CN111253324A - Preparation method of alogliptin impurity - Google Patents
Preparation method of alogliptin impurity Download PDFInfo
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- CN111253324A CN111253324A CN202010185799.1A CN202010185799A CN111253324A CN 111253324 A CN111253324 A CN 111253324A CN 202010185799 A CN202010185799 A CN 202010185799A CN 111253324 A CN111253324 A CN 111253324A
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Abstract
The invention discloses a preparation method of alogliptin impurities, which comprises the following steps: (1) reacting cheap and easily-obtained compound A serving as a raw material with benzyl halide to generate an intermediate B; (2) reacting the intermediate B with sodium methoxide to generate an intermediate C; (3) under the action of hydrogen, removing benzyl from the Pd/C catalytic intermediate C to obtain an intermediate D; (4) carrying out nucleophilic substitution reaction on the intermediate D and the intermediate B to generate an intermediate E; (5) under the action of acid, the intermediate E simultaneously removes benzyl and methyl in the structure to generate an intermediate F; (6) and reacting the intermediate F with a chlorinating agent to chlorinate the hydroxyl in the structure to generate the intermediate F. The preparation method provided by the invention has the advantages of cheap and easily available reaction raw materials, high yield and purity and the like, and provides reliable substance guarantee for subsequent quality control research and safety property research in the preparation process of the alogliptin.
Description
Technical Field
The invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of alogliptin impurities.
Background
Alogliptin (trade name: nixin) is a dipeptidyl peptidase 4(DPP-4) inhibitor developed by the pharmaceutical industry of wutian japan, and its chemical name is 2- [ [6- [ (3R) -3-aminopiperidin-1-yl ] -3-methyl-2, 4-dioxopyrimidin-1-yl ] methyl ] benzonitrile, and its structural formula is shown in formula I.
Drugs often introduce impurities during their preparation, which are mainly derived from process impurities and degradation products. The research on impurities is an important content in the development process of new drugs, and simultaneously, the research also directly relates to the safety and effectiveness of the drugs. Therefore, preparing potential drug impurities, establishing a detection method, analyzing the content of impurities, and determining reasonable impurity limits play a crucial role. Various impurities are also introduced in the process of preparing alogliptin, wherein the compound II is one of the main impurities, but the preparation method is not reported in the literature at present.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of alogliptin impurities.
In order to solve the problems, the technical scheme of the invention is as follows:
the invention provides a preparation method of alogliptin impurities, which adopts the following synthetic route:
the method comprises the following operation steps:
s1, reacting a compound A, alkali and benzyl halide in a first organic solvent at 20-80 ℃ until the compound A disappears; adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and n-hexane in sequence, and performing vacuum drying to obtain an intermediate B;
s2, dissolving the intermediate B in a second organic solvent, adding sodium methoxide into the reaction liquid at 0 ℃, adjusting the temperature of the system to 10-100 ℃ after the sodium methoxide is added, and stirring for reaction until the intermediate B disappears; and then adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and n-hexane in sequence, and performing vacuum drying to obtain an intermediate C.
S3, adding the intermediate C, a third solvent and Pd/C into a reaction bottle, reacting at 10-60 ℃ under the action of hydrogen until the intermediate C disappears, carrying out suction filtration on reaction liquid, and removing the solvent through reduced pressure evaporation to obtain an intermediate D;
s4, sequentially adding the intermediate D, the intermediate B, the alkali and a fourth organic solvent into a reaction bottle, and stirring for reaction at the temperature of 20-100 ℃ until the compound D disappears; adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and isopropanol in sequence, and performing vacuum drying to obtain an intermediate E;
s5, adding the intermediate E, acid and a fifth solvent into a reaction bottle, and stirring at 30-110 ℃ for reaction until the compound E disappears; then cooling the system to room temperature, adding a proper amount of water into the reaction solution, extracting, and drying the organic layer by using anhydrous sodium sulfate; carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing the crude product by acetonitrile to obtain a compound F;
s6, adding the compound F and a sixth solvent into a reaction bottle, adding a chlorinating agent at 0 ℃, and then stirring for reaction at 10-100 ℃ until the compound F disappears; cooling the system to 0 deg.C, adding appropriate amount of water, extracting, and drying the organic layer with anhydrous sodium sulfate; and (4) carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing the crude product with ethyl acetate to obtain a compound II.
Preferably, the first organic solvent used in step S1 is one or more of N, N-dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide, and more preferably, the first solvent is N, N-dimethylformamide.
Preferably, the benzyl halide in step S1 is one or more of benzyl chloride, benzyl bromide and benzyl iodide, and preferably benzyl bromide.
Preferably, the base in step S1 is one or more of sodium carbonate, potassium carbonate, tripotassium phosphate and sodium hydride, preferably potassium carbonate.
Preferably, the molar ratio of the compound A, the base and the benzyl halide in the step S1 is 1: 1-2, and the preferred molar ratio is 1: 1.2-1.5: 1-1.2; the preferable reaction temperature is 60-70 ℃.
Preferably, the second organic solvent used in step S2 is one or more selected from methanol, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide, preferably N, N-dimethylformamide.
Preferably, the molar ratio of the compound B to the sodium methoxide in the step S2 is 1: 1-2, and preferably 1: 1.2-1.5.
Preferably, the reaction temperature in step S2 is 30-40 ℃.
Preferably, the third organic solvent used in step S3 is one or more selected from methanol, ethanol, tetrahydrofuran, acetonitrile and N, N-dimethylformamide, and ethanol is preferred.
Preferably, the reaction temperature in the step S3 is 20-30 ℃.
Preferably, the fourth organic solvent used in step S4 is one or more of tetrahydrofuran, acetonitrile, acetone and N, N-dimethylformamide, preferably N, N-dimethylformamide.
Preferably, the base used in step S4 is one or more of sodium carbonate, potassium carbonate, tripotassium phosphate and sodium hydride, preferably potassium carbonate.
Preferably, the molar ratio of the compound D, the base and the intermediate B in the step S4 is 1: 1-2, and preferably 1: 1.2-1.5: 1-1.2.
Preferably, the reaction temperature in step S4 is 60-70 ℃.
Preferably, the fifth organic solvent used in step S5 is one or more of dichloromethane, chloroform, tetrahydrofuran and acetonitrile, preferably chloroform.
Preferably, the acid used in step S5 is one or more of trifluoroacetic acid, hydrochloric acid and hydrobromic acid, preferably hydrobromic acid.
Preferably, the molar ratio of the intermediate E to the acid in the step S5 is 1: 1-20, and preferably 1: 8-10.
Preferably, the reaction temperature in step S5 is 70-80 ℃.
Preferably, the sixth organic solvent used in step S6 is one or more of tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and chloroform, preferably dichloromethane.
Preferably, the chlorinating agent used in step S6 is one or more of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and concentrated hydrochloric acid, and thionyl chloride is preferred.
Preferably, the molar ratio of the intermediate F to the chlorinating agent in the step S6 is 1: 1-10, and preferably 1: 3-4.
Preferably, the reaction temperature in the step S6 is 20-30 ℃.
The invention has the beneficial effects that: the invention provides a preparation method of alogliptin impurities, which has the advantages of cheap and easily available raw materials, high total yield and high purity of final products; the preparation method provided by the invention provides reliable substance guarantee for the follow-up quality control research and safety property research in the alogliptin preparation process.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
The invention provides a preparation method of alogliptin impurities, which adopts the following synthetic route: this writing is not seen in the following, which is a partial duplication of the content and inventive content.
The method comprises the following operation steps:
s1, reacting a compound A, alkali and benzyl halide in a first organic solvent at 20-80 ℃ until the compound A disappears; adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and n-hexane in sequence, and performing vacuum drying to obtain an intermediate B;
s2, dissolving the intermediate B in a second organic solvent, adding sodium methoxide into the reaction liquid at 0 ℃, adjusting the temperature of the system to 10-100 ℃ after the sodium methoxide is added, and stirring for reaction until the intermediate B disappears; and then adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and n-hexane in sequence, and performing vacuum drying to obtain an intermediate C.
S3, adding the intermediate C, a third solvent and Pd/C into a reaction bottle, reacting at 10-60 ℃ under the action of hydrogen until the intermediate C disappears, carrying out suction filtration on reaction liquid, and removing the solvent through reduced pressure evaporation to obtain an intermediate D;
s4, sequentially adding the intermediate D, the intermediate B, the alkali and a fourth organic solvent into a reaction bottle, and stirring for reaction at the temperature of 20-100 ℃ until the compound D disappears; adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and isopropanol in sequence, and performing vacuum drying to obtain an intermediate E;
s5, adding the intermediate E, acid and a fifth solvent into a reaction bottle, and stirring at 30-110 ℃ for reaction until the compound E disappears; subsequently, the temperature of the system was lowered to room temperature, an appropriate amount of water was added to the reaction solution, extraction was performed, and the organic layer was dried over anhydrous sodium sulfate. Carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing the crude product by acetonitrile to obtain a compound F;
s6, adding the compound F and a sixth solvent into a reaction bottle, adding a chlorinating agent at 0 ℃, and then stirring for reaction at 10-100 ℃ until the compound F disappears; then, the temperature of the system is reduced to 0 ℃, a proper amount of water is added, extraction is carried out, and an organic layer is dried by using anhydrous sodium sulfate; and then, carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing the crude product with ethyl acetate to obtain a compound II.
In some preferred embodiments, the first organic solvent used in step S1 is one or more of N, N-dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide, and more preferably, the first solvent is N, N-dimethylformamide.
In some preferred embodiments, the benzyl halide used in step S1 is one or more of benzyl chloride, benzyl bromide and benzyl iodide, and benzyl bromide is preferred.
In some preferred embodiments, the base used in step S1 is one or more of sodium carbonate, potassium carbonate, tripotassium phosphate and sodium hydride, preferably potassium carbonate.
In some preferred embodiments, the molar ratio of the compound A, the alkali and the benzyl halide is 1: 1-2, and more preferably the molar ratio of the compound A to the benzyl halide is 1: 1.2-1.5: 1-1.2, wherein the molar ratio can ensure that the reaction is fully performed and can avoid the waste of raw materials.
In some preferred embodiments, the reaction temperature used in step S1 is 20-80 deg.C, and more preferably, the reaction temperature used is 60-70 deg.C.
In some preferred embodiments, the second organic solvent used in step S2 is one or more of methanol, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone, and dimethylsulfoxide, and more preferably, the second solvent is N, N-dimethylformamide.
In some preferred embodiments, the molar ratio of the compound B to sodium methoxide is 1: 1-2, and more preferably the molar ratio of the compound a to benzyl halide is 1: 1.2-1.5, within the range of the amount ratio, the reaction can be fully performed, and the waste of raw materials can be avoided.
In some preferred embodiments, the reaction temperature used in step S2 is 10-100 deg.C, and more preferably, the reaction temperature used is 30-40 deg.C.
In some preferred embodiments, the third organic solvent used in step S3 is one or more selected from methanol, ethanol, tetrahydrofuran, acetonitrile, and N, N-dimethylformamide, and more preferably, the third solvent is ethanol.
In some preferred embodiments, the reaction temperature of step S3 is 10 to 60 ℃, preferably 20 to 30 ℃.
In some preferred embodiments, the fourth organic solvent used in step S4 is one or more selected from tetrahydrofuran, acetonitrile, acetone, and N, N-dimethylformamide, and more preferably, the fourth solvent is N, N-dimethylformamide.
In some preferred embodiments, the base used in step S4 is one or more of sodium carbonate, potassium carbonate, tripotassium phosphate and sodium hydride, preferably potassium carbonate.
In some preferred embodiments, the molar ratio of the compound D, the base and the intermediate B is 1: 1-2, and more preferably, the molar ratio of the compound D, the base and the intermediate B is 1: 1.2-1.5: 1-1.2, and within the dosage ratio, the reaction can be fully carried out, and the waste of raw materials can be avoided.
In some preferred embodiments, the reaction temperature of step S4 is 20 to 100 ℃, preferably 60 to 70 ℃.
In some preferred embodiments, the fifth organic solvent used in step S5 is one or more selected from dichloromethane, chloroform, tetrahydrofuran and acetonitrile, and more preferably, the fifth solvent is chloroform.
In some preferred embodiments, the acid used in step S5 is one or more of trifluoroacetic acid, hydrochloric acid, and hydrobromic acid, preferably hydrobromic acid.
In some preferred embodiments, the molar ratio of the intermediate E to the acid is 1:1 to 20, and more preferably, the molar ratio of the intermediate E to the acid is 1:8 to 10, and within the range of the dosage ratio, the reaction can be fully performed, and the waste of raw materials can be avoided.
In some preferred embodiments, the reaction temperature of step S5 is 30 to 110 ℃, preferably 70 to 80 ℃.
In some preferred embodiments, the sixth organic solvent used in step S6 is one or more of tetrahydrofuran, dichloromethane, 1, 2-dichloroethane, and chloroform, and more preferably, the sixth solvent is dichloromethane.
In some preferred embodiments, the chlorinating agent used in step S6 is one or more of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and concentrated hydrochloric acid, and more preferably, the chlorinating agent used is thionyl chloride.
In some preferred embodiments, the molar ratio of the intermediate F to the chlorinating agent is 1: 1-10, and more preferably, the molar ratio of the intermediate F to the chlorinating agent is 1: 3-4, within the range of the dosage ratio, the reaction can be fully carried out, and the waste of raw materials can be avoided.
In some preferred embodiments, the reaction temperature of step S6 is 10 to 100 ℃, preferably 20 to 30 ℃.
The progress of the above reaction can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC, or NMR), typically ending when compound II and intermediate III have disappeared.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1:
embodiment 1 of the present invention provides a preparation method of an intermediate B, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
feed A (4.0g, 24.9mmol) and N, N-dimethylformamide (50mL) were added to a reaction flask, and potassium carbonate (4.48g, 32.4mmol) and benzyl bromide (4.7g, 27.4mmol) were added with stirring. The reaction was then stirred at 65 ℃ for 12h and the disappearance of starting material A was detected by TLC. And adding water (70mL) into the reaction solution to separate out a solid, continuously stirring for 15min, carrying out suction filtration, washing a filter cake with water and n-hexane, and carrying out vacuum drying to obtain an intermediate B.
The preparation method is adopted to obtain 6.0g of white solid with the yield of 96%.
The identification of intermediate B prepared in this example gave the following results:
ESI-MS(m/z):251.3；
1HNMR(400MHz,CDCl3):δ7.27-7.31(m,5H),6.01(s,1H),4.27(s,2H),3.15(s,3H).
example 2:
embodiment 2 of the present invention provides a preparation method of an intermediate B, which specifically adopts the following method:
feed A (3.0g, 18.9mmol) and N, N-dimethylformamide (40mL) were charged to a reaction flask, and sodium hydride (60%, 1.1g, 28.0mmol) and benzyl bromide (3.5g, 20.6mmol) were added with stirring. The reaction was then stirred at 60 ℃ for 10h and the disappearance of starting material A was detected by TLC. And adding water (70mL) into the reaction solution to separate out a solid, continuously stirring for 15min, carrying out suction filtration, washing a filter cake with water and n-hexane, and carrying out vacuum drying to obtain an intermediate B.
The yield of the white solid obtained by the method was 81% and was 3.8 g.
Example 3:
embodiment 3 of the present invention provides a preparation method of an intermediate C, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
compound B (3.5g, 14.0mmol) and N, N-dimethylformamide (20mL) were added to the reaction flask and stirred until compound B was completely dissolved. Sodium methoxide (0.9g, 16.8mmol) was added at 0 ℃. After the addition, the temperature of the reaction system was raised to 30 ℃, the reaction was stirred for 8 hours, and the disappearance of compound B was detected by TLC. And adding water (70mL) into the reaction solution to separate out a solid, continuously stirring for 15min, carrying out suction filtration, washing a filter cake with water and n-hexane, and carrying out vacuum drying to obtain an intermediate C.
The yield of the white solid obtained by the method is 3.1g and 90 percent.
The compound C prepared in this example was identified with the following results:
ESI-MS(m/z):247.1；
1HNMR(400MHz,CDCl3):δ7.29-7.33(m,5H),5.78(s,1H),4.29(s,2H),3.81(s,3H),3.16(s,3H).
example 4:
embodiment 4 of the present invention provides a preparation method of an intermediate C, which specifically adopts the following method:
compound B (3.2g, 12.8mmol) and N, N-dimethylformamide (20mL) were added to the reaction flask and stirred until compound B was completely dissolved. Sodium methoxide (0.8g, 15.3mmol) was added at 0 ℃. After the addition, the temperature of the reaction system was raised to 60 ℃, the reaction was stirred for 3 hours, and compound B disappeared by TLC. And adding water (70mL) into the reaction solution to separate out a solid, continuously stirring for 15min, carrying out suction filtration, washing a filter cake with water and n-hexane, and carrying out vacuum drying to obtain an intermediate C.
2.6g of white solid obtained by the method was obtained with a yield of 83%.
Example 5:
embodiment 5 of the present invention provides a preparation method of an intermediate D, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
intermediate C (3.0g, 12.2mmol), Pd/C (10%, 0.3g) and ethanol (25mL) were added to a reaction flask, the system was pumped three times using a hydrogen balloon and water pump, then the reaction was stirred at 25 ℃ for 18h, and disappearance of intermediate C was detected by TLC. And (5) carrying out suction filtration, and carrying out reduced pressure evaporation to remove ethanol to obtain a white solid, namely an intermediate D.
1.8g of white solid is obtained by the method, and the yield is 95%.
The compound D prepared in this example was identified with the following results:
ESI-MS(m/z):157.2；
1HNMR(400MHz,CDCl3):δ8.34(s,1H),5.58(s,1H),3.80(s,3H),3.19(s,3H).
example 6:
embodiment 6 of the present invention provides a preparation method of an intermediate E, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
intermediate D (2.0g, 12.8mmol), intermediate B (3.9g, 15.4mmol) and N, N-dimethylformamide (40mL) were added to a reaction flask and potassium carbonate (2.7g, 19.2mmol) was added with stirring. Subsequently, the reaction temperature was raised to 70 ℃, the reaction was stirred for 14 hours, and the disappearance of intermediate D was detected by TLC. And adding water (60mL) into the reaction solution to precipitate a solid, continuously stirring for 15min, carrying out suction filtration, washing a filter cake with water and isopropanol, and carrying out vacuum drying to obtain an intermediate E.
4.4g of white solid obtained by the process, yield 93%.
The compound E prepared in this example was identified with the following results:
ESI-MS(m/z):371.2；
1HNMR(400MHz,CDCl3)δ7.30-7.34(m,5H),5.95(s,1H),5.64(s,1H),4.27(s,2H),3.80(s,3H),3.64(s,3H),3.20(s,3H).
example 7:
embodiment 7 of the present invention provides a preparation method of compound E, specifically adopting the following method:
intermediate D (2.1g, 13.5mmol), intermediate B (4.1g, 16.1mmol) and N, N-dimethylformamide (40mL) were charged to a reaction flask and sodium hydride (0.81g, 20.2mmol) was added with stirring. Subsequently, the reaction temperature was raised to 60 ℃, the reaction was stirred for 10 hours, and the disappearance of intermediate D was detected by TLC. And adding water (60mL) into the reaction solution to precipitate a solid, continuously stirring for 15min, carrying out suction filtration, washing a filter cake with water and isopropanol, and carrying out vacuum drying to obtain an intermediate E.
4.0g of white solid obtained by the method is obtained, and the yield is 80%.
Example 8:
embodiment 8 of the present invention provides a preparation method of an intermediate F, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
intermediate E (4.0g, 10.8mmol) and chloroform (20mL) were added to the reaction flask and hydrobromic acid (47%, 12.5mL, 108.0mmol) was added dropwise while ice bath. Subsequently, the temperature was raised to 75 ℃, the reaction was stirred for 14h and intermediate E disappeared by TLC. The temperature of the system was lowered to room temperature, an appropriate amount of water was added to the reaction solution, extraction was performed, and the organic layer was dried over anhydrous sodium sulfate. And (4) carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing by acetonitrile to obtain a compound F.
2.4g of white solid obtained by the method is obtained, and the yield is 84%.
The compound F prepared in this example was identified as follows:
ESI-MS(m/z):267.2；
1HNMR(400MHz,DMSO-d6):δ10.2(s,1H),8.41(s,1H),5.89(s,1H),5.60(s,1H),3.68(s,3H),3.19(s,3H).
example 9:
embodiment 9 of the present invention provides a preparation method of an intermediate F, which specifically adopts the following method:
intermediate E (3.5g, 9.5mmol) and chloroform (20mL) were added to the reaction flask and concentrated hydrochloric acid (37%, 7.9mL, 94.5mmol) was added dropwise while cooling on ice. The temperature was then raised to 80 ℃ and the reaction stirred for 16h and intermediate E disappeared by TLC. The temperature of the system was lowered to room temperature, an appropriate amount of water was added to the reaction solution, extraction was performed, and the organic layer was dried over anhydrous sodium sulfate. And (4) carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing by acetonitrile to obtain a compound F.
1.9g of white solid was obtained by the method, yield 76%.
Example 10:
example 10 of the present invention provides a method for preparing compound II, which comprises the following steps:
the preparation method specifically comprises the following steps:
compound F (2.0g, 7.5mmol) and dichloromethane (15mL) were added to the reaction flask and thionyl chloride (2.2mL, 30.1mmol) was added at 0 ℃. Subsequently, the reaction was stirred at 25 ℃ for 8h and intermediate F disappeared by TLC. The temperature of the system was lowered to 0 ℃, water (10mL) was added, extraction was performed, and the organic layer was dried using anhydrous sodium sulfate. And (4) carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing by ethyl acetate to obtain a compound F.
The white solid obtained by the method is 1.8g, the yield is 84 percent, and the purity is 99 percent.
The compound II prepared in this example was identified with the following results:
ESI-MS(m/z):285.2；
1HNMR(400MHz,DMSO-d6):δ8.32(s,1H),6.01(s,1H),5.62(s,1H),3.65(s,3H),3.22(s,3H).
example 11:
embodiment 11 of the present invention provides a method for preparing a compound II, which specifically comprises the following steps:
compound F (2.0g, 7.5mmol) and dichloromethane (15mL) were added to a reaction flask and phosphorus trichloride (2.9mL, 33.1mmol) was added at 0 ℃. Subsequently, the reaction was stirred at 25 ℃ for 6h and intermediate F disappeared by TLC. The temperature of the system was lowered to 0 ℃, water (10mL) was added, extraction was performed, and the organic layer was dried using anhydrous sodium sulfate. And (4) carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing by ethyl acetate to obtain a compound F.
The white solid obtained by the method is 1.9g, the yield is 81 percent, and the purity is 99 percent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. The preparation method of alogliptin impurities is characterized by adopting the following synthetic route:
the method comprises the following operation steps:
s1, reacting a compound A, alkali and benzyl halide in a first organic solvent at 20-80 ℃ until the compound A disappears; adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and n-hexane in sequence, and performing vacuum drying to obtain an intermediate B;
s2, dissolving the intermediate B in a second organic solvent, adding sodium methoxide into the reaction liquid at 0 ℃, adjusting the temperature of the system to 10-100 ℃ after the sodium methoxide is added, and stirring for reaction until the intermediate B disappears; adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and n-hexane in sequence, and performing vacuum drying to obtain an intermediate C;
s3, adding the intermediate C, a third solvent and Pd/C into a reaction bottle, reacting at 10-60 ℃ under the action of hydrogen until the intermediate C disappears, carrying out suction filtration on reaction liquid, and removing the solvent through reduced pressure evaporation to obtain an intermediate D;
s4, sequentially adding the intermediate D, the intermediate B, the alkali and a fourth organic solvent into a reaction bottle, and stirring for reaction at the temperature of 20-100 ℃ until the compound D disappears; adding a proper amount of water into the reaction solution, separating out a solid, performing suction filtration, washing a filter cake with water and isopropanol in sequence, and performing vacuum drying to obtain an intermediate E;
s5, adding the intermediate E, acid and a fifth solvent into a reaction bottle, and stirring at 30-110 ℃ for reaction until the compound E disappears; subsequently, the temperature of the system was lowered to room temperature, an appropriate amount of water was added to the reaction solution, extraction was performed, and the organic layer was dried over anhydrous sodium sulfate. Carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing the crude product by acetonitrile to obtain a compound F;
s6, adding the compound F and a sixth solvent into a reaction bottle, adding a chlorinating agent at 0 ℃, and then stirring for reaction at 10-100 ℃ until the compound F disappears; cooling the system to 0 deg.C, adding appropriate amount of water, extracting, and drying the organic layer with anhydrous sodium sulfate; and (4) carrying out suction filtration, carrying out reduced pressure evaporation to remove filtrate, and recrystallizing the crude product with ethyl acetate to obtain a compound II.
2. The method for preparing alogliptin impurities according to claim 1, wherein the first organic solvent used in step S1 is one or more selected from N, N-dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide; the benzyl halide is one or more of benzyl chloride, benzyl bromide and benzyl iodide; the alkali is one or more of sodium carbonate, potassium carbonate, tripotassium phosphate and sodium hydride.
3. The method for preparing alogliptin impurity according to claim 1, wherein in step S1, the molar ratio of the compound A, the base and the benzyl halide is 1: 1-2.
4. The method for preparing alogliptin impurity according to claim 1, wherein the second organic solvent used in step S2 is one or more selected from methanol, tetrahydrofuran, N-dimethylformamide, N-methylpyrrolidone and dimethylsulfoxide.
5. The method for preparing alogliptin impurity according to claim 1, wherein in step S2, the molar ratio of compound B to sodium methoxide is 1: 1-2.
6. The method for preparing alogliptin impurity according to claim 1, wherein the third organic solvent used in step S3 is one or more selected from methanol, ethanol, tetrahydrofuran, acetonitrile and N, N-dimethylformamide.
7. The method for preparing alogliptin impurity according to claim 1, wherein the fourth organic solvent used in step S4 is one or more selected from tetrahydrofuran, acetonitrile, acetone and N, N-dimethylformamide; the alkali is one or more of sodium carbonate, potassium carbonate, tripotassium phosphate and sodium hydride.
8. The method for preparing alogliptin impurities according to claim 1, wherein in step S4, the molar ratio of the compound D, the base and the intermediate B is 1: 1-2, preferably 1: 1.2-1.5: 1-1.2.
9. The method for preparing alogliptin impurities according to claim 1, wherein the fifth organic solvent used in step S5 is one or more selected from dichloromethane, chloroform, tetrahydrofuran and acetonitrile; the acid used is one or more of trifluoroacetic acid, hydrochloric acid and hydrobromic acid; the molar ratio of the intermediate E to the acid is 1: 1-20.
10. The method for preparing alogliptin impurities according to claim 1, wherein the sixth organic solvent used in step S6 is one or more selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and chloroform; the chlorinating agent is one or more of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride and concentrated hydrochloric acid; the molar ratio of the intermediate F to the chlorinating agent is 1: 1-10.
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