CN104447600B - A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application - Google Patents

A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application Download PDF

Info

Publication number
CN104447600B
CN104447600B CN201310433884.5A CN201310433884A CN104447600B CN 104447600 B CN104447600 B CN 104447600B CN 201310433884 A CN201310433884 A CN 201310433884A CN 104447600 B CN104447600 B CN 104447600B
Authority
CN
China
Prior art keywords
compound
formula
methyl
formula iii
phenylbenzene
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201310433884.5A
Other languages
Chinese (zh)
Other versions
CN104447600A (en
Inventor
赵俊
吉同琴
宗在伟
张艳阳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Aosaikang Pharmaceutical Co Ltd
Original Assignee
Jiangsu Aosaikang Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Jiangsu Aosaikang Pharmaceutical Co Ltd filed Critical Jiangsu Aosaikang Pharmaceutical Co Ltd
Priority to CN201310433884.5A priority Critical patent/CN104447600B/en
Publication of CN104447600A publication Critical patent/CN104447600A/en
Application granted granted Critical
Publication of CN104447600B publication Critical patent/CN104447600B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The invention provides a kind of intermediate impurities is controlled after obtained Parecoxib Sodium.Specifically provide a kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application.3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol is as the intermediate 5-methyl-3 preparing Parecoxib Sodium, 4-phenylbenzene-4, the isomer impurities of 5-dihydro-isoxazole-5-alcohol, in Parecoxib Sodium preparation, quality control is carried out to it, require that foreign matter content does not have great importance for the quality product of Parecoxib Sodium higher than 0.5% specifically.The present invention is by obtaining 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol, this important 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-Alkanol isomer impurity, and further it has been carried out to the research of preparation technology and characterization processes, purifying technique, to the technique being suitability for industrialized production raw material with 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol, there is important quality monitoring meaning.

Description

A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application
Technical field
The invention belongs to medical production technical field, be specifically related to a kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application.
Background technology
Parecoxib Sodium (Parecoxibsodium) is developed by Pharmacia (being now Pfizer) company, it is selective epoxidation enzyme-2 (COX-2) inhibitor of first intravenously administrable in the whole world, be the prodrug of Valdecoxib (valdecoxib), be mainly used in the short of postoperative pain.Parecoxib Sodium structure is such as formula shown in IV.
2002, Parecoxib Sodium got permission list marketing, 2008 in 15 EU Countries and Norway and Iceland, and Chinese SFDA ratifies Parecoxib Sodium in Discussion on Chinese Listed, commodity special resistance to (Dynastat) by name.Owing to being parenteral administration, Parecoxib Sodium compensate for former times dry goods medicine to unsuitable oral patient as the Treatment defect of postoperative acute pain-suffered patient, have and suppress super quick, eradicate the unique advantage of pain, the combination of quick and durable analgesic characteristic and good safety, selects for doctor provides the analgesia more optimized.
Disclose with 1,2-phenylbenzyl ketone for raw material in CN1578774A, WO2005123701A1, through different path, obtained formula V compound (5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol), then the method for Parecoxib or its sodium salt is prepared by formula V compound.
But we find that its industrialization synthetic yield is not high, therefore to its synthetic route, and the research that the factor affecting productive rate that may exist in synthetic method is carried out.
Summary of the invention
The object of the invention is to find and affect the factor affecting end product purity in Parecoxib and salt building-up process thereof, and by searching and controlling this factor, improve the purity of the finished product as far as possible.
Specifically, the invention discloses the Parecoxib sodium compound shown in a kind of formula IV, with formula V compound for raw material obtains;
Before described formula V compound feeds intake, detect in advance to formula V compound purity, the formula III compound quality percentage ratio wherein contained is not higher than 0.5%;
This innovative point of further explanation, one disclosed by the invention is with 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol (i.e. formula V compound) prepares Parecoxib or its pharmaceutically acceptable method, described 5-methyl-3 for raw material, 4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol is used as before raw material, detects, 5-methyl-3 to wherein contained formula III compounds content, 4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol after testing should substantially containing formula III compound.The so-called formula III compound that substantially do not contain refers to that the mass percent of 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol sample compound of formula III is not higher than 0.5%, preferably not higher than 0.2%, more preferably no higher than 0.1%.
Especially preferably lower than 0.5%, more preferably lower than 0.2%, most preferably lower than 0.1%.
Further, we disclose in Parecoxib Sodium preparation process, for in starting materials of formulae V compound, the detection method of formula III compound, a kind of 5-methyl-3,4-phenylbenzene-4, the method for detecting purity of 5-dihydro-isoxazole-5-alcohol, described method for detecting purity is HPLC method, described HPLC moving phase is the disodium phosphate soln system of methyl alcohol-0.01mol/L, wherein the volume ratio of the disodium phosphate soln of methyl alcohol and 0.01mol/L is 40:60, and used detecting instrument is Ultraviolet Detector, and described determined wavelength is 225nm.The retention time of described 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol is about 3.599min, and so-called left and right refers to the limit of error allowing to include 2% here; Preferred scope is 3.58 ~ 3.62min, and preferred scope is 3.59 ~ 3.61min; The retention time of formula III compound is about 2.910min, and so-called left and right refers to the limit of error allowing to include 2% here; Preferred scope is 2.90 ~ 2.94min, and preferred scope is 2.91 ~ 2.93min.
Especially, disclosed in us, HPLC testing conditions is:
Chromatographic column: ACEPhenyl post (150mm*3.0mm)
Moving phase: methyl alcohol-0.01mol/L disodium phosphate soln (with phosphoric acid adjust ph to 3.5 ± 0.2) (40:60)
Column temperature: 40 DEG C
Determined wavelength: 225nm
Flow velocity: 0.5mL/min
Sample size: 20 μ L
Formula III Compound Retention time is 2.910 minutes substantially.
Meanwhile, the invention provides a kind of formula III compound or its salt, be preferably formula III compound, be i.e. 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol.
Inventor finds under study for action, in synthesis type V compound process (synthetic method is with reference to WO2005/123701A1), can produce a kind of impurity (contriver is called impurity V-1); As shown in Figure 1, formula V compound H PLC retention time 3.599min, impurity V-1 retention time 2.910min; By HPLC-MS, contriver finds that impurity V-1 has [M+H] further +=254, [M+Na] +the molecular ion peak of=276.Contriver knows isomer 3-methyl-4,5-phenylbenzene-4, the 5-dihydro-isoxazole-5-alcohol that impurity V-1 is formula V compound by inference, i.e. formula III compound.Contriver has synthesized formula III compound further, and compare the HPLC retention time (Fig. 1 of impurity V-1 in formula V compound, 2.910min) with retention time (Fig. 2 of formula III compound of synthesis, 2.917min), both are consistent, can confirm that impurity V-1 is formula III compound.
Formula III compound, as formula V compound isomers impurity, easily produces corresponding Valdecoxib and Parecoxib Sodium isomer impurities in subsequent reactions.Formula III compound is close with formula V compound structure, and character is similar; The quality controllability of the pharmaceutical prod prepared by formula V compound can be improved the Detection & Controling of formula III compound, have important practical value.
Therefore, the invention also discloses formula III compound can as the purposes of formula V compound (5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol) defects inspecting reference substance.
Simultaneously, because formula V compound can prepare intermediate or raw material as a lot of medicine, so formula III compound is as the purposes taking 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol as defects inspecting reference substance in the medicine synthesising process of raw material or intermediate.
Meanwhile, preparing purposes as a kind of main 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol, is the intermediate of preparation Parecoxib or its pharmacy acceptable salt, Valdecoxib or its pharmacy acceptable salt.
Therefore the formula III compound in the present invention can as defects inspecting reference substance in Parecoxib or its pharmacy acceptable salt or Valdecoxib or its pharmacy acceptable salt production process.
Formula III compound preferably in the present invention can as defects inspecting reference substance in Parecoxib or Parecoxib Sodium production process.
Meanwhile, a kind of method preparing formula III compound provided by the present invention:
(1) formula I is dissolved in acetonitrile, adds 2,6-lutidine, drip Acetyl Chloride 98Min., react to obtain the solution of formula II compound;
(2) in step (1), the solution of gained formula II compound drops in the mixed aqueous solution of oxammonium hydrochloride and sodium-acetate, reaction, and formula III compound is separated out with solid, filters, obtains formula III compound.
Disclose with 1,2-phenylbenzyl ketone and Pyrrolidine for raw material in prior art, preparation I compound.Formula I in the present invention can be prepared by the following method: add 1,2-phenylbenzyl ketone, Glacial acetic acid, hexanaphthene and Pyrrolidine in reaction vessel, reflux, and reaction is to anhydrous generation, and removal of solvent under reduced pressure, obtains formula I.
Preferably, in described step (2), the solution time dropped in the mixed aqueous solution of oxammonium hydrochloride and sodium-acetate of formula II compound is 0.5-6 hour, is more preferably 3 ~ 5 hours.
Preferably, the solution of described step (2) compound of formula H is added dropwise to complete the rear reaction times and is not less than 2 hours; Preferably be not less than 4 hours; More preferably 4 ~ 8 hours.
Preferably step (2) gained formula III compound can be separated by the following method, purifying: step (2) gained solid is after filtration, water washing, drying, column chromatography obtain formula III crude compound.Formula III crude compound sherwood oil and ethyl acetate are eluent, carry out silica gel column chromatography, obtain 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol.Preferably, the volume ratio of sherwood oil and ethyl acetate is 100:1 ~ 1:1, is more preferably 20:1 ~ 4:1.
The present invention is by obtaining 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol, this important 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-Alkanol isomer impurity, and further it has been carried out to the research of preparation technology and characterization processes, purifying technique, to the technique being suitability for industrialized production raw material with 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol, there is important quality monitoring meaning.
Accompanying drawing explanation
The HPLC collection of illustrative plates of Fig. 1 formula V compound
The formula III compound H PLC collection of illustrative plates that Fig. 2 embodiment of the present invention 1 obtains
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.Following each embodiment is not only limitation of the present invention for illustration of the present invention.
Formula III compound and 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol are the different expression mode of same compound in the present invention.
The preparation of embodiment 13-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol
(1), in 1L there-necked flask, 1 is added, 2-phenylbenzyl ketone 71.3g, Pyrrolidine 64.6g, hexanaphthene 300mL and Glacial acetic acid 0.2g, be warming up to backflow, in water trap, have moisture to go out, until anhydrous generation stopped reaction, 50 DEG C of concentrating under reduced pressure reaction solutions, to without cut, obtain yellow oil formula I and are about 90g.
(2), by gained oily matter add 1L reaction flask, add acetonitrile 500mL and 2,6-lutidine 58g, less than 15 DEG C drip Acetyl Chloride 98Min. 112g, drip Bi Jixu reaction and disappear to raw material, obtain acylate formula II compound solution.
(3), slowly will drop in the mixed aqueous solution (oxammonium hydrochloride 101g and sodium-acetate 119g is dissolved in 470mL water) of oxammonium hydrochloride and sodium-acetate containing formula II compound solution, temperature control less than 30 DEG C, 3-3.5h drips off, and drips and finishes, and continues reaction 4h to reacting completely, solid is had to separate out, filter, washing, 40 DEG C of forced air dryings obtain 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol crude product 56g.
(4), by gained 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol crude product carry out column chromatography, eluent is sherwood oil: ethyl acetate=20:1 (V/V), obtains 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol 39g.
Mass spectrum: molecular ion peak [M+H] +=254.0, [M+Na] +=276.1
1HNMR(500MHz,d-DMSO)：δ：1.11(S，3H，-CH 3)；2.0(S，1H，-OH)；4.68(S，1H，-CH)；7.16～7.59(m，10H，-ArH)；
HPLC condition:
Chromatographic column: ACEPhenyl post (150mm*3.0mm)
Moving phase: methyl alcohol-0.01mol/L disodium phosphate soln (with phosphoric acid adjust ph to 3.5 ± 0.2) (40:60)
Column temperature: 40 DEG C
Determined wavelength: 225nm
Flow velocity: 0.5mL/min
Sample size: 20 μ L
Retention time: 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol 2.917 minutes
HPLC collection of illustrative plates, see Fig. 2.
The preparation of embodiment 23-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol
(1), in 1L there-necked flask, 1 is added, 2-phenylbenzyl ketone 72..5g, Pyrrolidine 75g, hexanaphthene 350mL and Glacial acetic acid 0.25g, be warming up to backflow, in water trap, have moisture to go out, until anhydrous generation stopped reaction, 50 DEG C of concentrating under reduced pressure reaction solutions, to without cut, obtain yellow oil formula I and are about 93.5g.
(2), by gained oily matter add 1L reaction flask, add acetonitrile 525mL and 2,6-lutidine 55g, less than 15 DEG C drip Acetyl Chloride 98Min. 128g, drip Bi Jixu reaction and disappear to raw material, obtain acylate formula II compound solution.
(3), slowly will drop in the mixed aqueous solution (oxammonium hydrochloride 103g and sodium-acetate 121g is dissolved in 490mL water) of oxammonium hydrochloride and sodium-acetate containing formula II compound solution, temperature control less than 30 DEG C, 4-4.5h drips off, and drips and finishes, and continues reaction 4.5h to reacting completely, solid is had to separate out, filter, washing, 40 DEG C of forced air dryings obtain 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol crude product 60.3g.
(4), by gained 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol crude product carry out column chromatography, eluent is sherwood oil: ethyl acetate=10:1 (V/V), obtains 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol 43g.
The HPLC TuPu method peak obtained and Fig. 2 coincide, and can confirm as same compound.Because collection of illustrative plates similarity is high, so no longer repeat to enclose.
The preparation of embodiment 33-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol
(1), in 1L there-necked flask, 1 is added, 2-phenylbenzyl ketone 63.5g, Pyrrolidine 70g, hexanaphthene 300mL and Glacial acetic acid 0.18g, be warming up to backflow, in water trap, have moisture to go out, until anhydrous generation stopped reaction, 50 DEG C of concentrating under reduced pressure reaction solutions, to without cut, obtain yellow oil formula I and are about 82.4g.
(2), by gained oily matter add 1L reaction flask, add acetonitrile 485mL and 2,6-lutidine 48g, less than 15 DEG C drip Acetyl Chloride 98Min. 118g, drip Bi Jixu reaction and disappear to raw material, obtain acylate formula II compound solution.
(3), slowly will drop in the mixed aqueous solution (oxammonium hydrochloride 98g and sodium-acetate 112g is dissolved in 490mL water) of oxammonium hydrochloride and sodium-acetate containing formula II compound solution, temperature control less than 30 DEG C, 4.5-5h drips off, and drips and finishes, and continues reaction 4h to reacting completely, solid is had to separate out, filter, washing, 40 DEG C of forced air dryings obtain 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol crude product 54.6g.
(4), by gained 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol crude product carry out column chromatography, eluent is sherwood oil: ethyl acetate=4:1 (V/V), obtains 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol 34g.
The HPLC TuPu method peak obtained and Fig. 2 coincide, and can confirm as same compound.Because collection of illustrative plates similarity is high, so no longer repeat to enclose.
Embodiment 4 Parecoxib Sodium synthesizes
(1) preparation of 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol
In 50L reactor, add 1,2-phenylbenzyl ketone 4kg, hexanaphthene 17.2kg, Glacial acetic acid 0.124kg, Pyrrolidine 3.62kg, stir and be warming up to backflow, start a point water.After reflux water-dividing is about 24h, reaction solution cools to 30 ± 5 DEG C.Be evaporated to dry oily matter.
Gained oily matter, acetonitrile 22.4kg, 2,6-lutidine 3.276kg are added in 100L vertical response still, opens and stir, in still, drip Acetyl Chloride 98Min. 6.24kg.Dropping terminates rear continuation reaction 5h.
By sodium acetate trihydrate 10.823kg, oxammonium hydrochloride 5.665kg, purified water 22.2kg, stir and be mixed with solution, for subsequent use.Drop in above-mentioned reaction solution by the oxammonium hydrochloride/sodium acetate aqueous solution prepared, in dropping process, control temperature is no more than 35 DEG C.Dropping terminates rear maintenance temperature 15-20 DEG C of reaction 2h.Centrifugal rejection filter gained filter cake, after 60 DEG C of forced air drying 24h, obtains 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol and is about 2.2kg.
(2) quality control of 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol
The 5-methyl-3 obtained in step (1), 4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol, detect through HPLC, absorption peak area shows, 5-methyl-3 in detected sample, the purity of 4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol is 97.15%, impurity 3-methyl-4, the content of 5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol is 0.94%.
HPLC condition: chromatographic column is ACEPhenyl post (150mm*3.0mm); Moving phase is methyl alcohol-0.01mol/L disodium phosphate soln (with phosphoric acid adjust ph to 3.5 ± 0.2) (40:60); Column temperature is 40 DEG C; Determined wavelength is 225nm; Flow velocity is 0.5mL/min; Sample size is 20 μ L.
By step (1) gained 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol carries out column chromatography, eluent is sherwood oil: ethyl acetate=8:1 (V/V), to the 5-methyl-3 after column chromatography, 4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol carries out HPLC detection, absorption peak area shows, 5-methyl-3,4-phenylbenzene-4 in detected sample, the purity of 5-dihydro-isoxazole-5-alcohol is 99.15%, the content of impurity 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol is 0.19%.As shown in figure-1, the retention time of 3-methyl-4,5-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol is the retention time of 2.910min, 5-methyl-3,4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol is 3.599min.
(3) Parecoxib Sodium preparation
To get in step (2) 5-methyl-3 after quality control, 4-phenylbenzene-4,5-dihydro-isoxazole-5-alcohol 2.05kg, 35% ethanol solution hydrochloride 250mL, ethanol 5.8kg joins in 20L reactor, stirs and is warming up to backflow, react about 1-3h, when underpressure distillation to salvage stores is original volume about 3/10, stop distillation.Reaction solution slowly cools to 15-25 DEG C, continues stirring and crystallizing 1 ~ 2h.Suction filtration, gained filter cake, in 40 ~ 60 DEG C of dried in vacuo overnight, obtains product and is about 2kg.
In 20L glass reaction still, add 5-methyl-3,4-phenylbenzene isoxazole 2.2kg and trifluoroacetic acid 6.75kg, add chlorsulfonic acid 7.64kg.Reaction solution is in 60 DEG C of reaction 3 ~ 6h, TLC monitoring reactions, and react complete, under ice bath, system is slowly added cancellation reaction in 22kg water, cancellation terminates, and toluene 7kg extracts 2 times, merges organic phase.25% ammoniacal liquor 3kg is added, 35 DEG C of reaction 1 ~ 2h in organic phase.TLC monitors reaction.React complete, filter, filter cake 17kg purified water making beating washing, filter cake to spend the night to obtain Valdecoxib crude product in 40 ~ 60 DEG C of forced air dryings.Valdecoxib crude product ethanol/water recrystallization obtains Valdecoxib.
In 20L glass reaction still, add Valdecoxib (2.092kg), tetrahydrofuran (THF) 11.17kg, add DMAP 0.084kg, propionic anhydride 1.569kg, triethylamine 0.837kg.Finish, 40 DEG C of reaction 3h.TLC monitors reaction.React complete, reaction solution is cooled to 10 ~ 20 DEG C, stirring and crystallizing 1 ~ 2h.Filter, drain, gained filter cake, in 40 ~ 60 DEG C of forced air drying 12h, obtains Parecoxib crude product.Parecoxib crude product obtains Parecoxib with 3 times amount tetrahydrofuran (THF)s are refining.
In 20L reactor, add sodium hydroxide 0.244kg and dehydrated alcohol 4.635kg, be warming up to 35 ± 5 DEG C, stir clearly molten, be mixed with the ethanolic soln of 5% sodium hydroxide, for subsequent use.Parecoxib (2.0kg) and dehydrated alcohol 16.061kg are joined in 50L glass reaction still, stir be warming up to 45 ± 5 DEG C clearly molten to reaction solution.The ethanolic soln of 5% sodium hydroxide prepared is added in reaction solution, 50 DEG C of reaction 1h.Cool to room temperature, stirring and crystallizing 1h.Filter, 45 DEG C of forced air dryings obtain Parecoxib Sodium.

Claims (7)

1. formula III compound or its salt
2. the compound of formula III described in claim 1 detects the purposes of reference substance as formula V compound impurities;
3. the compound of formula III described in claim 1 is as the purposes of defects inspecting reference substance in the medicine synthesising process being raw material or intermediate with formula V compound;
4. purposes according to claim 3, is characterized in that described formula III compound is as Parecoxib or its pharmacy acceptable salt, or the purposes of defects inspecting reference substance in Valdecoxib or its pharmacy acceptable salt production process.
5. the preparation method of the compound of formula III described in claim 1, its synthetic route is as follows,
Specifically comprise the following steps:
(1) formula I is dissolved in acetonitrile, adds 2,6-lutidine, drip Acetyl Chloride 98Min., react to obtain the solution of formula II compound;
(2) in step (1), the solution of gained formula II compound drops in the mixed aqueous solution of oxammonium hydrochloride and sodium-acetate, reaction, and formula III compound is separated out in solid form, filters, obtains formula III compound;
Wherein the solution of step (2) compound of formula H is added dropwise to complete the rear reaction times and is not less than 2 hours.
6., according to the preparation method described in claim 5, it is characterized in that the solution time for adding of step (2) compound of formula H is 0.5-6 hour.
7. according to the preparation method described in claim 5, it is characterized in that formula III compound after filtering, obtain the formula III compound after purifying further by washing, drying, column chromatography.
CN201310433884.5A 2013-09-22 2013-09-22 A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application Active CN104447600B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201310433884.5A CN104447600B (en) 2013-09-22 2013-09-22 A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201310433884.5A CN104447600B (en) 2013-09-22 2013-09-22 A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application

Publications (2)

Publication Number Publication Date
CN104447600A CN104447600A (en) 2015-03-25
CN104447600B true CN104447600B (en) 2016-03-30

Family

ID=52894427

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201310433884.5A Active CN104447600B (en) 2013-09-22 2013-09-22 A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application

Country Status (1)

Country Link
CN (1) CN104447600B (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146424A (en) * 2015-03-23 2016-11-23 上海医药工业研究院 A kind of preparation method of 5-methyl-3,4-diphenyl isoxazole
CN104749288B (en) * 2015-04-16 2017-03-29 上海秀新臣邦医药科技有限公司 A kind of liquid phase chromatography analytical method of Parecoxib Sodium about material
CN104965041B (en) * 2015-06-11 2016-06-29 成都克莱蒙医药科技有限公司 A kind of high-efficiency liquid chromatography method for detecting of Parecoxib Sodium isomer
CN105372376B (en) * 2015-11-26 2021-04-06 天津药物研究院有限公司 Detection method and application of parecoxib sodium genotoxic impurity
CN106008386B (en) * 2016-05-25 2018-11-06 台州宝诚科技服务有限公司 A method of preparing the SC 69124 for treating postoperative pain
CN106008388B (en) * 2016-05-25 2018-06-26 吴兴龙 A kind of preparation method for the SC 69124 for being used to treat postoperative pain
CN107976500B (en) * 2017-11-29 2021-09-28 浙江震元制药有限公司 Diaryl-substituted isoxazole compound and preparation method and application thereof
CN111257441B (en) * 2019-12-31 2022-07-29 河南润弘制药股份有限公司 Method for detecting impurities in parecoxib sodium synthesis process
CN113845488A (en) * 2020-06-28 2021-12-28 南京正大天晴制药有限公司 Preparation and refining method of parecoxib and intermediate thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1578774A (en) * 2001-10-02 2005-02-09 法玛西雅公司 Method for preparing benzenesulfonyl compounds

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005123701A1 (en) * 2004-06-14 2005-12-29 Pharmacia Corporation Method for the preparation of diarylisoxazole sulfonamide compounds and intermediates

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1578774A (en) * 2001-10-02 2005-02-09 法玛西雅公司 Method for preparing benzenesulfonyl compounds

Also Published As

Publication number Publication date
CN104447600A (en) 2015-03-25

Similar Documents

Publication Publication Date Title
CN104447600B (en) A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application
CN104387320B (en) A kind of preparation method of high-purity milrinone
CN104072390B (en) A kind of S-escitalopram compound and preparation method thereof
CN106478600B (en) A kind of refining methd of Lansoprazole
CN104418807A (en) Preparation method of 2-ethoxyl-1-[[2'-(hydroxyl amidino)-biphenylyl]-4-yl]methyl-1H-benzimidazole-7-carboxylic acid and ester derivatives thereof
CN114213327A (en) Synthesis method of (-) -huperzine A
CN106543076A (en) The method for preparing Acrivastine
CN105367508B (en) A kind of preparation method of Parecoxib Sodium synthesis technique impurity
CN109400577B (en) Rivaroxaban related compound and preparation method and application thereof
CN110467580B (en) Resolution method of Raxinard axis chiral enantiomer
EP2937348B1 (en) Process for the preparation of a compound used as mineralocorticoid receptor antagonist
KR20130086534A (en) Solid state forms of ixabepilone
CN108840816A (en) Acid imide midbody compound and its preparation method and application
CN111978266B (en) Parecoxib sodium, injection preparation and preparation method
CN104327073A (en) Semisynthetic production method of vinpocetine
CN107759519A (en) A kind of celecoxib impurity B preparation method
CN107382875A (en) A kind of synthetic method of rosuvastain calcium chiral isomer impurity
CN102321040A (en) A kind of method for preparing Linezolid midbody and Linezolid
CN106496089B (en) A method of preparing Oxiracetam
CN114105990A (en) Synthesis method of ibrutinib
CN105753820B (en) A kind of method of purification of dehydroandrographolide succinate
CN111484460B (en) Synthetic method of olanzapine related substance compound I and compound II
CN106279018B (en) Beta 2-receptor excitant and its preparation method and application
CN111995614B (en) Preparation method of thiohydroxy acetic anhydride
CN103923142B (en) Preparation method of roxithromycin intermediate

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CP01 Change in the name or title of a patent holder

Address after: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699

Patentee after: Jiangsu Aosaikang Pharmaceutical Co., Ltd.

Address before: 211112 Jiangsu Province, Nanjing City, Jiangning Science Park Road No. 699

Patentee before: Jiangsu Aosaikang Pharmaceutical Co., Ltd.

CP01 Change in the name or title of a patent holder