CN114195714A - Simple synthesis method of celecoxib - Google Patents
Simple synthesis method of celecoxib Download PDFInfo
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- CN114195714A CN114195714A CN202210041109.4A CN202210041109A CN114195714A CN 114195714 A CN114195714 A CN 114195714A CN 202210041109 A CN202210041109 A CN 202210041109A CN 114195714 A CN114195714 A CN 114195714A
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- celecoxib
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- trifluoroacetoacetate
- toluene
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- 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 35
- 229960000590 celecoxib Drugs 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title claims abstract description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 21
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 11
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- LIQBKSIZAXKCPA-UHFFFAOYSA-N 4,4,4-trifluoro-3-oxobutanoic acid Chemical compound OC(=O)CC(=O)C(F)(F)F LIQBKSIZAXKCPA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 4
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 19
- OCJKUQIPRNZDTK-UHFFFAOYSA-N ethyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)C(F)(F)F OCJKUQIPRNZDTK-UHFFFAOYSA-N 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- STYQHICBPYRHQK-UHFFFAOYSA-N 4-bromobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Br)C=C1 STYQHICBPYRHQK-UHFFFAOYSA-N 0.000 claims description 8
- 239000012535 impurity Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- LKMUBWWZTSZGGV-UHFFFAOYSA-N methyl 4,4,4-trifluoro-3-oxobutanoate Chemical compound COC(=O)CC(=O)C(F)(F)F LKMUBWWZTSZGGV-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- HHHDJHHNEURCNV-UHFFFAOYSA-N 4-chlorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(Cl)C=C1 HHHDJHHNEURCNV-UHFFFAOYSA-N 0.000 claims description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 2
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 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 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000006193 diazotization reaction Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000012824 chemical production Methods 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 4
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- AMIDUPFSOUCLQB-UHFFFAOYSA-N Lucidin Chemical compound C1=CC=C2C(=O)C3=C(O)C(CO)=C(O)C=C3C(=O)C2=C1 AMIDUPFSOUCLQB-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000003889 chemical engineering Methods 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- -1 hydrazine benzenesulfonamide hydrochloride Chemical compound 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- FHCVXRUNACSMBR-UHFFFAOYSA-N (4,4,4-trifluoro-3-oxobutanoyl) 4,4,4-trifluoro-3-oxobutanoate Chemical compound FC(F)(F)C(=O)CC(=O)OC(=O)CC(=O)C(F)(F)F FHCVXRUNACSMBR-UHFFFAOYSA-N 0.000 description 1
- VNQMMBHDIDLJEZ-UHFFFAOYSA-N 2-hydrazinylbenzenesulfonamide;hydrochloride Chemical compound Cl.NNC1=CC=CC=C1S(N)(=O)=O VNQMMBHDIDLJEZ-UHFFFAOYSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- QFVKOJSHXTWDPB-UHFFFAOYSA-N Linderoflavone A Natural products C1=C2OCOC2=CC(C=2OC3=C(OC)C(O)=C(C(=C3C(=O)C=2)O)OC)=C1 QFVKOJSHXTWDPB-UHFFFAOYSA-N 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000006254 arylation reaction Methods 0.000 description 1
- MLWPJXZKQOPTKZ-UHFFFAOYSA-N benzenesulfonyl benzenesulfonate Chemical compound C=1C=CC=CC=1S(=O)(=O)OS(=O)(=O)C1=CC=CC=C1 MLWPJXZKQOPTKZ-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
Abstract
The invention discloses a simple synthesis method of celecoxib. The method uses trifluoroacetoacetate and toluene as initial raw materials, firstly, a compound I is synthesized through a Friedel-crafts reaction under the catalysis of aluminum trichloride, and the compound I reacts with p-halobenzenesulfonamide under the existence of hydrazine hydrate under the alkaline condition to obtain celecoxib. The method avoids the preparation of the p-hydrazino benzene sulfonamide hydrochloride in the traditional method and the diazotization reaction step in the production process of the p-hydrazino benzene sulfonamide hydrochloride, thereby reducing the risk of industrial production. The method has the advantages of short synthesis steps, one-pot method, simple and easily-obtained raw materials, mild reaction conditions and suitability for chemical production amplification.
Description
Technical Field
The invention relates to a simple synthesis method of celecoxib, and belongs to the technical field of medicines.
Background
Celecoxib (celecoxib) is the first specific cyclooxygenase-2 (COX-2) inhibitor developed by siell, usa, for the treatment of osteoarthritis and rheumatoid arthritis. Celecoxib, chinese name: 4- [5- (4-methylphenyl) -3- (trifluoromethyl) pentixin-1-yl]Benzenesulfonamide, molecular formula: c17H14F3N3O2S, molecular weight: 381.38, the structural formula is as follows.
The current synthesis methods of celecoxib comprise: synthetic methods such as dehydration cyclization reaction, cycloaddition reaction, coupling reaction, Michael addition, copper-catalyzed one-pot boiling, and target-catalyzed arylation reaction (Luding Qiang, Shendong, Lingxiuquan. Synthesis research on celecoxib, a COX-2 specific inhibitor, J. chemical engineering progress, 2014,33(6), 1521-. The main synthetic routes comprise the following two types:
the first synthetic route is as follows: dehydration cyclization reaction
The dehydration cyclization reaction is the most traditional synthesis method, and the method comprises the following steps: the methyl acetophenone and ethyl trifluoroacetate are subjected to Claisen condensation under the action of sodium methoxide to obtain a B-diketone intermediate, and then the B-diketone intermediate is subjected to condensation cyclization with hydrazine benzenesulfonamide hydrochloride to obtain celecoxib (such as documents: Lumiao, Chenhuabao, Lihaquan, and the like. synthesis of celecoxib [ J ], university of Beijing chemical industry, 2005,32(6), 97-98). Since the final step of the synthetic route is a dehydrative ring closure which produces regioisomers, the product must be worked up by recrystallization, with a lower overall yield. The disadvantages of this synthetic route are: the total yield is low (less than 50 percent), and the reaction time is long.
The second synthetic route is as follows: cycloaddition method
Firstly, hydrazinylbenzenesulfonamide hydrochloride and trifluoroacetic anhydride (TFAA) are subjected to acylation reaction, then alkynyl is constructed under the conditions of benzenesulfonic anhydride, triethylamine and the like, and finally, 1, 3-cycloaddition reaction is carried out to obtain celecoxib (Lucidin, Shendong, Lingxiuquan. synthesis research on COX-2 specific inhibitor celecoxib progresses [ J ]. chemical engineering progress, 2014,33(6), 1521-cake 1525). The reaction still produces regioisomers, has low total yield (52%), high process cost, difficult purchase of raw materials and high price, and is not suitable for commercial production.
In addition, the two synthetic routes both adopt p-hydrazino benzenesulfonamide hydrochloride as an initial raw material, p-aminobenzenesulfonamide, sodium nitrite and hydrochloric acid are required to be adopted as raw materials for reaction, and a pure product of the p-hydrazino benzenesulfonamide hydrochloride is obtained through post-treatment, so that the synthesis process is relatively complicated.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a simple synthesis method of celecoxib. The method uses trifluoroacetoacetate and toluene as initial raw materials, firstly, a compound I is synthesized through a Friedel-crafts reaction under the catalysis of aluminum trichloride, and the compound I reacts with p-halobenzenesulfonamide under the existence of hydrazine hydrate under the alkaline condition to obtain celecoxib. The method avoids the preparation of the p-hydrazino benzene sulfonamide hydrochloride in the traditional method and the diazotization reaction step in the production process of the p-hydrazino benzene sulfonamide hydrochloride, thereby reducing the risk of industrial production.
The technical scheme of the invention is as follows: a simple synthesis method of celecoxib is characterized by comprising the following steps:
a) under the catalysis of Lewis acid, performing Friedel-crafts reaction on trifluoroacetoacetate and toluene to obtain a compound I;
b) under the alkaline condition, the compound I reacts with hydrazine hydrate and p-halobenzenesulfonamide to generate celecoxib.
The trifluoroacetylacetate in step a) is a Friedel-crafts acylation agent such as ethyl trifluoroacetylacetate, methyl trifluoroacetylacetate, trifluoroacetylacetic anhydride or the like, preferably ethyl trifluoroacetylacetate.
The Lewis acid in the step a) is Lewis acid such as aluminum trichloride, boron trifluoride diethyl etherate, boron trichloride, ferric trichloride and the like, and preferably aluminum trichloride.
The p-halobenzenesulfonamide in the step b) is p-bromobenzenesulfonamide or p-chlorobenzenesulfonamide, preferably p-bromobenzenesulfonamide.
The alkali in the step b) can be inorganic alkali such as sodium carbonate, potassium carbonate and the like, and organic alkali such as triethylamine, N-diisopropylethylamine and the like. Triethylamine is preferred in the present invention.
The synthetic route is as follows (taking the best raw materials as an example):
the solvent used in step a) may be a non-atomic solvent such as dichloromethane, chloroform, toluene, etc., preferably toluene, and serves as both the solvent and the reactant.
The reaction temperature in the step a) is-10 to 20 ℃, and preferably 0 to 5 ℃.
The solvent in the step b) can be conventional solvents such as methanol water, methanol, ethanol, isopropanol, toluene, xylene, etc., and 70% methanol water (70% methanol + 30% water by volume) is preferred in the present invention.
The reaction temperature in the step b) is 30-100 ℃, and the reflux temperature of methanol water is preferably 70-75 ℃.
Further, a preferred embodiment of the present invention comprises the steps of:
a) adding toluene and aluminum trichloride into a reaction container, dropwise adding ethyl trifluoroacetoacetate, reacting for 1-3 hours at 0-5 ℃, pouring the reaction solution into ice water, standing for layering, washing a toluene layer, and evaporating to dryness to be directly used for the next reaction;
b) and (b) adding the product obtained in the step a), 70% methanol water, hydrazine hydrate, p-bromobenzenesulfonamide and triethylamine into a reaction container, heating and refluxing for 10-15 hours, cooling to room temperature to separate out a product, and performing suction filtration to obtain celecoxib (wet product).
Further, the celecoxib (wet product) is refined, specifically as follows: heating and refluxing the celecoxib (wet product) and 70% methanol water until the celecoxib and the methanol water are completely dissolved, filtering mechanical impurities by suction filtration while the celecoxib and the methanol water are hot, slowly cooling and crystallizing, suction filtration, water washing and drying to obtain a pure celecoxib product with the purity of more than 99.5%.
In the step a), the molar ratio of the ethyl trifluoroacetoacetate to the aluminum trichloride is 1: 1.0-1.5, preferably 1: 1.2.
In the step b), the molar ratio of the p-bromobenzenesulfonamide to the hydrazine hydrate to the ethyl trifluoroacetoacetate is 1.0-1.2: 1.2-1.8: 1.0-1.5: 1.
The invention has the technical effects that:
1. the method avoids the preparation of the p-hydrazino benzene sulfonamide hydrochloride in the traditional method and the diazotization reaction step in the production process of the p-hydrazino benzene sulfonamide hydrochloride, thereby reducing the risk of industrial production.
2. The method has the advantages of short synthesis steps, one-pot method, simple and easily-obtained raw materials, mild reaction conditions, high product purity (more than or equal to 99.5 percent) and high yield (more than or equal to 85 percent), and is suitable for chemical production amplification.
Detailed Description
The effects of the present invention will be described below with reference to examples.
Example 1
a) Putting 1000ml of toluene into a 2000ml reaction bottle, cooling to 0-5 ℃, adding 160g of anhydrous aluminum trichloride, controlling the temperature to 0-5 ℃, dropwise adding 184g of ethyl trifluoroacetoacetate, continuing to react for 2 hours at 0-5 ℃, pouring the reaction solution into 1000g of ice water, stirring for 30 minutes, standing for layering, washing the toluene layer for 2 times with 500g of water, washing with 500g of saturated sodium bicarbonate solution for one time, and evaporating the toluene layer under reduced pressure to dryness for directly using in the next reaction (the yield is calculated by 100% in terms of ethyl trifluoroacetoacetate);
b) adding the product evaporated to dryness in the step a), 2300g of 70% methanol water, 90g of hydrazine hydrate (80%), 260g of p-bromobenzenesulfonamide and 120g of triethylamine into a 5000ml reaction bottle, heating to the reflux temperature, reacting for 12 hours, cooling to room temperature, separating out a large amount of white solid, and performing suction filtration to obtain 400g of a wet product;
c) adding 400g of the obtained wet product and 3000g of 70% methanol water into a reaction bottle, heating and refluxing until the wet product and the 70% methanol water are completely dissolved, filtering mechanical impurities by suction filtration while the wet product is hot, slowly cooling and crystallizing, suction filtration, water washing and drying to obtain 335g of a product, wherein the content of single impurities in the product is less than or equal to 0.1%, the purity is 99.7%, and the total yield in three steps is 87.7% calculated by ethyl trifluoroacetoacetate.
Example 2
a) Putting 1000ml of toluene into a 2000ml reaction bottle, cooling to 0-5 ℃, adding 162g of anhydrous aluminum trichloride, controlling the temperature to 0-5 ℃, dropwise adding 170g of methyl trifluoroacetoacetate, continuing to react for 2.5 hours at 0-5 ℃, pouring the reaction solution into 1000g of ice water, stirring for 30 minutes, standing for layering, washing the toluene layer for 2 times with 500g of water, washing with 500g of saturated sodium bicarbonate solution for one time, and evaporating the toluene layer under reduced pressure to dryness for directly using in the next reaction (the yield is calculated by 100% in terms of ethyl trifluoroacetoacetate);
b) adding the product evaporated to dryness in the step a), 2300g of 70% methanol water, 88g of hydrazine hydrate (80%), 255g of p-bromobenzenesulfonamide and 121g of triethylamine into a 5000ml reaction bottle, heating to the reflux temperature, reacting for 12 hours, cooling to room temperature, separating out a large amount of white solid, and performing suction filtration to obtain 395g of a wet product;
c) adding 395g of the obtained wet product and 3000g of 70% methanol water into a reaction bottle, heating and refluxing until the wet product and the 70% methanol water are completely dissolved, filtering mechanical impurities by suction filtration while the wet product is hot, slowly cooling and crystallizing, suction filtration, water washing and drying to obtain 329g of the product, wherein the content of single impurities in the product is less than or equal to 0.1%, and the purity of the product is 99.5%. The total yield of the three steps is 86.3 percent based on the ethyl trifluoroacetoacetate.
Example 3
a) Putting 1000ml of toluene into a 2000ml reaction bottle, cooling to 0-5 ℃, adding 158g of anhydrous aluminum trichloride, controlling the temperature to 0-5 ℃, dropwise adding 184g of ethyl trifluoroacetoacetate, continuing to react for 2 hours at 0-5 ℃, pouring the reaction solution into 1000g of ice water, stirring for 30 minutes, standing for layering, washing the toluene layer for 2 times with 500g of water, washing with 500g of saturated sodium bicarbonate solution for one time, and evaporating the toluene layer under reduced pressure to dryness for directly using in the next reaction (the yield is calculated by 100% in terms of ethyl trifluoroacetoacetate);
b) adding the evaporated product obtained in the step a), 2300g of 70% methanol water, 92g of hydrazine hydrate (80%), 200g of p-chlorobenzenesulfonamide and 118g of triethylamine into a 5000ml reaction bottle, heating to the reflux temperature, reacting for 13 hours, cooling to room temperature, separating out a large amount of white solid, and performing suction filtration to obtain 396g of a wet product;
c) adding 396g of the obtained wet product and 3000g of 70% methanol water into a reaction bottle, heating and refluxing until the wet product and the 70% methanol water are completely dissolved, filtering mechanical impurities by suction filtration while the wet product is hot, slowly cooling and crystallizing, suction filtration, water washing and drying to obtain 332g of the product, wherein the content of single impurities in the obtained product is less than or equal to 0.1%, and the purity of the obtained product is 99.7%. The total yield of the three steps is 87.0 percent based on the ethyl trifluoroacetoacetate.
Claims (10)
1. A simple synthesis method of celecoxib is characterized by comprising the following steps:
a) under the catalysis of Lewis acid, performing Friedel-crafts reaction on trifluoroacetoacetate and toluene to obtain a compound I;
b) under the alkaline condition, the compound I reacts with hydrazine hydrate and p-halobenzenesulfonamide to generate celecoxib;
the compound I is
2. The method for synthesizing celecoxib according to claim 1, wherein the trifluoroacetoacetate in step a) is any one of trifluoroacetoacetate ethyl ester, trifluoroacetoacetate methyl ester and trifluoroacetoacetate.
3. The method for easily synthesizing celecoxib in claim 1, wherein the Lewis acid in the step a) is one or more than two of aluminum trichloride, boron trifluoride diethyl etherate, boron trichloride and ferric trichloride.
4. The process of claim 1, wherein the p-halobenzenesulfonamide in step b) is p-bromobenzenesulfonamide or p-chlorobenzenesulfonamide.
5. The simple synthesis method of celecoxib according to claim 1, wherein the base in step b) is one or more of sodium carbonate, potassium carbonate, triethylamine and N, N-diisopropylethylamine.
6. The process of claim 1, wherein step a) is carried out using a solvent selected from the group consisting of dichloromethane, chloroform and toluene.
7. The process of claim 1, wherein step b) is carried out using a solvent selected from methanol water, methanol, ethanol, isopropanol, toluene, and xylene.
8. The simple synthesis method of celecoxib according to claim 1, wherein the reaction temperature in step a) is-10 to 20 ℃ and the reaction temperature in step b) is 30 to 100 ℃.
9. The simple synthesis method of celecoxib according to any one of claims 1-8, comprising the following steps:
a) adding toluene and aluminum trichloride into a reaction container, dropwise adding ethyl trifluoroacetoacetate, reacting for 1-3 hours at 0-5 ℃, pouring the reaction solution into ice water, standing for layering, washing a toluene layer, and evaporating to dryness to be directly used for the next reaction;
b) and (b) adding the product obtained in the step a), 70% methanol water, hydrazine hydrate, p-bromobenzenesulfonamide and triethylamine into a reaction container, heating and refluxing for 10-15 hours, cooling to room temperature to separate out a product, and performing suction filtration to obtain celecoxib.
10. The simple synthesis method of celecoxib according to claim 9, wherein the celecoxib obtained in step b) and 70% methanol water are heated and refluxed until being completely dissolved, filtered to remove mechanical impurities by suction filtration while hot, slowly cooled for crystallization, suction filtration, water washing and drying to obtain a pure celecoxib product.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20110001415A (en) * | 2009-06-30 | 2011-01-06 | 주식회사 대희화학 | New synthetic method of 4,4,4-trifluoro-1-(4-methylphenyl) butane-1,3-dione |
| CN102558056A (en) * | 2012-01-06 | 2012-07-11 | 湖南方盛制药股份有限公司 | Celecoxib and preparing method thereof |
| CN108558759A (en) * | 2018-04-26 | 2018-09-21 | 齐鲁天和惠世制药有限公司 | The method that one kettle way prepares celecoxib |
| CN113651710A (en) * | 2021-08-18 | 2021-11-16 | 杭州臻挚生物科技有限公司 | Preparation method of 3, 5-substituted-4-amino trifluoro acetophenone and its derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20110001415A (en) * | 2009-06-30 | 2011-01-06 | 주식회사 대희화학 | New synthetic method of 4,4,4-trifluoro-1-(4-methylphenyl) butane-1,3-dione |
| CN102558056A (en) * | 2012-01-06 | 2012-07-11 | 湖南方盛制药股份有限公司 | Celecoxib and preparing method thereof |
| CN108558759A (en) * | 2018-04-26 | 2018-09-21 | 齐鲁天和惠世制药有限公司 | The method that one kettle way prepares celecoxib |
| CN113651710A (en) * | 2021-08-18 | 2021-11-16 | 杭州臻挚生物科技有限公司 | Preparation method of 3, 5-substituted-4-amino trifluoro acetophenone and its derivative |
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