A process for the synthesis of sitagliptin intermediate
By using the aldol condensation reaction of 2-(2,4,5-trifluorophenyl)acetaldehyde with an enol salt, combined with specific catalysts and solvents, the synthesis process of sitagliptin intermediates has been simplified, solving the problems of cumbersome steps and low catalyst utilization in existing technologies, and achieving efficient and low-cost production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- JIANGSU ALPHA PHARM CO LTD
- Filing Date
- 2023-04-26
- Publication Date
- 2026-07-14
AI Technical Summary
The existing synthesis process of sitagliptin involves complex reaction steps, low catalyst utilization, high cost, and a wide variety of catalysts, especially expensive palladium on carbon.
Aldol condensation of 2-(2,4,5-trifluorophenyl)acetaldehyde with an enolate was used to generate an intermediate product. By reducing byproducts and increasing product yield through condensation reaction, catalysts such as hexamethylphosphoric triamine, phenyl thiochloroformate, and tributyltin hydride were used, and the reaction temperature and solvent selection were controlled to optimize the reaction process.
It simplifies the reaction steps, improves the utilization rate of catalysts, reduces production costs, and enhances the purity and yield of the product.
Smart Images
Figure CN116514656B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to a synthetic process for a sitagliptin intermediate, belonging to the field of pharmaceutical intermediate preparation. Background Technology
[0002] Sitagliptin is a potent DPP4 inhibitor that effectively inhibits DPP-4. It reduces the in vitro migration of isolated splenic CD4 T cells through pathways involving cAMP / PKA / Rac1 activation and stimulates intestinal L cells to secrete GLP-1 via DPP-4-independent protein kinase A- and MEK-ERK1 / 2-dependent pathways, thereby reducing the impact of autoimmunity on graft survival. As the first dipeptidyl peptidase-IV (DPP-IV) inhibitor used to treat type 2 diabetes, it is usually administered in phosphate form.
[0003] Patent document CN102574856B discloses the synthesis of sitagliptin, using 2,4,5-trifluorophenylacetic acid as a substrate, reacting it with cyclo(isopropyl)malonate under the catalysis of N,N'-carbonyldiimidazole. The synthesized product 19 is then refluxed in methanol to obtain product 21, which reacts with ammonium acetate to obtain product 28, and with acetonitrile borane to generate product 29. Finally, product 31 is obtained by catalysis with 3-indolepropionic acid. This scheme has a long reaction route, complex catalysts, and low catalyst utilization. The specific synthetic route is as follows:
[0004]
[0005] Patent document CN102574856B discloses a method for preparing sitagliptin intermediates, sitagliptin, or salts thereof. 2,4,5-trifluorobromobenzene is prepared as a Grignard reagent. Under the action of a catalyst, the Grignard reagent reacts with a triborate in an organic solvent to obtain compound III, 2,4,5-trifluorophenylboronic acid. Compound IV is then reacted with compound III, 2,4,5-trifluorophenylboronic acid, in a solvent under the action of a transition metal catalyst and a base to obtain compound V. This method uses expensive palladium on carbon to catalyze the reaction and involves a relatively large number of catalysts. The specific synthetic route is as follows:
[0006]
[0007] As can be seen from the above literature, their common drawbacks are that the production process requires the addition of complex catalysts to catalyze the reaction, and the catalysts also include relatively expensive palladium on carbon, the reaction route is long, and the utilization rate of the catalysts is low.
[0008] Therefore, there is an urgent need to find a preparation method that requires fewer catalysts, has a shorter reaction route, higher catalyst utilization, and lower cost. Summary of the Invention
[0009] To address the shortcomings of the prior art, this invention provides a synthesis process for sitagliptin intermediates, which solves the problems of reducing reaction steps, reducing reaction catalysts, and improving catalyst utilization.
[0010] The objective of this invention is achieved through the following technical solution: a synthetic process for a sitagliptin intermediate, comprising the following steps:
[0011] S1: In an organic solvent, 2-(2,4,5-trifluorophenyl)acetaldehyde is condensed with a compound of formula III in the presence of a catalyst to produce a compound of formula II;
[0012] S2: In an organic solvent, one of the hydroxyl groups of the compound of formula II is removed in the presence of a catalyst to obtain the compound of formula I.
[0013] In this invention, the enol salt of Formula III is subjected to aldol condensation with 2-(2,4,5-trifluorophenyl)acetaldehyde. Due to the stereodifferentiation of the enol salt and its reaction with stereospecific aldehydes and ketones, two aldol forms can be obtained, both of which can be used in subsequent reactions, thus avoiding waste of raw materials. The Formula I compound obtained by removing the hydroxyl group from the Formula II compound can be used for the preparation of sitagliptin.
[0014] In the above-mentioned synthesis process of sitagliptin intermediates, preferably, the organic solvent in step S1 is one of ethanol, diethyl ether, or tetrahydrofuran. Most preferably, ethanol is used as the solvent, resulting in the highest solubility of the reactants.
[0015] In the above-mentioned synthesis process of sitagliptin intermediate, preferably, the compound of formula III is an enol salt.
[0016] In the above-mentioned synthesis process of sitagliptin intermediate, preferably, the M in the MO group of the compound of formula III is selected from one of Li, Na, B, Al, Si, etc.
[0017] In the above-mentioned synthesis process of sitagliptin intermediate, preferably, the catalyst in step S1 is hexamethylphosphoric triamine. Most preferably, hexamethylphosphoric triamine results in a higher product yield.
[0018] In the above-mentioned synthesis process of sitagliptin intermediate, preferably, the reaction temperature in step S1 is -78 to -40°C. Most preferably, the reaction temperature is -78°C.
[0019] In the above-mentioned synthesis process of sitagliptin intermediate, preferably, the organic solvent in step S2 is one of tetrahydrofuran or dichloromethane. Most preferably, tetrahydrofuran is used as the solvent, resulting in a higher reaction yield.
[0020] In the above-mentioned synthesis process of sitagliptin intermediate, preferably, the activator in step S2 is one of phenyl thiochloroformate, 4-dimethylaminopyridine, or methanesulfonyl chloride. Most preferably, phenyl thiochloroformate is used to activate the hydroxyl group, resulting in a higher reaction rate.
[0021] In the above-mentioned synthesis process of sitagliptin intermediate, as a preferred option, the catalyst used in step S2 is tributyltin hydride.
[0022] In summary, compared with the prior art, the present invention has the following advantages:
[0023] In this invention, an intermediate product is obtained by aldol condensation of 2-(2,4,5-trifluorophenyl)acetaldehyde with an enolate. Compared with the original aldol reaction, which has the disadvantages of self-condensation and polycondensation, the formation of an enolate followed by condensation can inhibit its self-condensation, promote cross-condensation to generate the product, improve the product yield, and reduce the formation of by-products. Attached Figure Description
[0024] Figure 1 This is the synthetic route of the present invention. Detailed Implementation
[0025] The technical solution of the present invention will be further described in detail below through specific embodiments, but the present invention is not limited to these embodiments.
[0026] Example 1
[0027] 200 mL of tetrahydrofuran was placed in a reaction vessel, and 16.38 mL (0.2 mol) of methyl glycolate was added dropwise. 27.85 g (1.3 eq) of diisopropylaminolithium was added, and the mixture was stirred for 30 min. Then, 17.92 g (0.1 mol) of hexamethylphosphoric triamine was added. The mixture was cooled to -78 °C and reacted for 1 h. The reaction was stopped by heating to 0 °C. The solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added for extraction. The organic phases were combined and washed successively with saturated brine and water. The solution was removed, and the mixture was recrystallized. After filtration and crystallization, the product was dried to obtain 15.75 g of compound III. The product yield was 82%, and the product purity was 99%.
[0028] Example 2
[0029] 100 mL of ethanol was placed in a beaker, and 17.41 g (0.1 mol) of 2-(2,4,5-trifluorophenyl)acetaldehyde was added. After stirring until completely dissolved, 12.48 g (0.1 mol * 1.3) of compound III was added. The reaction was stirred for 1 h, and the reaction was quenched with water. The solution was removed under reduced pressure, and 100 mL of ethyl acetate was added for extraction. The organic phases were combined, washed with 200 mL of saturated brine, and the solution was removed. The solution was recrystallized, filtered, and dried to obtain 23.06 g of compound II. The product yield was 87.3%, and the product purity was 99.2%.
[0030] Example 3
[0031] 200 mL of tetrahydrofuran was added to a beaker, followed by 26.42 g (0.1 mol) of compound II and 17.26 g of phenyl thiochloroformate. The mixture was stirred for 15 min, then 12.22 g of 4-dimethylaminopyridine was added. The mixture was reacted at room temperature for 30 min. After the reaction was complete, 14.55 g (0.05 mol) of tributyltin hydride was added, and the mixture was heated to 45 °C and reacted for another 2 h. After the reaction was complete, a large amount of water was added to quench the reaction. The mixture was then desolvated under reduced pressure and extracted with 200 mL of ethyl acetate. The organic phases were combined and washed with saturated brine. The mixture was desolvated, recrystallized, filtered, and dried to obtain 19.71 g of compound I. The product yield was 79.4%, and the product purity was 99.6%.
[0032] Example 4
[0033] 200 mL of tetrahydrofuran was placed in a reaction vessel, and 16.38 mL (0.2 mol) of methyl glycolate was added dropwise. 27.85 g (1.3 eq) of diisopropylaminolithium was added, and the mixture was stirred for 30 min. Then, 17.92 g (0.1 mol) of hexamethylphosphoric triamine was added. The mixture was cooled to -78 °C and reacted for 1 h. The reaction was stopped by heating to 0 °C. The solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added for extraction. The organic phases were combined and washed successively with saturated brine and water. The solution was removed, and the mixture was recrystallized. After filtration and crystallization, the product was dried to obtain 14.75 g of compound III. The product yield was 76.8%, and the product purity was 98.6%.
[0034] Example 5
[0035] 100 mL of diethyl ether was placed in a beaker, and 17.41 g (0.1 mol) of 2-(2,4,5-trifluorophenyl)acetaldehyde was added. After stirring until completely dissolved, 12.48 g (0.1 mol * 1.3) of compound III was added. The reaction was stirred for 1 h, and the reaction was quenched with water. The solution was removed under reduced pressure, and 100 mL of ethyl acetate was added for extraction. The organic phases were combined, washed with 200 mL of saturated brine, and the solution was removed. The solution was recrystallized, filtered, and dried to obtain 22.48 g of compound II. The product yield was 85.1%, and the product purity was 98.8%.
[0036] Example 6
[0037] 100 mL of tetrahydrofuran was placed in a beaker, followed by 17.41 g (0.1 mol) of 2-(2,4,5-trifluorophenyl)acetaldehyde. After stirring until completely dissolved, 12.48 g (0.1 mol * 1.3) of compound III was added. The mixture was stirred for 1 h, and the reaction was quenched with water. The solution was removed under reduced pressure, and the mixture was extracted with 100 mL of ethyl acetate. The organic phases were combined and washed with 200 mL of saturated brine. The solution was removed, and the mixture was recrystallized. After filtration and drying, 22.03 g of compound II was obtained. The product yield was 83.4%, and the product purity was 99%.
[0038] Example 7
[0039] 200 mL of dichloromethane was added to a beaker, followed by 26.42 g (0.1 mol) of compound II and 17.26 g of phenyl thiochloroformate. The mixture was stirred for 15 min, then 12.22 g of 4-dimethylaminopyridine was added. The mixture was reacted at room temperature for 30 min. After the reaction was complete, 14.55 g (0.05 mol) of tributyltin hydride was added, and the mixture was heated to 45 °C and reacted for another 2 h. After the reaction was complete, a large amount of water was added to quench the reaction. The mixture was then desolvated under reduced pressure and extracted with 200 mL of ethyl acetate. The organic phases were combined and washed with saturated brine. The mixture was desolvated, recrystallized, filtered, and dried to obtain 19.53 g of compound I. The product yield was 78.7%, and the product purity was 99.2%.
[0040] Example 8
[0041] 200 mL of tetrahydrofuran was added to a beaker, followed by 26.42 g (0.1 mol) of compound II and 12.21 g of 4-dimethylaminopyridine. The mixture was stirred for 15 min, then another 12.22 g of 4-dimethylaminopyridine was added. The mixture was reacted at room temperature for 30 min. After the reaction was complete, 14.55 g (0.05 mol) of tributyltin hydride was added, and the mixture was heated to 45 °C and reacted for another 2 h. After the reaction was complete, a large amount of water was added to quench the reaction. The mixture was then desolvated under reduced pressure and extracted with 200 mL of ethyl acetate. The organic phases were combined and washed with saturated brine. The mixture was desolvated, recrystallized, filtered, and dried to obtain 18.52 g of compound I. The product yield was 74.6%, and the product purity was 98.5%.
[0042] Example 9
[0043] 200 mL of tetrahydrofuran was added to a beaker, followed by 26.42 g (0.1 mol) of compound II and 11.45 g of methanesulfonyl chloride. The mixture was stirred for 15 min, then 12.22 g of 4-dimethylaminopyridine was added. The mixture was reacted at room temperature for 30 min. After the reaction was complete, 14.55 g (0.05 mol) of tributyltin hydride was added, and the mixture was heated to 45 °C and reacted for another 2 h. After the reaction was complete, a large amount of water was added to quench the reaction. The mixture was then desolvated under reduced pressure and extracted with 200 mL of ethyl acetate. The organic phases were combined and washed with saturated brine. The mixture was desolvated, recrystallized, filtered, and dried to obtain 18.07 g of compound I. The product yield was 72.8%, and the product purity was 98.6%.
[0044] Comparative Example
[0045] The comparative example is an embodiment of patent CN102574856A:
[0046] 2,4,5-Trifluorophenylacetic acid (18) was suspended in tetrahydrofuran at 25-30°C, and the reaction mixture was stirred for 10-15 minutes. 1,1'-carbonyldiimidazole was added in four portions to this clear solution, and the reaction mixture was stirred at 25-30°C for 2-3 hours. After stirring for 2-3 hours, Michaelis-Menten acid was added, and the reaction mixture was heated at 50-55°C for 6 hours. After heating at 50-55°C for 6 hours, tetrahydrofuran was completely removed by distillation under reduced pressure at 50-55°C to obtain a dark yellow residue. The dark yellow residue was acidified at 0-5°C using a 1:1 mixture of 35% hydrochloric acid and water. The product was extracted from the aqueous solution using dichloromethane. The combined dichloromethane layers were further washed with water. After washing with water, distillation under reduced pressure was completely removed to obtain a dark yellow loose solid. The product was further washed with methanol at 0-5°C, with a molar yield of 60-65% and a chemical purity of 98-99.5% (as measured by HPLC).
[0047] The Michaelis adduct (19) was added to methanol at 25-30°C, and the particularly clear solution was refluxed at 60-63°C for 3-4 hours. After reflux for 3-4 hours, methanol was completely removed by distillation at 45-50°C under reduced pressure to obtain a pale yellow residue. The pale yellow residue was further treated with a 5% sodium carbonate solution to adjust the pH to 7-8. After pH adjustment, the product was extracted in dichloromethane. The combined dichloromethane layers were further washed with water. The dichloromethane was distilled under reduced pressure to obtain a pale yellow oily product with a molar yield of 85-90% and a chemical purity of 93-95% (as measured by HPLC).
[0048] Methyl 4-(2,4,5-trifluorophenyl)acetoacetate (21) and ammonium acetate were added to methanol, and the solution was refluxed at 60-63°C for 5-6 hours. After reflux for 5-6 hours, methanol was completely removed by distillation to obtain a pale yellow residue. The pale yellow residue was further stirred with ethyl acetate at 25-30°C. The precipitated ammonium acetate was filtered, and ethyl acetate was completely removed by distillation to obtain a pale yellow product. The product was further stirred with hexane at 25-30°C for 1 hour, filtered, and dried under reduced pressure at 45-50°C for 4-5 hours. Molar yield: 85-90%, chemical purity: 96-97% (as measured by HPLC).
[0049] Methyl(Z)-3-amino-4-(2,4,5-trifluorophenyl)but-2-enyl ester (28) was added to methanol at 25-30°C, and the reaction mixture was stirred for 10-15 minutes to obtain a clear solution. Sulfuric acid was added in a controlled manner to the clear, pale yellow solution at 0-10°C, and the solution was stirred for 10-15 minutes at 0-10°C. After stirring for 10-15 minutes at 0-10°C, sodium cyanoborohydride was added in 10 batches. The clear white suspension was stirred for 2 hours at 0-10°C. Methanol was completely removed by distillation at 45-50°C under reduced pressure to obtain a pale yellow residue. This residue was further treated at 0-5°C with a 1:1 mixture of 35% hydrochloric acid and water to bring the pH to 2. The suspension was stirred at 0-5°C for 10-15 minutes, and the suspension was further alkalized with 20% sodium carbonate to bring the pH to 8-9. The product was extracted with ethyl acetate. Wash the combined ethyl acetate layers with water. Separate the product by distillation of ethyl acetate to obtain a pale yellow oil. Molar yield: 75-80%, chemical purity: 78-85% (as measured by HPLC).
[0050] (3RS)-3-amino-4-(2,4,5-trifluorophenyl)butyrate methyl ester (29) was added to isopropanol at 25-30°C, and the reaction mixture was stirred for 15 minutes to obtain a clear solution. After stirring for 15 minutes, a controlled addition of (R)-(-)-mandelic acid was carried out. After the addition was complete, the reaction mixture was stirred at 25-30°C for 3 hours to obtain enantiomeric enriched crude (3R)-3-amino-4-(2,4,5-trifluorophenyl)butyrate methyl ester (R)-(-)-mandelic acid as a white product. The product was filtered, washed with isopropanol, and dried in a vacuum oven at 40-45°C for 4-5 hours to obtain enantiomeric enriched crude (3R)-3-amino-4-(2,4,5-trifluorophenyl)butyrate methyl ester (R)-(-)-mandelic acid. The dried, enantiomerically enriched crude (3R)-3-amino-4-(2,4,5-trifluorophenyl)butyrate (R)-(-)-mandelate product was added to isopropanol at 25-30°C, and the white suspension was further heated at 75-80°C to obtain a partially clear solution. The partially clear solution was clarified by adding water at 75-80°C. The clarified solution was further stirred for 0.5 hours. After stirring for 0.5 hours, the clarified solution was gradually cooled to 0-5°C over 3 hours to obtain enantiomerically enriched pure (3R)-3-amino-4-(2,4,5-trifluorophenyl)butyrate (R)-(-)-mandelate (30) as a white product. The product was filtered, washed with isopropanol, and dried in a vacuum oven at 40-45°C for 4-5 hours, with a molar yield of 80-85% and a chemical purity of 98-99.5% (as measured by HPLC).
[0051] Methyl (3R)-3-amino-4-(2,4,5-trifluorophenyl)butyrate (R)-(-)-mandelate (30) was added to water, and the suspension was stirred for 10-15 minutes. The suspension was further alkalized with 10% Na₂CO₃ solution until the pH of the reaction mixture reached 8-9. The product was extracted in ethyl acetate. The combined ethyl acetate layers were further washed with water. The product as a pale yellow oil was separated by complete distillation of ethyl acetate under reduced pressure at 45-50 °C, molar yield: 90-95%, chemical purity: 99-99.5% (as measured by HPLC).
[0052] Compared with the synthesis method in this invention, the reaction route in this comparative example is longer and the added catalysts are more complicated, which is not conducive to large-scale production.
[0053] The embodiments of the present invention are not limited to those described above. Without departing from the spirit and scope of the present invention, those skilled in the art can make various changes and improvements to the present invention in form and detail, and these are all considered to fall within the protection scope of the present invention.
Claims
1. A synthetic process for a sitagliptin intermediate, characterized in that, The roadmap for the synthesis process is as follows: ； In the compound of formula III, M is selected from the MO group, which is Li. The specific steps of the synthesis process are as follows: 200 mL of tetrahydrofuran was placed in a reaction vessel, 16.38 mL of methyl glycolate was added dropwise, followed by 27.85 g of diisopropylaminolithium. The mixture was stirred for 30 min, then 17.92 g of hexamethylphosphoric triamine was added. The temperature was lowered to -78 °C, and the reaction was carried out for 1 h. The temperature was then raised to 0 °C to stop the reaction. The solvent was removed under reduced pressure, and 100 mL of ethyl acetate was added for extraction. The organic phases were combined, washed sequentially with saturated brine and water, and the solution was removed. The mixture was recrystallized, filtered, and dried to obtain 15.75 g of compound III. The product yield was 82%, and the product purity was 99%. 100 mL of ethanol was placed in a beaker, and 17.41 g of 2-(2,4,5-trifluorophenyl)acetaldehyde was added. After stirring until completely dissolved, 12.48 g of compound III was added, and the reaction was stirred for 1 h. The reaction was quenched with water, and the solution was removed under reduced pressure. 100 mL of ethyl acetate was added for extraction. The organic phases were combined, washed with 200 mL of saturated brine, and the solution was removed. The solution was recrystallized, filtered, and dried to obtain 23.06 g of compound II. The product yield was 87.3%, and the product purity was 99.2%. 200 mL of tetrahydrofuran was added to a beaker, followed by 26.42 g of compound II and 17.26 g of phenyl thiochloroformate. The mixture was stirred for 15 min, then 12.22 g of 4-dimethylaminopyridine was added. The mixture was reacted at room temperature for 30 min. After the reaction was complete, 14.55 g of tributyltin hydride was added, and the mixture was heated to 45 °C and reacted for another 2 h. After the reaction was complete, a large amount of water was added to quench the reaction. The mixture was then desolvated under reduced pressure and extracted with 200 mL of ethyl acetate. The organic phases were combined and washed with saturated brine. The mixture was desolvated, recrystallized, filtered, and dried to obtain 19.71 g of compound I. The product yield was 79.4%, and the product purity was 99.6%.