CN113979896A - Sitagliptin impurity I and preparation method thereof - Google Patents

Sitagliptin impurity I and preparation method thereof Download PDF

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CN113979896A
CN113979896A CN202111368797.7A CN202111368797A CN113979896A CN 113979896 A CN113979896 A CN 113979896A CN 202111368797 A CN202111368797 A CN 202111368797A CN 113979896 A CN113979896 A CN 113979896A
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impurity
sitagliptin
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trifluorophenyl
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李总领
顾坚雄
张峰
孔佳辉
夏海建
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Zhejiang Yongtai Pharmaceutical Co ltd
ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Zhejiang Yongtai Handxin Pharmaceutical Technology Co ltd
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Zhejiang Yongtai Pharmaceutical Co ltd
ZHEJIANG YONGTAI TECHNOLOGY CO LTD
Zhejiang Yongtai Handxin Pharmaceutical Technology Co ltd
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Abstract

The invention provides a sitagliptin impurity I and a preparation method thereof, and relates to the field of organic synthetic drug chemistry. The preparation method comprises the following steps: taking P1 as a raw material, carrying out esterification reaction under the action of a catalyst to obtain P2, further reacting with a condensing agent to obtain P3, and finally carrying out alkaline hydrolysis to obtain an impurity I. The novel preparation method has the advantages of easily available raw materials, mild reaction conditions, high safety coefficient and high purity of the obtained impurity I. The method is high in operability and easy to operate in a laboratory, and the impurity I can be used for supporting the quality research and analysis method development work of sitagliptin.

Description

Sitagliptin impurity I and preparation method thereof
Technical Field
The invention relates to the field of organic synthetic pharmaceutical chemistry, and particularly relates to a sitagliptin impurity I and a preparation method thereof.
Background
In the process of drug production, impurity research is an indispensable and very important part, and the residual impurities of drug intermediates can bring potential risks to the drug finished products in the later period. The existence of these impurities not only affects the efficacy of the drug, but also has problems during production and storage, and some impurities may even cause toxic and side effects. Therefore, the analysis and research on the medicine impurities can ensure the safety, effectiveness and stability of the medicine application and provide a basis for the quality assurance of the production and circulation processes. The impurity standard substance is a standard substance for identifying, checking and measuring the content of impurities. Therefore, it is very necessary to prepare and study impurity standards during the production and quality control processes.
Sitagliptin belongs to a novel hypoglycemic medicament, namely a dipeptidyl peptidase-4 (DDP-4) inhibitor, is used for treating type 2 diabetes, and can improve the capability of reducing excessive blood sugar level of a human body. Statistically, the number of diabetes patients in the whole world in 2010 is about 2.85 hundred million, and a trend of increasing year by year appears, wherein type 2 diabetes accounts for 90-95% of the total number of diabetes. Currently, the commonly used oral hypoglycemic agents are mainly of the following types: biguanides, sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors, but these types often have varying degrees of side effects such as hypoglycemia, weight gain, cardiovascular events, and the like.
Figure BDA0003361833580000011
The first generation synthesis of sitagliptin was disclosed in the compound patent US6699871B filed by the original US merck corporation. The synthetic route uses (3R) -3- (tert-butyloxycarbonylamino) -4- (2,4, 5-trifluorophenyl) butyric acid as a raw material to be in butt joint with 3- (trifluoromethyl) -5,6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride, and then deprotection is carried out to obtain sitagliptin. The preparation method has mild reaction, simple operation and relatively few side reactions, and is a mainstream process for the large-scale industrial production of sitagliptin at present. However, in the study of the above process, the inventor found that an unknown impurity exists in the detection of the sitagliptin bulk drug, and the peak area ratio of the impurity is generally 0.005-0.05%.
Figure BDA0003361833580000021
The impurity is sitagliptin impurity I, and the structure of (3R,3'R) -3,3' - (carbonyldiamino) bis (4- (2,4, 5-trifluorophenyl) butyric acid) is as follows by high resolution mass spectrum and nuclear magnetic resonance characterization:
Figure BDA0003361833580000022
in the processes of sitagliptin analysis method development and subsequent finished product inspection, the impurity in sitagliptin needs to be positioned and quantitatively researched by using the standard substance of the impurity, so that a large amount of standard substance of sitagliptin impurity I needs to be used. To prepare sitagliptin impurity I, a conventional impurity separation method can be adopted: target impurities are separated from a sitagliptin raw material medicine sample, but the highest content of the target impurities can only reach 0.11% through HPLC (high performance liquid chromatography) detection, the sample also contains a plurality of similar impurities with similar contents, the separation is interfered, the separation period is long, a pure product can be obtained through multiple times of separation, and the total yield is generally only about 0.03%.
Based on this, the present application provides sitagliptin impurity I and a preparation method thereof.
Disclosure of Invention
The invention aims to provide a preparation method of sitagliptin impurity I, (3R,3'R) -3,3' - (carbonyldiamino) bis (4- (2,4, 5-trifluorophenyl) butyric acid), which is used for researching impurity standard products.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the invention provides a sitagliptin impurity I, chemical name: (3R,3'R) -3,3' - (carbonyldiamino) bis (4- (2,4, 5-trifluorophenyl) butanoic acid) having the following structure:
Figure BDA0003361833580000031
a precursor compound P3 for the preparation of sitagliptin impurity I, said compound P3 having the formula:
Figure BDA0003361833580000032
wherein R is selected from C1-C6The alkyl group of (b) is preferably one of alkyl groups such as a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, an isobutyl group and a tert-butyl group.
In another aspect, the present invention also provides a preparation method of the above compound P3, comprising the following steps:
1) reacting the compound P1 with alcohol under the action of a catalyst to obtain a compound P2;
2) the compound P2 is subjected to the action of a condensing agent to obtain a compound P3;
Figure BDA0003361833580000033
wherein R is selected from C1-C6The alkyl group of (b) is preferably one of alkyl groups such as a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, an isobutyl group and a tert-butyl group.
The method for synthesizing the impurity I comprises the following steps:
1) reacting the compound P1 with alcohol under the action of a catalyst to obtain a compound P2;
2) the compound P2 is subjected to the action of a condensing agent to obtain a compound P3;
3) hydrolyzing the compound P3 in alkaline to obtain an impurity I;
Figure BDA0003361833580000041
as some preferred embodiments of the present invention, the alcohol of step 1) is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, isobutanol, and tert-butanol;
further preferably, the alcohol of step 1) is methanol.
As some preferred embodiments of the present invention, the catalyst of step 1) is selected from one or more of sulfuric acid, hydrochloric acid, thionyl chloride, TMSCl, acetyl chloride, oxalyl chloride and phosgene;
further preferably, the catalyst of step 1) is thionyl chloride.
As some preferred embodiments of the present invention, the esterification reaction temperature in step 1) is from-10 to 70 ℃;
further preferably, the esterification reaction temperature in step 1) is 20-30 ℃.
As some preferred embodiments of the present invention, the condensing agent in step 2) is selected from one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, benzyl chloroformate, phosgene, diphosphine, triphosgene, dimethyl carbonate or Boc anhydride;
further preferably, the condensing agent in step 2) is benzyl chloroformate.
As some preferred embodiments of the present invention, the molar equivalent ratio of the condensing agent to the compound P2 in step 2) is 0.3 to 2: 1;
further preferably, the molar equivalent ratio of the condensing agent to the compound P2 in step 2) is 0.4-0.6: 1.
As some preferred embodiments of the present invention, the condensation reaction of step 2) is carried out in the presence of a solvent and a base;
wherein the solvent is selected from one or more of ethyl acetate, acetonitrile, toluene, xylene, dichloromethane, tetrahydrofuran, methyl tert-ether, DMF, chloroform and isopropyl acetate;
the alkali is selected from one or more of sodium hydroxide, sodium carbonate, potassium carbonate, triethylamine, pyridine, DIPEA, 2-ethylpyridine, sodium hydrogen, sodium methoxide and sodium ethoxide;
the molar equivalent ratio of the base to the compound P2 is 0.8-2: 1;
the reaction temperature of the condensation reaction is-20 ℃ to 30 ℃.
Further preferably, the solvent in step 2) is acetonitrile and/or dichloromethane;
the base is triethylamine;
the molar equivalent ratio of the base to the compound P3 is 1-1.2: 1;
the reaction temperature of the condensation reaction is 10-30 ℃.
As some preferred embodiments of the present invention, the base in step 3) is selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate and sodium carbonate;
0.5-2.0 of the equivalent molar ratio of the base to compound P3: 1;
the temperature of the hydrolysis reaction is 20-80 ℃.
Further preferably, the base in step 3) is sodium hydroxide or lithium hydroxide;
the equivalent molar ratio of the base to the compound P3 is 1.0-1.2: 1;
the temperature of the hydrolysis reaction is 30-45 ℃.
The preparation method has the advantages of safe and environment-friendly reagents, mild reaction conditions, simple treatment, short reaction period, high product yield and good quality.
The invention provides an application of the impurity I in quality control of sitagliptin.
The invention provides a sitagliptin quality control method, which comprises the step of controlling the content of an impurity I in the preparation process of sitagliptin.
The invention provides a sitagliptin quality control method, which comprises the step of controlling the content of an impurity I in an intermediate product BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid to be below 0.30% in the preparation process of sitagliptin, wherein the content is the weight percentage content.
According to the synthesis process of BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid used in the preparation of sitagliptin:
Figure BDA0003361833580000051
the applicant has unexpectedly found that this impurity I is unavoidable during the synthesis of BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid, and that if the content of this impurity I in the liquid-phase detection is greater than 0.30%, it results in a high single known impurity of BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid, which is generated in the subsequent synthesis of sitagliptin, resulting in an unacceptable product quality of sitagliptin. And the process of removing the impurities by traditional recrystallization can reduce the yield and improve the cost, and is not beneficial to industrial production.
By synthesizing the impurity I with high purity, the peak position of the impurity is positioned in liquid phase detection, so that the change condition of the impurity I can be monitored by a liquid area normalization method in the reaction liquid for synthesizing BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid.
In the detection of the finished product of BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid, the content of the impurity I with high purity is taken as a standard substance, and an external standard method is used for monitoring the content of the impurity. The product quality of BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid can be strictly controlled, and the qualified sitagliptin product can be obtained through subsequent reaction.
Research shows that the impurity I obtained by the invention can be used as an important index in quality control of sitagliptin, an intermediate thereof or a preparation thereof, and has the advantages of simple and convenient preparation method and environmental friendliness.
The invention also provides application of the sitagliptin impurity I in research of impurity standard substances.
The sitagliptin impurity I prepared by the invention is characterized by a nuclear magnetic resonance structure, the structure of a synthesized product is determined to be correct, the nuclear magnetic resonance hydrogen spectrum of the synthesized product is analyzed, and the compound is numbered as follows:
Figure BDA0003361833580000061
TABLE 1 Nuclear magnetic analysis of sitagliptin impurity I
Table 1:
proton type Chemical shift Home H encoding Number of protons
C-H 2.0～2.5ppm H-6,6’ 4H
C-H 2.5～3.5ppm H-3,3’ 4H
C-H 4.0～4.1ppm H-4,4’ 2H
N-H 6.0～6.1ppm H-5,5’ 2H
C-H 7.0～8.0ppm H-1,1’,2,2’ 4H
COO-H 12.0～12.5ppm H-7,7’ 2H
The method for preparing sitagliptin impurity I provided by the application has the following advantages:
1) the method provided by the application is adopted to prepare the sitagliptin impurity I, the yield of the sitagliptin impurity I can reach 70-90%, and the yield is greatly improved; compared with the traditional method, the yield can be improved by more than one thousand times.
2) According to the method provided by the application, the adopted solvent can be organic solvents such as methanol and dichloromethane, the organic solvents which are not commonly used or expensive are not involved, the chiral center of the product is stable under the acidic condition, isomerization cannot occur, the purity of the obtained impurity I is high, and the impurity I can be better used as a standard substance.
3) The impurity I prepared by the method has high purity and yield, and can be used as a standard substance to monitor the content of the impurity, so that the quality of sitagliptin can be better controlled;
4) in the whole preparation process, special equipment and raw materials are not needed, the preparation period is short, the operation is easy, and the cost is low.
Drawings
FIG. 1 is a liquid phase spectrum of sitagliptin;
FIG. 2 is a liquid phase spectrum of sitagliptin impurity I;
FIG. 3 is a mass spectrum of compound P3 prepared according to the present invention;
FIGS. 4 and 5 are nuclear magnetic spectra of compound P3 prepared according to the present invention;
FIG. 6 is a mass spectrum of impurity I prepared according to the present invention;
FIGS. 7 and 8 are nuclear magnetic spectra of impurity I prepared according to the present invention.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the present invention in any way.
Example 1: synthesis of P2
Figure BDA0003361833580000071
Example 1-1 (sulfoxide chloride as catalyst, reaction temperature 20 ℃ C.)
233g of substrate P1 were dissolved in 800mL of methanol and the temperature was reduced to 5 ℃. Slowly adding 130g of thionyl chloride, heating to 20 ℃ after adding, stirring for 2h, keeping the temperature, distilling methanol under reduced pressure, adding 800mL of dichloromethane into the concentrate, adjusting the pH value of the concentrate to 7-8 with sodium carbonate aqueous solution, separating the liquid, drying the organic phase sodium sulfate, and directly carrying out the next step, wherein the organic phase contains 242g of P2 through liquid phase analysis, the yield is 98%, and the purity is 99.1%.
Example 1-2 (sulfoxide chloride as catalyst, reaction temperature 30 ℃ C.)
233g of substrate P1 were dissolved in 800mL of methanol and the temperature was reduced to 5 ℃. Slowly adding 130g of thionyl chloride, heating to 30 ℃ after adding, stirring for 2h, keeping the temperature, distilling methanol under reduced pressure, adding 800mL of dichloromethane into the concentrate, adjusting the pH value of the concentrate to 7-8 with sodium carbonate aqueous solution, separating the liquid, drying the organic phase sodium sulfate, and directly carrying out the next step, wherein the organic phase contains about 240g of P2 through liquid phase analysis, the yield is 97%, and the purity is 98.9%.
Examples 1 to 3: (TMSCl as catalyst, 20 ℃ C.)
233g of substrate P1 were dissolved in 800mL of methanol and the temperature was reduced to 5 ℃. Slowly adding 119g of TMSCl, heating to 20 ℃ after the addition, stirring for 2h, keeping the temperature, distilling methanol under reduced pressure, adding 800mL of dichloromethane into the concentrate, adjusting the pH value to 7-8 with sodium carbonate aqueous solution, separating, drying organic phase sodium sulfate, and directly carrying out the next step, wherein the organic phase contains about 235g of P2 by liquid phase analysis, the yield is 95%, and the purity is 99.0%.
Examples 1 to 4: (TMSCl as catalyst at 30 ℃ C.)
233g of substrate P1 were dissolved in 800mL of methanol and the temperature was reduced to 5 ℃. Slowly adding 119g of TMSCl, heating to 20 ℃ after the addition, stirring for 2h, keeping the temperature, distilling methanol under reduced pressure, adding 800mL of dichloromethane into the concentrate, adjusting the pH value to 7-8 with sodium carbonate aqueous solution, separating, drying organic phase sodium sulfate, and directly carrying out the next step, wherein the organic phase contains about 238g of P2 through liquid phase analysis, the yield is 96%, and the purity is 98.7%.
Examples 1 to 5: (the catalyst is thionyl chloride, the reaction temperature is 40 ℃.)
233g of substrate P1 were dissolved in 800mL of methanol and the temperature was reduced to 5 ℃. Slowly adding 130g of thionyl chloride, heating to 40 ℃ after adding, stirring for 2h, keeping the temperature, distilling methanol under reduced pressure, adding 800mL of dichloromethane into the concentrate, adjusting the pH value of the concentrate to 7-8 with sodium carbonate aqueous solution, separating the liquid, drying the organic phase sodium sulfate, and directly carrying out the next step, wherein the organic phase contains about 225g of P2 through liquid phase analysis, the yield is 91%, and the purity is 98.2%.
Examples 1 to 6: (the catalyst is thionyl chloride, the reaction temperature is 50 ℃.)
233g of substrate P1 were dissolved in 800mL of methanol and the temperature was reduced to 5 ℃. Slowly adding 130g of thionyl chloride, heating to 50 ℃ after adding, stirring for 2h, keeping the temperature, distilling methanol under reduced pressure, adding 800mL of dichloromethane into the concentrate, adjusting the pH value of the concentrate to 7-8 with sodium carbonate aqueous solution, separating the liquid, drying the organic phase sodium sulfate, and directly carrying out the next step, wherein the organic phase contains 228g of P2 through liquid phase analysis, the yield is 92%, and the purity is 98.6%.
Example 2: synthesis of P3
Figure BDA0003361833580000081
Example 2-1 (condensing agent is benzyl chloroformate)
247g of substrate P2 are dissolved in 800mL of dichloromethane, cooled to 5 ℃ and 101g of triethylamine are added. And slowly adding 85g of benzyl chloroformate, heating to 10-20 ℃, stirring for 2h, keeping the temperature, adding 500mL of water, extracting, separating, and concentrating and drying an organic phase to obtain white solid P3, 247g, with the yield of 95% and the purity of 99.3%.
Example 2-2: (the condensing agent is methyl chloroformate)
247g of substrate P2 are dissolved in 800mL of dichloromethane, cooled to 5 ℃ and 101g of triethylamine are added. Slowly adding 47g of methyl chloroformate, heating to 10-20 ℃, stirring for 2h, keeping the temperature, adding 500mL of water, extracting, separating, and concentrating and drying an organic phase to obtain white solid P3, 243g, yield of 93% and purity of 99.1%.
Example 3: synthesis of impurity I
Figure BDA0003361833580000091
Example 3-1 (base is lithium hydroxide monohydrate)
260g of substrate P3 were dissolved in 800mL of methanol, 200mL of water were added, the temperature was raised to 30-40 ℃ and 21g of lithium hydroxide monohydrate were added. Stirring for 2-4h under heat preservation, dropwise adding hydrochloric acid to adjust pH to 2-3 after heat preservation, adding 500mL of water, separating out a large amount of solid, cooling to 15-20 ℃, filtering, and drying a filter cake to obtain white solid impurity I, 229g, yield 93%, and purity 99.6%.
Example 3-2: (the base is sodium hydroxide)
260g of substrate P3 were dissolved in 800mL of methanol, 200mL of water were added, the temperature was raised to 30-40 ℃ and 20g of sodium hydroxide were added. Stirring for 2-4h under heat preservation, dropwise adding hydrochloric acid to adjust pH to 2-3 after heat preservation, adding 500mL of water, separating out a large amount of solid, cooling to 15-20 ℃, filtering, and drying a filter cake to obtain white solid impurity I, 224g, yield of 91% and purity of 99.2%.
The prepared impurity I is subjected to liquid phase detection, the obtained spectrogram is shown as 2, and the peak-out time is 16.9 minutes.
The applicant synthesizes sitagliptin according to a conventional method, and carries out liquid phase detection on a reaction liquid, and an obtained spectrogram is shown in figure 1, wherein 12.266 minutes is the peak-out time of sitagliptin, and 16.9 minutes is the peak-out time of impurity I.
The impurity with the peak-out time of 16.9 minutes in the sitagliptin acid reaction liquid is consistent with the peak-out time of the high-purity impurity I liquid phase obtained by synthesis in the application.
FIG. 1 is a liquid phase spectrogram of the finished sitagliptin, which is consistent with the time of the liquid phase peak of the synthesized high-purity impurity I. This indicates that the finished sitagliptin contains the condensation impurities claimed in the present application.
Example 4 use of sitagliptin impurity I in sitagliptin
BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid with the content of sitagliptin impurity I of 0.10%, 0.20%, 0.30%, 0.40% and 0.50% is respectively obtained by weighing BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid with different masses (the purity is more than 99.5% and the standard product which does not contain sitagliptin impurity I) and sitagliptin impurity I (the purity is more than 99.5%) and mixing uniformly. The method is shown in table 2:
TABLE 2
Figure BDA0003361833580000101
And after weighing, uniformly mixing BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid and sitagliptin impurity I to obtain BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid with the sitagliptin impurity I content of 0.10%, 0.20%, 0.30%, 0.40% and 0.50%.
The specific experimental procedure for preparing sitagliptin using BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid having a sitagliptin impurity I content of 0.10% is as follows:
in a 250ml three-necked flask, 100 ml of dichloromethane was added, BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid (6.6g, 0.02mol) and 3-trifluoromethyl-5, 6,7, 8-tetrahydro- [1,2,4] triazolo [4,3-a ] pyrazine hydrochloride (4.6g, 0.02mol) were added, cooled to 0 ℃ with an ice salt bath, 1-Hydroxybenzotriazole (HOBT) (2.7g, 0.02mol), 1-ethyl-3- (3-dimethylaminopropyl) carboximidic acid (edc.hcl) (3.82g, 0.02mol) were added, triethylamine (6g, 0.03mol) was added dropwise, reaction was carried out for 24 hours, the reaction solution was washed twice with 50ml of distilled water, dried, filtered, concentrated to obtain a crude product (9.70g, 0.019mol), yield 95.8%.
To a 250mL round bottom flask were added (3R) -3-tert-butoxycarbonylamino-1- [3- (trifluoromethyl) -5,6,7, 8-tetrahydro-1, 2, 4-triazolo [4,3-a ] pyrazin-7-yl ] -4- (2,4, 5-trifluorophenyl) butan-1-one (9.70g, 0.019mol) and 80mL of methanol to dissolve, 80mL of a mixed solution of concentrated hydrochloric acid and methanol 1: 5(v/v) was added to the round bottom flask, stirred at room temperature for 3 hours, the solvent was concentrated under reduced pressure, neutralized by adding 2mol/L of aqueous ammonia, the aqueous phase was extracted three times with 100 mL of ethyl acetate, the organic phases were combined and washed with saturated brine, dried, filtered, concentrated to give a crude product, recrystallized from toluene to give a white solid (7.05g, 0.017mol), yield 91.2%.
In a 1000mL round bottom flask, (3R) -3-amino-1- [3- (trifluoromethyl) -5,6,7, 8-tetrahydro-1, 2, 4-triazolo [4,3-a ] pyrazin-7-yl ] -4- (2,4, 5-trifluorophenyl) butan-1-one (69.2g, 0.17mol) and 110g of isopropanol were added, with stirring, 61.2g of purified water and 19.4g of phosphoric acid were added, after which the mixture was heated to reflux, after which the reaction system was cooled to room temperature and filtered to obtain a white solid, i.e., sitagliptin.
The liquid phase purity of the obtained sitagliptin and western sitagliptin impurity I is 0.03%.
The analysis method of the finished sitagliptin is as follows:
the instrument comprises the following steps: agilent 1260
A chromatographic column: EC-C182.7um 4.6 x 100mm or similar columns
The instrument parameters are as follows:
mobile phase A: measuring 1ml of perchloric acid, putting the perchloric acid into a 1000ml volumetric flask containing 500ml of water, shaking up, diluting the perchloric acid to a scale with water, shaking up, filtering, and ultrasonically degassing.
Mobile phase B of acetonitrile
Gradient:
Figure BDA0003361833580000111
flow rate: 0.6mL/min
Column temperature: 25 degree
A detector: ultraviolet detector with wavelength of 210nm
Operating time: 40min
Diluent agent: water: 1:1 acetonitrile
Test solutions: precisely weighing 50mg of test sample, placing in a 25ml volumetric flask, adding 5-10ml of diluent for dissolution, diluting with the diluent to the scale, and shaking up (2 mg/ml).
The preparation process of sitagliptin is repeated by using BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid with the impurity content of 0.20%, 0.30%, 0.40% and 0.50%, and the liquid phase purity of the sitagliptin impurity I in the sitagliptin is respectively 0.06%, 0.09%, 0.13% and 0.16%.
The effect of different amounts of this impurity I in BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid on the quality of sitagliptin prepared from BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid containing this impurity I is shown in table 3:
TABLE 3
Figure BDA0003361833580000121
And (4) conclusion: the united states pharmacopeia and european pharmacopeia require that sitagliptin related substances detect less than 0.10% of a single impurity. When the content of the impurity I in BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid is 0.30%, the impurity I in sitagliptin is generated by the impurity in BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid through a series of synthesis steps, the impurity I is an index of 0.09% close to 0.10%, the content of the impurity in BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid is strictly controlled to be less than 0.30%, and the impurity I in sitagliptin can be ensured to meet the requirement of quality standard.
Preparing a standard solution with the concentration of the impurity I of 0.006mg/mL (the concentration of a BOC-butyric acid sample is 2mg/mL, the quality control limit of the impurity I in the sample is 0.30%, and the concentration of the prepared standard solution is 0.006mg/mL), and performing 5 times of sample injection on the same standard solution, wherein the relative standard deviation is less than 1%, and the standard is met. The content of the impurity I in the sample was calculated as a standard solution for the external standard method.
Figure BDA0003361833580000122
A sample solution of BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid of 2mg/ml was prepared and injected 3 times. Respectively taking the peak areas of the standard solutions of the impurity I as the reference, calculating the content of the impurity I in the BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid sample, and finally calculating the average value of the content of the impurity I.
Figure BDA0003361833580000123
Figure BDA0003361833580000131
And (4) conclusion: detecting a BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid sample, and detecting the content of the impurity I to be 0.16 percent and less than 0.30 percent by using an external standard method, wherein the content meets the requirement of quality standard.
If the content of the impurity I in the intermediate BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid is monitored to be higher than 0.3 percent in the experimental process, the intermediate BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid needs to be refined and purified, and the subsequent reaction is carried out when the content of the impurity I is lower than 0.3 percent.
According to the detection results, the sitagliptin impurity I prepared by the method provided by the application has the yield of 70-90% and is greatly improved; the adopted solvent can be organic solvents such as methanol, dichloromethane and the like, and does not relate to unusual or expensive organic solvents, and the chiral center of the product is stable under the acidic condition and cannot be isomerized; in the whole preparation process, special equipment and raw materials are not needed, the preparation period is short, the operation is easy, and the cost is low.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (10)

1. Sitagliptin impurity I, characterized in that: the structural formula of the sitagliptin impurity I is as follows:
Figure FDA0003361833570000011
2. a compound P3, characterized in that: the structural formula of the compound P3 is as follows:
Figure FDA0003361833570000012
wherein R is independently selected from C1-C6Alkyl group of (1).
3. A process for the preparation of compound P3, characterized in that: the method comprises the following steps:
1) reacting the compound P1 with alcohol under the action of a catalyst to obtain a compound P2;
2) the compound P2 is subjected to the action of a condensing agent to obtain a compound P3;
Figure FDA0003361833570000013
wherein R is independently selected from C1-C6Alkyl group of (1).
4. A preparation method of sitagliptin impurity I is characterized by comprising the following steps: the method comprises the following steps:
1) reacting the compound P1 with alcohol under the action of a catalyst to obtain a compound P2;
2) the compound P2 is subjected to the action of a condensing agent to obtain a compound P3;
3) hydrolyzing the compound P3 in an alkaline environment to obtain an impurity I;
Figure FDA0003361833570000021
wherein R is independently selected from C1-C6Alkyl group of (1).
5. The method according to claim 3 or 4, characterized in that: the alcohol in the step 1) is selected from one or more of methanol, ethanol, isopropanol, propanol, butanol, isobutanol and tert-butanol, and is preferably methanol;
the catalyst is selected from one or more of sulfuric acid, hydrochloric acid, thionyl chloride, trimethyl silicon chloride, acetyl chloride, oxalyl chloride and phosgene, and is preferably thionyl chloride.
6. The method according to claim 3 or 4, characterized in that: the condensing agent in the step 2) is selected from one of methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, benzyl chloroformate, phosgene, diphosphine, triphosgene, dimethyl carbonate or Boc anhydride, and is preferably benzyl chloroformate; the molar equivalent ratio of the condensing agent to the compound P2 is 0.3-2:1, preferably 0.4-0.6: 1.
7. The method according to claim 3 or 4, characterized in that: the condensation reaction in step 2) is carried out in the presence of a solvent and a base;
wherein the solvent is selected from one or more of ethyl acetate, acetonitrile, toluene, xylene, dichloromethane, tetrahydrofuran, methyl tert-ether, DMF, chloroform and isopropyl acetate, preferably acetonitrile and/or dichloromethane;
the alkali is selected from one or more of sodium hydroxide, sodium carbonate, potassium carbonate, triethylamine, pyridine, DIPEA, 2-ethylpyridine, sodium hydrogen, sodium methoxide and sodium ethoxide, and is preferably triethylamine;
the molar equivalent ratio of the base to the compound P2 is 0.8-2: 1, preferably 1-1.2: 1;
the reaction temperature of the condensation reaction is-20 ℃ to 30 ℃, and preferably 10 ℃ to 30 ℃.
8. Use of sitagliptin impurity I as claimed in claim 1 in quality control of sitagliptin.
9. A method for controlling the quality of sitagliptin, which comprises controlling the content of the sitagliptin impurity I in claim 1 in the preparation process of a sitagliptin intermediate BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butanoic acid.
10. A quality control method of sitagliptin comprises the step of controlling the content of impurity I in sitagliptin to be below 0.3% in the preparation process of a sitagliptin intermediate BOC- (R) -3-amino-4- (2,4, 5-trifluorophenyl) butyric acid.
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