Amplification preparation method of tiopronin
A three-step synthesis of thiopronin using glycine tert-butyl ester and thioglycolic acid in a Mitsunobu reaction addresses the challenges of existing methods, achieving high yield and cost-effective production suitable for industrial use.
Patent Information
- Application Number
- CN202510588522.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-08
- Publication Date
- 2025-07-15
AI Technical Summary
The existing sulphonin preparation method has problems such as harsh reaction conditions, difficult supply of raw materials, complex operation and low yield, making it difficult to achieve industrial production.
Intermediate 1 is formed by amine transesterification reaction under alkaline conditions, and 2-hydroxypropionylglycine tert-butyl ester and thioacetic acid are reacted in Mitsunobu to form intermediate 2, and hydrolyzed and protected under acid-base action to form thiopronin.
It provides a simple operation, stable and environmentally friendly preparation method, which reduces production costs and increases yields, and is suitable for industrial production.
Smart Images
Figure CN120309522A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and particularly relates to a method for large-scale preparation of tiopronin. Background Art
[0002] Tiopronin, English name: Tiopronin, CAS: 1953-02-2. It is a new type of glycine derivative containing a free sulfhydryl group. It is mainly used for improving liver function in acute / chronic liver diseases. Long-term use abroad has confirmed that tiopronin can comprehensively and significantly improve the liver function indicators and related symptoms of viral hepatitis and alcoholic liver injury, with definite curative effect, safety and reliability.
[0003] Currently, the preparation methods of tiopronin mainly include the following several: 1. Using α-mercaptopropionic acid as the starting material, acyl chloride is prepared through benzyl protection, and then condensed with glycine to remove the protecting group to obtain the target compound. Among them, removing the protecting group requires reacting with sodium in liquid nitrogen at -55°C, and the yield is 30%. The reaction conditions of this route are harsh and it is difficult to industrialize; 2. Condensing α-bromopropionyl glycine with a compound containing a potential sulfhydryl group (such as thiosalicylic acid), and then obtaining the target compound through aminolysis, with the highest yield of 52%. The raw materials required for this route are in short supply, difficult to prepare, and highly toxic; 3. Using propionic acid as the starting material, first acylating with phosphorus trichloride, then introducing chlorine through chlorination and substitution reactions to obtain α-chloropropionyl chloride, condensing with glycine, then introducing a sulfur-containing group through disulfurization, and finally obtaining tiopronin through reduction. This route generally uses sodium disulfide for the disulfurization reaction. Sodium disulfide is easy to absorb moisture, extremely unstable, and has a strong odor. Therefore, it is necessary to develop a synthesis method with easily available raw materials, convenient operation, easy reaction control, and appropriate overall yield. Summary of the Invention
[0004] The purpose of the present invention is to provide a method for preparing tiopronin with easily available raw materials, convenient operation, easy reaction control, and appropriate overall yield. The process is carried out in three steps. In the first step, tert-butyl glycinate and methyl lactate are subjected to an amine-ester exchange reaction in an organic solvent under the action of a base to generate intermediate 1; in the second step, 2-hydroxypropionyl glycine tert-butyl ester and thioacetic acid undergo a Mitsunobu reaction under the action of a dialkyl azodicarboxylate and a triarylphosphine / trialkylphosphine to generate intermediate 2; in the third step, intermediate 2 is hydrolyzed and deprotected in an organic solvent under the action of an acid and a base in sequence to obtain the product. The technical solution of the present invention is simple and stable in operation, the products of each step are easy to separate, the yield is high, and it is environmentally friendly, providing a new synthetic route for this compound.
[0005] The synthetic route of the preparation method of tiopronin of the present invention is as follows:
[0006]
[0007] In the first step, tert-butyl glycinate and methyl lactate undergo an aminolysis reaction in an organic solvent under the action of a base to form intermediate 1.
[0008] Further, in the above technical solution, the molar ratio of tert-butyl glycinate to methyl lactate is 1:1 to 1.2.
[0009] Further, in the above technical solution, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or methanol.
[0010] In the second step, 2-hydroxypropionyl glycine tert-butyl ester and thioacetic acid undergo a Mitsunobu reaction under the action of a dialkyl azodicarboxylate and a triarylphosphine / trialkylphosphine to form intermediate 2.
[0011] Further, in the above technical solution, the molar ratio of 2-hydroxypropionyl glycine tert-butyl ester to thioacetic acid is 1:1 to 2.
[0012] Further, in the above technical solution, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or dichloromethane.
[0013] In the third step, intermediate 2 is hydrolyzed and deprotected in an organic solvent under the action of an acid and a base in sequence to form the product.
[0014] Further, in the above technical solution, the molar ratio of intermediate 2, the acid and the base is 1:3 - 10:3 - 10.
[0015] Further, in the above technical solution, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or dioxane.
[0016] Further, in the above technical solution, the acid is selected from hydrochloric acid, phosphoric acid, trifluoroacetic acid and formic acid.
[0017] Further, in the above technical solution, the base is selected from potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.
[0018] Compared with the prior art, the present invention has the following remarkable advantages:
[0019] A. The comprehensive production cost of the present invention is much lower than that of the currently known process, and the synthesis process is more competitive in the market. The technical solution of the present invention is simple and stable in operation, the products of each step are easy to separate, the yield is high, it is environmentally friendly, and provides a new synthetic route for this compound.
[0020] B. Using tert-butyl glycinate, methyl lactate and thioacetic acid as raw materials, the raw materials are cheap and easily available, reducing the raw material cost. In particular, 2-hydroxypropionyl glycine tert-butyl ester undergoes a Mitsunobu reaction with thioacetic acid and then deprotection to obtain the product with high selectivity. Description of the Drawings
[0021] Figure 1 It is the HNMR spectrum of tiopronin obtained in Example 1; Detailed Embodiments
[0022] The present invention will be further described below in conjunction with specific embodiments. These embodiments should be understood as only for illustrating the present invention and not for limiting the protection scope of the present invention. After reading the content recorded in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.
[0023] Example 1
[0024] The first step:
[0025] Add N-methylmorpholine (4.05 g, 0.04 mol, 1 eq) and tert-butyl glycinate (5.24 g, 0.04 mol, 1 eq) to tetrahydrofuran (20 ml), stir to dissolve and then add methyl lactate (4.16 g, 0.04 mol, 1 eq). The reaction solution is stirred at room temperature for 5 hours. After the reaction is completed, water is added and the mixture is extracted with ethyl acetate. The crude product obtained after evaporation is purified by column chromatography to obtain 2-hydroxypropionyl glycine tert-butyl ester (7.47 g, yield: 92%).
[0026] The second step:
[0027] Add diisopropyl azodicarboxylate (13.75 g, 0.068 mol, 2 eq) to a solution of triphenylphosphine (8.92 g, 0.034 mol, 1 eq) in tetrahydrofuran (40 ml) at 5-10 °C. Add 2-hydroxypropionyl glycine tert-butyl ester (6.91 g, 0.034 mol, 1 eq) and thioacetic acid (5.18 g, 0.068 mol, 2 eq) dropwise to the above reaction solution sequentially at -10 to 0 °C. The reaction solution is stirred at room temperature for 24 hours. After the reaction is completed, water is added to quench the reaction, and the mixture is extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotary evaporated to obtain Intermediate 2 (7.19 g, yield: 81%).
[0028] The third step:
[0029] Intermediate 2 (7.05 g, 0.027 mol, 1 eq) was added portionwise to a solution of phosphoric acid (26.46 g, 0.27 mol, 10 eq) in tetrahydrofuran (35 ml). The mixture was stirred at room temperature for 4 hours, and potassium carbonate (37.32 g, 0.27 mol, 10 eq) was added to the above reaction solution. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, water was added for dilution, and the mixture was extracted with ethyl acetate. The solvent was evaporated to obtain the product (3.66 g, yield: 83%).
[0030] Example 2
[0031] The first step:
[0032] N-Methylmorpholine (26.91 g, 0.266 mol, 1 eq) and tert-butyl glycinate (34.89 g, 0.266 mol, 1 eq) were added to 2-methyltetrahydrofuran (150 ml). After stirring and dissolving, methyl lactate (33.31 g, 0.32 mol, 1.2 eq) was added, and the reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, water was added, and the mixture was extracted with ethyl acetate. The crude product obtained after evaporation of the solvent was purified by column chromatography to obtain tert-butyl 2-hydroxypropionylglycinate (49.19 g, yield: 91%).
[0033] The second step:
[0034] Diethyl azodicarboxylate (83.59 g, 0.48 mol, 2 eq) was added to a solution of tributylphosphine (48.56 g, 0.24 mol, 1 eq) in dioxane (250 ml) at 5 - 10 °C. tert-Butyl 2-hydroxypropionylglycinate (48.75 g, 0.24 mol, 1 eq) and thioacetic acid (27.40 g, 0.36 mol, 1.5 eq) were sequentially and slowly added dropwise to the above reaction solution at -10 - 0 °C. The reaction solution was stirred at room temperature for 24 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to obtain Intermediate 2 (52.03 g, yield: 83%).
[0035] The third step:
[0036] Intermediate 2 (49.65 g, 0.19 mol, 1 eq) was added portionwise to a solution of trifluoroacetic acid (216.64 g, 1.9 mol, 10 eq) in 2-methyltetrahydrofuran (250 ml). The mixture was stirred at room temperature for 4 hours, and sodium hydroxide (76 g, 1.9 mol, 10 eq) was added to the above reaction solution. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, water was added for dilution, and the mixture was extracted with ethyl acetate. The solvent was evaporated to obtain the product (26.05 g, yield: 84%).
[0037] Example 3
[0038] The first step:
[0039] N-methylmorpholine (134.53 g, 1.33 mol, 1 eq) and tert-butyl glycinate (174.46 g, 1.33 mol, 1 eq) were added to methanol (700 ml). After stirring and dissolving, methyl lactate (166.57 g, 1.60 mol, 1.2 eq) was added, and the reaction solution was stirred at room temperature for 5 hours. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The crude product obtained after evaporation was purified by column chromatography to obtain tert-butyl 2-hydroxypropionylglycinate (251.38 g, yield: 93%).
[0040] Step 2:
[0041] Diethyl azodicarboxylate (428.41 g, 2.46 mol, 2 eq) was added to a solution of triphenylphosphine (322.62 g, 1.23 mol, 1 eq) in dichloromethane (1.25 L) at 5 - 10 °C. tert-Butyl 2-hydroxypropionylglycinate (249.84 g, 1.23 mol, 1 eq) and thioacetic acid (102.76 g, 1.35 mol, 1.1 eq) were slowly added dropwise to the above reaction solution in turn at -10 - 0 °C. The reaction solution was stirred at room temperature for 24 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and rotary evaporated to obtain Intermediate 2 (263.44 g, yield: 82%).
[0042] Step 3:
[0043] Intermediate 2 (258.72 g, 0.99 mol, 1 eq) was added in batches to a solution of formic acid (455.70 g, 9.9 mol, 10 eq) in dioxane (1.3 L), and the mixture was stirred at room temperature for 4 hours. Sodium carbonate (1.05 g, 9.9 mol, 10 eq) was added to the above reaction solution. The mixture was stirred at room temperature for 4 hours. After the reaction was completed, water was added for dilution and the mixture was extracted with ethyl acetate. After evaporation, the product (137.32 g, yield: 85%) was obtained.
[0044] As described above, it is only a preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and all should be covered within the protection scope of the present invention.
Claims
1. A preparation method of tiopronin, characterized in that, It includes the following steps: In the first step, tert-butyl glycinate and methyl lactate undergo an aminolysis reaction in an organic solvent under the action of a base to form tert-butyl 2-hydroxypropionylglycinate; In the second step, tert-butyl 2-hydroxypropionylglycinate and thioacetic acid react under the action of a dialkyl azodicarboxylate and a triarylphosphine / trialkylphosphine to form Intermediate 2; In the third step, Intermediate 2 undergoes hydrolysis and deprotection in an organic solvent under the sequential action of an acid and a base to form the product.
2. The preparation method of tiopronin according to claim 1, characterized in that: In the first step, the molar ratio of tert-butyl glycinate to methyl lactate is 1:1 to 1.
2.
3. The preparation method of tiopronin according to claim 1, wherein: In the first step, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or methanol.
4. The preparation method of tiopronin according to claim 1, characterized in that: In the second step, the molar ratio of tert-butyl 2-hydroxypropionylglycinate to thioacetic acid is 1:1 to 2.
5. The preparation method of tiopronin according to claim 1, characterized in that: In the second step, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, dioxane or dichloromethane.
6. The preparation method of tiopronin according to claim 1, wherein: In the third step, the molar ratio of Intermediate 2, the acid and the base is 1:3 - 10:3 - 10.
7. The preparation method of tiopronin according to claim 1, characterized in that: In the third step, the organic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran or dioxane.
8. The preparation method of tiopronin according to claim 1, characterized in that: In the third step, the acid is selected from hydrochloric acid, phosphoric acid, trifluoroacetic acid and formic acid.
9. The preparation method of tiopronin according to claim 1, characterized in that: In the third step, the base is selected from potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.