CN115536597A - Preparation method of high-purity alogliptin benzoate intermediate - Google Patents
Preparation method of high-purity alogliptin benzoate intermediate Download PDFInfo
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- CN115536597A CN115536597A CN202211199042.3A CN202211199042A CN115536597A CN 115536597 A CN115536597 A CN 115536597A CN 202211199042 A CN202211199042 A CN 202211199042A CN 115536597 A CN115536597 A CN 115536597A
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- 229960000447 alogliptin benzoate Drugs 0.000 title claims abstract description 29
- KEJICOXJTRHYAK-XFULWGLBSA-N alogliptin benzoate Chemical compound OC(=O)C1=CC=CC=C1.C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 KEJICOXJTRHYAK-XFULWGLBSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000012452 mother liquor Substances 0.000 claims abstract description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000012046 mixed solvent Substances 0.000 claims abstract description 30
- 239000012535 impurity Substances 0.000 claims abstract description 28
- 239000000945 filler Substances 0.000 claims abstract description 22
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002244 precipitate Substances 0.000 claims abstract description 16
- QGXNHCXKWFNKCG-UHFFFAOYSA-N 2-(bromomethyl)benzonitrile Chemical compound BrCC1=CC=CC=C1C#N QGXNHCXKWFNKCG-UHFFFAOYSA-N 0.000 claims abstract description 12
- SGLXGFAZAARYJY-UHFFFAOYSA-N 6-Chloro-3-methyluracil Chemical compound CN1C(=O)C=C(Cl)NC1=O SGLXGFAZAARYJY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006482 condensation reaction Methods 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 11
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 14
- 229960001667 alogliptin Drugs 0.000 abstract description 11
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 abstract description 11
- 239000000047 product Substances 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000000243 solution Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000012264 purified product Substances 0.000 abstract description 3
- 239000010413 mother solution Substances 0.000 abstract description 2
- 239000002245 particle Substances 0.000 description 6
- 238000007670 refining Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- BVUJISIVAHYNLI-UHFFFAOYSA-N 2-[(6-chloro-3-methyl-2,4-dioxopyrimidin-1-yl)methyl]benzonitrile Chemical compound O=C1N(C)C(=O)C=C(Cl)N1CC1=CC=CC=C1C#N BVUJISIVAHYNLI-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 description 1
- 102100039994 Gastric inhibitory polypeptide Human genes 0.000 description 1
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other 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 with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A preparation method of a high-purity alogliptin benzoate intermediate belongs to the technical field of drug synthesis. The method is characterized in that: uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 17-26; carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent to obtain a mixed mother solution; distilling and concentrating the mixed mother liquor to 35-45% of the total amount of the original mixed solvent to obtain concentrated mother liquor; and (3) passing the concentrated mother liquor through a chromatographic column of gel filler to remove impurities, and enriching the precipitate for 35-38 min. The invention provides a method for separating impurities in an alogliptin intermediate to obtain a purified product, which comprises the steps of carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent, carrying out chromatography on the obtained concentrated solution, and separating out the impurities, so that the alogliptin intermediate with higher purity is obtained, and further the purity of the product is ensured.
Description
Technical Field
A preparation method of a high-purity alogliptin benzoate intermediate, belonging to the technical field of drug synthesis.
Background
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. 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. 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.
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. Most of the traditional synthesis processes of alogliptin benzoate start from 6-chloro-3-methyluracil, toluene is used as a solvent, and the alogliptin benzoate firstly undergoes a condensation reaction with 2-cyanobenzyl bromide to obtain an intermediate 2- [ (6-chloro-3, 4-dihydro-3-methyl-2, 4-dioxo-1 (2H) -pyrimidinyl) methyl ] benzonitrile, so that the impurity types are more in the process, and a method capable of preparing the alogliptin intermediate with high purity in a short process is lacked at present.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: overcomes the defects of the prior art, and provides a preparation method of a high-purity alogliptin benzoate intermediate with short process and more thorough impurity removal.
The technical scheme adopted by the invention for solving the technical problems is as follows: the preparation method of the high-purity alogliptin benzoate intermediate is characterized by comprising the following steps of:
1) Uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 17-26;
2) Carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent to obtain a mixed mother liquor;
3) Distilling and concentrating the mixed mother liquor to 35-45% of the total amount of the original mixed solvent to obtain concentrated mother liquor;
4) And (3) passing the concentrated mother liquor through a chromatographic column of gel filler to remove impurities, and enriching the precipitate for 35-38 min.
The invention provides a method for separating impurities in an alogliptin intermediate to obtain a purified product, which comprises the steps of carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent, carrying out chromatography on the obtained concentrated solution, and separating out the impurities, so that the alogliptin intermediate 2- [ (6-chloro-3, 4-dihydro-3-methyl-2, 4-dioxo-1 (2H) -pyrimidinyl) methyl ] benzonitrile with higher purity is obtained, and further the purity of the product is ensured.
The preferable preparation method of the high-purity alogliptin benzoate intermediate is that the mixed solvent in the step 1) is obtained by uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 20-23. Preferably, the two reactants in the mixed solvent react sufficiently with less side reactions. During chromatography, impurities are easily separated.
In a preferable preparation method of the high-purity alogliptin benzoate intermediate, the mixed mother liquor is distilled and concentrated to 39% -41% of the total amount of the original mixed solvent in the step 3) to obtain a concentrated mother liquor. Impurities are more easily separated out under the optimized concentration amount, and the purity of the product is better ensured.
Preferably, in the preparation method of the high-purity alogliptin benzoate intermediate, the gel filler in the step 4) has a particle size of 60-100 meshes, 100-200 meshes, 200-300 meshes, 300-400 meshes according to a volume ratio of 6-12. The preferable particle size collocation of the gel filler can form relatively uniform precipitation rate for different impurities, and the gel filler can be synchronously precipitated in a short time, so that the product purity is improved under the condition of ensuring the product yield.
More preferably, in the preparation method of the high-purity alogliptin benzoate intermediate, the gel filler in the step 4) has a particle size of 60-100 meshes, 100-200 meshes, 200-300 meshes, 300-400 meshes according to a volume ratio of 9.5. The more preferable particle size matching of the gel filler can be synchronously precipitated in a shorter time.
Preferably, in the preparation method of the high-purity alogliptin benzoate intermediate, the developing solvent used for the chromatography in the step 4) is a mixed solution of ethyl acetate and petroleum ether in a mass ratio of 1. The preferable developing agent can meet the requirements of the developing agent, impurities are separated out within a short time as much as possible within a relatively small range of chromatography rate, the production process is shortened, and the product yield is ensured.
More preferably, in the preparation method of the high-purity alogliptin benzoate intermediate, the developing solvent used for the chromatography in the step 4) is a mixed solution of dichloromethane and n-hexane according to a mass ratio of 1. The more preferable developing solvent has a more uniform and faster precipitation rate of impurities.
Preferably, in the method for preparing the alogliptin benzoate intermediate, the precipitate obtained in the step 4) is recrystallized in a recrystallization purification solvent. And (4) recrystallizing and purifying the precipitate to purify the components of the impurities, so that the component analysis of the impurities is facilitated.
Preferably, in the preparation method of the high-purity alogliptin benzoate intermediate, the recrystallization refining solvent is one or a mixed solvent of more than two of acetone, acetonitrile and absolute ethyl alcohol in any proportion. The preferred recrystallization refining solvent facilitates the separation and purification of impurities.
Preferably, in the preparation method of the high-purity alogliptin benzoate intermediate, the recrystallization refining solvent is acetone and acetonitrile in a mass ratio of 10:3 to 7. The selected recrystallization refining solvent can better ensure the purity of the impurities and is more beneficial to the component analysis of the impurities.
Compared with the prior art, the preparation method of the high-purity alogliptin benzoate intermediate has the beneficial effects that: the invention provides a method for separating impurities in an alogliptin intermediate to obtain a purified product, which comprises the step of carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent, wherein two reactants in the preferable mixed solvent are fully reacted, and side reactions are few. Impurities are easily separated during chromatography. And (3) performing chromatography on the obtained concentrated solution, wherein the preferable particle size matching of the gel filler can form relatively uniform precipitation rate for different impurities, and the impurities are synchronously precipitated in a short time, so that the product purity is improved under the condition of ensuring the product yield. The invention can obtain the alogliptin intermediate with higher purity, thereby ensuring the purity of the product.
Detailed Description
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, and furthermore, the terms "comprises" and "having", and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict.
The invention is further illustrated by the following specific examples, of which example 1 is the best mode of practice.
Example 1
1) Uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 22;
2) Carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent to obtain a mixed mother liquor;
3) Distilling and concentrating the mixed mother liquor to 40% of the total amount of the original mixed solvent to obtain concentrated mother liquor;
4) The concentrated mother liquor is purified by passing through a chromatographic column of gel filler, wherein the gel filler is prepared by mixing the gel filler with the grain sizes of 60-100 meshes, 100-200 meshes, 200-300 meshes and 300-400 meshes according to a volume ratio of 9.5; and (3) enriching a precipitate for 35-38 min, and recrystallizing the precipitate in a mixed solvent of acetone and acetonitrile according to a mass ratio of 10.
Example 2
1) Uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 20;
2) Carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent to obtain a mixed mother solution;
3) Distilling and concentrating the mixed mother liquor to 41% of the total amount of the original mixed solvent to obtain concentrated mother liquor;
4) And (3) purifying the concentrated mother liquor by passing the concentrated mother liquor through a chromatographic column of a gel filler, wherein the gel filler is a mixed solution of dichloromethane and n-hexane in a mass ratio of 1. And (3) enriching precipitates for 35-38 min, and recrystallizing the precipitates in a mixed solvent of acetone and acetonitrile according to a mass ratio of 10.
Example 3
1) Uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 23;
2) Carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent to obtain a mixed mother liquor;
3) Distilling and concentrating the mixed mother liquor to 39% of the total amount of the original mixed solvent to obtain concentrated mother liquor;
4) And (2) purifying the concentrated mother liquor by passing the concentrated mother liquor through a chromatographic column of a gel filler, wherein the gel filler is a mixed solution of dichloromethane and n-hexane according to a mass ratio of 1. And (3) enriching a precipitate for 35-38 min, and recrystallizing the precipitate in a mixed solvent of acetone and acetonitrile according to a mass ratio of 10.
Example 4
1) Uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 17;
2) Carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent to obtain a mixed mother liquor;
3) Distilling and concentrating the mixed mother liquor to 35% of the total amount of the original mixed solvent to obtain concentrated mother liquor;
4) And (3) purifying the concentrated mother liquor by passing the concentrated mother liquor through a chromatographic column of gel filler, wherein the gel filler is a mixed solution of ethyl acetate and petroleum ether in a mass ratio of 1. Enriching the precipitate for 35-38 min, and recrystallizing the precipitate in absolute ethyl alcohol.
Example 5
1) Uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 26;
2) Carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent to obtain a mixed mother liquor;
3) Distilling and concentrating the mixed mother liquor to 45% of the total amount of the original mixed solvent to obtain concentrated mother liquor;
4) And (2) removing impurities from the concentrated mother liquor through a chromatographic column of gel filler, wherein the gel filler is a mixed solution of methanol and n-heptane with the particle size of 60-100 meshes, 100-200 meshes, 200-300 meshes and 300-400 meshes according to a volume ratio of 12. And (3) enriching precipitates for 35-38 min, and recrystallizing the precipitates in acetone.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (10)
1. A preparation method of a high-purity alogliptin benzoate intermediate is characterized by comprising the following steps:
1) Uniformly mixing toluene and carbon tetrachloride according to a mass ratio of 17-26;
2) Carrying out condensation reaction on 6-chloro-3-methyluracil and 2-cyanobenzyl bromide in a mixed solvent to obtain a mixed mother liquor;
3) Distilling and concentrating the mixed mother liquor to 35-45% of the total amount of the original mixed solvent to obtain concentrated mother liquor;
4) And (3) passing the concentrated mother liquor through a chromatographic column of gel filler to remove impurities, and enriching the precipitate for 35-38 min.
2. The preparation method of the high-purity alogliptin benzoate intermediate as claimed in claim 1, is characterized in that:
the mixed solvent in the step 1) is obtained by uniformly mixing toluene and carbon tetrachloride according to the mass ratio of 20-23.
3. The preparation method of the high-purity alogliptin benzoate intermediate as claimed in claim 1, is characterized in that:
distilling and concentrating the mixed mother liquor in the step 3) to 39-41% of the total amount of the original mixed solvent to obtain concentrated mother liquor.
4. The preparation method of the alogliptin benzoate intermediate according to claim 1, characterized in that:
the gel filler in the step 4) is prepared from the following components in percentage by volume of 6-12.
5. The preparation method of the alogliptin benzoate intermediate according to claim 1 or 4, wherein the preparation method comprises the following steps:
the gel filler in the step 4) is prepared from the following components in percentage by volume of 9.5.
6. The preparation method of the high-purity alogliptin benzoate intermediate as claimed in claim 1, is characterized in that:
the developing agent used in the chromatography in the step 4) is a mixed solution of ethyl acetate and petroleum ether according to a mass ratio of 1.
7. The preparation method of the high-purity alogliptin benzoate intermediate according to claim 1 or 6, characterized in that:
the developing agent used in the chromatography in the step 4) is a mixed solution of dichloromethane and n-hexane according to a mass ratio of 1.
8. The preparation method of the alogliptin benzoate intermediate according to claim 1, characterized in that:
recrystallizing the precipitate obtained in the step 4) in a recrystallization purification solvent.
9. The preparation method of the high-purity alogliptin benzoate intermediate as claimed in claim 8, is characterized in that:
the recrystallization refined solvent is one or a mixed solvent of more than two of acetone, acetonitrile and absolute ethyl alcohol in any proportion.
10. The preparation method of the high-purity alogliptin benzoate intermediate as claimed in claim 1, is characterized in that:
the recrystallization refined solvent is acetone and acetonitrile in a mass ratio of 10:3 to 7.
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| CN109734673A (en) * | 2019-02-27 | 2019-05-10 | 浙江华贝药业有限责任公司 | A kind of purification process of compound |
| CN111484457A (en) * | 2020-04-21 | 2020-08-04 | 山东新华制药股份有限公司 | Method for separating alogliptin impurities |
| CN112250664A (en) * | 2020-09-30 | 2021-01-22 | 辰欣药业股份有限公司 | Preparation method of alogliptin benzoate |
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