A kind of synthesis process of celecoxib

Abstract

The present invention relates to the field of drug synthesis, and in particular to a synthesis process of celecoxib, comprising the following steps: the route uses A compound p-methylacetophenone, B compound 4-sulfonamidophenylhydrazine hydrochloride and C compound trifluoroacetaldehyde as starting materials, and obtains intermediate D compound through Mannich reaction under certain conditions. Under certain conditions, D compound undergoes intramolecular condensation reaction to obtain 2,3-dihydropyrazole intermediate products, and the 2,3-dihydropyrazole intermediate products are aromatized under the action of MnO2 or DDQ, and the target product celecoxib is obtained by "one pot method". A synthesis process of celecoxib provided by the present invention, the whole route is short and novel, the raw materials are cheap and easy to obtain, the reaction conditions are mild, economical and effective, and the yield is higher than the existing preparation method, and it is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a synthesis process of celecoxib. 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 synthesis process of celecoxib with short route, simple operation and low cost.

[0023] In order to achieve the above object, the technical solution of the present invention is: a synthesis process of celecoxib, comprising the following steps:

[0024] (1) Compound A, compound B and compound C react to obtain compound D, and the reaction formula is as follows:

[0025]

[0026] A is p-methylacetophenone, B is 4-sulfonamidophenylhydrazine hydrochloride, and C is trifluoroacetaldehyde;

[0027] (2) Compound D is used to prepare celecoxib under certain reaction conditions:

[0028]

[0029] This route uses compound A, compound B and compound C as starting materials, and obtains intermediate compound D through Mannich reaction under certain conditions. Under certain conditions, compound D undergoes intramolecular condensation reaction to obtain 2,3-dihydropyrazole intermediate product. The 2,3-dihydropyrazole intermediate product is oxidized to MnO 2 Or aromatization under the action of DDQ, the target product celecoxib was prepared by the "one-pot method".

[0030] The molar ratio of the three raw materials A, B and C in step (1) is A:B:C=1:1:1.05-1.2, preferably 1:1:1.05-1.1; the protic solvent is selected from one or more of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol and isopropanol; if the solvent is a polar aprotic solvent, it can be one or more of DMSO, DMF and acetonitrile, preferably DMSO.

[0031] In step (1), an acidic catalyst needs to be added, and its molar amount is 5%-15% of the molar amount of compound A. A protonic acid or a Lewis acid can be selected. The protonic acid is selected from concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphotungstic acid, aminosulfonic acid, p-toluenesulfonic acid, etc., preferably concentrated hydrochloric acid; the Lewis acid is selected from ytterbium trichloride (YbCl 3 ), Ytterbium trifluoromethanesulfonate (OTf) 3 , copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, etc., preferably ytterbium trichloride (YbCl 3 ), copper trifluoromethanesulfonate.

[0032] During the reaction, the compound B, 4-sulfonamidophenylhydrazine hydrochloride, and the compound C, trifluoroacetaldehyde are first reacted to obtain the corresponding condensation product, hydrazone. After the two react completely, the compound A, p-methylacetophenone, is added to finally react to obtain the compound D. Since trifluoroacetaldehyde is unstable, stable trifluoroacetaldehyde hydrate or trifluoroacetaldehyde hemiethanol acetal are commercially available, and we use trifluoroacetaldehyde hydrate (75% aqueous solution).

[0033] The reaction time of step (1) is 3-10 hours, and the reaction temperature is 20-80°C.

[0034] The reaction solvent in step (2) is an aromatic hydrocarbon solvent such as toluene and xylene, preferably toluene. A condensation catalyst is added during the reaction, selected from p-toluenesulfonic acid, concentrated sulfuric acid, etc., preferably p-toluenesulfonic acid, and its molar amount is 5%-15% of the molar amount of the compound of formula D, preferably 8%-10%.

[0035] In step (2), a certain oxidant is added as an aromatizing agent, selected from MnO 2 , DDQ, etc., wherein the molar ratio of the compound of formula D to the aromatizing agent is: 1:1-4, preferably 1:1.5-4.

[0036] The reaction temperature of step (2) is 60°C to 120°C, and the reaction time is 5 to 10 hours.

[0037] In the reaction process of step (2), compound D undergoes an intramolecular condensation reaction under certain conditions to obtain a 2,3-dihydropyrazole intermediate product, which is then aromatized to obtain the target product celecoxib in a one-pot process. The structural formula of the 2,3-dihydropyrazole intermediate is as follows:

[0038]

[0039] The beneficial effects of the present invention are as follows: 1. Using p-methylacetophenone, 4-sulfonamidophenylhydrazine hydrochloride and trifluoroacetaldehyde as raw materials, a β-aminoketone compound is obtained through a classic Mannich reaction, and then the compound is first condensed into a ring through an intramolecular condensation to obtain a 2,3-dihydropyrazole intermediate, and celecoxib is obtained under the action of an aromatization agent. The route design is ingenious, and the generation of regional isomer impurity B is fundamentally avoided through the first step of the Mannich reaction, which is very beneficial to the improvement of the yield of the final product.

[0040] 2. In step 2, celecoxib is prepared by a one-pot method using condensation and aromatization, which has high atom economy, simplifies operation and saves costs.

[0041] 3. The entire reaction route is short, easy to operate, high in yield, low in cost, in line with the concept of green chemistry, and suitable for industrial production. DETAILED DESCRIPTION

[0042] 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.

[0043] Example 1

[0044] Step 1, preparation of intermediate D compound:

[0045]

[0046] (1) 22.3 g of 4-sulfonylaminophenylhydrazine hydrochloride, 13.4 g of 75% trifluoroacetaldehyde aqueous solution and 200 ml of ethanol were added to a 500 ml reaction bottle, 0.4 ml of concentrated hydrochloric acid was added dropwise, and the mixture was heated under reflux for 2 hours until 4-sulfonylaminophenylhydrazine hydrochloride was completely converted. The temperature was then slowly lowered to 30-40° C., 13.4 g of p-methylacetophenone in 30 ml of ethanol was added dropwise, and the addition was completed in about 10 minutes. The mixture was heated under reflux for 3 hours, and the reaction was monitored by TLC. After the reaction was completed, most of the ethanol was concentrated under reduced pressure, 300 ml of dichloromethane and 200 ml of water were added, and the layers were separated by extraction. The aqueous layer was washed with 2×100 ml of dichloromethane, and the organic phases were combined, dried and concentrated to obtain a crude product, which was purified with n-hexane / ethyl acetate to obtain 34 g of a light yellow solid with a yield of 85% and a purity of 95.6%.

[0047] MS (m / z): 402.21 [M+H]+; 1 H-NMR (CDCl 3 ,500MHz)δ7.85–7.78(m,2H)7.71–7.64(m,2H),7.23–7.17(m,2H),7.09–7.03(m,2H),4.77(s,1H),4.36( s,2H),4.17(m,1H),3.06(dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.70(s,1H),2.30(s,3H).

[0048] Example 2

[0049] (1) 35 g of 4-sulfonamidophenylhydrazine hydrochloride, 21.48 g of 75% trifluoroacetaldehyde aqueous solution and 300 ml of isopropanol were added to a 500 ml reaction bottle, 0.89 g of trifluoroacetic acid was added dropwise, heated to 80° C. and reacted for 2 hours until 4-sulfonamidophenylhydrazine hydrochloride was completely converted, then the temperature was slowly lowered to 30-40° C., 21.03 g of p-methylacetophenone in 30 ml of isopropanol solution was added dropwise, and the addition was completed in about 12 minutes. The reaction was continued to be heated to 80° C. and reacted for 2 hours. The reaction was monitored by TLC. After the reaction was completed, most of the isopropanol was concentrated under reduced pressure, 400 ml of dichloromethane and 300 ml of water were added, and the layers were extracted and separated. The obtained aqueous layer was washed with 2×100 ml of dichloromethane, and the organic phases were combined, dried and concentrated to obtain a crude product, which was purified with n-hexane / ethyl acetate to obtain 54.2 g of a light yellow solid with a yield of 86% and a purity of 94.6%.

[0050] MS (m / z): 402.21 [M+H]+; 1 H-NMR (CDCl 3,500MHz)δ7.85–7.78(m,2H)7.71–7.64(m,2H),7.23–7.17(m,2H),7.09–7.03(m,2H),4.77(s,1H),4.36( s,2H),4.17(m,1H),3.06(dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.70(s,1H),2.30(s,3H).

[0051] Example 3

[0052] (1) 10 g of 4-sulfonamidophenylhydrazine hydrochloride, 6.14 g of 75% trifluoroacetaldehyde aqueous solution and 80 ml of DMSO were added to a 250 ml reaction bottle, 0.62 g of ytterbium trichloride was added dropwise, heated to 50° C. and reacted for 1 hour until 4-sulfonamidophenylhydrazine hydrochloride was completely converted, 6 g of p-methylacetophenone was added to the reaction bottle, and the reaction was continued at 50° C. for 2 hours. The reaction was monitored by TLC. After the reaction was completed, 400 ml of water and 200 ml of ethyl acetate were added to the reaction system, and the layers were extracted and separated. The obtained aqueous layer was washed with 2×100 ml of ethyl acetate, and the organic phases were combined, dried and concentrated to obtain a crude product, which was purified with n-hexane / ethyl acetate to obtain 16.2 g of a light yellow solid with a yield of 90% and a purity of 95.7%.

[0053] MS (m / z): 402.21 [M+H]+; 1 H-NMR (CDCl 3 ,500MHz)δ7.85–7.78(m,2H)7.71–7.64(m,2H),7.23–7.17(m,2H),7.09–7.03(m,2H),4.77(s,1H),4.36( s,2H),4.17(m,1H),3.06(dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.70(s,1H),2.30(s,3H).

[0054] Example 4

[0055] (1) 20 g of 4-sulfonamidophenylhydrazine hydrochloride, 12.28 g of 75% trifluoroacetaldehyde aqueous solution and 150 ml of DMSO were added to a 250 ml reaction flask, 0.37 ml of concentrated hydrochloric acid was added dropwise, heated to 50° C. and reacted for 2 hours until 4-sulfonamidophenylhydrazine hydrochloride was completely converted, 12 g of p-methylacetophenone was added to the reaction flask, and the reaction was continued at 50° C. for 3 hours. The reaction was monitored by TLC. After the reaction was completed, 600 ml of water and 400 ml of ethyl acetate were added to the reaction system, and the layers were extracted and separated. The obtained aqueous layer was washed with 2×200 ml of ethyl acetate, and the organic phases were combined, dried and concentrated to obtain a crude product, which was purified with n-hexane / ethyl acetate to obtain 30.2 g of a light yellow solid with a yield of 84% and a purity of 96.6%.

[0056] MS (m / z): 402.21 [M+H]+; 1 H-NMR (CDCl 3 ,500MHz)δ7.85–7.78(m,2H)7.71–7.64(m,2H),7.23–7.17(m,2H),7.09–7.03(m,2H),4.77(s,1H),4.36( s,2H),4.17(m,1H),3.06(dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.70(s,1H),2.30(s,3H).

[0057] Example 5

[0058] (1) 22.3 g of 4-sulfonamidophenylhydrazine hydrochloride, 13.4 g of 75% trifluoroacetaldehyde aqueous solution and 200 ml of ethanol were added to a 500 ml reaction bottle, 1.8 g of copper trifluoromethanesulfonate was added dropwise, and the mixture was heated under reflux for 3 hours until 4-sulfonamidophenylhydrazine hydrochloride was completely converted. The temperature was then slowly lowered to 30-40° C., 13.4 g of p-methylacetophenone in 30 ml of ethanol was added dropwise, and the addition was completed in about 10 minutes. The mixture was heated under reflux for 4 hours, and the reaction was monitored by TLC. After the reaction was completed, most of the ethanol was concentrated under reduced pressure, 300 ml of dichloromethane and 200 ml of water were added, and the layers were separated by extraction. The aqueous layer was washed with 2×100 ml of dichloromethane, and the organic phases were combined, dried and concentrated to obtain a crude product, which was purified with n-hexane / ethyl acetate to obtain 31.2 g of a light yellow solid with a yield of 78% and a purity of 95.2%.

[0059] MS (m / z): 402.21 [M+H]+; 1 H-NMR (CDCl 3,500MHz)δ7.85–7.78(m,2H)7.71–7.64(m,2H),7.23–7.17(m,2H),7.09–7.03(m,2H),4.77(s,1H),4.36( s,2H),4.17(m,1H),3.06(dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.70(s,1H),2.30(s,3H).

[0060] Example 6

[0061] (1) 10 g of 4-sulfonamidophenylhydrazine hydrochloride, 6.14 g of 75% trifluoroacetaldehyde aqueous solution and 80 ml of DMSO were added to a 250 ml reaction flask, 0.8 g of copper trifluoromethanesulfonate was added dropwise, heated to 50° C. and reacted for 2 hours until 4-sulfonamidophenylhydrazine hydrochloride was completely converted, 6 g of p-methylacetophenone was added to the reaction flask, and the reaction was continued at 50° C. for 2 hours. The reaction was monitored by TLC. After the reaction was completed, 400 ml of water and 200 ml of ethyl acetate were added to the reaction system, and the layers were extracted and separated. The obtained aqueous layer was washed with 2×100 ml of ethyl acetate, and the organic phases were combined, dried and concentrated to obtain a crude product, which was purified with n-hexane / ethyl acetate to obtain 14.3 g of a light yellow solid with a yield of 80% and a purity of 95.6%.

[0062] MS (m / z): 402.21 [M+H]+; 1 H-NMR (CDCl 3 ,500MHz)δ7.85–7.78(m,2H)7.71–7.64(m,2H),7.23–7.17(m,2H),7.09–7.03(m,2H),4.77(s,1H),4.36( s,2H),4.17(m,1H),3.06(dd,J=12.4,6.9Hz,1H),2.91(dd,J=12.4,7.0Hz,1H),2.70(s,1H),2.30(s,3H).

[0063] Example 7

[0064] Step 2, preparing celecoxib from compound D:

[0065]

[0066] (2) 20 g of the compound D prepared in Example 1 and 200 ml of toluene were placed in a 500 ml reaction bottle, 0.85 g of p-toluenesulfonic acid was added, and the mixture was heated to 100° C. for reaction for 3 hours. TLC detected that the raw material was completely converted, and then the temperature was lowered to 20-30° C., 12.9 g of manganese dioxide was added, and the mixture was heated to 70° C. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, 200 ml of water was added to the filtrate, and the layers were separated by extraction. The aqueous layer was washed with 2×100 ml of ethyl acetate, and the organic phases were combined, dried and concentrated. The crude product was heated and dissolved with 75% ethanol solution, decolorized with activated carbon reflux, filtered hot, cooled and crystallized, filtered with suction, and dried to obtain 17.7 g of celecoxib with a yield of 88% and a purity of 99.7%. No isomeric impurity B was detected in both the crude product and the refined product.

[0067] MS (m / z): 382.3 [M+H] + ; 1 H-NMR (CDCl 3 ): 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).

[0068] Example 8

[0069] (2) 15 g of the compound D prepared in Example 2 and 150 ml of toluene were placed in a 500 ml reaction flask, and 0.64 g of p-toluenesulfonic acid was added, heated to 100° C., and reacted for 3 hours. TLC detected that the raw material was completely converted, and then the temperature was lowered to 20-30° C., 10.17 g of DDQ was added to the reaction flask, and heated to 80° C. After the reaction was completed, 100 ml of water was added to the reaction solution, and the layers were extracted and separated. The obtained aqueous layer was then washed with 2×50 ml of ethyl acetate, and the organic phases were combined, dried and concentrated. The obtained crude product was refined with 75% ethanol solution to finally obtain 8.45 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.

[0070] MS (m / z): 382.3 [M+H] + ; 1 H-NMR (CDCl 3 ): 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).

[0071] 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 celecoxib, characterized in that, The steps include: (1) Compound A, compound B and compound C react to obtain compound D, and the reaction formula is as follows: A is p-methylacetophenone, B is 4-sulfonamidophenylhydrazine hydrochloride, and C is trifluoroacetaldehyde; (2) Compound D is used to prepare celecoxib under certain reaction conditions: In step (2), a condensation catalyst is added, and its molar amount is 5%-15% of the molar amount of the D compound. In step (2), an oxidant is added as an aromatizing agent, wherein the molar ratio of the D compound to the aromatizing agent is 1:1-4.

2. The synthesis process according to claim 1, characterized in that In step (1), the molar ratio of the three raw materials A, B and C is A:B:C=1:1:1.05-1.2, and the reaction solvent is a protic solvent or a polar aprotic solvent.

3. The synthesis process according to claim 2, characterized in that: The protic solvent described in step (1) is selected from one or more of methanol, ethanol, isopropanol and tert-butanol.

4. The synthesis process according to claim 2, characterized in that: The polar aprotic solvent described in step (1) is selected from one or more of DMSO, DMF and acetonitrile.

5. The synthesis process according to claim 1, characterized in that: An acidic catalyst needs to be added in step (1).

6. The synthesis process according to claim 5, characterized in that: The acidic catalyst added in step (1) is a protonic acid or a Lewis acid, and its molar amount is 5%-15% of the molar amount of the A compound.

7. The synthesis process according to claim 6, characterized in that: The protonic acid added in step (1) is selected from one or more of concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphotungstic acid, aminosulfonic acid, and p-toluenesulfonic acid.

8. The synthesis process according to claim 6, characterized in that: The Lewis acid added in step (1) is selected from one or more of ytterbium trichloride (YbCl3), ytterbium trifluoromethanesulfonate Yb(OTf)3, copper trifluoromethanesulfonate, and zinc trifluoromethanesulfonate.

9. The synthesis process according to claim 1, characterized in that: The reaction time of step (1) is 3-10 hours, and the reaction temperature is 20-80°C.

10. The synthesis process according to claim 1, characterized in that: The reaction solvent in step (2) is an aromatic hydrocarbon solvent.

11. The synthesis process according to claim 10, characterized in that: The aromatic hydrocarbon solvent described in step (2) is one or both of toluene and xylene.

12. The synthesis process according to claim 1, characterized in that: The condensation catalyst described in step (2) is selected from one or both of p-toluenesulfonic acid and concentrated sulfuric acid.

13. The synthesis process according to claim 1, characterized in that: Features: The oxidant described in step (2) is selected from one or two of MnO2 and DDQ.

14. The synthesis process according to claim 1, characterized in that: Features: The reaction temperature of step (2) is 60°C to 120°C, and the reaction time is 5 to 10 hours.

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