Synthesis method of sitagliptin related impurities

Abstract

The invention relates to the technical field of pharmacy, in particular to a synthesis method of sitagliptin related impurities, which comprises the following steps: step one, taking 4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro-[1, 2, 4] triazolo [4, 3-a] pyrazine-7-(8H)-yl]-1-(2, 4, 5-trifluorophenyl)-2-butanone as a raw material, taking (S)-phenylethylamine as a raw material, and performing ammonification reaction to obtain the sitagliptin related impurities. Synthesizing a compound III; 2, synthesizing a compound IV by taking the compound III as a raw material through a carbon-carbon double bond reduction reaction; and 3, synthesizing a compound I, namely the sitagliptin related impurity, by taking the compound IV as a raw material through deamination protection reaction. The invention provides a brand-new directional synthesis method, the target chiral impurity is directly obtained, complex post-treatment such as chiral resolution and preparative chromatography purification is not needed, and a large number of impurity reference substances can be rapidly, simply, conveniently and efficiently obtained.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for synthesizing sitagliptin-related impurities. Background Technology

[0002] Sitagliptin, developed and marketed by Merck, had its phosphate form (brand name Januvia) approved by the FDA as the first DPP-4 inhibitor for the clinical treatment of type 2 diabetes. It was launched in the US on October 16, 2006. On March 30, 2007, the FDA approved it in combination with metformin for the treatment of type 2 diabetes. It was already available in several European countries. In August 2009, the EU approved it as a first-line treatment for type 2 diabetes. In December 2009, Ono launched sitagliptin in Japan for the treatment of type 2 diabetes. In May 2011, Japan approved its combination with an alpha-glucosidase inhibitor, and in September 2011, Japan approved its combination with insulin.

[0003] The chemical name of sitagliptin is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-(8H)-yl]-4-(2,4,5-trifluorophenyl)but-1-one, and its structure is shown below:

[0004] Its corresponding chiral impurity is (3S)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-(8H)-yl]-4-(2,4,5-trifluorophenyl)but-1-one, the structure of which is shown below:

[0005] Impurity I is listed in both the European Pharmacopoeia and the United States Pharmacopeia (USP) standards for sitagliptin. PCT application publication WO2010122578 reports on this impurity, but does not disclose its synthetic method. Chinese patent application publication CN113121546A reports a method for obtaining this impurity, but this method is not a direct synthesis; rather, it purifies the impurity from the mother liquor during the reaction process. This method has poor operability and is not guaranteed to yield the impurity. To improve the quality of sitagliptin phosphate tablets and sitagliptin-metformin tablets and reduce the risks of clinical use, it is necessary to study and monitor the impurities in sitagliptin phosphate and sitagliptin-metformin tablets. Strictly controlling the impurity content in sitagliptin phosphate and sitagliptin-metformin tablets is crucial; therefore, providing a rapid, simple, and efficient synthetic method for obtaining the impurity I reference standard is of paramount importance. Summary of the Invention

[0006] To address the problems of existing technologies, such as the inability to stably obtain sitagliptin impurity I through targeted synthesis and the poor operability of existing methods, this invention provides a method for synthesizing sitagliptin impurity I with a short reaction route, low energy consumption, simple operation, high yield, and high purity, enabling the targeted industrial production of this impurity and providing a reliable source of reference standards for the quality control of sitagliptin drugs.

[0007] To achieve the above objectives, the present invention adopts the following technical solution: A method for synthesizing sitagliptin-related impurities includes the following steps:

[0008] Step 1: Using 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8H)-yl]-1-(2,4,5-trifluorophenyl)-2-butanone as a starting material and (S)-phenylethylamine as a starting material, compound III was synthesized by amination reaction; Step 2: Using compound III as a raw material, compound IV is synthesized through a carbon-carbon double bond reduction reaction; Step 3: Using compound IV as a raw material, compound I, which is the sitagliptin-related impurity, is synthesized through a deamination protection reaction.

[0009] Preferably, in step one, the solvent used for the amination reaction is selected from any one or more of acetonitrile, isopropanol, methanol, ethanol, tetrahydrofuran, and acetone.

[0010] Preferably, in step one, the amination reaction is carried out at 35-60°C.

[0011] Preferably, in step two, the solvent used for the carbon-carbon double bond reduction reaction is selected from any one or more of dichloromethane, dichloroethane, and chloroform.

[0012] Preferably, in step two, the reducing agent used in the carbon-carbon double bond reduction reaction is selected from any one or more of sodium borohydride, potassium borohydride, and lithium aluminum hydride.

[0013] Preferably, in step two, the carbon-carbon double bond reduction reaction conditions are 15-60℃.

[0014] Preferably, in step three, the solvent used for the deamination protection reaction is selected from any one or more of isopropanol, methanol, and ethanol.

[0015] Preferably, in step three, the hydrogen source used for the deamination protection reaction is selected from any one or more of formic acid, acetic acid, hydrogen, ammonium formate, ammonium acetate, and ammonium chloride.

[0016] Preferably, in step three, the catalyst used for the deamination protection reaction is selected from any one or more of palladium hydroxide on carbon (20%), palladium hydroxide on carbon (10%), palladium on carbon (10%), and palladium on carbon (5%).

[0017] Preferably, in step three, the deamination protection reaction conditions are 45-60℃.

[0018] Compared with the prior art, the beneficial effects of the present invention are: 1. This invention provides a novel method for targeted synthesis, which directly obtains the target chiral impurity without the need for complex post-processing such as chiral resolution and preparative chromatographic purification. It can quickly, easily, and efficiently obtain a large number of impurity reference standards. 2. The reaction route is short (only three steps), with low energy consumption, simple operation, and low production cost, making it suitable for industrial production; 3. High product yield (up to 89%), high purity (up to 98.27%), and no problem of low ee value caused by incomplete separation; 4. The external standard method can strictly control the impurity content of sitagliptin drugs, significantly improve drug quality, and reduce the risk of clinical drug use. Attached Figure Description

[0019] Figure 1 This is a comparison diagram of the R and S configurations of sitagliptin.

[0020] Figure 2 Mass spectrometry of sitagliptin impurities.

[0021] Figure 3 The NMR spectrum of sitagliptin impurities is shown in the form of hydrogen NMR. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] Unless otherwise stated, all raw materials and reagents used in this invention are commercially available or can be prepared by known methods. Example 1

[0024] Synthesis of Compound III 10.0 g of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8H)-yl]-1-(2,4,5-trifluorophenyl)-2-butanone (compound II), 50 ml of isopropanol, and 3.9 g of (S)-phenylethylamine were added to a three-necked flask. The mixture was stirred, and 1.5 g of glacial acetic acid was added dropwise. The temperature was raised to 50 °C, and the solid in the system gradually dissolved. The reaction was stirred for 12 h, and the reaction was monitored by TLC until it was complete. The solvent was evaporated under reduced pressure to obtain the residual oily compound III for later use.

[0025] Synthesis of Compound IV Add 1.8 g sodium borohydride and 20 mL dichloromethane to a three-necked flask, cool to 30 ± 5 °C, and slowly add 15 mL glacial acetic acid dropwise while stirring. After the addition is complete, continue stirring for about 30 min, and slowly add a solution of compound III from the previous step dissolved in 20 mL dichloromethane. After the addition is complete, continue stirring for 2 h. Monitor the reaction for completion by TLC, and add 10 mL of 12 mol / L concentrated hydrochloric acid to terminate the reaction. Then add 3 mol / L sodium hydroxide solution to adjust the pH to 8, separate the aqueous layer, dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, dissolve the residue in 15 mL isopropanol, add 45 mL of n-heptane while stirring to induce crystallization, cool to 5-10 °C and stir for 30 min, filter, and wash the filter cake with n-heptane (15 mL × 2) to obtain a white solid compound IV.

[0026] Synthesis of Compound I Intermediate IV, a mixed solution of 10 mL isopropanol, 15 mL water, and 5 mL formic acid, and 1.0 g palladium hydroxide on carbon (20%) were added sequentially to a single-necked flask. The mixture was heated to 50 °C and stirred for 4 h. The reaction was monitored by TLC until completion. The palladium hydroxide on carbon was removed by filtration, and the filter cake was washed several times with isopropanol. The isopropanol was distilled off under reduced pressure. The pH of the residue was adjusted to 8 with a 3 mol / L sodium hydroxide aqueous solution, and the residue was extracted twice with ethyl acetate. The liquid and liquid phases were separated, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 50 mL of toluene was added to the residue and heated to dissolve it. After dissolution, the mixture was stirred for 30 min, cooled, stirred, and crystallized. The crystals were filtered, and the filter cake was washed with toluene (10 mL × 2). The crystals were dried by forced air at 50-55 °C to obtain 8.9 g of white solid compound I, with a total yield of 89% and a purity of 98.27%. Example 2

[0027] Synthesis of Compound III 10.0 g of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8H)-yl]-1-(2,4,5-trifluorophenyl)-2-butanone (compound II), 50 ml of ethanol, and 3.9 g of (S)-phenylethylamine were added to a three-necked flask. The mixture was stirred, and 1.5 g of glacial acetic acid was added dropwise. The temperature was raised to 50 °C, and the solid in the system gradually dissolved. The reaction was stirred for 12 h, and the reaction was monitored by TLC until the reaction was complete. The solvent was evaporated from the system under reduced pressure to obtain the residual oily compound III for later use.

[0028] Synthesis of Compound IV Add 2.6 g of potassium borohydride and 20 mL of dichloroethane to a three-necked flask. Cool to 30 ± 5 °C and slowly add 15 mL of glacial acetic acid dropwise while stirring. After the addition is complete, continue stirring for about 30 min. Slowly add a solution of compound III from the previous step dissolved in 20 mL of dichloromethane. After the addition is complete, continue stirring for 2 h. Monitor the reaction by TLC until it is complete. Add 10 mL of 12 mol / L concentrated hydrochloric acid to terminate the reaction. Then add 3 mol / L sodium hydroxide solution to adjust the pH to 8. Separate the aqueous layer and dry the organic layer with anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure. Dissolve the residue in 15 mL of isopropanol. Add 45 mL of n-heptane while stirring to induce crystallization. Cool to 5-10 °C and stir for 30 min. Filter and wash the filter cake with n-heptane (15 mL × 2) to obtain a white solid compound IV.

[0029] Synthesis of Compound I Intermediate IV, a mixed solution of 10 mL methanol, 15 mL water, and 5 mL formic acid, and 2.0 g palladium hydroxide on carbon (10%) were added sequentially to a single-necked flask. The mixture was heated to 50 °C and stirred for 4 h. The reaction was monitored by TLC until completion. The palladium hydroxide on carbon was removed by filtration, and the filter cake was washed several times with ethanol. The ethanol was evaporated under reduced pressure. The pH of the residue was adjusted to 8 with a 3 mol / L sodium hydroxide aqueous solution, and the residue was extracted twice with ethyl acetate. The liquid and liquid phases were separated, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 50 mL toluene was added to the residue and heated to dissolve it. After dissolution, the mixture was stirred for 30 min, cooled, stirred, and crystallized. The crystals were filtered, and the filter cake was washed with toluene (10 mL × 2). The crystals were dried by forced air at 50-55 °C to obtain 7.6 g of white solid compound I, with a total yield of 76% and a purity of 97.27%. Example 3

[0030] Synthesis of Compound III 10.0 g of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8H)-yl]-1-(2,4,5-trifluorophenyl)-2-butanone (compound II), 50 ml of tetrahydrofuran, and 3.9 g of (S)-phenylethylamine were added to a three-necked flask. The mixture was stirred, and 1.5 g of glacial acetic acid was added dropwise. The temperature was raised to 50 °C, and the solid in the system gradually dissolved. The reaction was stirred for 12 h, and the reaction was monitored by TLC until it was complete. The solvent was evaporated under reduced pressure to obtain the residual oily compound III for later use.

[0031] Synthesis of Compound IV Add 1.8 g of lithium aluminum hydride and 20 mL of chloroform to a three-necked flask, cool to 30 ± 5 °C, and slowly add 15 mL of glacial acetic acid dropwise while stirring. After the addition is complete, continue stirring for about 30 min, and slowly add a solution of compound III from the previous step dissolved in 20 mL of dichloromethane. After the addition is complete, continue stirring for 2 h. Monitor the reaction by TLC until it is complete, and add 10 mL of 12 mol / L concentrated hydrochloric acid to terminate the reaction. Then add 3N sodium hydroxide solution to adjust the pH to 8, separate the aqueous layer, dry the organic layer with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, dissolve the residue in 15 mL of isopropanol, add 45 mL of n-heptane while stirring to induce crystallization, cool to 5-10 °C and stir for 30 min, filter, and wash the filter cake with n-heptane (15 mL × 2) to obtain a white solid compound IV.

[0032] Synthesis of Compound I Intermediate IV, a mixed solution of 10 mL ethanol, 15 mL water, and 6.5 mL acetic acid, and 2.0 g palladium on carbon (10%) were added sequentially to a single-necked flask. The mixture was heated to 50 °C and stirred for 4 h. The reaction was monitored by TLC until completion. Palladium on carbon was removed by filtration, and the filter cake was washed several times with isopropanol. The isopropanol was distilled off under reduced pressure. The pH of the residue was adjusted to 8 with a 3 mol / L sodium hydroxide aqueous solution, and the residue was extracted twice with ethyl acetate. The liquid and liquid phases were separated, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. 50 mL toluene was added to the residue and heated to dissolve it. After dissolution, the mixture was stirred for 30 min, cooled, stirred, and crystallized. The crystals were filtered, and the filter cake was washed with toluene (10 mL × 2). The mixture was dried in a forced-air oven at 50–55 °C to obtain 7.7 g of white solid compound I, with a total yield of 77% and a purity of 98.02%.

[0033] The optical rotation of the sitagliptin impurity (compound I) obtained in the above examples was measured to be +25.9900 (the optical rotation of sitagliptin is -29.3179), compared with the chiral control of sitagliptin ( Figure 1 Mass spectrometry Figure 2 ) and nuclear magnetic resonance hydrogen spectrum ( Figure 3The data analysis results are as follows: ESI-MS (m / z): C16H15F6N5O, 408.0 [M+H]+, 1H NMR (400MHz, DMSO-d6) δ 7.42 (qd, J=10.9, 8.7, 5.5Hz, 2H), 4.96 (d, J=4.4Hz, 1H), 4.93–4.75 (m, 1H), 4.21 (t, J=5.5Hz, 1H), 4.08(q, J=6.0Hz, 1H), 3.94(ddd, J=23.4, 9.4, 5.4Hz, 2H), 3.30(s, 1 H), 3.24(dd, J=13.7, 7.0Hz, 1H), 2.71–2.54(m, 2H), 2.47–2.40(m, 1H, 1.50(s, 2H).

[0034] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing sitagliptin-related impurities, characterized in that, Includes the following steps: Step 1: Using 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7-(8H)-yl]-1-(2,4,5-trifluorophenyl)-2-butanone as a starting material and (S)-phenylethylamine as a starting material, compound III was synthesized by amination reaction; Step 2: Using compound III as a raw material, compound IV is synthesized through a carbon-carbon double bond reduction reaction; Step 3: Using compound IV as a raw material, compound I, which is the sitagliptin-related impurity, is synthesized through a deamination protection reaction.

2. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step one, the solvent used in the amination reaction is selected from any one or more of acetonitrile, isopropanol, methanol, ethanol, tetrahydrofuran, and acetone.

3. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step one, the amination reaction is carried out at 35-60°C.

4. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step two, the solvent used for the carbon-carbon double bond reduction reaction is selected from any one or more of dichloromethane, dichloroethane, and chloroform.

5. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step two, the reducing agent used in the carbon-carbon double bond reduction reaction is selected from any one or more of sodium borohydride, potassium borohydride, and lithium aluminum hydride.

6. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step two, the carbon-carbon double bond reduction reaction conditions are 15-60℃.

7. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step three, the solvent used for the deamination protection reaction is selected from any one or more of isopropanol, methanol, and ethanol.

8. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step three, the hydrogen source used in the deamination protection reaction is selected from any one or more of formic acid, acetic acid, hydrogen, ammonium formate, ammonium acetate, and ammonium chloride.

9. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step three, the catalyst used for the deamination protection reaction is selected from any one or more of palladium hydroxide on carbon (20%), palladium hydroxide on carbon (10%), palladium on carbon (10%), and palladium on carbon (5%).

10. The method for synthesizing sitagliptin-related impurities according to claim 1, characterized in that, In step three, the deamination protection reaction is carried out at 45-60°C.

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