CN111518097A - Refining method of apixaban - Google Patents
Refining method of apixaban Download PDFInfo
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- CN111518097A CN111518097A CN202010476965.3A CN202010476965A CN111518097A CN 111518097 A CN111518097 A CN 111518097A CN 202010476965 A CN202010476965 A CN 202010476965A CN 111518097 A CN111518097 A CN 111518097A
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- CN
- China
- Prior art keywords
- apixaban
- refining method
- mixing device
- purity
- solution
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229960003886 apixaban Drugs 0.000 title claims abstract description 67
- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000007670 refining Methods 0.000 title claims abstract description 28
- 238000002156 mixing Methods 0.000 claims abstract description 23
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000010438 heat treatment Methods 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 15
- PPUHOTDYJQGTAE-UHFFFAOYSA-N 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(O)=O)=N1 PPUHOTDYJQGTAE-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000002828 nitro derivatives Chemical class 0.000 claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 12
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims abstract description 11
- 235000011130 ammonium sulphate Nutrition 0.000 claims abstract description 11
- JBANFLSTOJPTFW-UHFFFAOYSA-N azane;boron Chemical compound [B].N JBANFLSTOJPTFW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims abstract description 11
- 239000011787 zinc oxide Substances 0.000 claims abstract description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 230000009467 reduction Effects 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000000706 filtrate Substances 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 7
- 230000001376 precipitating effect Effects 0.000 claims description 6
- 238000007599 discharging Methods 0.000 claims description 5
- 239000012044 organic layer Substances 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 abstract description 21
- 238000009776 industrial production Methods 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 6
- 238000006243 chemical reaction Methods 0.000 abstract description 5
- 238000001514 detection method Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004075 alteration Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention relates to the technical field of medicine preparation, and discloses a refining method of apixaban, which is characterized by comprising the following steps of: taking a nitro compound as a raw material, sequentially carrying out iron powder reduction amidation-cyclization and hydrolysis reaction to obtain apixaban acid; the Apixaban acid is placed in a mixing device, the nano zinc oxide, ammonia borane and ammonium sulfate are placed in the mixing device, and heating, mixing and stirring are carried out. According to the refining method of apixaban, the solution is layered, precipitated, filtered and dried, the color of apixaban can be ensured, the purity of apixaban is improved, the detection purity of apixaban produced by the method is 99.7%, the total yield is 68%, the yield is increased, the purity is also improved, and the refining method has the advantages of easiness in obtaining raw materials, low generation cost, mild reaction conditions, simplicity and convenience in operation, high process stability, high purity and yield of apixaban and the like, and is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a refining method of apixaban.
Background
Apixaban, chemically known as 1- (4-methoxyphenyl) -7-oxo-6 [4- (2-oxopiperidin-1-yl) phenyl ] -4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4-C ] pyridine-3-carboxamide, has the molecular formula of C25H25N5O4, the molecular weight of 459.49700, the density of 1.42g/cm3, the boiling point of 770.468 ℃ at 760mmHg, the flash point of 419.764 ℃ and the refractive index of 1.705, and is clinically used for adult patients with hip or knee joint phase-selective replacements to prevent venous thromboembolic events.
The existing preparation methods of apixaban in the market at present have the advantages of simple method and less time consumption, but the existing preparation methods of apixaban cannot ensure the precision of apixaban, and the prepared apixaban has low purity and is not suitable for industrial production, so the preparation method of apixaban is provided to solve the provided problems.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a refining method of apixaban, which has the advantages of high purity and the like, and solves the problems that the precision of the apixaban cannot be ensured by the existing preparation method of the apixaban, and the prepared apixaban has low purity and is not suitable for industrial production.
(II) technical scheme
In order to achieve the purpose of high purity, the invention provides the following technical scheme: the refining method of apixaban is characterized by comprising the following steps:
1) taking a nitro compound as a raw material, sequentially carrying out iron powder reduction amidation-cyclization and hydrolysis reaction to obtain apixaban acid;
2) placing the apixaban acid in a mixing device, placing the nano zinc oxide, ammonia borane and ammonium sulfate in the mixing device, and heating, mixing and stirring;
3) discharging the solution in the mixing device, filtering the solution through an active carbon filter screen, and collecting the filtered filtrate;
4) placing the filtrate in a container for natural cooling, and separating an organic layer;
5) adding n-hexane, stirring, precipitating to precipitate solid in the container, pouring out the solution in the container, filtering, and drying the product on the filtering device until the refined apixaban is obtained.
Preferably, the mass ratio of the nitro compound to the amidation-cyclization is: 1-3 to 0.3-0.5.
Preferably, the mass ratio of the nano zinc oxide to the ammonia borane to the ammonium sulfate is as follows: (0.8-1): (0.2-0.5): (1-1.4).
Preferably, the heating temperature in the step 2) is 25-35 ℃.
Preferably, the diameter of the filter hole of the activated carbon filter screen is 0.01-0.03 CM.
Preferably, the natural cooling temperature in the step 4) is 0-5 ℃.
Preferably, the precipitation time in the step 5) is 2 to 4 hours, the drying in the step 5) is performed by a heating lamp, and the temperature of the heating lamp is 15 to 30 ℃ during the drying.
(III) advantageous effects
Compared with the prior art, the invention provides a refining method of apixaban, which has the following beneficial effects:
1. according to the refining method of apixaban, nitro compounds are used as raw materials, and are subjected to iron powder reduction amidation-cyclization and hydrolysis reaction in sequence to obtain apixaban acid, the raw materials are common, the problems of high price of the raw materials and harsh reaction conditions are solved, the monitoring of the apixaban preparation process can be improved, the yield of apixaban can also be improved, the refining method is suitable for industrial production, the filtering effect can be improved by using an active carbon filter screen, unnecessary substances in a solution can be discharged and diluted, the influence on the apixaban preparation quality is avoided, the cost can be saved by the structure, the apixaban preparation quality is improved, and the refining method is more beneficial to users.
2. According to the refining method of apixaban, the solution is layered, precipitated, filtered and dried, the color of apixaban can be ensured, the purity of apixaban is improved, the detection purity of apixaban produced by the method is 99.7%, the total yield is 68%, the yield is increased, the purity is also improved, and the refining method has the advantages of easiness in obtaining raw materials, low generation cost, mild reaction conditions, simplicity and convenience in operation, high process stability, high purity and yield of apixaban and the like, and is suitable for industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The first embodiment is as follows: a refining method of apixaban comprises the following steps:
1) the method comprises the following steps of taking a nitro compound as a raw material, sequentially carrying out iron powder reduction amidation-cyclization and hydrolysis reaction to obtain apixaban acid, wherein the mass ratio of the nitro compound to the amidation-cyclization is as follows: 1: 0.3;
2) placing the apixaban acid in the mixing device, placing the nano zinc oxide, the ammonia borane and the ammonium sulfate in the mixing device, heating, mixing and stirring, wherein the mass ratio of the nano zinc oxide to the ammonia borane to the ammonium sulfate is as follows: 0.8: 0.2: 1;
3) discharging the solution in the mixing device, filtering the solution through an active carbon filter screen, wherein the diameter of a filter hole of the active carbon filter screen is 0.03CM, and collecting the filtered filtrate;
4) placing the filtrate in a container for natural cooling at 5 deg.C, and separating organic layer;
5) adding n-hexane for stirring, precipitating to precipitate the solid in the container, pouring out the solution in the container, filtering, drying the product on the filter device until refined apixaban is obtained, wherein the precipitation time is 4 hours, drying by a heating lamp during drying, and the temperature of the heating lamp during drying is 15 ℃.
The apixaban prepared by the formula and the process has low preparation cost, and the preparation speed is low due to small dosage of the prepared formula, so that the preparation efficiency of the apixaban is reduced, and the apixaban can be used as a common apixaban.
Example two: a refining method of apixaban comprises the following steps:
1) the method comprises the following steps of taking a nitro compound as a raw material, sequentially carrying out iron powder reduction amidation-cyclization and hydrolysis reaction to obtain apixaban acid, wherein the mass ratio of the nitro compound to the amidation-cyclization is as follows: 2: 0.4;
2) placing the apixaban acid in the mixing device, placing the nano zinc oxide, the ammonia borane and the ammonium sulfate in the mixing device, heating, mixing and stirring, wherein the mass ratio of the nano zinc oxide to the ammonia borane to the ammonium sulfate is as follows: 0.9: 0.35: 1.2;
3) discharging the solution in the mixing device, filtering the solution through an active carbon filter screen, wherein the diameter of a filter hole of the active carbon filter screen is 0.02CM, and collecting the filtered filtrate;
4) placing the filtrate in a container for natural cooling at 2.5 deg.C, and separating organic layer;
5) adding n-hexane for stirring, precipitating to precipitate the solid in the container, pouring out the solution in the container, filtering, and drying the product on the filter until refined apixaban is obtained, wherein the precipitation time is 3 hours, the drying is carried out by a heating lamp, and the temperature of the heating lamp is 22.5 ℃ during the drying.
The apixaban prepared according to the formula and the process has moderate material proportion value, can improve the success rate of preparation, has moderate effect and preparation cost, is suitable for industrial production, has high purity and moderate production speed, and is more convenient to popularize.
Example three: a refining method of apixaban comprises the following steps:
1) the method comprises the following steps of taking a nitro compound as a raw material, sequentially carrying out iron powder reduction amidation-cyclization and hydrolysis reaction to obtain apixaban acid, wherein the mass ratio of the nitro compound to the amidation-cyclization is as follows: -3: 0.5;
2) placing the apixaban acid in the mixing device, placing the nano zinc oxide, the ammonia borane and the ammonium sulfate in the mixing device, heating, mixing and stirring, wherein the mass ratio of the nano zinc oxide to the ammonia borane to the ammonium sulfate is as follows: 1: 0.5: 1.4;
3) discharging the solution in the mixing device, filtering the solution through an active carbon filter screen, wherein the diameter of a filter hole of the active carbon filter screen is 0.01CM, and collecting the filtered filtrate;
4) placing the filtrate in a container for natural cooling at 5 deg.C, and separating organic layer;
5) adding n-hexane for stirring, precipitating to precipitate the solid in the container, pouring out the solution in the container, filtering, drying the product on the filter device until refined apixaban is obtained, wherein the precipitation time is 2 hours, drying by a heating lamp during drying, and the temperature of the heating lamp during drying is 30 ℃.
The apixaban prepared according to the formula and the process has high preparation cost, the preparation speed is slow due to the dosage of the prepared formula, the preparation efficiency of the apixaban is reduced, and the prepared apixaban is thin and can be used as a special apixaban for special utilization.
The invention has the beneficial effects that: the refining method of apixaban uses nitro compound as raw material, and sequentially carries out iron powder reduction amidation-cyclization and hydrolysis reaction to obtain apixaban acid, the raw material is common, the problems of high price of the raw material and harsh reaction conditions are solved, the monitoring of the apixaban preparation process can be improved, the yield of apixaban can also be improved, the refining method is suitable for industrial production, the filtering effect can be improved by using an active carbon filter screen, unnecessary substances in a solution can be discharged and diluted, the influence on the preparation quality of apixaban can be avoided, the structure can save cost, the preparation quality of apixaban can be improved, and the refining method is more beneficial to users, the color of apixaban can be ensured by layering, precipitating, filtering and drying the solution, the purity of apixaban can be improved, the detection height of the apixaban purity produced by the refining method is 99.7%, the total yield is 68%, the yield is increased, the purity is improved, the method has the advantages of easily available raw materials, low generation cost, mild reaction conditions, simplicity and convenience in operation, high process stability, high purity and yield of apixaban and the like, is suitable for industrial production, and solves the problems that the precision of apixaban cannot be ensured by the existing preparation method of apixaban, the prepared apixaban is low in purity and is not suitable for industrial production.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (7)
1. The refining method of apixaban is characterized by comprising the following steps:
1) taking a nitro compound as a raw material, sequentially carrying out iron powder reduction amidation-cyclization and hydrolysis reaction to obtain apixaban acid;
2) placing the apixaban acid in a mixing device, placing the nano zinc oxide, ammonia borane and ammonium sulfate in the mixing device, and heating, mixing and stirring;
3) discharging the solution in the mixing device, filtering the solution through an active carbon filter screen, and collecting the filtered filtrate;
4) placing the filtrate in a container for natural cooling, and separating an organic layer;
5) adding n-hexane, stirring, precipitating to precipitate solid in the container, pouring out the solution in the container, filtering, and drying the product on the filtering device until the refined apixaban is obtained.
2. The refining method of apixaban according to claim 1, characterized in that the mass ratio of the nitro compound to the amidation-ring is: 1-3 to 0.3-0.5.
3. The refining method of apixaban according to claim 1, characterized in that the mass ratio of the nano zinc oxide to the ammonia borane to the ammonium sulfate is as follows: (0.8-1): (0.2-0.5): (1-1.4).
4. The refining method of apixaban according to claim 1, characterized in that the heating temperature in step 2) is 25-35 ℃.
5. The refining method of apixaban according to claim 1, wherein the diameter of the filter holes of the activated carbon filter screen is 0.01-0.03 CM.
6. The refining method of apixaban according to claim 1, characterized in that the natural cooling temperature in step 4) is 0-5 ℃.
7. The refining method of apixaban according to claim 1, characterized in that the precipitation time in step 5) is 2-4 hours, the drying in step 5) is performed by a heating lamp, and the temperature of the heating lamp is 15-30 ℃ during the drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010476965.3A CN111518097A (en) | 2020-05-29 | 2020-05-29 | Refining method of apixaban |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010476965.3A CN111518097A (en) | 2020-05-29 | 2020-05-29 | Refining method of apixaban |
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| Publication Number | Publication Date |
|---|---|
| CN111518097A true CN111518097A (en) | 2020-08-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010476965.3A Pending CN111518097A (en) | 2020-05-29 | 2020-05-29 | Refining method of apixaban |
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| Country | Link |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117201A (en) * | 2016-06-27 | 2016-11-16 | 青岛云天生物技术有限公司 | A kind of preparation method of antithrombotic reagent Eliquis |
| CN107400131A (en) * | 2017-08-24 | 2017-11-28 | 沈阳药科大学 | Eliquis derivative and its production and use |
-
2020
- 2020-05-29 CN CN202010476965.3A patent/CN111518097A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117201A (en) * | 2016-06-27 | 2016-11-16 | 青岛云天生物技术有限公司 | A kind of preparation method of antithrombotic reagent Eliquis |
| CN107400131A (en) * | 2017-08-24 | 2017-11-28 | 沈阳药科大学 | Eliquis derivative and its production and use |
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Application publication date: 20200811 |