CN105085425A - Method for preparing parecoxib - Google Patents
Method for preparing parecoxib Download PDFInfo
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- CN105085425A CN105085425A CN201410221008.0A CN201410221008A CN105085425A CN 105085425 A CN105085425 A CN 105085425A CN 201410221008 A CN201410221008 A CN 201410221008A CN 105085425 A CN105085425 A CN 105085425A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
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Abstract
The invention discloses a method for preparing parecoxib. The method comprises the following steps: an initial raw material 3-oxo-2-phenylbutanoyl chloride and benzene undergo a Friedel-Crafts reaction to generate 1,2-diphenylbutane-1,3-dione, 1,2-diphenylbutane-1,3-dione is sulfonated by chlorosulfonic acid or concentrated sulfuric acid/acetyl chloride to obtain 4-(1,3-dioxo-1-phenylbutyl-2-yl)-1-sulfonyl chloride, 4-(1,3-dioxo-1-phenylbutyl-2-yl)-1-sulfonyl chloride is acted by ammonia water to generate 4-(1,3-dioxo-1-phenylbutyl-2-yl)-1-sulfonamide, and 4-(1,3-dioxo-1-phenylbutyl-2-yl)-1-sulfonamide reacts with propionic anhydride or propionyl chloride to obtain N-(4-(1,3-dioxo-1-phenylbutyl-2-yl)phenylsulfonyl)propionamide, N-(4-(1,3-dioxo-1-phenylbutyl-2-yl)phenylsulfonyl)propionamide undergoes condensation by using hydroxylamine hydrochloride to synthesize a ring, and dehydration is carried out under an acidic condition to obtain parecoxib. The parecoxib is prepared from 3-oxo-2-phenylbutanoyl chloride as the initial raw material through the Friedel-Crafts reaction, a sulfonation reaction, an amidation reaction and a condensation reaction. The method has the advantages of low cost of the initial raw material, simple process, low requirements of reaction conditions, simple post-treatment operation, high product yield and purity, and realization of large-scale production.
Description
Technical field
The invention belongs to field of medicine preparing technology, be specifically related to a kind of method preparing Parecoxib.
Background technology
In recent years, NSAID (non-steroidal anti-inflammatory drug) shows multiple medical active, and especially as COX-2 (COX-2) selective depressant aspect, Parecoxib is then representative wherein.
Parecoxib, uses its sodium-salt form Parecoxib Sodium, English name: ParecoxibSodium clinically, chemical name: N-[[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] alkylsulfonyl] propionamide sodium salt.Molecular formula: C
19h
17n
2o
4sNa.Indication: for the short of postoperative pain.Parecoxib Sodium is highly selective inhibitor, clinical studies show, can reduce patient to the requirement of narcotic and untoward reaction in the short of pain after surgery.There are some researches show that Parecoxib Sodium has the effect of preemptive analgesia.Current data prompting Parecoxib receives the important component part becoming Multimodal analgesia and preemptive analgesia.
Parecoxib is water-soluble prodrug, can fully be converted into rapidly valdecoxib (valdecoxib) in vivo.Parecoxib is as the important composition of Multimodal analgesia, and other analgesic combined utilization, for the treatment of postoperative moderate and severe pain, post-operative pain scoring can be reduced, reduce the consumption of the narcotic analgesic medicines such as morphine, reduce the side effect that opioid drug is relevant, improve patient's satisfactory rate.Due to the controllability of former times dry goods safety issue, the celecoxib global marketing volume of Pfizer in 2009 23.8 hundred million dollars, keeps the brand position of global antirheumatic recipe quantity first.
At present, the synthetic route reported mainly contains:
Method one:
The main drawback of this route is: the enamine intermediates turnover ratio that the first step generates is not high, and routine preservation is unstable, needs to carry out purifying by the mode of underpressure distillation, higher to the equipment requirements of suitability for industrialized production; Second step acetylization reaction, needs to use 2,6-lutidine costly to do acid binding agent, improves the production cost of whole piece operational path.
Method two:
The main drawback of this route is: centre employs active very high butyllithium reagent, and the security requirement when use is amplified in industrialization of this reagent is very high, easily causes safety hazards.In CN103172583 patent; in same step; lithium diisopropylamine is used to replace butyllithium; although security obtains raising to a certain degree; but the use of lithium diisopropylamine needs the condition at-78 DEG C; this brings the high difficulty of equipment requirements to industrial amplification production again; when final step simultaneously generates Parecoxib by propionic anhydride acidylate; use the method for tetrahydrofuran solvent and the catalysis of 4-picolilamine; easily produce impurity in this method reaction process, refine purification to Parecoxib below and bring difficulty.
Method three:
The main drawback of this route is: second step acetylization reaction; the transformation efficiency that use pyridine does base catalysis raw material reaction is lower; the material obtained after reaction treatment is mixed with a large amount of responseless raw material; need to carry out separated product by the method for column chromatography; when industry's enlarging production, add at the purification difficulty of this step reaction intermediate and production cost.When the 3rd step and oxammonium hydrochloride reaction, be easily mixed with the by product removing ethanoyl and generate, also purifying to the intermediate of this step adds difficulty and cost.
Therefore, develop a kind of Parecoxib preparation method that can solve the problems of the technologies described above to be very important.
Summary of the invention
The object of the present invention is to provide a kind of method preparing Parecoxib.
The object of the present invention is achieved like this, comprises the following steps:
The preparation of A, 1,2-diphenyl butane-1,3-diketone:
Add in raw material 3-oxo-2-phenylbutyryl chloride in the organic solvent of solid-liquid volume ratio 1:10 ~ 1:5, add lewis acid catalyst and at 40 ~ 120 DEG C, react 6 ~ 12h obtain 1,2-diphenyl butane-1,3 diketone;
B, 4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-SULPHURYL CHLORIDE:
Method one, steps A is prepared 1,2-diphenyl butane-1,3 diketone join in the sulfonated reagent of weightmeasurement ratio 1:2 ~ 1:5 at-5 ~ 5 DEG C of temperature in batches, stirring reaction 4 ~ 8h at-5 ~ 5 DEG C of temperature, and reaction mixture is poured in trash ice and separates out white solid, collecting by filtration white solid, wash with the frozen water of-5 ~ 5 DEG C of temperature, after drying, obtain 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE;
Method two, steps A is prepared 1,2-diphenyl butane-1, in the vitriol oil that 3 diketone join weightmeasurement ratio 1:2 ~ 1:5 at-5 ~ 5 DEG C of temperature in batches or cigarette sulfuric acid, 4 ~ 10h is reacted at 20 ~ 50 DEG C, be cooled to-5 ~ 5 DEG C, reaction mixture is poured in trash ice and separates out white solid, white solid is dissolved in the thionyl chloride solvent of solid-liquid volume ratio 1:2 ~ 1:5,6 ~ 12h is reacted at 20 ~ 50 DEG C, again be poured in trash ice and separate out solid and obtain 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE;
C, 4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-sulphonamide:
The 4-(1 that step B is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE joins in the strong aqua of 10 ~ 40% of solid-liquid volume ratio 1:2 ~ 1:5, stirring reaction 10 ~ 15h at 40 ~ 90 DEG C, cooling, collecting by filtration white solid precipitation obtains 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide;
D, N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) preparation of propionic acid amide:
Method one, the 4-(1 that step C is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in the amidation reagent of solid-liquid volume ratio 1:2 ~ 1:5, add catalyzer, at 20 ~ 110 DEG C, react 2 ~ 12h obtain N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide;
Method two, the 4-(1 that step C is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in tetrahydrofuran (THF), ethyl acetate, the chloroform, 1 of solid-liquid volume ratio 1:2 ~ 1:5, in a kind of solvent in 2-methylene dichloride, acetonitrile, benzene, toluene or methylene dichloride, add 4-(1,3-dioxo-1-phenyl fourth-2-base) propionyl chloride of benzene-1-sulphonamide mol ratio 1:0.8 ~ 1.2, add basic catalyst, at 20 ~ 110 DEG C, react 6 ~ 12h obtain N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide;
The preparation of E, N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide:
The N-(4-(1 that step D is prepared, 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide is dissolved in 70 ~ 100% ethanol of solid-liquid volume ratio 1:2 ~ 1:5, add N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) oxammonium hydrochloride of propionic acid amide mol ratio 1:0.8 ~ 1.2, at 50 ~ 90 DEG C, react 0.5 ~ 6h obtain N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide;
The preparation of F, Parecoxib:
N-(4-(the 5-hydroxy-5-methyl base-3-phenyl-4 that step e is prepared; 5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide joins in the acid solvent of solid-liquid volume ratio 1:2 ~ 1:3 under the condition of ice bath of-5 ~ 5 DEG C, and under keeping 0 ~ 30 DEG C of temperature, stirring reaction 4 ~ 12h obtains target compound Parecoxib.
The present invention be with 3-oxo-2-phenylbutyryl chloride for starting raw material, prepare target compound Parecoxib through series of processes such as Friedel-Crafts reaction, sulfonation reaction, amidate action, condensation reactions.Starting raw material cost of the present invention is low, technological process is simple, to reaction conditions require relatively low, post-processing operation is easy, product yield and purity high and can accomplish scale production.
Accompanying drawing explanation
Fig. 1 is present invention process schematic flow sheet.
Embodiment
Below in conjunction with accompanying drawing, the present invention is further illustrated, but limited the present invention never in any form, and any conversion done based on training centre of the present invention or replacement, all belong to protection scope of the present invention.
The method preparing Parecoxib of the present invention, comprises the following steps:
The preparation of A, 1,2-diphenyl butane-1,3-diketone:
Add in raw material 3-oxo-2-phenylbutyryl chloride in the organic solvent of solid-liquid volume ratio 1:10 ~ 1:5, add lewis acid catalyst and at 40 ~ 120 DEG C, react 6 ~ 12h obtain 1,2-diphenyl butane-1,3 diketone;
B, 4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-SULPHURYL CHLORIDE:
Method one, steps A is prepared 1,2-diphenyl butane-1,3 diketone join in the sulfonated reagent of weightmeasurement ratio 1:2 ~ 1:5 at-5 ~ 5 DEG C of temperature in batches, stirring reaction 4 ~ 8h at-5 ~ 5 DEG C of temperature, and reaction mixture is poured in trash ice and separates out white solid, collecting by filtration white solid, wash with the frozen water of-5 ~ 5 DEG C of temperature, after drying, obtain 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE;
Method two, steps A is prepared 1,2-diphenyl butane-1, in the vitriol oil that 3 diketone join weightmeasurement ratio 1:2 ~ 1:5 at-5 ~ 5 DEG C of temperature in batches or cigarette sulfuric acid, 4 ~ 10h is reacted at 20 ~ 50 DEG C, be cooled to-5 ~ 5 DEG C, reaction mixture is poured in trash ice and separates out white solid, white solid is dissolved in the thionyl chloride solvent of solid-liquid volume ratio 1:2 ~ 1:5,6 ~ 12h is reacted at 20 ~ 50 DEG C, again be poured in trash ice and separate out solid and obtain 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE;
C, 4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-sulphonamide:
The 4-(1 that step B is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE joins in the strong aqua of 10 ~ 40% of solid-liquid volume ratio 1:2 ~ 1:5, stirring reaction 10 ~ 15h at 40 ~ 90 DEG C, cooling, collecting by filtration white solid precipitation obtains 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide;
D, N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) preparation of propionic acid amide:
Method one, the 4-(1 that step C is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in the amidation reagent of solid-liquid volume ratio 1:2 ~ 1:5, add catalyzer, at 20 ~ 110 DEG C, react 2 ~ 12h obtain N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide;
Method two, the 4-(1 that step C is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in tetrahydrofuran (THF), ethyl acetate, the chloroform, 1 of solid-liquid volume ratio 1:2 ~ 1:5, in a kind of solvent in 2-methylene dichloride, acetonitrile, benzene, toluene or methylene dichloride, add 4-(1,3-dioxo-1-phenyl fourth-2-base) propionyl chloride of benzene-1-sulphonamide mol ratio 1:0.8 ~ 1.2, add basic catalyst, at 20 ~ 110 DEG C, react 6 ~ 12h obtain N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide;
The preparation of E, N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide:
The N-(4-(1 that step D is prepared, 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide is dissolved in 70 ~ 100% ethanol of solid-liquid volume ratio 1:2 ~ 1:5, add N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) oxammonium hydrochloride of propionic acid amide mol ratio 1:0.8 ~ 1.2, at 50 ~ 90 DEG C, react 0.5 ~ 6h obtain N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide;
The preparation of F, Parecoxib:
N-(4-(the 5-hydroxy-5-methyl base-3-phenyl-4 that step e is prepared; 5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide joins in the acid solvent of solid-liquid volume ratio 1:2 ~ 1:3 under the condition of ice bath of-5 ~ 5 DEG C, and under keeping 0 ~ 30 DEG C of temperature, stirring reaction 4 ~ 12h obtains target compound Parecoxib.
Organic solvent described in steps A is the one in benzene, toluene, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, chloroform or acetonitrile.
Lewis acid catalyst described in steps A is the one in aluminum chloride, titanium tetrachloride, boron trifluoride, iron(ic) chloride, zinc chloride, Columbium pentoxide, three width sulfonate, tosic acid, and add-on is 5 ~ 20% of feed molar amount.
Sulfonated reagent described in step B is the one in chlorsulfonic acid, the vitriol oil, oleum, sulphur trioxide.
Described sulfonated reagent is chlorsulfonic acid.
Amidation reagent described in step D method one is the one in propionic anhydride, propionyl chloride, propionic acid.
Described amidation reagent is propionic anhydride.
Catalyzer described in step D method one is the one in p-methyl benzenesulfonic acid, Phenylsulfonic acid, 4-dimethylaminopyridine, silica gel, sulfuric acid, iron trichloride, titanium tetrachloride or boron trifluoride diethyl etherate.
Described catalyzer is p-methyl benzenesulfonic acid.
Basic catalyst described in step D method two is the one in Lewis acid, carbonate, triethylamine, diisopropyl ethyl amine, DMAP.
Acid solvent described in F step is the one in trifluoracetic acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid, phosphoric acid or oxalic acid.
The method preparing Parecoxib of the present invention, comprises the following steps:
Concrete steps are as follows:
A) with 3-oxo-2-phenylbutyryl chloride for starting raw material, in the solvent of benzene, add lewis acid catalyst, prepare 1,2-diphenyl butane-1,3-diketone by Friedel-Crafts reaction in a heated condition.Wherein said lewis acid catalyst is selected from: aluminum chloride, titanium tetrachloride, boron trifluoride, iron(ic) chloride, zinc chloride, columbium pentachloride, trifluoro sulfonate, tosic acid, the addition of catalyzer is 5% ~ 20% of described 3-oxo-2-phenylbutyryl chloride molar weight; Described Heating temperature is 40 DEG C ~ 120 DEG C.
B) prepared by step a 1,2-diphenyl butane-1,3-diketone joins in chlorsulfonic acid at low temperatures in batches, after reaction certain hour, be poured in trash ice and separate out white solid, collecting by filtration obtains 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE; Or by 1,2-diphenyl butane-1,3-diketone joins in the vitriol oil or oleum at low temperatures in batches, after heated and stirred reaction certain hour, be poured in trash ice after band cooling and separate out white solid, collect this dissolution of solid and be poured into again in trash ice after reacting by heating certain hour in thionyl chloride solvent, collect the solid of separating out and obtain 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE, described cryogenic temperature is-15 DEG C ~ 5 DEG C; Described Heating temperature is 40 DEG C ~ 90 DEG C.
C) 4-(1 prepared by step b, 3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE joins in ammonia soln, after heated and stirred certain hour, stopped reaction after cooling collecting by filtration white solid precipitation obtains 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide, described Heating temperature is 40 DEG C ~ 90 DEG C.
D) 4-(1 prepared by step c, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in a certain amount of propionic anhydride, add catalyzer, reaction prepares N-(4-(1 in a heated condition, 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide, or by 4-(1, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in a kind of solvent, add a certain amount of propionyl chloride and basic catalyst, under the condition of adding, reaction prepares N-(4-(1, 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide, described catalyzer is selected from: Lewis acid, carbonate, triethylamine, diisopropyl ethyl amine, DMAP, described Heating temperature is 40 DEG C ~ 100 DEG C, the consumption of described propionyl chloride is 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide molar weight be 100% ~ 110%.
E) N-(4-(1 prepared by steps d; 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide is dissolved in ethanol; add oxammonium hydrochloride; be obtained by reacting N-(4-(5-hydroxy-5-methyl base-3-phenyl-4 in a heated condition; 5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide; the consumption of described oxammonium hydrochloride is N-(4-(1; 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide molar weight 100% ~ 120%, described Heating temperature is 50 DEG C ~ 90 DEG C.
F) the N-(4-(5-hydroxy-5-methyl base-3-phenyl-4 prepared by step e; 5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide joins in acid solvent under condition of ice bath; keep stirring at room temperature after 4 ~ 12 hours; obtain Parecoxib, described acid solvent is selected from: the aqueous hydrochloric acid of trifluoracetic acid, 1M ~ 4M, the aqueous sulfuric acid of 1M ~ 4M.
Catalyzer used in synthesis step a is preferably aluminum chloride, and addition is 10% of described 3-oxo-2-phenylbutyryl chloride molar weight, and temperature controls at 100 ~ 105 DEG C.
Preferably use chlorsulfonic acid as sulfonated reagent in synthesis step b, temperature controls at-5 DEG C ~ 5 DEG C.
Preferably use propionic anhydride to be amidation reagent in synthesis step d, catalyzer preferably uses p-methyl benzenesulfonic acid, and temperature controls at 60 DEG C ~ 80 DEG C.
Acidic solution used in synthesis step f is preferably trifluoracetic acid.
Embodiment 1
The preparation of 1,2-diphenyl butane-1,3-diketone (III)
Take 3-oxo-2-phenylbutyryl chloride 4.0 grams of (20.4mmol, 1e.q) be dissolved in 40mL benzole soln, add 150 milligrams of aluminum chloride solids, reflux 12 hours, after TLC display raw material reaction is complete, stopped reaction, saturated sodium bicarbonate aqueous solution extraction is washed once, and saturated common salt is washed once, organic phase anhydrous sodium sulfate drying, solid product about 4.0 grams is obtained, productive rate 84% after being spin-dried for solvent.
1HNMR(500MHz,CDCl
3):
δ=7.6-7.1(m,10H),5.40(s,1H),2.26(s,3H)。
Embodiment 2
4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-SULPHURYL CHLORIDE (IV)
Take 2.4 gram of 1,2-diphenyl butane-1,3-diketone, under condition of ice bath, above-mentioned raw materials is joined in 5 milliliters of chlorsulfonic acids under agitation condition in batches, keep 0 DEG C of condition to stir 6 hours, after stopped reaction, reaction mixture is poured in 10 grams of trash ices, adularescent solid is separated out, and this white solid of collecting by filtration, washs with a small amount of frozen water, dried white solid product 3.1 grams, productive rate 91%.
1HNMR(500MHz,CDCl
3):
δ=7.70(dd,
J=8.1Hz,2H),7.60(dd,
J=8.1Hz,2H),7.53-7.41(m,5H),5.48(s,1H),2.26(s,3H)。
Embodiment 3
The preparation of (1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide (V)
Taking 3.4 grams of 4-(1,3-dioxo-1-phenyl fourth-2-bases) benzene-1-SULPHURYL CHLORIDE joins in 20 milliliters of strong aquas, is heated to 60 DEG C of stirring reactions 12 hours, and it is complete that TLC detects raw material reaction.Stopped reaction, question response liquid cooling is but placed in frozen water places overnight, and solid collected by filtration product, washs with a small amount of frozen water.3.0 grams of white product are obtained, productive rate about 95% after oven dry.
1HNMR(500MHz,CDCl
3):
δ=8.00(dd,
J=8.1Hz,2H),7.60-7.41(m,7H),6.0(br,2H),5.29(s,1H),2.26(s,3H)。
Embodiment 4
N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) preparation of propionic acid amide (VI)
Take 3.1 gram (1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in 6 milliliters of propionic anhydrides, add 20 milligrams of tosic acid, be heated to 70 DEG C of stirring reactions 12 hours, it is complete that TLC detects raw material reaction, naturally cooling reacts, there is crystalline solid to separate out, solid collected by filtration, wash by a small amount of t-butyl methyl ether, white solid about 3.2 grams is obtained, productive rate about 85% after oven dry.
1HNMR(500MHz,CDCl
3):
δ=9.86(br1H),7.85(dd,
J=8.1Hz,2H),7.61(dd,
J=7.8Hz,2H),7.59(dd,
J=8.1Hz,2H),7.53(m,1H),7.41(dd,
J=7.6Hz,2H),5.29(s,1H),2.47(q,
J=6.6Hz,6.3,2H),2.26(s,3H),1.15(t,
J=6.3Hz,3H).
Embodiment 5
The preparation of N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide (VII)
Take 3.8 grams of N-(4-(1; 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide is dissolved in 30 milliliters of ethanol; add 0.7 gram of oxammonium hydrochloride again, be heated to the reflux state reaction moon 6 hours, after stopped reaction; be spin-dried for most of ethanol; add 30 milliliters of ethyl acetate, wash once with saturated sodium bicarbonate aqueous solution and saturated common salt respectively, organic phase anhydrous sodium sulfate drying; be spin-dried for the white solid product 3.6 grams of organic phase, productive rate about 92%.
1HNMR(500MHz,CDCl
3):δ=7.98(dd,
J=8.1Hz,2H),7.74(dd,
J=7.7Hz,2H),7.46(dd,
J=7.7Hz,2H),7.38(m,1H),7.30(dd,
J=8.1Hz,2H),7.23(br,2H),4.3(s,1H),2.47(q,
J=6.3Hz,2H),1.48(s,3H),1.15(t,J=6.3Hz,3H)。
Embodiment 6
The preparation of Parecoxib (I)
Take above-mentioned N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide 4 grams, join in 15 milliliters of trifluoroacetic acid solutions, keep stirring at room temperature 2 hours, have a large amount of solid product to generate.After stopped reaction, solid collected by filtration product, with t-butyl methyl ether washing, dried white solid product 3.5 grams, productive rate 92%.
1HNMR(500MHz,D
2O):
δ=8.60（brs,1H），8.04(d,
J=8.7Hz,2H),7.38-7.31(m,7H),2.50(s,3H),2.32(q,
J=7.2Hz,2H),1.10(t,
J=7.2Hz,3H)。
Embodiment 7
The preparation of 1,2-diphenyl butane-1,3-diketone (III)
Take 3-oxo-2-phenylbutyryl chloride 1.9 grams of (10.0mmol, 1e.q) be dissolved in 30mL toluene solution, add 5 milliliters of boron trifluoride diethyl etherate, reflux 10 hours, after TLC display raw material reaction is complete, stopped reaction, saturated sodium bicarbonate aqueous solution extraction is washed once, and saturated common salt is washed once, organic phase anhydrous sodium sulfate drying, solid product about 1.7 grams is obtained, productive rate 73% after being spin-dried for solvent.
Embodiment 8
4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-SULPHURYL CHLORIDE (IV)
Take 2.6 gram 1, 2-diphenyl butane-1, 3-diketone, under condition of ice bath, above-mentioned raw materials is joined in batches in 6 milliliters of oleums under agitation condition, 0 DEG C of condition is kept to stir 6 hours, after stopped reaction, reaction mixture is poured in 10 grams of trash ices, adularescent solid is separated out, this white solid of collecting by filtration, be dissolved in 5 milliliters of thionyl chlorides, be heated to 50 DEG C of reactions 10 hours, after cooling, again be poured in 10 grams of trash ices, adularescent solid is separated out, this white solid of collecting by filtration, wash with a small amount of frozen water, dried white solid product 2.9 grams, productive rate 86.3%.
Embodiment 9
The preparation of (1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide (V)
Taking 3.5 grams of 4-(1,3-dioxo-1-phenyl fourth-2-bases) benzene-1-SULPHURYL CHLORIDE joins in the ammoniacal liquor of 50 milliliter 20%, is heated to 60 DEG C of stirring reactions 12 hours, and it is complete that TLC detects raw material reaction.Stopped reaction, question response liquid cooling is but placed in frozen water places overnight, and solid collected by filtration product, washs with a small amount of frozen water.2.5 grams of white product are obtained, productive rate about 78% after oven dry.
Embodiment 10
N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) preparation of propionic acid amide (VI)
Take 3.1 gram (1, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in 6 milliliters of propionyl chlorides, add 10 milligrams of 4-dimethylaminopyridine, be heated to 60 DEG C of stirring reactions 10 hours, it is complete that TLC detects raw material reaction, naturally cooling reacts, be extracted with ethyl acetate, use sodium bicarbonate successively, aqueous NaCl wash, organic phase anhydrous sodium sulfate drying, solid product heating for dissolving after being spin-dried for is in dehydrated alcohol, crystalline solid is had to separate out after cooling, solid collected by filtration, wash by a small amount of t-butyl methyl ether, white solid about 2.5 grams is obtained after oven dry, productive rate about 67%.
Embodiment 11
The preparation of N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide (VII)
Take 4.2 grams of N-(4-(1; 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide is dissolved in the ethanol of 30 milliliter 70%; add 1.2 grams of oxammonium hydrochlorides again, be heated to the reflux state reaction moon 10 hours, after stopped reaction; be spin-dried for most of ethanol; add 30 milliliters of ethyl acetate, wash once with saturated sodium bicarbonate aqueous solution and saturated common salt respectively, organic phase anhydrous sodium sulfate drying; be spin-dried for the white solid product 3.4 grams of organic phase, productive rate about 77%.
Embodiment 12
The preparation of Parecoxib (I)
Take above-mentioned N-(4-(5-hydroxy-5-methyl base-3-phenyl-4; 5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide 3.8 grams; join in the hydrochloric acid soln of 15 milliliters of 3M, keep stirring at room temperature 5 hours, have a large amount of solid product to generate.After stopped reaction, solid collected by filtration product, with t-butyl methyl ether washing, dried white solid product 3.1 grams, productive rate 83%.
Embodiment 13
The preparation of 1,2-diphenyl butane-1,3-diketone (III)
Take 3-oxo-2-phenylbutyryl chloride 1.9 grams of (10.0mmol, 1e.q) be dissolved in 30mL ethyl acetate solution, add 0.5 milliliter of titanium tetrachloride, reflux 10 hours, after TLC display raw material reaction is complete, stopped reaction, saturated sodium bicarbonate aqueous solution extraction is washed once, and saturated common salt is washed once, organic phase anhydrous sodium sulfate drying, solid product about 1.3 grams is obtained, productive rate 54% after being spin-dried for solvent.
Embodiment 14
4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-SULPHURYL CHLORIDE (IV)
Take 3.5 gram 1, 2-diphenyl butane-1, 3-diketone, under condition of ice bath, above-mentioned raw materials is joined in batches and passes into sulfur trioxide gas under agitation condition, 0 DEG C of condition is kept to stir 3 hours, after stopped reaction, reaction mixture is poured in 10 grams of trash ices, adularescent solid is separated out, this white solid of collecting by filtration, be dissolved in 5 milliliters of thionyl chlorides, be heated to 50 DEG C of reactions 10 hours, after cooling, again be poured in 10 grams of trash ices, adularescent solid is separated out, this white solid of collecting by filtration, wash with a small amount of frozen water, dried white solid product 3.1 grams, productive rate 63%.
Embodiment 15
The preparation of (1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide (V)
Taking 3.3 grams of 4-(1,3-dioxo-1-phenyl fourth-2-bases) benzene-1-SULPHURYL CHLORIDE joins in the ammoniacal liquor of 100 milliliter 15%, is heated to 60 DEG C of stirring reactions 12 hours, and it is complete that TLC detects raw material reaction.Stopped reaction, question response liquid cooling is but placed in frozen water places overnight, and solid collected by filtration product, washs with a small amount of frozen water.1.5 grams of white product are obtained, productive rate about 47% after oven dry.
Embodiment 16
N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) preparation of propionic acid amide (VI)
Take 3.2 gram (1, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in 6 milliliters of propionic acid, add 10 milligrams of 4-dimethylaminopyridine, be heated to 60 DEG C of stirring reactions 12 hours, it is complete that TLC detects raw material reaction, naturally cooling reacts, be extracted with ethyl acetate, use sodium bicarbonate successively, aqueous NaCl wash, organic phase anhydrous sodium sulfate drying, solid product heating for dissolving after being spin-dried for is in dehydrated alcohol, crystalline solid is had to separate out after cooling, solid collected by filtration, wash by a small amount of t-butyl methyl ether, white solid about 1.9 grams is obtained after oven dry, productive rate about 51%.
Embodiment 17
The preparation of N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide (VII)
Take 3.7 grams of N-(4-(1; 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide is dissolved in the ethanol of 40 milliliter 80%; add 1.1 grams of oxammonium hydrochlorides again, be heated to the reflux state reaction moon 10 hours, after stopped reaction; be spin-dried for most of ethanol; add 30 milliliters of ethyl acetate, wash once with saturated sodium bicarbonate aqueous solution and saturated common salt respectively, organic phase anhydrous sodium sulfate drying; be spin-dried for the white solid product 3.1 grams of organic phase, productive rate about 83%.
Embodiment 18
The preparation of Parecoxib (I)
Take above-mentioned N-(4-(5-hydroxy-5-methyl base-3-phenyl-4; 5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide 3.9 grams; join in the sulphuric acid soln of 15 milliliters of 3M, keep stirring at room temperature 5 hours, have a large amount of solid product to generate.After stopped reaction, solid collected by filtration product, with t-butyl methyl ether washing, dried white solid product 2.9 grams, productive rate 78%.
Claims (10)
1. prepare a method for Parecoxib, it is characterized in that comprising the following steps:
The preparation of A, 1,2-diphenyl butane-1,3-diketone:
Add in raw material 3-oxo-2-phenylbutyryl chloride in the organic solvent of solid-liquid volume ratio 1:10 ~ 1:5, add lewis acid catalyst and at 40 ~ 120 DEG C, react 6 ~ 12h obtain 1,2-diphenyl butane-1,3 diketone;
B, 4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-SULPHURYL CHLORIDE:
Method one, steps A is prepared 1,2-diphenyl butane-1,3 diketone join in the sulfonated reagent of weightmeasurement ratio 1:2 ~ 1:5 at-5 ~ 5 DEG C of temperature in batches, stirring reaction 4 ~ 8h at-5 ~ 5 DEG C of temperature, and reaction mixture is poured in trash ice and separates out white solid, collecting by filtration white solid, wash with the frozen water of-5 ~ 5 DEG C of temperature, after drying, obtain 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE;
Method two, steps A is prepared 1,2-diphenyl butane-1, in the vitriol oil that 3 diketone join weightmeasurement ratio 1:2 ~ 1:5 at-5 ~ 5 DEG C of temperature in batches or cigarette sulfuric acid, 4 ~ 10h is reacted at 20 ~ 50 DEG C, be cooled to-5 ~ 5 DEG C, reaction mixture is poured in trash ice and separates out white solid, white solid is dissolved in the thionyl chloride solvent of solid-liquid volume ratio 1:2 ~ 1:5,6 ~ 12h is reacted at 20 ~ 50 DEG C, again be poured in trash ice and separate out solid and obtain 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE;
C, 4-(1,3-dioxo-1-phenyl fourth-2-base) preparation of benzene-1-sulphonamide:
The 4-(1 that step B is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-SULPHURYL CHLORIDE joins in the strong aqua of 10 ~ 40% of solid-liquid volume ratio 1:2 ~ 1:5, stirring reaction 10 ~ 15h at 40 ~ 90 DEG C, cooling, collecting by filtration white solid precipitation obtains 4-(1,3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide;
D, N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) preparation of propionic acid amide:
Method one, the 4-(1 that step C is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in the amidation reagent of solid-liquid volume ratio 1:2 ~ 1:5, add catalyzer, at 20 ~ 110 DEG C, react 2 ~ 12h obtain N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide;
Method two, the 4-(1 that step C is prepared, 3-dioxo-1-phenyl fourth-2-base) benzene-1-sulphonamide is dissolved in tetrahydrofuran (THF), ethyl acetate, the chloroform, 1 of solid-liquid volume ratio 1:2 ~ 1:5, in a kind of solvent in 2-methylene dichloride, acetonitrile, benzene, toluene or methylene dichloride, add 4-(1,3-dioxo-1-phenyl fourth-2-base) propionyl chloride of benzene-1-sulphonamide mol ratio 1:0.8 ~ 1.2, add basic catalyst, at 20 ~ 110 DEG C, react 6 ~ 12h obtain N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide;
The preparation of E, N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide:
The N-(4-(1 that step D is prepared, 3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) propionic acid amide is dissolved in 70 ~ 100% ethanol of solid-liquid volume ratio 1:2 ~ 1:5, add N-(4-(1,3-dioxo-1-phenyl fourth-2-base) phenyl sulfonyl) oxammonium hydrochloride of propionic acid amide mol ratio 1:0.8 ~ 1.2, at 50 ~ 90 DEG C, react 0.5 ~ 6h obtain N-(4-(5-hydroxy-5-methyl base-3-phenyl-4,5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide;
The preparation of F, Parecoxib:
N-(4-(the 5-hydroxy-5-methyl base-3-phenyl-4 that step e is prepared; 5-dihydro-isoxazole-4-base) phenyl sulfonyl) propionic acid amide joins in the acid solvent of solid-liquid volume ratio 1:2 ~ 1:3 under the condition of ice bath of-5 ~ 5 DEG C, and under keeping 0 ~ 30 DEG C of temperature, stirring reaction 4 ~ 12h obtains target compound Parecoxib.
2. prepare the method for Parecoxib according to claim 1, it is characterized in that the organic solvent described in steps A is the one in benzene, toluene, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, chloroform or acetonitrile.
3. prepare the method for Parecoxib according to claim 1, it is characterized in that the lewis acid catalyst described in steps A is the one in aluminum chloride, titanium tetrachloride, boron trifluoride, iron(ic) chloride, zinc chloride, Columbium pentoxide, three width sulfonate, tosic acid, add-on is 5 ~ 20% of feed molar amount.
4. prepare the method for Parecoxib according to claim 1, it is characterized in that the sulfonated reagent described in step B is the one in chlorsulfonic acid, the vitriol oil, oleum, sulphur trioxide.
5. according to claim 1 or 4, prepare the method for Parecoxib, it is characterized in that described sulfonated reagent is chlorsulfonic acid.
6. prepare the method for Parecoxib according to claim 1, it is characterized in that the amidation reagent described in step D method one is the one in propionic anhydride, propionyl chloride, propionic acid.
7. according to claim 1 or 6, prepare the method for Parecoxib, it is characterized in that described amidation reagent is propionic anhydride.
8. prepare the method for Parecoxib according to claim 1, it is characterized in that the catalyzer described in step D method one is the one in p-methyl benzenesulfonic acid, Phenylsulfonic acid, 4-dimethylaminopyridine, silica gel, sulfuric acid, iron trichloride, titanium tetrachloride or boron trifluoride diethyl etherate.
9. prepare the method for Parecoxib according to claim 1, it is characterized in that the basic catalyst described in step D method two is the one in Lewis acid, carbonate, triethylamine, diisopropyl ethyl amine, DMAP.
10. prepare the method for Parecoxib according to claim 1, it is characterized in that the acid solvent described in F step is the one in trifluoracetic acid, hydrochloric acid, sulfuric acid, acetic acid, formic acid, phosphoric acid or oxalic acid.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216043A (en) * | 1996-04-12 | 1999-05-05 | G·D·瑟尔公司 | Substd. benzenesulfonamide derivs as prodrugs of COX-2 inhibitors |
| EP1550658A1 (en) * | 2003-12-30 | 2005-07-06 | Dr. Reddy's Laboratories Ltd. | Method for preparing 3,4-diphenyl-substituted isoxazole compounds |
| WO2005123701A1 (en) * | 2004-06-14 | 2005-12-29 | Pharmacia Corporation | Method for the preparation of diarylisoxazole sulfonamide compounds and intermediates |
| CN102329277A (en) * | 2011-10-24 | 2012-01-25 | 海南霞迪药业有限公司 | Method for preparing Parecoxib |
| CN103172583A (en) * | 2013-03-07 | 2013-06-26 | 深圳市资福药业有限公司 | Parecoxib preparation method |
-
2014
- 2014-05-23 CN CN201410221008.0A patent/CN105085425B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1216043A (en) * | 1996-04-12 | 1999-05-05 | G·D·瑟尔公司 | Substd. benzenesulfonamide derivs as prodrugs of COX-2 inhibitors |
| EP1550658A1 (en) * | 2003-12-30 | 2005-07-06 | Dr. Reddy's Laboratories Ltd. | Method for preparing 3,4-diphenyl-substituted isoxazole compounds |
| WO2005123701A1 (en) * | 2004-06-14 | 2005-12-29 | Pharmacia Corporation | Method for the preparation of diarylisoxazole sulfonamide compounds and intermediates |
| CN102329277A (en) * | 2011-10-24 | 2012-01-25 | 海南霞迪药业有限公司 | Method for preparing Parecoxib |
| CN103172583A (en) * | 2013-03-07 | 2013-06-26 | 深圳市资福药业有限公司 | Parecoxib preparation method |
Non-Patent Citations (1)
| Title |
|---|
| 王瑞廷: "COX-2抑制剂戊地昔布的合成", 《中国优秀博硕士学位论文全文数据库（硕士）医药卫生科技辑》 * |
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