CN113735877A - Refining method of clopidogrel hydrogen sulfate - Google Patents
Refining method of clopidogrel hydrogen sulfate Download PDFInfo
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- CN113735877A CN113735877A CN202111062369.1A CN202111062369A CN113735877A CN 113735877 A CN113735877 A CN 113735877A CN 202111062369 A CN202111062369 A CN 202111062369A CN 113735877 A CN113735877 A CN 113735877A
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- hydrogen sulfate
- clopidogrel hydrogen
- clopidogrel
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- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 title claims abstract description 49
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000007670 refining Methods 0.000 title claims abstract description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 30
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000008213 purified water Substances 0.000 claims abstract description 19
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 14
- 229960003958 clopidogrel bisulfate Drugs 0.000 claims abstract description 14
- FDEODCTUSIWGLK-RSAXXLAASA-N clopidogrel sulfate Chemical compound [H+].OS([O-])(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl FDEODCTUSIWGLK-RSAXXLAASA-N 0.000 claims abstract description 14
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 7
- 238000000605 extraction Methods 0.000 claims abstract description 5
- 239000012074 organic phase Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 239000007788 liquid Substances 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 6
- 238000003825 pressing Methods 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000002274 desiccant Substances 0.000 claims description 5
- 239000000047 product Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004042 decolorization Methods 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000012071 phase Substances 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 27
- 239000013078 crystal Substances 0.000 abstract description 9
- 239000003513 alkali Substances 0.000 abstract description 5
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 abstract description 3
- 229960003009 clopidogrel Drugs 0.000 abstract description 3
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000012046 mixed solvent Substances 0.000 abstract description 2
- 238000011112 process operation Methods 0.000 abstract description 2
- 238000001514 detection method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Abstract
The application belongs to the technical field of pharmaceutical chemical manufacturing, and particularly relates to a refining method of clopidogrel hydrogen sulfate. The method comprises the following steps: dissolving materials, performing organic extraction, removing an organic phase, dissolving and decoloring, crystallizing, preparing a finished product and the like. The main technical thought of the application is as follows: after clopidogrel bisulfate to be refined is treated by a purified water solvent, clopidogrel free alkali is prepared under the action of sodium carbonate, and then the free alkali reacts with sulfuric acid in a mixed solvent (acetone, methanol and purified water) and is further crystallized to prepare high-purity II type clopidogrel bisulfate. The refining process disclosed by the application better solves the quality problems of unstable crystal form, high impurity content and reddish color in the existing industrial production preparation of clopidogrel hydrogen sulfate, so that the quality standard of related products can better meet the existing pharmacopoeia standard, and the refining process has the technical advantages of suitability for industrial application, simple and feasible process operation, and better practical value and popularization and application significance.
Description
Technical Field
The application belongs to the technical field of pharmaceutical chemical manufacturing, and particularly relates to a refining method of clopidogrel hydrogen sulfate.
Background
The chemical name of clopidogrel hydrogen sulfate is as follows: methyl (+) - (S) -alpha-o-chlorophenyl-6, 7-dihydrothiophene [3,2-C ] pyridine-5 (4H) -acetate hydrogen sulfate, a new generation of anti-platelet aggregation agent, was first marketed in the United kingdom and the United states in 1998, and was marketed in China at 8 months in 2001.
Research has shown that clopidogrel hydrogen sulfate has various crystal forms: the crystal forms I, II, III, IV, V, VI and amorphous states, wherein only the crystal forms I and II can be used as medicines, and the other crystal forms contain a certain amount of solvent molecules, so that toxic and side effects are increased, and the crystal forms cannot be used as raw material medicines for preparation. In addition, the clopidogrel hydrogen sulfate II type is more stable than the clopidogrel hydrogen sulfate I type, and the solubility of the clopidogrel hydrogen sulfate II type in partial solution is better.
In the existing production, most of clopidogrel bisulfate is a light yellow solid and mixed crystal before refining, and according to the current pharmacopoeia standard, the main quality problems are that three unknown impurities do not meet the standard (the unknown single impurity is less than 0.1 percent), and the relative retention time is 0.90min, 0.97min and 2.17min respectively. In addition, clopidogrel hydrogen sulfate prepared by industrial production often has the problems of reddish color, unstable crystal form, high unknown single impurity and the like, so that further research is needed for a clopidogrel hydrogen sulfate refining method from the perspective of medical safety quality.
Disclosure of Invention
The application aims to provide a refining method of clopidogrel hydrogen sulfate, thereby laying a certain technical foundation for the quality stability of related yield.
The technical scheme adopted by the application is briefly described as follows.
A refining method of clopidogrel hydrogen sulfate specifically comprises the following steps:
(1) dissolution of the material
Dissolving clopidogrel bisulfate to be refined by pure water, wherein the temperature is controlled as follows in the dissolving process: 20 +/-10 ℃;
in terms of specific dosage, the dosage of the purified water is 3-10 times (preferably 4-6 times) of the mass of the clopidogrel hydrogen sulfate;
the clopidogrel hydrogen sulfate to be refined has the following specific quality standard references: maximum unknown single impurity 0.13%, impurity i: 0.01%, impurity II: 0.07 percent of total impurities, 0.4 to 0.5 percent of total impurities;
(2) organic extraction
Slowly (controlling the temperature to be 10-30 ℃) dropwise adding a sodium carbonate solution into the dissolved liquid in the step (1) to adjust the pH = 8-10 (so as to obtain clopidogrel free alkali), standing for not less than 30min, and separating liquid (separating into an organic phase and a water phase);
extracting the water phase by using an organic extractant, and further washing the extracted extract liquor by using purified water for 1-2 times;
the organic extracting agent is dichloromethane, and the dosage of the dichloromethane is 2-6 times (preferably 4-5 times) that of the clopidogrel hydrogen sulfate in terms of mass ratio; the washing water consumption is 5-10 times of the clopidogrel hydrogen sulfate consumption;
the mass concentration of the sodium carbonate solution is 6-7%;
(3) removal of the organic phase
Adding a drying agent into the extract liquor obtained in the step (2) for drying (anhydrous sodium sulfate is used as the drying agent, and the anhydrous sodium sulfate is added for drying treatment for 1-3 h), carrying out suction filtration, collecting filtrate, controlling the temperature below 40 ℃, and carrying out reduced pressure evaporation to remove dichloromethane to obtain light yellow oily liquid;
in terms of the dosage of the drying agent, the dosage of the anhydrous sodium sulfate is referred to be 0.3-0.5 time of the dosage of the clopidogrel hydrogen sulfate;
(4) dissolving and decolorizing
Adding acetone, methanol and purified water into the light yellow oily liquid obtained in the step (3) at the temperature of 10-30 ℃, and stirring until the solution is clear to ensure full dissolution; then, carrying out filter pressing to a decoloring tank, and adding a decoloring agent for decoloring;
in terms of the specific dosage, the dosage of the acetone is 3-6 times of the dosage of the clopidogrel hydrogen sulfate in terms of mass ratio;
the dosage of the methanol is 0.05 to 0.15 time of the dosage of the clopidogrel hydrogen sulfate;
the dosage of the purified water is 0.05 to 0.15 time of the dosage of the clopidogrel hydrogen sulfate;
the decolorizing agent is activated carbon and/or silica gel powder, and the dosage of the activated carbon is 0.05-0.1 time of that of clopidogrel hydrogen sulfate; the silica gel powder is 300-400 meshes, and the dosage of the silica gel powder is 0.05-0.1 time of that of the clopidogrel hydrogen sulfate;
(5) crystallization and preparation of finished products
Filter-pressing the liquid obtained after the decolorization treatment in the step (4) into a crystallizing tank, dropwise adding sulfuric acid at 40 +/-5 ℃, slowly heating to 55-60 ℃ after completing dropwise adding, and stirring for 1-3 hours;
then, cooling to 0 +/-5 ℃, and stirring for 3-5 h;
centrifuging (in a manner of throwing filtration), and drying the precipitate in vacuum at the temperature of below 50 ℃ to constant weight to obtain II-type clopidogrel hydrogen sulfate;
in the process, the mass concentration of the sulfuric acid is 75-80%, and the dosage of the sulfuric acid is 0.40-0.50 time of that of clopidogrel hydrogen sulfate.
The main technical thought of the application is as follows: after clopidogrel bisulfate to be refined is treated by a purified water solvent, clopidogrel free alkali is prepared under the action of sodium carbonate, and then the free alkali reacts with sulfuric acid in a mixed solvent (acetone, methanol and purified water) and is further crystallized to prepare high-purity II type clopidogrel bisulfate.
In general, preliminary experiment results show that the refining process of the application better solves the quality problems of unstable crystal form, high impurity content and reddish color in the existing industrial production of clopidogrel hydrogen sulfate, so that the quality standard of related products can better meet the standard of the existing pharmacopoeia, and the refining process has the technical advantages of suitability for industrial application, simple and feasible process operation, and shows better practical value and popularization and application significance.
Detailed Description
The present application is further illustrated by the following examples.
Example 1
The brief introduction of the specific operation steps of the method for refining clopidogrel bisulfate provided in the embodiment is as follows.
(1) Dissolution of the material
In a 200L glass lining reaction tank, 35Kg of purified water and 10Kg of unqualified clopidogrel hydrogen sulfate to be refined are added (slowly added),
the clopidogrel hydrogen sulfate to be refined has the following specific quality standards: maximum unknown single impurity 0.13%, impurity i: 0.01%, impurity II: 0.07 percent of the total impurities and 0.4 to 0.5 percent of the total impurities.
(2) Organic extraction
Slowly (controlling the temperature to be about 15 ℃) dropwise adding a sodium carbonate solution into the dissolved liquid in the step (1) to adjust the pH =9.5, standing for not less than 30min, and separating liquid;
the mass concentration of the sodium carbonate solution is 6.5 percent;
the aqueous phase is extracted with 30Kg of the organic extractant dichloromethane and the extract is washed 2 times with 50Kg of purified water.
(3) Removal of the organic phase
And (3) adding 5.0Kg of anhydrous sodium sulfate into the extract liquid obtained in the step (2) for drying (about 2 hours of drying treatment), carrying out suction filtration, collecting filtrate, controlling the temperature to be about 40 ℃, and carrying out reduced pressure evaporation to remove dichloromethane to obtain light yellow oily liquid.
(4) Dissolving and decolorizing
When the temperature of the yellowish oily liquid in the step (3) is reduced to 30 ℃, adding acetone, methanol and purified water, and stirring until the solution is clear to ensure full dissolution; then, carrying out filter pressing to a decoloring tank, and adding a decoloring agent for decoloring;
in terms of the specific dosage, the dosage of the acetone is 60Kg in terms of mass ratio;
the dosage of the methanol is 1 Kg;
the amount of purified water is 0.5 Kg;
the decolorizing agent is active carbon and silica gel powder, and the dosage of the active carbon is 0.5 Kg; the silica gel powder is 400 meshes, and the dosage of the silica gel powder is 1 Kg;
(5) crystallization and preparation of finished products
Filter-pressing the liquid obtained after the decolorization treatment in the step (4) into a crystallizing tank, dropwise adding sulfuric acid at 40 ℃, slowly heating to 60 ℃ after dropwise adding, and stirring for 1 h;
then, cooling to 4 ℃ and stirring for 5 hours;
centrifuging (in a manner of throwing filtration), and drying the precipitate in vacuum at the temperature of below 50 ℃ to constant weight to obtain II-type clopidogrel hydrogen sulfate;
in the process, the mass concentration of the sulfuric acid is 75 percent, and the dosage of the sulfuric acid is 4 Kg.
After weighing, 9.0Kg of clopidogrel bisulfate is finally obtained. After detection according to pharmacopeia standards, the prepared clopidogrel hydrogen sulfate is type II, the maximum unknown single impurity is 0 percent, and the impurity I: 0%, impurity II: 0.07 percent and total impurities 0.07 percent.
Example 2
The refining method of clopidogrel bisulfate provided by the embodiment is generally the same as the operation of the embodiment 1, and only part of process parameters are adjusted as follows:
in the step (1), 40Kg of purified water and 10Kg of unqualified clopidogrel hydrogen sulfate to be refined (the raw materials are the same as those in the example 1);
in step (2), pH =10.0 was adjusted (other parameters were the same as in example 1);
in the step (3), the operation was the same as in example 1;
in the step (4), the dosage of acetone is 58 Kg; the dosage of the methanol is 0.8 Kg; the amount of purified water was 0.5Kg (other parameters were the same as in example 1);
in the step (5), the mass concentration of the sulfuric acid is 80 percent, and the dosage of the sulfuric acid is 4.1 Kg.
9.1Kg of clopidogrel bisulfate is finally prepared. After detection according to pharmacopeia standards, the prepared clopidogrel hydrogen sulfate is type II, the maximum unknown single impurity is 0 percent, and the impurity I: not detected, impurity ii: 0.07 percent and total impurities 0.07 percent.
Example 3
The refining method of clopidogrel bisulfate provided by the embodiment is generally the same as the operation of the embodiment 1, and only part of process parameters are adjusted as follows:
in the step (1), 50Kg of purified water and 10Kg of unqualified clopidogrel hydrogen sulfate to be refined (the raw materials are the same as those in the example 1);
in step (2), pH =8.3 was adjusted (other parameters were the same as in example 1);
in the step (3), the operation was the same as in example 1;
in the step (4), the dosage of acetone is 60 Kg; the dosage of the methanol is 1.0 Kg; the amount of purified water was 0.6Kg (other parameters were the same as those in example 1);
in the step (5), the mass concentration of the sulfuric acid is 80 percent, and the dosage of the sulfuric acid is 4.3 Kg.
9.2Kg of clopidogrel bisulfate is finally prepared. After detection according to pharmacopeia standards, the prepared clopidogrel hydrogen sulfate is type II, the maximum unknown single impurity is 0 percent, and the impurity I: not detected, impurity ii: 0.06 percent and total impurities 0.06 percent.
Claims (7)
1. A refining method of clopidogrel hydrogen sulfate is characterized by comprising the following steps:
(1) dissolution of the material
Dissolving clopidogrel bisulfate to be refined by pure water, wherein the temperature is controlled as follows in the dissolving process: 20 +/-10 ℃;
(2) organic extraction
Dropwise adding a sodium carbonate solution into the dissolved liquid in the step (1) to adjust the pH = 8-10, standing for not less than 30min, and separating liquid
Extracting the water phase with an organic extractant;
(3) removal of the organic phase
Adding a drying agent into the extraction liquid in the step (2) for drying, carrying out suction filtration, collecting filtrate, controlling the temperature below 40 ℃, and carrying out reduced pressure evaporation to remove the organic extracting agent to obtain light yellow oily liquid;
(4) dissolving and decolorizing
Adding acetone, methanol and purified water into the light yellow oily liquid obtained in the step (3) at the temperature of 10-30 ℃, and stirring until the solution is clear to ensure full dissolution; then, carrying out filter pressing to a decoloring tank, and adding a decoloring agent for decoloring;
(5) crystallization and preparation of finished products
Filter-pressing the liquid obtained after the decolorization treatment in the step (4) into a crystallizing tank, dropwise adding sulfuric acid at 40 +/-5 ℃, heating to 55-60 ℃ after completing dropwise adding, and stirring for 1-3 hours;
then, cooling to 0 +/-5 ℃, and stirring for 3-5 h;
centrifuging, and vacuum drying the precipitate at 50 deg.C or below to constant weight.
2. The method for refining clopidogrel hydrogen sulfate according to claim 1, wherein the amount of the purified water used in the step (1) is 3 to 10 times the mass of clopidogrel hydrogen sulfate.
3. The method for refining clopidogrel hydrogen sulfate according to claim 1, wherein the organic extractant in the step (2) is dichloromethane, and the amount of dichloromethane is 2 to 6 times the amount of clopidogrel hydrogen sulfate in terms of mass ratio.
4. The method for refining clopidogrel bisulfate according to claim 1, wherein the drying agent in the step (3) is anhydrous sodium sulfate.
5. The method for refining clopidogrel hydrogen sulfate according to claim 1, wherein in the step (4), the amount of acetone is 3 to 6 times the amount of clopidogrel hydrogen sulfate in terms of mass ratio;
the dosage of the methanol is 0.05 to 0.15 time of the dosage of the clopidogrel hydrogen sulfate;
the dosage of the purified water is 0.05 to 0.15 time of the dosage of the clopidogrel hydrogen sulfate.
6. The refining method of clopidogrel hydrogen sulfate according to claim 1, wherein in the step (4), the decoloring agent is activated carbon and/or silica gel powder, and the amount of the activated carbon is 0.05 to 0.1 times that of clopidogrel hydrogen sulfate; the silica gel powder is 300-400 meshes, and the dosage of the silica gel powder is 0.05-0.1 time of that of the clopidogrel hydrogen sulfate.
7. The method for refining clopidogrel hydrogen sulfate according to claim 1, wherein the mass concentration of the sulfuric acid is 75 to 80% and the amount of the sulfuric acid is 0.40 to 0.50 times the amount of clopidogrel hydrogen sulfate.
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2021
- 2021-09-10 CN CN202111062369.1A patent/CN113735877A/en active Pending
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