CN115772136A - Preparation method of parecoxib sodium and intermediate thereof - Google Patents
Preparation method of parecoxib sodium and intermediate thereof Download PDFInfo
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- CN115772136A CN115772136A CN202111594243.9A CN202111594243A CN115772136A CN 115772136 A CN115772136 A CN 115772136A CN 202111594243 A CN202111594243 A CN 202111594243A CN 115772136 A CN115772136 A CN 115772136A
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- 229960003925 parecoxib sodium Drugs 0.000 title claims abstract description 30
- ICJGKYTXBRDUMV-UHFFFAOYSA-N trichloro(6-trichlorosilylhexyl)silane Chemical compound Cl[Si](Cl)(Cl)CCCCCC[Si](Cl)(Cl)Cl ICJGKYTXBRDUMV-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 claims abstract description 64
- 229960002004 valdecoxib Drugs 0.000 claims abstract description 64
- 239000002904 solvent Substances 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 40
- 238000003756 stirring Methods 0.000 claims abstract description 29
- 239000000047 product Substances 0.000 claims abstract description 28
- 238000001035 drying Methods 0.000 claims abstract description 21
- 239000007787 solid Substances 0.000 claims abstract description 21
- 239000000126 substance Substances 0.000 claims abstract description 21
- 239000012043 crude product Substances 0.000 claims abstract description 11
- 238000007670 refining Methods 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 98
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 17
- 238000001953 recrystallisation Methods 0.000 claims description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 13
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000005119 centrifugation Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 239000012670 alkaline solution Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910001415 sodium ion Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- 229960004662 parecoxib Drugs 0.000 abstract description 8
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 235000019441 ethanol Nutrition 0.000 description 35
- 239000012535 impurity Substances 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of medicinal chemistry, and particularly relates to a preparation method of a parecoxib sodium intermediate; the method comprises the following steps: (a) Adding the crude product of the compound shown in the formula (II) and an alkaline substance into a solvent A, recrystallizing, and separating out a precipitated solid B; (b) Mixing the solid B with a solvent C, stirring, and separating to obtain a solid D; (c) And drying the solid D to obtain a refined product of the compound shown in the formula (II). The refining method of the compound shown in the formula (II) provided by the invention can obviously improve the purity of the crude product of the compound shown in the formula (II) in a high-yield mode; has the advantages of simple operation, easy control of parameter conditions and low cost. The invention also relates to a method for preparing parecoxib sodium by the valdecoxib one-pot method, which does not need to separate parecoxib separately, has simpler and more convenient production process and is beneficial to industrial mass production.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a parecoxib sodium and a preparation method of a parecoxib sodium intermediate (valdecoxib).
Background
Parecoxib Sodium (Parecoxib Sodium) is a prodrug of Valdecoxib (Valdecoxib); the parecoxib sodium is used for short-term treatment of postoperative pain, and can be clinically used for treating moderate or severe postoperative acute pain.
As shown in formula (I), a common route for synthesizing parecoxib sodium is to obtain valdecoxib as an intermediate through reaction, then react with propionic anhydride to obtain parecoxib, and further prepare parecoxib sodium (for example, as described in CN 104447600A).
In the process of preparing the valdecoxib, a small amount of chlorosulfonic acid attacks the meta position of a benzene ring to generate impurities at the meta position of the valdecoxib, the impurities are isomers of the valdecoxib, have similar polarities and are difficult to remove, and the impurities enter parecoxib sodium along with reaction to generate impurities at the meta position of the parecoxib sodium, so that the quality of the parecoxib sodium raw material medicine is directly influenced. Meanwhile, the byproduct of the sulfation reaction is inorganic salt ammonium chloride, which can also reduce the content of valdecoxib.
Disclosure of Invention
In a first aspect of the present invention, there is provided a method for refining valdecoxib represented by formula (II), comprising the steps of:
(a) Mixing the crude valdecoxib product, an alkaline substance and a solvent A, recrystallizing, and separating a precipitated solid B;
(b) Mixing the solid B with a solvent C, stirring, and separating to obtain a solid D;
(c) And drying the solid D to obtain a valdecoxib refined product.
In a specific embodiment of the invention, the solvent A is a mixed solvent of alcohols and water; the alcohol is selected from methanol, ethanol, isopropanol, or ethylene glycol.
The mass ratio of the alcohol to the water in the solvent A is (4-20): 1, preferably (4-16): 1, more preferably (4-12): 1, and most preferably (4-8): 1. 1, 5. The increase of the proportion of alcohols in the solvent A can improve the refining effect, but can reduce the yield of the refined product; the inventor of the invention finds that when the mass ratio of the alcohol to the water in the solvent A is not less than 4. For example, when absolute ethanol is used instead of the solvent A, the yield of the purified product is remarkably reduced, but the purity is hardly increased.
The mass ratio of the solvent A to the crude valdecoxib is (4-20): 1, preferably (4-16): 1, more preferably (4-13): 1, and most preferably (4-10): 1. 1, 5. The use amount of the solvent A is increased to improve the refining effect, but the yield of the refined product is reduced; the inventor of the invention finds that when the mass ratio of the solvent A to the valdecoxib crude product is not less than 4.
When the alcohol in the solvent A is ethanol, the ethanol can adopt commercially available aqueous ethanol (including but not limited to 95% ethanol v/v), and the amount of ethanol and water in the aqueous ethanol is calculated according to actual conditions. That is, unless otherwise specified, when aqueous ethanol is employed to constitute solvent A; when considering the amount of water in solvent a, the amount of water in the aqueous ethanol is taken into account; when considering the amount of alcohol in solvent A, the amount of water in the aqueous ethanol is not counted.
In one particular embodiment of the invention, the basic substance is chosen from ammonia (NH) 3 ) Triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide.
The mass ratio of the alkaline substance to the crude valdecoxib in the step (a) is (0.01-0.2): 1, preferably (0.02-0.2): 1, more preferably (0.05-0.2): 1, and most preferably (0.05-0.15): 1. For example, 0.01.
When the basic substance is ammonia (NH) 3 ) When is ammonia (NH) 3 ) Ammonia gas may be used, or ammonia water may be used, preferably ammonia water.
In the present invention, when the basic substance is ammonia water, unless otherwise specified; when the amount of water in the solvent A is considered, the amount of water in the ammonia water is not counted; that is, the amount of water in the ammonia water is added to the amount of the alkaline substance, taking the ammonia water as a whole.
Recrystallization is one method of increasing the purity of the solid. The solubility of a solid in a solvent generally increases with increasing temperature; selecting a suitable solvent, dissolving the solid (containing the impurities) in a hot solvent to form a hot saturated solution (or a hot concentrated solution), optionally removing insoluble impurities while hot (e.g. by filtration), reducing the temperature of the solution (optionally to below room temperature) to precipitate the major component from the reduced temperature solution, leaving the soluble impurities in solution; thereby increasing the purity of the solid.
In one embodiment of the present invention, the method for separating solids from a solid-liquid mixture includes, but is not limited to, filtration, centrifugation. For example, in the case of laboratory scale development, it is preferable to perform the solid-liquid separation operation by filtration because of small batch size; in the case of industrial production, it is preferable to carry out the solid-liquid separation operation by centrifugation because of a large amount of the product.
In one embodiment of the present invention, the solvent C in step (b) is water. The mass ratio of the solvent C to the crude valdecoxib is (4-20): 1, preferably (6-17): 1, and most preferably (8-13): 1. For example 4. The inorganic salt impurities can be better removed by increasing the dosage of the solvent C; meanwhile, as the solubility of the intermediate valdecoxib in the solvent C is poor, the increase of the dosage of the solvent C does not have obvious influence on the reduction of the product yield; however, increasing the amount of solvent C puts higher demands on the volume of production equipment, and increases the workload of post-treatment of wastewater.
The stirring in the step (b) is 15-35 ℃, preferably 20-30 ℃; 20-30 ℃ is generally at room temperature, and can also be regarded as preferred at room temperature. The stirring time is 15min to 3 hours, preferably 30min to 2 hours, and more preferably 45min to 1.5 hours.
In a specific embodiment of the invention, the drying may be a drying mode with or without temperature rise, and a drying mode with normal pressure or reduced pressure may be adopted; for example, an atmospheric drying mode at room temperature, a reduced-pressure drying mode at room temperature, an atmospheric drying mode at a temperature higher than room temperature, a reduced-pressure drying mode at a temperature higher than room temperature; preferably, the drying is carried out in a manner of drying at an atmospheric pressure higher than room temperature or in a manner of drying at a reduced pressure higher than room temperature. The drying time may be, for example, 6 to 24 hours at 50 to 60 ℃ and 12 hours at 60 ℃.
In a second aspect of the invention, a method for preparing parecoxib shown in the formula (III) is provided, which comprises the steps of refining valdecoxib crude product to obtain a valdecoxib refined product according to the method in the first aspect of the invention, and reacting the valdecoxib refined product with propionic anhydride to obtain the parecoxib. Further, the parecoxib can be prepared into parecoxib sodium shown in a formula (IV).
In a third aspect of the invention, a method for directly preparing parecoxib sodium shown in a formula (IV) from valdecoxib is provided; the parecoxib sodium is further prepared by separating the obtained parecoxib without the method described in the second aspect of the invention.
In one embodiment of the present invention, a method for preparing parecoxib sodium represented by formula (IV) comprises the steps of:
(d) Mixing valdecoxib, propionic anhydride and a solvent E, and stirring for reaction;
(e) Adding an alkaline solution containing sodium ions into the reaction solution obtained in the step (d), and stirring for reaction;
(f) Heating the reaction solution in the step (e) to reflux, and filtering the reaction solution while the reaction solution is hot to obtain a filtrate G;
(g) Heating and concentrating the filtrate G, cooling the concentrated solution to-5-10 ℃ and separating out parecoxib sodium.
In a specific embodiment of the present invention, the valdecoxib in step (d) is the valdecoxib refined product obtained in step (c) of the process according to the first aspect of the present invention.
Preferably, the molar ratio of the valdecoxib to the propionic anhydride in the step (d) is 1 (3-6); more preferably 1 (3-5).
Preferably, the solvent E in step (d) is tetrahydrofuran, and the mass ratio of the valdecoxib to the solvent E is 1 (4-10), more preferably 1 (4-8), and most preferably 1 (4-6).
Preferably, step (d) comprises a catalyst, wherein the catalyst is 4-dimethylaminopyridine; more preferably, the molar ratio of the catalyst to the valdecoxib is (0.05-0.2): 1.
Preferably, the temperature for stirring reaction in the step (d) is 5-35 ℃; more preferably 5 to 30 ℃ or 10 to 35 ℃; most preferably from 10 to 30 deg.c. The stirring reaction time in the step (d) is 2 to 10 hours; more preferably 3 to 7 hours; most preferably 3 to 5 hours.
Preferably, the alkaline solution containing sodium ions in step (e) means that the alkaline substance containing sodium is dissolved in the solvent F. The sodium-containing alkaline substance is selected from one or more of sodium hydroxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide; preferably sodium hydroxide. The solvent F is selected from one or more of methanol, ethanol and isopropanol, and preferably ethanol. The molar ratio of the sodium-containing alkaline substance to the propionic anhydride in step (d) is (1-3): 1, preferably (1.5-2.5): 1.
Preferably, the temperature for stirring reaction in the step (e) is 5-35 ℃; more preferably 10 to 30 ℃; most preferably 15 to 25 deg.c. The stirring reaction time in the step (e) is 2 to 10 hours; more preferably from 3 to 8 hours; most preferably 4 to 7 hours.
In the step (f), the reaction solution is filtered while it is hot to remove part of impurities and salts.
In one embodiment of the present invention, optionally, the filter cake in step (F) is washed with solvent F, and the filtrate obtained from the washing is combined with filtrate G.
In a specific embodiment of the invention, the parecoxib sodium precipitated in step (g) can be further refined by recrystallization after separation; an exemplary recrystallization solution is ethanol. The method for separating the precipitated parecoxib sodium is filtration or centrifugation.
The refining method of the valdecoxib provided by the invention can obviously improve the purity of the valdecoxib crude product in a high-yield manner; for example, the purity of the crude valdecoxib (purity 93.23%) can be increased to more than 99.9% (and content is 99.5%) and the yield is 92% (if the actual content of valdecoxib in the crude product is considered, the corrected actual yield is about 98%). The refining method of the valdecoxib provided by the invention also has the advantages of simple and convenient operation, easily controlled parameter conditions and low cost in large-scale production process.
The method for preparing parecoxib sodium by the valdecoxib one-pot method does not need to separate parecoxib separately, is simpler and more convenient in production process, and is beneficial to industrial mass production.
Drawings
FIG. 1: HPLC profile of valdecoxib crude product
FIG. 2: the peak corresponding to the retention time of 36.982min in the HPLC chart shown in FIG. 1 is valdecoxib (peak area of 93.23%), the peak corresponding to the retention time of 34.399min is impurities in the meta-position of valdecoxib (peak area of 6.41%), and other 6 related substances (peak areas of 0.35% in total) are also shown in the chart.
FIG. 3: HPLC chromatogram of the refined product (example 1)
FIG. 4 is a schematic view of: the peak corresponding to the retention time of 36.735min in the HPLC chromatogram shown in FIG. 3 is valdecoxib (peak area 99.96%), and no impurities at meta-position of valdecoxib are detected, and the other 1 related substances (peak area 0.04%) are also shown in the chromatogram.
FIG. 5: HPLC profile of the parecoxib sodium recrystallized product obtained in example 9.
FIG. 6: the peak corresponding to the retention time of 33.165min in the HPLC chromatogram shown in FIG. 5 is parecoxib (parecoxib sodium) (peak area 99.97%).
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Example 1
Adding 20g of valdecoxib crude product (with the purity of 93.23%), 120g of ethanol, 20g of water mixed solvent (namely, solvent A) and 2g of ammonia water into a 250ml three-necked bottle, heating to 65 +/-5 ℃, stirring for 0.5h, cooling to 0-10 ℃, keeping the temperature of 0-10 ℃, stirring for crystallization for 1h, filtering, adding 200g of water (namely, solvent C) into a filter cake (namely, solid B), controlling the temperature to be 20-30 ℃, stirring for 1h, filtering, drying the filter cake (namely, solid D) for 12h at 60 ℃ to obtain 18.4g of valdecoxib refined product, wherein the yield is 92.0%, the purity is 99.96%, and impurities at the meta-position of valdecoxib are not detected; the content was 99.5%.
Ammonia water: the ammonia content of the ammonia water chemical reagent sold in the market is about 25 to 28 percent.
Example 2
Adding 20g of valdecoxib crude product (with the purity of 93.23%), 126.3g of 95% ethanol, 13.7g of water and 2g of ammonia water into a 250ml three-neck flask, heating to 65 +/-5 ℃, stirring for 0.5h, cooling to 0-10 ℃, keeping the temperature at 0-10 ℃, stirring for crystallization for 1h, filtering, adding 200g of water into a filter cake, controlling the temperature to be 20-30 ℃, stirring for 1h, filtering, and drying for 12h at 60 ℃ to obtain 18.3g of valdecoxib refined product, wherein the yield is 91.5%, the purity is not lower than 99.9%, and the content is not lower than 99%; no impurities in the meta-position of valdecoxib are detected.
Example 3
Adding 20g of valdecoxib crude product (with the purity of 93.23%), 120g of methanol, 20g of water and 0.8g of ammonia water into a 250ml three-necked bottle, heating to 65 +/-5 ℃, stirring for 0.5h, cooling to 0-10 ℃, keeping the temperature of 0-10 ℃, stirring and crystallizing for 1h, filtering, adding 200g of water into a filter cake, controlling the temperature to be 20-30 ℃, stirring for 1h, filtering, and drying at 60 ℃ for 12h to obtain 18.0g of valdecoxib refined product, wherein the yield is 90.0%, the purity is not lower than 99.9%, and the content is not lower than 99%; no impurities in meta-position of valdecoxib were detected.
Example 4
With reference to the method of example 1, the purified valdecoxib product was obtained in the same manner as in example 1, except that the ethanol was changed to isopropanol or ethylene glycol.
Example 5
Referring to the method of example 1, purified valdecoxib product with high purity was also obtained by changing ammonia to triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide.
Example 6
With reference to the method of example 1, the weight ratio of ethanol to water in the recrystallization solvent (120 g of ethanol and 20g of water) is adjusted from 6.
An increase in the proportion of alcohols reduces the yield of the refined product; for example, by using absolute ethyl alcohol instead of solvent A, the yield of the refined product is obviously reduced, but the purity is hardly increased. If industrial economy is not considered, the recrystallization solvent may be an alcohol containing no water.
Example 7
With reference to the method of example 1, the total mass of the recrystallization solvents (120 g ethanol, 20g water) is adjusted to be 4 times, 5 times, 6 times, 8 times, 9 times, 10 times, 11 times, 12 times, 13 times, 14 times, 15 times, 16 times, 17 times, 18 times, 19 times, 20 times of the mass of the crude valdecoxib, and highly purified valdecoxib products are obtained as well.
But the yield of the valdecoxib refined product is reduced along with the increase of the total mass of the recrystallization solvent; if the industrial economy is not considered, the total mass of the recrystallization solvent may be more than 20 times the mass of the crude valdecoxib product.
Example 8
With reference to the method of example 1, the amount of ammonia in the recrystallization solvent was adjusted from 2g to 4g, 3g, 2g, 1g, 0.4g, 0.2g, and highly purified valdecoxib was obtained.
Comparative example 1
Referring to the method of example 1, the recrystallization step did not contain ammonia. The purity of the obtained valdecoxib refined product is 98.9 percent, and the purity of valdecoxib meta-impurity is 0.55 percent (exceeding the limit of 0.5 percent).
Adding alkaline substance (such as ammonia water) in the recrystallization step, reacting with valdecoxib hydrolysate and unreacted sulfonyl chloride (transition product produced after adding chlorosulfonic acid) to generate corresponding salt, and dissolving in recrystallization solvent and subsequent solvent water; the purity and the content are improved, and the valdecoxib meta-impurities can be added and dissolved in the refined solvent, so that the meta-impurities are completely removed.
Comparative example 2
Referring to the method of example 1, after recrystallization, the cake was directly dried without beating with water (solvent C). The purity of the obtained product is about 99.90 percent; however, the content of the valdecoxib is detected to be lower than 97%.
Example 9
Adding 106g of tetrahydrofuran and 20.0g (63.6 mmol) of valdecoxib refined product into a 500ml three-necked bottle, adding 32g (245.9 mmol) of propionic anhydride and 0.8g (6.55 mmol) of 4-dimethylaminopyridine under stirring, keeping the temperature at 10-30 ℃, stirring for 4 hours, dropwise adding an ethanol solution of sodium hydroxide (16.7 g of sodium hydroxide (417.5 mmol) into 164g of ethanol), reacting for 5 hours at 15-25 ℃, monitoring the reaction by TLC (a developing agent is ethyl acetate: n-hexane = 1), dropwise adding 2 drops of thionyl chloride, developing by an ultraviolet lamp 254 nm), heating to reflux (66 filtering when the solution is hot,washing filter cake with 20ml ethanol, discarding filter cake, combining filtrate to 500ml three-necked bottle, heating to 75-80 deg.C, distilling off part tetrahydrofuran and ethanol under normal pressure (106-116.5 g after collecting gas phase fraction), cooling to 0-10 deg.C, filtering, adding 100g anhydrous ethanol into filter cake, heating to 70 deg.C, stirring, dissolving, filtering, drying at 50 + -5 deg.C under reduced pressure for 8 hr to obtain 18.75g white powder (parecoxib sodium), yield is 75.1%, purity is 99.97%, ESI-MS m/z is 369.2M-Na] - 。
Example 10
Referring to the method of example 9, high purity parecoxib sodium is obtained in the same high yield by replacing sodium hydroxide in an ethanol solution of sodium hydroxide with sodium methoxide, sodium ethoxide, or sodium tert-butoxide.
Example 11
With reference to the procedure of example 9, high purity parecoxib sodium was obtained in the same high yield by replacing ethanol in an ethanol solution of sodium hydroxide with methanol, isopropanol.
Claims (10)
1. A method for purifying a compound of formula (II), comprising:
(a) Mixing the crude product of the compound shown in the formula (II), an alkaline substance and a solvent A, recrystallizing, and separating out a precipitated solid B;
(b) Mixing the solid B with a solvent C, stirring, and separating to obtain a solid D;
(c) Drying the solid D to obtain a refined product of the compound shown in the formula (II);
the alkaline substance is selected from ammonia (NH) 3 ) Triethylamine, ethylenediamine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide, or potassium hydroxide;
the solvent A is a mixed solvent of alcohols and water; the solvent C is water.
2. The method of claim 1, characterized by one or more of the following features:
(1) The alkaline substance in the step (a) is ammonia water;
(2) The alcohol in the solvent A is selected from methanol, ethanol, isopropanol or ethylene glycol;
(3) The separation method of the solid B separated out in the step (a) is filtration or centrifugation;
(4) The separation method for separating the solid D obtained in the step (b) is filtration or centrifugation;
(5) The drying method in the step (c) is a normal pressure drying method higher than room temperature or a reduced pressure drying method higher than room temperature.
3. The method according to claim 1, wherein the mass ratio of the alcohol to the water in the solvent A is (4-20): 1;
preferably (4-16) 1; more preferably (4-12) 1; most preferably (4-8): 1.
4. The method as claimed in claim 1, wherein the mass ratio of the solvent A to the crude compound of the formula (II) is (4-20): 1;
preferably (4-16) 1; more preferably (4-13) 1; most preferably (4-10): 1.
5. The method according to claim 1, wherein the mass ratio of the basic substance to the crude compound of formula (II) in step (a) is (0.01-0.2): 1;
preferably (0.02-0.2): 1; more preferably (0.05-0.2) 1; most preferably (0.05-0.15): 1.
6. The method according to claim 1, wherein the mass ratio of the solvent C to the crude compound of formula (II) in step (b) is (4-20): 1;
preferably (6-17) 1; most preferably (8-13): 1.
7. A preparation method of parecoxib sodium shown in formula (IV) comprises the following steps:
(d) Mixing valdecoxib, propionic anhydride and a solvent E, and stirring for reaction;
(e) Adding an alkaline solution containing sodium ions into the reaction solution in the step (d), and stirring for reaction;
(f) Heating the reaction solution in the step (e) to reflux, and filtering the reaction solution while the reaction solution is hot to obtain a filtrate G;
(g) Heating and concentrating the filtrate G, cooling the concentrated solution to-5-10 ℃, and separating out parecoxib sodium;
the solvent E is tetrahydrofuran;
the alkaline solution containing sodium ions is formed by dissolving an alkaline substance containing sodium in a solvent F; the sodium-containing alkaline substance is selected from one or more of sodium hydroxide, sodium methoxide, sodium ethoxide and sodium tert-butoxide; the solvent F is selected from one or more of methanol, ethanol and isopropanol.
8. The method of claim 7,
in the step (d), the molar ratio of valdecoxib to propionic anhydride is 1 (3-6); more preferably 1 (3-5);
the mass ratio of the valdecoxib to the solvent E in the step (d) is 1 (4-10), more preferably 1 (4-8), and most preferably 1 (4-6);
the temperature of stirring reaction in the step (d) is 5-35 ℃; more preferably 5 to 30 ℃ or 10 to 35 ℃; most preferably 10 to 30 ℃;
the stirring reaction time in the step (d) is 2 to 10 hours; more preferably 3 to 7 hours; most preferably 3 to 5 hours.
9. The method of claim 7,
the sodium-containing alkaline substance in step (e) is sodium hydroxide;
the solvent F in the step (e) is ethanol;
the molar ratio of the sodium-containing basic substance in the step (e) to the propionic anhydride in the step (d) is (1-3): 1, preferably (1.5-2.5): 1;
the temperature of stirring reaction in the step (e) is 5-35 ℃; more preferably 10 to 30 ℃; most preferably 15 to 25 ℃;
the stirring reaction time in the step (e) is 2 to 10 hours; more preferably from 3 to 8 hours; most preferably 4 to 7 hours.
10. The method of claim 7, characterized by one or more of the following features:
(1) Said valdecoxib in step (d) is a refined product of a compound of formula (II) obtained according to the process of any one of claims 1 to 6;
(2) The step (d) contains a catalyst, and the catalyst is 4-dimethylaminopyridine;
(3) Washing the filter cake in the step (F) by using a solvent F, and combining the filtrate obtained by washing into a filtrate G;
(4) And (g) separating the parecoxib sodium precipitated in the step (g), and refining by a recrystallization method.
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