CN108558759A - The method that one kettle way prepares celecoxib - Google Patents
The method that one kettle way prepares celecoxib Download PDFInfo
- Publication number
- CN108558759A CN108558759A CN201810383733.6A CN201810383733A CN108558759A CN 108558759 A CN108558759 A CN 108558759A CN 201810383733 A CN201810383733 A CN 201810383733A CN 108558759 A CN108558759 A CN 108558759A
- Authority
- CN
- China
- Prior art keywords
- celecoxib
- reaction
- methylacetophenone
- temperature
- preparing
- Prior art date
- 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.)
- Granted
Links
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 46
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 45
- GNKZMNRKLCTJAY-UHFFFAOYSA-N 4'-Methylacetophenone Chemical compound CC(=O)C1=CC=C(C)C=C1 GNKZMNRKLCTJAY-UHFFFAOYSA-N 0.000 claims abstract description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 239000007788 liquid Substances 0.000 claims abstract description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 12
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims abstract description 11
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000967 suction filtration Methods 0.000 claims abstract description 9
- IKEURONJLPUALY-UHFFFAOYSA-N 4-hydrazinylbenzenesulfonamide;hydron;chloride Chemical compound [Cl-].NS(=O)(=O)C1=CC=C(N[NH3+])C=C1 IKEURONJLPUALY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 8
- 230000008025 crystallization Effects 0.000 claims abstract description 8
- 239000012043 crude product Substances 0.000 claims abstract description 6
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 6
- 230000008569 process Effects 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000005580 one pot reaction Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims 2
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 3
- 150000001298 alcohols Chemical class 0.000 abstract 1
- 238000004886 process control Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 13
- 238000010438 heat treatment Methods 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- -1 p-hydrazino benzenesulfonyl Chemical group 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000011112 process operation Methods 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- HXGXWPKABYTUOQ-UHFFFAOYSA-N CC(C(C=C1)S(N)(=O)=O)C=C1NN Chemical compound CC(C(C=C1)S(N)(=O)=O)C=C1NN HXGXWPKABYTUOQ-UHFFFAOYSA-N 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012527 feed solution Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000010865 sewage Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of methods that one kettle way prepares celecoxib.This method is：In the presence of ethylenediamine, melilotal and Trifluoroacetic Acid Ethyl Ester are mixed, are not necessarily to other solvents, in 40 DEG C of 80 DEG C of reactions to the reaction was complete, obtains the reaction solution of intermediate DO；Alcohols solvent is added in above-mentioned reaction solution, adds 4-hydrazinobenzene-1-sulfonamide hydrochloride, inorganic acid for adjusting pH value is then added to 36, control feed temperature is 50 DEG C of 80 DEG C of reactions to the reaction was complete；After completion of the reaction plus water, 10 30 DEG C of crystallizations are cooled to, suction filtration obtains celecoxib crude product；Crude methanol dissolves, and then feed liquid is added dropwise in water, and it is 40 50 DEG C that process control feed temperature, which is added dropwise, and drop, which finishes, is cooled to 10 30 DEG C of crystallizations, and suction filtration obtains celecoxib finished product.It is more than 85% using total yield of products prepared by the above method, purity >=99.90% is detected through HPLC.
Description
Technical Field
The invention relates to a preparation method of celecoxib, and belongs to the technical field of medicines.
Background
Celecoxib, chemical name: 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-yl ] benzenesulfonamide; the structural formula is as follows. Celecoxib is a new-generation non-steroidal anti-inflammatory analgesic, and achieves the effects of resisting inflammation and relieving pain by selectively inhibiting cyclooxygenase-2 (COX-2) to inhibit the generation of prostaglandin. Since celecoxib does not inhibit cyclooxygenase-1 (COX-1), a physiological enzyme with gastrointestinal tract protection, the risk of gastrointestinal adverse reactions of the celecoxib is obviously lower than that of the traditional non-steroidal anti-inflammatory analgesics.
the celecoxib preparation method is mainly characterized by that p-methylacetophenone and trifluoroacetate are undergone the process of Claisen condensation to obtain β -diketone intermediate, then said β -diketone intermediate is cyclized with p-hydrazino benzenesulfonyl amine hydrochloride to obtain celecoxib, and its chemical reaction formula is shown in the specification, for example, the celecoxib preparation method reported in the document [ J Med Chem, 1997,40 (9): 1347-1365] adopts said method, and said method has the defects of low yield, long reaction time, and more impurities, and has the complex steps of distillation, extraction, washing and drying, etc., and has recrystallization step, and the mixed solution is expensive and difficult to recover.
Chinese patent CN103570622A discloses a method for preparing celecoxib, which uses N, N-dimethylformamide as a solvent, reacts methyl acetophenone and ethyl trifluoroacetate to generate a β -diketone intermediate under the action of sodium methoxide, and reacts with p-hydrazino benzenesulfonyl amine hydrochloride in the N, N-dimethylformamide to form celecoxib, wherein the chemical equation is shown as follows.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a method for preparing celecoxib by a one-pot method. In the method, the intermediate DO is prepared by using the ethylenediamine with weak alkalinity to replace the conventional strong bases such as sodium alkoxide and the like, and a solvent is not required, so that the reaction is more moderate, and the byproducts are less; the refining adopts a reverse dripping mode to drip the feed liquid into water, and the impurity removal effect is better than that of forward addition; the method of 'one-pot boiling' is adopted, the purification and treatment processes of intermediate links are reduced, and the process operation is simplified. The total yield of the product prepared by the method is more than 85 percent, and the purity is more than or equal to 99.90 percent through HPLC detection.
The technical scheme of the invention is as follows: the method for preparing celecoxib by a one-pot method is characterized by comprising the following steps of:
1) in the presence of ethylenediamine, mixing p-methylacetophenone and ethyl trifluoroacetate, reacting at 40-80 ℃ without other solvents until the reaction is complete to obtain a reaction solution of an intermediate DO;
2) adding an alcohol solvent into the reaction liquid, adding p-hydrazino benzene sulfonamide hydrochloride, adding an inorganic acid to adjust the pH value to 3-6, and controlling the temperature of the feed liquid to be 50-80 ℃ to react until the reaction is complete; after the reaction is finished, adding water, cooling to 10-30 ℃ for crystallization, and performing suction filtration to obtain a celecoxib crude product;
3) dissolving the crude celecoxib product in methanol, then dropwise adding the feed liquid into water, controlling the temperature of the feed liquid to be 40-50 ℃ in the dropwise adding process, cooling to 10-30 ℃ after dropwise adding, crystallizing, and carrying out suction filtration to obtain a celecoxib finished product.
The reaction route is as follows:
wherein,
in the step 1), the molar ratio of p-methylacetophenone to ethyl trifluoroacetate to ethylenediamine is 1: (1-5): (1-3), preferably 1: (1.2-1.5): (1.5-2.0).
The reaction temperature in step 1) is preferably 55 to 65 ℃ and the reaction time is preferably 2 to 3 hours.
The alcohol solvent in step 2) may be methanol, ethanol, isopropanol, etc., preferably methanol.
The inorganic acid for adjusting the pH in step 2) is a conventional inorganic acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, and the pH of the feed solution is preferably adjusted to 3.0 to 3.5.
The reaction temperature of the step 2) is preferably 60 ℃ to 65 ℃, and the reaction time is preferably 3 to 4 hours.
Step 2), the molar ratio of the p-hydrazinylbenzenesulfonamide hydrochloride to the p-methylacetophenone is 0.95-1.1: 1, preferably 1: 1. the volume ratio of the alcohol solvent to the p-methylacetophenone is 10-20: 1, preferably 13 to 17: 1.
compared with the prior art, the invention has the advantages that:
1. solvent is not needed in the preparation of the intermediate DO, the ethylene diamine with weak alkalinity is used for replacing the common alkali such as sodium alkoxide and the like, the reaction is more moderate, and the byproducts are less;
2. the feed liquid is dripped into water in a reverse dripping mode for refining, so that the impurity removal effect is better than that of forward addition, and the product quality is more stable;
3. the method of 'one-pot boiling' is adopted, the purification and treatment processes of intermediate links are reduced, the process operation is simplified, the solvent usage amount and the sewage discharge amount are reduced, the production cost is reduced, the energy conservation and consumption reduction are realized, and the influence on the environment is reduced.
4. The total yield of the product prepared by the process is more than 85 percent, and the purity is more than or equal to 99.90 percent through HPLC detection. The method has the advantages of simple operation, high yield and high purity, and is beneficial to industrial large-scale production.
Detailed Description
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
It should be understood that the processing equipment or devices not specifically mentioned in the following examples are conventional in the art; all pressure values and ranges refer to absolute pressures.
Furthermore, it is to be understood that one or more method steps mentioned in the present invention does not exclude that other method steps may also be present before or after the combined steps or that other method steps may also be inserted between these explicitly mentioned steps, unless otherwise indicated; it is also to be understood that a combined connection between one or more devices/apparatus as referred to in the present application does not exclude that further devices/apparatus may be present before or after the combined device/apparatus or that further devices/apparatus may be interposed between two devices/apparatus explicitly referred to, unless otherwise indicated. Moreover, unless otherwise indicated, the numbering of the various method steps is merely a convenient tool for identifying the various method steps, and is not intended to limit the order in which the method steps are arranged or the scope of the invention in which the invention may be practiced, and changes or modifications in the relative relationship may be made without substantially changing the technical content.
Example 1
1) Preparation of intermediate I
34.6ml (291mmol) of ethyl trifluoroacetate and 26.7ml (400mmol) of ethylenediamine are added into a 1000ml three-neck flask, the mixture is stirred for 5 to 10 minutes, then 30ml (224mmol) of p-methylacetophenone is added, the temperature is raised to 60 ℃ for reaction for 2.5 hours, and then the TLC point plate detects that the p-methylacetophenone is completely reacted to obtain an intermediate DO.
2) Preparation of celecoxib crude product
Adding 500ml of methanol into the reaction liquid in the previous step, adding 50.1g (224mmol) of p-hydrazino benzene sulfonamide hydrochloride, adding concentrated hydrochloric acid (the concentration is 37.5 percent) to adjust the pH value to be 3.4, heating the material liquid to 65 ℃, and carrying out heat preservation reaction for 3.5 hours; and (3) after the reaction is finished, adding 530ml of purified water, cooling to 20 ℃, preserving the temperature for 1.5 hours, crystallizing, and filtering. 77.65g of crude celecoxib is obtained, the purity is 99.5%, and the yield is 90.9%.
3) Preparation of celecoxib finished product
Adding 40.0g (105mmol) of crude celecoxib into a 1000ml three-neck flask, adding 250ml of methanol, stirring, heating to 60 ℃ for dissolution, adding 1g of activated carbon for decoloration after the feed liquid is clear, and filtering; adding 300ml of purified water into the other three-necked bottle, heating to 40-50 ℃, dropwise adding the decolorized feed liquid into the water, controlling the temperature of the feed liquid at 43.5 ℃ in the dropwise adding process, cooling to 25.6 ℃ for crystallization, keeping the temperature for 1.5 hours, and performing suction filtration to obtain 38.1g of celecoxib, wherein the purity is 99.96%, and the yield is 95.2%.
The overall yield was 86.5%.
Example 2
1) Preparation of intermediate I
35.6ml (300mmol) of ethyl trifluoroacetate and 27ml (405mmol) of ethylenediamine are added into a 1000ml three-neck flask, stirred for 5-10 minutes, then 30ml (224mmol) of p-methylacetophenone is added, the temperature is raised to 65 ℃ for reaction for 2 hours, and then the TLC point plate detection shows that the p-methylacetophenone completely reacts to obtain an intermediate DO.
2) Preparation of celecoxib crude product
Adding 450ml of methanol into the reaction liquid in the previous step, adding 50.0g (223mmol) of p-hydrazinobenzenesulfonamide hydrochloride, adding concentrated hydrochloric acid (the concentration is 37.5%) to adjust the pH value to 3.3, heating the material liquid to 60 ℃, preserving heat for reaction for 4 hours, adding 500ml of purified water after the reaction is finished, cooling to 20 ℃, preserving heat for 1.5 hours, crystallizing, and filtering. 76.8g of crude celecoxib product is obtained, the purity is 99.6 percent, and the yield is 89.9 percent.
3) Preparation of celecoxib finished product
Adding 40.0g (105mmol) of crude celecoxib into a 1000ml three-necked bottle, adding 250ml of methanol, stirring and heating to 60 ℃ for dissolution, adding 1g of activated carbon for decoloration after the feed liquid is clear, filtering, adding 330ml of purified water into the other three-necked bottle, heating to 40-50 ℃, dropwise adding the decolored feed liquid into water, controlling the temperature of the feed liquid at 43.0 ℃ in the dropwise adding process, cooling to 25.0 ℃ for crystallization, keeping the temperature for 2 hours, and then carrying out suction filtration to obtain 38.5g of celecoxib with the purity of 99.95% and the yield of 96.4%.
The overall yield was 86.6%.
Example 3
1) Preparation of intermediate I
340ml (286mmol) of ethyl trifluoroacetate and 26.7ml (400mmol) of ethylenediamine are added into a 1000ml three-neck flask, the mixture is stirred for 5 to 10 minutes, then 30ml (224mmol) of p-methylacetophenone is added, the temperature is raised to 60 ℃ for reaction for 2.5 hours, and then the TLC point plate detects that the p-methylacetophenone completely reacts to obtain an intermediate DO.
2) Preparation of celecoxib crude product
Adding 500ml of isopropanol into the reaction liquid in the previous step, adding 49g (21.9mmol) of p-hydrazino benzene sulfonamide hydrochloride, adding concentrated sulfuric acid (98%) to adjust the pH value to 3.4, heating the feed liquid to 65 ℃, preserving heat for reaction for 3.5 hours, adding 550ml of purified water after the reaction is finished, cooling to 20 ℃, preserving heat for 1.5 hours, crystallizing, and filtering. 75.5g of crude celecoxib with the purity of 99.5 percent and the yield of 88.4 percent is obtained.
3) Preparation of celecoxib finished product
Adding 40.0g (105mmol) of crude celecoxib into a 1000ml three-necked bottle, adding 250ml of methanol, stirring and heating to 60 ℃ for dissolution, adding 1g of activated carbon for decoloration after the feed liquid is clear, filtering, adding 300ml of purified water into the other three-necked bottle, heating to 40-50 ℃, dropwise adding the decolored feed liquid into water, controlling the temperature of the feed liquid at 45.6 ℃ in the dropwise adding process, cooling to 25.6 ℃ for crystallization, keeping the temperature for 1.5 hours, and then carrying out suction filtration to obtain 38.7g of celecoxib with the purity of 99.97% and the yield of 96.8%.
The overall yield was 85.5%.
The above examples are intended to illustrate the disclosed embodiments of the invention and are not to be construed as limiting the invention. In addition, various modifications of the methods and compositions set forth herein, as well as variations of the methods and compositions of the present invention, will be apparent to those skilled in the art without departing from the scope and spirit of the invention. While the invention has been specifically described in connection with various specific preferred embodiments thereof, it should be understood that the invention should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described embodiments which are obvious to those skilled in the art to which the invention pertains are intended to be covered by the scope of the present invention.
Claims (10)
1. A method for preparing celecoxib by a one-pot method is characterized by comprising the following steps:
1) in the presence of ethylenediamine, mixing p-methylacetophenone and ethyl trifluoroacetate, reacting at 40-80 ℃ without other solvents until the reaction is complete to obtain a reaction solution containing an intermediate DO;
2) adding an alcohol solvent into the reaction liquid, adding p-hydrazino benzene sulfonamide hydrochloride, adding an inorganic acid to adjust the pH value to 3-6, and controlling the temperature of the feed liquid to be 50-80 ℃ to react until the reaction is complete; after the reaction is finished, adding water, cooling to 10-30 ℃ for crystallization, and performing suction filtration to obtain a celecoxib crude product;
wherein intermediate DO is
2. The method for preparing celecoxib by the one-pot method according to claim 1, wherein the crude celecoxib in the step 2) is dissolved in methanol, and then the feed liquid is dripped into water, the temperature of the feed liquid is controlled to be 40-50 ℃ in the dripping process, the temperature is reduced to 10-30 ℃ after dripping, crystallization is carried out, and a celecoxib finished product is obtained by suction filtration.
3. The method for preparing celecoxib in one-pot according to claim 1, wherein the molar ratio of p-methylacetophenone to ethyl trifluoroacetate and ethylenediamine in step 1) is 1: (1-5): (1-3).
4. The method for preparing celecoxib in one-pot according to claim 3, wherein the molar ratio of p-methylacetophenone to ethyl trifluoroacetate and ethylenediamine in step 1) is 1: (1.2-1.5): (1.5-2.0).
5. The process of claim 1, wherein the reaction temperature of step 1) is 55-65 ℃ and the reaction time is 2-3 hours.
6. The method for preparing celecoxib in one pot according to claim 1, wherein the alcoholic solvent in step 2) is methanol, ethanol or isopropanol.
7. The process of claim 1, wherein the inorganic acid used to adjust the pH in step 2) is hydrochloric acid, sulfuric acid, or phosphoric acid.
8. The process of claim 1, wherein the reaction temperature of step 2) is 60 ℃ to 65 ℃ and the reaction time is 3 to 4 hours.
9. The process for preparing celecoxib according to any one of claims 1-8, wherein the molar ratio of the p-hydrazinobenzenesulfonamide hydrochloride to the p-methylacetophenone in step 2) is from 0.95 to 1.1: 1.
10. the method for preparing celecoxib according to any one of claims 1-8, wherein the volume ratio of the alcoholic solvent to the p-methylacetophenone in the step 2) is 10-20: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810383733.6A CN108558759B (en) | 2018-04-26 | 2018-04-26 | Method for preparing celecoxib by one-pot method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810383733.6A CN108558759B (en) | 2018-04-26 | 2018-04-26 | Method for preparing celecoxib by one-pot method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108558759A true CN108558759A (en) | 2018-09-21 |
| CN108558759B CN108558759B (en) | 2020-06-19 |
Family
ID=63536888
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810383733.6A Active CN108558759B (en) | 2018-04-26 | 2018-04-26 | Method for preparing celecoxib by one-pot method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108558759B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698404A (en) * | 2019-11-26 | 2020-01-17 | 安徽恒星制药有限公司 | Preparation method of high-purity celecoxib |
| CN110981805A (en) * | 2019-11-21 | 2020-04-10 | 武汉光谷亚太医药研究院有限公司 | Preparation method of celecoxib genotoxic impurity |
| CN114195714A (en) * | 2022-01-14 | 2022-03-18 | 山东铂源药业有限公司 | Simple synthesis method of celecoxib |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010095024A2 (en) * | 2009-02-20 | 2010-08-26 | Aurobindo Pharma Limited | An improved process for the preparation of celecoxib |
| CN102391184A (en) * | 2011-10-17 | 2012-03-28 | 江西同和药业有限责任公司 | Synthesis method of celecoxib |
| CN102746231A (en) * | 2011-04-20 | 2012-10-24 | 天津药物研究院 | Celecoxib preparation process |
| CN103044329A (en) * | 2013-01-10 | 2013-04-17 | 齐河诚汇精细化工有限公司 | Preparation method of high-yield and high-purity celecoxib |
| CN103951549A (en) * | 2014-05-20 | 2014-07-30 | 河北科技大学 | Synthetic method of COX-2 enzyme inhibitor celecoxib intermediate |
-
2018
- 2018-04-26 CN CN201810383733.6A patent/CN108558759B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010095024A2 (en) * | 2009-02-20 | 2010-08-26 | Aurobindo Pharma Limited | An improved process for the preparation of celecoxib |
| CN102746231A (en) * | 2011-04-20 | 2012-10-24 | 天津药物研究院 | Celecoxib preparation process |
| CN102391184A (en) * | 2011-10-17 | 2012-03-28 | 江西同和药业有限责任公司 | Synthesis method of celecoxib |
| CN103044329A (en) * | 2013-01-10 | 2013-04-17 | 齐河诚汇精细化工有限公司 | Preparation method of high-yield and high-purity celecoxib |
| CN103951549A (en) * | 2014-05-20 | 2014-07-30 | 河北科技大学 | Synthetic method of COX-2 enzyme inhibitor celecoxib intermediate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981805A (en) * | 2019-11-21 | 2020-04-10 | 武汉光谷亚太医药研究院有限公司 | Preparation method of celecoxib genotoxic impurity |
| CN110698404A (en) * | 2019-11-26 | 2020-01-17 | 安徽恒星制药有限公司 | Preparation method of high-purity celecoxib |
| CN114195714A (en) * | 2022-01-14 | 2022-03-18 | 山东铂源药业有限公司 | Simple synthesis method of celecoxib |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108558759B (en) | 2020-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108558759B (en) | Method for preparing celecoxib by one-pot method | |
| CN103319414A (en) | Improved telmisartan preparation process | |
| US20120108821A1 (en) | Process for producing crystals of polymorphic 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecaboxylic acid by poor-solvent addition method | |
| US12024483B2 (en) | Synthesis method of hydroxybenzylamine | |
| CN103396406B (en) | Preparation method of candesartan cilexetil | |
| CN102584693B (en) | Preparation method for high purity 2-chlorine-3-aminopyridine hydrochloride | |
| CN109422642B (en) | Refining method of benzoic acid, production method and equipment of pharmaceutical grade sodium benzoate | |
| CN101541798B (en) | Process for production of mirtazapine | |
| CN103980249B (en) | A kind of process for purification of SYR-322 | |
| CN110713440B (en) | Preparation method of vigabatrin | |
| CN103304401A (en) | Preparation method of ibuprofen arginine salt with ultrahigh purity | |
| CN112142604A (en) | Preparation method of bromhexine hydrochloride and intermediate thereof | |
| CN110437083A (en) | The synthetic method of aramine enantiomter | |
| CN112979552A (en) | Preparation method of high-purity dexmedetomidine hydrochloride | |
| CN103102306A (en) | Preparation method for celecoxib | |
| CN106336352A (en) | Synthesis method of 6-fluorosalicylic acid | |
| CN112390815B (en) | Preparation method for preparing d-biotin by removing N-benzyl from Lewis acid | |
| CN103739502B (en) | A kind of separation and purification technique of ambroxol alkali | |
| CN111548302A (en) | Synthetic method of furotriptan | |
| CN104119307A (en) | Preparation method for (S)-2-(1,6,7,8-tetrahydro-2H-indeno[5,4-B]furan-8-yl)ethylamine | |
| CN114591246A (en) | Purification method of enzalutamide | |
| CN113666876B (en) | Production process of sulfachloropyridazine | |
| CN106187799B (en) | A method of preparing DL-lysine hydrochloride | |
| CN109761885A (en) | A kind of method for splitting of argatroban isomer impurities | |
| CN115466190B (en) | A kind of preparation method of tetracaine and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Applicant after: QILU TIANHE PHARMACEUTICAL Co.,Ltd. Applicant after: Shandong Anshun Pharmaceutical Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Applicant before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. Applicant before: QILU TIANHE (LAOLING) PHARMACEUTICAL Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20200320 Address after: No. 10678, Wenliang Road, Dongjia street, Licheng District, Jinan City, Shandong Province Applicant after: Shandong Anxin Pharmaceutical Co.,Ltd. Address before: 250105 No. 849 Dong Jia town, Licheng District, Shandong, Ji'nan Applicant before: QILU TIANHE PHARMACEUTICAL Co.,Ltd. Applicant before: Shandong Anshun Pharmaceutical Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |