A preparation method of non-steroidal anti-inflammatory drug celecoxib
A novel synthesis method for celecoxib using a substitution reaction and palladium carbon catalysis addresses low yield and impurity issues, achieving high yield and suitability for industrial production while avoiding regional isomer impurity B.
Patent Information
- Application Number
- CN202310158012.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-02-23
- Publication Date
- 2024-12-13
- Estimated Expiration
- 2043-02-23
AI Technical Summary
Existing methods for synthesizing celecoxib suffer from low yield, difficult separation and purification, generation of regional isomer impurity B, cumbersome operations, and high costs, making them unsuitable for industrial production.
A method involving a substitution reaction between compounds I and II to form intermediate III, followed by removal of the benzyloxycarbonyl group and intramolecular condensation to form a 4,5-dihydropyrazole intermediate, which is then aromatized using palladium carbon to produce celecoxib in a one-pot process.
The method achieves high yield and avoids the formation of regional isomer impurity B, is suitable for industrial production, and aligns with green chemistry principles by allowing palladium carbon recycling.
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Abstract
Description
Technical Field
[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing 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] 2. Patent WO2003024400A2 discloses a method for preparing celecoxib, and the reaction process is as follows:
[0010]
[0011] 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.
[0012] 3. The journal Tetrahedron Letter., 2006, 47, 7943 reported the preparation method of celecoxib
[0013]
[0014] 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.
[0015] 4. The preparation method of celecoxib disclosed in patent CN102558056A, the preparation process of which is as follows:
[0016]
[0017] 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, and the final copper-catalyzed coupling yield is not high.
[0018] 5. The journal Tetrahedron Letter., 2011, 52, 6000 reported a method for preparing celecoxib:
[0019]
[0020] 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.
[0021] 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
[0022] 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 preparation method of celecoxib, a non-steroidal anti-inflammatory drug, which has a short route, simple operation and high atom economy.
[0023] In order to achieve the above object, the technical solution of the present invention is: a method for preparing celecoxib, a non-steroidal anti-inflammatory drug, comprising the following steps:
[0024] (1) The compound of formula I reacts with the compound of formula II to obtain the compound of formula III:
[0025]
[0026] Wherein Cbz represents benzyloxycarbonyl, and X is selected from Cl, Br, and I;
[0027] (2) The compound of formula III is used to prepare celecoxib under certain conditions:
[0028]
[0029] In the first step of the route, the compound of formula I and the compound of formula II are used as starting materials to obtain the intermediate compound of formula III through a substitution reaction.
[0030] In the second step, the compound of formula III is subjected to palladium carbon and a hydrogen donor to remove the benzyloxycarbonyl group to obtain an intermediate with an exposed amino group, and then the amino group and the ketone carbonyl group undergo an intramolecular condensation reaction to form a ring to obtain a 4,5-dihydropyrazole intermediate, and finally this intermediate is dehydrogenated and aromatized under the action of palladium carbon to obtain celecoxib. The structural formula of the 4,5-dihydropyrazole intermediate is as follows:
[0031]
[0032] In step (1), the molar ratio of the compound of formula I to the compound of formula II is 1:1-1.1, preferably 1:1-1.05, and the solvent is selected from polar aprotic solvents such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, acetone, etc., preferably N,N-dimethylformamide and dimethyl sulfoxide.
[0033] In step (1), a base is required to be added, including an inorganic base and an organic base, the molar ratio of the compound of formula I to the base is 1:1-1.2, the inorganic base is selected from sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, etc., and the inorganic base is preferably sodium carbonate and potassium carbonate. The organic base is selected from sodium tert-butyl alcoholate, potassium tert-butyl alcoholate, sodium methoxide, sodium ethoxide, triethylamine, pyridine, NaH, etc., preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide. The reaction temperature is 30-80°C, and the reaction time is 1-5 hours.
[0034] In step (1), the preferred X of compound II is chlorine or bromine, and their structures are as follows: II(a) and II(b), respectively.
[0035]
[0036] During the reaction, the compound of formula I, a base and an appropriate amount of solvent are added to a reaction container and stirred. The temperature is controlled, and then the solution of the compound of formula II is added dropwise. After the addition is completed, the temperature is kept for reaction.
[0037] Palladium carbon needs to be added in step (2), and the palladium carbon is selected from commercially available wet palladium carbon with a mass fraction of 5%-10%, without any treatment, and its amount is 5%-15% (mass fraction) of the compound of formula III. The hydrogen donor for catalytic hydrogenolysis is selected from ammonium formate, formic acid, cyclohexadiene, 1,4-cyclohexadiene, preferably ammonium formate; its molar amount is 4-6 times the molar amount of the compound of formula III, preferably 4.5-6. The reaction solvent is selected from one or more solvents such as methanol, ethanol, isopropanol, acetonitrile, toluene, xylene, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, etc. Methanol, ethanol, acetonitrile, N,N-dimethylacetamide are preferred. The reaction temperature is 50°C to 120°C, and the reaction time is 2-10 hours.
[0038] The beneficial effects of the present invention are as follows: 1. The entire route designed by the present invention is short and novel. The first step fundamentally avoids the generation of regional isomer impurity B by replacing the nitrogen atom close to the benzene ring. The reaction conditions are mild and the yield is high.
[0039] 2. The compound of formula III obtained in the second step is firstly replaced with a hydrogen donor to remove the Cbz protection under the action of palladium carbon, and then undergoes intramolecular condensation to form a ring, and finally aromatized under the action of palladium carbon to obtain celecoxib through a "one-pot method".
[0040] 3. The entire reaction process is short and has high atom economy. In addition, palladium carbon can be recycled and reused, and the yield is higher than that of existing preparation methods. It conforms to the concept of green chemistry and is suitable for industrial production. DETAILED DESCRIPTION
[0041] 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.
[0042] Example 1
[0043] Step 1, preparation of the intermediate compound of formula III:
[0044]
[0045] (1) 32.1 g of the compound of formula I, 4.79 g of sodium hydroxide and 120 ml of DMSO were added to a 500 ml reaction bottle, heated to 30° C., stirred for 30 minutes, 25.2 g of the compound of formula II (a) was weighed, dissolved in 30 ml of DMSO, slowly added dropwise to the compound of formula I, heated to 70° C., reacted for 5 hours, and TLC detected that the raw material was completely converted. After the reaction was completed, 700 ml of water and 500 ml of ethyl acetate were added to the reaction solution, extracted and separated, the obtained water layer was washed with 2×100 ml of ethyl acetate, the organic phases were combined, dried and concentrated, and 45.5 g of light brown solid was obtained, with a yield of 85% and a purity of 95.2%.
[0046] MS (m / z): 536.14 [M+H] + ; 1 H NMR(CDCl3,500MHz)δ7.55–7.50(m,2H),7.45(dd,J=7.5,1.1Hz,2H),7.37–7.27(m,5H),7.18(dd,J=7.5,1.3Hz,2H),7.09–7.03(m, 2H),5.56–5.47(m,3H),5.09(s,1H),3.95(s,2H),3.26(dd,J=12.3,7.1Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.21(d,J=1.4Hz,3H).
[0047] Example 2
[0048] Step 1, preparation of the intermediate compound of formula III:
[0049] (1) 20.5 g of the compound of formula I, 3.8 g of sodium methoxide and 120 ml of N,N-dimethylformamide were added to a 250 ml reaction bottle and stirred for 30 minutes. 16.7 g of the compound of formula II (a) was weighed, dissolved in 20 ml of DMF, and slowly added dropwise to the compound of formula I. The mixture was heated to 80° C. and reacted for 4 hours. TLC detected that the raw material was completely converted. After the reaction was completed, 600 ml of water and 400 ml of ethyl acetate were added to the reaction solution, and the layers were separated by extraction. The obtained aqueous layer was washed with 2×80 ml of ethyl acetate, and the organic phases were combined, dried and concentrated to obtain 30.7 g of light brown solid with a yield of 89.6% and a purity of 96.5%.
[0050] MS (m / z): 536.14 [M+H] + ; 1H NMR(CDCl3,500MHz)δ7.55–7.50(m,2H),7.45(dd,J=7.5,1.1Hz,2H),7.37–7.27(m,5H),7.18(dd,J=7.5,1.3Hz,2H),7.09–7.03(m, 2H),5.56–5.47(m,3H),5.09(s,1H),3.95(s,2H),3.26(dd,J=12.3,7.1Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.21(d,J=1.4Hz,3H).
[0051] Example 3
[0052] Step 1, preparation of the intermediate compound of formula III:
[0053] (1) 20.5 g of the compound of formula I, 6.76 g of sodium tert-butoxide and 120 ml of DMSO were added to a 250 ml reaction bottle and stirred for 30 minutes. 16.7 g of the compound of formula II (a) was weighed, dissolved in 20 ml of DMSO, and slowly added dropwise to the compound of formula I. The mixture was heated to 60° C. and reacted for 3 hours. TLC detected that the raw material was completely converted. After the reaction was completed, 600 ml of water and 400 ml of ethyl acetate were added to the reaction solution, and the layers were separated by extraction. The obtained aqueous layer was washed with 2×80 ml of ethyl acetate, and the organic phases were combined, dried and concentrated to obtain 30.7 g of a light brown solid with a yield of 90.6% and a purity of 94.5%.
[0054] MS (m / z): 536.14 [M+H] + ; 1 H NMR(CDCl3,500MHz)δ7.55–7.50(m,2H),7.45(dd,J=
[0055] 7.5,1.1Hz,2H),7.37–7.27(m,5H),7.18(dd,J=7.5,1.3Hz,2H),7.09–7.03(m,2H),5.56–
[0056] 5.47(m,3H),5.09(s,1H),3.95(s,2H),3.26(dd,J=12.3,7.1Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.21(d,J=1.4Hz,3H).
[0057] Example 4
[0058] Step 1, preparation of the intermediate compound of formula III:
[0059]
[0060] (1) 10 g of the compound of formula I, 11.1 g of potassium carbonate and 60 ml of DMSO were added to a 100 ml reaction bottle, stirred and dispersed, 9.64 g of the compound of formula II (b) was weighed, dissolved in 10 ml of DMSO, and slowly added dropwise to the compound of formula I, heated to 50° C., and reacted for 2 hours. TLC detected that the raw material was completely converted. After the reaction was completed, 300 ml of water and 200 ml of ethyl acetate were added to the reaction solution, and the layers were extracted and separated. The obtained water layer was washed with 2×50 ml of ethyl acetate, and the organic phases were combined, dried and concentrated to obtain 15.32 g of light yellow solid, with a yield of 92% and a purity of 96.2%.
[0061] MS (m / z): 536.14 [M+H] + ; 1 H NMR(CDCl3,500MHz)δ7.55–7.50(m,2H),7.45(dd,J=
[0062] 7.5,1.1Hz,2H),7.37–7.27(m,5H),7.18(dd,J=7.5,1.3Hz,2H),7.09–7.03(m,2H),5.56–
[0063] 5.47(m,3H),5.09(s,1H),3.95(s,2H),3.26(dd,J=12.3,7.1Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.21(d,J=1.4Hz,3H).
[0064] Example 5
[0065] Step 1, preparation of the intermediate compound of formula III:
[0066] (1) 18g of the compound of formula I, 8.9g of sodium carbonate and 200ml of acetone were added to a 500ml reaction bottle, stirred and dispersed, 17.4g of the compound of formula II(b) was weighed, dissolved in 50ml of acetone, slowly added dropwise to the compound of formula I, heated to 60°C, reacted for 4 hours, and TLC detected that the raw material was completely converted. After the reaction was completed, most of the acetone was concentrated under reduced pressure, 300ml of water and 300ml of ethyl acetate were added to the remaining reaction solution, and the layers were extracted and separated. The obtained water layer was washed with 2×80ml of ethyl acetate, and the organic phases were combined, dried and concentrated to obtain 26.1g of light yellow solid, with a yield of 87% and a purity of 97.2%.
[0067] MS (m / z): 536.14 [M+H] + ; 1H NMR (CDCl3, 500MHz) δ7.55–7.50 (m, 2H), 7.45 (dd, J=
[0068] 7.5,1.1Hz,2H),7.37–7.27(m,5H),7.18(dd,J=7.5,1.3Hz,2H),7.09–7.03(m,2H),5.56–
[0069] 5.47(m,3H),5.09(s,1H),3.95(s,2H),3.26(dd,J=12.3,7.1Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.21(d,J=1.4Hz,3H).
[0070] Example 6
[0071] Step 2, preparation of celecoxib:
[0072]
[0073] (2) 10 g of the compound of formula III prepared in Example 1 and 100 ml of methanol were placed in a 250 ml reaction bottle, 5.9 g of ammonium formate and 1.05 g of palladium carbon (wet palladium carbon with a specification of 7 wt%) were added, and the reaction was carried out for 5 hours. TLC detected that the raw material was completely converted, and then the temperature was lowered to 20-30° C., the palladium carbon was filtered out, and the filtrate was concentrated to dryness. 150 ml of dichloromethane and 100 ml of water were added, and the layers were separated by extraction. The aqueous layer was washed with 2×50 ml of dichloromethane, and the organic phases were combined, dried and concentrated. The crude product was refined with 75% ethanol solution to finally obtain 6.4 g of celecoxib with a yield of 84% and a purity of 99.6%. No isomeric impurity B was detected in both the crude product and the refined product.
[0074] MS (m / z): 382.3 [M+H] + ; 1H-NMR (CDCl 3 ): δ2.38 (s, 3H), δ4.98 (s, 2H) δ6.74 (s, 1H), δ7.11 (d, 2H), δ7.18 (d, 2H), δ7.47 (d, 2H), δ7.90 (d, 2H).
[0075] Example 7
[0076] Step 2, preparation of celecoxib:
[0077] (2) 20 g of the compound of formula III prepared in Example 2 and 200 ml of ethanol were placed in a 500 ml reaction bottle, 11.8 g of ammonium formate and 2.1 g of palladium carbon (wet palladium carbon with a specification of 7 wt%) were added, and the mixture was heated to reflux and reacted for 3 hours. TLC detected that the raw material was completely converted, and then the temperature was lowered to 20-30° C., the palladium carbon was filtered out, and the filtrate was concentrated to dryness. 300 ml of dichloromethane and 200 ml of water were added, and the layers were extracted and separated. The aqueous layer was washed with 2×100 ml of dichloromethane, and the organic phases were combined, dried and concentrated. The crude product was refined with 75% ethanol solution to finally obtain 12.3 g of celecoxib, with a yield of 87% and a purity of 99.7%. No isomeric impurity B was detected in both the crude product and the refined product.
[0078] MS (m / z): 382.3 [M+H] + ; 1H-NMR (CDCl 3 ): δ2.38 (s, 3H), δ4.98 (s, 2H) δ6.74 (s, 1H), δ7.11 (d, 2H), δ7.18 (d, 2H), δ7.47 (d, 2H), δ7.90 (d, 2H).
[0079] Example 8
[0080] Step 2, preparation of celecoxib:
[0081] (2) 20 g of the compound of formula III prepared in Example 1 and 200 ml of methanol were placed in a 500 ml reaction bottle, 2.5 g of palladium carbon (wet palladium carbon with a specification of 10 wt%) and 11.8 g of ammonium formate were added, heated to reflux, and reacted for 2 hours. TLC detected that the raw material was completely converted, then the temperature was lowered to 20-30° C., the palladium carbon was filtered out, and the filtrate was concentrated to dryness. 300 ml of dichloromethane and 200 ml of water were added, and the aqueous layer was washed with 2×100 ml of dichloromethane. The organic phases were combined, dried and concentrated, and the crude product was refined with 75% ethanol solution to finally obtain 12.8 g of celecoxib, with a yield of 90% and a purity of 99.58%. No isomeric impurity B was detected in both the crude product and the refined product.
[0082] MS (m / z): 382.3 [M+H] + ; 1H-NMR (CDCl 3 ): δ2.38 (s, 3H), δ4.98 (s, 2H) δ6.74 (s, 1H), δ7.11 (d, 2H), δ7.18 (d, 2H), δ7.47 (d, 2H), δ7.90 (d, 2H).
[0083] Example 9
[0084] Step 2, preparation of celecoxib:
[0085] (2) 5 g of the compound of formula III prepared in Example 3 and 50 ml of N,N-dimethylacetamide were placed in a 100 ml reaction bottle, 0.5 g of palladium carbon (wet palladium carbon with a specification of 5 wt%) and 3 g of ammonium formate were added, heated to 100° C., reacted for 6 hours, and TLC detected that the raw material was completely converted. The temperature was then lowered to 20-30° C., the palladium carbon was filtered off, and 200 ml of dichloromethane and 300 ml of water were added to the reaction solution. The aqueous layer was then washed with 2×50 ml of dichloromethane, the organic phases were combined, dried and concentrated, and the crude product was refined with 75% ethanol solution to finally obtain 3.1 g of celecoxib, with a yield of 80% and a purity of 99.78%. No isomeric impurity B was detected in both the crude product and the refined product.
[0086] MS (m / z): 382.3 [M+H] + ; 1H-NMR (CDCl 3 ): δ2.38 (s, 3H), δ4.98 (s, 2H) δ6.74 (s, 1H), δ7.11 (d, 2H), δ7.18 (d, 2H), δ7.47 (d, 2H), δ7.90 (d, 2H).
[0087] 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 method for preparing a non-steroidal anti-inflammatory drug celecoxib, characterized in that: The steps include: (1) The compound of formula I reacts with the compound of formula II to obtain the compound of formula III: Wherein Cbz represents benzyloxycarbonyl, and X is selected from Cl, Br, and I; (2) The compound of formula III is used to prepare celecoxib under certain conditions: In step (2), palladium carbon, a hydrogen donor for catalytic hydrogenolysis, and a reaction solvent need to be added. The hydrogen donor is selected from ammonium formate, formic acid, and cyclohexadiene, and its molar amount is 4-6 times the molar amount of the compound of formula III.
2. The preparation method according to claim 1, characterized in that: In step (1), the molar ratio of the compound of formula I to the compound of formula II is 1:1-1.1, and the reaction solvent is a polar aprotic solvent.
3. The preparation method according to claim 2, characterized in that: The solvent in step (1) is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and acetone.
4. The preparation method according to claim 1, characterized in that: In step (1), a base needs to be added, and the base is an inorganic base or an organic base, and the molar ratio of the compound of formula I to the base is 1:1-1.
2.
5. The preparation method according to claim 4, characterized in that: The inorganic base is selected from one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and sodium bicarbonate.
6. The preparation method according to claim 4, characterized in that: The organic base is selected from one or more of sodium tert-butyl alcoholate, potassium tert-butyl alcoholate, sodium methoxide, sodium ethoxide, triethylamine, pyridine and NaH.
7. The preparation method according to claim 1, characterized in that: The reaction temperature of step (1) is 30-80° C., and the reaction time is 1-5 hours.
8. The preparation method according to claim 1, characterized in that: The palladium carbon is selected from wet palladium carbon with a mass fraction of 5%-10%, and its usage is 5%-10% of the mass of the compound of formula III.
9. The preparation method according to claim 1, characterized in that: The reaction solvent described in step (2) is one or more solvents selected from methanol, ethanol, isopropanol, acetonitrile, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, and tetrahydrofuran.
10. The preparation method according to claim 1, characterized in that: The reaction temperature of step (2) is 50°C to 120°C, and the reaction time is 2 to 10 hours.