A one-pot method for preparing vildagliptin using L-proline as a raw material
The one-pot method for preparing vildagliptin uses inexpensive concentrated sulfuric acid as a dehydrating agent, simplifying the process and solving the problems of high cost and solid waste in existing technologies, thus achieving the production of vildagliptin with high purity and high yield.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ZHEJIANG GUOBANG PHARMA
- Filing Date
- 2026-03-20
- Publication Date
- 2026-06-12
AI Technical Summary
Existing vildagliptin synthesis routes use expensive raw materials and catalysts, resulting in high production costs and generating large amounts of solid waste and high levels of impurities, making them unsuitable for industrial production.
Using L-proline as a raw material, vidagliptin is prepared by one-pot reaction of chloroacetyl chloride and triethylamine acylation, followed by condensation with cyanuric chloride and ammonium bicarbonate, and then in-situ dehydration with concentrated sulfuric acid. Vidagliptin is then directly reacted with 3-aminoadamantane alcoholamine, avoiding intermediate separation and protection steps, and using inexpensive concentrated sulfuric acid as a dehydrating agent.
It reduces production costs, decreases solid waste generation, improves product purity and yield, simplifies the process, and is suitable for industrial production.
Smart Images
Figure CN122187706A_ABST
Abstract
Description
Technical Field
[0001] This application relates to a one-pot method for preparing vildagliptin using L-proline as a raw material, belonging to the field of medicinal chemistry technology. Background Technology
[0002] Vildagliptin is an oral antidiabetic drug developed by Novartis, with its marketing application first submitted in 2006. This drug belongs to the dipeptidyl peptidase-IV (DPP-IV) inhibitor class and can be used alone or in combination with metformin, demonstrating significant efficacy in glycemic control. Currently, vildagliptin has been approved for marketing in many countries and regions, including the European Union, and is widely used in the global diabetes treatment field, holding a significant market position.
[0003] The current mainstream synthetic route uses L-prolylamide as a raw material, which is acylated to produce pyrrolamide (Formula III), then undergoes a dehydration reaction to obtain tetrahydropyrrole (Formula IV), and finally condenses with 3-aminoadamantanoolamine to prepare vildagliptin. However, L-prolylamide is expensive, which increases the production cost.
[0004] .
[0005] The relevant patents that adopt the above-mentioned routes differ in the settings of parameters such as the dehydrating agent. For example, WO2000034241 uses trifluoroacetic anhydride as the dehydrating agent; US2008167479 uses cyanuric trichloride as the dehydrating agent.
[0006] Some modified routes employ high-pressure amination during the L-proline reaction, which increases production costs. Alternatively, L-proline, a readily available raw material, is used, and after acylation, it is coupled with ammonium bicarbonate to prepare Formula III. This is then dehydrated with trifluoroacetic anhydride and alkylated to produce vildagliptin (Beilstein journal of organic chemistry, 2008, 4(1): 20). However, Formula II has a lower yield (81%), and the condensation reagent DCC and dehydrating agent trifluoroacetic anhydride are expensive. Another route uses L-proline, a readily available raw material, and is coupled with ammonium bicarbonate under Boc protection and PyBop catalysis to prepare an amidate. This is then dehydrated with cyanuric chloride (TCT) and hydrolyzed to prepare cyanopyrrole. Finally, it is coupled with adamantane alcohol to prepare vildagliptin. This route has an additional protection step, and the coupling reagent PyBop is very expensive, making it unsuitable for industrial production of vildagliptin.
[0007] In this regard, existing technologies not only require the application of large amounts of inorganic bases such as potassium carbonate and catalyst potassium iodide, as well as acid-binding agents, resulting in the generation of large amounts of solid alkali waste, but also require the use of additional solvents to separate the vildagliptin intermediate during the reaction. The product contains a considerable amount of chiral impurities and disubstituted impurities (the proportion of impurities in the intermediate reaction solution is about 2-3%). Summary of the Invention
[0008] In view of this, this application provides a method for preparing vildagliptin in a one-pot process using L-proline as a raw material.
[0009] Specifically, this application is implemented through the following scheme: A one-pot method for preparing vildagliptin from L-proline involves using L-proline as a raw material, adding chloroacetyl chloride and triethylamine for acylation, then adding cyanuric chloride and ammonium bicarbonate for condensation reaction, followed by the addition of concentrated sulfuric acid and in-situ dehydration to obtain the intermediate tetrahydropyrrole. After solvent substitution, the obtained substitution product is reacted with 3-aminoadamantanoylamine to prepare the target compound vildagliptin in a one-pot process. The molar equivalent of 3-aminoadamantanoylamine relative to L-proline is 1.5~3.0.
[0010] The above scheme uses L-proline as raw material. The intermediate obtained by acylation and condensation is directly dehydrated in situ with concentrated sulfuric acid and then replaced with solvent. It can then react with a large amount of the key material 3-aminoadamantanoylamine to produce vildagliptin. The whole process does not require intermediate separation or Boc protection and deprotection. The reaction conditions are mild, there are almost no chiral impurities, and the content of disubstituted impurities is even lower. It also does not require the introduction of inorganic bases, catalysts, acid-binding agents and other auxiliaries, which greatly reduces the generation of solid waste alkali. The excess 3-aminoadamantanoylamine can be recycled and reused in the post-treatment, achieving cost reduction from multiple aspects such as process and auxiliaries.
[0011] Furthermore, as a preferred option: In the acylation reaction, L-proline was added to DMF, followed by the addition of chloroacetyl chloride. After reacting at room temperature, triethylamine was added, and the mixture was filtered to obtain the acylated product.
[0012] The molar ratio of L-proline to chloroacetyl chloride is 1:1.0~1.5.
[0013] The molar ratio of L-proline to triethylamine is 1:1.0~1.5.
[0014] The cyanuric chloride is added in multiple stages at a temperature of 0-5°C.
[0015] The molar ratio of L-proline to cyanuric chloride is 1:0.8~1.2.
[0016] The molar ratio of L-proline to ammonium bicarbonate is 1:3~5.
[0017] The molar ratio of L-proline to concentrated sulfuric acid is 1:0.8~1.2.
[0018] During the addition of concentrated sulfuric acid, the temperature of the reaction solution is controlled at -5~0℃.
[0019] The solvent used for solvent replacement is any one of ethyl acetate, isopropyl acetate, ethyl formate, and tert-butyl formate.
[0020] The solvent replacement temperature is 0-5°C, and the pH is 5-6. More preferably: pH was adjusted using a 10% sodium hydroxide aqueous solution.
[0021] The solvent replacement process is as follows: Ethyl acetate is added to the reaction system after in-situ dehydration of concentrated sulfuric acid, and the pH is adjusted. The system is then filtered, and the filter cake is washed again with ethyl acetate. The liquid phase is separated, the aqueous phase is washed with ethyl acetate, and the organic phases are combined and then washed with saturated brine to obtain the replacement product.
[0022] The 3-aminoadamantanolamine was added to the ethyl acetate system, heated to reflux, and added dropwise to the substitution product. After reflux reaction, crude vildagliptin was obtained. The crude product was added to butanone and DBU, heated to dissolve, and then hot filtered. The filtrate was stirred and cooled to 5-10°C to crystallize. After filtration, it was dried under vacuum at 45-50°C to obtain the finished vildagliptin product.
[0023] This invention provides a simple one-pot process for preparing vildagliptin. The dehydrating agent, concentrated sulfuric acid, is cheaper than commercially available cyanuric chloride and trifluoroacetic anhydride, and the conditions are milder, resulting in higher product purity. Furthermore, process research has shown that by increasing the equivalent amount of the key material 3-aminoadamantaneol, the use of traditional inorganic bases such as potassium carbonate and catalysts like potassium iodide can be avoided. The reaction solution also contains lower levels of disubstituted impurities compared to conventional processes. The 3-aminoadamantaneol hydrochloride obtained after post-treatment can be recovered as 3-aminoadamantaneol after treatment with anion exchange resin, significantly reducing the generation of solid alkali waste. This one-pot patent greatly reduces the types of solvents and purification steps, making it particularly suitable for industrial production. Attached Figure Description
[0024] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application.
[0025] Figure 1 This is a high-performance liquid chromatogram of the acylated product in this application.
[0026] Figure 2 This is a high-performance liquid chromatogram of the product obtained from the condensation reaction in this application.
[0027] Figure 3 This is a high-performance liquid chromatogram of the product obtained by solvent displacement in this application.
[0028] Figure 4 This is the high-performance liquid chromatogram of the finished product, vildagliptin.
[0029] Figure 5 The image shows the high-performance liquid chromatogram of the finished product vildagliptin in Example 2.
[0030] Figure 6 The figures show the high-performance liquid chromatograms of the finished vildagliptin products using different dehydrating agents. (a) The dehydrating agent is cyanuric chloride, (b) The dehydrating agent is POCl3, and (c) The dehydrating agent is trifluoroacetic anhydride. Detailed Implementation
[0031] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the technical solutions in the embodiments of this application will be further described in detail below with reference to the accompanying drawings. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit the technical solutions of this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without creative effort are within the scope of protection of this application.
[0032] Example 1
[0033] This embodiment provides a one-pot method for preparing vildagliptin from L-proline, the reaction formula of which is expressed as follows: .
[0034] The specific process is as follows: L-proline (2 kg, 17.37 mol) was added to 10 L of DMF, and chloroacetyl chloride (2.09 kg, 18.51 mol) was added dropwise. The reaction was carried out at room temperature. After 2 h of reaction, the system was dissolved, and triethylamine (1.87 kg, 18.51 mol) was added dropwise. The mixture was filtered to prepare a DMF solution of carboxylic acid pyrrole (Formula II). A sample was taken for analysis, and its HPLC chromatogram is shown below. Figure 1 As shown: the yield of carboxylic acid pyrrole was 91.2% (external standard yield, based on L-proline), and the purity was 92.827%.
[0035] The DMF solution of the above-mentioned carboxylic acid pyrrole (Formula II) was cooled to 0°C, and cyanuric chloride (3.17 kg, 17.19 mol) was added in two batches, followed by ammonium bicarbonate (5 kg, 63.24 mol). The reaction was maintained at this temperature for 8 hours to prepare the condensation product (Formula III). Samples were taken for analysis, and its HPLC chromatogram is shown below. Figure 2 As shown: the yield of the condensation product was 75.4% (external standard yield, based on L-proline), and the purity was 93.10%.
[0036] Maintaining the temperature at 0°C, add concentrated sulfuric acid (1.4 kg, 14.23 mol) to the above reaction system and continue incubation for 6 hours. Detect the reaction endpoint using HPLC. Add 6 kg of ethyl acetate to the reaction system, maintain the temperature near 0°C, and adjust the pH to near 5 using 10% sodium hydroxide solution. Filter the mixture, and wash the filter cake with 1 kg of ethyl acetate. Separate the layers, washing the aqueous phase twice with 2 kg of ethyl acetate. Combine the organic phases and wash twice with saturated brine to prepare an ethyl acetate solution of cyanopyrrole (Formula IV). Sample and analyze the solution; its HPLC chromatogram is shown below. Figure 3 As shown: the yield of cyanopyrrole was 64.1% (external standard yield, based on L-proline), and the purity was 94.598%.
[0037] 3-Aminoadamantanol (5.9 kg, 34.75 mol) was added to 20 L of ethyl acetate. The mixture was heated to reflux, and the ethyl acetate solution of compound IV was added dropwise. After the addition was complete, the mixture was kept under reflux for 1 h. The mixture was cooled and filtered. The filter cake was washed with ethyl acetate and washed twice with saturated brine. The solution was concentrated to dryness. 14 L of ethanol was added to dissolve the solution. The mixture was slowly cooled to 0 °C, filtered, and dried at 40-50 °C to obtain crude vildagliptin. The crude product was added to 15 L of butanone and 30 g of DBU. The mixture was heated to reflux until dissolved, and the temperature was slowly lowered for 5-10 h. The mixture was stirred for 2-3 h. The mixture was filtered and dried under vacuum at 45-50 °C for 4-5 h to obtain 2.5 kg of vildagliptin product. Samples were taken for analysis, and the HPLC chromatogram is shown below. Figure 4 As shown: the overall yield was 47.4%, and the HPLC purity was 99.90%.
[0038] The ESI-MS spectral data of the vidagliptin product are as follows: 1 H-NMR(CDCl3,400MHz)δ4.81-4.85(m,0.2H),4.74-4.76(m,0.8H),3.35-3.68(m,4H),2.06-2.37(m,6H),1.51-1.85(m,14H); ESI-MS (m / z): 304.11 ([M+H]) + ).
[0039] Example 2
[0040] This embodiment has the same setup as Example 1, except that the molar equivalent of 3-aminoadamantanol relative to L-proline is replaced by 8.8 kg (52.11 mol). 2.7 kg of vildagliptin was obtained. Sampling and analysis were performed; the HPLC chromatogram is shown below. Figure 5 As shown: the overall yield was 51.2%, and the HPLC purity was 99.87%.
[0041] This application increases the amount of 3-aminoadamantanol used to 1.5 to 3.0 equivalents (e.g., 2 equivalents in Example 1 and 3 equivalents in Example 2). At this time, the disubstituted impurities in the reaction solution can be controlled to ≤3.0%. In addition, the reaction time can be greatly shortened, requiring only 1 hour of reflux to complete, and there is no need to use solid potassium carbonate and solid potassium iodide catalyst.
[0042] When the amount of 3-aminoadamantanol used decreases to 1.0~1.5 equivalents (e.g., when the amount of 3-aminoadamantanol used is replaced by 3.08 kg (18.24 mol, which is equivalent to 1.05), a large amount of raw material L-proline will remain, resulting in a lower yield and lower product purity.
[0043] Example 3
[0044] This embodiment has the same setup as Embodiment 1, except that the dehydrating agent concentrated sulfuric acid is replaced with cyanuric chloride, POCl3, and trifluoroacetic anhydride, respectively.
[0045] 2.5 kg of vildagliptin was obtained using cyanuric chloride. Samples were taken and analyzed; the HPLC chromatogram is shown below. Figure 6 As shown in (a): the overall yield was 47.4% and the HPLC purity was 99.84%.
[0046] Using POCl3, 2.2 kg of vildagliptin was obtained. Samples were taken and analyzed; the HPLC chromatogram is shown below. Figure 6 As shown in (b): the overall yield was 41.7% and the HPLC purity was 99.82%.
[0047] Using trifluoroacetic anhydride, 2.1 kg of vildagliptin was obtained. Sampling and analysis were performed; the HPLC chromatogram is shown below. Figure 6 As shown in (c): Overall yield 39.8%, HPLC purity 99.84%. The results showed that cyanuric chloride has a strong irritating odor and skin sensitization, POCl3 will severely corrode equipment, and trifluoroacetic anhydride reagent is very expensive. However, this application uses inexpensive and mild concentrated sulfuric acid as a dehydrating agent, and the reaction can be carried out under conditions of -5 to 0℃. The reaction conditions are milder, there are fewer impurities, and the reaction purity is improved.
[0048] Comparative Example 1
[0049] WO2000034241 is used as comparative example 1.
[0050] Comparative Example 2
[0051] CN113527167A is used as comparative example 2.
[0052] Table 1: Comparison of preparation effects of different schemes .
[0053] This application eliminates the use of traditional inorganic bases, significantly reducing waste. The overall synthetic route reduces the types of solvents and purification steps, greatly improving product yield and making it particularly suitable for industrial production.
[0054] The above-described embodiments are merely illustrative of several feasible implementations of the present invention, and their descriptions are relatively specific and detailed. However, they should not be construed as limiting the scope of the present invention, nor are the embodiments intended to limit the scope of protection in the claims of the present invention. For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention. All equivalent implementations or changes that do not depart from the present invention should be included in the technology of the present invention.
Claims
1. A method for preparing vildagliptin in a one-pot process using L-proline as a raw material, characterized in that: Using L-proline as a raw material, chloroacetyl chloride and triethylamine were added for acylation, followed by condensation reaction with cyanuric chloride and ammonium bicarbonate. Concentrated sulfuric acid was then added, and the intermediate tetrahydropyrrole was dehydrated in situ. After solvent substitution, the substituted product was reacted with 3-aminoadamantanoylamine in a one-pot method to prepare the target compound vildagliptin. The molar equivalent of 3-aminoadamantanoylamine relative to L-proline was 1.5~3.
0.
2. The method for preparing vildagliptin in a one-pot process using L-proline as a raw material according to claim 1, characterized in that: In the acylation reaction, L-proline was added to DMF, followed by the addition of chloroacetyl chloride. After reacting at room temperature, triethylamine was added, and the mixture was filtered to obtain the acylated product.
3. The method for preparing vildagliptin in a one-pot process using L-proline as a raw material according to claim 1, characterized in that: The molar ratio of L-proline to chloroacetyl chloride is 1:1.0~1.5, and the molar ratio of L-proline to triethylamine is 1:1.1~1.
5.
4. The method for preparing vildagliptin in a one-pot process using L-proline as a raw material according to claim 1, characterized in that: The cyanuric chloride is added in multiple stages at a temperature of 0-5°C.
5. The method for preparing vildagliptin from L-proline in a one-pot process according to claim 1, characterized in that: The molar ratio of L-proline to cyanuric chloride is 1:0.8~1.2, and the molar ratio of L-proline to ammonium bicarbonate is 1:3~5.
6. The method for preparing vildagliptin in a one-pot process using L-proline as a raw material according to claim 1, characterized in that: The molar ratio of L-proline to concentrated sulfuric acid is 1:0.8~1.
2.
7. The method for preparing vildagliptin from L-proline in a one-pot process according to claim 1, characterized in that: During the addition of concentrated sulfuric acid, the temperature of the reaction solution is controlled at -5~0℃.
8. The method for preparing vildagliptin in a one-pot process using L-proline as a raw material according to claim 1, characterized in that: The solvent used for solvent replacement is any one of ethyl acetate, isopropyl acetate, ethyl formate, and tert-butyl formate.
9. The method for preparing vildagliptin from L-proline in a one-pot process according to claim 1, characterized in that: The solvent replacement temperature is 0~5℃, and the pH is 5~6.
10. The method for preparing vildagliptin in a one-pot process using L-proline as a raw material according to claim 1, characterized in that: The solvent replacement process is as follows: Ethyl acetate is added to the reaction system after in-situ dehydration of concentrated sulfuric acid, and the pH is adjusted. The system is then filtered, and the filter cake is washed again with ethyl acetate. The liquid phase is separated, the aqueous phase is washed with ethyl acetate, and the organic phases are combined and then washed with saturated brine to obtain the replacement product.