CN111484457A - Method for separating alogliptin impurities - Google Patents
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- CN111484457A CN111484457A CN202010315563.5A CN202010315563A CN111484457A CN 111484457 A CN111484457 A CN 111484457A CN 202010315563 A CN202010315563 A CN 202010315563A CN 111484457 A CN111484457 A CN 111484457A
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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Abstract
The invention provides a separation method of alogliptin impurities, wherein toluene is used as a solvent, 6-chloro-3-methyluracil and 2-cyanobenzyl bromide are subjected to condensation reaction, toluene mother liquor is obtained through recovery, and a product is obtained through column separation and recrystallization for several times; the requirement of researching the impurity spectrum of the bulk drug when CTD data is declared is met, and the structure of the bulk drug is confirmed, so that the completeness of the impurity spectrum research is ensured.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for separating impurities from alogliptin condensation mother liquor.
Background
Alogliptin benzoate is a DPP inhibitor developed in martian, japan. On 4 months in 2010, approved for marketing by the japan ministry of health and welfare. Us FDA approval for alogliptin to be marketed in month 1 of 2013. CFDA approved imported alogliptin to market in 7 months in 2013. The alogliptin can maintain the level of glucagon-like peptide and glucose-dependent insulinotropic polypeptide in vivo, and promote the secretion of insulin, thereby achieving the curative effect of reducing blood sugar.
Because alogliptin has the characteristics of good blood sugar reducing effect, small side effect and the like, a plurality of pharmaceutical factories in China carry out research and development work of imitation drugs in succession. In the research and development of the imitation drugs, the impurity spectrum of the imitation drugs needs to be researched.
Most of the synthesis processes of alogliptin benzoate are from 6-chloro-3-methyluracil, toluene is used as a solvent, the alogliptin benzoate and 2-cyanobenzylbromide are subjected to condensation reaction to obtain an intermediate, when the intermediate is subjected to liquid phase analysis, 0.5-1% of large impurities are found, the residual content of other impurities is lower than 0.5% and can be ignored, and therefore the large impurities are separated and qualified. The invention provides a method for separating alogliptin impurities from toluene mother liquor of condensation reaction.
When CTD data is reported, the impurity spectrum of the raw material medicine needs to be researched, but some impurities cannot be obtained through purchase, so that the impurities can only be obtained through self synthesis or separation preparation. The invention researches a method for separating the impurity from the toluene mother liquor of alogliptin condensation reaction, and confirms the structure of the impurity, thereby ensuring the completeness of the impurity spectrum research.
Disclosure of Invention
The invention provides a separation method of alogliptin impurities, wherein toluene is used as a solvent, 6-chloro-3-methyluracil and 2-cyanobenzyl bromide are subjected to condensation reaction, and a toluene mother liquor is obtained by recovering:
(1) distilling and concentrating the recovered toluene mother liquor, passing through a column, filling crude silica gel, and enriching impurities for 40 minutes by liquid phase detection;
(2) fine silica gel filler, secondary column passing, liquid phase detection and impurity enrichment for 40 minutes;
(3) and recrystallizing the impurities for 40 minutes to finally obtain the target product.
The silica gel mesh number of the first column passing in the step (1) is 60-100,100-200,200-300, 300-400; the first column-passing developing agent is one of ethyl acetate and petroleum ether in a ratio of 1:5, dichloromethane and n-hexane in a ratio of 1:8, methanol in a ratio of 1:10 and methanol and petroleum ether in a ratio of n-heptane in a ratio of 1: 15; the silica gel mesh number of the second column passing in the step (2) is 60-100,100-200,200-300, 300-400; the second column chromatography developing solvent is one of ethyl acetate and petroleum ether in a ratio of 1:3, ethyl acetate and petroleum ether in a ratio of 1:8, dichloromethane and n-hexane in a ratio of 1:10, and methanol and n-heptane in a ratio of 1: 15.
The mesh number of the first column-passing silica gel in the step (1) is 60-100 meshes; the first column-passing developing solvent is dichloromethane and n-hexane with the ratio of 1: 8; the silica gel mesh number of the second column passing in the step (2) is 200-300 meshes; the second column-passing developing solvent is 1:8 ethyl acetate and petroleum ether.
The recrystallization refining solvent in the step (3) is one of acetone, acetonitrile and absolute ethyl alcohol.
And (3) recrystallizing to obtain acetonitrile as the refined solvent.
The invention provides a separation method of alogliptin impurities, which comprises the steps of firstly carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide, finding out a large unknown impurity after intermediate liquid phase detection, carrying out liquid phase analysis on recovered centrifugal mother liquor, finding out that the content of the unknown impurity in the mother liquor is high, then concentrating the mother liquor, carrying out separation and concentration on the mother liquor to obtain an oily substance, and confirming the structure, wherein a spectrogram is shown in attached figures 1-7.
1H-NMR gave 9 sets of peaks with an integral ratio (low to high field) of 1: 2: 1: 1: 2: 1: 2: 2: 3. from the chemical shifts, coupling constants and COSY correlations:
a.7.71(1H, dd) is the 9-position proton signal peak, and cosy spectrum shows that 7.71 is directly related to 7.43.
b.7.57-7.65(2H, m) are the 11-position proton signal peak 7.59 and the 19-position proton signal peak 7.63, respectively. cosy spectra showed a direct correlation between 7.63 and 7.33.
c.7.50(1H, td) is the 17-position proton signal peak.
d.7.43(1H, td) is the 10-position proton signal peak, and cosy spectrum shows that 7.43 and 7.71 have direct correlation.
e.7.28-7.34(2H, m) are the 16-position proton signal peak 7.30 and the 18-position proton signal peak 7.33, respectively. cosy spectra showed a direct correlation between 7.33 and 7.63.
f.7.26(1H, m) is the peak of the 12-position proton signal.
g.5.57(2H, s) is the 6-position proton signal peak.
h.4.15(2H, s) is the 14-position proton signal peak.
i.3.44(3H, s) is the 5-position proton signal peak.
13C-NMR gave 21 sets of peaks. According to chemical shift and corresponding hydrogen spectrum, the structure of the product contains 1 kind of primary carbon, 2 kinds of secondary carbon, 8 kinds of tertiary carbon and 10 kinds of quaternary carbon. 29 to 49 are saturated carbon signals, and 110 to 162 are unsaturated carbon signals.
a.161.28 is the peak of the 1-carbon signal, carbonyl carbon, HMBC indicates 161.28 is remotely related to 4.15, 3.44.
b.150.91 is the peak at carbon 4, carbonyl carbon, HMBC indicates 150.91 is remotely related to 5.57, 3.44.
c.144.17 is the peak at carbon 3, quaternary carbon, HMBC indicates 144.17 is remotely correlated with 5.57, 4.15.
d.141.82 is the 15 carbon signal peak, quaternary carbon, HMBC indicates 141.82 is remotely correlated with 7.63, 7.50, 4.15.
e.139.16 is the 7-carbon signal peak, quaternary carbon, HMBC indicates 139.16 is remotely correlated with 7.71, 7.59, 5.57.
f.133.46 is the 9-carbon signal peak, tertiary carbon, HSQC indicates 133.46 is directly related to 7.71, HMBC indicates 133.46 is remotely related to 7.59, 7.43 protons.
g.133.38 is the 19-carbon signal peak, tertiary carbon, HSQC indicated 133.38 in direct correlation with 7.63, and HMBC indicated 133.38 in remote correlation with 7.33 protons.
h.133.03 is the 11-carbon signal peak, tertiary carbon, HSQC shows 133.03 is directly related to 7.59, HMBC shows 133.03 is remotely related to 7.71, 7.43 protons.
i.132.96 is a 17-carbon signal peak, tertiary carbon, HSQC shows 132.96 is directly related to 7.50, HMBC shows 132.96 is remotely related to 7.63 and 7.33 protons.
j.128.77 is the 16-carbon signal peak, tertiary carbon, HSQC indicated 128.77 directly correlated with 7.30, and HMBC indicated 128.77 remotely correlated with 7.50, 7.33, 4.15 protons.
k.128.42 is the 10-carbon signal peak, tertiary carbon, HSQC indicates 128.42 is directly related to 7.43, HMBC indicates 128.42 is remotely related to 7.26 protons.
l.127.15 is the 18 carbon signal peak, tertiary carbon, HSQC indicated 127.15 in direct correlation with 7.33 and HMBC indicated 127.15 in remote correlation with 7.30 protons.
m.126.57 is the 12-carbon signal peak, tertiary carbon, HSQC shows that 126.57 is directly related to 7.26, and HMBC shows that 126.57 is remotely related to 7.43 and 5.57 protons.
n.117.90 is the 21 carbon signal peak, quaternary carbon, HMBC indicates 117.90 is remotely correlated with 7.63.
o.116.79 is the 13 carbon signal peak, quaternary carbon, HMBC indicates 116.79 is remotely correlated with 7.71.
p.112.57 is the 2-carbon signal peak, quaternary carbon, HMBC indicates 112.57 is remotely correlated with 7.30.
q.111.11 is the 20 carbon signal peak, quaternary carbon, HMBC indicates that there is a long range correlation between 111.11 and 4.15.
r.111.00 is the 8-carbon signal peak, quaternary carbon, HMBC indicates 111.00 is remotely correlated with 7.43, 7.26, 5.57.
s.48.65 is the 6-carbon signal peak, secondary carbon, HSQC indicates that 48.65 is directly related to 5.57, and HMBC indicates that 48.65 is remotely related to 7.26 protons.
t.31.62 is the 14-carbon signal peak, secondary carbon, HSQC indicates that 31.62 is directly related to 4.15, and HMBC indicates that 31.62 is remotely related to 7.30 protons.
u.29.16 is the peak of the 5-carbon signal, primary carbon, HSQC shows that there is a direct correlation between 29.16 and 3.44.
From the NMR spectrum, the NMR data of this product were consistent with the structure.
The mass-to-charge ratio of the [ M + H ] + peak of the product ionized substance is 391.10, and the mass-to-charge ratio of the [ M + Na ] + peak is 413.09. The molecular weight of the product free substance is 390.09, which is the same as the molecular weight of the presumed structure.
Drawings
The attached figure 1 is: nuclear magnetic hydrogen spectrum;
FIG. 2 is a drawing: nuclear magnetic carbon spectrum spectrogram;
FIG. 3 is a schematic diagram of: COSY spectrum;
FIG. 4 is a drawing of: HMBC spectrogram;
FIG. 5 shows HP L C spectrum;
FIG. 6 is a schematic representation of: HSQC spectrogram;
FIG. 7 is a schematic representation of: high resolution mass spectrometry spectrum.
The invention researches a method for separating the impurity from the alogliptin condensation reaction mother liquor and confirms the structure of the alogliptin condensation reaction mother liquor, thereby ensuring the completeness of the impurity spectrum research and meeting the research on the impurity spectrum of the bulk drug during CTD data reporting.
Detailed Description
The following examples are intended to further illustrate the invention, but not to limit it.
Example 1
Packing with 60-100 mesh silica gel, pouring out, adding 1:8 dichloromethane and n-hexane, stirring to remove bubbles, pouring the solution into a chromatographic column, and standing for 1 h.
80 g of the recovered toluene mother liquor concentrated product with the content of about 1% in 40 minutes is taken, the product is subjected to column chromatography by using dichloromethane and n-hexane with the ratio of 1:8 as developing agents, impurities are collected for 40 minutes through liquid phase tracing, the content is 32.58% in HP L C detection, and 2.46g of oily matter is obtained after concentration.
Example 2
Packing the solution into a column by using 100-plus 200-mesh silica gel, pouring out the column, adding 1:5 of ethyl acetate and petroleum ether, stirring the mixture until no bubbles exist, pouring the solution into a chromatographic column, and standing the chromatographic column for 1 hour.
20 g of the recovered toluene mother liquor was taken to concentrate the product, the content of which was about 1% in 40 minutes, and the product was subjected to column chromatography using 1:5 ethyl acetate and petroleum ether as developing agents, followed by liquid phase chromatography, mixed concentration was carried out to collect impurities for 40 minutes, the content of which was 22.45% in HP L C, and 0.89g of oil was obtained after concentration.
Example 3
Packing the solution into a 200-mesh 300-mesh silica gel column, pouring out the silica gel column, adding 1:10 methanol and n-heptane, stirring the mixture until no bubbles exist, pouring the solution into a chromatographic column, and standing the chromatographic column for 1 hour.
20 g of the recovered toluene mother liquor was taken to concentrate the product to a content of about 1% in 40 minutes, and the product was subjected to column chromatography using 1:10 methanol and n-heptane as developing agents, followed by liquid phase chromatography, mixed concentration to collect impurities for 40 minutes, and HP L C detected as a content of 11.92%, to obtain 1.68g of oil after concentration.
Example 4
Packing the solution into a column by 300-mesh 400-mesh silica gel, pouring out the column, adding methanol and petroleum ether in a ratio of 1:15, stirring the mixture until no bubbles exist, pouring the solution into a chromatographic column, and standing the chromatographic column for 1 hour.
20 g of the recovered toluene mother liquor was taken to concentrate the product, the content of which was about 1% in 40 minutes, and the product was subjected to column chromatography using 1:15 methanol and petroleum ether as developing agents, followed by liquid phase chromatography, mixed concentration was carried out to collect impurities for 40 minutes, and the content of HP L C detected was 8.56%, and 2.34g of oil was obtained after concentration.
Example 5
Packing with 60-100 mesh silica gel, pouring out, adding 1:3 ethyl acetate and petroleum ether, stirring until no air bubbles exist, pouring the solution into a chromatographic column, and standing for 1 h.
0.3 g of the concentrated product of example 1 was subjected to column chromatography using 1:3 ethyl acetate and petroleum ether as developing agents, followed by liquid phase chromatography, mixed and concentrated to collect impurities for 40 minutes, and the content of HP L C was found to be 66.98%, and the concentrated product was 145.9mg of oil.
Example 6
Packing the solution into a column by using 100-plus 200-mesh silica gel, pouring out the column, adding dichloromethane and n-hexane in a ratio of 1:10, stirring the mixture until no bubbles exist, pouring the solution into a chromatographic column, and standing the chromatographic column for 1 hour.
0.3 g of the concentrated product obtained in example 1 was subjected to column chromatography using 1:10 dichloromethane and n-hexane as developing agents, followed by liquid phase chromatography, mixed and concentrated to collect impurities for 40 minutes, and the content of HP L C detected was 55.23%, and the concentrated product was 177mg of an oil.
Example 7
Packing the solution into a column by 200-mesh 300-mesh silica gel, pouring out the column, adding 1:8 ethyl acetate and petroleum ether, stirring the mixture until no bubbles exist, pouring the solution into a chromatographic column, and standing the chromatographic column for 1 hour.
1.2 g of the concentrated product of example 1 was subjected to column chromatography using 1:8 ethyl acetate and petroleum ether as developing solvent, followed by liquid phase chromatography, mixed and concentrated to collect impurities for 40 minutes, and the content of HP L C was 87.55%, and the concentrate was concentrated to obtain 446.6mg of oil.
Example 8
Packing the solution into a column by 300-mesh 400-mesh silica gel, pouring out the column, adding 1:15 methanol and n-heptane, stirring the mixture until no air bubbles exist, pouring the solution into a chromatographic column, and standing the chromatographic column for 1 hour.
0.3 g of the concentrated product of example 1 was subjected to column chromatography using 1:15 methanol and n-heptane as developing agents, followed by liquid phase chromatography, mixed and concentrated to collect impurities for 40 minutes, and the content of HP L C was 45.67%, and the concentrate was concentrated to obtain 214mg of an oil.
Example 9
100mg of the concentrate of example 7 was weighed precisely, 10ml of acetone was added, the mixture was heated to reflux, 25ml of acetone was added in total to dissolve it, the mixture was cooled in an ice bath and crystallized for 1 hour, filtered with suction, and dried under vacuum at 60 ℃ for 1 hour to obtain 58mg of a white solid with a content of 91.58% by HP L C.
Example 10
100mg of the concentrate of example 7 was weighed precisely, 10ml of acetonitrile was added, the mixture was heated to reflux, 18ml of acetonitrile was added in total to dissolve it, the mixture was cooled in an ice bath and crystallized for 1 hour, and the mixture was filtered with suction and dried under vacuum at 60 ℃ for 1 hour to obtain 72mg of a white solid with a content of HP L C of 96.61%.
1H-NMR gave 9 sets of peaks with an integral ratio (low to high field) of 1: 2: 1: 1: 2: 1: 2: 2: 3. from the chemical shifts, coupling constants and COSY correlations:
a.7.71(1H, dd) is the 9-position proton signal peak, and cosy spectrum shows that 7.71 is directly related to 7.43.
b.7.57-7.65(2H, m) are the 11-position proton signal peak 7.59 and the 19-position proton signal peak 7.63, respectively. cosy spectra showed a direct correlation between 7.63 and 7.33.
c.7.50(1H, td) is the 17-position proton signal peak.
d.7.43(1H, td) is the 10-position proton signal peak, and cosy spectrum shows that 7.43 and 7.71 have direct correlation.
e.7.28-7.34(2H, m) are the 16-position proton signal peak 7.30 and the 18-position proton signal peak 7.33, respectively. cosy spectra showed a direct correlation between 7.33 and 7.63.
f.7.26(1H, m) is the peak of the 12-position proton signal.
g.5.57(2H, s) is the 6-position proton signal peak.
h.4.15(2H, s) is the 14-position proton signal peak.
i.3.44(3H, s) is the 5-position proton signal peak.
13C-NMR gave 21 sets of peaks. According to chemical shift and corresponding hydrogen spectrum, the structure of the product contains 1 kind of primary carbon, 2 kinds of secondary carbon, 8 kinds of tertiary carbon and 10 kinds of quaternary carbon. 29 to 49 are saturated carbon signals, and 110 to 162 are unsaturated carbon signals.
a.161.28 is the peak of the 1-carbon signal, carbonyl carbon, HMBC indicates 161.28 is remotely related to 4.15, 3.44.
b.150.91 is the peak at carbon 4, carbonyl carbon, HMBC indicates 150.91 is remotely related to 5.57, 3.44.
c.144.17 is the peak at carbon 3, quaternary carbon, HMBC indicates 144.17 is remotely correlated with 5.57, 4.15.
d.141.82 is the 15 carbon signal peak, quaternary carbon, HMBC indicates 141.82 is remotely correlated with 7.63, 7.50, 4.15.
e.139.16 is the 7-carbon signal peak, quaternary carbon, HMBC indicates 139.16 is remotely correlated with 7.71, 7.59, 5.57.
f.133.46 is the 9-carbon signal peak, tertiary carbon, HSQC indicates 133.46 is directly related to 7.71, HMBC indicates 133.46 is remotely related to 7.59, 7.43 protons.
g.133.38 is the 19-carbon signal peak, tertiary carbon, HSQC indicated 133.38 in direct correlation with 7.63, and HMBC indicated 133.38 in remote correlation with 7.33 protons.
h.133.03 is the 11-carbon signal peak, tertiary carbon, HSQC shows 133.03 is directly related to 7.59, HMBC shows 133.03 is remotely related to 7.71, 7.43 protons.
i.132.96 is a 17-carbon signal peak, tertiary carbon, HSQC shows 132.96 is directly related to 7.50, HMBC shows 132.96 is remotely related to 7.63 and 7.33 protons.
j.128.77 is the 16-carbon signal peak, tertiary carbon, HSQC indicated 128.77 directly correlated with 7.30, and HMBC indicated 128.77 remotely correlated with 7.50, 7.33, 4.15 protons.
k.128.42 is the 10-carbon signal peak, tertiary carbon, HSQC indicates 128.42 is directly related to 7.43, HMBC indicates 128.42 is remotely related to 7.26 protons.
l.127.15 is the 18 carbon signal peak, tertiary carbon, HSQC indicated 127.15 in direct correlation with 7.33 and HMBC indicated 127.15 in remote correlation with 7.30 protons.
m.126.57 is the 12-carbon signal peak, tertiary carbon, HSQC shows that 126.57 is directly related to 7.26, and HMBC shows that 126.57 is remotely related to 7.43 and 5.57 protons.
n.117.90 is the 21 carbon signal peak, quaternary carbon, HMBC indicates 117.90 is remotely correlated with 7.63.
o.116.79 is the 13 carbon signal peak, quaternary carbon, HMBC indicates 116.79 is remotely correlated with 7.71.
p.112.57 is the 2-carbon signal peak, quaternary carbon, HMBC indicates 112.57 is remotely correlated with 7.30.
q.111.11 is the 20 carbon signal peak, quaternary carbon, HMBC indicates that there is a long range correlation between 111.11 and 4.15.
r.111.00 is the 8-carbon signal peak, quaternary carbon, HMBC indicates 111.00 is remotely correlated with 7.43, 7.26, 5.57.
s.48.65 is the 6-carbon signal peak, secondary carbon, HSQC indicates that 48.65 is directly related to 5.57, and HMBC indicates that 48.65 is remotely related to 7.26 protons.
t.31.62 is the 14-carbon signal peak, secondary carbon, HSQC indicates that 31.62 is directly related to 4.15, and HMBC indicates that 31.62 is remotely related to 7.30 protons.
u.29.16 is the peak of the 5-carbon signal, primary carbon, HSQC shows that there is a direct correlation between 29.16 and 3.44.
From the NMR spectrum, the NMR data of this product were consistent with the structure.
The mass-to-charge ratio of the [ M + H ] + peak of the product ionized substance is 391.10, and the mass-to-charge ratio of the [ M + Na ] + peak is 413.09. The molecular weight of the product free substance is 390.09, which is the same as the molecular weight of the presumed structure.
Example 11
Accurately weighing 100mg of the concentrate in example 7, adding 10ml of absolute ethyl alcohol, heating to reflux, adding 12ml of absolute ethyl alcohol in total to dissolve, cooling in an ice bath for crystallization for 1h, performing suction filtration, and performing vacuum drying at 60 ℃ for 1h to obtain 61mg of white solid, wherein the content of HP L C is 92.34%.
Claims (5)
1. The method for separating the alogliptin impurities comprises the following steps of taking toluene as a solvent, carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide, and recovering to obtain a toluene mother liquor, wherein the method comprises the following steps:
(1) distilling and concentrating the recovered toluene mother liquor, passing through a column, filling crude silica gel, and enriching impurities for 40 minutes by liquid phase detection;
(2) fine silica gel filler, secondary column passing, liquid phase detection and impurity enrichment for 40 minutes;
(3) and recrystallizing the impurities for 40 minutes to finally obtain the target product.
2. The method for separating alogliptin impurities according to claim 1, wherein the method comprises: the silica gel mesh number of the first column chromatography in the step (1) is 60-100,100-200,200-300, 300-400; the first column-passing developing agent is one of ethyl acetate and petroleum ether in a ratio of 1:5, dichloromethane and n-hexane in a ratio of 1:8, methanol in a ratio of 1:10 and methanol and petroleum ether in a ratio of n-heptane in a ratio of 1: 15; the silica gel mesh number of the second column passing in the step (2) is 60-100,100-200,200-300, 300-400; the second column chromatography developing solvent is one of ethyl acetate and petroleum ether in a ratio of 1:3, ethyl acetate and petroleum ether in a ratio of 1:8, dichloromethane and n-hexane in a ratio of 1:10, and methanol and n-heptane in a ratio of 1: 15.
3. The method for separating alogliptin impurities according to claim 1, wherein the method comprises: the mesh number of the silica gel passing through the column for the first time in the step (1) is 60-100 meshes; the first column-passing developing solvent is dichloromethane and n-hexane with the ratio of 1: 8; the silica gel mesh number of the second column passing in the step (2) is 200-300 meshes; the second column-passing developing solvent is 1:8 ethyl acetate and petroleum ether.
4. The method for separating alogliptin impurities according to claim 1, wherein the method comprises: in the step (3), the recrystallization refining solvent is one of acetone, acetonitrile and absolute ethyl alcohol.
5. The method for separating alogliptin impurities according to claim 1, wherein the method comprises: in the step (3), the recrystallization refining solvent is acetonitrile.
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| CN115536597A (en) * | 2022-09-29 | 2022-12-30 | 山东新华制药股份有限公司 | Preparation method of high-purity alogliptin benzoate intermediate |
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| CN115536597A (en) * | 2022-09-29 | 2022-12-30 | 山东新华制药股份有限公司 | Preparation method of high-purity alogliptin benzoate intermediate |
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