained. And the condition that the 3-cyclohexylamino propanesulfonic acid is taken out when the organic solvent is delaminated and removed is effectively avoided.

Description

Technical Field

[0001] The invention belongs to the technical field of 3-cyclohexylaminopropanesulfonic acid preparation, and specifically relates to a method for preparing 3-cyclohexylaminopropanesulfonic acid. Background Art

[0002] 3-Cyclohexylaminopropanesulfonic acid (CAPS) is a white crystalline or powdered chemical with excellent buffering properties. CAPS excels in stabilizing pH, supporting enzyme activity, and inhibiting bacterial growth. Therefore, it is widely used as a biological buffer in biochemical diagnostic kits, DNA / RNA extraction kits, and PCR diagnostic kits. CAPS can also be used in water-based coatings, electroplating additives, and other fields, significantly improving product performance and quality. Its market demand continues to grow with the rapid development of related industries.

[0003] The commonly used preparation method at present is to react cyclohexylamine with 1,3-propane sultone in an organic solvent to produce 3-cyclohexylaminopropanesulfonic acid, which has a low yield and poor quality during production. Patent CN 110885299A discloses a method for preparing 3-cyclohexylamino-1-propanesulfonic acid, which specifically comprises dissolving 1,3-propane sultone and cyclohexylamine in different organic solvents, and then simultaneously pumping them into a microchannel reactor for reaction. The crude 3-cyclohexylamino-1-propanesulfonic acid product is precipitated by freezing and crystallizing, and then nitrogen is passed through the reactor for pressure filtration to obtain the finished 3-cyclohexylamino-1-propanesulfonic acid product. This method has a high yield, but uses expensive 1,3-propane sultone as a raw material, and the purity of the product is not specified; Patent CN Patent application 106117088A discloses reacting sulfite, bisulfite, and allyl alcohol in the presence of a specialized catalyst to produce 1,3-propanesulfonate, which is then reacted with carbonic acid to produce 1,3-propanesulfonic acid. The 1,3-propanesulfonic acid is then reacted with cyclohexylamine in a water bath at 70-90°C for 2-5 hours to produce a crude product of 3-cyclohexylamino-1-propanesulfonic acid. The product is then washed with acetone and then distilled water to obtain a refined product. This method is complex, yields are undocumented, and the product is water-soluble, preventing distilled water washing and purification.

[0004] Therefore, how to provide a method for preparing 3-cyclohexylamine-1-propanesulfonic acid with low cost, simple process, high yield and high purity becomes a technical problem to be solved urgently. Summary of the Invention

[0005] The present invention aims to provide a method for preparing 3-cyclohexylaminopropanesulfonic acid. The 3-cyclohexylaminopropanesulfonic acid prepared by the method has high yield and purity.

[0006] The preparation method of 3-cyclohexylaminopropanesulfonic acid of the present invention comprises the following steps: (1) Sodium sulfite and water are added to a reaction vessel, and the mixture is stirred and dissolved at 40° C. to prepare a sodium sulfite solution. Solution A and propylene alcohol are then added dropwise to the sodium sulfite solution. After the addition is completed, the mixture is kept warm for reaction to prepare a sodium hydroxypropanesulfonate aqueous solution, wherein the solution A is composed of sodium bisulfite, sodium sulfite, and water; (2) Dissolve cyclohexylamine in an organic solvent in a three-necked flask equipped with a condenser reflux device, add a phase transfer catalyst, stir and heat to reflux, then dropwise add the sodium hydroxypropanesulfonate aqueous solution prepared in step (1), and react for 4-6 hours after the addition is complete; (3) heating the solution obtained in step (2) to remove the organic solvent and then introducing dry hydrogen chloride gas or concentrated hydrochloric acid to carry out an acidification reaction; (4) The salt precipitated after the acidification reaction in step (3) is filtered, and then the remaining hydrochloric acid and water are evaporated from the resulting solution to prepare 3-cyclohexylaminopropanesulfonic acid.

[0007] in: In the sodium sulfite solution of step (1), the mass ratio of sodium sulfite to water is 1.2605:20~100.

[0008] In step (1), the dropwise addition time of liquid A and propylene alcohol is 2 hours, the temperature of the heat preservation reaction is 40° C., and the heat preservation reaction time is 5 hours.

[0009] The mass ratio of sodium bisulfite, sodium sulfite and water in step (1) solution A is 52.03:12.605:100~500.

[0010] The molar ratio of propylene glycol in step (1) to sodium bisulfite in solution A is 0.95-1.0:1.

[0011] The organic solvent in step (2) is one of toluene, chloroform, ethyl acetate, dichloroethane, N,N-dimethylformamide, n-hexane, cyclohexane or 1,4-dioxane.

[0012] The phase transfer catalyst in step (2) is one of 18-crown ether-6, polyethylene glycol, benzyltriethylammonium chloride (TEBA), tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride or tetrabutylammonium iodide, and the mass of the phase transfer catalyst is 0.18%-0.5% of the mass of cyclohexylamine.

[0013] The reflux temperature in step (2) is the boiling point of the organic solvent.

[0014] The temperature of the acidification reaction in step (3) is 60° C., and the time of the acidification reaction is 2 h.

[0015] When hydrogen chloride gas is used in the acidification reaction in step (3), the mass of hydrogen chloride gas added is calculated according to the following formula: m HCl =[36.5*(2n Na2SO3 +n NaHSO3 )+m 水 *0.2]*(1.0~1.5) Where: n Na2SO3 is the molar amount of all sodium sulfite used in step (1), n NaHSO3 is the molar amount of sodium bisulfite in step (1), m 水 is the mass of all water used in step (1).

[0016] When concentrated hydrochloric acid is used in the acidification reaction in step (3), the mass concentration of the concentrated hydrochloric acid is 31-37%, and the mass of the concentrated hydrochloric acid added is calculated according to the following formula: m 浓盐酸 ={[36.5*(2n Na2SO3 +n NaHSO3 )+m 水 *0.2]*( 1.0~1.5)} / (1.2*c HCl -0.2) Where: n Na2SO3 is the molar amount of all sodium sulfite used in step (1), n NaHSO3 is the molar amount of sodium bisulfite in step (1), m 水 is the mass of all water used in step (1), c HCl is the mass concentration of concentrated hydrochloric acid.

[0017] Compared with the prior art, the present invention has the following beneficial effects: (1) The method for preparing 3-cyclohexylaminopropanesulfonic acid of the present invention uses sodium hydroxypropanesulfonate, an intermediate product of producing 1,3-propane sultone, as a raw material. The method does not require a complicated process of preparing 1,3-propane sultone from sodium hydroxypropanesulfonate, and the cost of raw materials is low. When 1,3-propane sultone is used as a raw material, the sulfonic acid group in the molecular structure easily reacts with cyclohexylamine to form sulfonamide. The method uses sodium salt of hydroxypropanesulfonic acid as a raw material, thereby protecting the sulfonic acid group in the molecule and avoiding the generation of sulfonamide products. Therefore, there is no need for complicated post-treatment and washing processes, which simplifies the process and the prepared 3-cyclohexylaminopropanesulfonic acid has high purity.

[0018] (2) The method for preparing 3-cyclohexylaminopropanesulfonic acid of the present invention uses a phase transfer catalyst that can combine with sodium salt of hydroxypropanesulfonic acid in an aqueous solution, transfer to an organic phase, and react with cyclohexylamine in the organic phase to generate 3-cyclohexylaminopropanesulfonic acid. The solvent is subsequently evaporated rather than separated by layers, which effectively avoids the removal of 3-cyclohexylaminopropanesulfonic acid when the organic solvent is separated by layers. Moreover, when the organic solvent and water are azeotropically formed, a portion of water can be removed when the organic solvent is evaporated, thereby reducing the amount of acid used in the subsequent acidification step.

[0019] (3) The principle of using hydrochloric acid for acidification instead of other acids in the preparation method of 3-cyclohexylaminopropanesulfonic acid of the present invention is the common ion effect. The solubility of sodium chloride in hydrochloric acid decreases with the increase of hydrochloric acid concentration. If other acids are used, it is impossible to separate the by-product salt. Moreover, the hydrochloric acid acidification is a simple double decomposition reaction, which will not lead to a decrease in the quality of 3-cyclohexylaminopropanesulfonic acid. In addition, hydrochloric acid reacts with the sodium sulfite and sodium bisulfite remaining in step (1) to generate sodium chloride and sulfur dioxide. Therefore, there is no need to purify the sodium hydroxypropanesulfonate, which further ensures that there are no impurities remaining in the product. DETAILED DESCRIPTION

[0020] The present invention will be further described below with reference to the examples.

[0021] Example 1 The preparation method of 3-cyclohexylaminopropanesulfonic acid described in this embodiment 1 consists of the following steps: (1) Weigh 52.03 g of sodium bisulfite and 12.605 g of sodium sulfite and dissolve them in 100 ml of water to prepare solution A; add 1.2605 g of sodium sulfite and 50 ml of water into a three-necked flask and stir to dissolve at 40°C; then slowly dropwise add the prepared solution A and 29.0 g of allyl alcohol into the three-necked flask under stirring. The dropwise addition time of solution A and allyl alcohol is 2 h. After the dropwise addition is completed, react at 40°C for 5 h to obtain an aqueous solution of sodium hydroxypropanesulfonate.

[0022] (2) Dissolve 53.6 g of cyclohexylamine in 200 mL of chloroform in a three-necked flask with a reflux device, add 0.1 g of 18-crown ether-6, stir and heat to 62 ° C for reflux, then dropwise add the sodium hydroxypropanesulfonate aqueous solution prepared in step (1), and maintain the reaction at 62 ° C for 4 h after the addition is completed; (3) The solution obtained in step (2) was heated to remove chloroform, and then 60 g of HCl gas was introduced and acidified at 60°C for 2 h.

[0023] (4) The salt precipitated after the acidification reaction in step (3) was filtered, and then the remaining hydrochloric acid and water were distilled off from the resulting solution to obtain 105.2 g of 3-cyclohexylaminopropanesulfonic acid product with a purity of 99.0% and a calculated yield of 95.07%.

[0024] Example 2 The preparation method of 3-cyclohexylaminopropanesulfonic acid described in this embodiment 2 consists of the following steps: (1) Weigh 52.03 g of sodium bisulfite and 12.605 g of sodium sulfite and dissolve them in 100 ml of water to prepare solution A; add 1.2605 g of sodium sulfite and 50 ml of water into a three-necked flask and stir to dissolve at 40°C; then slowly dropwise add the prepared solution A and 29.0 g of allyl alcohol into the three-necked flask under stirring. The dropwise addition time of solution A and allyl alcohol is 2 h. After the dropwise addition is completed, react at 40°C for 5 h to obtain an aqueous solution of sodium hydroxypropanesulfonate.

[0025] (2) In a three-necked flask with a reflux device, 53.6 g of cyclohexylamine was dissolved in 200 mL of cyclohexane, 0.175 g of tetrabutylammonium bromide was added, and the mixture was stirred and heated to 82°C for reflux. Then, the aqueous solution of sodium hydroxypropanesulfonate prepared in step (1) was added dropwise. After the addition was completed, the reaction temperature was maintained at 82°C for 6 h.

[0026] (3) The solution obtained in step (2) was heated to remove cyclohexane, and then 60 g of HCl gas was introduced and acidified at 60°C for 2 h.

[0027] (4) The salt precipitated after the acidification reaction in step (3) was filtered, and then the remaining hydrochloric acid and water were distilled off from the resulting solution to obtain 106.4 g of 3-cyclohexylaminopropanesulfonic acid product with a purity of 99.2% and a calculated yield of 96.15%.

[0028] Example 3 The preparation method of 3-cyclohexylaminopropanesulfonic acid described in this embodiment 3 consists of the following steps: (1) Weigh 52.03 g of sodium bisulfite and 12.605 g of sodium sulfite and dissolve them in 100 ml of water to prepare solution A; add 1.2605 g of sodium sulfite and 50 ml of water into a three-necked flask and stir to dissolve at 40°C; then slowly dropwise add the prepared solution A and 29.0 g of allyl alcohol into the three-necked flask under stirring. The dropwise addition time of solution A and allyl alcohol is 2 h. After the dropwise addition is completed, react at 40°C for 5 h to obtain an aqueous solution of sodium hydroxypropanesulfonate.

[0029] (2) In a three-necked flask with a reflux device, 53.6 g of cyclohexylamine was dissolved in 200 mL of cyclohexane, 0.25 g of tetrabutylammonium bromide was added, and the mixture was stirred and heated to 82 °C for reflux. Then, the aqueous solution of sodium hydroxypropanesulfonate prepared in step (1) was added dropwise. After the addition was completed, the temperature was maintained at 82 °C for 6 h.

[0030] (3) The solution obtained in step (2) was heated to remove cyclohexane, and then 400 g of 31% by mass concentrated hydrochloric acid was added and acidified at 60° C. for 2 h.

[0031] (4) The salt precipitated after the acidification reaction in step (3) was filtered, and then the remaining hydrochloric acid and water were distilled off from the resulting solution to obtain 104.8 g of finished 3-cyclohexylaminopropanesulfonic acid with a purity of 99.1% and a calculated yield of 94.70%.

[0032] Comparative Example 1 The preparation method of 3-cyclohexylaminopropanesulfonic acid described in this comparative example 1 consists of the following steps: (1) Dissolve 61.07 g of 1,3-propanesulfonate in 500 ml of N,N-dimethylformamide, stir at 30 °C to dissolve, then add 49.59 g of cyclohexylamine dropwise for 2 h. After the addition is complete, keep the mixture at 30 °C for 4 h.

[0033] (2) After the reaction was completed, the solution was filtered to obtain 105 g of crude 3-cyclohexylaminopropanesulfonic acid.

[0034] (3) The crude 3-cyclohexylaminopropanesulfonic acid obtained in step (2) was dissolved in 100 g of hot water, cooled to 60°C, and then 500 ml of anhydrous ethanol was added. The mixture was cooled to 5°C and filtered to obtain a viscous solid. The solid was dried to obtain 84 g of 3-cyclohexylaminopropanesulfonic acid with a content of 92% and a calculated yield of 70%.

[0035] As can be seen from Comparative Example 1, when expensive 1,3-propane sultone is used as a raw material, its reaction with cyclohexylamine is not sufficient, the obtained product still contains a large amount of impurities, and additional solvents such as ethanol need to be added to precipitate the product. The overall process technology route is complex and costly, and post-processing is difficult.

Claims

1. A method for preparing 3-cyclohexylaminopropanesulfonic acid, characterized in that: It consists of the following steps: (1) Sodium sulfite and water are added to a reaction vessel, and the mixture is stirred and dissolved at 40° C. to prepare a sodium sulfite solution. Solution A and propylene alcohol are then added dropwise to the sodium sulfite solution. After the addition is completed, the mixture is kept warm for reaction to prepare a sodium hydroxypropanesulfonate aqueous solution, wherein the solution A is composed of sodium bisulfite, sodium sulfite, and water; (2) Dissolve cyclohexylamine in an organic solvent in a three-necked flask equipped with a condenser reflux device, add a phase transfer catalyst, stir and heat to reflux, then dropwise add the sodium hydroxypropanesulfonate aqueous solution prepared in step (1), and react for 4-6 hours after the addition is complete; (3) heating the solution obtained in step (2) to remove the organic solvent and then introducing dry hydrogen chloride gas or concentrated hydrochloric acid to carry out an acidification reaction; (4) The salt precipitated after the acidification reaction in step (3) is filtered, and then the remaining hydrochloric acid and water are evaporated from the resulting solution to prepare 3-cyclohexylaminopropanesulfonic acid.

2. The preparation method of 3-cyclohexylaminopropanesulfonic acid according to claim 1, wherein: In step (1), the dropwise addition time of liquid A and propylene alcohol is 2 hours, the temperature of the heat preservation reaction is 40° C., and the heat preservation reaction time is 5 hours.

3. The preparation method of 3-cyclohexylaminopropanesulfonic acid according to claim 1, wherein: The molar ratio of propylene glycol in step (1) to sodium bisulfite in solution A is 0.95-1.0:

1.

4. The preparation method of 3-cyclohexylaminopropanesulfonic acid according to claim 1, wherein: The organic solvent in step (2) is one of toluene, chloroform, ethyl acetate, dichloroethane, N,N-dimethylformamide, n-hexane, cyclohexane or 1,4-dioxane.

5. The preparation method of 3-cyclohexylaminopropanesulfonic acid according to claim 1, wherein: The phase transfer catalyst in step (2) is one of 18-crown ether-6, polyethylene glycol, benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride or tetrabutylammonium iodide, and the mass of the phase transfer catalyst is 0.18%-0.5% of the mass of cyclohexylamine.

6. The method for preparing 3-cyclohexylaminopropanesulfonic acid according to claim 1, wherein: The reflux temperature in step (2) is the boiling point of the organic solvent.

7. The method for preparing 3-cyclohexylaminopropanesulfonic acid according to claim 1, wherein: The temperature of the acidification reaction in step (3) is 60° C., and the time of the acidification reaction is 2 h.