Synthesis method of intermediate for preparing tirosamide hydrochloride

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a synthesis method of an intermediate for preparing tironomide hydrochloride. The synthesis method comprises the following steps: S1, dissolving L-tyrosine in a solvent which is a bicarbonate aqueous solution, dropwise adding benzoyl chloride, reacting under the condition that the temperature is less than or equal to 15 DEG C after dropwise adding is completed, then adjusting the pH value, stirring, crystallizing, filtering, leaching and drying to obtain N-benzoyl-L-tyrosine; s2, ethyl acetate and N, N-dimethylformamide are used as solvents, N-benzoyl-L-tyrosine is dissolved in the solvents, then an amide condensing agent and bicarbonate are added, stirring is conducted for 50-70 min at the temperature of 15-35 DEG C, dipropylamine is added, a heat preservation reaction is conducted for 6-7 h, aftertreatment is conducted after the reaction is finished, and an intermediate is obtained. According to the synthesis method disclosed by the invention, the intermediate with relatively high purity and yield can be prepared without using a complicated protecting group removal step.

Description

Technical Field

[0001] This application relates to the technical field of organic synthesis, and more specifically, it relates to a synthesis method for an intermediate for preparing tiaramide hydrochloride. Background Art

[0002] The mechanism of action of tiaramide hydrochloride is to directly relieve spasm in smooth muscle cells, regulate the relaxation of muscle contraction by adjusting the contraction of smooth muscle cells required for the spasmolytic effect of intracellular calcium ions; its main efficacy is for acute spastic pain, hepatobiliary colic, abdominal colic, renal and ureteral colic, abdominal spasm and pain, increased gastrointestinal motility, cholelithiasis, cholecystitis and postoperative adhesions.

[0003] The synthetic route for the traditional industrial production of tiaramide hydrochloride is shown in Figure 1 , specifically: ① Using L-tyrosine as a raw material, reacting with benzoyl chloride in an alkaline aqueous solution environment to form O,N-(2-benzoyl)-L-tyrosine; ② Preparing an active ester from O,N-(2-benzoyl)-L-tyrosine and ethyl chloroformate, and reacting with di-n-propylamine to synthesize O,N-(2-benzoyl)-L-tyrosine-di-n-propylamine; ③ Under an alkaline environment, hydrolyzing and removing the benzoyl group on the oxygen to form N-benzoyl-L-tyrosine-n-di-propylamine; ④ Reacting N-benzoyl-L-tyrosine-n-di-propylamine with 2-diethylaminoethyl chloride hydrochloride; ⑤ Passing in hydrogen chloride for salt formation to obtain tiaramide hydrochloride. However, the above synthetic route has the following defects: First, this synthetic method has cumbersome steps and requires multiple steps of synthesis to obtain the target product, resulting in low production efficiency and high costs; Second, in this synthetic method, ethyl chloroformate is used for catalytic reaction in acid amide condensation, but ethyl chloroformate is highly toxic and easily brings safety hazards to industrial production.

[0004] Numerous researchers have made many attempts to improve the problems in the above synthetic route. For example, in the Chinese patent with the publication number CN 107417560A, it first reacts L-tyrosine and benzoyl chloride as raw materials to obtain O,N-(2-benzoyl)-L-tyrosine, and then performs a high-temperature water-separating reflux reaction of O,N-(2-benzoyl)-L-tyrosine with di-n-propylamine to obtain N-benzoyl-L-tyrosyl di-n-propylamine. After that, N-benzoyl-L-tyrosyl di-n-propylamine and 2-diethylaminoethyl chloride hydrochloride are reacted to obtain tiaramide hydrochloride. However, in this synthetic route, two benzoyl groups need to be introduced in the first step, one of which is used as a protecting group and removed in the second step, with a cumbersome process. And due to the incomplete reaction, a high-temperature reflux water-separating reaction is required in the second step, and the yield of N-benzoyl-L-tyrosyl di-n-propylamine is low. At the same time, the process and equipment are complex, which is not conducive to large-scale industrial production.

[0005] For another example, in the Chinese patent with the publication number CN 115850107A, L-tyrosine and benzoyl chloride are first used as raw materials for reaction to obtain a first compound. Then, the first compound and 2-diethylaminoethyl chloride hydrochloride are reacted under carbonate conditions to obtain a second compound. After that, the second compound and di-n-propylamine are further reacted to prepare tirotamide hydrochloride. However, in this synthesis route, L-tyrosine and benzoyl chloride first react under the condition of a first inorganic base (strong base), which cannot ensure the specificity of the amide reaction. Therefore, the alkaline environment needs to be adjusted later, and a benzoyl protecting group is removed at high temperature. The process is also cumbersome and the yield is low. Summary of the Invention

[0006] In order to solve the above technical problems, the present application provides a synthesis method for an intermediate for preparing tirotamide hydrochloride. The intermediate has a high yield and purity, and the synthesis steps are simple, easy to operate, and do not require complex equipment. Using this intermediate to directly react with 2-diethylaminoethyl chloride hydrochloride to prepare tirotamide hydrochloride can make the yield and purity of tirotamide hydrochloride higher, and simplifies the preparation process of tirotamide hydrochloride, which is suitable for large-scale industrial production.

[0007] A synthesis method for an intermediate for preparing tirotamide hydrochloride provided by the present application adopts the following technical scheme: A synthesis method for an intermediate for preparing tirotamide hydrochloride includes the following steps: S1. Using an aqueous bicarbonate solution as a solvent, dissolve L-tyrosine in the solvent. Under the conditions of a temperature of 0-5°C and a pH value of 7-9, add benzoyl chloride dropwise. After the dropwise addition is completed, react for 1.8-2.2 h under the condition of a temperature ≤15°C, then adjust the pH value to 1-2, stir for crystallization and filter, wash, and dry to obtain N-benzoyl-L-tyrosine. The molar ratio of L-tyrosine, bicarbonate, and benzoyl chloride is 1:(2.0-5.0):(0.95-1.05); the reaction process is as follows: S2. Using ethyl acetate and N,N-dimethylformamide as solvents, dissolve N-benzoyl-L-tyrosine in the solvents, then add an amide condensing agent and bicarbonate, and stir at a temperature of 15-35°C for 50-70 min, then add di-n-propylamine, keep the temperature for reaction for 6-7 h, and after post-treatment after the reaction ends, obtain the intermediate; the reaction process is as follows:

[0008] By adopting the above technical solution, the present application efficiently synthesizes an intermediate for preparing tiaramide hydrochloride, and the intermediate has a high yield and purity. Specifically, in step S1, the present application adds benzoyl chloride dropwise to L-tyrosine under the conditions of a temperature of 0-5°C and a pH value of 7-9, while controlling the ratio among L-tyrosine, bicarbonate and benzoyl chloride, and controlling the reaction temperature not higher than 15°C, ensuring the specific reaction of amide, so that the present application can directly prepare N-benzoyl-L-tyrosine containing only one benzoyl group without high-temperature removal, significantly simplifying the synthesis steps, without the need for complex equipment, and being simple and easy to operate. Moreover, the present application greatly inhibits the occurrence of side reactions, reduces the generation of by-products, improves the yield of N-benzoyl-L-tyrosine, and ensures its high purity.

[0009] In step S2, the present application uses ethyl acetate and N,N-dimethylformamide as solvents, and combined with the action of an amide condensing agent and bicarbonate, can promote the efficient condensation reaction of N-benzoyl-L-tyrosine and dipropylamine under mild conditions, improve the reaction efficiency, and make the prepared intermediate have a high yield and purity. The intermediate prepared by the present application can be directly subjected to a one-step reaction with 2-diethylaminoethyl chloride hydrochloride to prepare tiaramide hydrochloride, greatly simplifying the preparation process of tiaramide hydrochloride, reducing the use of complex equipment, and the prepared tiaramide hydrochloride has a high yield and purity, being suitable for large-scale industrial production. The reaction process of the intermediate of the present application with 2-diethylaminoethyl chloride hydrochloride is a conventional step in the preparation of tiaramide hydrochloride.

[0010] Preferably, in step S1, the reaction temperature after the dropwise addition of benzoyl chloride is 0-10°C.

[0011] By adopting the above technical solution, the present application further optimizes the reaction temperature after the dropwise addition of benzoyl chloride, can further reduce the probability of side reactions, thereby improving the yield and purity of the target product N-benzoyl-L-tyrosine.

[0012] Preferably, in step S1, the molar ratio of L-tyrosine, bicarbonate, and benzoyl chloride is 1:(2-3):1.

[0013] By adopting the above technical solution, the present application further optimizes the ratio among L-tyrosine, bicarbonate and benzoyl chloride, further controls the specific reaction of amide, reduces the probability of generating products containing two benzoyl groups, and improves the yield and purity of the target product N-benzoyl-L-tyrosine.

[0014] Preferably, in step S2, the amide condensing agent includes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole.

[0015] By adopting the above technical solution, in the present application, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) and 1-hydroxybenzotriazole (HOBT) are mixed and used as an amide condensing agent, which can further improve the reaction efficiency of preparing the intermediate, and improve the yield and purity of the intermediate. Among them, HOBT can play a role in stabilizing the intermediate during the reaction, preventing it from generating stable urea by-products through rearrangement reactions, and the HOBT in the present application can be recycled and reused during the post-treatment process of step S2, further reducing the production cost.

[0016] Preferably, after the N-benzoyl-L-tyrosine is dissolved in the solvent, 1-hydroxybenzotriazole is first added and stirred for 30-40 min, and then bicarbonate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide are added.

[0017] By adopting the above technical solution, the present application can further optimize the activation effect by fully dissolving HOBT first. Specifically, as an activation reagent, after HOBT forms an active intermediate with carboxylic acid and then EDCI is added, it can promote the formation of amide bonds. And compared with the addition sequence of adding them simultaneously, the addition sequence in the present application can greatly reduce the risk of side reactions and improve the yield and purity of the target product.

[0018] Preferably, the molar ratio of the N-benzoyl-L-tyrosine to 1-hydroxybenzotriazole is 1:(0.7-1.1).

[0019] By adopting the above technical solution, the present application optimizes the ratio between the N-benzoyl-L-tyrosine and 1-hydroxybenzotriazole, making the dosage of HOBT in the reaction process more accurate. This not only improves the reaction selectivity and conversion rate, reduces the generation of by-products, but also reduces the waste of raw materials, thereby enhancing the overall efficiency and economy of the intermediate synthesis.

[0020] Optionally, the molar ratio of the N-benzoyl-L-tyrosine to the bicarbonate is 1:(2-10).

[0021] Preferably, the molar ratio of the N-benzoyl-L-tyrosine to the bicarbonate is 1:(2-3).

[0022] By adopting the above technical solution, the present application further optimizes the ratio between the N-benzoyl-L-tyrosine and the bicarbonate. While ensuring the efficient and full progress of the reaction, it reduces the waste of raw materials, lowers the production cost, and enhances the overall efficiency and economy of the intermediate synthesis.

[0023] Preferably, the molar ratio of N-benzoyl-L-tyrosine to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is 1:(1.0-1.2).

[0024] By adopting the above technical solution, the application optimizes the ratio between N-benzoyl-L-tyrosine and EDCI, improves the selectivity and conversion rate of the reaction, reduces the generation of by-products, and thus improves the purity and yield of the target product.

[0025] Preferably, the molar ratio of N-benzoyl-L-tyrosine to dipropylamine is 1:(1.1-2.0).

[0026] By adopting the above technical solution, N-benzoyl-L-tyrosine and dipropylamine in the application can fully react under this ratio. Compared with the use amount of more than 2.0 equivalents of dipropylamine in the traditional reaction, the application significantly reduces the use amount of dipropylamine, reduces the waste of raw materials, and lowers the production cost.

[0027] In summary, the application has the following beneficial technical effects: 1. In the synthesis method of the application, there is no need to use complex protecting group removal steps, which significantly simplifies the synthesis route, and there is no need to use complex equipment. It is simple and easy to operate, greatly improves the production efficiency, and at the same time, the used HOBT can be recycled, reducing the production cost, and is suitable for large-scale industrial production; 2. The synthesis method of the application greatly inhibits the occurrence of side reactions, reduces the generation of by-products, improves the yield and purity of the target product in each step of the reaction, and thus improves the yield and purity of the finally prepared tirotamide hydrochloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is a synthesis route diagram of the traditional industrial production of tirotamide hydrochloride. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0029] The following further elaborates on the application with reference to the embodiments.

[0030] All raw materials used in the application are commercially available products.

[0031] The bicarbonate in the application is sodium bicarbonate or potassium bicarbonate. Since there is no significant difference in the effects between the two, in the specific embodiments of the application, sodium bicarbonate is taken as an example for illustration.

[0032] The benzoyl chloride in the application has a CAS number of 98-88-4.

[0033] The 1-hydroxybenzotriazole (HOBT) in the application has a CAS number of 2592-95-2.

[0034] 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) of the present application has a CAS number of 25952-53-8.

[0035] Dipropylamine of the present application has a CAS number of 142-84-7.

[0036] Example 1.1 A synthesis method for an intermediate for preparing tiaramide hydrochloride, comprising the following steps: S1. Charge 500 kg of water into the reaction kettle, then charge 46.4 kg of sodium bicarbonate (552 mol). After stirring and dissolving, add 50 kg of L-tyrosine (275 mol) thereto and stir to dissolve. Then cool down to 0 °C and control the pH value to 7. Dropwise add 36.7 kg of benzoyl chloride (261.25 mol). After the dropwise addition is completed, react at a temperature of 15 °C for 1.8 h. Then adjust the pH value to 1, stir for crystallization for 1 h and filter. Then wash with pure water and collect the product after negative pressure drying for 10 h to obtain N-benzoyl-L-tyrosine with a purity greater than 99%. The yield of N-benzoyl-L-tyrosine is 98.6%. S2. Charge 300 kg of ethyl acetate and 20 kg of N,N-dimethylformamide into the reaction kettle, start stirring, and add 75 kg of N-benzoyl-L-tyrosine (263 mol) thereto. Then add 25 kg of HOBT (184 mol), stir for 30 min, add 44 kg of sodium bicarbonate (526 mol) and 50 kg of EDCI (263 mol), and stir at a temperature of 15 °C for 50 min. Then dropwise add 29 kg of dipropylamine (289 mol), keep the temperature for reaction for 6 h. After the reaction is completed, filter. The filter cake is washed with 50 kg of ethyl acetate and then recycled (after recycling 5 batches, wash and purify with water, continue to recycle HOBT. The recycling scheme and recovery method are: add 1 kg of HOBT after each recycling. After recycling 5 times, stir and wash with 200 kg of water for 30 min, filter, wash with 50 kg of water, and dry under negative pressure for 10 h to make the water separation less than 1%. After recovery, directly reuse it in the reaction); add 200 kg of pure water to the filtrate, adjust the pH to 1.5 with hydrochloric acid, stir for crystallization for 1 h, filter, wash with 100 kg of pure water, wash with 50 kg of ethyl acetate, and dry under negative pressure for 10 h to obtain an intermediate with a purity greater than 99.6%. The yield of the intermediate is 94.2%.

[0037] Example 1.2 A synthesis method for an intermediate for preparing tiaramide hydrochloride, comprising the following steps: S1. Charge 500 kg of water into the reaction kettle, then charge 46.4 kg of sodium bicarbonate (552 mol). After stirring and dissolving, add 50 kg of L-tyrosine (275 mol) and stir to dissolve. Then cool down to 5 °C and control the pH value to 9. Dropwise add 36.7 kg of benzoyl chloride (261.25 mol). After the dropwise addition is completed, react at 15 °C for 2.2 h. Then adjust the pH value to 2, stir for crystallization for 1 h and filter. Then wash with pure water, and collect the product after vacuum drying for 10 h to obtain N-benzoyl-L-tyrosine with a purity greater than 99%. The yield of N-benzoyl-L-tyrosine is 98.8%; S2. Charge 300 kg of ethyl acetate and 20 kg of N,N-dimethylformamide into the reaction kettle, start stirring, and add 75 kg of N-benzoyl-L-tyrosine (263 mol) into it. Then add 25 kg of HOBT (184 mol), stir for 40 min, then add 44 kg of sodium bicarbonate (526 mol) and 50 kg of EDCI (263 mol), and stir at 35 °C for 70 min. Then dropwise add 29 kg of dipropylamine (289 mol), keep the temperature for reaction for 7 h. After the reaction is completed, filter. The filter cake is washed with 50 kg of ethyl acetate and then recycled (after recycling 5 batches, wash and purify with water, and continue to recycle HOBT. The recycling scheme and recovery method are: add 1 kg of HOBT after each recycling. After recycling 5 times, stir and wash with 200 kg of water for 30 min, filter, wash with 50 kg of water, and vacuum dry for 10 h to make the water separation less than 1%. After recovery, directly reuse it in the reaction); Add 200 kg of pure water to the filtrate, adjust the pH to 1.5 with hydrochloric acid, stir for crystallization for 1 h, filter, wash with 100 kg of pure water, wash with 50 kg of ethyl acetate, and vacuum dry for 10 h to obtain an intermediate with a purity greater than 99.6%. The yield of the intermediate is 94.5%.

[0038] Example 2.1 A synthetic method for preparing an intermediate of telithromycin hydrochloride, which is different from Example 1.1 in that: in step S1, after the dropwise addition of benzoyl chloride is completed, the reaction is carried out at 10 °C, and the rest is the same as in Example 1.1. The obtained N-benzoyl-L-tyrosine has a purity greater than 99% and a yield of 99.0%.

[0039] Example 2.2 A synthetic method for preparing an intermediate of telithromycin hydrochloride, which is different from Example 1.1 in that: in step S1, after the dropwise addition of benzoyl chloride is completed, the reaction is carried out at 0 °C, and the rest is the same as in Example 1.1. The obtained N-benzoyl-L-tyrosine has a purity greater than 99% and a yield of 99.5%.

[0040] Example 3.1 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S1, the molar ratio of L-tyrosine, sodium bicarbonate, and benzoyl chloride is 1:5:1.05, where L-tyrosine is 275 mol, sodium bicarbonate is 1375 mol, and benzoyl chloride is 289 mol. The rest are the same as in Example 1.1. The purity of the obtained N-benzoyl-L-tyrosine is greater than 99%, and the yield is 98.8%.

[0041] Example 3.2 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S1, the molar ratio of L-tyrosine, sodium bicarbonate, and benzoyl chloride is 1:2:1, where L-tyrosine is 275 mol, sodium bicarbonate is 550 mol, and benzoyl chloride is 275 mol. The rest are the same as in Example 1.1. The purity of the obtained N-benzoyl-L-tyrosine is greater than 99%, and the yield is 99.2%.

[0042] Example 3.3 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S1, the molar ratio of L-tyrosine, sodium bicarbonate, and benzoyl chloride is 1:3:1, where L-tyrosine is 275 mol, sodium bicarbonate is 825 mol, and benzoyl chloride is 275 mol. The rest are the same as in Example 1.1. The purity of the obtained N-benzoyl-L-tyrosine is greater than 99%, and the yield is 99.3%.

[0043] Example 4.1 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, HOBT, sodium bicarbonate, and EDCI are added to the reaction kettle simultaneously. The rest are the same as in Example 1.1. The purity of the obtained intermediate is 99.2%, and the yield is 88.4%.

[0044] Example 5.1 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, the molar ratio of N-benzoyl-L-tyrosine and HOBT is 1:1.1, where N-benzoyl-L-tyrosine is 263 mol and HOBT is 289.3 mol. The rest are the same as in Example 1.1. The purity of the obtained intermediate is greater than 99.6%, and the yield is 95.0%.

[0045] Example 5.2 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, the molar ratio of N-benzoyl-L-tyrosine to HOBT is 1:1.5, where N-benzoyl-L-tyrosine is 263 mol and HOBT is 394.5 mol, and the rest are the same as in Example 1.1. The purity of the obtained intermediate is greater than 99.6%, and the yield is 95.0%.

[0046] Example 6.1 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, the molar ratio of N-benzoyl-L-tyrosine to sodium bicarbonate is 1:3, where N-benzoyl-L-tyrosine is 263 mol and sodium bicarbonate is 789 mol, and the rest are the same as in Example 1.1. The purity of the obtained intermediate is greater than 99.6%, and the yield is 94.8%.

[0047] Example 6.2 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, the molar ratio of N-benzoyl-L-tyrosine to sodium bicarbonate is 1:7, where N-benzoyl-L-tyrosine is 263 mol and sodium bicarbonate is 1841 mol, and the rest are the same as in Example 1.1. The purity of the obtained intermediate is greater than 99.6%, and the yield is 94.8%.

[0048] Example 6.3 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, the molar ratio of N-benzoyl-L-tyrosine to sodium bicarbonate is 1:10, where N-benzoyl-L-tyrosine is 263 mol and sodium bicarbonate is 2630 mol, and the rest are the same as in Example 1.1. The purity of the obtained intermediate is greater than 99.6%, and the yield is 94.8%.

[0049] Example 7.1 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, the molar ratio of N-benzoyl-L-tyrosine to EDCI is 1:1.2, where N-benzoyl-L-tyrosine is 263 mol and EDCI is 315.6 mol, and the rest are the same as in Example 1.1. The purity of the obtained intermediate is greater than 99.6%, and the yield is 94.3%.

[0050] Example 7.2 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, the molar ratio of N-benzoyl-L-tyrosine to EDCI is 1:1.5, where N-benzoyl-L-tyrosine is 263 mol and EDCI is 394.5 mol, and the rest are the same as in Example 1.1. The purity of the obtained intermediate is greater than 99.6%, and the yield is 94.3%.

[0051] Example 8.1 A synthetic method for an intermediate for preparing tiaramide hydrochloride, which is different from Example 1.1 in that: in step S2, the molar ratio of N-benzoyl-L-tyrosine to dipropylamine is 1:2, where N-benzoyl-L-tyrosine is 263 mol and dipropylamine is 526 mol, and the rest are the same as in Example 1.1. The purity of the obtained intermediate is greater than 99.6%, and the yield is 94.4%.

[0052] Comparative Example 1.1 It is different from Example 1.1 in that: sodium bicarbonate in step S1 is replaced by sodium hydroxide, and the rest are the same as in Example 1.1. The purity of the obtained N-benzoyl-L-tyrosine is 89.2%, and the yield is 106.7%.

[0053] Comparative Example 2.1 It is different from Example 1.1 in that: in step S1, the molar ratio of L-tyrosine, sodium bicarbonate, and benzoyl chloride is 1:5:2, where L-tyrosine is 275 mol, sodium bicarbonate is 1375 mol, and benzoyl chloride is 550 mol, and the rest are the same as in Example 1.1. The purity of the obtained N-benzoyl-L-tyrosine is 90.3%, and the yield is 83.5%.

[0054] Comparative Example 3.1 It is different from Example 1.1 in that: after the addition of benzoyl chloride is completed in step S1, the reaction is carried out at a temperature of 20 °C, and the rest are the same as in Example 1.1. The purity of the obtained N-benzoyl-L-tyrosine is 97.1%, and the yield is 93.2%.

[0055] Data analysis As can be seen from the data of the above embodiments, in this application, by optimizing the synthesis route, controlling the reaction conditions, and combining the post-treatment process, the occurrence of side reactions is greatly inhibited, the generation of by-products is reduced, and an intermediate for preparing tiaramide hydrochloride with high purity and yield is obtained. Using this intermediate, tiaramide hydrochloride with high purity and yield can be directly prepared by reacting with 2-diethylaminoethyl chloride hydrochloride. Moreover, in the synthesis method of this application, there is no need to use a complex protecting group removal step, which significantly simplifies the synthesis route, does not require complex equipment, is simple and easy to operate, greatly improves the production efficiency, and at the same time, the used HOBT can be recycled, reducing the production cost, and is suitable for large-scale industrial production.

[0056] Among the above-mentioned numerous embodiments, the difference between Example 1.1 and Examples 2.1 - 2.2 lies only in the reaction temperature after the addition of benzoyl chloride in step S1. From the data, it can be seen that when the reaction temperature after the addition of benzoyl chloride is not higher than 15°C, the purity of the obtained N-benzoyl-L-tyrosine is greater than 99%, and the yield is in the range of 98.6 - 99.5%. Among them, when the reaction temperature after the addition of benzoyl chloride is further controlled at 0 - 10°C, the yield of N-benzoyl-L-tyrosine can be further improved.

[0057] Among the above-mentioned numerous embodiments, the difference between Example 1.1 and Examples 3.1 - 3.3 lies only in the ratio of L-tyrosine, sodium bicarbonate, and benzoyl chloride in step S1. From the data, it can be seen that when the molar ratio of L-tyrosine, sodium bicarbonate, and benzoyl chloride is 1:(2 - 5):(0.95 - 1.05), the purity of the obtained N-benzoyl-L-tyrosine is greater than 99%, and the yield is in the range of 98.6 - 99.3%. Among them, when the molar ratio of L-tyrosine, sodium bicarbonate, and benzoyl chloride is further controlled at 1:(2 - 3):1, the yield of N-benzoyl-L-tyrosine can be further improved.

[0058] Among the above-mentioned numerous embodiments, the difference between Example 1.1 and Example 4.1 lies only in the addition order of HOBT and EDCI in step S2. From the data, it can be seen that when HOBT is added first and then EDCI, the purity of the obtained intermediate is greater than 99.6% and the yield is 94.2%, while when HOBT and EDCI are added simultaneously, the purity of the obtained intermediate is 99.2% and the yield is 88.4%. The experimental data show that compared with adding HOBT and EDCI simultaneously, adding HOBT first and then EDCI can further improve the conversion rate of this step of the reaction, thereby improving the purity and yield of the intermediate.

[0059] Among the above-mentioned numerous embodiments, the difference between Example 1.1 and Examples 5.1 - 5.2 lies only in the ratio of N-benzoyl-L-tyrosine to HOBT in step S2. It can be seen from the data that when the molar ratio of N-benzoyl-L-tyrosine to HOBT is 1:(0.7 - 1.1), the purity of the obtained intermediate is greater than 99.6%, and the yield is in the range of 94.2 - 95.0%. Moreover, when the amount of HOBT is further increased, there is no significant difference in the purity and yield of the obtained intermediate.

[0060] Among the above-mentioned numerous embodiments, the difference between Example 1.1 and Examples 6.1 - 6.3 lies only in the ratio of N-benzoyl-L-tyrosine to sodium bicarbonate in step S2. It can be seen from the data that when the molar ratio of N-benzoyl-L-tyrosine to sodium bicarbonate is 1:(2 - 10), the purity of the obtained intermediate is greater than 99.6%, and the yield is in the range of 94.2 - 94.8%. Moreover, when the molar ratio of N-benzoyl-L-tyrosine to sodium bicarbonate exceeds 1:3, there is no significant difference in the purity and yield of the obtained intermediate. Therefore, considering the raw material cost, the molar ratio of N-benzoyl-L-tyrosine to sodium bicarbonate is further optimized to 1:(2 - 3).

[0061] Among the above-mentioned numerous embodiments, the difference between Example 1.1 and Examples 7.1 - 7.2 lies only in the ratio of N-benzoyl-L-tyrosine to EDCI. It can be seen from the data that when the molar ratio of N-benzoyl-L-tyrosine to EDCI is 1:(1.0 - 1.2), the purity of the obtained intermediate is greater than 99.6%, and the yield is in the range of 94.2 - 94.3%. Moreover, when the amount of EDCI is further increased, there is no significant difference in the purity and yield of the obtained intermediate.

[0062] Among the above-mentioned numerous embodiments, the difference between Example 1.1 and Example 8.1 lies only in the ratio of N-benzoyl-L-tyrosine to dipropylamine. It can be seen from the data that when the molar ratio of N-benzoyl-L-tyrosine to dipropylamine is 1:(1.1 - 2.0), the purity of the obtained intermediate is greater than 99.6%, and the yield is in the range of 94.2 - 94.4%. The experimental data show that in this application, a relatively small amount of dipropylamine can achieve a better yield, significantly reducing the amount of dipropylamine used and lowering the production cost.

[0063] By comparing the data among Example 1.1, Comparative Example 1.1, Comparative Example 2.1, and Comparative Example 3.1, it can be seen that when the bicarbonate in Step S1 is replaced by sodium hydroxide, and the ratio of L-tyrosine, sodium bicarbonate, and benzoyl chloride is not within the scope of this application, or the reaction temperature after the addition of benzoyl chloride is not within the scope of this application, it will affect the specific reaction of the amide, increase the generation of by-products, and reduce the purity of the target product. The yield of Comparative Example 1.1 exceeds 100% because when the carbonate is replaced by sodium hydroxide, the resulting product will include substances containing two benzoyl protecting groups, and the substances containing two benzoyl protecting groups will also crystallize out and be collected together, so the yield increases, but the purity decreases significantly.

[0064] The examples of this specific implementation mode are all preferred examples of this application, and do not limit the protection scope of this application accordingly. Therefore, all equivalent changes made according to the structure, shape, and principle of this application should be covered within the protection scope of this application.

Claims

1. A synthetic method for an intermediate for preparing tiaramide hydrochloride, characterized in that, It includes the following steps: S1. Using an aqueous bicarbonate solution as a solvent, dissolve L-tyrosine in the solvent. Under the conditions of a temperature of 0 - 5°C and a pH value of 7 - 9, add benzoyl chloride dropwise. After the dropwise addition is completed, react for 1.8 - 2.2 h under the condition of a temperature ≤ 15°C. Then adjust the pH value to 1 - 2, stir for crystallization and filter, wash, and after drying, obtain N-benzoyl-L-tyrosine. The molar ratio of L-tyrosine, bicarbonate, and benzoyl chloride is 1:(2.0 - 5.0):(0.95 - 1.05); the reaction process is as follows: S2. Using ethyl acetate and N,N-dimethylformamide as solvents, dissolve N-benzoyl-L-tyrosine in the solvents. Then add an amide condensing agent and bicarbonate, and stir at a temperature of 15 - 35°C for 50 - 70 min. Then add dipropylamine, keep the temperature for reaction for 6 - 7 h, and after the reaction is completed, perform post-treatment to obtain an intermediate; the reaction process is as follows:

2. The synthetic method of an intermediate for preparing tiaramide hydrochloride according to claim 1, characterized in that, In step S1, the reaction temperature after the dropwise addition of benzoyl chloride is 0 - 10°C.

3. The synthetic method of an intermediate for preparing tiaramide hydrochloride according to claim 1, characterized in that, In step S1, the molar ratio of L-tyrosine, bicarbonate, and benzoyl chloride is 1:(2 - 3):

1.

4. The synthetic method of an intermediate for preparing telotiamide hydrochloride according to claim 1, characterized in that, In step S2, the amide condensing agent includes 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole.

5. The synthetic method of an intermediate for preparing tiaramide hydrochloride according to claim 4, characterized in that, After N-benzoyl-L-tyrosine is dissolved in the solvent, first add 1-hydroxybenzotriazole and stir for 30 - 40 min, and then add bicarbonate and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

6. The synthetic method of an intermediate for preparing tiaramide hydrochloride according to claim 5, characterized in that, The molar ratio of N-benzoyl-L-tyrosine and 1-hydroxybenzotriazole is 1:(0.7 - 1.1).

7. A synthetic method for an intermediate for preparing tiaramide hydrochloride according to claim 5, characterized in that, The molar ratio of N-benzoyl-L-tyrosine and bicarbonate is 1:(2 - 10).

8. A synthetic method for an intermediate for preparing tiaramide hydrochloride according to claim 7, characterized in that, The molar ratio of N-benzoyl-L-tyrosine and bicarbonate is 1:(2 - 3).

9. The synthetic method of an intermediate for preparing tiaramide hydrochloride according to claim 5, characterized in that, The molar ratio of N-benzoyl-L-tyrosine and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is 1:(1.0 - 1.2).

10. A method for synthesizing an intermediate for preparing tiaramide hydrochloride according to claim 5, characterized in that, The molar ratio of N-benzoyl-L-tyrosine and dipropylamine is 1:(1.1 - 2.0).

Images