A kind of synthesis process of non-steroidal anti-inflammatory drug celecoxib
Through the simplified celecoxib synthesis process, the condensation reaction of 1 compound and 2 compound and the oxidant condensation reaction are used to solve the problems of long routes and isomer impurities in the prior art, and the efficient and low-cost celecoxib is achieved. Cloth preparation, suitable for industrial production.
Patent Information
- Application Number
- CN202211644333.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-12-20
- Publication Date
- 2024-12-24
- Estimated Expiration
- 2042-12-20
AI Technical Summary
The existing celecoxib synthesis method has long routes, many steps, low reaction yields and inevitable generation of regioisomer impurity B, resulting in high process costs and unsuitable commercial production.
Using a simplified synthesis process, the intermediate 3 compounds were obtained through the condensation reaction of 1 compound and 2 compound, and a one-pot condensation reaction was carried out under the action of oxidizing agent, which avoided the generation of isomer impurities and improved the celecoxib. yield.
It achieves a short route, convenient operation, low cost and high yield, avoids the generation of isomer impurities, is suitable for industrial production, and is in line with the concept of green chemistry.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of drug synthesis, and in particular to a synthesis process of celecoxib, a non-steroidal anti-inflammatory drug. Background Art
[0002] Celecoxib, chemical name 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1-hydrogen-pyrazol-1-yl]benzenesulfonamide, has the following chemical structure:
[0003]
[0004] Celecoxib is a novel nonsteroidal anti-inflammatory drug and type 2 cyclooxyesterase (COX-2) inhibitor developed by Searle, USA, which shows excellent anti-inflammatory and analgesic effects and can be used to treat inflammations such as various acute and chronic arthritis and rheumatoid arthritis. Due to its wide application and large demand, the preparation process of celecoxib has become a key issue of concern to many scientific researchers and medical workers. Several preparation methods reported in the literature are now listed.
[0005] 1. Patents CN1699347A, US5466823A and the journal Med Chem, 1997, 40(9):1347-1365 disclose the mainstream preparation method of celecoxib. p-Methylacetophenone and trifluoroacetate are subjected to Claisen condensation reaction to obtain a β-diketone intermediate. The intermediate is not separated or purified, and then cyclized with p-aminosulfonylphenylhydrazine hydrochloride to prepare celecoxib. The chemical reaction equation is as follows:
[0006]
[0007] However, this method has the disadvantages of low yield, difficult separation and purification of the product, cumbersome operation, and more impurities, especially the inevitable generation of regional isomer impurity B, whose structure is as follows:
[0008]
[0009] Impurity B
[0010] 2. Patent WO2003024400A2 discloses a method for preparing celecoxib, and the reaction process is as follows:
[0011]
[0012] Toluene and ethoxytrifluorobutenone are reacted with zinc chloride to prepare a terminal substituted enone, which is further reacted with bromine to obtain an alkynone under alkaline conditions, and finally cyclized with p-sulfonamidophenylhydrazine to obtain celecoxib. This route is prone to produce an isomeric impurity B, and the ratio of the main product to the isomeric impurity can reach 90%:10%. It needs to be refined multiple times, and the use of liquid bromine will cause great pollution, which is not suitable for industrial production.
[0013] 3. The journal Tetrahedron Letter., 2006, 47, 7943 reported the preparation method of celecoxib
[0014]
[0015] This route is also prone to produce isomeric impurity B, and has long steps, cumbersome operations, low overall reaction yield, difficult and expensive raw materials to purchase, high process costs, and is not suitable for commercial production. In addition, the protective groups used can easily introduce genotoxic impurities such as benzenesulfonic acid fatty esters.
[0016] 4. The preparation method of the related celecoxib disclosed in patent CN102558056A, the preparation process of which is as follows:
[0017]
[0018] This method still produces the regioisomer impurity 4-[3-(4-methylphenyl)-5-(trifluoromethyl)-1-hydrogen-pyrazol-1-yl]benzenesulfonamide, namely impurity B, and the yield of 4-halobenzenesulfonamide is low.
[0019] 5. The journal Tetrahedron Letter., 2011, 52, 6000 reported a method for preparing celecoxib:
[0020]
[0021] The process uses p-iodobenzenesulfonyl chloride and dibenzylamine to prepare benzyl protected sulfonamide, which is sequentially condensed with trifluoromethylpyrazole and p-bromotoluene, and finally deprotected with concentrated sulfuric acid to obtain celecoxib. The raw materials of this route are difficult to purchase and expensive, the process cost is high, the total yield is low, and the total yield of the reaction is 30-40%, which is not suitable for commercial production.
[0022] In summary, the methods for synthesizing celecoxib in the prior art generally have the problems of long reaction routes, multiple steps, repeated purification of the production of regional isomer impurity B, and low yield and other costs that are difficult to control. In view of the wide application and large demand of celecoxib, it is urgent to develop an economical and efficient preparation method. Summary of the invention
[0023] In order to solve the problems of long route, low raw material utilization rate and large waste of production process materials in the existing synthesis method, the present invention provides a synthesis process of celecoxib, a non-steroidal anti-inflammatory drug, which has a short route, simple operation and short production cycle.
[0024] In order to achieve the above object, the technical scheme of the present invention is: a synthesis process of non-steroidal anti-inflammatory drug celecoxib, comprising the following steps:
[0025] (1) Compound 1 reacts with compound 2 to obtain compound 3, and the reaction formula is as follows:
[0026]
[0027] (2) 3 compounds are used under certain conditions to prepare celecoxib, and the reaction formula is as follows:
[0028]
[0029] In the first step of this route, compound 1 and compound 2 are used as starting materials to obtain intermediate compound 3 through condensation reaction. In the second step, compound 3 is oxidized to the corresponding ketone intermediate by the action of an oxidant, and then the amino group and the ketone carbonyl group undergo an intramolecular condensation reaction to obtain celecoxib in one pot.
[0030] In step (1), the molar ratio of compound 1 to compound 2 is 1:1-1.1, preferably 1:1-1.05, the reaction solvent is a polar protic solvent selected from methanol, ethanol, isopropanol, tert-butanol and the like, preferably ethanol and isopropanol, the reaction temperature is 50-90° C., and the reaction time is 2-7 hours.
[0031] In step (2), compound 3 is dissolved in a solvent, an oxidant is added, and after the benzyl secondary alcohol is oxidized to a keto carbonyl, a dehydration catalyst is added and the reaction is continued to obtain celecoxib.
[0032] The oxidant described in step (2) is selected from Dess-Martin oxidant, TEMPO oxidant, PDC oxidant, PCC oxidant, active MnO2, IBX, etc., preferably active MnO2, wherein the molar ratio of the 3 compound to the active MnO2 is 1:1-10, preferably 1:5-10. The dehydration catalyst is selected from p-toluenesulfonic acid, and its amount is 5-10mol%, preferably 5-8mol% of the 3 compound. The reaction solvent is selected from one or more of dichloromethane, tetrahydrofuran, toluene, acetone, acetonitrile, etc., preferably dichloromethane, tetrahydrofuran, toluene. The reaction temperature is 20°C to 100°C, and the reaction time is 2-8 hours.
[0033] The beneficial effects of the present invention are as follows: 1. The route design is simple and ingenious. By controlling the structure of the raw material 2 compound, only a single carbonyl group is retained, and a condensation reaction is selectively carried out with the raw material 1 compound, thereby fundamentally avoiding the generation of regional isomer impurity B, which is conducive to improving the final yield.
[0034] 2. In the second step, the intermediate compound 3 is subjected to oxidation and condensation in the presence of a suitable oxidant to obtain celecoxib in a one-pot reaction, which is efficient and easy to operate.
[0035] 3. The entire reaction conditions are mild, the steps are short, the yield is high, the cost is low, the atom economy is high, it conforms to the concept of green chemistry, and is suitable for industrial production. DETAILED DESCRIPTION
[0036] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.
[0037] Example 1
[0038] 3. Preparation of compounds
[0039]
[0040] 22.36g of compound 1, 23.22g of compound 2 and 250ml of ethanol were added to a 500ml reaction bottle, heated to 75°C, and reacted for 3 hours. TLC detected that the raw material was completely converted. After the reaction was completed, most of the ethanol was concentrated under reduced pressure, 500ml of dichloromethane was added to dissolve and disperse, and 200ml of water was added to extract and separate the layers. The obtained water layer was washed with 2×100ml of dichloromethane, and the organic phases were combined, dried and concentrated. The obtained solid was refined with ethyl acetate / petroleum ether to obtain 35.72g of light yellow solid, with a yield of 89% and a HPLC purity of 95.3%.
[0041] MS (m / z): 402.1 [M+H] + ; 1 H NMR (CDCl3, 400MHz): δ7.86–7.79(m,2H),7.40–7.33(m,2H),7.32–7.26(m,2H),7.21(dd,J=7.5,1.3Hz,2H),6.6 3(s,1H),4.84–4.76(m,1H),4.34(s,2H),3.26–3.18(m,2H),2.80(dd,J=12.4,7.0Hz,1H),2.21(d,J=1.5Hz,3H).
[0042] Example 2
[0043] 3. Preparation of compounds
[0044] (1) 35 g of compound 1, 38.1 g of compound 2 and 600 ml of isopropanol were added to a 1000 ml reaction bottle, heated to 85°C, and reacted for 2 hours. TLC detected that the raw material was completely converted. After the reaction was completed, most of the isopropanol was concentrated under reduced pressure, 600 ml of dichloromethane was added to dissolve and disperse, and 300 ml of water was added to extract and separate the layers. The obtained water layer was washed with 2×150 ml of dichloromethane, and the organic phases were combined, dried and concentrated. The obtained solid was refined with ethyl acetate / petroleum ether to obtain 57.78 g of light yellow solid with a yield of 92% and a HPLC purity of 93.8%.
[0045] MS (m / z): 402.1 [M+H] + ; 1 H NMR (CDCl3, 400MHz): δ7.86–7.79(m,2H),7.40–7.33(m,2H),7.32–7.26(m,2H),7.21(dd,J=7.5,1.3Hz,2H),6.6 3(s,1H),4.84–4.76(m,1H),4.34(s,2H),3.26–3.18(m,2H),2.80(dd,J=12.4,7.0Hz,1H),2.21(d,J=1.5Hz,3H).
[0046] Example 3
[0047] 3. Preparation of compounds
[0048] (1) Add 100 g of compound 1, 108.1 g of compound 2 and 1500 ml of ethanol to a 2500 ml reaction bottle, heat to reflux, and react for 3 hours. TLC detection shows that the raw material is completely converted. After the reaction is completed, most of the ethanol is concentrated under reduced pressure, 1000 ml of dichloromethane is added to dissolve and disperse, and 500 ml of water is added to extract and separate the layers. The obtained water layer is then washed with 2×200 ml of dichloromethane, and the organic phases are combined, dried and concentrated. The obtained solid is refined with ethyl acetate / petroleum ether to obtain 156.12 g of light yellow solid, with a yield of 87% and a HPLC purity of 94.6%.
[0049] MS (m / z): 402.1 [M+H] + ; 1H NMR (CDCl3, 400MHz): δ7.86–7.79(m,2H),7.40–7.33(m,2H),7.32–7.26(m,2H),7.21(dd,J=7.5,1.3Hz,2H),6.6 3(s,1H),4.84–4.76(m,1H),4.34(s,2H),3.26–3.18(m,2H),2.80(dd,J=12.4,7.0Hz,1H),2.21(d,J=1.5Hz,3H).
[0050] Example 4
[0051] Preparation of Celecoxib
[0052]
[0053] Take 20g of 3 compounds prepared in Example 1 and add them to a 500ml reaction flask, add 200ml dichloromethane to stir and dissolve clearly, weigh 21.66g active MnO2, add them to the reaction flask 5 times, add them in about 15 minutes, be heated to reflux, react for 3 hours, and TLC detects that 3 compounds are completely converted. After the reaction finishes, concentrating under reduced pressure removes dichloromethane, adds 200ml toluene and 0.8g p-toluenesulfonic acid, is heated to reflux, reacts for 3 hours, and TLC detects that the raw material is completely converted, and the reaction solution is cooled to room temperature, adds a certain amount of activated carbon, refluxes and decolorizes for 30 minutes, and is hot filtered. The filter cake is washed with 50ml toluene, and the filtrate is dried over anhydrous sodium sulfate, and is concentrated under reduced pressure. The obtained solid is refined with 75% ethanol to obtain 16.7g celecoxib, with a yield of 88%, HPLC purity of 99.75%, and no regioisomer impurity B is detected.
[0054] MS (m / z): 382.3 [M+H] + ; 1 H-NMR (CDCl3): δ7.90(d,2H), δ7.47(d,2H), δ7.18(d,2H), δ7.11(d,2H), δ6.74(s,1H), δ4.98(s,2H), δ2.38(s,3H).
[0055] Example 5
[0056] Preparation of Celecoxib
[0057] Take 30g of the 3 compounds prepared in Example 2 and add them to a 500ml reaction bottle, add 250ml acetone and stir to dissolve, weigh 38.89g active MnO2, add it to the reaction bottle in 5 times, add it in about 20 minutes, heat it to reflux, react for 2 hours, and detect that the 3 compounds are completely converted by TLC. After the reaction is completed, acetone is concentrated under reduced pressure, 300ml toluene and 1.4g p-toluenesulfonic acid are added, heated to reflux, react for 3 hours, and the raw materials are completely converted by TLC detection. The reaction solution is cooled to room temperature, a certain amount of activated carbon is added, reflux decolorization is carried out for 30 minutes, hot filtration, the filter cake is washed with 50ml toluene, the filtrate is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained solid is refined with 75% ethanol to obtain 25.62g celecoxib, with a yield of 90%, HPLC purity of 99.68%, and no regional isomer impurity B is detected.
[0058] MS (m / z): 382.3 [M+H] + ; 1 H-NMR (CDCl3): δ7.90(d,2H), δ7.47(d,2H), δ7.18(d,2H), δ7.11(d,2H), δ6.74(s,1H), δ4.98(s,2H), δ2.38(s,3H).
[0059] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any changes or substitutions that can be easily thought of by a person skilled in the art within the technical scope disclosed by the present invention should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.
Claims
1. A synthesis process for a non-steroidal anti-inflammatory drug celecoxib, characterized in that: The steps include: (1) Compound 1 reacts with compound 2 to obtain compound 3, and the reaction formula is as follows: (2) 3 compounds are used under certain conditions to prepare celecoxib, and the reaction formula is as follows: The conditions in step (2) include: dissolving the 3 compounds in a solvent, adding an oxidant, adding a dehydration catalyst after the oxidation reaction is completed, and continuing the reaction to obtain celecoxib.
2. The synthesis process according to claim 1, characterized in that In step (1), the molar ratio of compound 1 to compound 2 is 1:1-1.1, and the reaction solvent is a polar protic solvent.
3. The synthesis process according to claim 2, characterized in that: The polar protic solvent is selected from one or more of methanol, ethanol, isopropanol and tert-butanol.
4. The synthesis process according to claim 1, characterized in that The reaction temperature of step (1) is 50 to 90° C., and the reaction time is 2 to 7 hours.
5. The synthesis process according to claim 1, characterized in that: The oxidant described in step (2) is selected from one or more of Dess-Martin oxidant, TEMPO oxidant, PDC oxidant, PCC oxidant, activated MnO2, and IBX, wherein the molar ratio of the three compounds to the oxidant is 1:1-10.
6. The synthesis process according to claim 1, characterized in that: The dehydration catalyst described in step (2) is selected from p-toluenesulfonic acid, and its usage is 5-10 mol% of the 3 compounds.
7. The synthesis process according to claim 1, characterized in that: The reaction solvent described in step (2) is selected from one or more of dichloromethane, tetrahydrofuran, toluene, acetone and acetonitrile.