Preparation method of taurosulfonamide hydrochloride

Abstract

The invention relates to the technical field of compound preparation, and particularly provides a preparation method of taurine sulfonamide hydrochloride, which comprises the following steps: S1, reacting an amino protection reagent with 2-aminoethanesulfonic acid to generate 2-(2, 5-dimethyl-1H-pyrrole-1-yl) ethane-1-sulfonic acid, the amino protection reagent being any one of paratoluensulfonyl chloride, benzyl chloroformate and 2, 5-hexanedione; s2, the 2-(2, 5-dimethyl-1H-pyrrole-1-yl) ethane-1-sulfonic acid and a chlorination reagent are subjected to a reaction, and 2-(2, 5-dimethyl-1H-pyrrole-1-yl) ethane-1-sulfonyl chloride is generated; s3, the 2-(2, 5-dimethyl-1H-pyrrole-1-yl) ethane-1-sulfonyl chloride and ammonia water are subjected to a reaction, and 2-(2, 5-dimethyl-1H-pyrrole-1-yl) ethane-1-sulfonamide is generated; and S4, carrying out a deprotection reaction on the 2-(2, 5-dimethyl-1H-pyrrole-1-yl) ethane-1-sulfonamide, so as to generate the taurine sulfonamide hydrochloride. The preparation method provided by the embodiment of the invention has the advantages of high single-kettle efficiency, high product purity and less generated three wastes, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of compound preparation, and particularly relates to a method for preparing tauramide hydrochloride. Background Art

[0002] Tauramide hydrochloride (also known as 2-aminoethanesulfonamide hydrochloride) is of great significance in agriculture and medicine. It is widely used as an intermediate in the synthesis of sulfur- or nitrogen-containing heterocyclic compounds and is often used in the preparation of drugs, dyes or functional materials.

[0003] At present, the synthesis method of tauramide hydrochloride mainly comprises: using 2-aminoethanesulfonic acid as a raw material, using phthalic anhydride as an amino protecting agent to protect the amino group, and then sequentially undergoing chlorination, amidation, and finally deprotection.

[0004] However, this method requires the use of strong acid at a high temperature of up to 100°C during deprotection, which is not friendly to equipment and operability, and has problems such as poor safety. In addition, the use of phthalic anhydride as an amino protecting group has low atomic utilization, occupies reactor space, and has low efficiency per reactor, resulting in low productivity and is not suitable for industrial large-scale production.

[0005] Therefore, it is necessary to develop a preparation method of tauramide hydrochloride with high safety, friendly operation and high single-pot efficiency. Summary of the invention

[0006] In view of this, the object of the present invention is to provide a method for preparing tauramide hydrochloride with high safety, friendly operability and high single-pot efficiency.

[0007] In order to solve the above technical problems, the present invention adopts the following technical solutions: The preparation method of tauramide hydrochloride according to an embodiment of the present invention comprises the following steps: Step S1, allowing an amino protecting agent to undergo a nucleophilic addition elimination reaction with 2-aminoethanesulfonic acid to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid, wherein the amino protecting agent is any one of p-toluenesulfonyl chloride, benzyl chloroformate, and 2,5-hexanedione; Step S2, chlorinating the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid and a chlorinating agent to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride; Step S3, allowing the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride and ammonia water to undergo a nucleophilic substitution reaction to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide; Step S4, subjecting the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide to a deprotection reaction to generate tauramide hydrochloride.

[0008] In some embodiments of the present invention, the amino protecting agent is 2,5-hexanedione, and the step S1 comprises: 2,5-hexanedione, 2-aminoethanesulfonic acid, and p-toluenesulfonic acid are added to toluene to react and generate the 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid.

[0009] Furthermore, the molar ratio of 2-aminoethanesulfonic acid, 2,5-hexanedione and p-toluenesulfonic acid is 1.0:(1.0-1.5):(0-0.5), the reaction temperature is 50-60° C., and the reaction time is 3-5 h.

[0010] In some embodiments of the present invention, the chlorination reagent in step S2 is any one of thionyl chloride, oxalyl chloride, and phosphorus oxychloride.

[0011] Furthermore, the step S2 comprises: The chlorination reagent is added in batches to a toluene solution containing the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid to generate the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride.

[0012] Furthermore, the chlorination reagent is thionyl chloride, the molar ratio of the thionyl chloride to the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid is (1.0-1.2):1.0, the temperature for adding the thionyl chloride is 30-40°C, the reaction time is 2-6h, and the reaction temperature is 70-80°C.

[0013] In some embodiments of the present invention, step S3 includes: The 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride is added to acetonitrile, and thereafter aqueous ammonia is added dropwise thereto to generate 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide.

[0014] Furthermore, the molar ratio of 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride to aqueous ammonia is 1.0:(5.0-6.0), the temperature for dropping aqueous ammonia is 0-5°C, the reaction time is 2-6 h, and the reaction temperature is 25-35°C.

[0015] In some embodiments of the present invention, step S4 includes: 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide is added to ethanol containing hydrochloric acid, and hydroxylamine hydrochloride is added in portions to generate the tauramide hydrochloride.

[0016] Furthermore, the molar ratio of the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide to hydroxylamine hydrochloride and hydrochloric acid is 1.0:(1.5-2.0):(3.0-4.0), the temperature for adding the hydroxylamine hydrochloride is 40-50°C, the reaction time is 2-4 h, and the reaction temperature is 60-70°C.

[0017] The above technical solution of the present invention has at least one of the following beneficial effects: According to the preparation method of the embodiment of the present invention, the reaction conditions for protection and deprotection of the amino group are relatively mild, equipment-friendly, easy to operate, and highly safe; Furthermore, compared with the use of phthalic anhydride as an amino protecting agent for upper protection, the use of the amino protecting agent of the embodiment of the present invention greatly reduces the volume of the reaction system, significantly improves the single-reactor efficiency, and greatly improves the productivity; Furthermore, according to the preparation method of the present invention, the intermediate obtained in each step can be used in the next step after simple separation treatment, etc., without the need for purification, etc., resulting in less three wastes and being more environmentally friendly. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.

[0019] The following first describes in detail the preparation method of tauramide hydrochloride according to an embodiment of the present invention.

[0020] The preparation method of tauramide hydrochloride according to an embodiment of the present invention comprises the following steps: Step S1, allowing an amino protecting agent to undergo a nucleophilic addition elimination reaction with 2-aminoethanesulfonic acid to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid, wherein the amino protecting agent is any one of p-toluenesulfonyl chloride, benzyl chloroformate, and 2,5-hexanedione; Step S2, chlorinating the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid and a chlorinating agent to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride; Step S3, allowing the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride and ammonia water to undergo a nucleophilic substitution reaction to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide; Step S4, subjecting the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide to a deprotection reaction to generate tauramide hydrochloride.

[0021] That is to say, according to the preparation method of the embodiment of the present invention, compared with the prior art using phthalic anhydride as the amino protecting agent, any one of p-toluenesulfonyl chloride, benzyl chloroformate, and 2,5-hexanedione is used as the amino protecting agent, the volume of the reaction system is reduced, the single-pot efficiency is improved, and the reaction conditions during deprotection can be milder, which is equipment-friendly and easy to operate.

[0022] Below, each step is described in detail.

[0023] (a) Amino group protection step.

[0024] That is, a step of subjecting an amino protecting agent to a nucleophilic addition elimination reaction with 2-aminoethanesulfonic acid to generate 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid.

[0025] In the preparation method of the present invention, the amino protecting agent can be any one of p-toluenesulfonyl chloride, benzyl chloroformate, and 2,5-hexanedione. Compared with phthalic anhydride, these amino protecting agents have the characteristics of high single-pot efficiency and mild reaction conditions during deprotection, and are easy to obtain and have higher reaction yield.

[0026] In some embodiments of the present invention, the amino protecting agent is preferably 2,5-hexanedione. The use of 2,5-hexanedione has higher single-pot efficiency and the deprotection is simpler and easier to operate.

[0027] In some embodiments of the present invention, the amino protection step comprises: 2,5-hexanedione, 2-aminoethanesulfonic acid, and p-toluenesulfonic acid are added to toluene to react and generate the 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid.

[0028] The specific reaction formula is shown in the following formula (1):

[0029] Among them, p-toluenesulfonic acid acts as a dehydrating agent to remove the oxygen on the keto group of 2,5-hexanedione and form water with the hydrogen on the amino group of 2-aminoethanesulfonic acid, thereby promoting the nucleophilic addition elimination reaction between 2,5-hexanedione and 2-aminoethanesulfonic acid to generate 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid.

[0030] In addition, in a toluene environment, since the starting materials and the generated intermediates are well soluble in toluene, it is beneficial to promote the reaction and improve the yield, and they can be well separated from the by-product water by filtration.

[0031] Furthermore, the molar ratio of 2-aminoethanesulfonic acid, 2,5-hexanedione and p-toluenesulfonic acid is 1.0:(1.0-1.5):(0-0.5), preferably 1.0:1.1:0.05, the reaction temperature is 50-60° C., and the reaction time is 3-5 h.

[0032] In some embodiments of the present invention, the sampling point plate monitors the reaction process. When monitoring the reaction after completion, it is cooled to room temperature, washed, separated, dried, filtered, and a toluene solution containing 2-(2,5-dimethyl-1H-pyrrole-1-yl)ethane-1-sulfonic acid is obtained, and the toluene solution containing 2-(2,5-dimethyl-1H-pyrrole-1-yl)ethane-1-sulfonic acid can be directly used in the chlorination step of the next step. That is to say, after the reaction of step S1 is completed, it can be directly used in the next step through simple aftertreatment, which can reduce the generation of three wastes, is more environmentally friendly, and also helps to improve the yield.

[0033] (II) Chlorination step That is, 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid and a chlorinating agent undergo a chlorination reaction to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride.

[0034] That is, after obtaining 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid, the terminal hydroxyl group is chlorinated with a chlorinating agent to generate sulfonyl chloride.

[0035] In some embodiments of the present invention, the chlorination agent may be any one of thionyl chloride, oxalyl chloride, and phosphorus oxychloride.

[0036] In some embodiments of the invention, the chlorination step comprises: A chlorinating agent is added portionwise to a toluene solution containing 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride.

[0037] That is, a chlorination agent is added in batches to the filtrate obtained after simple post-treatment in the above amino protection step (i.e., a toluene solution containing the 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid) to carry out a chlorination reaction to generate 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride.

[0038] Furthermore, thionyl chloride is preferably used as the chlorinating agent. Compared with other chlorinating agents, the reaction using thionyl chloride is more complete, has fewer side reactions, and the post-processing is relatively simple.

[0039] Specifically, the chemical formula for the chlorination reaction using thionyl chloride is shown in the following formula (2):

[0040] In some embodiments of the present invention, the molar ratio of thionyl chloride to 2-(2,5-dimethyl-1H-pyrrole-1-yl)ethane-1-sulfonic acid is (1.0-1.2):1.0. By using a slightly excessive amount of thionyl chloride, it is beneficial to improve the reaction rate and yield. Preferably, the molar ratio of thionyl chloride to 2-(2,5-dimethyl-1H-pyrrole-1-yl)ethane-1-sulfonic acid is 1.1:1.0.

[0041] In addition, the temperature for adding the thionyl chloride can be set to, for example, 30-40° C., the reaction time can be 2-6 hours, and the reaction temperature can be 70-80° C. The reaction conditions are mild and the operation is convenient.

[0042] In some embodiments of the present invention, after the chlorination reaction is complete, the following treatment can be performed: concentration to dryness, adding n-heptane for pulping, filtering, washing, and obtaining 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride. In other words, it can be used in the subsequent nucleophilic substitution step only through simple post-treatment without purification and refining steps. The operation is simple, the three wastes are less, and the environmental pressure is small.

[0043] (III) Nucleophilic substitution step That is, after the chlorination reaction is completed, ammonia water is further used to replace the chlorine on the sulfonyl chloride group with an amino group to generate a sulfonamide.

[0044] In some embodiments of the invention, the nucleophilic substitution step comprises: The 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride is added to acetonitrile, and thereafter aqueous ammonia is added dropwise thereto to generate 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide.

[0045] Amidation is achieved by adding aqueous ammonia dropwise. Compared with ammonia gas, the reaction is relatively mild and more controllable.

[0046] By carrying out a nucleophilic substitution reaction in acetonitrile, the reaction system can achieve a uniform reaction and a faster reaction rate, thereby improving efficiency and productivity.

[0047] Specifically, the chemical reaction formula is shown in the following formula (3):

[0048] The ammonia water, for example, may contain 25% ammonia, which is more stable, has less odor, is gentler and more controllable, and is more operable than concentrated ammonia water.

[0049] Furthermore, the molar ratio of 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride to ammonia water is 1.0:(5.0-6.0). That is, 1 mole of 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride corresponds to 5-6 moles of ammonia water (taking 25% ammonia water as an example, the NH3 therein is 1.25-1.5 moles). By using a slightly excess amount of ammonia water (slightly higher than the equivalent number), the reaction rate and yield are greatly improved.

[0050] In addition, the temperature for dropping ammonia water is 0-5°C, the reaction time is 2-6 h, and the reaction temperature is 25-35°C.

[0051] In addition, after the nucleophilic substitution reaction is completed, a simple post-treatment can be performed, namely, filtering, washing with water, and drying to obtain 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide for the next deprotection reaction.

[0052] (IV) Deprotection reaction steps That is, 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide is de-2,5-hexanedione and salified to produce tauramide hydrochloride.

[0053] In some embodiments of the present invention, the deprotection reaction step comprises: 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide is added to ethanol containing hydrochloric acid, and hydroxylamine hydrochloride is added in portions to generate the tauramide hydrochloride.

[0054] Specifically, the chemical reaction formula is shown in the following formula (4):

[0055] Further, the molar ratio of the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide to hydroxylamine hydrochloride and hydrochloric acid is 1.0:(1.5-2.0):(3.0-4.0). A slight excess of hydroxylamine hydrochloride can make the reaction complete. In addition, the intermediate is added to ethanol containing hydrochloric acid, and the addition of hydrochloric acid makes the salt formation more thorough, the reaction more complete, and the yield is higher.

[0056] The temperature for adding the hydroxylamine hydrochloride is 40-50°C, the reaction time is 2-4 h, and the reaction temperature is 60-70°C.

[0057] That is to say, according to the preparation method of the embodiment of the present invention, by selecting an appropriate amino protecting agent, the deprotection reaction conditions are milder (reduced from the original high temperature and strong acid conditions of up to 100°C to reaction conditions of 60-70°C), with higher operability, higher safety, and more equipment-friendly.

[0058] In some embodiments of the present invention, after the deprotection reaction is complete, the mixture is concentrated to dryness, ethanol slurried, and dried to obtain the tauramide hydrochloride.

[0059] It can be seen from the above that the preparation method of the present invention produces less three wastes and is simple to operate. In addition, it can be known from the above records that after each step of the reaction of the present application is completed, the aftertreatment of the intermediate is simple and easy to operate (only simple separation is required, no special purification treatment is required), and it is safe and reliable. In addition, according to the preparation method of the present invention, each step of the synthetic route is very thorough, basically without side reactions, the purity of the intermediate is very high after simple treatment, and the purity of the finished product can be reached by simple treatment at a very high purity, which can be as high as more than 99.7%.

[0060] The preparation method of tauramide hydrochloride of the present invention is further described in detail below through specific examples.

[0061] Embodiment 1: Step 1: Take a 500ml three-necked flask, add toluene (200ml, 4P) and 2-aminoethanesulfonic acid (50g, 0.4mol, 1.0eq), 2,5-hexanedione (50.19g, 0.44mol, 1.1eq), p-toluenesulfonic acid (3.44g, 0.02mol, 0.05eq), and react at 50-60℃ for 4 hours. After the reaction is complete, cool to room temperature, wash once with 50ml water, separate, dry over anhydrous sodium sulfate, and filter to obtain the toluene solution containing 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid. (Theoretical yield is 100%, and one pot method is used for the next step).

[0062] Step 2: Take a 500ml three-necked flask and add the toluene solution containing 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid in the first step, control the temperature at 30-40°C, add thionyl chloride (51.88g, 0.44mol, 1.1eq) dropwise, raise the temperature to 75°C after addition, and react for 4 hours. After the reaction is complete, concentrate to dryness, add n-heptane to slurry, filter, and wash to obtain 81.2g of the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride, with a yield of 91.84%.

[0063] Step 3: Take a 500ml three-necked flask, add acetonitrile (150ml, 3P) and 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride (50g, 0.226mol, 1.0eq), control the temperature at 0-5°C, dropwise add ammonia water (25%) (39.63g, 1.11mol, 5eq), raise the temperature to 25-35°C after addition, and react at room temperature for 4 hours; after the reaction is complete, filter, wash with water, and dry to obtain 40g of the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide, with a yield of 87.5%.

[0064] Step 4: Take a 500ml three-necked flask, add ethanol (150ml, 3P) and 36% hydrochloric acid (27.1g, 0.742mol, 3.0eq), add 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide (50g, 0248mol, 1.0eq) at one time, control the temperature at 40-50℃, add hydroxylamine hydrochloride (25.62g, 0.371mol, 1.5eq) in batches, raise the temperature to 60-70℃ and react for 4 hours; after the reaction is complete, add concentrated acid to dry, ethanol to pulp, and dry to obtain 36.2g of tauramide hydrochloride, with a yield of 91.4%. HPLC: 99.75%.

[0065] The product was subjected to a nuclear magnetic resonance experiment to confirm the product structure, and the data are as follows: 1 H NMR (500 MHz, DMSO-d6) δH=8.56 (s, 3H); 7.24 (s, 2H); 3.43-3.40 (m,2H), 3.13-3.10 (m, 2H).

[0066] The test results were consistent with the structure of tauramide hydrochloride.

[0067] Experimental Example 2: Step 1: Take a 2L three-necked flask and add toluene (800ml, 4P) and 2-aminoethanesulfonic acid (200g, 1.6mol, 1.0eq), 2,5-hexanedione (200.76g, 1.76mol, 1.1eq), p-toluenesulfonic acid (13.76g, 0.08mol, 0.05eq), and control the temperature at 50-60℃ for 4 hours. After the reaction is complete, cool to room temperature, wash once with 200ml water, separate, dry with anhydrous sodium sulfate, and filter to obtain the toluene solution containing 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid. (Theoretical yield is 100%, and one pot method is used for the next step).

[0068] Step 2: Take a 2L three-necked flask and add the toluene solution containing 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid in the first step, control the temperature at 30-40°C, add thionyl chloride (207.52g, 1.76mol, 1.1eq) dropwise, heat to 75°C after addition, and react for 4 hours. After the reaction is complete, concentrate to dryness, add n-heptane to slurry, filter, and wash to obtain 326g of the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride, with a yield of 92.18%.

[0069] Step 3: Take a 2L three-necked flask, add acetonitrile (600ml, 3P) and 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride (200g, 0.904mol, 1.0eq), control the temperature at 0-5°C, dropwise add ammonia water (25%) (158.52g, 4.52mol, 5eq), raise the temperature to 25-35°C after addition, and react at room temperature for 4 hours; after the reaction is complete, filter, wash with water, and dry to obtain 160.8g of the 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide, with a yield of 88%.

[0070] Step 4: Take a 2L three-necked flask, add ethanol (600ml, 3P) and 36% hydrochloric acid (108.4g, 2.976mol, 3.0eq), add 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide (200g, 0.992mol, 1.0eq) at one time, control the temperature at 40-50℃, add hydroxylamine hydrochloride (102.48g, 1.488mol, 1.5eq) in batches, raise the temperature to 60-70℃ and react for 4 hours; after the reaction is complete, add concentrated acid to dry, ethanol to pulp, and dry to obtain 145.6g of tauramide hydrochloride, with a yield of 91.9%. HPLC: 99.72%.

[0071] The product was subjected to a nuclear magnetic resonance experiment to confirm the product structure, and the data are as follows: 1H NMR (500 MHz, DMSO-d6) δH=8.56 (s, 3H); 7.24 (s, 2H); 3.43-3.40 (m,2H), 3.13-3.10 (m, 2H).

[0072] The test results were consistent with the structure of tauramide hydrochloride.

[0073] In summary, the preparation method of taurine hydrochloride of the present invention has the advantages of high reaction efficiency, high yield, strong operability, and equipment friendliness.

[0074] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing tauramide hydrochloride, characterized in that: include: Step S1, allowing an amino protecting agent to undergo a nucleophilic addition elimination reaction with 2-aminoethanesulfonic acid to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid, wherein the amino protecting agent is any one of p-toluenesulfonyl chloride, benzyl chloroformate, and 2,5-hexanedione; Step S2, chlorinating the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid and a chlorinating agent to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride; Step S3, allowing the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride and ammonia water to undergo a nucleophilic substitution reaction to generate 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide; Step S4, subjecting the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide to a deprotection reaction to generate tauramide hydrochloride.

2. The preparation method according to claim 1, characterized in that The amino protecting agent is 2,5-hexanedione, and the step S1 comprises: 2,5-hexanedione, 2-aminoethanesulfonic acid, and p-toluenesulfonic acid are added to toluene to react and generate the 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid.

3. The preparation method according to claim 2, characterized in that The molar ratio of 2-aminoethanesulfonic acid, 2,5-hexanedione and p-toluenesulfonic acid is 1.0:(1.0-1.5):(0-0.5), the reaction temperature is 50-60° C., and the reaction time is 3-5 h.

4. The preparation method according to claim 1, characterized in that: In step S2, the chlorination reagent is any one of thionyl chloride, oxalyl chloride, and phosphorus oxychloride.

5. The preparation method according to claim 4, characterized in that: The step S2 comprises: The chlorination reagent is added in batches to a toluene solution containing the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid to generate the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride.

6. The preparation method according to claim 5, characterized in that The chlorination reagent is thionyl chloride, the molar ratio of the thionyl chloride to the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonic acid is (1.0-1.2):1.0, the temperature for adding the thionyl chloride is 30-40°C, the reaction time is 2-6h, and the reaction temperature is 70-80°C.

7. The preparation method according to claim 1, characterized in that: The step S3 comprises: The 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride is added to acetonitrile, and thereafter aqueous ammonia is added dropwise thereto to generate 2-(2,5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide.

8. The preparation method according to claim 7, characterized in that The molar ratio of 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonyl chloride to aqueous ammonia is 1.0:(5.0-6.0), the temperature for dropping aqueous ammonia is 0-5°C, the reaction time is 2-6 h, and the reaction temperature is 25-35°C.

9. The preparation method according to claim 1, characterized in that: The step S4 comprises: 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide is added to ethanol containing hydrochloric acid, and hydroxylamine hydrochloride is added in portions to generate the tauramide hydrochloride.

10. The preparation method according to claim 9, characterized in that The molar ratio of the 2-(2, 5-dimethyl-1H-pyrrol-1-yl)ethane-1-sulfonamide to hydroxylamine hydrochloride and hydrochloric acid is 1.0:(1.5-2.0):(3.0-4.0), the temperature for adding the hydroxylamine hydrochloride is 40-50°C, the reaction time is 2-4 h, and the reaction temperature is 60-70°C.

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